WO2010058730A1 - シワ改善剤 - Google Patents

シワ改善剤 Download PDF

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Publication number
WO2010058730A1
WO2010058730A1 PCT/JP2009/069261 JP2009069261W WO2010058730A1 WO 2010058730 A1 WO2010058730 A1 WO 2010058730A1 JP 2009069261 W JP2009069261 W JP 2009069261W WO 2010058730 A1 WO2010058730 A1 WO 2010058730A1
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Prior art keywords
group
carbon atoms
cysteine
hydrogen atom
acid
Prior art date
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PCT/JP2009/069261
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English (en)
French (fr)
Japanese (ja)
Inventor
末延　則子
千尋 近藤
山崎　貴史
Original Assignee
ポーラ化成工業株式会社
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Priority to RU2011124914/15A priority Critical patent/RU2503443C2/ru
Priority to MX2011004006A priority patent/MX2011004006A/es
Priority to EP17151667.7A priority patent/EP3173063B1/en
Priority to AU2009318483A priority patent/AU2009318483B2/en
Application filed by ポーラ化成工業株式会社 filed Critical ポーラ化成工業株式会社
Priority to ES09827511.8T priority patent/ES2650252T3/es
Priority to CA2742909A priority patent/CA2742909C/en
Priority to US13/126,714 priority patent/US8835498B2/en
Priority to JP2010539212A priority patent/JP5746864B2/ja
Priority to EP09827511.8A priority patent/EP2356979B1/en
Priority to BRPI0921303A priority patent/BRPI0921303B8/pt
Priority to CN200980146822.8A priority patent/CN102215812B/zh
Priority to UAA201107663A priority patent/UA107919C2/ru
Publication of WO2010058730A1 publication Critical patent/WO2010058730A1/ja
Priority to IL212909A priority patent/IL212909A/en
Priority to HK12101057.4A priority patent/HK1160405A1/zh

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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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/463—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfuric acid derivatives, e.g. sodium lauryl sulfate
    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/17—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/18—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton containing amino groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Definitions

  • the present invention relates to a wrinkle-improving agent, and further relates to a skin external preparation containing the wrinkle-improving agent, in particular, cosmetics and the like. Furthermore, it is related with the novel compound which has a wrinkle improvement effect.
  • the wrinkle formation mechanism includes cell damage caused by ultraviolet rays and the like, cell apoptosis that is enhanced by the damage, and fiber components such as collagen caused by enhanced expression of proteases such as matrix metalloproteinase (MMP).
  • MMP matrix metalloproteinase
  • hydrolysis of the fiber bundle and disruption of the fiber bundle due to enhancement of cytokines can be exemplified.
  • MMP has various functions such as extracellular matrix composed of collagen, proteoglycan and elastin, and degradation of proteins expressed on the cell surface, and there are many subtypes.
  • MMP1 degrades type I and type III collagens, which are the major components of the dermal matrix.
  • MMP2 and MMP9 degrade type IV collagen and laminin, which are basement membrane components, and elastin, which is a dermal matrix component.
  • MMP3 and MMP10 degrade proteoglycan, type IV collagen, laminin and the like. These degradation actions are considered to be one of the important factors that cause reduction / denaturation of the extracellular matrix and form wrinkles and sagging in the skin (see Patent Document 1).
  • inflammatory cytokines such as TNF- ⁇ , IL-1 and IL-6 are known to be involved in the formation of wrinkles and sagging by inducing the production of MMP (see Patent Document 2).
  • these factors that are deeply involved in the skin aging phenomenon such as wrinkles and sagging are not said to be independent factors, but are also said to influence each other. It can be said that it is complicated.
  • Non-Patent Document 1 Retinoic acid has been approved in the United States for the treatment of wrinkles and acne and is used by a large number of patients as a skin rejuvenating agent. In Japan, however, there are problems with safety such as skin irritation. Exists and is not authorized. In addition to attempts to improve wrinkles by adding collagen and hyaluronic acid (see Patent Documents 3 and 4), ascorbic acid (see Patent Document 5), tocopherol (see Patent Document 6), etc. Is known as a wrinkle improving agent.
  • the wrinkle-improving agent has a problem in safety or stability that the wrinkle-improving effect is not sufficient, an undesired medicinal effect is expressed at a concentration that exhibits the wrinkle-improving effect, and the like. For the reason, a sufficiently satisfactory wrinkle improving material has not been found, and the appearance of a new wrinkle improving agent has been strongly desired.
