Antimicrobial Compounds and Compositions

Abstract

An antimicrobial compound according to formula (I) is disclosed: wherein R is H, -OH, -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ; and X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group. The disclosed compounds can be used to form compositions and articles resistant to microbial contamination.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 044,139, filed on June 25, 2020, the entire content of which is incorporated herein by reference. Technical field

[0003] This disclosure relates to compounds and compositions having antimicrobial properties. Background art

[0004] Microbial contamination of materials intended for use in fields such as medical treatment, the manufacture and packaging of medical devices, consumer products, food preparation or packaging, etc. represents a long - standing concern. Sterilization techniques may be temporarily effective, and the procedures for manufacturing and using materials intended to remain sterile have proven to be less than perfect.

[0005] Alternative methods for reducing the microbial load on such materials include antimicrobial coatings or compositions incorporated into the material itself to impart antimicrobial properties. Accordingly, there remains a need for further means of imparting antimicrobial properties to materials for related fields. Summary of the invention

[0006] The present invention discloses compounds of formula (I):

[0007]

[0008] Wherein

[0009] R is H, - OH, - CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 Or -(CH 2 ) 2 OCH 3 ; And

[0010] X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group.

[0011] Compositions comprising a compound of formula (I) and a base material are also disclosed. The present disclosure also provides articles comprising such compositions.

[0012] The present disclosure also relates to methods for preparing compounds according to formula (I). Methods comprising combining a base polymer material with a compound of formula (I) are also provided. Detailed description

[0013] The present invention can be more easily understood by reference to the following detailed description in conjunction with the accompanying examples that form a part of this disclosure. It should be understood that these inventions are not limited to the specific formulations, methods, articles, or parameters described and / or shown herein, and the terms used herein are for the purpose of describing specific embodiments by way of example only and are not intended to be limitations of the claimed invention.

[0014] The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference into this document.

[0015] As used above and throughout this disclosure, unless otherwise indicated, the following terms and abbreviations shall be understood to have the following meanings.

[0016] In this disclosure, the singular forms "a", "an", and "the" include plural referents, and a reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a material" refers to one or more such materials known to those skilled in the art and their equivalents, and so forth. Additionally, when an element is indicated as "may be" X, Y, or Z, such usage is not intended to exclude other alternatives for the element in all cases.

[0017] When a value is expressed as approximate by use of the antecedent "about", it should be understood that the specific value forms another embodiment. As used herein, "about X" (where X is a numerical value) preferably refers to ±10% (inclusive) of that value. For example, the phrase "about 8" can refer to a value from 7.2 to 8.8 (inclusive). This value can include "exactly 8". Where present, all ranges are inclusive and can be combined. For example, when reciting the range "1 to 5", the range should be interpreted as optionally including the ranges "1 to 4", "1 to 3", "1 - 2", "1 - 2 & 4 - 5", "1 - 3 & 5", etc. Additionally, when a list of alternatives is provided affirmatively, such a list can also include embodiments in which any of the alternatives can be excluded. For example, when describing the range "1 to 5", such a description can support cases where any of 1, 2, 3, 4, or 5 is excluded; thus, the recitation of "1 to 5" can support "1 and 3 - 5, without 2", or simply "where 2 is not included".

[0018] Microbial (e.g., bacterial) contamination can have serious consequences, whether related to medical devices or materials that come into contact with food or pharmaceutical ingredients. When used to manufacture articles such as disposable gloves or medical tubing, materials such as polyvinyl chloride (PVC), nylon, or polycarbonate can be susceptible to microbial contamination. Previous efforts to impart antimicrobial properties to materials have focused on both surface coatings and additives to the materials themselves, which are commonly used in medical and other environments where microbial contamination is a problem. The present inventors have discovered new compounds that can be readily combined with common materials to impart antimicrobial properties. These compounds have a wide range of uses, are easy to prepare, and are highly effective even when used at low concentrations.

[0019] Provided herein are compounds according to formula (I):

[0020]

[0021] Wherein

[0022] R is H, -OH, -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ; and

[0023] X is a negative counterion, namely bromide, chloride, fluoride, or phosphate.

[0024] In certain embodiments, X is bromide. Relative to some of these embodiments, R is -CH 2 CH 3 , -(CH 2 ) 2 CH 3 or -(CH 2 ) 3 CH 3 . For example, in one embodiment, X is bromide and R is -CH 2 CH 3 .

[0025] In the final form, the compound represents a homopolymer that can have a molecular weight of about 10 kDa to about 200 kDa. For example, the homopolymeric compound can have a molecular weight of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 kDa.

[0026] There is also provided a mixture comprising at least two different compounds according to formula (I). For example, a mixture according to the present disclosure may comprise a compound according to formula (I) wherein X is a bromide ion and R is -CH 2 CH 3 and a compound according to formula (I) wherein X is a bromide ion and R is -OH. In one embodiment, the mixture comprises a compound according to formula (I) wherein X is a bromide ion and R is -CH 2 CH 3 and at least one additional compound of formula (I).

[0027] In some embodiments, the inventive mixtures may represent a single compound of formula (I) having a first molecular weight, combined with additional compounds, the additional compounds having the same substituents as the first compound (i.e., wherein the variable groups R and X are the same as the first compound), but having a molecular weight different from the first compound. For example, a mixture according to the present disclosure may comprise a first compound wherein X is a bromide ion and R is ethyl and having a molecular weight of about 50 kDa, and a second compound wherein X is a bromide ion and R is ethyl and having a molecular weight of about 150 kDa.

[0028] As used throughout this disclosure, "antimicrobial" refers to the ability to reduce the microbial load to a measurable extent, or to prevent or reduce microbial contamination that would otherwise occur. For example, an antimicrobial compound according to the present disclosure may reduce the microbial load relative to a base material with which it is mixed, or may prevent ongoing microbial contamination relative to the base material.

