WO1996019467A1 - Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents - Google Patents
Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents Download PDFInfo
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- WO1996019467A1 WO1996019467A1 PCT/US1995/013494 US9513494W WO9619467A1 WO 1996019467 A1 WO1996019467 A1 WO 1996019467A1 US 9513494 W US9513494 W US 9513494W WO 9619467 A1 WO9619467 A1 WO 9619467A1
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- thiadiazole
- scn
- compound
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- 0 CS*=C(*)C(*)=N Chemical compound CS*=C(*)C(*)=N 0.000 description 4
- YTIPDCIFYXKVMP-UHFFFAOYSA-N C=C(C(N)N=C=S)c(cc1)ccc1[IH]#C Chemical compound C=C(C(N)N=C=S)c(cc1)ccc1[IH]#C YTIPDCIFYXKVMP-UHFFFAOYSA-N 0.000 description 1
- QWDVYDNPFZDESD-POHAHGRESA-N COc(cc1)ccc1/C(/C(N)N=C=S)=C/S Chemical compound COc(cc1)ccc1/C(/C(N)N=C=S)=C/S QWDVYDNPFZDESD-POHAHGRESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
- C09D5/14—Paints containing biocides, e.g. fungicides, insecticides or pesticides
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
- C09D5/16—Antifouling paints; Underwater paints
- C09D5/1606—Antifouling paints; Underwater paints characterised by the anti-fouling agent
- C09D5/1612—Non-macromolecular compounds
- C09D5/1625—Non-macromolecular compounds organic
Definitions
- the present invention is directed to novel substituted thiadiazole compounds, compositions containing said compounds and the use of these compositions as antimicrobial and marine antifouling agents.
- EP 0433 616 A2 discloses antimicrobials for the control of bacteria and fungi and teaches the preparation of compounds of the formula :
- U.S. Patent 4,094,880 discloses antimicrobials for the control of bacteria and fungi and the preparation and the antimicrobial use of 2,5-bis(chloromethylthio)-1 ,3,4-thiadiazole and its isomer 3,5-bis(chloromethylthio)-1 ,2,4-thiadiazole of compounds of the formula :
- U.S. Patent 3,888,869 discloses the preparation of compounds of the formula : and which compounds are useful as antimicrobials.
- R represents -Br, -Cl, -OCH 3 , -SCN, -OCH 2 SCN, -SCH 2 SCN, -OCH 2 CH 2 SCN, -SCH 2 CH 2 SCN,
- Y represents -Br, -Cl, -OCH 3 , -SCN, -OCH 2 SCN, -SCH 2 SCN, -OCH 2 CH 2 SCN or -SCH 2 CH 2 SCN;
- X represents -Br, -Cl, -F, -CH 3 , -OCH 3 , -COOCH 3 , -NO 2 , -SCH 3 , -SO 2 CH 3 or -CF 3 and n is an integer of from 0-5, with the proviso that at least one of R or Y represents -SCN, OCH 2 SCN, -SCH 2 SCN, -OCH 2 CH 2 SCN or -SCH 2 CH 2 SCN and with further proviso that when R is
- Y is -SCN or -SCH 2 SCN.
- the present invention is also directed to antimicrobial compositions comprising an inert diluent and an antimicrobially-effective amount of a compound corresponding to Formula 1
- the present invention is further directed to a method for inhibiting microorganisms in a microbial habitat comprising contacting said microbial habitat with an antimicrobially-effective amount of a compound corresponding to Formula 1
- the antimicrobial compositions of the present invention can also be employed to treat surfaces exposed to a marine environment in which marine organisms grow to prevent the growth of said marine organisms on said surfaces .
- the preferred compounds of the present invention include those wherein R represents -Cl, phenyl or -SCN when Y is -SCN; those wherein R represents -Cl, phenyl or -SCH 2 SCN when Y is -SCH 2 SCN and those wherein R represents -Cl or -SCH 2 CH 2 SCN when Y is
- alkali metal is employed to designate sodium, potassium, lithium or cesium.
- halo is employed to designate bromo, chloro, fluoro or iodo.
- Sterically compatible may be further defined as reacting compounds having substituents whose physical bulk does not require confinement within volumes insufficient for the exercise of their normal behavior as discussed in Organic Chemistry by D. J. Cram and G. Hammond, 2nd edition, McGraw-Hill Book Company, N Y., page 215 (1964).
- Y represents -SCN or -SCH 2 SCN may be prepared in a two-stage reaction procedure wherein in the first stage or step, a 4-(substituted)-3-halo-1 ,2,5-thiadiazole wherein the substitution set forth hereinafter as R' and which represents Br, -Cl, or
- the reactions are typically carried out at a temperature from 25 to 40°C.
