WO2020032752A1 - Catechin compound and use thereof - Google Patents

Abstract

The present invention relates to a catechin compound or a pharmaceutically acceptable salt thereof, and a use thereof, and a catechin compound or a pharmaceutically acceptable salt thereof of the present invention is very effective in the treatment of wounds, particularly, peripheral ulcers.

Description

Catechin Compounds and Uses thereof

The present invention relates to a catechin compound and its use, and more particularly, to a novel catechin compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for treating wounds, a cosmetic composition for improving inflammatory skin disease, and skin A cosmetic composition for whitening and a cosmetic composition for skin regeneration.

Damage to skin tissue that protects the body from external invaders and maintains moisture and body temperature is a wound, and wound healing is an essential response to normalize the function and morphological properties of the damaged tissue (Woodley DT, et al., Cutaneous wound healing: a model for cell-matrix interactions, J. Am. Acad. Dermatol., 12 (2Pt2), 420-433, 1985.). If the wound is not properly treated, it may cause fatal damage to organs due to bacterial infection, so it is important to take measures to restore the damaged skin area as soon as possible and to resemble the original skin structure.

Wound treatment consists of three stages: hemostasis and inflammation, two stages of proliferation, and three stages of remodeling, each of which is continuous and overlapping (Bello YM, et al. ., Recent advances in wound healing, JAMA, 283 (6), 716-718, 2000.).

The first step is a hemostasis and an inflammatory reaction, which causes the platelets to collect within a few minutes to form a fibrin clot that prevents bleeding. Inflammatory reactions result in migration and mitosis of cells that are differentiated during the proliferation by release of cytokines from macrophages as bacteria or tissue debris are removed by phagocytosis. Will help.

In the second stage, the proliferative phase, neovascularization, collagen accumulation, granulation tissue formation, epithelialization and wound contraction occur. This is the initial stage for wound fusion and rearrangement of collagenous fibers, where fibroblasts appear at the wound site.

Finally, in the maturity phase, the wound space is completely replaced by granulation tissue, blood vessel production reaches its peak, and the amount of collagen fibers is abundant, and epithelial cells gradually recover to normal thickness, and the wound treatment is completed.

The role of the inflammatory phase is very important because the wound healing process is delayed when the transition to the proliferative phase, which is not removed by the inflammatory cells, unless tissues, foreign substances, and necrotic debris that are destroyed during the wound healing phase are removed.

If you look closely at the inflammatory response, tissue damage causes local blood vessels to contract and release histamine, bradykinin, prostaglandin, serotonin, and norepinephrine from the wound. As the blood vessels expand. The dilated blood vessels create gaps between the endothelial cells, causing plasma and leukocytes to escape into the interstitial fluid. Within hours after the tissue is damaged, polymorphonuclear leukocytes are affected by complement and migrate to the wound, where they feed on damaged tissue debris and bacteria. A few hours after wound formation, the macrophages reach the site of injury and undergo phagocytosis. The activated macrophages produce several cytokines and reactive oxygen species (ROS), which are NF-κB, an inflammatory transcription factor. (nuclear factor-κB) is activated, resulting in increased expression and activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) to produce excess nitric oxide (NO) and progetaglandin E2 (PGE2). Thereby causing an inflammatory response. In addition, reactive oxygen species generated from macrophages remove bacteria from the wound to prevent infection and act as a secondary messenger in the cell, thus playing an essential role in wound healing.

However, excessive generation of reactive oxygen species causes oxidative stress on the wound and regulates the expression of inflammatory mediators, which affects the inflammatory response during wound healing and slows the rate of wound healing. Attempts have been made to find antioxidants that inhibit the production of species, but the results are still not satisfactory.

Therefore, the development of effective methods for wound healing is continuously being studied.

Thus, the present invention provides novel catechin-based compounds or pharmaceutically acceptable salts thereof having surprising effects on wound and inflammatory responses through high expression of vascular and cell growth factors.

In another aspect, the present invention is the use of the catechin-based compound of the present invention or a pharmaceutically acceptable salt thereof, in particular, a pharmaceutical composition for wound treatment comprising a catechin-based compound or a pharmaceutically acceptable salt thereof, cosmetic composition for improving inflammatory skin disease It provides a cosmetic composition for skin whitening and a cosmetic composition for skin regeneration.

The present invention provides a novel catechin-based compound or a pharmaceutically acceptable salt thereof, wherein the catechin-based compound of the present invention is represented by the following formula (1).

[Formula 1]

(In Formula 1,

R ₁ is C ₁ -C 20 alkylcarbonyl, C 2 -C 30 alkenylcarbonyl,-(CH ₂ ) _d -Ar ₁ ,

,

or

ego;

R ₁₁ is hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^a , -CONR ^b R ^c , hydroxy OxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _e -Ar ₂ , -NR ^b R ^c ,

,

,

,

Or O - sugar residue (O -sugar residue) and;

R ₁₂ is hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^d , -CONR ^e R ^f , HydroxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _f -Ar ₃ , -NR ^e R ^f ,

,

,

,

Or O -sugar residues;

a is an integer from 1 to 4, and when a is an integer of 2 or more, R ₁₂ may be the same or different from each other;

m is an integer from 1 to 10;

R ₁₄ is hydroxy, C 1 -C 15 alkoxy, halogen, C 1 -C 15 alkylcarbonyloxy or an O-sugar residue;

R ₁₅ is hydrogen, C 1 -C ₁₅ alkyl, halogen, hydroxy or C 1 -C 15 alkoxy;

R ₁₆ is hydrogen or C1-C15 alkyl;

b is an integer from 1 to 4, and when b is an integer of 2 or more, R ₁₅ may be the same or different from each other;

R ₁₇ is hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1-C15 alkoxy C1-C15alkyl, C6-C20aryloxyC1-C15alkyl or O-sugar residues;

R ₁₈ is hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1- C 15 alkoxy C 1 -C 15 alkyl, C 6 -C 20 aryloxy C 1 -C 15 alkyl or an O-sugar residue;

c is an integer from 1 to 4, and when c is an integer of 2 or more, R ₁₈ may be the same or different from each other;

n is an integer from 1 to 10;

R ^a and R ^d are independently of each other hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl or C 6 -C 20 aryl;

R ^b , R ^c , R ^e and R ^f are independently of each other hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 6 -C 20 aryl or C 1 -C 15 alkylcarbonyl;

d, e and f are each independently an integer from 1 to 10;

Ar ₁ , Ar ₂ and Ar ₃ are independently of each other C 6 -C 20 aryl, wherein the aryl of Ar ₁ to Ar ₃ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy and C 1 -C 15 alkylcarbon May be further substituted with one or more selected from nil;

R ₂ is hydrogen, hydroxy, C1-C15 alkyl, haloC1-C15 alkyl, hydroxyC1-C15 alkyl, C1-C15 alkoxy, amino acid, C1-C15 alkylcarbonyl, C1-C15 alkoxycarbonyl, C2-C15 Alkenyl, hydroxyC2-C15alkenyl or C2-C15alkynyl.)

In addition, the present invention provides a pharmaceutical composition for treating wounds comprising the catechin-based compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a cosmetic composition for improving inflammatory skin disease comprising the catechin-based compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a cosmetic composition for skin whitening comprising the catechin-based compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a cosmetic composition for skin regeneration comprising the catechin-based compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The catechin-based compound according to the present invention or a pharmaceutically acceptable salt thereof is a novel compound of low molecular weight obtained by the sugar preparation in catechin natural products, and has excellent stability and water solubility, and no cytotoxicity.

In addition, the catechin-based compounds or pharmaceutically acceptable salts thereof according to the present invention significantly enhance the expression of various vascular and cell growth factors such as TGF-β, induce vasokinetic activity, and produce angiogenesis and tissues. It promotes regeneration and at the same time promotes the secretion of antimicrobial peptides, which is very effective in treating wounds and preventing and treating secondary infections of wounds.

In particular, the catechin-based compounds or pharmaceutically acceptable salts thereof according to the present invention may be used for the artery of the arteries (arterioles) and precapillary arterioles, as well as pulse activity (sphygmic activity) in capillaries and associated venules and It is effective in treating diabetic ulcers in disease animal models by increasing blood flow and causing vasodynamic and vasodilation effects, especially foot ulcers and pressure sores due to diabetic complications, peripheral ulcers with peripheral circulation or microcirculation disorders. It can be usefully used for treatment without side effects.

In addition, the catechin-based compounds according to the present invention do not cause unwanted ulceration in peripheral ulcers and surrounding tissues and are therefore well suited for topical administration.

In addition, the catechin-based compound according to the present invention promotes the regeneration of skin tissues and secretion of antimicrobial peptides, thereby effectively inhibiting the inflammatory response, which is a major symptom in inflammatory skin diseases accompanied by the accumulation of wounds, and regenerating cells. It can be used as an active ingredient for improving, whitening and skin regeneration of the cosmetic composition.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely. Unless otherwise defined in the technical and scientific terms used at this time, have a meaning commonly understood by those of ordinary skill in the art to which the present invention belongs, unnecessarily obscure the subject matter of the present invention in the following description Description of known functions and configurations that may be omitted.

