CN109890383B - Composition for skin whitening - Google Patents
Composition for skin whitening Download PDFInfo
- Publication number
- CN109890383B CN109890383B CN201780066049.9A CN201780066049A CN109890383B CN 109890383 B CN109890383 B CN 109890383B CN 201780066049 A CN201780066049 A CN 201780066049A CN 109890383 B CN109890383 B CN 109890383B
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- China
- Prior art keywords
- trans
- methylamino
- thiophene
- carboxamide
- cyclohexyl
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Classifications
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- A—HUMAN NECESSITIES
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
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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
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Birds (AREA)
- Dermatology (AREA)
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- Coloring Foods And Improving Nutritive Qualities (AREA)
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Abstract
According to an aspect of the present invention, there is provided a composition for skin whitening comprising 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, its optical or stereoisomeric form, its acceptable salt, its hydrate or its solvate as an effective ingredient, and a novel composition for skin whitening, which contributes to the development of new fields related to skin whitening and the expansion of the market through one aspect of the present invention.
Description
Technical Field
The present invention relates to a composition for skin whitening comprising 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, and more particularly to a composition comprising a substance exerting skin whitening efficacy by regulating the production and deposition of melanin.
Technical Field
Melanin (melanin) is a biopolymer of phenols having a complex form of black pigment and protein, and is observed in the skin, head, eye, and other parts of animals, as well as browning occurring when cut surfaces of apples, potatoes, and bananas are exposed to the air. When melanin is excessively produced, it is deposited on the skin to form spots and freckles, and thus, it is directly related to skin whitening, and melanin accelerates skin aging and induces skin cancer.
Melanocyte Stimulating Hormone (MSH) is secreted due to ultraviolet rays, inflammation, hormones, and the like, MSH reacts with a receptor, cAMP in melanocytes is increased to synthesize melanin, and the synthesized melanin is secreted to the outside of melanocytes to protect skin from damage of ultraviolet rays and the like. It is known that melanin synthesis is mainly regulated by α -MSH, and proteins involved in melanin synthesis are MITF, TYR, TRP1, TRP2 and the like.
Disclosure of Invention
Technical problem
In one aspect of the present invention, there is provided a composition for skin whitening comprising as an active ingredient 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, its optical or stereoisomer, its acceptable salt, its hydrate, or its solvate for the purpose of promoting the development of the fields related to skin whitening and satisfying the consumers concerned who have a need for skin whitening.
Technical scheme
In one aspect of the present invention, there is provided a composition for skin whitening comprising as an active ingredient 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof.
In another aspect of the invention, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide inhibits the production and deposition of melanin.
Furthermore, in another aspect of the present invention, the composition may be a pharmaceutical composition or a cosmetic composition.
In one aspect of the present invention, there is provided a method for skin whitening, which comprises administering 3-Chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide (3-Chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzol [ b ] thiophene-2-carboxamide), an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof to a subject.
In another aspect of the present invention, there is provided a use of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient for skin whitening. Further, the present invention provides a non-therapeutic cosmetic use of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, its optical or stereoisomer, its acceptable salt, its hydrate, or its solvate as an active ingredient for skin whitening.
Further, in another aspect of the present invention, there is provided a use of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof, for the preparation of a composition for skin whitening.
Advantageous effects
In one aspect of the present invention, a novel composition for skin whitening, which contains 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, its optical or stereoisomeric form, its acceptable salt, its hydrate, or its solvate as an active ingredient, has been developed and provided to contribute to the development of new fields related to skin whitening and the expansion of the market.
Drawings
FIG. 1 shows the change in melanin content when B16F1 cells were treated with 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ B ] thiophene-2-carboxamide and arbutin.
FIG. 2 shows the determination of the effect on tyrosinase, TRP1 expression when B16F1 cells were treated with α -MSH, 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ B ] thiophene-2-carboxamide and arbutin.
Figure 3 shows the determination of the change in brightness after treatment of a skin model with 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide.
Figure 4 shows the change in brightness assessed by colorimeter after treatment of a skin model with 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide.
Detailed Description
In the present specification, the term "skin" refers to a tissue covering a body surface of an animal, and is the broadest concept including not only a tissue covering a body surface such as a face or a body, but also a scalp and hair.
