Trisulfide compounds

Abstract

Disclosed is a compound represented by formula (1) or a salt thereof. # imgabs0 # [In the formula, R10 is a hydrogen atom or the like, R11 is a hydrogen atom or the like, and h and i are each independently 0 or 1].

Description

Technical Field

[0001] The present invention relates to a trisulfide compound. Background Art

[0002] A compound containing a covalent structure formed by three consecutive sulfur atoms is called a trisulfide compound. Since a trisulfide compound has redox ability depending on the valence of sulfur atoms constituting it, various physiological activity functions are expected. 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 (Patent Document 2) is known. Patent Document 2 discloses that pantethine trisulfide has a hydrogen sulfide removing effect, and the usefulness of pantethine trisulfide as a medicine is expected.

[0004] Prior Art Documents

[0005] Patent Documents

[0006] Patent Document 1: International Publication No. 2021 / 200487

[0007] Patent Document 2: International Publication No. 2022 / 045052 Summary of the Invention

[0008] Problems to be Solved by the Invention

[0009] An object of the present invention is to provide a new trisulfide compound.

[0010] Means for Solving the Problems

[0011] The present invention relates to, for example, the following [1] to

[10] .[[]END]]

[0012] [1] A compound represented by the following formula (1) or a salt thereof,

[0013]

[0014] [wherein, R 10 is a hydrogen atom or [wherein, is a bond] group, R 11 is a hydrogen atom or [wherein, is a bond] group, provided that R 10 and R 11 are not simultaneously hydrogen atoms, and R 1 , R 2 , R 3 and R 4Each independently represents a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an acyl group having 1 to 5 carbon atoms, R 1 and R 3 may together form a group or a carbonyl group represented by the following formula (2), R 2 and R 4 may together form a group or a carbonyl group represented by the following formula (2), wherein R 1 、R 2 、R 3 and R 4 at least one of them is an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, and h and i each independently represent 0 or 1]

[0015]

[0016] [In the formula, R 5 is a methylene group which may have an alkyl group having 1 to 4 carbon atoms as a substituent, is a bonding bond].

[0017] [2] The compound or its salt according to [1], wherein R 1 、R 2 、R 3 and R 4 each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an alkyl group having 1 to 4 carbon atoms.

[0018] [3] The compound or its salt according to [1], wherein R 1 、R 2 、R 3 and R 4 each independently represent a hydrogen atom or an acyl group having 1 to 5 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an acyl group having 1 to 5 carbon atoms.

[0019] [4] The compound or its salt according to [1], wherein R 1 and R 3 together form a group or a carbonyl group represented by the above formula (2), and R 2 and R 4 together form a group or a carbonyl group represented by the above formula (2).

[0020] [5] The compound or its salt according to any one of [1] to [4], wherein h and i are 0.

[0021] [6] The compound represented by the following formula (1a) or a salt thereof,

[0022]

[0023] [wherein, R 1 , R 2 , R 3 and R 4 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, and R 1 and R 3 may together form a group represented by the following formula (2) or a carbonyl group, and R 2 and R 4 may together form a group represented by the following formula (2) or a carbonyl group, wherein at least one of R 1 , R 2 , R 3 and R 4 is an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, and h and i are each independently 0 or 1]

[0024]

[0025] [wherein, R 5 is a methylene group which may have an alkyl group having 1 to 4 carbon atoms as a substituent, is a bonding bond].

[0026] [7] The compound or a salt thereof according to [6], wherein R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and at least one of R 1 , R 2 , R 3 and R 4 is an alkyl group having 1 to 4 carbon atoms.

[0027] [8] The compound or a salt thereof according to [6], wherein R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or an acyl group having 1 to 5 carbon atoms, and at least one of R 1 , R 2 , R 3 and R 4 is an acyl group having 1 to 5 carbon atoms.

[0028] [9] The compound or a salt thereof according to [6], wherein R 1 and R 3Together form the group or carbonyl group shown in the above formula (2), R 2 and R 4 Together form the group or carbonyl group shown in the above formula (2).

[0029]

[10] The compound or its salt according to any one of [6] to [9], wherein h and i are 0.

[0030] Advantages of the Invention

[0031] According to the present invention, a new trisulfide compound can be provided. Although pantethine trisulfide is expected to be a compound with excellent water solubility and stability, as a drug, a compound with higher liposolubility (a compound with a better balance of water solubility and liposolubility) is sometimes more suitable. The above-mentioned compound (1) is expected to have stability equal to or higher than that of pantethine trisulfide and to be a compound with a better balance of water solubility and liposolubility. The above-mentioned compound (1) can be said to be a compound in which the hydroxyl group of pantethine trisulfide is modified or protected. It is considered that by modifying or protecting the hydroxyl group, the number of hydrogen bonds present in the pantethine trisulfide molecule decreases, and thus the liposolubility increases. It is also considered that when at least one of h and i in compound (1) is 0, the number of amide bonds as hydrogen bonds decreases, and thus the liposolubility increases. Moreover, it is considered that in these cases, the molecular weight decreases, and thus the bioavailability can be improved. Brief Description of the Drawings

