JP2021028301A - Medication for dermatitis - Google Patents

Abstract

To provide a novel medication for dermatitis.SOLUTION: A medication for dermatitis comprises trans-astaxanthin derivatives represented by the formula (I), geometric isomers thereof, and a mixture of the geometric isomers, optical isomers thereof, or salts thereof. In the formula, m1, m2, n1, and n2 mean the same or different integers from 1 to 6, respectively.SELECTED DRAWING: None

Description

The present invention relates to a dermatitis therapeutic agent containing an astaxanthin derivative.

Topical steroids have been mainly used for dermatitis, which is a typical example of skin diseases, especially for atopic dermatitis.
Since atopic dermatitis is a chronic disease that develops against the background of atopic predisposition, it is necessary to use drugs continuously, but topical steroids have a sharp clinical effect, but the skin is thin. It has local side effects such as dermatitis, atrophy, moon face, flushing, hypertrichosis, and skin fissure, so it is not always easy to apply to facials with high drug absorption, patients with weak skin, children and women. There is a problem that it is not.
As mentioned above, atopic dermatitis is a chronic disease, so topical steroids are used for a long period of time, and topical steroids may become ineffective, so-called topical steroids. If the drug is stopped suddenly, it may suffer from a rebound phenomenon in which the symptoms worsen than before external use.

In this regard, Patent Documents 1 and 2 provide steroid compounds of the formula (I) having extremely few side effects. Such a steroid compound is a compound in which a sugar substituted with a functional group, which is not unexpectedly bulky, is added by converting the steroid to descyclesonide, and has a stronger anti-inflammatory effect than existing steroid drugs when administered externally. It also has the feature of reducing not only systemic side effects but also local side effects (Patent Document 2, paragraphs 0006 to 0011).

International Publication No. 2010/104187 Pamphlet Japanese Patent No. 541622

Even under such circumstances, since the steroid compounds of Patent Documents 1 and 2 are based on the steroid structure, it is considered that there are inherent problems of side effects and problems due to long-term use, and they can be replaced with steroids. It is desired to develop a new drug having a clear therapeutic effect on dermatitis.
A main object of the present invention is to provide a dermatitis therapeutic agent that can replace steroids and has a clear therapeutic effect on dermatitis.

As a result of diligent studies to find a new therapeutic agent as a therapeutic agent for dermatitis, the present inventors have obtained a trans-astaxanthin derivative represented by the formula (I), its geometric isomer, a mixture of these geometric isomers, and their optics. The present invention has been completed by finding that isomers or salts thereof have an excellent therapeutic effect on dermatitis.

That is, the present invention provides the following inventions [1] to [3].

[1] A dermatitis therapeutic agent containing a trans-astaxanthin derivative represented by the formula (I), a geometric isomer thereof, a mixture of the geometric isomers thereof, an optical isomer thereof or a salt thereof.

(In the equation, m ₁ , m ₂ , n ₁ and n ₂ mean the same or different integers 1 to 6, respectively.)

[2] Use of a trans-astaxanthin derivative represented by the above formula (I), a geometric isomer thereof, a mixture of these geometric isomers, an optical isomer thereof or a salt thereof for the production of a therapeutic agent for dermatitis.
[3] Dermatitis characterized by administering an effective amount of a trans-astaxanthin derivative represented by the formula (I), a geometric isomer thereof, a mixture of the geometric isomers thereof, an optical isomer thereof or a salt thereof. Treatment method.

The trans-astaxanthin derivative represented by the formula (I) of the present invention, its geometric isomer, a mixture of these geometric isomers, their optical isomers or their salts are used in all kinds of animals such as humans, dogs, cats and horses. A drug containing an astaxanthin derivative represented by the formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomers or salts thereof, which has excellent efficacy against dermatitis. The composition is excellent as a therapeutic agent for dermatitis.

It is a figure which shows the thickness increase value of the auricle part of the sham group, the medium group and the compound X administration group in an Example. It is a figure which shows the skin symptom score of the sham group, the medium group and the compound X administration group in an Example. It is a figure which shows the amount of IgE antibody in the blood of a sham group, a medium group and a compound X administration group in an Example.

The therapeutic agent for dermatitis of the present invention contains a trans-astaxanthin derivative represented by the above formula (I), its geometric isomers, a mixture of these geometric isomers, their optical isomers or salts thereof as an active ingredient. .. "Dermatitis" includes atopic dermatitis, contact dermatitis, drug-related eczema dermatitis, photoesthetic dermatitis, eczema dermatitis such as primary irritant dermatitis, urticaria, erythema, psoriasis, The dermatitis therapeutic agent of the present invention is particularly useful for the treatment of atopic dermatitis, including squamous dermatitis, aspergillus, aspergillus, and eczema-like dermatitis. Subjects that can be treated by the present invention include, but are not limited to, warm-blooded animals, including humans, such as dogs, cats, cows, pigs, horses, sheep, goats, monkeys, rabbits, rats or mice.

