WO2022045212A1 - トリスルフィド化合物及びその包接体 - Google Patents

トリスルフィド化合物及びその包接体 Download PDF

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WO2022045212A1
WO2022045212A1 PCT/JP2021/031222 JP2021031222W WO2022045212A1 WO 2022045212 A1 WO2022045212 A1 WO 2022045212A1 JP 2021031222 W JP2021031222 W JP 2021031222W WO 2022045212 A1 WO2022045212 A1 WO 2022045212A1
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group
cyclodextrin
trisulfide
formula
carbon atoms
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French (fr)
Japanese (ja)
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昌一郎 朝長
貴弘 磯部
悦男 大島
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Kyowa Pharma Chemical Co Ltd
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Kyowa Pharma Chemical Co Ltd
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Priority to CN202180050746.1A priority Critical patent/CN115989026A/zh
Priority to JP2022545682A priority patent/JP7684315B2/ja
Priority to EP21861635.7A priority patent/EP4194448A4/en
Priority to US18/042,693 priority patent/US12552764B2/en
Publication of WO2022045212A1 publication Critical patent/WO2022045212A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D341/00—Heterocyclic compounds containing rings having three or more sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present invention relates to a trisulfide compound and its inclusions.
  • a compound containing a covalent bond structure consisting of three consecutive sulfur atoms is called a trisulfide compound. Since the trisulfide compound has a redox ability depending on the possible valences of the constituent sulfur atoms, it is expected to have various bioactive functions.
  • Patent Document 1 discloses lipoic acid trisulfide obtained by trisulfating ⁇ -lipoic acid used for the treatment of diabetes and chronic hepatitis.
  • the present invention is to provide a new trisulfide compound for solving a problem, and in particular, a cyclodextrin inclusion body of a trisulfide compound having excellent water solubility and stability (hereinafter, "CD inclusion body”). "Or simply referred to as” inclusion body ").
  • the present inventors have made diligent efforts to solve the above problems, and have newly created a trisulfide compound having a carboxylic acid amide structure represented by the following formula (1).
  • a trisulfide compound having an ester structure modified by a hydrophilic functional group represented by the following formula (3) was newly created.
  • they have found that the CD clathrate of the trisulfide compound represented by the following formula (1) or (2) has excellent water solubility and stability, and have completed the present invention.
  • R 1 and R 2 are independently hydrogen atoms; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; -NR 6 R 7 and -N + R 9 R 10 R 11 Alkyl group having 1 or more substituents selected from the group; or-(CH 2 CH 2 O) n
  • R 8 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, and n is an integer of 2 to 5.
  • R 4 is an alkyl group having 1 to 6 carbon atoms having one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; ⁇ NR 6 R 7 and ⁇ N + R 9 R 10 Alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of R 11 ; or-(CH 2 CH 2 O) n R 8 is shown, and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.
  • At least one selected from the group consisting of a compound represented by the following formula (1), a compound represented by the following formula (2), and a salt of the compound represented by the following formula (2) is cyclo.
  • R 1 and R 2 are independently hydrogen atoms; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; -NR 6 R 7 and -N + R 9 R 10 R 11 Alkyl group having 1 or more substituents selected from the group; or-(CH 2 CH 2 O) n
  • R 8 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, and n is an integer of 2 to 5. Is.
  • R 3 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; ⁇ NR 6 R 7 and An alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of ⁇ N + R 9 R 10 R 11 ; or ⁇ (CH 2 CH 2 O) n R 8 indicating R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5.
  • the salt of the compound represented by the formula (2) is selected from the group consisting of a salt with an alkali metal, a salt with an alkaline earth metal, an ammonium salt, a salt with an inorganic acid and a salt with an organic acid.
  • a new trisulfide compound can be provided.
  • the CD clathrate of the trisulfide compound according to the present invention has excellent water solubility and stability. Therefore, in industrial applications such as pharmaceuticals, it is considered that problems such as restrictions on applicable pharmaceutical prescriptions and manifestation of individual differences in oral absorbability will be solved.
  • the trisulfide compound and the CD inclusion body of the trisulfide compound according to the present invention are expected to have an active oxygen removing action, a hydrogen sulfide removing action and the like.
