GB1560427A - Microcicidal meta-chlorophenols - Google Patents

Description

(54) MICROBICIDAL META-CHLOROPHENOLS (71) We, BAYER AKTIENGESELL SCHAPFT, a body corporate organised under the laws of Germany, of Leverkusen Bayerwerk, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to the use of known meta-chlorophenols for combating harmful micro-organisms.

It is known that phenolic compounds are antimicrobially active. Thus, even phenol itself is regarded as a standard compound which is used for comparing with the microbicidal activity of other compounds. As an antimicrobial compound, phenol itself suffers from the disadvantages that it is a relatively weak antimicrobial agent, causes severe irritation of living tissue of higher organisms at concentrations at which it effectively frees their surfaces from microorganisms, and exhibits a severe unpleasant odour (DAS (German Published Specification) 1216488).

In the attempt to discover substances which are more strongly active antimicrobial agents but exhibit less odour and show a markedly lower irritant action when used, numerous substituted phenols have been prepared and investigated. In the course of this, it has been found that in certain cases halogenation of the aromatic nucleus of a phenol causes a tendency both to increase the irritant action and the antimicrobial activity (DAS (German Published Specification) 1216488).

The microbial properties of some metahalogenophenols are also already known. Thus, for example, DAS (German Published Specification) 1005242 describes a process for disinfecting surfaces with the aid of 4 - chloro2 - hydroxytoluene.

Meta-halogenophenols which in the orthoposition to the hydroxyl group possess an alkyl radical with 2 to 12 carbon atoms and also possess a second halogen atom on the phenyl nucleus, are disclosed in DOS (German Published Specification) 2342917 as agents for combating micro-organisms, as feedstuff additive for domestic animals, and for the purpose of protection of materials.

Similar compounds in which, in contrast tD the meta-halogenophenols known from DOS (German Published Specification) 2342917, the second halogen atom is absent, are disclosed in DOS (German Published Specification) 2438853. These known meta-halogenophenols are suitable for use as preservatives and disinfectants of all kinds. A disadvantage of these known meta-halogenophenols is that there are gaps in the spectrum of action. Thus, these compounds only have a low activity against Pseudomonas pyocyanea (Pseudomonas aeruginosa).

The fact that the activity of the halogenophenols as preservatives is frequently inadequate is attributable to such gaps in their action. In spite of the presence of the halogenophenols, microbial growth, and/or deterioration, commences, especially if the materials are exposed to the weather or are left to stand for a very long time. In order nevertheless to achieve an adequate protective action it is necessary to add a large amount of preservative (DAS (German Published Specification) 1160140).

To solve this problem, DAS (German Published Specification) 1160140 proposes a combination of a halogenophenol with a polyalkyleneimine. However, the use of such active compound mixtures always entails expense and this restricts their application.

It has been found that meta-chlorophenols of the formula

wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, methoxy or the group

and R3 denotes hydrogen or chlorine, and wherein the radicals R1, R2 and R3 do not simul taneously denote hydrogen, have a powerful microbicidal action.

Surprisingly, the meta-chlorophenols according to the invention exhibit a substantially greater action than the halogenophenols known from the state of the art. The active compounds according to the invention thus represent an enrichment of the art.

The invention therefore provides a microbicidal composition comprising a compound of the formula (I) in admixture with an auxiliary material which does not consist solely of solvents of molecular weight less than 20G (preferably 300).

The auxiliary material may comprise a solid or liquefied gaseous diluent or carrier, a dyestuff, a pigment, a binder, a scent, a complexforming agent, a plasticiser, a softener, a filler, a disinfectant, an optical brightener, or a solvent of molecular weight less than 200 in combination with any of the foregoing.

Particular examples of microbicidal compositions in accordance with the invention are paint or printing compositions, cosmetic compositions and plastics composition as well as solutions, emulsions and dispersions of the compounds of the formula (I).

The invention also includes a process for combating microorganisms such as yeasts, algae, fungi and bacteria which comprises applying to the microorganisms, or to a habitat thereof, a compound of the formula (I). The process may be carried out using the compound alone or in admixture with any suitable diluent or carrier.

The preparation of the active compounds according to the invention is already known (DOS (German Published Specification) 2259433 and DOS (German Published Specification) 2344926). For example, active compounds according to the invention can be prepared by partial and selective dehalogenation of phenols which are more highly chlorinated on the nucleus, by means of hydrogen m the presence of sulphides or polysulphides of the metals iron, cobalt or nickel.

The following may be mentioned as examples of the active compounds according to the invention: 3,5 - dichloro - phenol, 3 5 - dichloro - 4 - methyl - phenol, 3,5 dichloro - 4 - methoxy - phenol, 2 - methyl3 - chloro - phenol, 3 - chloro - 4 - methylphenol, 2,4 - dimethyl - 3 - chloro - phenol and 4,4' - dihydroxy - 2,6,2',6' - tetrachlorodiphenyl.