[0029] When combined with a base material, the compounds of the present disclosure are effective in reducing the number of pathogens in or on the base material compared to the base material without the inventive compounds combined therewith. The antimicrobial efficacy of the inventive compounds may be expressed in terms of the minimum inhibitory concentration (MIC), the minimum bactericidal concentration (MBC), or both. As measured according to ISO 20776-1:2019, the MIC of the inventive compounds may be, for example, no greater than about 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.19%, 0.18%, 0.17%, 0.16% or 0.15%. As measured according to ISO 20776-1:2019, the MBC of the inventive compounds may be, for example, no greater than about 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.19%, 0.18%, 0.17%, 0.16% or 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.1%, 0.05%, 0.01%, 0.005% or 0.0005%.

[0030] The microorganisms against which the compounds of the present invention are effective in causing a reduction in number can be, for example, any single-celled organisms such as Gram-negative bacteria, Gram-positive bacteria, protozoa, viruses, bacteriophages, and archaea. The compounds of the present invention can have an antimicrobial effect against any such microorganism. Examples of bacteria against which the compounds of the present invention are effective in causing a reduction in number include Gram-positive bacteria and Gram-negative bacteria such as Salmonella enterica, Listeria monocytogenes, Escherichia coli, Clostridium botulinum, Clostridium difficile, Campylobacter, Bacillus cereus, Vibrio parahaemolyticus, Vibrio cholerae, Vibrio vulnificus, Staphylococcus aureus, Yersinia enterocolitica, Shigella, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, Legionella (e.g., Legionella pneumophila), Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens, Helicobacter pylori, Salmonella enteritidis, Salmonella typhi, and combinations thereof. Examples of Salmonella serovar variants that can be reduced using the compounds of the present disclosure include, for example, Salmonella enteritidis, Salmonella typhimurium, Salmonella puna, Salmonella heidelberg, and Salmonella anatum. Exemplary viruses against which the compounds of the present invention are effective in causing a reduction in number include coronaviruses, rhinoviruses, and influenza viruses.

[0031] The present disclosure also provides a composition comprising a compound according to formula (I) and a base material. The compound of formula (I) can be any compound as defined above or a mixture of such compounds. The base material can be any material used to at least partially form an article for medical diagnosis or treatment, including tubes, delivery devices, or protective clothing used by medical practitioners, packaging articles such as for packaging pharmaceuticals or food, or any other base material where avoidance of microbial contamination is desired.

[0032] For example, the base material can be polyvinyl chloride, chlorinated polyvinyl chloride, polycarbonate, nylon 6-6, nylon 6, nylon 10, polyethylene terephthalate, polyethylene terephthalate glycol, polybutylene terephthalate, polyether block amide, acrylate, acrylonitrile butadiene styrene, polystyrene, polylactic acid, polyhydroxyalkanoate, polyoxymethylene, low-density polyethylene, high-density polyethylene, polypropylene, ethylene-vinyl acetate, acrylonitrile styrene acrylate, epoxy resin, silicone, latex, or any other commercial bulk material (e.g., commercial bulk plastics) or any combination or mixture thereof. For example, the base material can be nitrile rubber, which is a copolymer of acrylonitrile and butadiene.

[0033] The compound of formula (I) may be present in the composition in an amount of about 0.05 to 15% by weight. In some embodiments, the compound of formula (I) is present in the composition in an amount of about 0.05 - 13, 0.1 - 15, 0.1 - 10, 0.2 - 13, 0.3 - 15, 0.3 - 13, 0.3 - 10, 0.4 - 15, 0.4 - 13, 0.4 - 10, 0.5 - 10, 1 - 10, 1 - 9, 1 - 8, 2 - 7, 3 - 7, 3 - 6, or 3 - 5% by weight. For example, the compound of formula (I) may be present in the composition in an amount of about 0.05, 0.07, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15% by weight.

[0034] The compositions of the present invention may optionally include one or more additional components, such as additional components that improve the processability or end - use performance of the composition, such as one or more fillers, plasticizers, ultraviolet absorbers, antioxidants, stabilizers, thickeners, colorants, rheological agents, and the like.

[0035] Fillers may be selected to impart additional strength or provide additional characteristics that may be based on the final selected characteristics of the composition. In some aspects, the filler may include inorganic materials, which may include clay, titanium oxide, asbestos fibers, silicates and silica powder, boron powder, calcium carbonate, talc, kaolin, sulfides, barium compounds, metals and metal oxides, wollastonite, glass spheres, glass fibers, flake fillers, fiber fillers, natural fillers and reinforcing materials; and reinforcing organic fiber fillers. In certain aspects, the composite may contain glass fiber filler. In further aspects, the composite may be free or substantially free of glass filler.

[0036] Suitable fillers or reinforcing agents may include, for example, mica, clay, feldspar, quartz, quartzite, perlite, weathered silica, diatomaceous earth, aluminum silicate (mullite), synthetic calcium silicate, fused silica, pyrogenic silica, sand, boron nitride powder, borosilicate powder, calcium sulfate, calcium carbonate (such as chalk, limestone, marble, and synthetic precipitated calcium carbonate), talc (including fibrous, modular, acicular, and lamellar talc), wollastonite, hollow or solid glass spheres, silicate spheres, coal balls, aluminosilicates or (armospheres), kaolin, silicon carbide, alumina, boron carbide, whiskers of iron, nickel or copper, continuous and chopped carbon or glass fibers, molybdenum disulfide, zinc sulfide, barium titanate, barium ferrite, barium sulfate, barite, titanium dioxide, alumina, magnesia, granular or fibrous aluminum, bronze, zinc, copper or nickel, glass flakes, flake silicon carbide, flake aluminum diboride, flake aluminum, steel flakes, natural fillers such as wood flour, fibrous cellulose, cotton, sisal, jute, starch, lignin, ground nut shells or rice husks, reinforcing organic fibrous fillers such as poly(ether ketone), polyimide, polybenzoxazole, poly(phenylene sulfide), polyester, polyethylene, aromatic polyamide, aromatic polyimide, polyetherimide, polytetrafluoroethylene and poly(vinyl alcohol) and combinations comprising at least one of the foregoing fillers or reinforcing agents. The fillers and reinforcing agents may be coated or surface treated, for example, with silanes to improve adhesion and dispersion in the polymer matrix. Based on 100 parts by weight of the total composition, the fillers can generally be used in an amount of 1 to 200 parts by weight.

