Trisulfide compound and its inclusion complex

Abstract

A compound represented by formula (1) or (3).　[Compound 1] [In the formula, R1 and R2 each independently are a hydrogen atom; a C1-6 alkyl group having one or more substituents selected from the group consisting of a carboxy group and -OR5; a C2-6 alkyl group having one or more substituents selected from the group consisting of -NR6R7 and -N+R9R10R11; or –(CH2CH2O)nR8, R5, R6, R7, R8, R9, R10, and R11 each independently are a hydrogen atom or a C1-3 alkyl group, and n is an integer of 2-5.]　[Compound 2] [In the formula, R4 represents a C1-6 alkyl group having one or more substituents selected from the group consisting of a carboxy group and -OR5; a C2-6 alkyl group having one or more substituents selected from the group consisting of -NR6R7 and -N+R9R10R11; or –(CH2CH2O)nR8, and R5-R11 and n are the same as above.]

Description

Technical Field

[0001] The present invention relates to trisulfide compounds and inclusion compounds thereof.

Background Art

[0002] A compound containing a covalent bond structure formed by three consecutive sulfur atoms is called a trisulfide compound. Since trisulfide compounds have redox ability depending on the possible valence of the constituent sulfur atoms, they are expected to have various physiological functions.

[0003] Patent Document 1 discloses lipoic acid trisulfide obtained by trisulfiding α-lipoic acid used for the treatment of diabetes and chronic hepatitis.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, the trisulfide compounds as disclosed in Patent Document 1 are poorly soluble in water.

[0006] An object of the present invention is to provide a new trisulfide compound for solving the problems, and in particular, to provide a cyclodextrin inclusion compound (hereinafter also referred to as "CD inclusion compound" or simply "inclusion compound") of a trisulfide compound having excellent water solubility and stability.

Means for Solving the Problems

[0007] In order to solve the above problems, the inventors of the present invention made intensive efforts and newly created a trisulfide compound having a carboxylic acid amide structure represented by the following formula (1). Further, a trisulfide compound having an ester structure modified with a hydrophilic functional group and represented by the following formula (3) was newly created. In addition, it was found that the CD inclusion complex of the trisulfide compound represented by the following formula (1) or (2) has excellent water solubility and stability, and the present invention has been completed.

[0008] That is, the present invention relates to the following [1] to [8]. [1] A compound represented by the following formula (1). [Chemical formula] [In the formula, R 1 and R 2 are each independently a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR 5 ; an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 ; or -(CH 2 CH 2 O) n R 8 ; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5. ] [2] The compound according to [1], wherein R 1 and R 2 are hydrogen atoms. [3] A compound represented by the following formula (3). [Chemical formula] [In the formula, R4 is an alkyl group having 1 to 6 carbon atoms and having one or more substituents selected from the group consisting of a carboxy group and -OR 5 ; an alkyl group having 2 to 6 carbon atoms and having one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 ; or -(CH 2 CH 2 O) n R 8 wherein R 5 ,R 6 ,R 7 ,R 8 ,R 9 ,R 10 and R 11 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.] [4]At least one selected from the group consisting of a compound represented by the following formula (1), a compound represented by the following formula (2), and a salt of the compound represented by the following formula (2) is a cyclodextrin clathrate in which the cyclodextrin is included. [Chemical formula] [In the formula, R 1 and R 2 each independently represents a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR 5 ; an alkyl group having 2 to 6 carbon atoms and having one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 ; or -(CH 2 CH 2 O) n R 8 wherein R 5 ,R 6 ,R 7 ,R 8 ,R 9 ,R 10 and R11 Each is independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.

Chemical Formula

Advantages of the Invention

[0009] According to the present invention, a novel trisulfide compound can be provided. Further, the CD inclusion complex of the trisulfide compound according to the present invention has excellent water solubility and stability. Therefore, in industrial applications such as pharmaceuticals, it is considered that problems such as restrictions on applicable formulation prescriptions and the manifestation of individual differences in oral absorbability are solved. Further, the trisulfide compound and the CD inclusion complex of the trisulfide compound according to the present invention are expected to have an active oxygen scavenging action, a hydrogen sulfide scavenging action, and the like.