  • amino acids there are many amino acids, including natural and non-natural amino acids. These amino acids are known to exhibit various physiological activities in addition to functional polymers that control biological structure maintenance and biological reactions. Natural amino acids or derivatives thereof are expected to have not only physiological activity but also high safety, and are widely used in the fields of food, cosmetics, pharmaceuticals and the like.
  • alanine has a whitening effect (see Patent Document 7)
  • an ⁇ -amino acid derivative has an inhibitory effect on keratinization, a pore-reducing effect, or a rough skin prevention / amelioration effect (see Patent Document 8).
  • homocysteic acid promotes skin exfoliation or epidermal hypersensitivity (see Patent Document 9)
  • N-acylamino acid promotes hair growth and moisturizing (see Patent Document 10)
  • essential amino acids such as glutamine activate cells.
  • Patent Document 11 alanine is known to have a wrinkle improving action (see Patent Document 12).
  • JP 2001-192317 A Japanese Patent Laying-Open No. 2005-089304 JP-A-33-500 JP 2007-191396 A JP 2003-267856 A JP-A-62-19511 JP 11-049629 A JP 2006-327971 A Japanese Patent Laid-Open No. 9-110627 JP-A-11-080105 JP-A 61-289016 JP 11-49628 A
  • the present invention has been made in view of the above situation, and an object of the present invention is to provide a wrinkle improving agent having a novel mother nucleus, which is suitable as a component of an external preparation for skin.
  • the present inventors have sought a new mother nucleus having a wrinkle-improving action.
  • the compounds represented by the following general formula (1), their stereoisomers, and their pharmacological properties The inventors have found that an acceptable salt has an excellent wrinkle improving effect against wrinkles formed by exposure to ultraviolet rays and the like, and have completed the invention.
  • a wrinkle improving agent comprising a compound represented by the following general formula (1), a stereoisomer thereof, or a pharmacologically acceptable salt thereof.
  • R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 2 represents —SH, —SO 3 H, —SS—X 1 , —S Represents —X 2 , —SO—X 3 , —SO 2 —X 4 , —SO 2 —NY 1 —X 5 , or —SO 2 —NY 2 —Y 3
  • X 1 to X 5 are independently A hydrogen atom or a carbon atom optionally substituted with a hetero atom, an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic moiety having 5 to 12 carbon atoms, wherein Y 1 to Y 3 are: Independently, it represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R 2
  • R 4 may have a unsubstituted or substituted group, an aromatic group or a polycyclic fused aromatic group having 5 to 12 carbon atoms, m is an integer of 0-3 The stands, n represents an integer of 1 or 2.
  • the wrinkle improving agent according to ⁇ 1> wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2).
  • R 5 represents a hydrogen atom, or a linear or branched alkyl group having a carbon number of 1 ⁇ 8
  • R 6 represents -S-X 2
  • X 2 is a hydrogen atom or a carbon atom
  • R 7 represents a hydrogen atom or a straight chain having 1 to 8 carbon atoms.
  • R 8 represents an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms or a polycyclic fused aromatic group
  • m represents , Represents an integer of 0 to 3, and n represents an integer of 1 or 2.
  • the wrinkle improving agent according to ⁇ 1> wherein the compound represented by the general formula (1) is a compound represented by the following general formula (4).
  • R 12 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 13 represents a carbon atom in which the hydrogen atom or carbon atom may be substituted with a hetero atom.
  • R 1 represents an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic part having 5 to 12 carbon atoms
  • R 14 is an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms or a multivalent group.
  • m represents an integer of 0 to 3.
  • the wrinkle improving agent according to ⁇ 1> wherein the compound represented by the general formula (1) is a compound represented by the following general formula (5).
  • R 15 represents a hydrogen atom, or a linear or branched alkyl group having a carbon number of 1 ⁇ 8
  • R 16 represents -SO 3 H, or -SO 2 -X 4, wherein X 4 Represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic part having 5 to 12 carbon atoms, in which a carbon atom may be substituted with a hetero atom
  • R 17 represents a hydrogen atom, or Represents an acyl group having a linear or branched alkyl chain having 1 to 8 carbon atoms
  • R 18 is an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms or a polycyclic fused aromatic group.
  • Represents a group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2.
