WO2019138995A1 - Dry eye remedy - Google Patents
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- WO2019138995A1 WO2019138995A1 PCT/JP2019/000192 JP2019000192W WO2019138995A1 WO 2019138995 A1 WO2019138995 A1 WO 2019138995A1 JP 2019000192 W JP2019000192 W JP 2019000192W WO 2019138995 A1 WO2019138995 A1 WO 2019138995A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- 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.
- tear secretion is governed by the parasympathetic nervous system (when relaxed), and a mechanism exists that decreases sympathetic dominance (during tension).
- tear secretion is governed by the parasympathetic nervous system (when relaxed), and a mechanism exists that decreases sympathetic dominance (during tension).
- Non-patent Document 1 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).
- 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.
- 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.
- trans-astaxanthin derivatives of the formula (I), their geometric isomers, and mixtures of these geometric isomers have been found.
- 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.
- the present invention provides the following inventions [1] to [5].
- n 1 , n 2 are the same or different and each represents an integer of 1 to 6).
- 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.
- 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.
- 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 pharmaceutical composition containing a salt is excellent as a dry eye improving agent and / or a tear volume reduction inhibitor.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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, tetrahydro
- 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.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid
- acetic 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
- 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.
- separation and purification means such as column chromatography, reprecipitation and crystallization.
- 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.
- the separated cis-form can be isolated and obtained by appropriately combining the purification and separation methods as described above.
- 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.
- (2A) A method for directly binding the entire side chain moiety to 3S, 3'S-astaxanthin
- 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.
- the solvent examples include organic solvents such as methylene chloride, chloroform and carbon tetrachloride.
- 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.
- the whole side chain part can be manufactured by the following method.
- 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).
- 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.
- a reagent such as a base in an inert solvent.
- 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) .
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- R means a protecting group (eg, tertiary butyl group or trimethylsilyl group).)
- 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).
- 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.
- 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.
- 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 can be administered as an eye drop, an eye ointment, an oral preparation or an injection.
- 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.
- pH adjusters include hydrochloric acid, sodium hydroxide, potassium hydroxide, triethanolamine and the like.
- sodium phosphate, sodium acetate, sodium borate, sodium citrate, sodium aspartate etc. can be mentioned, for example.
- 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.
- 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.
- sodium sulfite, sodium metasulfite, sodium citrate, sodium edetate, monoethanolamine, etc. can be mentioned, for example.
- the preservative examples 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
- 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.
- the administration method and dosage form may be selected appropriately.
- eye drops 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.
- the daily dose 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.
- 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.
- an appropriate amount of the ointment 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.
- tear secretion was used as an indicator of the pathological condition in this 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.
- PBS phosphate buffered saline
- 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).
- 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.
- 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.
- 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 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.
- 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.
- 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).
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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
本発明はアスタキサンチン誘導体を含有するドライアイ改善剤に関する。
The present invention relates to a dry eye improving agent containing an astaxanthin derivative.
ドライアイは、涙の乾きなど涙の異常により、目の表面の健康が損なわれる疾患である。涙の異常の背景は複雑であり、内科的疾患から起きるものや、角膜移植などの目の手術に伴うもの、服用している薬の副作用でも起きことがある。
一般的なドライアイは、環境要因が大きいと考えられている。現代社会は涙を乾かす要因に満ちており、パソコンやテレビ、ケータイ画面などのモニターを見続ける生活により、まばたきが減少して涙が乾きやすくなり、また室内の冷暖房などの空調により室内が乾燥しがちである。更に、涙の分泌は副交感神経(リラックスしたとき)に支配されており、交感神経優位(緊張時)には減少するメカニズムが存在する。このように、さまざまなストレスにより涙の分泌が抑制されているのではないかと考えられている。
加えて、コンタクトレンズの長期・長時間装用や、夜型の生活、食生活の変化、運動不足など、ライフスタイルの関与や加齢にともなう涙量の減少や安定性の低下なども指摘されている。 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.
一般的なドライアイは、環境要因が大きいと考えられている。現代社会は涙を乾かす要因に満ちており、パソコンやテレビ、ケータイ画面などのモニターを見続ける生活により、まばたきが減少して涙が乾きやすくなり、また室内の冷暖房などの空調により室内が乾燥しがちである。更に、涙の分泌は副交感神経(リラックスしたとき)に支配されており、交感神経優位(緊張時)には減少するメカニズムが存在する。このように、さまざまなストレスにより涙の分泌が抑制されているのではないかと考えられている。
加えて、コンタクトレンズの長期・長時間装用や、夜型の生活、食生活の変化、運動不足など、ライフスタイルの関与や加齢にともなう涙量の減少や安定性の低下なども指摘されている。 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.
ドライアイの治療薬としては、眼表面のムチンの分泌促進作用を有する薬剤ジアクホソルナトリウム点眼液やレバミピド点眼液が繁用されつつあるが、より十分な臨床効果を示す薬剤が望まれてきた。そんな中、最近新たな作用機作のドライアイ治療薬として期待されるlifitegrastが注目を浴びている。本剤は、ドライアイ症状のいくつかの主要評価項目を有意に改善した一方で改善効果を見出せなかった主要評価項目もある。このような状況から、より効果の優れたドライアイ治療薬が引続き望まれている(非特許文献1)。
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).
一方、アスタキサンチンは、優れた抗酸化活性を有し、光障害疾患領域、眼科疾患領域、皮膚科疾患領域、炎症性疾患領域、免疫疾患領域、心臓疾患領域、悪性腫瘍疾患領域、肝臓疾患領域、腎臓疾患領域、神経変性疾患領域、中毒性疾患領域、アレルギー性疾患領域、インスリン抵抗性疾患領域、糖尿病疾患領域、高脂血症疾患領域、心機能疾患領域、血管系疾患領域等に有用であることが知られている(非特許文献2及び3)。中でも、アスタキサンチンと同等以上の抗酸化活性を保持しつつ同化合物の水溶性及び経口吸収性を改善した化合物として下記式(I)の化合物が知られている(特許文献1)。
しかしながら、式(I)の化合物のドライアイに対する具体的効果の報告はなく、ましてや後述の涙液量低下抑制効果については、全く知られていない。 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.
しかしながら、式(I)の化合物のドライアイに対する具体的効果の報告はなく、ましてや後述の涙液量低下抑制効果については、全く知られていない。 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.
本発明の主な目的は、代表的ドライアイ治療薬lifitegrastに代替可能でそれと同等またはそれ以上のドライアイ改善効果を有するドライアイ改善剤を提供することにある。
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.
本発明者らは、ドライアイ改善のための治療薬として新たな治療薬を見出すべく鋭意検討した結果、式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩が、涙液量の低下に対する優れた抑制効果並びにドライアイに対し優れた改善効果を有することを見出し、本発明を完成した。
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.
すなわち、本発明は、次の発明〔1〕~〔5〕を提供するものである。
That is, the present invention provides the following inventions [1] to [5].
〔1〕式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を含有するドライアイ改善剤及び/または涙液量低下抑制剤。
[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.
(式中、m1、m2、n1およびn2は、それぞれ同じまたは異なって1~6の整数を意味する。)
(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〕前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を含有するドライアイ改善用及び/または涙液量低下抑制用医薬組成物。
〔3〕ドライアイ改善剤及び/または涙液量低下抑制剤製造のための、前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の使用。
〔4〕前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の有効量を投与することを特徴とするドライアイ改善及び/または涙液量低下抑制のための治療方法。
〔5〕ドライアイ改善及び/または涙液量低下抑制のための、前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それらの幾何異性体の混合物、それらの光学異性体またはそれらの塩。 [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.
