WO2019138995A1

WO2019138995A1 - Dry eye remedy

Info

Publication number: WO2019138995A1
Application number: PCT/JP2019/000192
Authority: WO
Inventors: 康弘西田; 横山　富久; 藤田　岳
Original assignee: アスタファーマシューティカルズ株式会社
Priority date: 2018-01-09
Filing date: 2019-01-08
Publication date: 2019-07-18
Also published as: JP2021054718A

Abstract

A novel dry eye remedy is provided. This dry eye remedy and/or agent for suppressing tear reduction contains a trans-astaxanthin derivative represented by formula (I), a geometric isomer thereof, a mixture of geometric isomers thereof, or optical isomers or salts thereof. (In the formula, m₁, m₂, n₁, and n₂ are the same or different, and are integers from 1 through 6.)

Description

Dry eye improver

The present invention relates to a dry eye improving agent containing an astaxanthin derivative.

Dry eye is a disease in which the health of the surface of the eye is impaired due to tear abnormalities such as dryness of the tears. The background of the abnormality of tears is complex, and it may also be caused by medical illness, by eye surgery such as corneal transplantation, or by side effects of the medicine being taken.
Common dry eye is considered to be a major environmental factor. The modern society is full of factors that dry tears, and by continuing to watch monitors such as personal computers, TVs and mobile phone screens, blinks are reduced and tears become dry more easily, and air conditioning such as indoor air conditioning also dries the room. I tend to. In addition, tear secretion is governed by the parasympathetic nervous system (when relaxed), and a mechanism exists that decreases sympathetic dominance (during tension). Thus, it is believed that various stresses may suppress the secretion of tears.
In addition, long-term and long-term wear of contact lenses, night life, changes in diet, lack of exercise, lifestyle involvement and tear reduction and stability decline with age are also pointed out. There is.

As therapeutic agents for dry eye, agents that promote the secretion of mucin on the ocular surface, such as diacfosol sodium ophthalmic solution and rebamipide ophthalmic solution, are being widely used, but drugs showing more sufficient clinical effects have been desired . Under such circumstances, litifemast, which is expected to be a dry eye treatment with a new mechanism of action, is drawing attention. While this drug significantly improved some of the primary endpoints for dry eye symptoms, there were also primary endpoints for which no improvement effect was found. Under such circumstances, more effective dry eye therapeutic agents are continuously desired (Non-patent Document 1).

On the other hand, astaxanthin has excellent antioxidative activity, and is a light disorder disease area, an ophthalmologic disease area, a dermatological disease area, an inflammatory disease area, an immune disease area, a heart disease area, a malignant tumor disease area, a liver disease area, Useful for kidney disease area, neurodegenerative disease area, toxic disease area, allergic disease area, insulin resistance disease area, diabetes disease area, hyperlipidemia disease area, cardiac function disease area, vascular system disease area, etc. It is known (non-patent documents 2 and 3). Among them, a compound of the following formula (I) is known as a compound having improved water solubility and oral absorbability of the same compound while maintaining antioxidative activity equal to or higher than astaxanthin (Patent Document 1).
However, no specific effect of the compound of the formula (I) on dry eye has been reported, and nothing is known about the tear volume reduction inhibitory effect described later.

WO 2015/178404 specification

The main object of the present invention is to provide a dry eye improving agent which can be substituted for the representative dry eye therapeutic drug litifast and has a dry eye improving effect equal to or higher than that.

As a result of intensive studies to find new therapeutic agents as therapeutic agents for improving dry eye, the present inventors have found that trans-astaxanthin derivatives of the formula (I), their geometric isomers, and mixtures of these geometric isomers The present inventors have completed the present invention by finding that their optical isomers or their salts have an excellent inhibitory effect on reduction in tear fluid volume and an excellent improving effect on dry eye.

That is, the present invention provides the following inventions [1] to [5].

[1] A trans-astaxanthin derivative represented by the formula (I), a geometric isomer thereof, a mixture of the geometric isomers thereof, a dry eye improving agent containing the optical isomer thereof or a salt thereof and / or reduction in tear fluid volume Inhibitor.

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ are the same or different and each represents an integer of 1 to 6).

