WO1996028459A1

WO1996028459A1 - Anti-microbial compositions

Info

Publication number: WO1996028459A1
Application number: PCT/GB1996/000610
Authority: WO
Inventors: Colin Townsley; Rolf Sköld
Original assignee: Castrol Limited; Akzo Nobel Surface Chemistry Ab
Priority date: 1995-03-15
Filing date: 1996-03-14
Publication date: 1996-09-19
Also published as: GB9505183D0; AU5113196A

Abstract

Compositions of use as water-based alkaline industrial fluids contain a sugar amine of formula (1), wherein A represents a monosaccharide, disaccharide, trisaccharide or polysaccharide group, and wherein R1 and R2 each represents hydrogen or an optionally substituted alkyl or aryl group having from 1 to 24 C atoms.

Description

ANTI-MICROBIAL COMPOSITIONS

This invention relates to anti-microbial

compositions and particularly to compositions

incorporating amino derivatives of sugar compounds, hereafter referred to as sugar amines.

It is known to use compositions containing sugar amines for uses such as in oral hygiene compositions, see, for example, EP-A-0550099 and EP-A-057323, and for the acceleration of wound healing, see, for example, US-A-4772591.

In such uses, the sugar portion of the sugar amine is used to "target" particular types of bacteria, e.g. streptococcus mutans, Haemophilus and the like, i.e. Gram positive bacteria according to the Gram test - Gram C 1884/2/185/FORTSCHR-MED. Sugar amines have also shown efficacy as plant protection agents, see GB-A-866734 and EP-A-0119539.

While the sugar amines are well suited to such uses, in that they are easily biodegradable, they are less well suited for application where elevated temperatures may be employed and/ or there is a need for their formulation into a composition of long storage life. Thus

decomposition problems may lead to the release of

secondary amines with consequent unwanted formation of nitrosamines. The release of free sugars may result in a nutrient source encouraging unwanted build up of

microorganisms. However we have now found that particular classes of sugar amines have particular applicability in industrial fluid formulations when used as aqueous alkaline

compositions where they may also be effectively used to treat Gram negative bacteria, Gram positive spore-forming bacteria, filamentous fungi and yeasts.

Accordingly, in one aspect, the invention provides the use as a water based alkaline industrial fluid of a composition containing a sugar amine of the formula:

wherein A represents a monosaccharide, disaccharide, trisaccharide or polysaccharide group

and wherein R₁ and R₂ each represents hydrogen or an optionally substituted alkyl or aryl group having from 1 to 24 C atoms.

Preferably R₁ and/ or R₂ represents an optionally substituted alkyl or aryl group having from 1 to 24 C atoms. Preferably one of R₁ and R₂ is hydrogen. The hydrolytic decomposition of such a secondary sugar amine will then result in the release of nitrosamine-inhibiting primary amine.

The alkyl or aryl groups may have substituted groups, e.g. substituted alkyl, alkenyl or aralkyl groups and they may contain heteroatoms, e.g. nitrogen or oxygen.

Thus, e.g., R₁ may be hydrogen or the group R'(Y1)_y1(X₁)_x1

in which R' is a hydrocarbon group or an acyl group containing 3-18, preferably 4-12 carbon atoms; X₁ is a divalent group selected from the groups consisting of

; -OC₃H₆-; -OC₂H₄OC₃H₆-; and -(NHC_n1H_2n1)_m1-

where m_τ is a number from 0 to 3 and n₁ is a number from 2 to 3; X₁ is 0 or 1; Y₁ is an oxyalkylene group having from 2 to 4 carbon atoms; y₁ is a number from 0 to

3 with the proviso that when X₁ is or -(NHC_n1H_2n1)m₁-

and x₁ is 1, then y₁ is zero;

R₂ may be a group R''(Y₂)_y2(X₂)_x2

in which R'' is a hydrocarbon group, a hydroxylated alkyl group or an acyl group containing 1-12, preferably 1-4 carbon atoms, or hydrogen; X₂ is a divalent group selected from the group

consisting of ; -OC₃H₆-;

and -(NHC_n2H_2n2)m₂-.

where m₂ is a number from 0 to 3 and n₂ is a number from 2 to 3; x₂ is 0 or 1; Y₂ is an oxyalkylene group having from 2 to 4 carbon atoms; y₂ is a number from 0 to

3 with the proviso that when X₂ is - or

-(NHC_n2H_2n2)m₂- and x₂ is 1, then y₂ is zero.