As used herein, the term "C _A -C _B " means "carbon number A or more and B or less", and the term "A to B" means "A or more and B or less".

"Alkyl" as used herein refers to a monovalent straight or pulverized saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, from 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, more preferably 1 to It may have seven carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, and the like.

"Aryl" described herein is an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by one hydrogen removal, each ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

“Heteroaryl” as used herein means a heteroaromatic monovalent radical that is an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeleton atoms and the remaining aromatic ring skeleton atoms are carbons. 5 to 6-membered monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present specification also includes a form in which one or more heteroaryl is connected by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisoxazole, thiophene, Benzothiophene, furan, benzofuran, and the like.

"Heterocycloalkyl" described herein is a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O and S, wherein the non-aromatic heterocycle is a saturated or unsaturated monocyclic ring, It includes both polycyclic or spirocyclic forms, and can be bonded via heteroatoms or carbon atoms, and nitrogen, carbon, oxygen or sulfur atoms in non-aromatic heterocyclic radicals can be oxidized, optionally in various oxidation states. In addition, the nitrogen atom in the non-aromatic heterocyclic radical may optionally be quaternized. Examples of such heterocycloalkyl radicals include aziridine, pyrrolidine, pyrrolidinone, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo [3.1.0] Monovalent radicals of non-aromatic heterocycles such as hexane, octahydropyrrolo [3,4-c] pyrrole, 2,7-diazaspiro [4.4] nonane, 2-azaspiro [4.4] nonane, and the like. .

As used herein, "halo" or "halogen" refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, "haloalkyl" refers to alkyl substituted with one or more halogens, for example trifluoromethyl and the like.

As used herein, "haloalkoxy" means alkoxy substituted with one or more halogens, and examples thereof include trifluoromethoxy and the like.

“Alkenyl” described herein may be partially saturated with straight or branched unsaturated hydrocarbon monovalent radicals that include one or more double bonds between two or more carbon atoms. Specifically ethenyl, propenyl, prop-1-en-2yl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl , 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, isoprenyl, geranyl, and the like.

"Alkynyl" described herein may be partially saturated with straight or branched unsaturated hydrocarbon monovalent radicals that include one or more triple bonds between two or more carbon atoms. Specifically, but not limited to ethynyl, propynyl, butynyl 1,3-butadiynyl, and the like.

"Cycloalkyl" described herein is a monovalent saturated carbocyclic radical composed of one or more rings, which may have 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

"Alkoxy" described herein is an -O-alkyl radical, which may have from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Where 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.

As used herein, "alkylcarbonyl" refers to an -C (= 0) alkyl radical, where 'alkyl' is as defined above. Examples of such alkylcarbonyl radicals include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, and the like.

As used herein, "alkylcarbonyloxy" refers to an -OC (= O) alkyl radical, where 'alkyl' is as defined above. Examples of such alkylcarbonyloxy radicals include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy and the like. But it is not limited thereto.

As used herein, "alkoxycarbonyl" refers to an -C (= 0) alkoxy radical, where 'alkoxy' is as defined above. Examples of such alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, and the like. It is not limited.

"Substituted" in the description of "substituted or unsubstituted" as used herein refers to a group or moiety having one or more substituents attached to the structural backbone of the group or moiety. Non-limiting groups or structural backbones selected from the group consisting of halogen, C1-C15 alkyl, haloC1-C15 alkyl, C6-C20 aryl, C3-C15 cycloalkyl, cyano, formyl, carboxyl or nitro It means to be substituted with one or more.

As used herein, the term "pharmaceutically acceptable salt" refers to a concentration that is relatively nontoxic to a patient and has a harmless effective action, wherein the side effects caused by the salt do not degrade the beneficial efficacy of the compounds of the present invention itself. Any organic or inorganic addition salt of a compound.

As used herein, the term “wound” refers to a state in which continuity of tissue has lost its original continuity by external action. The term “tissue” mainly refers to skin, which is the largest organ in the human body and serves as the primary defense against external irritation and risk of infection.

As used herein, the term "treatment" refers to any action by which administration of a composition of the present invention improves or advantageously alters the condition of a wound.

The term "improvement" herein refers to any action that at least reduces the parameters associated with the condition to be treated with the administration of a composition of the present invention, eg the extent of symptoms.

As used herein, the term "skin whitening" refers to any action that prevents the symptoms of excessive growth or deposition of pigments in the skin, or lightens the color of pigments deposited on existing skin from pigmentation diseases.

As used herein, the term “pigmentation disorder” may include without limitation any disease, lesion that may be caused by melanin produced abnormally in the skin, and is selected from the group consisting of hyperpigmentation after treatment of a wound or inflammation. It may be more than one disease.

As used herein, the term "skin regeneration" is a process of repairing skin tissue against damage to skin or cells caused by an external cause such as a wound or inflammation, which promotes proliferation of skin cells or promotes recovery of damaged skin. Means that.

As used herein, the term "pharmaceutically acceptable" refers to a property that is not toxic to an individual such as a cell or human being exposed to the composition, and means suitable for use as a pharmaceutical preparation, and generally for such use. It is considered safe and means that it is officially approved by the national authority for its use or on the list of Korean or US Pharmacopoeia.

The term "individual" as used herein refers to all animals, including humans, who have or are likely to develop a viral disease. The animal may be a mammal such as, but not limited to, a human, a cow, a horse, a sheep, a pig, a goat, a camel, a antelope, a dog, a cat, and the like, which require treatment of similar symptoms.

As used herein, the term "administration" means introducing a pharmaceutical composition of the present invention to an individual in any suitable manner, and the route of administration of the composition of the present invention may be directed to a variety of oral or parenteral routes as long as the target tissue can be reached. It can be administered through.

As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects, and the effective dose level is the sex, age of the patient. And other medical fields, including body weight, health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, and rate of release, duration of treatment, combination or drug used simultaneously. It can be easily determined by those skilled in the art according to factors well known in the art.

The present invention provides a catechin-based compound or a pharmaceutically acceptable salt thereof, which is very effective in treating wounds. The catechin-based compound of the present invention is represented by the following Chemical Formula 1.

[Formula 1]

(In Formula 1,

R ₁ is C ₁ -C 20 alkylcarbonyl, C 2 -C 30 alkenylcarbonyl,-(CH ₂ ) _d -Ar ₁ ,

,

or

ego;

R ₁₁ is hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^a , -CONR ^b R ^c , hydroxy OxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _e -Ar ₂ , -NR ^b R ^c ,

,

,

,

Or O - sugar residue (O -sugar residue) and;

R ₁₂ is hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^d , -CONR ^e R ^f , HydroxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _f -Ar ₃ , -NR ^e R ^f ,

,

,

,

Or O -sugar residues;

a is an integer from 1 to 4, and when a is an integer of 2 or more, R ₁₂ may be the same or different from each other;

m is an integer from 1 to 10;

R ₁₄ is hydroxy, C 1 -C 15 alkoxy, halogen, C 1 -C 15 alkylcarbonyloxy or an O-sugar residue;

R ₁₅ is hydrogen, C 1 -C ₁₅ alkyl, halogen, hydroxy or C 1 -C 15 alkoxy;

R ₁₆ is hydrogen or C1-C15 alkyl;

b is an integer from 1 to 4, and when b is an integer of 2 or more, R ₁₅ may be the same or different from each other;

R ₁₇ is hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1-C15 alkoxy C1-C15alkyl, C6-C20aryloxyC1-C15alkyl or O-sugar residues;

R ₁₈ is hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1- C 15 alkoxy C 1 -C 15 alkyl, C 6 -C 20 aryloxy C 1 -C 15 alkyl or an O-sugar residue;

c is an integer from 1 to 4, and when c is an integer of 2 or more, R ₁₈ may be the same or different from each other;

n is an integer from 1 to 10;

R ^a and R ^d are independently of each other hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl or C 6 -C 20 aryl;

R ^b , R ^c , R ^e and R ^f are independently of each other hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 6 -C 20 aryl or C 1 -C 15 alkylcarbonyl;

d, e and f are each independently an integer from 1 to 10;

Ar ₁ , Ar ₂ and Ar ₃ are independently of each other C 6 -C 20 aryl, wherein the aryl of Ar ₁ to Ar ₃ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy and C 1 -C 15 alkylcarbon May be further substituted with one or more selected from nil;

R ₂ is hydrogen, hydroxy, C1-C15 alkyl, haloC1-C15 alkyl, hydroxyC1-C15 alkyl, C1-C15 alkoxy, amino acid, C1-C15 alkylcarbonyl, C1-C15 alkoxycarbonyl, C2-C15 Alkenyl, hydroxyC2-C15alkenyl or C2-C15alkynyl.)

The catechin-based compound of the present invention is introduced with an apiofuranose group which is a sugar residue specific to position 5 of the (2R, 3S)-(+)-catechin ((2R, 3S)-(+)-catechin) backbone. In this structure, by having various substituents at the 3rd position, the stability and processability of the catechin-based compound are enhanced to induce a vascular dynamic effect, which is effective in treating various wounds.

