KR20170103359A - Novel Pseudoceramides, cosmetic composition and pharmaceutical composition comprising same - Google Patents
Novel Pseudoceramides, cosmetic composition and pharmaceutical composition comprising same Download PDFInfo
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- KR20170103359A KR20170103359A KR1020160026108A KR20160026108A KR20170103359A KR 20170103359 A KR20170103359 A KR 20170103359A KR 1020160026108 A KR1020160026108 A KR 1020160026108A KR 20160026108 A KR20160026108 A KR 20160026108A KR 20170103359 A KR20170103359 A KR 20170103359A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Abstract
The present invention relates to a novel pseudoceramide compound, a pharmaceutical composition containing the same, and a cosmetic composition, which comprises a pseudoceramide compound according to the present invention, a pharmaceutically acceptable salt or solvate thereof as an active ingredient, Has excellent effect of improving skin barrier function, and has an effect of improving inflammatory skin disease, and has excellent skin barrier improving function and skin moisturizing and strengthening effect.
Description
The present invention relates to novel pseudoceramide compounds having properties similar to those of natural ceramides, such as skin-protecting action, moisture retention ability and the like and their use.
Human skin acts as a barrier against physical and chemical stimuli from the external environment. However, it can be seen that the skin of a patient having an inflammatory skin disease such as atopic dermatitis is remarkably reduced in skin barrier function and / or water retention function in the stratum corneum compared with normal skin. (Non-Patent Document 1).
Ceramide is a kind of sphingolipid which has a structure in which fatty acids are connected to sphingosine, and it accounts for 40-50% of the intercellular lipids constituting the stratum corneum of the skin. Such a stratum corneum acts as a shield to protect pests and microorganisms from penetrating into skin tissue from the external environment. At this time, ceramide is known to form a stratum structure of the skin stratum corneum and plays a central role in water retention and barrier maintenance, which are basic functions of the skin. In order to maintain the basic function of the skin, the importance of ceramides is that not only the barrier function of the skin is restored when the ceramide biosynthesis is inhibited or the ceramide content is decreased, but also the moisture evaporation of the skin is increased, And the necessity of the experiment has been proved (non-patent document 2). In addition, it is known that ceramide can be supplemented and restored to normal skin when the aging of the skin progresses or when the ceramide content is decreased by external stimulation.
For the purpose of supplementing these ceramides, the search for natural flora and fauna has been made, and it has been known to extract from various flora and fauna and microorganisms (yeasts) containing ceramides. However, ceramides present in these plants, animals and microorganisms are extremely small, and their extraction production cost is too high, and they are disadvantageous in that they are very insoluble in raw materials used for various solvents, cosmetics and cleaning products. Therefore, the synthesis of pseudoceramides having the same structure as that of natural ceramides has been studied by many scientists. For example, Patent Documents 1 and 2 of Hwang Wang Co., Ltd., Patent Document 3 of Unilever Company of Germany In domestic, there are Patent Documents 4 and 5 of AMOREPACIFIC Corporation and Patent Document 6 of Aekyung Industrial Co., Ltd.
As a result of in-depth study on pseudoceramide, the applicant found a novel pseudoceramide compound having structural characteristics similar to that of natural ceramide I and excellent in effects of skin protecting action, water retention ability, and the like, thereby completing the present invention.
It is an object of the present invention to provide a novel pseudoceramide compound having a structural characteristic similar to that of natural ceramide I having properties similar to those of natural ceramide, such as skin protecting action, moisture retention ability and the like, a pharmaceutically acceptable salt or solvate thereof .
It is another object of the present invention to provide a pharmaceutical composition having a novel pseudoceramide compound, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient and having an effect of improving skin barrier function and improving inflammatory skin disease.
It is still another object of the present invention to provide a cosmetic composition having a skin barrier function improvement and skin moisturizing and strengthening effect containing a novel pseudoceramide compound, a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
The present invention provides a pseudoceramide compound represented by the following formula (1), a pharmaceutically acceptable salt or solvate thereof.