〔3〕ドライアイ改善剤及び/または涙液量低下抑制剤製造のための、前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の使用。
〔4〕前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の有効量を投与することを特徴とするドライアイ改善及び/または涙液量低下抑制のための治療方法。
〔5〕ドライアイ改善及び/または涙液量低下抑制のための、前記式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それらの幾何異性体の混合物、それらの光学異性体またはそれらの塩。 [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.
本発明の式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は、ヒト、犬、猫、馬などの各種動物全般のドライアイや涙液量低下に対し優れた有効性を有するものであり、式(I)で示されるアスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を含有する医薬組成物はドライアイ改善剤及び/または涙液量低下抑制剤として優れたものである。
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.
本発明のドライアイ改善剤及び/または涙液量低下抑制剤は、前記式(I)で表されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を有効成分として含有する。
「ドライアイ改善」とは、端的には、眼の乾きを改善するという意味である。ドライアイは大きく分けて「涙の量の異常(涙液分泌減少型ドライアイ)」、「涙の質の異常(蒸発亢進型ドライアイ)」、「涙の安定性の異常(BUT短縮型ドライアイ)」に分類される。ドライアイの薬物療法の面では、各種検査をおこない、ドライアイのタイプにあわせた薬物の主には点眼治療薬を選択していく。基本的には、眼表面に分泌される涙液量の低下を抑制することが、主要な治療方法といえる。
本発明によって処置し得る対象には、ヒトを含む温血動物、たとえばイヌ、ネコ、ウマ、サル、ウサギ、ラットまたはマウスが含まれるが、これらに限定されない。 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.
「ドライアイ改善」とは、端的には、眼の乾きを改善するという意味である。ドライアイは大きく分けて「涙の量の異常(涙液分泌減少型ドライアイ)」、「涙の質の異常(蒸発亢進型ドライアイ)」、「涙の安定性の異常(BUT短縮型ドライアイ)」に分類される。ドライアイの薬物療法の面では、各種検査をおこない、ドライアイのタイプにあわせた薬物の主には点眼治療薬を選択していく。基本的には、眼表面に分泌される涙液量の低下を抑制することが、主要な治療方法といえる。
本発明によって処置し得る対象には、ヒトを含む温血動物、たとえばイヌ、ネコ、ウマ、サル、ウサギ、ラットまたはマウスが含まれるが、これらに限定されない。 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.
(式中、m1、m2、n1およびn2は、それぞれ同じまたは異なって1~6の整数を示す。)
(Wherein, m 1 , m 2 , n 1 and n 2 are the same or different and each represents an integer of 1 to 6)
式(I)の化合物の中では、m1およびm2がそれぞれ1の整数であり、n1およびn2がそれぞれ3の整数を示す場合が好ましい。
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.
式(I)にかかる化合物、その幾何異性体、それら幾何異性体の混合物およびそれらの光学異性体は、分子内にカルボキシル基を有することから望まれる塩基物質或いは塩基化合物と通常の塩形成反応をさせることにより薬学上許容される塩を形成することができる。そのような塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩;カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩;リシン塩、オルニチン塩、アルギニン塩のようなアミノ酸塩を挙げることができ、中でもリシン塩を好ましいものとして挙げることができる。
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.
式(I)の化学構造式において、アスタキサンチン基本骨格中の中鎖炭素鎖部分における二重結合部分は化学構造上トランスおよびシスの幾何異性体の構造を取り得る。本発明にかかる有効成分については、式(I)のトランス体のみならず、以下の式(Ia)や式(Ib)に代表されるシス体も本発明にかかるドライアイ改善剤の有効成分として挙げることができる。また、本発明のドライアイ改善剤については、式(I)のトランス体やその幾何異性体であるシス体の各種混合比での混合物も有効成分として含むものである。
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.
(式中、m1、m2、n1およびn2は、前記と同じ意味を有する。)
(Wherein, m 1 , m 2 , n 1 and n 2 have the same meaning as described above)
(式中、m1、m2、n1およびn2は、前記と同じ意味を有する。)
(Wherein, m 1 , m 2 , n 1 and n 2 have the same meaning as described above)
また、式(I)の化合物、その幾何異性体およびそれら幾何異性体の混合物は、以下に代表される光学異性体(IA)を包含し得るものであり、その対掌体やそれらの混合物、ジアステレオマーも全て本発明にかかるドライアイ改善剤及び/または涙液量低下抑制剤の有効成分として包含する。
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.
(式中、m1、m2、n1およびn2は、前記と同じ意味を有する。)
(Wherein, m 1 , m 2 , n 1 and n 2 have the same meaning as described above)
式(I)の化合物、その幾何異性体、それら幾何異性体の混合物およびそれらの光学異性体の中では、上記の式(IA)のトランス体の化合物が好ましい。
また、上記式(IA)のトランス体の化合物中でも、m1およびm2はそれぞれ1の整数を意味しn1およびn2はそれぞれ3の整数を意味する化合物が好ましい。 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.
また、上記式(IA)のトランス体の化合物中でも、m1およびm2はそれぞれ1の整数を意味しn1およびn2はそれぞれ3の整数を意味する化合物が好ましい。 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.
前記のように、式(IA)で示される光学活性トランス-アスタキサンチン誘導体またはその塩がより好ましく、さらに式(IA)で示される光学活性トランス-アスタキサンチン誘導体に対応する光学活性シス-アスタキサンチン誘導体およびその塩を実質的に含有しない高純度の光学活性トランス-アスタキサンチン誘導体またはその塩がさらに好ましい。ここで、本発明にかかるドライアイ改善剤及び/または涙液量低下抑制剤の有効成分を「高純度」で含有するとは、当該有効成分中の純度が少なくとも95%以上、好ましくは98%以上である場合をいう。
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.
本発明にかかる式(I)の化合物、その幾何異性体、それらの光学異性体およびそれらの塩は、国際公開第2015/178404号明細書に記載の製造方法や同方法と公知の方法を適宜組み合わせることにより製造することができる。それらの製造方法の中で、式(I)の化合物の幾何異性体、それらの光学異性体の製造方法について上記式(IA)の光学異性体の製造方法を代表として以下に説明する。
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) 脱保護反応
(1A) Deprotection reaction
(式中、m1、m2、n1およびn2は、前記と同じ意味を有し、Rは保護基を意味する。)
(Wherein, m 1 , m 2 , n 1 and n 2 have the same meanings as described above, and R means a protecting group)
原料化合物である式(II)の化合物の保護基を脱離することにより、目的とする式(IA)の光学活性のトランス-アスタキサンチン誘導体を製造することができる。
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.
当該脱離反応は、保護基の通常の脱離反応が使用でき、具体的には、酸による脱離反応をあげることができる。
保護基としては、第三級ブチル基、トリメチルシリル基、テトラヒドロピラニル基等をあげることができ、好適なものとしては第三級ブチル基、トリメチルシリル基等をあげることができる。 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.
保護基としては、第三級ブチル基、トリメチルシリル基、テトラヒドロピラニル基等をあげることができ、好適なものとしては第三級ブチル基、トリメチルシリル基等をあげることができる。 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.