- the reactants may be added to the reaction mixture in any order of addition; conventionally they are added as a solution in the solvent used for the reaction.
- the reaction is conveniently allowed to continue over a period from 1 to 24 hours.
- the reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal sulfide per mole of the 4-(substituted)-3-halo-1 ,2,5-thiadiazole reactant.
- an excess of the alkali metal sulfide reactant is normally employed.
- the general scheme for this first reaction step is as follows:
- alkali metal salt product is then reacted in situ with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with
- halomethylthiocyanate such as chloromethylthiocyanate to prepare the desired 4 ⁇
- reaction consumes the reactants in the ratio of one mole equivalent of the cyanogen halide or halomethylthiocyanate per mole of the 4-(substituted)-3-mercapto-1 ,2,5-thiadiazole: alkali metal salt reactant. To assure the completion of the reaction, a slight excess of the cyanogen halide or
- the above second stage reactions are typically carried out at a temperature from 25 to 40°C
- the reactants may be added to the reaction mixture in any order of addition, conventionally they are added as a solution in the solvent used for the reaction Subsequent to the addition of the reactants, the reaction is allowed to continue over a period of 1 to 24 hours
- the reaction product may be isolated by adding a 3 to 10 volume excess of water which will precipitate the desired product Filtration followed by washing and drying yields the desired compounds of the present invention.
- the bis(thiocyanato)-1,2,5-thiadiazole compound of the present invention may be prepared by first reacting in the presence of a solvent an alkali metal sulfide, such as sodium sulfide, with a 4,5-dihalo-1,2,5-thiadiazole, such as 3,4-dichloro-1 ,2,5-thiadiazole, to produce a bis(mercapto)-1 ,2,5-thiadiazole: di(alkali metal) salt, such as the bis(mercapto)-1,2,5-thiadiazole: disodium salt
- a solvent such as sodium sulfide
- a 4,5-dihalo-1,2,5-thiadiazole such as 3,4-dichloro-1 ,2,5-thiadiazole
- the desired bis(thiocyanato)-1 ,2,5-thiadiazole is then prepared by reacting the thus prepared bis(mercapto)-1,2,5-thiadiazole: di(alkali metal) salt with a cyanogen halide, such as cyanogen bromide Two mole equivalents of the cyanogen halide are used per mole of the bis(mercapto)-1 ,2,5-thiadiazole, di(alkali metal) salt to prepare the
- halothiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole compounds of the present invention may be prepared by first preparing a (halomercapto)-1 ,2,5-thiadiazole, alkali metal salt, as described heremabove
- the halothiomethylthiocyanato-1 ,2,5-thiadiazole is then prepared by reacting the (halomercapto)-1 ,2,5-thiadiazole, alkali metal salt with a
- halomethyl(or ethyl)thiocyanate such as chloromethylthiocyanate or chloroethylthiocyanate
- halomethyl(or ethyl)thiocyanate such as chloromethylthiocyanate or chloroethylthiocyanate
- One mole equivalent of the halomethyl(or ethyl)thiocyanate is used per mole of (halomercapto)-1 ,2,5-thiadiazole: alkali metal salt to prepare the halothiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole.
- n 1 or 2.
- the bis(thiomethyl(or thioethyl)thiocyanato-1 ,2,5-thiadiazole compounds of the present invention wherein, for example, R and Y each represent -SCH 2 SCN or -SCH 2 CH 2 SCN, may be prepared by reacting a halomethyl(or ethyl)thiocyanate, such as
- Two mole equivalents of the halomethyl(or ethyl)thiocyanate is used per mole of the bis(mercapto)-1 ,2,5-thiadiazole: alkali metal salt to prepare the desired bis(thiomethyl(or thioethyl)-thiocyanato-1 ,2,5-thiadiazole
- n 1 or 2
- the hereinabove depicted reactions are carried out in the presence of an inert solvent such as dimethylformamide, methanol, ethanol, acetonitrile, acetone, or pyridine
- the reactions are carried out at 0°C under an ambient pressure of inert gas.
- the reaction mixture is allowed to stir at a temperature between 25°C to 60°C for a period between 2 to 24 hours in order to increase the reaction rate and promote extinction of the limiting reagent Final work-up of the reaction mixture then provides the desired final product.
- the thiadiazole compounds of the present invention may be prepared by first reacting a 4-halo-3-thiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole, as prepared hereinbefore, an alkali metal sulfide, such as sodium sulfide, followed by reacting the thus formed 4-mercapto-3-thiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole: alkali metal salt with a cyanogen halide, such as cyanogen bromide to form the desired 3-thiocyanato-4-thiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole.
