CA2058556A1

CA2058556A1 - Antimicrobial compositions comprising iodopropargyl compounds and isothiazolones and methods of controlling microbes

Info

Publication number: CA2058556A1
Application number: CA002058556A
Authority: CA
Inventors: Samuel Eugene Sherba; Raj J. Mehta
Original assignee: Samuel Eugene Sherba; Raj J. Mehta; Rohm And Haas Company
Current assignee: Rohm and Haas Co
Priority date: 1991-01-03
Filing date: 1991-12-30
Publication date: 1992-07-04
Also published as: DE69206278D1; GR3018424T3; ES2080917T3; DE69206278T2; US5156665A; BR9200005A; EP0493969B1; DK0493969T3; JPH0558818A; AU9002691A; AU661665B2; CN1066758A; ATE130726T1; EP0493969A1; KR920014409A; MX174032B

Abstract

Abatract of the Disclosure A synergistic antimicrobial composition comprising 2-alkyl-3-isothiazolones, preferably 4,5-dichloro-2-n-octyl-3-isothiazolone or 2-n-octyl-3-isothiazolone, and certain iodopropargyl compounds, in a ratio to each other which exhibits synergism is disclosed.

Description

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PATEhJT APPLI(::ATION OF
SAMUEL E. SHERE~A AND RAJ J. ME~HTA
FOR
ANTIMICROBIAL CONIPOSITIOINS COMPFIISING
IODOPROPAPIGYL COIUIPOUNDS AND ISOTHIA;20LONES
AND METHODS C)F C:C)NTIROLLING MIC:ROE~ES
DNgO-1 42 MBF/meb BACKGROlJND OF THE INVENTION
1. iQlci~o~thçi~ nt~n The presen~ invention r~lates to antimicrobial compositions and me~hods of c~ntrolling microb~s.

2. ~e~
The presence of microbes in various aqueous systems such as latices, paints, coatings, cooling water sys~ems, decorative ponds and the like, can cause deterioration or disfi~urement of these systems. For example, painted surfaces may be disflgured by the unsighlly buildup of microbes, thus detracting from th0 overall aesthetics of the pain~ed article; cooling towers may lose efficiency due to the buildup of microbss on surfaces, thus reducing ~he heat transfer capabilities of the tower. It is conventional to practice methods which inhibit the microbial det~rioration of such systerns by incorporating a variety of aWitives or combination of additives that ar~ characterized by having antimicrobial activity.

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S 5 ~i A wide variety of materials hava besn used to control microbes in different environments, some of which are: chlorine/bromine compounds, glutaraldehyde, isothia~olones, or~anotin formulations, copper salts, quaternary ammonium compounds (SD Strauss and PR
Puckorius in J. Power, S1, June 1984), and tnazines. Each has deficiencies related to toxici~y, pH and temperature sensitivity, limited cffectiveness, chcmical stability, and/or compatibility.
Based on the aforementionad performanc~ defici0ncies of conventional antimicrobial compounds there is a nee :I for more effective antimicrobial agents that can be usad at lower dosage rates, thus being more cost effective for the end user, reducing the pollution load on the affected anvironmental systems, and reducing the side effests to nearby non-target organisms, such as fish, useful crops, etc.
SUMMARY OF THE INVENTION
It is an object of this invention tv provide a methDd of con~rolling microbes at very low levels of activa ingredient. It is a further object to use compositions which arc compatible with a vari~ty of systems suscep~ible to deterior~tion by microbes. Another object is to provide a method of controlling microbes in cooling towers, paints, marine antifoutant coatings, spray washes, swimming pools, coatings, decorative .

ponds, fabric, le~ther, paper, wood, metal working fluids, cosmetic formulations, fuel systems, ~herapeu~ic pharrnaceutical formulations and the like, without objectionabls by-produc~ odors, discolora~ion, or otherwise detrimental cffects on the treated ~and controlled) systems.
These objects, and others which will b0come apparen~ from the tollowing disclosure, are achieved by the present inverltion which is, in one aspect a composition useful for controlling microbes comprising ~A) 2-alkyl-3-isothiazolones of the formula X O

x1~ (1) S/

wherein Y is a ~C5-C12)alkyl or a (C5-C8)cycloalkyl;
X is hydrogen, halogen, or (C1-C4)alkyl; and Xl is hydrogen, halogerl, or ((:~l-C4)alkyl,and (B) 1-~3-iodopropargyl)-4-(4-chlorophenyl)-1,2,4-triazolin-5-one, 4-(3-iodopropargyl)-2-propyl-1,3,4-oxadiazolin-~-one, 3-(3-ioclopropargyl)-2-benzoxa~olone ~)r N-iodopropargyloxycarbonyl glycine methyl ester, in a ratio to each other which exhibits syner~ism.

