Dihaloformaldoxime carbamates as antimicrobial agents

Disclosed is a method of inhibiting the growth of microorganisms in, at, or on a locus subject to microbial attack, comprising introducing to said locus an antimicrobially effective amount of at least one dihaloformaldoxime carbamate.

BACKGROUND OF THE INVENTION 
The present invention relates to a method for inhibiting the growth of 
microorganisms. In particular, the present invention relates to the use of 
certain dihaloformaldoxime carbamates as antimicrobial agents. 
Antimicrobial agents are used commercially to prevent microbial growth in 
water cooling towers, metalworking fluid systems, paints, and other loci. 
Currently available antimicrobial agents include mixtures of 
5-chloro-2-methyl-3-isothiazolone and 2-methyl-3-isothiazolones. While 
these isothiazolones are very effective in preventing microbial growth, 
they suffer from being slow killing and unstable under certain conditions. 
Nitrate salts are effective stabilizers for 3-isothiazolones, but the 
level of salt usually required can cause problems, such as coagulation of 
latices and salt build up in closed systems. There is therefore a 
continued need for antimicrobial agents which are stable, do not have a 
high salt content, have low use levels, provide quick speed of kill, 
degrade quickly upon use, and are safe to use in the environment. 
U.S. Pat. No. 3,553,264 (Addor) discloses certain dihaloformaldoxime 
carbamates, methods for their preparation, and their use as postemergence 
herbicides. This patent also teaches the use of such dihaloformaldoxime 
carbamates as intermediates in the preparation of insecticides. This 
patent neither teaches nor suggests the use of such compounds as 
antimicrobial agents. 
STATEMENT OF THE INVENTION 
The present invention provides a method of inhibiting the growth of 
microorganisms in, at, or on a locus subject to microbial attack, 
comprising introducing to said locus an antimicrobially effective amount 
of at least one antimicrobial agent, wherein such antimicrobial agent is 
applied at low use levels, provides quick speed of kill, degrades quickly 
upon use, and is safe to use in the environment, such antimicrobial agent 
being of the formula: 
##STR1## 
wherein: X, Y are independently selected from Br, Cl, or I; and R=(C.sub.1 
-C.sub.8)alkyl, aryl, or substituted aryl. 
DETAILED DESCRIPTION OF THE INVENTION 
As used in this specification, the term "antimicrobial agent" refers both 
to a compound capable of inhibiting microbial growth (a preservative), and 
a compound capable of reducing microbial concentration (a disinfecting 
agent), within a given system. The term "antimicrobial activity" refers to 
the activity of the antimicrobial agents to eliminate, inhibit or prevent 
the growth of microorganisms. The terms "microbial organism," "microbe" 
and "microorganism" are used interchangeably and refer to microorganisms 
such as, but not limited to, fungi, bacteria, and algae. The following 
abbreviations are used throughout this specification: L=liter; 
mL=milliliter; g=grams; mol=moles; mmol=millimoles; wt %=percent by 
weight; mp=melting point. These antimicrobial agents are effective against 
microorganisms, including but not limited to: fungi, bacteria, and algae. 
Ranges specified are to be read as inclusive, unless specifically 
identified otherwise. 
The compounds useful as antimicrobial agents in the present invention are 
those of formula (1), above. Preferred compounds of the present invention 
are those of formula (1) above, wherein X and Y are bromine. Especially 
preferred compounds of the present invention include the compounds listed 
in the following table. 
______________________________________ 
Cpd No. 
