JP3015879B1 - Metal complex, antibacterial material, antibacterial article, and method for producing the article - Google Patents

Abstract

To provide an antibacterial material having excellent antibacterial properties even with a small amount of antibacterial metal, an antibacterial article having excellent durability, and a method for producing an antibacterial article. SOLUTION: The following general formula (I): (In the above formula, M is iron ion, copper ion, cobalt ion, silver ion, zinc ion, tin ion, chromium ion,
Manganese ion, nickel ion, or ruthenium ion, R represents a carbamoyl group, a lower alkyl group-substituted carbamoyl group of C ₁ -C ₆ lower alkyl group of C ₁ -C _6, or an amino group. ), An antibacterial material comprising a metal complex which is a coordination compound having a coordinating group capable of coordinating with a metal ion in a molecule, and by treating the surface of various articles with this antibacterial material, can get.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel metal complex,
The present invention relates to an antibacterial material, an article provided with antibacterial properties, and a method for producing an antibacterial article. More specifically, a metal complex of a bleomycin model compound formed by coordinating a metal ion to a coordinating group, The present invention relates to an antibacterial material exhibiting a broad antibacterial spectrum against various pathogenic bacteria, an article provided with antibacterial properties treated using the antibacterial material, and a method for producing the antibacterial article.

[0002]

2. Description of the Related Art Recently, safety and cleanliness have been demanded for all kinds of products around us, and the tendency for cleanliness has been increasing especially for young people. I have. The development of low-toxic antibacterial agents and antibacterial products that do not lead to biological tissue and environmental pollution is being actively promoted.

[0003] The most common method for imparting antibacterial properties is to use an antibacterial metal such as silver or copper. Antimicrobial agents using such antimicrobial metals are often eluting drugs that exhibit antimicrobial properties due to elution of metal ions, and zeolite, clay mineral, glass, and the like are used as carriers for the eluting drugs. Such an antimicrobial metal-eluting drug has an excellent antimicrobial function.For example, it is easily used in the form of a spray containing zeolite in the form of fine powder containing antimicrobial metal ions as an active ingredient. The surface of the article can be made antimicrobial.

As antibacterial powders, silver, copper, zinc,
Alternatively, those containing a complex composed of these metals are known (see JP-A-9-263715). An article antibacterial-treated with such antibacterial powder has strong antibacterial properties.

[0005] Further, an antibacterial resin composition in which zeolite containing an antibacterial metal is kneaded is also known (see JP-A-63-265958).

It is also known that the surface of an article is coated with an antibacterial powder coating to impart antibacterial properties.

[0007]

The antimicrobial metal-eluting drug including silver ions as described above has excellent antibacterial function, but the metal is eluted and contaminates living and environmental systems. There was a problem. In the case of the conventional spray, there is a problem that the zeolite particles adhering to the surface of the treated article are easily detached by receiving a physical stimulus, and thus lack durability.

In the case of the complex described in JP-A-9-263715, an article subjected to antibacterial treatment has a strong antibacterial property, but a small amount of metal ions such as silver flows out of antibacterial inorganic particles for a long time. It is a cause of contaminating living tissues or the environment. Therefore, there is a demand for the development of an antibacterial material that does not allow metal ions to flow out of the antibacterial material and that can stably maintain the antibacterial function.

In the case of the composition described in JP-A-63-265958, the cost is high, and the resin is colored or discolored by the energy of light, which poses a practical problem.

When a powder coating having antibacterial properties is used, a step of heating to 150 to 200 ° C. at the time of baking is required. there were.

The present invention solves the above-mentioned problems, and provides an antibacterial material having excellent antibacterial properties even with a small amount of antibacterial metal, an article having excellent durability and imparted with antibacterial properties, and It is an object to provide a method for producing an antibacterial article.

[0012]

Before describing the bleomycin model compound in the present invention, bleomycin (hereinafter abbreviated as BLM) will be described first.
BLM is an antitumor antibiotic isolated from actinomycetes ( Streptromyces verticillus ), and is widely and clinically used as a therapeutic drug for malignant lymphoma, squamous cell carcinoma and the like.
BLM is composed of four different functional sites: a DNA cleavage site consisting of a metal coordination site, a DNA binding site, a sugar chain site, and a linker site. These functional sites work in concert to cut DNA. Have been.

The BLM molecule is composed of Fe (II), Fe (III), Cu (I), Cu (II) and C at the five nitrogens of the β-aminoalanine-pyrimidine-β-hydroxyhistidine moiety.
Coordinates with metals such as o (II) and Co (III). This BL
The M-metal complex has a structure represented by the following general formula (III).

[0014]

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Among the above BLM-metal complexes, the Fe (II) complex is easily oxidized by molecular oxygen to produce Fe (III).
, And catalytically activates molecular oxygen in this process. Its active species is as close to the ^{2- BLM-Fe (II) -O} 2. In addition, it has been reported that hydroxy radicals, which are active oxygens generated during the activation process, are involved in DNA cleavage. BLM-Fe (III)
The complex is easily regenerated to a Fe (II) complex by a reducing agent present in a living body under physiological conditions.

The bithiazole site of BLM acts specifically on the guanine base of DNA. BLM metal complex is B type D
In order to bind to the minor groove of NA and recognize the amino group at position 2 of guanine, DNA is selectively cleaved with a guanine-pyrimidine (5′-3 ′) sequence, particularly a guanine-cytosine base sequence. The linker site functions as a connection site for arranging the metal coordination site and the DNA binding site in an appropriate distance and positional relationship. The sugar chain site is a steric environmental factor for the metal complex of BLM to form a hydrophobic space for accommodating oxygen in the molecule, has cell membrane permeability, and is involved in accumulation in cancer cells. It has been suggested that

[0017] There are two routes for the cleavage reaction of DNA by BLM. In the route where a large amount of oxygen is present, D
The C-4 'hydrogen of the NA sugar chain is abstracted, producing a C-4' hydroperoxide intermediate, which further decomposes to yield a basic propenal derivative. On the other hand, in pathways that do not require additional oxygen, nucleobase release occurs and DNA
Completed by the formation of oxidatively damaged sugars in the chain. BLM is an antibiotic that specifically binds to a DNA base sequence and has a characteristic function such as generation of active oxygen, and is a mixture of homologues having different terminal amines. The mechanism of action is to form a complex with Fe (II), to which oxygen is bound and oxidized BLM-Fe (III) -O ₂ H ^- is activated, resulting in DNA molecule cleavage.

The present inventors have proposed that a metal complex of a model compound in which the metal coordination site of BLM is simplified as described above is BLM.
It has been found that it has an effect of activating oxygen similarly to.
Such a BLM model compound is represented by the following general formula (I).

[0019]

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In the above formula, M is iron ion (II, III), copper ion (I, II), cobalt ion (II, III), silver ion, zinc ion, tin ion, chromium ion, manganese ion, nickel (II, III) or a transition metal such as a ruthenium ion, and R is a carbamoyl group, a C ₁ -C ₆ , preferably a C ₁ -C ₄ lower alkyl-substituted carbamoyl group, a C ₁ -C 4 ₆ , preferably a C ₁ -C ₄ lower alkyl group or an amino group. The C ₁ -C ₆ lower alkyl groups include methyl, ethyl, n-propyl, i
-Propyl, n-butyl, i-butyl, s-butyl, t
-Butyl, pentyl, hexyl, and the like.

