JP2009227660A - Cysteine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cysteine derivative having good safety without malodor problems, and to provide a cosmetic comprising the cysteine derivative. <P>SOLUTION: The cysteine derivative (except thiazoline-2,4-dicarboxylic acid and 2-methylthiazoline-2,4-dicarboxylic acid) is represented by general formula (I) [wherein, X represents OR1 or NHR2 (wherein, R1 represents a hydrogen atom or a 1-22C alkyl group; and R2 represents a hydrogen atom or a 1-22C alkyl group); Y represents OR3 or NHR4 (wherein, R3 represents a hydrogen atom or a 1-22C alkyl group which may be substituted; and R4 represents a hydrogen atom or a 1-22C alkyl group); and Z represents a hydrogen atom or a 1-22C alkyl group] or a salt thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to certain cysteine derivatives. Furthermore, this invention relates to the cosmetics etc. containing a specific cysteine derivative.

  L-cysteine is an amino acid that has many physiological activities such as a reducing action, whitening effect, and is useful for living bodies. In human pigment cells (melanocytes) existing in the skin, melanin that determines the color of the skin is produced using L-cysteine or L-tyrosine. There are differences in the skin color such as black, yellow, and white. This difference is due to the difference in the amount of melanin produced in human pigment cells and the selection of amino acids (L-cysteine, L-tyrosine) as raw materials. . That is, when more L-tyrosine, which is a raw material of black melanin, is used during melanin synthesis, the production of black melanin is promoted and the skin becomes black. On the other hand, when more L-cysteine is used during melanin synthesis, the production of black melanin is suppressed and the skin approaches yellow (Non-patent Document 1).

  L-cysteine is also important as a biosynthetic material for glutathione (γ-glutamylcysteinylglycine), which is responsible for redox in vivo. Glutathione has various biological protective effects such as protection against skin damage caused by ultraviolet rays, but cysteine precursors such as N-acetyl-L-cysteine are known to increase intracellular glutathione (Non-patent Document 2). ).

  So far, many attempts have been made to use L-cysteine as a cosmetic, such as a whitening agent using L-cysteine. However, L-cysteine is easily oxidized, and when formulated as a cosmetic or an external preparation for skin, there are problems with poor stability and bad odor.

  In order to solve these problems, as an alternative to L-cysteine, attempts have been made to use more stable N-acetylcysteine (hereinafter sometimes abbreviated as NAC) and the like in cosmetics. A high effect was not necessarily obtained.

  On the other hand, development of cysteine prodrugs that have been chemically modified so that the drug effect appears only by metabolism in the body is also being studied. Patent Document 1 discloses a method for producing L-2-methylthiazolidine-2,4-dicarboxylic acid (cysteinyl pyruvic acid; hereinafter abbreviated as CP) by reacting cysteine with pyruvic acid. Are listed. Although the obtained L-2-methylthiazolidine-2,4-dicarboxylic acid is described as being extremely stable as compared with conventional cysteine derivatives, there is no description of formulation examples in cosmetics or skin external preparations. No mention is made regarding stability as a cosmetic or topical skin preparation.

  As a pharmacological effect of L-2-methylthiazolidine-2,4-dicarboxylic acid, its usefulness as a cysteine prodrug has been reported in an in vitro test using human hepatocytes (Non-patent Document 3). It has also been reported that by orally administering to mice, the active oxygen in liver plasma is reduced and the hepatotoxicity of acetaminophen is reduced (Non-patent Document 4). However, these studies are not aimed at stabilizing cysteine but are aimed at improving the toxicity of cysteine, and the stability is not described.

As described above, the use of L-2-methylthiazolidine-2,4-dicarboxylic acid in cosmetics or external preparations for skin, and the whitening effect and glutathione synthesis effect have not been reported so far. Further, Patent Document 2 describes a method for producing thiazolidine-2,4-dicarboxylic acid, but there is no description about examples of blending into cosmetics or skin external preparations, and as cosmetics or skin external preparations. There is no mention of stability.
Moreover, about the other cysteine derivative of this invention, the report about a synthesis example and its stability has not been made until now.

Japanese Patent Publication No. 48-15938 Japanese Patent Publication No. 48-15937

J. et al. Invest. Dermatol. (1997) 109796-800 Photochem. Photobiol. (1997) 66 665-671 ActaBiochimicaPolonia (1997) 44759-766 FundamClinPharmacol (1997) 11454-459

  An object of the present invention is to improve the stability of L-cysteine by derivatization. Another object of the present invention is to provide a cysteine derivative having good stability and no odor problem, and a cosmetic or skin external preparation containing the same.

  As a result of intensive studies, the inventors have found that by inducing L-cysteine to a specific derivative, its stability is greatly improved as compared to L-cysteine. The present invention was completed by confirming the whitening effect and the glutathione synthesis effect.

That is, the present invention is as follows.
[1] The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
Or a salt thereof (excluding thiazolidine-2,4-dicarboxylic acid and 2-methylthiazolidine-2,4-dicarboxylic acid);
[2] The cysteine derivative according to [1], which is an L-cysteine derivative;
[3] The cysteine derivative according to [1] or [2], wherein Z is a C _1-22 alkyl group;
[4] The cysteine derivative according to [1] or [2], wherein Z is a methyl group;
[5] The cysteine derivative according to any one of [1] to [4], wherein X is OR ¹ (wherein R ¹ is as defined in [1]);
[6] The cysteine derivative according to any one of [1] to [5], wherein Y is OR ³ (wherein R ³ is as defined in [1]);
[7] The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
A cosmetic comprising a cysteine derivative represented by the formula:
[8] The cosmetic according to [7], wherein the cysteine derivative is an L-cysteine derivative;
[9] The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
A whitening agent containing a cysteine derivative represented by the formula:
[10] The whitening agent according to [9], wherein the cysteine derivative is an L-cysteine derivative;
[11] The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
A glutathione synthesis promoter containing a cysteine derivative represented by the formula:
[12] The glutathione synthesis promoter according to [11], wherein the cysteine derivative is an L-cysteine derivative.

  According to the present invention, a cysteine derivative having good stability and no odor problem, a whitening agent containing this as an active ingredient, a glutathione synthesis accelerator, a stain improving or treating agent, a wrinkle improving or treating agent, and a The cosmetic or skin external preparation to contain can be provided.

FIG. 1 shows the results of a stability test over time of a cysteine derivative of the present invention at room temperature (Test Example 3). FIG. 2 shows the results of a stability test over time of the cysteine derivative of the present invention at room temperature (Test Example 3). FIG. 3 shows the results of a stability test over time of a cysteine derivative of the present invention at 50 ° C. (Test Example 4). FIG. 4 shows the results of a black melanin production inhibition test of the cysteine derivative of the present invention (Test Example 5).

  The terms used in this specification are defined below.

The “C _1-22 alkyl group” means a linear or branched hydrocarbon group having 1 to 22 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group, isopentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, tert-octyl group, nonyl group , Isononyl group, decyl group, isodecyl group, undecyl group, dodecyl group, tridecyl group, isotridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, isohexadecyl group, heptadecyl group, octadecyl group, isooctadecyl group, oleyl group, behenyl Groups and the like.

The “C _1-12 alkyl group” means a straight or branched hydrocarbon group having 1 to 12 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group, isopentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, tert-octyl group, nonyl group , Isononyl group, decyl group, isodecyl group, undecyl group, dodecyl group and the like.

The “C _1-7 alkyl group” means a linear or branched hydrocarbon group having 1 to 7 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, Examples include isobutyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, isopentyl, hexyl, heptyl and the like.

The “C _1-6 alkyl group” means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, Examples include isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group, isopentyl group, hexyl group and the like.

The “C _6-12 aryl group” means an aromatic hydrocarbon group having 6 to 12 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Preferably, it is a phenyl group.

  The “aromatic heterocyclic group” is an atom constituting a ring having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as an atom constituting the ring. Is an aromatic heterocyclic group having 5 to 14 members, and includes monocyclic and condensed cyclic groups. Preferably, it is a 5- or 6-membered monocyclic aromatic heterocyclic group.

  Examples of the “monocyclic aromatic heterocyclic group” include thienyl group (eg, thiophen-2-yl, thiophen-3-yl), furyl group (eg, furan-2-yl, furan-3-yl). Etc.), pyrrolyl group (eg, 2-pyrrol-1-yl, 3-pyrrol-3-yl, etc.), oxazolyl group (eg, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, etc.) , Isoxazolyl groups (eg, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, etc.), thiazolyl groups (eg, thiazol-2-yl, thiazol-4-yl, thiazole-5- Yl), isothiazolyl groups (eg, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), imidazolyl groups (eg, imidazole-1- 1H-imidazol-2-yl, 1H-imidazol-4-yl, etc.), pyrazolyl groups (eg, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, 1H -Pyrazol-4-yl, etc.), oxadiazolyl groups (eg, 1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadi Azol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl and the like), A thiadiazolyl group (eg, 1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazole-3 -Ile, 1,2,4-Chia Asia -5-yl, 1,2,5-thiadiazol-3-yl, etc.), triazolyl groups (eg, 1,2,4-triazol-3-yl, 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,3,4-triazol-1-yl, etc.), tetrazolyl groups (eg, tetrazol-1-yl, tetrazole) -2-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, etc.), pyridyl groups (eg, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl etc.), pyrimidinyl groups (Eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, etc.), pyridazinyl groups (eg, pyridazin-3-yl, pyridazin-4-yl etc.), pyrazinyl groups (eg, pyrazine-2) -B And triazinyl groups (eg, 1,3,5-triazinin-2-yl) and the like.