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In another aspect the invention comprises a microbicidal composition comprising a synergistic mixture of (A) 2-alkyl-3-isothiazolones of the formula X O

X~ Y (I) wherein Y is a (C5-C12)alkyl or a (Cs-C8)cycloalkyl;

X is hydrogen, halo~en, or ~C1-C4)alkyl; and X1 is hydrogen, halogen, or (C1~C4)alkyl, and (B) an iodopropargyl compound selected from the group consisting of compounds of the formula I = o~

wherein R1 is selected from ~he ~roup consisting of H, an amine protective group, and a moie~y of the formula , . :
.
, . ~
- . .

(111) wherein R2, R5, and R6 are independently salected ~rom H and an amine protective group;
R3 and R4 are independen~ly selscted from H, lower alkyl, aryl, arylalkyl, CH20R, CH2SR or CH(CH3)0R;
R = H, lower alkyl, arylalkyl or aryl;
wherein R1 and R2 or Rs and R6 can be pined to form a rin~; and wherein when R1 and R2 or R5 and R6 are both H, the compound is eithe in free base ~orm or in salt form;
r~ --~
A~
herein A is sel~cted from the group consisting of hydrogen, alkyl, aryl, and heterocyclic;
Y and Z are independently selected from ~he group consisting of C), S, and N-R;
R is selectod:from the grcup consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitut~d or unsubstituted ., . :

alkynyl, substituted or unsubstituted phenyl, and substitutad or unsubstitu~ed heterocyclic; and )( is selacted from tha group consisting of I and Br; and --- -X

Y~o (V) where X = I or Br, and Y= halo~en, H, NO2, (C1-C4)alkyl, (Cl-C4)alkoxy, CN, O(::O(C1-C4~alkyl, C: COPh or halo(Cl-C4) alkyl;
in a ratio to each other which exhibi~s synergism.
In another aspect, the inv~ntion comprisas a method for inhibiting the growth of a member sele~ed from the ~roup consis~ing of bacteria, fungi, algae and mixtures thereof in a locus subject to contamination Iby said member, which comprises incorporating onto or into ~he locus, in an amount which is effective to adversely affect the growth of said member, the aforemantioned oomposition.
Another aspect of ~he invention is a me~hod of controlling microbes in cooling tower water cornprising maintaining a concen~ration of the aforamentioned composi~iorl in th~ water.

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The invention also comprises microbe-resistant coating or impregnant compositions and marine antifoulan~ oompositions comprising the antimicrobial cornposition.
DE ï AILEl:) DFSCFllPTiON OF TllE INVENTION
AND THE PREFERRED EMBODIMENT
We have discovered an especially effective composition useful for controlling microbes comprisin~ (A~ a microbicidal composition comprising a synergistic mixture of ~A) 2-alkyl-3-isothiazolones of the formula X O

X'~'~s / (I) wherein Y is a (C5-C12)alkyl or a (C5-C8)cycloalkyl;

X is hydrogen, haiogen, or (C1-C4)alkyl; and . X1 is hydro~en, halogen, or (C~-C4)alkyl~

and (~ (3-iodopropargyl)-4-(4-chlorophenyl3-1,2,4-triazolin-5-one, 4-(3-iodopropargyl)-2-propyl-1,3,4-oxadiazotin-~-one, 3-(3-iodopropargyl)-2-benzoxazolonr~ or N-iodopropargy oxycarbonyl glycine methyl ester.