As described above, the hydroxyl radical of active oxygen generated in the activation process cuts the DNA strand. These radicals have an effect of oxidatively decomposing organic substances and exhibiting a deodorizing effect. In addition, since the BLM model compound has an asymmetric carbon, the complex is chiral, and it is expected that asymmetric induction will occur when olefin is oxidized in the same manner as the BLM complex. Is also possible. As described above, the BLM model compound has various biochemical properties, such as specifically cutting DNA, having a deodorizing function, and contributing to oxidative decomposition of organic substances.

The BLM model compound of the present invention in which the basic skeleton of BLM is simplified by chemical modification,
As revealed by the present invention, while having the properties of LM, it has an antibacterial function, which will be described in detail below, so that it is extremely useful as various industrial materials.

The present inventors have proposed a coordination compound having a specific coordination group capable of coordinating with a metal ion in a molecule, which is a metal complex of a model compound of BLM.
Organometallic complexes coordinated with copper, cobalt, silver, zinc, tin, chromium, manganese, nickel, or ruthenium ions effectively inhibit the growth of a wide range of pathogenic bacteria To do so for the first time, and completed the present invention.

That is, the present inventors have conducted intensive studies to solve the above-mentioned problems such as poor stability, poor durability, and easy outflow of metal ions, and thus reduced antibacterial activity. Clarifies that a metal complex consisting of a specific ligand and a metal ion has stable antibacterial properties. Using this aqueous solution of the metal complex, it is possible to produce articles such as fiber, plastic, wood, paper, metal, glass, and ceramic. Immersion treatment or spraying, and further, by insolubilizing the metal complex coating covering the surface of these articles with water, it has been found that an antibacterial article with excellent durability can be obtained, and the present invention has been completed. Reached.

In the present invention, to simplify the skeleton of BLM means to replace four kinds of sites with groups having a simple molecular form by a chemical reaction. The four types of sites include (1) a metal coordination site of BLM, (2) a sugar chain site of BLM, (3) a linker site connecting the metal coordination site of BLM and the DNA binding site, and (4) a BLM. Is a bithiazole site, which is a DNA binding site.

In addition, chemically modifying BLM means that BLM is chemically modified.
Means introducing a functional molecule such as acridine, polyamide nucleic acid, or cyclodextrin into a BLM model compound whose skeleton is simplified. Specifically, in the BLM model compound, the sugar chain site may be replaced with polyamide nucleic acid or cyclodextrin, or the DNA binding site may be replaced with acridine or polyamide nucleic acid.

In the present invention, a known antibacterial metal can be used without limitation as the metal of the metal complex, and a ligand having a metal coordinating group is coordinated with the metal. Examples of groups capable of coordinating with metal ions include groups containing nitrogen, sulfur, and oxygen.

Among the metal complexes of the present invention, Fe (II) is characterized in that it reacts in the presence of oxygen and a reducing agent to release active oxygen. Fe (II) takes in oxygen and Fe
Fe (III) is stable in an aqueous solution and in a crystalline powder state, though it is unstable in an aqueous solution because it tends to become (III).

When Fe (II), Fe (III), Cu complex, etc. react with acetone, their solubility is reduced and they precipitate. By utilizing this property, the metal complex of the present invention can be made water-insoluble. That is, in an aqueous solution of a metal complex, an article such as fiber, plastic, wood, paper, metal, glass, or ceramic is immersed or sprayed with the aqueous solution to coat a thin film of the metal complex on the surface of the article. The thin film can be made water-insoluble by treating it with acetone.

In order to reduce the Fe (III) complex to the Fe (II) complex, an ordinary reducing agent may be used. For example, dithiothreitol, ascorbic acid, mercaptoethanol and the like can be used. Among these reducing agents, dithiothreitol can be most preferably used. Dithiothreitol is considered to be particularly effective as a reducing agent for the following reasons. Dithiothreitol, which has two thiol groups in the molecule, has the property of easily dissociating after coordinating to the sixth ligand part of the BLM model compound to give electrons to Fe and reduce it. Would.

Among the metal complexes exhibiting antibacterial properties, iron ions exhibit a particularly effective antibacterial action. This is because a hydroxyl radical which is active oxygen is generated in the process of oxidizing the Fe (II) complex to form the Fe (III) complex. Hydroxy radical acts as an extremely strong oxidizing agent, and thus has a strong bactericidal activity and a deodorizing function. Utilizing this oxidizing power enables oxidative decomposition of organic substances.

Further, the iron complex contains one having the same two-dimensional structural formula but different atomic configuration in a three-dimensional space, that is, a chiral carbon. For this reason, it is expected that asymmetric induction will occur when the olefin is oxidized. In other words, there are trans-form and cis-form of olefin, and the oxidation product is often racemic in the ordinary oxidation reaction, but in this iron complex, the environment around the iron ion is chiral, so This is because the epoxide, which shows selectivity and is an oxidation product, is considered to be formed by adding oxygen by steric retention. Examples of the olefin include styrene, stilbene, cyclohexene, and chalcone, and examples of the oxygen donor include molecular oxygen and hydrogen peroxide.

In order to coat the surface of an article such as a silk fabric with an extremely thin metal complex, the article may be immersed in an aqueous solution of the metal complex. After the article surface is coated, the article may be immersed in an aqueous metal solution, and the coating method is not limited.

[0034] Main BL obtained by simplifying the sugar chain site of BLM
M model metal complexes include R-Metal Complex (however, R
Represents (1) -CONH ^t Bu, (2) -CONH ₂ , (3) -CH ₃ , and (4) -NH ₂ . ), And the structures of these complexes are represented by the general formula (I).

Of the above four types of BLM model metal complexes, (4) has excellent water solubility.

The BLM model metal complex can be synthesized by disposing a metal ion on a ligand. In order to attach the ligand to the surface of various articles, any known ligand may be used.
Complexes of metals of groups IB and VIII are most preferably used.
This is because these complexes dissolve well in water and do not require pH adjustment. For the metal complexes of (1), (2) and (3) above, the pH of the aqueous solution was adjusted using a pH buffer.
It is possible to improve the solubility of the ligand by adjusting. In the present invention, in order to effectively convert the metal complex into an aqueous solution, the pH of the aqueous solution is about 5-10, preferably about 6-.
8, more preferably about 7.0 to 7.7. If the pH is less than 5, there is a risk that the antibacterial metal is eliminated from the metal complex compound, and if the pH exceeds 10, the ligand of the metal complex is hydrolyzed.

The concentration of the aqueous solution of the metal complex that can be used for immersing various articles such as silk fabrics may be 0.3 wt% or more, preferably 0.8 to 1.3 wt%. If the concentration is less than 0.3 wt%, the metal complex film covering the surface of the article is too thin to sufficiently exhibit an antibacterial effect, and if the metal complex concentration exceeds 1.3 wt%, it is not economical.