Particularly preferred active compounds are 3,5 - dichlorophenol and 3,5 - dichloro - 4methyl - phenol.

The active compounds according to the invention exhibit powerful microbicidal actions.

They can be used, for example, for combating and destroying Gram-positive and Gramnegative bacteria, fungi, yeasts and algae.

The following may be mentioned as examples of bacteria: Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Mycobacterium phlei, Escherichia coli, Proteus vulgare, Pseudomonas aeruginosa, Klebsiella species, Bacillus mesenteriens and Bacterium prodigiosum.

The following may be mentioned as fungi and yeasts: Trichophyton pedis, Candida albicans, Aspergillus niger, Aspergillus flavusalbus, Penicillium glaucum, Trichoderma viride, Chaetomium globosum, Saccharomyees cerevisiae, Torula utilis, Rhodotorula mucilaginso, -Penicillium digitatum, Penicillin expansum and Mucor racemosus.

The following may be mentioned as examples of algae: Stichococcus bacillaris, Phormidium foreolarum, Oscillatoria germinata, Euglena gracilis and Chlorella pyrenoidosa.

The active compounds according to the invention can be employed simply and in large amounts. By doing so, microorganisms which are harmful to living tissue and which cause devaluation or destruction of materials of all kinds, can be combated and/or destroyed. The active compounds according to the invention are therefore particularly suitable for use as preservatives and/or disinfectants.

Advantageously, the active compounds according to the invention can be employed for protecting industrial materials against microbial degradation. Examples of industrial materials are water-based or solvent-based paints, binders, printing pastes and colour pastes, glues and doughy colour preparations, and similar materials which contain dyestuffs or coloured pigments, added cellulose derivatives, casein or synthetic binders. The active compounds according to the invention not only protect the paints but also the paint films against microbial attack. The active compounds according to the invention can be employed for preventing formation of slime and algae in industrial water circuits, for example in the paper industry. Textiles and fibres can be provided with a finish which is both microbistatic and microbicidal, by means of the active compounds according to the invention. By using the active compounds according to the invention it is also possible to impart deodorant properties to the textiles treated therewith.

The active conpounds can be used in solu tions, dispersions or emulsions and/or as d spray. It is also possible and advantageous for many applications, to combine them with anionic wetting agents, soaps or benzenesulphonates, or with cationic wetting agents, such as quaternary ammonium compounds, or non-ionic wetting agents, such as polyglycol ethers and higher fatty alcohols.

Equally, it is possible to mix the active compounds according to the invention with complex forming agents, such as sodium hexametaphosphate, or scents, such as sandalwood oil.

A combination with customary auxiliaries, such as plasticisers, softeners, fillers such as silicates or carbonates, and/or optical brighteners, as well as dressings or starch derivatives is also possible.

The amount of the active compound combination employed depends on the nature and occurrence of the micro-organisms, the germ count and the medium. In each case of application, the optimum amount to be employed can be determined by series of tests. How ever, in general it suffices to employ 0.005 to 10 parts, preferably 0.5 to 2 parts, of the active compound relative to roo parts of the microbicidal use form, that is to say of the formulated agent or of the material to be protected.

When using the active compounds accord ing to the invention in washing and cleaning agents, in general 0.01 to 8 parts3 preferably 0.2 to 2 parts, relative to 100 parts of the microbicidal use form, are employed.

When using the active compounds accord ing to the invention in cosmetic preparations, such as, for example, creams, face lotions, deodorants, bath salts, hair lotions, hair oil, colognes and lotions, powders and agents for protecting against sunburn, as well as in agents for the care of the mouth and the teeth, it is advantageous to employ 0.005 to 2 parts, preferably 0.05 to 1.5 parts, relative to 100 parts of the microbicidal use form.

When preparing disinfectants and indus trial preservatives, it is possible to combine the active compounds according to the inven tion with known disinfectants and preserva tives. Examples of known disinfectants and preservatives are phenols and phenolic deriva tives, aldehydes, such as formaldehyde, glutar aldehyde and salicylaldehyde, alcohols, such as ethyl alcohol, carboxylic acids and their derivatives, such as carboxylic acid amides, organo-metallic compounds, such as tributyl tin oxide, halogens and halogen compounds, such as chlorine and iodine compounds, car bonic acid derivatives, such as diethyl dicar bonate and dimethyl dicarbonate, amines and quaternary ammonium compounds, such as benzalkenium chlorides, phosphonium com pounds and heterocyclic compounds, such as halogenated and/or quaternised pyridine derivatives.