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In accordance with the invention a method of controlling mierobes comprises using an effective amount of the aforementioned composition.
Another important utility is in imparting microbial resistance to a coating or an impregnant composition comprising incorporation of the composition of the invention in the ooating or impregnant, preferably at a concentratiun of about 0.1 ppm to about 2 percent, more preferably at a concentration of about 1 ppm to 1 percent, and most preferably at a concentration of about 10 to 4000 ppm.
Algae-resistant coating or impre~nant compositions provided by the invention preferably cornprise about 0.1 ppm to about 2 percent of the antimicrobial composition, more preferably about 10 to 40~0 ppm.
In a marine antifoulant composition, on the other hand, the antimicrobial composi~ion of the invention comprises abou~ 1 ~o 10 percent of ths an~ifoulant composition.
In a therapeutic pharmac~utical formulation, e.g., lotion, crearn, ointment or topiçal treatment; in the treatment of metal workin~ fluids; and in the pro~ection of fabric, leather, paper or wood materials, the microbicidal composition is added at a concentration of from about 0.1 ppm to about 2 parcent by weight. In aqueous media, the microbicidal composition comprises from about 0.1 ppm to about 1 percent of the ~ ~ ", ~ , ' , ~?5~5~

aqueous system depending on the speoific snd use; ~or example, in cooling water tower applications and with pulp or paper manu~acturing processes, the microbicidal composition is added at a concentration from about 0.1 to about 1000 ppm by weight. In cosmetic formulations, e.g., face or hand creams, ~oiletries, etc.; and in ~he treatment of fuel systems, e.g., jet fuel, gasoiine, heating oil, etc., the microbicidal composition is added at a concentration af from about 0.1 ppm to about 1 percent by weight.
The microbial resistant compositions can also be used in construotion products such as stucco~ roof mastics, wall mastics, and masonry coatings for algae protection; in cl~ar finishes and coatings to protect underlying substrates from algae; for algae control in aquacuiture, including aquaria/ ~ish hateheri0s, shrimp ponds, finfish ponds, mollusc and c~us~acean cultivation, for algao control in recreational and decorative bodies of water such as swirnming pools, lakes, fountains and , . .
- decorative ponds; for algae conttol in bodies of water for industrial or muni~ipal use, such as settlin~ or ssparation ponds, waste treatrnent ponrls, and watar reservoirs; for al~ae control in hydroponic ~arming; for algae control in processing and manufacture of pulp and paper products;

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for inclusion in plastics or in coatings for plastics to protect against algae;
and in plastics or coatings for plastics for swimming pool liners.
We prefer an~imicrobial compositions wherein the weight ratio of (A) to (B) is about 0.1/100 to abou' 100/0.1. A particularly preferrecl ratio range is from about 1/20 to about 20/1 by weight.
The following examples represent just a few of the many uses and compounds of the invention. They are intended to be illustrative but no~
lirniting. Various modifications, alternatiYes, and improvements shoulcl become apparent to those skilled in the art without depar~ing from the spiri~ and scope of the invention.

XAMPLI~S

MIC values represent the Minimum Inhibitory Concen~ration. This is defined as the lowest level of compound required to completely inhibit (r~press) the growth of a given or~anism.
A synergistic effect is defined as the response of two variables which is greater ~han the sum of both parts alone. Synergy was determined from combination studies with two compounds by the method ' ,, ' , ~ .:

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of calculation described by F. C. Kull, P. t:~. Eisman, H. ~:). Sylwestrowicz and R. K. Mayer, App~ied ~VIicrobiology~,538 (1961):
Qa C )b _+_= synergismindex (Sl) QA QB

where:
QA= quantity of compound A, acting alonc, producing an end point (MIC) Qa = quantity of compound A~ in mixture, producing an end point (MIC) QB= quantity o~ compound B, acting alone, pr~dueing an end point (MIC) Qb= quantity of compound B, in mixture, producing an end point (MIC~
The following Sl values rnay be attained:

Sl > 1 represents antagonistic effect, Sl ,1 represents additive sffect, Sl < 1 represents synsrgy.