In the present specification, the term "3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide" may be denoted as a Smo agonist, a Smoothened agonist, a Smo agonst agonist, or SAG. The "3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide" may include a substance that induces the expression of a Smoothened protein, which has an important role in the Hedgehog signaling pathway.
In the present specification, the term "isomers" specifically includes reference not only to optical isomers (e.g., substantially pure enantiomers (essentiauy pure enantiomers), substantially pure stereoisomers or mixtures thereof, substantially pure diastereomers (essentiauy pure diastereomers)), but also to conformational isomers (i.e., isomers differing only in the angle of one or more chemical bonds), structural isomers, positional isomers (in particular tautomers) or geometric isomers (e.g., cis-trans isomers).
In the present specification, "substantially pure" means that, for example, when the relevant enantiomer, stereoisomer or diastereomer is used, the amount of the specific compound exemplified by enantiomer, stereoisomer or diastereomer is about 90% (w/w) or more, preferably about 95% (w/w) or more, more preferably about 97% (w/w) or more, or 98% (w/w) or more, more preferably about 99% (w/w) or more, even more preferably about 99.5% (w/w) or more.
In this specification, "acceptable" means that government or equivalent regulatory authorities' approval for use in animals, and more specifically, humans, may be obtained or obtained by avoiding significant toxic effects when using conventional or pharmaceutical dosages (dosage), or is otherwise identified as being listed in the Food code, health function Food code, or general pharmacopoeia, or as otherwise described in the general literature.
In the present specification, "acceptable salt" refers to a salt according to an aspect of the present invention, which is a conventional or pharmaceutically acceptable salt, and has a desirable activity of the parent compound (parent compound). The salts include (1) those formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or from acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts (acid addition salts) of organic acids such as 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2, 2, 2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl acetate, dodecylsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) a salt in which an acidic proton present in the parent compound is substituted.
In the present specification, the term "hydrate" refers to a compound that binds water, and is a broad concept including an inclusion compound that does not have a chemical bonding force between water and the compound.
In the present specification, the term "solvate" refers to a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.
In one aspect of the present invention, there is provided a composition for skin whitening comprising 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof as an effective ingredient.
In one embodiment, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl]-N- [ [3- (4-pyridinyl) phenyl ] carbonyl]Methyl radical]Benzo [ b ]]Thiophene-2-carboxamide (3-Chloro-N- [ trans-4- (methylamino) cyclohexyl)]-N-[[3-(4-pyridinyl)phenyl]methyl]benzo[b]thiophene-2-carboxamide) is a pentane compound containing C28H28ClN3OS, and can be represented by the following chemical formula.
[ chemical formula 1]
In another embodiment, the compounds may be obtained either synthetically or by processing other materials, and may be derived from organisms, microorganisms, and the like.
In another embodiment, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide inhibits the production or deposition of melanin.
According to another aspect of the invention, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide may promote the expression of Tyrosinase (Tyrosinase) or TRP1 (Tyrosinase-Related Protein 1 ). Since the expression of tyrosinase or TRP1 after the compound treatment was lower than that without the compound treatment, it was revealed that the compound was useful as an effective ingredient of a composition for skin whitening. In addition, when the compound was treated, the number of cells expressing tyrosinase or TRP1 was reduced, and thus it was also seen that the compound can be used as an effective ingredient of a composition for skin whitening.