Compound Name 
______________________________________ 
1 N-methyl-dibromoformaldoxime carbamate 
2 N-(2-chloroethyl)-dibromoformaldoxime carbamate 
3 N-(4-chlorophenyl)-dibromoformaldoxime carbamate 
4 N-(2,4-dichlorophenyl)-dibromoformaldoxime carbamate 
5 N-ethyl-dibromoformaldoxime carbamate 
6 N-(n-butyl)-dibromoformaldoxime carbamate 
7 N-(n-octyl)-dibromoformaldoxime carbamate 
8 N-(n-hexyl)-dibromoformaldoxime carbamate 
9 N-(4-methylphenyl)-dibromoformaldoxime carbamate 
______________________________________ 
As used in this specification, "alkyl" means straight or branched chain 
(C.sub.1 -C.sub.12)alkyl, and "substituted aryl" means an aryl group 
having one or more of its hydrogens replaced with another substituent 
group. Examples of suitable substituent groups include (C.sub.1 
-C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy, hydroxy, nitro, halo, cyano, 
(C.sub.1 -C.sub.3)alkylthio, and mercapto. Examples of substituted phenyl 
groups include 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 
4-chlorophenyl, 2-methoxyphenyl, and 4-methoxyphenyl. 
In the present invention, the carbamates of dibromoformaldoxime are 
generally synthesized by treating dibromoformaldoxime with alkyl or aryl 
isocyanates in methylene chloride in the presence of a catalyst, such as 
dibutyltin dilaurate, at a temperature between 0.degree. and 25.degree. C. 
The reaction time is between 2 and 48 hours, depending on the reactivity 
of the isocyanates. For example, the synthesis of N-butyl 
dibromoformaldoxime carbamate can be depicted by the following reaction 
scheme. 
##STR2## 
The preparation of starting materials, dibromoformaldoxime and 
dichloroformaldoxime, are known in the literature. For example, the 
synthesis of dibromoformaldoxime can be found in Tetrahedron Letters, 
25:487 (1984). This reference is hereby incorporated by reference to the 
extent it teaches preparation of dihaloformaldoximes. 
The antimicrobial agents of the present invention can be used to inhibit 
the growth of microorganisms by introducing a microbicidally effective 
amount of one or more of said agents onto, into, or at a locus subject to 
microbial attack. Suitable loci include, but are not limited to: cooling 
towers; air washers; boilers; mineral slurries; wastewater treatment; 
ornamental fountains; reverse osmosis filtration; ultrafiltration; ballast 
water; evaporative condensers; heat exchangers; pulp and paper processing 
fluids; plastics; emulsions and dispersions; paints; latexes; coatings, 
such as varnishes; construction products, such as mastics, caulks, and 
sealants; construction adhesives, such as ceramic adhesives, carpet 
backing adhesives, and laminating adhesives; industrial or consumer 
adhesives; photographic chemicals; printing fluids; household products, 
such as bathroom disinfectants or sanitizers; cosmetics and toiletries; 
shampoos; soaps; detergents; industrial disinfectants or sanitizers, such 
as cold sterilants, hard surface disinfectants; floor polishes; laundry 
rinse water; metalworking fluids; conveyor lubricants; hydraulic fluids; 
leather and leather products; textiles; textile products; wood and wood 
products, such as plywood, chipboard, flakeboard, laminated beams, 
oriented strandboard, hardboard, and particleboard; petroleum processing 
fluids; fuel; oilfield fluids, such as injection water, fracture fluids, 
and drilling muds; agriculture adjuvant preservation; surfactant 
preservation; medical devices; diagnostic reagent preservation; food 
preservation, such as plastic or paper food wrap; pools; and spas. 
Preferred loci are cooling towers; air washers; boilers; mineral slurries; 
wastewater treatment; ornamental fountains; reverse osmosis filtration; 
ultrafiltration; ballast water; evaporative condensers; heat exchangers; 
pulp and paper processing fluids; plastics; emulsions and dispersions; 
paints; latexes; and coatings. 
The amount of antimicrobial agents of the present invention suitable to 
inhibit the growth of microorganisms depends upon the locus to be 
protected, but is generally between 0.05 and 10,000 ppm, based on the 
volume of said locus to be protected. It is preferred to use between 0.1 
and 5000 ppm. For example, loci such as a cooling tower or pulp and paper 
processing fluids require 0.1 to 250 ppm of the compounds of the present 
invention to inhibit microorganism growth. In cooling towers or pulp and 
paper processing fluids, it is preferred to use between 0.1 and 50 ppm. 