Efficacy studies were conducted on a variety of microorganisms with iodopropargyl compounds and isothiazolone mixtures. The MIC
studies were conducted using microtiter plate assays. In this rnethod, a wida range of concentrations was tested by preparing ~wo-fold serial dilutions of tha compouncl in 96-wcll plastic microtiter plates. Ali liquid media transfers were performed with calibrated singl~ or multichannel ; ~ . - "

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digital pipetters. Slock solutions of compounds were prepared in appropriate solvents and dispens~d to the growth medium. All subse~u~nt dilutions in piates were mada using the dssired growth medium; total volume of liquid in eaoh well was 100 !11. Each plate contained a concentration of both compounds made by serially titrating equal volumes of liquids in two directions in the microtiter pla~e. Each plate contained a control row for each combination (one component only), hence, ~he individual compound MIC values were also d~termined.
B. ~b~
Isothiazolones included in th0 examples are designated as folloWs:
1 ) Isothiazolone A: 4,~-dichloro-2-n-octyl-3-isothiazolone 23 Isothiazolone B: 2-n-octyl-3-isothiazolone C. Iodo~D~YmD~
lodopropargyl compounds included in the examples ara designated as ~ollows:
1 ) lodopropar~yl A: 1-(3-iodopropargyl)-4-(4-chlorophenyl)-1,2,4-triazolin-5-one 2) lodopropargyi B: 4-~3-iodopropargyl)-2-propyl-1,3,4-oxadiazolin-5-one . . ~ .

2~5~

3) lodopropargyl C: 3-(3-iodopropar~yl)-2-benzoxazolone 4) loclopropargyl D: N-iodopropargyloxycarbonyl glycine methyl ester Using a pure culture of Aspe~gillus niger, various combinations of lodopropar~yl D and Isothiazolone B were subjacted to MIC
determinations in mycophil broth (pH = 7). Compound A is Isothiazolone B and Compound B is loclopropargyl D.

0 1.6 (QB) - 1.0 0.~2 ~.8 44/56 0.75 1.25 0.4 76/24 0-7 2.5 (QA) 0 1 0 :` ~
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Using a pure culture of Aspergillus niger, various combinations of IDdopropargyl C and Isothiazolona B were subjected to MIC
determinations in mycophil broth (pH = 7). Compound A is Isothiazolone B and Compound B is lodopropar~yl C.
Q~ Qb ~;at2 S I
0 1.6 (QB~
0.31 0.8 28/72 0.6?
0.62 0.~ 44/56 0.7~
1.25 0.4 76~2~ 0.7!~i 2.~ (QA) ~ 1.~

Using a pure culture of Aureobasidium pullvlans, various combinations of lodopropargyl B and isothiazolone B were subjaotecl to MIC doterminations in mycophil broth ~pH = 5). Compound A is Isothia~olone B and Compound B is lodopropargyl B.

0 2.5 (Q~3 - 1.0 0.31 1.25 20/80 0.62 0.62 1.2~ 33/67 0.7~
1.25 0.62 67/33 ~.75 1.25 û.31 80/20 0 62 2.5 (QA) - 1.0 .

Using a pure culture of Aureobasidium pullulans, variows combinations o~ lodopropargyl A and Isothiazolone B were subjected to MIC determinations in mycophii broth (pH = 5). Compound A is Isothiawlone B and Compound B is lodopropargyl A.
Q Qb Q~ ~j l 0 2-5 (QB) - ~-0.31 1.25 20/80 û.62 0.62 1.25 33/67 0.75 0.62 0.62 ~0/50 0.50 1.25 0.31 80/20 0.62 1.25 0.16 89/11 0.56 1.2~ 0.08 94/6 0.53 2.5 (QA) - 1.0 2~?5~

Using a pure culture of Aur~obasidium putlulans, Yarious combinations of lodopropargyl A and Isothiazolone A were subjected to MIC determinations in mycophil broth (pH = 5). Compound A is Isothiazolone A and Compound B is lodopropargyl A.
Q~ Qb Q~
0 0.62 (C;B) - 1.0 0.1 6 0.31 33/67 3.56 0.31 0.31 ~0150 0.62 0.31 0.1 6 67133 0.37 0.62 0.31 67/33 0.75 0.62 0.16 80/20 0.50 0.62 0.08 8gl11 0.37 1.25 0.16 8gl11 0.75 1.25 0.08 93/7 0.62 2.5 (QA) - 1.U