[0032] Figure 1 It is a graph showing the test results of the hydrogen sulfide scavenging ability (hydrogen sulfide removal effect) in Test Example 1. Detailed Description of the Invention

[0033] The compound of one embodiment of the present invention is the compound shown in the above formula (1). The compound of another embodiment of the present invention is the compound shown in the above formula (1a). In formula (1) and formula (1a), R 1 , R 2 , R 3 and R 4 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, and R 1 , R 2 , R 3 and R 4 at least one of them is an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms. It is also possible that R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R 1 , R 2 , R 3 and R4 At least one of them is an alkyl group having 1 to 4 carbon atoms. R can also be 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or an acyl group having 1 to 5 carbon atoms, and R 1 , R 2 , R 3 and R 4 At least one of them is an acyl group having 1 to 5 carbon atoms. In formula (1) and formula (1a), R 1 and R 2 can be the same, R 3 and R 4 can be the same, R 1 , R 2 and R 3 can be the same, R 2 , R 3 and R 4 can be the same, or R 1 , R 2 , R 3 and R 4 can all be the same.

[0034] In formula (1) and formula (1a), examples of the alkyl group having 1 to 4 carbon atoms include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl. In formula (1) and formula (1a), examples of the acyl group having 1 to 5 carbon atoms include methanoyl group, ethanoyl group, n-propionyl, isopropionyl, cyclopropionyl, n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, and cyclobutyryl. From the viewpoint of reducing the molecular weight of compound (1) and compound (1a), the alkyl group having 1 to 4 carbon atoms is preferably methyl or ethyl, and as the acyl group having 1 to 5 carbon atoms, methanoyl group or ethanoyl group is preferred.

[0035] An example of the combination of R 1 , R 2 , R 3 and R 4 is shown in Table 1. Combinations obtained by changing the methyl group in Table 1 (when there are two or more methyl groups in the same molecule, each methyl group is independent) to ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or cyclobutyl can also be considered.

[0036]

[0037] Regarding R 1 , R 2 , R 3 and R4 Another example of the combination is shown in Table 2. Combinations after changing the formyl group (when there are two or more formyl groups in the same molecule, each formyl group independently) in Table 2 to an acetyl group, a propionyl group, a butyryl group, or a valeryl group can also be considered. The butyryl group and the valeryl group can be linear, branched, or cyclic.

[0038]

[0039] When R 1 is combined with R 3 , R 2 is combined with R 4 , and when R 1 forms a group or a carbonyl group represented by the formula (2) together with R 3 , R 2 is combined with R 4 . An example of the combination is shown in Table 3. Combinations after changing the methyl group (when there are two or more methyl groups in the same molecule, each methyl group independently) in Table 3 to an ethyl group, a n-propyl group, an isopropyl group, a cyclopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a cyclobutyl group can also be considered. In addition, the number of substituents such as the methyl group can be 1 or 2.

[0040]

[0041] In the formula (1) and the formula (1a), h and i are each independently 0 or 1. h and i can be different or the same. When at least one of h and i is 0, it is considered that the liposolubility of the compound (1) and the compound (1a) is further improved, and the balance between water solubility and liposolubility is considered to be better. Moreover, in this case, the molecular weights of the compound (1) and the compound (1a) can be reduced, so the bioavailability is considered to be improved. It is considered that these tendencies are more significantly exhibited when both h and i are 0.

[0042] The molecular weights of the compound (1) and the compound (1a) and their salts can be 800 or less, 750 or less, or 700 or less, preferably 600 or less, 500 or less, or 450 or less. The molecular weights of the compound (1) and the compound (1a) and their salts can be 300 or more, 350 or more, or 400 or more. It is considered that when the molecular weights of the compound (1) and the compound (1a) and their salts are within these ranges, the bioavailability is further improved.

[0043] The ClogP of compound (1), compound (1a), and their salts can be -1 or more, -0.5 or more, 0 or more, 0.5 or more, 1 or more, or 1.5 or more. The ClogP of compound (1), compound (1a), and their salts can be 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, or 2.5 or less. It can be said that when the ClogP of compound (1), compound (1a), and their salts is within these ranges, the balance between the water solubility and lipid solubility of compound (1), compound (1a), and their salts is better. ClogP is the 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 / ).

[0044] The salts of compound (1) and compound (1a) only need to be pharmacologically acceptable salts, and examples include: salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; inorganic acid salts such as ammonium salts and hydrochloride salts; organic acid salts such as acetate salts, etc. When compound (1) or compound (1a) is obtained in the free form, it can be converted into a salt by a conventional method. In addition, when compound (1) or compound (1a) is obtained in the form of a salt, it can also be converted into the free form by a conventional method.

[0045] There may be four kinds of optical isomers, namely R,R form, R,S form, S,R form, and S,S form, for the compounds in this specification. 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 (1a) 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 also be replaced by a mixture containing these optical isomers in any ratio (such as a racemate).

