WO2022080765A1 - Skin whitening composition containing dihydrofuran-2(3h)-one dimer - Google Patents
Skin whitening composition containing dihydrofuran-2(3h)-one dimer Download PDFInfo
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- WO2022080765A1 WO2022080765A1 PCT/KR2021/013839 KR2021013839W WO2022080765A1 WO 2022080765 A1 WO2022080765 A1 WO 2022080765A1 KR 2021013839 W KR2021013839 W KR 2021013839W WO 2022080765 A1 WO2022080765 A1 WO 2022080765A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- integer
- skin whitening
- alkynyl
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- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940078752 magnesium ascorbyl phosphate Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- HTJNEBVCZXHBNJ-XCTPRCOBSA-H trimagnesium;(2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;diphosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.OC[C@H](O)[C@H]1OC(=O)C(O)=C1O HTJNEBVCZXHBNJ-XCTPRCOBSA-H 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
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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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to a skin whitening composition
- a skin whitening composition comprising a dihydrofuran-2(3H)-one dimer having melanogenesis inhibitory activity, or a pharmaceutically acceptable salt thereof.
- the compound of the present invention acts on the melanin biosynthesis signaling pathway induced by ⁇ -MSH (Melanocyte-stimulating hormone), and has an excellent effect of preventing or treating diseases of melanogenesis hyper-deposition.
- Melanin is a black pigment found in animals, plants, and microorganisms that is not essential for growth or development, but it is a substance that increases viability and competitiveness in the environment.
- Melanin is a stable pigment among the pigments found in living organisms, and is insoluble in almost all solvents, and the process of melanogenesis takes place in melanosomes, which are organelles of melanocytes, which are specially differentiated cells. It is known That is, skin color is determined according to the content and distribution of melanin, and is related to the number and distribution of melanosomes that are generated in melanocytes and released to the outside of cells.
- Melanin exists in the skin and plays an important role in protecting the body from UV rays, but when melanin is excessively produced, it promotes pigmentation and skin aging, and causes hyperpigmentation such as spots and freckles and melanoma. known to be an important factor.
- a person's skin color is determined by several factors, such as the activity of melanocytes that make melanin pigment, the distribution of blood vessels, the thickness of the skin, and the presence or absence of internal and external pigments such as carotenoids and bilirubin.
- melanin the black pigment
- melanin the black pigment
- the formation of melanin is influenced by genetic factors, hormone secretion, physiological factors related to stress, etc., and environmental factors such as UV irradiation.
- Melanin pigment is produced in melanocytes and then moves to keratinocytes to protect the skin from harmful environmental stimuli such as UV radiation.
- Ultraviolet rays from the sun are UVA in the 320 - 400nm region, depending on the wavelength; UVB in the region of 280 - 320 nm; And it can be classified into UVC of 200 - 280nm region, of which UVB causes the production of melanin.
- UVB induces melanin production through a complex process through the interaction between keratinocytes and melanocytes, or is a major regulator of melanin production through phosphorylation of Ser133 of CREB (cAMP-response element-binding protein) by increasing cAMP. It increases the production of melanin through a method of increasing the expression of MITF (Microphthalmia-associated transcription factor).
- keratinocytes When exposed to UVB, keratinocytes secrete paracrine factor to promote melanogenesis in melanocytes.
- paracrine factors Among the paracrine factors secreted, the most important agonist to stimulate melanogenesis is ⁇ -melanocytes. It is ⁇ -melanocyte stimulating hormone ( ⁇ -MSH).
- vitamin C and its derivatives have been used for the purpose of inhibiting melanin production, but these also have a problem in that they have low tyrosinase inhibitory activity.
- dihydrofuran-2(3H)-one dimer is ⁇ -melanocyte stimulating hormone ( ⁇ -Melanocyte stimulating hormone, ⁇ -MSH) was confirmed to exhibit an excellent effect in promoting the decomposition of melanosomes.
- Patent Document 1 Korean Patent No. 1890058
- the present inventors have completed the present invention by confirming that the dihydrofuran-2(3H)-one dimer has an excellent effect as a result of research to develop a material having the effect of inhibiting melanogenesis and promoting the decomposition of melanosomes .
- An object of the present invention is to provide a composition for skin whitening comprising, as an active ingredient, a dihydrofuran-2(3H)-one dimer, or a pharmaceutically acceptable salt thereof, which inhibits melanogenesis and promotes melanosome decomposition. do it with
- the present invention provides a novel compound of dihydrofuran-2(3H)-one dimer having the effect of inhibiting melanogenesis and promoting melanosome degradation.
- the present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:
- R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
- R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;
- R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
- R b is hydrogen or C 1 -C 6 alkyl
- n 1 to 20.
- the present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula II, an isomer thereof, or a pharmaceutically acceptable salt thereof:
- n is an integer from 1 to 20;
- the present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula III, an isomer thereof, or a pharmaceutically acceptable salt thereof:
- n is an integer from 1 to 20.
- the present invention provides a cosmetic composition for skin whitening, or a health functional food, comprising the compound of the present invention.
- the present invention provides a pharmaceutical composition for the treatment or prevention of melanin hyperpigmentation disease comprising the compound of the present invention.
- the present invention provides a novel compound of a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
- R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
- R 2 and R 4 are each independently hydrogen, C One -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, Halo, C One -C 6 Alkoxy, cyano, or -OR a ego;
- R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
- R b is hydrogen or C 1 -C 6 alkyl
- n 1 to 20.
- the present invention provides a novel compound of a dimer, an isomer thereof, or a pharmaceutically acceptable salt thereof of dihydrofuran-2(3H)-one of the following formula (II).
- n is an integer from 1 to 20;
- the dimer of dihydrofuran-2(3H)-one of the present invention does not have cytotoxicity and inhibits melanin production, so it is useful for skin whitening or improving, preventing or treating diseases of melanin hyperpigmentation.
- the dimer of the present dihydrofuran-2(3H)-one has a significantly superior effect compared to that of the monomer.
- Figure 2 shows the melanin production inhibitory effect according to the treatment concentration of the compound of Formula 2 (WJC-2020-68).
- Figure 3 shows the melanin production inhibitory effect according to the treatment concentration of the compounds of Formulas 5 to 7 (WJC-2020-69).
- Figure 4 shows the melanin production inhibitory effect according to the treatment concentration of the compounds of Formulas 3 to 5 (WJC-2020-70).
- Figure 5 shows the melanin production inhibitory effect according to the treatment concentration of arbutin (Arbutin).
- FIG. 6 shows the survival rate (%) of B16 melanoma (melanoma) cells according to the treatment concentration of the compound of Formula 1 (WJC-2020-67).
- Figure 10 shows the survival rate (%) of B16 melanoma (melanoma) cells according to the treatment concentration of arbutin (Arbutin).
- the present invention relates to a composition
- a composition comprising a dimer, an isomer thereof, or a pharmaceutically acceptable salt thereof of dihydrofuran-2(3H)-one of the following formula (I).
- R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
- R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;
- R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
- R b is hydrogen or C 1 -C 6 alkyl
- n is an integer from 1 to 20;
- the present invention provides
- R1 and R3 are each independently C 1 -C 6 alkyl
- R 2 and R 4 are each independently hydrogen or hydroxy
- n may be an integer from 1 to 20 in the composition.
- n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
- the present invention is a composition comprising a compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
- n may be an integer from 1 to 20 in the composition.
- n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
- the present invention is a composition comprising a compound represented by the following formula (III), an isomer thereof, or a pharmaceutically acceptable salt thereof.
- n is an integer of 1 to 20, preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
- the present invention may be a cosmetic composition for skin whitening comprising the compound of the present invention, or a health functional food.
- the present invention may be a pharmaceutical composition for the treatment or prevention of melanin hyperpigmentation disease comprising the compound of the present invention.
- the compound of the present invention inhibits melanogenesis or promotes melanosome degradation, and may be, for example, acting on a melanin biosynthesis signaling pathway induced by ⁇ -MSH.
- the "melanin hyperpigmentation disease" of the present invention may be melasma, freckles, spots, solar surplus, drug pigmentation, inflammatory pigmentation, senile pigmentation, or gestational pigmentation, but is not limited thereto.
- composition of the present invention has a whitening effect, hydroquinone (hydroquinone, Benzene-1,4-diol), mulberry extract, arbutin, ethyl ascorbyl ether, oil-soluble licorice extract, ascorbyl glucoside, magnesium ascorbyl phosphate, niacinamide, Alpha-bisabolol or ascorbyltetraisopalmitate may be further included.