  Examples of the “fused cyclic aromatic heterocyclic group” include quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group, phthalazinyl group, cinnolinyl group, naphthyridinyl group, indolyl group, benzoimidazolyl group, indolinyl group, benzofuranyl group, benzofuranyl group, Thienyl group, benzoxazolyl group, benzothiazolyl group, benzodioxinyl group, benzothiazolyl group, tetrahydroquinolyl group, dihydrobenzofuranyl group, dihydrobenzothienyl group, dihydrobenzodioxinyl group, indenothiazolyl group, Tetrahydrobenzothiazolyl group, 5,7-dihydropyrrolo [3,4-d] pyrimidinyl group, 6,7-dihydro-5H-cyclopentapyrimidinyl group, imidazo [2,1-b] thiazolyl group, pteridinyl group, Examples include a prynyl group

“C _3-10 cycloalkyl group” means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl. Groups and the like.

The “C _3-10 cycloalkenyl group” means a cyclic partially unsaturated hydrocarbon group having 3 to 10 carbon atoms and containing one or more double bonds, and examples thereof include a cyclopropenyl group and a cyclobutenyl group. Group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group and the like.

  “Non-aromatic heterocyclic group” has 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms as atoms constituting the ring, and constitutes a ring It means a non-aromatic heterocyclic group having 3 to 14 atoms and includes monocyclic and condensed cyclic groups. Preferably, it is a 3-8 membered (more preferably 5 or 6 membered) monocyclic non-aromatic heterocyclic group.

  Examples of the “monocyclic non-aromatic heterocyclic group” include oxiranyl group, thiolanyl group, aziridinyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, oxazolinyl group, oxazolidinyl group, Oxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, imidazolinyl group, imidazolidinyl group, pyrazolinyl group, pyrazolidinyl group, piperidinyl group, piperidino group, pyranyl group, tetrahydropyrani Group, morpholinyl group, morpholino group, thiomorpholinyl group, thiomorpholino group, piperazinyl group, hexahydro-1,3-oxazinyl group and the like.

  Examples of the “fused cyclic non-aromatic heterocyclic group” include, for example, isochromanyl group, dihydrobenzopyranyl group, isochromenyl group, chromenyl group (2H-chromenyl group, 4H-chromenyl group), 1,2,3,4 -Tetrahydroisoquinolyl group, 1,2,3,4-tetrahydroquinolyl group, 2,3-dihydrobenzofuranyl group, benzo [1,3] dioxolyl group and the like.

  When the “non-aromatic heterocyclic group” contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxidized.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

“C _1-7 alkoxy group” means a hydroxyl group substituted with the above “C _1-7 alkyl group”, for example, methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group Tert-butyloxy group, pentyloxy group, hexyloxy group, heptyloxy group and the like.

“C _1-7 alkylenedioxy group” means, for example, methylenedioxy group, ethylenedioxy group, trimethylenedioxy group, tetramethylenedioxy group, pentamethylenedioxy group, hexamethylenedioxy group, hepta Examples thereof include linear or branched alkylenedioxy groups having 1 to 7 carbon atoms such as a methylenedioxy group, preferably a methylenedioxy group and an ethylenedioxy group.

_{Examples of the} “C _1-7 acyl group” include an acyl group having 1 to 7 carbon atoms derived from an organic carboxylic acid. For example, a C _1-7 alkanoyl group (eg, C _1-6 alkyl-carbonyl group such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, hexanoyl group, heptanoyl group, etc.), benzoyl group, C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, etc.) And a phenoxycarbonyl group.

The “C _1-7 alkylamino group” means an amino group mono- or di-substituted with the above “C _1-7 alkyl group”, for example, methylamino group, ethylamino group, propylamino group, isopropylamino Group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, hexylamino group, heptylamino group and the like.

  Each substituent in the general formula (I) will be described below.

X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group).

The “C _1-22 alkyl group” represented by R ¹ is preferably a C _1-6 alkyl group, more preferably a methyl group, an ethyl group, and particularly preferably an ethyl group.

R ¹ is preferably a hydrogen atom or an ethyl group.

The “C _1-22 alkyl group” represented by R ² is preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group.

R ² is preferably a hydrogen atom, a methyl group, or an ethyl group.

X is preferably OR ¹ (wherein R ¹ is as defined above), more preferably a hydroxyl group or an ethoxy group.

Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group) .)

Represented by R ³ in the "optionally substituted _{C 1-22} alkyl group" as the _{"C 1-22} alkyl group" is preferably a _{C 1-12} alkyl group, more preferably _{C 1-6} An alkyl group, particularly preferably a methyl group, an ethyl group, or an isopropyl group.

Examples of the substituent that the “C _1-22 alkyl group” may have include a C _6-12 aryl group that may have a substituent, and an aromatic heterocyclic ring that may have a substituent. group, which may have a substituent C _3-10 cycloalkyl group which may have a substituent C _3-10 cycloalkenyl group, or may have a substituent non-aromatic heterocyclic ring Groups.

The “C _1-22 alkyl group” may have a “substituent _optionally substituted C _6-12 aryl group” or “substituent aromatic”. A heterocyclic group ”, an“ optionally substituted C _3-10 cycloalkyl group ”, an“ optionally substituted C _3-10 cycloalkenyl group ”, and an“ substituted group ”. The “C _6-12 aryl group”, “aromatic heterocyclic group”, “C _3-10 cycloalkyl group”, “C _3-10 cycloalkenyl group” and “non-aromatic heterocyclic group” which may be As the substituent that the “aromatic heterocyclic group” may have,
[1] hydroxyl group,
[2] an oxo group,
[3] a halogen atom,
[4] C _1-7 alkyl group (preferably methyl group, ethyl group),
[5] C _1-7 alkoxy group (preferably methoxy group, ethoxy group),
[6] C _1-7 alkylenedioxy group (preferably methylenedioxy group),
[7] C _1-7 acyl group,
_Examples include the same or different 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of [8] amino group and [9] C _1-7 alkylamino group.

As the “optionally substituted C _6-12 aryl group” as the substituent that the “C _1-22 alkyl group” may have, a hydroxyl group and a C _1-7 alkoxy are preferable. A C _6-12 aryl group (preferably substituted with 1 to 5 (preferably 1 to 3) substituents which are the same or different and selected from a group (preferably a methoxy group and an ethoxy group) Are a phenyl group and a naphthyl group, more preferably a 4-hydroxyphenyl group, a 4-methoxyphenyl group, a 3,4-dihydroxyphenyl group, a 4-hydroxy-3-methoxyphenyl group, and a 3-hydroxy-4. -It is a methoxyphenyl group or a 2,4-dihydroxyphenyl group. Particularly preferred are 4-hydroxyphenyl group and 3,4-dihydroxyphenyl group.

As the “ _optionally substituted aromatic heterocyclic group” as the substituent that the “C _1-22 alkyl group” may have, a pyridyl group (preferably pyridine- 2-yl group, pyridin-3-yl group, pyridin-4-yl group).

The “C _3-10 cycloalkyl group _optionally having substituent (s)” as the substituent that the “C _1-22 alkyl group” _optionally has is preferably a cyclohexyl group or a cyclopentyl group. is there.

The “C _3-10 cycloalkenyl group _optionally having substituent (s)” as the substituent that the “C _1-22 alkyl group” _optionally has is preferably a cyclohexenyl group.

The “non-aromatic heterocyclic group which may have a substituent” as the substituent which the “C _1-22 alkyl group” may have is preferably selected from a hydroxyl group and an oxo group. A non-aromatic heterocyclic group (preferably a pyranyl group, a tetrahydropyranyl group) which may be substituted with the same or different 1 to 5 (preferably 1 to 3) substituents, and more Preferred are a tetrahydro-2H-pyran-2-yl group and a 5-hydroxy-4-oxo-4H-pyran-2-yl group. Particularly preferred is a 5-hydroxy-4-oxo-4H-pyran-2-yl group.

R ³ is preferably a hydrogen atom or a C _6-12 aryl group which may have a substituent or a non-aromatic heterocyclic group which may have a substituent. A C _1-12 alkyl group, more preferably a hydrogen atom, a C _1-12 alkyl group (preferably a C _1-6 alkyl group), or an optionally substituted C _6-12 aryl group. A C _1-6 alkyl group substituted with a non-aromatic heterocyclic group which may have a group or a substituent.
Particularly preferably, a hydrogen atom, ethyl group, isopropyl group, hexyl group, dodecyl group, 4-hydroxyphenylethyl group (eg, 2- (4-hydroxyphenyl) ethyl group), 3,4-dihydroxyphenylethyl group (eg, 2- (3,4-dihydroxyphenyl) ethyl group) and (5-hydroxy-4-oxo-4H-pyran-2-yl) methyl group.

The “C _1-22 alkyl group” represented by R ⁴ is preferably a C _1-6 alkyl group, and more preferably a methyl group or an ethyl group.