[0046]

[0047]

[0048]

[0049]

[0050] Compound (1) and compound (1a) and their salts can be made into pharmaceutical compositions by adding pharmacologically acceptable additives as needed. When at least one of h, i, j, and k is 1 in the pharmaceutical composition containing compound (1) or compound (1a) or their salts, it can be used for the prevention and treatment of pantothenic acid deficiency in the same way as pantethine.

[0051] The pharmaceutical composition containing compound (1) or compound (1a) or their salts can be formulated, for example, into parenteral or oral preparations. As parenteral preparations, examples include injections, nasal drops, eye drops, sublingual preparations, transdermal preparations (paints, patches, etc.), pulmonary preparations (inhalants), nasal preparations (inhalants), enteral preparations (suppositories), vaginal preparations (vaginal suppositories), etc. As injections, examples include subcutaneous injections, intramuscular injections, intravenous injections, intraperitoneal injections, intra-articular administrations, intraocular administrations, etc. As oral preparations, for example, they can be formulated into tablets, granules, fine granules, powders, capsules. As additives, examples include 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.) and other stabilizers, sodium phosphate buffer, histidine buffer and other pH regulators, sodium chloride and other isotonic agents, and excipients such as mannitol, glycine, sodium chloride, sucrose, etc.

[0052] The above injection can be freeze-dried by a conventional method to prepare a dissolution-type freeze-dried preparation for use. The injection can be manufactured by a method commonly used in pharmaceutical manufacturing, etc. Specifically, for example, water is added to a container in an environment maintained at a constant temperature of 5 - 25°C, and the pre-weighed compound (1) or compound (1a) or their salts and additives are added while slowly stirring. It is adjusted to the desired pH value and sterilized by filtration through a filter, etc. The sterilized liquid is filled into a container such as a glass vial and sealed with a rubber stopper, etc. When preparing a freeze-dried preparation, the liquid preparation of the present invention obtained is freeze-dried by a method known per se. By preparing a freeze-dried preparation, compound (1) or compound (1a) or their salts can be maintained stable for a long time.

[0053] Compound (1a) of an embodiment of the present invention can be manufactured by the following method:

[0054] (A) Modify at least one of the hydroxyl groups of the trisulfide compound with an alkyl group having 1 - 4 carbon atoms or an acyl group having 1 - 5 carbon atoms, or protect at least one group of the diols of the trisulfide compound by cyclic ketalization;

[0055] (B-1) Modify at least one of the hydroxyl groups in the disulfide compound with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protect it by cycloketalizing at least one set of the diols in the disulfide compound, oxidize the modified or protected disulfide compound with an oxidizing agent to obtain a sulfoxide compound, and trisulfurize the obtained sulfoxide compound. Alternatively, oxidize the disulfide compound with an oxidizing agent to obtain a sulfoxide compound, modify at least one of the hydroxyl groups in the obtained sulfoxide compound with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protect it by cycloketalizing at least one set of the diols in the sulfoxide compound, and trisulfurize the modified or protected sulfoxide compound; or,

[0056] (B-2) Modify at least one of the hydroxyl groups in the thiol compound with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protect it by cycloketalizing at least one set of the diols in the thiol compound, oxidize the modified or protected thiol compound with an oxidizing agent to obtain a sulfoxide compound, and trisulfurize the obtained sulfoxide compound. Alternatively, oxidize the thiol compound with an oxidizing agent to obtain a sulfoxide compound, modify at least one of the hydroxyl groups in the obtained sulfoxide compound with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protect it by cycloketalizing at least one set of the diols in the sulfoxide compound, and trisulfurize the modified or protected sulfoxide compound.

[0057] Production method (A) includes a step of modifying at least one of the hydroxyl groups in compound (10a) with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protecting it by cycloketalizing at least one set of the diols in compound (10a). Compound (10a) can be synthesized by the method described in Patent Document 1. Production method (A) may include: a step of oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound (step A-1) or a step of oxidizing a thiol compound with an oxidizing agent to obtain a sulfoxide compound (step A-1'); a step of reacting the obtained sulfoxide compound with a sulfur source to obtain compound (10a) (step A-2); and a step of modifying the hydroxyl group in the obtained compound (10a) with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protecting it by cycloketalizing at least one set of the diols in the trisulfide compound (step A-3).

[0058]

[0059] In the case where h and i are 0, the production method (A) can obtain the compound (10a) with h and i being 0 by further including the step shown in the following reaction formula (I).

[0060]

[0061] The production method (B-1) can include: a step (step B-1-1) of modifying at least one of the hydroxyl groups of the compound (11a) with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or protecting the compound by cyclic ketalization of at least one group of the diols of the compound (11a) to obtain the compound (12a); and a step (step B-1-2) of trisulfurizing the compound (12a). Step B-1-2 can be carried out according to the method described in Patent Document 1. Step B-1-2 can include: a step (step B-1-2-1) of oxidizing the compound (12a) with an oxidizing agent to obtain a sulfoxide compound; and a step (step B-1-2-2) of reacting the obtained sulfoxide compound with a sulfur source to obtain the compound (1). In addition, the production method (B-1) can also be a method: directly carrying out step B-1-2-1 on the compound (11a), and successively carrying out step B-1-1 and step B-1-2-2 on the obtained sulfoxide compound, thereby producing the compound (1a). In the case where h and i are 0, the production method (B-1) can obtain the compound (11a) with h and i being 0 by further including the step shown in the above reaction formula (I).

