US2380877A

US2380877A - xcoox

Info

Publication number: US2380877A
Authority: US
Publication date: 1945-07-31
Anticipated expiration: 1962-07-31

Description

Patented July 31, 1945 I UNITED STATES CPA-TENT OFFICE COMPOSITION FOR CO CTING MICROODGANISMS v Robert S. Shelton, Mariemont, Ohio, ascignor to The vWm. S. Men-ell Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application Ju y 11,1942,

Serial No, 450,816

This invention relates to compositions of matwherein one or said We represents an acylated taxfor counteracting micr r i m igerms. aliphatic group containing an acetoxy group in includin ba fungi. a t i and more which the -co ogroup is connected to the esp ia y to compositions in which e all nitrogen-atom-containing portion or the quatof the following properties are utilized: ba'c- 5 emu-y ammonium c'ompound through o. tericidal, antiseptic, fungicidal, detoxifying, bacatom f said C0o group, teriostatici Prophylactic and novel chemical Another R represents a high molecular weight compounds f such properties The inven' aliphatic group, advantageously cetyl, but which relates particularly to such compositions may be a saturated or unsaturated radical conwhich possess some or all of the aforementioned ie to a marked dc ree and which comgigz z or more quaternary ammonium essential chain, and may be a' forked or a straight pounds. chain, and which may also contain substltuents, In a prior patent, No. 2,295,504, dated Septemfor ple. the hydroxyl, halogen, carbethoxy taining fourteen to eighteen carbon atoms in its her a, 1942, I have disclosed that the acylated l5 and amino groups which are such or so quaternary ammonium compounds, having an attached as to leave substantially the identity on aliphatic group of 14 t 18 carbon atoms attached the essential chain; and the remaining R's repto the ammonium nitrogen atom, are particularly resent low molecular weight groups, advanadvantageous in compositions for counteracting tageously hydrocarbon groups of not more than 4 microorganisms. Within that .class the cetyl 20- carbon atoms, which may be separate or joined dimethyl carbethoxy methyl ammonium cointogether to fo a betel-Owen, ring with the pounds were claimed as particularly advantaammonium nitrogen atom geous. I have now found that analogous quaterx stands for any acid ion constituent which nary ammonium compounds of the acetoxy type forms soluble quaternary ammonium com'pounds have similar advantages and in some respects of this type for example are surprisingly superior. Certain of these com- =80 0 pounds are among the most advantageous for beans 0C practical use in bactericidal, antiseptic, fungi- 0C OC 4 e cidal, bacteriostatic, etc., compositions. boxync and iillcarboxync acids Such tartaric The object of my invention, therefore, was to and and lower y. c acids insofar as make available novel compositions of matter they form soluble salts of these ernary amwhich combine high elllcacy as bactericidal, antimQnium COmDOImdS- Po yva ent acid radicals septic, fungicidal, detoxifying, bacteriostatic and m mb ne several similar quaternary ammoprophylactic agents against difl'erent types of mm gr upsof the above type into a single pathogenic micro-organisms, and compatability molecule, or'one such group may be combined in effective concentrations with human tissues with the acid while remaining valences of the and b y fluids d those 0! hig e Organacid radical are satisfied by different radical or isms as -well, as with common ingredients of cations or by hydrogen Pharmaceutical compositions and low cost of The acid ion constituent used in these commanufacture from readily available materials. 40 pounds may also influence the properties. and

I have achieved this object by compositions the essential feature of which is the chemical com-' especially solubility toxicity and surface activity For bactericidal purposes I have found that in ation e resented b the formula: hm p y general the bromides and chlorides are the best K compounds in these respects.

The following compounds will illustrate my invention specifically:

Aliphatic quaternary ammonium salts Crlticalkilling I (mutton Phenol cocillcient pproxi- Chcmlcal name malteglfier Sta Y an, m was,

p-Acctc thyl cetyl dimothyl ammonium bromide l: 000 i=44,ooo is: 488 1: p-Acetog thyl cetyl dlmcthyl ammonium iodide 1381M 1:420!!! 83 466 1:80 gel: fl-Aeetoxycthyl cetyl dimethyl ammonium p-hydroxy-' benzoate' 1:8,(0) 154,000 66 266 1:30 p-Acetoxyetllyl cetyl dimethyl ammonium nltrate'.--- 1:7,(110 l:38,000 58 422 1:40 fl-Acetoxyetllyl cetyl dicthyl ammonium bromide 1:12.01!) 1160,00!) 666 1:10 Cotyl di-n-butyl acetoryethyl ammonium bromide 1:16,) 1:52,000 133 577 Compounds marked with asterisk were not purified as well as the other compounds.