For immersing various articles in the aqueous metal complex solution, any temperature may be used, and the immersion time may be 2 minutes to 1 hour, preferably 5 to 30 minutes. Immersed in an aqueous solution of the metal complex,
The article taken out after a predetermined time is lightly dried (air-dried) at room temperature. Since the metal complex coating covering the surface of the article is water-soluble in this state, it may be lightly immersed in a solvent such as acetone and dried to make it water-insoluble depending on the application.
Other examples of the water insolubilizing solvent include alcohols such as methanol.

When various aqueous ligand solutions are used in place of the metal complex, the ligand concentration, immersion time and immersion temperature are the same as in the case where the metal complex is used. Also in this case, water insolubilization can be performed using an organic solvent. The ligand is susceptible to oxidizing action in an atmosphere containing oxygen. Therefore, it is desirable to replace the atmosphere of the ligand sample with an inert gas such as argon or nitrogen, and store it in a refrigerator at −20 ° C.
In such an ideal environment, the ligand can be stored for a long time. In order to coordinate a metal to a ligand, an aqueous solution of a metal salt may be added to an aqueous solution of the ligand to cause a reaction.
The pH of the aqueous solution is usually adjusted to 7-8,
A metal complex can be easily produced only by reacting for 20 minutes.
The metal salt may be, for example, a metal acetate, chloride, nitrate, or sulfate. As the metal salt which is easy to handle in operation, any one which is excellent in water solubility and has no deliquescent can be used.

[0040]

Next, the present invention will be described in more detail with reference to Production Examples and Examples, but the present invention is not limited to these Examples.

In the following examples, the phytopathogenic bacteria used for the evaluation of antibacterial activity are important phytopathogenic bacteria of tomato. By Corynebacterium
michiganese pv. michiganese ), and in addition, antibacterial evaluation was performed on white-spotted fungi (filamentous fungi) and anthrax fungi (filamentous fungi).

The antibacterial activity against bacteria and filamentous fungi in the examples was evaluated by the following method.

Assay for antibacterial activity against tomato canker bacteria: 25 ml of Wakimoto semi-synthetic medium or King B medium maintained at 55 ° C. after heating and dissolving, and a spore solution of the test bacteria (concentration 10 ⁹⁾
(Ml / ml) and 2 ml of the mixture, and the mixture was poured into a petri dish and solidified into a flat plate. 0.5 mg of the powdery metal complex having a coordinating group capable of coordinating with the metal ion of the present invention was placed on the surface of the culture medium with tweezers so that the powdered metal complex was collected at one place as much as possible. The silk fabric coated with the insoluble metal complex is 5
An antibacterial experiment was carried out in the same manner as in the case of the powdered metal complex by cutting into a square of mm with scissors. These were kept at 20 to 25 ° C., and the degree of inhibition of bacterial growth in the medium near the test sample was evaluated at predetermined intervals according to the following criteria in four steps.

++: Strong (formation of a clear growth inhibition zone with a width of 2 mm or more) +: Weak (formation of an unknown inhibition zone or a clear inhibition zone with a width of 1 mm or less) ±: Slight (slight inhibition is observed) -): No antibacterial activity is observed.

Evaluation of antibacterial activity against other pathogenic bacteria:
Staphylococcus aureus ATCC 6538
P) and Klebsiella pneumoniae ATCC 43
Whether or not the growth of 52) can be inhibited was evaluated by a bacteria count method based on a method for evaluating the effect of processing sanitary products by the Sanitary Textile Products Processing Council (see JP-A-10-204776). In this evaluation test, the antibacterial activity of the material is represented by the difference in the number of bacteria. The degree of bacterial growth inhibition was evaluated in two stages according to the following criteria.

+: Difference in increase / decrease value is 1.6 or more and less than 2.0-: Difference in increase / decrease value is less than 1.6 (Production Example 1) First, a ligand was synthesized in order to produce a metal complex. The scheme for synthesizing each compound will be described below so that the method for synthesizing the ligand can be easily understood.

Synthesis of Compound 1

[0048]

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(Z in the above formula represents a benzyloxycarbonyl group; the same applies hereinafter.) 6.7 ml (0.1 ml) of ethylenediamine was added to 50 ml of distilled water.
0 mol) and a 1N-sodium hydroxide aqueous solution 200 m
1 (0.200 mol) was added and the reaction was cooled to 0 ° C. Benzyloxycarbonyl chloride 3
4.2 ml (0.240 mol) was gradually added dropwise, and the mixture was returned to room temperature and stirred for 21 hours. The resulting white precipitate was filtered and dried under reduced pressure to give 31.0 of white plate-like compound 1 .
20 g (yield: 98%) was obtained. The melting point of this compound is 16
5.7-167.0 ° C. The results obtained by infrared absorption (IR) spectrum measurement of this compound are as follows.

IR (KBr, cm ⁻¹ ): 1699, 1547 Synthesis of Compound 2

[0051]

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Compound 1 28.970 g (88.224)
mmol) to a mixed solution system consisting of 10.2 ml (116 mmol) of concentrated hydrochloric acid and 106 ml of acetic acid.
For 1 hour. Return to room temperature and 900 ml of ether
In addition, the mixture was stirred overnight. The precipitate formed as a result of the reaction is filtered, dried under reduced pressure, and further dissolved in 250 ml of distilled water.
1 was repeated twice, 2N-sodium hydroxide was added to keep the pH at 9-10, and the mixture was extracted with dichloromethane to give pale yellow oily compound 2 ([2- (N-benzyloxycarbonylamino) ethyl Amine) 15.57
7 g (yield: 91%) was obtained. The results obtained by IR measurement of this compound are as follows.

IR (Nujol, cm ⁻¹ ): 3320, 1700 Synthesis of Compound 3

[0054]

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(Me in the above formula represents a methyl group; the same applies hereinafter.) 4.83 ml of thionyl chloride (6%) was added to 24 ml of methanol cooled to −15 ° C. using an ice-sodium chloride mixed bath.
1.5 mmol) was added dropwise. After the addition, add 15
Stir for 2 minutes and 3,000 of 2,6-pyridinedicarboxylic acid
g (18.00 mmol) was added and refluxed for 24 hours. After returning to room temperature, methanol was distilled off under reduced pressure, the residue was dissolved in 90 ml of ethyl acetate, washed repeatedly with 30 ml of a saturated aqueous sodium hydrogen carbonate solution three times, and further washed with 30 ml of distilled water.
Washed twice and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and Compound 3 (methyl 2,6-
2.108 g of pyridinedicarboxylate (yield: 6)
0%). The melting point of this compound is 123.4-12.
The temperature was 3.6 ° C., and the results obtained by the IR measurement are as follows.

