IL29605A - 3-isothiazolones - Google Patents

Description

29605/2 3-Isothiazolones KOHM AND HASS COMPANY C:28021 This invention is concerned with novel substituted 3-isothiazolones, salts thereof, their preparation, and bio- cidal compositions containing them.

The novel 3-isothiazolones (hereinafter referred to at times as "isothiazolones") provided by the invention may be represented by the formula wherein Y is /preferably 0^-C1Q alkyl; C^-Cg cycloalkyl, aralkyl of up to carbon atoms: aralkyl of up to 10 carbon atoms substituted with halogen, C^-C^ alkyl, or C-^-C^ alkoxy; aryl; aryl substituted with halogen, nitro, alkyl, alkylacylamino in which the alkyl group contains up to 4 carbon atoms, car- balkoxy in which the alkyl group contains up to 4 carbon atoms o or sulfam l; C-^-C^ hydroxyalkyl; C^-C^ haloalkyl; dialkyl- aminoalkyl in which each alkyl group contains up to 4 carbon unsubstituted or substituted /or thiocarbamoyl atoms; or aajcarbamoyl/group of the formula -c-iraR11 R and R each represent hydrogen, halogen or C,-C ^o thiocarbamoyl alkyl when Y is other than the carbamoyl group provided that I are both R and R aaay not £k hydrogen when Y is methyl or ethyl> R is hydrogen> C^-C^ alkyl, halogen or cyano when Y is the carbamoyl group5 R1 is hydrogen, halogen, C-j-C^ alkyl or C^-C^ haloalkyl when R is hydrogen, C^-C alkyl or halogen; C-^-C^ alkylsulfonyl when R is cyano; X is oxygen or sulfur; and R 1 is C^-C^g alkyl, C^- alkylsulfonyl, arylsulfonyl, halogen or C^-C^ alkyl substituted arylsulfonyl, or carbalkoxyalkyl of the formula: 8 R^-OC-R17 is an alkylene group of 1 to carbon atoms 5 or/ah aryl group of the formula V wherein R is C^-C^ alkyl, halogen, nitro or C-^-C^ alkoxy and n is B—xa hsx.. oi.0, tc 3- As regards the various C-^-C^ alkyl-containing substituents mentioned above these are typically methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.

Some of the isothiazolones described above can form novel salts which also exhibit biocidal activity. Such salt forming compounds fall within the scope of Formula I wherein Y is alkyl of 1 to 18 carbon atoms; cycloalkyl of 5 to 6 carbon atoms; aralkyl of up to 10 oarbon atoms; halogen, lower alkyl, or lower alkoxy substituted aralkyl of up to 10 carbon atoms; aryl; halogen, nitro, lower alkyl, lower alkylacylamino o lower carbalkoxy or sulfaml substituted aryl; lower hydroxy-alkyl; lower haloalkyl; or lower dialkylaminoalkyl; and R and R1 are selected from the group consisting of hydrogen, lower alkyl, or halogen.

Preparation of these biocidally active salts is readily achieved by reacting the above designated 3-isothia-zolones with a strong acid. Typical strong acids inelude Separation of the acid salts from the reaction medium is accomplished by any convenient means known to one skilled in the art.

Representative Y substituents include methyl, ethyl, propyl, isoprppyl, butyl, octyl, decyl, pentadecyl, octadecyl, cyclopropyl, cyclohexyl, benzyl, 3>4-dichlorobenzyl, 4-meth-oxybenzyl, 3,4-dichlorophenyl, hydroxymethyl , chloromethyl , chloropropyl, diethylaminoethyl , carbamoyl, thiocarbamoyl , methylcarbamoyl, propylcarbamoyl, t_-octylcarbamoyl, phenyl-carbamoyl, ethoxyphenylcarbamoyl, nitrophenylcarbamoyl, carbethoxymethylcarbamoyl, methylthiocarbamoyl and ethyl-thiocarbamoyl .

Representative R substituents include hydrogen, bromo, chloro, iodo, cyano, methyl, ethyl, propyl, isopropyl, butyl and t_-butyl.

Representative ^" substituents are hydrogen, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, chloromethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, bromo-butyl, methylthio, propylthio, methylsulfinyl, ethylsulfinyl, butylsulfinyl, methylsulfonyl , ethylsulfonyl, propylsulfonyl, and butylsulfonyl.

II Representative R substituents are methyl, ethyl, propyl, isopropyl, butyl, jt-butyl, pentyl, isopentyl, hexyl, cyclohexyl, heptyl, octyl, t_-octyl, nonyl, decyl, dodecyl, octadecyl, phenyl, 2-methylphenyl, 4-inethylphenyl , 4-ethylphenyl , 2,4-dimethylphenyl , 2-chlorophenyl , 3-chlorophenyl , 4-chlorophenyl , 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3»4-dibromophenyl , 2-bromophenyl, 3>4> -trichlorophenyl, 4-nii;ro-phenyl, 2,4-dinitrophenyl , 4-methoxyphenyl , 2-ethoxyphenyl, 3, -dimethoxyphenyl , methylsulfonyl, ethylsulfonyl, 4- phenylsulfonyl , carbethoxymethyl and carbethox ethyl.