[0062]

[0063] The production method (B-2) may include: a step (step B-2-1) of protecting at least one of the hydroxyl groups in compound (13a) and compound (14a) by modifying it with an alkyl group having 1 to 4 carbon atoms or an acyl group having 1 to 5 carbon atoms, or by cycloketalizing at least one group of the diols in compound (13a) and compound (14a) to obtain compound (15a) and compound (16a); and a step (step B-2-2) of obtaining a trisulfide compound from compound (15a) and compound (16a). Step B-2-2 may be carried out according to the method described in Patent Document 1. Step B-2-2 may include: a step (step B-2-2-1) of oxidizing compound (15a) and compound (16a) with an oxidizing agent to obtain a sulfoxide compound; and a step (step B-2-2-2) of reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound. Additionally, the production method (B-2) may also be a method in which step B-2-2-1 is directly carried out on compound (13a) and compound (14a), and step B-2-1 and step B-2-2-2 are successively carried out on the obtained sulfoxide compound, thereby producing compound (1a).

[0064]

[0065] The solvents used in step A-1, step A-1', step B-1-2-1, and step B-2-2-1 are solvents that dissolve thiol compounds, disulfide compounds, and oxidizing agents and do not inhibit the oxidation reaction. Examples thereof include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, and water is preferred. The amount of the solvent used in step A-1, step A-1', step B-1-2-1, and step B-2-2-1 may be set to 1 mL to 500 mL, preferably 10 mL to 20 mL, relative to 1 g of the thiol compound or disulfide compound.

[0066] As the oxidizing agent used in step A-1, step A-1', step B-1-2-1, and step B-2-2-1, potassium monopersulfate (sold under trade names such as Oxone (registered trademark)), peracetic acid, hydrogen peroxide, and sodium periodate can be cited. Hydrogen peroxide can be used together with a catalytic amount of methyltrioxorhenium. From the viewpoints of safety and cost, potassium monopersulfate is a preferred oxidizing agent. The amount of the oxidizing agent used may be set to 0.8 equivalent to 2.0 equivalents, preferably 1.0 equivalent to 1.3 equivalents, relative to 1 equivalent of the thiol compound or disulfide compound.

[0067] The reaction temperature in step A-1, step A-1', step B-1-2-1, and step B-2-2-1 may be set to -20°C to 30°C, preferably -5°C to 5°C.

[0068] The reaction time in Step A-1, Step A-1', Step B-1-2-1 and Step B-2-2-1 can be set to 5 minutes to 24 hours or 10 minutes to 24 hours, preferably 0.5 hours to 2 hours.

[0069] The solvents used in Step A-2, Step B-1-2-2 and Step B-2-2-2 are solvents that can dissolve the sulfoxide compound as an intermediate and do not inhibit the subsequent reaction. Examples include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, with water being preferred. The amount of the solvent used in Step A-2, Step B-1-2-2 and Step B-2-2-2 can be set to 1 mL to 500 mL relative to 1 g of the sulfoxide compound, preferably 10 mL to 20 mL.

[0070] Examples of the sulfur source used in Step A-2, Step B-1-2-2 and Step B-2-2-2 include sodium sulfide, potassium sulfide, sodium hydrosulfide, potassium hydrosulfide, and hydrogen sulfide. The amount of the sulfur source used can be set to 0.5 equivalent to 4.0 equivalents relative to 1 equivalent of the sulfoxide compound, preferably 0.9 equivalent to 1.2 equivalents.

[0071] The reaction temperature in Step A-2, Step B-1-2-2 and Step B-2-2-2 can be set to -20°C to 30°C, preferably -5°C to 25°C.

[0072] The reaction time in Step A-2, Step B-1-2-2 and Step B-2-2-2 can be set to 10 minutes to 2 days, preferably 0.5 hours to 2 hours.

[0073] Step A-3, Step B-1-1 and Step B-2-1 can be carried out by known methods in organic synthetic chemistry techniques. For example, alkylation of a hydroxyl group can be carried out by reacting Compound (10a), Compound (11a), or Compound (13a) and Compound (14a) with an alkylating agent such as dichloromethane, 2-dimethylaminoethyl chloride hydrochloride, (2-iodoethoxy)triisopropylsilane, etc. in a solvent such as N,N-dimethylformamide in the presence or absence of a base such as cesium carbonate or potassium carbonate. For example, esterification of a hydroxyl group can be carried out by reacting acetic anhydride, acetyl chloride, benzoyl chloride, etc. with Compound (10a), Compound (11a), or Compound (13a) and Compound (14a) in the presence of a base such as dichloromethane (Dichloromethane, DCM), pyridine, or triethylamine. For example, cyclic ketalization of a diol can be carried out by reacting 2-methoxypropene, 2,2-dimethoxypropane, triphosgene, etc. with Compound (10a), Compound (11a), or Compound (13a) and Compound (14a) in a solvent such as tetrahydrofuran in the presence of (+)-10-camphorsulfonic acid, pyridine, etc.

