Lactam compositions and uses

Abstract

The present invention relates to a composition comprising a lactam, a solvent and a film-forming polymer; the present invention also relates to a method of treating a surface to improve the bacterial contamination resistance of the surface; and also to the use of a lactam and a film-forming polymer as previously defined for improved bacterial species inhibition.

Description

[0001] Field of the invention

[0002] The present invention relates to improvements in the field of hygiene, in particular compositions comprising lactams which exhibit improved inhibition of bacterial species. BACKGROUND

[0003] Hygiene, in particular inhibition of bacterial species, is important to consumers.

[0004] Lactams are known to be inhibitors of bacterial species. They can be applied to a surface to inhibit bacterial species.

[0005] It is desirable to improve lactam-containing formulations in their activity to inhibit bacterial species. SUMMARY

[0006] We have found that by formulating a composition comprising a combination of a lactam with a solvent and a film-forming polymer, the resulting formulation exhibits improved inhibition of bacterial species.

[0007] In a first aspect, the present invention relates to a composition comprising:-

[0008] (a) 0.0001 to 5 wt%, preferably 0.0001 to 2.5 wt%, more preferably 0.0001 to 1 wt%, more preferably 0.001 to 1 wt% of a lactam; and

[0009] (b) 0.5 to 95 wt%, preferably 0.5 to 90 wt%, more preferably 0.5 to 80 wt% of a solvent; and

[0010] (c) 0.1 to 80 wt%, preferably 0.25 to 40 wt%, more preferably 0.5 to 35 wt% of a film-forming polymer;

[0011] wherein the film-forming polymer is selected from polysaccharides, quaternised polysaccharide derivatives, polyvinylpyrrolidone (PVP) and copolymers thereof and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol, and / or mixtures thereof; and

[0012] wherein the lactam is of formula (I) or (II):

[0013] (I) or (II)

[0014] wherein:

[0015] R1and R2are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, aryl and aralkyl; and

[0016] R3is selected from hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, aryl, aralkyl, -C(O)CR6=CH2, and (CH2)n n N + (R a )3, wherein n is an integer from 1 to 16, preferably 2 to 8, and wherein each R a is independently H or C 1-4 alkyl;

[0017] R4and R5are independently selected from hydrogen, aryl, heterocyclyl, heteroaryl, and arylalkyl; and

[0018] R6is selected from hydrogen and methyl; and

[0019] R7is selected from hydrogen and -C(O)CR6=CH2; and

[0020] Preferably at least one of R4and R5is hydrogen.

[0021] Preferably the lactam of formula (I) or (II), R1, R4and R5are H; R3is H or (CH2)n n N + (CH3)3, wherein n is an integer from 1 to 16, preferably 2 to 8; and R2is phenyl or mono-substituted phenyl; preferably R2is selected from phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, and 4-methylphenyl.

[0022] Preferably the lactam is a lactam selected from:

[0023] ; ; ; ;

[0024] ; and .

[0025] More preferably the lactam is selected from:

[0026] , and / or

[0027] Most preferably the lactam is:

[0028] 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one

[0029] Preferably the lactam is delivered from a water-based composition, preferably comprising 0.1 to 99 wt%, preferably 0.5 to 98 wt%, more preferably 1 to 98 wt% water.

[0030] The solvent is preferably selected from the group consisting of: an alcohol; an acetoacetate derivative; a lactate derivative; and a solvent having a dielectric constant of 15 or more, preferably the solvent is selected from the group consisting of: an alcohol, an acetoacetate derivative; and a lactate derivative; more preferably the solvent is selected from the group consisting of: an acetoacetate derivative and a lactate derivative.

[0031] Preferred examples of solvents are: an alcohol, preferably a C1-C4 alcohol, more preferably ethanol; a lactate derivative, preferably ethyl lactate and / or butyl lactate; an acetoacetate derivative, preferably 2-methyltetrahydrofuran, ethyl acetoacetate and / or ethyl acetoacetate glycerol ketal (LGK); and a solvent having a dielectric constant of 15 or more, preferably dimethyl sulfoxide (DMSO).

[0032] Preferably the solvent is selected from the group consisting of: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl acetoacetate and ethyl acetoacetate glycerol ketal (LGK), or mixtures thereof.

[0033] Preferably the solvent is selected from the group consisting of: an acetoacetate derivative; and a lactate derivative.

[0034] Even more preferably the solvent is selected from the group consisting of: ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl acetoacetate and ethyl acetoacetate glycerol ketal (LGK), or mixtures thereof.

