US3134711A - Halogenated salicylanilide-halogenated trifluoromethyldiphenyl urea synergistic composition - Google Patents

Description

United States Patent 3,134,711 LOGENATED SALICYLANEIDE HALOGEN- ATED TRIFLUOROMETHYLDIPHENYL UREA SYNERGISTIC COMPGSITIQN Herbert H. Keller and Wiiiiam E. Jordan, Cincinnati, Ohio, assigns-rs to The Procter & Gamble Company, Cincinnati, Ohio, a corporation of Ohio No Drawing. Filed Mar. 9, 1961, Ser. No. 94,437 1 Claim. Cl. 16730) This invention relates to improved anti-bacterial agents. More particularly, it relates to anti-bacterial agents which comprise in combination a halogenated salicylanilide and a halogenated trifluoromethyldiphenyl urea compound.

The application of halogenated salicylanilide and trifluoromethyldiphenyl urea compounds as anti-bacterial agents individually has been disclosed in the art. The brominated salicylanilides have been employed as antibacterial agents in detergent compositions such as deodorant toilet bars, and laundering detergent products.

Anti-bacterial agents which have heretofore been employed in detergent compositions including the said halogenated salicylanilides display certain inherent deficiencies which detract from their eificacy in such applications.

Gram-negative organisms are common contaminates of the skin and other surfaces upon which anti-bacterial detergent usage has been found desirable and it is therefore essential to reduce the population of these organisms as well as gram-positive organisms to obtain the maximum beneficial effect. In general, anti-bacterial agents which have been found satisfactory for use in detergent milieu otherwise, display only slight activity against gram-negative organisms. Both the halogenated salicylanilide and halogenated trifluoromethyldiphenyl urea compounds are subject to this deficiency, neither compound displaying significant activity against gram-negative organisms at feasible use concentrations.

A disadvantageous characteristic of the widely used bisphenolic compounds is photo-sensitivity. When bis(3, 5,6-trichloro-2-hydroxyphenyl) methane and bis(3,4-dichloro-2-hydroxy phenyl) sulfide for example, are incorporated in a toilet detergent bar in concentrations as low as 0.5%, exposure to ordinary daylight results in an unsightly discoloration of the bar. To attain a minimum acceptable level of deordorant effectiveness using the bisphenols in such a bar, at least 2% by weight has been recommended. The degree of discoloration of detergent bars containing this level of bisphenolic compounds is sufliciently great that gold or yellow coloring material must be incorporated in the formulation for masking purposes.

Other anti-bacterial agents, though effective in aqueous solutions are incompatible with detergent actives or at pH values generally characteristic of detergent systems. Thus, the anti-bacterial activity of phenols for example, is almost completely lost in soap milieu. Quaternary ammonium compounds are similarly incompatible with soap and anionic synthetic detergents.

It is an object of this invention to provide a composition having a high level of anti-bacterial activity.

It is a further object of this invention to provide an anti-bacterial composition which is effective against both gram-positive and gram-negative bacteria.

It is a still further object of this invention to provide an antibacterial composition which is adapted to use in detergent milieu.

Other objects and improvements will become apparent from the following description.

In general, this invention comprises a synergistic com bination of a halogenated salicylanilide and a halogenated trifiuoromethyldiphenyl urea compound. Synergistic combination as used herein refers to a mixture of two or 3,134,711 Patented May 26, 1964 X1 OHO Y wherein each X represents hydrogen or halogen, X represents a halogen, and Y represents hydrogen, halogen or trifluoromethyl.

The preferred halogenated salicylanilides which are encompassed by the above general formula include 3,5,4- tribromosalicylanilide, 5 bromosalicyl 3,5 di(trifluoromethyl) anilide, 5 -chlorosalicyl-3,5-di trifluoromethyl anilide, 3,5-dichlorosalicyl-3,4-dichloroanilide and 5-chlorosalicyl-3-trifluoromethyl-4-chloroanilide. Other halogenated salicylanilides which come within the above general formula and display synergistic activity in conjunction with the urea derivatives of this invention are disclosed by Bindler and Model in US. Patent 2,703,332, granted March 1, 1955. This patent further discloses a method for their preparation.

The trifiuoromethyldiphenyl urea compounds which can be used in this invention are represented by the general structural formula:

C F3 a) Z wherein Z represents hydrogen, halogen or trifluoromethyl,

X represents halogen or ethoxy, X represents hydrogenor halogen and Y represents hydrogen or trifiuoromethyl. The preferred compounds of this group include 3-trifluoromethyl-4,4-dichlorocarbanilide, 3-trifluoromethyl-3 ,4,4'- trichlorocarbanilide, 3,3 -bis (trifiuoromethyl) -4-ethoxy-4'- 'chlorocarbanilide, and 3,5-bis(trifiuoromethyl)-4-chlorocarbanilide. These and other operable halogenated tri fluoromethyldiphenyl urea compounds are more fully described in U.S. Letters Patent 2,745,874, granted May Halverson, H.O., Soap, vol. 10, #9, page 25.) Antibacterial activity is expressed herein in terms of the per cent reduction in number of viable microorganisms following exposure of a suspension of either Staphylococcus aureus as the representative gram-positive organism or Escherichia coli as the representative gram-negative or" ganism to a given concentration of the various anti bacterial combinations for 10 minutes at 37 C. The relative eifectiveness of the combinations is reflected in reduction of numbers of viable organisms.