- hydroquinone hydroquinone, Benzene-1,4-diol
- mulberry extract arbutin
- ethyl ascorbyl ether oil-soluble licorice extract
- ascorbyl glucoside oil-soluble licorice extract
- magnesium ascorbyl phosphate niacinamide
- Alpha-bisabolol or ascorbyltetraisopalmitate may be further included.
- the present invention relates to a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
- R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
- R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, C 1 -C 6 alkoxy, cyano, or —OR a ;
- R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
- R b is hydrogen or C 1 -C 6 alkyl
- n may be an integer from 1 to 20 in the composition.
- n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
- the present invention relates to a compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
- n may be an integer from 1 to 20 in the composition.
- n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
- alkyl is a hydrocarbon having primary, secondary, tertiary or quaternary carbon atoms and includes saturated aliphatic groups which may be straight-chain, branched or cyclic, or combinations thereof.
- an alkyl group has 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl).
- alkyl refers to C 1 -C 6 alkyl.
- alkyl groups examples include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl ( i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i- Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t -Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH
- alkyl as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-trifluoromethyl.
- alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone including haloalkyl groups such as roethyl, and the like.
- C xy or "C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, alkynyl or alkoxy is intended to include groups containing from x to y carbons in the chain.
- C 0 alkyl represents hydrogen when the group is in a terminal position and a bond when internal to the group.
- a C 1 -C 6 alkyl group contains 1 to 6 carbon atoms in the chain.
- Alkoxy refers to a group having the formula —O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom.
- the alkyl moiety of the alkoxy group may be, for example, 1 to 20 carbon atoms (ie C 1 -C 20 alkoxy), 1 to 12 carbon atoms (ie C 1 -C 12 alkoxy), 1 to 10 carbon atoms. (ie, C 1 -C 10 alkoxy), or 1 to 6 carbon atoms (ie, C 1 -C 6 alkoxy).
- alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), and t-butoxy (-OC(CH 3 ) 3 or -O-tBu ), but is not limited thereto.
- Alkenyl has primary, secondary, tertiary or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon-carbon sp It is a hydrocarbon with two double bonds.
- an alkenyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkenyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl).
- Alkynyl is a hydrocarbon having primary, secondary, tertiary or quaternary carbon atoms, including straight-chain, branched and cyclic groups, or combinations thereof, and having at least one carbon-carbon sp triple bond. am.
- an alkynyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkynyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl).
- suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
- halo includes chloro, fluoro, bromo, and iodo.
- pharmaceutically acceptable salt refers to a salt according to an aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
- pharmaceutically acceptable salts herein are intended to refer to all salts that can be used in pharmaceutical compositions as well as cosmetic compositions or food compositions.
- the salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used.
- the cosmetic composition of the present invention is, for example, a solution, a gel, a solid or kneaded anhydrous product, an emulsion obtained by dispersing an oil phase in an aqueous phase, a suspension, a microemulsion, a microcapsule, microgranule or ionic (liposome), non-ionic type. It may be provided in the form of a vesicular dispersant, cream, skin, lotion, powder, ointment, spray or in the form of a cone stick. In addition, it may be prepared in the form of a foam or an aerosol composition further containing a compressed propellant.
- the cosmetic composition includes a fatty substance, an organic solvent, a solubilizer, a thickening agent and a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, an ionic or non-ionic type.
- Cosmetics such as emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other ingredients commonly used in cosmetics. It may contain adjuvants commonly used in the field.
- the composition of the present invention may be a food composition, for example, a health functional food.
- a health functional food means a food manufactured and processed using raw materials or ingredients useful for the human body
- functionality means a health purpose such as regulating nutrients or physiological action with respect to the structure and function of the human body. It means to consume for the purpose of obtaining useful effects.
- the formulation of the food composition is not particularly limited, but, for example, may be formulated as tablets, granules, powders, liquids such as drinks, caramel, gels, bars, and the like.
- the food composition of each dosage form can be formulated by a person skilled in the art without difficulty according to the dosage form or purpose of use, which is commonly used in the field.
- the pharmaceutical composition of the present invention may be administered parenterally or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, etc. Its scope is diverse.
- the therapeutically effective amount of the composition may vary depending on the method of administration, the target site, and the condition of the patient.
- the compound of the present invention can be prepared by a preparation method as shown in Schemes 1 to 3 below.
- DMEM Dulbecco's modified eagle's medium
- FBS fetal bovine serum
- penicillin/streptomycin 100U/ml
- B16 melanoma cells 200 ⁇ L of B16 melanoma cells were dispensed in a 96-well plate to 3 X 10 3 cells/well, and then cultured at 37° C., 5% CO 2 in an incubator for 24 hours.
- B16 melanoma cells were treated with compounds of 0, 1, 3, 10, and 30 ⁇ M, respectively, for 2 hours, and stimulated with ⁇ -MSH (melanocyte-stimulating hormone) (100 nM) for 72 hours.
- ⁇ -MSH melanocyte-stimulating hormone
- the amount of melanin in the negative control group that was not treated with anything was set to 1, and the melanin amount of the positive control ( ⁇ -MSH only) and experimental group ( ⁇ -MSH, and compound treated group) was calculated as a ratio to the melanin amount of the negative control group. .
- the compounds of Examples 1 and 2 exhibited an effect of reducing the amount of melanin when the concentration was 10 ⁇ M, and even more excellent compared to the compound of Comparative Example 3 (Arbutin) It showed a reduction effect.
- the dimer compound (Examples 1 and 2) of the present invention has a superior melanogenesis inhibition and melanosome degradation effect compared to monomeric compounds (Comparative Examples 1 and 2) and arbutin (Comparative Example 3). Confirmed. From this, it can be seen that the compounds of the present invention exhibit excellent inhibitory effects on the melanin biosynthesis signaling pathway induced by ⁇ -MSH.
- B16 melanoma cells 200 ⁇ L of B16 melanoma cells were dispensed in a 96-well plate to 3 X 10 3 cells/well, and then cultured at 37° C., 5% CO 2 in an incubator for 24 hours. B16 melanoma cells were treated with the compound under the same conditions as in Example 2 for 2 hours.
- ⁇ -MSH was treated at a concentration of 100 nM for 76 hours, the medium was removed, and the results of measuring absorbance at 550 nm using MTT assay are shown in FIGS. 5 to 10 .
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Abstract
The present invention relates to a skin whitening composition comprising a dihydrofuran-2(3H)-one derivative having melanogenesis inhibition and melanosome decomposition activity, an isomer thereof, or a pharmaceutically acceptable salt thereof. Specifically, the composition of the present invention inhibits melanogenesis and promotes melanosome degradation by means of action of the dihydrofuran-2(3H)-one derivative on a melanin biosynthesis signaling pathway induced by α-MSH (Melanocyte-stimulating hormone).
Description
본 발명은 멜라닌 생성 억제 활성을 갖는 디하이드로퓨란-2(3H)-온 이량체(dimer), 또는 이의 약학적으로 허용가능한 염을 포함하는 피부 미백용 조성물에 관한 것이다. 구체적으로, 본 발명의 화합물은 α-MSH (Melanocyte-stimulating hormone)에 의해 유도된 멜라닌 생합성 신호전달 경로에 작용하여 멜라닌 생성 과다 침착 질환을 예방 또는 치료하는 우수한 효과를 갖는다.The present invention relates to a skin whitening composition comprising a dihydrofuran-2(3H)-one dimer having melanogenesis inhibitory activity, or a pharmaceutically acceptable salt thereof. Specifically, the compound of the present invention acts on the melanin biosynthesis signaling pathway induced by α-MSH (Melanocyte-stimulating hormone), and has an excellent effect of preventing or treating diseases of melanogenesis hyper-deposition.
멜라닌 (melanin)은 동물, 식물, 미생물 등에서 발견되는 검은 색소로 생육이나 발달에 필수적이진 않지만, 환경에 대한 생존력과 경쟁력을 높여주는 물질이다. 멜라닌은 생물체에서 발견되는 색소 중에서도 안정성이 있는 색소이고, 거의 모든 용매에 용해되지 않으며, 멜라닌 색소 합성 (melanogenesis) 과정은 특별히 분화된 세포인 멜라노사이트 (melanocytes)의 소기관인 멜라노좀 (melanosome)에서 일어나는 것으로 알려져 있다. 즉, 피부색은 멜라닌의 함량, 분포 등에 따라 결정되며 멜라노사이트 (melanocyte) 내에서 생성된 후 세포 외부로 방출되는 멜라노좀의 수와 분포에 연관되어 있다.Melanin is a black pigment found in animals, plants, and microorganisms that is not essential for growth or development, but it is a substance that increases viability and competitiveness in the environment. Melanin is a stable pigment among the pigments found in living organisms, and is insoluble in almost all solvents, and the process of melanogenesis takes place in melanosomes, which are organelles of melanocytes, which are specially differentiated cells. it is known That is, skin color is determined according to the content and distribution of melanin, and is related to the number and distribution of melanosomes that are generated in melanocytes and released to the outside of cells.
