MXPA94007653A - Complexes of metal and its salts with propertiesantimicrobia - Google Patents

Abstract

The present invention relates to a metal complex of a compound of the formula I. wherein the metal is copper or a metal of group VIII or IIB of the Periodic Table, A and B are independently selected from -C (R2) 2-, -CR2 = ó > C = NR2; D is -NR2- or sulfur, R is hydrogen, and R2 is hydrogen, C1-6 hydrocarbyl, C1-6 hydrocarbyl substituted by halogen or two R2 groups, which together with the carbon atom or carbon atoms to which they are attached, they form a hydrocarbon ring system of 5 to 6 member

Description

COMPLEXES OF METAL AND ITS SALTS WITH ANTIMICRO BIANAS PROPERTIES.

OWNER: IMPERIAL CHEMICAL INDUSTRIES PLC., A company of British nationality, domiciled at: Impe rial Chemical House Millbank, London SwlP 3JF, GRAN BRITAIN.

INVENTOR: PETER WILLIAM AUSTIN, British national, residing at: 45 Randale Drive Bury BL9 8NF Lancashire, GREAT BRITAIN.

E X T RA C T O.

Compounds having a five-membered ring containing nitrogen with a thione group adjacent to a nitrogen atom substituted with an OR group have antimicrobial properties. Metal complexes or salts of these compounds also have antimicrobial properties. The compounds, or the metal complexes or salts thereof, can be used as a preservative of cutting fluid, a preservative of wood, in cooling water applications or as an antimicrobial agent in a paint. Some of the compounds are new. The metal salts or complexes are new.

E S P E C I F I C A I N The present invention relates to a class of compounds, some of which are new compounds, which are useful as industrial biocides. Industrial biocides are useful to avoid industrial deterioration, in particular, that caused by bacteria and fungi. Materials that can be used as industrial biocides, have entimicrobianas properties and in particular, have antifungal or antibacterial properties or preferably both antifungal and antibacterial properties. Such materials are useful in the preservation of paints, nets, adhesives, leather or skins, wood, fluids for metalworking and cooling water. British Patent Specification No. 1 '113,634 discloses fungicidal compositions comprising an isothiazolothione in admixture with a solid diluent or a liquid diluent containing a surface active agent. Isothiazolothione has the formula: where R. and R »can, interalia, together with their adjacent carbon atoms, constitute a ring. Such ring systems include a cyclopentene or cyclohexene ring (compounds 8, 9 and 10) or a benzene ring (compounds 11 to 43). However, it is indicated that such compounds can be isomerized to a structure containing an oxime group. The structure of compounds of that type, such as the compound 41 described in the 'Great Britain 1' 113,634 patent, has been studied and has been concluded, in 11. Farmaco-Ed.Sci. , Vol. 23 p. 572 to 582, that in such compounds the oxime structure is more stable. The British Patent specification no. -1 '104,893, describes a biocidal composition, in which the active ingredient is described as at least one 3-imino-1,2-dithiol derivative, such as, for example, 3H-1, 2-benzodithiol-3-one oxime and 4,5,6,7-tetrahydro-3H-l, 2-benzodithiol-3-one oxime. Cyclo compounds comprising a thione group have been described in the literature, but these other references do not indicate that the compounds have any antimicrobial activity. The patent of the U.S.A. no. 3 '448, 116 desc? They are, as anticonvulsants, compounds such as 1-hydroxy-hydantoins and 1-hydroxythiohydantoins.

J.C.S. Perkin 2, (1981) p. 92ff; Chem.Ber. (1964), 97, p. 216ff; Chem.Ber. (1971), 104, p. 1512ff; and Arch. -Pharm. (1978), 311 (1), p. 39ff describe ionic compounds containing a thione group and having two nitrogen atoms in the ring adjacent to the thione group. J.C.S. Perkin 1 (1986 page 39 to 59 describes, inter alia, N-hydroxythiazolinthione derivatives and their preparation) However, there is no suggestion that the disclosed compounds have antimicrobial properties We have now found that certain cyclic compounds comprising a The thione group and at least one adjacent amino group have antimicrobial properties Some compounds of this type are new In accordance with the present invention, a biocidal composition containing at least one compound of the formula is provided: or a salt or a metal complex thereof; wherein: A is a nitrogen or carbon atom, which - may be substituted; B and D are, independently, an atom of oxygen or sulfur or a nitrogen or carbon atom, which may be substituted; or A and / or B and / or D may be part of a ring system; R is hydrogen, a hydrocarbyl group, a substituted hydrocarbyl group, an acyl group, a substituted acyl group or a -COOR group; and R is a hydrocarbyl group with the proviso that B and D are both sulfur or both oxygen. Group A and optionally one or both of the 2 groups B and D, can be a group -C (R) 2 ~ »a group -CR 2 =; a group ^ .C = NR2; a group -NR2- or a group -N =; wherein R 2 is a hydrogen atom, a hydrocarbyl group, a substituted hydrocarbyl group or two groups R, together with the carbon atom or carbon atoms, to which they are attached, form a ring. Groups A, B and D may be part of an additional ring system, but in general, no more than two of groups A, B and D are part of an additional ring system. The additional ring system is typically a hydrocarbon ring system containing 5 or 6 carbon atoms, for example, a ring ci. clopentene, cyclohexane, cyclohexene, cyclohexadiene or -benzene. The additional ring system, if present, typically contains one or both of groups A and B. If only group A is part of a ring system, this may be a cyclohexane ring of the type: where group A is a carbon atom with the two free valencies, which are linked to the group -OR- and B, respectively. If both A and B are part of a ring system, the additional ring is then fused to the azolethione ring system; for example-as in 3-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2 (3H) -thione. In many of the compounds used in the biocidal compositions of the present invention, groups A, B and / or D are not part of a ring system. In sequence, if A, B and / or D is a carbon atom, or a substituted carbon atom, it can be, among other things, a group -CH =, -C (CH3) =, -C ( C2H5) =, -C (CgH5) =, It will be appreciated that l, or that 2 above, the group R is a hydrogen atom, a methyl, ethyl, phenyl or chlorophenyl group. Typically, R is a hydrogen atom, a lower alkyl group, that is to say one containing up to 5 carbon atoms, an aryl group or a substituted alkyl or aryl group, in which the or each substituent is a hydroxy carbonyl group, an acyl group, an ester group (i.e. an acyloxy group), a halogen atom or a nitrile group. It is generally preferred that groups A and D are optionally substituted carbon atoms and group D is either a sulfur atom or an optionally substituted nitrogen atom. The groups A and B of preference are linked through a double bond as in the group -CH = CH-. It is preferred that D is a sulfur atom. The group R can be a hydrogen atom, an acyl group, such as benzoyl or acetyl or an alkoxycarbonyl group, such as an ethoxycarbonyl group. If the -R group is a substituted group, it may contain an additional ring system of the general formula 1, with the two ring systems being linked through the R group, for example as in the glutaryl bis ester, of the Formula: 0C0CH2CH2CH2C00 The biocidal composition may contain a metal salt or a complex of the compound of the general formula 1. The metal present in that salt or complex may be any metal. Accordingly, the metal can be a transition metal, for example a metal of group VIII, IB or 11B of the Periodic Table. Such metals include iron, copper and zinc, in particular those metals in their maximum possible valence. All references here to the Periodic Table are to the Periodic Table according to Mendeleeff, as indicated on the inside of the back cover - of "GENERAL AND INORGANIC CHEMISTRY" by J.R. Partington, Second edition published by MacMillan and Co. Limited, London. For convenience, in the following, the compounds of general formula 1, and the metal salts and complexes thereof, will be referred to simply as "com position 1".