[0035] Most preferably the solvent is selected from the group consisting of: 2-methyltetrahydrofuran, ethyl acetoacetate and ethyl acetoacetate glycerol ketal (LGK), or mixtures thereof.

[0036] The solvent is present at a level of 0.5 to 95 wt%, preferably 0.5 to 90 wt%, more preferably 0.5 to 80 wt%. The solvent can be present at a minimum level of 0.5 wt%, 0.75 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or even 5 wt%. The solvent can be present at a maximum level of 95 wt%, 90 wt%, 85 wt%, 80 wt%, 70 wt%, 60 wt%, 50 wt%, 40 wt%, 30 wt%, 25 wt%, 20 wt% or even 10 wt%. Any higher level of solvent is intended to be combinable with any lower level of solvent.

[0037] Preferred natural polymers are polysaccharides such as xanthan gum and hydroxypropyl methylcellulose (HPMC) and quaternised polysaccharide derivative polymers such as Celquat. Preferred synthetic polymers include polyvinylpyrrolidone (PVP) and copolymers thereof, polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol.

[0038] More preferred film forming polymers are polysaccharides, quaternized polysaccharide derivatives, polyvinylpyrrolidone (PVP) and copolymers thereof, and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol.

[0039] Most preferred film forming polymers are quaternized polysaccharide derivatives, polyvinylpyrrolidone (PVP) and copolymers thereof, and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol.

[0040] Preferably, the composition comprises one or more surfactants. The surfactant can be present at a level of 0.25 to 25 wt.%, preferably 0.25 to 20 wt.%, more preferably 0.25 to 15 wt.%, even more preferably 0.25 to 10 wt.% or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.

[0041] The surfactant can be present at a level of 0.25 to 25 wt.%, preferably 0.25 to 20 wt.%, more preferably 0.25 to 15 wt.%, even more preferably 0.25 to 10 wt.% or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.

[0042] The surfactant is preferably selected from anionic, non-ionic, cationic and / or amphoteric surfactants. Preferred surfactants are non-ionic surfactants.

[0043] In a second aspect, the present application relates to a non-therapeutic surface treatment method for improving the resistance of a surface to bacterial contamination by treatment with a composition according to the first aspect of the present application.

[0044] Preferably, the surface to be treated is selected from plastics, metals, wood, polymers, paper, fabrics and / or wipes.

[0045] Preferably, in the method, the lactam is selected from:

[0046] , and / or ; preferably .

[0047] In a third aspect, the present application further relates to the use of a combination of a lactam and a film forming polymer for improved inhibition of bacterial species.

[0048] wherein the film forming polymer is selected from polysaccharides, quaternized polysaccharide derivatives, polyvinylpyrrolidone (PVP) and copolymers thereof, and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol, and / or mixtures thereof; and

[0049] wherein the lactam is of formula (I) or (II):

[0050] (I) or (II)

[0051] wherein:

[0052] R1and R2are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, aryl, and aralkyl; and

[0053] R3is selected from the group consisting of hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, aryl, aralkyl, -C(O)CR6=CH2, and (CH2) n N + (R a )3, wherein n is an integer from 1 to 16, preferably 2 to 8, and wherein each R a is independently H or C 1-4 alkyl;

[0054] R4and R5are independently selected from the group consisting of hydrogen, aryl, heterocyclyl, heteroaryl, and arylalkyl; and

[0055] R6is selected from the group consisting of hydrogen and methyl; and

[0056] R7is selected from the group consisting of hydrogen and -C(O)CR6=CH2; and

[0057] Preferably, at least one of R4and R5is hydrogen.

[0058] Preferably, in use, the lactam is selected from:

[0059] , and / or ; preferably .

[0060] Specific embodiments

[0061] As used herein, the indefinite articles "a" or "an" and their corresponding plural forms "at least one" and "one or more" mean "one or more than one" unless otherwise indicated.

[0062] It is to be understood that all preferred are combinable unless otherwise explicitly stated.

[0063] Lactam

[0064] A lactam is a cyclic amide. Preferred lactams are gamma-lactams having 5 ring atoms.