- a cyanogen halide such as cyanogen bromide
- the thiadiazole compounds of the present invention may be prepared by first reacting a 3-halo-4-mercapto-1,2,5-thiadiazole: alkali metal salt, as prepared hereinbefore, with a dihaloethane such as 1-bromo-2-chloroethane to produce a 4-halo-3-halothioethyl-1,2,5-thiadiazole such as 4-chloro-3-chlorothioethyl-1,2,5-thiadiazole.
- the general scheme for this reaction step is as follows:
- This product can, without separation and purification, be reacted with a halomethylthiocyanate, such as chloromethylthiocyanate to form a 3-halothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole, such as 3-chlorothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole.
- a halomethylthiocyanate such as chloromethylthiocyanate
- 3-halothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole such as 3-chlorothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole.
- the above 3-halothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole product is dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours.
- a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours.
- the reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired 3-thioethylthiocyanato-4-thiomethylthiocyanatomethyl-1 ,2,5-thiadiazole.
- the reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided.
- the general scheme for this reaction step is as follows:
- halothiocyanatomethyloxo-1,2,5-thiadiazole compounds of the present invention wherein, for example, R represents -Cl or -Br and Y represents -OCH 2 SCN, may be prepared by first irradiating a solution of 4-halo-3-methoxy-1 ,2,5-thiadiazole such as 4 ⁇
- the reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided.
- the bis(thiomethyloxothiocyanato)-1 ,2,5-thiadiazole compounds of the present invention may be prepared by first irradiating a solution of a bis(methoxy)-1 ,2,5-thiadiazole in carbon tetrachloride with a sunlamp while adding a solution of sulfuryl chloride in carbon tetrachloride. The reaction mixture is washed with aqueous sodium bicarbonate and concentrated under reduced pressure to yield bis(chloromethoxy)-1 ,2,5-thiadiazole.
- the general scheme for this first reaction step is as follows:
- the reaction consumes the reactants in the ratio of two mole equivalents of the alkali metal thiocyanate per mole of the thiadiazole reactant and such amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.2-1.25 equivalents, of alkali metal thiocyanate is usually provided.
- the 4-methoxy-3-thiocyanatomethyloxo- 1 ,2,5-thiadiazole compound of the present invention may be prepared by first irradiating a solution of a bis(methoxy)-1 ,2,5-thiadiazole in carbon tetrachloride with a sunlamp while adding a solution of sulfuryl chloride in carbon
- reaction mixture is washed with aqueous sodium bicarbonate and concentrated un ⁇ er reduced pressure to yield 4-methoxy-3-halomethoxy-1 ,2,5-thiadiazole.
- This product is then dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours.
- the reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired 4-methoxy-3-thiocyanatomethyloxo-1 ,2,5-thiadiazole.
- the reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided.
- the general scheme for these reaction steps are as follows:
- the 4-methoxy-3-thiocyanatoethyloxo-1,2,5-thiadiazole compound of the present invention that is, wherein R represents -OCH 3 and Y represents -OCH 2 CH 2 SCN may be prepared by treating 4-chloro-3-methoxy-1 ,2,5-thiadiazole, prepared as set forth
- the 3-thiocyanatoethyloxo-4-thiocyanato-methyloxo-1 ,2,5-thiadiazole compound of the present invention may be prepared by treating a 4-haio-3-thiocyanatomethyloxo-1 ,2,5- -thiadiazole, such as 4-chloro-3-thiocyanatomethyloxo-1,2,5-thiadiazole, prepared as set forth hereinbefore, with an alkali metal hydroxide, such as sodium hydroxide, to prepare the corresponding 4-hydroxy-3-thiocyanatomethyloxo-1 ,2,5-thiadiazole which is then reacted with a haloethylthiocyanate, such as chloroethylthiocyanate to give the desired 3-thiocyan
- the 3-methoxy-4-thiocyanato-1 ,2,5-thiadiazole compound of the present invention may be prepared by reacting a 4-halo-3-methoxy-1,2,5-thiadiazole such as 4-chloro-3-methoxy-1 ,2,5-thiadiazole, prepared as set forth hereinbefore, with an alkali metal sulfide, such as sodium sulfide followed by reacting the thus formed 3-methoxy-4-mercapto-1,2,5-thiadiazole; alkali metal salt with a cyanogen halide, such as cyanogen bromide to form the desired 3-methoxy-4-thiocyanato-1 ,2,5-thiadiazole.
