WO2018038465A1 - 3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물 - Google Patents

3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물 Download PDF

Info

Publication number
WO2018038465A1
WO2018038465A1 PCT/KR2017/009033 KR2017009033W WO2018038465A1 WO 2018038465 A1 WO2018038465 A1 WO 2018038465A1 KR 2017009033 W KR2017009033 W KR 2017009033W WO 2018038465 A1 WO2018038465 A1 WO 2018038465A1
Authority
WO
WIPO (PCT)
Prior art keywords
trans
pyridinyl
methylamino
benzo
cyclohexyl
Prior art date
Application number
PCT/KR2017/009033
Other languages
English (en)
French (fr)
Korean (ko)
Inventor
최현정
배일홍
김형준
이영진
이태룡
조동형
Original Assignee
(주)아모레퍼시픽
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by (주)아모레퍼시픽 filed Critical (주)아모레퍼시픽
Priority to CN201780066049.9A priority Critical patent/CN109890383B/zh
Priority to JP2019506499A priority patent/JP6883090B2/ja
Publication of WO2018038465A1 publication Critical patent/WO2018038465A1/ko

Links

Images

Classifications

    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • 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
    • 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
    • A61K31/395—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
    • 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
    • A61K8/49—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
    • 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
    • A61K8/49—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
    • 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

