Classifications

• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
  • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • 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
• • 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
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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 whitening agent and a skin external preparation, and particularly, to an active ingredient thereof.
• Pigmentation in the skin such as pigmented spots and freckles are resulted from hyperpigmentation of melanin in the epidermis.
• the hyperpigmentation is caused by acceleration of melanin production in epidermal melanocytes triggered by hormone abnormality or UV stimulation.
• a whitening agent has been mixed into a skin external preparation with an aim to prevent and improve such abnormal melanin pigmentation.
• ingredients that are mixed into a skin external preparation as a whitening agent there are vitamin C derivative, kojic acid, arbutin (4-hydroxyphenyl- ⁇ -D-glucopyranoside), Rucinol (4-n-butylresorcinol), ellagic acid, etc, which are known to have an inhibitory action on melanin production.
• Patent Literature 1 describes a thiazoline compound having a pest control effect on a harmful organism.
• Patent Literature 1 Japanese Unexamined Patent Publication No. H6-25197
• An object of the present invention is to provide a compound having an excellent inhibitory action on melanin production and being useful as a whitening agent, and a skin external preparation containing the compound.
• the present inventors conducted thorough research to solve the aforementioned problem. As a result, they have found that a specific thiazoline or oxazoline compound has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity, thereby completing the present invention.
• the whitening agent of the present invention comprises, as an active ingredient, a heterocyclic compound represented by the following formula (1) or a pharmacologically acceptable salt thereof:
• R 1 , R 2 , and R 2 ′ are each independently C 1-3 alkyl
• Y is S or O
• R 1 is an integer of 0 to 3, wherein when p is 2 to 3, R 1 may be the same or different.
• the present invention also provides the aforementioned whitening agent, wherein Y is S.
• the present invention also provides the whitening agent, wherein R 2 and R 2 ′ are methyl.
• the present invention also provides the whitening agent, wherein p is 1 or 2.
• the present invention also provides the whitening agent, wherein R 1 is substituted at the ortho position and/or the para position of the —NH— group.
• the present invention also provides the whitening agent, wherein the active ingredient inhibits melanin production.
• the present invention also provides a skin external preparation and a cosmetic comprising any of the aforementioned heterocyclic compounds or a pharmacologically acceptable salt thereof.
• the whitening agent of the present invention has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity; therefore, it can be suitably mixed into a skin external preparation as a whitening agent.
• the whitening agent of the present invention is represented by the following formula (1):
• R 1 , R 2 , and R 2 ′ are each independently C 1-3 alkyl.
• the “C 1-3 alkyl” is a linear, branched, or cyclic saturated hydrocarbon group having from 1 to 3 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group.
• Preferred alkyl includes methyl and ethyl, and particularly preferred alkyl is methyl.
• the 5-membered hetero ring containing Y is thiazoline (in the case where Y ⁇ S) or oxazoline (in the case where Y ⁇ O).
• R 1 is an integer of 0 to 3.
• R 1 may be the same or different.
• An example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein Y is S.
• Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein R 2 and R 2 are methyl.
• Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein p is 1 or 2.
• Another example of the preferred compound as an active ingredient of the whitening agent of the present invention is the compounds wherein R 1 is substituted at the ortho position and/or the para position of the —NH— group.
• the compounds of the formula (1) can be tautomers as shown below. In the present invention, such tautomers are also included in the compounds of the formula (1).
• the compound of the formula (1) can be synthesized by a known method or commercially available.
• an appropriate protecting group is preferably used to allow the reaction to proceed efficiently.
• the use of the protecting group can be carried out according to, for example, Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts.
• an isomer such as a conformational isomer, a geometric isomer, and an optical isomer
• a pure isomer or geometric isomer can be obtained by appropriately selecting a raw material and a reaction condition and performing a separation operation.
• a pure isomer of the compound of the formula (1) as well as a mixture thereof are also included.
• a compound of the formula (1) can be obtained by, for example, a reaction shown in the following scheme 1.
• a reaction, of an iso(thio)cyanate compound (2) with an ethanolamine compound (3) can be carried out, for example, in an appropriate solvent such as chloroform, while heating as needed.
• a ring closure reaction of the (thio)urea compound (4) thus obtained can be carried out, for example, in the presence of an acid catalyst, while heating.
• This reaction can be carried out according to, for example, a method described in Japanese Unexamined Patent Publication No. S62-228089.