A broad scale of compound 1 can be used in the biocidal compositions of the present invention. The compounds 1 have anti-microbial activity against a wide variety of micro-organisms, including bacteria, fungi and algae. Compounds 1 that can be used in the compositions of the present invention include: 3-hydroxy-4-methylthiazole-2 (3H) -thione, 3-benzoyloxy-4-methylthiazole-2 (3H) -thione, 3-hydroxy- 4-phenylthiazole-2 (3H) -thione, 3-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2 (3H) -thione, 3-acetoxy-4-methylthiazole-2 (3H) -thione, bis-ester of glutaryl of 3-hydroxy-4-methylthiazole-2 (3 H) -thione, 5,5-dimethyl-l-hydroxy-4-imino-3-phenylimidazolidine-2-thio-na, l-hydroxy-4-imino- 3-phenyl-2-thione-l, 3-diazaspiro (4.5) decane, l-hydroxy-5-methyl-4-phenylimidazolidine-2-thione, 3-ethoxycarbonyloxy-4-methylthiazole-2 (3H) -thione, 4 , 5-dimethyl-3-hydroxythiazole-2 (3H) -thione, 4,5-dimethyl-3-acetoxythiazole-2 (3H) -thione, 4-ethyl-3-hydroxy-5-methylthiazole-2 (3H) - thione, 4-ethyl-3-acetoxy-5-methylthiazole-2 (3H) -thione, 4- (4-chlorophenyl) -3-hydroxythiazole-2 (3H) -thione. 3-hydroxy-5-methyl-4-phenylthiazole-2 (3H) -thione, 3-acetoxy-4-phenylthiazole-2 (3H) -thione, and the metal complexes and salts thereof. The metal compounds and salts thereof include ferric, copper, and zinc salts and complexes, such as the zinc complex of 3-hydroxy-4-methylthiazole-2 (3H) -thione, the 3-hydroxy complex, 4-methylthiazole-2 (3H) -thio na, the cupric complex of l-hydroxy-4-imino-3-phenyl-2-thione-1,3-diazaspiro (4.5) decane, the cupric complex of 4,5- dimethyl-3-hydroxythiazole-2 (3H) -thione, the zinc complex of 4,5-dimethyl-3-hydroxythiazole-2 (3H) thione and the zinc complex of 4-ethyl-3-hydroxy-5-methylthiazole -2 (3H) -thione. The compositions of the present invention provide for good preservation of the wet state, making the compositions advantageous for use as a cutting fluid conservator and also in cooling water applications. The preservation of wood and leather is another advantageous field of application of the compositions. The compositions of the present invention can also be incorporated into paint, as a fungicidal paint film, and many of the compositions can be used without the addition of a bactericide.