Typical compounds within the scope of Formula I include the followingj 2-propyl-3-isothiazolone, 2-butyl-3-isothiazolone, 2-t-ootyl-3-isothiazolone, 2-decyl-3-isothiazolone, 2-octyldecyl-5-isothiazolone, 2-cyclohexyl-3-isothiazolone, 4-chloro-2-methyl-3-isothiazolone, 4-bromo-2-methyl-3-isothiazolone, -chloro-2-methyl-3-isothiazolone, -chloro-2,4-dimethyl-3-isothiazolone, 4-bromo-5-chloro-2-methyl-3-isothiazolone, 4-bromo-2-cyclohexyl-3-isothiazolone, 4,5-dichloro-2-ethyl-3-isothiazolone, 4-methyl-2-octyl-3-isothiazolone, 4, 5-dimethyl-2-octyl-3-isothiazolone, 2-benzyl-3-isothiazolone, 2-benzyl-4,5-dichloro-3-isot iazolone, 2-benzyl-5-chloro-3-isothiazolone, 2-(2 > ,4· -dichlorobenzyl)-3-isothiazolone, 2-(41-methoxybenzyl)-3-isothiazolone 2-(4I-ethylbenzyl)-3-isothiazolone, 2-(3 · ,4» -dichlorophenyl)-3-isothiazolone, 2-(3 ! ,4'-dichlorophenyl)-4-methyl-3-isothiazolone, 2-(4' -methylp enyl)-3-isothiazolone, 2-hydroxymethy1-3- sothiazo1one, 2-(fl-diethylaminoethyl)-3-isothiazolone, -(N-ethylcarbamoyl)-3-isothiazolone, -(N-n-propylcarbamoyl)-3-isothiazolone, -(K-i-propylcarbamoyl)-3-isothiazolone, -(N-butylcarbamoyl)-3-isothiazolone, -(N-hexylcarbamoyl)-3-isothiazolone -(N-£-octylcarbamoyl)-3-isothiazolone, -^-decylcarbamoyl)-3-isothiazolone, -(N-dodecylcarbamoyl)-3-isothiazolone, -methyl-2-(N-methylcarbamoyl)-«3-isothiazolone, -methyl-2-(N-ethylcarbamoyl)-3-isothiazolone, -propyl-2-(N-methylcarbamoyl)-3-isothiazolone, -butyl-2-(N-methylcarbamoyl)-3-isothiazolone, -bromo-2-(N-methylcarbamoyl)-3-isothiazolone, -bromo-5-methyl-2-(N-methylcarbamoyl)-3-isothiazolone, -chloro-5-niethyl*-2-(N-methylcarbamoyl)-3-isothiazolone -cyano-5-methylthio-2-(N-methylcarbamoyl)-3-isothiazolone, -cyano-5-methylsulfinyl-2-( -methylcarbamoyl)-3-isothiazolone, -cyano-5-methylsulfonyl-2-(N-methylcarbamoyl)-3-isothiazolone, -methyl-2-(N-phenylcarbamoy1)-3-isothiazolone, -cyano-5-methylthio-2-(N-phenylcarbamoyl)-3-isothiazolone, -bromo-5-methyl-2-(N-3,-chlorophenylcarbamoyl)-3-isothiazolone, -bromomet¾yl-2-(N-3' -chlorophenylcarbamoyl)-3-isothiazolone, -bromoethyl-2-(N-3' -chlorophenylcarbamoyl)-3-isothiazolone, -methyl-2-(N-3'-chlorophenylcarbamoyl)-3-isothiazolone -cyano-5-methylthio-2-(N-31 -chlorophenylcarbamoyl)-3-isothiazolone, 4-cyano-5-methylsulfiny1-2-(N-31 -chlorophenylcarbamoyl)- 3-isothiazolone, 4-cyano-5-but lsulfin 1-2-(IT-3' -chlorophenylcarbamoyl)- 3-isothiazolone, 2-(W-31 -chlorophenylcarbamoyl)-3-isothiazolone, -methyl-2-(N-21 -chlorophenylcarbamoyl)-3-isothiazolone, 4-cyano-5-propylthio-2-(N-2' -chlorophenylcarbamoyl)-3- isothiazolone, -bromomethyl-2-(N-2 '-chlorophenylcarbamoyl)-3- isothiazolone, 4-bromo-5-methyl-2-(N-3 ' >4'-dichlorophenylcarbamoyl)-3- isothiazolone, 4-cyano-5-methylthio-2-(N-31 ,4' -dichlorophenylcarbamoyl)- 3-isothiazolone, 2-(N-3' ,4'-dichlorophenylcarbamoyl)-3-isothiazolone, -methyl-2-(N-3» ,4'-dichlorophenylcarbamoyl)-3-isothiazolone, 2-(N-2 ' , 5 '-dichlorophenylcaxbamoyl)-3-isothiazolone, 2-(N-3' -methylphenylcarbamoyl)-3-isothiazolone, 2-(K-3 4,-dimethylphenylcarbamoyl)-3-isothiazolone, 2-(N-2 ' -ethylphanylcarbamoyl)-3-isothiazolone, 2-(N-3 ' -butylphenylcarbamoyl)-3-isothiazolone, 2-(N- 1 -ethoxyphenylcarbamoyl)-3-isothiazolone, 2-(N- ' -nitrophenylcarbamoyl)-3-isothiazolone, 2-(N-2* ,4,-dinitrophenylcarbamoyl)-3-isothiazolone, -methyl-2-(N-4,-methylphenyls lfonylcarbamoyl)-3- isothiazolone, 4-cyano-5-methylthio-2-(N-4' -methyl henylsulfonyl- carbamoyl)-3-isothiazolone, 4-bromo-5-methyl-2-(l-4' -methylihenylsulfonyl- carbamoyl)-3- isothiazolone, 2-(N-methylthiocarbamoyl)-3-isothiazolone, -methyl-2-(N-ethyl hiocarbamoyl)-3-isothiazolone, 4-cyano-5-ethylsxilfinyl-2-(K-methylthiocarbamoyl)- - az l e a 29605/1 7a The antimicrobial activity of certain 1,2-benzisothiazolone derivatives was disclosed in Swiss Patent Specification No. 372,026 and also in Swiss Auslegeschrift No. 14372/65 which was published later than the priority date of the present application. As compared to those known compounds, the compounds of formula I according to this invention exhibit a broader spectrum of activity, including bactericidal, fungicidal and algaecidal activity and can be used in much smaller quantities for effective control of the microorganisms.

The novel 3-isothiazolones may be prepared by any appropriate method described in the literature such as by conversion of 3-hy^oxyisothiazoles, betathioketoamides, or ^substituted thiocyanoacrylamides or thiosulfatoacrylamides .

Preparation of the novel 2-carbamoyl and thio-carbamoyl substituted isothiazolones of this invention may be acomplished by reacting a 3-hydroxyisothiazole with an iso-cyanate or isothiocyanate on a substantially equimolar basis.

The unsubstituted 3-bydroxyisothiazole can be synthesized from propiolamide by the method of W.D. Crow and N.J. Leonard, .

J.Org. Chem. , ^O, 2660-2665 (1965). Substituted 3-hydroxy-isothiazoles are disclosed and can be prepared as shown in copending Application No. filed on even date herewith and incorporated herein by reference thereto.

A general reaction for the preparation of carbamoyl or thiocarbamoji substituted 3-isothiazolones from 3-hydroxyisothiazoles and isocyanates or isothiocyanates is shown below: wherein the symbols R, R , R and X are as previously defined.

Although an equimolar ratio of reactants is preferred an excess of up to 2 moles or more of isocyanate or isothiOM cyanate per mole of 3-^^xyisothiazole may be employed. In many situations, an inert organic solvent may be utilized in this reaction. Generally, those solvents from the classes of aromatic hydrocarbon, halogenated aromatic hydrocarbon, amide, those which include benzene, toluene, heptane, ethyl ether, and dioxane. When employing simple isocyanates, the reaction is spontaneous; but with less reactive long chain or aromatic isocyanates, a catalyst or promoter such as a tertiary amine can be profitably tilized. Representative tertiary ami es are pyridine and triethylamine. While the reaction temperature is not critical, it is usually conducted in a range of -20°C. to 80°C. or more.

