Asymmetric trisulfide compound

Abstract

Disclosed is a compound represented by formula (I) or (II), or a salt thereof. In the formulae, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each a hydrogen atom or the like.

Description

Asymmetric trisulfide compound

[0001] The present invention relates to an asymmetric trisulfide compound. More specifically, it relates to an asymmetric trisulfide compound in which one is pantethine and the other is glutathione or cysteine.

[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 according to the possible valences of the constituent sulfur atoms, they are expected to have various physiological activity functions. As a method for producing a trisulfide compound, the method described in Patent Document 1 is known.

[0003] As a trisulfide compound, for example, pantethine trisulfide is known (Patent Document 2). In Patent Document 2, it is shown that pantethine trisulfide has a hydrogen sulfide removing action, and the usefulness of pantethine trisulfide as a pharmaceutical is expected.

[0004] International Publication No. 2021 / 200487 International Publication No. 2022 / 045052

[0005] An object of the present disclosure is to provide a novel trisulfide compound.

[0006] The present disclosure relates to, for example, the following [1] to

[10] . [1] Formula (I) or formula (II): [In formula (I), R １ and R ２ are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, or R １ and R ２ together may be a methylene group or a carbonyl group having an alkyl group having 1 to 4 carbon atoms, R ３ and R ４ are each independently a hydrogen atom or a protecting group for a carboxy group, R ５ is a hydrogen atom or a protecting group for an amino group, In formula (II), R ６ and R ７Each of these is independently a hydrogen atom, a C1-C9 alkyl group, or a C1-C5 acyl group, or R ６ and R ７ Together, they form a methylene group or carbonyl group which may have an alkyl group having 1 to 4 carbon atoms, and R ８ R is a protecting group for a hydrogen atom or a carboxyl group. ９ [2] The above compound is a protecting group for a hydrogen atom or an amino group. [2] is a compound represented by R １ , R ２ , R ３ , R ４ and R ５ The compound described in [1] or a salt thereof, which is a compound represented by formula (I) in which all are hydrogen atoms. [3] The above compound is R ６ , R ７ , R ８ and R ９ [1] The compound or a salt thereof, which is a compound represented by formula (II) in which all atoms are hydrogen atoms. [4] A pharmaceutical composition comprising the compound or a salt thereof, which is any one of [1] to [3], and a pharmaceutically acceptable carrier. [5] The pharmaceutical composition according to [4], wherein the pharmaceutically acceptable carrier is a sugar. [6] The pharmaceutical composition according to [5], wherein the sugar is lactose. [7] The pharmaceutical composition according to any one of [4] to [6], which is for oral administration, pulmonary administration, nasal administration, oral administration, rectal administration, vaginal administration, intravenous administration, or subcutaneous administration. [8] The pharmaceutical composition according to any one of [4] to [7], which is in the form of a tablet, capsule, granule, powder, inhalation powder, nasal powder, sublingual tablet, lozenge, drop, suppository, or vaginal suppository. [9] The pharmaceutical composition according to any one of [4] to [8], which is a tablet, capsule, granule, powder, inhalation powder, or nasal powder.

[10] A pharmaceutical composition according to any one of [4] to [9], which is in powder form.

[0007] This disclosure provides novel trisulfide compounds. Such trisulfide compounds have hydrogen sulfide scavenging ability. Furthermore, such trisulfide compounds have superior physical properties compared to existing trisulfide compounds. More specifically, the compound represented by formula (I) has high water solubility, and therefore can provide a pharmaceutical composition that has a low risk of inducing pneumoconiosis even when used as an inhalation formulation. The compound represented by formula (II) has high water solubility and is not hygroscopic, and therefore can provide a pharmaceutical composition that has a low risk of inducing pneumoconiosis even when used as an inhalation formulation and is stable even in high humidity environments.

[0008] This graph shows the results of the hygroscopicity test in Test Example 2. This graph shows the results of the hydrogen sulfide scavenging ability test in Test Example 3. This graph shows the results of the solution stability test in Test Example 4.

[0009] The following describes the forms in which this disclosure will be implemented.

[0010] One embodiment of the present disclosure is formula (I): This relates to the compound represented by formula (I) or its salt. The compound represented by formula (I) is also referred to as compound (I).