[0074] Each step included in the production methods (A), (B-1), and (B-2) can be carried out by a one-pot method without isolating the sulfoxide compound as an intermediate product.

[0075] In the case of carrying out each step included in the production methods (A), (B-1), and (B-2) by a one-pot method, examples of the reaction solvent include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, with water being preferred. The amount of the solvent can be set to 1 mL to 500 mL, preferably 10 mL to 20 mL, per 1 g of the thiol compound or disulfide compound. Examples of the oxidizing agent used include potassium monopersulfate, peracetic acid, hydrogen peroxide (which can be used together with a catalytic amount of methyltrioxorhenium), and sodium periodate. The oxidizing agent used is preferably potassium monopersulfate. The amount of the oxidizing agent used can be set to 0.8 equivalent to 2.0 equivalents, preferably 1.0 equivalent to 1.3 equivalents, per 1 equivalent of the thiol compound or disulfide compound. Examples of the sulfur source used include sodium sulfide, potassium sulfide, sodium hydrosulfide, potassium hydrosulfide, and hydrogen sulfide. The amount of the sulfur source used can be set to 0.5 equivalent to 4.0 equivalents, preferably 0.9 equivalent to 1.2 equivalents, per 1 equivalent of the sulfoxide compound. The reaction temperature can be set to -20°C to 30°C, preferably -5°C to 25°C. The reaction time can be set to 15 minutes to 2 days, preferably 1 hour to 4 hours.

[0076] In the compound (1) according to one embodiment of the present invention, R 10 or R 11 A compound in which any one of them is a hydrogen atom can be produced by appropriately changing the starting materials in the production method of the above compound (1a). That is, by using the compound (10) as the starting material instead of the compound (10a), the compound (11) as the starting material instead of the compound (11a), and the compound (13) and the compound (14a), or the compound (13a) and the compound (14) as the starting materials instead of the compound (13a) and the compound (14a), and carrying out the same reaction, the desired compound can be obtained.

[0077]

[0078] Examples

[0079] The present invention will be described in detail below with reference to examples, but the present invention is not limited by these examples.

[0080] <Production of the acetonide of pantethine trisulfide - Example 1>

[0081]

[0082] 127 mg (0.22 mmol) of pantethine trisulfide (PTN-SSS) and 3.8 mL (33 v / w) of tetrahydrofuran (THF) were placed into a 10 mL test tube. After confirming that the contents of the flask had dissolved, 0.20 mL (2.16 mmol, 10 equivalents) of 2-methoxypropene and 8.2 mg (0.04 mmol, 0.2 equivalents) of (+)-10-camphorsulfonic acid (CSA) were added to the flask. After displacing the air in the flask with nitrogen, the reaction was carried out at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, 1 mL of methanol was added for dissolution. The dissolved solution was purified by column chromatography (ODS column, mobile phase: water / acetonitrile). Finally, it was concentrated under reduced pressure at an external temperature of 30 °C and dried with an oil pump to obtain 97.8 mg (0.15 mmol, yield 68%, HPLC purity: 95%) of the acetonide of pantethine trisulfide (Acetonide-PTN-SSS) as a white solid. The ClogP of Acetonide-PTN-SSS was 2.74, the logP was 1.56, and the molecular weight was 667. The ClogP of PTN-SSS was -1.99 and the logP was -0.39.

[0083] 1 H-NMR: (CDCl3, 400 MHz) δ (ppm) = 7.04 (t, 2H, J = 6.0 Hz), 6.72 (t, 2H, J = 6.0 Hz), 4.08 (s, 2H), 3.73 - 3.48 (m, 10H), 3.28 (d, 2H, J = 11.2 Hz), 3.03 (t, 4H, J = 6.4 Hz), 2.49 (td, 4H, J = 6.4, 1.2 Hz), 1.47 (s, 6H), 1.43 (s, 6H), 1.03 (s, 6H), 0.97 (s, 6H).

[0084] ESI-TOF-MS: m / z 667.2889 ([M+H] + ),calcd for [C 28 H 51 N4O8S3]-667.2869.