- the general scheme for this reaction is as follows:
- the 3-methoxy-4-thiomethyl(or ethyl)-thiocyanato-1 ,2,5-thiadiazole compounds of the present invention may be prepared by reacting at room temperature in dimethylformamide a 3-methoxy-4-mercapto-1 ,2,5-thiadiazole; alkali metal salt, such as 3-methoxy-4-mercapto-1 ,2,5-thiadiazole; sodium salt, prepared as set forth hereinbefore, with a halomethyl(or ethyl)thiocyanate, such as chloromethylthiocyanate or chloroethylthiocyanate.
- halomethyl(or ethyl)thiocyanate is used per mole of the 3-methoxy-4-mercapto)-1 ,2,5-thiadiazo!e: alkali metal salt to prepare the 3-methoxy-4-thiomethyl(or ethyl)thiocyanato-1,2,5-thiadiazole.
- n 1 or 2.
- the 3-thiocyanatomethyloxo-4-thiocyanato-1,2,5-thiadiazole compound of the present invention may be prepared by reacting a 4-chloro-3-halomethoxy-1 ,2,5-thiadiazole such as 4-chloro-3-chloromethoxy- 1 ,2,5-thiadiazole, prepared as set forth hereinbefore, with 2 equivalents of an alkali metal sulfide, such as sodium sulfide followed by reacting the thus formed 4-mercaptomethoxy-3-mercapto-1 ,2,5-thiadiazole, dialkali metal salt with 2 equivalents of a cyanogen halide, such as cyanogen bromide to form the desired 3-thiocyanatomethyloxo-4-thiocyanato-1 ,2,5-thiadiazole.
- the general scheme for this reaction is as follows:
- the 3-thiocyanato-4-thiocyanatoethyloxo-1 ,2,5-thiadiazole compound of the present invention may be prepared by first reacting a 3,4-dihalo-1 ,2,5-thiadiazole, such as 3,4-dichloro-1 ,2,5-thiadiazole with an alkali metal hydroxide, such as sodium hydroxide and the resulting 3-chloro-4-hydroxy-1 ,2,5-thiadiazole: sodium salt is then reacted at room temperature in dimethylformamide with chloroethyltosylate(Tso-CH 2 CH 2 CI).
- a 3,4-dihalo-1 ,2,5-thiadiazole such as 3,4-dichloro-1 ,2,5-thiadiazole
- an alkali metal hydroxide such as sodium hydroxide
- the 3-thiomethyl(or ethyl)cyanato-4-thiocyanatomethyloxo-1 ,2,5-thiadiazole compound of the present invention may be prepared by irradiating a solution of 3-methoxy-4-thiomethyl(or ethyl)thiocyanato1 ,2,5-thiadiazole, prepared as described hereinbefore, in a solvent such as carbon tetrachloride with a sunlamp while adding a solution of a sulfuryl halide such as sulfuryl chloride in a solvent such as carbon tetrachloride
- a solvent such as acetone containing an alkali metal thiocyanate
- the reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired above-indicated compound.
- the reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided.
- the general scheme for this reaction is as follows:
- the 3-thiomethylcyanato-4-thiocyanatoethyloxo-1 ,2,5-thiadiazole compound of the present invention may be prepared by first reacting a 4-halo-3-thiomethylcyanato-1 ,2,5-thiadiazole, such as 4-chloro-3-thiomethylcyanato-1 ,2,5-thiadiazole, prepared as described hereinbefore, with an alkali metal hydroxide, such as sodium hydroxide and the thus formed 4-hydroxy-3-thiomethylcyanato-1 ,2,5-thiadiazole: sodium salt is then reacted at room temperature in dimethylformamide with a haloethylthiocyanate, such as chloroethylthiocyanate to prepare the desired 3-thiomethylcyanato-4-thiocyanatoethyloxo-1,2,5-thiadiazole.
- the general scheme for this reaction is as follows:
- n is as hereinbefore defined.
- Chloromethylthiocyanate is well known and is described in JP-B-62215561 and JP-B-62215562.
- R is as hereinabove defined are known compounds.
- the compounds are well known in the literature.
- the compounds wherein R is phenyl or substituted phenyl are either specifically taught or they can be prepared as described by L. M. Weinstock et al. in the Journal of Organic Chemistry, Vol. 32, pages 2823-29, (1967); or in U.S. Patent 4,555,521.
- Other references include Japanese Patents JPO 5,163,257 A2; 5,163,258 A2; and 5,163,259 A2.
