Antibacterial, antifungal and antiviral agents

Abstract

To reduce damage to human health and economies caused by various kinds of pathogenic bacteria, mold and mildew, and virus.SOLUTION: Antibacterial, antifungal and antiviral agents are applied to pathogenic bacteria, mold and mildew, and virus, wherein the antibacterial, antifungal and antiviral agents contain carboxylated O-substituted monohydroxylamine derivatives or carboxylated oxime derivatives and their chemically acceptable salts.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an antibacterial, antifungal and antiviral agent and an antibacterial, antifungal and antiviral treatment method. [Background technology]

[0002] There are a wide variety of bacteria, molds, and viruses that have adverse effects on humans, animals, and plants, and numerous antibacterial, antifungal, and antiviral agents have been developed to combat them. In particular, the demand for antibacterial, antifungal, and antiviral agents has been increasing recently due to the global spread of the novel coronavirus (SARS-CoV-2).

[0003] Antibacterial, antifungal, and antiviral agents are broadly divided into inorganic and organic types. Organic antibacterial, antifungal, and antiviral agents are characterized by low cost and rapid action, and for example, benzalkonium chloride, a quaternary ammonium salt, is widely used (see, for example, Patent Document 1). However, such quaternary ammonium salts have issues such as discoloration and coloring, and emulsion aggregation. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2008-189645 A Summary of the Invention [Problem to be solved by the invention]

[0005] In order to reduce the damage to human health and the economy caused by a wide variety of pathogenic bacteria, fungi, and viruses, there is a strong need to discover and develop new types of antibacterial, antifungal, and antiviral agents.

[0006] The present invention has been made in view of the above-mentioned background art, and an object of the present invention is to provide an antibacterial, antifungal and antiviral agent containing a carboxyl group-containing O-substituted monohydroxylamine or a carboxyl group-containing oxime. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have found that specific carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes have antibacterial, antifungal and antiviral activity against bacteria, molds and viruses, thereby completing the present invention.

[0008] [1] An antibacterial, antifungal and antiviral agent comprising at least one of a carboxyl group-containing O-substituted monohydroxylamine derivative represented by the following general formula (1), a carboxyl group-containing oxime derivative represented by the following general formula (2), and a chemically acceptable salt thereof:

[0009] [ka]

[0010] [ka]

[0011] (In formulas (1) and (2), R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an arylalkyl group having 7 to 15 carbon atoms. n represents an integer of 1 to 6. Multiple Rs may be the same or different.) [2] The antibacterial, antifungal and antiviral agent according to [1], characterized in that in general formulas (1) and (2), R is any one of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a benzyl group and a phenyl group.

[0012] [3] The antibacterial, antifungal and antiviral agent according to [1], characterized in that the carboxyl group-containing O-substituted monohydroxylamine or its chemically acceptable salt is aminooxyacetic acid or its chemically acceptable salt.

[0013] [4] The antibacterial, antifungal and antiviral agent according to [1], characterized in that the carboxyl group-containing oxime derivative or its chemically acceptable salt is any one of 2-methylideneaminooxyacetic acid, 2-ethylideneaminooxyacetic acid and their chemically acceptable salts.

[0014] [5] A method for treating bacteria, fungi, or viruses using the antibacterial, antifungal, or antiviral agent according to any one of [1] to [4]. [Effects of the Invention]

[0015] The antibacterial, antifungal and antiviral agent of the present invention inhibits the activity of a wide variety of bacteria, fungi and viruses, thereby reducing the damage caused by bacteria, fungi and viruses to human health and the economy. DETAILED DESCRIPTION OF THE INVENTION

[0016] The antibacterial, antifungal and antiviral agent of the present invention is characterized by containing one or more of a carboxyl group-containing O-substituted monohydroxylamine derivative, a carboxyl group-containing oxime derivative, and a chemically acceptable salt thereof.

[0017] In the carboxyl group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) above, the carboxyl group-containing oxime derivative represented by the general formula (2) above, and chemically acceptable salts thereof, R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an arylalkyl group having 7 to 15 carbon atoms. Furthermore, n represents an integer of 1 to 6, and multiple Rs may be the same or different.