[0085] <Example 2: Preparation of the acetyl derivative of pantethine trisulfide>

[0086]

[0087] Add 229 mg (0.39 mmol) of pantethine trisulfide (PTN-SSS) and 14 mL (60 v / w) of dichloromethane (DCM) to a 25 mL eggplant-shaped flask, and cool to 0 °C. After adding 83 μL (1.17 mmol, 3.0 equiv) of acetyl chloride (AcCl) to the flask, add 95 μL (1.17 mmol, 3.0 equiv) of pyridine. After displacing the air in the flask with nitrogen, react at room temperature for 3 hours. After adding 4 mL of water at 0 °C, add 6 mL of a dichloromethane:methanol (10:1) mixture to extract the organic layer. Perform this extraction 3 times, and wash the obtained organic layer once with 6 mL of water. After concentrating the washed organic layer under reduced pressure at an external temperature of 30 °C, dissolve it in 2 mL of dichloromethane and a small amount of methanol, and purify the solution by column chromatography (mobile phase: dichloromethane / methanol). Finally, concentrate under reduced pressure at an external temperature of 30 °C, and dry with an oil pump to obtain 123 mg (0.18 mmol, yield 47%, HPLC purity: 99%) of the acetylated form of pantethine trisulfide (Ac-PTN-SSS) as a white solid. The ClogP of Ac-PTN-SSS is -0.10, the logP is 0.91, and the molecular weight is 671. The ClogP of PTN-SSS is -1.99 and the logP is -0.39.

[0088] 1 1H-NMR: (CDCl3, 400 MHz) δ (ppm) = 7.42 (br, 2H), 7.14 (br, 2H), 4.12 (d, 2H, J = 10.4 Hz), 3.92 (s, 2H), 3.84 (d, 2H, J = 11.2 Hz), 3.70 - 3.48 (m, 8H), 3.03 (t, 4H, J = 6.4 Hz), 2.49 (td, 4H, J = 5.6, 5.2 Hz), 2.09 (s, 6H), 1.03 (s, 6H), 0.95 (s, 6H).

[0089] ESI-TOF-MS: m / z 671.2481 ([M+H] + ), calcd for [C 26 H 47 N4O 10 S3]-671.2454.

[0090] The HPLC conditions in Examples 1 and 2 are as follows.

[0091] Detector: UV spectrophotometer (measurement wavelength: 220 nm)

[0092] Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 × 250 mm, 5 μm)

[0093] Column temperature: Constant temperature of about 40 °C

[0094] Mobile phase A: Aqueous phosphoric acid solution (pH 3)

[0095] Mobile phase B: Methanol

[0096] Delivery of the mobile phase: Control the concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 4.

[0097] [Table 4]

[0098]

[0099] Flow rate: 0.6 mL / min

[0100] Sample injection volume: 10 μL

[0101] <Example 3: Production of Compound 2>

[0102] Production of Compound 1

[0103]

[0104] After dissolving 5 g (22.2 mmol) of cystamine dihydrochloride in 5 mL of water (1 v / w), 2.6 mL (46.6 mmol, 2.1 equivalents) of 48% aqueous NaOH solution was added. Subsequently, 50 mL of EtOH was added, and the inorganic salts were filtered out. The filtrate was concentrated under reduced pressure using an evaporator, 5.78 g (44.4 mmol, 2.0 equivalents) of D-pantolactone was added to the concentrate, the temperature was raised to 95 °C, and the reaction was carried out for 5 hours. After adding 2 mL of EtOH to dissolve the reaction solution, it was purified by column chromatography (mobile phase A: ethyl acetate, mobile phase B: methanol) to obtain 8.51 g of Compound 12 (20.6 mmol, yield 93%, HPLC purity: 99%).

[0105] 1 1H-NMR: (D2O, 400 MHz) δ (ppm) = 3.95 (s, 2H), 3.53 (dd, 4H, J = 6.4, 6.0 Hz), 3.48 (d, 2H, J = 11.2 Hz), 3.35 (d, 4H, J = 11.2 Hz), 2.85 (dd, 4H, J = 6.4, 6.4 Hz), 0.90 (s, 6H), 0.86 (s, 6H).

[0106] Regarding the HPLC conditions, it was the same as in Examples 1 and 2 except that the measurement wavelength of the detector was set to 210 nm.

[0107] <Production of Compound 2>

[0108]

[0109] 252 mg of Compound 1 (611 μmol) and 3 mL of water (12 v / w) were placed into a reaction vessel and cooled to an internal temperature of 1 °C. 208 mg of Oxone® (672 μmol, 1.1 eq) was added thereto and the reaction was carried out for 90 minutes. Subsequently, an aqueous sodium sulfide solution obtained by dissolving 147 mg of sodium sulfide nonahydrate (611 μmol, 1.0 eq) in 1.5 mL of water was added dropwise and the reaction was carried out for about 1 hour. After adding 6 mL of ethanol to the reaction solution, the inorganic salts were filtered out and washed with 2 mL of ethanol. The filtrate was concentrated under reduced pressure using an evaporator, and the concentrated product was purified by an ODS column (mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: ethanol) to obtain 130 mg of Compound 2 (259 μmol, yield 48%, HPLC purity: 99%).

[0110] 1 1H-NMR: (D2O, 400 MHz) δ (ppm) = 3.97 (s, 2H), 3.62 (dd, 4H, J = 6.4, 6.0 Hz), 3.49 (d, 2H, J = 10.8 Hz), 3.37 (d, 4H, J = 11.2 Hz), 3.11 (dd, 4H, J = 6.4, 6.4 Hz), 0.92 (s, 6H), 0.88 (s, 6H).

