Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION APID USE
The present invention relates to compositions which are
useful as industrial biocides.
Industrial biocides are useful to prevent industrial
spoilage, in particular that caused hy bacteria and fungi.
Industrial biocides find application in the preservation of paints,
latices, adhesives, leather, wood, metal working fluids and cooling
water.
One class of compound which can be used as an industrial
biocide is based on the isothiaæolinone structure. There are many
disclosures of isothiazolinone derivatives which are stated to have
useful biocidal properties. US Patent 3761488 discloses
isothiazolinGne deriva~ives in which alkyl, alkenyl, alkynyl,
cycloalkyl, aralkyl or aryl groups, which may optionally be
substituted, are attached to the nitrogen atom and the 4 and 5
positions are unsubstituted or are substituted with halogen or lower
alkyl groups. US Patent 4165318 discloses a solution of an
isothia~olin-3-one in a polar organic solvent, wherein the solution
also contains a stabilising amount of formaldehyde. Stabilisation
of similar compounds is also claimed in US Patent 4,067,878 where the
stabilising compound is a nitrite or nitrate of a metal cation.
British Patent Specification 2087388 discloses
4,5-polymethylene-4-isothia~olin-3-ones and derivatives thereof in
which the polymethylene chain has three or four carbon atoms.
Compounds and compositions of the foregoing types, and
related compounds of the same general type, are effective to a
varying degree, depending on the particular compound or composition,
against a range of bacteria and/or fungi. However, to reduce the
cost of using these compounds it is desirable to improve their
effectiveness as antimicrobial materials.
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Compositions have been proposed which contain more than one
compound which has antimicrobial properties. In general such
compositions show an aggregate of the properties of the co~pounds
present in the composition. Typically such compositions contain one
compound which e~hibits useful antibacterial properties together with
a different compGund which exhibits useful antifungal properties.
We have now found that certain compositions possess
surprisingly useful antimicrobial properties, especially
antibacterial properties.
Thus, according to the present invention there is provided a
composition which comprises
(a) at least one 4,5 polymethylene-4-isothiazolin-3-one or a
derivative thereof, and
(b) at least one isothiazolin-3-one derivative which does not
lS contain a fused ring attached to the isothiazole ring.
The 4,5 polymethylene-4-isothia~olin-3-one derivative which
is component a) of the composition is typically z compound of the
general formula I.
- R \ / O\
\ 3
) ~ N - R
~-Rl \S/
wherein:
Rl and R2 taken together represent A polymethylene chain,
having 3 or 4 carbon a~oms or a polymethylene chain having 3 or 4
carbon atoms s~bstituted by at least one lower alkyl rad:Lcal having
from 1 to 4 carbon atoms;
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3_ S 35718
R represents hydrogen; a linear or branched alkyl group
having from 1 to 12 carbon atoms; a linear or branched alkyl group
having from 1 to 3 carbon atoms substituted by one or more hydroxyl
groups; an alk~nyl group having from 3 to 6 carbon atoms; a radical
of the formula
(R5)m
(C~IR4)
wherein:
; n is 0 or 1;
m is 1 or 2;
R4 represents hydrogen or a lower alkyl group; and
R5 represents hydrogen, lower alkyl, nitro, trifluoromethyl
or halogen, preferably chlorine, bromine or iodine; cyclo alkyl
having from 3 to 6 carbon atoms; and a radical of formula
o
_ C - NHR
wherein
R6 represents hydrogen, linear or branched alkyl having
from 1 to 12 carbon atoms or a radical of the formula
(R5)~
-(CEIR4) ~
as defined above, and their salts with a mineral or organic
Acid.
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In a preferred embodiment of the invention the
4,5-polymethylene-4-isothiazolin-3-one can be represented by the
general formula II
(cH2~t C82 ) f \ N - R3 II
\ CH \ S /
wherein t is l or 2 and R3 is as defined above. These
compounds are, thus, derivatives of 4,5-trimethylene or
4,5-tetramethylene-4-isothia701in-3--ones.
R3, in formulae I and II, may be a linear or branched alkyl
group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, hexyl, octyl or dodecyl.
When R3 represents alkyl substituted by one or more
hydroxyl groups, this includes, for instance, hydroxymethyl,
2-hydroxyethyl, 2-hydroxypropyl and l,2 dihydroxy propyl.
As an example of alkenyl as represented by R3, ~here may be
mentioned allyl.