Brief Description of the Drawings

[0010]

Figure 1

Modes for Carrying Out the Invention

[0011] The trisulfide compound according to one embodiment of the present invention is a compound represented by the following formula (1).

Chemical formula

[0012] R 1 or R 2 has one or more substituents selected from the group consisting of a carboxy group and -OR 5 and is an alkyl group having 1 to 6 carbon atoms; -NR 6 R 7 and -N + R 9 R 10 R 11 and has one or more substituents selected from the group consisting of an alkyl group having 2 to 6 carbon atoms; or -(CH 2 CH 2 O) n R 8 When this is the case, it is considered that the hydrophilicity of the compound represented by formula (1) is further improved.

[0013] In formula (1), R 1 and R 2 may be an alkyl group such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group. These alkyl groups may have one or more substituents selected from the group consisting of a carboxy group; and a substituent represented by -OR 5 such as a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group. In formula (1), R 1 and R 2 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and these alkyl groups have a substituent represented by -NR 6 R 7 such as an amino group, a dimethylamino group; and -N + H 3 , -N + (CH 3 ) 3 , -N + (C 2 H 6 ) 3 such as -N + R 9 R 10 R 11It may have one or more substituents selected from the group consisting of the substituents represented by . R 1 and R 2 may each have, for example, one or both substituents of an amino group and a carboxy group. R 1 and R 2 may be, for example, a group represented by the following formula (10) or (11) (wherein * represents a bond). R 1 and R 2 may be a group represented by -(CH 2 CH 2 O) n R 8 such as bis(2-ethoxyethyl) ether. Specific examples of the compound represented by the following formula (1) include, for example, a compound in which both R 1 and R 2 are hydrogen atoms, a compound in which R 1 is a hydrogen atom and R 2 is a group represented by the following formula (10), and a compound in which R 1 is a hydrogen atom and R 2 is a group represented by the following formula (11).

[0014]

Chemical formula

Chemical formula

[0015] The compounds in the present specification may have optical isomers and racemates, but in the present invention, they are not limited to any of them, and may be a racemate, any of the optically active forms, or a mixture containing any of the optically active forms in any ratio.

[0016] The trisulfide compound represented by formula (1) can be produced by oxidizing the disulfide compound represented by the following formula (1a) with an oxidizing agent to obtain a sulfoxide compound (step 1), and reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound (step 2).

Chemical formula

[0017] In the above production method, steps 1 and 2 may be carried out in one pot without isolating the sulfoxide compound.

[0018] The solvent used in step 1 is not particularly limited as long as it dissolves the disulfide compound and the oxidizing agent and does not inhibit the oxidation reaction. Examples of such solvents include water, aqueous sulfuric acid solution, aqueous ethanol solution, and aqueous acetonitrile solution, and preferably water. The amount of the solvent used in step 1 can be 1 mL to 500 mL per 1 g of the disulfide compound, and preferably 10 mL to 20 mL.

[0019] As oxidizing agents used in Step 1, potassium peroxymonosulfate (sold under trade names such as Oxone®), peracetic acid, hydrogen peroxide, and sodium periodate can be mentioned. Hydrogen peroxide may be used together with a catalytic amount of methyltrioxorhenium. From the viewpoints of safety and cost, potassium peroxymonosulfate is a preferred oxidizing agent. The amount of the oxidizing agent used can be 0.8 equivalents to 2.0 equivalents, preferably 1.0 equivalent to 1.3 equivalents, relative to 1 equivalent of the disulfide compound.

[0020] The reaction temperature in Step 1 can be -20°C to 30°C, preferably -5°C to 5°C.

[0021] The reaction time in Step 1 can be 5 minutes to 24 hours, preferably 0.5 hour to 2 hours.

[0022] The solvent used in Step 2 is not particularly limited as long as it can dissolve the sulfoxide compound and the sulfur source and does not inhibit the subsequent reaction. Examples of such solvents include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, and preferably water. The amount of the solvent used in Step 2 can be 1 mL to 500 mL, preferably 10 mL to 20 mL, per 1 g of the sulfoxide compound.

[0023] As the sulfur source used in Step 2, sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide can be mentioned. The amount of the sulfur source used can be 0.5 equivalents to 4.0 equivalents, preferably 0.9 equivalents to 1.2 equivalents, relative to 1 equivalent of the sulfoxide compound.

