WO2014157540A1

WO2014157540A1 - Anti-inflammatory agent

Info

Publication number: WO2014157540A1
Application number: PCT/JP2014/058920
Authority: WO
Inventors: 季之高橋; 砂田　太; 秀忠永井; 青柳　健一; 弘義米田
Original assignee: Ｊｘ日鉱日石エネルギー株式会社
Priority date: 2013-03-27
Filing date: 2014-03-27
Publication date: 2014-10-02
Also published as: TW201513851A; JP6178407B2; JPWO2014157540A1

Abstract

The objective of the present invention is to provide a therapeutic agent for dermatitis, which is an orally administrable agent. The present invention provides a therapeutic agent for dermatitis, which is an orally administrable agent and contains a compound represented by general formula W-X-C(CH₃)=CH-CH=CH-C(CH₃)=CH- CH=CH-CH=C(CH₃)-CH=CH-CH=C(CH₃)-Y-Z or a pharmaceutically acceptable salt thereof. In the general formula, W represents a 4-hydroxy-2,6,6-trimethyl-1-cyclohexenyl group or the like; each of X and Y represents a vinylene group or the like; and Z represents a 4-hydroxy-2,6,6-trimethyl-3-one-1-cyclohexenyl group or the like.

Description

Anti-inflammatory drug

The present invention relates to a therapeutic agent for oral dermatitis containing a xanthophyll compound having anti-dermatitis action. Specifically, it relates to a therapeutic agent for oral dermatitis containing adonixanthin and the like and a functional food.

Carotenoids are natural pigments useful as feed additives, food additives, cosmetic materials, pharmaceuticals, and the like. Carotenoids include astaxanthin, canthaxanthin, zeaxanthin, β-cryptoxanthin, lycopene, β-carotene, adonilvin, adonixanthin, echinone, asteroidenone, 3-hydroxyechinenone, and the like.

Among them, astaxanthin is useful as a feed additive such as a body color improving agent for salmon, trout, red sea bream, etc., which are farmed fish, and an egg yolk improving agent for poultry. Astaxanthin is known to have high industrial value as a safe natural food additive, health food material, and cosmetic material. Adnirubin is expected to be used as a feed additive, food additive, cosmetic material, pharmaceutical, and the like, similar to astaxanthin, as an industrial production method is established. Furthermore, β-carotene is used as a feed additive, food additive, cosmetic material, medicine, etc., canthaxanthin is used as a feed additive, food additive, cosmetic, etc., zeaxanthin is used as a food additive, feed additive, It is used as a cosmetic material. Furthermore, lycopene, echinenone, β-cryptoxanthin, 3-hydroxyechinenone, asteroidenone and the like are also expected to be used as feed additives, food materials, cosmetic materials and the like. Known methods for producing these carotenoids include chemical synthesis methods, extraction methods from natural products, and production methods using microorganisms (for example, Patent Documents 1 and 2).

However, the biological actions of carotenoids, especially xanthophylls such as adonixanthin, which are carotenoids containing heteroatoms represented by oxygen atoms in addition to carbon and hydrogen atoms, are still well known. It is not done.

On the other hand, there is still a need for the development of further therapeutic agents for dermatitis, particularly atopic dermatitis. That is, among the conventionally known therapeutic agents for atopic dermatitis, steroids are effective in treating inflammation, but have strong side effects such as thinning of the skin and are difficult to use for a long time. On the other hand, the immunosuppressive agent has a problem of becoming susceptible to other diseases because it has an effect of suppressing the immune system as a whole. Under such circumstances, there is a demand for the development of therapeutic agents that are effective in treating inflammation and have few side effects.

JP 2010-172293 A JP 2009-050237 A

An object of the present invention is to provide a dermatitis therapeutic agent or functional food for oral administration containing a xanthophyll compound having anti-dermatitis activity.

As a result of intensive studies to solve the above problems, the present inventors have found that specific xanthophyll compounds such as adonixanthin are orally administered for the prevention and treatment of dermatitis, particularly allergic dermatitis, by oral administration. As a result, the present invention has been found to work more effectively.

That is, the present invention is a therapeutic agent for oral allergic dermatitis containing a xanthophyll compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

[In the general formula (1), W represents a group represented by any one of the following general formulas (2) to (4), and X represents a group represented by any one of the following general formulas (5) to (8). W—X, which is a combination of W and X, represents a group represented by the following general formula (9), Y represents a group represented by any one of the following general formulas (10) to (12), Z represents a group represented by any one of the following general formulas (13) to (21), or YZ which is a combination of Y and Z is any one of the following general formulas (22) to (24) Represents a group represented by

(Here, in the general formulas (2) to (4) and the general formula (9), R ¹ and R ² are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR ³ ;
-COOR ⁴ ;
-CONR ⁵ R ⁶ ;
Represents —PO (OR ⁷ ) (OR ⁸ ); or —SO ₂ R ⁹ ,

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁹ are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R ⁷ and R ⁸ are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent
Represents.

In general formulas (13) to (15),
R ¹⁰ , R ¹¹ and R ¹² are each independently of each other, the same or different and each represents a hydrogen atom or —OQ ¹ ;
Q ¹ is
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR ¹⁶ ;
-COOR ¹⁷ ;
-CONR ¹⁸ R ¹⁹ ;
Represents —PO (OR ²⁰ ) (OR ²¹ ); or —SO ₂ R ²² ,
R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²² are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R ²⁰ and R ²¹ are each independently the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent.

In the general formulas (16), (18), (21), and (22), R ¹³ , R ^14, and R ¹⁵ are each independently the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR ²³ ;
-COOR ²⁴ ;
-CONR ²⁵ R ²⁶ ;
Represents —PO (OR ²⁷ ) (OR ²⁸ ); or —SO ₂ R ²⁹ ,
R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁹ are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R ²⁷ and R ²⁸ are each independently the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent. )]

In the present invention, examples of W include those represented by the general formula (2) or (3).
X is represented by the general formula (5), Y is represented by the general formula (10), and Z is any one of the general formulas (13), (14) and (15). What is shown.
Further, in the present invention, in the general formula (2) or (3), it can be exemplified in which R ¹ represents a hydrogen atom.

In the present invention, the xanthophyll compound is, for example, at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin and lutein, and pharmaceutically acceptable salts thereof. One can mention.

In the present invention, allergic dermatitis includes atopic dermatitis. Dermatitis can be exemplified, for example, due to IgE.

Furthermore, the present invention is a functional food containing the xanthophyll compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
General formula (1) and substituents in formula (1) (W, X, and W—X, which is a combination of W and X, and Y, Z, and Y—Z, which is a combination of Y and Z) ) Is as defined above.
The xanthophyll compound contained in the functional food of the present invention is selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin and lutein, and pharmaceutically acceptable salts thereof. There may be mentioned at least one selected.

Furthermore, the present invention includes at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin and lutein, and pharmaceutically acceptable salts thereof. A pharmaceutical composition for the treatment of atopic dermatitis is included.

The present invention provides a therapeutic agent for orally administered dermatitis, particularly allergic dermatitis. In one embodiment of the present invention, the therapeutic agent for dermatitis of the present invention results in a decrease in skin lesion score and / or blood IgE concentration observed in NC model mice in a concentration-dependent manner. It is useful for the treatment of dermatitis, allergic dermatitis, especially atopic dermatitis. In another embodiment of the present invention, since the therapeutic agent for dermatitis of the present invention does not show weight loss as a side effect, a therapeutic agent with fewer side effects is provided.

Hereinafter, the present invention will be described in detail. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

In addition, the publications cited in this specification are incorporated in this specification throughout.

The present invention has been completed on the basis of a new finding that a xanthophyll compound such as adonixanthin is effective for treating dermatitis that develops in NC mice by oral administration. Therefore, this invention provides the therapeutic agent of the dermatitis which is an orally administered agent containing the xanthophyll compound which has anti-dermatitis action, such as adonixanthin. Dermatitis is, for example, allergic dermatitis, preferably atopic dermatitis.

1. Xanthophyll having anti-dermatitis activity In the present invention, "xanthophyll" is not particularly limited as long as it has an anti-dermatitis activity and is effective in treating dermatitis.