When K3 represents a radical of formula
(RS)m
-tCHR4)n ~
this can be, for example, phenyl, chlorophenyl, 2,4-dichlorophenyl,
benzyl, 4-chlorob~nzyl or 2,4-dichlorobenzyl.
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When R3 represents cycloalkyl havirlg from 3 to 6 carbon
atoms, this can be, for example, cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl.
Finally, when R3 represents a radical of formula
o
Il 6
- C-NHR
it can be carbomoyl, N-methyl carbamoyl, N-ethylcarbamoyl,
N-isopropyl carbamoyl, N-propyl carbamoyl, N-phenyl carbamoyl,
N-cyclohexyl carbamoyl, N-butyl carbamoyl or N-octyl carba~oyl.
The tenm lower alkyl represented by R4 above includes
linear or branched alkyl chains containing up to 4 carbon atoms such
as methyl, ethyl, isopropyl, butyl and tertiary butyl.
As specific examples of compounds which may be used as
component (a) of the composition of the present invention, there may
be mentlonsd 2-methyl-4,5-trimethylene isothiazolin-3-one. (formula
II, in which t is 1 and R3 is methyl), and 4,5-trimethylene
lsothiazolin-3-one tformula II, in which t is 1 and R3 is hydrogen).
~;:
Component bj of the composition is an isothiazolin-3-one of
general formula III
~ / III
S
wherein
Y is a hydrogen atom, an alkyl, substitutsd alkyl, alkenyl,
alkynyl, cycloalkyl, aralkyl or aryl group;
:. . .
.: . . . .
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-6- S 35718
R7 is hydrogen, halogen or an alkyl group; and
R8 is hydrogen, halogen or an alkyl group.
When Y is alkyl, it is preferably an alkyl group containing
from 1 to 18 carbon atoms and especially from 1 to 4 carbon atoms and
particularly a methyl group.
When Y is cycloalkyl, it is preferably a cycloalkyl group
containing from 3 to 12 carbon atoms and especially fro~ 3 to 8
carbon atoms and particularly a cyclohexyl group.
When Y is alkyl or aralkyl, it preferably contains up to 10
carbon atoms. The aryl groups, themselves, may also carry
substituents such as halogen, particularly chlorine, or alkyl or
alkoxy groups containing up to 4 carbon atoms such as methyl and
methoxy.
When R andlor R8 is halogen, it is particularly chlorine
or bromine, and when R7 andlor R3 is alkyl it is particularly an
alkyl group containing from 1 to 4 carbon atoms and especially
methyl.
Particularly important within this group of compounds are
those in which Y represents a linear or branched alkyl group
containing up to 8 carbon atoms and where R7 and R8 represent
independently hydrogen or chlorine. Thus, as specific examples of
compounds which may be used as componen~ ~b) of the composition of
the present invention, there may be mentioned 2~methyl
isothiazolin-3-one ~formula III, in which Y is methyl, R7 and R~ are
both hydrogen), 5-chloro-2-methyl
-lsothia7,01in-3-one ~formula III, in which Y is methyl, R7 is
chlorine and R8 is hydrogen) and 4,5 dichloro-2-methyl
-isothiazolin-3-one ~formula III, in which Y is methyl, R7 and R8 are
both chlorine). Such compounds may represent component b) ln the
comyosition of the present invention as individual chemical compounds
or they may be preseDt in combination.
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A particularly useful combination has been found to be one
comprising ~-methyl-l~,5-trimethylene-4-iso~hiazolin-3-one together
with at least one of 2-methyl isothiazolin-3-one, S-chloro-~-methyl
isothiazolin-3-one and 4,5-dichloro-~-methyl isothia~olin-3-one.
In various types of applications, it is ~requently
necessary or convenient to formulate the isothiazolin-3-one as
represented by formula III in solution, especially using water or
polar organic solvents such as alcohols. While such formulation has
no effect on the stability or function of isothiazolin-3-ones as
anti-microbial agents if used relatively quickly, extanded storage of
the formulated solutions, especially at elevated temperature, may
result in chemical decomposition of the isothiazolin-3-one, thus
leading to reduced biocidal effectiveness. Consequently, it is
common to stabilise such formulations by incorporating nitrite or
nitrate salts of metals. It is also possible to stabilise such
compounds in the presence of formaldehyde or compounds which release
formaldehyde.
When isothizolin-3-ones of the afore-mentioned structures
as represented by formulae I and III are used in aqueous solution,
their solubility may be improved by forming their salts with strong
organic and/or inorganic acids such as hydrochloric acid, sulphuric
acid, succinic and citric acids.