酸による脱離反応の場合には、式(II)の化合物を不活性な溶媒中、酸を加え反応させることにより、目的とする式(IA)の化合物を製造することができる。
使用される溶媒は、本反応に不活性なものであれば特に限定はなく、例えば、ヘキサン、ヘプタン、リグロイン、石油エーテルのような脂肪族炭化水素類;ベンゼン、トルエン、キシレンのような芳香族炭化水素類;クロロホルム、塩化メチレン、1,2-ジクロロエタン、四塩化炭素のようなハロゲン化炭化水素類;アセトニトリル、プロピオニトリルのようなニトリル類;ギ酸エチル、ギ酸イソプロピル、ギ酸イソブチル、酢酸エチル、酢酸イソブチル、酢酸ブチルのような有機酸エステル類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルのようなエーテル類;ジメチルホルムアミド、ジメチルアセトアミド、ヘキサメチルリン酸トリアミドのようなアミド類;メタノール、エタノール、プロパノール、イソプロパノールのようなアルコール類;トリフルオロ酢酸、ギ酸、酢酸、プロピオン酸のような有機酸類;水;またはこれらの溶媒の混合溶媒をあげることでき、好適には、ハロゲン化炭化水素類、ニトリル類、エーテル類、アルコール類、有機酸類、アミド類、水、またはこれらの溶媒の混合溶媒であり、更に好適には、ハロゲン化炭化水素類、ニトリル類、アルコール類、有機酸類、エーテル類、水またはこれらの溶媒の混合溶媒であり、最も好適には、ハロゲン化炭化水素類、アセトニトリル、水、メタノール、エタノール、イソプロパノール、ギ酸、ジオキサン、テトラヒドロフラン、または水とこれらの有機溶媒の混合溶媒(保護基がC1-C6アルキル基である場合)をあげることができる。
使用され得る酸は、通常の反応において、酸として使用されるものであれば特に限定はなく、例えば、塩酸、臭化水素酸、硫酸、過塩素酸、燐酸のような無機酸;酢酸、ギ酸、蓚酸、メタンスルホン酸、p-トルエンスルホン酸、カンファースルホン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸のような有機酸;塩化亜鉛、四塩化スズ、ボロントリクロリド、ボロントリフルオリド、ボロントリブロミドのようなルイス酸;または酸性イオン交換樹脂であり得、好適には、無機酸または有機酸であり、最も好適には、塩酸、酢酸、ギ酸およびトリフルオロ酢酸をあげることができる。
反応温度は、反応させる原料化合物や使用する酸、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、0℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、通常式(II)の化合物の使用重量に対し10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。酸の使用量は、原料である式(II)の化合物に対し、無機酸であれば、通常5倍乃至50倍モル量、好適には10倍乃至30倍モル量使用すればよく、有機酸であれば、通常100倍乃至1000倍モル量、好適には200倍乃至600倍モル量使用すればよい。 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.
使用される溶媒は、本反応に不活性なものであれば特に限定はなく、例えば、ヘキサン、ヘプタン、リグロイン、石油エーテルのような脂肪族炭化水素類;ベンゼン、トルエン、キシレンのような芳香族炭化水素類;クロロホルム、塩化メチレン、1,2-ジクロロエタン、四塩化炭素のようなハロゲン化炭化水素類;アセトニトリル、プロピオニトリルのようなニトリル類;ギ酸エチル、ギ酸イソプロピル、ギ酸イソブチル、酢酸エチル、酢酸イソブチル、酢酸ブチルのような有機酸エステル類;ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルのようなエーテル類;ジメチルホルムアミド、ジメチルアセトアミド、ヘキサメチルリン酸トリアミドのようなアミド類;メタノール、エタノール、プロパノール、イソプロパノールのようなアルコール類;トリフルオロ酢酸、ギ酸、酢酸、プロピオン酸のような有機酸類;水;またはこれらの溶媒の混合溶媒をあげることでき、好適には、ハロゲン化炭化水素類、ニトリル類、エーテル類、アルコール類、有機酸類、アミド類、水、またはこれらの溶媒の混合溶媒であり、更に好適には、ハロゲン化炭化水素類、ニトリル類、アルコール類、有機酸類、エーテル類、水またはこれらの溶媒の混合溶媒であり、最も好適には、ハロゲン化炭化水素類、アセトニトリル、水、メタノール、エタノール、イソプロパノール、ギ酸、ジオキサン、テトラヒドロフラン、または水とこれらの有機溶媒の混合溶媒(保護基がC1-C6アルキル基である場合)をあげることができる。
使用され得る酸は、通常の反応において、酸として使用されるものであれば特に限定はなく、例えば、塩酸、臭化水素酸、硫酸、過塩素酸、燐酸のような無機酸;酢酸、ギ酸、蓚酸、メタンスルホン酸、p-トルエンスルホン酸、カンファースルホン酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸のような有機酸;塩化亜鉛、四塩化スズ、ボロントリクロリド、ボロントリフルオリド、ボロントリブロミドのようなルイス酸;または酸性イオン交換樹脂であり得、好適には、無機酸または有機酸であり、最も好適には、塩酸、酢酸、ギ酸およびトリフルオロ酢酸をあげることができる。
反応温度は、反応させる原料化合物や使用する酸、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、0℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、通常式(II)の化合物の使用重量に対し10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。酸の使用量は、原料である式(II)の化合物に対し、無機酸であれば、通常5倍乃至50倍モル量、好適には10倍乃至30倍モル量使用すればよく、有機酸であれば、通常100倍乃至1000倍モル量、好適には200倍乃至600倍モル量使用すればよい。 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.
以上の脱保護反応により得られる生成物は、前記の9-シス体や13-シス体等の幾何異性体を含有し得るので、カラムクロマトグラフィー、再沈殿や結晶化等の分離、精製手段を目的に応じて適宜組み合わせることにより、同幾何異性体を分離、除去し、目的とする式(IA)の光学活性のトランス-アスタキサンチン誘導体を高純度で単離、製造することができる。
また、分離した前記シス体は、上記の如き精製、分離方法を適宜組み合わせることにより単離取得することができる。 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.
また、分離した前記シス体は、上記の如き精製、分離方法を適宜組み合わせることにより単離取得することができる。 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) シス体からトランス体への変換方法
(1B) Method of converting cis form to trans form
(式中、m1、m2、n1およびn2は、前記と同じ意味を有する。)
(Wherein, m 1 , m 2 , n 1 and n 2 have the same meaning as described above)
本製造法で使用される代表的シス体は上記のごとき式(IAa)および(IAb)の化合物であり、これらは、単独の原料化合物として、或いはシス体の混合物として、或いはシス体を過剰に含むトランス体との混合物として不活性な溶媒に溶解後、ヨウ素等の転換試薬を用いて反応させることにより目的とする式(IA)の高純度の光学活性トランス-アスタキサンチン誘導体を製造することができる。
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. .
使用される溶媒は、本反応に不活性なものであれば特に限定はされず、例えばテトラヒドロフラン、酢酸エチル、アセトニトリル、アセトン、水等をあげることができる。
上記転換試薬として好適に使用されるものしては、ヨウ素をあげることができる。
反応温度は、反応させる原料化合物や使用する転換試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、通常式(IAa)または式(IAb)の化合物の使用重量に対し通常10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。転換試薬の使用量は、原料である式(IAa)または式(IAb)の化合物に対し通常0.01倍モル量以上、好適には0.1倍モル量以上使用すればよい。 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.
上記転換試薬として好適に使用されるものしては、ヨウ素をあげることができる。
反応温度は、反応させる原料化合物や使用する転換試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、通常式(IAa)または式(IAb)の化合物の使用重量に対し通常10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。転換試薬の使用量は、原料である式(IAa)または式(IAb)の化合物に対し通常0.01倍モル量以上、好適には0.1倍モル量以上使用すればよい。 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.
以上の転換反応により得られる生成物において、前記9-シス体や13-シス体等の幾何異性体を分離する方法としては、カラムクロマトグラフィー、再沈殿や結晶化等の方法をあげることができ、目的に応じてこれらの方法を適宜組み合わせることにより、同幾何異性体を分離し、目的とする式(IA)の光学活性のトランス-アスタキサンチン誘導体を高純度で単離、製造することができる。
また、分離されたシス体も上記の分離手段を適宜組み合わせて用いることにより、夫々のシス体として単離、製造することができる。 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.