In addition, the isothiazolones of the formula may be prepared by the method of Goerdeler and Mittler as described in Chem. Ber. , 36, 944-954 (1963) . In Formula II, Y> is defined in the same manner as Y in Formula I excepting therefrom only the lower hydroxyalkyl group and, Z is hydrogen or lower alkyl and ' is lower alkyl or lower haloalkyl.

This preparation involves the halogenation of a substituted betathioketo amide in an inert organic ester solvent, such as ethyl acetate. The betathioketo amide referred to may be represented by the formula wherein Z and Y1 are as defined above and Z" is lower alkyl.

Another process for preparing some of the compounds of this invention is that of Crow and Leonard as set forth in Their method entails the converting of a^S-substituted thiocyanoacrylamide or thiosulfatoacrylaini de to the isothiazolone. This reaction may be represented by the following equation: wherein Y is as defined for Formula I, Z"' is hydrogen or lower alkyl and M is -SON or -SgO^ · Generally and preferably, conversion of the substituted thiocyanoacrylamide or thiosul atoaorylami de to the isothiazolone is achieved by the treating thereof with an acid, such as for example, sulfuric acid. However, when M is SCN, then transition metal salts, such as nickel sulfate, ferrous sulfate, ferric sulfate, copper; 'sulfate and the like, are also readily utilized. In like manner, when M is S^O^ , then the conversion can be accomplished with iodine. Preparation of the thiocyanoacrylamide and thiosulfatoacrylamide as taught by Crow and Leonard involves the reacting of a substituted propiolamide with thiocyanic acid or thiosulfate.

The 2-hydroxyalkyl-3-isothiazolone derivatives disclosed herein are obtained by reacting formaldehyde or an alkylene oxide, such as ethylene oxide, propylene oxide and the like, with a 3-hyclroxyisothiazole. Preparation of the 2-haloalkyl-3-isothiazolones may be accomplished by reacting a 2-hydroxyalkyl-3-isothiazolone with a halogenat- ing agent, such as thionyl chloride, phosphorus tribromide, phosphorus trichloride and the like.

By way of demonstration, the following examples construed as limitations thereof. In Table I, the compounds prepared by the above-described processes and constituting Examples 1 through 81 are named and their embodiments indicated. Table II lists the elemental analyses and melting points for the examples previously described in Table I. Specific illustrative preparations of Examples 1, 3, 14» 25» 33 , 38 and 55 are set forth below.

EXAMPLE 1 A solution of 5.05 parts (0.05 mole) of 3-hydroxyisothiazole in 88 parts of dry benzene was agitated at 25°C. There was added to the above solution a 5<jfo benzene solution containing 2.85 parts (0.05 mole) of methyl-isocyanate. Immediately after addition, a white precipitate began to form which grew progressively thicker upon stirring. This stirring was continued overnight. Filtration of the reaction mixture gave 2.0 parts of white solid 2-(N-methyl-carbamoyl)-3-isothiazolone with a melting point of 138°C to 140°C. After addition of 35 parts of hexane, the filtrate yielded 3· parts of additional product with a melting point of 138° to 139°C In this manner, a total yield of 5· 5 parts (70 ) of 2-.(U-methylcarbamoyl)-3-isothiazolone was obtained.

EXAMPLE 3 To an agitating solution of 2.9 parts (0.029 mole) of 3-hy<iro3-yisothiazole in 88 parts of benzene, 2.1 parts (Ο.Ο29 mole) of methylisothiooyanate was added. The reaction was heated at 0° to 60°C. for 10 hours and the reaction medium evaporated to leave 2.5 parts of white solid 2-(N-methylthiocarbamoyl)-3-isothiazolone. The product was EXAMPLE 14 To an agitating solution of 3 · 0 parts (0.025 mole) of 3-hydroxy-5-methyl-isothiazole in 132 parts of dry benzene, 4.0 parts (0.025 mole) of 3-chlorophenylisocyanate was added. The temperature of the exothermic reaction rose from 27° to 48°C. After stirring for two hours, a white solid slurry formed. The solid was filtered off and dried to yield 7 · 0 parts of 5-nie'fchyl-2-(N-3-chlorophenylcarbamoyl)-3-isothia-zolone.

EXAMPLE 25 To an agitating solution of 4 parts (0.04 mole) of 3-hydroxyisothiazole in 88 parts of dry benzene, 2.84 parts (0.04 mole) of ethylisocyanate was added dropwise at 25°C. The solution was stirred at 25°C. for 12 hours5 then the solvent was evaporated under vacuum to yield 6.0 parts of yellow solid 2-(N-ethylcarbamoyl)-3-isothiazolone. Purification was accomplished by crystallization from a benzene-hexane solution.

EXAMPLE 55 A solution of benzene ( 66 parts), 3-hydroxyisothiazole ( · 0 parts, 0.04 mole) and 1 part of triethylamine was agitated. Then 8.45 parts (0.04 mole) of n-dodecyl-isocyanate in 22 parts of benzene was added dropwise at 2 ° C. After stirring for 12 hours, the reaction solution was evaporated to leave 13.0 parts of 2-(N-n-dodecylcarbamoyl)- 3-isothiazolone. The product was crystallized from ethanol.

EXAMPLE 58 - - - - - - ethylisothiocyanate according to the procedure of Example 3.

EXAMPLE 55 Aqueous formaldehyde (37 percent), 4·5 g. (Ο.Ο56 mole) was diluted with 25 ml. of water, and then 3·8 g. (0.028 mole) of potassium carbonate was added. Thereafter, 5-5 g< (Ο.Ο 5 mole) of 3-hydroxyisothiazole was added to the formaldehyde solution in one portion. A solid precipitate soon formed, and after 2 hours stirring, was filtered off to yield 1.8 g. of white solid 2-hydroxy-methyl-3-isothiazolone.