(In the equation, m ₁ , m ₂ , n ₁ and n ₂ indicate the same or different integers 1 to 6, respectively.)

In the compound of the formula (I), it is preferable that m ₁ and m ₂ are integers of 1 respectively, and n ₁ and n ₂ are integers of 3 respectively.

The compound according to the formula (I), its geometric isomer, a mixture of these geometric isomers, and their optical isomers undergo a normal salt forming reaction with a basic substance or a basic compound desired because they have a carboxyl group in the molecule. By allowing them to form a pharmaceutically acceptable salt. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts, lithium salts; alkaline earth metal salts such as calcium salts, magnesium salts, lysine salts, ornithine salts, amino acids such as arginine salts. Salts can be mentioned, with lysine salts being preferred.

In the chemical structural formula of the formula (I), the double bond portion in the medium chain carbon chain portion in the astaxanthin basic skeleton may have a trans and cis geometric isomer structure in terms of chemical structure. Regarding the active ingredient according to the present invention, not only the trans form of the formula (I) but also the cis form represented by the following formulas (Ia) and (Ib) are used as the active ingredient of the dermatitis therapeutic agent according to the present invention. Can be mentioned. The therapeutic agent for dermatitis of the present invention also contains as an active ingredient a mixture of the trans isomer of the formula (I) and the cis isomer which is a geometric isomer thereof at various mixing ratios, and a mixture of the trans isomer and the cis isomer.

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above.)

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above.)

In addition, the compound of formula (I), its geometric isomers and mixtures of these geometric isomers can include optical isomers (IA) represented below, and their antipode and mixtures thereof, All diastereomers are also included as active ingredients of the dermatitis therapeutic agent according to the present invention.

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above.)

Among the compounds of formula (I), their geometric isomers, mixtures of these geometric isomers and their optical isomers, compounds of the trans isomer of formula (IA) above are preferred.
Further, among the trans compounds of the above formula (IA), compounds in which m ₁ and m ₂ each mean an integer of ₁ and n _{1 and n 2} mean an integer of 3 are preferable.

As described above, the optically active trans-astaxanthin derivative represented by the formula (IA) or a salt thereof is more preferable, and the optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) and its salt thereof. High-purity optically active trans-astaxanthin derivatives that are substantially free of salts or salts thereof are more preferred. Here, the term "high-purity" content of the active ingredient of the dermatitis therapeutic agent according to the present invention means that the purity of the active ingredient is at least 95% or more, preferably 98% or more.

The compound of formula (I), its geometric isomers, their optical isomers and their salts according to the present invention are appropriately prepared by the production method described in International Publication No. 2015/178404 or a method known to the same method. It can be manufactured by combining them. Among those production methods, the geometric isomers of the compound of the formula (I) and the production methods of the optical isomers thereof will be described below with the production method of the optical isomer of the above formula (IA) as a representative.

(1A) Deprotection reaction

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meanings as described above, and R means a protecting group.)

By removing the protecting group of the compound of formula (II) which is the raw material compound, the target optically active trans-astaxanthin derivative of formula (IA) can be produced.

As the elimination reaction, a normal elimination reaction of a protecting group can be used, and specifically, an acid-based elimination reaction can be mentioned.
Examples of the protecting group include a tertiary butyl group, a trimethylsilyl group, a tetrahydropyranyl group and the like, and preferred examples thereof include a tertiary butyl group and a trimethylsilyl group.

In the case of the elimination reaction with an acid, the target compound of the formula (IA) can be produced by reacting the compound of the formula (II) with the addition of an acid in an inert solvent.
The solvent used is not particularly limited as long as it is inert to this reaction, and is, for example, aliphatic hydrocarbons such as hexane, heptane, ligroine and petroleum ether; aromatics such as benzene, toluene and xylene. Hydrocarbons; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride; nitriles such as acetonitrile, propionitrile; ethyl formate, isopropyl formate, isobutyl formate, ethyl acetate, Organic acid esters such as isobutyl acetate, butyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide Alcohols such as methanol, ethanol, propanol, isopropanol; organic acids such as trifluoroacetic acid, formic acid, acetic acid, propionic acid; water; or a mixed solvent of these solvents can be mentioned, preferably halogenated. It is a mixed solvent of hydrocarbons, nitriles, ethers, alcohols, organic acids, amides, water, or a solvent thereof, and more preferably halogenated hydrocarbons, nitriles, alcohols, organic acids. , Ethers, water or a mixed solvent of these solvents, most preferably of halogenated hydrocarbons, acetonitrile, water, methanol, ethanol, isopropanol, formic acid, dioxane, tetrahydrofuran, or water and their organic solvents. A mixed solvent (when the protective group is a C1-C6 alkyl group) can be mentioned.
The acid that can be used is not particularly limited as long as it is used as an acid in a normal reaction, and is, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid; acetic acid, formic acid. , Hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids; zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromid Such Lewis acids; or acidic ion exchange resins, preferably inorganic or organic acids, most preferably hydrochloric acid, acetic acid, formic acid and trifluoroacetic acid.
The reaction temperature varies depending on the raw material compound to be reacted, the acid used, the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material compound, solvent, reaction temperature and the like, but is usually 30 minutes to 10 days, preferably 30 minutes to 5 days. The amount of the solvent used may be 10 to 50 times the volume of the compound of the usual formula (II), and preferably 30 times the volume. The amount of the acid used may be 5 to 50 times the molar amount, preferably 10 to 30 times the molar amount of the inorganic acid with respect to the compound of the formula (II) which is the raw material. If this is the case, a 100-fold to 1000-fold molar amount, preferably a 200- to 600-fold molar amount may be used.