The xanthophyll compound used as the oral therapeutic agent of the present invention (hereinafter also referred to as “the xanthophyll compound of the present invention”) is represented by the following general formula (1), and includes pharmaceutically acceptable salts thereof. It is.

In the general formula (1), W represents a group represented by any one of the following general formulas (2) to (4), and X represents a group represented by any one of the following general formulas (5) to (8). Or W—X, which is a combination of W and X, represents a group represented by the following general formula (9), and Y represents a group represented by any one of the following general formulas (10) to (12), Represents a group represented by any one of the following general formulas (13) to (21), or YZ which is a combination of Y and Z is any one of the following general formulas (22) to (24) Represents the group shown.

Here, in the general formulas (2) to (4) and the general formula (9), R ¹ and R ² are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR ³ ;
-COOR ⁴ ;
-CONR ⁵ R ⁶ ;
Represents —PO (OR ⁷ ) (OR ⁸ ); or —SO ₂ R ⁹ ,

In the general formulas (16), (18), (21), and (22), R ¹³ , R ^14, and R ¹⁵ are each independently the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR ²³ ;
-COOR ²⁴ ;
-CONR ²⁵ R ²⁶ ;
Represents —PO (OR ²⁷ ) (OR ²⁸ ); or —SO ₂ R ²⁹ ,
R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁹ are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R ²⁷ and R ²⁸ are each independently the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent.

Hereinafter, each group in the xanthophyll compound represented by the formula (I) used in the present invention will be specifically described.

In the description of each group, for example, “C _1-20 ” means that the number of constituent carbon atoms is 1 to 20 (C ₁ -C ₂₀ ), and unless otherwise specified, linear, branched or cyclic Represents the number of carbon atoms in the group. The number of constituent carbon atoms includes the total number of carbon atoms of a linear or branched group substituted with a cyclic group, or a group containing a cyclic group substituted with a linear or branched group.
Thus, for example, a chain group in the case of “C _1-20 ” means a straight chain or branched chain having 1 to 20 carbon atoms. The cyclic group means a cyclic group having 1 to 20 carbon atoms in the ring. The group containing a chain group and a cyclic group means a group having 1 to 20 carbon atoms in total.
The same applies to the display of other numbers of carbon atoms.

The phrase “which may have a substituent” means that one substituent or a plurality of substituents arbitrarily combined may be present at a substitutable site.
Examples of the substituent in “may have a substituent” include a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a formyl group, a carboxyl group, an amino group, a silyl group, a methanesulfonyl group, and C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkoxy, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _2-7 acyl, C _2-7 alkoxycarbonyl, etc. Can be mentioned.
However, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5-10 member heteroaryl group, a 3-10 member Non-aromatic heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-8 cycloalkoxy group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, The C _2-7 acyl group and the C _2-7 alkoxycarbonyl group may each independently have 1 to 3 groups selected from the following substituent group.
(Substituent group: halogen atom, hydroxyl group, thiol group, nitro group, cyano group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _{6 -10} aryl group, 5-10 membered heteroaryl group, 3-10 membered non-aromatic heterocyclic group, C _1-6 alkoxy group and C _1-6 alkylthio group.)

The “alkyl group” represents a linear or branched alkyl group. For example, as the “C _1-20 alkyl group”, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2 , 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2- Trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2 -Methylpropyl, heptyl, 1-methylhexyl, octyl, 2-ethylhexyl, 1,1-dimethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. It is done.

The “alkenyl group” represents a linear, branched or cyclic alkenyl group. For example, the “C _2-20 alkenyl group” includes vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl, 1-cyclopropen-1-yl, 2-cyclopropen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3- Cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, 2,5-cyclohexadien-1-yl, heptenyl, octenyl, nonenyl, decenyl, 1-cyclohepten-1-yl, 1-cyclohexene-1- Irmethyl, 4-methyl-1-cyclohexen-1-yl, 4,4-dimethyl-1-cyclo Examples include hexen-1-yl and 3,3,5,5-tetramethyl-1-cyclohexen-1-yl.

The “alkynyl group” represents a linear, branched or cyclic alkynyl group. For example, examples of the “C _2-20 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.

The “cycloalkyl group” means a monocyclic or polycyclic saturated aliphatic hydrocarbon group. For example, the “C _3-22 cycloalkyl group” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl. 2-cyclobutylethyl, 2-methylcyclopropyl, cycloheptyl, cyclohexylmethyl, 2-cyclohexylethyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, etc. It is done.

The “aryl group” means a monocyclic or condensed ring aryl group. Examples of the “C _6-18 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthyl and the like, or (1-, 2-, 4- or 5-) indanyl, indenyl, tetrahydronaphthyl and the like. And a partially hydrogenated fused aryl group. Here, the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring, and the hydrogen atom or hydrogen of the aromatic ring portion of the condensed ring. Either of the hydrogen atoms in the converted moiety may be removed. For example, in the case of tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthalene (-1-yl, 2-yl, -3-yl, -4-yl, -5-yl, -6-yl,- 7-yl, -8-yl) and the like.

The “5- to 20-membered heteroaryl group” is an aromatic cyclic group having 5 to 20 atoms constituting the ring and containing 1 to 5 heteroatoms in the atoms constituting the ring. Means group. Examples of the “5- to 20-membered heteroaryl group” include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl , Purinyl, pteridinyl, quinolyl, isoquinolyl, naphthyridinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, imidazopyridyl, imidazolothiazolyl, imidazoloxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, isopyridyl Thienopyridyl, furopyridyl, benzothiadiazolyl, benzooxadiazo Le, pyridopyrimidinyl, benzofuryl, benzothienyl, thienofuryl, and the like.

The “3- to 20-membered non-aromatic heterocyclic group” means that the number of atoms constituting the ring is 3 to 20, and 1 to 2 heteroatoms are contained in the atoms constituting the ring. A cyclic group which may contain 1 to 2 double bonds and 1 to 3 carbonyl, sulfinyl or sulfonyl groups in the ring, and may be monocyclic or polycyclic Means a non-aromatic cyclic group of formula When a nitrogen atom is contained in the atoms constituting the ring, a bond may come out from the nitrogen atom.
Examples of the “3- to 20-membered non-aromatic heterocyclic group” include aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl). ), Tetrahydrothiopyranyl, tetrahydrothienyl, piperazinyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxadiazolinyl, oxadiazolidinyl, morpholinyl, thiomorpholinyl , Quinuclidinyl, oxepanyl and the like.

The “glycosyl group” is a group representing a sugar residue such as a monosaccharide such as glucose, galactose, fructose, and rhamnose, and a disaccharide such as rutinose, vicyanose, lactose, maltose, and sucrose. Accordingly, examples of the glycosyl group include a glucosyl group, a galactosyl group, a fructosyl group, a rhamnosyl group, and the like, and any combination of these groups is a 1 → 2 bond, a 1 → 3 bond, a 1 → 4 bond, or a 1 → Groups that are linked by 6 bonds to form disaccharides are also included.

The “silyl group” means a group represented by —Si (R ³⁰ ) ₃ .
R ^{30 s} are independent of each other and are the same or different,
Hydrogen atom;
An optionally substituted C _1-20 alkyl group;
An optionally substituted C _2-20 alkenyl group;
An optionally substituted C _2-20 alkynyl group;
An optionally substituted C _3-22 cycloalkyl group;
An optionally substituted C _6-18 aryl group;
It represents a 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent. The silyl group is, for example, —SiH ₃ .

In the present invention, it is preferable that W is represented by the general formula (2) or (3). In another embodiment of the present invention, X is represented by the general formula (5), Y is represented by the general formula (10), and Z is any one of the general formulas (13), (14), and (15). Is preferred. In another embodiment of the present invention, W is represented by the general formula (2) or (3), X is represented by the general formula (5), Y is represented by the general formula (10), and Z is Those represented by any one of formulas (13), (14) and (15) are preferred.
Furthermore, in the present invention, it is more preferable that R ¹ represents a hydrogen atom in the general formula (2) or (3).

Examples of xanthophyll compounds used in the present invention are shown below (Tables 1 to 5).

