Trisulfide compound and clathrate compound thereof

Abstract

A compound represented by formula (1) or a salt thereof. # imgabs0 # [in the formula, R1 is a group represented by formula (2), a group represented by formula (3), a group represented by formula (4), or a group represented by formula (5)] # imgabs1 # [in the formula, R2 and R3 are each independently an alkylene group having 1-4 carbon atoms, and # imgabs2 # represents a bond] # imgabs3 # [in the formula, R4 and R5 are each independently a hydrogen atom, an optionally substituted alkyl group having 1-4 carbon atoms; r4 and R5 may form a ring together with the atoms to which they are bound, # imgabs4 # represents a binding bond] # imgabs5 # [in the formula, # imgabs6 # represents a binding bond] # imgabs7 # [in the formula, # imgabs8 # represents a binding bond].

Description

Technical Field

[0001] The present invention relates to trisulfide compounds and their inclusion compounds. Background Art

[0002] Compounds containing a covalent bond structure formed by 3 consecutive sulfur atoms are called trisulfide compounds. Trisulfide compounds have redox ability according to the valence of sulfur atoms constituting them, and thus are expected to have various physiological activity functions.

[0003] Patent Document 1 discloses lipoic acid trisulfide obtained by trisulfiding α-lipoic acid for treating diabetes and chronic hepatitis. Lipoic acid trisulfide can be produced by the methods described in Patent Documents 2 and 3, for example.

[0004] Non-Patent Document 1 shows that neurodegeneration in a Parkinson's disease model mouse was alleviated by administering polysulfide. Glutathione trisulfide and lipoic acid trisulfide are disclosed as polysulfides in Non-Patent Document 1.

[0005] Although trisulfide compounds have various physiological activity functions and are expected to be applied to new medical uses, for example, it is recognized that the problems faced in their practical application are the problems in water solubility and stability required as an active ingredient of a drug. For example, Patent Document 3 discloses a method for improving water solubility. In addition, Non-Patent Document 2 describes a trisulfide compound having high water solubility. In addition, Non-Patent Document 3 reports on the stability of polysulfide compounds containing trisulfide and its improvement.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: Specification of Chinese Patent Application Publication No. 107652264

[0009] Patent Document 2: International Publication No. 2021 / 200487

[0010] Patent Document 3: International Publication No. 2022 / 045212

[0011] Non-Patent Documents

[0012] Non-Patent Document 1: F. Nagashima et al., “Sulfide:quinone oxidoreductase ameliorates neurodegeneration in a murine model of Parkinson’s disease”, Redox Biology, 59, 2023, 102562

[0013] Non-Patent Document 2: E. Kanemaru et al., “Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia”, Redox Biology, 60, 2023, 102620

[0014] Non-Patent Document 3: T. Sawa et al., “Chemical Biology of Reactive Sulfur Species: Hydrolysis-Driven Equilibrium of Polysulfides 1 as a Determinant of Physiological Functions”, Antioxidants & Redox Signaling, 36, 2022, 327 Summary of the Invention

[0015] Problems to be Solved by the Invention

[0016] An object of the present invention is to provide a novel trisulfide compound and its cyclodextrin clathrate (also referred to as a “CD clathrate” or simply a “clathrate”).

[0017] Means for Solving the Problems

[0018] The present inventors conducted in-depth studies from the viewpoints of the structure and stability of trisulfide compounds and found novel compounds with high stability. The present invention relates to, for example, the following [1] to [4].

[0019] [1] A compound represented by the following formula (1) or a salt thereof,

[0020]

[0021] [wherein, R 1 is a group represented by the following formula (2), a group represented by the following formula (3), a group represented by the following formula (4), or a group represented by the following formula (5)]

[0022]

[0023] [wherein, R 2 and R 3Each independently represents an alkylene group having 1 to 4 carbon atoms, represents a bonding site]

[0024]

[0025] [In the formula, R 4 and R 5 each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a substituent, and R 4 and R 5 may form a ring together with the atoms to which they are bonded, represents a bonding site]

[0026]

[0027] [In the formula, represents a bonding site]

[0028]

[0029] [In the formula, represents a bonding site].

[0030] [2] A CD inclusion compound formed by inclusion of the compound or a salt thereof described in [1] with cyclodextrin.

[0031] [3] The inclusion compound according to [2], wherein the salt of the compound (1) includes at least one selected from the group consisting of salts with alkali metals, salts with alkaline earth metals, ammonium salts, salts with inorganic acids, and salts with organic acids.