[0018] The alkyl group having 1 to 18 carbon atoms may be a linear, branched, or cyclic alkyl group, and is not particularly limited. Examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group (cetyl group), a heptadecyl group, an octadecyl group (stearyl group), an oleyl group, an elaidyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 3-methylbutyl group, a 2,2-dimethylpropyl group, a 1,1-dimethylpropyl group, a 2-ethylhexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

[0019] The aryl group having 6 to 14 carbon atoms is not particularly limited, but examples thereof include a phenyl group, a naphthyl group, an anthryl group, a tolyl group, a xylyl group, a cumenyl group, a vinylphenyl group, a biphenylyl group, and a phenanthryl group.

[0020] The arylalkyl group having 7 to 15 carbon atoms is not particularly limited, but examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, an anthrylmethyl group, a tolylmethyl group, a xylylmethyl group, a cumenylmethyl group, a vinylphenylmethyl group, a biphenylylmethyl group, and a phenanthrylmethyl group.

[0021] Among these, carboxyl group-containing O-substituted monohydroxylamines and carboxyl group-containing oximes, in which R in general formulas (1) and (2) is any one of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a benzyl group, and a phenyl group, are particularly preferred.

[0022] The hydroxylamino groups of the carboxyl group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) may be partially or entirely in the form of a chemically acceptable salt with an inorganic or organic acid. The type of salt is not particularly limited, but examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, perchlorate, silicate, tetrafluoroborate, hexafluorophosphate, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, citrate, fumarate, maleate, trifluoromethanesulfonate, trifluoroacetate, benzoate, and tosylate.

[0023] The carboxy groups of the carboxy group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) and the carboxy group-containing oxime derivative represented by the general formula (2) may be partially or entirely in the form of a chemically acceptable salt with an inorganic or organic base. The type of salt is not particularly limited, but examples thereof include metal salts such as sodium salts, potassium salts, rubidium salts, cesium salts, magnesium salts, calcium salts, strontium salts, barium salts, zinc salts, iron salts, copper salts, and silver salts, as well as ammonium salts with ammonium, methylamine, dimethylamine, trimethylamine, pyridine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, and polyethyleneimine.

[0024] The carboxy group of the carboxy group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) may form an intramolecular salt with the hydroxylamino group in the molecule, or may form an intermolecular salt.

[0025] The carboxyl group-containing oxime derivative represented by the above general formula (2) can take stereoisomers (syn isomer or anti isomer) due to the carbon-nitrogen double bond, and either stereoisomer can be used as the antibacterial, antifungal and antiviral agent of the present invention.

[0026] In the antibacterial, antifungal, and antiviral agent containing the carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) or the carboxyl group-containing oxime derivative represented by the above general formula (2), or a chemically acceptable salt thereof, the carboxyl group-containing O-substituted monohydroxylamine derivative or the carboxyl group-containing oxime derivative (or a chemically acceptable salt thereof) may be in the form of a solution dissolved in a solvent. The solvent is not particularly limited, but examples thereof include water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, dimethylformamide, isopropyl ether, dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, toluene, and xylene.

[0027] The carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) and the carboxyl group-containing oxime derivative represented by the above general formula (2) can be produced by known methods, or commercially available products can be used as they are or after being derivatized.

[0028] The carboxyl group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) is preferably aminooxyacetic acid, and the carboxyl group-containing oxime derivative represented by the general formula (2) is preferably 2-methylideneaminooxyacetic acid or 2-ethylideneaminooxyacetic acid.

[0029] That is, in the present invention, the antibacterial, antifungal and antiviral agent preferably contains aminooxyacetic acid, 2-methylideneaminooxyacetic acid or 2-ethylideneaminooxyacetic acid.

[0030] The carboxyl group-containing O-substituted monohydroxylamine derivatives represented by the above general formula (1) and the carboxyl group-containing oxime derivatives represented by the above general formula (2) can be suitably used as active ingredients of antibacterial, antifungal and antiviral agents. In this specification, "antibacterial, antifungal and antiviral" includes inhibiting the growth of bacteria, fungi and viruses, killing bacteria, fungi and viruses, reducing the infectivity of bacteria, fungi and viruses, etc.