IR (KBr, cm ⁻¹ ): 1584, 1009 Synthesis of compound 4

[0057]

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Compound3 2.360 g (12.09 mm
ol) in 100 ml of anhydrous methanol, and
While stirring, 0.594 g of sodium borohydride (1
5.7 mmol) in three portions, and after returning to room temperature, 3
Stirred for 0 minutes. 12 ml of 1N hydrochloric acid was added to adjust the pH to 6 to
The reaction was stopped at 7, and the reaction was stopped. The methanol is distilled off under reduced pressure and acetic acid
Mixture of ethyl and dichloromethane in a ratio of 1: 9
Using the solvent as the developing solvent, the residue is
Matography (Wako Pure Chemical Industries, Ltd., trade name: Wa
ko Gel C-200). Hexane is added to the obtained oil.
To give a white crystalline compound4
(Methyl 6-hydroxymethyl-2-pyridinecarbo
(Xylate) 1.856 g (yield: 92%) was obtained. This
Has a melting point of 87.3 to 87.7 ° C.
The results obtained by the R measurement are as follows.

IR (KBr, cm ^-1 ): 3288 (-O
H), 1745, 1009 Synthesis of compound 5

[0060]

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To 46 ml of anhydrous dichloromethane, 3.4 ml (39.8 mmol) of oxalyl chloride was added dropwise at room temperature. About -30 ° C using dry ice-ethanol bath
To 4.72 ml of anhydrous dimethyl sulfoxide (8
9.4 mmol) was slowly added dropwise over 5 minutes. After dripping,
Stirred at about -30 ° C for 15 minutes, followed by about -60 ° C. 3.122 g (18.68 mmol) of Compound 4 was dissolved in 32 ml of anhydrous dichloromethane and added dropwise over 5 minutes. After stirring at about −60 ° C. for 30 minutes, 16.32 ml (117.3 mmol) of anhydrous triethylamine was gradually dropped, and the temperature was returned to room temperature. Add 100 ml of distilled water,
Extraction was repeated 5 times with 200 ml of dichloromethane, and dried over anhydrous magnesium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wako Gel C-200) using a mixed solvent of ethyl acetate and dichloromethane at a ratio of 1: 1 as a developing solvent.
Compound 5 of yellow crystal (methyl 6-formylpyridine 2
3.049 g (yield: 99%). The melting point of this compound is 86.7 to 87.7 ° C., and the results obtained by its NMR and IR measurements are as follows.

¹ H-NMR (CDCl ₃ / TMS): δ =
_{4.08 (3H, -COO CH 3,} s), 8.06~
8.40 (3H, Pyr , m), 10.21 (1H, C
HO , s) IR (KBr, cm ^-1 ): 1718, 1321 Synthesis of compound 6

[0063]

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Compound 5 200 mg (1.21 mmol)
l), 560 mg (2.88 mmol of compound 2 and 2 g of powdered 4A molecular sieves dried by heating) were added to 10 ml of anhydrous acetonitrile, and the mixture was stirred overnight under a nitrogen atmosphere. The residue was dried in anhydrous methanol (10 ml).
And 55.0 mg (1.45 mmol) of sodium borohydride was added with stirring at 0 ° C., and the mixture was returned to room temperature and stirred for 2 hours. The reaction was stopped by adding 2 ml of 1N-tartaric acid, and 10 ml of distilled water was added.
Extraction was repeated 5 times with 0 ml and dried over anhydrous magnesium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wako Gel C-300) using a developing solvent having a methanol / dichloromethane ratio of 1: 4 to obtain a brown transparent oily compound 6. 265 mg (yield: 64%) of (methyl ({N- [2-benzyloxycarbonylamino) ethyl] amino} methyl) pyridine-2-carboxylate were obtained.

Synthesis of Compound 7

[0066]

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Compound 6 265 mg (0.772 mmol
l) was dissolved in 5 ml of dichloromethane, and a solution of 0.270 ml (1.08 mmol) of 4N sodium hydroxide dissolved in 5 ml of distilled water was added thereto. While stirring at 0 ° C., benzyloxycarbonyl chloride 0.154
ml (1.08 mmol) dissolved in dichloromethane was added. PH 9 to 10 with 4N sodium hydroxide
While keeping the temperature at room temperature, and stirred for 3 hours. Extraction was repeated 5 times with 30 ml of dichloromethane, dried in the presence of anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropanol to give compound 7 (methyl ({N- [2-benzyloxy Carbonylamino) ethyl] -N-benzyloxycarbonylamino} methyl) pyridine-2-carboxylate) 291 mg (yield: 7
9%). The melting point of this compound is 86.2-86.6.
° C, and the results obtained by NMR and IR measurement are as follows.

¹ H-NMR (CDCl ₃ / TMS): δ =
_{3.41~3.68 (4H, -N- CH 2 CH} 2 -N-,
m), 3.85 (3H, -COO CH 3, s), 4.7
_{5 (2H, Pyr- CH 2 -} , s), 4.98~5.1
_{2 (4H, -Ar- CH 2 -O} -, - Ar- CH 2 -O
-, M), 7.30 (5H, Ar , s), 7.31 (5
H, Ar , s), 7.63 to 8.05 (3H, Pyr ,
m) IR (KBr, cm ^-1 ): 1723, 1712, 150
9 (-CONH), 1262, 1138 Synthesis of Compound 8

[0069]

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(DPPA in the above formula means diphenylphosphoryl azide.) 480 mg (1.01 mmol) of compound 7 was dissolved in 8 ml of tetrahydrofuran, 15 ml of a 0.1N aqueous solution of lithium hydroxide was added, and the mixture was added at 0 ° C. for 2 hours. Stirred. After adding 15 ml of distilled water and distilling off tetrahydrofuran under reduced pressure, the pH was adjusted to 3 to 4 with 10% citric acid, extracted 6 times with 60 ml of dichloromethane, and dried in the presence of anhydrous magnesium sulfate. Subsequently, dichloromethane was distilled off under reduced pressure to obtain a carboxylic acid form (this was used for the next reaction without particular purification). A carboxylic acid form and 362 mg (1.50 mmol) of histidine methyl ester dihydrochloride were dissolved in 3 ml of anhydrous dimethylformamide and stirred at 0 ° C.
323 μl of diphenylphosphoryl azide (DPPA)
(1.50 mmol) in 3 m of anhydrous dimethylformamide
and 10 minutes later, anhydrous triethylamine 6
A solution of 27 μl (4.50 mmol) in 3 ml of anhydrous dimethylformamide was slowly added over 10 minutes.
The mixture was stirred at 0 ° C. for 3 hours and at room temperature for 2 days. After the solvent was distilled off under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was repeated twice with 20 ml of 5% -sodium bicarbonate.
2 times with 20 ml of saturated saline and 1 ml with 20 ml of saturated saline.
Washed twice and dried in the presence of anhydrous magnesium sulfate.
Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wa) using a mixed solvent in which the ratio of methanol to dichloromethane was 2:13 as a developing solvent.
ko Gel C-300) and purified oily substance 8

[0071]

[Outside 23]

615 mg (yield: 100%) were obtained. The results obtained by NMR measurement of this compound are as follows.