Since the product obtained by the above deprotection reaction may contain geometric isomers such as the 9-cis isomer and the 13-cis isomer, column chromatography, separation such as reprecipitation and crystallization, and purification means may be used. By appropriately combining them according to the intended purpose, the geometric isomers can be separated and removed, and the optically active trans-astaxanthin derivative of the desired formula (IA) can be isolated and produced with high purity.
In addition, the separated cis form can be isolated and obtained by appropriately combining the above-mentioned purification and separation methods.

(1B) Conversion method from cis form to trans form

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above.)

Typical cis isomers used in this production method are compounds of the formulas (IAa) and (IAb) as described above, which are used as a single raw material compound, as a mixture of cis isomers, or in excess of cis isomers. A high-purity optically active trans-astaxanthin derivative of the desired formula (IA) can be produced by dissolving it in an inert solvent as a mixture with the containing trans compound and then reacting it with a conversion reagent such as iodine. ..

The solvent used is not particularly limited as long as it is inert to the present reaction, and examples thereof include tetrahydrofuran, ethyl acetate, acetonitrile, acetone, water and the like.
Iodine can be mentioned as a suitable use as the conversion reagent.
The reaction temperature varies depending on the raw material compound to be reacted, the conversion reagent used, the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably 10 ° C. to 100 ° C. The reaction time varies depending on the raw material compound, solvent, reaction temperature and the like, but is usually 30 minutes to 10 days, preferably 30 minutes to 5 days. The amount of the solvent used may be usually 10 to 50 times the weight of the compound of the usual formula (IAa) or formula (IAb), and preferably 30 times the volume. The amount of the conversion reagent used may be usually 0.01 times molar amount or more, preferably 0.1 times molar amount or more with respect to the compound of the formula (IAa) or the formula (IAb) which is a raw material.

In the product obtained by the above conversion reaction, as a method for separating geometric isomers such as the 9-cis isomer and the 13-cis isomer, column chromatography, reprecipitation, crystallization and the like can be mentioned. By appropriately combining these methods according to the intended purpose, the geometrical isomers can be separated, and the optically active trans-astaxanthin derivative of the desired formula (IA) can be isolated and produced with high purity.
Further, the separated cis form can also be isolated and produced as each cis form by using the above-mentioned separation means in an appropriate combination.

Next, a typical production method of the above-mentioned raw material compound (II) will be described below.

(2A) Method of directly binding the entire side chain portion to 3S, 3'S-astaxanthin

(In the formula, m ₁ and n ₁ have the same meaning as described above, and R means a protecting group (for example, a tertiary butyl group).)

After dissolving 3S, 3'S-astaxanthin in an inert solvent, the compound of formula (II) is reacted by reacting the compound of formula (III) corresponding to the side chain portion of the compound of formula (I) in the presence of a condensation reagent. Can be manufactured.

Examples of the solvent include organic solvents such as methylene chloride, chloroform and carbon tetrachloride.
As the condensation reagent, those used for ordinary condensation reactions can be used, and specific examples thereof include water-soluble carbodiimide hydrochloride (for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride). , N, N-diisopropylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide and the like. The amount of the condensation reagent used may be usually 2 times or more, preferably 2.5 times to 20 times the molar amount of the raw material 3S, 3'S-astaxanthin.
The compound of the formula (III) corresponding to the side chain portion may be used in an amount of 2 times or more, preferably 2.5 times to 20 times the molar amount of 3S, 3'S-astaxanthin.
The reaction temperature varies depending on the raw material compound to be reacted, the condensation reagent used, the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably −10 ° C. to 100 ° C. The reaction time varies depending on the raw material compound, solvent, reaction temperature and the like, but is usually 30 minutes to 10 days, preferably 30 minutes to 5 days. The amount of the solvent used may be usually 10 to 50 times the volume of the weight of 3S, 3'S-astaxanthin used, and preferably 30 times the volume.

The obtained compound of formula (II) can usually be purified and isolated by appropriately combining purification means such as column chromatography, reprecipitation, and recrystallization.
The entire side chain portion can be manufactured by the following method.

(2A-1)

(In the formula, m ₁ , and n ₁ have the same meanings as described above, and R means a protecting group (for example, a tertiary butyl group).)