Other loci, such as construction products, oilfield fluids or emulsions, 
require 0.5 to 5000 ppm of the compounds of the present invention to 
inhibit microorganism growth, while loci such as disinfectants or 
sanitizers may require up to 10,000 ppm. 
It is known in the art that the performance of antimicrobial agents may be 
enhanced by combination with one or more other antimicrobial agents. Thus, 
other known antimicrobial agents may be combined advantageously with the 
antimicrobial agents of this invention. The compounds of the present 
invention may be combined with: methylenebis(thiocyanate); isothiazolones, 
such as 2-n-octyl-4-isothiazolin-3-one; 
4,5-dichloro-2-n-octyl-4-isothiazolin-3-one; 
5-chloro-2-methyl-4-isothiazolin-3-one; 2-methyl-4-isothiazolin-3-one; 
1,2-benzisothiazolin-3-one; and 
2-methyl-4,5-trimethylene-4-isothiazolin-3-one; carbamates, such as 
3-iodopropargyl-N-butylcarbamate; methyl benzimidazol-2-ylcarbamate; 
imidazolidinyl urea; diazolidinyl urea; 
N'-3,4-dichlorophenyl!-N,N-dimethylurea; 3,4,4'-trichlorocarbanilide; 
dimethyl dithiocarbamate; and disodium ethylene bisdithiocarbamate; 
heterocyclic compounds, such as zinc 2-pyridinethiol-1-oxide; sodium 
2-pyridinethiol-1-oxide; 10,10'-oxybisphenoxyarsine; 
N-trichloromethylthiophthalimide; 5-oxo-3,4-dichloro-1,2-dithiol; 
3-bromo-1-chloro-5,5-dimethylhydantoin; 
4,4-dimethyl-1,3-dimethylolhydantoin; 
2-(thiocyanomethylthio)benzothiazole; 2-methylthio-4-t-butylamino-6-cyclop 
ropylamino-s-triazine; iodopolyvinylpyrrolidone; 
3,5-dimethyl-1H-pyrazole-1-methanol; 
1-(2-hydroxyethyl)-2-octadecylimidazoline; 4-(2-nitrobutyl)morpholine; 
triazine; N,N'-methylenebis(5-methyl-1,3-oxazolidine); 
2,2'-oxybis(4,4,6-trimethyl-1,3,2-dioxaborinane); 
2,2'-(1-methyltrimethylenedioxy) bis(4-ethyl-1,3,2-dioxaborinane); 
hexahydro-1,3,5-tris(2-hydroxyethyl)-s-triazine; 4,4-dimethyloxazolidine; 
3,4,4-trimethyloxazolidine; 4,4'-(2-ethyl-nitrotrimethylene)dimorpholine; 
2-methylthio-4-t-butylamino-6-cyclopropylamino-s-triazine; 
2,3,5,6-tetrachloro-4-(methylsulfonyl)pyridine; 
alpha-2-(4-chlorophenyl)ethyl!-alpha-(1,1-dimethylethyl)-1H-1,2,4-triazol 
yl-(1)-ethanol; 
1-(2-(2',4'-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl-methyl!-1H-1,2,4-t 
riazole; didecyldimethylammonium chloride; copper-8-hydroxyquinoline; 
1-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl-methyl!-1H-1,2,4-triazole; 
2-(4-thiazolyl)-benzimidazole; 3,5-dimethyl-1,3,5-thiadiazine-2-thione; 
2-chloro-4,6-bis(ethylamino)-1,3,5-triazine; 
2-chloro-4-ethylamino-6-tert-butylamino-1,3,5-triazine; 
1-(3-chloroallyl)-3,5,7-triaza-1-azoniaadamantane chloride; copper 
naphthenate; 5-hydroxymethoxymethyl-1-aza-3,7-dioxabicyclo3.3.0!octane; 
5-hydroxymethyl-1-aza-3,7-dioxabicyclo3.3.0!octane; 
7-ethyl-1,5-dioxa-3-azabicyclooctane; cetylpyridinium chloride; 
3-bromo-1-chloro-5-dimethyl-5-ethylhydantoindodecyl-di(aminoethyl)-glycine 
