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Warning: fclose() expects parameter 1 to be resource, boolean given in /home/pde321/public_html/header.php on line 113 DODECYL HETEROCYCLISCHE VERBINDUNGEN ALS INDUSTRIELLE MIKROBIZIDE UND KONSERVIERUNGSMITTEL - Dokument EP0697813
DODECYL HETEROCYCLISCHE VERBINDUNGEN ALS INDUSTRIELLE MIKROBIZIDE UND KONSERVIERUNGSMITTEL
The present invention relates to a method of using N-dodecyl heterocyclic
compounds for industrial microbicidal and preservative purposes. N-Dodecyl heterocyclic
compounds have been found to inhibit, that is reduce or prevent, the growth of
Background of the Invention
A large number of commercial, industrial, agricultural, and wood
products are subject to microbiological attack which reduces or destroys their
economic value. Examples of materials that may be subject to microbiological degradation
are surface coatings, wood, agricultural seed, leather and plastics, including
flexible plastics. The temperature at which these products are stored and their
intrinsic characteristics make these products susceptible to the growth of microorganisms.
These microorganisms can be introduced during the manufacturing of these products
by exposure to air, tanks, pipes, equipment, and humans and/or during their use
from multiple openings and reclosures of packaged products and by the introduction
of contaminated objects to stir or remove material.
Aqueous systems containing organic materials are also highly subject
to microbiological attack. Such aqueous systems include latexes, surfactants, dispersants,
stabilizers, thickeners, adhesives, starches, waxes, proteins, emulsifying agents,
detergents, cellulose products, and resins formulated in aqueous solutions, emulsions
or suspensions. These systems frequently contain relatively large amounts of water
causing them to be well-suited environments for microbiological growth and thus
attack and degradation. Microbiological degradation of aqueous systems containing
organic materials may manifest itself as a variety of problems, such as loss of
viscosity, gas formation, objectionable odors, decreased pH, emulsion breaking,
color change, and gelling.
Another objectionable phenomenon occurring in industrial process
systems involving water is slime formation. Slime consists of matted deposits of
microorganisms, fibers and debris. It may be stringy, pasty, rubbery, tapioca-like,
or hard, and may have a characteristic undesirable odor that is different from
that of the liquid suspensions in which it is formed. The microorganisms involved
in its formation are primarily different species of spore-forming and nonspore-forming
bacteria, particularly capsulated forms of bacteria which secrete gelatinous substances
that envelop or encase the cells. Slime microorganisms also include filamentous
bacteria, filamentous fungi of the mold type, yeasts, and yeast-like organisms.
Slime reduces yields in paper production and causes plugging and other problems
in water systems.
Some N-dodecyl heterocyclic compounds are known to have pharmacological
uses. For example, N-dodecylmorpholine and N-dodecylimidazole, have been shown
to be lysosomotropic detergents which are useful as anti-cancer compounds and
spermicides. See R. A. Firestone and J. M. Pisano, "Solution Behavior of Surfactants:
Theoretical Applied Aspects" [Proc. Int. Symposium], Meeting Date 1980, Volume
2, 1455-64, edited by Mittal, K. L. and Fendler, Eleaner J. N-Dodecylimidazole
has been disclosed to be an inhibitor of cholesterol biosynthesis in rat liver
and an inhibitor of epoxidation of aldrin of rat liver. See, respectively, K.H.
Baggeley et al., Biochemical Pharmacology, 24 (20), 1975,
1902-3 and C.F. Wilkinson et al., Biochemical Pharmacology, 23 (17),
1974, 2377-86. N-Dodecyl- morpholine has been reported to help the transport
of anionic drugs. See N. Barker and J. Hadgraft, International Journal of Pharmacology,
8 (3), 193-202. Other pharmacological uses for N-dodecylated heterocyclic
compounds have also been mentioned in the literature.
Some N-dodecyl heterocyclic compounds are also known to have insecticidal
and fungicidal activity. See GB-A-1164004, DE-A-2738907, WO-A-87/04706, JP-A-1168602,
Chem.Abs. 94:134079g, Chem.Abs. 92:141626v and Chem.Abs. 15955w.