Among the above compounds, particularly preferred xanthophyl compounds include, for example, zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin, lutein and the like, and adonixanthin is particularly preferable. Adonixanthin is a precursor of astaxanthin in the carotenoid biosynthesis system, and astaxanthin is obtained by ketonizing adonixanthin. The oral dermatitis therapeutic agent of the present invention can be used by appropriately combining one or more xanthophyll compounds having an anti-dermatitis action, and is useful for the treatment of allergic dermatitis.

The structural formulas of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin, and lutein are extracted from Tables 1 to 5 below.

In the present invention, the xanthophyll compound can be produced by a person skilled in the art by a known method such as a chemical synthesis method or a method using a microorganism such as bacteria or yeast. For example, when chemical synthesis is carried out, it can be produced by the method described in Pure & Appl. &Lt; Chem. &Quot; When bacteria are used, the methods described in JP 2010-172293, JP 2005-087097, WO 2010/087400, WO 2010/044469, JP 2001-352995, etc. Can be manufactured. Furthermore, when yeast is used, it can be produced by the methods described in JP-A-5-76347, JP-A-6-319531, JP-A-8-214870 and the like.

A method for producing adonixanthin is shown below. The bacterium used in the present invention is not particularly limited as long as it is a bacterium that produces a xanthophyll compound, preferably a bacterium belonging to the genus Paracoccus, Sphingomonas, Brevundimonas or Erytrobacter, and among them, the bacterium belonging to the genus Paracoccus is preferable. . Among bacteria belonging to the genus Paracoccus, Paracoccus carotinifaciens, Paracoccus marcusii, Paracoccus haeundaensis and Paracoccus zeaxanthinifaciens are preferably used, and Paracoccus carotinifaciens is particularly preferably used. Specific examples of bacteria belonging to the genus Paracoccus include Paracoccus carotinifaciens E-396 (FERM BP-4283) and Paracoccus genus A-581-1 (FERM BP-4671), and these mutants Are also preferably used in the present invention.

As the xanthophyll compound-producing bacterium, preferably used is a bacterium whose DNA base sequence corresponding to 16S ribosomal RNA has high homology (identity) with the base sequence of the E-396 strain. Here, “having high homology” means that the base sequence of DNA corresponding to 16S ribosomal RNA of E-396 strain and the corresponding base sequence of the target bacterium are preferably 95% or more, more preferably 96 % Or more, more preferably 97% or more, particularly preferably 98% or more, and most preferably 99% or more. Bacteria having high homology with the base sequence of E-396 strain are used. The base sequence of DNA corresponding to the 16S ribosomal RNA of the E-396 strain is described, for example, in the sequence listing of WO 2010/044469.

The base sequence of DNA corresponding to 16S ribosomal RNA means a base sequence in which U (uracil) in the base sequence of 16S ribosomal RNA is replaced with T (thymine). In recent years, the classification method of microorganisms based on the homology of the base sequence of 16S ribosomal RNA has become mainstream. The conventional classification method of microorganisms is based on bacteriological properties such as conventional motility, auxotrophy, and sugar assimilation. Sometimes classified. On the other hand, since the base sequence of 16S ribosomal RNA is genetically extremely stable, the classification method based on the homology significantly improves the classification reliability compared to the conventional classification method.

The base sequence of 16S ribosomal RNA of Paracoccus carotinifaciens E-396 strain;
Other xanthophyll compound-producing bacteria, Paracoccus marcusii DSM 11574, Paracoccus sp. The homology with the base sequence of one strain of 16S ribosomal RNA is 99.7%, 99.7%, 99.6%, 99.4%, 95.7%, and 95.4%, respectively. It can be seen that is a very close strain in taxonomy. Therefore, it can be said that these strains form one group as bacteria that produce xanthophyll compounds. Therefore, these strains are preferably used in the present invention and can efficiently produce xanthophyll compounds.

In the present invention, mutant strains with improved productivity of xanthophyll compounds can also be used. Examples of improved mutant strains include strains with high astaxanthin-producing ability (JP-A-2001-95500), strains that selectively produce canthaxanthin (JP-A-2003-304875), zeaxanthin and β-cryptoxanthin Strains that selectively produce a large amount (JP-A-2005-87097), strains that selectively produce lycopene (JP-A-2005-87100), strains with improved sedimentation, and the like.

Mutants with improved xanthophyll compound productivity can be obtained by mutation treatment and screening. The method for mutation treatment is not particularly limited as long as it induces mutation. For example, chemical methods with mutants such as N-methyl-N′-nitro-N-nitrosoguanidine (NTG) and ethyl methanesulfonate (EMS), physical methods such as ultraviolet irradiation and X-ray irradiation, genetic recombination and Biological methods such as transposon can be used. The microorganism to be mutated is not particularly limited, but is preferably a xanthophyll compound-producing bacterium. In addition, the mutant strain may be generated by a naturally occurring mutation.

The screening method for mutant strains is not particularly limited. For example, in addition to the method of selecting a target mutant strain by the color of colonies on an agar medium, the mutant strain is cultured in a test tube, flask, fermentor, etc. Examples thereof include a method of selecting a target mutant strain by carotenoid dye analysis using liquid chromatography, thin layer chromatography, or the like. The mutation and screening steps may be performed once, or a mutant strain is obtained by, for example, mutation treatment and screening, and a mutant strain with improved productivity is obtained by further mutation treatment and screening. Mutation and screening steps may be repeated more than once.

In the present invention, a method for culturing the above bacteria and producing a xanthophyll compound will be described below.

(1) Bacterial Cell Production Method For example, according to the method of Japanese Patent Application Laid-Open No. 2010-172293, xanthophyll compound-producing bacteria are cultured to produce a cell body (culture).

In the present invention, the xanthophyll compound production medium used for bacterial culture may be any medium as long as xanthophyll compound-producing bacteria grow and produce xanthophyll compounds, but a carbon source, nitrogen source, inorganic salts, and as necessary. Accordingly, a medium containing vitamins or the like is preferably used.

Examples of the carbon source include sugars such as glucose, sucrose, lactose, fructose, trehalose, mannose, mannitol and maltose, and organic acids such as acetic acid, fumaric acid, citric acid, propionic acid, malic acid, malonic acid and pyruvic acid. Alcohols such as ethanol, propanol, butanol, pentanol, hexanol, isobutanol and glycenol, and fats and oils such as soybean oil, nuka oil, olive oil, corn oil, sesame oil and linseed oil, etc. Among them, one or more kinds can be appropriately selected and used. Among these, glucose or sucrose is preferably used. The amount to be added to the medium before culture (starting medium) varies depending on the type of carbon source and may be adjusted as appropriate, but is usually 1 to 100 g, preferably 2 to 50 g, per liter of the medium. In addition, the carbon source is preferably added not only to the starting medium, but also to be added continuously or continuously during the culture.

Examples of the inorganic nitrogen source include ammonium salts such as ammonium nitrate, ammonium sulfate, ammonium chloride, and ammonium phosphate, nitrates such as potassium nitrate, ammonia, and urea. From these, one or more kinds are appropriately selected. Can be used. The addition amount varies depending on the type of nitrogen source and may be adjusted as appropriate, but is usually 0.1 to 20 g, preferably 0.2 to 10 g, per 1 L of the medium.

Examples of the organic nitrogen source include corn steep liquor (including filtered products), pharma media, soybean meal, soybean meal, peanut meal, distillers solver, dry yeast, and sodium glutamate. One type or two or more types can be appropriately selected and used. The addition concentration varies depending on the type of nitrogen source and may be adjusted as appropriate, but is usually 0 to 80 g / L, preferably 0 to 30 g / L. The inorganic nitrogen source and the organic nitrogen source are usually added to the starting medium, but may be additionally supplied sequentially or continuously.

Examples of inorganic salts include phosphates such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate and disodium hydrogen phosphate, magnesium salts such as magnesium sulfate and magnesium chloride, iron salts such as iron sulfate and iron chloride, Calcium salts such as calcium chloride, calcium carbonate, sodium salts such as sodium carbonate and sodium chloride, manganese salts such as manganese sulfate, cobalt salts such as cobalt chloride, copper salts such as copper sulfate, zinc salts such as zinc sulfate, molybdic acid Molybdenum salts such as sodium, nickel salts such as nickel sulfate, selenium salts such as sodium selenate, boric acid and potassium iodide, etc. may be mentioned, and one or more of these may be appropriately selected and used. Can do. The addition amount varies depending on the type of inorganic salt and may be adjusted as appropriate, but is usually 0.0001 to 15 g with respect to 1 L of the medium. Inorganic salts are usually added to the starting medium, but they may be additionally supplied sequentially or continuously.