The following examples are merely illustrative of the present invention and the invention is not limited to them. Examples I to VI immediately following are indicative of the synergistic anti-bacterial activity obtained by conjoint use of agents of the two classes disclosed herein, the specific agents being fairly representative of the classes in question.

The activity of the mixtures of the above examples was determined in accordance with the method referred to above, i.e., suificient anti-bacterial agent was added to a tube of FDA nutrient broth (US. Dept. of Agriculture Circular 198, December 1931, page 4) to attain the desired concentration. The suspending fiuid and anti-bacterial agent were heated to 37 C. and inoculated with approximately five million cells of the test organisms. These mixtures were then incubated for minutes and an aliquot was removed, diluted in 0.1% peptone water diluent, and placed on B.B.L. trypticase soy agar (supplied by Baltimore Biological Laboratories, Baltimore, Maryland). After solidification of the agar, the petri dishes were incubated for 24 hours and the number of colonies arising in that time was determined. The number of cells surviving exposure to the anti-bacterial was compared to the number contained in the original inoculum and the figure thus derived was adjusted in consideration of appropriate controls to give the percentage reduction value here employed. It can be seen that neither anti-bacterial agent by itself displays the degree of antibacterial activity attained With the combinations.

The efficacy of the mixture of this invention in soap and non-soap synthetic detergent milieu may be observed from the following examples.

Various concentrations of 3,5,4-tribromosalicylanilide and 3-trifluoromethyl-4,4'-dichlorocarbanilide were added to an aqueous solution containing 250 micrograms/ml. of a neutral White, high grade soap consisting of a mixture of 80% sodium soap and potassium soap derived from a blend of 70% tallow and coconut fatty acids. Total anti-bacterial agent concentration was maintained at 5 micrograms/ml. or 2% by weight of the soap. The compositions thus prepared were tested for bactericidal activity using the method described supra. The following table presents the results of these tests, each value being an average obtained in several runs.

Concentration/micrograms Total Percent 3-trifluoro- 3,5,4-tri- Reduction methyl 4,4- broIno-salidichlorocar cylanilide banilide 4 (trifluoromethyl) anilidc, 3,5-dichlorosalicyl-3,4-dichloroanilide and 5-chlorosalicyl-3-trifluoromethyl-4-chlorocarbanilide, results in comparable reductions in numbers of viable organisms. Further, variation of the soap matrix does not have any significant influence on the relative increase in activity attributable to the anti-bacterial agent.

Regular use of a soap bar containing 1% of a 1:1 mixture of halogenated salicylanilide and halogenated trifluoromethyldiphenyl urea of this invention results in substantial reduction in the bacterial population of the skin and thus markedly reduces body odor attributable to bacterial degradation of perspiration.

The mixtures of this invention have been found to significantly increase the anti-bacterial activity of non-soap synthetic detergent compositions including both anionic and nonionic and solid or liquid types. Although some of the detergents in the anionic group, for example, alkyl benzene sulfonate, have substantial anti-bacterial effect against gram-positive microorganisms, few have significant effect against gram-negative organisms. The incorporation of a small amount of halogenated salicylanilide-halogenated trifluoromethyldiphenyl urea mixtures of this invention in synthetic detergent compositions will effect an increase in anti-bacterial activity against gram-positive organisms and will impart significant levels of antibacterial activity against gram-negative organisms.

The anionic synthetic detergent which can be employed with this invention is generally defined as a water-soluble salt of an organic sulfuric reaction product having in its noleeular structure an alkyl group containing from about 8 to about 22 carbon atoms and a radical selected from the group consisting of sulfonic acid and sulfuric acid ester radicals. Important examples of the synthetics of this group which may be benefited through the incorporation therein of the mixtures of this invention, are the sodium or potassium alkyl sulfates, especially those derived by sulfation of higher alcohols produced by reduction of glycerides of tallow or coconut oil; sodium or potassium alkyl benzene sulfonates, especially those of the types described in US. Letters Patents 2,220,099, granted November 5, 1940, and 2,477,383, granted July 26, 1949, in which the alkyl group contains from about 9 to about 15 carbon atoms; sodium alkyl glyceryl ether sulfonates, especially those ethers in which the alkyl group is derived from the higher alcohols obtained from tallow and coconut oil; sodium coconut oil fatty acid monoglyceride sulfates and sulfonates, sodium salts of sulfuric acid esters of the reaction product of one mole of a higher fatty alcohol (e.g., tallow or coconut oil alcohols) and about three moles of ethylene oxide, and others known in the art, a number being specifically set forth in Byerly, U.S. Letters Patent 2,486,921, granted November 1, 1949, and Strain, U.S. Letters Patent 2,486,922, granted November 1, 1949.