Melanin (melanin) is observed in animal epidermal feather, skin, head, eye, etc., and when melanin is excessively produced, it is deposited on skin to form spots and freckles, and skin aging is accelerated to induce skin cancer. The disease or symptom caused by the excessive production of melanin may be selected from the group consisting of spots, freckles, age spots, lentigo, Epidermal Melanocytic lesions (Epidermamal melanotic lesions), coffee spots (Cafe's aut lenticules), nevi, pigmented hair-coat nevi (Becker's Nevus), lentigo (Nevus Spilus), lentigo (Lentigines), black nevi, Dermal Melanocytic lesions (Dermal melanotic lesions), Mongolian lentigo (mongolian lentigo), Tata (Nevus of Ota), bilateral Acquired Paget's lentigo (Acired Lentigines of Ota-lenticulus), Ito nevi (Nevus of Ito), blue Nevus (blue Nevus), Melanocytic Nevus (Melococcus), junction lentigo (junction lentigo-leucovorus), lentigo-lentigo (Congenital Nevus), Nevus (Congenital Nevus (Congenital Nevus), Nevus parakeratosus (lentivus), Nevus neovorus (junction), Nevus (Congenital Nevus (Nevus vulgaris (Nevus), Nevus neovorus (Congenital Nevus) and Nevus (Nevus vulgaris (Nevus) or Nevus purpureus (Nevus of lentivus, Nevus purpureus, Nevus purpureus, Nevus lentivus, Nevus of lentivus Nevus, Nevus of lentivus, Nevus of lentivus of the skin, lentivus of lenti, One or more of Dysplastic nevus (dyplastic nevus), Melanoma (Melanoma), Lentigo maligna Melanoma (Lentigo maligna Melanoma), Superficial spreading Melanoma (Superspecific spreading Melanoma), acromelasma Melanoma (Acral lentiginous), Nodular Melanoma (Nodular Melanoma), pigmented basal cell carcinoma (pigment basal cell carcinoma), pigmented cutaneous fibroids (dermatiboses), pigmented dermatocysts (dermoid cysts), pigmented keloids (keloid), pigment precipitation caused by ultraviolet light, pigment precipitation caused by drugs, pigment precipitation after inflammation, pigment precipitation caused by dermatitis, and keratotic echinacodermatomas (keratocanthamas).
In one embodiment of the present invention, since the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide inhibits the production and accumulation of melanin, one or more of stains, freckles, moles, melanoma, pigmentation caused by ultraviolet rays, pigmentation caused by drugs, pigmentation after inflammation, and pigmentation caused by dermatitis can be prevented, improved, or treated.
In one aspect of the present invention, it has been demonstrated that the process of treating melanocytes with a substance for inducing melanin formation to form melanin is inhibited by 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide.
From these results, the present inventors have found that 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide can be used as a substance for skin whitening. Prevention, amelioration, and treatment of melanin-related diseases or symptoms can be promoted by utilizing the efficacy of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide.
According to yet another aspect of the present invention, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof may be present in the composition in an amount ranging from 0.0001% to 20% by weight relative to the total weight of the composition. In one embodiment, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof may be present in an amount of 0.0001 wt% or more, 0.0005 wt% or more, 0.001 wt% or more, 0.005 wt% or more, 0.01 wt% or more, 0.05 wt% or more, 0.1 wt% or more, 0.3 wt% or more, 0.5 wt% or more, 0.8 wt% or more, 1 wt% or more, 3 wt% or more, 5 wt% or more, 8 wt% or more, 10 wt% or more, 12 wt% or more, o, 15% by weight or more, or 18% by weight or more. Further, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, its optical or stereoisomers, acceptable salts thereof, its hydrates, or solvates thereof may be present in an amount of 20 wt% or less, 18 wt% or less, 15 wt% or less, 12 wt% or less, 10 wt% or less, 8 wt% or less, 5 wt% or less, 3 wt% or less, 1 wt% or less, 0.8 wt% or less, 0.5 wt% or less, 0.3 wt% or less, 0.1 wt% or less, 0.05 wt% or less, 0.01 wt% or less, 0.005 wt% or less, 0.001 wt% or less, based on the total weight of the composition, Or 0.0005 wt% or less.
According to another aspect of the present invention, the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof may be administered in a dose of 0.0001 mg/kg/day to 20 mg/kg/day. In one embodiment, the administration dose may be 0.0001 mg/kg/day or more, 0.0005 mg/kg/day or more, 0.001 mg/kg/day or more, 0.005 mg/kg/day or more, 0.01 mg/kg/day or more, 0.05 mg/kg/day or more, 0.1 mg/kg/day or more, 0.5 mg/kg/day or more, 0.8 mg/kg/day or more, 1 mg/kg/day or more, 2 mg/kg/day or more, 3 mg/kg/day or more, 5 mg/kg/day or more, 8 mg/kg/day or more, 10 mg/kg/day or more, 12 mg/kg/day or more, 15 mg/kg/day or more, or 18 mg/kg/day or more. Further, the administration dose may be 20 mg/kg/or less, 18 mg/kg/or less, 15 mg/kg/or less, 12 mg/kg/or less, 10 mg/kg/or less, 8 mg/kg/or less, 5 mg/kg/or less, 3 mg/kg/or less, 2 mg/kg/or less, 1 mg/kg/or less, 0.8 mg/kg/or less, 0.5 mg/kg/or less, 0.1 mg/kg/or less, 0.05 mg/kg/or less, 0.01 mg/kg/or less, 0.005 mg/kg/less, 0.001 mg/kg/or less, or 0.0005 mg/kg/less.
