WO2017122495A1 - Agents augmentant la teneur en céramides - Google Patents

Agents augmentant la teneur en céramides Download PDF

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WO2017122495A1
WO2017122495A1 PCT/JP2016/087537 JP2016087537W WO2017122495A1 WO 2017122495 A1 WO2017122495 A1 WO 2017122495A1 JP 2016087537 W JP2016087537 W JP 2016087537W WO 2017122495 A1 WO2017122495 A1 WO 2017122495A1
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optionally substituted
ceramide
formula
compound represented
hydrogen atom
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PCT/JP2016/087537
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Japanese (ja)
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敦 加藤
文博 石川
大介 三浦
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国立大学法人富山大学
株式会社伏見製薬所
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Priority to JP2017561557A priority Critical patent/JP6830580B2/ja
Publication of WO2017122495A1 publication Critical patent/WO2017122495A1/fr

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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
    • A61K8/60—Sugars; Derivatives thereof
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms
    • 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
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings

Definitions

  • the present invention relates to a ceramide content increasing agent comprising a sugar derivative and a composition containing the same.
  • Sphingolipid is a generic term for lipids containing sphingoid bases, and as a main component of lipid rafts, it is attracting attention as a cause of Alzheimer's disease, control of cancer cell motility, prevention of bacterial and viral infections, prevention of allergen invasion A relationship with ⁇ -secretase has been found (see Non-Patent Document 1). In addition, some sphingolipids function as signaling molecules that control cell death, proliferation, and differentiation, and researches are ongoing as important factors.
  • ceramide is synthesized in the endoplasmic reticulum and then sugars and phosphocholines are added to the Golgi body to form various complex sphingolipid skeletal molecules. For this reason, changes in the amount of intracellular ceramide can cause changes in the amount of various types of sphingolipids with ceramide as a precursor. It can be said that the constant maintenance of the quantity is essential.
  • sphingomyelin in which ceramide is modified with phosphocholine accounts for approximately 10% of the phospholipids that make up cell membranes, and is an important lipid that dramatically increases excitatory conduction velocity as the main component in the myelin sheath of myelinated nerve fibers. .
  • glucosylceramide a kind of sphingolipid, is closely related to Parkinson's disease (see Non-Patent Document 2).
  • ceramide exists as intercellular lipids in the stratum corneum, which is the outermost layer of the skin. This ceramide forms a lamella structure that is arranged regularly and overlaps with water molecules so as to sandwich water molecules. However, the ceramide has the highest composition ratio of about 55% among the lamella structures, and ceramide is mainly used to retain moisture. It can be said that. In addition, there is enough intercellular lipid to prevent moisture in the skin from evaporating and to protect the skin from external stimuli such as ultraviolet rays, viruses, fungi, and allergens.
  • Nonpatent literature 3 For example, familiar diseases in which ceramide is reduced include xeroderma and atopic dermatitis.
  • the main cause of xeroderma is a decrease in ceramide in the stroma of the stratum corneum, but especially senile xeroderma is thought to occur because the activity of ceramidase, a ceramide-degrading enzyme, increases with age. It has been.
  • atopic dermatitis it is known that the barrier function is lowered because the amount of ceramide is smaller than that of healthy skin (see Non-Patent Document 4). This suggests that a drug that increases the amount of ceramide is very useful for maintaining a healthy skin condition.
  • Examples of methods for increasing the amount of ceramide biosynthesized in vivo include a method for suppressing ceramide degradation and a method for promoting ceramide synthesis.
  • the ceramidase that metabolizes ceramide is also called acyl sphingosine deacylase, which hydrolyzes the acyl group to decompose ceramide, which has a double-stranded structure, into single-stranded sphingosine and fatty acids.
  • Ceramidases are classified into three families, acid ceramidase, neutral ceramidase, and alkaline ceramidase, due to differences in optimum pH.
  • acid ceramidase inhibitors include desipramine and N-oleoylethanolamine (see Non-Patent Document 5), and neutral ceramidase and alkaline ceramidase inhibitors include De-MAPP (D-erythro-2-N- Myristoylamino-1-phenyl-1-propanol) is known (see Non-Patent Documents 5 and 6).
  • Patent Document 1 includes extracts of turmeric, saxifrage, dextran, and diatomaceous earth
  • Patent Document 2 includes ginkgo, shirori, cucumber, tougan, bitter gourd, orange, grapefruit, lime, gagome, macombu, wakame, eucalyptus, and mugwort. It is disclosed that the extract has ceramidase activity inhibition.
  • Patent Document 3 reports that nicotinic acid or a derivative thereof, nicotinic alcohol or a salt thereof promotes ceramide synthesis of epidermal cells themselves.
  • Patent Document 4 includes rice, kudzu, apricot, honeysuckle, yukinoshita, tencha, rafuma, hawthorn, izayoibara, elephant kogi, jujube, perilla, auren, saishin, koganebana, yellowfin, mulberry, button, peonies, chimpi, mugwort, It has been disclosed that extracts of clove, lily, soybean, and white jellyfish promote ceramide synthesis.
  • acid ceramidase inhibitor desipramine has a low selectivity such as affecting other lysosomal enzymes, and N-oleoylethanolamine has a problem of low inhibitory activity.
  • Neutral ceramidase and alkaline ceramidase De-MAPP, an inhibitor is not satisfactory because of its weak inhibitory activity.
  • the extracts disclosed in Patent Document 1 and Patent Document 2 are also not sufficiently effective in inhibiting ceramidase, and conventionally known compounds and plant extracts are not necessarily satisfactory from the viewpoint of their effects. Therefore, a further highly active product has been desired.
  • One of the objects of the present invention is to provide a novel ceramide-degrading enzyme inhibitor excellent in ceramidase inhibitory effect and high in safety, and a composition containing the same.
  • Another object of the present invention is to provide a novel ceramide synthesis accelerator and a composition containing the same, which are excellent in ceramide synthesis effect and high in safety.
  • the present inventors have developed a skin moisturizing, barrier, and ceramidease inhibitors or ceramide synthesis promoters that regulate the amount of intracellular ceramide, and thus increase the amount of ceramide present between cells in the stratum corneum.
  • a ceramide content increasing agent comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • each R 1 is independently a hydrogen atom, hydroxy, an optionally substituted alkyloxy, an optionally substituted alkenyloxy, an optionally substituted alkynyloxy, or optionally substituted.
  • Cycloalkyloxy, optionally substituted cycloalkenyloxy, optionally substituted heterocycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted A good acyloxy, wherein two R 1 together may form ⁇ O;
  • Each R 2 independently represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, or optionally substituted; Cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl;
  • R 3 is a hydrogen atom, —CH 2 OR 4 , —CHOR 4 —CH 2 OR 4 ,
  • a ceramide degrading enzyme inhibitor comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • a ceramide synthesis promoter comprising a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof.