[2] Trans-astaxanthin derivative represented by the above formula (I), geometric isomer thereof, mixture of these geometric isomers, optical isomer thereof or their salt, for improving dry eye and / or tear fluid amount Pharmaceutical composition for suppression of depression.
[3] The trans-astaxanthin derivative represented by the above formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomer, for producing a dry eye improving agent and / or a tear volume decrease inhibitor Use of the body or their salts.
[4] A dry eye characterized by administering an effective amount of the trans-astaxanthin derivative represented by the above formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomers or their salts Therapeutic methods for improvement and / or suppression of tear loss.
[5] The trans-astaxanthin derivative represented by the above formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomer or their optical isomer or the like for improving dry eye and / or suppressing tear loss Their salt.

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 a salt thereof are various animals such as humans, dogs, cats and horses in general. The astaxanthin derivative represented by the formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomers or them, which have excellent efficacy against dry eye and tear fluid loss of The pharmaceutical composition containing a salt is excellent as a dry eye improving agent and / or a tear volume reduction inhibitor.

It is a figure which shows the effect of each chemical | medical agent on tear volume evaluation in a Schirmer test in an Example.

The dry eye improving agent and / or tear fluid level reduction inhibitor of the present invention comprises the trans-astaxanthin derivative represented by the above formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomer or These salts are contained as an active ingredient.
"Improved dry eye" means, in essence, improving the dryness of the eye. Dry eye is roughly divided into "abnormal tear volume (dry tear reduction type dry eye)", "abnormal tear quality (evaporation type dry eye)", "abnormal tear stability (BUT shortening dry type) Eye) is classified. In the dry eye medication, various tests will be conducted, and eye drop medications will be selected as drugs mainly for dry eye types. Basically, suppressing the decrease in the amount of tear fluid secreted to the ocular surface can be said to be the main therapeutic method.
Subjects that may be treated according to the invention include, but are not limited to, warm-blooded animals, including humans, such as dogs, cats, horses, monkeys, rabbits, rats or mice.

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ are the same or different and each represents an integer of 1 to 6)

Among the compounds of formula (I), preference is given to the case where m ₁ and m ₂ each represent an integer of ₁ and n ₁ and n ₂ each represent an integer of 3.

The compound according to formula (I), its geometric isomer, a mixture of these geometric isomers and optical isomers thereof have a common salt-forming reaction with a basic substance or a basic compound desired from having a carboxyl group in the molecule A pharmaceutically acceptable salt can be formed by Such salts include, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; amino acids such as lysine salts, ornithine salts and arginine salts Salts can be mentioned, among which lysine salts can be mentioned as preferred.

In the chemical structural formula of the formula (I), the double bond part in the medium chain carbon chain part in the astaxanthin basic skeleton can take on the structure of trans and cis geometric isomers in terms of chemical structure. With regard to the active ingredient according to the present invention, not only the trans form of formula (I) but also cis forms represented by the following formulas (Ia) and (Ib) may be used as active ingredients of the dry eye improving agent according to the present invention It can be mentioned. The dry eye improver of the present invention also includes, as an active ingredient, a mixture of trans form of formula (I) and cis form which is its geometric isomer in various mixing ratios.

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above)

In addition, the compound of the formula (I), its geometric isomer and a mixture of these geometric isomers may include the optical isomer (IA) represented by the following, and its enantiomer and a mixture thereof, All diastereomers are also included as active ingredients of the dry eye improving agent and / or tear fluid reduction inhibitor according to the present invention.

Among the compounds of the formula (I), their geometric isomers, mixtures of these geometric isomers and their optical isomers, the compounds of the trans form of the above-mentioned formula (IA) are preferred.
Further, among the trans compounds of the above formula (IA), compounds in which m ₁ and m ₂ each represent an integer of ₁ and n ₁ and n ₂ each represent an integer of 3 are preferable.

As described above, an optically active trans-astaxanthin derivative represented by the formula (IA) or a salt thereof is more preferable, and an optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) More preferred is a highly pure optically active trans-astaxanthin derivative substantially free of a salt or a salt thereof. Here, to contain the active ingredient of the dry eye improving agent and / or tear fluid level decrease inhibitor according to the present invention in "high purity" means that the purity in the active ingredient is at least 95% or more, preferably 98% or more Say the case.