[0032] [4] The inclusion compound according to [2] or [3], wherein the cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and their derivatives.

[0033] Advantages of the Invention

[0034] According to the present invention, a novel trisulfide compound and its CD inclusion complex can be provided. Thioctic acid trisulfide is considered to exhibit effects such as reactive oxygen species scavenging and hydrogen sulfide scavenging brought about by its trisulfide structure. Since the trisulfide compound of the present invention has two trisulfide structures in the molecule, these effects are expected to be further enhanced. In addition, the cyclic trisulfide structure is also expected to exhibit a scavenging effect on free radicals harmful to organisms. The trisulfide compound of the present invention is also expected to more effectively exhibit a termination effect on free radical chain reactions by arranging two cyclic trisulfide structures in its molecule. In addition, since the free radical chain reaction may also be a factor leading to the instability of the trisulfide structure, if the free radical chain reaction can be effectively terminated by arranging two cyclic trisulfide structures in the molecule, it is also possible to expect a delay in the reduction rate of the active ingredient due to decomposition in the form (solid, powder, solution, etc.) used for pharmaceutical purposes. In addition, since the linking group portion bonding two thioctic acid trisulfide structures of the trisulfide compound of the present invention contains a hydrogen bond and / or a hydrophilic structure, the water solubility is improved, and it is considered to be a compound with a better balance of water solubility and liposolubility. The trisulfide compound of the present invention is also considered to have stability equal to or higher than that of thioctic acid trisulfide. The trisulfide compound of the present invention has better thermal stability than thioctic acid trisulfide.

[0035] The CD inclusion complex of the present invention is considered to improve effects such as reactive oxygen species scavenging, hydrogen sulfide scavenging, and free radical scavenging in the same manner as the trisulfide compound of the present invention. In addition, it is considered that the water solubility and stability are further improved by forming the CD inclusion complex of the trisulfide compound of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is a graph showing the results of the thermal stability test of Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0037] The trisulfide compound of one embodiment of the present invention is Compound (1). Compound (1) can be said to be a compound in which two molecules of thioctic acid trisulfide are bonded through a linking group.

[0038] R 2 and R 3 Each independently represents an alkylene group having 1 to 4 carbon atoms. Examples of the alkylene group having 1 to 4 carbon atoms include methylene, ethylene, n-propylene, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, and the like.

[0039] R 4 and R 5 Each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a substituent, R 4 and R5 They can form a ring together with the atoms to which they are attached. As substituents, the following can be mentioned: hydroxyl group; alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, etc. As alkyl groups having 1 to 4 carbon atoms, the following can be mentioned: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, etc. R 4 and R 5 When forming a ring together with the atoms to which they are attached, the ring formed can be, for example, an oxetane ring.

[0040] Compound (1) can be produced by the following method:

[0041] (A) A step (Step 1) of subjecting a compound (lipoic acid trisulfide) represented by formula (1a) to a condensation reaction with a molecule for forming a linking group (a compound represented by the following formula (2a), a compound represented by the following formula (3a), o-phthalenediamine, m-phthalenediamine, p-phthalenediamine, piperazine, etc.); or,

[0042] (B) A step (Step 1’) of subjecting a compound (lipoic acid) represented by formula (1b) to a condensation reaction with the above molecule for forming a linking group, a step (Step 2) of oxidizing the obtained disulfide compound with an oxidizing agent to obtain a sulfoxide compound, and a step (Step 3) of reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound.

[0043] As the solvents used in Step 1 and Step 1’, for example, dichloromethane, chloroform, tetrahydrofuran can be mentioned, and dichloromethane is preferred. The amount of the solvent can be set to 1 mL to 200 mL, preferably 3 mL to 35 mL, relative to 1 g of compound (1a) or compound (1b). As the condensing agents used in Step 1 and Step 1’, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, EDC) and its salts, N,N’-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP), 1,1’-carbonyldiimidazole (CDI), etc. can be mentioned. When using these compounds as condensing agents, N-hydroxysuccinimide (NHS), 1-hydroxybenzotriazole (HOBt), etc. can be used as additives. The amount of the condensing agent used in Step 1 and Step 1’ can be set to 0.8 equivalent to 2.0 equivalents, preferably 1.0 equivalent to 1.5 equivalents, relative to 1 equivalent of compound (1a) or compound (1b). The reaction temperature of Step 1 and Step 1’ can be set to -10°C to 40°C, preferably 15°C to 25°C. The reaction time of Step 1 and Step 1’ can be set to 1 hour to 3 days, preferably 1 hour to 24 hours.