The target compound of formula (III) can be produced by sequentially reacting the compound of formula (IV) with carbonyldiimidazole (V) and the compound of formula (VII).
Specifically, the compound of formula (IV) is reacted with carbonyldiimidazole (V) in the presence or absence of a reagent such as a base in an inert solvent to form an intermediate of formula (VI). Compounds can be obtained. Further, the target compound of formula (III) can be produced by reacting the compound of formula (VII) with trimethylsilyl chloride in the presence of a reagent such as a base, and then reacting with the compound of formula (VI). ..

In the step of obtaining the compound of formula (VI), an organic solvent such as chloroform or methylene chloride can be used as the solvent, and the amount of these organic solvents used is usually 5 times the weight of the compound of formula (IV). A to 30 times capacity, preferably 15 times capacity may be used.
As the base reagent, those used for ordinary condensation reactions can be used, and specific examples thereof include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like. ..
The reaction temperature varies depending on the raw material compound to be reacted, the reagent used, the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 15 minutes to 10 days, and preferably 30 minutes to 2 days.
In the step of obtaining the target compound of formula (III), organic solvents such as chloroform, methylene chloride, and pyridine can be used as the solvent for reacting trimethylsilyl chloride with the compound of formula (VII). The amount used may be usually 5 to 50 times the volume, preferably 20 times the volume of the weight of the compound of the formula (VII).
As the base, those used in a normal condensation reaction can be used, and specific examples thereof include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like. The amount of the base and the reagent used may be usually 2 times or more, preferably 2.5 to 5.0 times the molar amount of the compound of the formula (VI) which is the raw material.
The reaction temperature varies depending on the raw material compound to be reacted, the reagent used, the solvent and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material compound, solvent, reaction temperature and the like, but is usually 15 minutes to 5 days, and preferably 30 minutes to 2 days. Next, the reaction temperature when the compound of formula (VI) is added and reacted varies depending on the raw material compound to be reacted, the reagent used, the solvent, etc., but is usually −20 ° C. to 150 ° C., preferably 10 ° C. To 60 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 4 days.

(2B) A method of sequentially binding the parts of the side chain to 3S, 3'S-astaxanthin.

(In the formula, m ₁ , m ₂ , n ₁ and n ₂ have the same meanings as described above, and R means a protecting group (for example, a tertiary butyl group or a trimethylsilyl group).)

In this production method, the side chain part (VIII) obtained by reacting the compound represented by the general formula (VII) with carbonyldiimidazole (V) is bound to 3S, 3'S-astaxanthin. This can then be achieved by binding the side chain part (XI) to the resulting product (IX).

In the step using carbonyldiimidazole (V), various reaction conditions shown in the above-mentioned production method (2A-1) may be used in the same manner.
Examples of the solvent include organic solvents such as chloroform and methylene chloride, and the amount of these organic solvents used is usually 2 to 30 times the weight of the compound of formula (VII), which is preferable. It is sufficient to use 7 times the capacity.
The reaction temperature varies depending on the raw material compound to be reacted, the reagent used, the solvent and the like, but is usually −20 ° C. to 150 ° C., preferably −10 ° C. to 100 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 5 days. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like.
The compound of formula (IX) can be produced by reacting the obtained side chain portion (VIII) with 3S, 3'S-astaxanthin in the same manner as in the above reaction of 2A. ..

The step of obtaining the desired general formula (II) can be achieved by reacting the compound having the general formula (IX) obtained above with the general formula (XI). This reaction is carried out according to the method for producing the above general formula (VIII).
The reaction temperature varies depending on the starting compound to be reacted, the reagent used, the solvent and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 30 hours.
The method for producing a compound having the general formula (XI) can be achieved according to (1) a method for synthesizing a generally known t-butyl ester of an amino acid when R is a t-butyl group. (2) When R is a trimethylsilyl group, it can be achieved by reacting a compound having the general formula (X) with trimethylsilyl chloride in the presence of a base in an inert solvent (the compound of the general formula (III) is prepared). Can be achieved according to the method). The reaction (2) can be achieved according to a generally known method for silylating a hydroxyl group or a carboxyl group. When R in the general formula (XI) is a trimethylsilyl group, the trimethylsilyl group can be easily eliminated by using water or weakly acidic water for the post-treatment of the reaction for producing the general formula (II). ..

The target compound of formula (II) can be produced by using the obtained product in an appropriate combination of purification means such as ordinary column chromatography, reprecipitation, and recrystallization.

The compounds of formula (I) according to the present invention, their geometric isomers, mixtures of these geometric isomers, their optical isomers or salts thereof can be administered as external preparations, oral preparations or injections, preferably. It should be administered as an external preparation.
The external preparation can be typically administered in the form of an ointment, a liquid, a lotion, a liniment, a gel, an aerosol, a plaster, a poultice, a cream or the like.
These external preparations include pharmaceutically acceptable additives such as solubilizers, bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plastics, pH regulators, absorption enhancers, gels. Ingredients such as agents, preservatives, fillers, preservatives, preservatives, pigments, fragrances, refreshing agents, thickeners, antioxidants, whitening agents, UV absorbers, etc. may be blended. Oral or injectable preparations can be produced by using conventional formulation techniques.
Oral preparations may be administered in any form such as tablets, capsules, granules, powders, etc., and are appropriately mixed with pharmaceutically acceptable pharmaceutical additives such as excipients, disintegrants, and binders. It can be produced by using a usual formulation technique.
The injectable preparation can be produced by a usual formulation technique using a pharmaceutically acceptable osmotic pressure regulator, stabilizer, solubilizer, PH regulator and the like in appropriate combinations.