[0024] The reaction temperature in Step 2 can be -20°C to 30°C, preferably -5°C to 25°C.

[0025] The reaction time in Step 2 can be 10 minutes to 2 days, preferably 0.5 hour to 2 hours.

[0026] When performing Step 1 and Step 2 in one pot, examples of the reaction solvent include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution. Preferably, it is water. The amount of the solvent can be 1 mL to 500 mL per 1 g of the disulfide compound, and preferably, it is 10 mL to 20 mL. Examples of the oxidizing agent used include potassium peroxymonosulfate, peracetic acid, hydrogen peroxide (which may be used together with a catalytic amount of methyltrioxorhenium), and sodium periodate. Preferably, it is potassium peroxymonosulfate. The amount of the oxidizing agent used can be 0.8 equivalent to 2.0 equivalents per 1 equivalent of the disulfide compound, and preferably, it is 1.0 equivalent to 1.3 equivalents. Examples of the sulfur source used include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of the sulfur source used can be 0.5 equivalent to 4.0 equivalents per 1 equivalent of the disulfide compound, and preferably, it is 0.9 equivalent to 1.2 equivalents. The reaction temperature can be -20°C to 30°C, and preferably, it is -5°C to 25°C. The reaction time can be 15 minutes to 2 days, and preferably, it is 1 hour to 4 hours.

[0027] In addition to Step 1 and Step 2, if necessary, it may include steps of protecting functional groups such as hydroxy group, carbonyl group, amino group, carboxy group, etc. and steps of deprotecting the protected functional groups. The protecting groups of these functional groups and the protection / deprotection reactions are well-known to those skilled in the art. By referring to "Greene’s Protective Groups in Organic Synthesis" etc., appropriate protecting groups and protection / deprotection reactions can be selected.

[0028] The disulfide compound represented by formula (1a) is lipoic acid and NHR 1 R 2It can be produced by condensation. Examples of the solvent for the condensation reaction include dichloromethane, chloroform, and tetrahydrofuran, and preferably tetrahydrofuran. The amount of the solvent can be 1 mL to 200 mL per 1 g of the disulfide compound, and preferably 3 mL to 35 mL. Examples of the condensing agent to be used include 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and its salts, N,N’-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) (N-hydroxysuccinimide (NHS), 1-hydroxybenzotriazole (HOBt) may be used as additives.), 4-dimethylaminopyridine (DMAP), 1,1’-carbonyldiimidazole di(1H-imidazol-1-yl)methanone (CDI), and the like. The amount of the condensing agent to be used can be 0.8 equivalent to 2.0 equivalents per 1 equivalent of the disulfide compound, and preferably 1.0 equivalent to 1.5 equivalents. The reaction temperature can be -10°C to 40°C, and preferably 15°C to 25°C. The reaction time can be 1 hour to 3 days, and preferably 1 hour to 24 hours.

[0029] The trisulfide compound represented by the formula (1) can also be produced by condensing lipoic acid trisulfide with NHR 1 R 2 The condensation conditions are the same as those described above.

[0030] The trisulfide compound according to one embodiment of the present invention is a compound represented by the following formula (3). [Chemical formula] [In the formula, R 4 is an alkyl group having 1 to 6 carbon atoms having one or more substituents selected from the group consisting of a carboxy group and -OR 5 ; -NR 6 R 7 and -N + R 9 R10 R 11 An alkyl group having 2 to 6 carbon atoms and having one or more substituents selected from the group consisting of; or -(CH 2 CH 2 O) n R 8 is shown, and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.]

[0031] The compound represented by formula (3) is considered to have good hydrophilicity.

[0032] In formula (3), R 4 may be an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc., and these alkyl groups have a substituent represented by -OR 5 . The substituent represented by -OR 5 is the same as above. In formula (3), R 4 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc., and these alkyl groups have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 . The substituent represented by -NR 6 R 7 is the same as above. The substituent represented by -N + R 9 R 10 R 11 is the same as above. In formula (3), R 4 may be a group represented by -(CH 2 CH 2 O) n R 8 , or may be a group represented by -(CH 2 CH 2 O) n R 8The group represented by is the same as described above. In formula (3), R 4 may be, for example, a group represented by the following formula (30) or (31) (wherein * represents a bond).

