Antimicrobial compounds and methods of use

Abstract

Compound having antimicrobial activity having the formula ##STR1## wherein R is (C.sub.1 -C.sub.18)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.6 -C.sub.18)aryl, (C.sub.7 -C.sub.18)aralkyl, or (C.sub.7 -C.sub.18)alkaryl,provided that aryl or the aryl portion of said aralkyl or alkaryl are optionally substituted with halo or methyl; andR.sub.1 is H, Cl or methyland method for inhibiting growth of microorganisms using said compound.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds having biocidal activity and their use as antimicrobials.

2. Description of the Prior Art

A. U.S. Pat. No. 3,546,235 (1970) and U.S. Pat. No. 3,712,908 (1973), assigned to Ciba-Geigy Corporation, disclose that 5-chloro-1,2-dithiol-3-one reacts with metal salts of thiols by nucleophilic substitution to give 5-substituted sulfides, unaccompanied by ring-opening. For example, 4,5-dichloro-1,2-dithiol-3-one reacted with sodium 2-mercaptobenzothizole to give compound of Formula I. ##STR2##

B. U.S. Pat. No. 3,914,301 (1975), assigned to Rohm & Haas Co., discloses that isothiazolone systems undergo ring-opening with nucleophiles such as mercaptans to give acrylamide derivatives.

U.S. Pat. No. 4,310,590, also assigned to Rohm and Haas Co., discloses 3-isothiazolones substituted with cyano, piperidino, thiocarbamoylthio, and the like.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel compounds having improved antimicrobial activity.

Another object is to provide new methods for inhibiting growth of bacteria, fungi, algae, and the like.

These objects and others as will become apparent from the following disclosure are achieved by the present invention which comprises in one aspect compounds having antimicrobial activity having the formula ##STR3## wherein R is (C.sub.1 -C.sub.18)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.6 -C.sub.18)aryl, (C.sub.7 -C.sub.18)aralkyl, or (C.sub.7 -C.sub.18)alkaryl, provided that aryl or the aryl portion of said aralkyl or alkaryl are optionally substituted with halo or methyl; and

R.sub.1 is H, Cl or methyl.

In another aspect the invention comprises a method for inhibiting the growth of bacteria, fungi, or algae which comprises incorporating into or onto a locus subject to contamination an effective amount of said compound, optionally with an agronomically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The compounds of the invention have the formula ##STR4## wherein R is (C.sub.1 -C.sub.18)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.6 -C.sub.18)aryl, (C.sub.7 -C.sub.18)aralkyl, or (C.sub.7 -C.sub.18)alkaryl, provided that aryl or the aryl portion of said aralkyl or alkaryl are optionally substituted with halo or methyl; and

R.sub.1 is H, Cl or methyl.

Preferred compounds are those wherein R is selected from the group consisting of methyl, n-octyl, cyclohexyl, and 4-chlorophenyl.

Specific examples of each compound are (2-methyl-4-isothiazolin-3-on-5-yl)-(benzothiazol-2'-yl)sulfide, [4-chloro-2-(n-octyl)-4-isothiazolin-3-on-5-yl]-(benzothiazol-2'-yl)sulfide and [4-methyl-2-(4-chlorophenyl)-4-isothiazolin-3-on-5-yl]-(benzothiazole-2'-yl)sulfide.

Compositions comprising an effective amount of a compound of formula II with an agronomically acceptable carrier are useful to inhibit the growth of bacteria, fungi, algae, and the like.

The methods of application include incorporating the compound or composition comprising the compound into or onto a locus subject to contamination by fungi, algae, or bacteria.

The locus can be an aqueous medium. Preferably the compound (or a salt thereof) is incorporated in an amount of about 0.1 to 10,000 ppm by weight.

The locus can be a cutting oil formulation comprising a cutting oil, water, and an emulsifying agent; a water cooling system; a solid protective film; fabric; leather; paper; wood; or laundry wash water.

As stated above, compositions comprising a compound according to formula I and either an agronomically acceptable carrier, a cosmetic agent, a cutting oil, a soap or synthetic detergent, a stabilizer, a film forming material, or the like have a wide range of utility for protecting against or controlling microorganisms from a wide variety of classes including fungus, bacteria, algae, viruses and yeasts. The preferred utilities of the compositions are to protect wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.