  • R 5 represents a hydrogen atom or an optionally substituted alkyloxy group
  • R 6 , R 7 , R 8 , and R 9 may each independently represent a hydrogen atom or a substituted atom.
  • [4] A composition comprising the ceramide content increasing agent according to [1], the ceramide degrading enzyme inhibitor according to [2], or the ceramide synthesis promoter according to [3].
  • [5] A compound represented by the following formula.
  • a method for increasing the amount of intracellular ceramide comprising a step of administering to an individual in need of increasing the amount of intracellular ceramide.
  • the ceramide-degrading enzyme inhibitor of the present invention has an excellent effect of being excellent in ceramidase inhibitory effect and having high safety.
  • the ceramide synthesis promoter of the present invention has an excellent effect of promoting activity against ceramide synthase and having high safety.
  • FIG. 1 is a diagram showing a correlation between an enzyme reaction and a human skin test.
  • FIG. 2 is a graph showing the ratio of ceramide synthesis when each sample (50 ⁇ M) is added.
  • FIG. 3 is a graph showing the wound healing effect when 6-galloyl-1,5-AG (50 ⁇ M) is added.
  • the ceramide content increasing agent of the present invention acts in the biosynthesis of ceramide in cells, and has the effect of regulating the amount of ceramide and thus increasing the amount of ceramide present between cells in the stratum corneum.
  • a ceramide degrading enzyme inhibitor and a ceramide synthesis promoter will be described from the viewpoint of the mechanism of action.
  • the ceramide-degrading enzyme inhibitor of the present invention is a derivative having a 5- or 6-membered sugar represented by the formula (I) as a basic skeleton.
  • the compound represented by the formula (I) and a pharmaceutically acceptable salt thereof may be collectively described as the compound of the embodiment 1 of the present invention.
  • group or “substituent” in the present specification means a monovalent group, for example, “alkyl group” means a monovalent saturated hydrocarbon group.
  • group may be omitted.
  • a group that does not clearly indicate the term “may be substituted” or “substituted” means a “non-substituted” substituent.
  • the number of substituents in the group is not particularly limited as long as substitution is possible, and is one or more.
  • the description of each group also applies when the group becomes a part of another group or a substituent.
  • alkyl means a linear or branched saturated hydrocarbon having 1 to 20 carbon atoms. Specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, decanoyl, lauryl, stearyl, dodecanoyl, myristyl, palmityl, Examples include 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Of these, octyl, lauryl, myristyl, stearyl and palmityl are preferable.
  • alkyloxy means a group in which one “alkyl” is substituted on an oxygen atom. Specifically, for example, methyloxy (methoxy), ethyloxy (ethoxy), propyloxy (propoxy), isopropyloxy, butyloxy (butoxy), isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, Ptyloxy, octyloxy, dodecyloxy, decanoyloxy, lauryloxy, stearyloxy, dodecanoyloxy, myristyloxy, palmityloxy, 1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy , 2-ethylbutyloxy and the like.
  • alkenyl means a linear or branched hydrocarbon having 2 to 20 carbon atoms and containing at least one carbon-carbon double bond. Specific examples include vinyl, allyl, isopropenyl, 1-propen-1-yl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, palmitolyl, oleinoyl, linoleyl and the like.
  • alkenyloxy means a group in which one “alkenyl” is substituted on an oxygen atom.
  • alkynyl means a linear or branched hydrocarbon having 2 to 20 carbon atoms and containing at least one carbon-carbon triple bond. Specific examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.
  • alkynyloxy means a group in which one “alkynyl” is substituted on an oxygen atom. Specific examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy and the like.
  • cycloalkyl means a saturated hydrocarbon ring in which the “alkyl” forms a ring. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkyloxy means a group in which one “cycloalkyl” is substituted on an oxygen atom.
  • Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • cycloalkenyl means an unsaturated hydrocarbon ring in which the “alkenyl” forms a ring.
  • Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
  • cycloalkenyloxy means a group in which one “cycloalkenyl” is substituted on an oxygen atom.
  • Specific examples include cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy and the like.
  • heterocycloalkyl means that at least one carbon of the ring constituting the “cycloalkyl” is substituted with one or more heteroatoms arbitrarily selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
  • heteroatoms arbitrarily selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
  • heterocycloalkyloxy means a group in which one “heterocycloalkyl” is substituted on an oxygen atom.
  • Specific examples include those in which an oxygen atom is covalently bonded to the above-mentioned “heterocycloalkyl” bond.
  • Cycloalkyl “cycloalkenyl”, and “heterocycloalkyl” form a ring according to the number of atoms constituting them, but in this specification, only if the atoms constitute a single ring. It also includes those constituting a condensed polycycle. These substituents may be collectively referred to as “non-aromatic hydrocarbon ring”. The number of polycycles is not particularly limited, and is about 2 to 5 rings. In addition, a group in which a non-aromatic hydrocarbon ring is condensed with “aryl” or “unsaturated cyclic substituent” described later is also included, in which case the “non-aromatic hydrocarbon ring” has a bond.
  • aryl means an aromatic hydrocarbon having 6 to 20 carbon atoms, and may be monocyclic or condensed polycyclic. Further, a group condensed with the “non-aromatic hydrocarbon ring” or a group condensed with a 5- to 7-membered unsaturated cyclic substituent is also included, in which case “aryl” has a bond.
  • unsaturated cyclic substituent even in the case of a 5- to 7-membered unsaturated hydrocarbon ring, at least one carbon in the 5- to 7-membered unsaturated hydrocarbon ring is substituted with the heteroatom described above. Heterocycle may be sufficient. Specific examples include substituents represented by the following formula.
  • aryloxy means a group in which one “aryl” is substituted on an oxygen atom.
  • Specific examples include those in which an oxygen atom is covalently bonded to the above-mentioned “aryl” bond.
  • heteroaryl specifically includes those having a structure represented by the following formula. Here, when it has two or more hetero atoms, they may be the same or different. Further, a group condensed with the above “non-aromatic hydrocarbon ring” or “aryl”, or a group condensed with a 5- to 7-membered unsaturated non-aromatic cyclic substituent is also included, in which case “heteroaryl” is Have a bond.
  • heteroaryloxy means a group in which one “heteroaryl” is substituted on an oxygen atom.
  • Specific examples include those in which an oxygen atom is covalently bonded to the above-mentioned “heteroaryl” bond.
  • acyl means an alkylcarbonyl in which the alkyl portion is the above “alkyl”, an alkenylcarbonyl in which the alkenyl portion is the above “alkenyl”, an alkynylcarbonyl in which the alkynyl portion is the above “alkynyl”, a cycloalkyl portion Is a cycloalkylcarbonyl in which the “cycloalkyl” is the cyclocycloalkylcarbonyl in which the cycloalkenyl moiety is the “cycloalkenyl”, a heterocycloalkylcarbonyl in which the heterocycloalkyl moiety is the “heterocycloalkyl”, and an aryl moiety is the above “ An arylcarbonyl that is “aryl” means a heteroarylcarbonyl in which the heteroaryl moiety is the aforementioned “heteroaryl”.