また、分離されたシス体も上記の分離手段を適宜組み合わせて用いることにより、夫々のシス体として単離、製造することができる。 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.
次に上記の原料化合物(II)の代表的製造方法を以下に説明する。
Next, a typical production method of the above starting compound (II) will be described below.
(2A) 3S,3’S-アスタキサンチンに側鎖部分全体を直接結合させる方法
(2A) A method for directly binding the entire side chain moiety to 3S, 3'S-astaxanthin
(式中、m1およびn1は、前記と同じ意味を有し、Rは保護基(例えば、第三級ブチル基)を意味する。)
(Wherein, m 1 and n 1 have the same meaning as described above, and R means a protecting group (eg, tertiary butyl group).)
3S,3’S-アスタキサンチンを不活性な溶媒に溶解後、縮合試薬存在下、式(I)の化合物における側鎖部分にあたる式(III)の化合物を反応させることにより、式(II)の化合物を製造することができる。
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.
溶媒としては、塩化メチレン、クロロホルム、四塩化炭素等の有機溶媒をあげることができる。
縮合試薬としては、通常の縮合反応に使用されるものを使用することができ、具体例としては水溶性カルボジイミド塩酸塩(例えば、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩)、N,N-ジイソプロピルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド等をあげることができる。縮合試薬の使用量は、原料である3S,3’S-アスタキサンチンに対し通常2倍モル量以上、好適には2.5倍モル量~20倍モル量使用すればよい。
側鎖部分にあたる式(III)の化合物については、3S,3’S-アスタキサンチンに対し通常2倍モル量以上、好適には2.5倍モル~20倍モル量使用すればよい。
反応温度は、反応させる原料化合物や使用する縮合試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、-10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、3S,3’S-アスタキサンチンの使用重量に対し通常10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。 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.
縮合試薬としては、通常の縮合反応に使用されるものを使用することができ、具体例としては水溶性カルボジイミド塩酸塩(例えば、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩)、N,N-ジイソプロピルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド等をあげることができる。縮合試薬の使用量は、原料である3S,3’S-アスタキサンチンに対し通常2倍モル量以上、好適には2.5倍モル量~20倍モル量使用すればよい。
側鎖部分にあたる式(III)の化合物については、3S,3’S-アスタキサンチンに対し通常2倍モル量以上、好適には2.5倍モル~20倍モル量使用すればよい。
反応温度は、反応させる原料化合物や使用する縮合試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、-10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間である。溶媒の使用量は、3S,3’S-アスタキサンチンの使用重量に対し通常10倍乃至50倍容量を使用すればよく、好適には30倍容量使用すればよい。 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.
得られる式(II)の化合物は、通常、カラムクロマトグラフィー、再沈殿、再結晶等の精製手段を適宜組み合わせることにより精製、単離することができる。
なお、側鎖部分全体は、以下の方法により製造することができる。 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.
なお、側鎖部分全体は、以下の方法により製造することができる。 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)
(2A-1)
(式中、m1、およびn1は、前記と同じ意味を有し、Rは保護基(例えば、第三級ブチル基)を意味する。)
(Wherein, m 1 and n 1 have the same meaning as described above, and R means a protecting group (eg, a tertiary butyl group).)
式(IV)の化合物にカルボニルジイミダゾール(V)および式(VII)の化合物を順次反応することにより目的とする式(III)の化合物を製造することができる。
具体的には、式(IV)の化合物を不活性な溶媒中、カルボニルジイミダゾール(V)を塩基等の試薬の存在下或いは非存在下反応させることにより、中間物である式(VI)の化合物を得ることができる。さらに、式(VII)の化合物を塩基等の試薬の存在下トリメチルシリルクロリドと反応させ、次いで式(VI)の化合物と反応させることにより、目的とする式(III)の化合物を製造することができる。 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) .
具体的には、式(IV)の化合物を不活性な溶媒中、カルボニルジイミダゾール(V)を塩基等の試薬の存在下或いは非存在下反応させることにより、中間物である式(VI)の化合物を得ることができる。さらに、式(VII)の化合物を塩基等の試薬の存在下トリメチルシリルクロリドと反応させ、次いで式(VI)の化合物と反応させることにより、目的とする式(III)の化合物を製造することができる。 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) .
式(VI)の化合物を得る工程では、溶媒としては、クロロホルム、塩化メチレン等の有機溶媒をあげることができ、これら有機溶媒の使用量は式(IV)の化合物の使用重量に対し通常5倍乃至30倍容量、好適には15倍容量を使用すればよい。
塩基試薬としては、通常の縮合反応に使用されるものを使用することができ、具体例としては、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、0℃乃至30℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、15分間乃至10日間であり、好適には、30分間乃至2日間をあげることができる。
目的とする式(III)の化合物を得る工程では、トリメチルシリルクロリドと式(VII)の化合物を反応させる溶媒としては、クロロホルム、塩化メチレン、ピリジン等の有機溶媒をあげることができ、これら有機溶媒の使用量は式(VII)の化合物の使用重量に対し通常5倍乃至50倍容量、好適には20倍容量を使用すればよい。
塩基としては、通常の縮合反応に使用されるものを使用することができ、具体例としては、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。塩基、試薬の使用量は、原料である式(VI)の化合物に対し通常2倍モル以上、好適には2.5倍モル乃至5.0倍モル使用すればよい。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至100℃であり、好適には、0℃乃至30℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、15分間乃至5日間であり、好適には、30分間乃至2日間をあげることができる。次いで式(VI)の化合物を加え、反応させるときの反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、10℃乃至60℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至4日間をあげることができる。 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.
塩基試薬としては、通常の縮合反応に使用されるものを使用することができ、具体例としては、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、0℃乃至30℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、15分間乃至10日間であり、好適には、30分間乃至2日間をあげることができる。
目的とする式(III)の化合物を得る工程では、トリメチルシリルクロリドと式(VII)の化合物を反応させる溶媒としては、クロロホルム、塩化メチレン、ピリジン等の有機溶媒をあげることができ、これら有機溶媒の使用量は式(VII)の化合物の使用重量に対し通常5倍乃至50倍容量、好適には20倍容量を使用すればよい。
塩基としては、通常の縮合反応に使用されるものを使用することができ、具体例としては、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。塩基、試薬の使用量は、原料である式(VI)の化合物に対し通常2倍モル以上、好適には2.5倍モル乃至5.0倍モル使用すればよい。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至100℃であり、好適には、0℃乃至30℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、15分間乃至5日間であり、好適には、30分間乃至2日間をあげることができる。次いで式(VI)の化合物を加え、反応させるときの反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、10℃乃至60℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至4日間をあげることができる。 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) 3S,3’S-アスタキサンチンに側鎖部分のパーツを順次結合させる方法
(2B) Method of sequentially bonding parts of side chain portion to 3S, 3'S-astaxanthin
(式中、m1、m2、n1およびn2は、前記と同じ意味を有し、Rは保護基(例えば、第三級ブチル基或いはトリメチルシリル基)を意味する。)
(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).)
本製造方法については、基本、一般式(VII)で示される化合物とカルボニルジイミダゾール(V)を反応させて得られる側鎖部分のパーツ(VIII)を3S,3’S-アスタキサンチンに結合させ、次に、得られた生成物(IX)に側鎖部分のパーツ(XI)を結合させることにより達成できる。
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).