[0011] In formula (I), R １ and R ２ Each of these is independently a hydrogen atom, a C1-C9 alkyl group, or a C1-C5 acyl group, or R １ and R ２ Together, they are a methylene group or carbonyl group which may have an alkyl group having 1 to 4 carbon atoms, and R ３ and R ４ Each of these is independently a protecting group for a hydrogen atom or a carboxyl group, and R ５ R is a protecting group for a hydrogen atom or an amino group. １ and R ２ Each of these may independently be a hydrogen atom or an acyl group having 1 to 5 carbon atoms.

[0012] In formula (I), examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl groups. In formula (I), examples of C1-C5 acyl groups include formyl (methanoyl), acetyl (ethanolyl), n-propanoyl, isopropanoyl, cyclopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, and cyclobutanoyl groups. From the viewpoint of lowering the molecular weight of compound (I), the C1-C4 alkyl group is preferably a methyl or ethyl group, and the C1-C5 acyl group is preferably a formyl or acetyl group.

[0013] R １ and R ２ One example of a combination is (R １ , R ２ Examples of combinations include (hydrogen atom, hydrogen atom), (hydrogen atom, methyl group), (methyl group, hydrogen atom), (methyl group, methyl group), (hydrogen atom, formyl group), (formyl group, hydrogen atom), and (formyl group, formyl group).

[0014] R １ and R ２ When these combine to form a methylene group or carbonyl group which may have an alkyl group having 1 to 4 carbon atoms, R １ and R ２ Examples of these combinations include a methylene group, a methylene group having one methyl group, a methylene group having two methyl groups, and a carbonyl group.

[0015] R ３ and R ４ In this context, "carboxyl protecting group" refers to carboxylic acid protecting groups that are generally known to those skilled in the art, such as the methyl group, ethyl group, isopropyl group, trialkylsilyl group, tert-butyl group, and benzyl group.

[0016] R ５In this context, "amino group protecting groups" can refer to amino group protecting groups that are generally known to those skilled in the art, such as amide protecting groups like formyl, acetyl, benzoyl, nicotinoyl, trichloroacetyl, and trifluoroacetyl; cyclic imide protecting groups like phthaloyl and 2,3-diphenylmaleoyl; sulfonamide protecting groups like p-toluenesulfonyl; and carbamate protecting groups such as tert-butyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzylcarbonyl, p-nitrobenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl.

[0017] Compound (I) is R １ , R ２ , R ３ , R ４ and R ５ Preferably, all of these atoms are hydrogen atoms, and such a compound is pantetheine glutathione trisulfide represented by formula (Ia) (Ptt-SSS-G; Ptt represents the group obtained by removing the sulfhydryl group from pantetheine, and G represents the group obtained by removing the sulfhydryl group from glutathione).

[0018] One embodiment of the present disclosure is formula (II): This relates to compounds represented by formula (II) or their salts. The compound represented by formula (II) is also referred to as compound (II).

[0019] In formula (II), R ６ and R ７ Each of these is independently a hydrogen atom, a C1-C9 alkyl group, or a C1-C5 acyl group, or R ６ and R ７ Together, they are a methylene group or carbonyl group which may have an alkyl group having 1 to 4 carbon atoms, and R ８ R is a protecting group for a hydrogen atom or a carboxyl group. ９ R is a protecting group for a hydrogen atom or an amino group. ６ and R ７Each of these may independently be a hydrogen atom or an acyl group having 1 to 5 carbon atoms.

[0020] In formula (II), examples of C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl groups. In formula (I), examples of C1-C5 acyl groups include formyl (methanoyl), acetyl (ethanolyl), n-propanoyl, isopropanoyl, cyclopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, and cyclobutanoyl groups. From the viewpoint of lowering the molecular weight of compound (II), the C1-C4 alkyl group is preferably a methyl or ethyl group, and the C1-C5 acyl group is preferably a formyl or acetyl group.

[0021] R ６ and R ７ One example of a combination is (R ６ , R ７ Examples of combinations include (hydrogen atom, hydrogen atom), (hydrogen atom, methyl group), (methyl group, hydrogen atom), (methyl group, methyl group), (hydrogen atom, formyl group), (formyl group, hydrogen atom), and (formyl group, formyl group).