  • acyloxy means a group in which one “acyl” is substituted on an oxygen atom.
  • Specific examples include those in which an oxygen atom is covalently bonded to the above-mentioned “acyl” bond.
  • R 1 in formula (I) is each independently a hydrogen atom, hydroxy, alkyloxy which may be substituted, alkenyloxy which may be substituted, alkynyloxy which may be substituted, May be substituted cycloalkyloxy, optionally substituted cycloalkenyloxy, optionally substituted heterocycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or substituted It may be acyloxy. However, the two R 1 groups may form ⁇ O together.
  • one or a plurality of saccharides may form a chain structure.
  • the saccharide include compounds having 3 to 7 carbon atoms such as aldose, ketose, alditol, deoxy sugar, anhydro sugar, amino sugar, inositol, aldonic acid, uronic acid, aldaric acid, carb sugar, thio sugar, imino sugar, aza sugar and the like.
  • sugar to comprise may be either cyclic
  • fatty acids are also exemplified, and may be those bound to the saccharides.
  • the fatty acid is preferably a fatty acid having 2 to 20 carbon atoms such as octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, icosanoic acid or palmitic acid, and more preferably an aliphatic acid having 8 to 20 carbon atoms.
  • galloic acid is also mentioned as a suitable example, and may be one bound to the saccharide or fatty acid.
  • R 1 include the groups shown below.
  • R 2 in formula (I) is each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, Cycloalkenyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, or acyl which may be substituted.
  • substituents include the fatty acids and galloic acid described above.
  • R 2 include the groups shown below.
  • R 3 in formula (I) is a hydrogen atom, —CH 2 OR 4 , —CHOR 4 —CH 2 OR 4 , or —COOR 4 , wherein R 4 is a hydrogen atom, an optionally substituted alkyl, a substituted Alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, Or an optionally substituted acyl.
  • substituents examples include saccharides.
  • R 3 include, for example, groups shown below are exemplified.
  • N in the formula (I) is 0 or 1, and a case of 0 has a 5-membered ring sugar skeleton.
  • the combination of the compound represented by the formula (I) is not particularly limited as long as it has the above-described substituents.
  • a compound containing at least one carbonyl group on the structure carbonyl Containing compounds.
  • a carbonyl group may be included as a member of a sugar skeleton.
  • at least one substituent selected from R 2 and R 3 may contain an optionally substituted acyl. That is, when R 3 is —CH 2 OR 4 or —CHOR 4 —CH 2 OR 4 , at least one substituent selected from R 2 and R 4 contains an optionally substituted acyl. May be. For example, the following are mentioned.
  • R 1 is either a hydrogen atom
  • R 3 is -COOR 4, where, R 4 is compounds are also alkyl optionally be a hydrogen atom or a substituent are preferable.
  • the alkyl of R 4 is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or n-octyl.
  • R 2 is not particularly limited, each independently, a hydrogen atom, galloyl, or acetyl are preferred.
  • R 1 is a hydrogen atom, the other is hydroxy, and R 3 is —COOR 4 , provided that R 4 is a hydrogen atom or an optionally substituted alkyl is preferable.
  • the alkyl of R 4 is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or n-octyl.
  • R 2 is not particularly limited, each independently, a hydrogen atom, galloyl, or acetyl are preferred.
  • R 1 is a hydrogen atom
  • the other is an optionally substituted alkyloxy
  • R 3 is —COOR 4 , provided that R 4 is a hydrogen atom or an optionally substituted alkyl.
  • the alkyloxy of R 1 is preferably methyloxy, ethyloxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, n-octyloxy, or an oxy group having a saccharide.
  • saccharides xylose, lyxose, arabinose, ribose, glucose, allose, galactose, idose, talose, mannose, altrose, erythritol, xylitol, ribitol, arabitol, mannitol, sorbitol, allitol, taritol, galactitol, iditol , Myo-inositol, ribulose, xylulose, fructose, psicose, tagose, sorbose, rhamnose, fucose, glucuronic acid, glucosamine, galactosamine and other monosaccharides; maltose, lactose, trehalose, isomaltose, sucrose, cellobiose, nigerose
  • the monosaccharide and disaccharide are ⁇ 1-2 bond, ⁇ 1-3 bond, ⁇
  • alkyloxy of R 1 hydroquinone, salicyl alcohol, phloretin, esculetin, apigenin, daidzein
  • an oxy group represented by a structure obtained by removing a hydrogen atom of one hydroxyl group among the intramolecular hydroxyl groups of the following compounds: Quercetin, hesperetin, naringenin, delphinidin, alizarin, indoxyl, digitoxigenin, digitogenin or glycyrrhetin are also preferred.
  • alkyl of R 4 methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or n-octyl is preferable. Also, in the case of the combinations, but R 2 is not particularly limited, each independently, a hydrogen atom, acetyl, galloyl, linoleyl, stearyl, Oreinoiru, or octanoyl is preferred.
  • R 2 is not particularly limited, but is preferably a hydrogen atom, acetyl, or galloyl.
  • n may be 0 or 1.
  • R 3 is —CH 2 OR 4 or —CHOR 4 —CH 2 OR 4 , provided that R 4 is a hydrogen atom or an optionally substituted acyl.
  • R 4 is a hydrogen atom or an optionally substituted acyl.
  • the acyl of R 4 is preferably acetyl, galloyl, octanoyl, stearyl, linoleyl, or oleinoyl.
  • R 2 is not particularly limited, each independently, acetyl, galloyl, octanoyl, stearyl, linoleyl, or a Oreinoiru is preferred.
  • a compound in which R 1 is a hydrogen atom and at least one of R 2 is an optionally substituted acyl is preferable.
  • the acyl of R 2 includes acetyl, galloyl, octanoyl, stearyl, linoleyl, oleinoyl, hexahydroxydiphenoyl, 3,5-dihydroxybenzoyl, 3,5-dimethoxy-4-hydroxybenzoyl, 3-methoxy- 4,5-dihydroxybenzoyl, 3-hydroxybenzoyl or 4-hydroxybenzoyl is preferred.
  • R 3 is not particularly limited, but acetyl, galloyl, octanoyl, stearyl, linoleyl, oleinoyl, hexahydroxydiphenoyl, 3,5-dihydroxybenzoyl, 3,5-dimethoxy-4-hydroxybenzoyl , 3-methoxy-4,5-dihydroxybenzoyl, 3-hydroxybenzoyl, or 4-hydroxybenzoyl.
  • R 1 is a hydrogen atom
  • the other is an optionally substituted acyloxy
  • at least one of R 2 is an optionally substituted acyl
  • R 3 is —CH 2 OR 4 ;
  • the compound whose R ⁇ 4 > is a hydrogen atom or the alkyl which may be substituted is preferable.