[0037] The composition may also contain a plasticizer. For example, plasticizers may include phthalates (such as dioctyl 4,5-epoxy-hexahydrophthalate), tris(2-ethylhexyl) trimellitate, glyceryl tristearate, epoxidized soybean oil, etc. or combinations comprising at least one of the foregoing plasticizers. Based on 100 parts by weight of the total composition excluding any fillers, the plasticizer is generally used in an amount of about 0.5 to about 3.0 parts by weight.

[0038] Ultraviolet (UV) absorbers may also be present in the disclosed compositions. Exemplary UV absorbers may include, for example, hydroxydibenzophenone; hydroxybenzotriazole; hydroxybenzotriazine; cyanoacrylate; oxanilide; benzoxazinone; 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)-phenol (CYASORB TM 5411); 2-hydroxy-4-n-octyloxybenzophenone (CYASORB TM 531); 2-[4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl]-5-(octyloxy)-phenol (CYASORB TM 1164); 2,2'-(1,4-phenylene)bis(4H-3,1-benzoxazin-4-one) (CYASORB TMUV-3638); 1,3-bis[(2-cyano-3,3-diphenylacryloyl)oxy]-2,2-bis[[(2-cyano-3,3-diphenylacryloyl)oxy]methyl]propane (UVINUL TM 3030); 2,2'-(1,4-phenylene)bis(4H-3,1-benzoxazin-4-one); 1,3-bis[(2-cyano-3,3-diphenylacryloyl)oxy]-2,2-bis[[(2-cyano-3,3-diphenylacryloyl)oxy]methyl]propane; nano-sized inorganic materials such as titanium oxide, cerium oxide, and zinc oxide, all having a particle size of less than 100 nanometers; and the like, or a combination comprising at least one of the foregoing UV absorbers. Based on 100 parts by weight of the total composition excluding any fillers, the UV absorber is typically used in an amount of 0.01 to 3.0 parts by weight.

[0039] In a further aspect, one or more light stabilizers may be present in the compositions of the present invention. Exemplary light stabilizers may include, for example, benzotriazoles such as 2-(2-hydroxy-5-methylphenyl)benzotriazole, 2-(2-hydroxy-5-tert-octylphenyl)-benzotriazole, and 2-hydroxy-4-n-octyloxybenzophenone, and the like, or a combination comprising at least one of the foregoing light stabilizers. Based on 100 parts by weight of the total composition excluding any fillers, the light stabilizer is typically used in an amount of about 0.1 to about 1.0 parts by weight.

[0040] The compositions of the present invention may contain heat stabilizers. By way of example, heat stabilizers may include, for example, organic phosphites such as triphenyl phosphite, tris(2,6-dimethylphenyl) phosphite, tris(mixed mono- and di-nonylphenyl) phosphite, and the like; phosphonates such as dimethyl phenylphosphonate, and the like; phosphates such as trimethyl phosphate, and the like, or a combination comprising at least one of the foregoing heat stabilizers. Based on 100 parts by weight of the total composition excluding any fillers, the heat stabilizer is typically used in an amount of 0.01 to 0.5 parts by weight.

[0041] The composition may comprise one or more antioxidants. The antioxidants may include primary or secondary antioxidants. For example, the antioxidants may include organic phosphites such as tris(nonylphenyl) phosphite, tris(2,4-di-tert-butylphenyl) phosphite, bis(2,4-di-tert-butylphenyl)pentaerythritol diphosphite, distearylpentaerythritol diphosphite, and the like; alkylated monophenols or polyphenols; alkylated reaction products of polyphenols with dienes such as tetrakis[methylene(3,5-di-tert-butyl-4-hydroxyhydrocinnamate)]methane, and the like; butylated reaction products of p-cresol or dicyclopentadiene; alkylated hydroquinones; hydroxylated thiodiphenyl ethers; alkylene-bisphenols; benzyl compounds; esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid with monoalcohols or polyalcohols; esters of β-(5-tert-butyl-4-hydroxy-3-methylphenyl)-propionic acid with monoalcohols or polyalcohols; esters of thioalkyl or thioaryl compounds such as distearyl thiodipropionate, dilauryl thiodipropionate, bis(tridecyl) thiodipropionate, octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, pentaerythritol tetra[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], and the like; amides of β-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid, and the like, or combinations comprising at least one of the foregoing antioxidants. Based on 100 parts by weight of the total composition excluding any fillers, the antioxidants are generally used in an amount of from 0.01 to 0.5 parts by weight.

[0042] The composition of the present invention may comprise pigments or colorants. Suitable colorants may include, but are not limited to, Solvent Green 3, Solvent Green 28, Solvent Green 38, Pigment Green 50, Pigment Green 36, Solvent Red 52, Solvent Red 101, Solvent Red 111, Solvent Red 135, Solvent Red 169, Solvent Red 179, Solvent Red 207, Pigment Red 101, Disperse Red 22, Vat Red 41, Solvent Orange 60, Solvent Orange 63, Disperse Orange 47, Solvent Violet 13, Solvent Violet 14, Solvent Violet 36, Solvent Violet 50, Disperse Violet 26 / 31, Pigment Blue 29, Pigment Blue 60, Copper Phthalocyanine Pigment Blue 15.4, Disperse Blue 73, Solvent Blue 97, Solvent Blue 101, Solvent Blue 104, Solvent Blue 122, Solvent Blue 138, Pigment Yellow 53, Pigment Yellow 138, Pigment Yellow 139, Disperse Yellow 201, Solvent Yellow 33, Solvent Yellow 114, Solvent Yellow 93, Solvent Yellow 98, Solvent Yellow 163, Solvent Yellow 160:1, Solvent Yellow 188, Pigment Brown 24, Aminoketone Black, Chromium Oxide, Carbon Black, Channel Black, and Pigment Black 6, and the like, as well as combinations comprising one or more of the foregoing. Any effective amount of the colorant may be included in the molded article. In some aspects, the colorant is present in the molded article in an amount of from about 0.00001 to about 0.01 wt% of the composition, or in certain aspects, in an amount of from about 0.00002 to about 0.0010 wt% of the composition, or even in an amount of from about 0.00002 to about 0.0005 wt% of the composition.