The saccharide group is preferably selected from amongst galactose, d-N-acetylgalactose, L-rhamnose, D-fucose, glucose, lactose, maltose, melibiose, cellobiose and maltotriose but it will be appreciated that many other saccharides may be employed. Mixtures of the amine sugars may, if desired, be employed and an amine sugar may be used in admixture with a hydrogenated, ring-opened amine sugar.

In one preferred embodiment the sugar amine has the following structural formula:

Thus in this embodiment the sugar amine is an alkyllactosylamine or aryllactosylamine.

In another preferred embodiment the sugar amine has the following structural formula:

Thus in this embodiment the sugar amine is an alkylmaltosylamine or arylmaltosylamine.

In a further preferred embodiment the sugar amine has the following structural formula:

Thus in this embodiment the sugar amine is an alkylmelibiosylamine or arylmelibiosylamine .

Thus in this embodiment the sugar amine is an alkylglucosylamine or arylglucosylamine (but it will be appreciated that an alkylgalactosylamine or

arylgalactosylamine could equally be used).

Thus in this embodiment the sugar amine is an alkylmaltotriosamine or an arylmaltotriosamine.

Organic salts of these materials, e.g. acetates and tartrates, as well as inorganic salts, e.g. chlorides and sulphates, can also be prepared.

Quaternary ammonium salts of these sugar amine derivatives can also be prepared and could include for example alkyl iodides and bromides. Specific preferred examples of the above embodiments include:

Similar alkyl lactosylamines include N-cyclohexyl, isopropyl, tertiary butyl, secondary butyl, isobutyl and N-methyl derivatives.

Moreover, as indicated above, tertiary sugar amines may be used, e.g. N-methyl or N-hydroxyalkyl

alkyllactosylamines.

In another aspect the invention provides as a novel compound with excellent antimicrobial effects a sugar amine of the formula:

wherein A represents a mono-, di-, tri- or higher polysaccharide group, wherein R₁ is the group R'(Y₁)_y1X₁ in which R' is a hydrocarbon group or an acyl group containing 3 to 18 C atoms;

X₁ is a divalent group selected from the groups consisting of

; -OC₃H₆-; -OC₂H₄-; -OC₂H₄OC₃H₆-; and

-(NHC_n1H_2n1)m₁- where m₁ is a number from 0 to 3 and n₁ is a number from 2 to 3; and Y₁ is an oxyalkylene group having from 2 to 4 C atoms, and y ₁ is a number from 0 to 3, with the proviso that when X ₁ is or - (NHC_n1H_2n1)m₁-, then y₁ is zero;

and; wherein R₂ is hydrogen or an optionally substituted alkyl or aryl group having from 1-24, preferably from 1- 12 and most preferably from 1-4 carbon atoms.

Preferably R₁ is R'O(CH₂)_n- where n = 2 or 3; or R'(OCH₂)_nCH(OH)CH₂- where n= 0 or 1; R'OCH₂CH₂OCH₂CH₂CH₂-; or R'CH(OH)CH₂-. Preferably R₂ is a group R''(Y₂)_y2(X₂)_x2 in which R'' is a hydrocarbon group, a hydroxylated alkyl group, or an acyl group containing 1-12, preferably 1-4 carbon atoms, or hydrogen; X₂ is a divalent group selected from the group consisting of

; -OC₃H₆-; -OC₂H₄-; and -(NHC_n2H_2n2)-_m2.