[0033] As specific examples of the compound represented by formula (3), for example, a compound in which R 3 is a group represented by the following formula (30), and a compound in which R 3 is a group represented by the following formula (31) can be mentioned. [Chemical formula] [Chemical formula]

[0034] The compound represented by formula (3) is obtained by, in the compound represented by formula (2) described later, R 3 is an alkyl group having 1 to 6 carbon atoms having one or more substituents selected from the group consisting of a carboxy group and -OR 5 , an alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 or -(CH 2 CH 2 O) n R 8 in the same manner as in the case where it is.

[0035] The CD inclusion complex of the trisulfide compound according to another embodiment of the present invention includes at least one selected from the group consisting of the compound represented by the above formula (1), the compound represented by the following formula (2), and the salt of the compound represented by the following formula (2), which is included by cyclodextrin. [Chemical formula] [In the formula, R 3 is a hydrogen atom; a carboxy group and -OR 5An alkyl group having 1 or more substituents selected from the group consisting of carbon atoms 1 to 6, which may have; -NR 6 R 7 And -N + R 9 R 10 R 11 An alkyl group having 1 or more substituents selected from the group consisting of carbon atoms 2 to 6; or -(CH 2 CH 2 O) n R 8 Indicates that R 5 、R 6 、R 7 、R 8 、R 9 、R 10 And R 11 Each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.]

[0036] In formula (2), R 3 May be, for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, or a group represented by R 4 In formula (3).

[0037] R 3 May have 1 or more substituents selected from the group consisting of a carboxy group and -OR 5 An alkyl group having 1 to 6 carbon atoms, -NR 6 R 7 And -N + R 9 R 10 R 11 An alkyl group having 1 or more substituents selected from the group consisting of carbon atoms 2 to 6 or -(CH 2 CH 2 O) n R 8The trisulfide compound represented by formula (2) can be produced by oxidizing the disulfide compound represented by the following formula (2a) with an oxidizing agent to obtain a sulfoxide compound (step 1), and reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound (step 2). In addition to steps 1 and 2, steps for protecting functional groups such as hydroxy groups, carbonyl groups, amino groups, and carboxy groups and steps for deprotecting the protected functional groups may be included as necessary. The reaction conditions are the same as described above. [Chemical formula] [In the formula, R 3 represents a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR 5 ; an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR 6 R 7 and -N + R 9 R 10 R 11 ; or -(CH 2 CH 2 O) n R 8 . R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.]

[0038] The disulfide compound represented by formula (2a) can be produced by condensing lipoic acid and R 3 OH. It is the same as described above.

[0039] R 3 is an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR 5 , -NR 6 R 7 and -N+ R 9 R 10 R 11 An alkyl group having 2 to 6 carbon atoms or -(CH 2 CH 2 O) n R 8 The trisulfide compound represented by the formula (2) which is R 3 OH can also be produced by condensing with lipoic acid trisulfide. The conditions for condensation are the same as above.

[0040] The salt of the compound represented by the above formula (2) may be a pharmacologically acceptable salt, for example, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, etc. These salts can be converted from lipoic acid trisulfide by conventional methods.

[0041] Cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or a derivative thereof. Here, "derivative" means that the hydrogen atom of at least one hydroxyl group possessed by each cyclodextrin is substituted by an alkyl group or sugar which may have a substituent. As cyclodextrin derivatives, for example, methyl-α-cyclodextrin, methyl-β-cyclodextrin, methyl-γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, hydroxyethyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, glucosyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, sulfobutyl ether-α-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, etc. can be used.

[0042] The CD inclusion complex can be produced by a step of dissolving cyclodextrin in a solvent (step a), a step of adding a trisulfide compound to the obtained solution and stirring (step b), and a step of filtering the stirred solution, washing it with the same solvent as the solvent used in step a, freezing the filtrate, and freeze-drying it (step c). Note that the filtration and washing operations in step c may be omitted.

[0043] The solvent used in step a is preferably water.

[0044] The amount of the solvent used in step a can be 1 to 350 ml with respect to 1 g of cyclodextrin, and is preferably 1 to 80 ml.