Y is preferably OR ³ (wherein R ³ is as defined above), more preferably a hydroxyl group, an ethoxy group, an isopropoxy group, a hexyloxy group, a dodecyloxy group, 2- (4- A hydroxyphenyl) ethoxy group, a 2- (3,4-dihydroxyphenyl) ethoxy group, and a (5-hydroxy-4-oxo-4H-pyran-2-yl) methoxy group.

Z represents a hydrogen atom or a C _1-22 alkyl group.

The “C _1-22 alkyl group” represented by Z is preferably a C _1-6 alkyl group, more preferably a methyl group, an ethyl group, and particularly preferably a methyl group.

  Z is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a methyl group.

  The cysteine derivatives represented by the above general formula (I) except for thiazolidine-2,4-dicarboxylic acid and 2-methylthiazolidine-2,4-dicarboxylic acid are novel compounds.

  In the cysteine derivative represented by the general formula (I), the following general formula

(In the formula, each symbol is as defined above.)
A cysteine derivative represented by the formula is particularly preferred.

  The cysteine derivatives represented by the above general formula (I) include L-, D-, and DL-cysteine derivatives. All of these are included in the cysteine derivative represented by the general formula (I).

  Examples of the compound represented by the general formula (I) include

(Wherein each symbol is as defined above), L-cysteine derivatives represented by

An L-cysteine derivative represented by the formula (wherein each symbol is as defined above) is preferable.

In addition, as a cysteine derivative represented by the above general formula, in the case where X = OR ¹ and Y = NHR ^{4 from} the viewpoint of being able to release cysteine with an appropriate stability at a site of action, X = NHR ^{4 2} and Y = OR ³ are preferred, X = OR ¹ and Y = OR ³ are preferred, X = NHR ² and Y = OR ³ are preferred, X = OR ¹ and Y = OR ³ are more preferred, The case where X = OR ¹ and Y = OR ³ is particularly preferred.

As the cysteine derivative represented by the general formula (I), X is preferably OR ¹ from the viewpoint of good crystallinity of the product and easy purification, and R ¹ is a hydrogen atom or C ₁ for ₆ alkyl group is more preferable. Similarly, Y is preferably OR ³ , and R ³ is preferably a hydrogen atom or a C _1-6 alkyl group, more preferably a methyl group, an ethyl group, an isopropyl group, or a hexyl group.

  Specific examples of the cysteine derivative represented by the general formula (I) include thiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid, and 2-methylthiazolidine-2,4-dicarboxylic acid. Acid 2-methyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 4-methyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid Acid 2-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid Acid 2-isopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 4-isopro Ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diisopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-amide, 2-methylthiazolidine-2,4-dicarboxylic acid 4-amide, 2-methylthiazolidine-2,4-dicarboxylic acid 2-amide-4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester-4-amide, 2-methylthiazolidine-2,4-dicarboxylic acid Acid 2,4-diamide, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylamide-4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester-4-ethylamide, 2-methyl Thiazolidine-2,4-dicarboxylic acid 2,4-diethylamide, 2-methylthiazolyl -2,4-dicarboxylic acid 2-dodecyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-hexyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (4-hydroxyphenyl) ) Ethyl} ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (3,4-dihydroxyphenyl) ethyl} ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy) -4-oxo-4H-pyran-2-ylmethyl) ester and the like. Preferably, thiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid Acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid Acid 2-dodecyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-hexyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (4-hydroxyphenyl) ethyl} ester, 2- Methyl thiazolidine-2,4-dicarboxylic acid 2- {2- (3,4-dihydroxy) Phenyl) ethyl} ester, 2-methyl-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo -4H- pyran-2-ylmethyl) ester.

  As the compound represented by the general formula (I), an L-cysteine derivative is particularly preferable, and as such an L-cysteine derivative, specifically, L-thiazolidine-2,4-dicarboxylic acid, L- 2-methylthiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 4-methyl ester, L- 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 4 -Ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, L-2-methylthiazolidine 2,4-dicarboxylic acid 2-isopropyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 4-isopropyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diisopropyl ester, L -2-methylthiazolidine-2,4-dicarboxylic acid 2-amide, L-2-methylthiazolidine-2,4-dicarboxylic acid 4-amide, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-amide- 4-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester-4-amide, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diamide, L-2- Methylthiazolidine-2,4-dicarboxylic acid 2-ethylamide-4-ethyl ester, L-2-methylthiazolidine-2, -Dicarboxylic acid 2-ethyl ester-4-ethylamide, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethylamide, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-dodecyl ester, L -2-methylthiazolidine-2,4-dicarboxylic acid 2-hexyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (4-hydroxyphenyl) ethyl} ester, L-2-methyl Thiazolidine-2,4-dicarboxylic acid 2- {2- (3,4-dihydroxyphenyl) ethyl} ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo-4H) -Pyran-2-ylmethyl) ester and the like. Preferably, L-thiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, L-2- Methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester Ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-dodecyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-hexyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid Acid 2- {2- (4-hydroxyphenyl) ethyl} ester, L-2-methylthiazolidine-2,4-di Rubonic acid 2- {2- (3,4-dihydroxyphenyl) ethyl} ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ) Esters.

2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester, 2-methylthiazolidine-, from the viewpoint of being able to release cysteine with moderate stability at the site of action while being stable as a cosmetic or external preparation for skin. 2,4-dicarboxylic acid 4-methyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine- 2,4-dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester, 2-methylthiazolidine- 2,4-dicarboxylic acid 4-isopropyl ester, 2-methylthiazolyl 2,4-dicarboxylic acid 2,4-diisopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-amide, 2-methylthiazolidine-2,4-dicarboxylic acid 4-amide, thiazolidine-2,4 -Dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2-dodecyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-hexyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- { 2- (4-hydroxyphenyl) ethyl} ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-{(3,4-dihydroxyphenyl) ethyl} ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2 -(5-hydroxy-4-oxo-4H-pyran-2-yl) methyl) ester is preferred, Thirthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, 2- Methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 4-isopropyl ester, thiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (4-hydroxyphenyl) ethyl} ester is more preferred.
Moreover, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine-2,4 from the viewpoint that only ethanol or pyruvic acid can be released as a safe decomposition product at the site of action such as the skin. -Dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester are particularly preferred.

  When the cysteine derivative of the present invention is used as a whitening agent, 2-methylthiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine-2,4- Dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo-4H-pyran-2 -Ylmethyl) ester, thiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2- {2- (4-hydroxyphenyl) ethyl} ester (preferably L-2-methylthiazolidine- 2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester Steal, L-2-methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-isopropyl ester, L-2-methylthiazolidine-2,4-dicarboxylic Acid 2- (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester, L-thiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid 2- {2 -(4-hydroxyphenyl) ethyl} ester), particularly 2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) ester (preferably L-2-methylthiazolidine-2,4-dicarboxylic acid 2- (5-hydroxy-4-oxo-4H-pyran-2-ylmethyl) Steal) is preferred.

  When the cysteine derivative of the present invention is used as a glutathione synthesis accelerator, 2-methylthiazolidine-2,4-dicarboxylic acid, 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, 2-methylthiazolidine-2, 4-dicarboxylic acid 4-ethyl ester, 2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester (preferably L-2-methylthiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine -2,4-dicarboxylic acid 2-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester) 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (preferably Properly is, L-2-methyl-2,4-dicarboxylic acid 2-ethyl ester) are preferred.

  Examples of the cysteine derivative of the present invention include L-2-methylthiazolidine-2,4-dicarboxylic acid, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, and L-2-methylthiazolidine-2. , 4-Dicarboxylic acid 4-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester are preferred.

  The cysteine derivative represented by the general formula (I) may have two diastereomers depending on the orientation of the substituents at the 2-position and 4-position of the thiazolidine ring, but the cysteine derivative represented by the above formula All of these isomers and mixtures thereof are intended to be included.

Examples of the salt of the cysteine derivative represented by the general formula (I) include a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, and a salt with an amino acid. It is done.
Examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
Examples of salts with organic acids include oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
Examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
Examples of salts with organic bases include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, and guanidine. , Salts with pyridine, picoline, choline, cinchonine, meglumine and the like.
Examples of the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
According to a method known per se, each salt can be obtained by reacting the cysteine derivative represented by the above general formula (I) with an inorganic base, organic base, inorganic acid, organic acid or amino acid.

  In the present specification, “stability” means a property that is not easily oxidized. The stability of cysteine and its derivatives can be compared using the effective S amount as an index. Each cysteine derivative has a reducing ability by finally becoming cysteine. That is, in this specification, the effective S amount is defined as a thiol agent including a cysteine, which finally has a reducing ability, and after a certain period of time with respect to the amount of thiol agent that was initially present. The amount of thiol active substance remaining in the system is expressed in mol%. That is, the effective S amount indicates stability that can be used as a cosmetic or a skin external preparation.

[Formula 1]
Effective S amount (%) = number of moles of all thiol active substance components after a certain period of time from the start of the test / number of moles of all thiol active substance components after 0 hour of the start of the test × 100

  The cysteine derivative of the present invention can be used as a cysteine prodrug. In the present specification, “cysteine prodrug” is a compound in which cysteine is subjected to some modification and improved in stability, etc., is enzymatically or non-enzymatically decomposed in vivo and converted to cysteine, A compound that exhibits physiological activity. That is, the cysteine derivative of the present invention can be used as a substitute for cysteine as long as it is effectively cysteine in the system.