• the compound of the formula (1) can be converted into an acid-addition salt by an ordinary method as needed.
• acid in the acid-addition salt include an inorganic salt such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and an organic acid such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and methanesulfonic acid.
• the compound of the formula (1) has an excellent inhibitory action on melanin production while exhibiting extremely low cytotoxicity. Therefore, the present compound is useful as a whitening agent and can be suitably mixed into various skin external preparations, particularly a skin external preparation intended to improve or prevent pigmented spots, freckles, skin dullness, and the like.
• the compound amount is, in the total amount of the external agent, typically 0.0002% by mass or more, preferably 0.002% by mass or more. When it is too low, the effect cannot be fully exerted. Although no limitation is imposed on the upper limit, it is typically 30% by mass or less, preferably 20% by mass or less, and more preferably 5% by mass or less. When the compound is excessively mixed in, not only a remarkable effect reasonably expected from the increased amount may not be obtained but also formulation designing and usability may be affected.
• the skin external preparation of the present invention can be produced by an ordinary method.
• ingredients normally used in a skin external preparation such as a cosmetic product and a pharmaceutical product can be appropriately added to the skin external preparation of the present invention as needed as far as the effect of the present invention is not adversely affected.
• an ingredient include oil, a humectant, an ultraviolet protective agent, an antioxidant, a metal ion chelating agent, a surfactant, a preservative, a moisturizer, a fragrance, water, an alcohol, a thickener, powder, a colorant, a crude drug, and various kinds of medicinal ingredients.
• whitening agents such as vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, Rucinol, ellagic acid, tranexamic acid, and linoleic acid can be appropriately added.
• the skin external preparation of the present invention is widely applicable to the fields of cosmetics, drugs, and quasi drugs. No particular limitation is imposed on the form of the skin external preparation as long as it is applicable to the skin. Any form such as a solution, an emulsion, a solid, a semi-solid, a powder, a powder dispersion, a water-oil-separated two-phase liquid, a water-oil-powder-separated three-phase liquid, an ointment, a gel, an aerosol, a mousse, and a stick can be applied.
• the skin external preparation can be provided in any use form including a facial cosmetic such as a lotion, an emulsion, a cream, a pack, an essence, and a gel, and a makeup cosmetic such as a foundation, a makeup base, and & concealer.
• a facial cosmetic such as a lotion, an emulsion, a cream, a pack, an essence, and a gel
• a makeup cosmetic such as a foundation, a makeup base, and & concealer.
• test for melanin production inhibition by the compounds of the formula (1) was conducted.
• the test method is as follows.
• the medium was removed by aspiration. Then 1 ml of EMEM medium containing 10% Alamar Blue solution was added, and a reaction was allowed to proceed at 37° C. After 30 minutes, 100 ⁇ L of the reaction mixture was transferred to a 96 well plate and fluorescence was measured at an excitation wavelength of 544 nm and a measurement wavelength of 590 nm. Using the value thus measured as a relative value of cell count, a ratio of the cell count (% cell count) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The higher the % cell count, the lower the cytotoxicity. It was determined that a compound having the % cell count of 80% or more was non-cytotoxic, and that a compound having the % cell count of less than 80% was cytotoxic.
• the cells after the cell proliferation test were washed with PBS three times, and then lysed by addition of 200 ⁇ l, of 1M NaOH to measure an absorbance at 475 nm. Using the value thus measured as a relative value of the melanin amount, a ratio of the melanin amount (%) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The lower the ratio of the melanin amount, the higher the melanin production-inhibitory effect.
• the minimum final concentration of the test substance at which the ratio of the melanin amount (%) was 80% or less was provided as a minimum concentration for inhibition of melanin production (ppm).
• the inhibitory effect on melanin production was evaluated according to the following criteria.
• heterocyclic compounds used for the whitening agent of the present invention will be shown.
• Various heterocyclic compounds can be obtained by carrying out a reaction according to the below-described synthesis examples using a corresponding raw material.
• N-(1-hydroxy-2-methylpropan-2-yl)-N-phenylthiourea (80.1 g, 0.36 mol) was dissolved in 2,400 mL of 35% HCl, and the resulting mixture was stirred while heating at 90° C. for 1.5 hours. After cooling, the mixture was neutralized with NaOH and extracted with diethyl ether. The extract was washed with saturated brine and then anhydrous sodium sulfate was added. The organic phase was distilled off under reduced pressure and the residue was washed three times with hexane. The crystals thus obtained were dried under reduced pressure at room temperature, and then recrystallized from methanol twice to give 22.4 g of the title compound (yield 18%).