[0045] In step b, the mass ratio of cyclodextrin to the trisulfide compound can be 2 to 20, preferably 5 to 16.5.

[0046] The stirring temperature in step b can be 20 to 50°C and can be room temperature.

[0047] The stirring time in step b can be 0.25 to 40 hours, preferably 2 to 35 hours.

[0048] In step b, after adding the trisulfide compound and before stirring, the same solvent as used in step a may be added. At this time, the amount of the solvent can be 0 to 30 ml per 1 g of cyclodextrin, preferably 0 to 20 ml.

[0049] The amount of the solvent used in step c can be 0 to 150 ml per 1 g of cyclodextrin, preferably 0 to 20 ml.

[0050] The freezing temperature in step c can be -30 to -20°C, preferably -20°C.

[0051] The freezing time in step c can be 10 to 50 hours.

[0052] The freeze-drying in step c can be carried out at an absolute pressure of 20 to 100 Pa, with an external temperature of 10 to 40°C, preferably an external temperature of 20°C.

[0053] The freeze-drying period in step c can be 1 to 5 days.

[0054] The trisulfide compound or the CD inclusion complex of the trisulfide compound according to the present invention can be made into a pharmaceutical composition by adding a pharmacologically acceptable additive as needed.

[0055] The pharmaceutical composition containing a trisulfide compound or a CD inclusion complex of a trisulfide compound according to the present invention can be formulated, for example, as an injection, an oral preparation, an eye drop, a topical preparation, or a suppository. Examples of the injection include a subcutaneous injection, an intramuscular injection, an intravenous injection, an intraperitoneal injection, etc. Examples of the oral preparation include tablets, granules, fine granules, powders, capsules. Examples of the eye drop include an aqueous eye drop, an oily eye drop, etc. Examples of the topical preparation include a plaster, an ointment, a cream, a lotion, etc. Examples of the suppository include a fatty base type suppository, a water-soluble base type suppository, etc. Examples of the additive include stabilizers such as saccharides (sucrose, trehalose, maltose, lactose, etc.), sugar alcohols (sorbitol, etc.), amino acids (L-arginine, etc.), water-soluble polymers (HES (hydroxyethyl starch), PVP (polyvinylpyrrolidone), etc.), nonionic surfactants (polysorbate, poloxamer, etc.), pH adjusters such as sodium phosphate buffer, histidine buffer, isotonic agents such as sodium chloride, and excipients such as mannitol, glycine, sodium chloride, sucrose, etc.

[0056] As preferred embodiments of the present invention, the following [Embodiment 1] to [Embodiment 7] can be mentioned. [Embodiment 1] A compound represented by the following formula (1). [Chemical formula] [In the formula, R 1 and R 2 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxyl group.] [Embodiment 2] The compound according to [Embodiment 1], wherein R 1 and R 2 are hydrogen atoms. [Embodiment 3] A cyclodextrin inclusion complex in which at least one selected from the group consisting of a compound represented by the following formula (1), a compound represented by the following formula (2), and a salt of the compound represented by the following formula (2) is included in cyclodextrin. [Chemical formula] [In the formula, R 1 and R 2 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxyl group.] [Chemical formula] [In the formula, R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.] [Embodiment 4] The inclusion compound according to [Embodiment 3], wherein the salt of the compound represented by the formula (2) contains at least one selected from the group consisting of a salt with an alkali metal, a salt with an alkaline earth metal, and an ammonium salt. [Embodiment 5] The inclusion compound according to [Embodiment 3] or [Embodiment 4], wherein the compound is the compound represented by the formula (2) and R 3 is a hydrogen atom. [Embodiment 6] The inclusion compound according to any one of [Embodiment 3] to [Embodiment 5], wherein the cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof. [Embodiment 7] The inclusion compound according to any one of [Embodiment 3] to [Embodiment 6], wherein the cyclodextrin is at least one selected from the group consisting of β-cyclodextrin and derivatives thereof. [Examples]

