WO2022097580A1

WO2022097580A1 - Compound having dipicolylamine moiety, production method for same, and antimicrobial composition using same

Info

Publication number: WO2022097580A1
Application number: PCT/JP2021/040089
Authority: WO
Inventors: 主馬安原; 有美井家; 美香石原; 美則山口; 孝仁三好; 優也小西
Original assignee: 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
Priority date: 2020-11-06
Filing date: 2021-10-29
Publication date: 2022-05-12
Also published as: JPWO2022097580A1

Abstract

The compound having a dipicolylamine moiety according to the present invention is represent by formula (I): A1-X-B1. In formula (I), X includes a repeating unit represented by formula (II) and having a dipicolylamine moiety, and A1 and B1 each represent a residue of a RAFT compound.

Description

A compound having a dipicorylamine moiety, a method for producing the same, and an antibacterial composition using the same.

The present invention relates to a compound having a dipicorylamine moiety, a method for producing the same, and an antibacterial composition using the same.

The emergence of drug-resistant bacteria against various antibacterial substances targeting proteins synthesized by bacteria has been reported. Therefore, in recent years, the development of antibiotics targeting substances other than proteins has been promoted.

In such development, for example, Non-Patent Document 1 reports a technique for producing a polymer having antibacterial activity by polymerizing a methacrylate monomer having a dipicorylamine (DPA) moiety.

However, many steps are required to produce the polymer described in Non-Patent Document 1. Further improvement was desired in this respect.

On the other hand, 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. .. However, 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.

International Publication No. 2019/230543

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):

It is a compound represented by
In formula (I),
X is a repeating unit having a dipicorylamine moiety and has the following formula (II) :.

(In 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. Is an integer of)
Represented by, a compound comprising a repeating unit, and A ¹ and B ¹ are residues of the RAFT compound.

In one embodiment, the above formula (II) is the following formula (IIa):

(In equation (IIa), n is an integer from 1 to 1000)
It is represented by.

In one embodiment, A ¹ in the above formula (I) is the following formula (III):

(In equation (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) :.

(In formula (IV),
Y ¹ has a divalent group represented by -S-, -CH _2- , -CH ₂ NZ- or -O-.
Z is

(Here, D ^- is a halide ion, a hydroxide ion, or a phosphate ion).
m is 0 or 1)
It is a group represented by.

In one embodiment, the above formula (I) is the following formula (Ib) :.

(In 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.

In one embodiment, X in the above formula (I) is further referred to as the following formula (V):

(In 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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
q is an integer from 1 to 1000)
Includes repeating units represented by.

In one embodiment, the above formula (I) is the following formula (Id):

(In formula (Id),
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 ). Is a phenyl group optionally substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms), and n is. It is an integer from 1 to 1000 and
q is an integer from 1 to 1000)
It is represented by.

The present invention is also a method for producing the above compound.
The following formula (VI):

(In the formula (VI),
R ¹ is a methyl group or a hydrogen atom
R ² is-(CH ₂ ) _p- (where p is an integer of 1-8), and R ³ and R ⁴ are independent hydrogen, halogen, nitro and cyano groups, respectively. Alternatively, 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.

In one embodiment, the mixture further comprises the following formula (VIII):

(In 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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
Contains the compound represented by.

In one embodiment, the living radical polymerization step is performed in the presence of an oil-soluble azo polymerization initiator.

In a further embodiment, the living radical polymerization step is carried out at a temperature of -196 ° C to 150 ° C.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

According to the present invention, it can be used as it is as an active ingredient of an antibacterial composition without performing a post-synthesis purification operation. In the compound of the present invention, no special temperature control means is particularly required for synthesis, and the molecular weight can be easily controlled by utilizing living radical polymerization.

First, the terms used in this specification are defined.

As used herein, the term "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. Group, 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.

In the present specification, the term "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. Further, the term "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. One includes a linear or branched group substituted with an alkyl group having 1 to 3 carbon atoms.

In the present specification, the term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term "halide ion" includes, for example, fluoride ion, chloride ion, bromide ion, and iodide ion.

Hereinafter, the present invention will be described in detail.

(Compound with dipicorylamine moiety)
The compound of the present invention has the following formula (I):

It is a compound represented by, and is a compound having a dipicorylamine moiety in its structure.