  • FIG. 1 is a graph showing the results of a stability test of a trisulfide compound in a CD inclusion body.
  • the trisulfide compound according to the embodiment of the present invention is a compound represented by the following formula (1).
  • R 1 and R 2 are independently hydrogen atoms; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; -NR 6 R 7 and -N + R 9 R 10 R 11 Alkyl group having 1 or more substituents selected from the group; or-(CH 2 CH 2 O) n
  • R 8 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, and n is an integer of 2 to 5. Is. ]
  • An alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of R 11 ; or-(CH 2 CH 2 O) n R 8 is represented by the formula (1). It is considered that the hydrophilicity of the compound is further improved.
  • R 1 and R 2 may be an alkyl group such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • These alkyl groups have one or more substituents selected from the group consisting of a carboxy group; and a substituent represented by ⁇ OR5 such as a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group and the like. You can do it.
  • R 1 and R 2 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, and these alkyl groups are an amino group, a dimethylamino group and the like.
  • Substituents represented by -NR 6 R 7 ; and -N + H 3 , -N + (CH 3 ) 3 , -N + (C 2 H 6 ) 3 , etc.-N + R 9 R 10 R 11 It may have one or more substituents selected from the group consisting of substituents represented by.
  • R 1 and R 2 may have, for example, one or both substituents of an amino group and a carboxy group.
  • R 1 and R 2 may be, for example, a group represented by the following formula (10) or (11) (in the formula, * indicates a bond).
  • R 1 and R 2 may be a group represented by ⁇ (CH 2 CH 2 O) n R 8 such as bis (2-ethoxyethyl) ether.
  • R 1 and R 2 are both hydrogen atoms
  • R 1 is a hydrogen atom
  • R 2 is a group represented by the following formula (10). Examples thereof include a compound in which R 1 is a hydrogen atom and R 2 is a group represented by the following formula (11).
  • the compounds in the present specification may contain optical isomers and racemates, but the present invention is not limited to any of them, and even racemates may be any of the optically active compounds. Alternatively, it may be a mixture containing each optically active substance in an arbitrary ratio.
  • the trisulfide compound represented by the formula (1) is a step (step 1) of oxidizing the disulfide compound represented by the following formula (1a) with an oxidizing agent to obtain a sulfoxide compound, and the obtained sulfoxide compound is sulfur. It can be produced by the step (step 2) of reacting with a source to obtain a trisulfide compound.
  • R 1 and R 2 are independently hydrogen atoms; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; -NR 6 R 7 and -N + R 9 R 10 R 11 Alkyl group having 1 or more substituents selected from the group; or-(CH 2 CH 2 O) n
  • R 8 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, and n is an integer of 2 to 5. Is. ]
  • steps 1 and 2 may be reacted in one pot without isolating the sulfoxide compound.
  • the solvent used in step 1 is not particularly limited as long as it dissolves the disulfide compound and the oxidizing agent and does not inhibit the oxidation reaction.
  • examples of such a solvent include water, an aqueous solution of sulfuric acid, an aqueous solution of ethanol and an aqueous solution of acetonitrile, and water is preferable.
  • the amount of the solvent used in step 1 can be 1 mL to 500 mL per 1 g of the disulfide compound, preferably 10 mL to 20 mL.
  • oxidizing agent used in step 1 examples include potassium peroxymonosulfate (sold under a trade name such as Oxone (registered trademark)), peracetic acid, hydrogen peroxide, and sodium periodate. Hydrogen peroxide may be used with a catalytic amount of methyltrioxorenium. Potassium peroxymonosulfate is the preferred oxidant from the standpoint of safety and cost.
  • the amount of the oxidizing agent used can be 0.8 equivalents to 2.0 equivalents, preferably 1.0 equivalents to 1.3 equivalents, relative to 1 equivalent of the disulfide compound.
  • the reaction temperature in step 1 can be ⁇ 20 ° C. to 30 ° C., preferably ⁇ 5 ° C. to 5 ° C.
  • the reaction time of step 1 can be 5 minutes to 24 hours, preferably 0.5 hours to 2 hours.
  • the solvent used in step 2 is not particularly limited as long as it dissolves the sulfoxide compound and the sulfur source and does not inhibit the subsequent reaction.