Definitions

  • the present invention relates to a composition for skin whitening comprising a composition for regulating the production and deposition of melanin, and a composition comprising a substance for exerting skin whitening efficacy.
  • Melanin is a biopolymer of phenols, a complex of black pigments and proteins, that is produced by browning when the cut surface of apples, potatoes, and bananas is exposed to the air, or in the skin feathers, skin, hair, and eyes of animals. Is observed. When melanin is excessively produced, it is deposited on the skin and thus forms blemishes, freckles, and the like, which are directly linked to skin whitening, and the like, and melanin promotes skin aging and skin cancer.
  • Melanocyte stimulating hormone is secreted by UV rays, inflammation, and hormones, and MSH reacts with receptors to enhance cAMP in melanocytes, thereby synthesizing melanin. It is secreted to the outside to protect the skin from ultraviolet rays. Synthesis of melanin is mainly regulated by ⁇ -MSH, and MITF, TYR, TRP1, TRP2 and the like are known as proteins involved in the synthesis of melanin.
  • the invention provides 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2 -To provide a skin whitening composition comprising a carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient to promote the development of the field of skin whitening, Its purpose is to meet consumer demand.
  • the invention provides 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2 It provides a composition for skin whitening comprising a carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.
  • the 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene- 2-carboxamide may be one that inhibits melanogenesis and deposition.
  • the composition may be a pharmaceutical composition or a cosmetic composition.
  • the invention provides 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2 -Carboxamide (3-Chloro- N- [ trans -4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2-carboxamide), its optical Or a method for skin whitening comprising administering a stereoisomer, an acceptable salt thereof, a hydrate thereof, or a solvate thereof to the subject.
  • the present invention also provides, in another aspect, 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) as an active ingredient for use in skin whitening applications.
  • Phenyl] methyl] benzo [ b ] thiophene-2-carboxamide, optical or stereoisomer thereof, acceptable salt thereof, hydrate thereof, or solvate thereof.
  • the present invention also provides, in another aspect, 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) for use in the preparation of a skin whitening composition.
  • Phenyl] methyl] benzo [ b ] thiophene-2-carboxamide, optical or stereoisomers thereof, acceptable salts thereof, hydrates thereof, or solvates thereof.
  • the invention provides 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2 Pioneering and marketing new fields of skin whitening by discovering and providing new skin whitening compositions comprising carboxamides, optical or stereoisomers thereof, acceptable salts thereof, hydrates thereof, or solvates thereof as active ingredients. It can contribute to expansion.
  • Figure 2 shows ⁇ -MSH, 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] ti on B16F1 cells.
  • arbutin was confirmed the effect on the expression of tyrosinase, TRP1.
  • FIG. 3 shows 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophen-2- in the skin model. After carboxamide treatment, the brightness change was observed.
  • Figure 4 shows 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophen-2- in the skin model. After carboxamide treatment, the change in brightness was measured with a colorimeter.
  • skin refers to a tissue covering the body surface of an animal, and is a broad concept including not only tissues covering the body surface such as the face or body, but also the scalp and hair.
  • 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophen-2-car Radiationamide ” may be expressed as Smo agonist, Smoothened agonist, Smo agonist, or SAG.
  • the 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2-carboxamide is hedge It may include a substance that induces the expression of the smoothened protein that plays a major role in the hedgehog signaling pathway.
  • isomers specifically refer to optical isomers (e.g., essentially pure enantiomers, original pure stereoisomers or mixtures thereof, as well as essentially pure diastereomers).
  • Conformation isomers ie, isomers that differ only in their angles of one or more chemical bonds
  • structural isomers ie, isomers that differ only in their angles of one or more chemical bonds
  • structural isomers ie, isomers that differ only in their angles of one or more chemical bonds
  • position isomers in particular, tautomers
  • geometric isomers eg, Cis-trans isomers
  • “essentially pure”, when used in the context of, for example, an enantiomer, stereoisomer, or diastereomer, includes about 90 specific compounds that may include enantiomers, stereoisomers, or diastereomers. At least%, preferably at least about 95%, more preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w) It means to exist.
  • “acceptable” means that it can be approved or approved by the government or equivalent regulatory body for use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional or pharmaceutical dosages. Recognized or enumerated as listed in the Food Code, Health Functional Food Code, or General Pharmacopoeia or as described in other general literature.
  • acceptable salt means a salt according to one aspect of the invention, either conventional or pharmaceutically acceptable and having the desired activity of the parent compound.
  • the salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
  • hydrate refers to a compound to which water is bound, and is a broad concept including an inclusion compound having no chemical bonding force between water and the compound.
  • solvate means a higher order compound produced between molecules or ions of a solute and molecules or ions of a solvent.
  • the invention provides 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2 It provides a composition for skin whitening comprising a carboxamide, an optical or stereoisomer thereof, an acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.
  • the opene-based compound may include C 28 H 28 ClN 3 OS, it may be represented by the following formula.
  • the compound may be obtained through synthesis, may be obtained by processing other materials, or may be derived from an organism or a microorganism.