The relative proportions of the components o the
composltion can vary and compositions having useful properties can be
obtained which contain from one part by weight o~ component (a) or
component (b) and correspondingly up to 1000 parts by weight of
component (b) or component (a). The preferred proportions are
dependent on the compouncls used as component (a) and component (b),
and also ~he particular system in which the mixture ls to be used.
In general the composition contains at least l part by weight of one
component and not more than 100 parts by weight of the other
component.
Particularly preferred compositions are those were the
ratio of component (a) to component (h) is be~ween 1:10 and 10:1 and
preferably between 1:5 and S:l such as, Eor ex~mple, 1:1.
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The compositions of the present invention have
antimicrobial properties. We have found that compositions in
accordance with the present invention are especially active against
bacteria. Furthermore, compositions in accordance with the presen~
invention are such that the sum of the fractional inhibitory
concentration (FIC) for all the components of the composition is less
than one and, with preferred compositions is less than 0.7.
Especially preferred compositions are those in which the sum of the
FIC for all the components of the composition is not more than 0.6.
The FIC is the ratio of the concentration of an individual component
to the minimum inhibitory concentration of that component. It will
be appreciated that if the value of the sum of the FIC for all the
components of the composition is less than one, the composition is
synergistic, the extent of synergy being indicated by the amount by
which the 9um of the E~'IC is below one. We have found that some
compositions in accordance with the present invention are such that
the sum of the FIC is less than 0.6.
The compositions of the present invention have antimicrobial
properties and are suitable for use as industrial bioc~des. They
exhibit good wet state preservation and hence may be used as a
cutting fluid preservative and also in cooling water applications.
They may be used to preserve industrially important formulations,
especially aqueous based formulations, which are used for coloration,
such as dyestuffs and printing inks. They may also be used in the
a~rochemical industries to preserve formulations such as herbicide
and pesticide flowables.
Still further important appllcations of the compositions of
the present invention include their use in hydrocarbon fluids such as
diesel fuels. They may also be incorporated into adhesives in order
to inhiblt microbial spoilage.
The preservation of wood and leather is yet another
important application of the compositions.
Especially important is the use of the composition of the
present invention in paints, particularly in aqueous based latices.
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A particularly preferred use of ~he compositions of the
present invention is for the preservation of poly vinyl acrylate and
particularly acrylic latices, espPcially those whose p~ is above 7,
and more especially those containing ammonia or amines.
The materials which are component (a) and component (b) of
the composition of the present invention are soluble in many polar
solvents, although the solubility is dependent on the nature of the
particular compounds which are present in the composition. Ho~ever,
many of the compounds are soluble in water, alcohols, ethers, ~etones
and other polar solvents or mixtures thereof.
The compositions of the present invention may be used alone
as an antimicrobial material but may also be used in, or on, a
suitable carrier material.
Thus, as a further aspect of the present invention there is
provided a biocide composition comprising a carrier and an effective
amount of a composition of components (a) and (b) in accordance with
the invention.
The carrier is typically a material which shows little, if
any, antimicrobial activity and may be, or include~ a material which
is susceptible to the growth of micro-organisms, particularly
bacteria. The carrier is preferably a liquid medium and the biocide
composition may be a solution, suspension or emulsion of the
composition of components (a~ and (b) ln a liquid carrier. The
carrier may be water, ln which one or both oE components (a) and (b)
are soluble, or may be a liquid such as acetic acid, N,N-dimethyl-
formamide, propylene glycol, dimethyl sulphoxide or N-methyl-
2-pyrrolidone in which at least one, and preferably both, o
componerlts (a) and (b) are soluble. Alternatively, a mix~ure of
liquids may be used, one being a solvent for component (a) and
component (b) and the other being a non-solvent Eor both components,
snd using such a mixture the composition typically comprises sn
emulsion or droplets of a solution of components (a) and (b) in the
solvent therefor dispersed ln ~he non-solvent. If a suspension or
emulsion is used, this conveniently contAins a surface active agent
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-10- S 3571
which is effective to maintain the non-continuous phase as a
suspension or emulsion. Any surface active agent known for use in
biocide compositions may be used in such a system, for example
alkylene oxide adducts of fatty alcohols, alkyl phenols and amines
such as ethylene diamine.
Whereas it is advantageous in using the composition of the
present invention to add component (a) and component (b)
simultaneously, it will be appreciated that in certain circumstances
it may be beneficial to add cornponent (a) and component (b)
sequentially.