3 with the proviso that when X₂ is or

-(NHC_n2H_2n2)m₂- and x₂ is 1, then y₂ is zero. Most

preferably R₂ is hydrogen.

Since the novel compounds comprise, in addition to the hydrophilic saccharide group and the hydrophobic groups R' and where appropriate R'', one or more polar groups, it is possible to adjust the HLB-balance and thereby the solubility of the compounds to suit the aqueous composition where it is intended to be used.

Especially, in a two-phase composition it is essential that the sugar amine is not completely dissolved in the hydrophobic phase, but at least an effective amount is present in the aqueous phase. Furthermore, the novel compounds have shown unexpected low irritating ability, when brought into contact with human beings.

The sugar amines to be used in the present invention may be synthesised by conventional methods of amine condensation with the desired sugar to form the ring-closed structures.

Although the examples given above show the amine linkage at the anomeric carbon position, this is not essential. It could be at any of the other carbon

(hydroxyl) positions around the ring of the sugar (or amino sugar) component and may also be at the primary alkoxy position attached to the ring. For example, amine derivatives at the primary hydroxy position can occur by reaction with epichlorohydrin followed by amine with suitable hydroxy group protection, and subsequent

deprotection, (e.g. diacetone glucose). Using protection, deprotection synthetic methods (known to those in this art), yields compounds in which the amine group can be linked to any position of the ring structure.

The compositions of the invention are water-based alkaline industrial fluids such as metal working fluids, hydraulic fluids, coolants and cleaning and sterilising fluids. Such fluids undergo, after some time of use or storage, undesirable changes which can be related to the fact that the components included in the fluids are degraded by micro-organisms. This microbial degradation can considerably reduce the life and performance of the fluids. For example, the microbial degradation of the fluids may destroy the corrosion-inhibiting and the lubricating properties of the fluid. It is, therefore, of great importance economically that microbial degradation of fluids of this type be minimised. As indicated above, we have now found that use of compositions of the present invention is particularly effective in preventing the harmful effects of both Gram positive and Gram negative bacteria and filamentous fungi and yeasts in industrial spoilage applications.

The composition of the invention, particularly when it is to be used as a metal-working fluid, preferably has a pH of at least 8, especially between 8 and 10 and preferably contains the sugar amine in an amount of from .001 to 0.5% by weight, preferably from 0.025 to 0.1% by weight. In addition to the sugar amine the fluid will normally contain lubricants and corrosion inhibitors and other materials known to the art such as surface active agents and buffering agents.

The corrosion inhibitors are normally present in an amount of 0.1 to 10% by weight, preferably 0.2 to 3% by weight. They may be for example, amino compounds, e.g. mono-, di- or tri-ethanolamines; alkali metal hydroxides; triazole or thiadiazole compounds; monocarboxylic acids having 6 to 11 carbon atoms, e.g. heptanoic acid or isononanoic acid; dicarboxylic acids, preferably having 6 to 12 carbon atoms, e.g. azelaic acid or sebacic acid; alkyl or aryl-sulphonamido-carboxylic acids; inorganic acids, e.g. boric acid; and conventional reaction products between boric acid and/ or carboxylic acids with organic compounds, e.g. alkanolamines. Examples of other corrosion inhibitors are also the amine compounds

described in European patent publication no. 180,561.

Suitable lubricants for incorporation in the fluid composition may, for example, be selected from the group consisting of oils, esters or amides of mono- or

dicarboxylic acids having at least 10 carbon atoms in the acyl groups; monocarboxylic acids having 12 or more carbon atoms; dicarboxylic acids having more than 12 carbon atoms; organic phosphate esters containing one or two hydrocarbon groups having 6 to 18 carbon atoms;

nonionic alkylene oxide adducts having a molecular weight above 400, such as polypropylene glycol or randomly distributed polypropylene-ethylene glycols or block polymers of ethylene and propylene oxide and mixtures thereof; and oils. The amount of the lubricant is

preferably 0.05 to 10%, especially 0.1 to 2%, by weight of the fluid. Preferably the monocarboxylic acid

lubricants are coconut fatty acids, oleic acid, groundnut acids and rapeseed acids and esters and amides of these acids with polyols, such as glycerol, trimethylolpropane, pentaerythritol and polalkyleneglycols, and alkanolamines respectively. The hydrocarbon groups of the organic phosphate esters can be octyl, nonyl, decyl, dodecyl, tetradecyl and hexadecyl as well as their corresponding unsaturated alkenyl groups. Anionic lubricants also have a corrosion-preventing capacity against iron.