[Chemical Formula 1]
In formula (1)
R 1 is hydrogen, (C1 ~ C30) alkyl, (C1 ~ C30) alkoxy, hydroxy (C1 ~ C30) alkyl, mono- or di (C1 ~ C30) alkylamino, (C1 ~ C30) alkylcarbonyl, (C1 C30) alkoxycarbonyl, (C1-C30) alkylsulfonyl, (C1-C30) alkylphosphoryl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy or hydroxy (C 1 -C 30) alkyl;
L 1 and L 2 are each independently a direct bond, (C 1 -C 30) alkylene, (C 2 -C 30) alkenylene or (C 2 -C 30) alkynylene.
The pseudoceramic compound, its pharmaceutically acceptable salt or solvate thereof according to an embodiment of the present invention may be represented by the following general formula (2), but is not limited thereto.
(2)
In formula (2)
R 1 is (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy, hydroxy (C 1 -C 20) alkyl or hydroxy;
R 2 and R 3 are each independently (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy or hydroxy (C 1 -C 20) alkyl;
m and n are each independently selected from an integer of 0 to 20;
The present invention provides a pharmaceutical composition comprising the pseudoceramide compound represented by the above formula (1), a pharmaceutically acceptable salt or solvate thereof as an active ingredient, for improving skin barrier function and improving inflammatory skin disease.
The present invention also provides a cosmetic composition having a skin barrier function and a skin moisturizing and enhancing effect, comprising the pseudoceramic compound represented by the above formula (1), a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
The pseudoceramide compound according to the present invention has a structure similar to that of natural ceramides, thereby enhancing the homogeneity and firmness of keratinocyte, thereby enhancing the skin barrier function and controlling the natural moisturizing factor, .
Further, the composition containing the pseudoceramic compound, pharmaceutically acceptable salt or solvate thereof according to the present invention as an active ingredient can be applied to medicines or cosmetics to improve the moisturizing ability, improve dry skin, improve atopy, and improve the itching Lt; / RTI >
FIG. 1 shows the result of measurement of transepithelial electrial resistance (TEER) for evaluating artificial skin integrity according to an embodiment of the present invention.
FIG. 2 is a result of observing the expression pattern of filaggrin, an indicator protein of the differentiation, on immunohistochemical staining for measuring the promoting effect of artificial skin differentiation according to the embodiment of the present invention.
The pseudoceramide compounds according to the present invention and their uses will be described in detail below. Unless otherwise defined in the technical terms and scientific terms used herein, the terms " In the following description, well-known functions and constructions that may unnecessarily obscure the gist of the present invention will not be described.
The terms used in this specification are defined as follows.
&Quot; Evaluation of artificial skin integrity " means a method of evaluating the degree of improvement of skin barrier by measuring electrical resistance of artificial skin.
&Quot; Pharmaceutically acceptable salt " means a salt or complex that retains the desired biological activity of the pseudoceramide compound according to the invention and exhibits minimal or no undesirable toxic effects. Specifically, the pharmaceutically acceptable salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (3-hydroxybenzoyl) benzoic acid, or an acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert But are not limited to, acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
&Quot; Solvate " means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent, and it is to be understood that hydrate combined with water is also included therein.
The term "pseudoceramide compound according to the present invention" or "compound of formula (1)" may be a compound itself, a pharmaceutically acceptable salt, a solvate and the like, and isomers and prodrugs thereof It is needless to say that the present invention can also be used as a concept including both.
The substituents comprising the " alkyl ", " alkoxy " and " alkyl " moieties described in the present invention include both linear and branched forms. In addition, " alkylamino " means mono or di (C1-C30) alkylamino.
The term "carboxy" used in the present invention means * -CO 2 M, "sulfonyl" means * -SO 2 M and "phosphoryl" means * -OP (O) (OM) 2 , Independently hydrogen or an alkali metal.
The present invention provides a novel pseudoceramide compound represented by the following formula (1) capable of exhibiting an effect equal to or higher than that of natural ceramide in skin protection action and / or moisture holding ability.
The Applicant has found that conventional pseudoceramides follow the morphology of ceramide 3 and / or ceramide 4, and that they use long chain omega-hydroxy fatty acid to inhibit keratinocyte quality A novel pseudoceramide compound having a structural characteristic that facilitates the constitution was synthesized and it was confirmed that it has an effect of promoting the differentiation of keratinocytes as well as an effect of improving the skin barrier function by using the same. It came.