In particular, the catechin-based compound of the present invention improves the expression of various blood vessels and cell growth factors in the wound site as well as vascular dynamic activity, which can lead to necrosis of the skin by delaying wound healing due to impaired blood circulation due to peripheral blood vessel damage. Very effective in the treatment of peripheral ulcers.

On the other hand, wounds such as peripheral ulcers are known to form hyperpigmentation after treatment, but due to the treatment of the catechin-based compounds of the present invention, it is possible to prevent or weaken hyperpigmentation that may occur simultaneously with the treatment of wounds such as peripheral ulcers. You can.

In addition, the catechin-based compound of the present invention promotes the regeneration of skin tissues and secretion of antimicrobial peptides, thereby effectively inhibiting the inflammatory response, which is a major symptom in inflammatory skin diseases accompanied by the accumulation of wounds, and regenerating cells. It is useful to ameliorate the disease, to lighten the skin tone after wound or inflammation treatment, or to regenerate skin.

In one example, the sugar residue removes one, particularly one or five, hydroxyl groups from a sugar selected from monosaccharides and oligosaccharides in which the monosaccharides are linked two to four. The remaining portion after the mean, but is not limited thereto. Preferably, arabinose, lyxose, ribose, ribose, xylose, deoxyribose, allose, altrose, galactose, Glucose, idose, mannose, talos, fructose, fucose, rhamnose, and other sugars, maltose and cellobiose sugar residues of disaccharides such as cellobiose, sucrose, lactose and the like, but are not limited thereto. Moreover, any of (alpha), (beta), D, and L may be sufficient as the structure of these sugars.

The sugar moiety also includes a sugar moiety having a protecting group, that is, a sugar derivative having a protecting group in a hydroxy group.

Examples of the protecting group for the hydroxy group include a C1-C15 alkyl group (e.g. methyl, ethyl), a C1-C15 alkoxy C1-C15 alkyl group (e.g., methoxymethyl, ethoxyethyl, etc.), tetrahydropyranyl group, C1-C15 Alkylcarbonyl groups (e.g., acetyl, propionyl, pivaloyl, etc.), C6-20 aryl C1-C15 alkyl groups (e.g., benzyl groups, etc.), C6-C20 arylcarbonyl groups (e.g., benzoyl groups, etc.), C1-C15 Alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), tri (C1-C15 alkyl) silyl groups (e.g. trimethylsilyl groups, triethylsilyl groups, triisopropylsilyl Group, tert-butyldimethylsilyl group, etc.), tri (C6-C20 aryl C1-C15 alkyl) silyl group, di (C6-C20 aryl) (C1-C15 alkyl) silyl group (e.g. tert-butyldiphenylsilyl group C2-C20 heteroarylcarbonyl group (e.g., pyridylcarbonyl, quinolylcarbonyl, furylcarbonyl, thienylcarbonyl, etc.), C6-C20 arylC2-C15 alkenylcarbonyl group (e.g. Tenylcarbonyl, etc.),

And the like, but are not limited thereto.

In one embodiment, the sugar residue may be selected from the following structures, but is not limited thereto.

In one embodiment, the amino acid means a carboxylic acid containing an amino group. The amino acid includes natural or unnatural amino acids, and is not particularly limited, but natural amino acids may be preferred.

The amino acids defined above are the three-dimensional of alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, or glutamic acid Isomeric forms, ie D- or L-forms, but are not limited to these.

The amino acids defined above are attached to the parent moiety through amino or carboxylic acids by condensation reactions or by forming thiol ether (-S-) or ether (-O-) bonds with thiols or hydroxyls. May be linked to a residue.

In the catechin-based compound according to an embodiment in terms of having an improved effect on wound healing, the R ₁ is C1-C20 alkylcarbonyl, C2-C30 alkenylcarbonyl,

,

,

or

ego; R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy; R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, C 1 -C 15 alkoxycarbonyl, carboxyl, C 6 -C 20 aryloxycarbonyl, carbamoyl,

,

,

,

Or an O-sugar residue; R _12a and R _12b are each independently of the other hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, C1-C15 Alkoxycarbonyl, carboxyl, C6-C20 aryloxycarbonyl, carbamoyl,

,

,

,

Or an O-sugar residue; m and n are each independently an integer from 1 to 5; R ₁₄ is hydroxy, C 1 -C 15 alkoxy or C 1 -C 15 alkylcarbonyloxy; R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy; R ₁₆ is hydrogen or C1-C15 alkyl; R ₁₇ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O-sugar residues; R _18a and R _18b are independently of each other hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1 -C 15 alkyl, C 1 -C 15 alkoxy C 1 -C 15 alkyl, C 6 -C 20 aryloxy C 1 -C 15 alkyl, or an O-sugar residue.

In the catechin-based compound according to an embodiment in terms of having an improved effect on wound healing, the R ₂ is hydrogen, hydroxy, C 1 -C 15 alkyl, haloC 1 -C 15 alkyl, hydroxy C 1 -C 15 alkyl, C 1 -C15alkoxy or amino acid.

More preferably, in the catechin-based compound according to one embodiment, R ₁ is C1-C20 alkylcarbonyl, C2-C30 alkenylcarbonyl,

,

,

or

ego; R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy; R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O -sugar residues; R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 1 -C 15 alkoxy,

or

ego; m is, independently from each other, an integer from 1 to 5; R ₁₄ is hydroxy, C 1 -C 15 alkoxy or C 1 -C 15 alkylcarbonyloxy; R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy; R ₁₆ is hydrogen or C1-C15 alkyl; R ₂ may be hydrogen, hydroxy, C 1 -C 15 alkoxy or amino acid.

More specifically, in the catechin compound according to one embodiment, R ₁ is -C (= 0)-(CH ₂ ) _x -CH ₃ , -C (= 0) -CH ₂ CH _2- (CH = CHCH). ₂ ) _y -CH ₃ , -C (= O) -CH ₂ CH ₂ CH _2- (CH = CHCH ₂ ) _z -CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

ego; R ₂ is hydrogen, hydroxy, methoxy or

ego; x is an integer of 1 to 20, and y and z are integers of 1 to 6 independently of each other.

In the catechin-based compound according to an embodiment, the catechin-based compound having a more improved effect on wound healing may be specifically selected from the following compound group, but is not limited thereto.

Catechin-based compound according to an embodiment is a catechin-based compound represented by the following formula (2) wherein β-D-apiopuranose group is introduced at position 5 of the (2R, 3S)-(+)-catechin backbone or a pharmaceutical thereof It may be an acceptable salt.

[Formula 2]

(In Formula 2,

R ₁ is C5-C20 alkylcarbonyl, C5-C25 alkenylcarbonyl,

,

,

or

ego;

R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy;

R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O -sugar residues;

R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 1 -C 15 alkoxy,

or

ego;

m is an integer from 1 to 3;

R ₁₄ is hydroxy or C 1 -C 15 alkoxy;

R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy;

R ₁₆ is hydrogen or C1-C15 alkyl;

R ₂ is hydrogen or hydroxy.)

The catechin-based compound according to one embodiment improves the expression of vascular and cell growth factors and at the same time has an improved effect on the treatment of wounds, in particular peripheral ulcers and inflammation due to microvasculokinetic activity at the venous and lymphatic levels. More preferably in terms of having a catechin-based compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof.

[Formula 3]

(In Chemical Formula 3,

R _A is C5-C20 alkyl, C5-C25 alkenyl,

,

or

ego;

R ₁₁ is hydroxy, halogen, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyloxy or O -sugar residues;

R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 7 alkyl, C 1 -C 7 alkoxy,

or

ego;

R ₁₄ is hydroxy or C 1 -C 7 alkoxy;

R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C7alkoxy;

R ₂ is hydrogen or hydroxy.)

The catechin-based compound according to an embodiment is located at position 5 of the (2R, 3S)-(+)-catechin skeleton in terms of regenerating skin tissue, promoting secretion of antimicrobial peptides, and having an improved effect on wound healing. It may be a catechin-based compound represented by the following formula (4), or a pharmaceutically acceptable salt thereof, wherein a β-D-apiopuranos group is introduced and a gallate derivative group is introduced at position 3.

[Formula 4]

(In Formula 4,

R ₁₁ is hydroxy, halogen, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyloxy or O -sugar residues;

R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 7 alkyl, C 1 -C 7 alkoxy,

or

ego;

R ₁₄ is hydroxy or C 1 -C 7 alkoxy;

R _15a and R _15b are independently of each other hydrogen, hydroxy or C 1 -C 7 alkoxy.)

In the catechin-based compound according to one embodiment, the O -sugar moiety may be formed by any hydroxyl functional group present in the sugar moiety, and when linked through the anionic hydroxyl functional group of the sugar, glycosidic bond Means that there is, and is not particularly limited, but preferably

Can be.