In the above formula (I),
X is a repeating unit having a dipicorylamine moiety and has the following formula (II) :.

(In 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.

In one embodiment, the above formula (II) is the following formula (IIa):

It is represented by.

In the compound of the formula (I) of the present invention, 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):

(In equation (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. As a specific example of A ¹ ,

Can be mentioned.

B ¹ in the above formula (I) is preferably the following formula (IV):

(Here, D ^- is a halide ion, a hydroxide ion, or a phosphate ion).
m is 0 or 1)
It is a group represented by. As a specific example of B ¹ ,

Can be mentioned.

In one embodiment, the compound of formula (I) of the present invention has the following formula (Ia) :.

(In 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).

For the reason that the compound of the formula (I) of the present invention is also useful as an antibacterial composition as described later, for example, the following formula (Ib):

(In formula (Ib),
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.

Further, 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). For example, in the compound of the formula (I) of the present invention, X in the formula (I) is the following formula (V) :.

(In 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 ). Is a phenyl group which may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms), and q is. 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.

By containing the repeating unit of the above formula (V), 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.

In one embodiment, the compound of formula (I) of the present invention has the following formula (Ic):

(In 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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
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.

For the reason that the compound of the formula (I) of the present invention is also useful as an antibacterial composition as described later, for example, the following formula (Id):

(In formula (Id),
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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
n is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably an integer of 2 to 10, and q is an integer of 1 to 1000, preferably an integer of 1 to 50, more preferably 2 to 10. Is an integer of)
It may be a compound represented by.

The compound of the above formula (Id) may be in any form of a random copolymer or a block copolymer.

(Method for producing a compound having a dipicorylamine moiety)
The compound of the above formula (I) can be produced, for example, as follows.

In the method of the present invention, the following formula (VI):

(In the formula (VI),
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), and 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) :.

(In formula (VII),
A ¹ is the following formula (III):

(In equation (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) :.

As a specific example of A ¹ constituting the RAFT compound represented by the formula (VII),

Can be mentioned.

As a specific example of B ¹ constituting the RAFT compound represented by the formula (VII),

Can be mentioned.

In the method of the present invention, 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.

In the method of the present invention, the above mixture further contains the following formula (VIII):

(In 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. In the above mixture, the compound of formula (VIII) can be added as a comonomer to the compound of formula (VI) (main monomer).

In the method of the present invention, 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. When the content of the compound of the formula (VIII) contained in the above mixture satisfies such a range, the obtained compound maintains the antibacterial activity and is miscible with other substances and adsorbable to the surface. Can be enhanced.

Here, in the present invention, 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. Alternatively, by performing the living radical polymerization of either the compound (main monomer) of the formula (VI) or the compound (comonomer) of the formula (VIII) first, and then adding the other to further carry out the living radical polymerization. , The compound of formula (Ic) or formula (Id) can be obtained in the form of a block copolymer.

In the method of the present invention, living radical polymerization is carried out in a state where the above mixture is added to a predetermined solvent. Examples of solvents that can be used include water and polar organic solvents and combinations thereof. Examples of the type of water include ultrapure water, pure water, ion-exchanged water, distilled water, RO water, and tap water. Examples of 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.

In the method of the present invention, the living radical polymerization is preferably carried out in the presence of a polymerization initiator. Examples of such polymerization initiators include azo compounds and peroxides. It is preferable to use an 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). Examples of oil-soluble azo polymerization initiators are 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), 2,2. '-Azobis (2-methylbutyronitrile), dimethyl 2,2'-azobis (2-methylpropionate), 2,2'-azobis (2,4,4-trimethylpentane), 4,4'- Azobis (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl4-cyanopentanoate), 2,2'-azobis (N-butyl) -2-Methylpropionamide), 1,1'-azobis (cyclohexane-1-carbonitrile), dimethyl 1,1'-azobis (1-cyclohexanecarboxylate), 2,2'-azobis (isoptilonitrile), etc. Can be mentioned. 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.

When an oil-soluble azo polymerization initiator is used, living radical polymerization using the above mixture can be carried out at a temperature of, for example, -196 ° C to 150 ° C. For example, from the viewpoint of increasing industrial productivity, such living radical polymerization is preferably carried out at a temperature of 20 ° C to 50 ° C, more preferably 25 ° C to 40 ° C. By performing the living radical polymerization in such a temperature range, the method of the present invention can easily produce the compound of the formula (I) without requiring a special temperature control means.