[0065] The lactam has the formula (I) or (II):

[0066] (I) or (II)

[0067] wherein:

[0068] R1and R2are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, aryl, and aralkyl; and

[0069] R3is selected from hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, aryl, aralkyl, -C(O)CR6=CH2, and (CH2) n N + (R a )3, wherein n is an integer from 1 to 16, preferably 2 to 8, and wherein each R a is independently H or C 1-4 alkyl;

[0070] R4and R5are independently selected from hydrogen, aryl, heterocyclyl, heteroaryl, and arylalkyl; and

[0071] R6is selected from hydrogen and methyl; and

[0072] R7is selected from hydrogen and -C(O)CR6=CH2; and

[0073] Preferably, at least one of R4and R5is hydrogen.

[0074] It will be understood that where appropriate, groups can be optionally substituted. Optional substituents can include halogen, C 1-4 alkyl, C 1-4 haloalkyl (e.g., CF3), and C 1-4 alkoxy.

[0075] Alkyl may, for example, be C 1-12 alkyl, for example C 1-6 alkyl. Aryl may, for example, be C 6-10 aryl, for example phenyl.

[0076] Preferably, at least one of R1and R2is selected from heterocyclyl, heteroaryl, aryl, and arylalkyl.

[0077] Preferably, R1is hydrogen. Preferably, R3is hydrogen or (CH2) n N + (R a )3, wherein n is an integer from 1 to 16, preferably 2 to 8, and wherein each R a is independently H or C 1-4 alkyl, more preferably R aR4is CH3; preferably, R4is hydrogen. Preferably, R5is hydrogen. Preferably, R6is hydrogen. Preferably, R7is hydrogen. Preferably, R2is aryl or aralkyl. More preferably, R2is phenyl or substituted phenyl, for example mono-substituted phenyl. The substitution can be at the ortho, meta or para position. Preferred substituents include halogen and methyl. For example, but not limited to, R2may be selected from phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl and 4-methylphenyl.

[0078] More preferably in the lactam of formula (I) or (II), R1, R4and R5are H; R3is H or (CH2) n N + (CH3)3, wherein n is an integer from 1 to 16, preferably 2 to 8; and R2is phenyl or mono-substituted phenyl; preferably R2is selected from phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl and 4-methylphenyl.

[0079] Even more preferably the lactam has formula (I), R1, R4and R5are H; R3is H or (CH2) n N + (CH3)3, wherein n is an integer from 1 to 16, preferably 2 to 8; and R2is phenyl or mono-substituted phenyl; preferably R2is selected from phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl and 4-methylphenyl.

[0080] In the case of cationic in nature, it can be used as is or suitably with a counterion (e.g. iodide).

[0081] Preferably the lactam is a lactam selected from:

[0082] ; ; ; ; ; and .

[0083] More preferably the lactam is selected from:

[0084] , and / or

[0085] Most preferably the lactam is:

[0086] 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one.

[0087] In the case of cationic lactam properties, it can be used as is or suitably with a counterion (e.g. iodide).

[0088] Level of lactam

[0089] Preferably the lactam is present at a level of 0.0001 to 2.5 wt%, preferably 0.0001 to 1 wt%. For example, the lactam can suitably be present at a level of 0.001 to 1 wt% or even 0.01 to 1 wt% or even 0.01 to 0.5 wt%.

[0090] Composition

[0091] Preferably the lactam is delivered from a water-based composition, which preferably comprises 0.1 to 99 wt%, preferably 0.5 to 98 wt%, more preferably 1 to 98 wt% water.

[0092] Alternatively, preferably the lactam is delivered from a water-based composition, which preferably comprises 0.1 to 98 wt%, preferably 0.5 to 80 wt%, more preferably 1 to 75 wt% water. The composition can comprise water in any amount ranging from a lower amount of water of 0.1, 0.5, 1, 1.5, 2 or even 5 wt% up to 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98 or even 99 wt% water. In a preferred embodiment, preferred levels of water include 60 to 98 wt%, preferably 70 to 98 wt%, more preferably 80 to 98 wt%, even more preferably 85 to 98 wt% or even 90 to 98 wt%.

[0093] Solvent

[0094] The composition comprises a solvent, which is preferably selected from the group consisting of: an alcohol; a levulinic ester derivative; a lactate ester derivative; and a solvent having a dielectric constant of 15 or more.

[0095] Examples of alcohol solvents include glycols, such as propylene glycol and polyethylene glycol; methanol, ethanol, propanol, butanol, isopropanol, benzyl alcohol, lanolin alcohol and fatty alcohols. Examples of other solvents include ethyl acetate, oleic acid and isopropyl myristate.