The catechin-based compounds according to the present invention can be used in the form of prodrugs, solvates and pharmaceutically acceptable salts to enhance absorption or increase solubility in vivo. Acceptable salts are also within the scope of the present invention.

The present invention also provides a method for preparing the catechin compound.

Catechin-based compound according to an embodiment of the present invention is the root muscle It can be prepared as shown in Scheme 1 by using uldavioside A (uldavioside A; (+)-catechin-5-O-β-D-apiofuranoside; compound a1) isolated from davidiana Planch) extract as a starting material, It is not limited.

Scheme 1

(In Scheme 1, PG represents a hydroxy protecting group, R _A is C1-C20 alkyl, C2-C30 alkenyl,

,

or

ego; R ₁₁ , R ₁₂ , a and m are the same as defined in Formula 1 above.)

As shown in Scheme 1, (a) after protecting the hydroxy group of the starting material with a protecting group, (b) 1,2-dihydroxy group again in the presence of a phosgene catalyst to prepare a cyclic carbonate intermediate compound And (c) react with R _A COOH, and then (d) deprotect the dihydroxy protecting group, and (e) deprotect the hydroxy protecting group to prepare a catechin compound according to the present invention.

The preparation method of Scheme 1 does not limit the method for preparing the catechin-based compound according to the present invention, and modifications of the preparation method will be apparent to those skilled in the art. The cyclic carbonate intermediate compound prepared above may be reacted with various substituents using a known organic reaction.

The present invention also provides a pharmaceutical composition for treating wounds comprising the catechin-based compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In the pharmaceutical composition for treating wounds according to one embodiment, the wound may be selected from the group consisting of wounds, cuts, cuts, burns, lacerations, abrasions and bruises.

In the pharmaceutical composition for treating wounds according to one embodiment, the wound may be a peripheral ulcer, more preferably the peripheral ulcer is diabetic ulcer, lower extremity ulcer, foot ulcer, hypertension ischemic ulcer, vein Ulcers or pressure sores, but are not limited thereto.

The catechin-based compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt can be prepared by conventional methods in the art, for example hydrochloric acid, bromic acid, sulfuric acid. Salts with inorganic acids such as sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, mandelic acid, cinnamic acid, stearic acid Salts with organic acids such as acids, palmitic acid, glycolic acid, glutamic acid, tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, ascorbic acid, salicylic acid, or acetylsalicylic acid (aspirin), glycine, alanine, vanillin, isoleucine Salts with amino acids, such as serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid, ethanesulfonic acid, ben Sulfonic acids include sulfonic acid salts, sodium salt by reaction with an alkali metal such as potassium, etc. or a salt with ammonium ions, such as toluene sulfonic acid.

The catechin-based compounds of the present invention may exist in solvated forms, for example hydrated and unsolvated forms, and solvates of catechin-based compounds according to the present invention include all solvated forms having pharmaceutical activity. will be. That is, the catechin compound of the present invention is dissolved in a solvent that can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized or recrystallized after adding a free acid or free base to include a hydrate. Solvates can be formed. Thus, the novel compounds of the present invention include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization.

The catechin-based compounds of the present invention can be administered in the form of prodrugs that are degraded in the human or animal body to provide the catechin-based compounds of the present invention. Prodrugs can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed if the parent compound contains suitable groups or substituents that can be induced to form the prodrug.

In addition, the pharmaceutical composition for treating wounds of the present invention may be prepared by adding conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients to the catechin-based compound or pharmaceutically acceptable salts thereof. In particular, it may be formulated as a preparation for parenteral administration.

For example, a pharmaceutically acceptable carrier that can be used in the pharmaceutical composition for treating wounds is commonly used in the preparation of lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, Alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and / or mineral oil And the like, but are not limited thereto.

For example, excipients that may be used in the pharmaceutical composition for treating wounds include binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. The proportion and nature of such excipients may be determined by the solubility and chemical properties of the selected tablet, the chosen route of administration, and standard pharmaceutical practice. Examples of excipients include lactose, dextrose, sucrose, mannitol, sorbitol, xylitol, erythritol, maltitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth Rubber, alginate, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, vanilla flavor and the like.

The pharmaceutical composition for wound treatment is formulated in a parenteral dosage form and administered by parenteral administration methods such as injections, external preparations, suppositories, etc., in the form of sterile aqueous or oily solutions for intravenous, subcutaneous, sublingual or intramuscular administration. Can be.

For example, the pharmaceutical composition for treating wounds may be sterile, or may further include adjuvants such as preservatives, stabilizers, thickeners, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutic agents. Useful materials may further be included and may be formulated according to conventional methods such as dissolution, dispersion, gelation and the like.

For example, the catechin-based compound or a pharmaceutically acceptable salt thereof, which is an active ingredient in the pharmaceutical composition for treating wounds, may be administered to a mammal including a human, including a formulation method, a patient's age, weight, sex, dosage form, It may vary depending on the state of health and degree of illness. Generally, the pharmaceutical composition may be included in the pharmaceutical composition in an effective amount of 0.01 to 500 mg / kg body weight, preferably 0.1 to 100 mg / kg body weight, and such pharmaceutical composition may be divided once or several times a day. And can be administered via the parenteral route. However, since the dose may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.

More preferably, the pharmaceutical composition for treating wounds is formulated for external parenteral administration in a form selected from powders, gels, ointments, creams, lotions, pastes, sprays, aerosols, oils and patches as parenteral preparations. It can be applied topically to the wound site. The external preparation for skin may be appropriately prepared according to methods well known in the art. The powder is a solid formulation for application or spraying to the wound site, a powder in the form of a powder, the gel is a formulation in the form of a gel to be applied to the skin, for example, an aqueous gel and an oily gel. It is a semi-solid preparation in which the active ingredient applied to the skin is dissolved or dispersed in a base, and the cream is a semi-solid preparation emulsified in oil-in-water or water-in-oil applied to the skin, and the patch is a preparation that adheres to the skin. Tape agent and puff agent are mentioned. In the case of a patch, the ointment, cream, gel or paste can be applied to a conventional support by a conventional method. As the support, a film or foam sheet such as a woven or nonwoven fabric made of cotton, staple fibers and chemical fibers, soft vinyl chloride, polyethylene, and polyurethane can be suitably used.

The pharmaceutical composition for wound treatment of the present invention can be directly administered to the wound site than oral administration to the wound, and the side effects are lower, and therefore, particularly in the treatment of wounds, it may have a more advantageous therapeutic effect through transdermal administration. . That is, the topical skin preparation of the present invention is locally administered to the target site (for example, the affected part) of the skin or mucous membrane, thereby further effecting the effect of the catechin compound or a pharmaceutically acceptable salt thereof as an active ingredient near the site of application. It can be expressed reliably and quickly. The content of the active ingredient, the catechin-based compound or a pharmaceutically acceptable salt thereof, can be appropriately adjusted according to the use of the composition, the form of application, the purpose of use, and the desired effect. The composition may be present at a concentration of 0.001 to 20% by weight, and at a concentration of 0.003 to 5% by weight, but is not limited thereto.

The pharmaceutical composition for wound treatment of the present invention may be administered alone or in combination with other therapeutic agents such as vasoprotectants, analgesics and the like. In combination administration, administration may be sequential or simultaneous.

The catechin-based compound or a pharmaceutically acceptable salt thereof does not induce cytotoxicity within a concentration range exhibiting a wound healing effect, and expresses an excellent wound healing effect.

In addition, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), HGF (hepatocyte growth factor), PD-EGF (plateletderived endothelial growth factor), Ang (angiopoietin), TGF (transforming growth factor), PDGF (platelet- Expression of various blood vessel and cell growth factors such as derived growth factor (EGF) and epidermal growth factor (EGF) may induce angiogenesis, increase pulse activity and blood flow of peripheral blood vessels, and restore peripheral blood flow and function. . In particular, it has excellent cell protection against glycosylated stress in the environment of high glucose level and promotes smooth blood circulation to peripheral blood vessels so that peripherals such as diabetic ulcers, lower extremity ulcers, foot ulcers, hypertensive ischemic ulcers, venous ulcers, pressure sores, etc. By increasing the healing rate of ulcers, you can maximize the healing effect of ulcers.

In another aspect, the present invention provides a cosmetic composition for improving inflammatory skin disease comprising the catechin-based compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In the cosmetic composition for improving inflammatory skin disease according to an embodiment, the inflammatory skin disease in the group consisting of atopic dermatitis, eczema, acne, inflammatory dermatitis, seborrhea and contact dermatitis Can be selected.

The present invention also provides a cosmetic composition for skin whitening comprising the catechin-based compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment, the catechin-based compound or a pharmaceutically acceptable salt thereof expresses the effect of preventing or ameliorating hyperpigmentation that may occur during and after treatment of a wound or inflammatory disease.

In another aspect, the present invention provides a cosmetic composition for skin regeneration comprising the catechin-based compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

The content of the catechin-based compound of Formula 1 contained as an active ingredient in the cosmetic composition may be appropriately adjusted according to the application form, the purpose of use, and the desired effect, and considering the content-to-content effect, for example, with respect to the total weight of the composition Preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, most preferably 0.001% to 30% by weight may be added, but is not limited thereto.