The following lists specific industries and applications of the compounds of compositions:

______________________________________Industry Application______________________________________Adhesives, sealants adhesives caulks sealantsAgriculture/food chain adjuvant preservation agricultural active ingredient agricultural chemical preservative agricultural formulations preservation animal feed preservation dairy chemicals fertilizer preservation food preservation food processing chemicals grain preservation post-harvest produce protection sugar processing tobaccoConstruction products asphalt/concrete cement modifiers construction products roof mastics synthetic stucco wall mastics joint cementCosmetics and toiletries cosmetics raw materials for cosmetics, toiletries toiletriesDisinfectants, antiseptics antiseptic disinfectantEmulsions, dispersions aqueous dispersions dispersed pigments latex photographic emulsions pigment slurries polymer laticesFormulated household fabric softenersproducts polishes waxes hand dish detergents raw materials liquid detergents hand soapsIndustrial processing, misc electrodeposition paint, baths, rinses. electrodeposition pre- treatment, post rinses industrial fluids preservation pasteurization baths process aid preservationIndustrial water treatment air washers cooling towers cooling water water cooling preservation/treatment of wooden cooling tower slats and structural members can warmers brewery pasteurization closed loop water cooling systemsLaundry household laundry products laundered goods laundry wash water sanitizers-laundryLeather, leather products leather and hide leather and hide productsLubricants, hydraulic aids automotive lubricants and fluids conveyor lubricants greases hydraulic fluids lubricantsMedical devices diagnostic enzymes diagnostic kits medical devicesMetalworking & related app's cutting fluids metal cleaning metalworking fluidsOdor control air conditioning(active ingredient) animal bedding cat litter chemical toilet prep'ns deodorizers humidifiers industrial deodorants sanitary formulations toilet bowlsPaints and coatings coating emulsions paintsPaper and wood pulp, absorbant materials or papertheir products and wood pulp packaging materials of paper and wood pulp paper paper products paper treatment soap wrap wood pulp wood pulp productsPaper mill paper mill slimicides pulp and paper slurriesPetroleum refining, fuels aviation fuels (jet fuel, aviation gas) crude oils burner, diesel and turbine fuel oils coal slurries diesel fuel additives diesel fuels fuels gasoline heating oils hydrocarbons kerosene liquified petroleum gas petrochemical feedstocks petroleum products, storage, transportation and production recycled petroleum products residual fuel oils turbine oilsPhotographic chemicals photographic processing -and process wash water, rinses photoprocessing photoplate processing chemicals (developers, stabilizers etc)Printing fountain solutions (printing) ink components (pigments, resins, solvents, etc) inksSanitizers (active) sanitizers sanitizers-dairy sanitizers-dental sanitizers-fermentation sanitizers-food preparation sanitizers-food processing sanitizers-medical sanitizers-rendering sanitizers-veterinarySoaps, detergents, cleaners cleaners detergents household cleaners industrial cleaners liquid soaps oil and grease remover powdered soaps raw materials for cleaning products soaps surfactantsTextiles, textile products bonded fabrics burlap canvas canvas goods carpet backing carpets clothing coated fabrics curtains draperies engineering textiles fibers geotextiles goods made of textiles knitted fabrics nets nonwoven fabrics rope rugs textile accessories textile products textiles upholstery woven fabrics yarnTextile processing dye fixatives dyes fiber lubricants hand modifiers sizes textile processing fluidsTherapeutic (active or animal health/veterinarypreservative) aquaculture dental human health pharmaceutical/therapeuticWater purification charcoal beds deionization resins filters membranes reverse osmosis membranes ultrafilters water purification water purification pipes, tubingWood applications lazures (wood stains) wood wood productsMiscellaneous alcohols bedding incorporating water or gels ceramic contact lens cases-leaching electronic circuitry electronics chemicals enzymes-food production enzymes enzymes-industrial gel cushions marine antifoulants mildewcides wood plastics laundry mining natural rubber latex oil field injection waters including enhanced recover injection fluids, drilling, fracturing and completion fluids pipes plastics polymer systems polymers and resins (synthetic and natural) reagent preservation rubber rubber products skin remover solid protective/decorative films stains swimming pools waste treatment water beds______________________________________

The amounts of the compound to be used depend on the application. The useful amounts for a particular application are similar to amounts used for other microbicide compounds.

The compound can be used in combination with other microbicides. The term "microbicide" is considered equivalent to "antimicrobial" as used herein.

Suitable methods of application of compounds of formula II to control fungi, bacteria, algae, viruses, yeasts, and the like are in amounts and with carriers, etc., as well known in the art.

