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Publication numberUS3493615 A
Publication typeGrant
Publication dateFeb 3, 1970
Filing dateOct 28, 1968
Priority dateOct 28, 1968
Publication numberUS 3493615 A, US 3493615A, US-A-3493615, US3493615 A, US3493615A
InventorsRobert Andrew Bauman
Original AssigneeColgate Palmolive Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Surfactant anti-microbial compounds
US 3493615 A
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Description  (OCR text may contain errors)

United States Patent O 3,493,615 SURFACTANT ANTI-MICROBIAL COMPOUNDS Robert Andrew Bauman, New Brunswick, N.J., assignor to Colgate-Palmolive Company, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 494,948, Oct. 11, 1965. This application Oct. 28, 1968, Ser. No. 771,284

Int. Cl. C07c 87/30, 141/00; A61k 27/00 US. Cl. 260-567.6 Claims ABSTRACT OF THE DISCLOSURE Antimicrobial long chain symmetrical tetrakisquaternary ammonium compounds are disclosed which have the formula:

wherein R is an alkyl of C to C R, R.and R are each alkyl of C to C or aralkyl; x is 3 to 10; y is 2 to 10, and A is an anion.

The present application is a continuation-in-part of applicants copending patent application S.N. 494,948, filed Oct. 11, 1965, now abandoned.

The present invention relates to novel long chain symmetrical tetrakisquaternary ammonium compounds and, more particularly to long chain symmetrical tetrakisquaternary ammonium compounds having anti-microbial properties.

The preparation of polyquaternary ammonium compounds per se is not novel. On the other hand, all polyquaternary ammonium compounds are not anti-microbial. For example, Lewis et al. have reported in the British Journal of Pharmacology 20, 307-18 (1963) that short chain tetrakisquaternaries are neuromuscular blocking agents. G. Sykes has shown that the presence of serum interferes with the anti-microbial capabilities of some quaternary ammonium salts. (Disinfection and Sterilization, page 296, D. Van Nostrand, Princeton, NJ. 1958.) Consequently, while many US. patents provide descrip tions of quaternary ammonium compounds which are said to possess preserving and/or disinfecting, bactericidal and/or fungicidal properties, the capabilities of new quaternary ammonium compounds are not predictable a pnori.

For example, in US. Patent No. 2,108,765 it is stated that alpha-dodecyloxy-beta-hydroxypropyl-diethylbenzylammonium chloride in a concentration of 1:50,000 kills colibacteria within 10 minutes and staphyloccoci within minutes. At the same concentration dodecyl-diethylbenzyl-ammoniumchloride kills colibacteria after 10 minutes and staphyloccoci after 2 /2 minutes. However, the description in this patent which issued about twenty years before the publication of Sykes treatise does not describe the effect of the presence of serum on the capabilities of these quaternary ammonium compounds.

In 1939 US. Patent No. 2,178,522 issued describing aliphatic polyamines prepared by hydrogenating a polymerized aliphatic nitrite. Of course, amines do not have the properties of quaternary ammonium compounds.

The germicidal properties of N-alkylated alkylene polyamines and their salts such as dodecyldiethylene triamine, C H NHC H NH-C H NH and hexadecyltriethylene tetramine,

are described in US. Patent No. 2,246,524. While the phenol coeflicients for a number of these polyamines are 3,493,615 Patented Feb. 3, 1970 given the presence of serum during the test is not indicated.

The bactericidal and/or fungicidal capabilities of numerous quaternary ammonium compounds or polyamine compounds are discussed in such US. patents as Nos. 2,261,002; 2,295,505; 2,375,853; 2,388,614; 2,454,547; 2,717,909; 2,818,434; 2,857,380; 2,879,200; and 3,079,436.

However, that all polyamine or quaternary ammonium compounds are not anti-microbial or fungicidal is manifest from the disclosures in US. Patent Nos. 2,918,464; 2,807,910; 3,009,761; and 3,064,039.