Example No. R Y 1 H H -CGNHCR-, 2- (N-methylcarbamoy 2 H OHj -CONHCH- 5-methyl-2-(N-raeth 3 3 H H -CSNHCIL^ 2- (N-methylthiocarb CN SCIL^ -CQNHCHj if-cyano-5-methylth 6 CN S0CH_ -CONHCH^ if- cyano-5-meth lsu 3 7 CN S02CH3 -CONHCR.. i -cyano-5-methylsu 8 H H -CONHC^Hg-n 2- (N-n-butylcarbam 9 H H -CONHCgH17-t 2- ( N- t-oc tylcarbam H CH3 5-meth l-2- (N-phen 11 CN SCH, -CONHC^H^ z -cyano-5-methylth 12 Br 2 Example No. R Y 13 H 5-bromoethyl 1 H 5~methyl-2-( CN -cyano-5-me 16 H 2-(N-3-chlor 17 H 5-methyl-2-( 18 H 5-broraomethy 19 Br c¾ -CONHCgH^Cl^,2* k~bromo-5-no H 5-meth 1-2-( 21 CN SCH^ -C0 HC6H^Cl2-3,4 4-cyano-5-me 22 H 5-meth l-2-( 23 CN SCH, -CCNHSO C£H,,CH,- 4-cyano-5-∞e 3 2 4 3 2k Br °¾ -COHSC^CgH^CE^ i-bromo-5-rae H H -CQNHC„HC 2-(N-ethylca 26 H H 2-(N-n-propy 27 H H -CONHC^-i 2-(N-i-propy 28 Br H -CONHCK-, 4-bromo-2-(N H H -COHCgH^-OCH^-4 2-(N-4-meth 29 xamp e No. K_ ή Y H H 2-(N-2-methox 31 H H 2-(N-3-nitrop 32 H H -CONHC H,-Cl -3Λ 2-(N- 14—dich o 3 . 33 H H -C0NHC12H25 2~(N-n-dodecy 3* H H -C0HC6H^Cl2-2,5 2-(N-2,5-dich H H -CONHCH^CO.C^H,. 2-(N-carbetho 37 H CH, -CONHC^H,. 5-methyl-2-(N 2 ^ 38 H -CSNHC„IL 5-methyl-2-(N CH3 2 5 39 H CI -CONHC H_. 5-chloro-2-(N 2 ho H H -C3H7 2-n-propyl-3- H H 2-t-butyl-3-i hz H H 2-n-butyl-3-i ½5 H H 2-cyclohex 1- -C6H11 k H H 2-t-octyl-3-i -°8Η17^ h5 H H 2-benzyl-3-is -°H2C6¾ 6 H CI -CH, -chloro-2-me 3 No. E_ Y 47 H Cl 5-chloro-2-be "°Η2°6¾ 48 CI CI ^,5-dichloro- 49 CHj H -CH, 2,½-dimethyl- 3 50 H -C6H3Cl2-3f 4 i-methyl-2-(3 CH3 51 H H -C6H5CI2-3, 2-(3, 4-dichlo 52 CI Cl ,5-dichloro- 3 Br Cl -CH, i-bromo-5-chl 3 ^ Br H -CH^ ^-bromo-2-met 55 H H -CH20H 2-hydroxymet 56 H H -CH2CH2N(CH2CH3) 2-(β-diethyl 57 H H -C^'HCl 2-n-propyl-3 58 H Cl -CH^'HCl 5-chloro-2-m 59 H H -C_H «HC1 2-ethyl-3-is 2 5 60 H H -CH «HC1 2-methyl-3-i 3 61 H H 2-benzyl-3-i 2 6 5 62 H H 2-n-dodecyl- "C12H25"≥ 63 H H 2-n-tetradec T o. R_ R Y H H 2- (2-chlorob 6 H H .CH2-C6H3-C12-2I^ 2-(2,^-dichl 7 H H -CH2-C6H^-Cl2-3,^ 2-(3»^-dichl 3 H H -0Η2-06¾-∞Η3-4 2- methoxy 9 H H 2- C-methylb 0 H H -σΗ2-οΐΗ :^Η9)σ2Η5 2-(2-ethylhe 1 H H -CH2CH2-C6H5 2- ( 2-phenyle 2 H CI -CH2CH2- 6H5 2-(2-phenyle 3 H H -CH(CH,)C.H._ 2- ( 1-phenyle 3 6 5 ^ H H 2-n-decyl-3- 5 H H 2-n-octyl-3- 6 CI H -C8H17-t 2-t-octyl-½- 7 Br H 2-t-octyl-'- 8 H H 2-n-nonyl-3- -°9Η19^ 9 H CI 2-n-octyl-5- -C8H17"S 0 H H 2- ( -nitroph ~C6Hi N02-J 1 . H H -CgH^COOC^-^ 2-(¾-carbeth A N A L Y S Example Melting No. Point in °C. C H N 1 138-140 38.16(37.9) 4.04(3.8) 17.45(17.1 2 138-145 41.55(41.8) 4.63(4.7) 15.60(16.3 3 155-158 34.62(34.5) 3.66(3.5) 15.76(16.1 4 191-1 5 28.74(28.7) 2.98(2.8) 10.90(11. 20 -2IO 35.96(36.7) 3.24(3.1) I7. K18. 6 I58- 6O 34.10(34.3) 2.95(2.9) 16.95(17.1 I ON 7 146-150 31.90(32.2) 3.07(2.7) 15.23(16; 8 oil 47.91(^7.8) 6.01(6.0) 13.92(14. 9 oil 11.41(10. 142-146 56.52(54.2) 4.29(V.5) 12.10(12. 11 I83-I86 49.00(49.5) 3.16(3.1) 14.51(14. 12 200-202 38.32(38.1) 2.37(2.3) 7.86(8.1) 13 I78-I8O 38.02(38.1) 2.56(2,3) 7.65(8.1) 14 142-144 49.38(49.2) 3.36C3.O 10.11(10. 192-194 43.29(44.3) 2.57(2.5) 12.78(12. a p e ng No. Point in °C. c H N ■ 16 120-123 47.90(47.1) 3.16(2.8) 10.98( 17 162-164 49.78(49.3) 3.58(3.^) 10.78( 18 199-201 38.28(38.1) 2.45(2.3) 8.19( 19 235-237 34.42(34.6) 1.84(1.9) 7.20( 195-207 44.42(43.4) 2.89(2.6) 8.56( 21 118-120 39.96(40.0) 2.10(2.0) 11.52( 22 170-173) 46.18(46.2) 4.03(3.9) 9.01( 23 163-168 39.50(42.2) 3-46(3.0) 11.65( 24 1 - 03 38.79(38.4) 2.98(2.9) 6.95( 5 IO3-IO5 41.91(41.8) 4.71(4.7) 16.10( 26 84-88 45.06(44.9) 5.67(5.4) 14.66( 27 53-56 44.86(44.9) 5.45(5.i 14.89( 28 1 - 7 25.80(25.3) 2.58(2.1) 11.60( 29 134-137 52.88(52.8) 4.19(4.0) 11.23( 140-145 52.16(52.8) 4.40(4.1) 11.13( 31 195-198 45.97(^5.3) 2.68(2.7) 15.79( 32 1 - 41.51(41.6) 2.10(2.1) 9.67( Example Melting No. Point in °C. iC H N 33 60-62 61.41(61.5) 8.84(9.0) 8.90(9 34 I7 - 8O 41.41(41.6) 2.27(2.1) 9.77(9 * 35 8O-83 42.02(41.7) 4.64(4.3) 11.41(1 36 2 -23Ο 45.59(45.3) 2.79(2.7) 15.75(1 37 53-56 44.77(45.2) 5.46(5.4) 14.41(1 38 73-103 41.44(41.7) 4.86(5.0) 13.79(1 39 53-55 35.12(34.87) 3.42(3.39) 13.47(1 40 65-68 50.28(50.3) 6.17(6.33) 9.83(9 41 75-79 46.76(53.5) 6.76(7.06) 8.42(8. 42 99 52.10(53.5) 7.11(7.06) 8.54(8. ^3 109-111 58.96(59.0) 7.20(7.10) 7.59(7. 44 97-100 61.9K62.O) 9.03(9.0) 6.55(6. 45 78-80 62.82(62.8) 4.84(4.7) 7.22(7. 46 44-47 32.80(32.1) 2.64(2.7) 9.55(9. ^7 57-59 53.19(53.2) 3.46(3.6) 6.18(6. 48 114-117 27.3K26.I) 1.43(1.6) 7.22(7. 49 58-68 45.99(46.4) 5.77(5.4) 11.38(1 Example Melting No. Point in °C« C H N 50 161-163 45.92(45.8) 2.88(2.7) 5.59(5 51 31- 33 43.95(43.9) 1.95(2.05) 5.66( 52 62-64 47.10(46.1 ) 2.86(2.7) 5.35( 53 86-87 22.24(21.0) 1.81 (1.3) 5.82( 54 94-97 25.68(24.7) 1.75(2.0) 7.22( 55 124-126 36.43(36.5) 3.75(3.7) 10.44(1 56 oil 52.70(54.1) 6.35(8.06) 14.17(1 57 87-90 38.64(40.2) 5.88(5.61 ) 7.50( 58 - 25.78(25.8) 3.17(2.7) 7.07( 59 144-146 36.44(36.3) 4.80(4.8) 8.30( 60 62-166 30.76(31.8) 4.27(4.0) 8.89( 61 147-153 52.78(52.8) 4.60(4.39) 6.33( 62 46-49 66.98(66.9) 9.90(10.0) 5.25( 63 53-55 68.86(68.7) 10.61 (10.5) 4.68( 64 87-88 52.78(53.2) 3.54(3.6) 6.02( 65 99-100 53.39(53.2) 3.69(3.6) 6.18( Example Melting No. Point in °C. C H N 66 122-124 46.18(46.2) 2.80(2.7) 5.25( 67 87-89 45.87(46.2) 2.62(2.7) 5.15( 68 8Ο-82 59.74(59.7) 4.96(5.0) 6.25( 69 76-77 64.60(64.4) 5.32(5 ) 6.60( 70 119-120( .005mm)b 60.8K62.O) 8.88(8.9) 6.46( 71 76-78 64.35(64.5) 5 9(5 ) 6.75( 72 55-59 55.22(55.2) 3.95(4.2) 5.62( 73 138- O( .003mm) 62.52(64.5) 5.27(5.4) 6.45( 7^ 41-42 64.80(64.7) 9.3K9.6) 5.46( 75 120(0.01mm) 62.00(62.0) 8.81 (8.9) 6.48( 76 137-1 0 52.38(53.5) 7.8 (7.3) 5.62( 77 138-1 2 44.76(45.2) 6.48(6.2) 4.58( 78 30-31 63.34(63.45) 9.40(9.29) 6.08( 79 oil 55.05(53 ) 7.76(7.3) 5.76( 80 170- 75 dec. 48.62(48.7) 2.78(2.72) 12.77( 81 141-142 58.12(57.8) 4.46(4.44) 5.70( * The number parenthesized represents the theoretical value empirical formula of each compound.