[0022] R ６ and R ７ When these combine to form a methylene group or carbonyl group which may have an alkyl group having 1 to 4 carbon atoms, R ６ and R ７ Examples of these combinations include a methylene group, a methylene group having one methyl group, a methylene group having two methyl groups, and a carbonyl group.

[0023] R ８ In this context, "carboxyl protecting group" refers to carboxylic acid protecting groups that are generally known to those skilled in the art, such as the methyl group, ethyl group, isopropyl group, trialkylsilyl group, tert-butyl group, and benzyl group.

[0024] R ９In this context, "amino group protecting groups" can refer to amino group protecting groups that are generally known to those skilled in the art, such as amide protecting groups like formyl, acetyl, benzoyl, nicotinoyl, trichloroacetyl, and trifluoroacetyl; cyclic imide protecting groups like phthaloyl and 2,3-diphenylmaleoyl; sulfonamide protecting groups like p-toluenesulfonyl; and carbamate protecting groups such as tert-butyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, p-methoxybenzylcarbonyl, p-nitrobenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl.

[0025] Compound (II) is R ６ , R ７ , R ８ and R ９ Preferably, all of these atoms are hydrogen atoms, and such a compound is a pantetheine cysteine ​​trisulfide represented by formula (IIa) (Ptt-SSS-Cys; Cys represents the group obtained by removing the sulfhydryl group from cysteine).

[0026] Compounds (I) and (II) may be in the form of free compounds or salts (especially pharmaceutically acceptable salts), or in the form of solvates (e.g., hydrates). Examples of pharmaceutically acceptable salts include 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; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine.

[0027] Compound (I) and Compound (II) can be prepared according to the following method. In the above reaction scheme, R Ａ teeth Represents RＢ teeth This represents X １ X represents hydrogen, 9-methylfluorene, etc. ２ This represents halogens, alkoxy groups, etc.

[0028] Examples of reaction solvents for step A include water, aqueous sulfuric acid solution, aqueous ethanol solution, and aqueous acetonitrile solution, and the amount of solvent is R Ａ -SS-R Ａ The amount can be 1 mL to 500 mL per 1 g. Examples of oxidizing agents that can be used include potassium peroxymonosulfate (sold under trade names such as Oxone®), peracetic acid, hydrogen peroxide (may be used together with a catalytic amount of methyltrioxorenium), and sodium periodate, and the amount of oxidizing agent used is R Ａ -SS-R Ａ The amount can be 0.8 to 4.0 equivalents per 1 equivalent. Examples of sulfur sources that can be used include sodium sulfide (sodium sulfide notahydrate), potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide, and the amount of sulfur source used is R Ａ -SS-R Ａ For every 1 equivalent, the amount can range from 0.5 to 4.0 equivalents. Ｂ -SS-R Ｂ The amount is R Ａ -SS-R Ａ The amount of 0.8 to 2.0 equivalents can be used per 1 equivalent. The reaction temperature can be -20°C to 30°C. The reaction time can be 15 minutes to 2 days.

[0029] Examples of reaction solvents for step B include water and isopropanol, and the amount of solvent is R Ａ - The amount can be 1 mL to 500 mL per 1 g of SH. Examples of condensing agents used include N,N'-Thiodymethalamide, and the amount of condensing agent used is R Ａ - The amount can be 0.8 to 2.0 equivalents relative to SH1 equivalent. Ｂ - The amount of SH is R Ａ- The amount can be 0.8 to 2.0 equivalents relative to the SH1 equivalent. The reaction temperature can be -20°C to 30°C. The reaction time can be 15 minutes to 2 days.

[0030] As the reaction solvent for Step C, for example, water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution can be mentioned. The amount of the solvent can be 1 mL to 500 mL per 1 g of R<000008​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​１ or R Ａ -S-X １ The amount of 0.8 to 2.0 equivalents can be used per 1 equivalent. The reaction temperature can be -20°C to 30°C. The reaction time can be 15 minutes to 2 days.

[0032] A pharmaceutical composition according to one embodiment of this disclosure comprises compound (I), compound (II), or salts thereof, and a pharmaceutically acceptable carrier.