[Chemical Formula 1]
In formula (1)
R 1 is selected from the group consisting of hydrogen, (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy, hydroxy (C 1 -C 30) alkyl, (C 1 -C 30) alkylamino, Alkoxycarbonyl, (C1-C30) alkylsulfonyl, (C1-C30) alkylphosphoryl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy or hydroxy (C 1 -C 30) alkyl;
L 1 and L 2 are each independently a direct bond, (C 1 -C 30) alkylene, (C 2 -C 30) alkenylene or (C 2 -C 30) alkynylene.
The pseudoceramic compound according to an embodiment of the present invention has a long chain aliphatic chain containing two amides and an ester unit in the molecule as shown in the following formula (2), and thus has excellent compatibility and affinity with the intercellular lipid lamellar layer So that it can be easily absorbed in the stratum corneum, and more stably located in the intercellular lipid lamellar layer. By having such a characteristic, it is possible to realize a high moisturizing effect while enhancing the skin barrier function.
(2)
In formula (2)
R 1 is (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy, hydroxy (C 1 -C 20) alkyl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy or hydroxy (C 1 -C 20) alkyl;
m and n are each independently selected from an integer of 0 to 20;
The pseudoceramide compounds represented by Formula 1 and / or Formula 2 according to an embodiment of the present invention are preferably those in which R 1 is selected from hydroxy, amino, carboxy, sulfonyl and phosphoryl in order to have a higher solubility And the carboxy, sulfonyl or phosphoryl may be an alkali or a metal oxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium oxide or magnesium oxide; Basic amino acids such as lysine, arginine and histidine; Amines such as triethanolamine or ammonia, cationic polymers such as polyquaternium-4, 6, 7, 10, 11, 16 and the like; And cationic surfactants such as lauryldimethylbenzylammonium chloride and stearyldimethylbenzylammonium chloride; May be present in the form of a pharmaceutically acceptable salt or solvate which is neutralized by, for example, a hydroxyl group, etc. In addition, from the viewpoint of high solubility, the R 1 may be hydroxy, but is not limited thereto.
According to an embodiment of the present invention, n and m of the pseudoceramide compound represented by Formula 2 are each independently selected from an integer of 1 to 18, and the number of carbon atoms of the R 2 substituent and the number of carbon atoms of n and R 3 substituent It is preferable that m has not more than 50 carbon atoms and has at least C10 or longer long chain of aliphatic chains.
In addition, the pseudoceramic compound according to an embodiment of the present invention may be selected from the following structures, but is not limited thereto.
The compound represented by Formula 1 according to the present invention shows strong affinity to the surface of the skin and the stratum corneum, which is the outer layer of the skin, when applied to the skin, and can densify the structure thereof to optimize the water retention function. At the same time, As an active ingredient of a cosmetic composition for improving dry skin or keeping the skin in a healthy state.
The cosmetic composition according to an embodiment of the present invention may further comprise a keratinocyte lipid or a similar lipid complex other than the compound represented by the formula (1). In this case, the intercellular lipid or similar lipid complex may be any lipid component that can be used in the cosmetic composition. Specific examples thereof include cholesterol, phytosterol, sphingosine, phytosphingocine, cerrebroid, ceramide I, ceramide II , Ceramide III, ceramide IIIB, ceramide IV, ceramide V, ceramide VI, myristoyl / palmitoyloxostearamide / arachamide miei, and dihydroxyisopropyl pharmaoylpamamide. May be at least one selected from ceramide III, ceramide IIIB, ceramide VI, myristoyl / palmitoyloxostearamide / arachamide miei and dihydroxyisopropylpharmoylpamamide, but is not limited thereto.
The cosmetic composition according to an embodiment of the present invention may contain 0.005 to 20 parts by weight of a pseudoceramide compound represented by Formula 1, based on the total weight.
In addition, the cosmetic composition according to an embodiment of the present invention is prepared by mixing the pseudoceramide compound according to the present invention with the above-described keratinocyte lipid or similar lipid complex in a mixing ratio of 1:10 to 10: 1 good.