  • examples of such a solvent include water, an aqueous solution of sulfuric acid, an aqueous solution of ethanol and an aqueous solution of acetonitrile, and water is preferable.
  • the amount of the solvent used in step 2 can be 1 mL to 500 mL per 1 g of the sulfoxide compound, preferably 10 mL to 20 mL.
  • sulfur source used in step 2 examples include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide and hydrogen sulfide.
  • the amount of sulfur source used can be 0.5 equivalents to 4.0 equivalents, preferably 0.9 equivalents to 1.2 equivalents, relative to 1 equivalent of the sulfoxide compound.
  • the reaction temperature in step 2 can be ⁇ 20 ° C. to 30 ° C., preferably ⁇ 5 ° C. to 25 ° C.
  • the reaction time of step 2 can be 10 minutes to 2 days, preferably 0.5 hours to 2 hours.
  • examples of the reaction solvent include water, an aqueous solution of sulfuric acid, an aqueous solution of ethanol and an aqueous solution of acetonitrile, preferably water, and the amount of the solvent is 1 g of the disulfide compound. It can be 1 mL to 500 mL, preferably 10 mL to 20 mL.
  • Oxidizing agents used include potassium peroxymonosulfate, peracetic acid, hydrogen peroxide (which may be used with a catalytic amount of methyltrioxolenium) and sodium periodate, preferably potassium peroxymonosulfate.
  • the amount of the oxidizing agent used can be 0.8 equivalents to 2.0 equivalents, preferably 1.0 equivalents to 1.3 equivalents, relative to 1 equivalent of the disulfide compound.
  • the sulfur source used include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide and hydrogen sulfide, and the amount of the sulfur source used is 0.5 equivalent to 1 equivalent of the disulfide compound. It can be 4.0 equivalents, preferably 0.9 equivalents to 1.2 equivalents.
  • the reaction temperature can be ⁇ 20 ° C. to 30 ° C., preferably ⁇ 5 ° C. to 25 ° C.
  • the reaction time can be from 15 minutes to 2 days, preferably 1 to 4 hours.
  • a step of protecting a functional group such as a hydroxy group, a carbonyl group, an amino group, and a carboxy group and a step of deprotecting the protected functional group may be included, if necessary. ..
  • the protecting groups and protection / deprotection reactions of these functional groups are well known to those skilled in the art, and appropriate protecting groups and protection / deprotection reactions are selected with reference to "Greene's Protective Groups in Organic Synthesis" and the like. be able to.
  • the disulfide compound represented by the formula (1a) can be produced by condensing lipoic acid with NHR 1 R 2 .
  • the solvent for the condensation reaction include dichloromethane, chloroform, and tetrahydrofuran, and tetrahydrofuran is preferable.
  • the amount of the solvent can be 1 mL to 200 mL per 1 g of the disulfide compound, preferably 3 mL to 35 mL.
  • Examples of the condensing agent to be used include 1- (3-Dimethyllaminopophil) -3-ethylcarbodiimide (EDC, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and a salt thereof, N, N'-dicyclohexylcarbodiimide (DCC). ), Diisopropylcarbodiimide (DIC) (N-hydroxysuccinimide (NHS), 1-hydroxybenzotriazole (HOBt) may be used as an additive), 4-dimethylaminopyridine (DMAP), 1,1'-carbonyl.
  • EDC 1- (3-Dimethyllaminopophil) -3-ethylcarbodiimide
  • DCC N, N'-dicyclohexylcarbodiimide
  • DIC Diisopropylcarbodiimide
  • NHS N-hydroxysuccinimide
  • HOBt 1-hydroxybenzotriazole
  • DMAP 4-
  • Diimidazole di (1H-imidazole-1-yl) metanone (CDI) and the like can be mentioned.
  • the amount of the condensing agent used can be 0.8 equivalents to 2.0 equivalents, preferably 1.0 equivalents to 1.5 equivalents, relative to 1 equivalent of the disulfide compound.
  • the temperature of the reaction can be ⁇ 10 ° C. to 40 ° C., preferably 15 ° C. to 25 ° C.