In this way, the compound of the formula (I) can be obtained. According to the method of the present invention, compounds of formula (I) range from monomers (corresponding to n = 1 of formula (II)) to polymers such as dimers, trimers and above. 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.

(Complex)
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. Examples of such 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 (weight average molecular weight of the compound of the formula (I) itself before complex formation with the metal) 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. If the 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. When the 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.

In the complex of the present invention, the compound of the formula (I) and a salt of the above metal (for example, nitrate, sulfate, hydrochloride, carbonate, acetate, phosphate, etc.) 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).

(Antibacterial composition)
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. Examples of other 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). 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.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

(Synthesis Example 1: Synthesis of N, N-bis (2-pyridylmethyl) -2-hydroxyethylamine (DPA-OH))

Ethanolamine (3.0 mL, 0.049 mol) was added dropwise to an aqueous solution of 80 mL of water and 2-picoryl chloride hydrochloride (16 g, 0.98 mol). The reaction mixture was stirred at 60 ° C. Sodium hydroxide in 40 mL of water (8.0 g, 0.20 mol was added dropwise and the resulting mixture was stirred overnight. After cooling to room temperature, the crude product was extracted 5 times with chloroform and the solvent under reduced pressure. The dark red oil obtained was purified by column chromatography using basic alumina with chloroform as an eluent to give the title DPA-OH as a pale yellow oil (7). .7 g, yield 63%). The physical property data of the obtained oil (DPA-OH) is shown in Table 1.

(Synthesis Example 2: Synthesis of Monomer 1)

DPA-OH (7.7 g, 31 mmol) and N, N-diisopropylethylamine obtained in Synthesis Example 1 of 50 mL of dry dichloromethane of methacryloyl chloride (3.0 mL, 31 mmol) under an argon atmosphere in an ice bath. It was added to a solution of (DIPEA) (5.4 mL, 31 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give a yellow oil. The crude product was purified by column chromatography using basic alumina together with chloroform as an eluent to give the title Monomer 1 as a pale yellow oil (7.9 g, 82% yield). Table 2 shows the physical property data of the obtained monomer 1.

(Example 1: Synthesis of methacrylate containing a dipicorylamine moiety and preparation of a complex formed in a complex with Zn ²⁺ (1))

2-Cyano-2-propylbenzodithioate (57.1 mg, 0.258 mmol) and the above-mentioned monomer 1 (401 mg, 1.29 mmol) were placed in a pre-baked, degassed and nitrogen-substituted test tube with a stopper. ), Oil-soluble azo polymerization initiator (V-70 manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) (23.9 mg, 0.077 mmol). After addition, it was dissolved in dimethylformamide (1.3 mL) and then subjected to nitrogen bubbling for 5 minutes. The test tube was heated to 30 ° C. in a closed state and stirred for 6 days. Then, the solvent was distilled off under reduced pressure. 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.

Further, 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.

Further, 5 μL of the aqueous solution of the polymer P1 was mixed with 5 μL of a zinc nitrate aqueous solution (final concentration 0.25 mM) on a microplate to obtain a complex S1 complexed with Zn ²⁺ . The results obtained are shown in Table 10.

(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.

Further, with respect to the polymer P2 obtained above, 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.

Further, a complex S2 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P2 was used instead of the polymer P1. The results obtained are shown in Table 10.

(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.

Further, with respect to the polymer P3 obtained above, 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.

Further, a complex S3 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P3 was used instead of the polymer P1. The results obtained are shown in Table 10.

(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.

Further, with respect to the polymer P4 obtained above, 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.

Further, a complex S4 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P4 was used instead of the polymer P1. The results obtained are shown in Table 10.

(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.

Further, with respect to the polymer P5 obtained above, 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.

Further, a complex S5 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P5 was used instead of the polymer P1. The results obtained are shown in Table 10.