  • the acyloxy of R 1 includes acetyloxy, galloyloxy, octanoyloxy, benzoyloxy, 4-nitrobenzoyloxy, 4-hydroxybenzoyloxy, stearyloxy, linoleyloxy, octanoyloxy, oleinoyloxy, or Hexahydroxydiphenoyl is preferred.
  • R 3 is preferably —CH 2 OR 4 , provided that R 4 is preferably a hydrogen atom or an optionally substituted alkyl.
  • the alkyl of R 4 includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-octyl, benzyl, 4-hydroxybenzyl, or 3,4,5-trihydroxy Benzyl is preferred.
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is —CH 2 OR 4 or —CHOR 4 —CH 2 OR 4 provided that R 4 is not substituted.
  • Preferred are compounds that are acyl.
  • the acyl of R 4 is preferably acetyl, galloyl, octanoyl, stearyl, linoleyl, or oleinoyl.
  • the compound represented by the formula (I) may be other than the carbonyl group-containing compound as long as it has the above-described substituent, and examples thereof include the following.
  • R 1 is a hydrogen atom
  • the other is an optionally substituted alkyloxy
  • R 3 is —CH 2 OR 4 , provided that R 4 is a hydrogen atom or an optionally substituted alkyl.
  • R 4 is a hydrogen atom or an optionally substituted alkyl.
  • the alkyloxy of R 1 is preferably methyloxy, ethyloxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, or n-octyloxy.
  • R 4 alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-octyl, benzyl, 4-hydroxybenzyl, or 3,4,5-trihydroxybenzyl. Is preferred.
  • R 2 is not particularly limited, but each independently represents a hydrogen atom, acetyl, galloyl, octanoyl, benzoyl, 4-nitrobenzoyl, 4-hydroxybenzoyl, stearyl, linoleyl, octanoyl, oleinoyl, or A case of hexahydroxydiphenoyl is preferred.
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is —CH 2 OR 4 or —CHOR 4 —CH 2 OR 4 , provided that R 4 is a hydrogen atom Certain compounds are preferred.
  • the compound represented by the formula (I) include, for example, compounds selected from the following. 1,5-anhydroglucitol, 1,4-anhydroglucitol, 1,5-anhydrogalactitol, 1,4-anhydrogalactitol, 1,4-anhydro-L-arabinitol, 1,4-anhydro-D-arabinitol, 1,5-anhydroxylitol, 1,4-anhydroxylitol, 1-deoxycellobiose, 1-deoxymaltose, 1-deoxylactose, trehalose, arbutin, salicin, phlorhizin, aesculin, apiin, daidzin, quercitrin, rutin, hesperidin, naringin, ruberythric acid, indicantonin, digit2 , 6-anhydro-L-gulonic acid, glucuronic acid, galacturonic acid, gluconolactone, baicalin, glycyrr
  • the following compounds (4,6-digalloyl-1,5-anhydroglucitol) are the compounds that the present inventors have found for the first time.
  • These compounds represented by the formula (I) may be either chemically synthesized or purified from the natural world, and the production method is not particularly limited.
  • the “pharmaceutically acceptable salt” is also included as a compound represented by the formula (I).
  • alkali metals lithium, sodium, potassium, etc.
  • alkaline earth metals magnesium, calcium, etc.
  • ammonium organic bases
  • organic bases triethanolamine, triethylamine, aminopropanediol, pyridine, piperidine, pyrimidine, Piperazine, morpholine, azepine, etc.
  • salts with amino acids inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, periodic acid, boric acid, etc.), organic acids (acetic acid, citric acid, etc.) Acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, carboxylic acid, sulfonic acid, phosphonic acid, sulfinic acid, trifluoroacetic acid and the
  • the carbon chain portion of the organic acid salt may be a linear, branched, or cyclic aliphatic acid salt or aromatic acid salt.
  • the salt with an organic base or organic acid may contain one or a plurality of heteroatoms selected from an oxygen atom and a nitrogen atom, for example, in the form of a hydroxyl group.
  • the compounds represented by the formula (I) and pharmaceutically acceptable salts thereof include solvates such as hydrates and ethanol solvates thereof. These can be prepared according to known methods.
  • hyaluronic acid sodium salt hyaluronic acid potassium salt
  • hyaluronic acid calcium salt hyaluronic acid ammonium salt
  • ceramide-degrading enzyme inhibitor of the present invention can be used alone or in combination of two or more, and the total content in the ceramide-degrading enzyme inhibitor of the present invention is not particularly limited, and is usually about 0.001 to 100% by mass.
  • the compound of aspect 1 of the present invention exhibits an excellent ceramide-degrading enzyme inhibitory action as described in the examples described later.
  • the ceramide-degrading enzyme inhibitory action refers to the action of reducing the activity of ceramidase as compared with the original activity of ceramidase, and can be confirmed by, for example, the method described in the examples below. is there.
  • the compound of aspect 1 of the present invention is not particularly limited as long as it reduces the original activity of ceramidase, but for example, 5% or more, preferably 10% or more, more preferably 20% or more, still more preferably It is desirable to have an inhibitory action that reduces it by 40% or more, more preferably 60% or more.
  • the ceramide-degrading enzyme inhibitor of the present invention suppresses the decrease in the amount of ceramide, thereby improving the moisturizing effect, improving wrinkles, improving the symptoms of atopic dermatitis, preventing / improving sebum deficiency (xeroderma), Symptoms and diseases based on a decrease in the amount of ceramide in the cell or skin, such as prevention of skin damage, improvement of skin tarmi, antipruritic action, melanin production suppression effect, improvement of barrier function, fibroblast activation effect, skin cell regeneration effect, etc. It can be suitably used as a preventive agent, an improving agent, and / or a therapeutic agent.
  • alopecia areata
  • contact dermatitis infectious impetigo
  • Kaposi's chickenpox-like rash cataract
  • retinal detachment prurigo
  • lysosomal disease Can be used.
  • the form of the ceramide-degrading enzyme inhibitor of the present invention is not particularly limited as long as the compound of aspect 1 of the present invention can be applied to the surface of the target substance or ingested into the body. You may prepare in the form which can be used for raw materials, such as a quasi-drug and cosmetics.
  • the ceramide synthesis promoter of the present invention may be described as a six-membered sugar (1,5-anhydro-D-glucitol, hereinafter referred to as “1,5-AG”, as shown in the above formula (II).
  • the compound is characterized in that it is a compound in which the carboxyl group of gallic acid is ester-bonded to at least one hydroxyl group.
  • the compound represented by the formula (II) and a pharmaceutically acceptable salt thereof may be collectively described as the compound of the embodiment 2 of the present invention.
  • group or “substituent” in the present specification means a monovalent group, and the term “group” may be omitted in the description of the substituent.
  • R 5 in the formula (II) is a hydrogen atom or an optionally substituted alkyloxy.