However, the utility and effectiveness of N-dodecyl heterocyclic
compounds as industrial microbicides and preservatives has not been known or appreciated
in the prior art.
Disclosure of the Invention
It is an object of this invention to provide a method for inhibiting
the growth of microorganisms in aqueous systems employing N-dodecyl heterocyclic
compounds as non-corrosive industrial microbicides.
A second object is to provide a method for inhibiting the formation
of slime in an aqueous medium such as industrial cooling water or pulp and paper
A third object of the present invention is to provide a method for
inhibiting the growth of microorganisms on a substance susceptible to deterioration
or disfigurement by microorganisms.
The first object of the present invention is accomplished by a method
for inhibiting the growth of microorganisms in an aqueous system comprising the
step of contacting an aqueous system susceptible to the growth of microorganisms
with an N-dodecyl heterocyclic compound in an amount effective to inhibit the
growth of the microorganisms.
The second object is achieved with a method of inhibiting the formation
of slime comprising the step of contacting an aqueous system susceptible to the
formation of slime with an N-dodecyl heterocyclic compound in an amount effective
to inhibit the formation of the slime.
The third object is realized using a method of inhibiting microbiological
deterioration or disfigurement comprising the step of contacting a substance susceptible
to microbiological deterioration or disfigurement with an N-dodecyl heterocyclic
compound in an amount effective to inhibit the growth of microorganisms.
Additional objects and advantages of the invention will be set forth
in the description which follows, and in part will be apparent from the description,
or may be learned by practice of the invention.
Detailed Description of the Invention
The N-dodecyl heterocyclic compounds employed in the present invention
preferably have the following general formula:
The heterocyclic ring defined by
may be a ring having five to ten members and is preferably a five-, six- or seven-membered
ring. Although the heterocyclic ring always contains one nitrogen atom, the remainder
is generally a carbocycle. However, the ring may contain one or more additional
heteroatoms selected from N, O, or S. The ring may be saturated or unsaturated.
The ring may also have common substituents such as alkyl groups, substituted alkyl
groups, alkenyl groups, substituted alkenyl groups, amino groups, an oxo group
to form a cyclic ketone, halogens, etc. The heterocyclic ring may also be part
of a multiple ring structure.
The following lists illustrate possible heterocylic ring structures
contemplated for the N-dodecyl heterocyclic compounds utilized in a preferred embodiment
of the present invention. One of ordinary skill will recognize that other ring
structures may also be used in the present invention. The rings may be substituted
or unsubstituted as described above. Examples of five-membered heterocyclic rings
include: pyrrolidinyl, 2-pyrrolidinonyl, pyrrollinyl, pyrazolidinyl, pyrazolinyl,
pryrazolyl, imidizolidinyl, substituted imidizolidinyl, imidizolinyl, imidazolyl
and oxazolinyl. Types of six-membered rings include: piperadinyl, piperazinyl,
and morpholinyl. Seven- and eight-membered rings such as hexamethyleneimine and
heptamethyleneimine are also usable in the present invention.
The nitrogen-containing heterocycles are available either commercially
from laboratory supply houses or can be prepared from readily available starting
materials using well-known literature methods.
The following N-dodecyl heterocyclic compounds are preferred in the
practice of the present invention and further illustrate preferred heterocyclic
groups: N-dodecylmorpholine, N-dodecyl- imidazole, N-dodecyl-2,6-dimethylmorpholine,
N-dodecyl-5-chloromethyl-2-oxazolidinone, N-dodecyl-2-pyrrolidinone, N-dodecylhexamethyleneimine,
N-dodecylpyrrolidine, N-dodecyl-3-methylpiperidine, N-dodecylpiperidine, N-dodecyl-4-methyl-
piperidine and N-dodecyl-2-methylpiperidine. Most preferred of these compounds
are N-dodecylmorpholine and N-dodecylimidazole.
The compounds of the present invention are preferably prepared by
reacting a nitrogen-containing heterocycle having at least one secondary amino
group within the ring structure, i.e. an amino group having a reactive hydrogen
atom, obtained as described above, with dodecyl bromide, chloride or iodide, and
potassium carbonate, or other suitable base, in the presence of a suitable solvent.