** Analysis for bromine. * Neutralization eq The new 3-isothiazolones can also be prepared by a new process involving the cyclization of a disulfide-amide of the formula wherein Z ^ and 7r- are hydrogen or C^-C^ alkyl and Y" is as previously defined for Y except that it is other than hydroxyalkyl , carbamoyl or thiocarbamoyl. Such cyclization is preferably accomplished by reacting the disulfide-amide with a halogenating agent. Typical halogenating agents include chlorine, bromine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinamide, N-bromosuccinamide and the like. Chlorine and sulfuryl chloride are the preferred halogenating agents.

Cyclization of the disulfide-amide will take place when 3 mole equivalents of halogenating agent, or to be more specific halogen, are employed in the reaction. By providing an excess of halogenating agent, the isothiazolone may be halogenated at the and/or 5 positions of Formula I. Where 5 mole equivalents of halogenating agent are available, mono-halogenation will take place. For di-halogenation, 7 mole equivalents of halogenating agent are required.

Preparation of isothiazolones having the 4 5 position substituted with different halogens is achieved by the halogenation of an isothiazolone already halogenated at one of the two positions in question. For example, if a 4- isothiazolone is, of course, prepared by the cyclization of a disulfide-anri de as described herein. Procedures and variations therein for what might be termed "secondary halogenation" would be evident to one skilled in the art.

Temperature is not critical to the reaction process; that is, the cyclization will proceed at any temperature.

Generally and preferably, it will be carried out in the range of 0° to 100°C.

The reaction is carried out in an inert nonaqueous solvent, such as benzene, toluene, xylene, ethyl acetate, ethylene dichloride and the like.

Isothiazolonium salts can be formed along with the isothiazolones during the cyclization process, e.g., when Y" in Formula III is alkyl of 1 to 18 carbon atoms or aralkyl of up to 10 carbon atoms. Such salts have the following structure t wherein Y", R, and R are as hitherto defined. Where desired or necessary, an acid scavenger can be incorporated in the reaction medium so as to avoid isothiazolonium salt formation.