  • the reaction time can be from 1 hour to 3 days, preferably 1 hour to 24 hours.
  • the trisulfide compound represented by the formula (1) can also be produced by condensing lipoic acid trisulfide with NHR 1 R 2 .
  • the conditions for condensation are the same as above.
  • the trisulfide compound according to the embodiment of the present invention is a compound represented by the following formula (3).
  • R 4 is an alkyl group having 1 to 6 carbon atoms having one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; ⁇ NR 6 R 7 and ⁇ N + R 9 R 10 Alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of R 11 ; or-(CH 2 CH 2 O) n R 8 is shown, and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5. ]
  • the compound represented by the formula (3) is considered to have good hydrophilicity.
  • R4 may be an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, and these alkyl groups are substituteds represented by ⁇ OR5 .
  • -The substituent represented by OR 5 is the same as above.
  • R 4 may be an alkyl group such as an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, and these alkyl groups are ⁇ NR 6 R 7 and ⁇ N + R 9 .
  • R 4 may be a group represented by-(CH 2 CH 2 O) n R 8 , and the group represented by-(CH 2 CH 2 O) n R 8 is described above. Is similar to.
  • R 4 may be, for example, a group represented by the following formula (30) or (31) (in the formula, * indicates a bond).
  • the compound represented by the formula (3) include, for example, a compound in which R 3 is a group represented by the following formula (30) and a compound in which R 3 is a group represented by the following formula (31). Can be mentioned.
  • the compound represented by the formula (3) is a compound represented by the formula (2) described later, which has 1 or more carbon atoms in which R 3 is selected from the group consisting of a carboxy group and ⁇ OR 5 and has 1 or more carbon atoms.
  • the CD inclusion body of the trisulfide compound according to another embodiment of the present invention is represented by the compound represented by the above formula (1), the compound represented by the following formula (2), and the following formula (2).
  • Cyclodextrin encapsulates at least one selected from the group consisting of salts of the compounds.
  • R 3 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; ⁇ NR 6 R 7 and An alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of ⁇ N + R 9 R 10 R 11 ; or ⁇ (CH 2 CH 2 O) n R 8 indicating R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5. ]
  • R 3 may be, for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, and is a group represented by R 4 in the formula (3). May be.
  • the alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of 11 or the trisulfide compound represented by the formula (2) having-(CH 2 CH 2 O) n R 8 is a trisulfide compound.
  • a step of protecting a functional group such as a hydroxy group, a carbonyl group, an amino group, and a carboxy group and a step of deprotecting the protected functional group may be included, if necessary. ..
  • the reaction conditions are the same as above.
  • R 3 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may have one or more substituents selected from the group consisting of a carboxy group and ⁇ OR 5 ; ⁇ NR 6 R 7 and An alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of ⁇ N + R 9 R 10 R 11 ; or ⁇ (CH 2 CH 2 O) n R 8 indicating R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and n represents an integer of 2 to 5. ]
  • the disulfide compound represented by the formula ( 2a) can be produced by condensing lipoic acid and R3 OH. Same as above.
  • the alkyl group having 2 to 6 carbon atoms having one or more substituents selected from the group consisting of 11 or the trisulfide compound represented by the formula (2) having-(CH 2 CH 2 O) n R 8 is a trisulfide compound. It can also be produced by condensing lipoic acid trisulfide with R 3 OH. The conditions for condensation are the same as above.
  • the salt of the compound represented by the above formula (2) may be a pharmacologically acceptable salt, for example, a salt with an alkali metal such as sodium or potassium, or an alkaline earth metal such as calcium or magnesium.
  • the cyclodextrin may be ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin or a derivative thereof.
  • “derivative” means that the hydrogen atom of at least one hydroxyl group of each cyclodextrin is substituted with an alkyl group or a sugar which may have a substituent.
  • Cyclodextrin derivatives include, for example, methyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, hydroxy.
  • Ethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ - Cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ - Cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin and the like can be used.
  • a step of dissolving cyclodextrin in a solvent (step a), a step of adding a trisulfide compound to the obtained solution and stirring (step b), and a step of filtering the stirred liquid are performed. It can be produced by the step (step c) of washing with the same solvent as the solvent used in step a, freezing the filtrate, and freeze-drying. The filtration and cleaning operations in step c may be omitted.