[0043] The composition may comprise one or more pigments, such as white pigments. The white pigments can impart opacity or a bright opaque appearance. Examples of white pigments may include titanium dioxide, zinc sulfide (ZnS), tin oxide, aluminum oxide (AlO 3 ), zinc oxide (ZnO), calcium sulfate, barium sulfate (BaSO 4 ), calcium carbonate (such as chalk), magnesium carbonate, antimony oxide (Sb 2 O 3 ), lead white (basic lead carbonate, 2PbCO 3 ·Pb(OH) 2 ), lithopone (a combination of barium sulfate and zinc sulfide), sodium silicate, aluminum silicate, silicon dioxide (SiO 2 , i.e., silica), mica, clay, talc, metal-doped versions of the foregoing materials, and combinations comprising at least one of the foregoing materials. The pigment may be present in an amount of from about 0.1 wt% to about 50 wt%. As an example, the composition may comprise titanium dioxide in an amount between 0.1 wt% - 50 wt%. In a further example, the composition may comprise titanium dioxide in an amount between 0.1 wt% - 20 wt%.

[0044] Also provided herein are articles comprising the composition according to any of the disclosed embodiments. An article according to the present disclosure may be a bulk commodity material at least partially for use in manufacturing a final product, or the article itself may be a component of a product, or a finished product. For example, the article may be a textile, or a sheet, ingot, pellet, or roll of material. In one embodiment, the article is an ethylene product, such as interior decorative ethylene. In another embodiment, the article is a natural product, such as tanned or raw leather. If the article represents a finished product or a component of a finished product, the article may be, for example, a product for medical treatment or otherwise used by a medical practitioner (e.g., doctor, dentist, nurse, hygienist, caregiver, assistant), such as disposable gloves, protective masks, medical gowns, shoe covers, medical caps, medical tubes, delivery devices, storage containers, implantable devices, implantable medical leads, sponges, or components thereof. The article may alternatively be a paint, sealant, coating, or wax or a component thereof. The presence of the compounds of the present invention in the article confers antimicrobial characteristics, such that the article is less susceptible to microbial contamination and can be used more safely in critical environments, such as medical treatment and food processing, storage, or service.

[0045] The present disclosure also provides a method for preparing a compound of formula (I):

[0046]

[0047] Wherein

[0048] R is H, -OH, -CH2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ;and

[0049] X is a negative counter ion, that is, bromide, chloride, fluoride or phosphate,

[0050] And wherein the method is according to Scheme 1:

[0051]

[0052] Any compound according to formula (I) as described above can be prepared using the present method. For example, the compound prepared by the method of the present invention can be such that X is a bromide ion. With respect to some of these embodiments, R is -CH 2 CH 3 、-(CH 2 ) 2 CH 3 or -(CH 2 ) 3 CH 3 For example, in one embodiment, X is bromide and R is -CH 2 CH 3 .

[0053] Additional aspects of the methods of the present invention are provided in conjunction with the examples provided below.

[0054] Also provided herein are methods comprising combining a base material with a compound of formula (I).

[0055]

[0056] Where R is H, -OH, -CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3; and X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group. The current method may involve using any compound according to formula (I) as described above. For example, the compound used in the method of the present invention may be a compound in which X is bromide ion. Relative to some of these embodiments, R is -CH 2 CH 3 -, -(CH 2 ) 2 CH 3 or -(CH 2 ) 3 CH 3 . For example, in one embodiment, X is bromide ion and R is -CH 2 CH 3 .

[0057] The base material can be any material described above in combination with the currently disclosed composition. Thus, the base material can be any material used to at least partially form an article for medical diagnosis or treatment, including tubes, delivery devices or protective clothing used by medical practitioners, packaging articles, such as for packaging pharmaceuticals or food, or any other base material where avoidance of microbial contamination is desired.

[0058] For example, the base material can be polyvinyl chloride, chlorinated polyvinyl chloride, polycarbonate, nylon 6-6, polyethylene terephthalate, polyethylene terephthalate glycol, polybutylene terephthalate, polyether block amide, acrylate, acrylonitrile butadiene styrene, polystyrene, polylactic acid, polyhydroxyalkanoate, polyoxymethylene, low density polyethylene, high density polyethylene, polypropylene, ethylene-vinyl acetate, acrylonitrile styrene acrylate, epoxy resin, silicone, latex, natural organic material or any other commercial bulk material (such as commercial bulk plastics) or any combination or mixture thereof. For example, the base material can be nitrile rubber, which is a copolymer of acrylonitrile and butadiene. "Natural organic materials" can include, for example, agricultural products, including materials made from crops and livestock, including but not limited to field crops, forage, cattle, sheep, pigs, goats, horses, poultry and fur-bearing animals. Specific examples of materials from livestock include hides (e.g., leather products) and furs.