When the compound of formula (I) according to the present invention, its geometric isomers, a mixture of these geometric isomers, their optical isomers or salts thereof are administered as an external preparation or an oral preparation, the external preparation of the present invention Alternatively, the frequency and dose of the oral preparation can be appropriately selected depending on the symptom to be treated, the dosage form, the route of administration, the age, weight, gender or general health condition of the patient, the base, etc. For example, when applied to a warm-blooded animal weighing about 70 kg, the daily dose is 0.01 to 500 mg, preferably 1 to 100 mg, more preferably 5 to 20 mg once or more per day, for example, 1 to 6 times. It may be administered at.
When the compound of formula (I) according to the present invention, its geometric isomers, a mixture of these geometric isomers, their optical isomers or salts thereof are administered as an injection, it is usually 5 per day for adults. .0 to 80.0 mg may be administered intravenously, and the dose may be adjusted according to the patient's symptoms.
The compounds of formula (I) according to the present invention, their geometric isomers, mixtures of these geometric isomers, their optical isomers or salts thereof, have no particular problem in terms of safety in the above dose range. Absent.

Hereinafter, examples of the present invention will be described.
However, the scope of the present invention is not limited to the following examples.
In this example, an atopic dermatitis model mouse in which a chronic dermatitis pathological condition is induced by a tick antigen is used, and an action on atopic dermatitis is performed using the auricular thickness, the skin symptom score, and the total blood IgE antibody level as indicators. It was investigated.

(1) Model preparation NC / Nga; slc mice were prepared, and under isoflurane inhalation anesthesia, a mite antigen-administered solution was intradermally administered to the right auricle of the mice to induce skin inflammation. This mite antigen administration was performed on the 0th, 3rd, 7th, 10th and 14th days when the first administration day was the 0th day.

(2) Preparation and administration of ointment The test substance (as compound X), the lysine salt of the optically active trans-astaxanthin derivative of the above formula (IA) (m1 and m2 are integers of 1 respectively, n1 and n2 are integers of 3 respectively, purity. 97.6%) was used. Compound X was produced according to the description in the following production example.
The required amount of compound X was weighed and the required amount of white petrolatum was mixed to prepare a 0.5 w / v% ointment, which was used as a 0.5% (high dose) coated ointment. For 0.05 w / v% and 0.005 w / v% ointments, medium is added to the 0.5 w / v% concentration ointment and serially diluted to 0.05 w / v% (medium dose) and 0.005 w / v. Made by preparing a% ointment (low dose).
White petrolatum (medium group) was used as a control group, and white petrolatum was used as a sham group to which the mite antigen was not administered.
Each ointment was applied to the right auricle of the mouse once a day from the 0th day to the 22nd day of the administration of the mite antigen so as to spread thinly with a cotton swab.

(3) Production Example of Compound X The geometric isomers in the middle chain carbon chain portion of the astaxanthin skeleton in the chemical structural formulas described below are shown by the chemical structural formulas of all trans isomers for convenience.

(3.1) Synthesis of 4- (imidazol-1-ylcarbonylamino) t-butyl butyrate (in this chemical name, t means tertiary; the same shall apply hereinafter):

Methylene chloride (79.6 kg) is added to carbonyldiimidazole (9.95 kg), stirred, and a solution of t-butyl hydrochloride 4-aminobutyrate (8.0 kg) in methylene chloride (53.1 kg) is -5 to 5 The mixture was added at 5 ° C. and the reaction mixture was stirred at the same temperature for 30 minutes. The mixture was heated to 15 to 25 ° C. and stirred at the same temperature for 1 hour. Water (40 kg) was added to the reaction mixture, and the mixture was stirred to separate the organic layer. The obtained solution was washed with 5% brine (42.1 kg), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title crude product (concentrated residue: 10.4 kg).
NMR spectrum (δppm, CDCl ₃ ): 8.22 (1H, s), 7.92 (1H, br), 7.28 (1H, d, J = 0.8Hz) 7.05 (1H, d, J) = 0.8Hz), 3.45 (2H, dt, J = 6.0, 6.0Hz), 2.40 (2H, t, J = 6.4), 1.92 (2H, tt, J =) 6.4, 6.4 Hz), 1.44 (9H, s).
Mass spectrum (+ ESI, m / z): 254.00 (M + H) ⁺ .