The formulation of the cosmetic composition according to one embodiment of the present invention is not particularly limited and may be appropriately selected according to the purpose. As a specific example, it may be a formulation selected from the group consisting of solutions, suspensions, emulsions, pastes, gels, creams, powders, soaps, oils and sprays, but is not limited thereto
Hereinafter, the cosmetic composition for moisturizing according to an embodiment of the present invention will be described in detail.
The cosmetic composition according to one aspect of the present invention can be used as a cosmetic composition in the form of a cosmetic composition that contains at least one selected from the group consisting of purified water, a stabilizer, an emulsifier, a thickening agent, a moisturizer, a liquid crystal film hardener, a pH adjusting agent, an antibacterial agent, At least one aqueous additive selected from the group consisting of an antioxidant, an antioxidant, an antioxidant, a preservative, a perfume, and the like; And at least one oil additive selected from oils, waxes, hydrocarbonaceous oils, higher fatty acid oils, higher alcohols, synthetic ester oils, and silicone oils.
The aqueous additive is not limited as long as it is a commonly used raw material in the art, and specific examples thereof include glycerin, dipropylene glycol, butyleneglycol, pentylene glycol, methylpropanediol, sorbitol, diglycerin, Erythritol, pentaerythritol, polybutylene glycol-10, polyglycerin-3, polyglycerin-4, polyglycerin-6, polyglycerin-10, polyglycerin-20, polyglycerin-40, sorbes- 6, sorbes-20, sorbes-30, sorbes-40, inositol, maltitol, maltose, mannan, mannitol, mannose, lactitol, lactose, dihydroxypropyl PG-glucoside, dithiaoctanediol, Glucosamine, glucose, 1,2,6-hexanediol, methylglucose-10, methylglucose-20, ozonized glycerin, pyranthiol, thioglycerin, traitol, trimethylol Ol propane, xylitol, (EDTA), guar gum, quinseed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin Sulfuric acid, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, traganth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethylguanoside, dextran, Carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite, methyl paraben, propyl paraben , Phenoxyethanol, 1,2-hexanediol, ethylhexyl glycerin, and the like. The oily additive is not limited as long as it is a raw material generally used in the art, and may be a liquid oil such as olive oil, camellia oil, jojoba oil, triglyceride, glycerin trioctanoate, glycerin triisopalmitate, palm oil, , Solid oils such as hardened oil and hardened castor oil, bees wax, candelilla wax, carnauba wax, lanolin and jojoba wax. Examples of the hydrocarbon flow path include liquid paraffin, squalane, petrolatum, microcrystalline wax and the like. Examples of the higher fatty acids include waxes such as lauric acid, myristic acid, palmitic acid, stearic acid and behenic acid, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol and cetostearyl alcohol And the synthetic ester oils may include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, hexyl laurate, myristyl myristate, cetyl lactate, isocetylisostearate, neopentyl Higher alcohols such as glycerol dicaprate, ethylhexyl glycerin, cetyl ethylhexanoate, ethylhexyl palmitate and cetostearyl alcohol, chain silicone oils such as dimethylpolysiloxane, methylphenylpolysiloxane and methylhydrogenpolysiloxane, dodecamethylcyclohexa Cyclic silicone oil such as siloxane, octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane, and the like It is, but is not limited thereto.
The present invention also provides a pharmaceutical composition having a pseudoceramide compound represented by Formula 1, a pharmaceutically acceptable salt or solvate thereof as an active ingredient and having an effect of improving skin barrier function and improving inflammatory skin disease.
The pharmaceutical composition according to one aspect of the present invention is a composition for improving skin inflammation, which is useful as a composition for improving skin inflammation, comprising at least one selected from the group consisting of atopic dermatitis, psoriasis, contact dermatitis, eczematous dermatitis, Pemphigus vulgaris, epidermolysis bullosa, systemic sclerosis, dermatomyositis, multiple myositis, inflammatory muscle lesions, leprosy or tricepsychiatric syndromes.
The pharmaceutical composition according to an embodiment of the present invention may include a pharmaceutically acceptable carrier according to a method that can be easily carried out by those having ordinary skill in the art to which the present invention belongs. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil no. The pharmaceutical composition of the present invention may further comprise a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, or a preservative agent in addition to the above components.