According to one aspect of the present invention, the composition may be a pharmaceutical composition for skin whitening.
The pharmaceutical composition may further contain preservatives, stabilizers, wettable powders or emulsifiers, pharmaceutical adjuvants such as salts and/or buffers for controlling osmotic pressure, and other substances useful for therapy, and may be formulated into various oral dosage forms or parenteral dosage forms according to conventional methods.
The oral dosage forms, for example, may be tablets, pills, hard and soft capsules, liquids, suspensions, emulsions, syrups, powders, fine granules, and pellets, etc., and these dosage forms may contain, in addition to the active ingredient, surfactants, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and polyethylene glycol). In addition, the tablet may further contain, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, a binder such as sodium carboxymethylcellulose and polyvinylpyrrolidone, and, as the case may be, a disintegrant of starch, agar, alginic acid or a sodium salt thereof, an absorbent, a colorant, a flavor, a sweetener, and the like. The tablets may be prepared by conventional mixing, granulating or coating methods.
In addition, the parenteral administration dosage form may be a transdermal administration dosage form, and for example, may be a dosage form of injection, drop, ointment, lotion, gel, cream, spray, suspension, emulsion, suppository, patch, etc., but is not limited thereto.
The pharmaceutical composition may be administered parenterally, rectally, topically, transdermally, subcutaneously, etc.
The administration dose of the effective ingredient is within the level of those of ordinary skill in the art, and the daily dose of the drug may vary depending on various factors such as the degree of progression, time of onset, age, health condition, and complications of the subject to be administered.
The pharmaceutical composition can be a skin external preparation, which is a general term including any preparation capable of being smeared outside the skin and can include medicaments in various dosage forms or quasi-medicaments.
According to another aspect of the present invention, the composition may be a cosmetic composition for skin whitening.
The cosmetic composition may further contain functional additives and ingredients generally contained in cosmetic compositions. The functional additive may comprise an ingredient selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymeric peptides, polymeric polysaccharides, sphingolipids and seaweed extracts. In addition, the composition may contain moisturizer, emollient, surfactant, organic and inorganic pigment, organic powder, ultraviolet absorbent, antiseptic, bactericide, antioxidant, plant extract, pH regulator, ethanol, pigment, perfume, blood circulation promoter, coolant, antiperspirant, purified water, etc.
The formulation of the cosmetic composition is not particularly limited and may be appropriately selected according to the purpose. For example, it may be prepared in any one or more dosage forms selected from the group consisting of skin lotion, skin softening lotion, face toilet, astringent lotion, milky lotion, nourishing lotion, moisturizing lotion, nourishing lotion, massage cream, nourishing cream, moisturizing cream, hand cream, foundation, essence, nourishing essence, pack, soap, cleansing foam, cleansing cream, body lotion and body wash, but is not limited thereto.
When the dosage form according to one aspect of the present invention is paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talc or zinc oxide, etc. may be used as a carrier ingredient.
When the formulation according to one aspect of the present invention is a powder or a spray, lactose, talc, silicon dioxide, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier ingredient, and particularly when it is a spray, a propellant such as chlorofluorocarbon, propane/butane or dimethyl ether may be further included.
When the formulation according to one aspect of the present invention is a solution or a latex, a solvent, a solvating agent or a demulsifier may be used as a carrier ingredient, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol oil, glycerol fatty acid ester, polyethylene glycol or fatty acid ester of sorbitan.
When the dosage form according to one aspect of the present invention is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, or the like may be used as a carrier ingredient.
When the formulation according to one aspect of the present invention is a surfactant-containing detergent, sodium fatty alcohol sulfate, sodium fatty alcohol ether sulfate, sulfosuccinic acid monoester, sodium isethionate, imidazolidine derivative, sodium methyltaurate, sodium sarcosinate, sodium fatty acid amide ether sulfate, alkylamide betaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linolenic acid derivative, or ethoxylated glycerol fatty acid ester, and the like may be used as a carrier component.