  • the wrinkle improving agent according to ⁇ 1> wherein the compound represented by the general formula (1) is a compound represented by the following general formula (6).
  • R 19 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R 20 may be unsubstituted or substituted, and may have 5 to 12 carbon atoms.
  • An aromatic group or a polycyclic fused aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2.
  • R 15 represents a hydrogen atom, or a linear or branched alkyl group having a carbon number of 1 ⁇ 8
  • R 16 represents -SO 3 H, or -SO 2 -X 4, wherein X 4 Represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic part having 5 to 12 carbon atoms, in which a carbon atom may be substituted with a hetero atom
  • R 17 represents a hydrogen atom, or Represents an acyl group having a linear or branched alkyl chain having 1 to 8 carbon atoms
  • R 18 is an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms or a polycyclic fused aromatic group.
  • Represents a group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2.
  • R 19 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 20 may be unsubstituted or substituted, and may have 5 to 12 carbon atoms.
  • An aromatic group or a polycyclic fused aromatic group, m represents an integer of 0 to 3, and n represents an integer of 1 or 2.
  • ⁇ 9> A skin external preparation containing 0.001 to 20% by mass of the wrinkle improving agent according to any one of ⁇ 1> to ⁇ 6>.
  • ⁇ 11> A method for improving wrinkles, comprising administering a compound represented by the following general formula (1), a stereoisomer thereof, or a pharmacologically acceptable salt thereof to a site where wrinkle improvement is necessary. A method characterized by.
  • R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 2 represents —SH, —SO 3 H, —SS—X 1 , —S Represents —X 2 , —SO—X 3 , —SO 2 —X 4 , —SO 2 —NY 1 —X 5 , or —SO 2 —NY 2 —Y 3
  • X 1 to X 5 are independently A hydrogen atom or a carbon atom optionally substituted with a hetero atom, an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic moiety having 5 to 12 carbon atoms
  • Y 1 to Y 3 are: Independently, it represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R 3 represents a hydrogen atom or an acyl group having a linear or branched alkyl chain having 1 to 8 carbon atoms.
  • R 4 may have a unsubstituted or substituted group, an aromatic group or a polycyclic fused aromatic group having 5 to 12 carbon atoms, m is an integer of 0-3 The stands, n represents an integer of 1 or 2.
  • a new wrinkle improving agent can be provided. Moreover, the skin external preparation and cosmetics containing a new wrinkle improving agent can be provided. Moreover, the novel compound which has a wrinkle improvement effect can be provided.
  • the compound represented by the general formula (1) contained in the wrinkle improving agent of the present invention is a compound represented by the following general formula (1), its stereoisomer, Or a pharmacologically acceptable salt thereof.
  • R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 2 represents —SH, —SO 3 H, —SS—X 1 , —S—X 2 , —SO—X 3 , —SO 2 —X 4 , —SO 2 —NY 1 —X 5 , or —SO 2 —NY 2 —Y 3 , wherein X 1 to X 5 are Independently, a hydrogen atom or a carbon atom may be substituted with a hetero atom, an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic moiety having 5 to 12 carbon atoms, and the above Y 1 to Y 3 independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, and R 3 represents a hydrogen atom or an acyl having a linear or branched alkyl chain having 1 to 8 carbon atoms.
  • R 4 represents an aromatic group or a polycyclic fused aromatic group unsubstituted or carbon atoms which may have a substituent 5 ⁇ 12
  • m is It represents an integer of ⁇ 3
  • n represents an integer of 1 or 2.
  • aromatic groups such as a phenyl group, pyridyl group, naphthyl group, and biphenyl group
  • the aromatic part includes aromatic hydrocarbon groups such as a toluyl group, a xylyl group, a benzyl group, and a naphthylmethyl group. Shall be included.
  • a compound represented by the general formula (2) described later and a compound represented by the general formula (5) described later can be exemplified as preferable examples.
  • the compounds represented by the general formula (2) more preferred are compounds represented by the general formula (3), and still more preferred are compounds represented by the general formula (4).
  • the compounds represented by the general formula (5) the compound represented by the general formula (6) is more preferable.
  • the compound in which R 2 is a thiol group forms a dimer by disulfide bonding of the thiol moiety. It is contained in the general formula (1) of the present invention.