The metal working compounds containing an oil as a lubricant have often the form of an emulsion or a

colloidal solution. With the term "oil" is here understood a class of substances of synthetic, mineral, vegetable or animal origin. Usually, they are from petroleum or are petroleum-derived but synthetic

hydrocarbons, e.g. poly-alpha-olefins (PAO's), or alkylates, e.g. alkyl benzenes, may also be used. These compositions may also include emulsifying agents which are usually non-ionic and/ or anionic surfactants.

Examples of anionic surfactants are alkylaryl

sulphonates, such as dodecylbenzene sulphonates,

alkylsulphates; such as sulphates of alcohols or

alkoxylated alcohols; sulphated esters, such as sulphated castor oil; and phosphates of alcohols or ethoxylated alcohols. Examples of nonionic surfactants are

alkoxylated alkyl phenols, alcohols, carboxylic acids, alkanolamines, alkylamines, polyalkylene glycols and alkylamides. The alkoxylation agent is normally an alkylene oxide containing 2 to 4 carbon atoms. Preferably at least 50% of the alkyleneoxy groups are ethyleneoxy groups and they may be either arranged in blocks or distributed at random. In a preferred embodiment the polyoxyalkylene is end-capped with propyleneoxy and/ or butyleneoxy units in order to obtain a low-foaming surfactant. The anionic and nonionic surfactants are normally so chosen that they contain 8 to 20 carbon atoms in a hydrocarbon residue. By the amount of ethyleneoxy units in the surfactant the HLB balance can be further regulated.

In addition to corrosion inhibitors and lubricants, the metal working fluid may advantageously also contain pH-adjusting agents, metal complex stabilisers,

defoamers, perfumes, viscosity-adjusting and solubility-improving agents in known manner. Suitable solubility- improving agents are glycols, such as ethylene glycol; alcohols, such as tridecanol and oleylalcohol; and glycol ethers, such as butyldioxitol and butyl-trioxitol. Aqueous heat transfer media are for instance used in cooling towers, municipal hot water distribution systems and building heating systems, while coolants are used in metal working and quenching processes. Compositions of the invention for use as heat transfer media and coolants contain usually, in addition to the sugar amine,

corrosion inhibitors, metal complexing agents,

antiscaling agents, dispersing agents and/ or pH

regulating agents. The hydraulic fluids may also contain lubricants and viscosity regulating agents.

Compositions of the invention for use as cleaning and sterilising fluids may contain a surfactant with micelle forming power. The surfactant is anionic, cationic, amphoteric or nonionic. Normally an anionic surfactant or a combination of a nonionic surfactant and an anionic surfactant is preferred. The cleaning fluids may also comprise conventional additives, such as

inorganic builders, defoamers, foam boosters, metal complexing agents, solubilizers and corrosion inhibitors.

When used as an industrial biocide the compound may be used in its neat form or as a dilute solution in a suitable solvent e.g. water, glycols, etc. The present invention is further illustrated by the following Examples.

EXAMPLE 1 Synthetic metal working fluid compositions were made to the following formulation:

The sugar amines were added in amounts of 2 to 8% by weight to provide 500, 1000 and 2000 ppm sugar amine when diluted with water to a fluid concentration of 2.5%. The diluted fluids were subsequently tested with respect to their bactericidal and fungicidal effects by adding standardised bacterial and fungal inocula which were originally isolated from contaminated metalworking fluids.