멜라닌은 피부에 존재하여 자외선 등으로부터 신체를 보호하는 중요한 기능을 하지만 멜라닌이 과다 생성되는 경우 색소침착 및 피부노화를 촉진하고 기미, 주근깨 등 피부색 침착 (hyperpigmentation) 및 흑색종 (melanomas) 등을 유발하는 중요 요인으로 알려져 있다.Melanin exists in the skin and plays an important role in protecting the body from UV rays, but when melanin is excessively produced, it promotes pigmentation and skin aging, and causes hyperpigmentation such as spots and freckles and melanoma. known to be an important factor.
사람의 피부색은 멜라닌 색소를 만드는 멜라노사이트 (melanocyte)의 활동성, 혈관의 분포, 피부의 두께, 및 카로티노이드, 빌리루빈 등 인체 내외의 색소 함유 유무와 같은 여러 요인들에 의해 결정된다.A person's skin color is determined by several factors, such as the activity of melanocytes that make melanin pigment, the distribution of blood vessels, the thickness of the skin, and the presence or absence of internal and external pigments such as carotenoids and bilirubin.
특히 멜라노사이트에서 타이로시나제 (tyrosinase) 등의 여러 효소가 작용하여 생성되는 멜라닌이라는 흑색 색소가 가장 중요한 요인이다. 멜라닌 색소의 형성에는 유전적 요인, 호르몬 분비, 스트레스 등과 관련된 생리적 요인 및 자외선 조사 등과 같은 환경적 요인이 영향을 미친다.In particular, the most important factor is the black pigment called melanin, which is produced by the action of several enzymes such as tyrosinase in melanocytes. The formation of melanin is influenced by genetic factors, hormone secretion, physiological factors related to stress, etc., and environmental factors such as UV irradiation.
멜라닌 색소 (melanin pigment)는 멜라닌 세포에서 생성된 후 각질형성세포로 이동하여 자외선 조사 (UV radiation)와 같이 해로운 환경적 자극으로부터 피부를 보호한다. 태양의 자외선은 파장에 따라 320 - 400nm 영역의 UVA; 280 - 320nm 영역의 UVB; 및 200 - 280nm 영역의 UVC로 분류할 수 있으며 그 중 UVB는 멜라닌의 생성을 유발한다.Melanin pigment is produced in melanocytes and then moves to keratinocytes to protect the skin from harmful environmental stimuli such as UV radiation. Ultraviolet rays from the sun are UVA in the 320 - 400nm region, depending on the wavelength; UVB in the region of 280 - 320 nm; And it can be classified into UVC of 200 - 280nm region, of which UVB causes the production of melanin.
UVB는 각질형성세포와 멜라닌 세포의 상호작용을 통하는 복잡한 공정을 통하여 멜라닌의 생성을 유도하거나, cAMP 증가에 의한 CREB (cAMP-response element-binding protein)의 Ser133의 인산화를 통해 멜라닌 생성의 주 조절자인 MITF (Microphthalmia-associated transcription factor)의 발현을 증가시키는 방법 등을 통해 멜라닌의 생성을 증가시킨다.UVB induces melanin production through a complex process through the interaction between keratinocytes and melanocytes, or is a major regulator of melanin production through phosphorylation of Ser133 of CREB (cAMP-response element-binding protein) by increasing cAMP. It increases the production of melanin through a method of increasing the expression of MITF (Microphthalmia-associated transcription factor).
UVB에 노출되면 각질형성세포는 측분비인자 (paracrine factor)를 분비하여 멜라닌세포의 멜라닌 생성을 촉진하는데 분비되는 측분비인자들 중 멜라닌 생성을 자극하는 가장 중요한 작용물질 (agonist)은 α-멜라닌세포자극호르몬 (α-melanocyte stimulating hormone, α-MSH)이다.When exposed to UVB, keratinocytes secrete paracrine factor to promote melanogenesis in melanocytes. Among the paracrine factors secreted, the most important agonist to stimulate melanogenesis is α-melanocytes. It is α-melanocyte stimulating hormone (α-MSH).
기존 피부 미백제는 멜라닌 과다 생성을 억제하는 기전을 통해 미백 효능을 나타내는 것으로서, 주로 자외선 조사 등의 외부적 자극에 따른 멜라닌 합성 억제에 의존하여 알부틴 (Arbutin), 코직산 (Kojic acid), 비타민 C 등이 사용되어 왔다.Existing skin whitening agents show whitening efficacy through a mechanism of suppressing excessive melanin production. Arbutin, Kojic acid, vitamin C, etc. has been used
그러나 이러한 미백제는 정신적 스트레스 또는 수면부족, 피로와 같은 내부적 요인으로 인하여 신경전달물질의 분비를 통해 멜라닌 합성이 증가하는 경우에 대해서는 큰 효과를 나타내지 못하며, 이들 억제제들은 활성이 약하거나 색소 세포를 변성시켜 세포 본래의 기능을 손상시키는 등의 부작용을 나타내는 문제가 있다.However, these whitening agents do not show a great effect when the melanin synthesis is increased through the secretion of neurotransmitters due to internal factors such as mental stress, lack of sleep, or fatigue. There is a problem of showing side effects such as impairing the original function of cells.
또한, 멜라닌 생성을 억제하기 위한 목적으로 비타민 C 및 그 유도체 등이 사용되어 왔으나, 이들 역시 타이로시나제 억제 활성이 낮다는 문제가 있다.In addition, vitamin C and its derivatives have been used for the purpose of inhibiting melanin production, but these also have a problem in that they have low tyrosinase inhibitory activity.
따라서, 세포독성이 낮고, 소량에 의해서도 타이로시나제 활성 및 멜라닌 생성을 억제할 수 있는 새로운 억제제의 개발이 시급한 실정이다.Therefore, there is an urgent need to develop a new inhibitor that has low cytotoxicity and can inhibit tyrosinase activity and melanin production even by a small amount.
이에, 본 발명자들은 상술한 종래의 멜라닌 생성 억제제보다 우수한 멜라노좀 분해 촉진 효능을 갖는 물질을 개발하기 위해 노력하던 중, 디하이드로퓨란-2(3H)-온 이량체가 α-멜라닌세포자극호르몬 (α-melanocyte stimulating hormone, α-MSH)에 의해 유도된 멜라노좀의 분해를 촉진하는데 우수한 효과를 나타내는 것을 확인하였다.Therefore, while the present inventors were trying to develop a material having a superior melanosome degradation promoting effect than the conventional melanogenesis inhibitor described above, dihydrofuran-2(3H)-one dimer is α-melanocyte stimulating hormone (α -Melanocyte stimulating hormone, α-MSH) was confirmed to exhibit an excellent effect in promoting the decomposition of melanosomes.
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
(특허문헌 1) 한국 등록특허 제1890058호(Patent Document 1) Korean Patent No. 1890058
본 발명자들은 멜라닌 생성을 억제하고 멜라노좀 분해를 촉진하는 효과를 갖는 물질을 개발하기 위하여 연구한 결과, 디하이드로퓨란-2(3H)-온 이량체가 우수한 효과를 갖는 것을 확인하여 본 발명을 완성하였다.The present inventors have completed the present invention by confirming that the dihydrofuran-2(3H)-one dimer has an excellent effect as a result of research to develop a material having the effect of inhibiting melanogenesis and promoting the decomposition of melanosomes .
본 발명은 멜라닌 생성을 억제하고 멜라노좀 분해를 촉진하는 디하이드로퓨란-2(3H)-온 이량체, 또는 이의 약학적으로 허용가능한 염을 활성 성분으로 포함하는 피부미백용 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a composition for skin whitening comprising, as an active ingredient, a dihydrofuran-2(3H)-one dimer, or a pharmaceutically acceptable salt thereof, which inhibits melanogenesis and promotes melanosome decomposition. do it with
또한, 본 발명은 멜라닌 생성을 억제하고 멜라노좀 분해를 촉진하는 효과를 갖는 디하이드로퓨란-2(3H)-온 이량체의 신규한 화합물을 제공한다.In addition, the present invention provides a novel compound of dihydrofuran-2(3H)-one dimer having the effect of inhibiting melanogenesis and promoting melanosome degradation.
본 발명은 하기 화학식 I의 디하이드로퓨란-2(3H)-온의 이량체 (dimer), 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물을 제공한다:The present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 I][Formula I]
상기 식에서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, 히드록시, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;
Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;
n은 1 내지 20이다.n is 1 to 20.