[0057] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[0058] Example 1 <Production of (R)-lipoic acid trisulfide> [Chemical formula] Into a 200 mL four-necked flask, 24.38 g (118.17 mmol) of (R)-α-lipoic acid and 488 mL (20.0 v / w) of 75% aqueous ethanol solution were charged. After confirming that the contents of the flask were dissolved, it was cooled to an internal temperature of 0 °C. Here, Oxone (registered trademark) (41.40 g, 124.20 mmol, 1.05 equivalents) was added in two portions, and then the reaction was carried out for about 50 minutes. After filtering off the insoluble matter in the reaction solution, it was washed with 65 mL (2.67 v / w) of ethanol. To the filtrate, at an internal temperature of 2 - 6 °C, an aqueous Na 2 S solution (70.70 g of Na 2 S·9H 2 O dissolved in 569 mL of water) 400 mL (206.93 mmol, 1.75 equivalents) was added dropwise over about 2.5 hours (during the addition and reaction, a 3 mol / L sulfuric acid aqueous solution was used to control the pH to 6 - 7, with a total usage of 14 mL). After reacting at an internal temperature of 3 °C and pH 7 for about 50 minutes, 41 mL (1.7 v / w) of 3 mol / L sulfuric acid aqueous solution was added dropwise to adjust the pH to 1.3. Next, 320 mL (13.1 v / w) of water and 320 mL (13.1 v / w) of ethyl acetate were added, and extraction was carried out with ethyl acetate. The aqueous layer was extracted 4 times with 160 mL (6.6 v / w) of ethyl acetate, the organic layers were combined, and concentrated under reduced pressure at an external temperature of 30 °C. After adding ethanol to the concentrate to dissolve it, column purification was carried out using ODS. After concentrating the fraction under reduced pressure at an external temperature of 30 °C, it was dried with an oil pump to obtain 10.69 g (44.84 mmol, yield 38%, HPLC purity 99.7%, white solid) of (R)-lipoic acid trisulfide.

[0059] <Production of (R)-lipamide trisulfide>

Chemical formula

[0060] Example 2 <Production of Lipamide Trisulfide (Racemic)>

Chemical Structure

[0061] <Purity Test (HPLC) of Lipoamide Trisulfide> Detector: Ultraviolet absorptiometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 mm I.D. × 250 mm, 5 μm) Column temperature: Constant temperature around 40 °C Mobile phase A: Aqueous phosphoric acid solution (pH 3) Mobile phase B: Methanol Delivery of mobile phase: The concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0062]

Table 1

[0063] Example 3 <Production of (R)-lipoic acid trisulfide - DEG ester>

Chemical formula

[0064] Example 4 <Production of (R)-Lipoic Acid Trisulfide-Choline Ester>

Chemical formula

[0065] Example 5 <Production of (R)-Lipamide Trisulfide Derivative (I)>

Chemical formula

[0066] Examples 6 - 12 Hereinafter, "HP" is an abbreviation for "hydroxypropyl", "Me" is an abbreviation for "methyl", and "Mal" is an abbreviation for "maltosyl".

[0067] <Production of lipoic acid trisulfide>

Chemical formula

[0068] 2.0 g (9.02 mmol) of lipoic acid and 40 mL of 75% aqueous ethanol solution were charged into a reaction vessel and cooled to an internal temperature of 0 °C. 3.4 g (10.20 mmol) of Oxone (registered trademark) was added thereto and reacted for about 2 hours. After filtering the inorganic salts in the reaction solution, it was washed with 7 mL of ethanol. To the filtrate, 5.8 g (24.1 mmol) of sodium sulfide nonahydrate was added and reacted for about 1 hour. After dropping 7 mL of 3 mol / L sulfuric acid aqueous solution into this reaction solution, subsequently, 20 mL of water and 45 mL of ethyl acetate (AcOEt) were added, and extraction was performed with AcOEt. The aqueous layer was extracted twice with 20 mL of AcOEt, and the organic layers were combined and concentrated under reduced pressure. After adding 3 mL of ethanol to the concentrate to dissolve it, the solution was purified by an ODS column (YMC Dispo Pack AT, mobile phase: aqueous acetonitrile solution) to obtain 0.7 g (2.39 mmol, HPLC purity: 100%) of lipoic acid trisulfide.

