WO2022097580A1 - Composé ayant une fraction dipicolylamine, son procédé de production et composition antimicrobienne l'utilisant - Google Patents

Composé ayant une fraction dipicolylamine, son procédé de production et composition antimicrobienne l'utilisant Download PDF

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WO2022097580A1
WO2022097580A1 PCT/JP2021/040089 JP2021040089W WO2022097580A1 WO 2022097580 A1 WO2022097580 A1 WO 2022097580A1 JP 2021040089 W JP2021040089 W JP 2021040089W WO 2022097580 A1 WO2022097580 A1 WO 2022097580A1
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group
formula
compound
integer
hydrogen atom
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PCT/JP2021/040089
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主馬 安原
有美 井家
美香 石原
美則 山口
孝仁 三好
優也 小西
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五洋紙工株式会社
国立大学法人 奈良先端科学技術大学院大学
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Priority to JP2022560754A priority Critical patent/JPWO2022097580A1/ja
Publication of WO2022097580A1 publication Critical patent/WO2022097580A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/10—Esters
    • C08F20/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/20—Esters of polyhydric alcohols or phenols, e.g. 2-hydroxyethyl (meth)acrylate or glycerol mono-(meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F4/00—Polymerisation catalysts
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/04—Homopolymers or copolymers of esters
    • C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical

Definitions

  • the present invention relates to a compound having a dipicorylamine moiety, a method for producing the same, and an antibacterial composition using the same.
  • Non-Patent Document 1 reports a technique for producing a polymer having antibacterial activity by polymerizing a methacrylate monomer having a dipicorylamine (DPA) moiety.
  • DPA dipicorylamine
  • Patent Document 1 discloses an amino group-based polymer having a dipicorylamine moiety having excellent antibacterial activity and a reduced production process as compared with that described in Non-Patent Document 1. ..
  • the polymer described in Patent Document 1 still requires many steps for its production. Considering the possibility of widespread use of polymers having antimicrobial activity in the future, it is desired to develop a technique more suitable for industrial production.
  • An object of the present invention is to solve the above-mentioned problems, and an object thereof is a compound having a dipicorylamine moiety that has excellent antibacterial activity and can be produced more easily, and a method for producing the same. Further, it is an object of the present invention to provide an antibacterial composition using the same.
  • the present invention has the following formula (I):
  • X is a repeating unit having a dipicorylamine moiety and has the following formula (II) :.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is-(CH 2 ) p- (where p is an integer from 1 to 8).
  • R 3 and R 4 are independently hydrogen atoms, halogen atoms, nitro groups, cyano groups or alkyl groups having 1 to 7 carbon atoms which may have a branch or a ring, and n is 1 to 1000.
  • n is an integer from 1 to 1000
  • a 1 in the above formula (I) is the following formula (III):
  • R5 is a hydrogen atom or a methyl group and is R 6 is a cyano group, a phenyl group, an ethoxycarbonyl group, a 2,2-dimethylpropyl group, or -CH 2 C (CH 3 ) 2 (OCH 3 ), and R 7 is a hydrogen atom, a methyl group or (Cyano group) It is a group represented by, and B 1 is the following formula (IV) :.
  • Y 1 has a divalent group represented by -S-, -CH 2- , -CH 2 NZ- or -O-.
  • Z is
  • D - is a halide ion, a hydroxide ion, or a phosphate ion).
  • m is 0 or 1) It is a group represented by.
  • the above formula (I) is the following formula (Ib) :.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is-(CH 2 ) p- (where p is an integer from 1 to 8).
  • R 3 and R 4 are independently hydrogen atoms, halogen atoms, nitro groups, cyano groups or alkyl groups having 1 to 7 carbon atoms which may have a branch or a ring, and n is 1 to 1000. Is an integer of) It is represented by.
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • q is an integer from 1 to 1000) Includes repeating units represented by.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is-(CH 2 ) p- (where p is an integer from 1 to 8).