¹ H-NMR (CDCl ₃ / TMS): δ =
_{3.22~3.43 (4H, -N- CH 2 CH} 2 -N-,
m), 3.52 (2H, - CH 2 -Im, t), 3.7
_{4 (3H, -COO CH 3,} s), 4.95~5.10
_{(4H, -Ar- CH 2 -O -} , - Ar- CH 2 -O-,
m), 4.71 (2H, Pyr- CH 2 -N-, s),
4.26~4.35 (1H, - CH -, dd), 7.3
3. 7.40 (12H, Ar , Ar , Im , m);
46-8.10 (3H, Pyr , m) Synthesis of Compound 9

[0074]

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3.56 ml of thionyl chloride (48.8 mm) was added to 16 ml of methanol at −15 ° C. using an ice-NaCl bath.
ol) was added dropwise. After the dropwise addition, the mixture was stirred at −15 ° C. for 15 minutes, added with 2.00 g (22.4 mmol) of β-alanine, and refluxed for 24 hours. After returning to room temperature, the temperature was adjusted to 0 ° C. in an ice bath, and ammonia gas was bubbled in three times for 7 hours. The methanol is distilled off under reduced pressure, and the residue is purified using an ion exchange resin (DOWEX, AG-1-2X) to obtain a transparent oily substance.
1.973 g of 9 (3-aminopropionamide) was obtained in an equivalent amount. The results obtained by NMR and IR measurements of this compound are as follows.

¹ H-NMR (D ₂ O / TMS): δ = 2.
_{72 (2H, - CH 2 -CO-} , m), 3.23~3.
_{31 (2H, - CH 2 -N-} , m) IR (Nujol, cm -1): 1683,1673,1
668,1651,1557 Synthesis of Compound 10

[0077]

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Compound 8 580 mg (0.944 mmol
l) was dissolved in 5 ml of tetrahydrofuran, and 0.1 ml was added thereto.
Add 15 ml of 1N aqueous lithium hydroxide solution and add
Stirred for hours. After adding 7.5 ml of distilled water, tetrahydrofuran was distilled off under reduced pressure, and then pH was adjusted with 10% citric acid.
Was extracted 3 times with 60 ml of dichloromethane, and dried in the presence of anhydrous magnesium sulfate. Subsequently, dichloromethane was distilled off under reduced pressure to obtain a carboxylic acid compound (this was used for the next reaction without particular purification).
Carboxylic acid compound and compound 9 119 mg (1.35 mm
ol) was dissolved in 3 ml of anhydrous dimethylformamide to give 0
Stirred at ° C. 291 μl of diphenyl phosphoryl azide
(1.35 mmol) in 3 m of anhydrous dimethylformamide
and 10 minutes later, anhydrous triethylamine 1
A solution of 88 μl (1.35 mmol) in 3 ml of anhydrous dimethylformamide was slowly added over 10 minutes.
The mixture was stirred at 0 ° C. for 3 hours and at room temperature for 2 days. After the solvent was distilled off under reduced pressure, 200 ml of ethyl acetate was added, and the mixture was repeated twice with 20 ml of a 5% aqueous solution of sodium hydrogencarbonate.
The mixture was washed twice with 20 ml each time, washed once with 20 ml of a saturated saline solution, and dried in the presence of anhydrous magnesium sulfate. The compound 10 of white crystals generated at this time

[0079]

[Outside 24]

530 mg were collected by filtration (yield: 84%). The melting point of this compound is 167.6 to 168.5 ° C., and the results obtained by its NMR and IR measurements are as follows.

[0081]¹H-NMR (DMSO / TMS): δ =
2.18 (2H,-CH ₂ -CO, t), 2.93-
3.52 (8H, -N-CH ₂ CH ₂ -N-,-CH ₂ −
Im,-CH ₂ -NHCO-, m), 4.60 (2H,
Pyr-CH ₂ -N-, s), 4.83 (1H,-CH
-, T), 4.99 to 5.10 (4H, Ar-CH ₂ −
O, Ar-CH ₂ -O-, m), 6.83 (1H,Im
(5), S), 7.22 to 7.45 (11H,Ar,A
r,Pyr (5), M), 7.53 (1H,Im
(2), M), 7.88-7.96 (2H,Pyr
(3, 4), M) IR (KBr, cm^-1): 3296, 1700, 168
6,1672,1653,1559,1543,152
6,1437,1262,695,670 compounds11Synthesis of

[0082]

Embedded image

Compound 10 160 mg (0.239 mm
ol) was dissolved in 10 ml of a mixed solvent of methanol: water: formic acid = 70: 29: 1, 24 mg of palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After filtering the palladium carbon with a cotton plug and neutralizing formic acid with ammonia, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-300) using a developing solvent having a ratio of dichloromethane: methanol: 20% ammonia water of 4: 1: 0.25.
ji Davison Chemical Co., NH- silica gel (trade name, DM1020 200M, MeOH) to give compound as white crystals 1
1

[0084]

[Outside 25]

96 mg was obtained in an equivalent amount.

Next, 96 mg (0.234 mmol) of the BLM model compound 11 thus obtained was dissolved in methanol, and 60% perchloric acid (77 μl /
0.286 mmol) -methanol solution (5 ml) was added dropwise. After evaporating the solvent under reduced pressure, the residue was recrystallized from isopropanol to obtain 157 mg of VI-a 3-perchlorate (yield: 94%). The melting point of this compound is 146.0-14.
The temperature was 8.3 ° C., and the results obtained by NMR, IR and optical rotation measurements were as follows.

[0087]¹H-NMR (D_TwoO / TMS): δ = 2.
44 (2H,-CH ₂ -CO, t), 2.98 to 3.2
4 (6H, -N-CH ₂ CH ₂ -N-,-CH ₂ -NHC
O-, m), 3.37 to 3.54 (4H,-CH ₂ -I
m-,CH ₂ -CONH_Two−, M), 4.07 (2H, P
yr-CH ₂ -N, s), 4.79 (1H,-CH,
t), 7.02 (1H,Im (5), S), 7.62
(1H,Pyr (5), D), 7.74 (1H,Im
(2), S), 7.92 to 8.05 (1H,Pyr
(3, 4), M) IR (KBr, cm^-1): 3295, 2923, 167
3,1651,1644,1567,1538,146
1, 1455, 1236, 638.

[Α] D ₂₀ = + 5.6 (C 0.25, MeO
H: H ₂ O = 4: 1) (Production Example 2) Instead of compound 9 of Production Example 1, NH ₂ CH _{2 was used.}
CH ₂ CH ₃ (propylamine), NH ₂ CH ₂ CH ₂ C (O)
NHC (CH ₃ ) ₃ (substituted carbamoyl) or NH ₂ CH ₂ C
Using H ₂ NHZ (where Z is a known protecting group), according to the synthesis procedure of compound 10 and compound 11 described in Preparation Example 1, each corresponding BLM model compound 15, 16,
17 was produced. Melting point of these compounds (however, compound 1
7 was not a crystal, so a clear melting point was not obtained), and the results obtained by NMR, IR, optical rotation, and MS measurements are as follows.