The pharmaceutical composition of the present invention may be formulated into a conventional preparation using pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. May be prepared in a dosage form or by intrusion into a multi-dose container. Typical formulations are, for example, oral (tablets, capsules, powders), intraoral, sublingual, rectal, vaginal, intranasal, topical or parenteral (intravenous, intracameral, intramuscular, subcutaneous Or intravenous) administration formulations. For example, the compounds according to the present invention may be in the form of tablets containing starch or lactose, alone or in the form of capsules containing excipients or in the form of suspensions containing flavoring or coloring chemicals, It can be administered sublingually. Liquid preparations may be suspensions (e. G., A mixture of apricot kernel oil and PEG-6 esters such as methylcellulose, witepsol, or the like, or a mixture of PEG-8 and caprylic / capric glycerin For example, as a mixture of glycerides, such as a mixture of glycerides, such as, for example, a mixture of glycerides, Most preferably in the form of an aqueous solution of a solution, wherein the solution may contain other substances (for example salt or monosaccharides such as mannitol, glucose) to have isotonicity with blood.
Specifically, the pharmaceutical composition according to one embodiment of the present invention can be used in the form of a percutaneous absorption patch or injectable preparation using tablets, pills, capsules, granules, powders, powders, solutions, patches and micro needles.
The compound of the present invention may be contained in the pharmaceutical composition in an amount sufficient to produce the desired effect depending on the process or disease state and is preferably 0.005 to 20% by weight, preferably 0.1 to 10% by weight %, But is not limited thereto.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the following examples are merely illustrative and not intended to limit the scope of the present invention in any way.
Step 1. Preparation of 16- (octanoyloxy) hexadecanoic acid
16-Hydroxyhexadecanoic acid 2.0 g (7.34 mmol) was dissolved in 60 ml of chloroform at 70 DEG C, and then 1.38 ml (8.07 mmol) of octanoyl chloride was added. The mixture was refluxed for 4 hours. The reaction temperature was lowered to room temperature (23 DEG C), and purified water and dichloromethane were added to the mixture and stirred. After the organic layer was separated and dried, the organic layer was concentrated under reduced pressure. The residue was separated by column chromatography (Dichloromethane: Methanol = 50: 1) to obtain a compound as a white solid (2.93 g, 7.34 mmol, yield = 100%).
Step 2. Preparation of pseudoceramide Compound 1
Dichloromethane (DCM, 14 mL, tertiary amine) and 1,3-diamino-2-propanol (0.29 g, 3.28 mmol, Sigma-Aldrich) 1.45 mL, purity of Samjeon) was added to prepare a reaction solution. (1.95 g, 7.02 mmol, Sigma-Aldrich), HOBt (0.95 g, 7.02 mmol, Sigma-Aldrich), 16- (octanoyloxy) hexadecanoic acid (1.87 g, 4.69 mmol) was dissolved in dichloromethane (DCM, 14 mL) was slowly added to the reaction solution, followed by stirring at room temperature for 12 hours. After stirring, 200 mL of dichloromethane, 200 mL of water and 50 mL of ethanol were added to the reaction solution, and the mixture was stirred, allowed to stand, and layered. The organic layer was collected and concentrated under reduced pressure. The residue was separated by column chromatography (Dichloromethane: Methanol = 40: 1) to obtain a white solid compound (1.6 g, yield: 80%). The resulting solid was analyzed by MS (Agilent, USA) and NMR (Varian, USA). The results of the analysis are as follows.
MS (ESI pos ion) m / z: 852 (MH < + >). 1H NMR (600 MHz, CDCl3): 6.38-6.44 (m, 2H), 4.06 (t, J = 6.6 Hz, 4H), 3.77-3.74 J = 7.8 Hz, 4H), 2.22 (t, J = 7.8 Hz, 4H), 1.63 1.59 (m, 12H), 1.31-1.25 (m, 60H), 0.88 (t, J = 6.6 Hz, 6H).