  • R 3 and R 4 are independently alkyl groups having 1 to 7 carbon atoms which may have a hydrogen atom, a halogen atom, a nitro group, a cyano group or a branched or ring.
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • the present invention is also a method for producing the above compound.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is-(CH 2 ) p- (where p is an integer of 1-8)
  • R 3 and R 4 are independent hydrogen, halogen, nitro and cyano groups, respectively.
  • it is an alkyl group having 1 to 7 carbon atoms which may have a branch or a ring).
  • It is a method including a step of living radical polymerization of a mixture containing a compound represented by the above and a RAFT compound.
  • the mixture further comprises the following formula (VIII):
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • the living radical polymerization step is performed in the presence of an oil-soluble azo polymerization initiator.
  • the living radical polymerization step is carried out at a temperature of -196 ° C to 150 ° C.
  • the content of the RAFT compound in the mixture is 0.01 mol% -40 mol%.
  • the present invention also comprises the above compound and a metal complexed with the dipicorylamine moiety of the compound, the metal being at least one selected from the group consisting of alkaline earth metals and transition metals. It is a complex.
  • the metal is at least one metal selected from the group consisting of zinc, copper, iron, nickel, cobalt, chromium, gallium, silver, cadmium, platinum, gold and mercury.
  • the weight average molecular weight (Mw) of the compound is 500 to 86000.
  • the present invention is also an antibacterial composition containing the above complex as an active ingredient.
  • the present invention can be used as it is as an active ingredient of an antibacterial composition without performing a post-synthesis purification operation.
  • no special temperature control means is particularly required for synthesis, and the molecular weight can be easily controlled by utilizing living radical polymerization.
  • alkyl group having 1 to 7 carbon atoms which may have a branched or ring refers to any alkyl group having 1 to 7 carbon atoms, for example, a linear alkyl group or a branched alkyl group.
  • Groups, and cyclic alkyl groups including, for example, alkyl groups comprising a cyclic moiety and a linear or branched moiety.
  • Specific examples of the alkyl group having 1 to 7 carbon atoms which may have a branch or a ring include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group and an n-hexyl.
  • n-heptyl group isopropyl group, isobutyl group, s-butyl group, t-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclopropylmethyl group, cyclobutylmethyl group, Cyclopentylmethyl group, cyclohexylmethyl group and the like can be mentioned.
  • linear or branched alkyl group having 1 to 3 carbon atoms includes a linear alkyl group having 1 to 3 carbon atoms or a branched chain alkyl group. Specific examples of the linear or branched alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group and an isopropyl group.
  • a linear or branched benzyl group optionally substituted with an alkyl group having 1 to 3 carbon atoms is a benzyl group, or at least a hydrogen atom constituting a (unsubstituted) benzyl group.
  • halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • halide ion includes, for example, fluoride ion, chloride ion, bromide ion, and iodide ion.
  • It is a compound represented by, and is a compound having a dipicorylamine moiety in its structure.
  • X is a repeating unit having a dipicorylamine moiety and has the following formula (II) :.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is ⁇ (CH 2 ) p ⁇ (where p is an integer of 1 to 8, preferably an integer of 1 to 3).
  • R 3 and R 4 are independently hydrogen atoms, halogen atoms, nitro groups, cyano groups or alkyl groups having 1 to 7 carbon atoms which may have a branch or a ring, and n is 1 to 1000.
  • Integer preferably an integer of 1 to 50, more preferably an integer of 2 to 10 Represented by, containing repeating units, and A 1 and B 1 are residues of the RAFT compound.
  • the "residue of the RAFT compound" corresponding to A 1 and B 1 is the RAFT used for RAFT (Reversible Addition Fragmentation Chain Transfer) polymerization. Includes organic groups that make up a compound (also referred to as a RAFT agent or CTA (Charge Transfer Agent)).