Compound 15 :

[0090]

Embedded image

Melting point: 126.1-126.8 ° C.¹ H-NMR (D_TwoO / TMS): δ = 0.82 (3H,
−CH ₃ , T), 1.37 to 1.54 (2H, -CH_Two−
CH ₂ -CH_Three, M), 2.78 to 3.01 (4H, -N
−CH ₂ CH ₂ -N-, m), 3.06 to 3.30 (4
H,-CH ₂ -Im,-CH ₂ -NHCO-, m);
00 (2H, Pyr-CH ₂ -N-, s), 4.78
(1H,-CH−, T), 7.01 (1H,Im
(5), S), 7.60 (1H,Pyr (5), D),
7.74 (1H,Im (2), S), 7.88-8.0.
2 (1H,Pyr (3, 4), M) IR (KBr, cm^-1): 3366, 1653, 156
0, 1542, 1458, 766, 624, 406 [α] D₂₀= +11.9 (C 0.25, MeOH) MS: 373 (M⁺) Compound16:

[0092]

Embedded image

Melting point: 126.0-128.8 ° C.¹ H-NMR (CDCl_Three/ TMS): δ = 1.29 (9
H, -C (CH ₃ )_Three, S), 2.27 to 2.36 (2H,
−CH ₂ -CO-, m), 2.53 (1H,-NH ₂ ,
b) 2.73 to 2.97 (2H,-CH ₂ -NHCO
-, M), 2.73 to 2.97 (4H, -N-CH ₂ C
H ₂ -N-, m), 3.10 to 3.20 (2H,-CH ₂
-Im, m), 3.31 to 3.77 (2H,-CH ₂ −
NHCO, m), 3.97 (2H, Pyr-CH ₂ −
N, d), 4.84 (1H,-CH-, T), 6.91
(1H,Im (5), S), 7.40 (1H,Pyr
(5), D), 7.56 (1H,Im (2), S),
7.77 to 7.80 (1H,Pyr (4), M), 8.
01 to 8.05 (1H,Pyr (3), M) IR (KBr, cm^-1): 3421, 1683, 165
3, 1646, 1540, 1523, 1522, 145
7, 1225, 668 [α] D₂₀= + 10.4 (C0.25, MeOH) MS: 458 (M⁺) Compound17:

[0094]

Embedded image

¹ H-NMR (D ₂ O / TMS): δ = 2.
_{45~2.71 (6H, -CONH-CH 2} CH 2 -NH
_{2, -NH- CH 2 -CH 2 -NH} 2, m), 3.08~
_{3.18 (4H, - CH 2 -Im} , -CONH- CH 2 -
_{CH 2 -, m), 3.81} (2H, Pyr- CH 2 -N
-, s), 4.62 (1H , - CH -, t), 6.88
(1H, Im (5H) , s), 7.45 (1H, Pyr
(5) , dd), 7.58 (1H, Im (2) , s),
7.73 to 7.85 (1H, Pyr (3,4) , m) IR (KBr, cm- ¹ ): 3420, 1700, 168
4, 1653, 1637, 1560, 1542, 152
3,670 [α] D ₂₀ = + 18.0 (C 0.25, MeOH) MS: 374 (M ⁺ ) Note that NH ₂ C (CH ₃ ) _{3 is used in} place of the above propylamine, substituted carbamoyl, and protected ethylenediamine. (t-
Butylamine) to produce a BLM model compound in the same manner as described above.

Example 1 Production of Iron Complex The compound VI-a (ligand) and ferrous sulfate heptahydrate obtained in Production Example 1 were dissolved in 500 μl of argon-degassed water.
The mixture was stirred under an argon atmosphere. 3.5 ml of argon-degassed acetone was added to the obtained reddish brown solution, followed by stirring.
After removing the solvent by decantation, acetone was added again, and the solvent was removed by decantation. The resulting red precipitate was dried under vacuum to obtain an iron (II) complex. The results obtained by IR measurement of this complex are as follows.

IR (Nujol, cm ^-1 ): 1649,
1603, 1670 (w), 1651 (s), 1635 (w),
1617 (w), 1557 (s), 1540 (s), 1521
(s), 1507 (s).

The iron (III) complex was obtained by blowing oxygen into the reddish brown solution obtained when the iron (II) complex was formed, and then performing the same operation.

Example 2 Production of Copper Complex Compound VI-a (ligand) obtained in Production Example 1 and copper acetate • 1
The hydrate was dissolved in 18 ml of methanol and stirred at room temperature for 3 hours. To this was added a solution of lithium perchlorate trihydrate in methanol (5 ml). The resulting solution was filtered through a glass filter and recrystallized at 4 ° C. for 14 days. The produced copper complex was collected by filtration.

The results obtained by IR measurement of this complex are as follows.

IR (Nujol, cm ^-1 ): 1657;
1651 (s), 1645 (s), 1615, 1583 (s),
1531 (s), 1080 (s).

The elemental analysis values of this complex are as follows. The calculated value is calculated by converting the metal complex to (ligand) Cu (ClO ₄
3 / 2H ₂ O).

[0103] Example 3 Production of Cobalt Complex Compound VI-a (ligand) obtained in Production Example 1 (350 mg /
0.87 mmol) and Na ₃ [Co (CO ₃ ) ₃ ] .3H ₂ O (2
61 mg / 0.73 mmol) was dissolved in 5 ml of water at 25 ° C. and stirred for 3 hours. The solution was adjusted to pH 5 with 0.5 N tetrafluoroboric acid over 2 hours to obtain a deep red solution. This solution was layered on a column (2.5 × 25 cm) packed with SP-C50-120 Sephadex and developed. The column contains 3 components from the component with the fastest elution rate toward the insoluble component.
Kinds of bands: Band 1 (color of cobalt complex: yellow to
Orange), band 2 (reddish brown) and band 3 (reddish brown) appeared. The components of each band were separately collected, dried under reduced pressure using an evaporator, and excess KCl was removed by repeatedly extracting the complex twice with methanol. The solvent of the extract containing the cobalt complex was distilled off with an evaporator, and a solvent in which an equal amount of ethanol and methanol was mixed was added to the residue to remove insolubles.

The orange-brown solution obtained by dissolving the green solid of band 2 in 2 ml of water was added to a solution containing silver nitrate (192 mg / 1.12 mmol) in 2 ml of water, and the white insoluble material was added. Precipitated. Add this solution to 50
The mixture was stirred vigorously at 10 ° C. for 10 minutes and the precipitated silver chloride was filtered. The orange solution was left at room temperature for 3 hours and the silver chloride was removed again by filtration. The filtrate was dried under reduced pressure with an evaporator to obtain a cobalt complex. The same operation was performed for the red-brown solid of band 3 to purify the cobalt complex. In this manner, the cobalt complex obtained from band 2 and band 3 was changed to cobalt 2 and cobalt 3
Hereafter, it is abbreviated. Although any of the three types of cobalt complexes that can be separated by column chromatography can be used in the present invention, it is convenient to use cobalt 2 and cobalt 3 having a relatively high isolation yield as the cobalt complex. The separation of the bands is considered to be due to the change in mobility due to the difference in water, chloride ions, and NO ₃ bonded to the cobalt complex.

The results obtained by NMR and IR measurements of the obtained cobalt complex are as follows.

¹ H-NMR (D ₂ O / TMS): δ = 2.
07 to 2.16 (m), 2.30 to 2.37 (m),
2.58-2.61 (d), 2.66-2.69
(D), 2.95 to 3.65 (m), 4.57 (s),
4.65 to 4.69 (m), 5.04 to 5.32
(M), 7.29 (s), 7.63 to 8.13 (m),
8.27 to 8.96 (m), 8.52 to 8.56 (d) IR (Nujol, cm ^-1 ): 1559 (s), 1624
(s), 1599 (s), 1377 The iron, copper, and cobalt complexes of the respective compounds obtained in Production Example 2 could be produced in the same manner as in Examples 1 to 3.