Examples of vitamins include cyanocobalamin, riboflavin, pantothenic acid, pyridoxine, thiamine, ascorbic acid, folic acid, niacin, p-aminobenzoic acid, biotin, inositol, choline, and the like. More than one species can be appropriately selected and used. The addition ratio varies depending on the type of vitamins and may be adjusted as appropriate, but is usually 0.001 to 1000 mg, preferably 0.01 to 100 mg per 1 L of the medium. Vitamins are usually added to the starting medium, but may be supplemented sequentially or continuously.

In the present invention, an antifoaming agent can be used to suppress foaming of the culture. Any type of antifoaming agent may be used as long as it suppresses the generation of bubbles or eliminates the generated bubbles and has little inhibitory effect on the produced bacteria. Examples thereof include alcohol-based antifoaming agents, polyether-based antifoaming agents, ester-based antifoaming agents, fatty acid-based antifoaming agents, silicon-based antifoaming agents, and sulfonic acid-based antifoaming agents. The amount added varies depending on the type of antifoaming agent and may be adjusted as appropriate, but is usually 0.01 g to 10 g per 1 L of the medium. Antifoam is usually added to the starting medium before sterilization. Furthermore, it may be added continuously or intermittently during the culture.

The xanthophyll compound production medium used in the present invention is sterilized and then used for bacterial culture. A person skilled in the art can appropriately perform the sterilization treatment. For example, the medium in a suitable container may be heat sterilized with an autoclave. Or what is necessary is just to sterilize by filtration with a sterilization filter.

The initial pH of the xanthophyll compound production medium used in the present invention is adjusted to 2 to 12, preferably 6 to 9, and more preferably 6.5 to 8.0. It is preferable to maintain the pH in the above range during the culture. Examples of the pH adjuster include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, ammonia water, ammonia gas, sulfuric acid aqueous solution or a mixture thereof.

In the present invention, the xanthophyll compound-producing bacterium is inoculated into the xanthophyll compound-producing medium prepared as described above and cultured under predetermined conditions. Inoculation is performed by appropriately increasing the number of strains by seed culture using a test tube, flask, or fermenter, and adding the obtained culture to the xanthophyll compound production medium. The medium used for seed culture is not particularly limited as long as it is a medium in which xanthophyll compound-producing bacteria grow well.

Culture is performed in an appropriate culture vessel. The culture vessel can be appropriately selected depending on the culture volume, and examples thereof include a test tube, a flask, and a fermenter. The culture temperature is 15 to 80 ° C., preferably 20 to 35 ° C., more preferably 25 to 32 ° C., usually 1 to 20 days, preferably 2 to 12 days, more preferably 3 to 9 days, aerobic Cultivate under conditions. Examples of the aerobic condition include shaking culture or aeration stirring culture, and it is preferable to control the dissolved oxygen concentration within a certain range. The dissolved oxygen concentration can be controlled, for example, by changing the number of rotations of stirring, the amount of ventilation, the internal pressure, and the like. The dissolved oxygen concentration is preferably controlled to 0.3 to 10 ppm, more preferably 0.5 to 7 ppm, and still more preferably 1 to 5 ppm.

(2) Removal of bacterial cells Based on a known technique, only the medium components are removed from the culture such as the bacterial culture broth after the cultivation. Then, you may dry a microbial cell with a drum dryer. As a drying method, in addition to a drum dryer, spray drying, granulated spray drying, freeze drying, and the like can be used. Details will be described below.

The concentrate containing the xanthophyll compound and the cells is separated from the culture obtained by culturing the xanthophyll compound-producing bacteria as described above by centrifugation, filtration or decantation. The separation step can also be performed under acidic conditions (see JP 2010-172293 A). Here, in the present specification, the “culture” means any one of a culture supernatant, a cultured cell, or a crushed cell.

The culture can be subjected to a separation operation as it is, but it is also preferably performed after diluting the culture with water in order to enhance the effect of removing unnecessary components. In this case, the pH of the culture may be adjusted before adding water or after adding water. It is also possible to add water during operations such as centrifugation, filtration and decantation. The amount of water added for dilution is not limited, but is preferably 0 to 10 times, more preferably 0.5 to 3.0 times the culture volume. In addition, heat sterilization can be performed in order to kill cultured microorganisms after culturing and before separation. The pH adjustment in this case may be before or after the heat sterilization.

The method for separating xanthophyll compounds in the present invention may be any method that separates based on sedimentation or a method that separates based on particle size, but preferably, centrifugal separation, filtration separation, or decantation is used. These may be used alone or in combination of two or more. Further, the same kind of separation may be repeated twice or more, such as by performing centrifugation once and subjecting only the supernatant liquid to centrifugation once again in order to further collect the xanthophyll compound remaining in the supernatant liquid.

The centrifuge used for the centrifugation may be a continuous type or a batch type, but a continuous type is preferably used. Any type of centrifuge may be used, and examples thereof include a cage type, a multi-chamber type, a decanter type, a disc type (nozzle type, a disperse type), a tubular type, and a rotor type centrifuge. The centrifugal acceleration may be any level as long as it is used for general bacterial cell separation, but is preferably 500 to 100,000 × g, more preferably 1,000 to 50,000 × g.

The membrane filtration device used for filtration separation may be either a static type or a cross flow type, but a cross flow type that is easy to prevent clogging is preferable. Examples of the material of the membrane used include filter paper, filter cloth, chemical fiber, and ceramic. Moreover, you may use diatomaceous earth etc. as a filter aid. Examples of the force type that promotes filtration include a pressure type, a reduced pressure type, a centrifugal filtration type, and a filter press type. Examples of the shape of the membrane include a flat membrane, a hollow fiber membrane, and a cylindrical membrane. The pore size of the membrane may be any as long as it is usually suitable for separating bacteria, but is preferably 0.001 to 100 μm, more preferably 0.01 to 10 μm, and still more preferably 0.1 to 1 μm. A microfiltration membrane and an ultrafiltration membrane are preferable, and a microfiltration membrane is particularly preferably used.

Any container can be used for decantation. For example, a normal cylindrical tank is used. The time for allowing the culture to stand by decantation is not particularly limited, but is preferably 0.5 h to 48 h, more preferably 1 h to 24 h.
The temperature of the culture to be subjected to separation is not particularly limited as long as it is a usual temperature, but is preferably 0 ° C. to 90 ° C., more preferably 2 ° C. to 75 ° C., and further preferably 4 ° C. to 60 ° C.

The xanthophyll compound and the bacterial cells are concentrated in the precipitate concentrate obtained from the culture by the above separation step, that is, centrifugation, filtration separation or decantation, or a combination thereof. It is also preferable to appropriately adjust the separation speed, separation strength and the like so that the precipitate concentrate has a viscosity and water content suitable for the next step. The recovery rate of the xanthophyll compound in the concentrate in the separation step may vary due to the influence of decomposition / degradation of the xanthophyll compound, adhesion to the inner surface of the apparatus, leakage to the supernatant, etc., preferably 70 to 100%, More preferably, it is 80 to 100%, and still more preferably 90 to 100%.

The dried precipitate containing the xanthophyll compound can be obtained by drying the obtained precipitate concentrate. The dried cells thus obtained can be used as a feed additive as they are. Moreover, it is possible to extract a xanthophyll compound from a dry microbial cell, refine | purify as needed, and use it for foodstuffs, cosmetics, and feed. The xanthophyll compound can be produced by extracting and recovering the xanthophyll compound without drying the precipitate concentrate. The drying method is not particularly limited, and examples thereof include spray drying, fluid drying, spray granulation drying, spray granulation fluid drying, rotary drum drying, and freeze drying. In addition, in the culture, precipitation concentrate, or dry cell stage, chemical treatment using an alkaline reagent or surfactant, biochemical treatment using a lytic enzyme, lipolytic enzyme, proteolytic enzyme, etc. Alternatively, one or two or more of physical processes such as ultrasonic waves, pulverization, and heating may be performed.