- the desired product can be separated from the reaction product of the above preparative procedures employing conventional separatory procedures known to those skilled in the art including steps of solvent extraction, filtration, water washing, column
- a solution of sodium sulfide (3.43 g, 0.044 mole) in 70 percent ethanol/30 percent water (75 mL) was treated with 4,5-dichloro-1 ,2,5-thiadiazole (6.20 g, 0.04 mole). After stirring for 1 hour the solution was treated with chloromethylthiocyanate (6.48 g, 0.06 mole) and stirred overnight. The reaction mixture was concentrated and extracted with methylene chloride. The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated .
- a solution of sodium sulfide (3.12 g, 0.04 mole) in 70 percent ethanol/30 percent water (75 mL) was treated with 4,5-dichloro-1 ,2,5-thiadiazole (3.10 g, 0.02 mole) After stirring for 1 hour the solution was concentrated to dryness and extracted with ethanol (2 extractions of 30 mL each). Removal of ethanol under reduced pressure gave the disodium salt of the bis(mercapto)-1,2,5-thiadiazole. The disodium salt was dispersed in dimethylformamide (15 mL) and treated with chloromethylthiocyanate (4.32 g, 0.04 mole) and stirred overnight The reaction mixture was diluted with water and extracted with methylene chloride.
- a solution comprised of 5 g of 60 percent pure 4-chloro-3-methoxy-1 ,2,5-thiadiazole in 30 mL of carbon tetrachloride was irradiated over a period of 45 minutes at 80°C with a sunlamp while adding a solution comprised of 5 g of sulfuryl chloride in 20 mL of carbon tetrachloride
- the reaction mixture was then washed with 30 mL of a saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to yield 4 87 g of 4-chloro-3-chloromethoxy-1 ,2,5-thiadiazole.
- CDCI 3 ⁇ 38.32, 1 1.36, 115.85, 1 16.44, 127.15, 130.04, 130.16, 151.51 , 156.51, 161.79, 165.12.
- the compounds of this invention are useful as antimicrobial additives, and they can be added to industrial products such as paints, inks, adhesives, soaps, cutting oils, textiles, paper pigment slurries and styrene-butadiene latexes used for paper coatings to provide needed antimicrobial properties.
- the compounds are also used as antimicrobial additives in such personal care products as hand creams, lotions, shampoos and hand soaps.
- a further advantage in the use of the compounds of this invention is their cost-effectiveness for applications which need to have an antimicrobial continuously replenished, such as in cooling towers and pulp and paper mills.
- each of the compounds disclosed herein are not necessarily active at the same concentrations or against the same microbial species. There may be some compound-to-compound variation in antimicrobial potency and spectrum of antimicrobial activity.
- the antimicrobial compounds of the present invention may be added to formulations susceptible to microbial growth. They may be added either undiluted or dissolved in inert diluents such as organic solvents such as glycols, alcohols or acetone They may also be added alone or in combination with other preservatives
- microorganism is meant to refer to bacteria, fungi, viruses, algae, subviral agents and protozoa.
- the term "antimicrobially-effective amount” refers to that amount of one or a mixture of the compounds, or of a composition comprising such compound or compounds, of this invention needed to exhibit inhibition of selected microorganisms Typically, this amount varies from providing 1 part per million (ppm) to 5,000 ppm by weight of the compound to a microbial habitat being contacted with the compound Such amounts typically vary depending upon the particular compound tested and microorganism treated Additionally, the exact concentration of the compounds to be added in the treatment of industrial and consumer formulations may vary within a product type depending upon the components of the formulation.
- a preferred effective amount of the compound is from 1 ppm to 500 ppm, more preferably from 1 ppm to 50 ppm by weight, of a microbial habitat.
- habitat refers to a place or site where a microorganism naturally or normally lives or grows Typically, such a habitat will be an area that provides a moisture source, nutrient source, and/or an oxygen source such as, for example, a cooling water tower or an air washing system.
- inhibitors refer to the suppression, stasis, kill, or any other interference with the normal life processes of microorganisms that is adverse to such microorganisms, so as to destroy or irreversibly inactivate existing microorganisms and/or prevent or control their future growth and reproduction
- the antimicrobial activity of the compounds of the present invention is set forth as the minimum inhibitory concentration (MIC) for the active compounds and is determined for nine (9) bacteria, using nutrient agar, and seven (7) yeast and fungi, using malt yeast agar. This determination is conducted using a one percent solution of the test compound prepared in a mixture of acetone and water.
- MIC minimum inhibitory concentration
- Nutrient agar is prepared at pH 6.8, representing a neutral medium, and at pH 8.2, representing an alkaline medium.
- the nutrient agars are prepared by adding 23 g of nutrient agar to one-liter of deionized water.