또한, 본 발명은 하기 화학식 II의 디하이드로퓨란-2(3H)-온의 이량체 (dimer), 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물을 제공한다:In addition, the present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula II, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 II][Formula II]
상기 식에서, 
은 단일결합 또는 이중결합을 나타내고; 및In the above formula, represents a single bond or a double bond; and
n은 1 내지 20의 정수이다.n is an integer from 1 to 20;
또한, 본 발명은 하기 화학식 III의 디하이드로퓨란-2(3H)-온의 이량체 (dimer), 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물을 제공한다:In addition, the present invention provides a composition comprising a dimer of dihydrofuran-2(3H)-one of formula III, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 III][Formula III]
상기 식에서, n은 1 내지 20의 정수이다.In the above formula, n is an integer from 1 to 20.
본 발명은 본 발명의 화합물을 포함하는 피부미백용 화장료 조성물, 또는 건강기능식품을 제공한다. 또한, 본 발명은 본 발명의 화합물을 포함하는 멜라닌 색소 과다침착 질환의 치료 또는 예방용 약학 조성물을 제공한다.The present invention provides a cosmetic composition for skin whitening, or a health functional food, comprising the compound of the present invention. In addition, the present invention provides a pharmaceutical composition for the treatment or prevention of melanin hyperpigmentation disease comprising the compound of the present invention.
본 발명은 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염의 신규한 화합물을 제공한다.The present invention provides a novel compound of a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
상기 식에서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, C1-C6 알콕시, 시아노, 또는 -ORa이고;R2 and R4are each independently hydrogen, COne-C6 alkyl, C2-C6 alkenyl, C2-C6 Alkynyl, Halo, COne-C6 Alkoxy, cyano, or -ORaego;
Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;
n은 1 내지 20이다.n is 1 to 20.
또한, 본 발명은 하기 화학식 II의 디하이드로퓨란-2(3H)-온의 이량체 (dimer), 이의 이성질체, 또는 이의 약학적으로 허용가능한 염의 신규한 화합물을 제공한다. In addition, the present invention provides a novel compound of a dimer, an isomer thereof, or a pharmaceutically acceptable salt thereof of dihydrofuran-2(3H)-one of the following formula (II).
[화학식 II][Formula II]
상기 식에서, 
은 단일결합 또는 이중결합을 나타내고; 및In the above formula, represents a single bond or a double bond; and
n은 1 내지 20의 정수이다.n is an integer from 1 to 20;
본 발명의 디하이드로퓨란-2(3H)-온의 이량체 (dimer)는 세포 독성을 갖지 않고, 멜라닌 생성을 억제하므로, 피부 미백용 또는 멜라닌 색소 과다침착 질환의 개선, 예방 또는 치료용으로 유용하게 사용될 수 있다. 특히, 본 디하이드로퓨란-2(3H)-온의 이량체 (dimer)는 일량체 (monomer)와 비교하여 월등하게 우수한 효과를 갖는다.The dimer of dihydrofuran-2(3H)-one of the present invention does not have cytotoxicity and inhibits melanin production, so it is useful for skin whitening or improving, preventing or treating diseases of melanin hyperpigmentation. can be used In particular, the dimer of the present dihydrofuran-2(3H)-one has a significantly superior effect compared to that of the monomer.
도 1은 화학식 1의 화합물 (WJC-2020-67)의 처리 농도에 따른 멜라닌 생성 억제효과를 나타낸다.1 shows the melanin production inhibitory effect according to the treatment concentration of the compound of Formula 1 (WJC-2020-67).
도 2는 화학식 2의 화합물 (WJC-2020-68)의 처리 농도에 따른 멜라닌 생성 억제효과를 나타낸다.Figure 2 shows the melanin production inhibitory effect according to the treatment concentration of the compound of Formula 2 (WJC-2020-68).
도 3은 화학식 5 내지 7의 화합물 (WJC-2020-69)의 처리 농도에 따른 멜라닌 생성 억제효과를 나타낸다.Figure 3 shows the melanin production inhibitory effect according to the treatment concentration of the compounds of Formulas 5 to 7 (WJC-2020-69).
도 4는 화학식 3 내지 5의 화합물 (WJC-2020-70)의 처리 농도에 따른 멜라닌 생성 억제효과를 나타낸다.Figure 4 shows the melanin production inhibitory effect according to the treatment concentration of the compounds of Formulas 3 to 5 (WJC-2020-70).
도 5는 알부틴 (Arbutin)의 처리 농도에 따른 멜라닌 생성 억제효과를 나타낸다.Figure 5 shows the melanin production inhibitory effect according to the treatment concentration of arbutin (Arbutin).
도 6은 화학식 1의 화합물 (WJC-2020-67)의 처리 농도에 따른 B16 melanoma (흑색종) 세포의 생존율(%)를 나타낸다.6 shows the survival rate (%) of B16 melanoma (melanoma) cells according to the treatment concentration of the compound of Formula 1 (WJC-2020-67).
도 7는 화학식 2의 화합물 (WJC-2020-68)의 처리 농도에 따른 B16 melanoma (흑색종) 세포의 생존율(%)를 나타낸다.7 shows the survival rate (%) of B16 melanoma (melanoma) cells according to the treatment concentration of the compound of Formula 2 (WJC-2020-68).
도 8은 화학식 5 내지 7의 화합물 (WJC-2020-69)의 처리 농도에 따른 B16 melanoma (흑색종) 세포의 생존율(%)를 나타낸다.8 shows the viability (%) of B16 melanoma (melanoma) cells according to the treatment concentration of the compounds of Formulas 5 to 7 (WJC-2020-69).
도 9는 화학식 3 내지 5의 화합물 (WJC-2020-70)의 처리 농도에 따른 B16 melanoma (흑색종) 세포의 생존율(%)를 나타낸다.9 shows the viability (%) of B16 melanoma (melanoma) cells according to the treatment concentration of the compounds of Formulas 3 to 5 (WJC-2020-70).
도 10는 알부틴 (Arbutin)의 처리 농도에 따른 B16 melanoma (흑색종) 세포의 생존율(%)를 나타낸다.Figure 10 shows the survival rate (%) of B16 melanoma (melanoma) cells according to the treatment concentration of arbutin (Arbutin).
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시태양 및 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 형태로 구현될 수 있으며 여기에서 설명하는 실시태양 및 실시예에 한정되지 않는다.Hereinafter, embodiments and examples of the present invention will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout this specification, when a part "includes" a component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명은 하기 화학식 I의 디하이드로퓨란-2(3H)-온의 이량체, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물에 관한 것이다.The present invention relates to a composition comprising a dimer, an isomer thereof, or a pharmaceutically acceptable salt thereof of dihydrofuran-2(3H)-one of the following formula (I).
[화학식 I][Formula I]
상기 식에서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, 히드록시, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;
Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;
n은 1 내지 20의 정수이다.n is an integer from 1 to 20;
일 실시태양에서, 본 발명은 In one embodiment, the present invention provides
상기 식에서, R1 및 R3은 각각 독립적으로 C1-C6 알킬이고;wherein R1 and R3 are each independently C 1 -C 6 alkyl;
R2 및 R4은 각각 독립적으로 수소 또는 히드록시이고;R 2 and R 4 are each independently hydrogen or hydroxy;
n은 1 내지 20의 정수인 조성물일 수 있다.n may be an integer from 1 to 20 in the composition.
상기 식에서, n은 바람직하게는 5 내지 15의 정수이고, 더욱 바람직하게는 8 내지 12의 정수일 수 있다.In the above formula, n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
본 발명은 하기 화학식 II로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물이다.The present invention is a composition comprising a compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 II][Formula II]
상기 식에서, 
은 단일결합 또는 이중결합을 나타내고;In the above formula, represents a single bond or a double bond;
n은 1 내지 20의 정수인 조성물일 수 있다.n may be an integer from 1 to 20 in the composition.
상기 식에서, n은 바람직하게는 5 내지 15의 정수이고, 더욱 바람직하게는 8 내지 12의 정수일 수 있다.In the above formula, n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
본 발명은 하기 화학식 III으로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물이다.The present invention is a composition comprising a compound represented by the following formula (III), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 III][Formula III]
상기 식에서, n은 1 내지 20의 정수이고, 바람직하게는 5 내지 15의 정수이고, 더욱 바람직하게는 8 내지 12의 정수일 수 있다.In the above formula, n is an integer of 1 to 20, preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
본 발명은 본 발명의 화합물을 포함하는 피부 미백용 화장료 조성물, 또는 건강기능식품일 수 있다. 또한, 본 발명은 본 발명의 화합물을 포함하는 멜라닌 색소 과다침착 질환의 치료 또는 예방용 약학 조성물일 수 있다.The present invention may be a cosmetic composition for skin whitening comprising the compound of the present invention, or a health functional food. In addition, the present invention may be a pharmaceutical composition for the treatment or prevention of melanin hyperpigmentation disease comprising the compound of the present invention.