  • the 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophen-2- Carboxamide may be one that inhibits melanogenesis or deposition.
  • the 2-carboxamide may be one that enhances the expression of tyrosinase or Tyrosinase-Related Protein 1 (TRP1). Since the expression of tyrosinase or TRP1 after the compound treatment is less than before the compound treatment, it can be seen that the compound can be used as an active ingredient of the composition for skin whitening. In addition, the treatment of the compound may reduce the number of cells expressing tyrosinase or TRP1, it can also be seen that the compound can be used as an active ingredient of the skin whitening composition.
  • Melanin is observed in the animal's outer skin feathers, skin, hair, eyes, etc., when the excessive production of melanin is deposited on the skin to form blemishes, freckles and the like, promote skin aging, skin cancer may also be induced.
  • the diseases or symptoms caused by the excessive production of melanin include blemishes, freckles, blotch, blemishes, epidermal melanocytic lesions, milky coffee spots (Cafe's au lait macules), birthmarks, Becker's Nevus, and stingles Nevus Spilus, Lentigines, Melanoma, Dermal melanocytic lesions, Mongolian spot, Nevus of Ota, Acquired bilateral nevus of Ota-like macules, Nevus of Ito, Blue nevus, Melanocytic nevus, Junction nevus, Compound nevus, Intradermal nevus Intradermal nevus, Halo nevus, Congenital nevocytic nevus, Spitz nevus, Dysplastic nevus, Melanoma, Malignant black melanoma (Lentigo maligna melanoma) ), Superficially expand
  • the 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene 2-carboxamide inhibits melanin production and accumulation, so pigments from blemishes, freckles, melanoma, nevus, melanoma, pigmentation by ultraviolet light, pigmentation by drugs, pigmentation after inflammation, and dermatitis It may be to prevent, ameliorate or treat one or more selected from the group consisting of deposition.
  • the process of forming melanin by treating a melanin-forming substance with melanin forming cells is 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3 It was confirmed that it was inhibited by-(4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2-carboxamide.
  • 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b in the composition ]
  • the content of thiophene-2-carboxamide, isomer thereof, acceptable salt thereof, hydrate thereof, or solvate thereof may be from 0.0001% to 20% by weight relative to the total weight of the composition.
  • the content is at least 0.0001 wt%, at least 0.0005 wt%, at least 0.001 wt%, at least 0.005 wt%, at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, 0.3 wt%, based on the total weight of the composition. At least 0.5 wt%, at least 0.8 wt%, at least 1 wt%, at least 3 wt%, at least 5 wt%, at least 8 wt%, at least 10 wt%, at least 12 wt%, at least 15 wt%, or 18 wt% It may be more than%.
  • the content is 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, based on the total weight of the composition, 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, or 0.0005 wt% or less Can be.
  • Dosages of offen-2-carboxamide, isomers thereof, acceptable salts thereof, hydrates thereof, or solvates thereof may be from 0.0001 mg / kg / day to 20 mg / kg / day.
  • the dosage is at least 0.0001 mg / kg / day, at least 0.0005 mg / kg / day, at least 0.001 mg / kg / day, at least 0.005 mg / kg / day, at least 0.01 mg / kg / day, 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 Can be more than / day.
  • the dosage is 20 mg / kg / day or less, 18 mg / kg / day or less, 15 mg / kg / day or less, 12 mg / kg / day or less, 10 mg / kg / day or less, 8 mg / kg / Day or less, 5 mg / kg / day or less, 3 mg / kg / day or less, 2 mg / kg / day or less, 1 mg / kg / day or less, 0.8 mg / kg / day or less, 0.5 mg / kg / day Or less, 0.1 mg / kg / day or less, 0.05 mg / kg / day or less, 0.01 mg / kg / day or less, 0.005 mg / kg / day or less, 0.001 mg / kg / day or less, or 0.0005 mg / kg / day or less Can be.
  • the composition may be a composition for skin whitening which is a pharmaceutical composition.
  • the pharmaceutical composition may further contain pharmaceutical supplements such as preservatives, preservatives, stabilizers, hydrating or emulsifying accelerators, salts for regulating osmotic pressure and / or buffers, and other therapeutically useful substances, And can be formulated in various oral or parenteral dosage forms.
  • pharmaceutical supplements such as preservatives, preservatives, stabilizers, hydrating or emulsifying accelerators, salts for regulating osmotic pressure and / or buffers, and other therapeutically useful substances.
  • the oral dosage forms include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, powders, powders, fine granules, granules, pellets, and the like, and these formulations include surfactants in addition to active ingredients. , Diluents (eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), glidants (eg silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycols). .
  • Diluents eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine
  • glidants eg silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally starch, agar, alginic acid or its sodium salt Pharmaceutical additives such as disintegrants, absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally starch, agar, alginic acid or its sodium salt
  • Pharmaceutical additives such as disintegrants, absorbents, colorants, flavors, and sweeteners.
  • the tablets can be prepared by conventional mixing, granulating or coating methods.
  • parenteral dosage form may be a transdermal dosage form, for example, an injection, drop, ointment, lotion, gel, cream, spray, suspension, emulsion, suppository, patch, or the like. It may be, but is not limited thereto.
  • the pharmaceutical composition may be administered parenterally, rectally, topically, transdermally, subcutaneously, and the like.
  • the daily dosage of the drug may vary depending on various factors such as the progress of the subject to be administered, the onset, age, health condition, complications.
  • the pharmaceutical composition may be an external preparation for skin, and the external preparation for skin may be included herein as a generic term that may include anything applied outside the skin.
  • the composition may be a composition for skin whitening which is a cosmetic composition.
  • the cosmetic composition may further include a functional additive and components included in the general cosmetic composition.