  • wrinkle improvement containing a compound contained in the general formula (1) which is not included in any of the compound represented by the general formula (2) and the compound represented by the general formula (5)
  • the agent is also a wrinkle improving agent of the present invention.
  • Y 1 to Y 3 in R 1 and R 2 include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group.
  • a linear or branched alkyl group having 1 to 4 carbon atoms is preferable, and more preferable are a hydrogen atom, a methyl group, and an ethyl group.
  • X 1 to X 6 in R 2 are methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, phenyl group, toluyl group, benzyl group, phenethyl group, Examples include phenylpropyl group, pyridyl group, quinolyl group, naphthyl group, biphenyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group and the like.
  • R 2 —SO 3 H, —S—X 2 , and —SO 2 —X 4 are preferable.
  • R 3 include a hydrogen atom, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, and octanoyl group. Of these, preferred are a hydrogen atom, an acetyl group, and a propionyl group.
  • R 4 include phenyl group, toluyl group, ethylphenyl group, propylphenyl group, butylphenyl group, pentylphenyl group, hexylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, Butyloxyphenyl group, pentyloxyphenyl group, hexyloxyphenyl group, hydroxyphenyl group, aminophenyl group, fluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, dichlorophenyl group, nitrophenyl group, cyanophenyl group, (N- Methylamino) phenyl group, (N-ethylamino) phenyl group, (N-propylamino) phenyl group, (N-butylamino) phenyl group, N, N- (dimethylamino)
  • phenyl preferred are phenyl, toluyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl, trifluorophenyl, naphthyl, biphenyl and the like.
  • the compound represented by the general formula (1) can be produced by a method described later.
  • Such a compound is excellent in the potency of the compound for the wrinkle improving effect and / or the skin retention of the compound, and as a result, has an advantage of having an excellent wrinkle improving effect for wrinkles formed by ultraviolet exposure or the like.
  • skin safety is extremely high, such as low skin irritation and sensitization.
  • since it is highly soluble not only in nonpolar solvents but also in polar solvents there is no possibility of limiting the compounding amount of the compound itself, or the possibility thereof is extremely low.
  • These compounds have a procollagen production promoting action and express wrinkle improving effects.
  • the wrinkle improving effect is expressed through the inhibitory action of the above MMPs or IL-1 or IL-6.
  • R 5 represents a hydrogen atom, or a linear or branched alkyl group having a carbon number of 1 ⁇ 8
  • R 6 represents -S-X 2
  • X 2 is hydrogen
  • X 2 is hydrogen
  • R 7 represents a hydrogen atom or 1 carbon atom
  • R 8 represents an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms or a polycyclic condensed aromatic group.
  • M represents an integer of 0 to 3
  • n represents an integer of 1 or 2.
  • R 9 represents a hydrogen atom, or a linear or branched alkyl group having a carbon number of 1 ⁇ 8
  • R 10 represents -S-X 2
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 is hydrogen
  • X 2 represents an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic moiety having 5 to 12 carbon atoms in which an atom or a carbon atom may be substituted with a hetero atom
  • R 11 is unsubstituted or has a substituent.
  • an optionally substituted aromatic group having 5 to 12 carbon atoms or a polycyclic fused aromatic group m represents an integer of 0 to 3
  • n represents an integer of 1 or 2.
  • R 12 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 13 may be a hydrogen atom or a carbon atom substituted with a hetero atom.
  • R 14 is an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms.
  • the general formula (2) is a preferred form of the general formula (1)
  • the general formula (3) is a more preferred form
  • the general formula (4) is a more preferred form.