It is also possible, for the purpose of combating microbes or protecting materials against microbial attack, to incorporate the active compounds according to the invention directly into the material to be protected, such as, for example, into plastics of all kinds, such as polyamides, polycarbonates, polyesters, polyvinyl chloride, polyvinylpropionate, polyvinyl alcohol or oils and fats. The active compounds according to the invention can furthermore be dispersed in powders or dusting powders and in pigments for paints. They can furthermore be dissolved in organic solvents, such as hydrocarbons, halogenohydrocarbons and/or alcohols, and be added to, or sprayed onto, the substance to be protected.

The active compounds according to the invention are advantageously colourless and can therefore be employed without changing the colour of the medium in which they are used.

It is advantageous that the active compounds according to the invention have only a low intensity of odour and can therefore be used without causing an objectionable odour.

The microbiologically broad spectrum of action of the active compounds according to the invention is of particular advantage. It is particularly important that the active compounds according to the invention are suitable, in contrast to known halogenophenols, for combating Pseudomonas aeruginosa. Pseudomonas aeruginosa is one of the hospital germs which are to be found in the vicinity of the patients and cause infcctions (Zbl. Bakt. Hyg.

1 Abt. Orig. B. 159, 277 to 287 (1974). The active compounds according to the invention provide an effective agent for combating Pseudomonas aeruginosa.

The active compounds according to the invention thus make it possible advantageously to replace the previously available microbicidal agents by more effective agents and to reduce the amount of biocide required for combating microorganisms.

The following Examples, including Com parative Examples 16 and 17 illustrate the invention.

Examples.

Determination of the minimum inhibitory concentration (hereinafter abbreviated MIC) against bacteria and fungi.

The active compounds according to the invention are dissolved in acetone, ethanol or mixtures of both solvents and these stock solutions are subsequently diluted with dis tilled water in such a way that in each case 0.1 to 0.3 ml of the stock solutions or of their dilutions in 2V ml of an agar contamin ated with bacteria or fungi in concentration series give between 500 and down to 1 ppm of active compound in agar. The mixture, whilst still warm, is poured into slant tubes and after having cooled is inoculated with the test germs listed below.

Bacteria Staphylococcus aureas Streptococcus faecalis Bacillus subtilis Mycobacterium phlei Escherichia coli Proteus vulgare Pseudomonas aeruginosa Fungi Trichophyton pedis Candida albicans Aspergillus niger Aspergillus flavus-albus Penicillium glaucum Trichoderma viride Chaetomium globosum After an incubation of three times 24 hours in the case of bacteria or 2 weeks in the case of fungi and 280C + 2 C the minimum inhibitory concentration (in mg/l = ppm) of the active compounds at which the growth of the test germs is prevented is determined.

Determination of the microbicidal action.

In determining the MIC, contaminated areas occur which remain free from growth of germs. In order to be able to decide whether the active compounds have destroyed the germs employed or have merely inhibited their multiplication, sterile round paper filters ot 10 mm diameter are placed on these contamination areas and, after a contact time of 20 minutes, are transferred under sterile conditions onto sterile bacterial agar or fungal agar to which polyoxyethylene(20)-sorbitan monooleate has been added. The contact time Oil these new plates is 30 minutes. If no growth of the transferred germs is found on the subculture plate, the active compound concentrations suffice for destruction.

In addition, the suspension test is carried out in order to determine the microbicidal activity: The active compounds according to the invention are dissolved in alcohol or acetone, dimethylformamide or dimethylsulphoxide.

10% by weight of active compound should be dissolved in the stock solution.

Aliquot portions of these stock solutions are diluted with sterile distilled water and are then contaminated with a germ suspension (about 109 germs/ml). The following test germs are used: Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa.

After exposure times of 5 or 10 minutes at 20 !C, 2 drops of the contaminated dilutions are transferred by means of a pipette into 10 ml of sterile nutrient broth to which poly oxyethylene(20)-sorbitan monooleate has been added. Thereafter the medium is incubated twice for 24 hours at ±280C and examined for germ growth (that is to say turbidity of the solution).

Examples 1 to 7 Minimum inhibitory concentration (MIC)

Penicillium Chaetomium Aspergillus Bacterium Pseudomonas glaucum globosum niger coli aeruginosa 1. 3,5-Dichlorophenol 50 < 20 50 50 200 2. 3,5-Dichloro-4-methyl-phenol 35 35 50 50 500 3. 3,5-Dichloro-4-methoxy-phenol 75 50 200 1,500 1,500 4. 2-Methyl-3-chloro-phenol 100 100 100 150 750 5. 3-Chloro-4-methyl-phenol 1,500 50 150 200 750 6. 2,4-Dimethyl-3-chloro-phenol 50 50 50 100 1,000 7. 4,4'-Dihydroxy-2,6,2',6'-tetrachloro-diphenyl 100 50 100 1,000 2,000 Comparative active substance (DOS (German Published Specification) 23 42 917) 8. 2-Butyl-3,5-dichlorophenol 50 20 50 50 5,000 It can be seen from this survey that the MIC values of the active compounds according to the invention are balanced and show no gap in the action, for example against Pseudomonas bacteria (in the present case in connection with the very widespread type aeruginosa).