The above data represent the results of actual tests with the respective compounds of the highest purity available at the time. With the exception of the compounds marked with an asterisk. these are believed to be substantially pure-i. e. of a purity such as one would expect to use for pharmaceutical applications of my invention. However, as the degree of purity is not absolutely uniform among these several compounds tested, allowances must be made in comparing the respective in cases where comparative tests have been made with the partially purified or commercial grade chemicals as against the corresponding highly purified compounds has produced significant increases in activity. Thus, for example, p-acetoxyethyl eetyl dimethyl ammonium bromide. made from chemicals as purchased commercially showed critical killing dilution of 1:12.000 against E. iyphi and 1136,000 against Staphylococcus aureus and when further purified and retested these were shown to be increased respectively to 1:40.000 and. 134,000.

It will be noted that the compounds above listed have the cetyl group as their high molecular weight aliphatic hydrocarbon group, that is, the groups containing sixteen carbon atoms. These compounds have been found to be of especially high bactericidal efilcacy on various yp s of pathogenic organisms, low toxicity to higher animals and humans. good surface tension depressing. penetrating and emulsifying power, are nonirritating in eifective concentrations and have good detoxifying power.

For the three low molecular weight hydrocarbon groups of the formula hereinabove described it has been found. in practice, that the methyl, ethyl, butyl and acetoxyethyl groups are especial- 1y satisfactory.

The bromides. chlorides and the metho-suliates are most active of the compounds tested: and, generally speaking, the nitrates and the ledides are suitable In general, organic salts are not so good as the mineral acid salts. although the benzoates, salicylates, tartrates, and aromatic aliphatic acids such as the hydrocinnamates are quite good. The higher fatty acids give the poorest results especially in aqueous compositions and usually give relatively insoluble salts, and for this reason fatty acidsand fatty acid soaps should be avoided in using compositions of my invention. Benaoates and salicylstes which easily form gels have been found particularly suitable for lotions. etc. 'lhe compounds similar to the metho-sulfates having low molecular weight organic groups and a quaternary ammonium group of the type defined both with a polybasic acid, are found as a group to be very good and relatively mor highly eifective against E. typhi.

It should be imderstood, f course, that although these conclusions are drawn from tests with numerous compounds which have been syn thesizedandtestedforthemirposeofdeterminvalues given. Increase in purity lug trends toward better antiseptic. germicidal.

etc., properties, still they should not be regarded as absolute, but are given rather as indications in ordertoassist others in choosing thebest compounds and perhaps discovering better compounds within the scope of my invention. Like all conclusions in chemistry, these should be taken andused with caution, and it shouldb'e understood that my invention does not depend upon the correctness or these conclusions; and I do not wish to be bound thereby.

It will be understood, of course, that the figincressa their solubiliia asses" ures given for activity against the two organisms named cannot be taken as absolute, since they willvarytosomedegree fromtesttotestwith variations in the cultures used: and I have found also that impurities present may have a substantial infiuenceon the. exact figure obtained by such a test, although it is an advantage of these compositions that they retain strong activity in the presence of substances which would normally occur during use.

' As will be seen from the above fi r s. these compositions are among the most active thus far discovered, and at the same time they are among the best with respect to low toxicity to humans and animals and with respect to retention of activity in the presence of carbohydrates, especial- 1y s gars. proteins. serum or other substances with which such micro-organisms are commonly found in their active life.

The compounds of my invention are active in aqueous and oleaginous compositions and tinctures.

Another valuable quality of these compounds is their-relative immunit to acidity and alkalinity. This quality and particularly the relative immunity to presence or iron. calcium and magnesium are especially important in mouth washes, tooth pastes. tooth powders, and antiseptic cleaning compositions for general use, in all of which an alkaline reaction may be important.

These qualities and immunities and the fact that the compounds are comparatively tasteless. odorless and non-staining. make it possible to use compositions including these quaternary ammonium compounds in compositions which contain flavoring. coloring, therapeutic 01' healing ingredients, and in various pharmaceutical, cosmetic and prophylactic compositions. The compositions or my invention may also be used as preservatives in all kinds of materials. including biological materials, fruits. vegetables and grains, etc.. and in general wherever organiedecomposition or putrefaction might occur. when used on fruits or vegetables it is foimd that their penetrating and emulsifying power assists in removal of spray residues as well Is assuring destruction of decay infections.