  • the functional additive may include a component selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids and seaweed extract.
  • oils and fats moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, blood circulation And accelerators, cooling agents, limiting agents, purified water, and the like.
  • the cosmetic composition is not particularly limited in formulation, and may be appropriately selected as desired.
  • skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizing cream, hand cream, foundation, essence, nutrition essence, pack, soap, cleansing It may be prepared in any one or more formulations selected from the group consisting of foam, cleansing lotion, cleansing cream, body lotion and body cleanser, but is not limited thereto.
  • the carrier component is animal fiber, vegetable fiber, wax, paraffin, starch, trakant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. And the like can be used.
  • lactose talc
  • silica aluminum hydroxide
  • calcium silicate or polyamide powder may be used as the carrier component, in particular, in the case of a spray, additionally chlorofluoro Propellants such as hydrocarbon, propane / butane or dimethyl ether.
  • a solvent, solvating agent or emulsifying agent is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Fatty acid esters of propylene glycol, 1,3-butylglycol oil, glycerol aliphatic esters, polyethylene glycols or sorbitan.
  • the carrier component is water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester.
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester.
  • Microcrystalline cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
  • the dosage form according to one aspect of the present invention is a surfactant-containing cleansing agent, as a carrier component, an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, isethionate, an imidazolinium derivative, methyltaurate, and sarcosy Nates, fatty acid amide ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
  • Melan-A a melanogenesis cell derived from C57BL / 6 J (black, a / a) mice, obtained from normal human epidermal melanocytes (NHEMs, Cascade Biologics, Portland, OR, USA) -A) Cell lines were obtained from Dr. Dorothy C. Bennett (St. George's Hospital Medical School, London, UK). B16F1 mouse melanoma cell line was obtained from ATCC (Manassas, VA, USA).
  • Human epidermal melanocyte forming cells were maintained under Human Melanocyte Growth Supplements (HMGS) (Cascade Biologics, Inc., Mansfield, UK) in M-254 medium.
  • Melan-A cells were maintained under 10% (v / v) fetal bovine serum, 1% (v / v) penicillin-streptomycin, and 0.2 ⁇ M phorbol 12-myristate 13-acetate in RPMI 1640 medium.
  • B16F1 mouse melanoma cell lines were cultured in DMEM with 10% (v / v) fetal bovine serum and 1% (v / v) penicillin-streptomycin.
  • Three-dimensional human skin substitutes (MelanoDerm TM, MEL-312-B, MatTek, Seoul, Korea) were obtained, followed by keratinocyte growth factor (KGF), fibroblast growth factor (b-FGF), and It was maintained according to the manufacturer's instructions in EPI-100-NMM-113 medium optimized with alpha-melanocyte stimulating hormones ( ⁇ -MSH).
  • KGF keratinocyte growth factor
  • b-FGF fibroblast growth factor
  • SAG which is 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl] benzo [ b ] thiophene-2-carboxamide ”Was obtained from Calbiochem (San Diego, CA, USA). ⁇ -MSH, arbutin, and kojic acid were obtained from Sigma-Aldrich (St. Louis, MO, USA).
  • Anti-actin antibody (MAB1501, 1: 10,000) was obtained from Millipore (Temecula, Calif., USA), and anti- ⁇ PEP7 (tyrosinase) antibody, 1 : 1000) and anti- ⁇ PEP1 (TRP1) antibody (anti- ⁇ PEP1 (TRP1) antibody, 1: 1000) were obtained from VJ Hearing (NIH, Bethesda, MD).
  • TRP1 anti- ⁇ PEP1 antibody, 1: 1000
  • the membrane was incubated with an HRP- conjugated secondary antibody gated signal was measured using a SuperSignal ® West Dura HRP Detection Kit ( Pierce Inc., Rockford, IL, USA).
  • B16F1 cells were pretreated with ⁇ -MSH (1 ⁇ M) and after 24 hours 3-chloro- N- [trans-4- (methylamino) cyclohexyl] -N -[[3- (4-pyridinyl) phenyl] methyl ] Benzo [ b ] thiophene-2-carboxamide (5 ⁇ ) or arbutin (500 ⁇ ) were treated. After 24 hours, the cellular melanin content, tyrosinase and TRP1 protein expression levels were analyzed by Western blot. As a result, the compound inhibited melanin production in B16F1 cells cultured by treatment with ⁇ -MSH (Fig. 1). The compound also reduced the expression levels of tyrosinase, TRP1 protein (FIG. 2).
  • the regulation of melanin production was tested using a three-dimensional human skin substitute (reconstituted epidermal model comprising normal human epidermal keratinocytes and NHEMs).
  • Health food was prepared by conventional methods according to the compositions described in the table below.
  • Vitamin A Acetate 70 ⁇ g Vitamin E 1.0 mg Vitamin B1 0.13 mg Vitamin B2 0.15 mg Vitamin B6 0.5 mg Vitamin B12 0.2 ⁇ g Vitamin c 10 mg Biotin 10 ⁇ g Nicotinic acid amide 1.7 mg Folic acid 50 ⁇ g Calcium Pantothenate 0.5 mg Mineral mixture Ferrous sulfate 1.75 mg Zinc oxide 0.82 mg Magnesium carbonate 25.3 mg Potassium phosphate monobasic 15 mg Dicalcium Phosphate 55 mg Potassium citrate 90 mg Calcium carbonate 100 mg Magnesium chloride 24.8 mg
  • composition ratio of the vitamin and inorganic mixture is a composition that is relatively suitable for health foods, for example, the composition ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method, and then the conventional method. According to the health food composition can be used.
  • Health food was prepared by conventional methods according to the compositions described in the table below.
  • the remaining amount of purified water was added to a total volume of 900 ml, and the above ingredients were mixed according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ° C. for about 1 hour. Obtained in a sterilized 2 liter container, sterilized sealed, and then refrigerated to prepare a healthy beverage.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Non-Alcoholic Beverages (AREA)
  • Cosmetics (AREA)
PCT/KR2017/009033 2016-08-24 2017-08-18 3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물 WO2018038465A1 (ko)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780066049.9A CN109890383B (zh) 2016-08-24 2017-08-18 用于皮肤美白的组合物
JP2019506499A JP6883090B2 (ja) 2016-08-24 2017-08-18 ３−クロロ−Ｎ−［トランス−４−（メチルアミノ）シクロヘキシル］−Ｎ−［［３−（４−ピリジニル）フェニル］メチル］ベンゾ［ｂ］チオフェン−２−カルボキサミドを含む皮膚美白用組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020160107873A KR102610930B1 (ko) 2016-08-24 2016-08-24 3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물
KR10-2016-0107873 2016-08-24