(3) Xanthophyll compound crude extraction from cells and (4) Purification from xanthophyll compound crude extract The extraction can be carried out by those skilled in the art based on known techniques as shown below. Examples of the method include (i) to (iii), but are not limited thereto.
(I) High temperature ethanol extraction by the method described in Japanese Patent No. 4969370.
(Ii) Put the cells in acetone at 50 ° C., suspend for 2 hours (or 6 hours at room temperature), and then filter. Subsequently, the solvent is removed and dried (known technique).
(iii) The cells are placed in a room temperature chloroform solution, suspended for 3 hours, and then filtered. Subsequently, the solvent is removed and dried (known technique).

When extracting xanthophyll compounds from the culture, the solvent used for extraction and washing is not particularly limited, but lower alcohols such as methanol, ethanol, isopropanol, acetone, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, chloroform, dimethylformamide , Dimethyl sulfoxide, hexane and the like.

The extract thus obtained can be used as it is as a xanthophyll compound, and can be used after further purification. The method for separating the cells and the like from the extract after the extraction operation is not particularly limited, and filtration, centrifugation, decantation, and the like are used. Examples of the method for obtaining a xanthophyll compound precipitate from the extract include precipitation using cooling, heating, concentration under reduced pressure, addition of a poor solvent, addition of various salts such as acid / alkali agents, etc. alone or in combination as appropriate. Can be mentioned. The obtained xanthophyll compound precipitate may be suspended and stirred using a small amount of a solvent such as a lower alcohol as necessary for washing. The method of washing is not particularly limited, and examples include practically preferable methods such as a method of filtering after suspension and stirring or a method of passing liquid from above the precipitate.

When it is desired to minimize the oxidative decomposition of the xanthophyll compound in the culture, precipitate concentrate, dried microbial cell, extract, purified product, and each step operation, it can be performed in an inert gas atmosphere such as nitrogen gas. Moreover, you may select and add the antioxidant currently used by the pharmaceutical and the foodstuff. Alternatively, these processes may be combined. Moreover, in order to prevent the decomposition | disassembly of the xanthophyll compound by light as much as possible, you may carry out on the conditions which do not irradiate light.

The precipitate concentrate, dried cell body, extract or purified product obtained as described above can be used alone as a xanthophyll compound, or these can be mixed and used at an arbitrary ratio.

In the present invention, the xanthophyll compound, when present, may be in the form of a pharmaceutically acceptable salt, and these salts are also included in the xanthophyll compound in the present invention. In the present invention, the xanthophyll compound may form a salt with an acid or a base. In the present invention, the pharmaceutically acceptable salt is not particularly limited as long as it forms a pharmaceutically acceptable salt with a xanthophyll compound having an anti-dermatitis action. Specifically, for example, hydrohalide (for example, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid (for example, sulfate, nitrate, perchloric acid) Salt, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonate ( For example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary amines Examples thereof include, but are not limited to, salts, alkali metal salts (for example, sodium salts, potassium salts and the like), alkaline earth metal salts (for example, magnesium salts and calcium salts), and the like.

In the present invention, the xanthophyll compound may have optical isomers, and these optical isomers are also included in the xanthophyll compound in the present invention. The xanthophyll compound included in the present invention may be a racemate.

In xanthophyl compounds having a hydroxyl group such as zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin, lutein, etc. There may be forms of existence such as free bodies. In the present invention, the xanthophyll compound having anti-dermatitis action may be in any form, but is preferably free.

2. Therapeutic Agent for Dermatitis The therapeutic agent for dermatitis that is the oral administration agent of the present invention (hereinafter also referred to as “therapeutic agent of the present invention”) contains the xanthophyll compound of the present invention having an anti-dermatitis action as an active ingredient. . In the therapeutic agent of the present invention, the xanthophyll compound having an anti-dermatitis action is preferably zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin or lutein, more preferably adonixanthin. is there. The xanthophyll compound having an anti-dermatitis action contained in the therapeutic agent of the present invention includes a pharmaceutically acceptable salt, optical isomer, ester or glucoside thereof.

The xanthophyll compound contained in the therapeutic agent of the present invention has an action of reducing IgE level in blood by oral administration. Therefore, the therapeutic agent of the present invention is effective for treating dermatitis caused by IgE. It may also be effective for dermatitis with pruritus. In addition, since IgE is one of the factors of allergic diseases, the therapeutic agent of the present invention can be used as a therapeutic agent for oral allergic dermatitis. Furthermore, as shown in Examples, the xanthophyll compound contained in the therapeutic agent of the present invention calmed down the symptoms of dermatitis in NC mice by oral administration. NC mice are a model animal that spontaneously develops dermatitis due to mite antigens, and the symptoms of the dermatitis are similar to those of atopic dermatitis, and are therefore widely used as model animals for atopic dermatitis. Therefore, the therapeutic agent of the present invention can be used as a therapeutic agent for oral atopic dermatitis. Moreover, it can be effectively used not only for atopy, but also for improvement of pruritus caused by sensitive skin and dry skin and treatment of allergic symptoms.

In the present invention, “treatment” of dermatitis means prevention, suppression, alleviation, delay in severity, stop or cure of dermatitis symptoms.

The xanthophyll compound having an anti-dermatitis action may be useful as an active ingredient of a preventive agent for dermatitis. Therefore, the preventive agent of dermatitis containing the xanthophyll compound which has an anti-dermatitis action is also contained in this invention. In the present invention, “prevention” of dermatitis means the onset delay or prevention of dermatitis and the like.

Judgment whether it is effective for the treatment of dermatitis is macroscopic findings, skin lesion score, blood IgE concentration, pathological findings evaluation by HE staining, mast cell count by Giemsa staining, CD4 positive helper T cell count by CD4 immunohistochemistry , F4 / 8-positive macrophage count by F4 / 80 immunohistochemistry, IgE positive cell count by IgE immunohistochemistry, and the like. If it is an expert, each method can be implemented based on a regular method.

As the therapeutic agent of the present invention, the xanthophyll compound having an anti-dermatitis action can be used as it is, or it can be formulated by blending a carrier commonly used in preparations or a known pharmaceutically acceptable carrier. is there. Examples of such carriers include excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives. , Antioxidants, preservatives, humectants and the like. The therapeutic agent of the present invention can also be provided as a formulated pharmaceutical composition. That is, the pharmaceutical composition of the present invention is a pharmaceutical composition for treating allergic dermatitis, preferably a pharmaceutical composition for treating atopic dermatitis, comprising the xanthophyll compound of the present invention.

Moreover, the administration form of the therapeutic agent of the present invention is oral administration. Therefore, the therapeutic agent of the present invention is an oral administration agent.

Examples of dosage forms for formulation include tablets, powders, fine granules, granules, capsules, syrups and the like used for oral dosage forms.

The therapeutic agent of the present invention contains a xanthophyll compound having an anti-dermatitis action as an active ingredient. The effective dose of xanthophyll compound having anti-dermatitis action is the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, administration period, formulation properties, formulation, type, Although it varies depending on the type of active ingredient, it can be appropriately set by those skilled in the art. For example, the content of the xanthophyll compound having an anti-dermatitis action with respect to the total amount of the therapeutic agent of the present invention is preferably 0.001 to 5.0% by weight, 0.01 to 5.0% by weight, more preferably 0.01 to 1.0% by weight, 0.05 to 1.0. It can mix | blend so that it may become weight%. Alternatively, 0.01-500 mg, 0.1-500 mg, preferably 0.5-200 mg, more preferably 1-100 mg, and most preferably 60 mg per day can be administered to an adult (body weight 60 kg).