  As one aspect of the present invention, the cysteine derivative of the present invention can be used as a black melanin production inhibitor, a whitening agent, or a preventive or therapeutic agent for stains. As another aspect of the present invention, the cysteine derivative of the present invention can be used as a glutathione synthesis promoter, or a preventive or therapeutic agent for wrinkles. These uses make use of the property that the cysteine derivative of the present invention exhibits a stable dosage form, but is decomposed into cysteine relatively rapidly at the site of action through skin absorption.

  As a further aspect of the present invention, the cysteine derivative of the present invention can be incorporated into various cosmetics or skin external preparations. The cosmetic or external preparation for skin of the present invention is not particularly limited in form, and can take any form such as solution, paste, gel, solid, and powder. Specifically, lotion, lotion, cream, milky lotion, serum, shampoo, hair rinse, hair conditioner, enamel, foundation, eyeliner, eyebrow pencil, mascara, lipstick, funny, powder, pack, perfume, eau de cologne, cleansing Examples include foams, cleansing oils, cleansing gels, toothpastes, soaps, aerosols, bath preparations, hair nourishing agents, sunscreen agents.

  The lower limit when the cysteine derivative of the present invention is blended with a cosmetic or an external preparation for skin is not particularly limited as long as the effect is exhibited, but 0.0001% by weight is preferably the lower limit. If it is less than 0.0001% by weight, the whitening effect may be poor. From the viewpoint that an effective effect can be exhibited, 0.001% by weight is more preferable, 0.01% by weight is further preferable, 0.1% by weight is still more preferable, 0.5% by weight is even more preferable, and 1% by weight. % Is particularly preferred.

  The upper limit in the case of blending the cysteine derivative of the present invention into a cosmetic or an external preparation for skin is not particularly limited as long as the effect is exhibited, but 20% by weight is preferably the upper limit. If it exceeds 20% by weight, it may be separated, precipitated or precipitated. 18% by weight is more preferred, 16% by weight is still more preferred, 14% by weight is even more preferred, 12% by weight is even more preferred, and 10% by weight is particularly preferred.

A cosmetic having a whitening synergistic effect can be obtained by further combining various whitening agents with the cysteine derivative of the present invention. The various whitening agents are not particularly limited, but are antioxidants such as ascorbic acid; tyrosinase activity inhibitors such as kojic acid, arbutin, ellagic acid and lucinol; α such as d-2-Nal-Arg-Leu-NH ₂ -MSH (α-melanocyte stimulating hormone) antagonists. These may be used alone or in admixture of two or more. Ascorbic acid, vitamin C ethyl (ethylascorbic acid), kojic acid, arbutin, tranexamic acid, 4-methoxysalicylic acid potassium salt, ellagic acid, in terms of having a whitening synergistic effect by combining with a whitening agent having a different mechanism of action It is preferably combined with one selected from lucinol and d-2-Nal-Arg-Leu-NH ₂ , more preferably two or more, and one selected from kojic acid, arbutin, ellagic acid and lucinol. Or it is still more preferable to mix | blend 2 or more types and ascorbic acid.

  In the case of a cosmetic or skin external preparation, in addition to the cysteine derivative of the present invention, various ingredients that can be used in normal cosmetics, skin external preparations, and quasi drugs are blended within a range that does not impair the effects of the present invention. Also good. For example, oil components, surfactants, amino acids, amino acid derivatives, lower alcohols, polyhydric alcohols, sugar alcohols and their alkylene oxide adducts, water-soluble polymers, bactericides and antibacterial agents, anti-inflammatory agents, analgesics, Antifungal agent, keratin softening agent, skin colorant, hormone agent, UV absorber, hair restorer, whitening agent, antiperspirant and astringent active ingredient, sweat deodorant, vitamin agent, vasodilator, herbal medicine, pH adjustment Agents, viscosity modifiers, pearlizing agents, natural fragrances, synthetic fragrances, dyes, antioxidants, preservatives, emulsifiers, fats and waxes, silicone compounds, perfume oils and the like.

  Oily components include saturated or unsaturated fatty acids and higher alcohols obtained therefrom, myristyl myristate, myristyl palmitate, myristyl stearate, myristyl isostearate, myristyl oleate, myristyl behenate, myristyl erucate, cetyl myristate, Cetyl palmitate, cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetyl elcaate, stearyl myristate, stearyl palmitate, stearyl stearate, stearyl isostearate, stearyl oleate, stearyl behenate, erucic acid Stearyl, isostearyl myristate, isostearyl palmitate, isostearyl stearate, isostearyl isostearate, oleic acid Stearyl, isostearyl behenate, isostearyl erucate, behenyl myristate, behenyl palmitate, behenyl stearate, behenyl isostearate, behenyl oleate, behenyl behenate, behenyl erucate, erucyl myristate, erucyl palmitate, stearic acid Linear or branched fatty alcohol esters such as erucyl, erucyl isostearate, erucyl oleate, erucyl behenate, erucyl erucate, squalane, squalene, castor oil and / or hydrogenated castor oil and derivatives thereof, hydroxystearic acid monoglyceride Hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, Oleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride and malic acid diglyceride and their glycerides Glycerides such as 1-30 mol adduct of ethylene oxide, beeswax, lanolins and derivatives thereof including liquid and refined lanolin, almond oil, avocado oil, olive oil, rapeseed oil, coconut oil, macadamia nut oil, jojoba oil, carnauba wax, sesame oil, Oily raw materials derived from animals and plants such as cacao oil, palm oil, mink oil, tree wax, candelilla wax, whale wax, paraffin, microcrystalline wax , Oil-based raw materials derived from petroleum and minerals such as liquid paraffin, petrolatum, ceresin, methylpolysiloxane, polyoxyethylene / methylpolysiloxane, polyoxypropylene / methylpolyoxysiloxane, poly (oxyethylene, oxypropylene) / methyl Examples include silicones such as silicone polymers such as polysiloxane, methylphenyl polysiloxane, fatty acid-modified polysiloxane, aliphatic alcohol-modified polysiloxane, and amino acid-modified polysiloxane, resin acids, fatty acid esters, and ketones.

  As the surfactant, N-long chain acyl acidic amino acid salt such as N-long chain acyl glutamate, N-long chain acyl aspartate, N-long chain acyl glycine salt, N-long chain acyl alanine salt, N N-long chain acyl amino acid salts such as N-long chain acyl neutral amino acid salts such as long chain acyl threonine salts, N-long chain fatty acid acyl-N-methyl taurine salts, alkyl sulfates and alkylene oxide adducts thereof, fatty acids Amide ether sulfates, fatty acid metal salts and weak base salts, sulfosuccinic acid surfactants, alkyl phosphates and alkylene oxide adducts thereof, anionic surfactants such as alkyl ether carboxylic acids; glycerin ethers and alkylene oxide adducts thereof, etc. Ether type surfactants, glycerin esters and Ester surfactants such as alkylene oxide adducts, ether ester surfactants such as sorbitan esters and their alkylene oxide adducts, polyoxyalkylene fatty acid esters, glycerol esters, fatty acid polyglycerol esters, acylamino acid polyglycerol esters, sorbitan Nonionics such as esters, ester surfactants such as sucrose fatty acid esters, alkyl glucosides, hydrogenated castor oil pyroglutamic acid diester and its ethylene oxide adduct, and nitrogen-containing nonionic surfactants such as fatty acid alkanolamides Surfactants: Aliphatic amine salts such as alkylammonium chloride and dialkylammonium chloride, their quaternary ammonium salts, and fragrances such as benzalkonium salts Cationic surfactants such as quaternary ammonium salts, fatty acid acyl arginine esters and alkyloxyhydroxypropyl arginine salts; and betaine type surfactants such as alkyl betaines, alkylamido betaines, aminopropionates and carboxybetaines, aminocarboxylic acid types Examples include amphoteric surfactants such as surfactants and imidazoline type surfactants.

  Examples of amino acids include glycine, alanine, serine, threonine, arginine, glutamic acid, aspartic acid, leucine, and valine.

  Examples of amino acid derivatives include pyrrolidone carboxylic acid and its salt, trimethylglycine, lauroyllysine and the like.

  Examples of the lower alcohol include ethanol, propanol, isopropanol, and butanol.

  Examples of the polyhydric alcohol include glycerin, diglycerin, ethylene glycol, 1,3-butylene glycol, propylene glycol, and isoprene glycol.

  Examples of sugar alcohols and their alkylene oxide adducts include mannitol and erythritol.

  Examples of water-soluble polymers include polyglutamic acid, polyamino acids including polyaspartic acid and salts thereof, polyethylene glycol, gum arabic, alginate, xanthan gum, hyaluronic acid, hyaluronic acid salt, chitin, chitosan, water-soluble chitin, carboxyvinyl Polymer, carboxymethylcellulose, hydroxyethylcellulose, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyltrimethylammonium chloride, polydimethylmethylenepiperidinium chloride, polyvinylpyrrolidone derivative quaternary ammonium, cationized protein, collagen degradation product and its derivatives, acylation Examples include protein and polyglycerin.