(Example 6: Synthesis of methacrylate (random copolymer) containing a dipicorylamine moiety and preparation of a complex formed in a complex with Zn ²⁺ (6))

2-Cyano-2-propylbenzodithioate (49 mg, 0.222 mmol) in pre-baked, degassed, and nitrogen-substituted test tubes with stoppers, Monomer 1 (484 mg, 1.55 mmol) obtained above. , Methyl methacrylate (67 mg, 0.67 mmol), oil-soluble azo polymerization initiator (V-70 manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) ( 21 mg (0.067 mmol) was added, dissolved in dimethylformamide (2.2 mL), and then nitrogen bubbling was performed for 5 minutes. The test tube was heated to 30 ° C. in a closed state and stirred for 7 days, and then the solvent. Was distilled off under reduced pressure to obtain the title polymer P6 (random copolymer) as a red oily substance. This polymer P6 was used without purification. The physical property data of the obtained polymer P6 is shown in the table. Shown in 8.

Further, a complex S6 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P6 was used instead of the polymer P1. The results obtained are shown in Table 10.

(Example 7: Synthesis of methacrylate (random copolymer) containing a dipicorylamine moiety and preparation of a complex formed in a complex with Zn ²⁺ (7))

2-Cyano-2-propylbenzodithioate (48 mg, 0.217 mmol), monomer 1 (472 mg, 1.52 mmol) obtained above, in a pre-baked, degassed and nitrogen-substituted test tube. Benzyl methacrylate (116 mg, 0.65 mmol), oil-soluble azo polymerization initiator (V-70 manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) (20 mg) , 0.065 mmol) was added, dissolved in dimethylformamide (2.2 mL), and then nitrogen bubbling was performed for 5 minutes. The test tube was heated to 30 ° C. with a closed state and stirred for 7 days, and then the solvent was reduced under reduced pressure. 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. ..

Further, a complex S7 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer P7 was used instead of the polymer P1. The results obtained are shown in Table 10.

(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 μL 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.

(Comparative Example 1: Synthesis of methacrylate containing a dipicorylamine moiety (C1))

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.

For this polymer CP1, 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.

Further, a complex CS1 complexed with Zn ²⁺ was obtained in the same manner as in Example 1 except that the polymer CP1 was used instead of the polymer P1. The results obtained are shown in Table 10.

(Examples 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.

The measurement procedure was in accordance with NCCLS Applied standards M7-A3. Escherichia coli (E. coli) ATCC25922 and Staphylococcus aureus (S. aureus) ATCC25923 are grown in Mueller-Hinton (MH) medium at pH 7.4 until mid-logous growth phase (OD600 = 0.5-0.6). , OD600 = 0.001. 90 μL of the prepared culture solution was mixed with a 10 μL 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 μg / 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.

These results (MIC (E. coli) M ²⁺ (+) and MIC (S. coli) M ²⁺ (+)) were used as the result of control without using the above complex (MIC (E. coli) M ²⁺ ). (-) And MIC (S. aures) M ²⁺ (-)) are shown in Table 11.

(Examples 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. 1 mL of whole blood dispersion was diluted with 9 mL of phosphate buffered saline (PBS, 10 mM phosphate, 150 mM NaCl, pH = 7.4) and centrifuged at 1000 rpm for 5 minutes. 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 μL of the measurement stock was mixed with 10 μL 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). Instead of the complex solution, 10 μL phosphate buffer or 10 μL 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 μL of the supernatant was diluted with 90 μL of phosphate buffer and the absorbance at 405 nm was measured using a Molecular Devices SpectraMax M2 microplate reader. The percentage of hemolysis was calculated as the absorbance reading divided by the average of the readings from the positive control wells. Hemolysis was plotted as a function of polymer concentration and the experimental data were fitted to Hill's equation expressed as H = 1 / (1+ (HC ₅₀ / [P] ⁿ ), where H is the measured percentage of hemolysis. , [P] is the total concentration of the polymer). Note that the fitting parameters n and HC50 correspond to the Hill coefficient and the polymer concentration, which cause 50% of hemolysis, respectively.

These results (HC50 M ²⁺ (+)) are shown in Table 12 together with the results of the control without the complex (HC50 M ²⁺ (−)).

As shown in Tables 11 and 12, among the complexes obtained in Examples, the complexes obtained in Examples 1, 2, 4 and 5 having a relatively small weight average molecular weight (Mw) of the polymer used. S1, S2, S4 and S5 had particularly excellent antibacterial activity against both Escherichia coli and Staphylococcus aureus (see Examples 9-13 in Table 11). Further, among the complexes having particularly excellent antibacterial activity, 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.