[0096] Preferred examples of solvents are: an alcohol, preferably a C1-C4 alcohol, more preferably ethanol; a lactate ester derivative, preferably ethyl lactate and / or butyl lactate; a levulinic ester derivative, preferably 2-methyltetrahydrofuran, ethyl levulinate and / or ethyl levulinate glycerol ketal (LGK); and a solvent having a dielectric constant of 15 or more, preferably dimethyl sulfoxide (DMSO).

[0097] Preferably, the solvent is selected from the group consisting of: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran (2Me-THF), ethyl levulinate and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.

[0098] Preferably the solvent is selected from the group consisting of: levulinate derivatives; and lactate derivatives.

[0099] Most preferably the solvent is selected from the group consisting of: 2-methyltetrahydrofuran, ethyl levulinate and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.

[0100] 2Me-THF, ethyl levulinate and LGK can be classified as levulinate derivatives (or levulinate derivatives). Levulinic acid can be derived from lignocellulosic biomass (i.e. corn husks, sugar cane bagasse etc.) and can be converted in a cyclization reaction to 2Me-THF, in a one-step esterification to ethyl levulinate, and in a two-step (esterification and ketal synthesis) to LGK.

[0101] Ethyl lactate and butyl lactate are lactate derivatives. Lactic acid is a by-product of fermentation which is then reacted with ethanol or butanol to produce ethyl lactate and butyl lactate.

[0102] Most preferably the solvent is selected from the group consisting of: 2-methyltetrahydrofuran, ethyl levulinate and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.

[0103] The solvent is present at a level of 0.5 to 95 wt%, preferably 0.5 to 90 wt%, more preferably 0.5 to 80 wt%. The solvent can be present at a minimum level of 0.5 wt%, 0.75 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or even 5 wt%. The solvent can be present at a maximum level of 95 wt%, 90 wt%, 85 wt%, 80 wt%, 70 wt%, 60 wt%, 50 wt%, 40 wt%, 30 wt%, 25 wt%, 20 wt% or even 10 wt%. Any higher level of solvent is intended to be combinable with any lower level of solvent.

[0104] The solvent can be present at a level of 1 to 80 wt%, preferably 1 to 50 wt%, more preferably 1 to 40 wt%. The solvent level can also be 1 to 30 wt%, 1 to 20 wt% or even 1 to 15 wt% or 1 to 10 wt%.

[0105] Film-forming polymer

[0106] The composition comprises a film-forming polymer.

[0107] The film-forming polymer is a substance that is capable of forming a film when applied to a solid surface.

[0108] The most commonly used materials as film-forming substances include reactive (irreversible) oligomers such as alkyd resins, phenolic resins, epoxy resins and polyester resins, and relatively low molecular weight non-reactive (reversible) polymers, including chlorinated polyvinyl chloride resins, polyacrylates and nitrocellulose. Natural film-forming materials include, in particular, vegetable oils and rosin derivatives.

[0109] Film-forming materials are most commonly used in the form of solutions and dispersions in organic solvents; they can also be aqueous solutions or dispersions and are applied by various methods known to those skilled in the art. Non-reactive film-forming materials form films as a result of evaporation of the solvent; film formation of reactive materials is accompanied by a chemical transformation.

[0110] The general properties of film-forming materials can include (1) good wetting of the surface to be protected; (2) firm binding of any particles in the film; (3) rapid drying in thin layers (a few minutes to 24 hours at 15°C to 200°C), in which a strong moisture- and air-impermeable film is formed that can withstand the action of external media for a prolonged period; and (4) good adhesion to the surface being protected. In many cases, these properties are obtained by combining two or more film-forming materials and by introducing plasticizers.

[0111] A range of useful film-forming polymers include:

[0112] Hydroxy (propyl methyl) cellulose (HPMC) commercially available under the trade name Methocel TM commercially available; (including grades E4M; E15; E50M; K4M)

[0113] Ethyl cellulose (EC) commercially available under the trade name Ethocel TM commercially available, including grades 100, 200, 300

[0114] Poly (vinyl pyrrolidine) (PVP) commercially available under the trade name Kolidon® 30; Kolidon® 64; PVP K-30

[0115] Poly (vinyl alcohol) (PVA) commercially available under the trade name Selvol™ 205; 503; 805; 823; 840; Mowiol™ 18-88; 5-88

[0116] Methacrylic acid copolymers commercially available under the trade name Eudragit® L-30; D-55; E; RS 100, RL 100, NE, RS30D, S 100

[0117] Chitosan polysaccharide commercially available from KitoZyme

[0118] Acrylates, commercially available under the trade name Avalure™ 120 PF; AC 118; UR 424

[0119] Polydimethylsiloxanes, commercially available under the trade name Dowsil™ 200; 1418; 1515

[0120] Poly(ethylene oxide), commercially available under the trade name Polyox™ WSR N10; N 750

[0121] Preferred molecular weight ranges for the film-forming polymer are 3,000-800,000 Daltons.