  • Specific examples of the compound represented by the general formula (4) include (N-benzoyl) cysteine, (N-toluyl) cysteine, (N-methoxybenzoyl) cysteine, (N-biphenylcarbonyl) cysteine, (N -Benzylcarbonyl) cysteine, (N-benzoyl-S-methyl) cysteine, (S-methyl-N-toluyl) cysteine, [N- (ethylbenzoyl) -S-methyl] cysteine, [S-methyl-N- ( Propylbenzoyl)] cysteine, [N- (butylbenzoyl) -S-methyl] cysteine, [N- (methoxybenzoyl) -S-methyl] cysteine, [N- (ethoxy
  • N- (benzoyl) cysteine N- (toluyl) cysteine, N- (methoxybenzoyl) cysteine, N- (biphenylcarbonyl) cysteine, N- (benzylcarbonyl) cysteine, [N -(Benzoyl) -S-methyl] cysteine, [N- (toluyl) -S-methyl) cysteine, [N- (methoxybenzoyl) -S-methyl] cysteine, [N- (biphenylcarbonyl) -S-methyl] Cysteine, [N- (benzylcarbonyl) -S-methyl] cysteine, [N- (benzoyl) cysteine] methyl ester, [N- (toluyl) cysteine] methyl ester, [N- (methoxybenzoyl) cysteine] methyl ester, [N- (biphenylcarbonyl) cysteine
  • compounds represented by the general formula (3) that are not included in the general formula (4) include (N-benzoyl-S-ethyl) homocysteine, (N-benzoyl-S--). Propyl) homocysteine, (N-benzoyl-S-butyl) homocysteine, (N-benzoyl-S-phenyl) homocysteine, (N-benzoyl-S-benzyl) homocysteine, (N-benzoyl-S-phenylethyl) ) Homocysteine, (N-benzoyl-S-pyridyl) homocysteine, (N-benzoyl-S-quinolyl) homocysteine, (N-benzoyl-S-naphthyl) homocysteine, (N-benzyl-S-biphenyl) homo Cysteine, (S-ethyl-N-toluyl) homoc
  • compounds represented by the general formula (2) that are not included in the general formulas (3) and (4) include (N-acetyl-N-benzoyl-S-methyl) cysteine, (N-benzoyl-N-propionyl-S-methyl) cysteine, (N-benzoyl-N-butyryl-S-methyl) cysteine, (N-acetyl-N-toluyl-S-methyl) cysteine, (S-methyl- N-propionyl-N-toluyl) cysteine, (N-butyryl-S-methyl-N-toluyl) cysteine, (N-acetyl-S-methyl-N-methoxybenzoyl) cysteine, (N-methoxybenzoyl-S-methyl) -N-propionyl) cysteine, (N-butyryl-N-methoxybenzoyl-S-methyl) cysteine, (N-acetyl-N-biphen
  • R 15 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 16 represents —SO 3 H or —SO 2 —X 4 .
  • X 4 represents a hydrogen atom or an aliphatic part having 1 to 8 carbon atoms or an aromatic part having 5 to 12 carbon atoms, in which a hydrogen atom or a carbon atom may be substituted with a hetero atom
  • R 17 is Represents a hydrogen atom, or an acyl group having a linear or branched alkyl chain having 1 to 8 carbon atoms
  • R 18 is an unsubstituted or substituted aromatic group having 5 to 12 carbon atoms, or Represents a polycyclic fused aromatic group
  • m represents an integer of 0 to 3
  • n represents an integer of 1 or 2.
  • R 19 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms
  • R 20 is a carbon atom that may be unsubstituted or substituted.
  • general formula (5) is a preferred form of general formula (1)
  • general formula (6) is a more preferred form.
  • Specific examples of the compound represented by the general formula (6) include N- (benzoyl) cysteic acid, N- (toluyl) cysteic acid, N- (ethylbenzoyl) cysteic acid, and N- (propylbenzoyl) cysteine.
  • N- (butylbenzoyl) cysteic acid N- (pentylbenzoyl) cysteic acid, N- (hexylbenzoyl) cysteic acid, N- (heptylbenzoyl) cysteic acid, N- (octylbenzoyl) cysteic acid, N- ( Methoxybenzoyl) cysteic acid, N- (ethoxybenzoyl) cysteic acid, N- (propyloxybenzoyl) cysteic acid, N- (butyloxybenzoyl) cysteic acid, N- (hydroxybenzoyl) cysteic acid, N- (aminobenzoyl) Cysteinic acid, N- (N'-methylaminoben Yl) cysteic acid, N- (N′-ethylaminobenzoyl) cysteic acid, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid, N- (N-
  • N- (benzoyl) cysteic acid, N- (toluyl) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (biphenylcarbonyl) cysteic acid, N- (benzylcarbonyl) are more preferable.
  • Cysteinic acid, N- (benzoyl) homocysteic acid, N- (toluyl) homocysteic acid, N- (methoxybenzoyl) homocysteic acid, N- (biphenylcarbonyl) homocysteic acid, N- (benzylcarbonyl) homocysteic acid Its stereoisomers, and pharmacologically acceptable salts thereof.