Step 1. Preparation of 10-hydroxydecyl palmitate
20.0 g (114.76 mmol) of 1,10-decanediol was dissolved in 600 ml of chloroform at 65 DEG C and 17.5 ml (57.38 mmol) of palmitoyl chloride was slowly added. The mixture is refluxed for 12 hours, and the solvent of the reaction is concentrated to about 300 ml. The remaining 1,10-Decandiol was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was separated with a column chromatograph (Dichloromethane: Methanol = 50: 1) to obtain a white solid compound (20.9 g, 50.64 mmol, yield = 88%).
Step 2. Preparation of 10- (palmitoyloxy) decanoic acid
32.9 g (151.9 mmol) of pyridinium dichromate was added to 629 ml of chloroform, 20.9 g (50.6 mmol) of 10-hydroxydecyl palmitate was added to the suspension, and 209 ml Was added slowly and stirred at room temperature for 24 hours. Purified water was added to the reaction mixture, stirred and allowed to stand, and the organic layer was separated and dried, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (Dichloromethane: Methanol = 40: 1) to obtain a white solid compound (10.0 g, 23.4 mmol, yield = 46%).
Step 3. Preparation of pseudoceramide compound 2
Dichloromethane (DCM, 10 mL, pure heptane) and triethylamine (TEA, 2-propanol) were added to 1,3-diamino-2-propanol (0.13 g, 1.41 mmol, Sigma- 0.98 mL, Shinjeon Pure Chemical) was added to prepare a reaction solution. After 5 minutes at room temperature, EDC · HCl (0.67 g, 3.51 mmol, Sigma-Aldrich)) and HOBt (0.47 g, 3.51 mmol, Sigma-Aldrich) were added to the reaction solution. A solution of 10- (palmitoyloxy) decanoic acid (1.00 g, 2.34 mmol) in dichloromethane (DCM, 10 mL) was slowly added to the reaction solution and stirred at room temperature for 12 hours. After stirring, 400 mL of dichloromethane, 200 mL of water and 100 mL of ethanol were added to the reaction solution, and the mixture was stirred, allowed to stand, and layered. The organic layer was collected and concentrated under reduced pressure. The residue was separated by column chromatography (Dichloromethane: Methanol = 40: 1) to obtain a white solid (0.5 g, yield: 48%). The obtained compound was analyzed in the same manner as in Example 1 above.
MS (ESI pos ion) m / z: 908 (MH < + >). 1H), 3.41 (s, 1H), 3.41 (m, 2H), 4.04 (br s, 2H) J = 7.8 Hz, 4H), 1.64 1.58 (m, 12H), 1.30 - 1.25 (m, 68H) , 0.88 (t, J = 7.2 Hz, 6H).
1,9-nonanediol and octanoyl chloride instead of 1,10-decanediol and palmitoyl chloride in step 1 of Example 2 above. ), A white solid (70 mg, yield: 43%) was obtained in the same manner as in Example 2. The obtained compound was analyzed in the same manner as in Example 1 above.
MS (ESI pos ion) m / z: 655 (MH < + >). (T, J = 7.2 Hz, 4H), 3.76 (br s, IH), 3.40 (m, 2H), 4.16 J = 7.8 Hz, 4H), 1.65 1.59 (m, 12H), 1.32-1.27 (m, 32H) ), 0.88 (t, J = 7.2 Hz, 6H).
1,4-butanediol and octanoyl chloride instead of 1,10-decanediol and palmitoyl chloride in step 1 of Example 2, (100 mg, yield: 45%) was obtained in the same manner as in Example 2. The obtained compound was analyzed in the same manner as in Example 1 above.
MS (ESI pos ion) m / z: 515 (MH < + >). (M, 4H), 3.97 (d, J = 4.2 Hz, 1H), 3.80 (m, 1H), 3.41 2H), 3.31 (m, 2H), 3.31-2.66 (m, 2H), 2.31-2.88 (m, 4H), 2.22 (t, J = 7.8 Hz, , 1.31 1.27 (m, 16H), 0.88 (t, J = 7.2 Hz, 6H).
Preparation of cosmetic composition
The composition of the following Table 1 was prepared.
Evaluation of artificial skin perfection and artificial skin differentiation promoting effect measurement of the cosmetic composition was carried out by the following method, and the results are shown in Figs. 1 and 2.