  • a 1 in the above formula (I) is preferably the following formula (III):
  • R5 is a hydrogen atom or a methyl group and is R 6 is a cyano group, a phenyl group, an ethoxycarbonyl group, a 2,2-dimethylpropyl group, or -CH 2 C (CH 3 ) 2 (OCH 3 ), and R 7 is a hydrogen atom, a methyl group or (Cyano group) It is a group represented by.
  • a 1 is a specific example of A 1 ,
  • Y 1 has a divalent group represented by -S-, -CH 2- , -CH 2 NZ- or -O-.
  • Z is
  • D - is a halide ion, a hydroxide ion, or a phosphate ion).
  • m is 0 or 1) It is a group represented by.
  • B 1 As a specific example of B 1 ,
  • the compound of formula (I) of the present invention has the following formula (Ia) :.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is ⁇ (CH 2 ) p ⁇ (where p is an integer of 1 to 8, preferably an integer of 1 to 3).
  • R 3 and R 4 are independently alkyl groups having 1 to 7 carbon atoms which may have a hydrogen atom, a halogen atom, a nitro group, a cyano group or a branched or ring.
  • n is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably an integer of 2 to 10, and A 1 and B 1 are residues of the RAFT compound).
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is ⁇ (CH 2 ) p ⁇ (where p is an integer of 1 to 8, preferably an integer of 1 to 3).
  • R 3 and R 4 are independently hydrogen atoms, halogen atoms, nitro groups, cyano groups or alkyl groups having 1 to 7 carbon atoms which may have a branch or a ring, and n is 1 to 1000.
  • Integer preferably an integer of 1 to 50, more preferably an integer of 2 to 10. It may be a compound represented by.
  • the compound of the formula (I) of the present invention may contain a repeating unit other than the above formula (II) as X of the formula (I).
  • X in the formula (I) is the following formula (V) :.
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • An integer of 1 to 1000 preferably an integer of 1 to 50, more preferably an integer of 2 to 10). It may include a repeating unit represented by.
  • the compound of the formula (I) of the present invention improves miscibility when mixed with other materials and promotes adsorption to a hydrophobic surface. be able to.
  • the compound of formula (I) of the present invention has the following formula (Ic):
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is ⁇ (CH 2 ) p ⁇ (where p is an integer of 1 to 8, preferably an integer of 1 to 3).
  • R 3 and R 4 are independently alkyl groups having 1 to 7 carbon atoms which may have a hydrogen atom, a halogen atom, a nitro group, a cyano group or a branched or ring.
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • n is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably an integer of 2 to 10.
  • q is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably an integer of 2 to 10, and A 1 and B 1 are residues of the RAFT compound).
  • the compound of the above formula (Ic) may be in any form of a random copolymer or a block copolymer.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is ⁇ (CH 2 ) p ⁇ (where p is an integer of 1 to 8, preferably an integer of 1 to 3).
  • R 3 and R 4 are independently alkyl groups having 1 to 7 carbon atoms which may have a hydrogen atom, a halogen atom, a nitro group, a cyano group or a branched or ring.
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a hydrogen atom; a linear or branched alkyl group having 1 to 3 carbon atoms; or ⁇ (CH 2 ) u ⁇ R 10 (where u is an integer of 1 to 3 and R 10 ).
  • n is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably an integer of 2 to 10
  • q is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably 2 to 10.
  • the compound of the above formula (Id) may be in any form of a random copolymer or a block copolymer.
  • R 1 is a methyl group or a hydrogen atom
  • R 2 is-(CH 2 ) p- (where p is an integer of 1-8, preferably an integer of 1-3)
  • R 3 and R 4 are independent hydrogen atoms, respectively. It is an alkyl group having 1 to 7 carbon atoms which may have a halogen atom, a nitro group, a cyano group, or a branched or ring).
  • a mixture containing the compound represented by and the RAFT compound is subjected to living radical polymerization.