[0031] The target bacteria for the antibacterial, antifungal and antiviral agent of the present invention are not particularly limited, but examples thereof include Staphylococcus aureus, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Bordetella gastrogrenata, Moraxella, Clostridium perfringens, Streptococcus, Hemolyticus, Salmonella typhimurium, Bacillus cereus, Trichophyton, Vibrio cholerae, Vibrio parahaemolyticus, Salmonella, Shigella, Bordetella pertussis, Haemophilus influenzae, Yersinia pestis, Bacillus anthrax, and Clostridium tetani.

[0032] Furthermore, target fungi include, but are not limited to, Aspergillus niger, Aspergillus terreus, Eurotium tonohilum, Penicillinium citrinum, Penicillinium funiculosum, Rhizopus oryzae, Cladosporium cladosporioides, Aureobasidium pullulans, Gliocladium virens, Chaetomium globosum, Fusarium moniliforme, and Myrothecium verrucaria.

[0033] Furthermore, target viruses include, but are not limited to, Lassa fever virus, AIDS virus, West Nile virus, dengue fever virus, Japanese encephalitis virus, influenza virus, avian influenza virus, swine influenza virus, smallpox virus, herpes virus, papillomavirus, Sindbis virus, coronavirus, SARS virus, feline calicivirus, norovirus, adenovirus, Marburg virus, measles virus, rabies virus, poliovirus, rhinovirus, rotavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, tobacco ringspot virus, tobacco rattle virus, tobacco mosaic virus, potato virus, cucumber mosaic virus, beet necrotic yellow vein virus, pepper mild mottle virus, common bean mosaic virus, common bean yellow mosaic virus, peanut stunt virus, bacteriophage, and the novel coronavirus (SARS-CoV-2).

[0034] The antibacterial, antifungal and antiviral agent of the present invention can be used in various dosage forms depending on its intended use, including, but not limited to, a solution, emulsion, suspension, dispersion, aerosol, wettable powder, dust, granules, microgranules, flowable formulation, etc.

[0035] The antibacterial, antifungal and antiviral agent of the present invention may consist solely of the above-mentioned carboxy group-containing O-substituted monohydroxylamine derivative, carboxy group-containing oxime derivative, or chemically acceptable salt thereof (hereinafter referred to as "carboxy group-containing O-substituted monohydroxylamine or carboxy group-containing oxime"). However, depending on the purpose, application and the like, the agent may also contain known additives such as microbial control agents (antibacterial agents, bactericides, preservatives, antialgicides, antimold agents, etc.), other antiviral agents, solvents, binders, carriers, dispersants, emulsifiers, buffers, stabilizers, excipients, binding agents, disintegrants, lubricants, thickeners, humectants, colorants, fragrances, chelating agents, pH adjusters, antioxidants, light stabilizers, antifoaming agents and the like, within limits that do not affect the antibacterial, antifungal and antiviral activity and stability.

[0036] The antibacterial, antifungal and antiviral agent of the present invention can be applied in a variety of fields.

[0037] By spraying the antibacterial, antifungal, and antiviral agent of the present invention onto a target object, it is possible to exert an antibacterial, antifungal, and antiviral effect against bacteria, mold, and viruses that are attached to the target object or that adhere to the target object after spraying. The target object is not particularly limited, but examples thereof include interior and exterior materials for automobiles, ships, airplanes, homes, etc., home appliances, elevator switches and touch panels, staircase handrails, doorknobs, etc.

[0038] When a solution of carboxy group-containing O-substituted monohydroxylamines or carboxy group-containing oximes is sprayed onto a target article, the concentration of the carboxy group-containing O-substituted monohydroxylamines or carboxy group-containing oximes in the solution is not particularly limited, but may be, for example, in the range of 0.01 to 50% by weight, and from the viewpoints of workability and antibacterial, antifungal, and antiviral properties, the range of 0.05 to 20% by weight is preferred, and the range of 0.1 to 10% by weight is more preferred.