Typical scavengers which might be so utilized would include t_-amine bases, such as for example, pyridine and triethyl-amine. It should be noted at this point that the isothiazolonium salts can also be transformed or neutralized to free The disulfide-amides which are cyclized to form the isothiazolones are known and may "be prepared in several ways. Typically, an alpha or beta mono- or di-substituted acrylate or acrylic acid is reacted with thiol acetic acid. Upon completion of the reaction, the product is hydrolyzed so as to obtain a beta-mercapto^propionic acid, which is, in turn, oxidized to the disulfide acid. This material is then converted to a diacid chloride-disulfide, and in turn, treated with ammonia or substituted ammonia derivatives, such as alkyl amine, aniline, amide, cyanamide, sulfonamide or urea.

The above-described cyclization process is illustrated by the following further examples.

EXAMPLE 82 Preparation of 2-methyl-3-isothiazolone and 5-chloro-2-meth.yl-3-isothiazolone To an ethylene dichloride (l litre) slurry of dithio-N,N'-dimethyldipropionamide, 70- g» (θ· 3 mole), there was added at 10-15° C. over 1.5 hour 121.5 g. (0.9 mole) of sulfuryl chloride. After addition, the reaction slurry was allowed to warm to 20-25°C. and stirred overnight to assure completion of the reaction. The slurry was then filtered to give 37 · 1 g« of 2-methyl-3-isothiazolone hydrochloride, which could be converted to the free 3-iso-thiazo-lone by continuous ether extraction from water. The ethylenedichloride filtrate, upon evaporation to approximately one-half volume, yielded an additional quantity 11.5 S- of 5-chloro-2-methyl-3-isothiazolone, m.p. 44-47°C.

EXAMPLE 85 Preparation of 2-(5»4-dichlorophenyl)- 4-methyl-3-isothiazolone Dithio-(3' >4'-iictiloro)-diisobutyranilicle, 12.8 g. (O.0254 mole), was slurried in 250 ml. of ethylene dichloride, and a solution of 9· g« (0.0702 mole) of sulfuryl chloride in 2 ml. of ethylene dichloride was added dropwise at 25-30°C. over one hour. The slurry was stirred overnight to insure completion of the reaction and then filtered to give 8.6 g. of gray 2-(3,4-dichlorophenyl)-4-roethyl-5-isothiazo-lone, m.p. l60-l6l°C. The product was crystallized from ethyl acetate to give a m.p. of l6l-l65°C.

The novel isothiazolones and salts of this invention are biocidally active compounds, and as such, are suitable for the control of living organisms and particularly microorganisms. For this reason, they are especially effective bactericidal, algaecidal, fungicidal and pestici-dal agents. Furthermore, these novel compounds possess the unexpected property of being resistant to inhibition by common additives or contaminants, such as lecithin, normal horse serum, alk lbenzene sulfonates, water-soluble lanolin, sodium chromate, sodium nitrite, glycerol, propylene glycol and the like.

It was also determined that other isothiazolones, -methyl-3 namely, 2 isothiazolone and 2-ethyl-5-isothiazolone are likewise effective for the control of living organizms. properties to the compounds in question. Such characteristics were unknown until the present discovery.

Fungicidal evaluation of the isothiazolones of this invention along with the Leonard and Crow compounds was carried out by the standard slide spore germination test (cf. Phytopathology, 22., ^27 (1943) > utilizing spores of Alternaria solani (Alt.), Sclerotinia fructicola (Scl.) and Stemphylium sarcinaeforme (Stem.) or Botrtis Cinerea (Bot.). The values obtained for the concentration in parts per million (ppm) which effectively controlled 50/? of the spores are given in Table III.

Antibacterial activity was evaluated by the Serial Dilution Test (Broth Titer Test) wherein a series of broths containing varying dilutions of a test compound and an organism are halved starting with Is 1000. The values obtained, which are also shown in Table III, represent the maximum dilution at which the compound under evaluation renders complete control of the organism.

Staphylococcus aureus (S. aureus and Escherichia coli (E. coli) were the bacterial organisms employed in this test.

Example No.

Fungicidal Evaluation Alt. Scl. Stem 1 2 1-10 3 4 <* 6 10-50 10-50 7 10-50 10-50 8 <i <1 9 10-50 10-50 10-50 10-50 11 50-200 50-200 12 10-50 10-50 13 50-200 50-200 .

Alt. Scl. St 14 1000 16 1-10 17 10-50 18 200-1000 3 200-1000 24 50-200 10-50 26 10-50 27 50-200 28 29 Example No. Punericidal Evaluation Alt. Scl. Ste 31 32 1-10 50-200 33 1000 ^> 1000 34 10- 0 10-50 <1 10-50 36 10*50 50-200 37 50-200 38 10-50 50-200 39 40 <i 41 10-50 1-10 42 <1 10-50 43 <1 44 45 46 47 Example No. Fungicidal Evaluation Alt. Scl. St 46 - 52 53 - - 54 ··> 55 56 _ - 57 1-10 10-50 58 - 59 10-50 50-200 60 <i 61 1-10 1-10 62 _ - 63 _ _ 64 Example No. Fungicidal Evaluation Alt. Scl. S 65 - - 66 - V 67 - - 68 - - 69 - - 70 - - 71 - - 72 - - 73 - - 74 - - 78 - - 79 - - -methyl-J-isothiazolone -ethyl-3-isothiazolone <i Selected isothiazolonea were also evaluated as algaecides "by the Fitzgerald Test (Applied Microbiology, 2> 205-211 , No. , I 5 ) and found to be exceptionally effective.

Further fungicidal activity on the part of the isothiazolones was demonstrated by their utilization in seed treatment applications. By seed treatment is meant the disseminating of a biocidally active material over a seed subject to the attack of microorganisms, and partic-ularly fungi, in an amount which is effective to control such microorganisms without deleteriously effecting such seed. In most circumstances, the biocidally active material, in this case, the isothiazolones or compositions thereof will be applied to the surface area of the seeds to be treated. This may be accomplished by varying means common to the art, such as slurrying, soaking, dusting, spraying and the like.

The amount of isothiazolone required so as to be effective in a seed treatment application will vary depend-ing upon conditions, such as the type of seed, the method of application, soil and atmospheric conditions and the like. Generally, an application in the range of about 0.25 to 20 ounces of active ingredient, namely, the isothiazolone per 100 pounds of seed will be effective to control any undesirable microorganisms and so provide protection to the seed. An application of active agent in the range of about 1.0 to 10 ounces per 100 pounds of seed is preferred. each with the iso-thiazolone under evaluation at a level of 1 to 2 ounces per bushel of seed. For purposes of comparison, an untreated control was also included. After drying, the seeds were planted in a muck soil infested with Pythium and having a high moisture content. The corn seeds were maintained in this soil for a week at about 10°C. so as to permit infection. Upon completion of this period of time, the temperature was elevated and maintained at about 21° to 27°C. so as to permit germination of the non-infected seed. The number of seeds germinating were counted after emergence of the plant and such data is set forth in Table IV.