カルボニルジイミダゾール(V)を使用した工程では上記(2A-1)の製造法に示した各種反応条件を同様に使用すればよい。
溶媒としては、クロロホルム、塩化メチレン等の有機溶媒をあげることができ、これら有機溶媒の使用量は式(VII)の化合物の使用重量に対し通常2倍乃至30倍容量を使用すればよく、好適には7倍容量使用すればよい。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、-10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間をあげることができる。塩基はトリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。
得られる側鎖部分のパーツ(VIII)と3S,3’S-アスタキサンチンとの結合反応については、上記の2Aの反応と同様に反応させることにより、式(IX)の化合物を製造することができる。 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. .
溶媒としては、クロロホルム、塩化メチレン等の有機溶媒をあげることができ、これら有機溶媒の使用量は式(VII)の化合物の使用重量に対し通常2倍乃至30倍容量を使用すればよく、好適には7倍容量使用すればよい。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至150℃であり、好適には、-10℃乃至100℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至5日間をあげることができる。塩基はトリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン、N,N-ジメチルアミノピリジン等をあげることができる。
得られる側鎖部分のパーツ(VIII)と3S,3’S-アスタキサンチンとの結合反応については、上記の2Aの反応と同様に反応させることにより、式(IX)の化合物を製造することができる。 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. .
目的とする一般式(II)を得る工程は、上記で得られた一般式(IX)を有する化合物に一般式(XI)を反応させることにより達成できる。本反応は上記一般式(VIII)を製造する方法に準じて行われる。
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至100℃であり、好適には、0℃乃至40℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至30時間をあげることができる。
なお、一般式(XI)を有する化合物を製造する方法は、(1)Rがt―ブチル基の場合は一般的に知られたアミノ酸のt-ブチルエステルを合成する方法に準じて達成でき、(2)Rがトリメチルシリル基の場合は、一般式(X)を有する化合物とトリメチルシリルクロリドを不活性溶媒中、塩基の存在下に反応させることにより達成できる(前記一般式(III)の化合物を作る方法に準じて達成できる)。(2)の反応は一般的に知られたヒドロキシル基やカルボキシル基をシリル化する方法に準じて達成できる。なお、一般式(XI)におけるRがトリメチルシリル基の場合は一般式(II)を生成する反応の後処理に水或いは弱酸性水を使用することにより、トリメチルシリル基を容易に脱離させることが出来る。 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). .
反応温度は、反応させる原料化合物や使用する試薬、溶媒等により異なるが、通常、-20℃乃至100℃であり、好適には、0℃乃至40℃である。反応時間は、原料化合物、溶媒、反応温度等により異なるが、通常、30分間乃至10日間であり、好適には、30分間乃至30時間をあげることができる。
なお、一般式(XI)を有する化合物を製造する方法は、(1)Rがt―ブチル基の場合は一般的に知られたアミノ酸のt-ブチルエステルを合成する方法に準じて達成でき、(2)Rがトリメチルシリル基の場合は、一般式(X)を有する化合物とトリメチルシリルクロリドを不活性溶媒中、塩基の存在下に反応させることにより達成できる(前記一般式(III)の化合物を作る方法に準じて達成できる)。(2)の反応は一般的に知られたヒドロキシル基やカルボキシル基をシリル化する方法に準じて達成できる。なお、一般式(XI)におけるRがトリメチルシリル基の場合は一般式(II)を生成する反応の後処理に水或いは弱酸性水を使用することにより、トリメチルシリル基を容易に脱離させることが出来る。 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). .
得られた生成物を、通常のカラムクロマトグラフィー、再沈殿、再結晶等の精製手段を適宜組わせて使用することにより、目的とする式(II)の化合物を製造することができる。
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.
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は、点眼剤、眼軟膏、経口剤または注射剤として投与可能であり、経口剤としては、錠剤等の固形製剤やドリンク剤を挙げることができる。
ドリンク剤、点眼剤及び注射剤などの液剤は、有効成分を必要に応じてpH調製剤、緩衝剤、溶解剤、懸濁剤等、等張化剤、安定化剤、防腐剤などの存在下、通常の製剤化技術を使用して製造すればよい。pH調製剤としては、例えば、塩酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミンなどを挙げることができる。緩衝材としては、例えば、リン酸ナトリウム、酢酸ナトリウム、ホウ酸ナトリウム、クエン酸ナトリウム、アスパラギン酸ナトリウムなどを挙げることができる。懸濁剤としては、例えば、ポリソルベート80、メチルセルロース、ヒドロキシエチルセルロース、ナトリウムカルボキシルメチルセルロース、ポリオキシエチレンソルビタンモノラウレート、アラビアガム、粉末トラガント、ポリビニルピロリドン、モノステアリン酸グリセリンなどを挙げることができる。溶解剤としては、例えば、ポリソルベート80、水添ポリオキシエチレンヒマシ油、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、ヒマシ油脂肪酸エチルエステル、ワセリン、グリセリン、プロピレングリコールなどを挙げることができる。安定化剤としては、例えば亜硫酸ナトリウム、メタ亜硫酸ナトリウム、クエン酸ナトリウム、エデト酸ナトリウム、モノエタノールアミンなどを挙げることができる。防腐剤としては、例えば、p-ヒドロキシ安息香酸メチル、p-ヒドロキシ安息香酸エチル、安息香酸ナトリウム、ソルビン酸、フェノール、クレゾール、クロロクレゾール、塩化ベンザルコニウム、パラベンなどを挙げることができる。
固形の経口剤については錠剤、カプセル剤、顆粒剤、散剤等いずれの形態で投与されてもよく、有効成分を、薬学的に許容される賦形剤、崩壊剤、結合剤等の医薬添加剤と適宜混合し、通常の製剤化技術を用いることにより製造することができる。
眼軟膏については、有効成分を白色ワセリン、流動パラフィン等の汎用される軟膏基剤と組み合わせて通常の製剤化技術を用いることにより製造することができる。 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.
ドリンク剤、点眼剤及び注射剤などの液剤は、有効成分を必要に応じてpH調製剤、緩衝剤、溶解剤、懸濁剤等、等張化剤、安定化剤、防腐剤などの存在下、通常の製剤化技術を使用して製造すればよい。pH調製剤としては、例えば、塩酸、水酸化ナトリウム、水酸化カリウム、トリエタノールアミンなどを挙げることができる。緩衝材としては、例えば、リン酸ナトリウム、酢酸ナトリウム、ホウ酸ナトリウム、クエン酸ナトリウム、アスパラギン酸ナトリウムなどを挙げることができる。懸濁剤としては、例えば、ポリソルベート80、メチルセルロース、ヒドロキシエチルセルロース、ナトリウムカルボキシルメチルセルロース、ポリオキシエチレンソルビタンモノラウレート、アラビアガム、粉末トラガント、ポリビニルピロリドン、モノステアリン酸グリセリンなどを挙げることができる。溶解剤としては、例えば、ポリソルベート80、水添ポリオキシエチレンヒマシ油、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、ヒマシ油脂肪酸エチルエステル、ワセリン、グリセリン、プロピレングリコールなどを挙げることができる。安定化剤としては、例えば亜硫酸ナトリウム、メタ亜硫酸ナトリウム、クエン酸ナトリウム、エデト酸ナトリウム、モノエタノールアミンなどを挙げることができる。防腐剤としては、例えば、p-ヒドロキシ安息香酸メチル、p-ヒドロキシ安息香酸エチル、安息香酸ナトリウム、ソルビン酸、フェノール、クレゾール、クロロクレゾール、塩化ベンザルコニウム、パラベンなどを挙げることができる。
固形の経口剤については錠剤、カプセル剤、顆粒剤、散剤等いずれの形態で投与されてもよく、有効成分を、薬学的に許容される賦形剤、崩壊剤、結合剤等の医薬添加剤と適宜混合し、通常の製剤化技術を用いることにより製造することができる。
眼軟膏については、有効成分を白色ワセリン、流動パラフィン等の汎用される軟膏基剤と組み合わせて通常の製剤化技術を用いることにより製造することができる。 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.