Publications (1)

Publication Number Publication Date
WO2018038465A1 true WO2018038465A1 (ko) 2018-03-01

Family

ID=61246138

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/009033 WO2018038465A1 (ko) 2016-08-24 2017-08-18 3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물

Country Status (4)

Country Link
JP (1) JP6883090B2 (enrdf_load_stackoverflow)
KR (1) KR102610930B1 (enrdf_load_stackoverflow)
CN (1) CN109890383B (enrdf_load_stackoverflow)
WO (1) WO2018038465A1 (enrdf_load_stackoverflow)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110506220B (zh) 2016-12-30 2023-09-15 图达通智能美国有限公司 多波长lidar设计
KR102511934B1 (ko) * 2021-04-27 2023-03-21 재단법인 아산사회복지재단 피부 색소침착의 예방, 개선, 또는 치료용 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010022159A1 (en) * 2008-08-19 2010-02-25 Biosynergo Cyclohexylamines, phenylamines and uses thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100422290C (zh) * 2003-09-10 2008-10-01 株式会社资生堂 抗氧剂、美白剂以及配合其的皮肤外用剂
WO2011122840A2 (ko) * 2010-03-31 2011-10-06 (주)아모레퍼시픽 멜라닌 색소 생성 억제제 및 이를 함유하는 화장료 조성물
CN101993415B (zh) * 2010-09-15 2013-08-14 北京韩美药品有限公司 作为Hedgehog通路抑制剂的化合物以及包含该化合物的药物组合物及其应用
CN102731373B (zh) * 2012-07-19 2013-11-27 南京药石药物研发有限公司 抗肿瘤药物gdc-0449中间体的制备方法
JP6232547B2 (ja) * 2012-11-28 2017-11-22 国立大学法人名古屋大学 聴覚障害又は小脳性運動失調症の予防・治療剤
KR101480600B1 (ko) * 2013-01-22 2015-01-08 경북대학교 산학협력단 레스베라트롤 유도체의 피부미백 용도
KR101628282B1 (ko) * 2013-07-12 2016-06-08 주식회사 바이오랜드 알부틴 유도체를 함유하는 피부 미백용 조성물
GB2519344A (en) * 2013-10-18 2015-04-22 Redx Pharma Ltd Compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010022159A1 (en) * 2008-08-19 2010-02-25 Biosynergo Cyclohexylamines, phenylamines and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEN, J. K. ET AL.: "Small Molecule Modulation of Smoothened Activity.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 99, no. 22, 2002, pages 14071 - 14076, XP002251705 *
FRANK-KAMENETSKY, M. ET AL.: "Small-molecule Modulators of Hedgehog Signaling: Identification and Characterization of Smoothened Agonists and Antagonists.", JOURNAL OF BIOLOGY, vol. 1, no. 2, 2002, pages 1 - 19, XP021007684 *
MAK, S. K. ET AL.: "Small Molecules Greatly Improve Conversion of Human-induced Pluripotent Stem Cells to the Neuronal Lineage.", STEM CELLS INTERNATIONAL, vol. 2012, 2012, XP055411520 *
YANG, H. ET AL.: "Converse Conformational Control of Smoothened Activity by Structurally Related Small Molecules.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, no. 31, 2009, pages 20876 - 20884, XP008152186 *