  • Specific examples of the compound represented by the general formula (5) that are not included in the general formula (6) include (N-acetyl-N-benzoyl) cysteic acid, (N-benzoyl-N— Propionyl) cysteic acid, (N-benzoyl-N-butyryl) cysteic acid, (N-benzoyl-N-isobutyryl) cysteic acid, (N-benzoyl-N-valeryl) cysteic acid, (N-benzoyl-N-isovaleryl) Cysteinic acid, (N-benzoyl-N-pivaloyl) cysteic acid, (N-benzoyl-N-hexanoyl) cysteic acid, (N-benzoyl-N-octanoyl) cysteic acid, (N-acetyl-N-toluyl) cysteic acid , (N-propionyl-N-toluyl) cysteic acid, (N
  • the excellent wrinkle-improving effect on wrinkles formed by exposure to ultraviolet rays, etc., possessed by the compounds represented by the general formulas (1) to (6), is exerted by the procollagen production promoting action.
  • a wrinkle improvement effect is expressed through a matrix metalloprotease inhibitory action such as MMP1, MMP9, MMP13 or a cytokine production inhibitory action such as IL-1, IL-6.
  • the compounds represented by the general formulas (1) to (6) can be produced according to the method shown in the production examples described later using commercially available reagents as raw materials. Such a compound can be used as it is as a wrinkle-improving agent of the present invention, but can also be treated with a pharmacologically acceptable acid or base to be converted into a salt form and used as a salt.
  • mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, monoethanol Preferred examples include organic amine salts such as ruamine salt and piperidine salt, and basic amino acid salts such as lysine salt and alginate.
  • organic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulf
  • L-methionine 5 (g) (33.5 mmol) (Wako Pure Chemical Industries), 1,4-dioxane 20 (mL) (Wako Pure Chemical Industries), and water 10 (mL) were added to a 100 (mL) eggplant type flask. After putting, it was cooled in an ice bath. After sufficiently cooling, 9.21 (mL) of 8 (N) aqueous sodium hydroxide solution and 4.21 (mL) of p-toluyl chloride (Aldrich) were successively added dropwise so that the liquid temperature did not increase. After completion of dropping, the ice bath was removed and the mixture was stirred at room temperature.
  • 1,4-dioxane was distilled off under reduced pressure.
  • the obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid.
  • the precipitated crystals were dissolved and extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • the obtained ethyl acetate solution was concentrated and crystallized.
  • the obtained crystals were washed with diisopropyl ether, filtered and dried to obtain crude crystals.
  • the obtained crude crystals were suspended in ethyl acetate and heated to 60 ° C.
  • L-cysteic acid monohydrate 5 (g) (26.7 mmol) (Aldrich), 1,4-dioxane 20 (mL) (Wako Pure Chemical Industries), and water 10 (mL) were added to 100 (mL) eggplant. After putting in the mold flask, it was cooled in an ice bath. After sufficiently cooling, 10.7 (mL) of 8 (N) aqueous sodium hydroxide solution and 3.36 (mL) of p-toluyl chloride (Aldrich) were successively added dropwise so that the liquid temperature did not rise. After completion of dropping, the ice bath was removed and the mixture was stirred at room temperature.
  • L-cysteic acid 2 (g) (11.8 mmol) (Tokyo Kasei), tetrahydrofuran 12 (mL) (Wako Pure Chemical Industries), and water 12 (mL) were placed in a 100 (mL) eggplant-shaped flask, and then iced. Cooled in bath. After sufficiently cooling, potassium carbonate 2.94 (g) (21.3 mmol) (Wako Pure Chemicals) and 4-phenylbenzoyl chloride 2.05 (g) (Tokyo Kasei) were added sequentially so that the liquid temperature did not rise. did. After reacting in an ice bath for 1.5 hours, 1.02 (g) of 4-phenylbenzoyl chloride (Tokyo Kasei) was added again.
  • L-cysteic acid 2 (g) (11.8 mmol) (Tokyo Kasei), tetrahydrofuran 12 (mL) (Wako Pure Chemical Industries), and water 12 (mL) were placed in a 100 (mL) eggplant-shaped flask, and then iced. Cooled in bath. After sufficiently cooling, potassium carbonate 2.94 (g) (21.3 mmol) (Wako Pure Chemical Industries) and 4-methoxybenzoyl chloride 1.61 (g) (Tokyo Kasei) were added in order so that the liquid temperature would not rise. did. After reacting for 1 hour in an ice bath, 4-methoxybenzoyl chloride 0.81 (g) (Tokyo Kasei) was added again.