- the alkaline medium is prepared by adjusting a 0.04 M solution of N-(tris-(hydroxymethyl)methyl)glycine buffered deionized water with concentrated sodium hydroxide to a pH of 8.5.
- Malt yeast agar is prepared by adding 3 g yeast extract and 45 g malt agar per liter of deionized water. The specific agar is dispensed in 30 mL aliquots into 25 ⁇ 200 mm test tubes, capped and autoclaved for 15 minutes at 1 15°C.
- test tubes containing the agar are cooled in a water bath until the temperature of the agar is 48°C. Then, an appropriate amount of the one percent solution of the test compound is added (except in the controls where no compound is added) to the respective test tubes so that the final concentrations are 500, 250, 100, 50, 25, 10, 5, 2.5, 1.0 and zero parts per million of the test compound in the agar, thus having a known concentration of test compound dispersed therein.
- the contents of the test tubes are then transferred to respective petri plates. After drying for 24 hours, the petri plates containing nutrient agar are inoculated with bacteria and those containing malt yeast agar are inoculated with yeast and fungi.
- the inoculation with bacteria is accomplished by using the following procedure.
- Twenty-four hour-cultures of each of the bacteria are prepared by incubating the respective bacteria in tubes containing nutrient broth for 24 hours at 30°C in a shaker. Dilutions of each of the 24 hour-cultures are made so that nine separate suspensions (one for each of the nine test bacteria) are made, each containing 10 8 colony forming units (CFU) per mL of suspension of a particular bacteria. Aliquots of 0.3 mL of each of the bacterial suspensions are used to fill the individual wells of Steer's Replicator. For each microbial suspension, 0.3 mL was used to fill three wells (that is, three wells of 0.3 mL each) so that for the nine different bacteria, 27 wells are filled. The Steer's Replicator is then used to inoculate both the neutral and alkaline pH nutrient agar petri plates.
- the inoculated petri plates are incubated at 30°C for 48 hours and then read to determine if the test compound which is incorporated into the agar prevented growth of the respective bacteria.
- the inoculation with the yeast and fungi is accomplished as follows. Cultures of yeast and fungi are incubated for seven days on malt yeast agar at 30°C. These cultures are used to prepare suspensions by the following procedure. A suspension of each organism is prepared by adding 10 mL of sterile saline and 10 microliters of octylphenoxy polyethoxy ethanol to the agar slant of yeast or fungi. The sterile saline/octylphenoxy polyethoxy ethanol solution is then agitated with a sterile swab to suspend the microorganism grown on the slant.
- Each resulting suspension is diluted into sterile saline (1 part suspension: 9 parts sterile saline). Aliquots of these dilutions are placed in individual wells of Steer's Replicator and petri plates inoculated as previously described. The petri plates are incubated at 30°C and read after 48 hours for yeast and 72 hours for fungi.
- Table I lists the bacteria, yeast and fungi used in the MIC test described above along with their respective American Type Culture Collection (ATCC) identification numbers.
- ATCC American Type Culture Collection
- Tables II and III the MIC values of the compounds of the present invention as compared to the MIC of a standard commercial preservative (with 1-(3-chloroallyl)-3,5,7-triaza- -1-azoniaadamantane chloride as the active agent and referred to in Tables III and IV as "STANDARD I") are set forth for the bacteria organisms and yeast/fungi organisms which are listed in Table I.
- the present invention is also directed to a method for inhibiting marine organisms
- marine organisms is meant to include marine animals, such as barnacles, serpuhd, bryozoa, oysters and hydroids, and marine plants, such as green algae and brown algae
- the method for inhibiting marine organisms comprises contacting a surface exposed to a marine environment in which marine organisms grow with a marine antifouhng effective amount of the compound of this invention
- a compound's marine antifouhng activity may be dependent on the specific materials with which the compound is formulated to form a marine antifouhng composition
- marine antifouhng effective amount refers to that amount of one or a mixture of two or more of the compounds of this invention needed to exhibit inhibition of selected marine organisms. Typically, this amount varies from providing 1 weight percent to 30 weight percent of the compound to a marine antifouhng composition which is used to treat a surface exposed to a marine environment in which marine organisms live or grow Such amounts vary depending upon the particular compound tested and marine organism to be treated. Also, the exact concentration of the compounds to be added in the preparation of industrial and consumer formulations may vary within a product type depending upon the components of the formulation.
- a composition comprising a marine antifouhng effective amount of the compound will also comprise an inert diluent which may be, for example, in the form of a paint.
- an inert diluent which may be, for example, in the form of a paint.
- paints having a vinyl resin binder such as, for example, a plasticized polyvinyl chloride or a polyvinyl chloride-polyvinyl acetate type.