The cosmetic composition may be in the form of emulsions, suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes), nonionic vesicle dispersants obtained by dispersing an oil phase in a solution, gel, solid or pasty anhydrous product, aqueous phase, It may be provided in the form of a cream, skin, lotion, powder, ointment, spray or cone stick. It may also be prepared in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

Cosmetic composition according to an embodiment of the present invention is a component of the catechin-based compound represented by the formula (1) of the present invention or pharmaceutically acceptable salts thereof, all kinds of components that can be used in conventional commercialization or formulation, such as perfumes, pigments, Fungicides, antioxidants, preservatives, moisturizers, stabilizers, emulsifiers, thickeners, liquid crystal film strengthening agents, pigments, excipients, diluents, inorganic salts and synthetic polymer materials may be further included, the type and content of the final product It can be adjusted appropriately according to the use and purpose of use.

The additive which may be further included is not limited as long as it is a raw material generally used in the art, and specific examples thereof include propanediol, 1,2-hexanediol, ethylhexylglycerine, phenoxyethanol, caprylhydroxamic acid and Preservatives such as glyceryl caprylate; Methoxy cinnamic acid derivatives, diphenylacrylic acid derivatives, salicylic acid derivatives, paraaminobenzoic acid derivatives, triazine derivatives, benzophenone derivatives, benzalmalonate derivatives, anthranyl derivatives, imidazoline derivatives, 4,4-diarylbutadiene derivatives and phenyl Ultraviolet absorbers such as benzimidazole derivatives; Fatty alcohols such as cetearyl alcohol, cetyl alcohol and behenyl alcohol, and bispig 15 / methylethyldimethyl silane, dimethicone / dimethicone Fiji-10 / 15, dimethicone / polyglycerine-3, dimethicone Chicon / Dimethiconol, Dimethicone / Dimethicone Vinyl Dimethicone, Cyclomethicone / Dimethicone, Cyclomethicone / Dimethicone, Cyclomethicone / Trimethylsiloxysilicate, Cyclopentasilonic acid / Dimethicone, Cyclopentasil Choose from silicone polymers such as Lonic Acid / Pig-12 Dimethicone, Cyclopentasilonic Acid / Cetaryl Dimethicone / Vinyl Dimethicone, Cyclopentasilonic Acid / Dimethicone / Vinyl Dimethicone, Dimethicone / Vinyl Dimethicone Crosspolymer Stabilizers; Emulsifiers selected from cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, etc. may be mixed, preferably polyglyceryl-4 caprylate / caprate, polyglyceryl-5 ka Prylate / Caprate, Polyglyceryl-6 Caprylate / Caprate, Polyglyceryl-7 Caprylate / Caprate, Polyglyceryl-8 Caprylate / Caprate, Polyglyceryl-9 Caprylate / Caprate, polyglyceryl-10 caprylate / caprate, polyglyceryl-4 caprate, polyglyceryl-5 caprate, polyglyceryl-6 caprate, polyglyceryl-7 caprate, polyglycerol Reyl-8 Caprate, Polyglyceryl-9 Caprate, Polyglyceryl-10 Caprate, Polyglyceryl-4 Laurate, Polyglyceryl-5 Laurate, Polyglyceryl-6 Laurate, Polyglyceryl- 7 Urate, polyglyceryl-8 laurate, polyglyceryl-9 laurate, polyglyceryl-10 laurate, polyglyceryl-6 cocoate, polyglyceryl-7 cocoate, polyglyceryl-8 cocoate , Polyglyceryl-9 cocoate, polyglyceryl-10 cocoate, polyglyceryl-11 cocoate, polyglyceryl-12 cocoate, polyglyceryl-6 myristate, polyglyceryl-7 myristate, poly Glyceryl-8 myristate, polyglyceryl-9 myristate, polyglyceryl-10 myristate, polyglyceryl-11 myristate, polyglyceryl-12 myristate, polyglyceryl-10 oleate, polyglyceryl Polyglyceryl papers such as -11 oleate, polyglyceryl-12 oleate, polyglyceryl-10 stearate, polyglyceryl-11 stearate, polyglyceryl-12 stearate, polyglyceryl-6 behenate Purchase that directly formed by reacting an acid polyglyceryl ester and a fatty acid or a surface active agent commercially available are used in. FIG. The thickener may be selected from carbomer, carbopol, gelatin, xanthan gum, natural cellulose, high cell, methyl cellulose, etc. to impart proper viscosity of the cosmetic composition to improve the feeling of use and stability of the formulation. no. The liquid crystal film strengthening agent increases the strength of the liquid crystal, and serves to maintain the long-term stability of the liquid crystal by connecting the fence tightly, phytosphingosine, bishydroxyethyl biscetyl malamide, cholesterol isostearate, cholesterol Oleate, cholesterol stearate, lecithin, ceramides (eg, ceramide 3, ceramide 6) and the like, but is not limited thereto.

In addition, the pigments include sieving pigments, white pigments, colored pigments, pearlescent pigments, metal powders, organic powders, etc., the sieving pigments are talc, mica, kaolin, calcium carbonate, mica, talc, kaolin, alumina, silicic acid Barium, zeolite, dolomite, magnesium carbonate, barium sulfate, etc. are possible, and the white pigment may be titanium oxide, zinc oxide, etc., and the coloring pigment may be bengara, iron sulfate, black iron oxide, chromium oxide, ultramarine blue, bluish blue, Carbon black, and the like, and pearlescent pigments include titanium dioxide, mica titanium, iron titanate and titanium oxide coated mica, silica, tinoxite, and ferric ferrocyanide, and the like. Copper, palladium, platinum and the like can be used, and as the organic powder, polymethyl methacrylate, nylon, cellulose, starch and the like can be used. In addition, all natural, inorganic, and organic pigments as commonly known in cosmetics may be used, and the natural pigments include Gardenia yellow, Gardenia blue, Gardenia green, Gardenia red, Red chrysanthemum pigment, Red yellow pigment, Red safflower pigment. , Anato pigment, cochinyl pigment, lac pigment, high pigment, grape skin pigment, red cabbage pigment, elderberry pigment, blueberry pigment, puffica pigment, caramel pigment, red radish pigment, dye, electrochemical pigment, riboflavin, Beta carotene, cacao pigment, turmeric pigment, cone pigment, beet red pigment, anthocyanin, anthocyanin, phycocyanin, phycocyanin, chlorophyll pigments, and one selected from the group consisting of these, may be used as an inorganic pigment Metal oxides, especially iron oxides (red, black, yellow, brown), titanium dioxide, zinc oxide, chromium oxide, bismuth oxychloride, aluminum oxide, zirconium oxide, acids Consisting of cobalt, cerium oxide, nickel oxide, calcium hydroxide, iron hydroxide, aluminum hydroxide, chromium hydroxide, magnesium hydroxide, ferric ammonium ferrocyanide, Prussian blue, iron sulfide, manganese violet, carbon black, mica, kaolin, and combinations thereof Organic pigments may be selected from the group, and organic pigments include indigo lakes, carmine lakes, lakes derived from the well-known FD & C and D & C dye series, such as D & C Red 21 aluminum lakes, D & C Red 7 calcium lakes, aromatic azos, indigoids, tree Natural or synthetic organic dyes such as phenylmethane, anthraquinone and quentin dyes can be used.

The cosmetic composition of the present invention may be external, dermal or subcutaneous administration, preferably, external or transdermal, more preferably external skin administration, and external dermatological agents are preferable.

In addition, the cosmetic composition may be one containing a solvent usually included in the applied form, for example, ethanol, glycerin, butylene glycol, propylene glycol, polyethylene glycol, 1,2,4-butanetriol, sorbitol ester , 1,2,6-hexanetriol, benzyl alcohol, isopropanol, butanediol, diethylene glycol monoethyl ether, dimethylisosorbide, N-methyl-2-pyrrolidone, propylene carbonate, glycerin-26, methylglu At least one selected from ces-20, isocetyl myristate, isocetyl octanoate, octyl dodecyl myristate, octyl dodecanol, isostearyl isostearate, cetyl octanoate and neopentyl glycol dicaprate It may include. When the composition of the present invention is prepared using such a solvent, the solubility of the compound in the solvent is slightly different depending on the type of compound or the mixing ratio of the solvent. The type and amount of usage can be selected and applied appropriately.

In addition, the cosmetic composition may include various substances for enhancing the transdermal penetration during transdermal administration. For example, lauroamram derivatives and oleic acid, ester derivatives of monooleate derivatives, adapalene, tritinoin, retinaldehyde, tazarotine, salicylic acid, aziraic acid, glycolic acid, ethoxydiglycol, twin 80, lecithin organogel, and the like. In addition, the cosmetic composition of the present invention, in order to impart additional functions, cosurfactants, surfactants, keratin softeners, blood circulation accelerators, within the range that does not impair the effect of the composition imparting the action effect of the catechin-based compound of the present invention, Auxiliary ingredients such as cell activators, fresheners, humectants, antioxidants, pH adjusters, purified water and the like may be added, and may contain additives such as flavors, pigments, preservatives, excipients and the like, depending on the form applied.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments. However, this is presented as an example of the present invention by any means is not limited by the scope of the present invention, the scope of the present invention is defined only in accordance with the claims to be described later.