  • Alkyl in “alkyloxy” includes linear or branched saturated hydrocarbon having 1 to 20 carbon atoms. Specific examples of “alkyloxy” include methyloxy (methoxy), ethyloxy (ethoxy), propyloxy (propoxy), isopropyloxy, butyloxy (butoxy), isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyl Oxy, heptyloxy, octyloxy, dodecyloxy, decanoyloxy, lauryloxy, stearyloxy, dodecanoyloxy, myristyloxy, palmityloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3, Examples include 3-dimethylbutyloxy and 2-ethylbutyloxy.
  • R 6 , R 7 , R 8 , and R 9 in formula (II) are each independently a hydrogen atom or an optionally substituted galloyl group, and R 6 , R 7 , R 8 , and R 9 There is no case where 9 is a hydrogen atom or a galloyl group at the same time.
  • the galloyl group in the present invention at least one of the three hydroxyl groups is unsubstituted. However, even if all the three hydroxyl groups are unsubstituted, one or two hydroxyl groups are substituted. Means that it may be. Here, being substituted means that the hydrogen atom of the hydroxyl group is substituted to form alkyloxy, ester, silyloxy, acetal, or ketal.
  • alkyloxy examples include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, dodecyloxy, decanoyloxy, Examples include lauryloxy, stearyloxy, dodecanoyloxy, myristyloxy, palmityloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy and the like. .
  • cycloalkyloxy in which the carbon constituting the alkyl group forms a ring may be used, and examples thereof include cyclohexyloxy. It may be a functional group in which a part of the alkyl group is substituted, for example, a carboxymethyloxy group.
  • ester examples include carbonate ester, ortho ester, sulfonate ester, sulfinate ester, and carbamate ester.
  • Examples of the carbonate ester include methyl carbonate ester, ethyl carbonate ester, n-propyl carbonate ester, iso-propyl carbonate ester, n-butyl carbonate ester, iso-butyl carbonate ester, tert-butyl carbonate ester, cyclohexyl carbonate ester, n -Octyl carbonate, lauryl carbonate, benzyl carbonate, vinyl carbonate and allyl carbonate are exemplified.
  • orthoesters examples include ethoxymethylene acetal.
  • sulfonic acid ester examples include methanesulfonic acid ester, ethanesulfonic acid ester, propanesulfonic acid ester, butanesulfonic acid ester, and octanesulfonic acid ester.
  • sulfinic acid ester examples include methane sulfinic acid ester, ethane sulfinic acid ester, propane sulfinic acid ester, butane sulfinic acid ester, and pentadecane sulfinic acid ester.
  • carbamic acid ester examples include N-methylcarbamic acid ester, N, N-dimethylcarbamic acid ester, N -ethylcarbamic acid ester, N, N-diethylcarbamic acid ester, N-propylcarbamic acid ester, N-methyl- Examples thereof include N-propylcarbamic acid ester and N-cyclohexylcarbamic acid ester.
  • esters are exemplified.
  • formic acid ester acetic acid ester, monochloroacetic acid ester, dichloroacetic acid ester, trichloroacetic acid ester, trifluoroacetic acid ester, methoxyacetic acid ester, pivalic acid ester, benzoic acid ester, 4-nitrobenzoic acid ester, 4-fluorobenzoic acid ester 3,5-dichlorobenzoate, 3-hydroxybenzoate, 3-acetyloxybenzoate, 3-galloyloxybenzoate, 3-methoxybenzoate, 4-hydroxybenzoate, 4-galloyloxybenzoate Acid ester, 4-acetyloxybenzoic acid ester, 4-methoxybenzoic acid ester, 3,4-dihydroxybenzoic acid ester, 3,4-digalloylbenzoic acid ester, 3-methoxy-4-galloylbenzoic acid ester, 3-methoxy-4-galloylbenzoic acid
  • silyloxy examples include trimethylsilyloxy, triethylsilyloxy, triphenylsilyloxy, tert-butyldimethylsilyloxy, diilopropylmethylsilyloxy, and triisopropylsilyloxy.
  • acetals include methylene acetal, ethylidene acetal, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl, and n-propoxymethyl.
  • ketal is isopropylidene ketal.
  • R 9 is a galloyl group
  • a combination in which R 9 is a galloyl group is preferable from the viewpoint of excellent ceramide synthesis effect.
  • the following compounds are exemplified.
  • These compounds represented by the formula (II) may be either chemically synthesized or purified from the natural world, and the production method is not particularly limited.
  • the “pharmaceutically acceptable salt” is also included as a compound represented by the formula (II).
  • alkali metals lithium, sodium, potassium, etc.
  • alkaline earth metals magnesium, calcium, etc.
  • ammonium organic bases
  • organic bases triethanolamine, triethylamine, aminopropanediol, pyridine, piperidine, pyrimidine, Piperazine, morpholine, azepine, etc.
  • salts with amino acids inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, periodic acid, boric acid, etc.), organic acids (acetic acid, citric acid, etc.) Acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, carboxylic acid, sulfonic acid, phosphonic acid, sulfinic acid, trifluoroacetic acid and
  • the carbon chain portion of the organic acid salt may be a linear, branched, or cyclic aliphatic acid salt or aromatic acid salt.
  • the salt with an organic base or organic acid may contain one or a plurality of heteroatoms selected from an oxygen atom and a nitrogen atom, for example, in the form of a hydroxyl group.
  • the compound represented by the formula (II) and pharmaceutically acceptable salts thereof include solvates such as hydrates and ethanol solvates thereof. These can be prepared according to known methods.
  • a compound selected from the following is preferable.
  • the total content in the ceramide synthesis accelerator of the present invention is not particularly limited, and is usually about 0.0001 to 100% by mass.
  • the compound of the aspect 2 of the present invention exhibits an excellent ceramide synthesis promoting action as described in Examples described later.
  • the ceramide synthesis promoting action refers to an action to increase compared with the normal intracellular ceramide amount, and can be confirmed, for example, by the method described in the examples described later.
  • the compound of aspect 2 of the present invention is, for example, 5% or more, preferably 10% or more, more preferably 20% or more, still more preferably 40% or more, still more preferably 60%, compared with the normal intracellular ceramide amount. It is desirable to have an effect of increasing the above.
  • the ceramide synthesis promoter of the present invention increases the amount of ceramide in the cells, and consequently increases the amount of ceramide in the stratum corneum, thereby improving the moisturizing effect, improving wrinkles, improving the symptoms of atopic dermatitis, sebum deficiency ( Prevention / improvement of xeroderma), prevention of stains, improvement of skin talmi, anti-pruritic action, melanin production suppression effect, improvement of barrier function, fibroblast activation effect, skin cell regeneration effect, wound healing effect
  • it can be suitably used as a prophylactic, ameliorating and / or therapeutic agent for symptoms and diseases based on a decrease in the amount of ceramide in cells or in the skin.