The synthesis of N-dodecyl heterocyclic compounds can generally be
carried out in an organic solvent which may be a solvent for at least one of the
reactants but which is generally a solvent for the desired product. The temperature
at which these reactions can be run preferably varies from ambient to 100°C, more
preferably the reaction temperature is between 50 and 70°C. The reactions are generally
stirred for 2 to 16 hours, preferably for 6 to 10 hours.
After the reaction is complete, as shown by gas chromatographic analysis,
the reaction product can be worked up using well-known techniques to isolate and
purify the desired N-dodecyl heterocyclic compound. Excess base and any solids
formed during the reaction can be filtered off, and the filtrate evaporated to
yield the crude product. The crude product, in most cases, is an oily liquid which
can be distilled to yield the pure compound. In case the desired N-dodecyl heterocyclic
compound is a solid, it can be recrystallized from an appropriate organic solvent
to yield a pure compound. It should be noted, however, that both pure and crude
compounds can be used for the purposes of this invention.
The preparation of the N-dodecyl heterocyclic compounds is not limited
to the exact process or steps described above. Any equivalent procedure which yields
the desired end product may be used.
According to the methods of the present invention, inhibition of
the growth of microorganisms includes both the reduction and/or the prevention
of such growth.
The N-dodecyl heterocyclic compounds can be used in a method for
inhibiting the growth of microorganisms in an aqueous system which comprises contacting
the system susceptible to the growth of microorganisms with the N-dodecyl heterocyclic
compound in an amount effective to inhibit the growth of the microorganisms. The
N-dodecyl heterocyclic compounds are non-corrosive and may be added directly to
the system under working conditions. Representative aqueous systems include aqueous
solutions, emulsions and suspensions. Specific systems include water-based paints
and metalworking fluids.
The present invention uses a microbicidal composition comprising
an N-dodecyl heterocyclic compound present in an amount effective to inhibit the
growth of microorganisms and a non-pharmaceutically acceptable carrier. Non-pharmaceutically
acceptable carriers include solvents, surfactants and other carriers used in industrial
applications as would be known to those skilled in the art. These non-pharmaceutically
acceptable carriers do not have the low toxicity profiles and purity required of
pharmaceutically accetable carriers. Non-pharmaceutical grade water is specifically
included in these non-pharmaceutical carriers.
The N-dodecyl heterocyclic compounds used in the present invention
can also be used in a method for inhibiting the formation of slime in an aqueous
system susceptible to slime formation which comprises the step of contacting the
aqueous system with an N-dodecyl heterocyclic compound in an amount effective
to prevent the formation of slime. The N-dodecyl heterocyclic compound may be added
directly to the system under working conditions. These compounds can be used to
kill slime forming organisms, both bacteria and fungi. This method is effective
in aqueous liquids such as a pulp slurry for use in papermaking or liquids contained
in a water cooling device.
A further use of the compounds in the present invention resides in
a method of inhibiting microbiological deterioration or disfigurement comprising
the step of contacting a substance susceptible to microbiological deterioration
or disfigurement with an N-dodecyl heterocyclic compound in an amount effective
to inhibit the growth of microorganisms. These microorganisms include fungi. The
N-dodecyl heterocyclic compound may be applied to the substance or admixed with
the components which make up the substance. This method is effective on substances
such as wood, paint-film, leather, flexible plastic, textiles and the like. In
the preservation of leather, these compounds can be absorbed onto the hides and
thus can be used in the long term preservation of leather. Similarly, in wood preservation
applications, the N-dodecyl heterocyclic compounds provide a method for inhibiting
the growth of wood-decaying organisms over a short or long period of time.
The compounds used in accordance with the present invention have
a number of advantages over other known microbicides. They are excellent microbicides
to be used for both preservation of paint while in the can and after application
on the painted surface. They are hydrolytically stable over a wide pH range (3-11)
and can be used in both latex and oil-based systems. They are soluble in many
solvents, and may therefore be readily diluted for convenience of use. Their compatibility,
low color, and efficiency makes them advantageous for use as a microbicide in
plastic, and for impregnation in or application on the surface of wood, paper,
cloth or other materials.