  • the compound of the formula (VI) contained in the above mixture is, for example, S.I. C. Hong et al., Micromolecules, 2002, 35, pp. N, N-bis (2-pyridylmethyl) -2-hydroxyethylamine (DPA-OH) or a derivative thereof is prepared using the method described in 7592-7605, and those skilled in the art based on DPA-OH or a derivative thereof. It can be easily produced by a method known to those skilled in the art.
  • the RAFT compound is a RAFT agent or CTA used for RAFT polymerization as described above.
  • RAFT compounds that can be used in the production method of the present invention include dithiobenzoate-type RAFT agents, trithiocarbonate-type RAFT agents, and dithiocarbamate-type RAFT agents, and combinations thereof. Specific examples of such a RAFT compound include the following formula (VII) :.
  • a 1 is the following formula (III):
  • R5 is a hydrogen atom or a methyl group and is R 6 is a cyano group, a phenyl group, an ethoxycarbonyl group, a 2,2-dimethylpropyl group, or -CH 2 C (CH 3 ) 2 (OCH 3 ), and R 7 is a hydrogen atom, a methyl group or (Cyano group) Is a group represented by, and B 1 is the following formula (IV) :.
  • Y 1 has a divalent group represented by -S-, -CH 2- , -CH 2 NZ- or -O-.
  • Z is
  • D - is a halide ion, a hydroxide ion, or a phosphate ion).
  • m is 0 or 1) It is a group represented by.
  • the content of the RAFT compound contained in the mixture is preferably 0.01 mol% to 40 mol%, more preferably 1 mol% to 35 mol%, still more preferably 5 mol% to. It is 30 mol%. If the content of the RAFT compound contained in the mixture is less than 0.01 mol%, the living radical polymerization itself may not proceed smoothly, and it may be difficult to produce the compound of the formula (I) itself. If the content of the RAFT compound contained in the above mixture exceeds 40 mol%, the desired polymerization itself may not proceed.
  • the above mixture further contains the following formula (VIII):
  • R8 is a methyl group or a hydrogen atom
  • R 9 is a benzyl group that may be substituted with a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, or a linear or branched chain alkyl group having 1 to 3 carbon atoms. be
  • It may contain a compound represented by.
  • the compound of formula (VIII) can be added as a comonomer to the compound of formula (VI) (main monomer).
  • the content of the compound of the formula (VIII) that can be contained in the above mixture is preferably 99 mol% or less, more preferably 50 mol% or less.
  • the obtained compound maintains the antibacterial activity and is miscible with other substances and adsorbable to the surface. Can be enhanced.
  • the compound of the formula (Ic) or the formula (Id) when the compound of the formula (Ic) or the formula (Id) is produced among the compounds of the formula (I), the compound of the formula (VI) (main monomer) and the compound of the formula (VIII) (
  • the compound of the formula (Ic) or the formula (Id) can be obtained in the form of a random copolymer by mixing the comonomer together with the living radical polymerization.
  • the compound of formula (Ic) or formula (Id) can be obtained in the form of a block copolymer.
  • living radical polymerization is carried out in a state where the above mixture is added to a predetermined solvent.
  • solvents that can be used include water and polar organic solvents and combinations thereof.
  • the type of water include ultrapure water, pure water, ion-exchanged water, distilled water, RO water, and tap water.
  • polar organic solvents include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropyl alcohol, acetonitrile, dioxane, tetrahydrofuran, acetone, and combinations thereof.
  • the amount of the solvent used is not particularly limited and may be appropriately selected by those skilled in the art.
  • the living radical polymerization is preferably carried out in the presence of a polymerization initiator.
  • polymerization initiators include azo compounds and peroxides.
  • oil-soluble azo polymerization initiator because it is soluble in a solvent containing the above mixture and enables radical polymerization at a relatively low temperature (for example, 20 ° C to 50 ° C).