  Examples of the disinfectant and antibacterial agent include 4-hydroxybenzoic acid and salts and esters thereof, triclosan, chlorhexidine, phenoxyethanol, menthol, mint oil, glyceryl caprate, glyceryl caprylate, and salicylic acid-N-alkylamide.

  Anti-inflammatory agent, analgesic agent, antifungal agent, keratin softening agent, skin colorant, hormone agent include hinokitiol, hydrocortisone (V), ε-aminocarboxylic acid, azulene, allantoin, glycyrrhizic acid derivative, β-glycyrrhetic acid Etc.

  An ultraviolet absorber is, for example, an organic substance (photoprotective filter) that is liquid or crystalline at room temperature, absorbs ultraviolet rays, and can release the absorbed energy as longer-wavelength radiation (for example, heat). And UV-B filters and UV-A filters. The UV-B filter can be oil-soluble or water-soluble. Examples of the oil-soluble substance include 3-benzylidene camphor or 3-benzylidene norcamphor and derivatives thereof (eg, 3- (4-methylbenzylidene) -camphor); 4-aminobenzoic acid derivatives (preferably 4- ( Dimethylamino) -benzoic acid-2-ethylhexyl ester, 4- (dimethylamino) -benzoic acid-2-octyl ester, 4- (dimethylamino) -benzoic acid pentyl ester); cinnamic acid ester (preferably 4-methoxycinnamic acid) 2-ethylhexyl ester, 4-methoxycinnamic acid propyl ester, 4-methoxycinnamic acid isopentyl ester, 2-cyano-3,3-phenylcinnamic acid-2-ethylhexyl ester [Octocrylene]]); salicylic acid ester (Preferably, Licylic acid-2-ethylhexyl ester, salicylic acid-4-isopropylbenzyl ester, salicylic acid homomenthyl ester); benzophenone derivatives (preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone) , 2,2′-dihydroxy-4-methoxybenzophenone); benzalmalonic acid ester (preferably 4-methoxybenzalmalonic acid di-2-ethylhexyl ester); triazine derivatives (eg, 2,4,6-trianilino- ( p-carbo-2′-ethyl-1′-hexyloxy) -1,3,5-triazine, octyl triazone, dioctyl butamide triazone [Uvasorb® HEB]); propane-1,3-dione (For example, - (4-t-butylphenyl) -3- (4'-methoxyphenyl) - propane-1,3-dione); Ketotorishikuro (5.2.1.0) include decane derivatives. Examples of the water-soluble substance include 2-phenylbenzimidazole-5-sulfonic acid and its alkali metal salt, alkaline earth metal salt, ammonium salt, alkylammonium salt, alkanolammonium salt and glucamonium salt; benzophenone sulfonic acid Derivatives (preferably 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts); sulfonic acid derivatives of 3-benzylidene camphor (eg 4- (2-oxo-3-bornylidenemethyl) -benzene Examples thereof include sulfonic acid and 2-methyl-5- (2-oxo-3-bornylidene) -sulfonic acid and salts thereof As the UV-A filter, benzoylmethane derivatives are used, for example, 1- (4′-t-butylphenyl) -3 (4′-methoxyphenyl) -propane-1,3-dione, 4-t-butyl-4′-methoxydibenzoylmethane (Parsol® 1789), 1-phenyl-3- (4′-isopropylphenyl) ) -Propane-1,3-dione and enamine compounds.

  Examples of the hair restoring agent include pantothenic acid and derivatives thereof, placenta extract, allantoin and the like.

  Examples of whitening agents include arbutin, kojic acid, vitamin C and derivatives thereof.

  Antiperspirants and astringent active ingredients, sweat deodorants include aluminum, zirconium or zinc salts such as aluminum chloride, aluminum chlorohydrate, aluminum zirconium trichlorohydrate, aluminum zirconium tetrachlorohydrate, zinc pyrrolidone carboxylate, etc. Is mentioned.

Examples of the vitamin agent include vitamin A, B ₁ , B ₂ , B ₆ , E, and derivatives thereof.

  Examples of the vasodilator include assembly extract and cephalanthin.

  Herbal medicines include, for example, apricot extract, avocado extract, aloe extract, turmeric extract, orange extract, chamomile extract, kiwi extract, ginkgo extract, tea extract, sage extract, assembly extract, tonin extract, rose extract, sunflower extract, grape extract, loofah Extract, peach leaf extract, eucalyptus extract, lavender extract, green tea extract, apple extract, lemon extract, rosemary extract and the like.

  Examples of the pH adjuster include citric acid, adipic acid, ascorbic acid, phosphoric acid, glutamic acid, lactic acid, sulfuric acid, hydrochloric acid, ammonium, sodium hydroxide, potassium hydroxide, arginine, hydroquinone and derivatives thereof, and γ-oryzanol. .

  Examples of the viscosity modifier include agar and organically modified clay minerals.

  Examples of the pearling agent include alkylene glycol esters, fatty acid alkanolamides, fatty acid monoglycerides, fatty ethers and the like.

  Examples of the natural fragrances include fragrances extracted from flowers (lily, lavender, rose, jasmine, etc.), stems and leaves (geranium, patchouli, etc.), fruits and pericarp (lemon, orange, anise).

  Synthetic fragrances include esters, ethers, aldehydes, ketones, alcohols and hydrocarbon-type fragrances.

  Examples of the dye include cochineal red A (C.I. 16255), patent blue (C.I. 42051), chlorophyllin (C.I.75810), and the like.

  Examples of the antioxidant include tocopherol and sodium sulfite.

  Examples of the preservative include phenoxyethanol, paraben, and pentanediol.

  The emulsifier is, for example, a nonionic surfactant and contains a linear fatty alcohol having 8 to 22 carbon atoms, a fatty acid having 12 to 22 carbon atoms, and 8 to 15 carbon atoms in the alkyl group. Addition products of 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide to alkylphenols and alkylamines containing 8 to 22 carbon atoms in the alkyl group; 8 to 22 in the alkyl (alkenyl) group Alkyl and / or alkenyl oligoglycosides containing 1 carbon atom, and their ethoxylates; castor oil and / or hydrogenated castor oil ethylene oxide 1-15 mol adduct; castor oil and / or hydrogenated castor oil ethylene oxide 15 ~ 60 mole adduct; unsaturated straight chain containing 12-22 carbon atoms or Partial esters of saturated branched fatty acids and / or hydroxycarboxylic acids containing 3 to 18 carbon atoms with glycerin and / or sorbitan, and adducts thereof with 1 to 30 mol of ethylene oxide; polyglycerin (2 Average self-condensation of ˜8, polyethylene glycol (molecular weight 400-5000), trimethylolpropane, pentaerythritol, sugar alcohol (eg sorbitol), alkyl glucoside (eg methyl glucoside, butyl glucoside, lauryl glucoside) and polyglucoside (eg Cellulose) and partial esters of saturated and / or unsaturated linear or branched fatty acids containing 12 to 22 carbon atoms and / or hydroxycarboxylic acids containing 3 to 18 carbon atoms, and And Ethile 1-30 moles of oxide adducts; pentaerythritol, fatty acids, mixed esters of citric acid and fatty alcohols, and / or fatty acids containing 6-22 carbon atoms and methyl glucose and polyols (preferably glycerol or polyglycerol Mixed esters with mono-, di-, trialkyl phosphates and mono-, di- and / or triPEG-alkyl phosphates and their salts; wool wax alcohols; polysiloxane / polyalkyl / polyether copolymers and corresponding A block copolymer (eg, polyethylene glycol-30 dipolyhydroxystearate); a polymer emulsifier (eg, Goodrich Pemulen type (TR-1, TR-2)); a polyalkylene glycol, and And glycerol carbonate. Ethylene oxide adducts include, for example, ethylene oxide of fatty alcohols, fatty acids, alkylphenols, or castor oil, and propylene oxide adducts include known commercial products. Examples of the partial glyceride include hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid Examples include acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglyceride, malic acid monoglyceride, malic acid diglyceride and the like. Furthermore, ethylene oxide 1-30 mol (preferably 5-10 mol) adducts of the above partial glycerides are also suitable. Examples of sorbitan esters include sorbitan monoisostearate, sorbitan sesquiisostearate, sorbitan diisostearate, sorbitan triisostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan dioleate, sorbitan trioleate, sorbitan monoelcate, sorbitan sesquito Elcate, sorbitan dielcate, sorbitan trielcate, sorbitan monoricinolate, sorbitan sesquilicinolate, sorbitan diricinolate, sorbitan triricinolate, sorbitan monohydroxystearate, sorbitan sesquihydroxystearate, sorbitan dihydroxystearate, sorbitan trihydroxystearate Rate, sol Vitan monotartrate, sorbitan sesquitate, sorbitan ditartrate, sorbitan tritartrate, sorbitan monocitrate, sorbitan sesquitrate, sorbitan dicitrate, sorbitan tricitrate, sorbitan monomaleate, sorbitan sesquiterate, sorbitan dimate, mixed sorbitan dimaleate, sorbitan dimaleate Is mentioned. Furthermore, 1-30 mol (preferably 5-10 mol) addition product of ethylene oxide of the sorbitan ester is also suitable. Examples of the polyglycerol ester include polyglyceryl-2 dipolyhydroxystearate (Dehymuls (registered trademark) PGPH), polyglycerin-3-diisostearate (Lameform (registered trademark) TGI), polyglyceryl-4 isostearate ( Isolan® GI 34), polyglyceryl-3 oleate, diisostearoyl polyglyceryl-3 diisostearate (Isolan® PDI), polyglyceryl-3 methylglucose distearate (Tego Care® 450), polyglyceryl -3 beeswax (Cera Bellina (registered trademark)), polyglyceryl-4 caprate (Polyglycerol Caprate T2010 / 90), Glyceryl-3 cetyl ether (Chimexane® NL), polyglyceryl-3 distearate (Cremophor® GS 32) and polyglyceryl polylysinolate (Admul® WOL 1403), polyglyceryl dimerate isostearate, and mixtures thereof Etc. Examples of polyol esters include mono-, di- and triesters of trimethylolpropane or pentaerythritol with lauric acid, coconut oil fatty acid, tallow fatty acid, palmitic acid, stearic acid, oleic acid, behenic acid, etc. Can react with 1 to 30 moles of ethylene oxide.