The present invention also provides a method for treating dermatitis, which comprises orally administering an effective amount of a xanthophyll compound having an anti-dermatitis action to a patient. Furthermore, the present invention also includes a xanthophyll compound having an anti-dermatitis action for the oral therapeutic agent for dermatitis of the present invention. Here, the xanthophyll compound having an anti-dermatitis action is preferably zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin or lutein, more preferably adonixanthin. In another aspect of the present invention, preferred xanthophyll compounds also include xanthophyll, eg, optical isomers and modifications of adonixanthin. In the method of the present invention, the administration route and administration method of the xanthophyll compound having an anti-dermatitis action are not particularly limited, but the description of the therapeutic agent of the present invention can be referred to.

3. Functional food The functional food of the present invention contains a xanthophyll compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof, and has an anti-dermatitis action. Used as a sex food (including supplements and health foods).

Examples of the form of the food of the present invention include supplements (powder, granules, soft capsules, hard capsules, tablets, chewable tablets, quick-disintegrating tablets), but also beverages (tea, carbonated drinks, lactic acid drinks, sports) Beverages, etc.), confectionery (gummy, jelly, gum, chocolate, cookies, candy, etc.), oil, oil and fat foods (mayonnaise, dressing, butter, cream, margarine, etc.), seasonings (ketchup, sauce, etc.), liquid food, milk Products (milk, yogurt, cheese, etc.), breads, noodles (noodles, soba, ramen, pasta, yakisoba, kishimen, somen, cold wheat, rice noodles, etc.), etc. However, it is not limited to these forms.

The functional food of the present invention includes various nutrients, various vitamins as necessary (vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin E, etc.), various minerals, dietary fiber, and many Unsaturated fatty acids, other nutrients (coenzyme Q10, carnitine, sesamin, α-riboic acid, inositol, D-kaileunositol, pinitol, phosphatidylserine, phosphatidyl DHA, phosphatidylinositol, taurine, glucosamine, chondroitin sulfate, S-adno Sylmethionine, etc.), stabilizers such as dispersants, emulsifiers, sweeteners, taste ingredients (citric acid, malic acid, etc.), flavors, royal jelly, propolis, agarics and the like. Also, herbs such as peppermint, bergamot, chamomile, lavender and thyme may be blended. In addition, materials such as theanine, dehydroepiandosterone, and melatonin can be blended.

In the present invention, when the xanthophyll compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof is used as a functional food or supplement, the usage and dose are not particularly limited, The usage and dosage described in the section on dermatitis therapeutic agent can be applied.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the examples.

Hereinafter, examples of the oral allergic dermatitis treatment agent and health food of the present invention will be described.

[Example 1]
0.03g of adonixanthin is suspended in 50mL of corn oil, stirred and dissolved at 60 ° C under a nitrogen atmosphere, cooled to room temperature, and red adonixanthin corn oil as a dermatitis drug. 50 mL of liquid was obtained.

[Example 2]
Suspend 0.03 g of adnirubin in 50 mL of corn oil, stir and dissolve at 60 ° C. in a nitrogen atmosphere, and then cool to room temperature to obtain 50 mL of red adonirubin corn oil solution as a dermatitis drug. It was.

[Example 3]
In 50 mL of corn oil, 0.03 g of α-cryptoxanthin is suspended and dissolved by stirring at 60 ° C. in a nitrogen atmosphere, then cooled to room temperature, and red α-cryptoxanthin as a dermatitis drug. 50 mL of corn oil solution was obtained.

[Example 4]
In 50 mL of corn oil, 0.03 g of β-cryptoxanthin is suspended, stirred and dissolved at 60 ° C. in a nitrogen atmosphere, cooled to room temperature, and red β-cryptoxanthin as a dermatitis drug. 50 mL of corn oil solution was obtained.

[Example 5]
Suspend 0.03 g of lutein in 50 mL of corn oil, stir and dissolve at 60 ° C. in a nitrogen atmosphere, then cool to room temperature to obtain 50 mL of red lutein corn oil solution as a dermatitis treatment agent It was.

[Example 6]
0.03 g of asteroidenone is suspended in 50 mL of corn oil, stirred and dissolved at 60 ° C. in a nitrogen atmosphere, cooled to room temperature, and red asteroidenone corn oil as a dermatitis drug. 50 mL of liquid was obtained.

[Example 7]
Suspend 0.15 g of adonixanthin in 50 mL of olive oil, stir and dissolve at 60 ° C. in a nitrogen atmosphere, cool to room temperature, and add 50 mL of red adonixanthin-containing olive oil as a dermatitis drug. Obtained.

[Example 8]
Suspend 0.15 g of adonixanthin in 50 mL of canola oil, stir and dissolve at 60 ° C in a nitrogen atmosphere, then cool to room temperature to obtain 50 mL of red adonixanthin-containing canola oil as a health food It was.

[Example 9]
0.15 g of adonixanthin was suspended in 50 mL of squalene, stirred and dissolved at 60 ° C. in a nitrogen atmosphere, and then cooled to room temperature to obtain 50 mL of red adonixanthin-containing squalene as a health food.

[Example 10]
175 mg calcium lactate, 175 mg calcium glycerophosphate, 250 mg sodium bicarbonate, 0.5 mg calcium aspartate, 12 mg colloidal silicon dioxide, 15 mg corn starch, 10 mg dextrose, 3 mg maltodextrin, 6 mg mannitol, 3 mg pregelatinized starch, 6 mg adonixanthin After completely blending, the tablets were tableted to obtain 10 mg tablets as health food tablets.

[Example 11]
175 mg calcium lactate, 175 mg calcium glycerophosphate, 250 mg sodium bicarbonate, 0.5 mg calcium aspartate, 12 mg colloidal silicon dioxide, 15 mg corn starch, 10 mg dextrose, 3 mg maltodextrin, 6 mg mannitol, 3 mg pregelatinized starch, 6 mg zeaxanthin After mixing, the tablets were tableted to obtain 10 mg tablets as health food tablets.

[Example 12]
175 mg calcium lactate, 175 mg calcium glycerophosphate, 250 mg sodium bicarbonate, 0.5 mg calcium aspartate, 12 mg colloidal silicon dioxide, 15 mg corn starch, 10 mg dextrose, 3 mg maltodextrin, 6 mg mannitol, 3 mg pregelatinized starch, 6 mg β-cryptoxanthin Was completely mixed and then tableted to obtain 10 mg tablets as health food tablets.

[Test example]
<Method for separating xanthophyll compound in Paracoccus>
(1) Production of concentrated and dried product from living Paracoccus cells Xanthophyll compound-producing bacteria were cultured according to a conventional method. 100 g of viable cells obtained by removing the supernatant to some extent from the culture after culturing by centrifugation was used for the extraction step. Acetone 500 mL was added to 100 g of viable cells and allowed to stand at room temperature for 6 hours, and then separated into extract (i) and cells (i). A further 500 mL of acetone was added to the bacterial cell (i), and the mixture was allowed to stand at room temperature for 6 hours, and then separated into an extract (ii) and a bacterial cell (ii). Furthermore, the same operation was performed on the bacterial cell (ii) to obtain an extract (iii) and a bacterial cell (iii). Extracts (i) to (iii) were mixed to obtain about 1.5 L of total extract. The obtained total extract was concentrated by an evaporator until water and oil were separated, and then 100 mL of a hexane / chloroform 1: 1 solution was added, and the organic solvent layer and the aqueous layer were separated by a liquid separation operation. The organic solvent layer was concentrated by an evaporator at 40 ° C. or lower to obtain a concentrated dry product. If moisture remained during evaporation of the evaporator, a small amount of ethanol was added and azeotropically removed at 50 ° C.

(2) Manufacture of concentrated and dried product from dried Paracoccus cells After removing only the medium components from the culture that had been cultured as in (1) above, the cells were dried to obtain dried cells. What added the water | moisture content of the extent which a microbial cell gets wet to the obtained dried microbial cell was used for the extraction process (100g). Acetone 500 mL was added and allowed to stand at room temperature for 6 hours, and then separated into an extract (iv) and a cell (iv). A further 500 mL of acetone was added to the microbial cells (iv) and allowed to stand at room temperature for 6 hours, and then separated into an extract (v) and microbial cells (v). Extracts (iv) to (v) were mixed to obtain a total extract. A concentrated dry product was obtained from the whole extract by the same method as in (1) above.

(3) Separation of xanthophyll compound from concentrated dried product After the concentrated dried product was dissolved in tetrahydrofuran according to a conventional method (JP2009-019935), the xanthophyll compound was separated using a high performance liquid chromatograph (HPLC). went.