본 발명의 화합물은 멜라닌 생성을 억제하거나 멜라노좀 분해를 촉진하며, 예를 들어 α-MSH에 의해 유도된 멜라닌 생합성 신호전달 경로에 작용하는 것일 수 있다.The compound of the present invention inhibits melanogenesis or promotes melanosome degradation, and may be, for example, acting on a melanin biosynthesis signaling pathway induced by α-MSH.
본 발명의 "멜라닌 색소 과다침착 질환"은 기미, 주근깨, 반점, 일광흑자, 약물성 색소침착, 염증성 색소침착, 노인성 색소침착 또는 임신성 색소침착일 수 있으나, 이에 제한되는 것은 아니다.The "melanin hyperpigmentation disease" of the present invention may be melasma, freckles, spots, solar surplus, drug pigmentation, inflammatory pigmentation, senile pigmentation, or gestational pigmentation, but is not limited thereto.
또한, 본 발명의 조성물은 미백 효능을 갖는 히드로퀴논 (hydroquinone, Benzene-1,4-diol), 닥나무추출물, 알부틴, 에틸아스코빌에텔, 유용성감초추출물, 아스코빌글루코사이드, 마그네슘아스코빌포스페이트, 나이아신아마이드, 알파-비사보롤 또는 아스코빌테트라이소팔미테이트 등을 추가로 포함할 수 있다.In addition, the composition of the present invention has a whitening effect, hydroquinone (hydroquinone, Benzene-1,4-diol), mulberry extract, arbutin, ethyl ascorbyl ether, oil-soluble licorice extract, ascorbyl glucoside, magnesium ascorbyl phosphate, niacinamide, Alpha-bisabolol or ascorbyltetraisopalmitate may be further included.
본 발명은 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염에 관한 것이다.The present invention relates to a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
상기 식에서, In the above formula,
R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, C 1 -C 6 alkoxy, cyano, or —OR a ;
Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;
Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;
n은 1 내지 20의 정수인 조성물일 수 있다.n may be an integer from 1 to 20 in the composition.
상기 식에서, n은 바람직하게는 5 내지 15의 정수이고, 더욱 바람직하게는 8 내지 12의 정수일 수 있다.In the above formula, n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
또한, 본 발명은 하기 화학식 II로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염에 관한 것이다.In addition, the present invention relates to a compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 II][Formula II]
상기 식에서, 
은 단일결합 또는 이중결합을 나타내고; 및In the above formula, represents a single bond or a double bond; and
n은 1 내지 20의 정수인 조성물일 수 있다.n may be an integer from 1 to 20 in the composition.
상기 식에서, n은 바람직하게는 5 내지 15의 정수이고, 더욱 바람직하게는 8 내지 12의 정수일 수 있다.In the above formula, n is preferably an integer of 5 to 15, and more preferably an integer of 8 to 12.
본 명세서에서 "알킬"은 1차, 2차, 3차 또는 4차 탄소 원자를 갖는 탄화수소이며, 직쇄형, 분지형 또는 환형, 또는 이들의 조합일 수 있는 포화 지방족 기를 포함한다. 예를 들어, 알킬기는 1 내지 20개의 탄소 원자 (즉, C1-C20 알킬), 1 내지 10개의 탄소 원자 (즉, C1-C10 알킬), 또는 1 내지 6개의 탄소 원자 (즉, C1-C6 알킬)를 가질 수 있다. 달리 정의되지 않는 한, 바람직한 실시양태에서, 알킬은 C1-C6 알킬을 지칭한다. 적합한 알킬기의 예로는 메틸 (Me, -CH3), 에틸 (Et, -CH2CH3), 1-프로필 (n-Pr, n-프로필, -CH2CH2CH3), 2-프로필 (i-Pr, i-프로필, -CH(CH3)2), 1-부틸 (n-Bu, n-부틸, -CH2CH2CH2CH3), 2-메틸-1-프로필 (i-Bu, i-부틸, -CH2CH(CH3)2), 2-부틸 (s-Bu, s-부틸, -CH(CH3)CH2CH3), 2-메틸-2-프로필 (t-Bu, t-부틸, -C(CH3)3), 1-펜틸 (n-펜틸, -CH2CH2CH2CH2CH3), 2-펜틸 (-CH(CH3)CH2CH2CH3), 3-펜틸 (-CH(CH2CH3)2), 2-메틸-2-부틸 (-C(CH3)2CH2CH3), 3-메틸-2-부틸 (-CH(CH3)CH(CH3)2), 3-메틸-1-부틸 (-CH2CH2CH(CH3)2), 2-메틸-1-부틸 (-CH2CH(CH3)CH2CH3), 1-헥실 (-CH2CH2CH2CH2CH2CH3), 2-헥실 (-CH(CH3)CH2CH2CH2CH3), 3-헥실 (-CH(CH2CH3)(CH2CH2CH3)), 2-메틸-2-펜틸 (-C(CH3)2CH2CH2CH3), 3-메틸-2-펜틸 (-CH(CH3)CH(CH3)CH2CH3), 4-메틸-2-펜틸 (-CH(CH3)CH2CH(CH3)2), 3-메틸-3-펜틸 (-C(CH3)(CH2CH3)2), 2-메틸-3-펜틸 (-CH(CH2CH3)CH(CH3)2), 2,3-디메틸-2-부틸 (-C(CH3)2CH(CH3)2), 3,3-디메틸-2-부틸 (-CH(CH3)C(CH3)3), 및 옥틸 (-(CH2)7CH3)을 들 수 있으나 이에 제한되는 것은 아니다.As used herein, "alkyl" is a hydrocarbon having primary, secondary, tertiary or quaternary carbon atoms and includes saturated aliphatic groups which may be straight-chain, branched or cyclic, or combinations thereof. For example, an alkyl group has 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C 1 -C 6 alkyl. Examples of suitable alkyl groups include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl ( i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i- Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t -Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (- CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (- CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH (CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C( CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH) 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), and octyl (-(CH 2 ) 7 CH 3 ). However, the present invention is not limited thereto.
더욱이, 명세서, 실시예 및 청구항 전반에 걸쳐 사용되는 용어 "알킬"은 비치환된 및 치환된 알킬기 모두를 포함하는 것으로 의도되며, 이들 중 후자는 트리플루오로메틸 및 2,2,2-트리플루오로에틸과 같은 할로알킬기 등을 포함하는, 탄화수소 골격의 1개 이상의 탄소 상의 수소를 대체하는 치환기를 갖는 알킬 잔기를 지칭한다. Moreover, the term “alkyl” as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-trifluoromethyl. Refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as roethyl, and the like.
용어 "Cx-y" 또는 "Cx-Cy"는 알킬, 알케닐, 알키닐 또는 알콕시와 같은 화학적 잔기와 함께 사용되는 경우, 사슬 내에 x 내지 y개의 탄소를 함유하는 기를 포함하는 것으로 여겨진다. C0알킬은 기가 말단 위치에 있는 경우에는 수소, 내부에 있는 경우에는 결합을 나타낸다. 예를 들어, C1-C6 알킬기는 사슬 내에 1 내지 6개의 탄소 원자를 함유한다.The term "C xy " or "C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, alkynyl or alkoxy is intended to include groups containing from x to y carbons in the chain. C 0 alkyl represents hydrogen when the group is in a terminal position and a bond when internal to the group. For example, a C 1 -C 6 alkyl group contains 1 to 6 carbon atoms in the chain.
"알콕시"는 상기 정의된 바와 같은 알킬기가 산소 원자를 통해 모 화합물에 부착된 것인 화학식 -O-알킬을 갖는 기를 지칭한다. 알콕시기의 알킬 잔기는 예를 들어, 1 내지 20개의 탄소 원자 (즉, C1-C20 알콕시), 1 내지 12개의 탄소 원자 (즉, C1-C12 알콕시), 1 내지 10개의 탄소 원자 (즉, C1-C10 알콕시), 또는 1 내지 6개의 탄소 원자 (즉, C1-C6 알콕시)를 가질 수 있다. 적합한 알콕시기의 예로는 메톡시 (-O-CH3 또는 -OMe), 에톡시 (-OCH2CH3 또는 -OEt), 및 t-부톡시 (-OC(CH3)3 또는 -O-tBu)를 들 수 있으나 이에 제한되는 것은 아니다.“Alkoxy” refers to a group having the formula —O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom. The alkyl moiety of the alkoxy group may be, for example, 1 to 20 carbon atoms (ie C 1 -C 20 alkoxy), 1 to 12 carbon atoms (ie C 1 -C 12 alkoxy), 1 to 10 carbon atoms. (ie, C 1 -C 10 alkoxy), or 1 to 6 carbon atoms (ie, C 1 -C 6 alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), and t-butoxy (-OC(CH 3 ) 3 or -O-tBu ), but is not limited thereto.