  • alopecia areata
  • contact dermatitis infectious impetigo
  • Kaposi's chickenpox-like rash cataract
  • retinal detachment prurigo
  • lysosomal disease Can be used.
  • the form of the ceramide synthesis promoter of the present invention is not particularly limited as long as the compound of aspect 2 of the present invention can be applied to the surface of the target substance or ingested into the body. You may prepare in the form which can be used for raw materials, such as a quasi-drug and cosmetics.
  • the present invention also provides a composition containing the ceramide-degrading enzyme inhibitor or ceramide synthesis promoter of the present invention.
  • the form of the composition is not particularly limited as long as the compound of aspect 1 or aspect 2 of the present invention can be taken into cells.
  • the form as an external preparation composition from the viewpoint of exhibiting the effect From the viewpoint of being easily ingested a form as an internal use composition is exemplified.
  • an external preparation composition it can be provided as a pharmaceutical composition, a quasi-drug composition, and a cosmetic composition.
  • the form of the external preparation composition examples include solid, semi-solid or liquid preparations for transdermal administration or transmucosal (intraoral or intranasal) administration. Suppositories are also included. For example, emulsions such as emulsions and lotions, tinctures for external use, liquid preparations such as liquids for transmucosal administration, ointments such as oily ointments and hydrophilic ointments, transdermal administration such as films, tapes, and poultices Or for transmucosal administration, aerosols, sprays such as sprays, bathing agents and the like.
  • emulsions such as emulsions and lotions, tinctures for external use
  • liquid preparations such as liquids for transmucosal administration
  • ointments such as oily ointments and hydrophilic ointments
  • transdermal administration such as films, tapes, and poultices Or for transmuco
  • a cosmetic composition for example, basic cosmetics such as lotions, emulsions, creams, oils, packs, gels, makeup cosmetics such as foundations, blushers, lipsticks, waxes, hair artnics, soaps, In any form such as shampoo, facial cleansing foam, cleansing, body cleansing and other cleansing agents, eau de cologne, deodorant, perfume skin perfume, mouthwash, toothpaste gel, toothpaste, oral cosmetics such as oral gel, bathing agent, etc. Can be used.
  • an internal use composition it can be provided as a pharmaceutical composition, a quasi-drug composition, and a cosmetic composition (beauty composition).
  • Examples of the form of the internal use composition include a form that can be easily blended (for example, powder form and granule form) and a tablet form and a liquid form from the viewpoint of being easily ingested.
  • a form that can be easily blended for example, powder form and granule form
  • a tablet form and a liquid form from the viewpoint of being easily ingested.
  • composition of the present invention having the above-described form contains at least one compound of the first or second aspect of the present invention
  • a carrier or group usually used in the pharmaceutical field, cosmetic field or the like according to a conventional method.
  • An agent and / or an additive and the like can be appropriately blended and prepared within a range that achieves the object of the present invention.
  • Carriers, bases, and / or additives used in the pharmaceutical field include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hydrogenated vegetable oil, talc, etc.
  • Binder distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrator sodium alginate, agar, sodium bicarbonate, Calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.
  • disintegration inhibitors sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.
  • disintegration inhibitors sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.
  • disintegration inhibitors sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic
  • Carriers, bases, and / or additives used in the cosmetics field include oils (butyl myristate, isobutyl myristate, butyl palmitate, isobutyl palmitate, butyl stearate, isobutyl stearate, butyl isostearate, myristine Cetyl acid, isostearyl laurate, isostearyl myristate, propylene glycol dicaprate, isostearyl adipate, squalane, liquid paraffin, isoparaffin, beef tallow, lard, mink oil, fish oil, corn oil, cocoa butter, almond oil, beeswax Lanolin, reduced lanolin, liquid lanolin, etc.), higher alcohols (lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, hexyl) Decyl alcohol, etc.), fatty acids (caprylic acid, capric acid, unde
  • compositions are prepared according to a known production method when at least one compound of Embodiment 1 or Embodiment 2 of the present invention is used as a raw material when preparing a known pharmaceutical, quasi-drug, or cosmetic. be able to.
  • At least one of the compounds of Embodiment 1 or Embodiment 2 of the present invention is used as it is or a combination of two or more thereof is mixed with a highly water-soluble solvent or compound such as purified water, ethanol or glycerin. Then, the dissolved product is slowly mixed with a pre-mixed fat-soluble substance such as squalane, jojoba oil, glycerin monostearate to prepare a cosmetic liquid and / or cosmetic cream. I can do it.
  • At least one of the compounds of Embodiment 1 or Embodiment 2 of the present invention is used as it is, or a combination of two or more thereof is dried, various solutions, pastes, etc., and various additives, carriers, groups Ingredients, etc. are formulated into solid preparations such as tablets, granules, powders, powders, capsules, etc., and liquid preparations such as normal solutions, suspensions, emulsions, etc. according to conventional methods in the art. Can do.
  • composition of the present invention can be used for other components that can be used in the same applications as the compound of the aspect 1 or aspect 2 of the present invention, such as a known ceramide degrading enzyme inhibitory action and / or a known ceramide synthesis promoting action or a known action.
  • Moisturizing ingredients eg, aloe vera, betaine, pullulan, petrolatum, glycerin, sodium lactate, urea, propylene glycol, sodium ribonucleic acid, 1,3-butylene glycol, chitosan, trehalol, royal jelly, niacinamide, ceramide, tocopheryl Sodium phosphate, lactoferrin, oligomarine, extensin, hyaluronic acid, collagen) and the like.
  • Moisturizing ingredients eg, aloe vera, betaine, pullulan, petrolatum, glycerin, sodium lactate, urea, propylene glycol, sodium ribonucleic acid, 1,3-butylene glycol, chitosan, trehalol, royal jelly, niacinamide, ceramide, tocopheryl Sodium phosphate, lactoferrin, oligomarine, extensin, hyaluronic acid,
  • the compound of Embodiment 1 of the present invention and a component having a known ceramide synthesis promoting action, or a known ceramide degrading enzyme inhibitory action
  • the component described here can use a natural product, a synthetic product, and a commercial item together in particular without limitation.
  • composition of the present invention may contain an antioxidant.
  • the antioxidant include, but are not limited to, for example, tocopherol, tocopherol acetate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, coenzyme Q10, ⁇ -lipoic acid, fullerene, astaxanthin, organic germanium, dimethylaminoethanol, hydroxytyro Sole and platinum nanocolloid.
  • the content of the compound of embodiment 1 or 2 of the present invention in the composition of the present invention is such that the desired effect of the present invention can be obtained in consideration of its use form, method of use, etc.
  • the content of the compound of Embodiment 1 or Embodiment 2 of the present invention is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, and still more preferably 0.
  • content of the compound of the aspect 1 or aspect 2 of this invention becomes like this from the viewpoint of exhibiting the effect, Preferably it is 0.01 mass% or more, More preferably, it is 0.1. It is at least mass%, more preferably at least 1.0 mass%.