(Example 9: Synthesis of methacrylate (random copolymer and block copolymer) containing a dipicorylamine moiety and preparation of a complex complexed with Zn ²⁺ (9)).
(1) Synthesis of catechol protected monomer

3,4-Dihydroxyacetic acid (10 g, 59.5 mmol) was dissolved in methanol (100 mL), and 5 drops of concentrated hydrochloric acid was added. The obtained reaction solution was refluxed for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained reaction product was purified by column chromatography using chloroform-methanol as an eluent and silica gel to obtain compound S1 as a yellow oil. The physical characteristic data of the obtained compound S1 are shown in Table 13.

Compound S1 (11.6 g, 63.7 mmol) and p-toluenesulfonic acid monohydrate (610 mg, 3.20 mmol) were dissolved in 200 mL of nitrogen bubbled toluene and stirred. 2,2-Dimethoxypropane (78 mL, 636.7 mmol) was added to this reaction solution, and the mixture was refluxed for 3 hours. After cooling to room temperature, the residue was washed with water and saturated brine, and the solvent was distilled off under reduced pressure. Purification was performed by column chromatography using chloroform-methanol as an eluent and silica gel to obtain compound S2 as a yellow oil. The physical characteristic data of the obtained compound S2 are shown in Table 14.

Lithium aluminum hydride (0.81 g, 21.3 mmol) was dissolved in tetrahydrofuran (THF) (50 mL) under ice-cooling and stirred. Then, a solution of compound S2 (4.77 g, 21.5 mmol) in THF (100 mL) was slowly added dropwise over 15 minutes. The reaction mixture was refluxed under a nitrogen atmosphere for 2 hours, cooled to room temperature, ice was added until the bubbles disappeared, and the mixture was filtered through Celite. After distilling off the reaction solvent under reduced pressure, purification was performed by column chromatography using chloroform-methanol as an eluent and silica gel to obtain compound S3 as a yellow oil. The physical characteristic data of the obtained compound S3 are shown in Table 15.

Compound S4 (2.57 g, 13.2 mmol) was dissolved in nitrogen bubbling dichloromethane (80 mL). Then, dimethylaminopyridine (66 mg, 0.54 mmol), methacrylic anhydride (2.16 mL, 14.6 mmol) and triethylamine (2.02 mL, 14.6 mmol) were added thereto, and the mixture was stirred under a nitrogen atmosphere for 1 day. .. The obtained reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then purified by column chromatography using silica gel using chloroform-methanol as an eluent and recycled HPLC (solvent: chloroform) to turn the monomer S4 yellow. Obtained as an oil. Table 16 shows the physical property data of the obtained monomer S4.

(2) Synthesis of catechol-protected random copolymer

In a pre-baked, degassed, and nitrogen-substituted test tube with a stopper, 2-cyano-2-propylbenzodithioate (15.7 mg, 0.071 mmol), the monomer 1 obtained above (3955 mg, 1. 27 mmol), Monomer S4 (37.8 mg, 0.14 mmol), Oil-soluble azo polymerization initiator (V-70 manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 2,2'-azobis (4-methoxy-2,4-dimethyl) Valeronitrile) (6.4 mg, 0.021 mmol) was added, dissolved in dimethylformamide (1.45 mL), and then nitrogen bubbling was performed for 5 minutes. The test tube was heated to 30 ° C. in a sealed state for 7 days. After stirring, the solvent was distilled off under reduced pressure to obtain the above-mentioned polymer P9R-1 (catechol-protected random copolymer) as a red oily substance. The physical property data of the obtained polymer P9R-1 is shown in the table. Shown in 17.

(3) Catechol protection Deprotection of catechol groups in random copolymers

2 mL of concentrated hydrochloric acid was added to the polymer P9R-1 (231.5 mg) obtained above, ultrasonic irradiation was performed until all of the polymer was dissolved, and then the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction solution to adjust the pH to 7, and then extraction was performed with chloroform to obtain a polymer P9R-2 (random copolymer) as a red solid. The physical property data of the obtained polymer P9R-2 are shown in Table 18.