The organic solvent used in the reaction was refluxed under sodium metal and benzophenone to remove water and distilled immediately before use. ¹ H-NMR analysis of the synthesized ligand and catalyst was carried out using Bruker 400 or 500 MHz at room temperature. IR was analyzed 5 mg of compound using Bruker ATR-IR in the solid state.

Bn: benzyl, DMF: Dimethylformamide, DCM: Dichloromethane, DMP: Dess-Martin periodinane, IPA: Isopropyl alcohol, EDCI: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide, HOBT: 1-Hydroxybenzotriazole, DMAP 4- (Dimethylamino) pyridine

Preparation Example 1 Preparation of Intermediate Compound a-3

Preparation of Compound a-2

Compound a-1 (2.0 g, 4.73 mmol) was dissolved in anhydrous DMF (50 mL) under argon atmosphere. 55% NaH (830 mg, 18.94 mmol) was added in an ice-water bath and stirred for 30 minutes. Benzyl bromide (2.3 mL, 18.94 mmol) was then added dropwise. Slowly raised to room temperature and reacted overnight. Distilled water was added to terminate the reaction, followed by concentration under reduced pressure. Extracted with EtOAc (50 mL X 4), and the combined organic layers were washed twice with distilled water. After drying over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, Hex: EA = 1: 2 or DCM: MeOH = 20: 1 to 10: 1) to give Compound a-2 (2.2 g, 59%).

¹ H NMR (400 MHz) δ 7.45-7.31 (m, 20H), 6.99 (m, 3H), 6.30 (dd, 2H, J = 1.8 Hz, J = 13.7 Hz), 5.68 (s, 1H), 5.18 ( s, 4H), 5.04 (s, 2H), 4.73 (dd, 2H, J = 11.5 Hz, J = 28.5 Hz, 4.63 (d, 1H, J = 8.1 Hz) 4.09 (s, 1H), 3.96 (s, 2H), 3.69 (s, 2H), 3.43 (s, 1H), 3.10 (dd, 1H, J = 5.5 Hz, J = 16.5 Hz), 2.65 (dd, 1H, J = 8.9 Hz, J = 16.5 Hz)

Preparation of Compound a-3

A-2 (300 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL) under argon atmosphere and pyridine (93 μL, 1.15 mmol) was added. 20% phosgene in toluene (424 μL, 0.80 mmol) was added dropwise in an ice-water bath. The reaction was carried out at room temperature. 1 hour later sat. NaHCO ₃ aqueous solution was added to stop the reaction. The product was extracted with dichloromethane, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (Hex: EA = 1: 1) to give compound a-3 (230 mg, 74%).

¹ H NMR (400 MHz) δ 7.45-7.29 (m, 20H), 6.98 (m, 3H), 6.26 (dd, 2H, J = 2.2 Hz, J = 13.1 Hz), 5.71 (d, 1H, J = 3.3 Hz), 5.18 (s, 2H), 5.17 (s, 2H), 5.05 (s, 2H), 4.82 (d, 1H, J = 12.2 Hz), 4.65 (dd, 2H, J = 10.1 Hz, J = 24.4 Hz), 4.30 (dd, 2H, J = 8.1 Hz, J = 16.5 Hz), 4.28 (d, 1H, J = 12.5 Hz), 4.09 (d, 1H, J = 9.2 Hz), 4.07 (d, 1H, J = 2.0Hz), 3.98 (d, 1H, J = 8.1Hz), 3.11 (dd, 1H, J = 5.8Hz, J = 16.7Hz), 2.65 (dd, 1H, J = 8.9Hz, J = 16.5Hz )

Example

Example 1 Preparation of Catechin Compound 1

Preparation of Compound 1-a

Compound a-3 was dissolved in anhydrous DCM under an argon atmosphere, 4-dimethylaminopyridine and N, N'-dicyclohexylcarbodiimide were added thereto, followed by stirring at room temperature for 30 minutes. 3,4,5-tris (benzyloxy) benzoic acid was added and reacted at room temperature overnight. The solid was filtered off and the product was extracted with DCM. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The product residue was purified by column chromatography to obtain compound 1-a (60%).

Preparation of Compound 1-b

Compound 1-a and aluminum isopropoxide were dissolved in IPA / toluene (= 1/4 (v / v)) under argon atmosphere, and warmed to react at 110 ° C. overnight. After cooling to room temperature, poured into ice-water, and acidified with 1N H ₂ SO ₄ aqueous solution. The water layer was extracted three times with EtOAc, and the combined organic layers were washed with distilled water. Treatment with MgSO ₄ followed by filtration and concentration under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 20: 1) to give compound 1-b (72%).

Preparation of Catechin Compound 1

Compound 1-b was dissolved in EtOAc and 20% Pd (OH) ₂ (50 wt%) was added and reacted overnight under H ₂ atmosphere (balloon). After the reaction, the mixture was filtered through celite-pad and concentrated under reduced pressure to give catechin compound 1 (98%).

Examples 2 to 13 Preparation of Catechin Compound

Catechin-based compounds 2 to 13 were prepared using the method of Example 1.

The structures of the prepared catechin compounds 1 to 13 are shown in Table 1 below.

TABLE 1

Experimental Example 1 Expression Level of Growth Factor by Catechin Compounds

In order to determine the growth factor expression level in vascular endothelial cells by the catechin-based compounds prepared in Examples 1 to 13, the experiment was carried out as follows.

Human umbilical vein endothelial cells (HUVEC) were purchased from Thermo Fisher's HUVEC cell line (C0035C) and cultured in a 37 ° C., 5% CO 2 incubator. As a medium, 1X Low Serum Growth Supplement (LSGS) and 1% penicillin-streptomycin were added to Media 200. The HUVECs used in the experiment used cells that were passaged between 3 and 7, with 70% to 90% of the area cold.

HUVECs were seeded in 6-well plates at 3 × 10 ⁵ cells per well and incubated for 24 hours, followed by adding catechin compounds 1 to 13 at 0.625 μg / mL and incubating for 24 hours. It was. After incubation, the expression level of growth factors was confirmed by real-time PCR. At this time, HUVEC treated with nothing was used as a control.

The results are shown in Table 2 below.

TABLE 2

As described above, all of the catechin-based compounds according to the present invention can be confirmed that the expression of vascular and cell growth factors such as TGF-β, VEGF, PDGF-β and the like, in particular, the gallate derivative at position 3 When substituted it showed better levels of growth factor expression.

Therefore, the catechin-based compound according to the present invention may promote angiogenesis by expression of various blood vessels and cell growth factors, increase pulse activity and blood flow of peripheral blood vessels, and restore peripheral blood flow and restore function. Furthermore, the catechin-based compounds according to the present invention promote smooth blood circulation to peripheral blood vessels, thereby increasing the healing rate of peripheral ulcers such as diabetic ulcers, lower extremity ulcers, foot ulcers, hypertension ischemic ulcers, venous ulcers, pressure sores, etc. Maximize the effectiveness of treatment.

Experimental Example 2 Confirmation of Skin Regeneration of Catechin Compound

Animal experiments were conducted to confirm the skin regeneration effect by the catechin compounds prepared in Examples 1 to 13.

In order to compare cell regeneration ability, the back of the experimental rat was epilated, a wound of the same size was made using a scalpel to stop bleeding with a sterile gauze, and a predetermined amount of the prepared catechin-based compound was applied.

As a result of visual observation of the wound healing for 3 weeks, the recovery state of the control group not treated with the catechin compound was very slow, whereas the group treated with the catechin compound prepared in Examples 1 to 13 was wound. As the traces of the cloud were blurred, the recovery rate was faster than that of the control group. That is, the catechin compound of the present invention was found to be excellent in cell regeneration ability.

Experimental Example 3 Antioxidant Activity of the Catechin Compound

In order to confirm the antioxidant effect of the catechin-based compounds prepared in Examples 1 to 13, an experiment using a hydrogen peroxide (H ₂ O ₂ ) detection kit was performed.

Hydrogen peroxide (H ₂ O ₂ ), an oxide produced in mitochondria that generates energy while performing intracellular respiration in normal metabolism, was used as an indicator of antioxidant activity.

Animal cells were first cultured before the experiment. At this time, the animal cells were used as myoblast C2C12, fibroblast NIH3T3 cells. Each cell was loaded with Dulbecco's Modified Eagle's Medium (DMEM) medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin and 100 μg / mL streptomycin. Cultured in a% CO 2 incubator.

After incubating the cultured C2C12 and NIH3T3 cells in a 24-well plate to be 5 × 10 ⁵ cells per well and incubating for 24 hours, the catechin-based compounds prepared in Examples 1 to 13 were treated with cells for 1 hour. After pre-reaction, glucose oxidase was treated to 7mU / ml to produce hydrogen peroxide and incubated for 24 hours. At this time, C2C12 or NIH3T3 cells treated with nothing were used as a control.