[0033] A pharmaceutically acceptable carrier is, for example, a sugar. The sugar may be, for example, a monosaccharide, an oligosaccharide, or a polysaccharide, and in one preferred embodiment it may be a monosaccharide or an oligosaccharide, and in one more preferred embodiment it may be a monosaccharide or a disaccharide. In this disclosure, oligosaccharides mean sugars (disaccharides to hexasaccharides) consisting of two to six glycosidic bonds of monosaccharides, and polysaccharides mean sugars consisting of seven or more glycosidic bonds of monosaccharides.

[0034] The sugars relating to the pharmaceutical composition of this disclosure may, for example, have a molecular weight of 10,000 or less, 3,000 or less, 1,000 or less, 500 or less, or 350 or less.

[0035] Examples of monosaccharides relating to the pharmaceutical composition of this disclosure include glucose, fructose, xylitol, D-sorbitol, and D-mannitol. Examples of oligosaccharides relating to the pharmaceutical composition of this disclosure include lactose, sucrose, maltose, trehalose, and cyclodextrin. Examples of polysaccharides relating to the pharmaceutical composition of this disclosure include starch, hypmellose, and dextran. In one embodiment of this disclosure, the sugars relating to the pharmaceutical composition may be any sugar other than cyclodextrin.

[0036] The sugars relating to the pharmaceutical composition of this disclosure may be, for example, lactose, glucose, sucrose, maltose, or trehalose, and in one preferred embodiment, it may be lactose or sucrose, and in one more preferred embodiment, it may be lactose.

[0037] A pharmaceutical composition according to one embodiment of this disclosure may further contain, in addition to the above-mentioned compound (I), compound (II) or salts thereof, and a pharmaceutically acceptable carrier, other additives as components. Examples of additives include stabilizers such as amino acids (such as L-arginine), water-soluble polymers (such as HES (hydroxyethyl starch) and PVP (polyvinylpyrrolidone)), nonionic surfactants (such as polysorbate and poloxamer), isotonic agents such as sodium chloride, and excipients such as glycine and sodium chloride.

[0038] A pharmaceutical composition according to one embodiment of this disclosure may be for, for example, oral administration, transdermal administration, transpulmonary administration, ophthalmic administration, transnasal administration, oral administration, transrectal administration, transvaginal administration, intravenous administration, or subcutaneous administration. In other words, a pharmaceutical composition according to one embodiment of this disclosure may be in a form suitable for oral administration, transdermal administration, transpulmonary administration, ophthalmic administration, transnasal administration, oral administration, transrectal administration, transvaginal administration, intravenous administration, or subcutaneous administration. In a pharmaceutical composition according to one embodiment of this disclosure, if the pharmaceutically acceptable carrier is a sugar, the pharmaceutical composition may be for, for example, oral administration, transpulmonary administration, ophthalmic administration, transnasal administration, oral administration, transrectal administration, transvaginal administration, intravenous administration, or subcutaneous administration, and in one preferred embodiment it may be for oral administration, transpulmonary administration, transnasal administration, or oral administration, and in one more preferred embodiment it may be for oral administration.

[0039] A pharmaceutical composition according to one embodiment of the present disclosure may be in the form of, for example, tablets, capsules, granules, powders, ointments, poultices, gels, inhalation powders, nasal powders, sublingual tablets, lozenges, drops, suppositories, or vaginal suppositories. In a pharmaceutical composition according to one embodiment of the present disclosure, if the pharmaceutically acceptable carrier is a sugar, the pharmaceutical composition may be in the form of, for example, tablets, capsules, granules, powders, inhalation powders, nasal powders, sublingual tablets, lozenges, drops, suppositories, or vaginal suppositories, and in one preferred embodiment it may be in the form of tablets, capsules, granules, powders, inhalation powders, or nasal powders, and in one more preferred embodiment it may be in the form of tablets, capsules, granules, or powders. In these cases, tablets, capsules, granules, or powders may be administered orally; ointments or poultices may be administered transdermally; gels may be administered ophthalmically, nasally, orally, or vaginally; inhaled powders may be administered pulmonaryly; nasal powders may be administered nasally; sublingual tablets, lozenges, or drops may be administered orally; suppositories may be administered rectally; and vaginal suppositories may be administered vaginally.