TABLE IV SEED TREATMENT Number of Plants Test Compound Germinating/200 se s Untreated 10 2-_t-butyl-3-isothiazolone 100 2-n-octyl-3-isothiazolone 144 2-t_octyl-3-isothiazolone IQ 2-n-nonyl-3-isothiazolone I64 2-methyl-5-chloro-3-isothiazolone 150 2-methyl-4, 5-dichloro-3-isothiazolone I40 2-n-octyl-5-chloro-3-isothiazolone 150 2_t-octyl-4-chloro-3-isothiazolone 160 2-ti-octyl-4-bromo-3-isothiazolone I48 2- (2 , 4-dichlorobenzyl )-3-isothiazolone 80 2- ( 2-ethylhexyl) -3-isothiazolone 182 Evaluation of the isothiazolones with regard to pesticidal activity demonstrated their exceptional control of numerous nematodes, mites, insects, such as beetles and aphids, and the like. Some typical nematodes, insects and mites which were controlled when contacted with the compounds of this invention included the following: Northern root knot nematode (Meloidogyne hapla) , Mexican bean beetle (Epilachna varivesta) , black carpet beetle (Attagenus piceus), confused flour beetle ( ribolium confusum), granary weevil (Sitophilus granarius ) , two spotted mite (Tetranychus urticae), house fly (Musca domestica) , Southern armyworm (Prodenia eridania) , German cockroach (Blattella germanica), and green peach aphid (ifcrzus persicae) .

Generally, control of a living organism is achieved in accordance with this invention by contacting the organism with an isothiazolone in an amount which is effective to control said organism. Any of the techniques known ir. the art may be employed to dissemi ate the isothiazolones in a manner so as to achieve the desired contact with the organism to be controlled. Spraying and fumigating are typical of such techniques.

The compounds of this invention may be readily utilized as slimicides, algaeoides, bactericides, fungicides or combinations thereof in any loci and particularly in aqueous media, such as for example, water-cooling systems, swimming pools, paper pulp processes, etc. In addition, these compounds and/or compositions thereof may serve functions, such as for example, preservatives, especially r In general, a loci subject to attack by microorganisms may be protected in accordance with this invention by incorporating into said loci an isothiazolone or salt thereof in an amount which is effective to control said microorganisms. The exact amount of isothiazolone required will, of course, vary with the medium being protected, the microorganisms being controlled, the particular isothia-zolones or compositions thereof being employed and the like. Typically, in a liquid media, excellent control is obtained when the isothiazolones are incorporated in the range of 0.1 to 10,000 parts per million (ppm) or 0.00001 to Vfo based on the weight of the medium. A range of 1 to 2000 ppm is preferred.

The term "control", as employed in the specification and claims of this application is to be construed as any means which adversely affects the existence or growth of any living organism or microorganism. Such means may comprise a complete killing action, eradication, arresting in growth, inhibition, reduction in number or any combination thereof.

Outstanding fungistatic activity by the isothiazolones was exhibited when they were employed as paint-preservatives and paint fungistats. Microbial activity in acrylic based paint emulsions is effectively inhibited when these compounds are incorporated at the rate of about 2-20 pounds or more per 100 gallons of paint.

The biocidal compositions provided by the invention may be in the form of concentrates for dilution by compounds provided by the invention and one or more of the following, namely a solid diluent which may or may not be herbicidally inert and which is usually finely divided, a liquid diluent which may or may not be herbicidally inert and which may or may not be a common organic solvent, a surfactant, an adhesive agent, and a pesticide such as another fungicide, an acaricide, molluscicide, or an insecticide. Surfactants of some sort, e.g. eniulsifying or dispersing agents, are practically always present.

Ready-for-use biocidal compositions usually contain an agronomically acceptable carrier. By"agronomically acceptable carrier" is meant any substance which can be utilized to dissolve, dispense or diffuse the chemical incorporated therein without impairing the effectiveness of the toxic agent and which does no permanent damage to such environment as soil, equipment and agronomic crops.

For use as biocides, the compounds of this invention are usually formulated so as to render them suitable for subsequent dissemination. For example, the isothiazolones may be formulated as wettable powders, emulsion concentrates, dusts, granular formulations, aerosols or flowable emulsifiable concentrates. In such formulations, the isothiazolones are extended with a liquid or solid carrier and, when desired, suitable surfactants are likewise incorporated.

Compounds provided by this invention may be dissolved in a water-miscible liquid, such as ethanol, with a finely particled solid carrier, as for example, clays inorganic silicates, carbonates, and silicas. Organic carriers may also be employed. Dust concentrates are commonly made wherein isothiazolones are present in the by weight „. range of 20 to 8O7V For ultimate applications, these concentrates are normally extended with additional solid from about 1 to 20^ bv weight 9 Wettable powder formulations are made by incorporating the compounds of this invention in an inert, finely divided solid carrier along with a surfactant which may be one or more emulsifying, wetting, dispersing or spreading agents or blend of these. The isothiazolones are usually present in the range of 10 to 80o by weight, and the surfactants in from 0.5 to lOfi by weight. Commonly used emulsifying and wetting agents include polyoxyethy-lated derivatives of alkylphenols, fatty alcohols, fatty acids, and alkylamines? alkylarene sulfonates and dialkyl sulfosuccinates. Spreading agents include such materials as glycerol mannitan laurate and a condensate of polyglycer-ol and oleic acid modified with phthalic anhydride.

Dispersing agents include such materials as the sodium salt of the copolymer of maleic anhydride and an olefin such as diisobutylene, sodium lignin sulfonate and sodium formalde- h hydena faialene sulfonates.

One convenient method for preparing a solid formulation is to impregnate the isothiazolone toxicant onto the solid carrier by means of a volatile solvent, such as Emulsifiable concentrate formulations may be prepared by dissolving the isothiazolones provided by this invention in an agronomically acceptable organic solvent and adding a solvent-soluble ennilsifying agent. -Suitable solvents are usually water-immiscible and may be found in the hydrocarbon, chlorinated hydrocarbon, ketone, ester, alchohol and amide classes of organic solvents. Mixtures of solvents are commonly employed. The surfactants useful as emulsifying agents may constitute about 0.5 to 10 by weight of the emulsifiable concentrate and may be anionic, cationic, or non-ionic in character. Anionic surfactants include alcohol sulfates or sulfonates, alkylarene sulfonates and sulfosuccinates. Cationic surfactants include fatty acid „ compounds y / alkylamine salts and fatty acid alkyl quaternaries-/ Non- ionic emulsifying agents include ethylene oxide adducts of alkylphenols, fatty alcohols, mercaptans and fatty acids.