[0039] The solvent used to prepare the solution is the same as the solvent described above, but from the viewpoint of exposure safety, it is preferable to use water, ethanol, isopropanol, glycerol, polypropylene glycol, or a mixed solvent thereof.

[0040] By blending the antibacterial, antifungal and antiviral agent of the present invention into an article or coating the surface of the article, the article can be treated with an antibacterial, antifungal and antiviral agent, thereby imparting the ability to reduce or inhibit bacteria, fungi and viruses to the article. Examples of the antibacterial, antifungal and antiviral agent include, but are not limited to, paints, adhesives, synthetic rubber latex, inks, polyvinyl alcohol films, polyvinyl chloride films, resin products, gypsum boards, roofing materials, wall materials, flooring materials, building materials, coated paper, wallpaper, floor coverings, office automation equipment, home appliances, air conditioning equipment, vacuum cleaners, desks, chairs, sofas, benches, windows, handrails, handles, seats, automatic ticket gates, automatic ticket vending machines, vending machines, doors, fences, handrails, tableware, cooking utensils, packaging films, packaging bags, bottles, bottles, packaging packs, sinks, toilets, stationery, books, shelves, teeth, etc. Examples include brushes, mirrors, filters, masks, coats, jackets, trousers, skirts, dress shirts, knit shirts, blouses, sweaters, cardigans, nightwear, underwear, diapers, supports, socks, tights, stockings, hats, scarves, mufflers, collars, stoles, gloves, clothing linings, clothing interlinings, clothing padding, work clothes, uniforms, school uniforms and other clothing, curtains, screen doors, bedding, bedding batting, bedding covers, pillowcases, sheets, mats, carpets, towels, handkerchiefs, wall cloth, adhesive plasters, bandages, etc.

[0041] When a carboxyl group-containing O-substituted monohydroxylamine or a carboxyl group-containing oxime is blended into an article, the blending amount (content concentration) is not particularly limited, but the amount of the carboxyl group-containing O-substituted monohydroxylamine or the carboxyl group-containing oxime relative to the article can be in the range of 0.001 to 20% by weight, and from the viewpoints of workability and antibacterial, antifungal, and antiviral properties, the range of 0.01 to 10% by weight is preferred. [Example]

[0042] The present invention will be specifically described below, but it should not be construed that the present invention is limited to these examples.

[0043] [Virus inactivation test] "Test conditions" 1.Test microorganism Influenza virus: swine influenza virus H1N1 IOWA strain Cultured cells: MDCK cells (canine kidney-derived cell line) 2. Test Method The test was carried out with reference to "Virus Experimental Science, General Theory, Revised Second Edition, Maruzen Co., Ltd., Virus Neutralization Test Method."

[0044] "District Settings" Control group (Comparative example 1) Comparative Example 1 Add 0.1 mL of influenza virus fluid to 1 mL of phosphate buffer solution Sensitization time is 0 minutes and 5 minutes after the start of the test. Test plots (Examples 1-2) Example 1 Test material: 3% by weight aqueous solution of aminooxyacetic acid Add 0.1 mL of influenza virus fluid to 1 mL of test material Sensitization time is 5 minutes after the start of the test. Example 2 Test material: Aqueous solution containing 3% by weight each of aminooxyacetic acid and polyethyleneimine (Epomin P-1000, manufactured by Nippon Shokubai) Add 0.1 mL of influenza virus fluid to 1 mL of test material Sensitization time is 5 minutes after the start of the test. Test Procedure 1. Preliminary Exam Prior to this test, the effects (cytotoxicity) of the test materials of Examples 1 and 2 on cultured cells were investigated. Each test material was diluted with phosphate buffer and then inoculated into the cultured cells. The highest concentration that showed a normal state of the cells after culture was confirmed, and the influenza virus concentration to be used in the test was determined.

[0045] As a result, poor cell growth was confirmed even when the test material in Example 1 was diluted up to 100 times, and the test material in Example 2 was diluted up to 1000 times. For this reason, in this test, it was decided to inoculate the cells with diluted materials at a dilution ratio greater than the dilution ratio at which an effect on the cells was observed. In addition, the lower limit of measurement for each test material was 10 3.5TCID 50 / mL, and 10 in Example 2 4.5 TCID 50 / mL.