Example 4 The antibacterial properties of the various metal complexes obtained in Examples 1 and 2 were evaluated as described above.
Table 1 shows the obtained results. However, an antibacterial evaluation experiment was performed in a state where light was blocked by placing a black cloth on the culture vessel.
In addition, the inhibitory effect of cobalt 3 obtained in Example 3 on the growth of tomato canker disease bacteria was evaluated. However, the antibacterial activity of cobalt 3 was evaluated under 30 W under a fluorescent lamp of 27 W.
The culture was performed by placing the culture vessel in a bright position of about cm. The sample name is abbreviated as Cobalt 3 for convenience. Table 1 shows the obtained results.

[0108] (Table 1) specimen tomato canker bacteria Shiromon rot anthracnose copper divalent complex ± ± + iron divalent complexes ++ - - cobalt 3 Akira ++ control group - - - As is evident from Table 1 In addition, copper complexes exhibit antibacterial activity. Since iron (II) is oxidized to iron (III), active oxygen is released at this time, which contributes to antibacterial properties. When the weight of the sample is large, it has been shown to kill bacteria of the tomato canker.

The iron, copper and cobalt complexes of each compound of Production Example 2 obtained in the same manner as in Examples 1 to 3
When the inhibitory effect on the growth of tomato canker disease bacteria was evaluated in the same manner as described above, it was confirmed that all the samples exhibited antibacterial activity (criterion: ±).

[0110] Staphylococcus aureu
s ATCC 6538P) and Klebsiella pneumoniae ( Klebsiella pneumon
iae ATCC 4352) was evaluated for the inhibitory effect of the iron divalent complex of Example 1 on proliferation as described above. Table 2 shows the obtained results.

(Table 2) Sample Staphylococcus aureus Klebsiella pneumoniae Iron divalent complex ++ Control group −− As is clear from Table 2, the iron divalent complex weakens the growth of Staphylococcus aureus and Klebsiella pneumoniae. But still inhibits.

Example 5 2.5 g of silk fabric derived from silkworm was completely dissolved in 20 ml of an aqueous 8.5 M lithium bromide solution at 55 ° C., and the aqueous solution was placed in a cellulose dialysis membrane. The impurities were removed by substituting distilled water at 5 ° C. for 5 days to prepare a pure silk fibroin aqueous solution. Distilled water was added to the silk fibroin aqueous solution thus prepared so that the absolute dry concentration was 0.3%, thereby preparing a stock solution of the silk fibroin aqueous solution.

0.30 g of the copper (II) complex obtained in Example 2 was added to 5 ml of distilled water and dissolved well to prepare an aqueous copper (II) complex solution. 1 ml of an aqueous copper (II) complex solution was added to the above 5 ml of 0.3 wt% silk fibroin aqueous solution, and the mixture was gently stirred with a glass rod. The aqueous solution was spread on a polyethylene film membrane and allowed to stand at 25 ° C. for 8 hours. The water was evaporated to produce a silk fibroin membrane containing a copper (II) complex and having excellent mechanical strength.

Next, a dilute acetic acid aqueous solution was added little by little to the silk fibroin aqueous solution containing the copper (II) complex, and the pH of the aqueous solution was adjusted to 3.5, whereby the aqueous solution gradually solidified. Put this in a refrigerator at 5 ° C for one day and night at -30 ° C.
, And then dried by a freeze dryer to produce a silk fibroin powder containing a copper (II) complex.

The effect of the silk fibroin membrane containing the copper (II) complex and the silk fibroin powder on the growth inhibition of tomato canker bacterium was evaluated in the same manner as in Example 4. It was confirmed that it would block.

Example 6 A 14-mesh silk feather double (hereinafter abbreviated as silk fabric) was immersed in the aqueous solution of copper (II) complex used in Example 5 at 25 ° C. for 30 minutes.
C. and dried under standard conditions of 65% RH. The silk fabric thus dried was immersed in an acetone solution at 25 ° C. for 30 minutes to prepare a silk fabric coated with a thin film of a water-insoluble copper (II) complex. When the effect on the growth inhibition of tomato canker bacterium was evaluated in the same manner as in Example 4, it was confirmed that the compound exhibited antibacterial activity (criterion: ±).

Example 7 0.3 g of the ligand (VI-a) synthesized in Production Example 1 was added to distilled water, and the pH was adjusted with a pH buffer.
Was adjusted to 7.3 and dissolved. After immersing the silk fabric used in Example 6 in this ligand aqueous solution at 22 ° C. for 30 minutes,
It was removed and dried under standard conditions of 20 ° C. and 65% RH. Next, the silk fabric was immersed in an aqueous solution of copper sulfate at 22 ° C., and was taken out after 30 minutes. By this reaction, the copper ion was selectively bonded to the ligand, and the copper complex was surely coated on the surface of the silk fabric. In this state, since the copper complex was water-soluble, a sample in which the metal complex covering the silk fabric surface became water-insoluble was obtained by simply immersing the sample in an acetone solution as necessary. The effect of these water-soluble and water-insoluble samples on the growth inhibition of tomato canker bacteria was evaluated in the same manner as in Example 4, and it was confirmed that both exhibited antibacterial activity (criterion: ±).

Example 8 The method of Example 7 was repeated using copper acetate instead of the copper sulfate used in Example 7. As a result, even when immersed in a copper acetate aqueous solution, a sample in which the copper complex covered the silk fabric surface was obtained.

Example 9 The method of Example 7 was repeated using iron sulfate instead of the copper sulfate used in Example 7. As a result, even when immersed in an aqueous solution of iron sulfate, a sample in which the surface of the silk fabric was covered with the iron complex was obtained.

Example 10 Silk fibroin fiber was mixed with 60
The solution was completely dissolved with an 8M aqueous solution of lithium bromide at 8 ° C., and dialyzed in a cellulose dialysis membrane while substituting pure water for 5 days to prepare an aqueous solution of silk fibroin. 200 mg of the copper metal complex synthesized in Example 2 was added to 5 ml of the 0.5% silk fibroin aqueous solution thus prepared, and after gentle stirring, the aqueous solution was spread on a polyethylene membrane and evaporated to dryness. A silk fibroin membrane containing a copper metal complex was produced. The silk fibroin membrane was immersed in a 50% by weight aqueous methanol solution at room temperature for 10 minutes, and then dried at room temperature.
A water-insoluble silk fibroin membrane was produced. When the effects of these water-soluble and water-insoluble silk fibroin membranes on the growth inhibition of tomato canker bacterium were evaluated in the same manner as in Example 4, both had antibacterial activities (criterion: ±).
Was confirmed.

(Example 11) In the same manner as in Example 10, except that the iron metal complex synthesized in Example 1 was added instead of the copper metal complex, a silk fibroin film having an antibacterial function containing the iron metal complex was added. Was manufactured. When the effect of this silk fibroin membrane on the growth inhibition of tomato canker bacterium was evaluated in the same manner as in Example 4, the antibacterial activity (criterion:
±) was confirmed.