The column used was two Wakosil-II 5 SIL-100 (Wako Pure Chemical Industries) linked together. The mobile phase was a n-hexane: tetrahydrofuran: methanol mixture (40: 20: 1) and flowed at 4 mL / min at a constant temperature near room temperature.

The peak position of the xanthophyll compound was confirmed in advance, the required peak separation was performed, and the xanthophyll compound was fractionated. The fractionated xanthophyll compounds were further fractionated by HPLC under the same conditions.

The degree of purification was confirmed by ¹ H-NMR and ¹³ C-NMR to obtain a purified xanthophyll compound.

<Test Example 1> Anti-atopic dermatitis action test of adonixanthin using NC mice Atopy is a non-clinical test on the effectiveness of adonixanthin (ADX) regarding anti-dermatitis action, particularly anti-atopic dermatitis action. Adonixanthin was orally administered to NC mice suffering from atopic dermatitis for 28 days, and changes in lesions and side effects (weight loss) were examined by the tests described later during the period.

(Method)
(1) Administration liquid (test substance)
Corn oil was added to and suspended in adonixanthin (ADX) powder, and three kinds of administration solutions were prepared so as to have concentrations of 0.0002 mg / mL, 0.02 mg / mL, and 0.2 mg / mL, respectively. Corn oil without adonixanthin was used as a negative control.

(2) Test system Females aged 8 weeks: 70 NC mice (NC / Nga Tnd Crlj strain) were used for the test, and mite antigen Biosta (registered trademark) AD (stock) that causes atopic dermatitis in NC mice. Company Biosta) was administered. For these mice, 32 animals can be selected based on the body weight, dermatitis score and total blood IgE measured before administration of the test substance, and the average body weight and dermatitis score of each group can be obtained by the complete random sampling method. Assigned to 4 groups to be as equal as possible. In addition, as a completely negative control group, administration was also performed on NC mice (non-treated mice) that do not develop atopic dermatitis. As for the untreated mice, 10 mice were selected based on the body weight measured immediately before the start of administration of the test substance, and assigned to 2 groups so that the average value of each group became equal by a complete random sampling method using a computer.

(3) Group structure and administration Table 6 shows the administration substance, its concentration, and the amount of administration liquid per day (once) for each experimental group. Administration was performed using a disposable syringe and an oral sonde for 28 days (the start date of administration of the test substance was counted as the first day).

(4) Test item Body weight measurement: Body weight was measured once a week during the test period.
Observation of lesions: Skin lesions were observed before biosta AD administration, 8 days after biosta AD administration, before test substance administration (15 days after biosta AD administration), and 8, 15, 22 and 29 days after test substance administration. In the observation, the degree of symptom was scored at 1 point for mild, 2 points for medium, and 3 points for severe for each part of the auricle, head, and back of the neck, and the total score was evaluated. Photographs were taken simultaneously with the observation of skin lesions.

Blood total IgE measurement: Before biosta AD administration, before test substance administration (14 days after biosta AD administration) and 15 days after test substance administration, blood was collected from the tail vein of mice without anesthesia. On the 29th day after administration of the test substance, whole blood was collected from the abdominal aorta under halothane anesthesia. The collected blood was centrifuged at 1,000 × g, room temperature, and 15 μmin to collect plasma. The total amount of IgE was determined by ELISA using a capture antibody: anti-mouse IgE antibody (rat monoclonal ab99571, Abcam Inc.), detection antibody: biotin-labeled anti-mouse IgE antibody (rat monoclonal ab11580, Abcam Inc.). . For blood IgE (immunoglobulin), IgE increases when an allergic reaction occurs, which is an indicator of whether an allergic reaction has occurred.

Tissue weight measurement and tissue preservation: After blood collection under halothane anesthesia, the spleen and lymph nodes were removed and weighed and fixed with 10% neutral buffered formalin. Thereafter, the skin on the back of the neck was removed and fixed with 10% neutral buffered formalin or embedded in an OCT compound for frozen section preparation and stored frozen.

(5) Statistical method The measured value was represented by the average value +/- standard error. For statistical analysis, Excel 2003 and Excel 2004 (Microsoft Corporation) and StatLight (registered trademark) (Yukmus Corporation) were used, and the significance level was set to less than 5%.

(result)
(1) Skin lesion score Table 7 shows the mean value and standard deviation of the skin lesion score for each experimental group.

As shown in Table 7, a dose-dependent decrease in skin lesion score was observed in the 0.2 mg / mL adonixanthin administration group at an early stage as compared with the control group.

(2) IgE
Table 8 shows relative values of blood IgE values on the 15th day after administration and after the end of the period in each group, with the pre-dose value being 100. In Table 8, “Carotenoid X” represents adonixanthin.

In Table 8, on the 15th day after administration, a significant change in blood IgE concentration was observed in all adonixanthin administration groups compared to the control group. On the 29th day after the end of the administration period, a difference from the control group was confirmed in the adonixanthin 0.2 mg / mL group. Thereby, it was found that adonixanthin has a function of suppressing an allergic reaction.
In the non-treated group, no increase in IgE was observed because atopic dermatitis was not developed.

(3) Body weight Body weight was measured as a side effect determination of the test substance. Table 9 shows the measurement results. Table 10 shows the results of weight increase / decrease from the start of the test.

From Table 9 and Table 10, as compared with the control group (corn oil administration group), the weight loss as a side effect was not confirmed in the adonixanthin administration group.

From the above results, it was confirmed that adonixanthin has an effect of suppressing or improving atopic skin inflammation in NC mice in a dose-dependent manner by oral administration. Under the conditions of the examples, an effect on the skin lesion score was seen at the initial stage of the concentration of adonixanthin 0.2 mg / mL. Furthermore, since the IgE concentration in the body also decreased, the effect of adonixanthin to suppress inflammation could be confirmed. Furthermore, the side effects of weight loss as seen with steroids generally known as anti-inflammatory drugs did not occur in the adonixanthin group. From these facts, it is considered that a xanthophyll compound having an anti-dermatitis action such as adonixanthin can be used as an anti-dermatitis therapeutic agent, particularly an anti-atopic drug.

<Test Example 2> Skin Histopathological Examination Using NC Mice Test Example 2 is a hematoxylin-eosin staining of the skin tissues of the control group (corn oil administration group) and adonixanthin (ADX) administration group collected in Test Example 1. (HE staining), Giemsa staining, and histopathological examination under various immunostainings were performed, and based on the results, it was carried out for the purpose of examining the anti-dermatitis effect of adonixanthin from histopathology.

In this example, the following items were examined. Details of each item will be described later.
・ Neck dorsal skin collection, frozen section preparation: 3 x 16
(a) CD4 immunohistochemistry: CD4 positive helper T cell count
(b) IgE immunohistochemistry: IgE positive cell count
(c) F4 / 80 immunohistochemistry: F4 / 80 positive macrophage count and paraffin section preparation: 2 x 16
(d) HE staining: pathological findings evaluation
(e) Giemsa staining: mast cell count

(Method)
A. Hematoxylin and eosin (HE) staining, Giemsa staining (1) Target skin tissue: NC mouse neck dorsal skin collected in Test Example 1 was fixed with 10% neutral buffer formalin and subjected to histopathological examination. Specifically, half of the cervical dorsal skin was fixed with 10% neutral buffered formalin and then embedded in paraffin according to a conventional method to prepare two paraffin sections having a thickness of about 3 μm. Paraffin sections were subjected to HE staining or Giemsa staining. Table 11 shows the group structure.

(2) Preparation of specimen The skin of the back of the neck was cut out according to a conventional method, embedded in paraffin, sliced, and then stained with hematoxylin and eosin (HE) or Giemsa to prepare a histopathological specimen.

(3) Observation items Histopathological diagnosis was performed on HE-stained specimens. For the Giemsa-stained specimen, mast cells per visual field (magnification: × 400) were measured.

(4) Statistical analysis Statistical significance test was performed between the control group (corn oil) and the adonixanthin (ADX) group, and the significance level was set to 5% and 1%. Since all histopathological findings were moderate lesions, statistical analysis was performed using the Wilcoxon test (both sides).