The N-dodecyl heterocyclic compounds may be applied in various ways
or incorporated into a coating or composition, applied as dust by mixing with powdered
diluents, dissolved in a solvent, or emulsified into water and then dispersed
into a non-solvent. One of ordinary skill would therefore recognize that the particular
application desired will generally dictate the method of use.
The effective amount or percentage of active compounds necessary
to achieve the desired result will vary somewhat depending on the substrate or
aqueous system to be protected, the conditions for microbial growth, and the degree
of protection desired. The concentration of the compounds of the present invention
generally ranges from about 0.0001% to 4% (w/w); preferably 0.0001% to 0.2%, and
more preferably 0.0005% to 0.0050% in the composition applied. One of ordinary
skill can readily determine the effective amount required for a particular application
by simply testing various concentrations prior to treatment of the entire effected
substrate or system.
With aqueous systems, a preferred effective amount of active compound
ranges from about 20 to 5000 parts per million, and more preferably, from about
250 to 2000 parts per million of the aqueous system. The amount of N-Dodecyl heterocyclic
compound effective to prevent the formation of slime in an aqueous liquid preferably
ranges from about 1 to 200 parts per million, and more preferably, from about 1
to 25 parts per million of the aqueous liquid.
The following examples are given to illustrate the nature of the
invention. It should be understood, however, that the invention is not to be limited
to the specific conditions or details set forth in these examples.
EXAMPLESExample 1Preparation of N-Dodecylmorpholine (Compound 1)
174.2 g of morpholine (1 mole), 69 g of potassium carbonate (0.5
mole) and 300 mL of acetone were heated to reflux. To the above solution 124.5
g (0.5 mole) of dodecylbromide were added dropwise. After the addition was complete,
the reaction mixture was heated at reflux for four hours. The reaction mixture
was filtered, and the solvent evaporated in vacuo to leave an oil, which was distilled
under vacuum to give a colorless liquid. Yield is 112.9 g (90% of the theory).
Proton NMR δ 0.8 (S,3Hz), 1.2 (M, 22Hz), 2.3 (M,4Hz) and 3.5 (M,4Hz). Elemental
analysis, observed (theory) is carbon 74.96 (75.25), hydrogen 13.21 (13.02), and
nitrogen 5.38 (5.48). Close proximity between the observed and theoretical values
indicates the positive identification of this compound. Similarly prepared compounds
are shown in Table I:
The preferred compounds of the present invention were tested by the
pulp substrate method and basal salts method described in U.S. Patent No. 2,881,070
at column 5, beginning at line 12 and extending to column 6, line 53. The disclosure
of U.S. Patent No. 2,881,070 is specifically incorporated by reference herein.
As set forth therein, a percentage kill of 80% or higher represents an extremely
useful microbicidal composition, but it does not follow that higher kills are
necessarily better or more desirable. The minimum inhibitory concentrations are
those in which a percentage kill of at least 80% is obtained. The results are
presented in Table II.
The micoorganism growth inhibiting activity of N-dodecyl heterocyclic
compounds on the fungus Aspergillus niger was evaluated. The method is described
in U.S. Patent No. 4,945,109, column 5 beginning at line 47 to column 6, line
33. The disclosure of U.S. Patent No. 4,945,109 is incorporated herein by reference.
The minimum inhibitory concentrations are those that completely prevented the growth
of fungi. The results are presented in Table III.
Minimum inhibitory concentration of N-dodecyl heterocyclic compounds
against fungi in parts per millionCompound Aspergillus niger pH 6.0 1> 100 232 3128 4> 512 532 6256 7128 8256 932 101000 111000
The growth inhibiting activity of the method of the invention against
the three algae Chlorella pyrenoidosa, Chlorococcum hypnosporum and Phormidium
inundatum was evaluated in Difco Algae Broth, the content of which was as
Forty-gram portions of the algae medium were added to 250 mL Pyrex
Erlenmeyer flasks fitted with loose metal caps and then sterilized. Each of the
following substances was then added to the flasks in the order listed:
1. Sterile algae medium as required to bring the total weight of the contents
of each flask to 50 grams, after allowing for all subsequent additions specified
2. A solution of the N-dodecyl hetetocyclic toxicant or of a control agent
to be evaluated in each test, to give the concentration desired in parts per million
3. Chlorella pyrenoidosa, Chlorococcum hypnosporum and Phormidium
inundatum in amounts sufficient to give excellent growth in the controls after
14 days. This was achieved by adding 1 milliliter of a 14 day old culture having
luxuriant growth. The Chlorella pyrenoidosa culture was obtained from American
Type Culture Collection No. 7516; Chlorococcum hynosporum, from the University
of Texas at Austin; and Phormidium inundatum, Wisconsin No. 1093, from the
University of Washington.