Compounds 1, which are present in the biocidal composition of the present invention, are soluble in many polar solvents, although the solubility depends on the nature of groups A, B, D and R. However, many of the compounds 1, are soluble in water, alcohols, ethers, ketones and other polar solvents or mixtures thereof. The compositions of the present invention may consist solely of compound 1. However, the composition typically comprises compound 1 as a solution, suspension or emulsion in a suitable liquid medium, such as water. The composition may comprise a suspension or emulsion of compound 1 or a solution thereof, in a liquid medium in which compound 1 is insoluble. The composition can be incorporated into the medium to be protected using any suitable mixing technique. The composition is incorporated into the medium to be protected in an amount to provide-from 0.00002 to 5% by weight of compound 1 relative to the total composition, more preferably from 0.00005 to -1% by weight of compound 1. It will be appreciated that the amount of compound 1 required will depend on several factors, such as the medium to be protected, the micro organisms against which protection is desired and the degree of protection required. If the composition is to be used to preserve a solid substrate, such as leather or wood, the composition of the composition is The coating can be applied directly to the substrate or can be incorporated into a coating composition, such as a paint, varnish or lacquer, which is then applied to the substrate. Alternatively, the solid material may be impregnated with the composition of the present invention. The compositions of the present invention, can be used for the treatment of various means to inhibit the development of microorganisms. Accordingly, as a further aspect of the present invention, there is provided a method for inhibiting the growth of microorganisms on or in a medium comprising treating the medium with a compound 1 as defined hereinbefore. Compound 1 can be used under conditions in which microorganisms develop and cause problems, such as, for example, in aqueous environments, including cooling water systems, liquors in paper mills, metalworking fluids, lu for geological drilling, polymeric emulsions and emulsion paints. Compound 1 can also be used to impregnate solid materials, such as wood or leather, or they can be applied on their surfaces directly or incorporated in a paint, varnish or lacquer. Compound 1 can also be used to inhibit the development of microorganisms in agricultural and horticultural environments, such as plant maintenance, seeds, etc. The antimicrobial activity of the compositions of the present invention against bacteria and fungi has been found to be surprisingly advantageous when compared to analogous compounds, for example the formers described in U.S. Pat. 1 '113,634, which are described as isothiazoles, but which can be isomerized to give an isomeric oxime. As a still further aspect of the present invention, new compounds of the formula are provided: or a metal salt or complex thereof; wherein: A is a carbon or nitrogen atom, which may be substituted; B and D are, independently, an oxygen or sulfur atom or a nitrogen or carbon atom, which may be substituted; or A and / or B, and / or B and / or D may be part of a ring system; R is hydrogen, a hydrocarbyl group, a substituted hydrocarbyl group, an acyl group, a substituted aci group or a -COOR group; and R is a hydrocarbyl group with the proviso that B and D are not both sulfur or both oxygen and with the additional conditions that if the compound is different from a metal complex or a salt thereof, when D is -NH- and R is H or COOH-, A and B are not - they are both C (CH3) 2 groups; when D is -NH- and R is H, group A is different from = C (CH3) - or = C (CgH5) - when group B is = C (CgHg) - or = C (CH3) - respectively; when D is -N (CgH5) - and R is H, group A is other than -C (CH3) 2 when B is C = NH; and when D is -S- and R is H or C0C - ,. H-1, group A is different from = C (CH3) - or = C (CfiH) - when B is = CH-. As a particular feature of the present invention, there is provided a salt or metal complex of formula 1, subject only to the condition that B and D, are not both sulfur or both oxygen. The metal salts or complexes according to this aspect of the present invention include ferric, copper and zinc salts or complexes. New compounds of formula 1 include: 3-benzoyloxy-4-methylthiazole-2 (3H) -thione, 3-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2 (3H) -thione, 3-acetoxy-4- methylthiazole-2 (3H) -thione, the glutaryl bis-ester of 3-hydroxy-4-methylthiazole-2- (3H) -thione, 3-ethoxycarbonyloxy-4-methylthiazole-2 (3H) -thione, 4, 5 dimethyl-3-hydroxythiazole-2 (3H) -thione, 4,5-dimethyl-3-acetoxythiazole-2 (3H) -thione, 4-ethyl-3-hydroxy-5-methylthiazole-2 (3H) -thione, 4 -ethyl-3-acetoxy-5-methylthiazole-2 (3H) -thione, 4- (4-chlorophenyl) -3-hydroxythiazole-2 (3H) -thione, 3-hydroxy-5-methyl-4-phenylthiazole-2 (3H) -thione, 3-acetoxy-4-phenylthiazole-2 (3H) -thione, and the metal salts or complexes thereof. The compounds of the present invention can be prepared by known methods, for example, as described in J.C.S. Perkin 1, (1986) pages 39 to 59. A convenient method for preparing the compounds where the group is hydrogen is by cyclization under basic conditions of corrective co-occurring dithiocarbonate. Derivatives in which R is not hydrogen are conveniently prepared by known methods from the corresponding compound in which R s H, for example by reaction with an acid chloride or acid anhydride with a chloroformic acid ester. The metal derivatives are conveniently prepared by reaction of the compound, in particular one in which the R group is hydrogen, with a metal salt, for example a sulphate or metal acetate. The preparation of the compound, or metal salt or complex, can be carried out in any suitable solvent such as, for example, water, a lower alkanol, an aqueous lower alkanol, a ketone such as acetone, N, N-dimethylformamide, N- methylpyrrolidone, glima, diglima and Celosolve. The reaction is preferably carried out at a relatively low temperature, for example, no more than -80 ° C and especially no more than 30 ° C, which may be room temperature or lower, for example 15 ° C. If the reaction is carried out at a temperature above the ambient temperature, it is conveniently carried out in acetone under reflux, which is at a temperature between 55 and 60 ° C. The desired compound can be isolated and purified using any suitable technique. Thus, the compound can be recrystallized from a suitable solvent or mixture of solvents for example from a mixture of methylene chloride and a low boiling petroleum ether fraction. Alternatively, the compound can be purified by a chromatographic technique, for example, by flash evaporation chromatography. Additional aspects of the present invention are described in the following illustrative examples. In the examples that follow, the products obtained were subjected to microbiostatic evaluation. The microbiological test was carried out, under sterile conditions in all, as follows: PREPARATION OF INOCULATE.

BACTERIA The bacterial inoculation consisted of 24-hour cultures. of organisms developed in an oxoid nutritive broth, subcultured daily at 37 ° C incubated.

MUSHROOMS Spore suspensions of each of the tested bacteria were prepared as follows: to 250 cc conical flasks containing well-sporulated cultures of the organisms, grown on oxoid malt extract agar, a number of glass globules were added. 3 mm sterile, and approximately 50 ce of a sterile 0.01% vol / vol solution of polyoxyethylene (20) sorbitan monooleate (available from Imperial Chemical-Industries PLC, as Tween 80) (Tween is a Trade Mark Registered) in water. Each flask was shaken so that the globules removed the spores and the resulting suspension was emptied into a 100 g sterile medical flat bottle containing approximately 50 cc of the 0.01% v / v sterile Tween 80 solution. The suspension could be stored up to 4 weeks at 4 ° C. In the microbiological test, the products were tested for antimicrobial activity against bacteria and / or fungi. The bacteria used were one or more of Escherichia coli, Staphy, locoecus aureus and Pseudomonas ae ruginosa. The fungi used were one or more of Aspergillus niger, Aureobasidum pullulans, Cladosporium, spharospermum, Aspergillus versicolor and Chaetomium globosum. These test organisms will be referred to hereinafter as EC. S.A. PA., AN, AP, Cs, AV and CG respectively. MICROBIOSTATIC EVALUATION. METOD 0.3 g of the product to be tested is disjointed. they saw in 3.0 ce of N, N-dimethylformamide to give a solution at 10% w / v. For each of the products being tested, five bottles containing 50 cc of nutrient oxide agar were heated by steam to melt the contents. The bottles were cooled to 50 ° C and a sufficient amount of the product solution was added to give a product concentration on the agar of 1 ppm, 5 ppm, 25 ppm, 125 ppm or 625 ppm. Low concentrations of the product were obtained by diluting the initial solution at 10% w / v to 1% w / v or 1000 ppm and adding the diluted solution to the molten agar. From each bottle-treated as described, two dis-petri plates were emptied and allowed to stand overnight. The test organisms were inoculated on the surface in the test plates by means of a multi-tip inoculator. The tested plates obtained from the malt agar were inoculated with fungi and the plates were incubated at 25 ° C for five days. The test plates obtained from nutritive agar were inoculated with bacteria and the plates were incubated for 24 hours at 37 ° C. At the end of the incubation period, the plates were visually estimated for micro-organism development. The concentration of the product that inhibited the development of a particular micro-organism was recorded.