The amount of the composition which is present in the
biocide composition may be just sufficient to have an antimicrobial
effect or the composition may be present in a substantially greater
proportion. It will be appreciated that the biocide composition may
be provided as a concentrated solution which is subsequently diluted
for use as an anti~icrobial material. The higher concentrations of
the biocide composition are useful for example in the bulk
transportation of the composition. Thus, the amount of the
composition of components (a) and (b) which is present in the
biocide composition is typically in the range from 0.00001% up to 30
by weight of the biocide composition.
The composition of the present invention is especially
effective in providing anti-bacterial activity. Thus, the
compositions can be used for the treatment of various media to
inhibit the growth of micro-organisms.
As a furthar aspect of the present invention there is
provided a method for inhlbiting the growth o micro-organisms on, or
in, a medium which comprises treating the medium with a composition
of components (a) and (b) as hereinbefore defined.
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The composition can be used in conditions in which
micro-organisms grow and cause problems. Systems in which
micro-organisms cause problems include liquid, particularly aqueous,
systems such as coollng water liquors~ paper mill liquors, metal
working fluids, geological drilling lubricants, polymer emulsions and
surface coating compositions such as paints, varn~shes and lacquers
and also solid materials such as wood and leather. The composition
of thP present invention can be included in such materials to provide
an anti-microbial effect. The amount of the composition is
l¢ typically in the ran8e from 0.00001 up to lOZ, preferably 0.00002 up
to 5z and especially 0.00002 to 1% by weight of the composition
relative to the system to which it is added. In many cases,
microbial inhibition has been obtained with between 0.00002 and O.OlZ
by weight of the composition.
lS Components (a) and (b) of the composition of the present
invention may be the only antimicrobial compounds or may be used
together with ~urther compounds having antimicrobial characteristics.
The composition may contain more than one compound which is
component (a) together with one or more compound which is component
(b). Alternatively, a composition of components (a) and (b~ in
accordance with the present invention may be used together with one
or more known antimicrobial compounds. The use of a mixture of
anti-microbial compounds can provide a co~position having a broader
anti-microbial spectrum and hence one which is more generally
effective than the components thereof. The known antimicrobial may
be one possessing anti-bacterial, antl-fungal, anti-algal or other
antimicrobial characteristic. The mixture o the composition of the
present invention with other antimicrobial compounds typically
contains from 1 to 9gZ by weight, relative to the weight of total
antimicrobially active compounds, of the composition of components
(a) and (b), and particularly from 40 to 60Z by weight of the
composition of components (a) and (b).
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As examples of known antimicrobial compounds which may be
used, together with the composition of the present invention, there
may be mentioned quaternary ammonium compounds such as
diPthyldodecylbenzyl ammonium chloride; dimethyloctadecyl-
(dimethylbenzyl)ammonium chloride; dimethyldidecylammonium chl.oride;
dimethyldidodecylammonium chloride; trimethy-tetradecylammonium
chloride; benzyldimethyl(Cl2-C18 alkyl)ammonium chloride;
dichlorobenzyldimethyldodecylammonium chloride; hexadecylpyridinium
chloride; hexadecylpyridinium bromide; hexadecyltrimethylammonium
bromide; dodecylpyridinium chloride; dodecylpyridini~m bisulphate;
benzyldodecyl-bi~(beta-hydroxyethyljammonium chloride; dodecyl-
benzyltrimethylammonium chloride; benzyldimethyl(C12-C18 alkyl~
ammonium chloride; dodecyl.dimethylethyl ammonium ethylsulphate;
dodecyldimethyl-(l-naphthylmethyl)ammoni~ chloride; hexadecyl-
dL~ethylbenzyl ammonium chloride; dodecyldimethylbenzyl ammlonium
chloride and l-(3-chloroallyl)-3,5,7-triaza l-azonia-adamantane
chloride; urea derivatives such as 1,3-bis(hydroxymethyl)-
5,5-dimethylhydan~oin; bis(hydroxymethyl)urea; tetrakis(hydroxy-
methyl)acetylene diurea; l-(hydroxymethyl)-5,5-dime~hylhydantoin and