The bacterial preparation was as follows:

100 ml mineral salts media containing 2% trisodium citrate as sole carbon source (pH9) in Erlenmeyer flasks were inoculated with 1 ml of a culture of Pseudomonas eruginosa at an optical cell density of 2.0 measured at 650 nm (Perkin-Elmer UV-Vis Spectrophotometer, model Lambda 2). These inocula were incubated at 30°C in an orbital incubator rotating at 200 rpm. During exponential growth, further media were subinoculated in the same way, and the remaining culture harvested for testing of the diluted formulations. This sub-culturing procedure was continued until the end of the test period.

The cultures were harvested by centrifugation at 4000 rpm for 20 minutes (MSE Mistral 2000) . The resulting bacterial pellet was resuspended in sterile Hanks

buffered saline solution and recentrifuged. Three such washes were performed. Prior to the final wash, the optical density was adjusted to 2.0 (650nm) and the volume of suspension noted. After the third wash the bacterial cells were resuspended in Hanks buffered saline to one tenth of the original volume to provide a

concentrated inoculum containing approximately 1 × 10¹⁰ cells ml^-1. This suspension was used as inoculum in the tests.

The fungal preparation was as follows. 100 ml mineral salts media containing 2% glucose as sole carbon source were introduced into Erlenmeyer flasks and inoculated with 1 ml of a homogenised culture of

Cephalosporium sp. The inocula were incubated at 30°C in an orbital incubator rotating at 200 rpm. After 24 hours the fungus was homogenised and subcultured as already described into glucose supplemented mineral salts media. The remaining culture was centrifuged at 4000 rpm for 20 minutes. After decanting the spent growth medium, the fungal pellet was resuspended in Hanks buffered saline and recentrifuged. After 3 washes, the final fungal pellet was resuspended in one tenth of the original volume of buffer used to provide a concentrated inoculum. This material was used as inoculum in the testing of the diluted formulations.

Teat Method

2.5 ml of the formulations were diluted with 97.5 ml of sterile mineral salts media introduced in 250 ml Erlenmeyer flasks. These dilutions were adjusted to pH 9.0 by adding HCl or KOH. 200 microlitres of the

standardised inocula were then added daily for the full experimental period providing a multiple inoculation. In this way, the investigation compared the efficacy of the sugar amines following repeated additions where fresh supplementary biomass was introduced over a period to simulate a continuous contamination situation (i.e.

multiple inoculum test).

The fluid types were inoculated separately with the bacterial and fungal biomass to avoid possible inhibitory interactions. All fluids were incubated throughout the test at 30°C in an orbital incubator rotating at 200 rpm.

The survival of inocula was monitored daily. Fungi were monitored using conventional plate counting

following growth on malt extract agar (plus

chloramphenicol) after serial dilution. Bacteria were enumerated directly using the rapid automated bacterial impedance technique (RABIT).

The following results were obtained.

Multiple Challenge test with Pseudomonas aeruginosa in a Synthetic Fluid

Multiple Challenge test with Cephalosporium sp in a

Synthetic Fluid

The listed values above in each multiple challenge test are log₁₀ viable counts (cells ml^-1). Especially good antimicrobial effects are shown by sugar amines against fungi.

EXAMPLE 2

Minimum inhibitory concentration values were

obtained for the sugar amines. Compounds were tested according to standard methodology for determining mic's in suspension tests or according to in-house methodology using a Bioscreen (Life-Sciences International (UK) Ltd).

In-House Test Inocula were prepared as in Example 1. The inoculum was then diluted 1/50 and 50μl added to 350μl test medium in a multiwell plate. The optical density change was measured over a wide band (white filter) for a period of 18-24 hours. Multiwell plates were incubated at 30°C with shaking. The Bioscreen was operated according to the manufacturer's instructions.

The ingredients were dissolved in a small volume of distilled water. The pH was adjusted to pH 9.0 using SMP sodium hydroxide and the volume was made up to 1 litre using distilled water. The medium was then autoclaved at 121°C for 15 minutes.