METHOD B 100 mg of the product to be tested were dissolved in 2ce of N, N-dimethylformamide and the obtained solution was diluted with an additional amount of N, N-di-methylformamide to give a product concentration of 2500 ppm. To bottles containing 50 ce of Czapek Dox agar containing peptone 0.5% v / v at 50 ° C, an amount of the product in solution was added to give a concentration of 500 ppm or 25 ppm of the product. In some tests, concentrations of 250 ppm -50 ppm and / or 5 ppm of the product were also examined. From each bottle, two petri dishes were emptied and left to rest overnight. The test organisms were inoculated on the surface in the test plates by means of a multipunct inoculator. Each test plate was inoculated with both bacteria and fungi. The plates were inoculated for four days at a temperature of 25 ° C. At the end of the incubation period, the plates were estimated physically for the development of micro-organisms. The concentration of the product that inhibited the development of a particular micro-organism was recorded. In all the examples that follow the parts - they are by weight, except for solvents where the parts are by volume.

EXAMPLE 1 A compound of the formula 1 was prepared in which the group A is -C (CH3) =, the group B is -CH =, the group D is -S- and R is hydrogen. 0.885 parts of 0-ethyl-5- (2-oxyiminopropyl) di-thiocarbonate were added to 30 parts of methylene chloride. The solution was stirred at 0-5 ° C and 10 parts of a 2N aqueous potassium hydroxide solution were added dropwise. Then 25 parts of methylene chloride and 25 parts of water were added, the aqueous layer was separated and carefully acidified by the cautious addition of 2N aqueous hydrochloric acid. The aqueous fraction was then extracted with ethyl acetate, the extract was dried using anhydrous magnesium sulfate and evaporated to dryness. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether (dew point 60-80 ° C) to give 3-hydroxy-4-methylthiazole-2 (3H) -thione, p. of f. 95-96.5 ° C. By analysis it was found that the composition is C 32.8% weight; H 3.3% weight; and N 9.5% pe so. C.H NOS2 requires C 32.6% weight; H 3.4% weight; and N - 9.5% weight.

EXAMPLE 2 A zinc salt of the product of Example 1 was prepared. 0.98 parts of 3-hydroxy-4-methylthiazole-2 (3H) -thione, was stirred in 50 parts of water and 2N aqueous sodium hydroxide was added until it was reached a clear solution (pH 8). 0.96 parts of zinc sulfate heptahydrate was added and the reaction mixture was stirred for one hour at room temperature. The product was collected by filtration, washed with cold water and dried. The product was dissolved by boiling in 100 parts by volume of chloroform and the resulting solution was filtered off. 100 parts per volume of petroleum ether (p.of 60-80 ° C) were added to the clear filtrate to precipitate the zinc complex which was collected by filtration after cooling and drying. The product had a melting point of 268-270 ° C. By analysis it was found that the composition was C 26.8% weight; H 2.2% weight; N 7.7% weight; S 35.2% weight and Zn 17.7% weight; (C4H.NOS2) 2 requires C 26.9% weight; H 2.2% weight; N 7.8% weight; S 25.8% weight and Zn 18.3% weight.

EXAMPLE 3 The benzoyl derivative of the product of example 1 was prepared, that is R is COC-H,., A, B and D are as in example 1. 0.735 parts of 3-hydroxy-4-methylthiazole-2 (3H) - tiona, were stirred in 50 parts of water and 0.84 parts of sodium acid carbonate. The solution was filtered and 0.9 parts of benzoyl chloride were added. The reaction mixture was stirred overnight at room temperature. A precipitate formed which was filtered off, washed with cold water and recrystallized from ethanol to give 3-benzoyloxy-4-methylthiazole-2 (3H) -thione, melting point 100-102 ° C. By analysis it was found that the composition is C 52.4% weight; H 3.6% weight; -N 5.6% weight; and S 25% weight. C ,, H_N02S2 requires C 52.6% -weight; H 3.6% weight; N 5.6% weight and S 25.5% weight.

EXAMPLE 4 For comparison purposes, the following compounds were prepared.

COMPOSITE A.

One gram of 4,5,6,7-tetrahydro-3H-l, 2-benzodi-thiol-3-thione, was mixed with 2.2 g of anhydrous sodium acetate and 2 g of hydroxylamine hydrochloride in 22 ce-of vapors methylated The mixture was stirred under reflux for four hours and allowed to cool to room temperature overnight. The mixture was heated to boiling, filtered and evaporated to dryness. The residue was washed with two 10-cent portions of methylated vapors at 65 ° C. The combined washings were evaporated to dryness and the solid was redissolved in methanol. a small proportion of the melting product was crystallized from 114 to 116 ° C. The liquid separated, water was added and a precipitate formed. The precipitate was separated by filtration and dried to give a solid of melting point 146-148 ° C. The infra-red spectrum of this material contained a peak-sharpened at 1600 cm characteristic of the oxime group (C = NOH), indicating that the product was an oxime of 4.5, 6,7-tetrahydro-3H-1, 2 -benzodithiol-3-one, in place of the isomeric thione compound which is compound 10 in the British patent number 1 '113,634.