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を投与する場合には、症状、患者の年齢、体重、性別もしくは一般的な健康状態に応じて、投与方法及び投与製剤を適宜選択すればよい。例えば点眼剤として投与する場合には、片眼として0.0001%~4%の濃度の点眼液を1日1回~10回点眼、より好ましくは、0.01%~1%の濃度の点眼液を1日2回~4回点眼すればよい。また、体重約70kgの温血動物に経口投与するときは、1日当たり0.01~500mg、好ましくは1~100mg、より好ましくは5~20mgを1日1回またはそれ以上、例えば、1~6回で投与すればよい。また、注射剤として投与する場合には、通常成人に対し1日あたり5.0~80.0mgを静脈内に投与すればよく、症状に応じて適宜増減すればよい。
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の好ましい投与方法としては、点眼投与をあげることができ、この場合には、症状に応じて数滴を点眼すればよい。さらに、眼軟膏として投与する場合には、軟膏の適量を眼の粘膜表面に塗布すればよい。
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は、上記の投与量の範囲においては、安全性においても特に問題はない。 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.
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩の好ましい投与方法としては、点眼投与をあげることができ、この場合には、症状に応じて数滴を点眼すればよい。さらに、眼軟膏として投与する場合には、軟膏の適量を眼の粘膜表面に塗布すればよい。
本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は、上記の投与量の範囲においては、安全性においても特に問題はない。 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.
以下、本発明の実施例について説明する。
ただし、本発明の範囲は下記実施例に何ら限定されるものではない。 Hereinafter, examples of the present invention will be described.
However, the scope of the present invention is not limited to the following examples.
ただし、本発明の範囲は下記実施例に何ら限定されるものではない。 Hereinafter, examples of the present invention will be described.
However, the scope of the present invention is not limited to the following examples.
(1)モデル作製
当試験ではラットの眼窩外涙腺摘出モデルを用いた。このモデルでは涙腺の摘出により涙液量減少型のドライアイ症状を示す(非特許文献1)。なお、一般的に眼窩外涙腺以外にクラウゼ腺やウォルフリング腺などの副涙腺やあるいはマイボーム腺(ハーダー腺)や杯細胞など残存した腺組織も涙液分泌に関与する。眼窩外涙腺やこれらから分泌される水分、油分、ムチンなどが涙液層の安定化に寄与し角膜を保護しているが、ドライアイでは涙液量の減少による涙液層の不安定化が認められる。従って当試験では涙液分泌量を病態の指標とした。試験として、雄性SDラットに3種混合麻酔剤(メデトミジン+ミダゾラム+ブトルファノール;0.15+2.0+2.5mg/kg)を腹腔内投与して麻酔を行った。眼周辺の術部を消毒し、耳の下方約7mmの箇所を約7mm切開、両側の眼窩外涙腺を摘出した。その後切開部の皮膚を縫合し、抗生物質(エンロフロキサシン、5mg/kg、s.c.)及び鎮痛剤(カルプロフェン、5mg/kg、s.c.)を投与した。なお、抗生物質と鎮痛剤の処置は、手術日を含めて3日間実施した。涙腺摘出手術実施日をDay 0とし、涙液量(Day 12に評価)、体重(Day 13に測定)及びフルオレセイン角膜染色スコア(Day 13に評価)を基に、群間に偏りが生じないよう5群への群分けを実施した。
(2)点眼液調製および投与
上記式(IA)において「m1およびm2はそれぞれ1の整数、n1およびn2はそれぞれ3の整数」の光学活性トランスーアスタキサンチン誘導体のリシン塩(純度97.6%)を代表化合物として被験物質(化合物X)に使用した。化合物Xは後述する製造例の記載に従い製造した。
点眼剤として、以下表1に示す濃度になるように化合物Xをリン酸緩衝生理食塩液(PBS、サーモフィッシャーサイエンティフィック株式会社製造)で調整した。点眼処置は涙腺摘出の2週間後から、以下項で示すごとく点眼を開始した。点眼の溶媒対象群としてリン酸緩衝生理食塩液を陽性対象として、市販のLifitegrast 5.0%溶液(商品名 Xiidra点眼剤、Shire US Inc.)を用いた。点眼は1日4回(化合物Xおよび生理食塩水)ないし陽性対照の点眼回数は薬剤の添付文書に従い2回を合計36日間(Day 14~Day 49)実施した。
(3)涙液量の評価
Day 12(点眼開始前)、及びDay 20(点眼1週間)、Day 27(点眼2週間)、Day 34(点眼3週間)、Day 41(点眼4週間)Day 48(点眼5週間)の初回点眼の約30分後に涙液量の測定を行った。
ラットの涙液量の評価は、シルマー法に依った。具体的にはシルメル試験紙(あゆみ製薬株式会社)を用い、覚醒下でラットの下眼瞼の結膜嚢に1mm幅に裁断したシルメル試験紙の先端を挿入し、角形オープンフィールド(87×65cm、壁高25cm)に放った。挿入から1分後に試験紙を抜き取り、直ちに濡れた部分の長さを、定規を用いて0.5mm単位で読み取り、その数値を涙液量とした。測定中の1分間の間にシルメル試験紙が眼から脱落した場合は、直ちに新たな試験紙を用いて再測定を行った。 (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.
当試験ではラットの眼窩外涙腺摘出モデルを用いた。このモデルでは涙腺の摘出により涙液量減少型のドライアイ症状を示す(非特許文献1)。なお、一般的に眼窩外涙腺以外にクラウゼ腺やウォルフリング腺などの副涙腺やあるいはマイボーム腺(ハーダー腺)や杯細胞など残存した腺組織も涙液分泌に関与する。眼窩外涙腺やこれらから分泌される水分、油分、ムチンなどが涙液層の安定化に寄与し角膜を保護しているが、ドライアイでは涙液量の減少による涙液層の不安定化が認められる。従って当試験では涙液分泌量を病態の指標とした。試験として、雄性SDラットに3種混合麻酔剤(メデトミジン+ミダゾラム+ブトルファノール;0.15+2.0+2.5mg/kg)を腹腔内投与して麻酔を行った。眼周辺の術部を消毒し、耳の下方約7mmの箇所を約7mm切開、両側の眼窩外涙腺を摘出した。その後切開部の皮膚を縫合し、抗生物質(エンロフロキサシン、5mg/kg、s.c.)及び鎮痛剤(カルプロフェン、5mg/kg、s.c.)を投与した。なお、抗生物質と鎮痛剤の処置は、手術日を含めて3日間実施した。涙腺摘出手術実施日をDay 0とし、涙液量(Day 12に評価)、体重(Day 13に測定)及びフルオレセイン角膜染色スコア(Day 13に評価)を基に、群間に偏りが生じないよう5群への群分けを実施した。
(2)点眼液調製および投与
上記式(IA)において「m1およびm2はそれぞれ1の整数、n1およびn2はそれぞれ3の整数」の光学活性トランスーアスタキサンチン誘導体のリシン塩(純度97.6%)を代表化合物として被験物質(化合物X)に使用した。化合物Xは後述する製造例の記載に従い製造した。
点眼剤として、以下表1に示す濃度になるように化合物Xをリン酸緩衝生理食塩液(PBS、サーモフィッシャーサイエンティフィック株式会社製造)で調整した。点眼処置は涙腺摘出の2週間後から、以下項で示すごとく点眼を開始した。点眼の溶媒対象群としてリン酸緩衝生理食塩液を陽性対象として、市販のLifitegrast 5.0%溶液(商品名 Xiidra点眼剤、Shire US Inc.)を用いた。点眼は1日4回(化合物Xおよび生理食塩水)ないし陽性対照の点眼回数は薬剤の添付文書に従い2回を合計36日間(Day 14~Day 49)実施した。
(3)涙液量の評価
Day 12(点眼開始前)、及びDay 20(点眼1週間)、Day 27(点眼2週間)、Day 34(点眼3週間)、Day 41(点眼4週間)Day 48(点眼5週間)の初回点眼の約30分後に涙液量の測定を行った。
ラットの涙液量の評価は、シルマー法に依った。具体的にはシルメル試験紙(あゆみ製薬株式会社)を用い、覚醒下でラットの下眼瞼の結膜嚢に1mm幅に裁断したシルメル試験紙の先端を挿入し、角形オープンフィールド(87×65cm、壁高25cm)に放った。挿入から1分後に試験紙を抜き取り、直ちに濡れた部分の長さを、定規を用いて0.5mm単位で読み取り、その数値を涙液量とした。測定中の1分間の間にシルメル試験紙が眼から脱落した場合は、直ちに新たな試験紙を用いて再測定を行った。 (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)結果
結果を以下表2および図1に示す。 (4) Results The results are shown in Table 2 and FIG. 1 below.