1. Evaluation of artificial skin integrity
After applying the cosmetic composition prepared in Example 5 (about 500 mg) to the artificial skin (Keraskin ™ from MCTT, Seoul, Korea), the integrity of the skin before and 24 hours after the application of the cosmetic composition was measured by trans- epithelial electrical resistance ), And the results are shown in Fig.
As a result, it was confirmed that the cosmetic composition containing Example 1 (Example 5) had an effect of maintaining skin integrity of 13.2% or more as compared with Comparative Example 1.
2. Measuring the promotion effect of artificial skin differentiation
The cosmetic composition prepared in Example 5 (about 500 mg) was applied to the artificial skin (Keraskin ™ from MCTT, Seoul, Korea), and the expression pattern of filaggrin, the differentiation index protein after 24 hours, And the results are shown in Fig. 2, respectively.
As a result, in the case of the cosmetic composition containing Example 1 (Example 5), it was confirmed that the expression of the filament protein (filaggrin) in the artificial skin was markedly increased as compared with Comparative Example 1. As a result, It was confirmed that the formulation is effective for the differentiation of the skin.
(Comparative Example 1) Preparation of cosmetic composition
The composition of the following Table 1 was prepared.
Claims (11)
[Chemical Formula 1]
In formula (1)
R 1 is hydrogen, (C1 ~ C30) alkyl, (C1 ~ C30) alkoxy, hydroxy (C1 ~ C30) alkyl, mono- or di (C1 ~ C30) alkylamino, (C1 ~ C30) alkylcarbonyl, (C1 C30) alkoxycarbonyl, (C1-C30) alkylsulfonyl, (C1-C30) alkylphosphoryl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy or hydroxy (C 1 -C 30) alkyl;
L 1 and L 2 are each independently a direct bond, (C 1 -C 30) alkylene, (C 2 -C 30) alkenylene or (C 2 -C 30) alkynylene.
CLAIMS 1. A pseudoceramide compound represented by the following formula (2), a pharmaceutically acceptable salt or solvate thereof.
(2)
In formula (2)
R 1 is (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy, hydroxy (C 1 -C 20) alkyl, hydroxy, amino, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 20) alkyl, (C 1 -C 20) alkoxy or hydroxy (C 1 -C 20) alkyl;
m and n are each independently selected from an integer of 0 to 20;
Wherein R < 1 > is hydroxy, amino, carboxy, sulfonyl or phosphoryl, a pharmaceutically acceptable salt or solvate thereof.
A pseudoceramide compound selected from the following structures, a pharmaceutically acceptable salt or solvate thereof.
[Chemical Formula 1]
In formula (1)
R 1 is hydrogen, (C1 ~ C30) alkyl, (C1 ~ C30) alkoxy, hydroxy (C1 ~ C30) alkyl, mono- or di (C1 ~ C30) alkylamino, (C1 ~ C30) alkylcarbonyl, (C1 C30) alkoxycarbonyl, (C1-C30) alkylsulfonyl, (C1-C30) alkylphosphoryl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy or hydroxy (C 1 -C 30) alkyl;
L 1 and L 2 are each independently a direct bond, (C 1 -C 30) alkylene, (C 2 -C 30) alkenylene or (C 2 -C 30) alkynylene.
The inflammatory skin disease is selected from the group consisting of atopic dermatitis, psoriasis, contact dermatitis, eczematous dermatitis, dermatitis dermatitis, dermatitis dermatitis, herpes dermatitis, herpes zoster dermatitis, squamous cellulitis, scleroderma, gangrenous epidermolysis, , Multiple myositis, inflammatory muscle lesions, leprosy or triceps.
The pharmaceutical composition according to claim 1, wherein the composition comprises 0.005 to 20% by weight of a pseudoceramide compound represented by the general formula (1), a pharmaceutically acceptable salt or solvate thereof.