COMPOSITE B 2.5 g of 3H-1, 2-benzodithiol-3-one was mixed with 5 g of anhydrous sodium acetate and 5 g of hydroxylamine hydrochloride in 100 g of methylated essence. The mixture was stirred, heated to reflux and refluxed for ten minutes. The mixture was cooled, water was added to form a precipitate, the mixture was filtered and the solid was washed with water at 10-15 ° C. The solid dissolved in methylated essence at 65 ° C, the solution slipped while it was still hot and the solid crystallized and dried. The solid obtained had a melting point of 212-214 ° C, which closely corresponds to the reported melting point (208 ° C) of 3H-l, 2-benzodithiol-3-one oxime, indicating that the Oxime had been obtained in place of the compound-isomeric thione which is compound 41 of the -Patient of GB 1 * 113,634. The compounds of Examples 1 to 3 and Compounds A and B, obtained as described, were evaluated against a scale of bacteria and fungi, using method A as previously described. Control was obtained for the test organisms at the levels indicated in the table: TABLE.

Compound Microorganisms (a) (Concentration in ppm) Te PA SA AN P cl A "6-C5 1 25 625 125 1 1 1 1 1 2 25 125 25 5 5 5 5 5 3 125 NA 125 25 25 25 25 25 A NA NA NA 125 125 125 125 125 B NA NA NA NA 625 NA NA 625 Notes to the Table (at 1 »2 and 3 are the products of examples 1, 2 and 3 respectively, A and B are compounds A and B respec- tively. NA means, control not reached at the highest levels. tested items (^ 2) Levels below 1 ppm were not tested The number represents the lowest level (in ppm) at which control was achieved EXAMPLE 5.

A ferric salt of the product of example 1 was prepared. 0.5 parts of the compound obtained as described in example 1, were dissolved in one part of ethanol. Four parts of a cold saturated aqueous solution of ferrous sulfate were added dropwise with stirring to the alcohol solution. The mixture was stirred at room temperature for 15 min. and the solid product formed was obtained by filtration. The precipitate was washed successively with water and ethanol, boiled with chloroform, refiltered and dried. By analysis it was found that the product is a 3: 1 complex that indicates the oxidation of the iron to the trivalent state. The product had a melting point of 220 ° C with decomposition. By analysis it was found that the composition is C 29.5% by weight; H 2.5% weight; N 8.3% weight and Pe 9.7% weight. (C4H4NOS2) 3Fe requires C 29.1% weight; H 2.4% weight; N 8.5% weight and Fe 11.3% weight. In microbiostatic evaluation, using method A, the compound provided control of the test organisms as follows: AP 25 ppm CS 25 ppm AB 25 ppm CG 25 ppm EXAMPLE 6 A compound of formula 1 was prepared in which group A is -C (CgH) =, group B is -CH =, group D is -S- and R is hydrogen. 7.96 parts of phenacyl bromide and 8.34 parts of hydroxylamine hydrochloride were stirred overnight at room temperature in 75 parts of methanol and 25 parts of water. Then, 200 additional parts of water and a separate solid product were added, which was filtered, dried and recrystallized from ether-oil (boiling point 60-80 ° C) to yield 3.5 parts of the oxime (melting point 88). -89ßC). 3.89 parts of the oxime, 2.9 parts of potassium ethyl xanthate and 22 parts of acetone, were stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in water. The resulting aqueous solution was extracted with 3 portions of diethyl ether (each portion was 50 parts per volume). The diethyl ether extract was dried using anhydrous magnesium sulfate and the ether was removed by evaporation to give the xanthate (3.9 parts) as a yellow oil. The oil was dissolved in 15 parts of ether and the solution was added to a mixture of 2.3 g. of zinc chloride powder in 30 part of diethyl ether which was being stirred at 0-5 ° C. The mixture was stirred overnight and allowed to warm to room temperature. The ether layer was separated by decantation and the residual syrup was digested with an additional 30 parts of ether. The residue was then vigorously stirred, with a mixture of 15 parts of methylene chloride, 15 parts of water, 15 parts of 36% aqueous hydrochloric acid, was separated by filtration and recrystallized from propan-1-ol to yield 0.14 parts of 3-hydroxy -4-phenylthiazole-2 (3H) -thione of melting point 149-151 ° C. In microbiostatic evaluation, using method A, the compound provided control of the test organisms as follows: EC 125 ppm AN 125 ppm AP 125 ppm CS 25 ppm AV 25 ppm CG 25 ppm EXAMPLE 7 A compound of the formula 1 was prepared in which the group D is -S-, R is hydrogen and A and B together, - form a cyclohexene ring. 6.63 parts of 2-chlorocyclohexanone were used in a process essentially as described in Example 6 to form, as intermediates, oxime - (melting point 72-73 ° C) and xanthan (fume-point) 67-72 ° C). The final product was 3-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2 (3H) -thione having a melting point of 111.5 to 114 ° C. By analysis it was found that the composition is C 44.5% weight; H 5.0% weight; N 7.6% weight; and S 34.1% weight. C7HgONS2 requires C 44.9% weight; H 4.8% weight; N 7.5% weight and S 34.2% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: EC 25 ppm CA 25 ppm AN 125 ppm AP 125 ppm CS 125 ppm AV 125 ppm CG 125 ppm EXAMPLE 8 The acetoxy derivative of the product of example 1 was prepared, that is R is COCH-, A, B and D are as in example 1. 0.74 parts of 3-hydroxy-4-methylthiazole-2 (3H) -thione, 0.84 parts of sodium bicarbonate and 30 parts of water were stirred at 0.5 ° C while a drop was added dropwise to 0.52 parts of acetic anhydride and the reaction mixture was stirred at 0-5 ° C for an additional hour. formed a precipitate that separated by filtration and was recrystallized from aqueous methanol. 0.33 parts of 3-acetoxy-4-methylthiazole-2 (3H) -thione were obtained, with a melting point of 100-101 ° C. By analysis it was found that the composition is C 38% weight; H 3.7% weight; N 7.3% weight and S 34.0% -weight. C, H -.) 2NS? requires C 38.1% weight; H 3.7% weight; N 7.4% weight and S 33.9% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: EC 25 ppm SA 125 ppm AN 25 ppm AP 5 ppm CS 5 ppm AV 5 ppm CG 5 ppm EXAMPLE 9 A bis-ester of the product of Example 1 and glutaric acid was prepared. The procedure of Example 8 was repeated using 0.42 parts of glutaric chloride instead of acetic anhydride. The glutaryl ester bis, of P. of F. 104.5-106.5 ° C, was obtained. Through analysis it was found that the composition is C 39.8% weight; H 3.8% weight; N 6.7% weight and S 32.5% weight. Cj3H14N20.S4 requires C 40.0% weight; H 3.6% weight; N 7.2% weight and S 32.8% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: EC 25 ppm SA 25 ppm AN 25 ppm AP 5 ppm CS 5 ppm AV 5 ppm CG 5 ppm EXAMPLE 10 A compound of formula 1 was prepared in which group A is -C (CH3) 2 ~, group B is -C (CH) -, group D is -N (CgHg) - and R is hydrogen. 11.6 parts of acetone, 15 parts of hydroxylamine hydrochloride and 66 parts of water, were stirred vigorously at 0-5 ° C while adding a solution of 11 parts of potassium cyanide in 33 parts of water for a period of 0.5 hours . The formed solution was added at room temperature for two days and then neutralized to a pH of 6-7 with sodium acetate. The neutral solution was stored for an additional five days and then extracted with chloroform. The chloroform extract was dried and evaporated to dryness. The residue was recrystallized twice from petroleum ether (boiling point 60-80 ° C) to yield 1.4 parts of 1-hydroxylamino-1-methylpropionitrile with a melting point of 98-105 ° C. The nitrile product was dissolved in 28 portions of stirred toluene at room temperature and 1.9-parts of phenyl isothiocyanate were added. The reaction mixture was stirred overnight, evaporated to dryness and purified by flash evaporation chromatography on Kieselgel 60 (a silica gel available from Merck GmbH of Darmstadt, Germany). The elution was carried out using petroleum ether (eg, 60-80 ° C) with increased proportions of chloroform. - 0.18 parts of 5,5-dimethyl-l-hydroxy-4-imi-3-phenylimidazolidine-2-thione were obtained as an amorphous solid. By analysis it was found that the composition is C 56.3% by weight; H 5.4% weight; N 16.5% weight and S 13.0% weight. C. -H -... N..0S requires C 56.1% weight; H 5.5% weight; N 17.9% weight and S 13.6% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: AN 25 ppm AP 25 ppm CS 25 ppm AV 25 ppm GC 25 ppm EXAMPLE 11 A compound of formula 1 and -the cupric complex thereof, wherein group A is a spirocyclohexyl group were prepared and B, D and R are as in example 10. The procedure of example 10 - using cyclohexanone was repeated. The product obtained was converted to the cupric complex 2: 1, by reaction with cupric sulfate, using the procedure of example 2. By analysis it was found that the composition is N 12.9% weight and Cu 8.9% weight. C14H16N3OS) 2Cu3H2 ° re < 3uiere N 12.6% weight and Cu 9.4% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: AN 25 ppm AP 25 ppm CS 25 ppm AV 25 ppm GC 25 ppm.