[0046] 2. Main test: Mixing test liquids According to the test category, 1 mL of each test material and phosphate buffer solution was taken, and influenza virus fluid was added to the concentration determined in the preliminary test.

[0047] After adding the influenza virus solution, the mixture was allowed to stand at room temperature (25°C) for a predetermined period of time.

[0048] 3. Main test: Cell inoculation and bacterial count After sensitization for each test group, the mixture was diluted 10-fold and 100 μL of each was inoculated into cells cultured in a 96-well plate. After culturing at 37°C in 5% carbon dioxide for 5 days, the culture supernatant from each well was collected and the presence or absence of influenza virus growth was confirmed by hemagglutination, and the concentration was calculated.

[0049] The results of the virus inactivation test are shown in Table 1. In the control group (Comparative Example 1), no change in the amount of influenza virus was observed from the start of the test until 5 minutes after the start of the test (10 6.7 TCID 50 / mL).

[0050] On the other hand, 5 minutes after the start of the test, in the test group (Example 1), the 3.5 TCID 50 (>99.93% reduction), and in Example 2, <10 4.5 TCID 50 (>99.36% decrease).

[0051] [Table 1]

[0052] This time, we conducted an inactivation test of the test materials against influenza viruses, and found that by reacting with the influenza virus for more than 5 minutes, Example 1: >99.93% Example 2: >99.36% It was found to have a virus inactivation effect.

[0053] [Antiviral activity test] Example 3 A 3% by weight aqueous solution of aminooxyacetic acid was applied to a commercially available cotton cloth at a concentration of 20 g / m. 2 After impregnation at a ratio of 1:1, the material was dried at 60°C for 1 hour to prepare a sample for antiviral activity testing. This sample was subjected to a quantitative test of antiviral activity value as specified in JIS L1922. Using influenza virus (H3N2 strain) as the test virus, the antiviral activity value was calculated to be 4.3.

[0054] As is clear from Examples 1 to 3, the antibacterial, antifungal and antiviral agent of the present invention exhibited a high inactivation effect against viruses.

[0055] [Antibacterial activity test] Synthesis Example 1 9.11 g (100 mmol) of aminooxyacetic acid, 4.85 g (110 mmol) of acetaldehyde, and 30 g of water were placed in a 100 mL recovery flask and stirred at room temperature for 1 hour. Water and excess acetaldehyde were removed by distillation under reduced pressure to obtain 11.7 g (100 mmol, 100% yield) of 2-ethylideneaminooxyacetic acid.

[0056] Examples 4 to 15, Comparative Examples 2 to 3 A commercially available cotton cloth was impregnated with the chemicals shown in Table 2 and then dried at 60°C for 1 hour to prepare a sample for antibacterial activity testing. This sample was subjected to a quantitative test of antibacterial activity value using the bacterial liquid absorption method (pour plate culture method) specified in JIS L1902 "Antibacterial test method and antibacterial effect of textile products."

[0057] The results of the above antibacterial activity tests are shown in Table 2. As is clear from Table 2, the antibacterial, antifungal and antiviral agent of the present invention exhibited higher antibacterial activity than existing antibacterial agents.

[0058] [Table 2]

[0059] [Antifungal activity test] Examples 16-17 The chemicals shown in Table 3 were applied to a commercially available cotton cloth at 20 g / m 2 After impregnation at a ratio of 1:1, the fabric was dried at 60°C for 1 hour to prepare a sample for antifungal activity testing. This sample was subjected to quantitative testing of antifungal activity using the absorption method specified in JIS L1921 "Testing methods for antifungal activity and antifungal effect of textile products." The test fungus used was Cladosporium cladosporioides.

[0060] The results of the above antifungal activity tests are shown in Table 3. As is clear from Table 3, the antibacterial, antifungal and antiviral agent of the present invention exhibited a high inactivation effect against mold.

[0061] [Table 3]

Claims

[Claim 1] An antibacterial, antifungal and antiviral agent comprising one or more of 2-methylideneaminooxyacetic acid, 2-ethylideneaminooxyacetic acid and chemically acceptable salts thereof.

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