The quaternary ammonium compounds represented by the formula wherein R and R are either each a phenyl group or they together form with the neighboring nitrogen atom a carbazole, a phenoxazine or a phenothiazine ring system or the sulphoxide or the sulphone of a phenothiazine ring system; n is an integer from 2 to 10; N'+ is a quaternary nitrogen atom carrying two methyl or ethyl groups; N-+ is a quaternary nitrogen carrying at least one methyl or ethyl group and either two additional methyl or ethyl groups or forming a part of a pyrrolidine, piperidine or morpholine ring; Y is an alkylene chain having 2 or 3 carbon atoms; and A is an anion of an inorganic or organic acid are said to have the property of blocking ganglion transmission.

The polyquaternary ammonium compounds represented by the formula Y is C1 or Hal Hal is halogen, and n is a number between 4 and 29 are useful in the after-treatment in the conventional manner of dyed textiles.

The fact that a priori determination of the capabilities of the polyammonium compounds is not possible is further illustrated by the peculiarities of the polyquaternary ammonium compounds described in US. Patent No. 2,807,910. These polyquaternary ammonium compounds, the formulae of thirty-eight of which are given by the patentees, are said to react with the soil particles and tend to bind individual particles into aggregates of larger size which no longer possess the colloidal properties of clay when wet and hence are useful for conditioning clay soil for agricultural purposes.

In view of the foregoing brief recital of the capabilities of some polyquaternary ammonium compounds it is manifest that one skilled in the art cannot determine from the formula of the quaternary the capabilities thereof.

The novel polyquaternary ammonium compounds of the present invention are represented by the formula where R is a long alkyl chain, straight or branched, having to inclusive carbon atoms; R, R", R' are alkyl chains having one to four carbon atoms or aralkyl groups; A is an anion such as Cl, Br, I, CH COO, CH SO x is three to ten inclusive; and y is 2 to 10 inclusive. For R and R" the preferred aralkyl groups are phenalkyl radicals having l-2 carbon atoms in the alkyl group and for R the preferred aralkyl groups are phenalkyl radicals having 1-8 carbon atoms in the alkyl group as illustrated by the specific examples appearing below. It is to be observed that since R is the same alkyl group having 10 to 20 inclusive carbon atoms these polyquaternary ammonium compounds are symmetrical polyquaternary ammonium compounds and particularly tetrakisquaternary ammonium compounds. As those skilled in the art know the symmetrical polyquatemary ammonium compounds are distinguished from the unsymmetrical polyquarternary ammonium compounds generally by the fact that the distinguishing substituents of the terminal quaternary ammonium nitrogens are different in the unsymmetrical quaternaries but the same in the symmetrical quaternaries.

It is an object of the present invention to provide a method of preparing symmetrical tetrakisquaternary ammonium compounds described hereinbefore. It is another object of the present invention to provide novel symmetrical tetrakisquaternary ammonium compounds described hereinbefore. It is a further object of the present invention to provide microbial agents comprising a pharmaceutical acceptable carrier and an effective amount of at least one symmetrical tetrakisquaternary ammonium compound described hereinbefore. It is also within the purview of the present invention to provide microbial agents comprising pharmaceutically acceptable carrier and an amount of at least one hereinbefore described tetrakisquaternary ammonium compound effective in the presence of serum against at least one Staphylococcus aureus, Coiynebacterium acne, Bacillus subtilis, Escherichia coli, Pseud monas aeruginosa, Candida albicans, trichlorophyton mentagrophytes, and Aspergillus niger. These and other objects of the present invention will become apparent to those skilled in the art from the following description of the present invention.

Illustrative of the preparation of the tetrakisquaternary ammonium compounds hereinbefore described and the microbial capabilities of the tetrakisquaternary ammonium compounds of the present invention is the following.

EXAMPLE I Compound A represented by the formula [RN(R) (CH NR" CH CH NR (CH NR" R]Br where R is dodecyl, R is methyl, x and y each is three, 1.e,.

is prepared by refluxing for twenty minutes 0.02 mol of dodecyl-dimethyl(3-bromopropyl) ammonium bromide and 0.01 mol of N,N,N',N'-tetramethylethylenediamine in milliliters of methyl ethyl ketone. A precipitate formed which is separated from the reaction mixture by filtration. The filter cake is washed with water and dried. After recrystallization from acetone-methanol the crystalline product melts at 2062l0 C.