  Examples of the fat and wax include 12-hydroxystearic acid, lanolin, beeswax, candelilla wax, carnauba wax and the like.

  Examples of the silicone compound include dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicone, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and / or alkyl-modified silicone compounds ( And those which can be liquid or resin-like at room temperature), simethicone which is a mixture of dimethicone having an average chain length of 200 to 300 dimethylsiloxane units and hydrogenated silicate.

  Perfume oils include mixtures of natural and synthetic fragrances. Natural fragrances include, for example, flowers (lily, lavender, rose, jasmine, neroli, iran-iran), stems and leaves (geranium, patchouli, petitgren), fruit (anis, coriander, caraway, juniper), peel (bergamot) , Lemon, orange), roots (nutmeg, angelica, celery, cardamom, costas, iris, shrub), trees (pine, sandalwood, guayak, cedar, rosewood), herbs and grass (taragon, lemongrass, sage, thyme), Examples include plant materials such as needles and branches (spruce, fir, pine, shrub pine), resin and balsam (galvanum, elemi, benzoin, myrrh, frankincense, opopanax), and animal materials such as civet and beaver. . Furthermore, as a relatively low volatile essential oil often used as an aromatic component, for example, sage oil, chamomile oil, clove oil, Melissa oil, mint oil, cinnamon leaf oil, lime flower oil, juniper berry oil, vetiver oil , Balm oil, galvanum oil, labdanum oil and lavandin oil, bergamot oil, dihydromyrsenol, lyial, ryal, citronellol, phenylethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, Boisambrene Forte, Ambroxan, indole, Hedione, Sandelice, citrus oil, mandarin oil, orange oil, allylpentyl glycolate, cyclovertal (Cyclo) vertal), lavandin oil, clary oil, β-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix Coeur, Iso-E-Super, Fixolide NP, evanyl, Iraldein gamma, phenylacetic acid, benzyl acetate , Rose oxide, lomirat, irotil and floramat, peppermint oil, spearmint oil, anise oil, daikyo oil, caraway oil, eucalyptus oil, fennel oil, citrus oil, wintergreen oil, clove Examples include oil and menthol.

  As a further aspect of the present invention, the L-cysteine derivative of the present invention may be used as a cysteine substitute as a food or beverage such as an infusion solution, a nutrient, or a supplement. Specific examples thereof include pigmentation improvers, flavor raw materials, bread fermentation aids, health foods, infant formulas, antioxidants, and the like. The blending amount can be appropriately set and used similarly to the amount used in cosmetics. L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, L-2-methylthiazolidine-2,4-dicarboxylic acid from the viewpoint that only ethanol and pyruvic acid can be released as safe decomposition products in the body Acid 4-ethyl ester and L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester are preferred.

  The method for producing the cysteine derivative represented by the general formula (I) (hereinafter sometimes abbreviated as cysteine derivative (I)) is not particularly limited, and is produced by combining known methods. be able to. For example, the cysteine derivative (I) may be synthesized by reacting cysteine with substituted pyruvic acid to construct a thiazolidine skeleton and then performing esterification or amidation. Alternatively, the cysteine derivative (I) may be synthesized by reacting a cysteine protector with a pyruvic acid derivative to construct a thiazolidine skeleton and a carboxylic acid derivative at a time.

Specifically, it can be synthesized by the following method, but is not limited thereto.
The thiazolidine derivative is obtained by reacting a cysteine derivative and a pyruvic acid derivative in water or an alcohol such as ethyl alcohol at room temperature for 5 to 24 hours. Among cysteine derivatives, for example, cysteine ester can be obtained by reacting in ethyl alcohol in the presence of hydrochloric acid or thionyl chloride at room temperature for about 5 to 24 hours. Cysteinamide is a solvent such as methylene chloride or N, N-dimethylformamide in the presence of a dehydrating condensing agent such as EDC (1-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride). The compound obtained by reacting at room temperature for 5 to 24 hours is obtained by deprotection. Another method is to react a protected cysteine such as cysteine t-butyl ester with pyruvic acid in the same manner as above to obtain a thiazolidine derivative, and then esterify or amidate the carboxyl group of the obtained thiazolidine derivative. is there. Esterification and amidation can be carried out under the same conditions as the above-mentioned esterification and amidation of cysteine. A carboxylic acid derivative is obtained by hydrolyzing the t-butyl ester of the obtained compound under an acid catalyst. Further, a thiazolidine derivative in which two carboxyl groups are esterified or amidated can be synthesized by esterifying or amidating the carboxyl group under the same conditions as the esterification and amidation of cysteine. As yet another method, first, cysteine and pyruvic acid are reacted in water or an alcohol such as ethyl alcohol at room temperature for 5 to 24 hours to obtain 2-methyl-thiazolidine 2,4-dicarboxylic acid. An ester or amide derivative of 2-methyl-thiazolidine 2,4-dicarboxylic acid can be obtained by reacting under the same conditions as in the esterification or amidation of cysteine.

Manufacturing method (1)

(In the formula, each symbol is as defined above.)
Cysteine is esterified or amidated in advance to obtain compound (II), which is reacted with compound (III) to form a ring to synthesize cysteine derivative (I).

Manufacturing method (2)

(In the formula, P represents a carboxylic acid protecting group, and other symbols are as defined above.)
The protected cysteine (IV) is reacted with the compound (V) to form a ring to obtain the compound (VI), and then the carboxylic acid at the 2-position is esterified or amidated to obtain the compound (VII). This is deprotected to synthesize compound (VIII), and the carboxylic acid at position 4 is esterified or amidated to give cysteine derivative (I).

Manufacturing method (3)

(In the formula, each symbol is as defined above.)
Cysteine (IX) is reacted with compound (V) to form a ring to synthesize compound (X), and then each carboxylic acid is esterified or amidated to synthesize cysteine derivative (I).

  Hereinafter, the present invention will be described more specifically with reference to synthesis examples, examples, test examples, and blending examples, but the present invention is not limited thereto.

[Synthesis Example 1] L-2-methylthiazolidine-2,4-dicarboxylic acid (cysteinyl pyruvic acid; hereinafter may be abbreviated as CP)
Under an argon atmosphere, L-cysteine (15 g) and anhydrous methanol (35 mL) were added to a 100 mL eggplant flask and stirred. Pyruvate (18.6 mL) was added thereto at room temperature, and the mixture was stirred for 3 hours. The resulting solid was filtered under reduced pressure and washed with ice-cold ethanol to obtain the target compound, L-2-methylthiazolidine-2,4-dicarboxylic acid (diastereomer mixture) (23 g, yield 97%).

¹ H-NMR (DMSO-d ₆ ) δ; 4.19 (1H, dd), 3.98 (1H, dd), 3.40 (1H, dd), 3.26 (1H, dd), 2. 97 (1H, dd), 2.76 (1H, dd), 1.72 (3H, s), 1.59 (3H, s); MS spectrum m / z; 190 (M ⁻ )

[Synthesis Example 2] L-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (hereinafter sometimes abbreviated as CP2Et)
Under an argon atmosphere, L-cysteine (10 g) and pure water (150 mL) were added to a 200 mL eggplant flask and stirred. Thereto, pyruvic acid ethyl ester (19.7 mL) dissolved in ethanol (10 mL) was gradually added at room temperature, and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained solid was dissolved in a small amount of pure water, extracted with chloroform three times, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance. This oily substance was recrystallized from chloroform / hexane to obtain the target compound, L-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester (diastereomer mixture) (12.7 g, yield 70). %).