  • an upper limit is not set in particular, For example, 50 mass% or less is preferable.
  • composition of the present invention is used in an appropriate usage according to its form. Specifically, for example, it can be used by internal use, external use, and injection.
  • the usage amount of the composition of the present invention is appropriately set according to the form, usage method, purpose of use, and age, weight, and symptom of the patient who is the subject of the composition, and is not constant.
  • an external preparation composition usually about 0.1 ⁇ g to 5 g / day is preferably exemplified per weight of about 50 kg per adult, within a desired use amount range, once in a day, or It may be used in several times.
  • the period of use is also arbitrary.
  • “use” includes not only “use” but also “administration” and “intake”.
  • the subject of the composition of the present invention is preferably a human who needs to increase the amount of ceramide by inhibiting ceramide-degrading enzyme in the skin and requiring an increase in the amount of ceramide or promoting ceramide synthesis in the skin. It may be a pet animal or the like. Specifically, it can be used in the same applications as the ceramide-degrading enzyme inhibitor of the present invention and the ceramide synthesis accelerator of the present invention, and the above can be referred to.
  • Example 1-1 The in vitro ceramide-degrading enzyme inhibitory activity of each compound was measured. In addition, except the sample manufactured in the said manufacture example 1, what was synthesize
  • a rat brain-derived ceramidase enzyme solution was prepared by the method of Yavin, Gatt et al. Rat brain-derived enzyme solution 5 ⁇ L, sample compound 15 ⁇ L (final concentration 10 mM, with some exceptions) and C6-NBD-ceramide (manufactured by Matreya) as substrate were mixed and reacted at 37 ° C. for 15 hours. The reaction was stopped by adding 100 ⁇ L of methanol, and solidified using nitrogen gas. This was dissolved in 20 ⁇ L of methanol and spotted on TLC.
  • Example 1-2 The increase in the amount of ceramide in vivo by each compound was measured.
  • A, B, and C were defined as application sites.
  • the A part contains 50% ethanol aqueous solution containing 2% by mass of n-octyl- ⁇ -D-glucopyranoside
  • the B part contains 1,5-anhydroglucitol- 50% aqueous ethanol solution containing 2% by mass of 6-octanoic acid ester (6-Octanoyl-1,5-anhydroglucitol)
  • C part contains 2,3-digalloyl-1,5-anhydroglucitol (2,3- Digalloyl-1,5-anhydroglucitol) containing 50% ethanol aqueous solution containing 2% by mass was applied twice a day in the morning and evening for 28 days.
  • the stratum corneum was sampled by tape stripping from the application sites A, B, C and the non-application site (D portion), and the amount of skin ceramide was calculated by performing the following operations for the application site or the non-application site, respectively. .
  • the results are shown in Table 8.
  • the ceramidase inhibition rate of each compound is the result of Example 1-1.
  • the obtained spot is analyzed using ImageJ, the relative values of the application sites A, B, and C when the color development of the non-application site D is set to 1 are calculated, and the degree of increase in the amount of skin ceramide by sample application is analyzed .
  • Example 2-1 The in vitro ceramide synthesis amount of each compound was measured. Except for the samples produced in Production Examples 1 and 2, commercially available products and those synthesized according to known methods were used.
  • human keratinocyte cell line PHK16-0b cells obtained from JCRB cell bank
  • NBD-hexanoic acid was added to a final concentration of 10 ⁇ M 24 hours after the start of the culture, and at the same time, a measurement sample was added to a final concentration of 50 ⁇ M.
  • the cells were washed with PBS ( ⁇ ), and a cell suspension was obtained by trypsinization. Protein quantification was performed by the BCA method, and the protein amount between each test sample was corrected. Lipid extraction was performed using the Bligh & Dyer method and solidified using nitrogen gas.
  • the obtained lipid extract was dissolved by adding 20 ⁇ L of methanol and spotted on TLC.
  • the amount of NBD-ceramide developed using chloroform / methanol / ammonia (90/20 / 0.5) (v / v / v) as the developing solvent and purified in the cells was measured with an image analyzer (Fuji Film, GE Healthcare). Quantitative analysis was performed using ImageQuant LAS-4000), and the ratio to the amount of ceramide in untreated cells was calculated to obtain the ratio of the amount of ceramide synthesized. The results are shown in FIG. Quercetin was used as a negative control.
  • FIG. 2 confirms that ceramide synthesis promoting action by these components is confirmed, and it is considered that the effect of maintaining the skin barrier function and moisturizing is high.
  • Example 2-2 The wound healing effect of 6-galloyl-1,5-anhydro-D-glucitol was evaluated.
  • Example 2-1 using a wound healing assay kit (CytoSelect 24-well Wound Healing Assay: manufactured by Cell Biolabs), first, the same human as in Example 2-1 was mounted on a 24-well culture plate equipped with an insert (partition plate). After corneum cells were seeded and after confirming that the cells were confluent about 12 hours later, the insert was removed from the 24-well culture plate to form a gap (wound part). Cells were washed and aspirated with PBS to remove floating cells. Then, a medium containing 50 ⁇ M of the compound was newly added and cultured under the conditions of 37 ° C. and 5% CO 2 , and the state in which the gap was filled was observed with a microscope over time. As a control, a culture cultured without adding the compound was prepared in the same manner. The results are shown in FIG.
  • the compound-added group has a quicker gap filling than the non-added group, and the wound healing effect is high.
  • each formulation example means mass% of each component.
  • the ceramide-degrading enzyme inhibitor and ceramide synthesis promoter of the present invention increase the amount of ceramide in cells or skin.
  • moisturizing effect improvement of wrinkles, improvement of symptoms of atopic dermatitis, prevention / improvement of dry skin disease It is suitably used for the prevention of spots, the improvement of skin tarmi, the anti-pruritic action, the melanin production inhibitory effect, the improvement of the barrier function, the fibroblast activation effect, and the skin cell regeneration effect.

Abstract

L'invention concerne un inhibiteur de céramidase comprenant un composé représenté par une formule (I) ou son sel pharmaceutiquement acceptable ; et un activateur de synthèse de céramides comprenant un composé représenté par une formule (II) ou son sel pharmaceutiquement acceptable. L'inhibiteur de céramidase et l'activateur de synthèse de céramides, selon la présente invention, peuvent augmenter la quantité de céramide dans des cellules ou dans la peau et ainsi, peuvent être tout à fait appropriés pour, par exemple, l'hydratation, l'atténuation des rides, l'amélioration de symptômes d'une dermatite atopique, la prévention/le traitement de la xérodermie, empêcher l'apparition de taches, raffermir une peau flasque, contrer les démangeaisons, supprimer la mélanogénèse, renforcer la fonction barrière, activer les fibroblastes et régénérer les cellules cutanées.