As a control experiment, WSCP was used as a positive control agent.
WSCP is a known toxicant which kills C. pyrenoidosa at 2 ppm,
C. hypnosporum at 2 ppm and P. inundatum at 10 ppm.
Control experiments were also carried out where no toxicants were also employed.
In the algicidal tests the growth of algae in the nutrient medium is lush green
and can be seen with the naked eye. Because the minimum inhibitory concentrations
of the compounds in this example are those which result in complete inhibition
evaluation of the test results is not subjective.
After the inoculum of the test algae was added, the flasks were incubated
at a temperature of 28°±2°C under fluorescent illumination of 250 foot-candle intensity
(8 hours light, 16 hours darkness) for a period adequate for growth in the controls
(those portions of medium which contained no toxicant). Observations of growth
were made at 7-day intervals. Minimum inhibitory concentrations are those that
prevented complete growth after 28 days. The results are summarized in Table IV.
Minimum inhibitory concentration of N-dodecyl heterocyclic compounds
against algae in parts per millionCompound C. pyrenoidosa pH 7.0 C. hypnosporum pH 7.0 P. inundatum pH 7.0 111-- 184.108.40.206 310< 11000 4100100100 5101010 61110 7111 810110 91110 10< 1< 1< 1 11< 1< 15
Verfahren zur Hemmung des Wachstums von mindestens einem Mikroorganismus in
einem industriellen wäßrigen System, wobei das genannte System anfällig für das
Wachstum des Mikroorganismus ist, umfassend den Schritt, des in Kontakt bringens
des genannten industriellen wäßrigen Systems mit einer N-Dodecyl heterocyclischen
Verbindung mit der folgenden allgemeinen Formel:
worin der durch
definierte heterocyclische Ring eine substituierte oder unsubstituierte Gruppe
ist, ausgewählt aus Pyrrolidinyl, 2-Pyrrolidinonyl, Pyrrollinyl, Pyrazolidinyl,
Pyrazolinyl, Pyrazolyl, Imidizolidinyl, Imidizolinyl, Imidazolyl, Oxazolinyl, Piperadinyl,
Piperazinyl, Morpholinyl, Hexamethylenimin oder Heptamethylenimin, in einer zur
Hemmung des Wachstums des genannten Mikroorganismus wirksamen Menge.
Verfahren nach Anspruch 1, wobei das genannte wäßrige System eine auf Wasser
basierende Lösung, eine auf Wasser basierende Emulsion oder eine auf Wasser basierende
Verfahren nach Anspruch 2, wobei das genannte System eine Anstrich- oder eine
Verfahren nach Anspruch 1, wobei die genannte N-Dodecyl heterocyclische Verbindung
ausgewählt ist aus der Gruppe von N-Dodecylmorpholin, N-Dodecylimidazol, N-Dodecyl-2,6-dimethylmorpholin,
N-Dodecyl-5-chlormethyl-2-oxazolidinon, N-Dodecyl-2-pyrrolidinon, N-Dodecylhexamethylenimin,
N-Dodecylpyrrolidin, N-Dodecyl-3-methylpiperidin, N-Dodecylpiperidin, N-Dodecyl-4-methylpiperidin
Verfahren nach Anspruch 4, wobei die N-Dodecyl heterocyclische Verbindung N-Dodecylmorpholin
oder N-Dodecylimidazol ist.
Verfahren nach Anspruch 1, wobei die genannte wirksame Menge etwa 20 bis etwa
5000 ppm des genannten wäßrigen Systems ist.