(3.2) Synthesis of t-butyl 4- (3-carboxymethylureide) butyrate:

4- (Imidazole-1-ylcarbonylamino) t-butyl butylate (compound of (3.1) above) (10.4 kg), methylene chloride (185.7 kg), glycine (7.4 kg), triethylamine (8. 3 kg) was added and stirred, chlorotrimethylsilane (8.9 kg) was added at −5-5 ° C. and the reaction mixture was stirred at 15-30 ° C. for 60 hours. The reaction mixture was concentrated under reduced pressure, a mixture of ethyl acetate (208 kg), hydrochloric acid (5.66 kg) and 20% saline (106 kg) was added, and the mixture was stirred to separate the organic layer. The obtained solution was washed with a mixed solution of hydrochloric acid (5.66 kg) and 20% saline solution (106 kg). The aqueous layer was extracted with ethyl acetate (57.4 kg) and the organic layer and the extract were combined. The resulting solution was washed with 20% brine (100 kg), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (14.4 kg) was added and stirred to give a homogeneous solution at 45-55 ° C. The solution was cooled to 20 to 30 ° C., n-heptane (108.7 kg) was added dropwise, and after confirming the precipitation of crystals, the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to obtain the title compound (7.98 kg, purity 99.2%) as white crystals.
The purity of the product was determined by high performance liquid chromatography (column: YMC-Triart C18 ExRS manufactured by YMC Co., Ltd. and mobile phase: acetonitrile / pH8 phosphate buffer = 3/7, flow velocity: 1 mL / min, detection wavelength. : 210 nm) was used to determine.
NMR spectrum (δppm, CDCl ₃ ): 6.16 (1H, t, J = 5.6Hz), 6.01 (1H, t, J = 5.6Hz), 3.67 (2H, d, J = 6) .0Hz), 2.97 (2H, dt, J = 6.4, 6.4Hz), 2.17 (2H, t, J = 7.2Hz), 1.56 (2H, tt, J = 7. 2,7.2 Hz), 1.39 (9H, s).
Mass spectrum (+ ESI, m / z): 260.92 (M + H) ⁺ .

(3.3) 4- (3- {4- [18- (4 (S)-[3- (3-t-butoxycarbonylpropyl) ureidoacetoxy] -2,6,6-trimethyl-3-oxocyclohexyl] Sa-1-enyl) -3,7,12,16-tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E), 15 (E), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid t- Butyl synthesis:

3 (S), 3'(S) -astaxanthin (1.8 kg), t-butyl 4- (3-carboxymethylureide) butyrate (compound of (3.2) above) (2.75 kg), N, N-Dimethyl-4-aminopyridine (2.95 kg) and methylene chloride (71.6 kg) were added and stirred to prepare a solution. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.63 kg) was added to the solution at −5 to 5 ° C., and the mixture was stirred at the same temperature for 4 hours. Water (3.6 kg) was added to the reaction mixture and stirred, and ethyl acetate (48.4 kg) was further added, and the mixture was stirred and concentrated under reduced pressure. Ethyl acetate (48.4 kg) and water (45 kg) were added to the concentrated residue, and the mixture was stirred to separate the organic layer. The obtained solution was mixed with hydrochloric acid water (0.3 M, 46.4 kg) three times with 10% saline solution (45.9 kg), aqueous sodium hydrogen carbonate solution (about 7%, 48.2 kg), and 20% saline solution (45 kg). ), Dryed with anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give the title compound (concentrated residue, 3.26 kg, purity 98.1%).
The purity of the product is determined by high performance liquid chromatography (column: YMC-TriartC18 ExRS manufactured by YMC Co., Ltd. and mobile phase: acetonitrile containing 0.025% trifluoroacetic acid / 0.025% trifluoroacetic acid water = 30 to 98 /. 70-2, flow velocity: 1 mL / min, detection wavelength: 474 nm) was used for determination.
NMR spectrum ( _{δppm, CDCl 3} ): 6.18-6.72 (14H, m), 5.56 (2H, dd, J = 6.4, 13.2Hz), 5.04 (2H, t, J) = 5.3Hz), 4.81 (2H, t, 5.7Hz), 4.25 (2H, dd, J = 18.1, 6.6Hz), 4.03 (2H, dd, J = 18. 3,4.6Hz), 3.19-3.26 (4H, m), 2.29 (4H, t, J = 7.3Hz), 2.02-2.13 (4H, m), 1. 99 (12H, s), 1.90 (3H, s), 1.76-1.83 (4H, m), 1.44 (18H, s), 1.34 (6H, s), 1.23 (6H, s).
Mass spectrum (+ ESI, m / z): 1081.88 (M + H) ⁺ , 1103.67 (M + Na) ⁺ .