結果を以下表2および図1に示す。 (4) Results The results are shown in Table 2 and FIG. 1 below.
各データは測定平均値±標準誤差を示した。溶媒対象群のG1は群分け時と比較し試験期間何れも涙液量の低下が認められた。化合物Xは何れの濃度も溶媒対象群と比較し、涙液分泌量が高値を示した。また、陽性対照群のLifitegrast5%も溶媒対象群と比較し、涙液量は高値を示したが、点眼5週目(day 48)では、涙液量の低下が認められ、溶媒対照群と同等の涙液分泌量を示した。
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)まとめ
以上の結果により、眼窩外涙腺摘出モデルにおいて対照薬であるLifitegrast及び本発明に関わる化合物Xともに涙液量の低下の抑制効果を示し、且つ化合物XはLifitegrastと同等以上の効果を有することが確認された。
従って、本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は優れた涙液量の低下抑制効果、即ちドライアイ改善効果を有することが確認された。 (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
以上の結果により、眼窩外涙腺摘出モデルにおいて対照薬であるLifitegrast及び本発明に関わる化合物Xともに涙液量の低下の抑制効果を示し、且つ化合物XはLifitegrastと同等以上の効果を有することが確認された。
従って、本発明に係る式(I)の化合物、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩は優れた涙液量の低下抑制効果、即ちドライアイ改善効果を有することが確認された。 (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
<化合物Xの製造例>
以下の記載における化学構造式中のアスタキサンチン骨格中鎖炭素鎖部分における幾何異性体は便宜的に全トランス体の化学構造式で示す。 <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.
以下の記載における化学構造式中のアスタキサンチン骨格中鎖炭素鎖部分における幾何異性体は便宜的に全トランス体の化学構造式で示す。 <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)4-(イミダゾール-1-イルカルボニルアミノ)酪酸t-ブチル(本化学名中、tは第三級を意味する。以下、同様とする。)の合成:
(3.1) Synthesis of t-butyl 4- (imidazol-1-ylcarbonylamino) butyrate (in this chemical name, t means tertiary, hereinafter the same shall apply):
カルボニルジイミダゾール(9.95kg)に塩化メチレン(79.6kg)を加えて、撹拌し、4-アミノ酪酸t-ブチル塩酸塩(8.0kg)の塩化メチレン(53.1kg)溶液を-5~5℃で加え、反応混合物を同温度で30分間撹拌した。15~25℃に加温し、同温度で1時間撹拌した。反応混合物に、水(40kg)を加えて、撹拌し、有機層を分離した。得られた溶液を5%食塩水(42.1kg)で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下で濃縮し、標記粗生成物(濃縮残分、10.4kg)を得た。
NMRスペクトル(δppm、CDCl3):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、6.4Hz)、1.44(9H、s)。
マススペクトル(+ESI、m/z):254.00(M+H)+。 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) <+> .
NMRスペクトル(δppm、CDCl3):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、6.4Hz)、1.44(9H、s)。
マススペクトル(+ESI、m/z):254.00(M+H)+。 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)4-(3-カルボキシメチルウレイド)酪酸t-ブチルの合成:
(3.2) Synthesis of t-butyl 4- (3-carboxymethylureido) butyrate:
4-(イミダゾール-1-イルカルボニルアミノ)酪酸t-ブチル(上記(3.1)の化合物)(10.4kg)に塩化メチレン(185.7kg)、グリシン(7.4kg)、トリエチルアミン(8.3kg)を加えて、撹拌し、-5~5℃でクロロトリメチルシラン(8.9kg)を加え、該反応混合物を15~30℃で60時間撹拌した。反応混合物を減圧で濃縮し、酢酸エチル(208kg)、塩酸(5.66kg)と20%食塩水(106kg)の混合液を加えて、撹拌し、有機層を分離した。得られた溶液を塩酸(5.66kg)と20%食塩水(106kg)の混合液で洗浄した。水層を酢酸エチル(57.4kg)で抽出し、有機層と抽出液を合わせた。得られた溶液を20%食塩水(100kg)で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下で濃縮した。酢酸エチル(14.4kg)を加えて、撹拌し、45~55℃で均一溶液とした。該溶液を20~30℃に冷却し、n-ヘプタン(108.7kg)を滴下し、結晶の析出を確認後、1時間撹拌した。析出した結晶を濾取し、標記化合物(7.98kg、純度99.2%)を白色結晶として得た。
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-Triart C18 ExRS 及び移動相:アセトニトリル/pH8のリン酸塩緩衝液=3/7、流速:1mL/min、検出波長:210nm)を用いて、決定した。
NMRスペクトル(δppm、CDCl3):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、7.2Hz)、1.39(9H、s)。
マススペクトル(+ESI、m/z):260.92(M+H)+。 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) <+> .
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-Triart C18 ExRS 及び移動相:アセトニトリル/pH8のリン酸塩緩衝液=3/7、流速:1mL/min、検出波長:210nm)を用いて、決定した。
NMRスペクトル(δppm、CDCl3):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、7.2Hz)、1.39(9H、s)。
マススペクトル(+ESI、m/z):260.92(M+H)+。 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-ブトキシカルボニルプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸t-ブチルの合成:
(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)-アスタキサンチン(1.8kg)、4-(3-カルボキシメチルウレイド)酪酸t-ブチル(上記(3.2)の化合物)(2.75kg)に、N,N-ジメチル-4-アミノピリジン(2.95kg)及び塩化メチレン(71.6kg)を加えて、撹拌し、溶液とした。該溶液に-5~5℃で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(4.63kg)を加え、同温度で4時間撹拌した。反応混合物に水(3.6kg)を加えて、撹拌し、更に、酢酸エチル(48.4kg)を加えて、撹拌し、減圧下にて濃縮した。濃縮残渣に酢酸エチル(48.4kg)、水(45kg)を加えて、撹拌し、有機層を分離した。得られた溶液を塩酸水(0.3M、46.4kg)で3回、10%食塩水(45.9kg)、炭酸水素ナトリウム水溶液(約7%、48.2kg)、20%食塩水(45kg)で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて濃縮乾固し、標記化合物(濃縮残渣、3.26kg、純度98.1%)を得た。
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。
NMRスペクトル(δppm、CDCl3):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)。
マススペクトル(+ESI、m/z):1081.88(M+H)+、1103.67(M+Na)+。 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) <+> .