Minimum Inhibitory concentration (ppm sugar amine)

N.B. All above compounds tested according to standard suspension test employing plate methods except for ② which were tested using a Bioscreen (Life Sciences International (UK) Ltd). * 3-octoxy 2-hydroxy propyl-1 amine.

The above compounds were tested according to the standard suspension test.

Claims

1. The use as an industrial fluid of a water based alkaline composition containing a sugar amine of the formula:

wherein A represents a monosaccharide, disaccharide, trisaccharide or polysaccharide group; and

wherein R₁ and R₂ each represents hydrogen or an alkyl or aryl group having from 1 to 24 C atoms.

2. The use of a composition according to claim 1, which has a pH of at least 8.

3. The use of a composition according to claim 2 , which has a pH of between 8 and 10.

4. The use of a composition according to claim 1, 2 or

3, wherein the composition is a metal working fluid, a hydraulic fluid, a coolant, a cleaning fluid or a

sterilising fluid.

5. The use of a composition according to any preceding claim, wherein R₁ and/ or R₂ have substituted alkyl, alkenyl or aralkyl groups.

6. The use of a composition according to any preceding claim, wherein R₁ is the group R'(Y₁)_y1(X₁)_x1, in which R' is a hydrocarbon group or an acyl group containing 3 to 18 C atoms; consisting of

-OC₃H₆ - ; - OC₂H₄ - ; -OC₂H₄OC₃H₆ - ; and

-(NHC_n1H_2n1)m₁- where % is a number from 0 to 3 and n. is a number from 2 to 3; and x₁ is 0 or 1; and

Y₁ is an oxyalkylene group having from 2 to 4 C atoms, and y₁ is a number from 0 to 3, with the proviso that when X₁ is

or -(NHC_n1H_2n1)m₁- and X₁ is 1, then y₁ is zero.

7. The use of a composition according to any preceding claim, wherein the saccharide group is selected from galactose; d-N-acetylgalactose; L-rhamnose; d-fucose; glucose; lactose; maltose; melibiose; cellobiose and maltotriose.

8. The use of a composition according to any preceding claim, wherein the sugar amine is a secondary sugar amine.

9. The use of a composition according to any preceding claim, wherein the composition contains the sugar amine in an amount of from 0.001 to 0.5% by weight.

10. A sugar amine of the formula:

wherein A represents a mono-, di-, tri- or higher polysaccharide, wherein R₁ is the group R'(Y₁)y₁X₁ in which R' is a hydrocarbon group or an acyl group containing 3 to 18 C atoms; X₁ is a divalent group selected from the groups consisting of

-OC₃H₆-; -OC₂H₄OC₃H₆-; and

-(NHC_n1H_2n1)m₁- where m₁ is a number from 0 to 3 and n₁ is a number from 2 to 3; and Y₁ is an oxyalkylene group having from 2 to 4 C atoms, and y ₁ is a number from 0 to 3, with the proviso that when X ₁ is or -(NHC_n1H_2n1)_m1-,

then y₁ is zero; and where R₂ is hydrogen or an optionally substituted alkyl or aryl group having 1-24 carbon atoms.

11. A sugar amine according to claim 10, wherein R₁ is R'O(CH₂)_n- where n = 2 or 3; or R'(OCH₂)_nCH(OH)CH₂- where n= 0 or 1; R'OCH₂CH₂OCH₂CH₂CH₂-; or R'CH(OH)CH₂-.

12. A sugar amine according to claim 10 or 11, wherein R₂ is a group R''(Y₂)_y2(X₂)_x2 in which R'' is a hydrocarbon group, a hydroxylated alkyl group, or an acyl group containing 1-12, preferably 1-4 carbon atoms, or

hydrogen; X₂ is a divalent group selected from the group consisting of -OC₃H₆-; -OC₂H₄-; and -(NHC_n2H_2n2) -_m2.

3 with the proviso that when X₂ is or

-(NHC_n2H_2n2)m₂- and x₂ is 1, then y₂ is zero.