  • the solvent used in step a is preferably water.
  • the amount of the solvent used in the step a can be 1 to 350 ml with respect to 1 g of cyclodextrin, preferably 1 to 80 ml.
  • the mass ratio of cyclodextrin to the trisulfide compound can be 2 to 20, preferably 5 to 16.5.
  • the stirring temperature in step b can be 20 to 50 ° C. and may be room temperature.
  • the stirring time in step b can be 0.25 to 40 hours, preferably 2 to 35 hours.
  • step b after adding the trisulfide compound and before stirring, the same solvent as that used in step a may be added.
  • the amount of the solvent can be 0 to 30 ml with respect to 1 g of cyclodextrin, preferably 0 to 20 ml.
  • the amount of the solvent used in the step c can be 0 to 150 ml with respect to 1 g of cyclodextrin, preferably 0 to 20 ml.
  • the freezing temperature in step c can be ⁇ 30 to ⁇ 20 ° C., preferably ⁇ 20 ° C.
  • the freezing time of step c can be 10 to 50 hours.
  • Freeze-drying in step c can be performed at an absolute pressure of 20 to 100 Pa and an outside temperature of 10 to 40 ° C, preferably an outside temperature of 20 ° C.
  • the freeze-drying period of step c can be 1 to 5 days.
  • the CD clathrate of the trisulfide compound or the trisulfide compound according to the present invention can be made into a pharmaceutical composition by adding a pharmacologically acceptable additive, if necessary.
  • the pharmaceutical composition containing the trisulfide compound or the CD inclusion body of the trisulfide compound according to the present invention can be formulated as, for example, an injection, an oral preparation, an eye drop, a coating agent or a suppository.
  • the injection include a subcutaneous injection, an intramuscular injection, an intravenous injection, an intraperitoneal injection and the like.
  • the oral preparation include tablets, granules, fine granules, powders and capsules.
  • the eye drops include aqueous eye drops, oil-based eye drops and the like.
  • the coating agent include a plaster, an ointment, a cream, a lotion and the like.
  • Examples of the suppository include oil-based base type suppositories and water-soluble base type suppositories.
  • Examples of additives include sugars (sucrose, trehalose, maltose, lactose, etc.), sugar alcohols (sorbitol, etc.), amino acids (L-arginine, etc.), water-soluble polymers (HES (hydroxyethyl starch), PVP, etc.).
  • Stabilizers such as nonionic surfactants (polysorbitol, poroxamar, etc.), pH adjusters such as sodium phosphate buffer, histidine buffer, isotonic agents such as sodium chloride, and , Mannitol, glycine, salt, sucrose and other excipients.
  • Preferred embodiments of the present invention include the following [Embodiments 1] to [Embodiments 7].
  • [Embodiment 1] A compound represented by the following formula (1). [In the formula, R 1 and R 2 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more substituents selected from the group consisting of an amino group and a carboxy group. May have. ]
  • [Embodiment 2] The compound according to [Embodiment 1], wherein R 1 and R 2 are hydrogen atoms.
  • Embodiment 3 At least one selected from the group consisting of a compound represented by the following formula (1), a compound represented by the following formula (2), and a salt of the compound represented by the following formula (2). , Cyclodextrin clathrate encapsulated in cyclodextrin.
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is one or more substituents selected from the group consisting of an amino group and a carboxy group. May have.
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • the salt of the compound represented by the above formula (2) contains at least one selected from the group consisting of a salt with an alkali metal, a salt with an alkaline earth metal, and an ammonium salt. Form 3].
  • [Embodiment 5] The inclusion body according to [Embodiment 3] or [Embodiment 4], wherein the compound is a compound represented by the above formula ( 2 ) and R3 is a hydrogen atom.
  • Example 1 ⁇ Production of (R) -lipoic acid trisulfide> A 200 mL four-diameter flask was charged with 24.38 g (118.17 mmol) of (R) - ⁇ -lipoic acid and 488 mL (20.0 v / w) of a 75% ethanol aqueous solution. After confirming that the contents of the flask had melted, the flask was cooled to an internal temperature of 0 ° C. To this, Oxone® (41.40 g, 124.20 mmol, 1.05 eq) was added in two portions and then reacted for about 50 minutes.