Tests that have been made show that these compounds have a remarkable detoxifying action even in fairly dilute solutimis.

In the concentration required for disinfection and purification procelestheyd'onot'iniuroor stain the human skin and may. therefore, be used for disinfecting the skin, particularly the hands. Furthermore, it has been observed that these compoundsin dilutionsofito 1.000 endlesshave slow surface tension forthe moetpartinthe range between 80-40 dynes/cmi, thus insuring good penetration.

' Iheammoniumofthepresent|n-' aresolubleto aeertainex't'ent suchas-oliveoraimondoibandthat'ths enceoi'asmallamountof in oil. compoundswi-llbeofdesirableusein olntment'boses bactericidal, for

addition to their use in the oil soluble ointmenttype, we also find that they have decided germicidal action in water soluble jellies, for example, in a tragacanth base.

It is not necessary that other ingredients should be used, but generally we find that a simplewater solution or tincture will be most useful as a general antiseptic.

One very valuable composition, for example, isan aqueous solution diluted 1:1,000. This may be further diluted for use in cleansing or dress- These, of course, are only examples; and it should be understood that their proportions can be varied substantially and that numerous other types of compositions are within the scope of the invention.

In dentifrices and mouthwashes the sugar and acid immunity of the germioide are especially important qualities in view of the recent evidence that dental caries is due to growth of lactic acid bacillus. In oil base compositions, the emulsifying or surface tension reducing quality of these germicides is of utmost importance, because it breaks down the barrier of the interface and allows the germicide in the oil solution to become effective in the body fluids and/or the cell fluids of the organisms against which they are used.

These germicides also lend themselves well to germicidal hand cleaners of the type in which a wetting or lathering agent is absorbed on a carrier such as a colloidal clay, e. g., bentonite, diatomaceous earth, pumice, etc. (which may also act as an abrasive or scouring agent), and pressed into cakes with or without a binder adapted to delay disintegration in water. Such wetting agents, for example, as sulfonated aromatic ether alcohols (e. g., Triton Suds), sodium salt of alkyl naphthalene sulfate (Alkanol), aromatic sodium sulfonates (Ultra Wet), sodium oleyl amino ethyl sulfate (Igepon), may be used in this way combined with the germicides of my present invention to the extent of 1 to 10%, or a crude quaternary ammonium compound of the type above described may serve both as the detergent wetting agent and as antiseptic when mixed with a suitable carrier.

The compounds of my present invention also have the valuable property of forming remark ably stable dispersions of colloidal metals and inmethods known to those skilled in the art, for

example, by reacting upon an aliphatic amine with a reactive halide of a higher molecular aliphatic hydrocarbon.

- fates, nitrates, salicylates', benzoates, acetates, tar- Mouth wash:

Germicide per cent .02.04 Boric acid do 1 Alcohol do 20-30 Flavor As required Color As required Water q. s per cent Skin antiseptic:

Germicide per cent .1-.5 .Dye As required Alcohol per cent 40-50 Water q. s do 100 Cough drops:

Germicide per cent .1 Aromatics As required Sugar q. s per cent 100 Lipstick: v

Germicide per cent .1 Beeswax do 33 ,Lard do 12 Castor oil do 49 Perfume and color q. s As required Dentifrice (paste or powder):

Germicide. per cent .1 CaCOsdo 50 Tricalcium phosphate d0 25 Magnesium carbonate or hydroxide) d0- 24 Saccharin and flavor do .9 Wetting agent"; do .1 Nose drops:

Germicide per cent .04-.02 Ephedrine S04 d0 1 Dextrose do 4 Water (1. s do 100 Germicidal ointment:

Germicide per cent 0.1

, Hydrous lanolin do 50.0 Petrolatum 'do 50.0 Antiseptic medicated skin cream:

Germicide per cent 0.1 Glyceryl ,monostearate do 10.0 Glycerin do 50 Water do 85.0 Lubricating jelly:

Germicide per cent 0.1 Tragacanth do 1.0 Glycerin do Water q. s do 100 Alternatively, amines, which already contain a higher molecular aliphatic group, may be reached with aliphatic halide, sulfate, acetate, etc., to form the same type of ammonium salt. It has also been observed that the corresponding halides, sultrates, etc., can easily be prepared by a prolonged boiling of the bromide in an organic solvent with the corresponding salt of the alkali, alkaline earth or heavy metal. By the above reactions high molecular weight quatem-ary ammonium compounds are obtained, some of which are crystalline, some viscous liquids, and some wax-like substances, which, in general, depending upon the acid radicals, readily dissolve in water, forming stable, odorless, colorless and relatively nontoxic solutions.