TABLE 1______________________________________Structure and Physical Data ofRepresentative Compounds of Formula IICompound No. R R.sub.1 Melting Point______________________________________1 CH.sub.3 H 143.0-145.0.degree. C.2 n-octyl Cl 78.0-80.0.degree. C.3 4-chlorophenyl CH.sub.3 180-182.5.degree. C.______________________________________

The compounds of formula II may be prepared according to Scheme 1. The 5-chloro-3-isothiazolone derivative is allowed to undergo nucleophilic substitution at the 5-position with sodium 2-mercaptobenzothiazole in aqueous ethanol solution to give compounds of formula II. The reaction takes place at room temperature, under alkaline condition (pH=8-10) and is complete within 1-96 hours.

The compounds may also be prepared in an anhydrous organic solvent as follows: 2-mercaptobenzothiazole is treated with sodium hydride in an anhydrous solvent such as dimethyl formamide or acetonitrile at 0.degree. C. under nitrogen. Then a solution of 5-chloro-3-isothiazolone derivative in the same solvent is added. The mixture is allowed to warm to room temperature and then stirred for 1-24 hours to complete the reaction. The product precipitates out of solution or is obtained by extraction. ##STR5##

Compound 3 (R=4-chlorophenyl, R.sub.1 =CH.sub.3) may be prepared from the acrylamide derivative III (Scheme 2). Treatment of an ethanol solution of III with 50% aqueous solution of sodium 2-mercaptobenzothiazole at pH 8-10 at room temperature yielded the product. The reaction takes place within 1-48 hours.

The acrylamide derivative III is postulated to initially undergo a rapid ring-closure initially under the basic reaction medium (pH 8-10) to PG,15 give the isothiazolone derivative. Subsequently, the reaction follows scheme 1 to give the product. ##STR6##

The following examples are presented to illustrate a few embodiments of the invention. All parts and percentages are by weight unless otherwise indicated.

EXAMPLE 1

(2-methyl-4-isothiazolin-3-on-5-yl)-benzothiazol-2'-yl) sulfide (Compound 1)

To a solution of 5-chloro-2-methyl-4-isothiazolin-3-one (1 g, 0.0067 mol) in 25 ml of ethanol, 2 g of 50% aqueous solution of sodium 2-mercaptobenzothiazole was added. The resulting solution was adjusted to pH 8.5. The reaction mixture was allowed to stand at room temperature for 24 hours. The solid precipitate which formed was removed by filtration, washed with fresh water, followed by cold ethanol and then dried to give 0.9 g of the desired product. The compound was recrystallized from ethanol; m.p. 143.0.degree.-145.0.degree. C.

.sup.1 H-NMR (CDCl.sub.3) .delta.7.3-8.1 (m 4H, arom.); 6.4 (s,1H, vinyl); 3.4 (s,3H,N-CH.sub.3). IR (KBr) 1630 cm.sup.-1.

EXAMPLE 2

[4-methyl-2-(4-chlorophenyl)-4-isothiazolin-3-on-5-yl]-(benzothiazol-2'-yl)sulfide (Compound 3)

To a stirred suspension of sodium hydride (60% dispersion in oil, 0.4 g, 0.01 mole) in 10 ml of dimethylformamide at 0.degree. C. and under nitrogen, a solution of 2-mercaptobenzothiazole (1.67 g, 0.01 mole) in 10 ml of dimethylformamide was added dropwise. After stirring the mixture for 15 minutes at 0.degree. C., a solution of 5-chloro-4-methyl-2-(4-chlorophenyl)-4-isothiazolin-3-one (2.6 g, 0.01 mole) in 10 ml of dimethylformamide was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 hours. The precipitate which formed was removed by filtration and washed with ether. The solid was dried to give 3.2 g of product. The solid was recrystallized from chloroform/methanol solution; mp 180.degree.-182.5.degree. C. IR(KBr) 1635 cm.sup.-1. .sup.1 H-NMR(CDCl.sub.3) .delta.2.15 (s,3H,CH.sub.3); 7.35-8.0 (m, 8H, Arom).