; and 
5-hydroxypoly-methyleneoxyethyl!methyl-1-aza-3,7-dioxabicyclo3.3.0!octan 
e; oxidants, such as hydrogen peroxide; t-butyl hydrogen peroxide; cumene 
hydroperoxide; sodium or calcium hypochlorite; sodium or calcium 
hypobromite; dichloroisocyanuric acid; trichloroisocyanuric acid; 
peroxyacetic acid; ozone; chlorine; bromine; chlorine dioxide; potassium 
peroxymonosulfone; percarbonate; sodium perborate; bromamines; and bromine 
chloride; carboxylic acids and their derivatives, such as 
(E,E)-2,4-hexadienoic acid; benzoic acid; sodium or calcium propionate; 
ethylenediaminetetraacetic acid disodium salt; and sodium 
hydroxymethylglycinate; benzyl ester of 4-hydroxybenzoic acid; (C.sub.1 
-C.sub.4)alkyl esters of 4-hydroxybenzoic acid; (C.sub.1 -C.sub.4)alkyl 
esters of 4-hydroxybenzoic acid sodium salts; dimethylamide of tall oil 
fatty acids; and 2,2-dibromo-3-nitrilopropionamide; alcohols and amines, 
such as 1-(alkylamino)-3-amino-propane; 2-bromo-2-nitro-1,3-propanediol; 
phenoxyethanol; benzyl alcohol; 2-hydroxymethylaminoethanol; 
n-2-hydroxypropylaminomethanol; 2-hydroxypropyl methanethiosulfonate; 
p-nitrophenol; and 4-chloro-3,5-dimethylphenol; ammonium and phosphonium 
salts, such as n-alkyl dimethyl benzylammonium chloride; 
cetyltrimethylammonium chloride; didecyldimethylammonium chloride; 
poly(hexamethylenebiguanide) hydrochloride; 
polyoxyethylene(dimethyliminio) ethylene(dimethyliminio)ethylene 
dichloride!; alkyl dimethyl dichlorobenzylammonium chloride; 
dodecylguanidine hydrochloride; 2-(decylthio)ethaneamine hydrochloride; 
quaternary ammonium compounds; tetrakis(hydroxymethyl)phosphonium 
chloride; tetrakis(hydroxymethyl)phosphonium sulfate; aldehydes, ketones 
and formaldehyde releasers, such as pentane-1,5-dial; 
1,2-benzenedicarboxaldehyde; formaldehyde; 2-bromo-4'-hydroxyacetophenone; 
tris(hydroxymethyl)nitromethane; and 5-bromo-5-nitro-1,3-dioxane; 
haolgenated aromatic compounds, such as 
2,4,5,6-tetrachloroisophthalonitrile; 2,4,4'-trichloro-2'-hydroxydiphenyl 
ether; 2,2'-dihydroxy-5,5'-dichlorodiphenylmethane; and 
1,6-di-(4'-chlorophenyldiguanide)-hexane; halogenated aliphatic compounds, 
such as 1,2-dibromo-2,4-dicyanobutane; diiodomethyl-p-tolysulfone; 
dibromonitroethane; hexachlorodimethylsulfone; alkenes, such as 
.beta.-bromo-.beta.-nitrostyrene; 1,4-bis(bromoacetoxy)-2-butene; terpene; 
and limonene; inorganic compounds, such as bismuth; copper; silver; copper 
amine complexes; mono copper nitrate; borate salts; zinc oxide; sodium 
bromide; ammonium bromide; disodium octaborate tetrahydrate; tributyltin 
oxide; and chromated copper arsenate; enzymes, such as cellulase; 
alpha-amylase; protease; polysaccharidase; levan hydrolase; and 
surfactants, such as alkyl aryl esters, polyethoxylated alcohols, 
polyoxyethylated ethers, phosphate esters, sulfonates, sulfonated fatty 
materials, sulfosuccinates, and dodecylbenzene sulfonic acids. 