Also Published As

Publication number Publication date
CN109890383B (zh) 2022-06-07
JP6883090B2 (ja) 2021-06-09
JP2019526545A (ja) 2019-09-19
KR102610930B1 (ko) 2023-12-08
CN109890383A (zh) 2019-06-14
KR20180022439A (ko) 2018-03-06

Similar Documents

Publication Publication Date Title
CN101102746A (zh) 包含笃斯越桔提取物的用于改善皮肤状况的组合物及其制备方法
WO2017003114A1 (ko) 피부 미백용 조성물 및 피부 미백 효능 물질을 스크리닝하는 방법
WO2020040432A1 (ko) 인삼열매 추출물을 유효성분으로 함유하는 근육 질환의 예방 또는 치료용 약학적 조성물
WO2018038465A1 (ko) 3-클로로-N-[트랜스-4-(메틸아미노)사이클로헥실]-N-[[3-(4-피리디닐)페닐]메틸]벤조[b]티오펜-2-카복사마이드를 포함하는 피부 미백용 조성물
WO2015108394A1 (ko) 히드록시 피라논 유도체 화합물을 포함하는 지방세포 분화 촉진용 화장료 조성물
WO2016117762A1 (ko) 구스베리 추출물 또는 글루타티온을 포함하는 조성물
WO2018038425A1 (ko) 사이토칼라신 d를 포함하는 피부 미백용 조성물
WO2012173382A2 (ko) 탄시논ⅱａ를 유효성분으로 함유하는 피부 외용제 조성물
WO2016159580A1 (ko) 티아사포제놀 유도체를 유효성분으로 포함하는 조성물
WO2018080039A1 (ko) 단풍콩잎 추출물을 함유하는 탈모방지 또는 발모개선용 조성물
WO2018230906A1 (ko) 신규한 퀘르세틴계 화합물을 포함하는 미백용 조성물
WO2020091295A1 (ko) 저근백피 추출물을 유효성분으로 함유하는 여드름성 피부 개선용 또는 피지 분비 억제용 조성물
WO2019083132A1 (ko) 사이토칼라신 d 또는 sag를 포함하는 항노화용 조성물 및 항노화 물질 스크리닝 방법
WO2016003120A1 (ko) 알피나 골무꽃 추출물을 포함하는 미백용 조성물
KR102182651B1 (ko) 4-(4-메틸피페라진-1-일)-N-(5-(피리딘-3-일)-1H-피라졸로[3,4-b]피리딘-3-일)벤즈아미드 유도체, 또는 이의 약학적으로 허용 가능한 염의 미백용 소재 용도
KR102105533B1 (ko) 아마이드 유도체 화합물
WO2018044029A1 (ko) 2,4-디클로로-a-(3,4-디하이드로-4-옥소-2(1H)-퀴나졸리닐리덴)-β-옥소-벤젠프로판니트릴을 포함하는 멜라닌 증진용 조성물
WO2020096348A1 (ko) 테아시넨신 a를 포함하는 화장료 조성물
WO2018230909A1 (ko) 후발효차 유래의 신규한 캄페롤계 화합물을 포함하는 항염 조성물
WO2015152552A1 (ko) 알파인 웜우드 추출물을 포함하는 조성물
WO2018016783A1 (ko) 3-o-갈로일-3,3',5,5',7-펜타하이드록시플라반을 포함하는 보습용 조성물
WO2021167269A1 (ko) 자두 씨 추출물을 유효성분으로 함유하는 미백용 조성물
WO2023008615A1 (ko) 엘라그산을 유효성분으로 포함하는 피지 분비 억제용 조성물
WO2018230910A1 (ko) 후발효차 유래의 신규한 캄페롤계 화합물을 포함하는 미백용 조성물
KR20140009660A (ko) Ａｒｐ１０１을 포함하는 피부 미백용 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17843885

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019506499

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17843885

Country of ref document: EP

Kind code of ref document: A1