(4) Synthesis of catechol protective block copolymer

In a 20 mL eggplant flask, a chloroform solution of monomer S4 (239 mg / mL, 1.1 mL, 262 mg, 1.0 mmol) was concentrated, degassed, replaced with nitrogen, and then 2-cyano-2-propylbenzo under a nitrogen flow. Dithioate (66.11 mg, 0.3 mmol), oil-soluble azo polymerization initiator (V-70 manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 2,2'-azobis (4-methoxy-2,4-dimethylvaleronitrile) (28.20 mg, 0.09 mmol) was added, dissolved in dimethylformamide (1.0 mL), and then nitrogen bubbling was performed for 5 minutes. 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.

(5) Deprotection of catechol group in catechol protection block copolymer

4 mL of concentrated hydrochloric acid was added to the polymer P9B-1 (454 mg) obtained above, ultrasonic irradiation was performed until all of the polymer was dissolved, and then the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction solution for neutralization. The precipitated solid was extracted with a mixed solution of chloroform-methanol (volume ratio 80:20). After concentrating the organic phase, it was dissolved in a small amount of methanol and reprecipitated with diethyl ether. The suspension was centrifuged and the obtained red solid was dried to obtain polymer P9B-2 (block copolymer) as a red solid. The physical property data of the obtained polymer P9B-2 are shown in Table 20.

The compound of the present invention is useful in various technical fields such as cosmetics, pharmaceuticals / medical devices, metal processing, and water treatment.

Claims

The following formula (I):

It is a compound represented by
In formula (I),
X is a repeating unit having a dipicorylamine moiety and has the following formula (II) :.

(In 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. Is an integer of)
A compound, represented by, comprising a repeating unit, and A 1 and B 1 are residues of the RAFT compound.
The formula (II) is the following formula (IIa):

(In equation (IIa), n is an integer from 1 to 1000)
The compound according to claim 1.
A1 in the above formula ( I ) is the following formula (III):

(In equation (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 a cyano group. Is the basis)
It is a group represented by, and B 1 is the following formula (IV) :.

(In formula (IV),
Y 1 has a divalent group represented by -S-, -CH 2- , -CH 2 NZ- or -O-.
Z is

(Here, D - is a halide ion, a hydroxide ion, or a phosphate ion).
m is 0 or 1)
The compound according to claim 1 or 2, which is a group represented by.
The formula (I) is the following formula (Ib):

(In 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)
The compound according to claim 1.
X in the above formula (I) is further changed to the following formula (V):

(In 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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
q is an integer from 1 to 1000)
The compound according to any one of claims 1 to 3, which comprises a repeating unit represented by.
The formula (I) is the following formula (Id):

(In formula (Id),
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 ). Is a phenyl group optionally substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms), and n is. It is an integer from 1 to 1000 and
q is an integer from 1 to 1000)
The compound according to claim 1.
The method for producing a compound according to claim 1.
The following formula (VI):

(In the formula (VI),
R 1 is a methyl group or a hydrogen atom
R 2 is-(CH 2 ) p- (where p is an integer of 1-8), and R 3 and R 4 are independent hydrogen, halogen, nitro and cyano groups, respectively. Alternatively, it is an alkyl group having 1 to 7 carbon atoms which may have a branch or a ring).
A method comprising 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):

(In 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 ). Is a phenyl group that may be substituted with at least one group selected from the group consisting of a hydroxyl group and a linear or branched alkyl group having 1 to 3 carbon atoms).
The method according to claim 7, which comprises the compound represented by.
The method according to claim 7 or 8, wherein the living radical polymerization step is carried out in the presence of an oil-soluble azo polymerization initiator.
The method according to claim 9, wherein the living radical polymerization step is performed at a temperature of -196 ° C to 150 ° C.
The method according to any one of claims 7 to 10, wherein the content of the RAFT compound in the mixture is 0.01 mol% to 40 mol%.
At least the compound according to any one of claims 1 to 6 and a metal complexed with the dipicorylamine moiety of the compound, wherein the metal is selected from the group consisting of alkaline earth metals and transition metals. A complex that is one type.
The composite according to claim 12, wherein 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 complex according to claim 12 or 13, wherein the compound has a weight average molecular weight (Mw) of 500 to 86000.
An antibacterial composition containing the complex according to any one of claims 12 to 14 as an active ingredient.