[0122] Preferred film-forming polymers are PVA, vinyl alcohol / vinyl acetate copolymer, PVP, polysaccharides, and mixtures of any of the foregoing.

[0123] The film-forming polymer can be further modified with various agents commonly used in the art, such as plasticizers, surfactants, antifoams, defoamers, biocides, and the like. Suitable plasticizers include glycerol, polyethylene glycol, trimethylolpropane, polyglycerol, alkanediols such as diethylene glycol, triethylene glycol, tetra(ethylene glycol), and 1,3-butanediol; alkanolamines such as triethanolamine; alkanolamine acetates such as triethanolamine acetate; and alkanol acetamides such as ethanol acetamide. The plasticizer can be used in amounts conventionally used in the film-forming art to provide sufficient plasticization, for example, about 20-40% by weight of the film-forming polymer.

[0124] Particularly preferred film-forming polymers include natural film-forming polymers and synthetic film-forming polymers. Preferred natural polymers are polysaccharides, such as xanthan gum and hydroxypropylmethylcellulose (HPMC) and quaternized polysaccharide derivative polymers, such as Celquat. Preferred synthetic polymers include polyvinylpyrrolidone (PVP) and copolymers thereof, polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol.

[0125] The film-forming polymer is a polysaccharide, a quaternized polysaccharide derivative, polyvinylpyrrolidone (PVP) and copolymers thereof, and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol.

[0126] Most preferred film-forming polymers are selected from the group consisting of quaternized polysaccharide derivatives, polyvinylpyrrolidone (PVP) and copolymers thereof, and polyvinyl alcohol (PVA) and copolymers of polyvinyl alcohol, and / or mixtures thereof; and

[0127] The level of film-forming polymer is 0.1 to 80 wt%, preferably 0.25 to 40 wt%, more preferably 0.5 to 35 wt%. Further preferred weight ranges for the film-forming polymer include 0.5 to 20 wt%, 0.5 to 15 wt%, or even 0.5 to 10 wt%.

[0128] Surfactant

[0129] Preferably, the composition comprises one or more surfactants. The surfactant can be present at a level of 0.25 to 25 wt.%, preferably 0.25 to 20 wt.%, more preferably 0.25 to 15 wt.%, even more preferably 0.25 to 10 wt.% or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.

[0130] The surfactant is preferably selected from anionic, non-ionic, cationic and / or amphoteric surfactants. Preferred surfactants are non-ionic surfactants.

[0131] Buffer

[0132] The composition can preferably comprise a buffering agent to maintain any resulting composition within a specified pH range. The buffering system can be any of the commonly used buffering systems known in the art. These can for example include citrate, acetate, phosphate and / or carbonate buffers or mixtures thereof.

[0133] Other ingredients

[0134] The composition can comprise other ingredients such as surfactants, chelating agents, thickening agents, pH adjusting agents and perfumes.

[0135] The following non-limiting examples will further describe the present application.

[0136] Examples

[0137] Example 1 - Preparation of preferred lactam examples

[0138] Preparation of 4-(4-chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one

[0139]

[0140] Combine 1-(4-chlorophenyl)propan-2-one (40.00 g, 34.75 mL, 237.2 mmol), glyoxylic acid monohydrate (32.75 g, 355.8 mmol), and phosphoric acid (69.74 g, 711.7 mmol) at room temperature, then heat to 85 °C overnight. After cooling to room temperature, pour the mixture into a mixture of water (500 mL) and ethyl acetate (500 mL). Separate the layers and extract the aqueous phase with ethyl acetate (500 mL). Wash the combined organic layers with a 1 : 1 mixture of water and brine (2 x 500 mL), dry (MgS04), and concentrate under reduced pressure to give 4-(4-chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one (66.00 g, >100% yield) as a brown oil. This material is used without further purification in the next step.