The nonionie synthetic detergents hereinbefore described as beneficially affected by the antibacterial mixtures of this invention may be broadly defined as compounds produced by the condensation of alkylene oxide groups with an organic hydrophobic compound which may be aliphatic or alkyl aromatic in nature.

For example, a well-known class of nonionics to which significant levels of anti-bacterial activity will be imparted through the incorporation of minor amounts of a halogenated salicylanilide-trilluoromethylcarbanilide mixture is marketed under the trade name Pluronic by the Wyandotte Chemical Co. of Wyandotte, Michigan. These compounds are formed by condensing ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol.

Other nonionics which are suitable for use with the mixtures of this invention include the polyethylene oxide condensates of alkyl phenols, e.g., the condensation prodnets of alkyl phenols having a straight or branched chain alkyl group containing from about 6 to 12 carbon atoms, with from about 10 to about 25 moles of ethylene oxide per mole of alkyl phenol. The alkyl substituent in each compound can be conveniently derived from polymerized propylene diisobutylene, octane, or nonane or from any other natural or artificial source which will provide alkyl chains with the requisite number of carbon atoms as specified hereinbefore.

Other suitable nonionics may be derived by the condensation of ethylene oxide with the product resulting from the reaction of propylene oxide and ethylene diamine.

A minor amount of a 1:1 mixture of 3,5,4'-tribromosalicylanilide and 3-trifluoromethyl-4,4-dichlorocarbanilide, for example, renders a composition containing any of the above detergents or mixtures thereof, antibacterially active against a broad range of microorganisms including some which are gram-negative.

Detergent compositions containing the anti-bacterial mixtures of this invention find utility in a variety of applications and physical forms as will be recognized by those skilled in the art. Such products may be used as toilet detergent bars, for example, the anti-bacterial mixture being present in amounts varying from 0.1% to by weight of the total composition. Preferably, the bar would contain the said anti-bacterial mixtures in amount varying from .5% to 2% by weight of the total composition.

Example X and sulfates) 9.2 3-trifiuoromethyl-4,4-dichlorocarbanilide 1.0 3,5,4'-tribromosalicylanilide 1.0 Water and miscellaneous 11.7

Middle-cut coconut alcohols having a chain length distribution substantially as follows: 2%C10, 66%C1.., 23%- C14, and 9%C1e.

A marked reduction in body odor was noted by users of this bar in a panel comparison with a control bar comprised as above, but without the anti-bacterial agent. This deodorant eifectiveness is also possessed by toilet detergent bars formulated as above but containing 3- trifluoromethyl 3',4,4' trichlorocarbanilide, 3,3'-bis (trifluoromethyl)-4-ethoxy-4-chlorocarbanilide or 3,5-bis- (trifiuoromethyl)-4-chlorocarbanilide in place of 3-trifluorornethyl-4,4-dichlorocarbanilide. Similarly, 3,5,4- tribromosalicylanilide can be replaced by any of the other halogenated salicylanilides of this invention, such as 5-bromosalicyl-3,5-di(trifiuoromethyl) anilide, 5- chlorosalicyl-3,5-di(trifiuoromethyl) anilide, 3,5-dichlorosalicyl-3,4-dichloroanilide or 5-chlorosalicyl-3-trifluoromethyl-4-chloranilide without decreasing the deodorant efiicacy of the product.

Example XI A granular built synthetic anionic laundry detergent composition having the following formulation was prepared by conventional means.

Parts Sodium alkyl benzene sulfonate (the alkyl radical averaging about 12 carbon atoms and being derived from polypropylene) 17.5 Sodium tripolyphosphate 49.7 Sodium sulfate 13.3 Silicate solids 7.0 3-trifiuoromethyl-3,4,4'-trichlorocarbanilide .05 3,5,4'-tribromosalicylanilide .05

Fabrics laundered in this product were imparted with substantial levels of anti-bacterial activity as was demonstrated by a marked reduction in surviving organisms when a suspension of viable test organisms were exposed to the laundered material.

The invention has been described above in conjunction with various illustrative examples of anti-bacterial compositions, toilet and laundry detergents. It will be obvious to those skilled in the art, however, that the antibacterial mixtures can also be beneficially employed in such products as tooth powder, toothpaste, mouth-Wash, antiseptic ointment, foot powders and the like.

What is claimed is:

An anti-bacterial composition comprising in combination (1) 3,5,4-tribromosalicylanilide and (2) 3-trifluoromethyl-4,4-dichlorocarbanilide, and the ratio (1) to (2) being between 1:9 and 9: 1.

References Cited in the file of this patent UNITED STATES PATENTS 2,703,332 Bindler Mar. 1, 1955 2,745,874 Schetty et al. May 15, 1956 2,906,711 Stecker Sept. 29, 1959 2,951,786 Pullen et al. Sept. 6, 1960 2,965,575 Beaver et al. Dec. 20, 1960 2,995,488 Jones et al. Aug. 8, 1961