PCT/JP2016/087537 2016-01-13 2016-12-16 Agents augmentant la teneur en céramides WO2017122495A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066237A1 (fr) * 2017-09-26 2019-04-04 주식회사 아모레퍼시픽 COMPOSITION DE PRÉPARATION CUTANÉE EXTERNE POUR HYDRATER LA PEAU CONTENANT DU 1,2,3,4,6-PENTA-O-GALLOYL-β-D-GLUCOSE
WO2020104687A1 (fr) * 2018-11-24 2020-05-28 Momentive Performance Materials Gmbh Utilisation de composés polyhydroxyaromatiques pour le traitement de substrats fibreux à base d'acides aminés
US10953027B2 (en) 2018-06-05 2021-03-23 Flagship Pioneering Innovations V, Inc. Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease
US11058698B2 (en) 2018-06-05 2021-07-13 Flagship Pioneering Innovations V, Inc. Acylated active agents and methods of their use for the treatment of autoimmune disorders

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242526A (ja) * 1994-03-03 1995-09-19 Sogo Yatsukou Kk 化粧料
JPH11255656A (ja) * 1998-03-10 1999-09-21 Nippon Beet Sugar Mfg Co Ltd 抗アトピー性皮膚炎組成物
WO1999047541A1 (fr) * 1998-03-19 1999-09-23 Nissin Food Products Co., Ltd. Composes steroides glycosyles a substitution en position 21
JP2004517109A (ja) * 2000-12-30 2004-06-10 エルジー ハウスホールド アンド ヘルスケア カンパニー．， リミテッド． グルコースアシル化誘導体またはシュークロースアシル化誘導体を含有する皮膚美白剤｛Ｃｏｓｍｅｔｉｃｆｏｒｓｋｉｎｗｈｉｔｅｎｉｎｇｃｏｎｔａｉｎｉｎｇａｃｙｌｓｕｂｓｔｉｔｕｔｅｄｄｅｒｉｖａｔｉｖｅｓｏｆｇｌｕｃｏｓｅｏｒｓｕｃｒｏｓｅ｝
JP2011006341A (ja) * 2009-06-24 2011-01-13 Hiroshima Univ アトピー性皮膚炎用皮膚外用剤
JP2014088329A (ja) * 2012-10-29 2014-05-15 Picaso Cosmetic Laboratory Ltd 美容用組成物
WO2014171279A1 (fr) * 2013-04-15 2014-10-23 国立大学法人富山大学 Accélérateur de production de collagène contenant du 1,5-anhydro-d-glucitol
WO2015154074A1 (fr) * 2014-04-04 2015-10-08 Rhode Island Board Of Education, State Of Rhode Island & Providence Plantations Procédés de blanchiment de la peau à l'aide d'un gallotannin

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0977660A (ja) * 1995-09-08 1997-03-25 Pola Chem Ind Inc メラニン産生抑制剤及び皮膚外用剤
JPH1028726A (ja) * 1996-07-17 1998-02-03 Mitsubishi Plastics Ind Ltd 創傷被覆材
JP4601088B2 (ja) * 1998-08-07 2010-12-22 ピアス株式会社 スフィンゴミエリナーゼ活性を亢進するセラミド合成促進剤
JP2008201772A (ja) * 2007-01-26 2008-09-04 Shiseido Co Ltd 抗しわ剤およびａｄａｍ阻害剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242526A (ja) * 1994-03-03 1995-09-19 Sogo Yatsukou Kk 化粧料
JPH11255656A (ja) * 1998-03-10 1999-09-21 Nippon Beet Sugar Mfg Co Ltd 抗アトピー性皮膚炎組成物
WO1999047541A1 (fr) * 1998-03-19 1999-09-23 Nissin Food Products Co., Ltd. Composes steroides glycosyles a substitution en position 21
JP2004517109A (ja) * 2000-12-30 2004-06-10 エルジー ハウスホールド アンド ヘルスケア カンパニー．， リミテッド． グルコースアシル化誘導体またはシュークロースアシル化誘導体を含有する皮膚美白剤｛Ｃｏｓｍｅｔｉｃｆｏｒｓｋｉｎｗｈｉｔｅｎｉｎｇｃｏｎｔａｉｎｉｎｇａｃｙｌｓｕｂｓｔｉｔｕｔｅｄｄｅｒｉｖａｔｉｖｅｓｏｆｇｌｕｃｏｓｅｏｒｓｕｃｒｏｓｅ｝
JP2011006341A (ja) * 2009-06-24 2011-01-13 Hiroshima Univ アトピー性皮膚炎用皮膚外用剤
JP2014088329A (ja) * 2012-10-29 2014-05-15 Picaso Cosmetic Laboratory Ltd 美容用組成物
WO2014171279A1 (fr) * 2013-04-15 2014-10-23 国立大学法人富山大学 Accélérateur de production de collagène contenant du 1,5-anhydro-d-glucitol
WO2015154074A1 (fr) * 2014-04-04 2015-10-08 Rhode Island Board Of Education, State Of Rhode Island & Providence Plantations Procédés de blanchiment de la peau à l'aide d'un gallotannin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAMORI, A. ET AL.: "Dual action of acertannins as potential regulators of intracellular ceramide levels", TETRAHEDRON : ASYMMETRY, vol. 27, no. 22, 12 October 2016 (2016-10-12), pages 1177 - 1185, XP029789149, DOI: 10.1016/j.tetasy.2016.09.006 *
LEE, YOUN-SUN. ET AL.: "Protective effect of ginsenoside Rg1 on H2O2-induced cell death by the decreased ceramide level in LLC- PK 1 cells", JOURNAL OF GINSENG RESEARCH, 2006, pages 30 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019066237A1 (fr) * 2017-09-26 2019-04-04 주식회사 아모레퍼시픽 COMPOSITION DE PRÉPARATION CUTANÉE EXTERNE POUR HYDRATER LA PEAU CONTENANT DU 1,2,3,4,6-PENTA-O-GALLOYL-β-D-GLUCOSE
US11185488B2 (en) 2017-09-26 2021-11-30 Amorepacific Corporation Skin external preparation composition for moisturizing skin containing 1,2,3,4,6-penta-O-galloyl-β-D-glucose
US10953027B2 (en) 2018-06-05 2021-03-23 Flagship Pioneering Innovations V, Inc. Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease
US11058698B2 (en) 2018-06-05 2021-07-13 Flagship Pioneering Innovations V, Inc. Acylated active agents and methods of their use for the treatment of autoimmune disorders
US11813272B2 (en) 2018-06-05 2023-11-14 Flagship Pioneering Innovations V, Inc. Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease
WO2020104687A1 (fr) * 2018-11-24 2020-05-28 Momentive Performance Materials Gmbh Utilisation de composés polyhydroxyaromatiques pour le traitement de substrats fibreux à base d'acides aminés
CN113329993A (zh) * 2018-11-24 2021-08-31 迈图高新材料有限责任公司 多羟基芳族化合物用于处理基于氨基酸的纤维状基质的用途

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