[0141] Preparation of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1 H-pyrrol-2(5H)-one

[0142]

[0143] Dissolve 4-(4-chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one (66.00 g, 293.8 mmol) in thionyl chloride (196.8 g, 120.0 mL, 1654 mmol) and heat at 40 °C for 1 h, then at 80 °C for 2 h. Concentrate the mixture under reduced pressure and azeotrope with 2-methyltetrahydrofuran (200 mL). Dilute the residue with 2-methyltetrahydrofuran (160 mL) and add the solution to a cooled, stirred mixture of 28% aqueous ammonia (180 mL) in 2-methyltetrahydrofuran (20 mL) at 0 °C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and ethyl acetate (200 mL) and separate the layers. Extract the aqueous phase with ethyl acetate (200 mL), dry (MgS04) the combined organic extracts and concentrate under reduced pressure. Purify by dry flash column chromatography (5-60% ethyl acetate in heptane) to give 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1H-pyrrol-2(5H)-one (23.18 g, 35% yield) as a cream colored solid.

[0144] 1 H NMR (400 MHz, d6-DMSO) 8.55 (brs, 1H), 7.88-7.83 (m, 2H), 7.51-7.46(m, 2H), 6.37 (d, 1H), 6.32 (s, 1H), 1.45 (s, 3H)

[0145] UPLC (basic) 1.51 / 5.00 min, 100% purity, M+H + 224

[0146] MP 177 ℃

[0147] Preparation of 4-(4-chlorophenyl)-5-methylene-1 H-pyrrol-2(5H)-one

[0148]

[0149] To a cooled solution of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1 H-pyrrol-2(5H)-one (10.00 g, 44.51 mmol) in dry dichloromethane (100 mL) at 0 °C was added a solution of boron trifluoride etherate (8.213 g, 7.142 mL, 57.87 mmol) in dry dichloromethane (45 mL) over 15 minutes. The mixture was stirred at 0 °C then slowly allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with ice water (100 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers washed with a 1 :1 mixture of water and saturated aqueous sodium bicarbonate solution (100 mL), dried (MgS04) and filtered. Silica was added to the filtrate and the mixture stirred for 10 minutes then filtered through a plug of silica, washing well with dichloromethane then a 3:1 mixture of dichloromethane:diethyl ether. The fractions containing the desired product were combined and concentrated under reduced pressure. A precipitate formed upon concentration, which was collected by filtration, washing with diethyl ether to give 4-(4-chlorophenyl)-5-methylene-1 H-pyrrol-2(5H)-one (5.25 g, 57% yield) as a cream coloured solid.

[0150] 1 H NMR (400 MHz, d6-DMSO) 10.10 (s, 1H), 7.54-7.47 (m, 4H), 6.36 (s,1H), 5.04 (t, 1H), 4.85 (s, 1H)

[0151] UPLC (basic) 1.87 / 5.00 min, 100% purity, M+H + 206

[0152] MP 182 ℃

[0153] Preparation of 5-hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one

[0154]

[0155] Combine 1-(p-tolyl)propan-2-one (25.00 g, 24.00 mL, 168.7 mmol), glyoxylic acid monohydrate (23.29 g, 253.0 mmol), and phosphoric acid (49.60 g, 506.1 mmol) at room temperature, then heat at 90 °C overnight. After cooling to room temperature, pour the mixture into a stirred mixture of ice water (400 mL) and ethyl acetate (400 mL). Separate the layers, wash the organic phase with water (100 mL), dry (MgS04), and concentrate under reduced pressure. Azeotrope the mixture with 2-methyltetrahydrofuran (50 mL) to give 5-hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one (16.50 g, 48% yield) as a brown solid.

[0156] 1 H NMR (400 MHz, d6-DMSO) 7.86 (s, 1H), 7.75 (d, 2H), 7.28 (d, 2H),6.59 (s, 1H), 2.32 (s, 3H), 1.61 (s, 3H)

[0157] Preparation of 5-hydroxy-5-methyl-4-(p-tolyl)-1 H-pyrrol-2(5H)-one

[0158]

[0159] Dissolve 5-hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one (16.50 g, 80.80 mmol) in thionyl chloride (48.06 g, 29.47 mL, 404.0 mmol) and heat at 50 °C for 1 h, then at reflux for 1 h. After cooling to room temperature, concentrate the mixture under reduced pressure and azeotrope with 2-methyltetrahydrofuran (2 x 50 mL). Dilute the residue with 2-methyltetrahydrofuran (60 mL) and add the solution to a cooled, stirred mixture of 28% aqueous ammonia (55 mL, 808.0 mol) in 2-methyltetrahydrofuran (10 mL) at 0 °C. Warm the mixture to room temperature and stir overnight. Remove 1,2-methyltetrahydrofuran under reduced pressure, dilute the residue with water (200 mL) and diethyl ether (100 mL), and stir the mixture at room temperature for 20 min. Collect the solid by filtration and stir in water (100 mL) and diethyl ether (50 mL) at room temperature for 10 min. Collect the solid by filtration, wash with water, diethyl ether, and dry under vacuum at 50 °C to give 5-hydroxy-5-methyl-4-(p-tolyl)-1H-pyrrol-2(5H)-one (10.49 g, 31% yield) as a light beige solid.