  • oil-soluble azo polymerization initiators are 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), 2,2.
  • 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) is preferable because it can be polymerized near room temperature.
  • 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) is commercially available, for example, from Fujifilm Wako Pure Chemical Industries, Ltd. under the trade name of V-70.
  • living radical polymerization using the above mixture can be carried out at a temperature of, for example, -196 ° C to 150 ° C.
  • living radical polymerization is preferably carried out at a temperature of 20 ° C to 50 ° C, more preferably 25 ° C to 40 ° C.
  • the form of the compound can be obtained.
  • the compound of the formula (I) obtained by the production method of the present invention can be used as it is, for example, as an active ingredient of an antibacterial composition, without performing a post-synthesis purification operation.
  • the complex of the present invention contains the compound of the above formula (I) and a metal complexed with the dipicorylamine moiety in the compound.
  • Examples of the metal constituting the complex of the present invention include alkaline earth metals and transition metals, and combinations thereof.
  • metals include zinc, copper, iron, nickel, cobalt, chromium, gallium, silver, cadmium, platinum, gold and mercury, and combinations thereof.
  • the metal constituting the complex of the present invention is preferably zinc, copper, or a combination thereof, because it is useful as an antibacterial composition as described later. This metal can form a complex with the compound of the above formula (I) in the form of a metal ion.
  • the complex of the present invention has the form of a polymer in that the compound of the above formula (I) can provide excellent antibacterial activity against, for example, Escherichia coli and Staphylococcus aureus. Is preferable.
  • the weight average molecular weight (Mw) of the compound of the formula (I) contained in the complex of the present invention is preferably 500 to It is 86000, more preferably 500 to 6000, even more preferably 1000 to 4000, and even more preferably 1000 to 3000.
  • weight average molecular weight (Mw) of the compound of the above formula (I) contained in the complex of the present invention is less than 500, appropriate antibacterial activity may not be exhibited in the obtained complex.
  • weight average molecular weight (Mw) of the compound of the above formula (I) contained in the complex of the present invention exceeds 86000, the antibacterial activity of the obtained complex may rather decrease.
  • the compound of the formula (I) and a salt of the above metal are mixed in water or a predetermined aqueous solution. By doing so, it can be easily formed.
  • the complex thus obtained is useful as an active ingredient of, for example, the following antibacterial composition (for example, an antibacterial agent).
  • the following antibacterial composition for example, an antibacterial agent.
  • the antibacterial composition of the present invention contains the above complex (that is, a complex of the compound of formula (I) and a metal) as an active ingredient.
  • the antibacterial composition of the present invention includes a drug composition having an effect of suppressing or killing the growth of microorganisms such as bacteria, fungi, and bacteria.
  • the antibacterial composition of the present invention may contain additives other than the above complex.
  • additives include buffers, pH regulators, tonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, diluents, solubilizers, stabilizers, fillings. Agents, binders, surfactants, and stabilizers, and combinations thereof.
  • the content of other additives that can be contained in the antibacterial composition is not particularly limited, and an appropriate content can be appropriately selected by those skilled in the art.
  • the antibacterial composition of the present invention may also contain a solvent such as water (eg, pure water, ion-exchanged water, distilled water, RO water, and tap water) or alcohol (eg, ethanol).
  • a solvent such as water (eg, pure water, ion-exchanged water, distilled water, RO water, and tap water) or alcohol (eg, ethanol).
  • the content of the solvent that can be contained in the antibacterial composition is not particularly limited, and an appropriate content can be appropriately selected by those skilled in the art.
  • the antibacterial composition of the present invention can be used for various purposes. Examples of such applications include preservatives for metal processing oils, antibacterial treatment agents for water treatment membranes, antibacterial soaps, antibacterial coatings, cosmetics, sanitary products, pharmaceuticals, surface processing agents for medical devices, and the like.