[0059] The compound of formula (I) can be provided such that it is present in the composition (i.e., which results from the combination of the base material and any other components) in an amount of about 0.5 to 15% by weight based on the total weight of the composition. In some embodiments, the compound of formula (I) is present in the composition in an amount of about 0.5 - 10, 1 - 10, 1 - 9, 1 - 8, 2 - 7, 3 - 7, 3 - 6, or 3 - 5% by weight. For example, the compound of formula (I) can be present in an amount of about 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15% by weight.

[0060] The compound of formula (I) can be combined with the base material according to the method of the present invention using any acceptable technique, such as mixing or blending. Those of ordinary skill in the art can identify suitable laboratory and industrial equipment for combining the compound with the base material, such as turbines, mixers (e.g., cross-gap, static, vacuum, jet, high-viscosity, horizontal, hybrid, turbine, planetary, Banbury), blenders (e.g., V-type blender, twin-screw, conical screw, double-cone), or other suitable equipment.

[0061] Examples

[0062] The following examples are presented to provide a complete disclosure and description to those of ordinary skill in the art of how the formulations, methods, and articles claimed herein can be developed and evaluated, and are intended to be a complete illustration of the invention, and not intended to limit the scope that the inventors regard as their invention. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts), some error and deviation should be accounted for.

[0063] Example 1 - Preparation of the Compound of Formula (I)

[0064] The compound of formula (I) was prepared as follows according to Scheme 1:

[0065]

[0066] wherein R is -CH 2 CH 3 , and X is a bromide ion.

[0067] First, the secondary amine precursor (6.81 g, 50.0 mmol) and triethylamine (7.3 mL, 52.5 mmol) were dissolved in a flask equipped with a stir bar, N 2In toluene (100 mL) in a 250 mL three-necked flask with an inlet and a thermocouple sleeve. Cool the mixture to -12 °C in an ice-methanol bath. Add acryloyl chloride (4.06 mL, 50.0 mmol) dropwise. The first drop produced yellow chunks, so the remaining acryloyl chloride was diluted in toluene (20 mL) and added dropwise at the maximum stirring rate. Control the addition rate and manually stir the cooling bath to keep the internal temperature below -4 °C throughout the addition. Warm the mixture to near ambient temperature (7 °C) and filter it under vacuum to remove the precipitated Et 3 N·HCl. Wash the filter cake with toluene (2 x 20 mL) and load the combined filtrate onto a silica gel column (48 g) prepared in toluene. Elute the product with EtOAc. The first fraction of the desired product eluted just before the EtOAc solvent front and was contaminated with higher R f impurities. The yield of the mixed fraction was 1.48 g. The remainder of the product was eluted in pure EtOAc and purified by TLC and NMR (except for residual EtOAc, which was removed by further drying overnight under slow rotation). The yield of the pure fraction was 4.50 g (47%), and the total yield was 5.98 g (63%). Dissolve monomer 501PAL25 (pure fraction, 4.47 g, 23.5 mmol) in methanol (45 mL) in a 100 mL three-necked flask equipped with an inlet for an N 2 line-bubbler, a thermocouple sleeve, and a stir bar. Seal the third neck with a polyethylene stopper and use a needle through the stopper to introduce an N 2 spray solution. After 20 min, heat the solution to 60 °C. Add AIBN (19.3 mg, 117 μmol, 0.5 mol%) dropwise against an N 2 stream and seal the flask with a new polyethylene stopper. Manual stirring is required to wash the AIBN down from the neck of the flask. After stirring at 60 °C under N 2 for 21 h, withdraw a 0.2 mL sample with a syringe, dry it under N 2 and analyze it by 3 H NMR in CDCl 1 3, showing approximately 25% polymerization. Add the second sample (1 mL) dropwise to rapidly stirred MTBE (10 mL). Dissolve the resulting gummy yellow precipitate in DCM, dry it, redissolve it in DCM, aspirate it into a syringe (total volume 0.3 mL), and reprecipitate it in rapidly stirred MTBE (3 mL). Collect the resulting white powdery precipitate by filtration (cotton-stoppered Pasteur pipette), wash it with MTBE, dry it under N 2 stream, and analyze it by 3 H NMR in CDCl 1HNMR analysis showed only broad peaks consistent with the polymer. A second portion of AIBN (19 mg, 0.5 mol %) was added and the mixture was stirred at 60 °C for an additional 24 h. NMR showed just over 50% conversion. A third portion of 0.5 mol % AIBN was added and the mixture was stirred at 60 °C for an additional 45 h. After cooling, the mixture was concentrated to a foamy glassy solid. The residue was taken up in DCM, diluted to 16 mL, and a small sample was dried for NMR analysis, showing 70% conversion. The remaining orange-brown solution was added dropwise to rapidly stirred MTBE (160 mL). After stirring for 10 min, the precipitate was collected by filtration, dried under N 2 flow, redissolved in DCM (15 mL), and reprecipitated in MTBE (150 mL). The product was collected by filtration and dried overnight at room temperature under vacuum (75 mtorr). NMR in CDCl 3 showed a residual MTBE content of 0.39 equivalent (15% mass). Based on mass loss and NMR in CD 3 OD, further drying at 45 °C for 4 h reduced the MTBE content to 12%. The final yield was 3.22 g (corrected to 63% with respect to solvent content).