- the binders are formulated as latexes or emulsions.
- the compound of the present invention is preferably used in an amount from 1 to 30 weight percent and, most preferably, from 10 to 25 weight percent.
- a surface exposed to a marine environment refers to a surface where a marine organism naturally or normally lives or grows. Typically, such a surface will be an area that is in continual or periodic contact with a marine environment such as an ocean or other body of water. Typical surfaces include, for example, a ship hull.
- the marine antifouhng activity of the compounds of the present invention is demonstrated by the following techniques.
- Test panels are prepared from clear, rigid polyvinyl chloride film that is
- test panels are 0.1524 m by 0.1524 m squares that have 0.00635 m holes punched at corners on 0.127 m centers.
- a 0.102 square template, with a 0.067 m diameter hole at the center, is attached to the center of the textured surface of the test panels.
- a candidate marine antifoulant compound (1.0 g) is stirred into a resinous latex binder (9.0 g). A portion of the compound/binder mixture (1.5 g) is added to the center of the test panel and uniformly spread over the circular area inside the template.
- Water is added dropwise as needed to properly spread the compound/binder mixture.
- the template prevents the compound/binder mixture from spreading beyond the uncovered area.
- the test panel is allowed to sit for between 10 to 30 minutes until the edge of the spread compound/binder mixture has dried.
- the template is then removed.
- the test panel is then allowed to dry for 8 to 12 hours at room temperature.
- test panels are prepared for each candidate marine antifoulant compound.
- Two control test panels are also prepared by only treating with the resinous latex binder.
- One test panel of each candidate marine surfactant compound is attached over a white background to the topside of an exposure support apparatus.
- the second test panel is attached over a black background to the underside of the exposure support apparatus.
- the exposure support apparatus is placed horizontally 0.0254 m under a marine surface with the white background topside facing up.
- the exposure support apparatus is exposed to the marine environment for both 3 and 6 weeks during which time the control test panels become substantially covered with mature marine organism growth on both the topside and underside exposures.
- each test panel After being removed from the exposure support apparatus, each test panel is inspected and rated for marine organism growth on both the treated and untreated areas of the test panel. The marine organisms present on the treated and untreated areas are noted. The presence of algae spores and bacterial slime are noted but not included in rating each test panel. The test panels are rated on a scale from 10 (representing completely free of marine organism growth) to 0 (representing completely covered with marine organism growth).
- test panels were prepared using tributyl tin oxide, a known marine antifouhng compound.
- One set of such panels used the tributyl tin oxide in a commercially available ship-hull paint (referred to in Table IV as "STANDARD II") which was employed in the same manner as the resinous latex binder used on the other test panels.
- a second set of such panels used the tributyl tin oxide at a 10 percent concentration in the resinous latex binder (referred to in Table IV as "STANDARD III").
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95944021A EP0799216A1 (en) | 1994-12-21 | 1995-10-10 | Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents |
JP8519772A JPH11502503A (en) | 1994-12-21 | 1995-10-10 | Substituted thiadiazoles, compositions containing them and their use as inhibitors against contamination by antimicrobial agents and marine products |
NO972914A NO308299B1 (en) | 1994-12-21 | 1997-06-20 | Substituted thiadiazoles, mixtures containing them and their use for inhibiting microbial growth in a microbial habitat |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/360,497 | 1994-12-21 | ||
US08/360,496 | 1994-12-21 | ||
US08/360,496 US5488060A (en) | 1994-12-21 | 1994-12-21 | Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents |
US08/360,497 US5491155A (en) | 1994-12-21 | 1994-12-21 | Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996019467A1 true WO1996019467A1 (en) | 1996-06-27 |