imidazolidinyl urea; amino compounds such as 1,3-bis~2-ethyl-
hexyl)-S-methyl-5-aminohexahydropyrimidine; hexamethylene tetra
amine; 1,3-bis(4-aminophenoxy)propane; and 2-[(hydroxymethyl)-
amino]ethanol; imidazole derivatives such as 1[2-(2,4 dichloro-
phenyl)-2-(2-propenyloxy)ethyl~ -imidazole; 2-(methoxycarbonyl-
amino)-benzimidazole; nitrile compounds such as 2,4,5,6-tetra-
chloroisophthalodinitrile and 1,2-dibromo-2,4-dicyanobutane;
thiocyanate derivatives such as methylene bis thiocyanate; tin
compounds or complexes such as tributyl~in-oxide, chlorlde,
naphthoate, benzoate or 2-hydroxybenzoate; thiaæole derivatives such
as 2--(thiocyanomethylthio)-benzthiazole; and mercaptobenzthiazole;
nitro compounds such as tris(hydroxymethyl)nitromethane; 5-bromo-
S-nitro-1,3-dioxane and 2-bromo-2-nitropropane-1,3-diol; aldehydes
and derivatives such as gluteraldehyde ~pentanedial)
p-chlorophenyl-3-iodopropargyl formaldehyde and g:Lyoxal; amides such
as chloracetamide; ~,N-bis(hydroxymethyl)chloracetamide;
N-hydroxymethyl-chloracetamide and dithio-2,2-bis(benzmethyl amide);
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guanidine derivatives such as poly hexamethylene biguanide and
1,6 hexamet~ylene-bis[5-(4-chlorophenyl)biguanide]; thiones such as
3,5-dimethyltet~ahydro-1,3,5-2EI-thiodiazine-2-thione; triazine
derivatives such as hexahydrotriazine and 1,3,5-tri-(hydroxyethyl)-
1,3,5-hexahydrotriazine; oxazolidine and derivatives thereof such as
bis-oxazolidine; furan and derivatives thereof such as
2,5-dlhydro-2,5-dialkoxy-2,5-dialkylfuran; carboxylic acids and the
salts and esters thereof such as sorbic acid and the salts thereof
and 4-hydroxybenzoic acid and the salts and esters thereof; phenol
and derivatives thereof such as 5-chloro-2-(2,4-dichloro-
phenoxy)phenol; thio-bis(4-chlorophenol) and 2-phenylphenol;
sulphone derivatives such as diiodomethyl-paratolyl sulphone,
2,3,5,6 ~etrachloro-4-(methylsulphonyl) pyridine and
hexachlorodimethyl sulphone.
Further aspects of ~he present invention are described in
the following illustrative exa~tples.
In the following examples, compositions in accordance with
the present invention were subjected to evaluation of the
antmticrobial properties especially anti-bacterial properties~ of the
compositions. The evaluation was effected, under sterile conditions
throughout, as &etailed below.
Microbiolo~ical evaluation
The materials, or mixture of materials, to be tested were
added to a mltrient broth in amounts to give a clc~ired concentration
of the added material. The added materials were added at
concentrations from zero to above the minimum inhlbitory
concentration of the particular material In the mixtures, the
concentrations of each material were varied in a systematic fashion
to give a matrlx of mixtures o~ different relative proportions ancl
different total concentrations.
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The effect on ~he inhibition of growth of bacteria was
investigated by inoculating each sample of broth with sufficient of
the test micro-organism to give about lO5 cells cm~3. The mixture
was incubated at 30C for 48 hours. At the end of the test period
the presence of turbidity in the broth indicated that growth of the
test micro-organism had occurred. A lack of turbidity was
indicative that no growth had occurred. The results were used to
draw an isobologram from which the sum of the fractional inhibitory
concentration for a mixture can be determined.
Example 1
The microbiological evaluation as described was carried out
using the bacterium, Escherichla coli. The composition tested was a
mixture of 2-methyl-4,5-trimethylene-4-isothiazolin-3-one and
5-chloro-2-methyl-isothiazolin-3-one.
An isobologram was drawn using concentrations of 0, 0.2,
0.5, 0.7, 0.9, l.l, l.4, l,6, l.8 and 2 microgram cm 3 of the
trimethylene-isothiazolinone and 0, 0.2, 0.5, 0.7, 0.9, l.l, l.~,
1.6, l.8 and 2 microgr~m cm~3 of the chloro isothiazolinone.
From the results obtained, it was found that the lowest sum
of the fractional inhibitory concentration was 0.54 which was
obtained with a mixture of 0.2 microgram cm~3 of the
2-methyl-4,5-trimethylene-4-isothiazolin-3-one and 0.2 microgram cm 3
of the S-chloro-2-methyl-isothiazolin 3~one. This may be contrasted
with the minimum inhibitory concentrations (MIC) for the two
individual compounds against the ~amo micro-organism which were found
to be 1.4 microgram cm~3 and 0.5 mlcrogram cm~3 respectively.
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