¹ H-NMR (DMSO-d ₆ ) δ; 4.20 (2.6 H, q), 4.16 (1 H, dd), 4.09 (2 H, m), 4.03 (1.3 H, dd ), 3.42 (1.3H, dd), 3.29 (1H, dd), 2.97 (1H, dd), 2.81 (1.3H, t), 1.75 (3H, s) , 1.62 (3H, s), 1.23 (3.9 H, t), 1.19 (3H, t); MS spectrum m / z; 220 (M ⁺ )

[Synthesis Example 3] L-2-methylthiazolidine-2,4-dicarboxylic acid 4-ethyl ester (hereinafter sometimes abbreviated as CP4Et)
Under an argon atmosphere, ethanol (15 mL) was added to and dissolved in L-cysteine ethyl ester (2.08 g) desalted with an aqueous potassium carbonate solution from L-cysteine ethyl ester hydrochloride (3 g). After cooling the reaction solution to 0 ° C., pyruvic acid (1.23 g) was gradually added dropwise, and after completion of heat generation, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting oily substance was slurry washed with hexane three times and dried under reduced pressure at 45 ° C. to obtain the target compound, L-2-methylthiazolidine-2,4-dicarboxylic acid. The acid 4-ethyl ester (diastereomeric mixture) was obtained as an oily substance (3.09 g, yield 87%).

¹ H-NMR (DMSO-d ₆ ) δ; 4.27 (1H, dd), 4.19 (2.6 H, m), 4.17 (2H, m), 4.08 (1H, dd), 3.39 (1.3H, dd), 3.24 (1H, dd), 3.01 (1H, dd), 2.79 (1.3H, t), 1.71 (3H, s), 1 .60 (3H, s), 1.24 (3H, t), 1.23 (3H, t); MS spectrum m / z; 220 (M ⁺ )

[Synthesis Example 4] L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester (hereinafter sometimes abbreviated as CPdiEt)
Under an argon atmosphere, L-cysteine ethyl ester hydrochloride (5 g) was dissolved in pure water (20 mL). Potassium carbonate (1.86 g) and pure water (7 mL) were added and dissolved therein. Thereafter, pyruvic acid ethyl ester (6.28 mL) dissolved in ethanol (10 mL) was gradually added dropwise to the reaction solution at room temperature and stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in a small amount of pure water, followed by extraction with methylene chloride three times. Then, it was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain an oily substance. The oily substance was purified by silica gel column chromatography with chloroform / methanol = 400/1 to obtain the target compound, L-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester as a transparent oily substance. (6.0 g, 91% yield).

¹ H-NMR (CDCl ₃ ) δ; 3.9-4.1 (4H, m), 4.02 (1H, m), 3.40 (1H, dd), 2.88 (1H, t), 1.89 (1H, s), 1.72 (3H, s), 1.34 (3H, t), 1.33 (3H, t); MS spectrum m / z; 248 (M ⁺ )

  The following compounds were prepared in the same manner as described above.

[Test Example 1] Odor test (model solution)
L-cysteine (hereinafter sometimes abbreviated as Cys), N-acetylcysteine (hereinafter sometimes abbreviated as NAC), 0.03M solution of cysteine derivatives of Synthesis Examples 1 and 2 (pH 7) 25 mM phosphate buffer solution) was sealed in a 50 ° C. constant temperature bath and stored for 8 days. Each sample immediately after taking out from a 50 degreeC thermostat was evaluated whether the four panelists smelled and the smell of sulfur. As the evaluation criteria, a four-step evaluation of 1 to 4 was made, 1 for a strong sulfur odor, 2 for a strong one, 3 for a slight one, and 4 for no. Table 2 shows the average evaluation score of each paneler.

  The cysteine derivatives of Synthesis Example 1 and Synthesis Example 2 were found to have a reduced sulfur odor than L-cysteine and N-acetylcysteine. Thereby, it turned out that the cysteine derivative of this invention can provide the cosmetics or skin external preparation with no odor problem rather than using L-cysteine or N-acetylcysteine.

[Test Example 2] Odor test (milky lotion)
An emulsion containing 0.3% by weight of Cys, NAC and the cysteine derivatives of Synthesis Examples 1 to 4 was formulated, sealed in a 40 ° C. constant temperature bath, and stored for 29 days. Each sample immediately after taking out from a 40 degreeC thermostat was evaluated whether the four panelists sniff and whether a sulfur smell is made. Table 3 shows the components of the emulsion (Examples 1 to 4) containing the cysteine derivatives of Synthesis Examples 1 to 4 and the emulsion (Comparative Examples 1 and 2) containing Cys or NAC, respectively. In addition, a mixture ratio is weight%.

  The emulsions of Examples and Comparative Examples were prepared by adding B to A completely dissolved at 80 ° C., mixing and emulsifying, cooling to 40 ° C., and adding D and C. As the evaluation criteria, a four-step evaluation of 1 to 4 was made, 1 for a strong sulfur odor, 2 for a strong one, 3 for a slight one, and 4 for no. Table 4 shows the average evaluation score of each paneler.

  In both Example 1 and Example 2, it was found that the sulfur odor was reduced compared to Comparative Example 2. Thereby, it turned out that the cosmetics which mix | blend the cysteine derivative of this invention are cosmetics without an odor problem rather than the cosmetics which mix | blend N-acetylcysteine.

[Test Example 3] Time-dependent stability test at room temperature A time-dependent stability test at room temperature of the cysteine derivatives of each synthesis example in pH 7, 25 mM phosphate buffer was performed. The results are shown in FIG. 1 and FIG. L-cysteine and / or N-acetylcysteine was used as a comparison target. In addition, in this stability test over time, HPLC (pump) Waters 600E multisolvent liquid feeding system, (autosampler) Waters 717 autosampler, (detector) Waters 996 PDA detector were used.

  The effective S amount (%) was used as an index for the time-dependent stability test at room temperature in FIG. The effective amount of S is defined as a thiol active substance including a compound having a reducing ability in the end, including cysteine, and the thiol action remaining in the system after a certain time with respect to the amount of the thiol active substance initially present. The amount of substance is expressed in mol%.

  In the cysteine derivative of the present invention, an equilibrium reaction between the cysteine derivative and the pyruvate derivative is established. For example, in the cysteine derivatives of Synthesis Examples 2 to 4, after the ester is hydrolyzed to CP over time, the thiazolidine ring is opened to cysteine, and the cysteine is further oxidized to cystine. Of the four compounds generated in the system under stability test described above, cysteine derivatives, CP and cysteine (including cysteine ethyl ester (CysOEt)) have the ability to ultimately reduce. These compounds having reducing ability are defined as thiol active substances including cysteine, converted to mol from the HPLC analysis results using the respective calibration curves, and the amount of thiol active substances after 0 hours from the start of the stability test. The total remaining amount (mol) of the thiol active substance after a certain time from the start of the test with respect to (mol) can be calculated in%. That is, in the stability test of each thiazolidine compound, the total mol of the following thiol active substances was calculated, and the residual ratio of the total mol was used as an effective S amount and used as a stability index. Total remaining amount of thiol active substance in cysteine derivative of Synthesis Example 1 (mol) = CP (mol) + Cys (mol), Total remaining amount of thiol active substance in cysteine derivative of Synthesis Example 2 (mol) = CP2Et (mol) + CP (mol ) + Cys (mol), the total remaining amount of thiol active substance in the cysteine derivative of Synthesis Example 3 (mol) = CP4Et (mol) + CP (mol) + CysOEt (mol) + Cys (mol), the thiol agonist of the cysteine derivative of Synthesis Example 4 Total remaining amount (mol) = CPdiEt (mol) + CP4Et (mol) + CP2Et (mol) + CP (mol) + CysOEt (mol) + Cys (mol).

HPLC analysis condition detector for cysteine derivative, Cys and NAC of Synthesis Example 1; ultraviolet absorptiometer (measurement wavelength: 210 nm)
Column; Inertcil ODS (GL Sciences) (particle size 5 μm, inner diameter 4.6 mm, length 250 mm)
Eluent; 4 mL / L aqueous phosphoric acid flow rate; 1 mL / min column temperature; 45 ° C.
Sample concentration: 100 mg / dL
Injection volume: 15 μL
Retention time (min); CP: 6.9, 7.9 (diastereomeric mixture), Cys: 2.9, NAC: 16.3

Detector for HPLC analysis condition of cysteine derivatives of Synthesis Example 2 and Synthesis Example 3; UV absorption photometer (measurement wavelength: 210 nm)
Column; Inertcil ODS (GL Sciences) (particle diameter 5 μm, inner diameter 4.6 mm, length 250 mm)
Eluent: 4 mL / L phosphoric acid aqueous solution: methanol = 60: 40 (v / v)
Flow rate; 1 mL / min column temperature; 45 ° C
Sample concentration: 100 mg / dL
Injection volume: 15 μL
Retention time (min); 9.8, 10.3 (diastereomeric mixture)

Detector for HPLC analysis conditions of the cysteine derivative of Synthesis Example 4; UV absorptiometer (measurement wavelength: 210 nm)
Column; Inertcil ODS (GL Sciences) (particle size 5 μm, inner diameter 4.6 mm, length 250 mm)
Eluent A; 0.05% TFA aqueous solution Eluent B; Methanol gradient program; 0 min A / B = 90/10, 10 min A / B = 30/70, 15 min A / B = 30 / 70,15. 1 minute A / B = 90/10, 40 minutes A / B = 90/10 (end)
Flow rate; 1 mL / min column temperature; 45 ° C
Sample concentration: 100 mg / dL
Injection volume: 15 μL
Retention time (min); CP: 3.8, 4.0 (diastereomeric mixture), CP2Et: 18.4, 18.7 (diastereomeric mixture), CP4Et: 16.2 (diastereomeric mixture), CPdiEt: 22.3, 23.0 (diastereomeric mixture)

  As an index of the time-dependent stability test at room temperature in FIG. 2, the remaining amount (%) of the target substance itself was used. The amount (mol) of the target substance after change over time was calculated in% with respect to the amount (mol) of the target substance 0 hours after the start of the stability test. In addition, HPLC; (pump) Waters 600E multi-solvent liquid feeding system, (auto sampler) Waters 717 auto sampler, (detector) Waters 996 PDA detector was used for the analyzer of this temporal stability test.