[Chemical Formula 1]
In formula (1)
R 1 is hydrogen, (C1 ~ C30) alkyl, (C1 ~ C30) alkoxy, hydroxy (C1 ~ C30) alkyl, mono- or di (C1 ~ C30) alkylamino, (C1 ~ C30) alkylcarbonyl, (C1 C30) alkoxycarbonyl, (C1-C30) alkylsulfonyl, (C1-C30) alkylphosphoryl, hydroxy, amino, formyl, carboxy, sulfonyl or phosphoryl;
R 2 and R 3 are each independently (C 1 -C 30) alkyl, (C 1 -C 30) alkoxy or hydroxy (C 1 -C 30) alkyl;
L 1 and L 2 are each independently a direct bond, (C 1 -C 30) alkylene, (C 2 -C 30) alkenylene or (C 2 -C 30) alkynylene.
Wherein the cosmetic composition further comprises keratinocyte lipid or a similar lipid complex.
The keratinocyte lipid or similar lipid complex may be selected from the group consisting of cholesterol, phytosterol, sphingosine, phytosphingocine, cervulocide; Ceramide I; Ceramide II; Ceramide III; Ceramide IIIB; Ceramide IV; Ceramide V; And at least one selected from ceramide VI, myristoyl / palmitoyloxostearamide / arachamide miei, and dihydroxyisopropylpharmoylpamamide.
Wherein the cosmetic composition is a formulation selected from the group consisting of a solution, a suspension, an emulsion, a paste, a gel, a cream, a powder, a soap, an oil and a spray.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101878491B1 (en) * | 2017-11-27 | 2018-07-13 | 애경산업(주) | Novel Pseudoceramide Compound with improved stability and composition comprising it |
| KR102265343B1 (en) * | 2021-05-27 | 2021-06-14 | 손동희 | Basalt fiber sheet for repairing and reinforcing concrete structure and repairing and reinforcing method for concrete structure using same |
| US11345655B2 (en) * | 2018-10-16 | 2022-05-31 | Neopharm Co., Ltd. | Pseudoceramide compound and skin external composition comprising the same |
| KR102405326B1 (en) * | 2021-12-06 | 2022-06-07 | 주식회사 에이텍 | Composition for preventing or treating of atopic dermatitis |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL156901A0 (en) | 2001-01-16 | 2004-02-08 | Univ Ben Gurion | Amphiphilic derivatives for the production of vesicles, micelles and complexants, and precursors thereof |
| JP2003049155A (en) | 2001-08-07 | 2003-02-21 | Mitsubishi Rayon Co Ltd | Method for treating chelating agent and method for recovering heavy metal |
| KR101545527B1 (en) | 2014-01-13 | 2015-08-19 | (주)네오팜 | Novel Pseudoceramides, cosmetic composition and pharmaceutical composition comprising same |
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2016
- 2016-03-04 KR KR1020160026108A patent/KR101827469B1/en active IP Right Grant
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101878491B1 (en) * | 2017-11-27 | 2018-07-13 | 애경산업(주) | Novel Pseudoceramide Compound with improved stability and composition comprising it |
| WO2019103433A1 (en) * | 2017-11-27 | 2019-05-31 | 애경산업(주) | Novel pseudoceramide compound with improved stability and composition comprising same |
| CN111356674A (en) * | 2017-11-27 | 2020-06-30 | 爱敬产业株式会社 | Novel ceramide-like compounds with improved stability and compositions comprising the same |
| US11518735B2 (en) | 2017-11-27 | 2022-12-06 | Ae Kyung Industrial Co., Ltd. | Pseudoceramide compound with improved stability and composition comprising same |
| CN111356674B (en) * | 2017-11-27 | 2022-12-23 | 爱敬产业株式会社 | Novel ceramide-like compounds having improved stability and compositions comprising the same |
| US11345655B2 (en) * | 2018-10-16 | 2022-05-31 | Neopharm Co., Ltd. | Pseudoceramide compound and skin external composition comprising the same |
| KR102265343B1 (en) * | 2021-05-27 | 2021-06-14 | 손동희 | Basalt fiber sheet for repairing and reinforcing concrete structure and repairing and reinforcing method for concrete structure using same |
| KR102405326B1 (en) * | 2021-12-06 | 2022-06-07 | 주식회사 에이텍 | Composition for preventing or treating of atopic dermatitis |
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| Publication number | Publication date |
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| KR101827469B1 (en) | 2018-02-09 |
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