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~5~55 EXAMPLE~ 6 Using a pure culture of Avreobasidium pulllJlans, various combinations of iodopropargyl A and Isothiazolone A were subj~cted to MIC determinations in mycophii broth (pH - 7). Compound A is Isothiazolone A and Compound B is lodopropargyl A.
Q~ ~Ib QalClb ~ i 0 3.1 (QB) - 1.0 0.15 1.56 9/91 0.56 0.31 1.56 17/83 0.62 0.31 0.78 29/71 0.37 0.62 1.56 29/71 0.75 û.62 0.78 45/~5 0.50 0.62 0.39 62/38 0.37 1.25 0.78 62/38 G.75 1.2~ 0.39 76/24 0.62 1.~5 0.2 86/14 0.56 2.5 (QA) S5~5 EXAI\APLE 7 Using a pure culture of Aureobasidium pullulans, various combinations of lodopropargyl B and Isothiazolone A were subjected to MIC determinations in rnycophil broth (pH = 5,~ Compound A is Isothia~olone A and Compound B is lodopropargyl B.
Q~l Q~ Qa~Qb ~.L
0 2.5 (QB) - 1.0 0.16 1.25 11/89 0.62 0.16 0.~2 20/80 0.37 0.31 1.25 20/80 0.75 0.3~ 0.62 33/67 0.50 0.31 0.31 50/50 0.7~
0.6~ 0.~2 50/~0 0.75 0.62 0.31 67/33 0.62 1.25 ~QA) - 1 0 1f3 EXAMPLE ~
Using a pure culture of Aur~obasidium pullulans, various combinations of lodoprcpargyl B and Isothiazolone A were subjected to MIC determinations in mycophil broth (pH = 7). Compound A is Isothiazolone A and Compound B is lodopropargyl E3.
Q~ Q~ Q~
0 3.1 (QE~) - 1.0 0.16 1.56 9/91 0.56 0.31 ~ .~6 1 7/83 0.62 0.31 0.7~ 2~/72 0.37 0.62 1.56 28/72 0.75 0.62 0.78 44/5~ ~.50 0.62 û.39 ~2/38 0.37 1.25 0.7~ 62/38 0.75 1.25 0.39 76/24 , 0.62 1.25 0.2 B6/14 0.56 2.~ tA) O - 1.0 ~g 2~?5~ 5~;
EXAMPLE~ ~
Using a pure culture of Aureobasidium pullulans, various combinations of lodopropargyl C and Isothiazolone A were subjected to MIC determinations in mycophil broth (pH = 7). Compound A is Isothiazolone A and Compound B is lodopropargyl C.
Ç~ ~b Qa/Q~ S I
0 3.1 (Q~) - 1.0 0.16 1.56 9/91 0.56 0.16 0.78 17183 0.31 0.31 1.S6 17/83 0.62 0.31 0.78 28/72 0.37 0.31 0.39 44/56 0.2~
0.~2 1.56 28/72 ~.75 0.62 0.78 44/56 ~.50 0.62 ~.39 62138 0.37 0.62 O.Z 76124 0.31 1.25 0.78 62/38 0.75 1.25 0.39 76/24 0.62 1.25 0.2 86/14 0.56 1.25 0.1 9317 0.53 2.5 (QA) :' ~0 ~, 2~.,'5~5~i Using a pure culture of Aureobasidium pullulans, various combinations of lodopropargyl D and Isothiazolone A were subjected to MIC determinations in rrlycophil broth (pH - 7~. Compound A is Isothiazolone A and Compound B is lodopropargyl D.
b ~ b ~l 0 6.25 ~QB) - 1.0 0.~6 3.1 ~/95 0.5~
0.31 3.1 9/91 0.62 0.62 3.1 1 7/83 0.75 1.25 1.56 441~6 0.75 1 .25 0.79 61 /39 0.62 2 5 (C2~) 0 - 1.0 ,

Claims

1. A microbicidal composition comprising a synergistic mixture of (A) a 2-alkyl-3-isothiazolone of the formula (I) wherein Y is a (C5-C12)alkyl or a (C5-C8)cycloalkyl;
X is hydrogen, halogen, or (C1-C4)alkyl; and X1 is hydrogen, halogen, or (C1-C4)alkyl;
and (B) an iodopropargyl compound selected from the group consisting of compounds of the formula (II) wherein R1 is selected from the group consisting of H, an amine protective group, and a moiety of the formula (III) wherein R2, R5, and R6 are independently selected from H and an amine protective group;
R3 and R4 are independently selected from H, lower alkyl, aryl, arylalkyl, CH2OR, CH2SR or CH(CH3)OR;
R = H, lower alkyl, arylalkyl or aryl;
wherein R1 and R2 or R5 and R6 can be joined to form a ring; and wherein when R1 and R2 or R5 and R6 are both H, the compound is either in free base form or in salt form;