[0040] A pharmaceutical composition according to one embodiment of this disclosure may be in powder form.

[0041] A pharmaceutical composition according to one embodiment of this disclosure is excellent in ease of handling (easy to handle). In this disclosure, ease of handling of a pharmaceutical composition may mean, for example, that the pharmaceutical composition has low hygroscopicity, or that the pharmaceutical composition has excellent water solubility.

[0042] Example 1: Synthesis of pantetheine glutathione trisulfide (Ptt-SSS-G)

[0043] Manufacturing Example 1

[0044] 475 mg (1.46 mmol, 1 eq.) of N,N'-Thiodhiphosphate and 4 mL (9 v / w) of isopropanol were charged into a 25 mL round-bottom flask. After confirming that the contents of the flask had dissolved, 450 mg (1.44 mmol, reference) of glutathione was charged, and after stirring for 1 hour, 400 mg (1.44 mmol, 1 eq.) of pantetheine was charged. After reacting at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (ODS column, mobile phase: water / ethanol). Finally, the mixture was concentrated under reduced pressure at ambient temperature of 30°C and dried with an oil pump to obtain 47.5 mg (0.077 mmol, yield 5%, HPLC purity: 93%) of Ptt-SSS-G as a white solid. １ H-NMR: (D ２ O, 400MHz) δ (ppm) = 3.95-3.94 (m, 3H), 3.77 (dd, 1H, J = 6.4, 6.4Hz), 3.56-3.34 (m, 7H), 3.16 (dd, 2H, J = 6.4, 6.4Hz) ), 3.03 (dd, 2H, J = 6.4, 6.4Hz), 2.54-2.47 (m, 4H), 2.13 (ddd, 2H, J = 13.6, 7.2, 3.2Hz), 0.89 (s, 3H), 0.85 (s, 3H). ESI-TOF-MS: m / z 616.1788 ([M+H] ＋ ), calcd for [C ２１ H ３８ N ５ O １０ S ３ ] - 616.1781.

[0045] Manufacturing Example 2

[0046] In a 300 mL square flask, 4.02 g (5.80 mmol, reference) of 80% pantethine aqueous solution, 4.18 g (5.80 mmol, 1 eq.) of oxidized glutathione hexahydrate, and 96 mL (24 v / w) of tap water were charged and cooled to 0°C. 4.16 g (12.8 mmol, 2.2 eq.) of Oxone® was added and the mixture was allowed to react for approximately 1 hour. Subsequently, an aqueous solution of sodium sulfide, prepared by dissolving 2.78 g (11.6 mmol, 2.0 eq.) of sodium sulfide notahydrate in 154 mL (19.2 v / w) of tap water, was added dropwise to the mixture. After refrigeration overnight, the reaction solution was purified by column chromatography (ODS column, mobile phase: water / ethanol). Finally, the sample was concentrated under reduced pressure at an ambient temperature of 30°C and dried with an oil pump to obtain 1.12 g (1.82 mmol, yield 31%, HPLC purity: 97%) of Ptt-SSS-G as a white solid.

[0047] Example 2: Synthesis of pantetheine cysteine ​​trisulfide (Ptt-SSS-Cys)