[0068] Partially quaternized polymer: The neutral pyridine polymer (2.4 g, 11.1 mmol monomer units) was dissolved in methanol (9 mL) and bromohexane (3.1 mL, 22 mmol) was added. The mixture was refluxed under N 2 for 14 h and the sample was blown dry under N 2 and further dried under vacuum and analyzed by H NMR in CD 3 OD, showing just over 70% quaternization. After an additional 25 h at 60 °C and then 4 days at rt, NMR showed complete consumption of the free pyridine groups but two sets of signals consistent with pyridinium groups. Samples (0.2 mL each) of the reaction mixture were added to vials containing THF, EtOAc, or iPrOAc (3 mL each of each solvent). EtOAc gave the most filterable precipitate. The latter was collected by filtration, dried under N 1 flow, and analyzed by H NMR in CD 2 OD, which again showed two sets of pyridinium signals. Et 3 N (10 μL) was added to the NMR sample and the spectrum was run again. The pyridinium signals split into groups consistent with N-hexylpyridinium (85%) and free pyridine (15%), showing that quaternization had stopped due to competing protonation. With Bu 1 H NMR analysis, which again showed two sets of pyridinium signals. The pyridinium signals split into groups consistent with N-hexylpyridinium (85%) and free pyridine (15%), showing that quaternization had stopped due to competing protonation. With Bu 3 N (10 μL) was added to the NMR sample and the spectrum was run again. The pyridinium signals split into groups consistent with N-hexylpyridinium (85%) and free pyridine (15%), showing that quaternization had stopped due to competing protonation. With Bu 3A second sample of the reaction mixture was treated with N(0.1 mL), diluted to a single phase with MeOH, and precipitated into EtOAc. NMR of the resulting precipitate (501PAL32p2) showed the same pyridinium / free pyridine ratio as above, and Bu 3 N was not retained in the polymer. The remainder of the reaction mixture was treated with Bu 3 N (2.6 mL, 1 equivalent) and precipitated into rapidly stirred EtOAc (170 mL). The resulting gummy orange precipitate was separated by decantation, triturated with EtOAc to a powder, collected by filtration, dissolved in EtOH (9 mL), and precipitated into EtOAc (180 mL). The powdery precipitate was collected by filtration under N 2 and dried by rotary evaporation under vacuum with a vortex pump at 45 °C. NMR showed 88% hexylpyridinium and 12% free pyridine groups. Yield: 2.79 g (75%).

[0069] Fully quaternized polymer: A partially quaternized polymer (2.50 g, 7.45 mmol monomer units, based on weighted average MW) was dissolved in MeCN (7.5 mL). Bromohexane (1.04 mL, 7.45 mmol) was added and the mixture was refluxed for 24.5 h under N 2 . The sample was dried under N 2 and analyzed by NMR in CD 3 OD, which was consistent with full quaternization. This was confirmed by the addition of Et 3 N (10 μL), which caused no change in the aromatic region. The remainder of the reaction mixture was diluted with EtOH (2.5 mL), passed through a 0.45 μm syringe filter, and precipitated into rapidly stirred EtOAc (180 mL). After stirring for 15 min, the product was collected by filtration under N 2 , washed twice with EtOAc, and dried under a stream of N 2 . The resulting powder was further dried by rotary evaporation under vacuum at 50 °C for 2.5 h (65 mtorr final) to give a pale orange powder. Yield: 2.39 g (90%). NMR showed complete removal of solvent under these drying conditions.

[0070] Example 2 – Antimicrobial Efficacy

[0071] The compound according to formula (I), the N-hexylpyridinium-N-ethylacrylamide polymer, which was formed according to the procedure described in Example 1, was tested to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against two bacterial species commonly associated with the contamination of medical devices and food processing and storage materials, namely Salmonella aureus (ATCC 6538) and Pseudomonas aeruginosa (ATCC 9027).

[0072] Reconstitute the test compound (prepared in powder form) in sterile DI water. Mix 0.25 gm with 2.0 mL of sterile DI water to make a solution for a 12.5% initial concentration.

[0073] Prepare the test inoculum by introducing the test microorganism from the freezer stock into a 10.0 mL tryptic soy broth (TSB) plate and incubating at 36.0 ± 1 °C for 18 - 24 hours. After incubation, centrifuge the culture and resuspend it in 10.0 mL of sterile phosphate buffered saline (PBS). Transfer 0.200 mL of the culture to 9.0 ml of sterile PBS to achieve a 0.5 McFarland standard concentration of ~1.5x10 8 CFU / mL. Further dilute the culture in PBS by transferring 0.500 mL of the original culture of the McFarland standard to 10.0 mL of PBS to produce the test inoculum to achieve a target concentration of 2x10 5 to 8x 10 5 CFU / mL. Use the prepared test inoculum within 30 min of completing the inoculum preparation.

[0074] Broth microdilution MIC Perform serial 1:1 dilutions (1 part test compound: 1 part diluent) in a 96-well microtiter plate. Use Mueller Hinton broth (MHB) as the well diluent. Add 0.100 mL of MHB to wells 2 - 10. Add 0.200 mL of the test compound to well 1, then dilute by taking 0.100 mL from well 1 and adding it to well 2 and mixing. Then take 0.100 mL from well 2 and add it to well 3, then mix well. Continue transferring 0.100 mL from the previous well to the subsequent well until well 10. Discard 0.100 mL from well 10 after the contents are well mixed. Broth microdilution MIC is performed in a single replicate.

[0075] Add the prepared inoculum in an amount of 0.010 mL to each well for the appropriate microorganism. Inoculate all wells with the test inoculum within 30 minutes of diluting the culture for testing.

[0076] Control Make a positive control well in well 12 by placing 0.100 mL of MHB in the well, adding 0.010 mL of the appropriate test inoculum to the broth, and mixing the well thoroughly. Do not add the test substance to the positive control well. Make a negative control well in well 11 by placing 0.200 mL of MHB in the well. The negative well is not inoculated and no test substance is added to this well.

[0077] Turbidity control wellDue to the turbidity of the test substance, a control well was established for each test substance. The control well contained the test substance and MHB in the same manner as described above in the broth microdilution MIC section, without adding the inoculum to the well.

[0078] Zero-time concentration of the well The zero-time concentration of the well was determined by removing 0.010 mL from the positive well and adding it to 10.0 mL of sterile PBS. The appropriate dilution was plated onto tryptic soy agar.

[0079] Medium control A purity streak of each test microorganism was performed on TSA. The sterility of all media used in the test was performed on TSA.