[0111] ESI-TOF-MS: m / z 445.1544 ([M+H] + ),calcd for [C 16 H 33 N2O6S3]-445.1501.

[0112] Regarding the HPLC conditions, they were the same as in Examples 1 and 2 except that the measurement wavelength of the detector was set to 210 nm.

[0113] <Example 4: Preparation of Compound 4>

[0114]

[0115] 1.01 g of Compound 3 (2.38 mmol) and 13 mL of water (13 v / w) were charged into a reaction vessel and cooled to an internal temperature of 1 °C. 892 mg (2.62 mmol, 1.1 eq) of Oxone (registered trademark) was added thereto and reacted for 90 minutes. Subsequently, an aqueous sodium sulfide solution prepared by dissolving 571 mg (2.38 mmol, 1.0 eq) of sodium sulfide nonahydrate in 5.6 mL of water was added dropwise and reacted for about 1 hour. The reaction solution was purified by an ODS column (mobile phase A: aqueous formic acid solution, mobile phase B: ethanol) to obtain 372 mg of Compound 4 (0.82 mmol, yield 34%, HPLC purity: 96%).

[0116] 1 1H-NMR: (D2O, 400 MHz) δ (ppm) = 3.89 (s, 1H), 3.58 - 3.36 (m, 8H), 3.18 (t, 2H, J = 6.9 Hz), 2.98 (dt, 4H, J = 6.9, 6.4 Hz), 2.60 (t, 2H, J = 6.9 Hz), 2.42 (t, 2H, J = 6.4 Hz), 1.08 (dd, 2H, J = 6.9, 7.3 Hz), 0.83 (s, 3H), 0.79 (s, 3H).

[0117] ESI-TOF-MS: m / z 457.1653 ([M+H] + ),calcd for [C 16 H 33 N4O5S3]-457.1613.

[0118] The HPLC conditions are as follows.

[0119] Detector: UV spectrophotometer (measurement wavelength: 220 nm)

[0120] Column: Meteoric Core C18 (YMC, 4.6 × 150 mm, 2.7 μm)

[0121] Column temperature: Constant temperature of about 40 °C

[0122] Mobile phase A: Aqueous phosphoric acid solution (pH 3)

[0123] Mobile phase B: Methanol

[0124] Delivery of the mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0125] [Table 5]

[0126]

[0127] Flow rate: 0.4 mL / min

[0128] Sample volume: 10 μL

[0129] <Example 5: Preparation of Compound 5>

[0130]

[0131] 117 mg (0.20 mmol) of pantethine trisulfide (PTN-SSS) and 6 mL (60 v / w) of dichloromethane were placed in a 10 mL eggplant-shaped flask, and 168 mg (1.03 mmol, 5.2 equivalents) of carbonyldiimidazole (CDI) was added. After displacing the air in the flask with nitrogen, the reaction was carried out at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure at an external temperature of 30 °C, it was purified by column chromatography (mobile phase: water / methanol). Finally, it was concentrated under reduced pressure at an external temperature of 30 °C, then separated and extracted with ethyl acetate, and again concentrated under reduced pressure at an external temperature of 30 °C. Dried with an oil pump to obtain 2.7 mg of Compound 5 as a brown oil (0.04 mmol, yield 2%, HPLC purity: 99%).

[0132] 1 1H-NMR: (MeOH-D4, 400 MHz) δ (ppm) = 4.72 (s, 2H), 3.82 - 3.68 (m, 4H), 3.51 - 3.37 (m, 8H), 2.98 (dd, 4H, J = 6.9, 6.4 Hz), 2.51 (t, 4H, J = 6.86), 1.02 (s, 6H), 0.99 (s, 6H).

[0133] ESI-TOF-MS: m / z 639.1821 ([M+H] + ), calcd for [C 24 H 39 N4O 10 S3] - 639.1828.

[0134] The HPLC conditions were the same as in Example 4.

[0135] <Test Example 1>

[0136] The ability of the compound represented by formula (1) to capture hydrogen sulfide (hydrogen sulfide removal effect) was evaluated by methylene blue spectrophotometry.

[0137] <Preparation of H2S Standard Solution>

[0138] Sodium sulfide nonahydrate (Na2S·9H2O) was dissolved in purified water to prepare a 50 μmol / L sodium sulfide nonahydrate solution, which was used as the H2S standard solution.

[0139] <Preparation of p-Aminodimethylaniline (DPDA) Solution>

[0140] Dissolve p-aminodimethylaniline in 10N sulfuric acid to prepare a 1 mmol / L DPDA solution.

[0141] <Preparation of Iron(III) Chloride Solution>

[0142] Dissolve iron(III) chloride hexahydrate in 1% sulfuric acid to prepare a 3 mmol / L FeCl3 solution.

[0143] <Preparation of Trisulfide Compound Solution>

[0144] Dissolve the trisulfide compound in 25 mmol / L phosphate buffer (pH 7, hereinafter referred to as "PBS") to prepare a solution with a concentration of 50 μmol / L in terms of the trisulfide compound.