[0048] In a 20 mL test tube, 409 mg (1.70 mmol, reference) of cystine and 6 mL (14.7 v / w) of 1 mol / L hydrochloric acid were charged and cooled to 0°C. 610 mg (1.87 mmol, 1.1 eq.) of Oxone® was added and the mixture was allowed to react for approximately 1 hour. In another 20 mL test tube, 1.18 g (1.70 mmol, 1.0 eq.) of 80% pantethine aqueous solution and 6 mL (14.7 v / w) of tap water were charged and cooled to 0°C. 610 mg (1.87 mmol, 1.1 eq.) of Oxone® was added and the mixture was allowed to react for approximately 1 hour. The solutions from each reaction were mixed and cooled to 0°C. Next, an aqueous sodium sulfide solution, prepared by dissolving 817 mg (3.40 mmol, 2.0 eq.) of sodium sulfide notahydrate in 9.6 mL (23.5 v / w) of tap water, was added dropwise to the mixture. After refrigeration overnight, the reaction solution was purified by column chromatography (ODS column, mobile phase: water / ethanol). Finally, the mixture was concentrated under reduced pressure at an ambient temperature of 30°C and dried with an oil pump to obtain 309 mg (1.7 mmol, yield 42%, HPLC purity: 97%) of white solid Ptt-SSS-Cys. １ H-NMR: (D ２O, 400MHz) δ (ppm) = 4.13 (dd, 1H, J = 8.0, 2.7Hz), 3.95 (s, 1H), 3.59-3.45 (m, 6H), 3.36 (d, 1H, J = 11.2Hz), 3.30 (dd, 1H, J=14.8, 8.0Hz), 3.06 (dd, 2H, J=6.4, 6.4Hz), 2.49 (dd, 2H, J=6.4, 6.4Hz), 0.89 (s, 3H), 0.85 (s, 3H). ESI-TOF-MS: m / z 430.1143 ([M+H] ＋ ), calcd for [C １４ H ２８ N ３ O ６ S ３ ] - 430.1140.

[0049] Comparative Example 1: Synthesis of cysteine ​​trisulfide (Cys-SSS-Cys), glutathione trisulfide (G-SSS-G), and pantethine trisulfide (Ptt-SSS-Ptt)

[0050] Cys-SSS-Cys, G-SSS-G, and Ptt-SSS-Ptt were synthesized according to the methods described in International Publication No. 2021 / 200487 and International Publication No. 2022 / 045052.

[0051] Test Example 1: Solubility of Trisulfide Compounds in Water The trisulfide compounds of the examples and comparative examples were dissolved in water at 20°C and their solubility was evaluated.

[0052] The results are shown in Table 1.

[0053]

[0054] For reference, the solubility of the racemic and R-forms of trisulfide lipoate in water at 20°C, as described in International Publication No. 2022 / 045212, is also shown in Table 1.

[0055] As shown in Table 1, lipoic acid trisulfide, G-SSS-G, and Cys-SSS-Cys had low solubility in water, while Ptt-SSS-G and Ptt-SSS-Cys had high solubility in water.

[0056] Test Example 2: Hygroscopicity of Trisulfide Compounds The hygroscopicity of the trisulfide compounds in the examples and comparative examples was evaluated under conditions of a temperature of 23±1°C and a relative humidity of 66±2%. For the evaluation of hygroscopicity, Ptt-SSS-G and Ptt-SSS-Cys were stored in a desiccator with a constant humidity using the saturated salt method, and their weight was measured for 25 hours from the start of storage. The amount of moisture absorbed was calculated from the change in weight.

[0057] The results are shown in Figure 1. As shown in Figure 1, Ptt-SSS-Ptt and Ptt-SSS-G were confirmed to be hygroscopic, while Ptt-SSS-Cys was not.

[0058] Test Example 3: Hydrogen Sulfide Scavenging Ability (Hydrogen Sulfide Removal Effect) of Trisulfide Compounds The hydrogen sulfide scavenging ability of the trisulfide compounds in the examples and comparative examples was evaluated by methylene blue spectrophotometric analysis.

[0059] The specific testing method is as follows: <H ２ Preparation of S standard solution > Sodium sulfide notahydrate (Na ２ S.9H ２ Dissolve O) in purified water to prepare a 100 μmol / L sodium sulfide nonahydrate solution, and then H ２ S standard solution was used. <Preparation of p-aminodimethylaniline (DPDA) solution> p-aminodimethylaniline was dissolved in 10N sulfuric acid to prepare a 2 mmol / L DPDA solution. <Preparation of iron(III) chloride solution> Iron(III) chloride hexahydrate was dissolved in 1% sulfuric acid to prepare a 6 mmol / L FeCl solution. ３ A solution was prepared. <Preparation of trisulfide compound solution> The trisulfide compound was dissolved in 25 mmol / L phosphate buffer (pH 7, hereinafter referred to as "PBS") to prepare a solution with a concentration of 100 μmol / L of trisulfide compound. <Test method> H ２ Ten mL (1 μmol, reference) of S standard solution was added to a stoppered test tube and stirred. To this solution, one mL (1 μmol, 1 equivalent) of PBS (blank) or trisulfide compound solution was added and stirred for a predetermined time (0 minutes, 5 minutes, 15 minutes, or 30 minutes). After stirring, one mL (2 μmol, 2 equivalents) of DPDA solution and FeCl were added.３ One mL (6 μmol, 6 equivalents) of the solution was added and the mixture was stirred further. The absorbance of the solution (wavelength: 668 nm) was measured after the absorbance of the solution stopped changing (i.e., after the color development due to methylene blue formation was complete). This test was performed under room temperature conditions.

