JP2019043884A - Sepsis therapeutic agent - Google Patents

Abstract

To provide a new sepsis therapeutic agent.SOLUTION: A sepsis therapeutic agent contains a trans-astaxanthin derivative represented by the following formula (I), geometric isomers thereof, a mixture of the geometric isomers, optical isomers thereof, or salts thereof (where m, m, nand nare the same or different to represent an integer of 1-6).SELECTED DRAWING: None

Description

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

  Sepsis is a disease in which bacteria, viruses, or fungi enter the blood and travel throughout the body, and causes systemic symptoms such as organ failure. This disease is caused by infection with the above-mentioned microorganisms, so its therapeutic agent is antibacterial. Agents, antivirals and antifungals are at the core. However, it is still a serious disease for which there is no breakthrough treatment or treatment.

  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 1 and 2). 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).

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

  So far, it has been reported that astaxanthin has been administered to animal models of sepsis before sepsis treatment to have a preventive effect (Non-patent Document 3).

WO 2015/178404 specification

Alternative Medicine Review, 2000, 16 (4), 355-364 Trends in Biotechnology, 2003, 21 (5), 210-216 J Surg Res. 2015 May 15; 195 (2): 559-67. Doi: 10.1016 / j.jss. 2015.02.026. Epub 2015 Feb 18.

  However, since sepsis is a serious and sudden disease, post-onset treatment and drug treatment are mainly involved from the preventive point of view, and reports of administration of astaxanthin after onset and confirmation of its effects are human Of course, there is absolutely no clinical model for this in animal models.

  Therefore, an object of the present invention is to provide a completely new therapeutic agent for sepsis.

  Therefore, as a result of intensive investigations to find a completely different new therapeutic agent as a therapeutic agent for sepsis as a therapeutic agent for sepsis, the present inventors have found that trans-astaxanthin derivatives represented by the formula (I), their geometric isomers, their geometric isomers The present inventors have completed the present invention by finding that the mixture of (1), their optical isomers and their salts have excellent therapeutic effect on sepsis.

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

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

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

[2] Use of the trans-astaxanthin derivative represented by the above formula (I), a geometric isomer thereof, a mixture of these geometric isomers, an optical isomer thereof or a salt thereof for producing a therapeutic agent for sepsis.
[3] A trans-astaxanthin derivative represented by the above formula (I), a geometric isomer thereof, a mixture of these geometric isomers, an optical isomer thereof or an effective amount of a salt thereof Method of treatment.

  The trans-astaxanthin derivative represented by the formula (I) of the present invention, its geometric isomer, optical isomers thereof and salts thereof are excellent against sepsis in humans and all kinds of animals such as dogs, cats and horses. A pharmaceutical composition containing an astaxanthin derivative represented by the formula (I), a geometric isomer thereof, an optical isomer thereof or a salt thereof which is a compound of the present invention is excellent as a sepsis therapeutic agent.

  The therapeutic agent for sepsis according to the present invention contains, as an active ingredient, the trans-astaxanthin derivative represented by the above formula (I), its geometric isomer, a mixture of these geometric isomers, their optical isomer or a salt thereof.

In formula (I), m ₁ , m ₂ , n ₁ and n ₂ are the same or different and each represents an integer of 1 to 6. Among the compounds of formula (I), m ₁ and m ₂ each represent an integer of ₁ and n ₁ and n ₂ each represent an integer of 3, and m ₁ , m ₂ , n ₁ and n ₂ represent The case where each represents an integer of 2 is preferable, and the case where m ₁ , m ₂ , n ₁ and n _{2 each} represent an integer of 2 is particularly preferable.

  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 base substance or a base compound desired from having a carboxyl group in the molecule A pharmaceutically acceptable salt can be formed by Such salts include, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts, amino acids such as lysine salts, ornithine salts and arginine salts Salts can be mentioned, among which lysine salts can be mentioned as preferred.

  In the chemical structural formula of the formula (I), the double bond part in the medium chain carbon chain part in the astaxanthin basic skeleton can take on the structure of trans and cis geometric isomers in terms of chemical structure. With regard to the active ingredient according to the present invention, not only the trans form of formula (I) but also cis forms represented by the following formulas (Ia) and (Ib) are listed as active ingredients of the agent for treating sepsis according to the present invention be able to. The therapeutic agent for sepsis according to the present invention 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 and a mixture of trans form and cis form.

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

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

  In addition, the compound of the formula (I), its geometric isomer and a mixture of these geometric isomers can include an optical isomer (IA) represented by the following, and its enantiomer and a mixture thereof, All diastereomers are also included as active ingredients of the therapeutic agent for sepsis according to the present invention.