[0080] Neutralization verification Neutralization effectiveness and neutralization toxicity tests were performed on each microorganism prior to MBC. Verification was performed in duplicate. Neutralization verification was only performed on the highest concentration of the test substance used in the test. Neutralization effectiveness verification was performed using the test microorganism with the McFarland standard. The test microorganism was serially diluted in sterile PBS to achieve a concentration of ∼10 - 100 CFU / mL in the neutralizer suspension. 0.900 mL of sterile Dey-Engley neutralization broth (D / E broth) was inoculated with 0.010 mL of the diluted test microorganism. And 0.100 mL of the test substance was added to the inoculated D / E broth suspension. The suspension was allowed to stand for >10 minutes, and then the entire tube was plated onto TSA. Neutralization agent toxicity verification was performed using the diluted test microorganism used for the neutralization effectiveness test. 0.900 mL of sterile Dey-Engley neutralization broth (D / E broth) was inoculated with 0.010 mL of the diluted test microorganism, and 0.100 mL of PBS was added to the inoculated D / E broth suspension. The suspension was allowed to stand for >10 minutes, and then the entire tube was plated onto TSA.

[0081] Determine the minimum inhibitory concentration (MIC) After incubation, the turbidity of the microtiter wells was visually inspected. Turbidity and / or the presence of large microbial aggregates in the microtiter wells indicated growth at a dilution. The growth was compared to the positive control well and the control well. The MIC was determined as the lowest concentration at which no growth (turbidity) was visually observed.

[0082] Determine the minimum bactericidal concentration (MBC)Take 0.050 mL from the well corresponding to the observed MIC and the two consecutive wells with higher test substance concentrations. Add the aliquots taken from the well corresponding to the observed MIC and the two consecutive wells with higher test substance concentrations to 0.900 mL of D / E broth and vortex. Inoculate the suspension onto a TSA pour plate. The plate is inoculated with the entire contents of the microtiter tube with the D / E suspension. The MBC is the lowest concentration of the test substance that shows a 3 log10 reduction in CFU / mL compared to the zero-time concentration of the well.

[0083] The study success criteria are as follows: 1. The positive control well is positive for growth; 2. The negative control well is negative for growth; 3. All media sterility controls are negative for growth; 4. The purity streak shows pure growth of the target microorganism; 5. The concentration in the positive control well is between 2x105 - 8x105 CFU / mL; 6. The concentration of the microorganism recovered from the neutralizer effectiveness test should be ≥70% of the concentration recovered from the neutralizer toxicity test.

[0084] The performance success criteria are as follows: 1. The MIC determination is the lowest concentration of the test substance in the well that completely inhibits the growth of the test microorganism; 2. The MBC determination is the lowest concentration of the test substance that shows a 99.9% reduction in CFU / mL compared to the zero-time count.

[0085] The relevant calculations are performed as follows:

[0086] Log reduction = Log10(B / A), where A = the viable microorganism concentration in the well and B = the initial digital control concentration

[0087] Percent reduction = (A - B) / A, where A = the initial digital control concentration and B = the viable microorganism concentration in the well

[0088] Table 1 below provides the evaluation results of percent reduction and log reduction for the inoculated wells with respect to Staphylococcus aureus ATCC 6538.

[0089] Table 1

[0090]

[0091] *Values below the detection limit of <1.00E+00 were detected

[0092] Table 2 below provides the evaluation results of percent reduction and log reduction for the inoculated wells with respect to Pseudomonas aeruginosa ATCC 9027.

[0093] Table 2

[0094]

[0095] *The numerical value is below the detection limit of <1.00E+00

[0096] Table 3 below provides the measured MIC / MBC results against Staphylococcus aureus ATCC 6538.

[0097] Table 3

[0098]

[0099] N.T. = No turbidity

[0100] T. = Turbidity

[0101] Table 4 below provides the measured MIC / MBC results against Pseudomonas aeruginosa ATCC 9027.

[0102] Table 4

[0103]

[0104]

[0105] N.T. = No turbidity

[0106] T. = Turbidity

[0107] Table 5 below provides the neutralization verification results against Pseudomonas aeruginosa ATCC 9027.

[0108] Table 5

[0109]

[0110] Table 6 below provides the neutralization verification results against Staphylococcus aureus ATCC 6538.

[0111] Table 6

[0112]

[0113] Table 7 below provides the evaluation results of the control plates.

[0114] Table 7

[0115] Control Result Purity of Staphylococcus aureus ATCC 6538 Pure growth Purity of Pseudomonas aeruginosa ATCC 9027 Pure growth Negative control well No turbidity Positive control well Turbidity Sterility of Mueller Hinton broth No growth Sterility of phosphate buffered saline culture diluent No growth Sterility of phosphate buffered saline dilution No growth Dey-Engley neutralizing broth (D / E broth) No growth Sterility of tryptic soy agar No growth

[0116] Table 8 below provides the cultivation conditions of various test plates.

[0117] Table 8

[0118]

[0119] Example 3 – Antimicrobial efficacy when used with plastic materials

[0120] Antimicrobial efficacy has also been demonstrated in solid, non-porous plastics, including polypropylene, which can be used in spunbond, meltblown, nonwoven fabrics, and woven textiles.

[0121] The Japanese Industrial Standards Committee (JIS) is an international organization that develops and standardizes test methods for various products and materials. The JIS method Z 2801 is a quantitative test designed to evaluate the performance of antimicrobial finishes on hard, non-porous surfaces. This method can be conducted using contact times ranging from 10 minutes to 24 hours. For the JIS Z 2801 test, a non-antimicrobial control surface is used as the baseline for calculating microbial reduction. This method is versatile and can be used to determine the antimicrobial activity of a variety of surfaces, including plastics, metals, and ceramics.