  • DL-homocysteic acid 2 (g) (10.9 mmol) (Aldrich), tetrahydrofuran 12 (mL) (Wako Pure Chemical Industries), and water 12 (mL) were placed in a 100 (mL) eggplant type flask, and then iced. Cooled in bath. After sufficiently cooling, potassium carbonate 2.71 (g) (19.6 mmol) (Wako Pure Chemical Industries) was added.
  • p-Toluyl chloride 1.49 (g) (Aldrich) was sequentially added so as not to raise the liquid temperature. After reacting for 1 hour in an ice bath, 0.76 g of p-toluyl chloride (Aldrich) was added again.
  • L-cysteic acid 3 (g) (17.7 mmol) (Tokyo Kasei), tetrahydrofuran 18 (mL) (Wako Pure Chemical Industries), and water 18 (mL) were placed in a 100 (mL) eggplant-shaped flask, and then iced. Cooled in bath. After sufficiently cooling, potassium carbonate 4.40 (g) (31.6 mmol) (Wako Pure Chemicals) and m-toluyl chloride 2.19 (g) (Tokyo Kasei) were sequentially added so as not to raise the liquid temperature. . After reacting for 1 hour in an ice bath, m-toluyl chloride 1.09 (g) (Tokyo Kasei) was added again.
  • L-cysteic acid 3 (g) (17.7 mmol) (Tokyo Kasei), tetrahydrofuran 18 (mL) (Wako Pure Chemical Industries), and water 18 (mL) were placed in a 100 (mL) eggplant-shaped flask, and then placed in an ice bath. And cooled. After sufficiently cooling, 4.40 (g) (31.6 mmol) of potassium carbonate (Wako Pure Chemical Industries) was added. o-Toluyl chloride 3.28 (g) (Tokyo Kasei) was sequentially added so that the liquid temperature did not rise. After the addition, the ice bath was removed and the mixture was stirred at room temperature.
  • the above production example is an example of a method for producing the compound represented by the general formula (1), and compounds other than the above compounds 1 to 8 can be synthesized by appropriately changing raw materials and reaction conditions.
  • the wrinkle improving agent of the present invention exhibits an excellent wrinkle improving action against wrinkles formed by exposure to ultraviolet rays, it is useful as an external preparation for skin.
  • the wrinkle improving agent of the present invention that is, the compounds represented by the general formulas (1) to (6), is 0.001 in total with respect to the total amount of the external preparation for skin. It is preferable to contain from 0.01% by mass to 20% by mass, more preferably from 0.01% by mass to 10% by mass, and still more preferably from 0.1% by mass to 5% by mass.
  • the effect based on the wrinkle-improving action may be reduced, and even if an amount exceeding 20% by mass is used, the effect reaches a peak. , May impair prescription freedom.
  • Some of the compounds represented by the general formula (1) exhibit effects other than the excellent wrinkle improving action against wrinkles formed by exposure to ultraviolet rays or the like. Even if it is a skin external preparation containing the wrinkle improving agent of the present invention for the purpose of expressing such an action, the effect of the present invention is used when the wrinkle improving effect is exhibited. It belongs to the technical scope of the invention.
  • Examples of actions other than wrinkle improvement include moisturizing action, actinic keratosis or non-actinic keratosis improving action, skin peeling, epidermal renewal stimulation, and aging improving action.
  • the skin external preparation of the present invention can contain any component used in normal skin external preparations in addition to the wrinkle improving agent of the present invention.
  • optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, Liquid lanolin, hydrogenated coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax and other oils, waxes; liquid paraffin, squalane, pristane, ozokerite , Hydrocarbons such as paraffin, ceresin, petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stea
  • Moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface-treated mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride Powders such as (silica), aluminum oxide, barium sulfate, etc .; inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide, which may be treated on the surface ; The surface may be treated; pearl agents such as titanium mica, fish phosphorous foil, bismuth oxychloride; red 202 which may be laked, red Color 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane
  • the skin external preparation of the present invention such as lotion, emulsion, essence, cream, pack cosmetic, cleansing agent, etc. is produced by treating the wrinkle improving agent of the present invention and the above optional ingredients according to a conventional method. it can.