"알케닐"은 1차, 2차, 3차 또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 불포화 영역, 즉, 탄소-탄소 sp2 이중 결합을 갖는 탄화수소이다. 예를 들어, 알케닐기는 2 내지 20개의 탄소 원자 (즉, C2-C20 알케닐), 2 내지 12개의 탄소 원자 (즉, C2-C12 알케닐), 2 내지 10개의 탄소 원자 (즉, C2-C10 알케닐), 또는 2 내지 6개의 탄소 원자 (즉, C2-C6 알케닐)를 가질 수 있다. 적합한 알케닐 기의 예로는 비닐 (-CH=CH2), 알릴 (-CH2CH=CH2), 시클로펜테닐 (-C5H7), 및 5-헥세닐 (-CH2CH2CH2CH2CH=CH2)을 들 수 있으나 이에 제한되는 것은 아니다."Alkenyl" has primary, secondary, tertiary or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon-carbon sp It is a hydrocarbon with two double bonds. For example, an alkenyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkenyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ), and 5-hexenyl (-CH 2 CH 2 CH). 2 CH 2 CH=CH 2 ), but is not limited thereto.
"알키닐"은 1차, 2차, 3차 또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 탄소-탄소 sp 삼중 결합을 갖는 탄화수소이다. 예를 들어, 알키닐 기는 2 내지 20개의 탄소 원자 (즉, C2-C20 알키닐), 2 내지 12개의 탄소 원자 (즉, C2-C12 알키닐), 2 내지 10개의 탄소 원자 (즉, C2-C10 알키닐), 또는 2 내지 6개의 탄소 원자 (즉, C2-C6 알키닐)를 가질 수 있다. 적합한 알키닐 기의 예로는 아세틸레닉 (-C≡CH) 및 프로파르길 (-CH2C≡CH)을 들 수 있으나 이에 제한되는 것은 아니다."Alkynyl" is a hydrocarbon having primary, secondary, tertiary or quaternary carbon atoms, including straight-chain, branched and cyclic groups, or combinations thereof, and having at least one carbon-carbon sp triple bond. am. For example, an alkynyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkynyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH 2 C≡CH).
본 명세서에서 사용되는 용어 "할로"는 클로로, 플루오로, 브로모, 및 요오도를 포함한다.As used herein, the term “halo” includes chloro, fluoro, bromo, and iodo.
본 명세서에서 "이성질체"는 부분입체 이성질체와 거울상 이성질체를 포함하는 의미이다.As used herein, "isomer" is meant to include diastereomers and enantiomers.
본 명세서에서 "약학적으로 허용 가능한 염"은 약학적으로 허용 가능하고 모 화합물 (parent compound)의 바람직한 약리 활성을 갖는 본 발명의 일측면에 따른 염을 의미한다. 또한 본원에서 약학적으로 허용 가능한 염은 약학 조성물뿐 아니라, 화장료 조성물 또는 식품 조성물에 사용될 수 있는 모든 염을 지칭하는 것으로 의도된다. 상기 염으로는 약학적으로 허용되는 것이면 특별히 한정되지 않으며, 예를 들어 염산, 황산, 질산, 인산, 불화수소산, 브롬화수소산, 포름산 아세트산, 타르타르산, 젖산, 시트르산, 푸마르산, 말레산, 숙신산, 메탄술폰산, 벤젠술폰산, 톨루엔술폰산, 나프탈렌술폰산 등을 사용할 수 있다.As used herein, "pharmaceutically acceptable salt" refers to a salt according to an aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In addition, pharmaceutically acceptable salts herein are intended to refer to all salts that can be used in pharmaceutical compositions as well as cosmetic compositions or food compositions. The salt is not particularly limited as long as it is pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used.
본 발명의 화장료 조성물은, 예를 들면 용액, 겔, 고체 또는 반죽 무수 생성물, 수상에 유상을 분산시켜 얻은 에멀젼, 현탁액, 마이크로에멀젼, 마이크로캡슐, 미세과립구 또는 이온형 (리포좀), 비이온형의 소낭 분산제의 형태, 크림, 스킨, 로션, 파우더, 연고, 스프레이 또는 콘실 스틱의 형태로 제공될 수 있다. 또한, 포말 (foam)의 형태 또는 압축된 추진제를 더 함유한 에어로졸 조성물의 형태로도 제조될 수 있다.The cosmetic composition of the present invention is, for example, a solution, a gel, a solid or kneaded anhydrous product, an emulsion obtained by dispersing an oil phase in an aqueous phase, a suspension, a microemulsion, a microcapsule, microgranule or ionic (liposome), non-ionic type. It may be provided in the form of a vesicular dispersant, cream, skin, lotion, powder, ointment, spray or in the form of a cone stick. In addition, it may be prepared in the form of a foam or an aerosol composition further containing a compressed propellant.
또한, 상기 화장료 조성물은 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제 (foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온봉쇄제 및 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 화장품에 통상적으로 사용되는 임의의 다른 성분과 같은 화장품 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다.In addition, the cosmetic composition includes a fatty substance, an organic solvent, a solubilizer, a thickening agent and a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, an ionic or non-ionic type. Cosmetics such as emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other ingredients commonly used in cosmetics. It may contain adjuvants commonly used in the field.
또다른 실시 태양에서, 본 발명의 조성물은 식품 조성물, 예를 들어, 건강기능식품일 수 있다. 상기 "건강기능식품"은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In another embodiment, the composition of the present invention may be a food composition, for example, a health functional food. The "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body, and "functionality" means a health purpose such as regulating nutrients or physiological action with respect to the structure and function of the human body. It means to consume for the purpose of obtaining useful effects.
상기 식품 조성물의 제형은 특별히 한정되지 않으나, 예를 들어, 정제, 과립제, 분말제, 드링크제와 같은 액제, 캐러멜, 겔, 바 등으로 제형화될 수 있다. 각 제형의 식품 조성물은 유효 성분 이외에 해당 분야에서 통상적으로 사용되는 성분들을 제형 또는 사용 목적에 따라 당업자가 어려움 없이 적의 선정하여 배합할 수 있다.The formulation of the food composition is not particularly limited, but, for example, may be formulated as tablets, granules, powders, liquids such as drinks, caramel, gels, bars, and the like. In addition to the active ingredient, the food composition of each dosage form can be formulated by a person skilled in the art without difficulty according to the dosage form or purpose of use, which is commonly used in the field.
본 발명의 약학 조성물은 목적하는 방법에 따라 비경구투여 또는 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 또한 상기 조성물의 치료적으로 유효한 양은 투여방법, 목적부위, 환자의 상태에 따라 달라질 수 있으며, 인체에 사용시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다.The pharmaceutical composition of the present invention may be administered parenterally or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, etc. Its scope is diverse. In addition, the therapeutically effective amount of the composition may vary depending on the method of administration, the target site, and the condition of the patient.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원 발명의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
본 발명의 실시예에서 사용된 화학식 1 내지 7의 화합물은 다음과 같다.The compounds of Formulas 1 to 7 used in Examples of the present invention are as follows.
| 화학식chemical formula | |
| 1One |
 |
| 22 |
 |
| 33 |
 |
| 44 |
 |
| 55 |
 |
| 66 |
 |
| 77 |
 |
본 발명의 화합물은 하기 반응식 1 내지 3과 같은 제조방법으로 제조할 수 있다.The compound of the present invention can be prepared by a preparation method as shown in Schemes 1 to 3 below.