  • the title polymer P1 was obtained as a red oily substance.
  • the polymer P1 was used without purification.
  • the physical property data of the obtained polymer P1 are shown in Table 3.
  • the polymer P1 obtained above was numerically averaged by gel permeation chromatography (GPC) using LC-2000Plus manufactured by Nippon Kogaku Co., Ltd., Shodex OHpak SB-806M column, and 10 mM LiBr-containing dimethylformamide as a mobile phase.
  • the molecular weight (Mn), weight average molecular weight (Mw), polydispersity (Mw / Mn) and peak top molecular weight (Mp) were measured.
  • Example 2 Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed with Zn 2+ (2)
  • Polymer P2 was obtained as a red oily substance in the same manner as in Example 1 except that the amount of RFAT agent used was changed to 30 mol%. This polymer P2 was used without purification.
  • the physical property data of the obtained polymer P2 are shown in Table 4.
  • the number average molecular weight (Mn), the weight average molecular weight (Mw), the polydispersity (Mw / Mn) and the peak top molecular weight (Mp) by GPC were determined in the same manner as in Example 1. It was measured.
  • Example 3 Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed with Zn 2+ (3)
  • Polymer P3 was obtained as a red oily substance in the same manner as in Example 1 except that the amount of RFAT agent used was changed to 0.1 mol%. This polymer P3 was used without purification.
  • the physical property data of the obtained polymer P3 are shown in Table 5.
  • the number average molecular weight (Mn), the weight average molecular weight (Mw), the polydispersity (Mw / Mn) and the peak top molecular weight (Mp) by GPC were determined in the same manner as in Example 1. It was measured.
  • Example 4 Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed with Zn 2+ (4)
  • Polymer P4 was obtained as a red oily substance in the same manner as in Example 1 except that the amount of RFAT agent used was changed to 5.0 mol%. This polymer P4 was used without purification.
  • the physical property data of the obtained polymer P4 are shown in Table 6.
  • the number average molecular weight (Mn), the weight average molecular weight (Mw), the polydispersity (Mw / Mn) and the peak top molecular weight (Mp) by GPC were determined in the same manner as in Example 1. It was measured.
  • Example 5 Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed with Zn 2+ (5)
  • Polymer P5 was obtained as a red oily substance in the same manner as in Example 1 except that the amount of RFAT agent used was changed to 10 mol%. This polymer P5 was used without purification.
  • the physical property data of the obtained polymer P5 are shown in Table 7.
  • the number average molecular weight (Mn), the weight average molecular weight (Mw), the polydispersity (Mw / Mn) and the peak top molecular weight (Mp) by GPC were determined in the same manner as in Example 1. It was measured.
  • Example 7 Synthesis of methacrylate (random copolymer) containing a dipicorylamine moiety and preparation of a complex formed in a complex with Zn 2+ (7)
  • the title polymer P7 (random copolymer) was obtained as a red oily substance by distillation in Table 9. The physical property data of the obtained polymer P7 was used without purification. ..
  • Example 8 Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed in a complex with Cu 2+ (8)
  • a complex S8 complexed with Cu 2+ was obtained in the same manner as in Example 1 except that a 5 ⁇ L copper chloride aqueous solution (final concentration 0.5 mM) was used instead of the zinc nitrate aqueous solution.
  • the results obtained are shown in Table 10.
  • Polymer CP1 was obtained as a brown oily substance in the same manner as in Example 1 except that the RAFT agent was not used (0 mol%). This polymer CP1 was used without purification.
  • the number average molecular weight (Mn), weight average molecular weight (Mw), polydispersity (Mw / Mn), and peak top molecular weight (Mp) were measured by GPC in the same manner as in Example 1.