[0160] 1H NMR (400 MHz, d6-DMSO) 8.44 (br s, 1H), 7.73 (d, 2H), 7.21 (d, 2H), 6.24 (s, 2H), 2.29 (s, 3H), 1.45 (s, 3H)

[0161] 13 C NMR (400 MHz, d6-DMSO) 170.4 (s, 1C), 161.1 (s, 1C), 139.8 (s, 1C), 129.7 (s, 2C), 128.9 (s, 1C), 128.2 (s, 2C), 119.1 (s, 1C), 87.8 (s, 1C), 26.7 (s, 1C), 21.5 (s, 1C)

[0162] UPLC (basic) 1.41 / 5.00 min, 100% purity, M+H + 204

[0163] MP 178 °C decomposition

[0164] Preparation of 5-methylene-4-(p-tolyl)-1 H-pyrrol-2(5H)-one

[0165]

[0166] To a cooled solution of 5-hydroxy-5-methyl-4-(p-tolyl)-lH-pyrrol-2(5H)-one (8.68 g, 42.7 mmol) in dry dichloromethane (87 mL) at 0 °C was added a solution of boron trifluoride etherate (6.85 g, 5.96 mL, 55.5 mol) in dry dichloromethane (40 mL) over 15 minutes. After 1 hour, the mixture was allowed to slowly warm to room temperature. After a further 3 hours, the reaction was diluted with dichloromethane (50 mL) and ice water (100 mL) and stirred for 10 minutes. The layers were separated and the organic layer washed with water (100 mL), a 1 : 1 mixture of water and saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), the organic layer was filtered through celite, washing with dichloromethane. Any excess water was removed by pipette and the filtrate was then dried (MgS04) and concentrated under reduced pressure to a brown solid. The solid was stirred in hot dichloromethane (120 mL) for 15 minutes, then allowed to cool slowly to room temperature, then to 0 °C. The solid was collected by filtration to give 5-methylene-4-(p-tolyl)-lH-pyrrol-2(5H)-one (3.87 g, 49% yield) as a yellow solid. Silica was added to the filtrate and the mixture stirred for 10 minutes, then filtered through a plug of silica, washing well with dichloromethane, then with a 4: 1 mixture of dichloromethane: ethyl ether. The filtrate was concentrated under reduced pressure to give 5-methylene-4-(p-tolyl)-lH-pyrrol-2(5H)-one (0.58 g, 7%) as a yellow solid. The total yield of 5-methylene-4-(p-tolyl)-lH-pyrrol-2(5H)-one (4.45 g, 56% yield).

[0167] 1H NMR (400 MHz, d6-DMSO) 10.11 (br s, 1H), 7.35 (d, 2H), 7.25 (d, 2H), 6.25 (s, 1H), 5.01 (s, 1H), 4.85 (s, 1H), 2.31 (s, 3H)

[0168] UPLC (basic) 1.83 / 5.00 min, 100% purity, M+H + 186

[0169] MP 200 °C decomposition

[0170] Substances used

[0171] In the following examples, the lactam used is Lactam 488.

[0172] which is 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one and has the structure shown below:

[0173] which is 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one and has the structure shown below:

[0173] which is 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one and has the structure shown below:

[0173]

[0174] Solvent used: butyl lactate (BL) or ethyl levulinate glycerol ketal (LGK)

[0175] Film forming polymer used: Celquat (quaternized polysaccharide derivative polymer), HPMC hydroxypropyl methylcellulose (substituted natural polysaccharide film forming polymer), xanthan gum (natural polysaccharide film forming polymer)

[0176] Example 2

[0177] This example shows the effect of film forming polymer in combination with lactam.