Hydrogen peroxide secreted in cell culture was measured using a H2O2 detection kit (biovision, USA). Experimental method was based on the experimental method provided in the kit.

As a result, a small amount of hydrogen peroxide was generated in the experimental group treated with the catechin-based compounds prepared in Examples 1 to 13 compared to the control group. These results indicate that the catechin-based compound of the present invention inhibits the generation of hydrogen peroxide (H ₂ O ₂ ), an oxide that causes chronic inflammation and skin aging, significantly inhibiting the generation of free radicals during cell metabolism. have.

On the other hand, diabetes is a disease that causes the most complications due to oxidative stress in the process of decomposition of sugar in the blood. During the breakdown of sugars in cells, glucose oxidase produces hydrogen peroxide (H ₂ O ₂ ) to induce glycooxidative stress. As the catechin-based compound of the present invention inhibits the production of hydrogen peroxide, it was found that the wound healing effect due to glycation stress is excellent.

Experimental Example 4 Antimicrobial Effect of Catechin Compounds

In order to determine the antimicrobial effect of the catechin-based compounds prepared in Examples 1 to 13, a bactericidal test was performed on E. coli , a Gram-negative bacterium, and S. aureus , a Gram-positive bacterium.

E. coli and Staphylococcus aureus ( S. aureus ) were cultured in LB broth, and then the cultured bacteria were diluted and adjusted to 10 ⁵ ~ 10 ⁶ CFU / mL for the test. After the test bacteria were added to 20 ml of the test solution (stock solution) and mixed, the number of bacteria was measured when left for 1 hour at room temperature to determine the rate of bactericidal reduction against the initial number of bacteria. Bacterial counts were measured using physiological saline as a control group and expressed as initial bacterial counts. At this time, all experiments were tested by neutralizing using D / E Neutralizing Broth in the initial dilution step. In the case of not proliferating, less than 10 (<10) was expressed by multiplying the dilution factor in the neutralization step. The viable cell count and the sterilization reduction rate were determined as follows.

Viable cell count = colony count (mean of two colonies) × dilution factor (dilution factor of diluent)

% Reduction in sterilization = [(initial number of bacteria-number of bacteria after a certain time) / initial number of bacteria] × 100

From this, it can be seen that the catechin-based compound of the present invention has a very good bactericidal effect against bacterial microorganisms.

Experimental Example 5 Checking the Anti-Inflammatory Effect of the Catechin Compound

In order to confirm the anti-inflammatory effects of the catechin-based compounds prepared in Examples 1 to 13, experiments were conducted to determine the effect of inhibiting the production of Nitric Oxide and PGE2.

1) Cell Culture

RAW 264.7 cells, a mouse macrophage line, were cultured by the Korea Cell Line Bank (KCLB), and DMEM medium containing 1% penicillin-streptomycin and 10% FBS was used for cell culture. Cells were incubated at 37 ° C., 5% CO ₂ .

2) Cell viability measurement

Cell viability was measured using an MTT assay. The cultured RAW 264.7 cells were dispensed in 96 × well plates at 1 × 10 ⁴ cells / well, and the catechin compounds prepared in Examples 1 to 13 were prepared by concentrations (10, 25, 50, 100, 250, 500, 750, 1000 μg / ml) for 24 hours. Thereafter, 20 μl MTT solution was added per well for 4 hours at 37 ° C. and 5% CO ₂ incubator, and then the absorbance at 540 nm was measured using a microplate reader (Multiskan ^TM GO Microplate Spectrophotometer). The cell viability relative to the control without catechin compound was expressed as a percentage. At this time, the cell viability of the experimental group treated with catechin-based compounds 1 to 13 at various concentrations (10, 25, 50, 100 250, 500, 750, 1000 μg / ml) was not different from the control group. From this, it can be seen that the catechin-based compound according to the present invention does not cause cytotoxicity.

3) Measurement of NO (Nitric Oxide) Inhibitory Effect

The nitrite concentration in the cell culture medium of RAW 264.7 cells induced inflammation with LPS (Lipopolysaccharide) was measured using Griess reagent to quantify how NO the catechin compounds prepared in Examples 1 to 13 were inhibited. Samples in RAW 264.7 cells were pretreated by concentration within concentrations that did not cause cytotoxicity, and cultured for 24 hours with 1 μg / ml of LPS after 1 hour. 50 ul of the cell culture solution and the same amount of Griess reagen were mixed and reacted at room temperature for 10 minutes, and then absorbance at 540 nm was measured using a microplate reader (Multiskan ^™ GO Microplate Spectrophotometer). Sodium nitrite was treated by concentration to obtain a standard curve, and the NO concentration in the culture solution treated with catechin compound was quantified. At this time, it was confirmed that the catechin-based compounds prepared in Examples 1 to 13 lowered NO increased due to LPS. From this, it can be seen that the catechin-based compound according to the present invention has anti-inflammatory effect in a manner of inhibiting NO production.

4) Measurement of PGE2 production inhibitory effect

By measuring the PGE2 in the cell culture, it was confirmed by the ELISA assay how much cytokine inhibitory effect of the catechin compounds prepared in Examples 1 to 13. Samples in RAW 264.7 cells were pretreated by concentration within concentrations that did not cause cytotoxicity, and cultured for 24 hours with 1 μg / ml of LPS after 1 hour. 100 μl of the cell culture solution was added to a 96 well plate coated with goat-anti-mouse, and then 50 μl of the primary antibody solution and the PGE2 conjugate were added overnight, and then overnight at 4 ° C. After washing four times using a washing buffer, the substrate solution was treated with 200 μl for 5 minutes, and then treated with 50 μl stop solution, and then absorbance was measured at 450 nm. The amount of PGE2 produced was expressed as a fold value for the wells that were not treated with catechin compounds. As a result, it was confirmed that the catechin compounds prepared in Examples 1 to 13 inhibit the concentration of PGE2 increased by LPS. From this, it can be seen that the catechin-based compound according to the present invention has anti-inflammatory efficacy in a manner that inhibits PGE2.

Experimental Example 6 Diagnosis of Diabetic Ulcer Treatment of Catechin Compounds

Animal experiments were conducted to confirm the treatment of diabetic ulcers with the catechin-based compounds prepared in Examples 1-13.

Diabetes was induced by intraperitoneal injection of streptozotocin (60 mg / kg) into male Sprague-Dawley white rats weighing about 300 g at 7 weeks of age. Three days later, venous blood was collected from the tail vein, and blood glucose was measured using a blood glucose meter. Only white rats having a blood glucose of 300 mg / dL or more were selected. After shaving the back of the selected white rat, circular cuts were made to have a diameter of 1 cm or 1.5 cm using a punch on the back of the back 4 ~ 5 cm from the ear. After making circular sections, white rats were randomly divided into untreated controls and treated groups of the catechin compounds prepared in Examples 1 to 13.

As shown in Table 3, ointments containing catechin-based compounds 1 to 13 in an amount of 0.004% by weight were each formulated according to a conventional method.

TABLE 3

Immediately after the round cuts were induced to the treated group, the ointment containing the catechin-based compound was treated and wound with sterile hanji, and the wound was fixed using a band and a bandage to maintain a humid environment. No system compound was treated. Thereafter, the wound site was observed for 8 days at two-day intervals after the circular induction, and the size of the wound site was observed.

As a result, in the group treated with the catechin-based compounds prepared in Examples 1 to 13 compared to the control group, it was visually confirmed that the wound size was remarkably reduced as the wound site was recovered from the fourth day.

Through this, the catechin-based compound of the present invention was found to have a therapeutic effect of diabetic ulcer which is a complication of diabetes.

The catechin-based compound according to the present invention or a pharmaceutically acceptable salt thereof is a novel compound of low molecular weight obtained by the sugar preparation in catechin natural products, and has excellent stability and water solubility, and no cytotoxicity.

In addition, the catechin-based compounds or pharmaceutically acceptable salts thereof according to the present invention significantly enhance the expression of various vascular and cell growth factors such as TGF-β, induce vasokinetic activity, and produce angiogenesis and tissues. It promotes regeneration and at the same time promotes the secretion of antimicrobial peptides, which is very effective in treating wounds and preventing and treating secondary infections of wounds.

In particular, the catechin-based compounds or pharmaceutically acceptable salts thereof according to the present invention may be used for the artery of the arteries (arterioles) and precapillary arterioles, as well as pulse activity (sphygmic activity) in capillaries and associated venules and It is effective in treating diabetic ulcers in disease animal models by increasing blood flow and causing vasodynamic and vasodilation effects, especially foot ulcers and pressure sores due to diabetic complications, peripheral ulcers with peripheral circulation or microcirculation disorders. It can be usefully used for treatment without side effects.

In addition, the catechin-based compounds according to the present invention do not cause unwanted ulceration in peripheral ulcers and surrounding tissues and are therefore well suited for topical administration.