Compounds of the formula (I) according to the present invention, geometric isomers thereof, optical isomers thereof and salts thereof can be produced by appropriately using the production method described in WO 2015/178404 and the same method as the known methods. It can manufacture by combining. Among these production methods, the geometric isomer of the compound of the formula (I) and the production method of the optical isomer thereof will be described below by using the production method of the optical isomer of the above formula (IA) as a representative.

(1A) Deprotection reaction

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

The target optically active trans-astaxanthin derivative of the formula (IA) can be produced by removing the protecting group of the compound of the formula (II) which is a starting compound.

The elimination reaction may be a conventional elimination reaction of a protecting group, and specifically, an elimination reaction with an acid can be mentioned.
As a protecting group, a tertiary butyl group, a trimethylsilyl group, a tetrahydropyranyl group etc. can be mentioned, A tertiary butyl group, a trimethylsilyl group etc. can be mentioned as a suitable thing.

In the case of the elimination reaction with acid, the compound of formula (IA) can be produced by reacting the compound of formula (II) with an acid in an inert solvent.
The solvent used is not particularly limited as long as it is inert to the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatics such as benzene, toluene and xylene Hydrocarbons; Halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and carbon tetrachloride; Nitriles such as acetonitrile and propionitrile; ethyl formate, isopropyl formate, isobutyl formate, ethyl acetate, Organic acid esters such as isobutyl acetate and butyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide Amides such as: Alcohols such as methanol, ethanol, propanol and isopropanol; Organic acids such as trifluoroacetic acid, formic acid, acetic acid and propionic acid; Water; or mixed solvents of these solvents, and preferred Are halogenated hydrocarbons, nitriles, ethers, alcohols, organic acids, amides, water, or a mixed solvent of these solvents, more preferably halogenated hydrocarbons, nitriles, Alcohols, organic acids, ethers, water or mixed solvents of these solvents, most preferably halogenated hydrocarbons, acetonitrile, water, methanol, ethanol, isopropanol, formic acid, dioxane, tetrahydrofuran or water Mixed solvent of these organic solvents (protecting group is C1-C6 alkyl group) If) can be mentioned.
The acid which can be used is not particularly limited as long as it is used as an acid in a usual reaction, and, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid; acetic acid, formic acid Organic acids such as boric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide Or a acidic ion exchange resin, preferably an inorganic or organic acid, 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, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 5 days. The amount of the solvent used may be 10 to 50 times, preferably 30 times the volume of the weight of the compound of formula (II). The amount of the acid used is usually 5 to 50 times by mole, preferably 10 to 30 times by mole, as long as it is an inorganic acid relative to the compound of the formula (II) which is the raw material, an organic acid In this case, the molar amount is usually 100 to 1000 times, preferably 200 to 600 times.

The product obtained by the above deprotection reaction can contain geometric isomers such as the above 9-cis form and 13-cis form, so that separation and purification means such as column chromatography, reprecipitation and crystallization can be obtained. By combining as appropriate according to the purpose, the same geometric isomer can be separated and removed, and the objective optically active trans-astaxanthin derivative of the formula (IA) can be isolated and manufactured with high purity.
Further, the separated cis-form can be isolated and obtained by appropriately combining the purification and separation methods as described above.

(1B) Method of converting cis form to trans form

Representative cis-forms used in this production method are the compounds of the formulas (IAa) and (IAb) as described above, which may be used as sole raw material compounds, as a mixture of cis-forms, or in excess of cis-forms. The desired optically active trans-astaxanthin derivative of the formula (IA) can be produced by dissolving it in an inert solvent as a mixture with the trans form and reacting it with a conversion reagent such as iodine. .

The solvent to be used is not particularly limited as long as it is inert to the reaction, and examples thereof include tetrahydrofuran, ethyl acetate, acetonitrile, acetone, water and the like.
Preferred examples of the conversion reagent include iodine.
The reaction temperature varies depending on the raw material compound to be reacted, the conversion reagent to be 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. The amount of the solvent used is usually 10 times to 50 times the used weight of the compound of formula (IAa) or formula (IAb), preferably 30 times the volume. The amount of conversion reagent used may be usually 0.01 times or more by mole, preferably 0.1 times or more by mole, of the compound of the formula (IAa) or formula (IAb) as a raw material.