[0122]

Industrial Applicability The metal complex of the present invention is a compound having a ligand coordinated with a metal and having a three-dimensional configuration, and has excellent antibacterial properties. In addition, since the organometallic complex is water-soluble, when an article such as a plastic molded article is immersed in the aqueous metal solution or when this aqueous solution is sprayed on various articles, the active ingredient is extremely thinly coated on the article surface, and the durability is maintained. An antibacterial article having high stability and high stability can be prepared.

Since the antibacterial agent of the present invention contains an antibacterial metal and is in a complex, the antibacterial component does not elute or volatilize, and is an excellent antibacterial agent which is not present in conventional organic antibacterial agents. Has features. In addition, since the antibacterial component is firmly attached to the surface of the article, the antibacterial component does not desorb even when a person touches the treated article.

Since the antibacterial agent of the present invention can be applied, for example, in the form of a spray, it can easily impart antibacterial properties to any article such as fiber, plastic, wood, paper, metal, glass, and ceramic.

The iron divalent complex has better antibacterial activity than the iron trivalent complex. The iron divalent complex is easily oxidized into molecular trivalent iron by molecular oxygen, and has a property of generating a hydroxyl radical which is an active oxygen in this process, and this effectively inhibits the growth of pathogenic bacteria. Since the iron divalent complex is oxidized to be trivalent, it can be reduced again to an iron divalent complex by a general reducing agent, and thus can be repeatedly converted to a material that suppresses the growth of pathogenic bacteria and used. This is because in an iron complex, a redox cycle is established in the presence of an oxygen molecule and a reducing agent. Hydroxy radical is a very strong oxidizing agent, has a strong bactericidal activity, and can oxidatively decompose organic substances in addition to sterilization, so that it can also exert effects such as deodorization.

Further, the iron complex is chiral, and asymmetric induction occurs when olefin is oxidized. In other words, there are trans-form and cis-form of olefin, and the oxidation product is racemic in the ordinary oxidation reaction, but in this iron complex, the environment around the iron ion is chiral, so the enantioselectivity is increased. As shown, the epoxide, which is an oxidation product, can be formed while maintaining its steric configuration.

Compounds having an asymmetric carbon include d-form and l-form, and alkenes having a double bond include isomers such as trans-form and cis-form. different. In order to be used as pharmaceuticals, trans and cis-forms must be strictly isolated.
Oxidation of various substrates with common oxidizing agents results in racemic forms. However, the iron complex of the present invention exhibits enantioselectivity because the environment around the iron ion is chiral, as is clear from the structural formula, so that an oxide to which oxygen is stereo-retained can be generated. As described above, the use of the iron complex of the present invention is convenient in that the configuration generated when a specific substrate is oxidized can be controlled.

In the present invention, since the antibacterial metal ion is chemically coordinated with the coordination compound having a coordinating group, the elution of the metal ion, which is a problem with the conventional antibacterial substance, does not occur. The release rate can be controlled, and there is no danger of contaminating biological systems and environmental systems. In addition, by using a plurality of organometallic complexes to which a certain metal is coordinated, various metal ions can be immobilized on the same material surface and simultaneously supported, so that the antibacterial spectrum can be further controlled and expanded.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-48-88287 (JP, A) JP-A-54-63089 (JP, A) JP-A-60-6698 (JP, A) JP-A 58-88 116497 (JP, A) Tetrahedron Letters, 32 [47] (1991), 6869-6872. J. Chem. , 76 [3] (1998), 260-264. (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 1/08 A01N 59/16 A01N 59/20 C07F 15/02 CAPLUS (STN) REGISTRY (STN) WPIDS (STN)

Claims (8)

(57) [Claims] (1) The following general formula (I): (In the above formula, M is an iron ion, copper ions, or cobalt ions, R represents a lower alkyl group-substituted carbamoyl group of C ₁ -C _6, or an amino group.) Represented by the molecular A metal complex which is a coordination compound having a coordination group capable of coordinating with a metal ion. 2. The following general formula (I): (Where M is iron ion, copper ion, cobalt ion
Silver, zinc, tin, chromium,
Manganese ion, nickel ion, or ruthenium ion
R is a carbamoyl group, a lower alkyl group having ₁ to ₆ carbon atoms.
It is a carbamoyl group substituted with a kill group or an amino group. )so
Has a coordinating group that can coordinate with metal ions in the molecule.
An antibacterial material comprising a metal complex that is a coordinating compound. 3. The following general formula (I): (In the above formula, M is iron ion, copper ion, cobalt ion, silver ion, zinc ion, tin ion, chromium ion,
R is a carbamoyl group, a lower alkyl group having ₁ to ₃ carbon atoms, a manganese ion, a nickel ion, or a ruthenium ion;
It is a carbamoyl group substituted with a kill group or an amino group. The antimicrobial thin film composed of a metal complex, which is a coordination compound having a coordination group capable of coordinating with a metal ion in the molecule, represented by
An antibacterial article having a surface. 4. The article according to claim 1, wherein said article is fiber, plastic, wood,
4. A paper, metal, glass or ceramic material.
The antimicrobial article of. Claim 5.The following general formula (II): Embedded image (Wherein R is a carbamoyl group, C ₁ ~ C ₆ Low grade al
It is a carbamoyl group substituted with a kill group or an amino group. )so
A compound represented by the following general formula is treated with a complexing agent.
(I): Embedded image (Where M is iron ion, copper ion, cobalt ion
Silver, zinc, tin, chromium,
Manganese ion, nickel ion, or ruthenium ion
And R is as defined above. ),
Coordination with a coordinating group capable of coordinating with metal ions in the molecule
Compound, and then an aqueous solution of this metal complex
And, if necessary, adjusting the pH to 5-10 if necessary.
To prepare an aqueous solution, and immerse the article to be treated in this aqueous solution.
Or spraying the aqueous solution on the article to be treated,
The article is coated with a thin film of a metal complex to obtain an antibacterial article.
For producing an article provided with antibacterial properties, characterized in that:
Law. 6. An aqueous solution of the compound of the formula (II) is prepared.
And immerse the article to be treated in this aqueous solution, or
The solution is sprayed on the article to be treated and the article is
Coated with a thin film of the compound and then the coated article
Immersed in an aqueous solution of a metal salt, or the coated article
Is sprayed with the aqueous metal salt solution, and the general formula is sprayed on the article.
Reacting the compound of (II) with the complexing agent to form the article;
Coating with a thin film of the metal complex of the general formula (I)
The method for producing an article provided with antibacterial properties according to claim 5, characterized in that : 7. An article to be treated is coated with a thin film of the metal complex.
Then, a poor solvent is further applied to the metal complex thin film.
To make the metal complex insoluble in water
Item 7. The method for producing an article provided with antibacterial properties according to item 5 or 6 . 8. The article to be treated is made of fiber, plastic,
Wood, paper, metal, Claim glass, or a ceramic
8. The method for producing an article provided with antimicrobial properties according to any one of 5 to 7 .