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

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), m ₁ and m ₂ each represent an integer of ₁ and n ₁ and n ₂ each represent an integer of 3 and m ₁ , m ₂ , n ₁ And n ₂ is preferably a compound having an integer of ₂ respectively, and in particular, a compound having the latter m ₁ , m ₂ , n ₁ and n ₂ having an integer of 2 in view of activity and salts thereof are preferable.

  As described above, an optically active trans-astaxanthin derivative represented by the formula (IA) or a salt thereof is more preferable, and an optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) More preferred is a highly pure optically active trans-astaxanthin derivative or a salt thereof substantially free of a salt. Here, containing the active ingredient of the sepsis therapeutic agent according to the present invention with high purity means that the purity of the active ingredient is at least 95% or more, preferably 98% or more.

  The compound of the formula (I) according to the present invention, its geometric isomer, optical isomers thereof and salts thereof may be produced by appropriately combining the production method described in Patent Document 1 and the same method with known methods. Can. Among these production methods, the geometric isomer of the compound of the formula (I) and the production method of the optical isomer thereof will be described below by using the production method of the optical isomer of the above formula (IA) as a representative.

(1A) Deprotection reaction

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

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

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

  In the case of the elimination reaction with acid, the compound of formula (IA) can be produced by reacting the compound of formula (II) with an acid in an inert solvent. The solvent used is not particularly limited as long as it is inert to the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatics such as benzene, toluene and xylene Hydrocarbons; Halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and carbon tetrachloride; Nitriles such as acetonitrile and propionitrile; ethyl formate, isopropyl formate, isobutyl formate, ethyl acetate, Organic acid esters such as isobutyl acetate and butyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide Amides such as: alcohols such as methanol, ethanol, propanol and isopropanol; organic acids such as trifluoroacetic acid, formic acid, acetic acid and propionic acid; water; or mixed solvents of these solvents, 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, and most preferably halogenated hydrocarbons, acetonitrile, water, methanol, ethanol, isopropanol, formic acid, dioxane, tetrahydrofuran or water and A mixed solvent of these organic solvents (when the protecting group is a C1-C6 alkyl group) It can gel. 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 is usually 10 to 50 times, preferably 30 times the volume of the used 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, For example, 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, and therefore, it is possible to use column chromatography, separation such as reprecipitation or crystallization, and purification means. By combining as appropriate according to the purpose, the same geometric isomer can be separated and removed, and the objective optically active trans-astaxanthin derivative of the formula (IA) can be isolated and manufactured with high purity.
Further, the separated cis-form can be isolated and obtained by appropriately combining the purification and separation methods as described above.

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

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ have the same meaning 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 contained therein and then reacting it using 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., and 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 the compound of the formula (IAa) or the formula (IAb), preferably 30 times the volume. The amount of conversion reagent used may be usually 0.01 times or more by mole, preferably 0.1 times or more by mole, of the compound of the formula (IAa) or formula (IAb) as a raw material.

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

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

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

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

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

  Examples of the solvent include organic solvents such as methylene chloride, chloroform and carbon tetrachloride. As the condensation reagent, those used for ordinary condensation reactions can be used, and 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 2 times or more, preferably 2.5 times to 20 times the molar amount of 3S, 3'S-astaxanthin as the raw material. 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, and preferably -10 ° C to 100 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 5 days. The amount of the solvent used is usually 10 to 50 times the used weight of 3S, 3'S-astaxanthin, preferably 30 times the volume.

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

(2A-1)

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

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

In the step of obtaining the compound of the formula (VI), organic solvents such as chloroform and methylene chloride can be exemplified as the solvent, and the amount of these organic solvents used is usually 5 times the used weight of the compound of the formula (IV) A volume of 30 to 30 volumes, preferably 15 volumes, may be used. As the basic reagent, those used in 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 to be 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 used is usually at least equimolar, preferably equimolar to 5.0 times the molar amount of the compound of the formula (VII) 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. Then, the compound of the formula (VI) is added and reacted. The reaction temperature varies depending on the starting compound to be reacted, the reagent used, the solvent and the like, but is usually -20 ° C to 150 ° C, preferably 10 ° C. To 60 ° C. The reaction time varies depending on the raw material compound, the solvent, the reaction temperature and the like, but is usually 30 minutes to 10 days, and preferably 30 minutes to 4 days.

(2B) Method of sequentially bonding parts of side chain portion to 3S, 3'S-astaxanthin

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

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

In the process 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 used, the solvent and the like, but is usually -20 ° C to 150 ° C, and 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 above reaction 2A. .

  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 (III). 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 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. In addition, the method for producing a compound having the general formula (XI) can be achieved according to the method for synthesizing a generally known t-butyl ester of amino acid when (1) R is a t-butyl group, (2) When R is a trimethylsilyl group, it can be achieved by reacting a compound having the general formula (X) with trimethylsilyl chloride in the presence of a base in an inert solvent (to form a compound of the general formula (III) It can be achieved according to the method). The reaction of (2) can be achieved according to generally known methods for silylation of hydroxyl and carboxyl groups. When R in the general formula (XI) is a trimethylsilyl group, the trimethylsilyl group can be easily eliminated by using water or weakly acidic water for post-treatment of the reaction to generate the general formula (II). .