[0178] Method description

[0179] The solvent, butyl lactate (BL) or ethyl levulinate glycerol ketal (LGK) was used to dissolve lactam 488 to form a 5 mg / ml solution. This was added to an aqueous base formulation containing 2 wt% non-ionic surfactant and 4 wt% citric acid. The total amount of lactam in the composition was 0.01 wt%. The amount of solvent was 2 wt%; the amount of film forming polymer (if present) was 0.5 wt% and the remainder to 100 wt% was water. For comparative examples of film forming polymers alone, the base formulation described above included the polymer but not the lactam.

[0180] The inhibitory activity of dissolved lactam against various microorganisms (Pseudomonas aeruginosa and Proteus mirabilis) was tested. Comparative examples of base formulations with film forming polymers and selected solvents were also tested for inhibitory effect. These comparative examples were found not to inhibit bacterial regrowth.

[0181] The samples were dried neat in the wells of a microtitre plate, then bacterial suspension was added for 1 hour. Unattached cells were removed and culture medium was added. The remaining cells were then grown overnight. Inhibition was determined by the frequency of samples (from 18 replicates) in which no further growth was detected.

[0182] P. aeruginosa - film-forming polymer alone

[0183]

[0184] P. aeruginosa - lactam alone

[0185]

[0186] P. mirabilis - film-forming polymer alone

[0187]

[0188] P. mirabilis - lactam alone

[0189]

[0190] Certain combinations of lactams and film forming polymers as prepared above were tested and the combinations of lactams with film forming polymers provided statistically significant improvements compared to the polymer alone or the lactam alone or the additive effect of the polymer + lactam alone.

[0191] P. aeruginosa

[0192]

[0193] P. mirabilis

[0194]

[0195] The results clearly show that the inhibitory effect of the lactams on the regrowth of bacteria is improved by the addition of the film forming polymer. This is demonstrated with various film forming polymers and different solvents.

[0196] These results are particularly surprising since the inhibitory effect was observed even in the absence of rinsing the surface prior to the microbial challenge.

Claims

1. A composition comprising: (a) 0.0001 to 5% by weight of lactam; and (b) 0.5 to 95% by weight of a solvent, wherein the solvent is selected from: ethyl lactate, butyl lactate, ethyl levulinate, ethyl levulinate glycerol ketal (LGK), or mixtures thereof; (c) 0.1 to 80% by weight of a film-forming polymer, wherein the film-forming polymer is selected from xanthan gum, hydroxypropyl methylcellulose, Celquat, or mixtures thereof; and The lactam mentioned above is selected from the following lactams: and / or .

2. The composition according to claim 1, wherein the composition comprises 0.0001 to 2.5% by weight of lactam.

3. The composition according to claim 1, wherein the composition comprises 0.0001 to 1% by weight of lactam.

4. The composition according to claim 1, wherein the composition comprises 0.001 to 1% by weight of lactam.

5. The composition according to claim 1, wherein the composition comprises 0.5 to 90% by weight of a solvent.

6. The composition according to claim 1, wherein the composition comprises 0.5 to 80% by weight of a solvent.

7. The composition of claim 1, wherein the composition comprises 0.25 to 40% by weight of a film-forming polymer.

8. The composition of claim 1, wherein the composition comprises 0.5 to 35% by weight of a film-forming polymer.

9. The composition according to any one of claims 1-8, wherein the lactam is 。 10. The composition according to any one of claims 1-8, wherein the lactam is a water-based composition.

11. The composition of claim 10, wherein the water-based composition comprises 0.1% by weight to 99% by weight of water.

12. The composition of claim 10, wherein the water-based composition comprises 0.5% by weight to 98% by weight of water.

13. The composition of claim 10, wherein the water-based composition comprises 1% to 98% by weight water.

14. The composition according to any one of claims 1-8, wherein the solvent is selected from butyl lactate, ethyl levulinate glycerol ketal (LGK), or a mixture thereof.

15. A non-therapeutic surface treatment method for improving the resistance of a surface to bacterial contamination by treating it with the composition according to any one of claims 1 to 14.

16. The method of claim 15, wherein the surface to be treated is selected from plastics, metals, wood, polymers, paper, fabrics and / or wiping materials.

17. The method according to claim 15 or 16, wherein the lactam is 。 18. Use of combinations of lactams and film-forming polymers in the preparation of compositions for improving inhibition of bacterial species. The film-forming polymer is selected from xanthan gum, hydroxypropyl methylcellulose, Celquat, or mixtures thereof; and The lactam mentioned above is selected from the following lactams: and / or .

19. The use according to claim 18, wherein the lactam is 。

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