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。
NMRスペクトル(δppm、CDCl3):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)。
マススペクトル(+ESI、m/z):1081.88(M+H)+、1103.67(M+Na)+。 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-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸の合成:
(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-ブトキシカルボニルプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸t-ブチル(上記(3.3)の化合物)(18.12g)にギ酸(272mL)を加えて、25~35℃で1時間撹拌した。反応混合物を水(1087mL)に加えて、撹拌し、酢酸エチル(1087mL)を加えて、撹拌し、有機層を分離した。有機層を水(543mL)で2回、10%食塩水(543.4g)で2回、順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧下に濃縮した。濃縮残渣をテトラヒドロフラン(81.1mL)、水(8.11mL)で溶解し、該溶液にアセトニトリル(486.8mL)を滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、標記化合物(4.48g、純度90.7%)を暗紫~暗赤色固体として得た。
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。 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).
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。 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-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸の合成:
(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-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸(上記(3.4)の粗生成物)(4.0g)に、テトラヒドロフラン(18.4mL)、水(2.0mL)を加え、撹拌し、溶解した。該溶液にアセトニトリル(60mL)を滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、暗紫~暗赤色固体を得た(3.31g、純度96.9%)。得られた固体(3.26g)に、テトラヒドロフラン(15.0mL)、水(1.6mL)を加え、撹拌し、溶解した。該溶液にアセトニトリル(49mL)を滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、暗紫~暗赤色固体を得た(2.93g、純度98.9%)。得られた固体(2.38g)に、テトラヒドロフラン(10.9mL)、水(1.2mL)を加え、撹拌し、溶解した。該溶液にアセトニトリル(36mL)を滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、標記化合物(2.18g、純度99.3%)を暗紫~暗赤色固体として得た。
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。 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).
なお、生成物の純度は、高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC-TriartC18 ExRS 及び移動相:0.025%トリフルオロ酢酸入りアセトニトリル/0.025%トリフルオロ酢酸水=30~98/70~2、流速:1mL/min、検出波長:474nm)を用いて、決定した。 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-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸二リシン塩;化合物Xの合成:
4-(3-{4(S)-[18-(4-[3-(3-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸(上記(3.5)の化合物)(0.50g、)に、エタノール(10mL)、水(0.5mL)を加えて撹拌した。該懸濁溶液にL-リシン1水和物(0.174g、)の水(2mL)溶液を室温で加えた。該反応混合物に水(7.5mL)を加えて、撹拌し、溶解した。該反応混合物にエタノール(32mL)を室温で滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、標記化合物(0.47g、純度98.6%、光学純度99.0%de)を暗紫~暗赤色固体として得た。
なお、生成物の純度は、上記同様に高速液体クロマトグラフィーを用いて決定した。光学純度は高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC CHIRAL ART Amylose・SA(5μm,4.6mmI.D.x250mm)、カラム温度:25℃及び移動相:THF/水/TFA(40:60:0.1)、流速:1mL/min、検出波長:474nm、カラム保持時間:15.4分(S、S)、17.6分(meso)、20.6分(R、R))を用いて、決定した。 (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.
4-(3-{4(S)-[18-(4-[3-(3-カルボキシプロピル)ウレイドアセトキシ]-2,6,6-トリメチル-3-オキソシクロヘキサ-1-エニル)-3,7,12,16-テトラメチルオクタデカ-1(E),3(E),5(E),7(E),9(E),11(E),13(E),15(E),17(E)-ノナエニル]-3,5,5-トリメチル-2-オキソシクロヘキサ-3-エニル-1(S)-オキシカルボニルメチル}ウレイド)酪酸(上記(3.5)の化合物)(0.50g、)に、エタノール(10mL)、水(0.5mL)を加えて撹拌した。該懸濁溶液にL-リシン1水和物(0.174g、)の水(2mL)溶液を室温で加えた。該反応混合物に水(7.5mL)を加えて、撹拌し、溶解した。該反応混合物にエタノール(32mL)を室温で滴下し、固体の析出を確認した後、1時間撹拌した。析出した固体を濾取、乾燥し、標記化合物(0.47g、純度98.6%、光学純度99.0%de)を暗紫~暗赤色固体として得た。
なお、生成物の純度は、上記同様に高速液体クロマトグラフィーを用いて決定した。光学純度は高速液体クロマトグラフィー(カラム:株式会社ワイエムシィ製 YMC CHIRAL ART Amylose・SA(5μm,4.6mmI.D.x250mm)、カラム温度:25℃及び移動相:THF/水/TFA(40:60:0.1)、流速:1mL/min、検出波長:474nm、カラム保持時間:15.4分(S、S)、17.6分(meso)、20.6分(R、R))を用いて、決定した。 (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 (8)
- 式(I)で示されるトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を含有するドライアイ改善剤及び/または涙液量低下抑制剤。
- 式(I)において、m1およびm2がそれぞれ1の整数であり、n1およびn2はそれぞれ3の整数である請求項1記載のドライアイ改善剤及び/または涙液量低下抑制剤。 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.
- 塩がリシン塩である請求項1または2記載のドライアイ改善剤及び/または涙液量低下抑制剤。 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.
- 式(IA)で示される光学活性トランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物またはそれらの塩を含有するドライアイ改善剤及び/または涙液量低下抑制剤。
- 式(IA)において、m1およびm2がそれぞれ1の整数であり、n1およびn2がそれぞれ3の整数である請求項4記載のドライアイ改善剤及び/または涙液量低下抑制剤。 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.
- 式(IA)で示される光学活性トランス-アスタキサンチン誘導体に対応する光学活性シス-アスタキサンチン誘導体およびその塩を実質的に含有しない、請求項4または5記載のドライアイ改善剤及び/または涙液量低下抑制剤。 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.
- 塩がリシン塩である請求項4~6のいずれか1項記載の高純度の光学活性トランス-アスタキサンチン誘導体の塩を含有するドライアイ改善剤及び/または涙液量低下抑制剤。 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.
- 請求項1-7の何れか1項記載のトランス-アスタキサンチン誘導体、その幾何異性体、それら幾何異性体の混合物、それらの光学異性体またはそれらの塩を含有するドライアイ改善用及び/または涙液量低下抑制用医薬組成物。 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.
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JP2008127303A (en) * | 2006-11-17 | 2008-06-05 | Suntory Ltd | Agent for ameliorating functional disorder of exocrine gland, and food and drink for ameliorating functional disorder |
WO2015178404A1 (en) * | 2014-05-20 | 2015-11-26 | 富士化学工業株式会社 | Carotenoid derivative, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable ester or amide thereof |
JP2017534607A (en) * | 2014-10-10 | 2017-11-24 | ピーター エフ. ケイドー, | Antioxidant eye drops |
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JP2008127303A (en) * | 2006-11-17 | 2008-06-05 | Suntory Ltd | Agent for ameliorating functional disorder of exocrine gland, and food and drink for ameliorating functional disorder |
WO2015178404A1 (en) * | 2014-05-20 | 2015-11-26 | 富士化学工業株式会社 | Carotenoid derivative, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable ester or amide thereof |
JP2017534607A (en) * | 2014-10-10 | 2017-11-24 | ピーター エフ. ケイドー, | Antioxidant eye drops |
Non-Patent Citations (1)
Title |
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KAWAKITA, TETSUYA: "Effects of astaxanthin oral administration on dry eye model mice", PROGRAM OF SCIENTIFIC MEETING OF THE JAPANESE SOCIETY OF ANTI-AGING MEDICINE, vol. 12, 2012, pages 241 * |
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