Among products obtained by the above conversion reaction, methods such as column chromatography, reprecipitation, crystallization and the like can be mentioned as methods for separating geometric isomers such as 9-cis and 13-cis. By combining these methods as appropriate depending on the purpose, the same geometric isomer can be separated, and the objective optically active trans-astaxanthin derivative of the formula (IA) can be isolated and produced in high purity.
In addition, the separated cis form can also be isolated and manufactured as each cis form by using the above separation means in combination as appropriate.

Next, a typical production method of the above starting compound (II) will be described below.

(2A) A method for directly binding the entire side chain moiety to 3S, 3'S-astaxanthin

(Wherein, m ₁ and n ₁ have the same meaning as described above, and R means a protecting group (eg, tertiary butyl group).)

A compound of formula (II) is obtained by dissolving 3S, 3'S-astaxanthin in an inert solvent and then reacting the compound of formula (III) corresponding to the side chain moiety in the compound of formula (I) in the presence of a condensing 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 in ordinary condensation reactions can be used, and as a specific example, water-soluble carbodiimide hydrochloride (eg, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) And N, N-diisopropylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide and the like. The amount of the condensation reagent used is usually at least 2 times the molar amount, 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 moiety may be used usually in a 2-fold molar amount or more, preferably 2.5-fold molar to 20-fold molar amount with respect to 3S, 3'S-astaxanthin.
The reaction temperature varies depending on the raw material compound to be reacted, the condensation reagent to be 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. The amount of the solvent used is usually 10 to 50 times the used weight of 3S, 3'S-astaxanthin, preferably 30 times the volume.

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

(2A-1)

(Wherein, m ₁ and n ₁ have the same meaning as described above, and R means a protecting group (eg, a tertiary butyl group).)

The desired compound of formula (III) can be produced by sequentially reacting the compound of formula (IV) with the compound of carbonyldiimidazole (V) and the compound of formula (VII).
Specifically, the compound of formula (IV) is an intermediate compound of formula (VI) by reacting carbonyldiimidazole (V) in the presence or absence of a reagent such as a base in an inert solvent. Compounds can be obtained. Furthermore, the desired 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 the formula (VI), organic solvents such as chloroform and methylene chloride can be exemplified as the solvent, and the amount of these organic solvents used is usually 5 times the used weight of the compound of the formula (IV) A volume of 30 to 30 volumes, preferably 15 volumes, may be used.
As the basic reagent, those used for ordinary condensation reactions can be used, and specific examples can 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 can be mentioned.
In the step of obtaining the desired compound of formula (III), organic solvents such as chloroform, methylene chloride, pyridine and the like can be mentioned as solvents for reacting trimethylsilyl chloride and the compound of formula (VII). The amount used is usually 5 times to 50 times the volume, preferably 20 times the volume of the used weight of the compound of the formula (VII).
As the base, those used for ordinary condensation reactions can be used, and specific examples can include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like. The amount of the base or reagent used is usually at least 2 moles, preferably 2.5 to 5.0 moles, per mole of the compound of the formula (VI) as 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., and 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 5 days, and preferably 30 minutes to 2 days can be mentioned. Next, the compound of formula (VI) is added and reacted at a reaction temperature which varies depending on the starting compound to be reacted, the reagent to be used, the solvent and the like, 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) Method of sequentially bonding parts of side chain portion to 3S, 3'S-astaxanthin

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning as described above, and R means a protecting group (eg, tertiary butyl group or 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 coupling part (XI) of the side chain part to the obtained product (IX).

In the step using carbonyldiimidazole (V), various reaction conditions shown in the production method of the above (2A-1) may be used similarly.
As the solvent, organic solvents such as chloroform and methylene chloride can be mentioned, and the amount of these organic solvents used is usually 2-fold to 30-fold volume with respect to the weight used of the compound of formula (VII). You can use 7 times capacity for
The reaction temperature varies depending on the raw material compound to be reacted, the reagent to be 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 bases include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like.
The compound of the formula (IX) can be produced by reacting the resulting part of the side chain part (VIII) with 3S, 3'S-astaxanthin in the same manner as in the reaction of 2A above. .