Preferred known antimicrobial agents to be combined with the antimicrobial 
agents of the present invention are methylenebis(thiocyanate); 
5-chloro-2-methyl-4-isothiazolin-3-one; 2-methyl-4-isothiazolin-3-one; as 
2-n-octyl-4-isothiazolin-3-one; 
4,5-dichloro-2-n-octyl-4-isothiazolin-3-one; 1,2-benzisothiazolin-3-one; 
zinc 2-pyridinethiol-1-oxide; sodium 2-pyridinethiol-1-oxide; 
N'-3,4-dichlorophenyl!-N,N-dimethylurea; 
3-iodopropargyl-N-butylcarbamate; 10,10'-oxybisphenoxyarsine; 
2-(thiocyanomethylthio)benzothiazole; 
3-bromo-1-chloro-5,5-dimethylhydantoin; 2,2-dibromo-3-nitrilopropionamide; 
pentane-1,5-dial; and 2-bromo-2-nitro-1,3-propanediol. 
The compounds of the present invention may also be used in conjuction with 
non-chemical methods of microbial control, such as ultraviolet light; 
ionizing radiation; copper electrodes; silver electrodes; and enzymes, 
such as cellulase, alpha-amylase, protease, polysaccharidase, and levan 
hydrolase. 
If one of the antimicrobial agents of the invention is to be combined with 
a second antimicrobial agent, the weight ratio of the first antimicrobial 
agent to the second antimicrobial agent is 99:1 to 1:99; preferably, 75:25 
to 25:75. The total of the combined antimicrobial agents necessary to 
inhibit or prevent the growth of microbes is generally 0.05 to 10,000 ppm, 
based on the volume of said locus to be protected. 
The antimicrobial agents of the present invention may be added directly to 
a locus to be protected or may be added as a formulation. The 
antimicrobial agents of the present invention may be formulated in a 
variety of liquid or solid formulations. The particular type (that is, 
solid or liquid) and composition of the formulation used will depend on 
the locus to be protected and the characteristics of the formulation 
sought. For example, where splash hazards are a concern or where 
controlled release is desired, solid formulations may be preferred. Liquid 
formulations may be preferred where the formulation is metered into a 
locus over a period of time. Solid formulations are particularly useful in 
loci such as cooling towers, latexes, and plastics. Liquid formulations 
are particularly useful in loci such as paints, cosmetics; household 
cleaners; and water treatment applications. 
In general, the antimicrobial agents of the present invention may be 
formulated in liquid form by dissolving the antimicrobial agent in a 
carrier. Suitable carriers include water, organic solvent, or mixtures 
thereof. Any organic solvent is suitable as long as it is compatible with 
the end use and does not destabilize the antimicrobial agent. Suitable 
organic solvents include, but are not limited to: aliphatic and aromatic 
hydrocarbons, such as xylene and mixtures of alkylbenzenes; halogenated 
aliphatic and aromatic hydrocarbons, such as ethylene dichloride and 
monochlorobenzene; alcohols, such as monohydric, dihydric, and polyhydric 
alcohols; aldehydes; ketones, such as acetone, methyl ethyl ketone, and 
methyl iso-butyl ketone; ethers; glycol ethers; glycol ether acetates; 
saturated and unsaturated fatty acids having at least four carbon atoms; 
esters, such as ethyl acetate, butyl acetate, glycol esters, and phthalate 
esters; and phenols. Preferred organic solvents are glycol ethers; glycol 
ether acetates; aliphatic and aromatic hydrocarbons; and alcohols. 