Hereinafter, technical solutions and effects of an aspect of the present invention will be described in more detail with reference to examples and experimental examples. However, the following examples are only for the purpose of aiding understanding of the present invention, and the scope and scope of the present invention are not limited thereto.
[ example 1]
Preparation of cell and skin models
Human epidermal melanocytes (NHEM, Cascade Biologics, Portland, OR, USA), Melan-a cell lines derived from melanocytes of C57BL/6J (black, a/a) mice were obtained from Dorothy c.bennett, doctor saint georges hospital medical school, london, UK, B16F1 mouse melanoma (melanoma) cell lines were obtained from ATCC (manassas, VA, USA).
Human epidermal melanocytes were maintained in Human Melanocyte Growth Supplements (HMGS) in M-254 medium (Cascade Biologics, Mansfield, UK). Melan-A cells were maintained in 10% (v/v) fetal bovine serum, 1% (v/v) penicillin-Streptomyces and 0.2. mu.M phorbol 12-myristate 13-acetate in RPMI 1640 medium. B16F1 mouse melanoma cell lines were cultured in DMEM supplemented with 10% (v/v) fetal bovine serum and 1% (v/v) penicillin-streptomyces.
Obtaining a Three-dimensional human skin substitute (Three-dimensional human skin substitete, MelanoDerm)TMMEL-312-B, MatTek, seoul, korea) was maintained in EPI-100-NMM-113 medium optimized via KGF (keratinocyte growth factor), B-FGF (fibroblast growth factor) and α -MSH (α -melanocyte stimulating hormone) as per the manufacturer's instructions.
The luminance change (Δ L) index of the skin model was calculated by first measuring the L index (L value, luminance index) by a colorimeter (CR-300, Konica Minolta co., tokyo, japan), and then calculating the Δ L as L (treated skin) -L (control skin) for 13 days or 20 days. An increase in the Δ L index shows a further decrease in pigmentation due to compound induction in the skin (Lee et al, 2013).
Reagent
"SAG" as 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide was obtained from Calbiochem (san Diego, CA, USA). alpha-MSH, arbutin and kojic acid were obtained from Sigma-Aldrich (St. Louis, MO, USA).
Melanin assay
After treatment of the cells with trypsin/EDTA, they were centrifuged at 1000 Xg for 5 minutes and washed twice with PBS. Photographs of the final cell pellet in the tube were taken and the cell pellet was dissolved in 1N NaOH. The homogenized cell extracts were transferred to 96-well plates and the relative melanin amounts were measured by using an ELISA plate reader at an absorbance of 405 nm.
Western blot analysis
By using 2 × Laemmli sample buffer (2 × Laemmli sample buffer, 62.5mM Tris-HCl, pH 6.8, 25% [ v/v ]]Glycerol, 2% w/v SDS, 5% [ v/v ]]Beta-mercaptoethanol, and 0.01% [ w/v ]]Bromophenol blue) (Bio-Rad, Hercules, Calif., USA), all lysates were prepared. All cellular proteins were measured by using Bradford solution (Bio-Rad). The samples were then separated by SDS-PAGE and transferred to PVDF membrane (Bio-Rad). By using TBST (25mM Tris, 140mM NaCl and 0.05% [ v/v ]]
) After blocking with 4% (w/v) skim milk (skim milk), the membrane was incubated overnight with the specified primary antibody.
Anti-actin antibodies (anti-actin antibodies, MAB1501,1:10,000) were obtained from Millipore (Temecula, CA, USA), anti-alpha PEP7(tyrosinase) antibodies (anti-alpha PEP7(tyrosinase) antibodies, 1:1000) and anti-alpha PEP1(TRP1) antibodies (anti-alpha PEP1(TRP1) antibodies, 1:1000) were obtained from VJHearing (NIH, Bethesda, Md.). For detection of proteins, the membrane was incubated by using HRP-conjugated secondary antibody, and by using
The West Dura HR detection kit (Pierce, Rockford, IL, USA) measures signals to detect proteins.
Statistical analysis
Each data was obtained by at least 3 independent experiments and expressed as mean ± SE (standard error). The results were statistically evaluated by using one-way ANOVA (1-way ANOVA) (. p <0.05,. p < 0.01).
[ Experimental example 1] Regulation of melanogenesis
3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide is a substance represented by the following chemical formula 1.