(3.4) 4- (3- {4 (S)-[18- (4- {3- (3-carboxypropyl) ureidoacetoxy} -2,6,6-trimethyl-3-oxocyclohexa-1) -Enyl) -3,7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E) ), 15 (E), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) Butyric acid synthesis:

4- (3- {4- [18- (4 (S)-[3- (3-t-butoxycarbonylpropyl) ureidoacetoxy] -2,6,6-trimethyl-3-oxocyclohexa-1-enyl) ) -3,7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E), 15 (E), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) t-butyl butyrate ((3) above .3) Compound) (18.12 g) was added with formic acid (272 mL), and the mixture was stirred at 25 to 35 ° C. for 1 hour. The reaction mixture was added to water (1087 mL) and stirred, ethyl acetate (1087 mL) was added and stirred to separate the organic layer. The organic layer was washed twice with water (543 mL) and twice with 10% brine (543.4 g), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was dissolved in tetrahydrofuran (81.1 mL) and water (8.11 mL), acetonitrile (486.8 mL) was added dropwise to the solution, and after confirming the precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give the title compound (4.48 g, purity 90.7%) as a dark purple to dark red solid.
The purity of the product is determined by high performance liquid chromatography (column: YMC-TriartC18 ExRS manufactured by YMC Co., Ltd. and mobile phase: acetonitrile containing 0.025% trifluoroacetic acid / 0.025% trifluoroacetic acid water = 30 to 98 /. 70-2, flow velocity: 1 mL / min, detection wavelength: 474 nm) was used for determination.

(3.5) 4- (3- {4 (S)-[18- (4- {3- (3-carboxypropyl) ureidoacetoxy} -2,6,6-trimethyl-3-oxocyclohexa-1) -Enyl) -3,7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E) ), 15 (E), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) Butyric acid synthesis:

4- (3- {4 (S)-[18- (4- {3- (3-carboxypropyl) ureidoacetoxy} -2,6,6-trimethyl-3-oxocyclohexa-1-enyl) -3 , 7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E), 15 (E) ), 17 (E) -Nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) Butyric acid (crude production of (3.4) above) Tetrahydrofuran (18.4 mL) and water (2.0 mL) were added to (4.0 g), and the mixture was stirred and dissolved. Acetonitrile (60 mL) was added dropwise to the solution, and after confirming the precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to obtain a dark purple to dark red solid (3.31 g, purity 96.9%). Tetrahydrofuran (15.0 mL) and water (1.6 mL) were added to the obtained solid (3.26 g), and the mixture was stirred and dissolved. Acetonitrile (49 mL) was added dropwise to the solution, and after confirming the precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to obtain a dark purple to dark red solid (2.93 g, purity 98.9%). Tetrahydrofuran (10.9 mL) and water (1.2 mL) were added to the obtained solid (2.38 g), and the mixture was stirred and dissolved. Acetonitrile (36 mL) was added dropwise to the solution, and after confirming the precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give the title compound (2.18 g, purity 99.3%) as a dark purple to dark red solid.
The purity of the product is determined by high performance liquid chromatography (column: YMC-TriartC18 ExRS manufactured by YMC Co., Ltd. and mobile phase: acetonitrile containing 0.025% trifluoroacetic acid / 0.025% trifluoroacetic acid water = 30 to 98 /. 70-2, flow velocity: 1 mL / min, detection wavelength: 474 nm) was used for determination.

(3.6) 4- (3- {4 (S)-[18- (4- {3- (3-carboxypropyl) ureidoacetoxy} -2,6,6-trimethyl-3-oxocyclohexa-1) -Enyl) -3,7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E) ), 15 (E), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureide) Butyric acid diricin salt; compound Synthesis of X:
4- (3- {4 (S)-[18- (4- {3- (3-carboxypropyl) ureidoacetoxy} -2,6,6-trimethyl-3-oxocyclohexa-1-enyl) -3 , 7,12,16-Tetramethyloctadeca-1 (E), 3 (E), 5 (E), 7 (E), 9 (E), 11 (E), 13 (E), 15 (E) ), 17 (E) -nonaniel] -3,5,5-trimethyl-2-oxocyclohexa-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid (compound of (3.5) above) Ethanol (10 mL) and water (0.5 mL) were added to (0.50 g,) and stirred. A solution of L-lysine monohydrate (0.174 g,) in water (2 mL) was added to the suspension at room temperature. Water (7.5 mL) was added to the reaction mixture, and the mixture was stirred and dissolved. Ethanol (32 mL) was added dropwise to the reaction mixture at room temperature, and after confirming the precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give the title compound (0.47 g, purity 98.6%, optical purity 99.0% de) as a dark purple to dark red solid.
The purity of the product was determined by using high performance liquid chromatography in the same manner as described above. Optical purity is high performance liquid chromatography (column: YMC CHIRAL ART Amylose SA (5 μm, 4.6 mm IDx250 mm) manufactured by YMC Co., Ltd., column temperature: 25 ° C. and mobile phase: THF / water / TFA (40:60) : 0.1), Flow velocity: 1 mL / min, Detection wavelength: 474 nm, Column retention time: 15.4 minutes (S, S), 17.6 minutes (meso), 20.6 minutes (R, R)) Used to determine.

(4) Auricle thickness increase value (4.1) Measurement / calculation of auricle thickness increase value Day 1, 4, 8, 11, 15, 18 and 22 with the mite antigen administration start date as day 0 The thickness of the right pinna of the mouse was measured under isoflurane anesthesia. The auricle thickness increase value at each measurement point was calculated by subtracting the initial auricle thickness measurement value on the grouping day from the auricle thickness measurement value at each point.

