Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
• • 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
  • A61K8/60—Sugars; Derivatives thereof
  • A61K8/602—Glycosides, e.g. rutin
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

Definitions

• Novel galactosylceramide analogs i3--dalcocereb mouth oxidase activator, skin external preparation and method for activating / 3--dalcocerebrosidase using the same
• the present invention relates to novel galactosylceramide analogs, an activator of / 3-dalcocere procidase, an external preparation for skin and a method of activating 3-dalcocerebrosidase using the same. More specifically, a specific galactosylceramide analogue activates (3-Dalcocereb oral lipase in the epidermis) 3-Dalcocerebrosidase activating agent, an external preparation for skin and / 3-Dalcocereb oral lipase Regarding the activation method, these are expected to improve rough skin and various skin diseases.
• Rough skin refers to dry skin in which exfoliation of keratinocytes is generally observed. Such rough skin elutes lipids between keratinocytes such as cholesterol, ceramide, and fatty acids, and degeneration of keratinocytes and proliferation of epidermal cells due to ultraviolet rays and detergents. It is caused by failure or the like. For the purpose of preventing or healing this rough skin, it supplies a keratinocyte intercellular lipid component or a synthetic keratinocyte lipid similar thereto, and epidermal cells such as epidermal growth factor (EGF). Researches such as administration of growth and keratinizing substances have been conducted.
• EGF epidermal growth factor
• the stratum corneum intercellular lipid consists of stratum corneum, which is biosynthesized in the cells of the spinous layer and the stratum granulosum. It is widespread.
• the lamellar granules are composed of dalcosylceramide, cholesterol, ceramide, phospholipids, etc., but darcosylceramide is scarcely contained in the intercellular lipids of the stratum corneum.
• darcosylceramide in lamellar granules is: It is hydrolyzed by prosidase and converted to ceramide, which takes a lamella structure.As a result, it improves the formation of a corneal cell-penetrating barrier as intercellular lipids and acts as a barrier to rough skin. it is conceivable that. For example, pathologically rough skin is observed in patients with Gaucher disease type 2 who have a genetic deficiency of / 3-Darcoseleb oral sidase completely. An abnormality is found in the structure.
• activators of 3-dalcocele foid oral lipase include SAP-2, which was previously found in the guinea pig spleen, and A1a and savosine C, which were found in the spleen of human goose disease. are known.
• these activators are proteins, and using them externally to activate epidermal i3-darcocerebrosidase poses a major problem in terms of transdermal absorption and safety. In addition, it is extremely difficult to isolate these proteins for industrial use in terms of cost.
• ⁇ -galactosylceramide is known as an activator of i3-Dalcocereb oral sidase other than protein.
• the present invention provides a galactosylceramide analog represented by the following general formula (1) or (2), and a galactosylceramide analog using the same.
• RR 2 is an alkyl group or alkenyl group having 9 to 35 carbon atoms.
• R 3 is an alkyl group or alkenyl group having 2 to 30 carbon atoms. is there. )
• FIG. 1 shows a test of the ability of epidermal cells to activate [3-Dalcocereb oral sidase (Test Example It is a figure which shows the result of 1).
• FIG. 2 is a view showing the effect of the compound application of Example 4 on the rough skin due to UVB (the result of Test Example 2).
• FIG. 3 is a graph showing the effect of applying the compound of Example 4 on the rough skin due to UVB (the result of Test Example 2).
• the galactosylceramide analog used in the present invention is represented by the general formula (1) or (2).
• XY is a sulfur atom or an oxygen atom, and is preferably a sulfur atom from the viewpoint of the effect.
• R 1 and R 2 have 935 carbon atoms, preferably 1422, and most preferably 1620 carbon atoms.
• R 3 has 230 carbon atoms, preferably 14 22 carbon atoms, and most preferably 614 carbon atoms. Further, R 1 , R 2 R 3 may be saturated or unsaturated. Specific examples include those represented by the following general formulas (3) and (6).
• amide synthesis method a compound represented by the general formula (2) having two alkyl chains can be subjected to galactosylation reaction with amine, serine or cysteine whose carboxylic acid moiety is protected. After the introduction of carboxylic acid, one amino group is introduced by deprotection and condensation reaction of the amino group, then the protecting group of the carboxylic acid is removed, phosphorus trichloride is reacted to form an acid chloride, It can be produced by reacting with amine. Further, a compound represented by the general formula (1) having a single-chain compound can be produced in the same manner.
• the activator of the present invention is a galactosylceramide analog represented by the above general formula (1) or (2) as an active ingredient for improving rough skin.
• the activator for 3 / 3-dalcocele mouth and the external preparation for the skin may be in various dosage forms such as ointment, mouth lotion, emulsion, milk, cataplasm, pack, mist, foam, granule, powder, gel, etc. Can be.
• the external preparation for skin is intended for all skin of the body including the scalp, and includes bath salts.
• the substrate is not particularly limited as long as it is a commonly used external base.
• the final form can be cosmetics, pharmaceuticals, and quasi-drugs.