In addition, the catechin-based compound according to the present invention promotes the regeneration of skin tissues and secretion of antimicrobial peptides, thereby effectively inhibiting the inflammatory response, which is a major symptom in inflammatory skin diseases accompanied by the accumulation of wounds, and regenerating cells. It can be used as an active ingredient for improving, whitening and skin regeneration of the cosmetic composition.

Claims (16)

1. The catechin-based compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In Formula 1,

   R ₁ is C ₁ -C 20 alkylcarbonyl, C 2 -C 30 alkenylcarbonyl,-(CH ₂ ) _d -Ar ₁ ,

   

   ,

   

   or

   

   ego;

   R ₁₁ is hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^a , -CONR ^b R ^c , hydroxy OxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _e -Ar ₂ , -NR ^b R ^c ,

   

   ,

   

   ,

   

   ,

   

   Or O - sugar residue (O -sugar residue) and;

   R ₁₂ is hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, -COOR ^d , -CONR ^e R ^f , HydroxyC1-C15alkyl, C1-C15alkoxyC1-C15alkyl, C6-C20aryloxyC1-C15alkyl,-(CH ₂ ) _f -Ar ₃ , -NR ^e R ^f ,

   

   ,

   

   ,

   

   ,

   

   Or O -sugar residues;

   a is an integer from 1 to 4, and when a is an integer of 2 or more, R ₁₂ may be the same or different from each other;

   m is an integer from 1 to 10;

   R ₁₄ is hydroxy, C 1 -C 15 alkoxy, halogen, C 1 -C 15 alkylcarbonyloxy or an O-sugar residue;

   R ₁₅ is hydrogen, C 1 -C ₁₅ alkyl, halogen, hydroxy or C 1 -C 15 alkoxy;

   R ₁₆ is hydrogen or C1-C15 alkyl;

   b is an integer from 1 to 4, and when b is an integer of 2 or more, R ₁₅ may be the same or different from each other;

   R ₁₇ is hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1-C15 alkoxy C1-C15alkyl, C6-C20aryloxyC1-C15alkyl or O-sugar residues;

   R ₁₈ is hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1-C15 alkyl, C1- C 15 alkoxy C 1 -C 15 alkyl, C 6 -C 20 aryloxy C 1 -C 15 alkyl or an O-sugar residue;

   c is an integer from 1 to 4, and when c is an integer of 2 or more, R ₁₈ may be the same or different from each other;

   n is an integer from 1 to 10;

   R ^a and R ^d are independently of each other hydrogen, C1-C15 alkyl, C3-C15 cycloalkyl or C6-C20 aryl;

   R ^b , R ^c , R ^e and R ^f are independently of each other hydrogen, C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, C 6 -C 20 aryl or C 1 -C 15 alkylcarbonyl;

   d, e and f are each independently an integer from 1 to 10;

   Ar ₁ , Ar ₂ and Ar ₃ are independently of each other C 6 -C 20 aryl, wherein the aryl of Ar ₁ to Ar ₃ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy and C 1 -C 15 alkylcarbon May be further substituted with one or more selected from nil;

   R ₂ is hydrogen, hydroxy, C1-C15 alkyl, haloC1-C15 alkyl, hydroxyC1-C15 alkyl, C1-C15 alkoxy, amino acid, C1-C15 alkylcarbonyl, C1-C15 alkoxycarbonyl, C2-C15 Alkenyl, hydroxyC2-C15alkenyl or C2-C15alkynyl.)
2. The method of claim 1,

   R ₁ is C1-C20 alkylcarbonyl, C2-C30 alkenylcarbonyl,

   

   ,

   

   ,

   

   or

   

   ego;

   R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy;

   R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyl, C 1 -C 15 alkylcarbonyloxy, C 1 -C 15 alkoxycarbonyl, carboxyl, C 6 -C 20 aryloxycarbonyl, carbamoyl,

   

   ,

   

   ,

   

   ,

   

   Or an O-sugar residue;

   R _12a and R _12b are each independently of the other hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, C1-C15 Alkoxycarbonyl, carboxyl, C6-C20 aryloxycarbonyl, carbamoyl,

   

   ,

   

   ,

   

   ,

   

   Or an O-sugar residue;

   m and n are each independently an integer from 1 to 5;

   R ₁₄ is hydroxy, C 1 -C 15 alkoxy or C 1 -C 15 alkylcarbonyloxy;

   R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy;

   R ₁₆ is hydrogen or C1-C15 alkyl;

   R ₁₇ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O-sugar residues;

   R _18a and R _18b independently of one another are hydrogen, hydroxy, halogen, C1-C15 alkyl, C2-C15 alkenyl, C1-C15 alkoxy, C1-C15 alkylcarbonyl, C1-C15 alkylcarbonyloxy, hydroxyC1 Catechin-based compounds or pharmaceutically acceptable salts thereof, which are -C 15 alkyl, C 1 -C 15 alkoxy C 1 -C 15 alkyl, C 6 -C 20 aryloxy C 1 -C 15 alkyl or an O-sugar residue.
3. The method of claim 1,

   R ₂ is hydrogen, hydroxy, C 1 -C 15 alkyl, haloC 1 -C 15 alkyl, hydroxyC 1 -C 15 alkyl, C 1 -C 15 alkoxy or an amino acid, a catechin-based compound or a pharmaceutically acceptable salt thereof.
4. The method of claim 1,

   R ₁ is C1-C20 alkylcarbonyl, C2-C30 alkenylcarbonyl,

   

   ,

   

   ,

   

   or

   

   ego;

   R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy;

   R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O -sugar residues;

   R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 1 -C 15 alkoxy,

   

   or

   

   ego;

   m is, independently from each other, an integer from 1 to 5;

   R ₁₄ is hydroxy, C 1 -C 15 alkoxy or C 1 -C 15 alkylcarbonyloxy;

   R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy;

   R ₁₆ is hydrogen or C1-C15 alkyl;

   R ₂ is hydrogen, hydroxy, C 1 -C 15 alkoxy or an amino acid, a catechin compound or a pharmaceutically acceptable salt thereof.
5. The method of claim 4, wherein

   To catechin-based compound represented by the formula (2) or a pharmaceutically acceptable salt thereof.

   [Formula 2]

   

   (In Formula 2,

   R ₁ is C5-C20 alkylcarbonyl, C5-C25 alkenylcarbonyl,

   

   ,

   

   ,

   

   or

   

   ego;

   R _100a , R _100b and R _100c are each independently halogen, C 1 -C 15 alkoxy or hydroxy;

   R ₁₁ is hydroxy, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkylcarbonyloxy or O -sugar residues;

   R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 15 alkyl, C 1 -C 15 alkoxy,

   

   or

   

   ego;

   m is an integer from 1 to 3;

   R ₁₄ is hydroxy or C 1 -C 15 alkoxy;

   R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C15 alkoxy;

   R ₁₆ is hydrogen or C1-C15 alkyl;

   R ₂ is hydrogen or hydroxy.)
6. The method of claim 5,

   Catechin-based compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof.

   [Formula 3]

   

   (In Chemical Formula 3,

   R _A is C5-C20 alkyl, C5-C25 alkenyl,

   

   ,

   

   or

   

   ego;

   R ₁₁ is hydroxy, halogen, C 1 -C 7 alkoxy, C 1 -C 7 alkylcarbonyloxy or O -sugar residues;

   R _12a and R _12b independently of one another are hydrogen, hydroxy, halogen, C 1 -C 7 alkyl, C 1 -C 7 alkoxy,

   

   or

   

   ego;

   R ₁₄ is hydroxy or C 1 -C 7 alkoxy;

   R _15a and R _15b are, independently from each other, hydrogen, hydroxy or C1-C7alkoxy;

   R ₂ is hydrogen or hydroxy.)
7. The method of claim 6,

   The O -sugar residue is

   

   Phosphorus, catechin compounds or pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition for treating wounds comprising the catechin-based compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The method of claim 8,

   The wound is a wound, wound, cut, burn, laceration, abrasion and bruise pharmaceutical composition for wound treatment that is selected from the group consisting of.
10. The method of claim 8,

    The wound is a peripheral ulcer (peripheral ulcer) pharmaceutical composition for wound treatment.
11. The method of claim 10,

    The peripheral ulcer is selected from the group consisting of diabetic ulcers, lower extremity ulcers, foot ulcers, hypertension ischemic ulcers, venous ulcers and bedsores.
12. The method of claim 8,

    The composition is a pharmaceutical composition for wound treatment that is formulated as an external preparation for the skin.
13. A cosmetic composition for improving inflammatory skin disease comprising the catechin-based compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
14. The method of claim 13,

    The inflammatory skin disease is selected from the group consisting of atopic dermatitis (atopicdermatitis), eczema, acne, inflammatory dermatitis, seborrhea and contact dermatitis (cosmetic dermatitis) cosmetic composition for improving inflammatory skin disease.
15. A cosmetic composition for skin whitening comprising the catechin-based compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
16. A cosmetic composition for skin regeneration comprising the catechin-based compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.