[0060] The results are shown in Table 2 and Figure 2.

[0061]

[0062] As shown in Table 2 and Figure 2, hydrogen sulfide scavenging ability was confirmed for all tested trisulfide compounds. In particular, Ptt-SSS-Cys showed high hydrogen sulfide scavenging ability, exhibiting activity approximately 1.5 times stronger than that of the other trisulfide compounds.

[0063] Test Example 4: Solution Stability of Trisulfide Compounds The trisulfide compounds of the examples and comparative examples were dissolved in phosphate buffer, and their solution stability was evaluated. <Preparation of Trisulfide Compound Solutions> Trisulfide compounds were dissolved in phosphate buffer (pH 7.0) to prepare a solution with a concentration of 5 mmol / L of trisulfide compound. <Test Method> 5 mL of each trisulfide compound solution was added to a test tube and stirred at 40°C. This solution was sampled at 0, 5, 8, 25, 30, and 96 hours from the start of stirring, and the HPLC area % of the trisulfide compound was confirmed by HPLC.

[0064] The results are shown in Table 3 and Figure 3.

[0065]

[0066] As can be seen from the results shown in Table 3 and Figure 3, G-SSS-G and Ptt-SSS-Ptt showed high solution stability, while Ptt-SSS-G and Ptt-SSS-Cys were confirmed to decompose significantly. The main decomposition products of Ptt-SSS-G were Ptt-SSS-Ptt (22%; HPLC area%, the same applies below) and G-SSS-G (15%), suggesting that Ptt-SSS-G can be a precursor of Ptt-SSS-Ptt and / or G-SSS-G. Furthermore, the main decomposition products of Ptt-SSS-Cys were Ptt-SSS-Ptt (32%), Ptt-SS-Cys (20%), Ptt-SS-Ptt (8%), Cys-SS-Cys (6%), and Cys-SSS-Cys (5%), suggesting that Ptt-SSS-Cys can be a precursor to Ptt-SSS-Ptt and / or Cys-SSS-Cys. Ptt-SSS-Ptt is amorphous and highly deliquescent, making it difficult to handle as it can immediately transform into a highly viscous liquid. On the other hand, Ptt-SSS-G and Ptt-SSS-Cys are powders and are easy to handle. Ptt-SSS-G and Ptt-SSS-Cys, which can serve as easily handled precursors to Ptt-SSS-Ptt, are considered to have high potential for use in pharmaceutical compositions.

[0067] Detector: UV absorbance spectrophotometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 × 250 mm, 5 μm) Column temperature: Constant temperature around 40°C Mobile phase A: Phosphate aqueous solution (pH 3) Mobile phase B: Methanol Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 4.

Claims

1. Formula (I) or formula (II): [In formula (I), R １ and R ２ are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, or R １ and R ２ together may be a methylene group or a carbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, R ３ and R ４ are each independently a hydrogen atom or a protecting group for a carboxy group, R ５ is a hydrogen atom or a protecting group for an amino group, in formula (II), R ６ and R ７ are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, or R ６ and R ７ together may be a methylene group or a carbonyl group optionally having an alkyl group having 1 to 4 carbon atoms, R ８ is a hydrogen atom or a protecting group for a carboxy group, R ９ is a hydrogen atom or a protecting group for an amino group.], a compound represented thereby or a salt thereof.

2. The compound is R １ , R ２ , R ３ , R ４ and R ５ The compound or salt thereof according to claim 1, wherein the compound is represented by formula (I), where all atoms are hydrogen atoms.

3. The aforementioned compound is R ６ , R ７ , R ８ and R ９ The compound or salt thereof according to claim 1, wherein the compound is represented by formula (II) in which all atoms are hydrogen atoms.

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