Verfahren nach Anspruch 6, wobei die genannte wirksame Menge etwa 250 bis etwa
2000 ppm des genannten wäßrigen Systems ist.
A method for inhibiting the growth of at least one microorganism in an industrial
aqueous system, said system being susceptible to the growth of a microorganism,
comprising the step of contacting said industrial aqueous system with an N-dodecyl
heterocyclic compound having the following general formula:
wherein the heterocyclic ring defined by
is a substituted or unsubstituted group selected from pyrrolidinyl, 2-pyrrolidinonyl,
pyrrollinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidizolidinyl, imidizolinyl,
imidazolyl, oxazolinyl, piperadinyl, piperazinyl, morpholinyl, hexamethyleneimine
or heptamethyleneimine, in an amount effective to inhibit the growth of said microorganism.
The method of claim 1 wherein said aqueous system is an aqueous-based solution,
an aqueous-based emulsion or an aqueous-based suspension.
The method of claim 2 wherein said system is a paint or a metalworking fluid.
The method of claim 1 wherein said N-dodecyl heterocyclic compound is selected
from the group of N-dodecylmorpholine, N-dodecylimidazole, N-dodecyl-2,6-dimethylmorpholine,
N-dodecyl-5-chloromethyl-2-oxazolidinone, N-dodecyl-2-pyrrolidinone, N-dodecylhexamethyleneimine,
N-dodecylpyrrolidine, N-dodecyl-2-methylpiperidine, N-dodecylpiperidine, N-dodecyl-4-methyl-piperidine
The method of claim 4 wherein the N-dodecyl heterocyclic compound is N-dodecylmorpholine
The method of claim 1 wherein said effective amount is from about 20 to about
5000 ppm of said aqueous system.
The method of claim 6 wherein said effective amount is from about 250 to about
2000 ppm of said aqueous system.
Procédé pour inhiber la croissance d'au moins un micro-organisme dans un système
aqueux industriel, lequel système est sensible à la croissance d'un micro-organisme,
caractérisé en ce qu'il comprend l'étape consistant à mettre ledit système aqueux
industriel en contact avec un composé N-dodécylhétérocyclique répondant à la formule
générale suivante :
dans laquelle le noyau hétérocyclique défini par
est un radical substitué ou non substitué choisi parmi les groupes pyrrolidinyle,
2-pyrrolidinonyle, pyrrollinyle, pyrazolidinyle, pyrazolinyle, pyrazolyle, imidizolidinyle,
imidizolinyle, imidazolyle, oxazolinyle, pipéradinyle, pipérazinyle, morpholinyle,
hexaméthylèneimine ou heptaméthylèneimine, en une proportion pour inhiber la croissance
Procédé suivant la revendication 1, caractérisé en ce que ledit système aqueux
est une solution à base aqueuse, une émulsion à base aqueuse ou une suspension
à base aqueuse.
Procédé suivant la revendication 2, caractérisé en ce que ledit système est
une peinture ou un liquide pour l'usinage de métaux.
Procédé suivant la revendication 1, caractérisé en ce que ledit composé N-dodécylhétérocyclique
est choisi dans le groupe formé par les composés qui suivent : N-dodécylmorpholine,
N-dodécylimidazole, N-dodécyl-2,6-diméthylmorpholine, N-dodécyl-5-chlorométhyl-2-oxazolidinone,
N-dodécyl-2-pyrrolidinone, N-dodécylhexaméthylèneimine, N-dodécylpyrrolidine,
N-dodécyl-3-méthylpipéridine, N-dodécylpipéridine, N-dodécyl-4-méthylpipéridine
Procédé suivant la revendication 4, caractérisé en ce que le composé N-dodécylhétérocylique
est la N-dodécylmorpholine ou le N-dodécylimidazole.
Procédé suivant la revendication 1, caractérisé en ce que ladite proportion
efficace varie d'environ 20 à environ 5000 ppm par rapport audit système aqueux.
Procédé suivant la revendication 6, caractérisé en ce que ladite proportion
efficace varie d'environ 250 à environ 2000 ppm par rapport audit système aqueux.