[0044]

[0045]

[0046]

[0047]

[0048] In order to bond two molecules of compound (1a) or compound (1b) via a linking group, it is sufficient to set the amount of the molecule for forming the linking group in Step 1 and Step 1' to be 0.45 to 1.00 equivalents relative to the amount of lipoic acid trisulfide. However, as long as the target compound can be obtained, other equivalents can also be set.

[0049] The compound (lipoic acid trisulfide) represented by the following formula (1a) can be produced by the methods described in Patent Documents 2 and 3. The procedures and conditions of Steps 2 and 3 in Production Method (B) can follow, for example, the procedures and conditions of Steps 1 and 2 in Patent Document 3.

[0050] R in formula (aa) 2 and R 3 are the same as R in formula (2) 2 and R 3 respectively. Examples of the compound represented by formula (aa) include dialkylene glycols having 4 to 6 carbon atoms. Examples of the compound represented by formula (aa) include diethylene glycol, linear or branched dipropylene glycol, and the like.

[0051] R in formula (bb) 4 and R 5 are the same as R in formula (3) 4 and R 5 respectively. Examples of the compound represented by formula (bb) include 2,2-dimethyl-1,3-propanediamine, 2-oxetane-1,3-propanediamine, 2-methoxy-1,3-propanediamine, and the like.

[0052] Examples of compound (1) include compounds (compounds (11) to (16)) represented by the following formulas (11) to (16).

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] The molecular weights and ClogP of Compounds (11) to (16) are shown in Table 1.

[0060] [Table 1]

[0061]

[0062] The molecular weight of Compound (1) and its salts can be 800 or less, 750 or less, or 700 or less, preferably 600 or less. The molecular weight of Compound (1) and its salts can be 400 or more, 450 or more, or 500 or more. It is considered that when the molecular weight of Compound (1) and its salts is within these ranges, the absorption rate in the living body is further increased.

[0063] The ClogP of Compound (1) and its salts can be 1 or more, 2 or more, 3 or more, or 4 or more. The ClogP of Compound (1) and its salts can be 8 or less, 7 or less, or 6 or less. It can be said that when the ClogP of Compound (1) and its salts is within these ranges, the balance between the water solubility and lipid solubility of Compound (1) and its salts is more excellent. ClogP is a partition coefficient calculated by computer and can be determined according to the principles described in "CLOGP Reference Manual Daylight Version 4.9 (Release Date: August 1, 2011, https: / / www.daylight.com / dayhtml / doc / clogp / )".

[0064] The salts of Compound (1) may be pharmaceutically acceptable salts, and examples thereof include 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 hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; 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. When Compound (1) is obtained in the free form, it can be converted into a salt by a conventional method. In addition, when Compound (1) is obtained in the form of a salt, it can also be converted into the free form by a conventional method.

[0065] The compounds in this specification may exist in four optical isomers: R,R, R,S, S,R, and S,S. The compounds in this specification can be replaced by their optical isomers or a mixture containing their optical isomers in any ratio (such as a racemate). For example, compound (1) can be the optical isomer shown in the following formula (1-1), the optical isomer shown in the following formula (1-2), the optical isomer shown in the following formula (1-3), or the optical isomer shown in the following formula (1-4), or it can be replaced by a mixture containing these optical isomers in any ratio (such as a racemate).

[0066]

[0067]

[0068]

[0069]

[0070] The CD inclusion complex of another embodiment of the present invention is a compound formed by cyclodextrin inclusion of at least one selected from the group consisting of compound (1) and its salts.

[0071] The cyclodextrin can be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or their derivatives. Here, "derivative" means that at least one hydrogen atom of the hydroxyl group possessed by each cyclodextrin is replaced by an alkyl group or a 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.

[0072] The CD inclusion complex can be manufactured by the method described in Patent Document 3. More specifically, the CD inclusion complex can be manufactured through the following steps: the step of dissolving cyclodextrin in a solvent (step a); the step of adding a trisulfide compound or its salt to the obtained solution and stirring (step b); and the step of filtering the stirred liquid, washing it with the same solvent as used in step a, and freeze-drying the filtrate by freezing (step c). It should be noted that the filtration and washing operations in step c can be omitted.

[0073] The compound (1), its salt or their CD inclusion complex can be made into a pharmaceutical composition by adding pharmaceutically acceptable additives as needed.