(4.2) Comparison of measurement and calculation results of auricle thickness increase value Ear auricle thickness increase on days 1, 4, 8, 11, 15, 18 and 22 with the mite antigen administration start date as day 0 The values were calculated and compared with the mean values of the medium group and the other test groups (FIGS. 1 and 1).
As a result, the sham group showed a statistically significant increase in auricular thickness increase compared to the medium group at all measurement points. On the other hand, the compound X administration group showed a lower mean value of the auricle thickness increase value at many measurement points as compared with the medium group, and the compound X low dose group and the medium dose group were particularly on the 4th day. It showed a statistically significant lower value of auricular thickness increase compared to the medium group.

(5) Skin symptom score (5.1) Measurement of skin symptom score Mice under isoflurane anesthesia on days 1, 4, 8, 11, 15, 18 and 22, respectively, with the mite antigen administration start date as day 0. The following skin symptoms in the right pinna of the auricle were observed with the naked eye, and their strength was scored as asymptomatic (0 points), mild (1 point), moderate (2 points), and severe (3 points). And evaluated.
1) Redness / flushing 2) Crust / epidermis peeling 3) Bleeding / blood clot 4) Hardening

(5.2) Comparison of measurement results of skin symptom score With the mite antigen administration start date as day 0, the skin symptom score on days 1, 4, 8, 11, 15, 18 and 22 was measured and compared with the vehicle group. The average values of the other test groups were compared (Fig. 2 and Table 2).
As a result, the sham group showed a statistically significant high skin symptom score as compared with the medium group at all measurement points except the first day. On the other hand, all of the compound X groups showed lower average skin symptom scores than the medium group at many measurement points. In addition, the Compound X low dose group showed statistically significant lower skin symptom scores on days 11, 15 and 18 compared to the vehicle group.

(6) Total IgE antibody amount (6.1) Measurement of total IgE antibody amount Heparin from the abdominal vena cava of mice under isoflurane anesthesia 1 hour after the final administration on the 22nd day, with the start date of tick antigen administration as the 0th day. Blood was collected using an additive syringe. Plasma was separated from the collected blood by centrifugation, and the total amount of IgE in the blood was measured by the total IgE measurement ELISA method.

(6.2) Comparison of measurement results of total IgE antibody amount The total IgE antibody amount in the blood collected 1 hour after the final administration on the 22nd day was measured with the mite antigen administration start date as the 0th day. The average values of the other test groups were compared (Fig. 3 and Table 3).
As a result, the sham group showed a statistically significantly higher total antibody amount than the medium group. The low dose group of Compound X showed lower values than the vehicle group, but did not show statistically significant values.

(7) Summary The results of this example are summarized below.
In this example, the auricular thickness increase value, the skin symptom score, and the blood IgE antibody level were measured in a mite antigen-induced atopic dermatitis model mouse exhibiting chronic skin inflammation.
On the other hand, the compound X low-dose group and the medium-dose group showed significantly lower values in the thickening of the auricle as compared with the vehicle group at the point 4 days after the mite antigen administration day. The compound X low dose group showed statistically significant lower skin symptom scores on days 11, 15 and 18 compared to the vehicle group. The compound X-administered group showed lower values in the auricle thickness increase value and the skin symptom score as compared with the medium group at many measurement points. In the comparison of the total blood IgE antibody level, the compound X low-dose group showed a lower value than the medium group at the point on the 22nd day.
From the above results, it is inferred that compound X can be replaced with a steroid depending on the dose and has a clear therapeutic effect on atopic dermatitis.

Claims (7)

A dermatitis therapeutic agent containing a trans-astaxanthin derivative represented by the formula (I), its geometric isomers, a mixture of these geometric isomers, their optical isomers or salts thereof.
(In the equation, m ₁ , m ₂ , n ₁ and n ₂ mean the same or different integers 1 to 6, respectively.) The dermatitis therapeutic agent according to claim 1, wherein in the formula (I), m ₁ and m ₂ are each an integer of _1, and n _{1 and n 2 are each an integer of 3.} The dermatitis therapeutic agent according to claim 1 or 2, wherein the salt is a ricin salt. A therapeutic agent for dermatitis containing an optically active trans-astaxanthin derivative represented by the formula (IA), a geometric isomer thereof, a mixture of the geometric isomers thereof, or a salt thereof.
(In the equation, m ₁ , m ₂ , n ₁ and n ₂ mean the same or different integers 1-6.) The dermatitis therapeutic agent according to claim 4, wherein in the formula (IA), m ₁ and m ₂ are each an integer of _1, and n _{1 and n 2 are each an integer of 3.} The dermatitis therapeutic agent according to claim 4 or 5, which is substantially free of the optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) and a salt thereof. A dermatitis therapeutic agent containing a salt of a high-purity optically active trans-astaxanthin derivative according to any one of claims 4 to 6, wherein the salt is a lysine salt.