[0069] <Production of CD inclusion complex of lipoic acid trisulfide> Example 6: β-CD inclusion complex of lipoic acid trisulfide (racemate) 1020.0 mg (0.899 mmol) of β-CD and 80 mL of water were charged into a 100 mL eggplant flask. After confirming that the contents of the flask were dissolved, 99.8 mg (0.419 mmol) of lipoic acid trisulfide was added, and the inside of the flask was rinsed with 20 mL of water. After stirring at 45 °C for 15 minutes, filtration was performed, and the inside of the flask and the crystals were washed with 10 mL of water. The obtained filtrate was frozen in a freezer at -20 °C for 23 hours. Freeze-drying was performed at an external temperature of 20 °C for about 4.5 days to obtain 980.0 mg (white solid) of the inclusion complex.

[0070] Example 7: HP-β-CD inclusion complex of lipoic acid trisulfide (racemate) 1291.0 mg of HP-β-CD and 16 mL of water were charged into a 50 mL eggplant flask. After confirming that the contents of the flask were dissolved, 100.0 mg (0.419 mmol) of lipoic acid trisulfide was added. After stirring at room temperature for about 28 hours, filtration was performed, and the inside of the flask and the crystals were washed with 10 mL of water. The obtained filtrate was frozen in a freezer at -20 °C for about 2 days. Freeze-drying was performed at an external temperature of 20 °C for about 2 days to obtain 1330.0 mg (white solid) of the inclusion complex.

[0071] Example 8: HP-β-CD Inclusion Complex of (R)-Lipoic Acid Trisulfide A 50 mL eggplant flask was charged with 969.9 mg of HP-β-CD and 10 mL of water. After confirming that the contents of the flask had dissolved, 100.3 mg (0.421 mmol) of (R)-lipoic acid trisulfide was added, and the inside of the flask was rinsed with 4 mL of water. After stirring at room temperature for about 25 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 12 mL of water. The obtained filtrate was frozen in a freezer at -20 °C for 15 hours. Lyophilization was carried out at an external temperature of 20 °C for about 2 days to obtain 1040.0 mg (white solid) of the inclusion complex.

[0072] Example 9: Me-β-CD Inclusion Complex of Lipoic Acid Trisulfide (Racemic) A 50 mL eggplant flask was charged with 1616.0 mg of Me-β-CD (multi-methylated mixture) and 12 mL of water. After confirming that the contents of the flask had dissolved, 101.0 mg (0.424 mmol) of lipoic acid trisulfide was added, and the inside of the flask was rinsed with 4 mL of water. After stirring for 21 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 12 mL of water. The obtained filtrate was frozen in a freezer at -20 °C for 20 hours. Lyophilization was carried out at an external temperature of 20 °C for about 4 days to obtain 1665.2 mg (white solid) of the inclusion complex.

[0073] Example 10: Me-β-CD Inclusion Complex of (R)-Lipoic Acid Trisulfide A 50 mL eggplant flask was charged with 1616.0 mg of Me-β-CD (multi-methylated mixture) and 16 mL of water. After confirming that the contents of the flask had dissolved, 99.9 mg (0.420 mmol) of (R)-lipoic acid trisulfide was added, and the inside of the flask was rinsed with 4 mL of water. After stirring at room temperature for 6 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 13 mL of water. The obtained filtrate was frozen in a freezer at -20 °C for 28 hours. Lyophilization was carried out at an external temperature of 20 °C for about 3 days to obtain 1610.9 mg (white solid) of the inclusion complex.

[0074] Example 11: Mal-β-CD Inclusion Complex of Lipoic Acid Trisulfide (Racemic) A 50 mL eggplant flask was charged with 1224.2 mg (0.839 mmol) of Mal-β-CD and 14 mL of water. After confirming that the contents of the flask had dissolved, 100.4 mg (0.421 mmol) of lipoic acid trisulfide was added and the inside of the flask was rinsed with 2 mL of water. After stirring at room temperature for 31 hours, it was filtered, and the inside of the flask and the crystals were washed with 10 mL of water. The resulting filtrate was frozen in a freezer at -20 °C for 22 hours. Freeze-drying was carried out at an external temperature of 20 °C for about 46 hours to obtain 1180.0 mg (white solid) of the inclusion complex.