[0074] The pharmaceutical composition containing the compound (1), its salt or their CD inclusion complex can be formulated into, for example, injections, oral preparations, eye drops, nasal drops, inhalants, intraoral retention agents, paints, suppositories, etc. As injections, for example, subcutaneous injections, intramuscular injections, intravenous injections, intraperitoneal injections, etc. can be cited. As oral preparations, for example, tablets, granules, fine granules, powders, capsules, etc. can be cited. As eye drops, for example, aqueous eye drops, oily eye drops, etc. can be cited. As nasal drops, aqueous nasal drops, oily nasal drops, etc. can be cited. As inhalants, aqueous inhalants, dry powder inhalants, etc. can be cited. As intraoral retention agents, lozenges, sublingual tablets, OD agents (oral disintegrants), etc. can be cited. As paints, plasters, ointments, creams, lotions, patches, etc. can be cited. As suppositories, fatty base type suppositories, water-soluble base type suppositories, etc. can be cited. As additives, for example, 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 regulators such as sodium phosphate buffer solution, histidine buffer solution, isotonizing agents such as sodium chloride, and excipients such as mannitol, glycine, sodium chloride, sucrose, etc. can be cited.

[0075] Examples

[0076] The following examples are given to illustrate the present invention in detail, but the present invention is not limited by these examples.

[0077] <Example 1>

[0078]

[0079] Add 100 mg (0.42 mmol) of lipoic acid trisulfide and 1 mL (10 v / w) of dichloromethane to a 5 mL eggplant-shaped flask. After confirming that the contents of the flask have dissolved, add 25.6 mg (0.21 mmol, 0.5 equiv) of 4-dimethylaminopyridine (DMAP), 88.5 mg (0.46 mmol, 1.1 equiv) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), and 0.4 mL (4 v / w) of dichloromethane. Then, cool to 0 °C and add 44.5 mg (0.42 mmol, 1.0 equiv) of diethylene glycol (DEG) and 0.4 mL (4 v / w) of dichloromethane. After purging the air in the flask with nitrogen, react overnight at room temperature. Then, at room temperature, wash the organic layer three times with 2 mL (20 v / w) of 1 mol / L hydrochloric acid aqueous solution, and once each with 2 mL (20 v / w) of 10% sodium bicarbonate aqueous solution and 2 mL (20 v / w) of saturated brine. Dry the organic layer over sodium sulfate and filter. After concentrating the obtained filtrate under reduced pressure, purify the concentrated residue by column chromatography (mobile phase: hexane / ethyl acetate mixture). Concentrate the obtained fraction under reduced pressure to obtain 16.7 mg (0.03 mmol, yield 15%, yellow oil) of compound (11).

[0080] 1 H-NMR: (CDCl3, 400 MHz) δ (ppm) = 4.23 (t, 4H, J = 4.8 Hz), 3.69 (t, 4H, J = 4.8 Hz), 3.51 - 3.13 (m, 6H), 2.35 (t, 4H, J = 8.0 Hz), 2.28 - 2.11 (m, 2H), 1.91 (tt, 2H, J = 13.2, 11.6 Hz), 1.72 - 1.40 (m, 12H)

[0081] <Example 2>

[0082]

[0083] To a 25 mL eggplant-shaped flask, add 200 mg (0.84 mmol) of (R)-lipoic acid trisulfide and 4 mL (20 v / w) of dichloromethane, and cool to 0 °C. After confirming that the contents of the flask have dissolved, add 193 mg (1.01 mmol, 1.2 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), 116 mg (1.01 mmol, 1.2 eq) of N-hydroxysuccinimide (NHS), and 32.5 mg (0.38 mmol, 0.45 eq) of piperazine to the flask. After purging the air in the flask with nitrogen, stir overnight at room temperature. Then, at room temperature, wash the organic layer twice with 4 mL (20 v / w) of 10% aqueous sodium bicarbonate solution and then once with 4 mL (20 v / w) of saturated brine. After concentrating the obtained organic layer under reduced pressure at an external temperature of 30 °C, purify the concentrated residue by column chromatography (mobile phase: dichloromethane / methanol mixture). Concentrate the fraction under reduced pressure to obtain 58 mg (0.11 mmol, yield 27%, white solid) of compound (12-1).