  • Example 9 to 15 and Comparative Example 2 Evaluation of antibacterial activity (minimum growth concentration against bacteria) of a complex containing a metal ion) Regarding the antibacterial activity of the complexes S1, S2 and S4 to S8 obtained in Examples 1, 2 and 4 to 8, and the complex CS1 obtained in Comparative Example 1, the minimum inhibitory concentration against bacteria (Minimum inhibitory concentration, MIC) was evaluated as one index as follows.
  • E. coli Escherichia coli
  • S. aureus Staphylococcus aureus ATCC25923
  • MH Mueller-Hinton
  • OD600 0.5-0.6
  • OD600 0.001.
  • 90 ⁇ L of the prepared culture solution was mixed with a 10 ⁇ L solution containing the above complex on a sterile polypropylene 96-well plate (# 3359, Corning Life Sciences, Corning, NY, USA).
  • the maximum concentration of the complexes was 250 ⁇ g / mL each, and these complexes were serially diluted 2-fold. Colonization in each well was visually confirmed after incubation at 37 ° C. for 18 hours. In this plate, the minimum polymer concentration at which colonization was not confirmed was defined as MIC.
  • Example 16 to 19 and Comparative Example 3 Evaluation of hemolytic toxicity of a complex containing a metal ion
  • the hemolytic toxicity of the complexes S1, S2, S4 and S5 obtained in Examples 1, 2, 4 and 5 and the complex CS1 obtained in Comparative Example 1 were evaluated as follows.
  • Hemolytic toxicity was assessed using sheep erythrocytes.
  • the erythrocytes were washed by removing the supernatant and repeating the same procedure twice more.
  • the resulting 10% (v / v) erythrocyte suspension was diluted 3-fold with phosphate buffer to give a stock for measurement.
  • 90 ⁇ L of the measurement stock was mixed with 10 ⁇ L of the complex solution in the same procedure as for antibacterial activity.
  • the final concentration of erythrocytes on the 96-well microplate was 3% (v / v).
  • 10 ⁇ L phosphate buffer or 10 ⁇ L 1% v / v Triton X-100 aqueous solution was added to make negative and positive control systems, respectively. Plates were incubated in an orbital shaker at 250 rpm for 60 minutes at 37 ° C. The plates were then centrifuged at 1000 rpm for 10 minutes. 10 ⁇ L of the supernatant was diluted with 90 ⁇ L of phosphate buffer and the absorbance at 405 nm was measured using a Molecular Devices SpectraMax M2 microplate reader.
  • S1, S2, S4 and S5 had particularly excellent antibacterial activity against both Escherichia coli and Staphylococcus aureus (see Examples 9-13 in Table 11).
  • the complexes S4 and S5 obtained in Examples 4 and 5 are more hemolyzed than the complexes S1 and S2 obtained in Examples 1 and 2. It can be seen that the toxicity was low.
  • the eggplant flask was heated to 30 ° C. in a closed state and stirred for 3 days. After confirming the consumption of the monomer S4 by 1 H NMR, the monomer 1 (616.55 mg, 2.00 mmol) obtained above was dissolved in dimethylformamide (2.0 mL) and then added, and the mixture was further stirred for 5 days. Then, the solvent was distilled off under reduced pressure to obtain the above-mentioned polymer P9B-1 (catechol protected block copolymer) P9B-1 as a red oily substance. The physical property data of the obtained polymer P9B-1 is shown in the table. Shown in 19.
  • the compound of the present invention is useful in various technical fields such as cosmetics, pharmaceuticals / medical devices, metal processing, and water treatment.

Abstract

Le composé ayant une fraction dipicolylamine selon la présente invention est représenté par la formule (I) : A1-X-B1. Dans la formule (I), X comprend une unité de répétition représentée par la formule (II) et ayant une fraction dipicolylamine, et A1 et B1 représentent chacun un résidu d'un composé RAFT.
PCT/JP2021/040089 2020-11-06 2021-10-29 Composé ayant une fraction dipicolylamine, son procédé de production et composition antimicrobienne l'utilisant WO2022097580A1 (fr)

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