  From the results of FIG. 1 and FIG. 2, it was found that the cysteine derivative of the present invention shows better stability than cysteine and N-acetylcysteine. In particular, the cysteine derivatives of Synthesis Example 2, Synthesis Example 3, Synthesis Examples 4 to 6, and Synthesis Example 10 were found to be highly useful compounds with higher stability than the cysteine derivative (CP) of Synthesis Example 1. .

[Test Example 4] Stability test over time at 50 ° C. The L-cysteine derivatives of Synthesis Example 1 and Synthesis Example 2 were dissolved in lauroylglycine isopropyl ester (ELDEWSL-205) at a concentration of 1 mg / mL, respectively. Each sample was stored in a tank, sampled 500 μL each day, and diluted 4-fold with methanol, and analyzed by HPLC to confirm the thermal stability of each. The results are shown in FIG.

  As an index for the stability test over time at 50 ° C., the remaining amount (%) of the cysteine derivative itself of each synthesis example was used. The amount (mol) of cysteine derivatives of Synthesis Example 1 and Synthesis Example 2 after change with respect to the amount of cysteine derivatives (mol) of Synthesis Example 1 and Synthesis Example 2 after 0 hours from the start of the stability test was calculated in%. In addition, HPLC; (pump) Waters 600E multi-solvent liquid feeding system, (auto sampler) Waters 717 auto sampler, (detector) Waters 996 PDA detector was used for the analyzer of this temporal stability test.

  From the results of FIG. 3, the cysteine derivative (CP) of Synthesis Example 1 was not satisfactory in thermal stability in lauroylglycine isopropyl ester, whereas the cysteine derivative of Synthesis Example 2 was very stable. I understood it.

[Test Example 5] Black melanin production inhibition test B16 melanoma was cultured in DMEM (Dulbecco's Modified Eagle Medium) (high glucose, containing 10% serum). Confluent cells were detached with trypsin and seeded in 6-well plates. The next day, after the cells adhered to the plate, the medium was replaced with DMEM to which each sample (control (no sample added), Cys, cysteine derivatives of Synthesis Example 1 and Synthesis Example 3) was added at a predetermined concentration (50, 250, 500 μM), Cultured for 3 days. After 3 days, a certain amount of medium from each well was collected in an Eppendorf tube, mixed with HEPES buffer (pH 6.8, concentration 0.4 mM, containing 10% ethanol) at a volume ratio of 1: 1, and the absorbance of the medium at 450 nm. Was measured with a spectrophotometer. When the measurement value (absorbance) of the control is defined as 100%, the absorbance of each sample when the amount of black melanin in the control is set to 100% by making the absorbance 3 days after the addition of the predetermined concentration of each sample is relative%. The amount of black melanin was calculated as a relative%. The results are shown in FIG. Both L-cysteine derivatives of Synthesis Examples 1 and 3 suppressed the amount of black melanin released from the cells in a concentration-dependent manner as compared to the control, and the suppression effect was found to be equivalent to that of L-cysteine.
The spectrophotometer used in the black melanin production inhibition test is SPECTROTOPOMETER DU640, manufactured by Beckman Coulter.

[Test Example 6] Black melanin production inhibition test B16 melanoma was cultured in DMEM (Dulbecco's Modified Eagle Medium) (high glucose, containing 10% serum). Confluent cells were detached with trypsin and seeded in a 96-well plate. On the next day, after the cells adhere to the plate, each evaluation sample (control (no sample added), cysteine derivative of each synthesis example) was replaced with DMEM to which a predetermined evaluation concentration (diluted from 10 mM according to the sample) was added. Cultured for days. The 96-well plate was shaken for 5 minutes with a plate shaker, and the absorbance at 450 nm was measured with a microplate reader. When the measured value (absorbance) of the control (no sample added) is defined as 100%, and the amount of black melanin in the control is set to 100% by making the absorbance 3 days after the addition of each sample's predetermined concentration. The concentration required to suppress the black melanin production of each sample by 50% was calculated as the 50% melanin production inhibitory concentration. The results are shown in Table 5.
The microplate reader used in the black melanin production inhibition test is a Benchmark microplate reader, manufactured by BIORAD.

  It was found that the cysteine derivative of the present invention has an effect of suppressing the amount of black melanin released from the cells as compared with the control. In particular, it was found that the cysteine derivative of Synthesis Example 9 has a higher black melanin inhibitory effect than the cysteine derivative (CP) of Synthesis Example 1 and can be a very effective whitening agent.

[Test Example 7] Glutathione synthesis promotion test Normal human epidermal keratinocytes (derived from neonatal foreskin, NHEK) and HuMedia-KG2 as a medium were purchased from Kurabo Industries. NHEK is grown until it becomes sub-confluent with HuMedia-KG2, and it is detached from the petri dish with a trypsin / EDTA solution at the time of evaluation, seeded at a cell number of 2.5 × 10 ⁴ / well in a 96-well plate in a CO ₂ incubator. Cultured. After confirming complete adherence and confluence, the sample was replaced with a growth factor-free medium (HuMedia-KB2) and cultured overnight, then diluted with HuMedia-KB2 (sample free (control), NAC, L-Cys, Synthesis Example 1, Synthesis Example 2, Synthesis Example 3 or Synthesis Example 4 L-cysteine derivatives) are added to the cells to a predetermined concentration (4 mM, 0.4 mM, 0.04 mM), and further 24 hours The cells were cultured in a CO ₂ incubator. NHEK after the culture was washed twice with PBS (−), and the intracellular total GSH was measured according to the protocol of total Glutathione Quantification Kit (manufactured by Dojindo Laboratories).
The results are shown in Table 6. The control value was 100%, and the intracellular total GSH content at the time of each sample addition in a concentration range where no cytotoxicity was expressed was shown.

  From these results, it was found that the cysteine derivative of the present invention has a glutathione synthesis promoting action from 0.4 mM or more. In particular, it was found that the cysteine derivative of Synthesis Example 1 has a high glutathione synthesis promoting action and can be a very effective glutathione synthesis promoter.

  Hereinafter, although the general compounding example of the cysteine derivative of this invention is shown, this invention is not limited to these.

[Formulation Example 1] (Lotion)

[Formulation Example 2] (Emulsion)

[Formulation 3] (Cream)

[Formulation Example 4]

[Formulation Example 5]

[Composition Example 6]

[Composition Example 7]

[Formulation Example 8]

[Formulation Example 9]

[Formulation Example 10]

[Formulation Example 11]

[Composition Example 12]

[Formulation Example 13]

[Formulation Example 14]

[Formulation Example 15]

  The cysteine derivative of the present invention has been found to have the same effects on the whitening effect and the glutathione synthesis promoting action while succeeding in improving stability and odor compared to L-cysteine. As a result, whitening agents, glutathione synthesis accelerators, stain-improving agents or therapeutic agents, and wrinkle-improving agents or therapeutic agents, which have not been provided by L-cysteine, have good stability and have no odor problems, and contain these It has become possible to provide cosmetics or skin external preparations.

Claims (12)

The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
Or a salt thereof (excluding thiazolidine-2,4-dicarboxylic acid and 2-methylthiazolidine-2,4-dicarboxylic acid).   The cysteine derivative according to claim 1, which is an L-cysteine derivative. The cysteine derivative according to claim 1 or 2, wherein Z is a _C1-22 alkyl group.   The cysteine derivative according to claim 1 or 2, wherein Z is a methyl group. The cysteine derivative according to any one of claims 1 to 4, wherein X is OR ¹ (wherein R ¹ has the same meaning as in claim 1). Y is (wherein, ^{R 3} represents. The same meanings as claim 1) OR ³ is a cysteine derivative according to any one of claims 1 to 5. The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
A cosmetic comprising a cysteine derivative represented by the formula:   The cosmetic according to claim 7, wherein the cysteine derivative is an L-cysteine derivative. The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
The whitening agent containing the cysteine derivative represented by these, or its salt.   The whitening agent according to claim 9, wherein the cysteine derivative is an L-cysteine derivative. The following general formula

[Wherein, X represents OR ¹ or NHR ² (wherein R ¹ represents a hydrogen atom or a C _1-22 alkyl group, and R ² represents a hydrogen atom or a C _1-22 alkyl group);
Y represents OR ³ or NHR ⁴ (wherein R ³ represents a hydrogen atom or an optionally substituted C _1-22 alkyl group, and R ⁴ represents a hydrogen atom or a C _1-22 alkyl group). Show;
Z represents a hydrogen atom or a C _1-22 alkyl group. ]
A glutathione synthesis promoter containing a cysteine derivative represented by the formula:   The glutathione synthesis promoter according to claim 11, wherein the cysteine derivative is an L-cysteine derivative.

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