[ chemical formula 1]
B16F1 cells were pretreated with α -MSH (1 μ M) and after 24 hours, treated with 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ B ] thiophene-2-carboxamide (5 μ M) or arbutin (500 μ M). After 24 hours, the cells were analyzed for melanin content and expression levels of tyrosinase, TRP1 protein by western blotting. The results show that the compound inhibits melanin production in B16F1 cells cultured after alpha-MSH treatment (fig. 1). The compounds also reduced the expression levels of tyrosinase and TRP1 proteins (fig. 2).
Experimental example 2 Artificial skin experiment
Experiments to control melanogenesis were performed by using three-dimensional human skin substitutes (reconstituted epidermal models containing normal human epidermal keratinocytes and NHEMs).
Specifically, 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide (5 μ M) and kojic acid (KA,5mM) were applied to a three-dimensional human skin substitute once every three days for 13 days and 20 days, respectively, and the effect on pigmentation was evaluated. The pigmentation was evaluated by using a colorimeter (colorimeter), and in fig. 4, Δ L was calculated by calculating the difference in brightness between the control group and the substance-treated group.
The results show that skin pigmentation was reduced by the compounds (fig. 3 and 4). It was thus demonstrated that the compounds can regulate melanin production and pigmentation even on three-dimensional human skin replacement.
Hereinafter, formulation examples of the composition according to an aspect of the present invention will be described, but other various formulations are also applicable, which are not intended to limit the present invention but are intended to explain the present invention in detail.
Formulation example 1 Soft capsules
20mg of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 80-140mg of L-carnitine, 180mg of soybean oil, 2mg of palm oil, 8mg of hydrogenated vegetable oil, 4mg of beeswax and 6mg of lecithin were mixed and filled in one capsule according to a conventional method to prepare a soft capsule.
Formulation example 2 tablets
20mg of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 200mg of galacto-oligosaccharide, 60mg of lactose and 140mg of maltose were mixed, and after granulation was performed using a fluid bed dryer, 6mg of sugar ester (sugar ester) was added thereto, and tablets were prepared by compression with a tablet press.
[ formulation example 3] granules
20mg of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 250mg of anhydrous crystalline glucose and 550mg of starch were mixed, and prepared into granules using a fluidized bed granulator, followed by filling into a coating to prepare granules.
[ formulation example 4] drink
20mg of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 10g of glucose, 0.6g of citric acid and 25g of liquid oligosaccharide were mixed, 300ml of purified water was added, and 200 ml of each bottle was filled. The mixture was filled into a bottle and sterilized at 130 ℃ for 4 to 5 seconds to prepare a drink.
[ formulation example 5] injection
An injection was prepared according to a conventional method by using 50mg of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, an appropriate amount of sterilized distilled water for injection, an appropriate amount of pH adjusting agent.
Formulation example 6 skin lotion (emollient Water)
An emollient lotion (emollient lotion) was prepared by using 3.0 wt% of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 1.00 wt% of magnesium L-ascorbate-2-phosphate, 1.00 wt% of water-soluble collagen (1% aqueous solution), 0.10 wt% of sodium citrate, 0.05 wt% of citric acid, 0.20 wt% of licorice extract, 3.00 wt% of 1, 3-butanediol, the remainder being purified water.
[ formulation example 7] cream
A cream-type preparation was prepared by using 3.00% by weight of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 2.00% by weight of polyethylene glycol monostearate, 5.00% by weight of self-emulsifying glycerin monostearate, 4.00% by weight of propylene glycol, 6.00% by weight of squalane, 6.00% by weight of tris (2-ethylhexane) glycerin, 1.00% by weight of glycosphingolipid, 7.00% by weight of 1, 3-butanediol, 5.00% by weight of beeswax, and the balance purified water.
Formulation example 8 facial mask
A facial mask was prepared by using 3.00% by weight of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, 13.00% by weight of polyvinyl alcohol, 1.00% by weight of magnesium L-ascorbate-2-phosphate, 1.00% by weight of lauroyl hydroxyproline, 2.00% by weight of water-soluble collagen (1% aqueous solution), 3.00% by weight of 1, 3-butanediol, 5.00% by weight of ethanol, the remainder of purified water.
[ formulation example 9] health food
Health foods were prepared according to the conventional methods with the compositions shown in the following table.