The step of obtaining the target 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 raw material compound to be reacted, the reagent to be 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 the method for synthesizing t-butyl ester of generally known amino acid when (1) 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 (to form a compound of the general formula (III) It can be achieved according to the method). The reaction of (2) can be achieved according to generally known methods for silylation of hydroxyl and carboxyl groups. 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 post-treatment of the reaction to generate the general formula (II). .

The desired product of the formula (II) can be produced by appropriately combining and using the obtained purification means such as ordinary column chromatography, reprecipitation, recrystallization and the like.

The compound of the formula (I) according to the present invention, its geometric isomer, a mixture of these geometric isomers, their optical isomers or a salt thereof can be administered as an eye drop, an eye ointment, an oral preparation or an injection. As an oral preparation, solid preparations such as tablets and drinks can be mentioned.
Liquid preparations such as drinks, eye drops and injections contain active ingredients, if necessary, in the presence of pH adjusting agents, buffers, dissolving agents, suspending agents, etc., tonicity agents, stabilizers, preservatives, etc. And may be manufactured using conventional formulation techniques. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, potassium hydroxide, triethanolamine and the like. As a buffer material, sodium phosphate, sodium acetate, sodium borate, sodium citrate, sodium aspartate etc. can be mentioned, for example. Examples of suspending agents include polysorbate 80, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate, gum arabic, powdered tragacanth, polyvinyl pyrrolidone, glycerin monostearate and the like. As the solubilizer, for example, polysorbate 80, hydrogenated polyoxyethylene castor oil, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester, petrolatum, glycerin, propylene glycol etc. may be mentioned. it can. As a stabilizer, sodium sulfite, sodium metasulfite, sodium citrate, sodium edetate, monoethanolamine, etc. can be mentioned, for example. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sodium benzoate, sorbic acid, phenol, cresol, chlorocresol, benzalkonium chloride, paraben and the like.
The solid oral preparation may be administered in any form such as tablet, capsule, granule, powder and the like, and the active ingredient is a pharmaceutical additive such as pharmaceutically acceptable excipient, disintegrant, binder and the like And the appropriate formulation, and can be produced by using conventional formulation techniques.
The eye ointment can be produced by combining the active ingredient with a commonly used ointment base such as white petrolatum, liquid paraffin and the like by using a conventional formulation technique.

When administering the compound of the formula (I) according to the present invention, its geometric isomer, a mixture of these geometric isomers, their optical isomers or a salt thereof, symptoms, patient's age, weight, sex or general Depending on the physical condition, the administration method and dosage form may be selected appropriately. For example, when administered as eye drops, eye drops of a concentration of 0.0001% to 4% for one eye once to 10 times a day, more preferably an eye drop of a concentration of 0.01% to 1% The solution may be instilled twice to four times a day. When orally administered to a warm-blooded animal having a weight of about 70 kg, the daily dose is 0.01 to 500 mg, preferably 1 to 100 mg, more preferably 5 to 20 mg once a day or more, for example, 1 to 6 It may be administered at once. In the case of administration as an injection, usually, 5.0 to 80.0 mg per day may be intravenously administered to an adult, and the dose may be appropriately increased or decreased according to the symptoms.
As a preferred method of administration of the compound of the formula (I) according to the present invention, its geometric isomer, a mixture of these geometric isomers, their optical isomers or their salts, mention may be made of eye drop administration. You may instill a few drops depending on the symptom. Furthermore, when administered as an eye ointment, an appropriate amount of the ointment may be applied to the mucosal surface of the eye.
The compounds of the formula (I) according to the present invention, their geometric isomers, mixtures of their geometric isomers, their optical isomers or their salts are particularly problematic in terms of safety within the above-mentioned 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.