Since, as stated above, the activity of these compounds is decreased by substituting aliphatic groups of higher or lower molecular weight, especially above 18 carbon atoms or below 14, it is desirable to purify either the final compounds or to use pure reagents in their manufacture. If substantial amounts of the hi e or lower homologs are permitted in the final product, they will aifect the antiseptic, etc., strength or activity of the product which, therefore, can beaccurately specifled only after careful analysis and calculation or actual quantitative tests.

The following examples will serve to illustrate some methods of preparing products embodying the principles of this invention which are suitable for use in the illustrative compositions given above, without being restricted thereto:

Example No. 1

17 parts by weight of p-bromoethylacetate and parts by weight of diethylamine are kept at 40 C. for two days, then diluted with an equal volume of ether and the precipitate of diethylamine hydrobromide filtered. The filtrate was distilled to give 15 parts of p-diethylaminoethyl- Example No. 2

A mixture of 13.5 parts of pure cetyl dimethylamine and 8.4 parts of fl-bromoethyl acetate is heated at 70 C. for 24 hours, then crystallized from 75-100 parts of acetone, washed with ether, 'and dried to give a crystalline product consistin essentially of B-acetoxyethyl cetyl dimethyl ammonium bromide, M. P. 83-85 C. and dissolving readily in five parts of water.

What is claimed is:

1. A germ counteracting composition which comprises as the essential germ counteracting ingredient therein a cetyl beta-acetoxy-ethyl dimethyl ammonium salt.

2. A germ counteracting composition which comprises as the essential germ counteracting ingredient therein a cetyl beta-acetoxy-ethyl dimethyl ammonium bromide.

3. A germ counteracting composition which comprises as the essential germ counteracting ingredient therein a cetyl beta-acetoxy-ethyl diethyl ammonium salt.

4. A germ counteractng composition which comprises as the essential germ counteracting in- ,gredient therein a cetyl beta-acetoxy-ethyl diethyl ammonium bromide.

v to, besides an anion which forms an oil-soluble comprises as the essential germ counteracting ingredient therein a cetyl beta-acetoxy-ethyl di- N-butyl ammonium salt.

6. A germ counteracting composition which comprises as the essential germ counteracting ingredient therein a cetyl beta-acetoxy-ethyl di-N- butyl ammonium bromide.

7. A germ counteracting composition whic comprises as the essential germ counteracting ingredient therein a quaternary ammonium compound having attached to the quaternary nitrogen atom one cetyl group, one acetoxy group, two hydrocarbon radicals of less than live carbon atoms, each, and an anion which forms soluble quaternary ammonium compounds.

8. A germ counteracting composition which comprises, as the essential germ counteracting ingredient therein, a soluble quaternary ammonium compound, the ammonium nitrogen of which has attached thereto, besides an anion which forms a soluble quaternary ammonium compound, one higher aliphatic radical of not less than 14 nor more than 18 carbon atoms, and one acylated lower molecular weight aliphatic radical including an acetoxy group, the carboxyl of which is connected through its O atom to the ammonium-nitrogen-containing portion of the molecule, and has attached thereto by two of its remaining valence linkages at least one lower molecular weight hydrocarbon radical, the sum of the carbon atoms in the portion of the molecule thus attached through said two valence linkages being less than 8.

9. A germ counteracting composition which comprises an oleaginous vehicle and, as the essential germ counteracting ingredient therein, a soluble quaternary ammonium compound, the ammonium nitrogen of which has attached therequatemary ammonium compound, one higher aliphatic radical of not less than 14 nor more than 18 carbon atoms, and one acylated lower molecular weight aliphatic radical including an acetoxy group, the carboxyl of which is connected through its O- atom to the ammonium-nitrogen-containing portion of the molecule, and has attached thereto by two of its remaining valence linkages at least one lower molecular weight hydrocarbon radical, the sum or the carbon atoms in the portion of the molecule thus attached through said two valence linkages being less than 8.

ROBERT S. SHELTON.