[0145] <Test Method>

[0146] Add 10 mL (0.5 μmol, reference) of the H2S standard solution to a stoppered test tube and stir. Add 1 mL (0.5 μmol, 1 equivalent) of PBS (blank) or the trisulfide compound solution to this solution and stir for a specified time (0 minutes, 5 minutes, 15 minutes, or 30 minutes). After stirring, add 1 mL (1 μmol, 2 equivalents) of the DPDA solution and 1 mL (3 μmol, 6 equivalents) of the FeCl3 solution, stir further, and measure the absorbance of the solution at a wavelength of 668 nm after the absorbance of the solution no longer changes (i.e., after the color development due to the formation of methylene blue is completed). This test is carried out under room temperature conditions.

[0147] <Test Results>

[0148] The results are shown in Figure 1 . Figure 1 . The stirring time on the horizontal axis in [ ] represents the stirring time of the mixed solution of the H2S standard solution and PBS (blank) or the trisulfide compound solution before adding the color-developing agents (DPDA solution and FeCl3 solution). It was confirmed that the longer the contact time (reaction time) between H2S and the trisulfide compound, the more the absorbance decreased compared to the blank. It is speculated that this is because H2S reacts with the trisulfide compound and consumes H2S, resulting in a decrease in the amount of methylene blue formed compared to the blank. From the above, it can be confirmed that the compound or its salt represented by formula (1) has hydrogen sulfide capture ability (hydrogen sulfide removal effect).

[0149] <Test Example 2>

[0150] Purified water (10 mL) was added to pantethine trisulfide (PTN-SSS, 6.7 mg), Acetonide-PTN-SSS (Example 1, 5.3 mg), and Ac-PTN-SSS (Example 2, 5.3 mg) for dissolution. Then, octanol (10 mL) was added to each aqueous solution, and the mixture was shaken for 1 minute. Samples (2 mL each) were taken from both the aqueous layer and the octanol layer, centrifuged, and then allowed to stand for 1 hour. Exactly 1 mL was accurately measured from the standing solution, and 2-propanol was added to make the volume up to 10 mL. The compound concentrations in each layer were calculated based on the HPLC analysis results, and the partition coefficient (logP) was calculated. (logP = log 10 (concentration in the octanol layer / concentration in the aqueous layer))

[0151] The results are shown in Table 6.

[0152] [Table 6]

[0153]

[0154] The values of the partition coefficient increased in the order of PTN-SSS < Ac-PTN-SSS < Acetonide-PTN-SSS. It is speculated that this result is due to the protection of the hydroxyl group of PTN-SSS. Since the values of the partition coefficients of Acetonide-PTN-SSS and Ac-PTN-SSS are higher than that of PTN-SSS, it can be seen that the compound represented by formula (1) or its salt has increased lipophilicity compared to PTN-SSS.

Claims

1. A compound represented by the following formula (1) or a salt thereof, In formula (1), R 10 is a hydrogen atom or the group shown below, where is a bonding link R 11 is a hydrogen atom or the group shown, where is a bonding bond However, R 10 and R 11 are not simultaneously hydrogen atoms, R 1 、R 2 、R 3 and R 4 each independently represents a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, R 1 and R 3 may together form a group represented by the following formula (2) or a carbonyl group, R 2 and R 4 may together form a group represented by the following formula (2) or a carbonyl group, wherein, R 1 、R 2 、R 3 and R 4 at least one of which is an alkyl group having 1 to 9 carbon atoms or an acyl group having 1 to 5 carbon atoms, and h and i are each independently 0 or 1, In formula (2), R 5 is a methylene group which may have an alkyl group having 1 to 4 carbon atoms as a substituent, is a bonding bond.

2. The compound or a salt thereof according to claim 1, wherein, R 10 is the group shown below, where is a bonding link R 11 is the group shown below, wherein is a bonding moiety.

3. The compound or its salt according to claim 1, wherein, R 1 、R 2 、R 3 and R 4 each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an alkyl group having 1 to 4 carbon atoms.

4. The compound or its salt according to claim 1, wherein, R 1 、R 2 、R 3 and R 4 each independently represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an acyl group having 1 to 5 carbon atoms.

5. The compound or its salt according to claim 1, wherein, R 1 and R 3 together form the group or carbonyl group shown in formula (2), R 2 and R 4 together form the group or carbonyl group shown in formula (2).

6. The compound or its salt according to claim 2, wherein R 1 、R 2 、R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an alkyl group having 1 to 4 carbon atoms.

7. The compound or its salt according to claim 2, wherein, R 1 、R 2 、R 3 and R 4 are each independently a hydrogen atom or an acyl group having 1 to 5 carbon atoms, and at least one of R 1 、R 2 、R 3 and R 4 is an acyl group having 1 to 5 carbon atoms.

8. The compound or its salt according to claim 2, wherein, R 1 and R 3 together form the group or carbonyl group shown in the formula (2), R 2 and R 4 together form the group or carbonyl group shown in the formula (2).

9. The compound or its salt according to any one of claims 1 to 8, wherein, h and i are 0.

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