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

The compound of the formula (I) according to the present invention, geometric isomers thereof, optical isomers thereof and salts thereof can be administered as oral preparations such as tablets, capsules, granules, powders and the like, and also injections It can also be administered.
The above-mentioned oral preparation can be produced by mixing it with a pharmaceutical additive such as a pharmaceutically acceptable excipient, a disintegrant and a binder as appropriate, and using a conventional formulation technique. Moreover, about the said injection, it can manufacture by a normal formulation technique, using the pharmaceutically acceptable osmotic pressure regulator, the stabilizer, the solubilizer, and the pH regulator suitably in combination.

When a compound of the formula (I) according to the present invention, a geometric isomer thereof, a mixture of these geometric isomers, an optical isomer thereof or a salt thereof is administered as an injection, it is usually 5 per day for adults. .0 mg to 20.0 mg may be administered intravenously, and may be increased or decreased appropriately according to the symptoms.
The compounds of the formula (I) according to the present invention, their geometric isomers, mixtures of these geometric isomers, their optical isomers and their salts are particularly problematic in terms of safety within the above-mentioned dose range. Absent.

  EXAMPLES The present invention will be described in more detail by way of examples, which should not be construed as limiting the invention thereto.

Example Test using a sepsis animal model (test method)
It was tested using the CLP (Cecal ligation puncture) model, which is the golden standard of the sepsis study model.
1. Test substance Compound A: 3- [3- (2- {4- [18- (4- {3- [3- (2-carboxyethyl) ureido] propionyloxy] -2,6,6-trimethyl-3- Oxocyclohex-1-enyl) -3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl] -3,5,5-trimethyl -2-Oxocyclohex-3-enyloxy carbonyl} ethyl) ureido] propionic acid ((patent document 1) compound of Example 14 of WO 2015/178404)

2. Used animals (purchased from Charles River)
Sprague Dawley male rat (weight: 250-275 g)
3. Administration method, dose amount and evaluation method The test compound was dissolved in physiological saline and continuously administered for 72 hours to test animals at a predetermined concentration. The infusion rate was 4 mL / kg / hr. This was a compound A administration group, and physiological saline alone was intravenously administered by the same method and rate as a control.
The test animals were anesthetized with 1 mL / kg of buprenofin intravenously and anesthetized, and CLP was performed to induce the onset of sepsis. Administration of the test compound in saline or saline according to the method described above is started 3 hours after CLP is performed, and the survival of the test animal is observed to evaluate the protective / therapeutic effect of the test compound on sepsis did. The results are shown in Table 1.

  As described in Table 1, the dose of Compound A was 0.75 mg / kg / hr. To 1.2 mg / kg / hr. The survival time was extended as the From the above results, it was confirmed that Compound A has excellent protective effect and therapeutic effect against sepsis.

Claims (9)

The trans-astaxanthin derivative shown by following formula (I), its geometric isomer, the mixture of those geometric isomers, those optical isomers, or their salts contain the sepsis therapeutic agent.

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ are the same or different and mean an integer of 1 to 6) The agent for treating sepsis according to claim _1, wherein in the formula (I), m ₁ and m ₂ are each an integer of _1, and n ₁ and n ₂ are each an integer of 3.   The agent for treating sepsis according to claim 1 or 2, wherein the salt is a lysine salt. The agent for treating sepsis according to claim ₁ , wherein m ₁ , m ₂ , n ₁ and n ₂ in the formula (I) are each an integer of 2. An agent for treating sepsis, comprising the optically active trans-astaxanthin derivative represented by the formula (IA), a geometric isomer thereof, a mixture of these geometric isomers or a salt thereof.

(Wherein, m ₁ , m ₂ , n ₁ and n ₂ are the same or different and mean an integer of 1 to 6) The agent for treating sepsis according to claim 5, wherein m ₁ and m ₂ are each an integer of ₁ and n ₁ and n ₂ are each an integer of 3 in formula (IA).   The agent for treating sepsis according to claim 5 or 6, which is substantially free of the optically active cis-astaxanthin derivative corresponding to the optically active trans-astaxanthin derivative represented by the formula (IA) and a salt thereof.   The agent for treating sepsis containing a salt of a highly pure optically active trans-astaxanthin derivative according to any one of claims 5 to 7, wherein the salt is a lysine salt. 9. The high purity optically active trans-astaxanthin derivative according to claim 5, 7 or 8 wherein m ₁ , m ₂ , n ₁ and n ₂ are each an integer of 2 in the formula (IA), their geometric isomers, their geometry. Therapeutic agent for sepsis containing a mixture of isomers or a salt thereof.