[0075] Example 12: Inclusion of (R)-lipoic acid trisulfide with Mal-β-CD A 50 mL eggplant flask was charged with 1224.2 mg (0.839 mmol) of Mal-β-CD and 10 mL of water. After confirming that the contents of the flask had dissolved, 100.1 mg (0.420 mmol) of (R)-lipoic acid trisulfide was added and the inside of the flask was rinsed with 5 mL of water. After stirring at room temperature for 4.5 hours, it was filtered, and the inside of the flask and the crystals were washed with 11 mL of water. The resulting filtrate was frozen in a freezer at -20 °C for 24 hours. Freeze-drying was carried out at an external temperature of 20 °C for about 41 hours to obtain 1319.6 mg (white solid) of the inclusion complex.

[0076] The yields and solubilities of the inclusion complexes obtained in Examples 6 to 12 are shown in Table 2.

[0077]

Table 2

[0078] Next, a stability test was conducted on (R)-lipoic acid trisulfide contained in the inclusion compounds obtained in Examples 8, 10, and 12. In the stability test, a part (sample) of (R)-lipoic acid trisulfide contained in the inclusion compounds of Examples 8, 10, and 12 was allowed to stand at 40°C for 3 months. At this time, samples were prepared with the sample being allowed to stand under light-shielded conditions and without light shielding. After standing for 3 months, the content of each sample was examined by HPLC, and the ratio (residual rate) to the content before standing was examined. As the CDs, β-CD, HP-β-CD, Me-β-CD, and Mal-β-CD were used. The results are shown in Figure 1. In the figure, "SSS" is an abbreviation for "trisulfide".

[0079] The conditions for HPLC are as follows. Detector: Ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 mm I.D. × 250 mm, 5 μm) Column temperature: Constant temperature around 40°C Mobile phase A: Aqueous phosphoric acid solution (pH 3) Mobile phase B: Methanol Liquid feeding of the mobile phase: The concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0080]

Table 3

Claims

1. A compound represented by the following formula (1). 【Chemical 1】 [In the formula, R １ and R ２ are each independently a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR ５ ; an alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of -NR ６ R ７ and -N ＋ R ９ R １０ R １１ ; or -(CH ２ CH ２ O) ｎ R ８ wherein R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.]

2. R １ and R ２ The compound according to claim 1, wherein R and R are each a hydrogen atom.

3. A compound represented by the following formula (3). 【Chemical Formula 2】 [wherein, R ４ is an alkyl group having 1 to 6 carbon atoms and having one or more substituents selected from the group consisting of a carboxy group and -OR ５ ; an alkyl group having 2 to 6 carbon atoms and having one or more substituents selected from the group consisting of -NR ６ R ７ and -N ＋ R ９ R １０ R １１ ; or -(CH ２ CH ２ O) ｎ R ８ ; R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.]

4. A cyclodextrin clathrate in which at least one selected from the group consisting of a compound represented by the following formula (1), a compound represented by the following formula (2), and a salt of the compound represented by the following formula (2) is included in cyclodextrin. 【Chemical 3】 [In the formula, R １ and R ２ each independently represents a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR ５ ; an alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of -NR ６ R ７ and -N ＋ R ９ R １０ R １１ ; or -(CH ２ CH ２ O) ｎ R ８ wherein R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n is an integer of 2 to 5.] 【Chemical Formula 4】 [In the formula, R ３ represents a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and -OR ５ ; an alkyl group having 2 to 6 carbon atoms which may have one or more substituents selected from the group consisting of -NR ６ R ７ and -N ＋ R ９ R １０ R １１ ; or -(CH ２ CH ２ O) ｎ R ８ ; R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.]

5. The clathrate according to claim 4, wherein the salt of the compound represented by the formula (2) includes at least one selected from the group consisting of a salt with an alkali metal, a salt with an alkaline earth metal, an ammonium salt, a salt with an inorganic acid, and a salt with an organic acid.

6. The compound is a compound represented by the formula (2), and R ３ is a hydrogen atom. The clathrate according to claim 4 or 5.

7. The clathrate according to any one of claims 4 to 6, wherein the cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof.

8. The clathrate according to any one of claims 4 to 7, wherein the cyclodextrin is at least one selected from the group consisting of β-cyclodextrin and derivatives thereof.

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