B. Immunostaining (1) Target skin tissue NC mouse neck dorsal skin collected in Test Example 1 was subjected to histopathological examination. Table 12 shows the group configuration.

(2) Specimen preparation Half of the central part of the back of the neck was embedded in an OCT compound and cryopreserved to prepare a frozen section having a thickness of about 6 μm. The frozen section is
Anti-CD4 (Rat monoclonal (GK1.5), sc-13573, Santa Cruz Biotechnology inc., × 200 dilution),
Anti-F4 / 80 (Rat monoclonal (3H21113), sc-71088, Santa Cruz Biotechnology inc., X200 dilution) or Mouse IgE Antibody (FITC Conjugated, A90-115F, Bethyl Laboratories Inc., × 2000 dilution)
Immunohistochemical staining using was performed. Specifically, Anti-CD4 and Anti-F4 / 80 were performed by the ABC method (VECTASTAIN ABC Kit Elite, Code No. PK-6104, Vector Laboratories, Inc.), and Anti-IgE was performed by the direct method.

(3) Observation Items The number of positive cells in the 5 magnified fields was measured for the immunostained specimen.

(4) Statistical analysis As for the number of positive cells in the immunostained specimen, variance was found to be uniform between the two groups of the control group and the ADX group by F test, so Student t test was performed. Significance levels were 5% and 1%.

(result)
A. HE staining and Giemsa staining (1) Pathological findings Table 13 shows the results. In corn oil (control), ADX-1 and ADX-2, epidermal scab formation, hyperkeratinization, thickening of the granule layer or thickening of the epidermis were observed, cell infiltration in the upper and deep dermis, and in the dermis Papilloma and melanophage were observed. Therefore, in these groups, the appearance of contact sensitization dermatitis and the accompanying epidermal lesion due to chronic curettage behavior and dermal papillomatosis were confirmed. The frequency and severity of these symptoms in each ADX group decreased compared to the control group, but no statistical significance was observed.

As a result of HE staining, in the lesions commonly observed in animal models of atopic dermatitis (ulcer, epidermal hyperplasia, hyperkeratosis, inflammatory cell infiltration, hair follicle atrophy), compared to the control group, the ADX administration group The improvement effect was recognized.

B. Immunostaining (1) Measurement of immunostaining positive cells Table 15 shows the relative values of the measurement results when the control (A-1) corn oil was taken as 100. Compared with the control group, the ADX (carotenoid X) group had a low but not significant change in the number of CD4 positive cells, the number of F4 / 80 positive cells, and the number of IgE positive cells.

By immunostaining with HE staining and Giemsa staining, the ADX group showed changes in epidermis (scab formation, ulceration, hyperkeratosis, thickening of the granule layer, thickening of the epidermis) and dermal cell infiltration as compared with the control group. A reduction tendency was observed.

From the results of immunostaining, reductions were observed in the formation of scabs, ulceration, hyperkeratinization, thickening of the granule layer, and squamous cell disease according to the concentration of adonixanthin.

From the above results, it was confirmed in the histopathological examination of skin tissue that adonixanthin has an inhibitory effect on atopic skin inflammation in NC mice by oral administration.

Claims

A therapeutic agent for oral allergic dermatitis comprising a xanthophyll compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

[In the general formula (1), W represents a group represented by any one of the following general formulas (2) to (4), and X represents a group represented by any one of the following general formulas (5) to (8). W—X, which is a combination of W and X, represents a group represented by the following general formula (9), Y represents a group represented by any one of the following general formulas (10) to (12), Z represents a group represented by any one of the following general formulas (13) to (21), or YZ which is a combination of Y and Z is any one of the following general formulas (22) to (24) Represents a group represented by

(Here, in the general formulas (2) to (4) and the general formula (9), R 1 and R 2 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 3 ;
-COOR 4 ;
-CONR 5 R 6 ;
Represents —PO (OR 7 ) (OR 8 ); or —SO 2 R 9 ,
R 3 , R 4 , R 5 , R 6 and R 9 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 7 and R 8 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent
Represents.
In general formulas (13) to (15),
R 10 , R 11 and R 12 are each independently of each other, the same or different and each represents a hydrogen atom or —OQ 1 ;
Q 1 is
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 16 ;
-COOR 17 ;
-CONR 18 R 19 ;
Represents —PO (OR 20 ) (OR 21 ); or —SO 2 R 22 ,
R 16 , R 17 , R 18 , R 19 and R 22 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 20 and R 21 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent.
In the general formulas (16), (18), (21), and (22), R 13 , R 14, and R 15 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 23 ;
-COOR 24 ;
-CONR 25 R 26 ;
Represents —PO (OR 27 ) (OR 28 ); or —SO 2 R 29 ,
R 23 , R 24 , R 25 , R 26 and R 29 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 27 and R 28 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent. )]
The therapeutic agent according to claim 1, wherein W is represented by the general formula (2) or (3).
X is represented by the general formula (5),
Y is represented by the general formula (10),
Z is represented by any one of the general formulas (13), (14) and (15),
The therapeutic agent according to claim 2.
The therapeutic agent of Claim 2 or 3 in which R < 1 > represents a hydrogen atom in General formula (2) or (3).
The xanthophyll compound is at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin and lutein, and pharmaceutically acceptable salts thereof. The therapeutic agent according to any one of 1 to 4.
The therapeutic agent according to any one of claims 1 to 5, wherein the allergic dermatitis is atopic dermatitis.
The therapeutic agent according to any one of claims 1 to 6, wherein the dermatitis is caused by IgE.
A functional food containing a xanthophyll compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

[In the general formula (1), W represents a group represented by any one of the following general formulas (2) to (4), and X represents a group represented by any one of the following general formulas (5) to (8). W—X, which is a combination of W and X, represents a group represented by the following general formula (9), Y represents a group represented by any one of the following general formulas (10) to (12), Z represents a group represented by any one of the following general formulas (13) to (21), or YZ which is a combination of Y and Z is any one of the following general formulas (22) to (24) Represents a group represented by

(Here, in the general formulas (2) to (4) and the general formula (9), R 1 and R 2 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 3 ;
-COOR 4 ;
-CONR 5 R 6 ;
Represents —PO (OR 7 ) (OR 8 ); or —SO 2 R 9 ,
R 3 , R 4 , R 5 , R 6 and R 9 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 7 and R 8 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent.
In general formulas (13) to (15),
R 10 , R 11 and R 12 are each independently of each other, the same or different and each represents a hydrogen atom or —OQ 1 ;
Q 1 is
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 16 ;
-COOR 17 ;
-CONR 18 R 19 ;
Represents —PO (OR 20 ) (OR 21 ); or —SO 2 R 22 ,
R 16 , R 17 , R 18 , R 19 and R 22 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 20 and R 21 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent.
In the general formulas (16), (18), (21), and (22), R 13 , R 14, and R 15 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
An optionally substituted 3- to 20-membered non-aromatic heterocyclic group;
A glycosyl group which may have a substituent;
A silyl group optionally having a substituent;
-COR 23 ;
-COOR 24 ;
-CONR 25 R 26 ;
Represents —PO (OR 27 ) (OR 28 ); or —SO 2 R 29 ,
R 23 , R 24 , R 25 , R 26 and R 29 are each independently of each other, the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
A 5- to 20-membered heteroaryl group which may have a substituent; or a 3- to 20-membered non-aromatic heterocyclic group which may have a substituent;
R 27 and R 28 are each independently the same or different,
Hydrogen atom;
An optionally substituted C 1-20 alkyl group;
An optionally substituted C 2-20 alkenyl group;
An optionally substituted C 2-20 alkynyl group;
An optionally substituted C 3-22 cycloalkyl group;
An optionally substituted C 6-18 aryl group;
An optionally substituted 5- to 20-membered heteroaryl group;
A 3- to 20-membered non-aromatic heterocyclic group which may have a substituent; or a silyl group which may have a substituent. )]
The xanthophyll compound is at least one selected from the group consisting of zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, asteroidenone, adonixanthin and lutein, and pharmaceutically acceptable salts thereof. 8. The functional food according to 8.