[반응식 1][Scheme 1]
(n은 1 내지 20의 정수임)(n is an integer from 1 to 20)
[반응식 2][Scheme 2]
(시약 및 조건 : (Reagents and conditions:
a : LDA, HMPA, THF, -78℃ to -30℃, overnight;a: LDA, HMPA, THF, -78°C to -30°C, overnight;
b : MsCl, Et3N, CH2Cl2, 0℃, 3h, 그 후, Et3N, 50℃, overnight)b: MsCl, Et 3 N, CH 2 Cl 2 , 0° C., 3 h, after that, Et 3 N, 50° C., overnight)
[반응식 3][Scheme 3]
(시약 및 조건 :(Reagents and conditions:
a : LDA, HMPA, THF, -78℃ to -30℃, overnight;a: LDA, HMPA, THF, -78°C to -30°C, overnight;
b : 2nd generation Grubb's catalyst, 톨루엔, -10℃, overnight;b: 2nd generation Grubb's catalyst, toluene, -10°C, overnight;
c : 10% Pd/C, H2, MeOH, rt, 5h;c: 10% Pd/C, H 2 , MeOH, rt, 5h;
d : MsCl, Et3N, CH2Cl2, 0℃, 3h, 그 후, Et3N, 50℃, overnight)d: MsCl, Et 3 N, CH 2 Cl 2 , 0° C., 3h, after that, Et 3 N, 50° C., overnight)
[시험예 1] [Test Example 1]
세포배양cell culture
B16 melanoma 세포를 0.25% 트립신 (trypsin) 용액으로 희석 처리한 후 세포를 분리하였다. 10% fetal bovine serum (FBS)과 1% 페니실린/스트렙토마이신(penicillin/streptomycin) (100U/ml)을 첨가한 Dulbecco's modified eagle's medium (DMEM) 배지에 분리된 세포를 넣고, 37℃, 5% CO2 incubator에 적응시켜 배양하였다.After diluting B16 melanoma cells with 0.25% trypsin solution, the cells were isolated. The separated cells were placed in Dulbecco's modified eagle's medium (DMEM) medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (100U/ml), 37°C, 5% CO 2 Adapted to the incubator and cultured.
시험예 1에서 배양된 세포를 가지고, 하기 표 2의 비교예 1, 2, 실시예 1, 2 및 알부틴을 대상으로 실험을 수행하였다.Using the cells cultured in Test Example 1, experiments were performed on Comparative Examples 1 and 2, Examples 1 and 2 and arbutin in Table 2 below.
| 화합물compound | |
| 실시예 1(WJC-2020-69)Example 1 (WJC-2020-69) |
화학식 5의 화합물 (15%) 화학식 6의 화합물 (35%) 화학식 7의 화합물 (50%)compound of formula 5 (15%) compound of formula 6 (35%) compound of formula 7 (50%) |
| 실시예 2(WJC-2020-70)Example 2 (WJC-2020-70) |
화학식 3의 화합물 (15%)화학식 4의 화합물 (35%) 화학식 5의 화합물 (50%)Compound of Formula 3 (15%) Compound of Formula 4 (35%) compound of formula 5 (50%) |
| 비교예 1(WOJ-2002-67)Comparative Example 1 (WOJ-2002-67) |
화학식 1의 화합물compound of |
| 비교예 2(WJC-2020-68)Comparative Example 2 (WJC-2020-68) |
화학식 2의 화합물compound of |
| 비교예 3Comparative Example 3 | 알부틴arbutin |
[시험예 2] [Test Example 2]
멜라닌 생성 억제 및 멜라노좀 분해 효과Inhibition of melanin production and decomposition of melanosomes
B16 melanoma 세포를 이용하여, 실시예 1-2, 및 비교예 1-3의 화합물의 멜라닌 생성 억제 및 멜라노좀 분해 효과를 확인하였다.Using B16 melanoma cells, the melanogenesis inhibition and melanosome degradation effects of the compounds of Examples 1-2 and Comparative Examples 1-3 were confirmed.
B16 melanoma 세포를 96 well plate에 3 X 103 cells/well이 되도록 200 μL 분주한 후 37℃, 5% CO2 incubator에서 24시간 배양하였다. B16 melanoma 세포를 각각 0, 1, 3, 10, 30 μM의 화합물로 2 시간 동안 처리하고, α-MSH (melanocyte-stimulating hormone) (100 nM)를 이용하여 72 시간 동안 자극하였다.200 μL of B16 melanoma cells were dispensed in a 96-well plate to 3 X 10 3 cells/well, and then cultured at 37° C., 5% CO 2 in an incubator for 24 hours. B16 melanoma cells were treated with compounds of 0, 1, 3, 10, and 30 μM, respectively, for 2 hours, and stimulated with α-MSH (melanocyte-stimulating hormone) (100 nM) for 72 hours.
이 후 405nm에서 흡광도를 측정하여 B16 melanoma 세포에서 배지로 방출된 멜라닌양을 평가하였다.After measuring the absorbance at 405 nm, the amount of melanin released from B16 melanoma cells into the medium was evaluated.
아무것도 처리하지 않은 음성대조군의 멜라닌 양을 1로 하여, 양성대조군 (α-MSH만 처리) 및 실험군 (α-MSH, 및 화합물 처리군)의 멜라닌 양을 음성대조군의 멜라닌 양에 대한 비율로 계산하였다.The amount of melanin in the negative control group that was not treated with anything was set to 1, and the melanin amount of the positive control (α-MSH only) and experimental group (α-MSH, and compound treated group) was calculated as a ratio to the melanin amount of the negative control group. .
도 1 및 도 2에 나타낸 바와 같이, 비교예 1의 화합물로 처리한 경우 양성대조군과 비교하여 멜라닌 양에 변화가 없었으며 (도 1), 비교예 2의 화합물를 처리한 경우 농도가 30 μM일 때 멜라닌 양의 감소 효과가 나타났다 (도 2).1 and 2, when treated with the compound of Comparative Example 1, there was no change in the amount of melanin compared to the positive control group (FIG. 1), when the compound of Comparative Example 2 was treated when the concentration was 30 μM The effect of reducing the amount of melanin was shown (Fig. 2).
반면, 도 3 내지 도 5에 나타낸 바와 같이, 실시예 1 및 2의 화합물은 농도가 10 μM일 때부터 멜라닌 양의 감소 효과가 나타나타고, 비교예 3의 화합물(Arbutin)과 비교하여도 더욱 우수한 감소효과를 나타내었다.On the other hand, as shown in FIGS. 3 to 5 , the compounds of Examples 1 and 2 exhibited an effect of reducing the amount of melanin when the concentration was 10 μM, and even more excellent compared to the compound of Comparative Example 3 (Arbutin) It showed a reduction effect.
따라서, 본 발명의 이량체 화합물 (실시예 1 및 2)은 일량체 화합물 (비교예 1 및 2) 및 알부틴 (비교예 3)과 비교하여 월등하게 우수한 멜라닌 생성 억제 및 멜라노좀 분해 효과를 갖는 것을 확인하였다. 이로부터 α-MSH에 의해 유도된 멜라닌 생합성 신호전달 경로에 본 발명의 화합물들이 우수한 억제 효과를 나타내는 것을 알 수 있다.Therefore, the dimer compound (Examples 1 and 2) of the present invention has a superior melanogenesis inhibition and melanosome degradation effect compared to monomeric compounds (Comparative Examples 1 and 2) and arbutin (Comparative Example 3). Confirmed. From this, it can be seen that the compounds of the present invention exhibit excellent inhibitory effects on the melanin biosynthesis signaling pathway induced by α-MSH.
또한, IC50 값을 측정한 결과를 하기 표 3에 나타내었다.In addition, the results of measuring IC50 values are shown in Table 3 below.
| IC50 값 (μM)IC50 value (μM) | |
| 실시예 1Example 1 | 12.312.3 |
| 실시예 2Example 2 | 14.214.2 |
| 비교예 2Comparative Example 2 | 2525 |
| 비교예 3 (알부틴)Comparative Example 3 (Arbutin) | 166.3166.3 |
또한, 상기 표에 나타낸 바와 같이, 본 발명의 이량체 화합물 (실시예 1 및 2)은 일량체 화합물 (비교예 2) 및 알부틴 (비교예 3)과 비교하여 월등하게 낮은 IC50값을 나타내는 것을 확인하였다.In addition, as shown in the table above, it was confirmed that the dimer compounds (Examples 1 and 2) of the present invention exhibit a significantly lower IC50 value compared to the monomeric compounds (Comparative Example 2) and Arbutin (Comparative Example 3). did.
[시험예 3] [Test Example 3]
세포 독성 분석Cytotoxicity assay
B16 melanoma 세포를 이용하여, 실시예 1 내지 2, 비교예 1 내지 3의 화합물의 세포 독성을 MTT assay를 통해 측정하였다.Using B16 melanoma cells, the cytotoxicity of the compounds of Examples 1 to 2 and Comparative Examples 1 to 3 was measured by MTT assay.
B16 melanoma 세포를 96 well plate에 3 X 103 cells/well이 되도록 200 μL 분주한 후 37℃, 5% CO2 incubator에서 24시간 배양하였다. B16 melanoma 세포에 실시예 2와 동일한 조건으로 상기 화합물을 2시간 동안 처리하였다.200 μL of B16 melanoma cells were dispensed in a 96-well plate to 3 X 10 3 cells/well, and then cultured at 37° C., 5% CO 2 in an incubator for 24 hours. B16 melanoma cells were treated with the compound under the same conditions as in Example 2 for 2 hours.