Family
ID=27000922
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/013494 WO1996019467A1 (en) | 1994-12-21 | 1995-10-10 | Substituted thiadiazoles, compositions containing them and their use as antimicrobial and marine antifouling agents |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0799216A1 (en) |
JP (1) | JPH11502503A (en) |
CA (1) | CA2208518A1 (en) |
NO (1) | NO308299B1 (en) |
WO (1) | WO1996019467A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998001035A1 (en) * | 1996-07-10 | 1998-01-15 | The Dow Chemical Company | The use of 5-alkyl-1,3,4-oxadiazol(and thiadiazol)-2-thiomethylthiocyanates as marine antifouling agents |
WO1998001037A2 (en) * | 1996-07-10 | 1998-01-15 | The Dow Chemical Company | (54) Title: THIOCYANOMETHYLOXY-AND THIOCYANOMETHYLTHIO-1,2,3-BENZOTRIAZIN-4-ONES, AS ANTIMICROBIAL AND MARINE ANTIFOULING AGENTS |
US10919915B2 (en) | 2016-04-08 | 2021-02-16 | Mankind Pharma Ltd. | Compounds as GPR119 agonists |
US10954229B2 (en) | 2016-04-08 | 2021-03-23 | Mankind Pharma Ltd. | GPR119 agonist compounds |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US3446813A (en) * | 1964-11-02 | 1969-05-27 | Lilly Co Eli | Certain 3-hydroxy 1,2,5-thiadiazoles and a process for preparing them |
FR2181527A1 (en) * | 1972-04-27 | 1973-12-07 | Roussel Uclaf | 3-Phenoxy-1,2,5-thiadiazoles - with fungicidal activity |
US3888869A (en) * | 1973-08-13 | 1975-06-10 | Dow Chemical Co | Bis (thiocyanomethylthio) thiadiazoles |
EP0433616A2 (en) * | 1989-12-22 | 1991-06-26 | Degussa Aktiengesellschaft | Use of heterocyclic thiocyanates as microbicides and agents containing such microbicides |
EP0621272A1 (en) * | 1993-04-21 | 1994-10-26 | Tosoh Corporation | 3,4-Dioxy-1,2,5-thiadiazoles partly useful as fungicides |
-
1995
- 1995-10-10 WO PCT/US1995/013494 patent/WO1996019467A1/en not_active Application Discontinuation
- 1995-10-10 EP EP95944021A patent/EP0799216A1/en not_active Withdrawn
- 1995-10-10 JP JP8519772A patent/JPH11502503A/en active Pending
- 1995-10-10 CA CA002208518A patent/CA2208518A1/en not_active Abandoned
-
1997
- 1997-06-20 NO NO972914A patent/NO308299B1/en not_active IP Right Cessation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3446813A (en) * | 1964-11-02 | 1969-05-27 | Lilly Co Eli | Certain 3-hydroxy 1,2,5-thiadiazoles and a process for preparing them |
FR2181527A1 (en) * | 1972-04-27 | 1973-12-07 | Roussel Uclaf | 3-Phenoxy-1,2,5-thiadiazoles - with fungicidal activity |
US3888869A (en) * | 1973-08-13 | 1975-06-10 | Dow Chemical Co | Bis (thiocyanomethylthio) thiadiazoles |
EP0433616A2 (en) * | 1989-12-22 | 1991-06-26 | Degussa Aktiengesellschaft | Use of heterocyclic thiocyanates as microbicides and agents containing such microbicides |
EP0621272A1 (en) * | 1993-04-21 | 1994-10-26 | Tosoh Corporation | 3,4-Dioxy-1,2,5-thiadiazoles partly useful as fungicides |
Non-Patent Citations (1)
Title |
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A.G.M. WILLEMS ET AL.: "The chemistry and fungicidal and phytotoxic properties of heterocyclic sulfonyl-, sulfinyl-, and thio-methyl thiocyanates", RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS, vol. 90, no. 1, 1971, THE HAGUE NL, pages 97 - 104, XP002002841 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998001035A1 (en) * | 1996-07-10 | 1998-01-15 | The Dow Chemical Company | The use of 5-alkyl-1,3,4-oxadiazol(and thiadiazol)-2-thiomethylthiocyanates as marine antifouling agents |
WO1998001037A2 (en) * | 1996-07-10 | 1998-01-15 | The Dow Chemical Company | (54) Title: THIOCYANOMETHYLOXY-AND THIOCYANOMETHYLTHIO-1,2,3-BENZOTRIAZIN-4-ONES, AS ANTIMICROBIAL AND MARINE ANTIFOULING AGENTS |
WO1998001037A3 (en) * | 1996-07-10 | 1998-05-22 | Dow Chemical Co | (54) Title: THIOCYANOMETHYLOXY-AND THIOCYANOMETHYLTHIO-1,2,3-BENZOTRIAZIN-4-ONES, AS ANTIMICROBIAL AND MARINE ANTIFOULING AGENTS |
US10919915B2 (en) | 2016-04-08 | 2021-02-16 | Mankind Pharma Ltd. | Compounds as GPR119 agonists |
US10954229B2 (en) | 2016-04-08 | 2021-03-23 | Mankind Pharma Ltd. | GPR119 agonist compounds |
Also Published As
Publication number | Publication date |
---|---|
EP0799216A1 (en) | 1997-10-08 |
CA2208518A1 (en) | 1996-06-27 |
NO308299B1 (en) | 2000-08-28 |
NO972914L (en) | 1997-08-20 |
JPH11502503A (en) | 1999-03-02 |
NO972914D0 (en) | 1997-06-20 |
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