• the amount of the galactosylceramide analog to be added to the / 3--dalcocerebrosidase activator and the external preparation for skin is preferably 0.005 to 5.0% by mass based on the total amount of the composition. , 0.01 to 3.0% by mass. If the amount is less than 0.05% by mass, the effect of the present invention may not be sufficient. On the other hand, if the amount exceeds 5.0% by mass, the effect corresponding to the increase is not improved. There is. Example
• Example 1 Example 1
• the reaction mixture was extracted with ethyl acetate, washed with 2 mol / L hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
• the reaction mixture was extracted with ethyl acetate, washed with 2 mol / L hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
• the reaction mixture was diluted with chloroform, washed with 2 mol 1 ZL hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and then dried at room temperature over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
• N- [2- (2,3,4,6-tetra-benzoyl-1) 3-D-galacto viranosylthio) ethyl] octanedecanoylamide 44 Omg 1,4-dioxane 1 OmL and methanol It was dissolved in 15 mL of a mixed solvent, a catalytic amount of a 28% methanol solution of sodium methylate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with a cation exchange resin (Dowex 7 "50-X8), the resin was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was crystallized from methanol. As a result, 209 mg of N- [2-(] 3-D-galactopyranosylthio) ethyl] octadecanoylamide was obtained as white crystals.
• Test Example 1 Test for determining the ability of epidermal cells to activate / 3-Dalcocerebrosidase
• the medium used was Medium uml 54S (Kurabo), and the growth factor additive HKGS (Kurabo) was used as a growth factor.
• the number of normal human epidermal cells was adjusted to 2.5 ⁇ 1 O SZmL with Medimix 54S, and 4 mL of each was seeded on a 6 Omm collagen-coated plate (Falcon), and 95% air (VZV) — 5 The culture was allowed to stand still at 37 ° C. for 4 days in an atmosphere of% carbon dioxide (VZV).
• the culture supernatant was removed by suction, and 200 ml of a 200 mo 1 ZL ethanol solution of each of the drugs prepared in Examples 1, 2, and 4 was added to each of 4 mL of Medi urn 154S to a final concentration of 5 mo 1 ZL. Added to the dish. The dishes were incubated at 37 ° C. for 4 days in an atmosphere of 95% air (VZV) —5% carbon dioxide (VZV). In addition, only Comparative Example 1 containing ethanol containing no galactosylceramide analog was used.
• the measurement was carried out according to the method of Miel and Van der Kli (Pretty Journal, ob. Del Matologi, Vol. 95, pp. 271-274, 1976). That is, to 50 L of the crude enzyme solution, 500 L of 10 Ommo 1 L citrate-20 Ommo 1 L phosphate buffer (pH 5.6) and 1 Ommo 1 ZL taurocholate-1 0 Ommo 1 ZL citrate-500 zL of 20 Ommo 1 ZL phosphate buffer (pH 5.6) was added, and the mixture was heated at 37 ° C for 10 minutes. Then, add 50 / L of 0-SmmolZL 4-methylbenbellifel) -D-Dalcoside (Sigma).
• the fluorescence intensity was measured at 450 nm. Enzyme activity was calculated based on a calibration curve created from the fluorescence intensity of a standard product, 4-methylambelliferone (Sigma).
• Example 2 a compound represented by the general formula (4)]
• Example 1 compound represented by general formula (5)
• Octadecanoylamide [Example 4; compound represented by general formula (6)] has all 13-Dalcoceleb mouth-sidase activity. A conversion effect was observed.
• Test Example 2 Rough skin recovery test in mice
• TEWL transepidermal water loss
• Example 4 [compound represented by the general formula (6)] was prepared at a concentration of 0.1% and 1.0%. 0.05 mL of this prepared sample was applied to the back skin (2.5 cm in diameter) of a hairless mouse whose TEWL was measured in advance, once a day, five times a week for four consecutive weeks. Then, on the third day from the final application of the pre-application, ultraviolet B wavelength (UVB) was irradiated once at 0.15 JZcm 2 . TEWL before UVB irradiation and on days 3 and 4 after irradiation were measured and compared with the ratio to TEWL before base application.
• UVB ultraviolet B wavelength
• N- [2- (0-D-galactopyranosyloxy) —1- (hexylcarbamoyl) ethyl] octanedecanoylamide [Compound of Example 4; The compound of the general formula (6)] shows a significant decrease in TEWL at 1.0% concentration, with a p ⁇ 0.01 (Dunnett's multiple test). The rough skin had been improved.
• the present invention can provide an epidermal 0-dalcocerebrosidase activator which can be synthesized easily and easily. Further, the present invention enables prevention and protection of rough skin and improvement of various skin diseases.

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Citations (4)

• 2001
  • 2001-06-28 JP JP2001196016A patent/JP4070966B2/ja not_active Expired - Lifetime
• 2002
  • 2002-06-27 EP EP02743752A patent/EP1408045B1/en not_active Expired - Lifetime
  • 2002-06-27 US US10/482,110 patent/US7183261B2/en not_active Expired - Lifetime
  • 2002-06-27 TW TW091114141A patent/TWI322151B/zh not_active IP Right Cessation
  • 2002-06-27 CN CNB028131487A patent/CN1247605C/zh not_active Expired - Lifetime
  • 2002-06-27 KR KR1020037016943A patent/KR100739250B1/ko not_active Expired - Lifetime
  • 2002-06-27 DE DE60232449T patent/DE60232449D1/de not_active Expired - Lifetime
  • 2002-06-27 TW TW098132688A patent/TW201002734A/zh unknown
  • 2002-06-27 WO PCT/JP2002/006532 patent/WO2003002584A1/ja not_active Ceased
• 2007
  • 2007-01-11 US US11/651,978 patent/US20070111951A1/en not_active Abandoned

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