  • the external preparation for skin of the present invention can be applied without particular limitation as long as it is applied externally to the skin, and can be applied to cosmetics including quasi-drugs, external preparations for skin, and general items for external use. Particularly preferred are cosmetics including quasi drugs. This is because the wrinkle improving agent of the present invention is highly safe and can be used continuously.
  • Fig. 1 shows the wrinkle improvement effect of Compound 1. From this figure, it can be seen that Compound 1 of the present invention has an excellent wrinkle-improving effect.
  • DMEM medium manufactured by SIGMA
  • 10% FBS 2.5 ⁇ 10 4 cells of human-derived normal skin fibroblast cultured cells were seeded in a 24-well plate, 37 ° C., carbon dioxide concentration 5% Incubated in.
  • a medium was prepared by adding compounds 1 to 8 to DMEM medium (manufactured by SIGMA) supplemented with 2% FBS to a final concentration of 10 ⁇ M.
  • dimethyl sulfoxide manufactured by Sigma-Aldrich
  • 50% ethanol 50% ethanol
  • the cultured keratinocytes were washed with PBS (manufactured by Wako Pure Chemical Industries, Ltd.), and then replaced with a medium containing each of the above compounds, and a medium containing dimethyl sulfoxide and 50% ethanol. For 24 hours. After 24 hours, the culture supernatant was collected. The cultured fibroblast was washed with PBS, then replaced with the collected culture supernatant, and cultured at 37 ° C. in a carbon dioxide concentration of 5% for 48 hours. After 48 hours, the fibroblast was washed with PBS and then replaced with DMEM (manufactured by SIGMA). After culturing at 37 ° C.
  • PBS manufactured by Wako Pure Chemical Industries, Ltd.
  • DMEM manufactured by SIGMA
  • the wrinkle improving agent of the present invention can be applied to skin external preparations such as cosmetics. It is highly useful as a cosmetic raw material because of its high safety and excellent wrinkle improving effect.

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CA2742909A CA2742909C (en) 2008-11-19 2009-11-12 Anti-wrinkle agents
EP17151667.7A EP3173063B1 (en) 2008-11-19 2009-11-12 Anti-wrinkle agents
AU2009318483A AU2009318483B2 (en) 2008-11-19 2009-11-12 Anti-wrinkle agents
JP2010539212A JP5746864B2 (ja) 2008-11-19 2009-11-12 シワ改善剤
ES09827511.8T ES2650252T3 (es) 2008-11-19 2009-11-12 Agentes antiarrugas
MX2011004006A MX2011004006A (es) 2008-11-19 2009-11-12 Agentes antiarrugas.
US13/126,714 US8835498B2 (en) 2008-11-19 2009-11-12 Anti-wrinkle agents
RU2011124914/15A RU2503443C2 (ru) 2008-11-19 2009-11-12 Средства против морщин
EP09827511.8A EP2356979B1 (en) 2008-11-19 2009-11-12 Anti-wrinkle agents
BRPI0921303A BRPI0921303B8 (pt) 2008-11-19 2009-11-12 Agente redutor de rugas, composto, e, preparação externa para a pele.
CN200980146822.8A CN102215812B (zh) 2008-11-19 2009-11-12 抗皱剂
UAA201107663A UA107919C2 (en) 2008-11-19 2009-12-11 Anti-wrinkle means
IL212909A IL212909A (en) 2008-11-19 2011-05-16 Wrinkles and preparations containing them
HK12101057.4A HK1160405A1 (zh) 2008-11-19 2012-02-03 抗皺劑

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JP2011213632A (ja) * 2010-03-31 2011-10-27 Pola Chemical Industries Inc 肌荒れ予防又は改善剤
JP2011241166A (ja) * 2010-05-18 2011-12-01 Pola Chemical Industries Inc 組成物
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JP2013001660A (ja) * 2011-06-14 2013-01-07 Pola Chemical Industries Inc 皮膚外用剤
JP2013018713A (ja) * 2011-07-07 2013-01-31 Pola Chemical Industries Inc 皮膚外用剤
JP2014097942A (ja) * 2012-11-14 2014-05-29 Pola Chem Ind Inc 高い紫外線吸収効果を有する皮膚外用組成物
WO2015152384A1 (ja) * 2014-04-03 2015-10-08 ポーラ化成工業株式会社 Ｄ－パントテニルアルコールからなるメラニン産生抑制剤、及び該メラニン産生抑制剤を含む美白化粧料
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