그 후 α-MSH를 100 nM 농도로 76시간 동안 처리한 후, 배지를 제거하고 MTT assay를 이용하여 550 nm에서 흡광도를 측정한 결과를 도 5 내지 도 10에 나타내었다.Thereafter, α-MSH was treated at a concentration of 100 nM for 76 hours, the medium was removed, and the results of measuring absorbance at 550 nm using MTT assay are shown in FIGS. 5 to 10 .
도 5 내지 10에 나타낸 바와 같이, 실시예 1 내지 2, 비교예 1 내지 3의 화합물을 처리한 실험군은 모두 10 μM 이하 농도에서, α-MSH 만을 처리한 대조군과 비교하여 동등한 수준의 세포 생존율을 나타내어 세포 독성이 없는 것을 확인하였다.5 to 10, the experimental groups treated with the compounds of Examples 1 to 2 and Comparative Examples 1 to 3 showed the same level of cell viability at a concentration of 10 μM or less, compared to the control group treated only with α-MSH. It was confirmed that there is no cytotoxicity.
Claims (14)
- 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 피부 미백용 화장료 조성물:A cosmetic composition for skin whitening comprising a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 I][Formula I]
상기 식에서, In the above formula,R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, 히드록시, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;은 단일결합 또는 이중결합을 나타내고; 및
represents a single bond or a double bond; andn은 1 내지 20의 정수이다.n is an integer from 1 to 20; - 제1항에 있어서,According to claim 1,R1 및 R3은 각각 독립적으로 C1-C6 알킬이고;R 1 and R 3 are each independently C 1 -C 6 alkyl;R2 및 R4은 각각 독립적으로 수소 또는 히드록시이고;R 2 and R 4 are each independently hydrogen or hydroxy;은 단일결합 또는 이중결합을 나타내고; 및
represents a single bond or a double bond; andn은 1 내지 20의 정수인 것을 특징으로 하는 피부 미백용 화장료 조성물.n is an integer from 1 to 20. A cosmetic composition for skin whitening. - 하기 화학식 II로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 피부 미백용 화장료 조성물:A cosmetic composition for skin whitening comprising a compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 II][Formula II]
상기 식에서,은 단일결합 또는 이중결합을 나타내고; 및In the above formula,
represents a single bond or a double bond; andn은 1 내지 20의 정수이다.n is an integer from 1 to 20; - 제3항에 있어서, n은 5 내지 15의 정수인 것을 특징으로 하는 피부 미백용 화장료 조성물.The cosmetic composition for skin whitening according to claim 3, wherein n is an integer of 5 to 15.
- 제3항에 있어서, n은 8 내지 12의 정수인 것을 특징으로 하는 피부 미백용 화장료 조성물.The cosmetic composition for skin whitening according to claim 3, wherein n is an integer of 8 to 12.
- 하기 화학식 III으로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 피부 미백용 화장료 조성물:A cosmetic composition for skin whitening comprising a compound represented by the following formula (III), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 III][Formula III]
상기 식에서, n은 1 내지 20의 정수이다.In the above formula, n is an integer from 1 to 20. - 제6항에 있어서, n은 5 내지 15의 정수인 것을 특징으로 하는 피부 미백용 화장료 조성물.The cosmetic composition for skin whitening according to claim 6, wherein n is an integer of 5 to 15.
- 제6항에 있어서, n은 8 내지 12의 정수인 것을 특징으로 하는 피부 미백용 화장료 조성물.The cosmetic composition for skin whitening according to claim 6, wherein n is an integer of 8 to 12.
- 제1항에 있어서, 상기 화합물은 멜라닌 합성을 억제하거나 멜라노좀의 분해를 촉진하는 것을 특징으로 하는 피부 미백용 화장료 조성물.The cosmetic composition for skin whitening according to claim 1, wherein the compound inhibits melanin synthesis or promotes the decomposition of melanosomes.
- 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 피부 미백용 건강기능식품:A health functional food for skin whitening comprising a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 I][Formula I]
상기 식에서, In the above formula,R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, 히드록시, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;은 단일결합 또는 이중결합을 형성하고; 및
forms a single bond or a double bond; andn은 1 내지 20의 정수이다.n is an integer from 1 to 20; - 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 멜라닌 색소 과다침착 질환의 치료 또는 예방용 약학 조성물:A pharmaceutical composition for the treatment or prevention of melanin hyperpigmentation disease comprising a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 I][Formula I]
상기 식에서, In the above formula,R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, 히드록시, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxy, C 1 -C 6 alkoxy, cyano, or —OR a ;Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;은 단일결합 또는 이중결합을 형성하고; 및
forms a single bond or a double bond; andn은 1 내지 20의 정수이다.n is an integer from 1 to 20; - 제11항에 있어서, 상기 멜라닌 색소 과다침착 질환은 기미, 주근깨, 반점, 일광흑자, 약물성 색소침착, 염증성 색소침착, 노인성 색소침착 및 임신성 색소침착으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는, 멜라닌 색소 과다침착 질환의 치료 또는 예방용 약학 조성물.12. The method of claim 11, wherein the melanin hyperpigmentation disease is melanin, characterized in that it is selected from the group consisting of melasma, freckles, spots, solar surplus, drug pigmentation, inflammatory pigmentation, senile pigmentation, and gestational pigmentation. A pharmaceutical composition for the treatment or prevention of hyperpigmentation disease.
- 하기 화학식 I로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 I][Formula I]
상기 식에서, In the above formula,R1 및 R3은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, 또는 C2-C6 알키닐이고;R 1 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;R2 및 R4은 각각 독립적으로 수소, C1-C6 알킬, C2-C6 알케닐, C2-C6 알키닐, 할로, C1-C6 알콕시, 시아노, 또는 -ORa이고;R 2 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, C 1 -C 6 alkoxy, cyano, or —OR a ;Ra는 -C(O)Rb 또는 C1-C6 알킬로 치환되거나 비치환된 Si이고;R a is Si unsubstituted or substituted with -C(O)R b or C 1 -C 6 alkyl;Rb는 수소 또는 C1-C6 알킬이고;R b is hydrogen or C 1 -C 6 alkyl;은 단일결합 또는 이중결합을 형성하고; 및
forms a single bond or a double bond; andn은 1 내지 20이다.n is 1 to 20. - 하기 화학식 II로 표시되는 화합물, 이의 이성질체, 또는 이의 약학적으로 허용 가능한 염:A compound represented by the following formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof:[화학식 II][Formula II]
상기 식에서, n은 1 내지 20의 정수이다.In the above formula, n is an integer from 1 to 20.
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| KR20090084624A (en) * | 2008-02-01 | 2009-08-05 | 마리 케이 인코포레이티드 | Methods of treating skin with aromatic skin-active ingredients |
| CN102491963A (en) * | 2011-11-23 | 2012-06-13 | 常州亚当生物技术有限公司 | Compound I and II, their application and preparation method in preparing medicines for preventing formation of melanins |
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| KR20090084624A (en) * | 2008-02-01 | 2009-08-05 | 마리 케이 인코포레이티드 | Methods of treating skin with aromatic skin-active ingredients |
| CN102491963A (en) * | 2011-11-23 | 2012-06-13 | 常州亚当生物技术有限公司 | Compound I and II, their application and preparation method in preparing medicines for preventing formation of melanins |
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| CASSADY JOHN M, ET AL: "Potential antitumor agents. Synthesis, reactivity, and cytotoxicity of .alpha.-methylene carbonyl compounds", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 21, no. 8, 1 January 1978 (1978-01-01), US , pages 815 - 819, XP002502138, ISSN: 0022-2623, DOI: 10.1021/jm00206a020 * |
| GHARPURE SANTOSH J., NANDA LAXMI NARAYAN, SHUKLA MANOJ KUMAR: "Donor–Acceptor Substituted Cyclopropane to Butanolide and Butenolide Natural Products: Enantiospecific First Total Synthesis of (+)-Hydroxyancepsenolide", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 16, no. 24, 19 December 2014 (2014-12-19), US , pages 6424 - 6427, XP055920945, ISSN: 1523-7060, DOI: 10.1021/ol503246k * |
| WANG HUI-MIN, CHEN CHUNG-YI, WEN ZHI-HONG: "Identifying melanogenesis inhibitors from Cinnamomum subavenium with in vitro and in vivo screening systems by targeting the human tyrosinase : Targeting the human tyrosinase", EXPERIMENTAL DERMATOLOGY, BLACKWELL MUNSGAARD, COPENHAGEN; DK, vol. 20, no. 3, 5 November 2010 (2010-11-05), COPENHAGEN; DK , pages 242 - 248, XP055777764, ISSN: 0906-6705, DOI: 10.1111/j.1600-0625.2010.01161.x * |
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