Aqueous formulations of the antimicrobial agents of the present invention 
may be prepared as dispersions, such as polymeric dispersions; emulsions; 
emulsive concentrates; microemulsions; and microemulsive concentrates. The 
dispersions, emulsions, and microemulsions can have either oil continuous 
or water continuous phases. Aqueous formulations typically contain 0.001 
to 50 wt % of the antimicrobial agent of the present invention, up to 99 
wt % organic solvent, 0.5 to 55 wt % surfactant, up to 15 wt % adjuvants, 
and up to 95 wt % water. Suitable surfactants are anionic, such as 
alkyllauryl sulfonate salts and fatty alcohol ethoxylate sulfates; 
cationic; nonionic, such as ethylene oxide-propylene oxide copolymers; and 
amphoteric. Typical adjuvants suitable for use in aqueous formulations 
include, but are not limited to: thickeners, anti-freeze agents, and 
defoamers. 
Suitable solid formulations of the antimicrobial agents of the present 
invention include, but are not limited to: polymeric encapsulants, such as 
those prepared by interfacial condensation, coacervation, in-situ 
polymerization, and physical methods; inclusion complexes, such as 
clathrates; liposomes; matrix blends, such as granulars, dispersible 
granulars, and wettable powders; and ion exchange resins. Polymeric 
encapsulants can be prepared having either a core shell or monolithic 
structure. Suitable polymeric encapsulants include, but are not limited 
to: polyureas, polyamides, polyesters, urea-formaldehydes, 
melamine-formaldehydes, polyacrylic acid and its esters, 
phenol-formaldehydes, and acetoacetates. 
Inclusion complexes may be prepared by incorporating the antimicrobial 
agent of the present invention in a host molecule. Suitable host molecules 
include, but are not limited to: .alpha.-cyclodextrin; 
.beta.-cyclodextrin; .gamma.-cyclodextrin; cyclodextrin derivatives, such 
as methyl-.beta.-cyclodextrin; crown ethers; ureas; hydroquinones; 
dichlorophene; hydroxybenzophenone; and 
1,1,2,2-tetrakis(4-hydroxyphenyl)ethane. The inclusion complex can be used 
as a solid composition, adsorbed onto a solid carrier, or dispersed in a 
non-reactive solvent. Inclusion complexes are useful in water treatment, 
metalworking fluid, and paint applications. 
Liposomes can be prepared by dissolving the antimicrobial agents of the 
present invention and a lipid, such as a phospholipid, in a suitable 
solvent, such as chloroform. The solvent is removed, a buffer added, and 
the composition is agitated to produce the desired particle size. The 
liposomes may be multilamellar, unilamellar, or have large or small 
particle size. Liposomes are useful in solvent based paint and cosmetics 
applications. 
Matrix blends can be prepared by adsorbing the antimicrobial agents of the 
present invention onto a solid carrier with the addition of appropriate 
additives in order to make granulars, wettable powders, and dispersible 
granulars. These matrix blends may be used as is or may be further be 
processed into pellets, tablets, or briquettes by any conventional means. 
Granulars typically comprise 1 to 60 wt % antimicrobial agent of the 
present invention; 30 to 98 wt % of an absorbent carrier, such as 
diatomaceous earth, water soluble solids, magnetic particles, or fumed 
inorganics, such as silica, titania, and zinc oxide; and 1 to 10 wt % 
adjuvants. Wettable powders typically comprise 1 to 60 wt % antimicrobial 
agent of the present invention; 1 to 5 wt % wetting agent; 1 to 20 wt % 
dispersant; 10 to 95 wt % adsoptive carrier, such as fumed inorganics or 
clay; and up to 10 wt % adjuvants. Dispersible granulars typically 
comprise 1 to 60 wt % antimicrobial agent of the present invention; 30 to 
95 wt % adsoptive carrier, such as fumed inorganics or clay; 5 to 40 wt % 
dispersant; up to 10 wt % surfactant; and up to 15 wt % adjuvant. 
Dispersible granulars may be further extruded, dried and processed into 
granulars. 
The following examples are presented to illustrate further various aspects 
of the present invention, but are not intended to limit the scope of the 
invention in any respect.