EXAMPLE 12 A compound of formula 1 was prepared in which group A is -C (CH3) =, group B is -C (CgH5) =, group D is -NH- and R is hydrogen. 15.1 parts of C-phenylglycine, 100 parts of acetic anhydride and 100 parts of pyridine were heated to 90 ° C until the evolution of carbon dioxide ceased. The reaction mixture was evaporated to give an oil. 300 parts of toluene were added and this mixture was evaporated to give a solid residue. The solid residue was stirred under reflux with 200 parts of 5N aqueous hydrochloric acid. The resulting solution was filtered and evaporated to dryness. The solid residue was recrystallized from ethanol to yield 11.65 parts of alpha-acetylbenzylamine hydrochloride, melting point 204.5-206.5 ° C. About 4.65 parts of this hydrochloride and 3.5 parts of hydroxylamine hydrochloride were stirred in 25 parts of water. The mixture was stirred while boiling and 8.25 parts of sodium acetate dissolved in 20 parts of water were added. The reaction mixture was stirred during the novhe while it was allowed to cool to room temperature. 1.75 additional parts of hydroxylamine hydrochloride and 4.15 parts of sodium acetate dissolved in 10 parts of water were added, the reaction mixture was stirred for four hours at 50 ° C and then the reaction mixture was cooled to 0-5 °. C. A precipitate formed which was separated by filtration and dissolved in 40 parts of water containing one part of sodium carbonate. This solution was extracted with chloroform and the cyano roform was evaporated to give 1.99 parts of an oxime of melting point 73-74.5 ° C. 1.64 parts of the oxime and 2.8 parts of triethylamine were dissolved in 33 parts of tetrahydrofuran (solution A). 0.8 parts of thiophosgene were dissolved in 33 parts of tetrahydrofuran (solution B). Solutions A and B were added simultaneously for a period of 1 hour to 133 parts of tetrahydrofuran which were being stirred at -65 ° C. The reaction mixture was heated to 0 ° C overnight and then slit and evacuated to dryness. The solid was recrystallized from -ethanol to give 0.27 parts of l-hydroxy-5-methyl-4-phenylalimidazoline-2-thione, which has a melting point of 202 ° C. By analysis it was found that the compound contains 12.9% by weight of nitrogen. C, QH, 0 2OS, requires -13.6% nitrogen weight. In microbiostatic evaluation using Method B, the compound provided control of the test organisms as follows: EC 500 ppm SA 500 ppm AN 500 ppm AP 25 ppm CS 500 ppm AV 25 ppm GC 25 ppm EXAMPLE 13 The ethoxycarbonyl derivative of the product of Example 1 was prepared, this is R is C2H, .OCO, A, B and D, they are as in Example 1. 0.98 parts of the product of example 1 were dissolved in 20 parts of toluene and they were treated with 0.6 parts of triethylamine and 0.72 parts of ethyl chloroformate at room temperature. Additional portions of triethylamine and ethyl chloroformate were added at-intervals until the starting material was no longer present, as indicated by thin-layer chromatography. The reaction mixture was filtered, evaporated to dryness and the product was purified by flash chromatography (as in Example 10) to obtain 3-ethoxycarbonyloxy-4-methylthiazole-2 (3H) -thione, as a semisolid gum.