(1) Model preparation The extraorbital lacrimal gland excision model of the rat was used in this test. In this model, lacrimal fluid reduction-type dry eye symptoms are exhibited by extraction of the lacrimal gland (Non-patent Document 1). Generally, in addition to extraorbital lacrimal gland, accessory lacrimal glands such as the creases and Wolfling's glands, or remaining glandular tissues such as meibomian glands (Harder's glands) and goblet cells are involved in tear secretion. The extraorbital lacrimal gland and the water, oil and mucin secreted from them contribute to the stabilization of the tear film to protect the cornea, but with dry eye, the tear film is destabilized by the decrease in tear volume. Is recognized. Therefore, tear secretion was used as an indicator of the pathological condition in this test. As a test, male SD rats were anesthetized by intraperitoneal administration of three mixed anesthetics (medetomidine + midazolam + butorphanol; 0.15 + 2.0 + 2.5 mg / kg). The operative part around the eye was disinfected, and an about 7 mm incision was made about 7 mm below the ear, and the extraorbital lacrimal gland on both sides was removed. The skin at the incision was then sutured and antibiotics (enrofloxacin, 5 mg / kg, sc) and analgesics (carprofen, 5 mg / kg, sc) were administered. Antibiotics and analgesics were treated for 3 days including the day of surgery. The day the lacrimal gland extraction surgery is performed is Day 0, and there is no bias among the groups based on tear volume (assessed on Day 12), body weight (measured on Day 13) and fluorescein corneal staining score (assessed on Day 13) Grouping into 5 groups was performed.
(2) Ophthalmic solution preparation and administration In the above formula (IA), a lysine salt of optically active trans-astaxanthin derivative (purity 97.6%), wherein "m1 and m2 are each an integer of 1 and n1 and n2 are each an integer of 3" Was used as a representative compound for the test substance (compound X). Compound X was prepared according to the description of the preparation examples described later.
As an eye drop, Compound X was adjusted with phosphate buffered saline (PBS, manufactured by Thermo Fisher Scientific Co., Ltd.) to a concentration shown in Table 1 below. Instillation treatment was started two weeks after lacrimal gland extraction, as described in the following section. A phosphate-buffered saline solution was used as a positive target as a solvent target group of eye drops, and a commercially available Lifitegrass 5.0% solution (trade name: Xiidra eye drop, Shire US Inc.) was used. Instillation was carried out 4 times a day (compound X and physiological saline) to the number of instillation of positive control according to the package insert of drug for a total of 36 days (Day 14 to Day 49).
(3) Evaluation of tear fluid amount: Day 12 (before start of instillation), and Day 20 (one week of instillation), Day 27 (two weeks of instillation), Day 34 (three weeks of instillation), Day 41 (four weeks of instillation) Day 48 The tear fluid volume was measured about 30 minutes after the first instillation (5 weeks of instillation).
Evaluation of tear fluid volume in rats was by Schirmer method. Specifically, using a Schilmer test paper (Ayumi Pharmaceutical Co., Ltd.), insert the tip of the Silmer test paper cut into 1 mm width into the conjunctival sac of rat lower eyelid under awakening, and open the square open field (87 x 65 cm, wall 25 cm high). One minute after the insertion, the test paper was removed, and the length of the wet part was immediately read in 0.5 mm units using a ruler, and the value was used as the tear fluid volume. If the Schirmel test strip fell out of the eye during the one minute of the measurement, remeasurement was immediately performed using a new test strip.

(4) Results The results are shown in Table 2 and FIG. 1 below.

Each data showed the measurement mean value ± standard error. G1 in the solvent control group showed a decrease in tear fluid volume in any of the test period as compared to the time of grouping. Compound X showed high tear secretion levels compared to the solvent control group at all concentrations. The tear fluid volume was higher than that of the solvent control group, but the tear fluid volume decreased at 5th week (day 48) of the positive control group compared to the solvent control group, and was equivalent to the solvent control group. Showed lacrimal secretion.

(5) Summary According to the above results, both Lifitegrat as a reference drug and Compound X related to the present invention show the effect of suppressing the decrease in tear volume in the extraorbital lacrimal gland excision model, and Compound X has an effect equal to or more than Lifiteburst. It was confirmed to have.
Therefore, the compound of the formula (I) according to the present invention, its geometric isomer, a mixture of these geometric isomers, their optical isomers or their salts have an excellent effect of suppressing the reduction in tear fluid volume, ie the dry eye improvement effect It was confirmed to have

<Production Example of Compound X>
The geometric isomer in the astaxanthin skeleton medium chain carbon chain portion in the chemical structural formula in the following description is conveniently represented by a chemical structure of all trans form.