(IV) wherein A is selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic;
Y and Z are independently selected from the group consisting of O,S,and N-R;

R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted phenyl, and substituted or unsubstituted heterocyclic; and X is selected from the group consisting of I and Br; and (V) where X = I or Br, and Y = halogen, H, NO2, (C1-C4)alkyl, (C1-C4)alkoxy, CN, OCO(C1-C4)alkyl, OCOPh or halo(C1-C4) alkyl, wherein (A) and (B) are in a ratio to each other which exhibits synergy.

2. The composition according to claim 1 wherein the ratio of (A) to (B) is from about 0.1/100 to about 100/0.1.

3. A coating or impregnant composition comprising from about 0.1 ppm to about 2 percent by weight of the composition of claim 1.

4. A marine antifoulant composition comprising about 1-10 percent by weight of the composition of claim 1.

5. A therapeutic pharmaceutical composition comprising from about 0.1 ppm to about 2 percent by weight of the composition of claim 1.

6. A method for inhibiting the growth of a member selected from the group consisting of bacteria, fungi, algae and mixtures thereof in a locus subject to contamination by said member, which comprises incorporating onto or into the locus, in an amount which is effective to adversely affect the growth of said member, the composition of claim 1.

7. The method of claim 6 wherein the locus is an aqueous medium and the composition is used in an amount from about 0.1 ppm to about 1 percent by weight.

8. The method of claim 6 wherein the locus is a coating or impregnant composition and the composition of claim 1 is used in an amount from about 0.1 ppm to about 2 percent by weight.

9. The method of claim 6 wherein the locus is a marine antifoulant composition and the composition of claim 1 is used in an amount from about 1 to about 10 percent by weight.

10. The method of claim 6 wherein the locus is a pulp or paper manufacturing process and the composition is used in an amount from about 0.1 to about 1000 ppm by weight.

11. The method of claim 6 wherein the locus is cooling tower water and the composition is used in an amount from about 0.1 to about 1000 ppm by weight.

12. The method of claim 6 wherein the locus is a metal working fluid and the composition is used in an amount from about 0.1 ppm to about 2 percent by weight.

13. The method of claim 6 wherein the locus is fabric, leather, paper or wood and the composition is used in an amount from about 0.1 ppm to about 2 percent by weight.

14. The method of claim 6 wherein the locus is a cosmetic formulation and the composition is used in an amount from about 0.1 ppm to about 1 percent by weight.

15. The method of claim is wherein the locus is a fuel system and the composition is used in an amount from about 0.1 to about 1 percent by weight.

16. The method of claim 6 wherein the locus is a topical therapeutic pharmaceutical formulation and the composition is used in an amount from about 0.1 ppm to about 2 percent by weight.

17. The composition according to claim 1 wherein (A) is selected from 4,5-dichloro-2-n-octyl-3-isothiazolone and 2-n-octyl-3-isothiazolone.

18. The composition according to claim 1 wherein (B) is selected from the group consisting of 1-(3-iodopropargyl)-4-(4-chlorophenyl)-1,2,4-triazolin-5-one, 4-(3-iodopropargyl)-2-propyl-1,3,4-oxadiazolin-5-one, 3-(3-iodopropargyl)-2-benzoxazolone and N-iodopropargyloxycarbonyl glycine methyl ester.

19. The composition according to claim 17 wherein (B) is selected frorn the group consisting of 1-(3-iodopropargyl)-4-(4-chlorophenyl)-1,2,4-triazolin-5-one, 4-(3-iodopropargyl)-2-propyl-1,3,4-oxadiazolin-5-one, 3-(3-iodopropargyl)-2-benzoxazolone and N-iodopropargyloxycarbonyl glycine methyl ester.

20. The composition according to claim 19 wherein the ratio of (A) to (B) is from about 1/20 to about 20/1.