[0084] 1 H-NMR: (CDCl3, 400 MHz) δ(ppm) = 3.64 - 3.60 (m, 4H), 3.47 - 3.43 (m, 4H), 3.34 - 3.16 (m, 6H), 2.34 (t, 4H, J = 7.2 Hz), 2.30 - 2.10 (m, 2H), 1.90 (tt, 2H, J = 12.8, 12.0 Hz), 1.67 - 1.44 (m, 12H)

[0085] ESI-TOF-MS: m / z 527.1051 ([M+H] + ), calcd for [C 20 H 35 N2O2S6] - 527.1023

[0086] <Example 3>

[0087]

[0088] Add 200 mg (0.84 mmol) of (R)-lipoic acid trisulfide and 4 mL (20 v / w) of dichloromethane to a 25 mL eggplant-shaped flask, and cool to 0 °C. After confirming that the contents of the flask have dissolved, add 193 mg (1.01 mmol, 1.2 equivalents) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), 116 mg (1.01 mmol, 1.2 equivalents) of N-hydroxysuccinimide (NHS), and 45 μL (0.38 mmol, 0.45 equivalents) of 2,2-dimethyl-1,3-propanediamine to the flask. After purging the air in the flask with nitrogen, stir overnight at room temperature. Then, at room temperature, wash the organic layer twice with 4 mL (20 v / w) of 10% aqueous sodium bicarbonate solution. After concentrating the obtained organic layer under reduced pressure at an external temperature of 30 °C, purify the concentrated residue by column chromatography (mobile phase: dichloromethane / methanol mixture). Concentrate the fraction under reduced pressure to obtain 112 mg (0.21 mmol, yield 51%, white solid) of compound (13-1).

[0089] 1 1H-NMR: (CDCl3, 400 MHz) δ (ppm) = 6.54 (t, 2H, J = 6.4 Hz), 3.35 - 3.04 (m, 6H), 2.98 (d, 4H, J = 6.4 Hz), 2.25 - 2.17 (m, 6H), 1.89 (tt, 2H, J = 12.4, 12.0 Hz), 1.66 - 1.43 (m, 12H), 0.86 (s, 6H)

[0090] ESI-TOF-MS: m / z 543.1389 ([M+H] + ), calcd for [C 21 H 39 N2O2S6] - 543.1336

[0091] <Test Example 1>

[0092] Conduct the following test to evaluate the thermal stability of (R)-α-lipoic acid, (R)-lipoic acid trisulfide, and compound (12-1). Take each compound into an eggplant-shaped flask and heat at 100 °C for 5 hours. Take samples from the eggplant-shaped flask every 1 hour, dissolve them in a dichloromethane / methanol mixture (1:1), and use them for HPLC analysis. Calculate the residual rate over time from the area values of each component.

[0093] <Test Results>

[0094] The results are shown in Figure 1 . At Figure 1In this case, the residual rate on the vertical axis is calculated from the degree of decomposition over time of each sample with the amount before heating set to 100%. The residual rate of (R)-α-lipoic acid is less than 60% at the 1-hour mark and then decomposes slowly, reaching a residual rate of approximately 50% after 5 hours. Decomposition of (R)-trisulfide lipoic acid could not be confirmed at the 2-hour mark, but it decomposes slowly after 3 hours and reaches a residual rate of approximately 70% after 5 hours. Compound (12-1) hardly decomposes even after 5 hours, and the residual rate remains above 95%. In addition, (R)-α-lipoic acid and (R)-trisulfide lipoic acid immediately melt after the start of heating, and insoluble substances are by-produced. However, Compound (12-1) does not melt and remains in a solid state. It is speculated that this is because the high melting point of Compound (12-1) inhibits intermolecular polymerization. From the above, it was confirmed that the compound represented by formula (1) or a salt thereof has higher thermal stability than (R)-α-lipoic acid and (R)-trisulfide lipoic acid.

Claims

1. A compound represented by the following formula (1) or a salt thereof, In formula (1), R 1 is a group represented by the following formula (2), a group represented by the following formula (3), a group represented by the following formula (4), or a group represented by the following formula (5). In formula (2), R 2 and R 3 each independently represents an alkylene group having 1 to 4 carbon atoms, represents a bonding site, In formula (3), R 4 and R 5 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may have a substituent, and R 4 and R 5 may together with the atoms to which they are bonded form a ring, represents a bonding site, In formula (4), represents a bonding key, In formula (5), represents a bonding key.

2. A cyclodextrin clathrate, which is formed by clathrating the compound or a salt thereof according to claim 1 with cyclodextrin.

3. The clathrate according to claim 2, wherein The salt of the compound represented by the formula (1) includes at least one selected from the group consisting of salts with alkali metals, salts with alkaline earth metals, ammonium salts, salts with inorganic acids, and salts with organic acids.

4. The clathrate according to claim 2 or 3, wherein, The cyclodextrin is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and their derivatives.

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