EXAMPLE 3

[4-methyl-2-(4-chlorophenyl)-4-isothiazolin-3-on-5-yl]-(benzothiazol-2'-yl)sulfide (Compound 3)

To a stirred 50% aqueous solution of sodium 2-mercaptobenzothiazole (0.53 g, 0.0014 mol) diluted with 10 ml of water, a solution of 4-chlorophenyl-2-methyl-3-chloro-3-thio (1-acetylpropan-2-on-1-yl) acrylamide (0.5 g, 0.0014 mol) in 15 ml of ethanol was added dropwise at room temperature. Stirring was continued for 2 hours. The precipitate which formed was removed by filtration, washed with water and then dried to give 0.57 g of product. The solid was recrystallized from chloroform/methanol solution to give pale-yellow compounds; mp 180.degree.-182.5.degree. C.; IR (KBr) 1635 cm.sup.-1. .sup.1 NMR (CDCl.sub.3) .delta.2.15 (s,3H,CH.sub.3); 7.35-8.0 (m, 8H, Arom).

EXAMPLE 4

Biological Activity

Efficacy tests against eight fungi and four bacteria was carried out. A minimum inhibitory concentration (MIC) value was obtained using Trypticase Soy Broth, pH 7.0, and by preparing serial dilutions with a starting concentration of 500 ppm. A stock solution of the test compound was made in dimethyl sulfoxide (DMSO) or acetone.

The test organisms used to demonstrate biocidal activity are listed in Table 2. The MIC's of the compounds of this invention against the test organisms are shown in Table 3.

TABLE 2______________________________________Microorganisms used in the Biocide TestName Abbreviations Used______________________________________Bacteria1. Pseudomonas aeruginosa Psae2. Staphylococcus aureus Saur3. Escherichia coli Ecol4. Pseudomonas fluorescens PsflFungi1. Aspergillus niger Anig2. Penicillium funiculosum Pfun3. Cladosporium resinae Cres4. Aureobasidium pullulans Apul5. Chaetomium globosum Cglo6. Saccharomyces cerevisiae Scer7. Rhodotorula rubra Rrub8. Gleophyllum trabeum Gtra______________________________________ TABLE 3__________________________________________________________________________MIC Test Data in PPMTest was run in Trypticase Soy Broth, pH 7.0 Starting concentration = 500pmCompoundNo. A. nig P. fun C. res A. pul C. glo G. tra S. cer R. rub Ps. fl Ps.ae E. col S. Chorella__________________________________________________________________________1 8 8 1 16 32 <0.1 8 16 8 >500 500 42 63 32 >250 >250 1 43 12.5 0.4 12.5__________________________________________________________________________

While the invention has been described with reference to specific examples and applications, other modifications and uses for the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention defined in the appended claims.

Claims

1. Compound or salt thereof having the formula ##STR7## wherein R is (C.sub.1 -C.sub.18)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.6 -C.sub.18)aryl, (C.sub.7 -C.sub.18)aralkyl, or (C.sub.7 -C.sub.18)alkaryl,

provided that aryl or the aryl portion of said aralkyl or alkaryl are optionally substituted with halo or methyl; and

R.sub.1 is H, Cl or methyl.

2. Compound according to claim 1 wherein R is selected from the group consisting of methyl, n-octyl, cyclohexyl, and 4-chlorophenyl.

3. Compound according to claim 1 wherein said compound is selected from the group consisting of (2-methyl-4-isothiazolin-3-on-5-yl)-(benzothiazol-2'-yl)sulfide, [4-chloro-2-(n-octyl)-4-isothiazolin-3-on-5-yl]-(benzothiazol-2'-yl)sulfide and [4-methyl-2-(4-chlorophenyl)-4-isothiazolin-3-on-5-yl]-(benzothiazole-2'-yl)sulfide.

4. Composition for inhibiting the growth of bacteria, fungi, or algae comprising an effective amount of a compound according to claim 1 and an agronomically acceptable carrier.

5. Method for inhibiting the growth of bacteria, fungi, or algae in a locus subject to contamination by bacteria, fungi or algae which comprises incorporating onto or into the locus an amount which is effective to adversely affect the growth of bacteria, fungi or algae of a compound according to claim 1.

6. Method of claim 5 wherein the locus is an aqueous medium.

7. Method of claim 6 wherein the compound or salt thereof is incorporated in an amount of 0.1 to 10,000 ppm parts by weight.

8. Method of claim 5 wherein the locus is a cutting oil formulation comprising a cutting oil, water, and an emulsifying agent.

9. Method of claim 5 wherein the locus is water cooling system.

10. Method of claim 5 wherein the locus is a solid protective or decorative film.

11. Method of claim 5 wherein the locus is a fabric, leather, paper or wood.

12. Method of claim 5 wherein the locus is laundry wash water.

13. Method of claim 5 comprising contacting the bacteria, fungi or algae with said compound.