By analysis it was found that the composition is C 37.7% weight; H 4.3% weight; N 6.4% weight and S 31.3% weight. C-HgNO-S, requires C 38.4% weight; H 4.1% weight; N 6.4% weight and S 29.2% weight. In microbiostatic evaluation using method B, the compound provided control of the test organisms as follows: EC 25 ppm PA 500 ppm SA 50 ppm AN 25 ppm AP 5 ppm CS 25 ppm AB 25 ppm CG 5 ppm EXAMPLE 14 A compound of the formula 1 was prepared in which the group A is -C (CH3) =, the group B is -C (CH ^) =, the group D is -S- and R is hydrogen. 53.25 parts of 3-chloro-2-butanone were added dropwise over a period of 15 min to a rapidly stirred aqueous slurry of 52.12 parts of hydroxylamine hydrochloride in 50 parts of water at room temperature. The mixture was stirred for 1 hour at room temperature, and then cooled to -0-5 ° C. The mixture at 0-5 ° C was neutralized with a sodium carbonate solution and stirred an additional hour in - as it was warmed to room temperature. The solution was contacted with diethyl ether and the ether extract was dried and evaporated to dryness to give 51 parts of the oxime as a pale yellow oil (proton magnetic resonance using CDCl_ as solvent and tetramethylsilane as internal reference, showed a maximum double at a Delta value of 1.6 ppm, a maximum singlet at a delta value of 1.9 ppm, a maximum quadruplet at a delta value of 4.6 ppm and a maximum singlet width at a -value delta of 9 ppm.). 12.15 parts of the oxime were reacted with potassium ethyl xanthate, using the procedure as generally described in Example 6, to obtain a solid xanthate having a melting point of 62-64 ° C. The xanthate was cyclized, using potassium hydroxide diluted with the procedure as that generally described in example 1., 5-dimethyl-3-hydroxy thiazol-2 (3H) -thione was isolated as a white crystalline solid.

By analysis, it was found that the compound contains 8.3% by weight of nitrogen. CcH7NOS2 requires 8.7% by weight of nitrogen. The proton magnetic resonance spectrum, obtained as previously described, showed singlets at delta values of 2.18 and 2.2ppm. In microbiostatic evaluation, using method B, the compound provided control of the test organisms as follows: EC 25 ppm SA 500 ppm AN 25 ppm AP 25 ppm CS 5 ppm AV 5 ppm CG 5 ppm EXAMPLE 15 The acetoxy derivative of the product of Example 14 was prepared, ie R is C0CH3, A, B and D are as -in Example 14. The procedure of Example 8 was repeated, with the exception that 0.8 parts of the product were used. -Example 14. Obtained as a white solid 4,5-dimethyl-3-acetoxythiazole-2 (3H) -thione. By analysis, it was found that the composition is C 41.3% weight; H 4.5% weight; N 6.9% weight and S 32.1% weight. C.H NO.S ,, requires C 41.3% weight; H 4.4% weight; N 6.9% weight and S 31.5% weight. In microbistatic evaluation, using Method B, the compound provided control of the test organisms as follows: EC 25 ppm AN 25 ppm AP 25 ppm AV 25 ppm GC 25 ppm EXAMPLE 16 The cupric complex of the compound was prepared from Example 14. 0.99 parts of cupric acetate dissolved in 50 parts of methanol was added with stirring to a stirred solution of 1.61 parts of 4,5-dimethyl-3-hydroxythia-zol-2. (3H) -thione in 50 parts of methanol at room temperature. This mixture was stirred at room temperature for four hours, a green precipitate was isolated by filtration from the cupric complex 2: 1 and then washed with water at 10-15 ° C and dried. The solid had a melting point of 250-252 ° C. By analysis it was found that the composition was C 31.0% weight; H 3.1% weight; N 7.1% weight and Cu 16.6% weight. In microbiostatic evaluation using Method B, the compound provided control of the test organisms as follows; AP 25 ppm AV 25 ppm GC 25 ppm.