Examples 9 to 17.

It the suspension test, as described above, is carried out to determine the microbicidal activity, the following results (MIC values in % by weight) are obtained for the three guideline germs (B1, B2 and B8):

B1 B2 B3 Staphylococcus Escherichia Pseudomonas aureus coli aeruginosa 9. 3,5-Dichlorophenol 0.05 0.03 0.05 0.035 Fe 0.05 Fo 0.05 Fo 0.15 Sm 0.075 Sm 0.075 Sm 10. 3,5-Dichloro-4-methyl-phenol 0.02 0.02 0.01 0.025 Fo 0.015 Fo 0.025 Fo 0.075 Sm 0.05 Sm 0.05 Sm 11. 3,5-Dichloro-4-methoxy-phenol 0.075 0.05 0.075 0.075 Fo 0.025 Fo 0.015 Fo 0.1 Sm 0.15 Sm 0.075 Sm 12. 2-Methyl-3-chloro-phenol 0.075 0.075 0.05 0.075 Fo 0.075 Fo 0.075 Fo 0.22 Sm 0.15 Sm 0.1 Sm 13. 3-Chloro-4-methyl-phenol 0.15 0.1 0.075 0.075 Fo 0.075 Fo 0.05 Fo 0.2 Sm 0.1 Sm 0.1 Sm 14. 2,4-Dimethyl-3-chloro-phenol 0.03 0.03 0.05 0.025 Fo 0.025 Fo 0.035 Fo 0.1 Sm 0.05 Sm 0.05 Sm 15. 4,4'-Dihydroxy-2,6,2',6'-tetrachloro-diphenyl 0.01 1.0 1.0 0.02 Fo 0.05 Fo 0.2 Fo 0.15 Sm 0.3 Sm 0.3 Sm Comparative active substance (DOS (German Patent Specification) 23 42 917) 16. 2-Butyl-3,5-dichlorophenol 0.007 0.007 0.5 0.01 Fo 0.02 Fo 0.1 Fo 0.08 Sm 0.2 Sm 0.5 Sm 17. 2-Ethyl-3,5-dichlorophenol 0.01 0.01 0.08 Fo = formulated with soap Sm = in the presence of 20% cattle serum The comparison shows that the active compounds according to the invention do not have any gaps in their action against Pseudomonas aeruginosa.

We hereby disclaim processes for the treatment of human beings for the prevention or cure of diseases.

Claims (12)

Subject to this disclaimer, WHAT WE CLAIM IS:

1. A microbicidal composition comprising a metachlorophenol of the formula (I)

wherein R1 denotes hydrogen or methyl, R2 denotes hydrogen, methyl, methoxy or the group

and R8 denotes hydrogen or chlorine and wherein the radicals R1, R2 and Rs do not simul taneously denote hydrogen. in admixture with an auxiliary material which does not consist solely of solvents or molecular weight less than 200.

2. A composition according to claim 1 wherein the auxiliary material comprises a solid or liquefied gaseous diluent or carrier, a dyestuff, a pigment, a binder, a scent, a complex-forming agent, a plasticiser, a softener, a filler, a disinfectant, an optical brightener, or a solvent of molecular weight less than 200 in combination with any of the foregoing.

3. A paint or printing ink composition comprising a compound of the formula (I), a pigment and a solvent.

4. A microbicidal composition comprising a compound of the formula (I), dissolved or dispersed in a liquid diluent or carrier together with a wetting agent.

5. A cosmetic composition comprising a compound of the formula (I) and a dermatologically acceptable filler, carrier or diluent.

6. A plastics composition comprising a plastics material and a compound of the formula (I).

7. A composition according to any one of claims 1 to 6 wherein the compound of the formula (I) is 3,5-dichlorophenol.

8. A composition according to any one of claims 1 to 6 wherein the compound of the formula (I) is 3,5-dichloro-4-methylphenol.

9. A composition according to any one of claims 1 to 6 containing any of the compounds of the formula (I) specifically named herein.

10. A composition according to any one of claims 1 to 9 containing at least 0.005 parts by weight of a compound of the formula (I) per 100 parts by weight of the composition.

1'1. A process for combating microorganisms which comprises applying to the microorganisms, or to a habitat thereof, a compound of the formula (I).

12. A process for preserving textiles and textile fibres which comprises applying to the textile or textile fibres a compound of the formula (I).