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

Methylene chloride (79.6 kg) is added to carbonyldiimidazole (9.95 kg) and stirred to give a solution of t-butyl 4-aminobutyric acid hydrochloride (8.0 kg) in methylene chloride (53.1 kg) At 5 ° C., the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was warmed to 15-25 ° C. and stirred at the same temperature for 1 hour. To the reaction mixture, water (40 kg) was added and stirred, and the organic layer was separated. The resulting solution was washed with 5% brine (42.1 kg), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title product (10.2 kg of concentrated residue).
NMR spectrum (δ ppm, CDCl ₃ ): 8.22 (1 H, s), 7.92 (1 H, br), 7. 28 (1 H, d, J = 0.8 Hz), 7.05 (1 H, d, J = 0.8 Hz), 3.45 (2H, dt, J = 6.0, 6.0 Hz), 2.40 (2H, t, J = 6.4), 1.92 (2H, tt, J = 6.4, 6.4 Hz), 1.44 (9 H, s).
Mass spectrum (+ ESI, m / z): 254.00 (M + H) ^<+> .

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

Methylene chloride (185.7 kg), glycine (7.4 kg), triethylamine (8 kg), t-butyl 4- (imidazol-1-ylcarbonylamino) butyrate (the compound of the above (3.1)) (10.4 kg). 3 kg) was added and stirred, chlorotrimethylsilane (8.9 kg) was added at -5 to 5 ° C, and the reaction mixture was stirred at 15 to 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% brine (106 kg) was added and stirred, and the organic layer was separated. The resulting solution was washed with a mixture of hydrochloric acid (5.66 kg) and 20% brine (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 a homogeneous solution at 45-55 ° C. The solution was cooled to 20-30 ° C., n-heptane (108.7 kg) was added dropwise, and after confirming the precipitation of crystals, the solution was stirred for 1 hour. The precipitated crystals were collected by filtration to give the title compound (7.98 kg, purity 99.2%) as white crystals.
The purity of the product is determined by high performance liquid chromatography (column: YMC-Triart C18 ExRS manufactured by YMC Co. and mobile phase: acetonitrile / pH 8 phosphate buffer = 3/7, flow rate: 1 mL / min, detection wavelength : 210 nm).
NMR spectrum (δ ppm, CDCl ₃ ): 6.16 (1 H, t, J = 5.6 Hz), 6.01 (1 H, t, J = 5.6 Hz), 3.67 (2 H, d, J = 6) .0 Hz), 2.97 (2 H, dt, J = 6.4, 6.4 Hz), 2.17 (2 H, t, J = 7.2 Hz), 1.56 (2 H, tt, J = 7. 2, 7.2 Hz), 1.39 (9 H, 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-oxocyclohexene S-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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid t- Synthesis of butyl:

3 (S), 3 '(S) -astaxanthin (1.8 kg), t-butyl 4- (3-carboxymethylureido) butyrate (compound of the above (3.2)) (2.75 kg), N, N-Dimethyl-4-aminopyridine (2.95 kg) and methylene chloride (71.6 kg) were added and stirred to give a solution. To the solution was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.63 kg) at -5 to 5 ° C, and 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, 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, and the organic layer was separated. The obtained solution was treated three times with hydrochloric acid (0.3 M, 46.4 kg), 10% saline (45.9 kg), aqueous sodium hydrogen carbonate solution (about 7%, 48.2 kg), 20% saline (45 kg) The extract was successively washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 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 / It was determined using 70-2, flow rate: 1 mL / min, detection wavelength: 474 nm).
NMR spectrum (δ ppm, CDCl ₃ ): 6.18-6.72 (14 H, m), 5.56 (2 H, dd, J = 6.4, 13.2 Hz), 5.04 (2 H, t, J = 4.8 Hz), 4.81 (2 H, t, 5.7 Hz), 4. 25 (2 H, dd, J = 18.1, 6.6 Hz), 4.03 (2 H, dd, J = 18. 3, 4.6 Hz), 3.19-3.26 (4 H, m), 2. 29 (4 H, t, J = 7.3 Hz), 2.02-2.13 (4 H, m), 99 (12H, s), 1.90 (3H, s), 1.76 to 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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid:

4- (3- {4- [18- (4 (S)-[3- (3-t-butoxycarbonylpropyl) ureidoacetoxy] -2,6,6-trimethyl-3-oxocyclohex-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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido t-butyl butyric acid (above (3) Formic acid (272 mL) was added to the compound of 3) (18.12 g) and 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, and the organic layer was separated. The organic layer was washed twice with water (543 mL), 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 precipitation of a solid was confirmed, followed by stirring 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 / It was determined using 70-2, flow rate: 1 mL / min, detection wavelength: 474 nm).