• Formulation Examples of the skin external preparation of the present invention are shown.
• one or more compounds of the present invention can be used.
• Any of the skin external preparations shown in Formulation Examples below exerts a whitening effect because of the by the addition of the compound of the present invention.
• Propylene glycol and caustic potash were dissolved in ion-exchanged water, and the resulting mixture was heated to and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase, and after the complication of the addition, the resulting mixture was maintained at 70° C. for some time to allow a reaction to proceed. Subsequently, the mixture was homogeneously emulsified by a homomixer, and cooled to 30° C. while thoroughly stirring.
• Propylene glycol and disodium ethylenediaminetetraacetate were dissolved in ion-exchanged water and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase. The mixture was preliminarily emulsified at 70° C., homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.
• Powder soap and borax were added to ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring, the oil phase was gradually added to the aqueous phase to allow a reaction to proceed. Upon completion of the reaction, the mixture was homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.
• Carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A).
• Phase A Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase).
• Other components were mixed and melted by heat, and maintained at 70° C. (oil phase).
• the oil phase was added to the aqueous phase and preliminarily emulsified.
• the resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.
• Propylene glycol was added to ion-exchanged water, and the resulting mixture was heated and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring the oil phase, the aqueous phase was gradually added to the oil phase. The resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.
• Ethanol 10.0% by mass Dipropylene glycol 15.0 POE (50) oleyl ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Compound of the present invention 5.0 Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Trisodium ethylenediaminetetraacetate dihydrate 0.05 Methylparaben 0.2 Fragrance q.s. Ion-exchanged water balance
• Carboxyvinyl polymer was homogeneously dissolved in ion-exchanged water. Separately, the compound of the present invention and POE (50) oleyl ether were dissolved in 95% ethanol and then added to the aqueous phase. After addition of the remaining components, the resulting mixture was neutralized by caustic soda and L-arginine to increase the viscosity.
• Phase A Ethyl alcohol (95%) 10.0% by mass POE (20) octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Compound of the present invention 2.0 Methylparaben 0.15
• Phase B Potassium hydroxide 0.1
• Phase C Glycerol 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance
• Phase A and Phase C were homogeneously dissolved, and Phase A was added to Phase C to be solubilized. After addition of Phase B, the resulting mixture was packed in a container.
• Phase A Dipropylene glycol 5.0% by mass POE (60) hydrogenated castor oil 5.0
• Phase B Compound of the present invention 0.05 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Fragrance 0.2
• Phase C Sodium bisulfite 0.03 Polyvinyl alcohol (saponification degree of 90 13.0 and polymerization degree of 2,000) Ethanol 7.0 Purified water balance
• Phase A Phase A
• Phase B Phase B
• Phase C Phase C
• Powdery components from talc to black iron oxide shown above were thoroughly mixed by a blender. To this mixture were added oily components from squalane to isocetyl octanoate shown above, the compound of the present invention, preservative, and fragrance. The resulting mixture was thoroughly kneaded, packed in a container, and then formed.
• the aqueous phase was stirred with heat and then the powder part, which had been fully mixed and pulverized, was added.
• the mixture was treated with a homomixer and then the oil phase, which had been mixed with heat, was added.
• the mixture was treated with a homomixer and then fragrance was added while stirring. The mixture thus obtained was cooled to room temperature.
• A Alcohol phase Ethanol 5.0% by mass POE oleyl ether 2.0 2-Ethylhexyl-p-dimethylaminobenzoate 0.18 Compound of the present invention 0.1 Fragrance 0.05 B: Aqueous phase 1,3-Butylene glycol 9.5 2-O-Ethyl ascorbic acid 0.5 Sodium pyrrolidonecarboxylate 0.5 Whey extract 5.0 Nicotinamide 0.3 Glycerol 5.0 Hydroxypropyl- ⁇ -cyclodextrin 1.0 Trisodium hydroxyethylethylenediamine triacetate 1.0 Lysine 0.05 Tranexamic acid 1.0 Purified water balance
• Alcohol phase A was added to Aqueous phase B and solubilized to provide a lotion.

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