EXAMPLE 17 The zinc complex of the compound was prepared - from Example 14. Using the procedure of Example 16, 1.2 parts of 4,5-dimethyl-3-hydroxythia zol-2 (3H) -thione was reacted with acetate in methanol. The 2: 1 zinc com- pound was obtained as a white solid of melting point 235-238 ° C. By analysis it was found that the composition is C 31.3% by weight; H 3.1% weight; N 7.1% weight and Zn 16.6% weight (C5H, NOS2) 2Zn requires C 31.2% weight; H 3.1% weight; - N 7.3% weight and Zn 16.9% weight. In microbiostatic evaluation, using method B, the compound provided control of the test organisms as follows: EC 25 ppm SA 500 ppm AN 25 ppm AP 25 ppm CS 25 ppm AB 25 ppm GC 25 ppm EXAMPLE 18. A compound of the formula 1 was prepared, in which the group A is -C (C2H5) =, B is -C (CH3) =, D is -S- and R is hydrogen. 33 parts of 2-bromopentan-3-one were treated -as described in example 14, to obtain the oxime and the xanthate as intermediates and finally to obtain, as the final product, 4-ethyl-3-hydroxy-5- methyl thiazole-2 (3H) -thione as a solid with a melting point of 87-89 ° C. By analysis, it was found that the composition is C 41.3% weight; H 5.6% weight; N 8.1% weight and S 36.2% weight. C6HgNOS2 requires C 41.1% weight; H 5.1% weight; N - 8.0% weight and S 36.6% weight. In microbiostatic evaluation, using method A, the compound provided control of the test organisms as follows: EC 25 ppm AN 125 ppm AP 25 ppm CS 125 ppm AV 25 ppm CG 5 ppm EXAMPLE 19 The acetoxy derivative of the product was prepared - from Example 18, this is R is COCH3, A, B and D, they are as - in Example 18. The procedure of Example 8 was repeated with the exception that 0.82 parts of the product were used. -of Example 18. Through analysis it was found that the composition is C 44% weight; H 5.2% weight; N 6.5% weight and S 29.5% -weight. c8HnN02S2 retJuiere c 44.2% weight; H 5.1% weight; N 6.5% weight and S 29.5% weight. In microbiostatic evaluation using Method B, the compound provided control of the test organisms as follows: EC 25 ppm AN 500 ppm AP 500 ppm CS 500 ppm AV 500 ppm GC 500 ppm EXAMPLE 20 The zinc complex of the compound was prepared from Example 18. The procedure was as described in Example 17 with the exception that 1.35 parts of the compound of Example 18 were used. The solid zinc complex had a fusion of 204-210 ° C. By analysis it was found that the composition is C 35% weight; H 4.0% weight; N 6.8% weight; S 30.4% pe so and Zn 15.6% peso. (C, H8NOS2) 2Zn requires C 34.9% weight; H 3.9% weight; N 6.8% weight; S 31% weight and Zn 15.3% weight. In microbiostatic evaluation using Method B, the compound provided control of the test organisms as follows: EC 25 ppm AN 500 ppm AP 500 ppm CS 500 ppm AV 500 ppm GC 25 ppm EXAMPLE 21 A compound of the formula 1 was prepared in which the group A is -C (CgH4Cl) =, B is -CH =, D is -S- and R is H. The procedure of example 6 was repeated with the exception that 4-chlorophenacyl bromide was used in place of phenacyl bromide. The final product was 4- (4-chlorophenyl) -3-hydroxythiazole-2 (3H) -thione, which was obtained - as a white solid. By analysis it was found that the composition was N 5.2% weight and S 25.6% weight. CgH6ClNOS2 requires N 5.7% weight and S 26.3% weight. In microbiostatic evaluation using Method A, the compound provided control of the test organisms as follows: EC 25 ppm SA 125 ppm AN 125 ppm AP 125 ppm CS 125 ppm AV 125 ppm CG 125 ppm EXAMPLE 22 A compound of formula 1 was prepared in which group A is -C (C6H5) =, B is -C (CH3) =, D is -S- and R is hydrogen. The procedure of Example 6 was repeated with the exception that w-chloro-w-methylacetophenone was used in place of phenacyl bromide to obtain 3-hydroxy-5-methyl-4-phenylthiazole-2 (3H) -thione. The proton magnetic resonance spectrum, obtained as described in example 14, showed singlets at delta values of 2.05 ppm and 7.3 ppm. In micriobiostatic evaluation using Method A, the compound provided control of the test organisms as follows: EC 125 ppm SA 125 ppm AN 125 ppm AP 5 ppm CS 25 ppm AV 25 ppm CG 5 ppm.

EXAMPLE 23 The acetoxy derivative of the product of example 6 was prepared, that is R is C0CH3, A, B and D are as in example 6. The procedure of example 8 was repeated with the exception that a part of the product of example 6 was used. 3-Acetoxy-4-phenylthiazole-2 (3H) -thione was obtained as a white solid. The proton magnetic resonance spectrum, obtained as described in Example -14, showed singlets at delta values of 2.1 ppm, 6.45 ppm and 7.35 ppm. By analysis, it was found that the compound contained 5.6% - nitrogen weight. C ^ H-NO ^ S ,, requires 5.6% weight of nitrogen. In microbiostatic evaluation using Method B, the compound provided control of the test micro-organisms as follows: EC 25 ppm SA 500 ppm AN 500 ppm AP 500 ppm CS 500 ppm AV 500 ppm GC 25 ppm.

Claims (7)

R E I V I N D I C A C I O N S

1. - Metal complex and its salts are antimicrobial properties, of the formula: wherein: 2 D is -NR- or sulfur; R is hydrogen; and 2 R is hydrogen, hydrocarbyl, substituted hydrocarbon or two R groups which, together with the carbon atom to which they are attached, form a 5- or 6-membered hydrocarbon ring system; wherein each hydrocarbyl group is an alkyl group containing up to five carbon atoms or is a phenyl group; and any substituent on a hydrocarbyl group is a hydrocarbonoxy group, an acyl group, an ester group, a halogen atom or a nitrile group.

2. - Metal complex according to clause 1, where A and B are -CR 2 = and D is sulfur.

3. - Goal complex according to clause 1, in - where the metal is a metal of group VIII, IB or IIB of - the periodic table.

4. - Salt of metal according to clause 1, where the metal is iron, copper or zinc.

5. - Metal complex according to clause 1, 3-hydroxy-4-methylthiazole-2 (3H) -thione, 3-hydroxy-4-phenylthiazole-2 (3H) -thione, 3-hydroxy-4, 5,6 , 7-tetrahydrobenzothiazole-2 (3H) -thione, 3-acetoxy-4-methylthiazole-2 (3H) -thione, 5,5, dimethyl-l-hydroxy-4-amino-3-phenylimidazolidin-2-thio-na , l-hydroxy-4-imino-3-phenyl-2-thione-1, 3-diazaspiro [4, 5] decane, 4,5-dimethyl-3-hydroxythiazole-2 (3H) -thione, 4-ethyl- 3-hydroxy-5-methylthiazole-2 (3H) -thione, 4-. { 4-chlorophenyl) -3-hydroxythiazole-2 (3H) -thione, 3-hydroxy-5-methyl-4-phenylthiazole-2 (3H) -thione, l-hydroxy-5-methyl-4-phenyl-imidazolin-2 -thione or 3-hydroxy-5-methyl-4-phenylthiazole-2 (3H) -thione.

6. - zinc complexes of clause 1, of: 3-hydroxy-4-methylthiazole-293H) -thione, 4,5-dimethyl-3-hydroxythiazole-2 (3H) -thione and 4-ethyl-3-hydroxy-5 -meththiazole-2 (3H) -thione.

7. - Metal complex according to clause 1, in 2 where R is selected from the group of hydrogen, methyl, -ethyl, phenyl or chlorophenyl. Under protest of the truth, it is manifest that the best known method for carrying out the present invention is that which is indicated in the description of this request. In testimony of which we sign the present in: Mexico, D.F., on October 3, 1994. IMPERIAL CHEMICAL INDUSTRIES PLC.