The calculated nitrogen and bromine contents of are respectively 5.92 percent and 33.76 percent. On analyzing the recrystallized reaction product for nitrogen and bromine concentrations of 5.71 percent and 33.38 percent respectively are found. By paper chromatography the recrystallized reaction product is shown to be different from the starting material and the bisquaternary From the foregoing it is concluded that the recrystallized reaction product obtained as described hereinbefore (Compound A) is represented by the formula EXAMPLE II In a similar manner the tetrakisquaternary ammonium compound (Compound B) is represented by the formula The anti-microbial activity of the symmetrical tetrakisquaternary ammonium compounds of the present invention in which the cationic moiety is represented by the formula nnna nong)xr 'in nonn fin nonnxfin' a'm where R, R, R", R, x, y have the significance given hereinbefore is illustrated by the anti-microbial activity of compound A, i.e., 12 25 2( 2)3 2( 2)2 N+Me 3N+M2C12H25] BI'4 and the anti-microbial activity of compound B, i.e.,

The anti-microbial activity is measured in test tube serial dilution test in the absence and in the presence of serum. The numerical values set forth in the following tabulation are minimum effective concentrations in micrograms per milliliter (g./ ml).

Organism 1 2 3 4 5 6 7 8 Compound A. 3. 13 12. 5 1. 25 25 25 6. 25 31. 3 31. 3 Compound A with 10% Serum 12. 5 25 6. 25 25 Compound B 12. 5 12. 5 3. 13 12. 5 25 6. 25 31. 3 15. 6 Compound B with 10% Serum 25 25 6. 25 50 Organisms-1. Staphylococcus aureus; 2. Coryncbacterium acne: 3. Bacillus subtilis; 4. Escherichia coli; 5. Pseudomonas aeruginusa; 6, Candida albicans; 7. Trichophyton mentagrophytes; 8. Axpergillus niger.

As is to be anticipated the anti-microbial activity is not uniform with all of the tested organisms and each compound does not exhibit anti-microbial activity of the same order against each organism. For example, compound A is eifective against staphylococcus aureus in the absence of serum at a minimum concentration of 3.13 micrograms per milliliter whereas compound B is effective against the same organism in the absence of serum only at a concentration about 4 times that of compound B. On the other hand, compound B is elfective against Escherichia coli in the absence of serum in a minimum concentration of 12.5 micrograms per milliliter whereas compound A is only effective against the same organism in concentrations twice that of compound B. While both compound A and compound B retain their efiicacies in the presence of semm it is of interest that serum has a greater apparent affect on one compound than on the other. For example, the minimal concentration of compound A must be quadrupled to obtain an effective concentration against Staphylococcus aureus in the presence of serum whereas the concentration of compound B need only be doubled. Whereas compound A is effective against Bacillus subtilis in the absence of serum in a minimal concentration of 1.25 micrograms per milliliter and compound B is effective in a minimal concentration of 3.13 micrograms per milliliter in the presence of serum both compound A and compound B are effective at the same minimal concentration of 6.25 micrograms per milliliter.

These results indicate the substantial activity of these compounds. What is of at least as great importance is that a substantial proportion of the activity of these compounds is manifested in the presence of ten percent of serum which as reported by G. Sykes (ibid) interferes with the performance of some quaternary ammonium anti-microbials.

EXAMPLE III Example I is repeated except that in place of 0.02 mol of the dodecyl quaternary compound there are used, in separate preparations, 0.02 mols of the following:

(A) decyl dimethyl(3-bromopropyl)ammonium bromide (B) hexadecyl dimethyl(3-brornopropyl)ammonium bromide (C) eicosyl dimethyl(3-bromopropyl)ammonium bromide (D) decyl diethyl(3-bromopropyl)ammonium chloride (E) tetiadecyl diisopropyl(3-bromopropyl)ammonium bromide (F) octadecyl di-n-butyl(3-bromopropyl)ammonium bromide (G) dodecyl diethyl(6-bromo-n-hexyl) ammonium bromide (H) hexadecyl di-n-propyl(l0-bromo-n-decyl) ammonium bromide (I) dodecyl dibenzyl(3-bromopropy1)ammonium bromide (J) tetradecyl di-phenethyl(4-bromobutyl)ammonium bromide EXAMPLE IV Example I is again repeated except that the cliamine is replaced (same mols) in separate preparations, by the following:

(A) N,N,N',N-tetraethyl ethylenediamine (B) N,N,N',N'-tetraisopropyl ethylenediamine (C) N,N,N',N'-tetrabenzy1 ethylenediamine (D) N,N,N',N'-tetramethyl propylenediamine (E) N,N,N',N'-tetra-n-butyl ethylenediamine (F) N,N,N',N-tetra-n-butyl butylenediamine (G) N,-N,N'.N'-tetra-n-butyl decylenediamine (H) N,N,N',N'-tetramethyl nonylenediamine (I) N,N,N',N'-tetrabenzyl hexylenediamine (J) N,N,N,N'-tetraphenethyl pentylenediamine 6 EXAMPLE v Examples IIIA, IIIC, IIIF and IIIH are each repeated except that in place of the diamine used in those examples there are used in separate preparations equimolar amounts of the following:

(A) N,N,N',N-tetraethyl ethylenediamine (B) N,N,N,N'-tetraethyl butylenediamine (C) N,N,N',N'-tetraethyl nonylenediamine (D) N,N,N,N-tetra-t-butyl propylenediamine (E) N,N,N',N'-tetra-t-butyl decylenediamine (F) N,N,N',N'-tetrabenzyl hexylenediamine (G) N,N,N',N-tetraphenbutyl hexylenediamine (H) N,N,N',N'-tetraphenoctyl ethylenediamine Although the present invention has been described with reference to particular embodiments and examples, it will be apparent to those skilled in the art that variations and modifications of this invention can be made and that equivalents can be substituted therefor without departing from the principles and true spirit of the invention.

What is claimed is:

1. Tetrakisquaternary ammonium compounds having the following formula:

wherein R is an alkyl of C to C R and R" are each alkyl of C to C or phenalkyl having 1 to 2 carbon atoms in the alkyl group; R' is an alkyl of C to C or phenalkyl having 18 carbon atoms in the alkyl group; x is to 3 to 10; y is 2 to 10; and A is an anion selected from the group consisting of chloride, bromide, iodide, acetate and methylsulfate.

2. A compound, as defined in claim 1 wherein R is dodecyl; R, R" and R are each methyl; x is 3; and y is 3.

3. A compound as defined in claim 1 wherein R is dodecyl; R, R" and R' are each methyl; x is 4; and y is 4.

4. A compound as defined in claim 2 wherein A is bromine.

5. A compound as defined in claim 3 wherein A is bromine.

References Cited FOREIGN PATENTS U.S. Cl. X.R.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
GB892413A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3943255 *May 22, 1974Mar 9, 1976Nalco Chemical CompanyAlkyl polymaine microbiocides
US3966904 *Jul 7, 1975Jun 29, 1976Millmaster Onyx CorporationQuaternary ammonium co-polymers for controlling the proliferation of bacteria
US4016209 *Apr 23, 1975Apr 5, 1977Merck & Co., Inc.3-[N'-(3-Halopropyl)-N-'-methylamino]-N,N,N-trimethyl-1-propanaminium halide and acid addition salts thereof
US4025617 *Jul 7, 1975May 24, 1977Millmaster Onyx CorporationAnti-microbial quaternary ammonium co-polymers
US4038303 *Feb 20, 1976Jul 26, 1977Colgate-Palmolive CompanyQuaternary ammonium carbamide compounds
US4166073 *Aug 22, 1977Aug 28, 1979Colgate Palmolive CompanyUnsymmetrical oligoquaternary ammonium compounds
US4205064 *Apr 11, 1979May 27, 1980Merck & Co., Inc.Bile acid sequestering composition containing poly[{alkyl-(3-ammoniopropyl)imino}-trimethylenedihalides]
US20100081844 *Dec 4, 2009Apr 1, 2010Charles LittlePolycationic organic compounds
Classifications
U.S. Classification564/295, 558/27, 562/607, 564/290
Cooperative ClassificationA61K31/14