  • Oxone® 41.40 g, 124.20 mmol, 1.05 eq
  • Example 2 Manufacturing of lipoamide trisulfide (racemic mixture)> A 500 mL four-diameter flask was charged with 1.00 g (4.87 mmol) of lipoamide (racemic mixture) and 182 mL (182.0 v / w) of an 85% dimethylformamide aqueous solution. After confirming that the contents of the flask had melted, the flask was cooled to an internal temperature of 4 ° C. To the flask, 1.63 g (4.89 mmol, 1.00 eq) of Oxone® was added in 3 portions every 10 minutes and reacted for about 1 hour.
  • Example 3 Provide of (R) -Lipoic acid trisulfide-DEG ester> A 50 mL three-diameter flask was charged with 1.00 g (4.19 mmol) of (R) -lipoic acid trisulfide and 10 mL (10 v / w) of methylene chloride.
  • the reaction was carried out at room temperature overnight. Then, at room temperature, the organic layer was washed once with 20 mL (20 v / w) of a 1 mol / L aqueous solution of hydrochloric acid and 20 mL (20 v / w) of a saturated aqueous sodium hydrogen carbonate solution, and further, 20 mL (20 v / w) of a saturated saline solution was washed. Washed once with. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (mobile phase: hexane / ethyl acetate mixed solution).
  • Example 4 ⁇ Production of (R) -lipoic acid trisulfide-choline ester> 1.03 g (4.32 mmol) of (R) -lipoic acid trisulfide and 20 mL (19.4 v / w) of methylene chloride were placed in a 100 mL four-diameter flask and cooled to 0 ° C.
  • Example 6 A 100 mL eggplant flask of a ⁇ -CD inclusion body of lipoic acid trisulfide (racemic acid) was charged with 1020.0 mg (0.899 mmol) of ⁇ -CD and 80 mL of water. After confirming that the contents of the flask were dissolved, 99.8 mg (0.419 mmol) of lipoic acid trisulfide was added, and the inside of the flask was washed with 20 mL of water. After stirring at 45 ° C. for 15 minutes, the mixture was filtered, and the inside of the flask and the crystals were washed with 10 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 23 hours. Freeze-dried at an outside temperature of 20 ° C. for about 4.5 days to obtain 980.0 mg (white solid) of the inclusion body.
  • Example 7 HP- ⁇ -CD inclusion body of lipoic acid trisulfide (racemic acid)
  • a 50 mL eggplant flask was charged with 1291.0 mg of HP- ⁇ -CD and 16 mL of water. After confirming that the contents of the flask were dissolved, 100.0 mg (0.419 mmol) of lipoic acid trisulfide was added. After stirring at room temperature for about 28 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 10 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for about 2 days. Freeze-dried at an outside temperature of 20 ° C. for about 2 days to obtain 1330.0 mg (white solid) of the inclusion body.
  • Example 8 HP- ⁇ -CD inclusion body of (R) -lipoic acid trisulfide 50 mL eggplant flask was charged with HP- ⁇ -CD969.9 mg and 10 mL of water. After confirming that the contents of the flask were dissolved, 100.3 mg (0.421 mmol) of (R) -lipoic acid trisulfide was added, and the inside of the flask was washed with 4 mL of water. After stirring at room temperature for about 25 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 12 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 15 hours. Freeze-dried at an outside temperature of 20 ° C. for about 2 days to obtain 1040.0 mg (white solid) of the inclusion body.
  • Example 9 Me- ⁇ -CD inclusion body of lipoic acid trisulfide (racemic acid)
  • a 50 mL eggplant flask was charged with 1616.0 mg of Me- ⁇ -CD (number methylated mixture) and 12 mL of water. After confirming that the contents of the flask were dissolved, 101.0 mg (0.424 mmol) of lipoic acid trisulfide was added, and the inside of the flask was washed with 4 mL of water. After stirring for 21 hours, the flask was filtered, and the inside of the flask and the crystals were washed with 12 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 20 hours. Freeze-dried at an outside temperature of 20 ° C. for about 4 days to obtain 1665.2 mg (white solid) of the inclusion body.