[0122] The JIS Z 2801 test procedure can be summarized as follows: Prepare the test microorganisms, typically by growing them in a liquid medium. The suspension of test microorganisms is standardized by dilution in nutrient broth, which gives the microorganisms the opportunity to multiply during the test. Inoculate the control and test surfaces with the microorganisms, and then cover the microbial inoculum with a sterile film. Covering the inoculum spreads it, prevents evaporation, and ensures close contact with the antimicrobial surface. Determine the microbial concentration at "zero time" by elution, followed by dilution and plating onto agar. Run a control to verify that the neutralization / elution method effectively neutralizes the antimicrobial agent in the antimicrobial surface being tested. Allow the inoculated, covered control and antimicrobial test surfaces to incubate undisturbed for 24 hours in a humid environment, typically at body temperature. After incubation, determine the microbial concentration. Calculate the reduction of microorganisms relative to the control surface.

[0123] For a JIS Z 2801 study to be scientifically valid, the following criteria must be met: (1) The average number of viable cells recovered from the zero-time sample must be close to 1 x 10 4 cells / cm 2 or greater; (2) Ordinary consistency between replicates must be observed for the zero-time sample; (3) The number of viable cells recovered from the control surface after the contact time must not be significantly (>2-Log10) less than the initial inoculum concentration; (4) The positive / growth control must show appropriate growth of the test microorganisms; (5) The negative / purity control must show no growth of the test microorganisms.

[0124] The pass criterion specifies a performance standard of antimicrobial efficacy greater than or equal to 2 Log10 or 99% reduction of test microorganisms when comparing the treated surface to the control surface after the contact time.

[0125] Table 9 below shows the bactericidal efficacy of polypropylene mixed with 6% w / w N-hexylpyridinium-N-ethylacrylamide polymer used as an additive against Staphylococcus aureus and Pseudomonas aeruginosa over 24 h. This material has shown over 3 log reduction against the test organisms with a 24 h inoculation time while still being processable into nonwoven fabrics.

[0126] Table 9

[0127]

[0128] *Limit of detection. For S. aureus, the plate count was below the limit of detection of <5.00E+00 CFU / carrier

[0129] Example 4 – Antimicrobial Efficacy When Used with Porous Materials

[0130] As shown below, the test compound according to formula (I), N-hexylpyridinium-N-ethylacrylamide polymer, can also be used to impart antimicrobial properties to porous materials such as raw hide leather.

[0131] A treated leather sample was prepared by soaking in a mixture of 3% N-hexylpyridinium-N-ethylacrylamide polymer in ethanol for 10 minutes and then drying it for 24 h. Table 10 below shows the results of testing the bactericidal efficacy against a panel of pathogens specifically at a 24 h inoculation time. In many cases, the log reduction exceeded the test limit.

[0132] Table 10

[0133]

[0134]

[0135] *Indicates that the plate count was below the detectable limit of the test

Claims

1. A compound of formula (I): wherein R is H, -OH, -CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ;and X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group.

2. The compound according to claim 1, wherein X is bromide ion.

3. A compound according to claim 1 or claim 2, wherein R is -CH 2 CH 3 .

4. A mixture comprising at least two different compounds according to claim 1.

5. A composition comprising the compound according to claim 1 and a base material.

6. The composition according to claim 5, wherein X is bromide ion.

7. The composition according to claim 5 or claim 6, wherein R is -CH 2 CH 3 .

8. The composition according to claim 5 or claim 6, wherein the base material is polyvinyl chloride, chlorinated polyvinyl chloride, polycarbonate, nylon 6-6, polyethylene terephthalate, polyethylene terephthalate glycol, polybutylene terephthalate, polyether block amide, acrylate, acrylonitrile butadiene styrene, polystyrene, polylactic acid, polyhydroxyalkanoate, polyoxymethylene, low density polyethylene, high density polyethylene, polypropylene, ethylene-vinyl acetate, acrylonitrile styrene acrylate, epoxy resin, silicone, latex, natural organic material or any combination thereof.

9. The composition according to claim 5 or claim 6, wherein the base material is polyvinyl chloride.

10. The composition according to claim 5 or claim 6, wherein the compound of formula (I) is present in the composition in an amount of about 1-10% by weight.

11. The composition according to claim 5 or claim 6, wherein the compound of formula (I) is present in the composition in an amount of about 2-7% by weight.

12. The composition according to claim 5 or claim 6, wherein the compound of formula (I) is present in the composition in an amount of about 3-5% by weight.

13. An article comprising the composition according to any one of claims 5 to 12.

14. The article according to claim 13, which includes disposable gloves, masks, medical gowns, shoe covers, medical caps, medical tubes, delivery devices, storage containers, implantable devices, implantable medical leads, textiles or sponges.

15. The article according to claim 13, which contains paint, coating, sealant or wax.

16. A method for preparing a compound of formula (I) wherein R is H, -OH, -CH 2 CH 3 、-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ; and X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group, wherein the method is according to Scheme 1: Scheme 1 17. The method according to claim 16, wherein X is bromide ion.

18. The method according to claim 16 or claim 17, wherein R is -CH 2 CH 3 .

19. A method for preparing the composition according to claim 5, the method comprising combining a base material with a compound of formula (I), wherein R is H, -OH, -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 or -(CH 2 ) 2 OCH 3 ; and X is a negative counterion, namely bromide ion, chloride ion, fluoride ion or phosphate group.

20. The method according to claim 19, wherein X is bromide ion.

21. The method according to claim 19 or claim 20, wherein R is -CH 2 CH 3 .

22. The method according to claim 19 or claim 20, wherein the base material is polyvinyl chloride, chlorinated polyvinyl chloride, polycarbonate, nylon 6-6, polyethylene terephthalate, polyethylene terephthalate glycol, polybutylene terephthalate, polyether block amide, acrylate, acrylonitrile butadiene styrene, polystyrene, polylactic acid, polyhydroxyalkanoate, polyoxymethylene, low density polyethylene, high density polyethylene, polypropylene, ethylene-vinyl acetate, acrylonitrile styrene acrylate, epoxy resin, silicone, latex or any combination thereof.

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