(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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid:

4- (3- {4 (S)-[18- (4- [3- (3-carboxypropyl) ureidoacetoxy] -2,6,6-trimethyl-3-oxocyclohex-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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid (crude form of (3.4) above) Tetrahydrofuran (18.4 mL) and water (2.0 mL) were added to substance (4.0 g), and the mixture was stirred and dissolved. Acetonitrile (60 mL) was added dropwise to the solution, and after confirming precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give a dark purple to dark red solid (3.31 g, purity 96.9%). To the obtained solid (3.26 g), tetrahydrofuran (15.0 mL) and water (1.6 mL) were added and stirred to dissolve. Acetonitrile (49 mL) was added dropwise to the solution, and after confirming precipitation of a solid, the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give a dark purple to dark red solid (2.93 g, purity 98.9%). To the obtained solid (2.38 g), tetrahydrofuran (10.9 mL) and water (1.2 mL) were added and stirred to dissolve. Acetonitrile (36 mL) was added dropwise to the solution, and after confirming 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 / It was determined using 70-2, flow rate: 1 mL / min, detection wavelength: 474 nm).

(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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid dilysine salt; Synthesis of X:
4- (3- {4 (S)-[18- (4- [3- (3-carboxypropyl) ureidoacetoxy] -2,6,6-trimethyl-3-oxocyclohex-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) -nonaenyl] -3,5,5-trimethyl-2-oxocyclohex-3-enyl-1 (S) -oxycarbonylmethyl} ureido) butyric acid (compound of the above (3.5)) To (0.50 g,), ethanol (10 mL) and water (0.5 mL) were added and stirred. To the suspension was added a solution of L-lysine monohydrate (0.174 g,) in water (2 mL) at room temperature. Water (7.5 mL) was added to the reaction mixture and stirred to dissolve. Ethanol (32 mL) was added dropwise to the reaction mixture at room temperature, and after confirming 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 using high performance liquid chromatography as described above. Optical purity is determined by high performance liquid chromatography (column: YMC, Inc. YMC CHIRAL ART Amylose SA (5 μm, 4.6 mm ID x 250 mm), column temperature: 25 ° C and mobile phase: THF / water / TFA (40:60) : 0.1), flow rate: 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.

Claims

A dry eye improver and / or a tear loss inhibitor comprising the trans-astaxanthin derivative represented by the formula (I), a geometric isomer thereof, a mixture of these geometric isomers, an optical isomer thereof or a salt thereof.

(Wherein, m 1 , m 2 , n 1 and n 2 are the same or different and each represents an integer of 1 to 6).
The dry eye improving agent and / or tear loss reduction 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 dry eye improving agent and / or the tear volume decrease inhibitor according to claim 1 or 2, wherein the salt is a lysine salt.
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, and a dry eye improving agent and / or an inhibitor of tear loss.

(Wherein, m 1 , m 2 , n 1 and n 2 are the same or different and mean an integer of 1 to 6).
The dry eye improving agent and / or tear loss reduction 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 dry eye improving agent and / or tear volume reduction according to claim 4 or 5, wherein the optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) and the salt thereof are substantially free. Inhibitor.
7. A dry eye improving agent and / or a tear loss reduction agent comprising a salt of the optically active trans-astaxanthin derivative according to any one of claims 4 to 6, wherein the salt is a lysine salt.
The trans-astaxanthin derivative according to any one of claims 1 to 7, its geometric isomer, a mixture of these geometric isomers, its optical isomer, or a salt thereof, for improving dry eye and / or tear fluid Pharmaceutical composition for suppressing amount reduction.