  • Example 10 A 50 mL eggplant flask of a Me- ⁇ -CD inclusion body of (R) -lipoic acid trisulfide was charged with 1616.0 mg of Me- ⁇ -CD (number methylated mixture) and 16 mL of water. After confirming that the contents of the flask were dissolved, 99.9 mg (0.420 mmol) of (R) -lipoic acid trisulfide was added, and the inside of the flask was washed with 4 mL of water. After stirring at room temperature for 6 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 13 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 28 hours. Freeze-dried at an outside temperature of 20 ° C. for about 3 days to obtain 1610.9 mg (white solid) of the inclusion body.
  • Example 11 Mal- ⁇ -CD inclusion body of lipoic acid trisulfide (racemic acid)
  • a 50 mL eggplant flask was charged with Mal- ⁇ -CD1224.2 mg (0.839 mmol) and 14 mL of water. After confirming that the contents of the flask were dissolved, 100.4 mg (0.421 mmol) of lipoic acid trisulfide was added, and the inside of the flask was washed with 2 mL of water. After stirring at room temperature for 31 hours, the mixture was filtered, and the inside of the flask and the crystals were washed with 10 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 22 hours. Freeze-dried at an outside temperature of 20 ° C. for about 46 hours to obtain 1180.0 mg (white solid) of the inclusion body.
  • Example 12 Mal- ⁇ -CD inclusion of (R) -lipoic acid trisulfide A 50 mL eggplant flask was charged with Mal- ⁇ -CD1224.2 mg (0.839 mmol) and 10 mL of water. After confirming that the contents of the flask were dissolved, 100.1 mg (0.420 mmol) of (R) -lipoic acid trisulfide was added, and the inside of the flask was washed with 5 mL of water. After stirring at room temperature for 4.5 hours, the mixture was filtered, and the inside of the flask and crystals were washed with 11 mL of water. The obtained filtrate was frozen in a freezer at ⁇ 20 ° C. for 24 hours. Freeze-dried at an outside temperature of 20 ° C. for about 41 hours to obtain 1319.6 mg (white solid) of the inclusion body.
  • Table 2 shows the yield and solubility of the inclusions obtained in Examples 6 to 12.
  • the HPLC conditions are as follows. Detector: Ultraviolet absorptiometer (measurement wavelength: 220 nm) Column: LiCrosorb RP-18 (Kanto Chemical, 4.0 mm ID x 250 mm, 5 ⁇ m) Column temperature: Constant temperature mobile phase around 40 ° C. A: Phosphoric acid aqueous solution (pH 3) Mobile phase B: Methanol mobile phase feed: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient.

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WO2024143231A1 (ja) 2022-12-27 2024-07-04 協和ファーマケミカル株式会社 トリスルフィド化合物及びその包接体
WO2024185596A1 (ja) 2023-03-07 2024-09-12 協和発酵バイオ株式会社 肝細胞増殖因子の生理活性増強剤
WO2025028521A1 (ja) 2023-08-01 2025-02-06 キリンホールディングス株式会社 肝機能障害の予防又は改善用組成物
WO2025070464A1 (ja) 2023-09-28 2025-04-03 協和ファーマケミカル株式会社 トリスルフィド化合物を含有する医薬組成物
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CN115716817A (zh) * 2022-11-22 2023-02-28 国药集团威奇达药业有限公司 6,8-环三硫辛酸的制备方法
CN115716817B (zh) * 2022-11-22 2024-04-19 国药集团威奇达药业有限公司 6,8-环三硫辛酸的制备方法
WO2024143231A1 (ja) 2022-12-27 2024-07-04 協和ファーマケミカル株式会社 トリスルフィド化合物及びその包接体
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WO2024185596A1 (ja) 2023-03-07 2024-09-12 協和発酵バイオ株式会社 肝細胞増殖因子の生理活性増強剤
WO2025028521A1 (ja) 2023-08-01 2025-02-06 キリンホールディングス株式会社 肝機能障害の予防又は改善用組成物
WO2025070464A1 (ja) 2023-09-28 2025-04-03 協和ファーマケミカル株式会社 トリスルフィド化合物を含有する医薬組成物

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