[ TABLE 1]
Although the composition ratio of the vitamin and mineral mixture is mixed according to the ingredients suitable for the health food, the mixture ratio of the vitamin and mineral mixture can be changed arbitrarily, and the ingredients can be used for preparing the health food composition according to the conventional method after being mixed according to the conventional preparation method of the health food.
[ formulation example 10] health drink
Health beverages were prepared according to conventional methods, with the compositions shown in the following table.
[ TABLE 2]
As shown in table 2 above, the remaining amount of purified water was added to make a total volume of 900ml, and the above components were mixed according to a conventional health drink preparation method, stirred at 85 ℃ for about 1 hour, and the resulting solution was filtered, hermetically sterilized by a sterilized 2-liter container, and stored in a refrigerator, thereby preparing a health drink.
While certain features of the invention have been described in detail above, it will be apparent to those skilled in the art that these specific details are merely illustrative of preferred embodiments of the invention, and the scope of the invention is not limited thereto. Accordingly, the actual scope of the invention is to be defined by the following claims and their equivalents.
Claims (9)
- Use of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide or an acceptable salt thereof in the manufacture of a composition for skin lightening.
- 2. Use according to claim 1, characterized in that said 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide inhibits the production or deposition of melanin.
- 3. Use according to claim 1, characterized in that said 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide reduces the expression of tyrosinase or TRP1 (tyrosinase related protein 1).
- 4. The use according to claim 1, wherein the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide prevents, ameliorates or treats one or more of stains, freckles and nevi, wherein the nevi comprise black nevi.
- 5. The use according to claim 1, wherein the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide prevents, ameliorates or treats one or more of pigmentation caused by uv light, pigmentation caused by drugs and post-inflammatory pigmentation, wherein post-inflammatory pigmentation comprises pigmentation caused by dermatitis.
- 6. Use according to claim 1, characterized in that the content of 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide or an acceptable salt thereof in said composition is comprised between 0.0001% and 20% by weight relative to the total weight of said composition.
- 7. Use according to claim 1, characterized in that the 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide, or an acceptable salt thereof, is administered in a dose of 0.0001 mg/kg/day to 20 mg/kg/day.
- 8. Use according to any one of claims 1 to 7, wherein the composition is a pharmaceutical composition.
- 9. Use according to any one of claims 1 to 7, characterized in that the composition is a cosmetic composition.
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| KR10-2016-0107873 | 2016-08-24 | ||
| KR1020160107873A KR102610930B1 (en) | 2016-08-24 | 2016-08-24 | COMPOSITION FOR SKIN-WHITENING COMPRISING 3-CHLORO-N-[TRANS-4-(METHYLAMINO)CYCLOHEXYL]-N-[[3-(4-PYRIDINYL)PHENYL]METHYL]BENZO[b]THIOPHENE-2-CARBOXAMIDE |
| PCT/KR2017/009033 WO2018038465A1 (en) | 2016-08-24 | 2017-08-18 | Skin-whitening composition containing 3-chloro-n-[trans-4-(methylamino)cyclohexyl]-n-[[3-(4-pyridinyl)phenyl]methyl]benzo[b]thiophene-2-carboxamide |
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| CN1849381A (en) * | 2003-09-10 | 2006-10-18 | 株式会社资生堂 | Antioxidant, whitening agent and skin preparation for external use containing the same |
| CN104994831A (en) * | 2013-01-22 | 2015-10-21 | 国立庆北大学校产学协力团 | Use of a resveratrol derivative for skin whitening |
| CN105407863A (en) * | 2013-07-12 | 2016-03-16 | 百朗德株式会社 | Skin whitening composition containing arbutin derivative |
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| KR101823036B1 (en) * | 2010-03-31 | 2018-01-31 | (주)아모레퍼시픽 | Inhibitor of melanin synthesis and the cosmetic composition containing the same |
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| CN1849381A (en) * | 2003-09-10 | 2006-10-18 | 株式会社资生堂 | Antioxidant, whitening agent and skin preparation for external use containing the same |
| CN104994831A (en) * | 2013-01-22 | 2015-10-21 | 国立庆北大学校产学协力团 | Use of a resveratrol derivative for skin whitening |
| CN105407863A (en) * | 2013-07-12 | 2016-03-16 | 百朗德株式会社 | Skin whitening composition containing arbutin derivative |
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