The concentration of the active ingredients may vary from by weight, ,by weight to 80%/ preferably in the range of 25 to 50 /.

For use as phytopathogenic agents, the isothiazolones should be applied in an effective amount sufficient to exert the desired biocidal activity by techniques well known in the art. Usually, this will involve the application of the isothiazolones to the loci to be protected in an effective amount when incorporated in an agronomically acceptable carrier. However, in certain situations it may be desirable and advantageous to apply the compounds directly onto the loci to be protected without the benefit volume" application, that is, when the compounds are in liquid form or substantially soluble in higher boiling solvents.

The application rate will, of course, vary depend-ing upon the purpose for such application, the isothiazol-ones being utilized, the frequency of dissemination and the like.

For use as agricultural bactericides and fungicides, dilute sprays may be applied at concentrations of 0.05 to 20 pounds of the active isothiazolone ingredient per 100 U.S. gallons of spray. They are usually applied at 0.1 to 10 pounds per 100 U.S. gallons and preferably at 0.125 to 5 pounds per 100 U.S. gallons. In more concentrated sprays, the active ingredient is increased by a factor of 2 to 12. With dilute sprays, applications are usually made to the plants until run-off is achieved, whereas with more contrated or low-volume sprays the materials are applied as mists.

The compounds of this invention may be utilized as the sole biocidal agents or they may be employed in conjunction with other fungicides, insecticides, miticides and comparable pesticides.

In field tests, the isothiazolones described above were effective in controlling fungi which cause broccoli downy mildew (Peronospora parasitica), bean powdery mildew (Erysiphe polygon!), wheat powdery mildew (Erysiphe graminis), rice blast (Piricularia oryzae), - 42 29605/2

Claims (31)

1. A compound of the general formula a 0 wherein Y is ^-^β allcyl, ^""^ cycloalkyl, aralkyl of up to 10 carbon a toias, aryl, halogen or (C^-C^)-alkyl-substituted ar l, C-^-C^ hydroxyalk l, ^j^^A haloalkyl, dialkylaminoalkyl in which each alkyl group contains up to 4 carbon atoms or an unsubstituted or substituted carbamoyl or thiocarbamoyl group of the formula - C - NHR11 I! X in which R and are hydrogen, halogen or O^-^ alkyl when I is other than the carbamoyl or thiocarbamoyl group/ provided that both R and may not be hydrogen when Y is methyl or ethyl; R is hydrogen, C^-C^ alkyl, halogen or cyano when o- Cx-C4 alkylthio/alkylsulfinyl or G^C^ alkylsulfonyl when R is cyano; X is oxygen or sulfur; and R 1 is alkyl, C^-C^ alkylsulfonyl , ar lsulfonyl, halogen or (C^-C^J-alk l-substituted arylsulfon l, or carbalkoxyalkyl of the formula 0 \ III " IV wher alkylene group or R s an ary group o e ormu a - 43 - 29605/2 v wherein R is C-^-C^ alkyl, halogen, nitro or c-j.~^4 ^^o and n is 0, 1, 2 or 3· 1

2. A compound according to Claim/wherein Y is ^"^IS alkyl, cycloalkyl, aralkyl of up to 10 carbon atoms, aryl, halogen or (C^-C^J-alkyl-substituted aryl, c-j_-°4 hydroxy-alkyl, C^-C^ haloalkyl or dialkylamino-alkyl in which each alkyl group contains up to 4 carbon atoms .

3. A compound according to Claim 1 wherein Y is the carbamoyl or tbiocarbamoyl group as defined in Claim 1.

4. A compound according to Claim 3 wherein X is oxygen* II

5. Δ compound according to Claim 4 wherein R is C1-C18 alkyl.

6. A compound according to Claim 2 wherein Y is alkyl and the acid salts thereof.

7. A compound according to Claim 1 wherein R is halogen.

8. A compound according to Claim 1 or 2 wherein is halogen. II

9. A compound according to Claim 8 wherein R is chloro .

10. A compound as defined in Claim 1 except that Y may also represent aralkyl of up to 10 carbon atoms substituted with halogen, C^-G^ alkyl or C^-C^ alkoxy or aryl substituted - with nitro, alkylacylamino or carbalkoxy in each of which the alk l group contains up to 4 carbon atoms, or sulfamoyl and I except that R may also represent hydrogen or halogen when R is hydrogen, C^-C^ alkyl or halogen, with the proviso that R and are not hydrogen when Y is methyl or ethyl.

11* 2-( 2, -Dichlorophenyl)-3-isothiazolone.

12. 2-Benzyl-3-isothiazolone.

13. 2-n-Propyl-3-isothiazolone.

14. 2-Cyclohexyl-3-isothiazolone.

15. 5-Chloro-2-methyl-3-iao hiazolone·

16. 2-(Methylcarbamoyl)-3-isothiazolone.

17. 4-Bromo-5-meth 1-2-(ΪΓ-methylcarbamoyl)-3-isothiazolone.

18. 2-(N-n-But lcarbamoyl)-3-isothiazolone .

19. A salt of a compound according to Claim 1 in which Y is other than carbamoyl or thiocarbamoyl.

20. A salt of a compound according to Claim 10 in which Y is other than carbamoyl or thiocarbamoyl.

21. A biocidal compound according to Claim 10 being any of those individual compounds (or salts thereof) disclosed in the foregoing specification with the exception of the compounds claimed in Claims 11-18.

22. A biocidal composition containing (i) at least one compound according to Claim 10 or 2-methyl-3-isothiazolone or 2-ethyl-3-isothiazolone or a salt of any of such compounds and (il) a surfactant, adhesive agent, another pesticide or a solid diluent.

23· A composition according to Claim 23 containing a compound according to any one of Claims 11 - 18.

24. Seeds treated with a compound according to Claim 10 or a salt thereof.

25. Seeds treated with a compound according to any one of Claims 11 - 18.

26. An aqueous film-forming composition such as a paint containing a compound as specified in Claims 22 or 23.

27. A method of controlling a living organism which comprises contacting said organism with a compound as specified in Claim 22 or 23 in an amount which is effective to control said organism.

28. A method for protecting a locus subject to the attack of microorganisms which comprises incorporating into said locus a compound as specified in Claim 22 or 2 in an amount which is effective to control said microorganisms.

29. A method according to Claim 28 wherein said loci - ≠ - 29605/2

30. A method according to Claim 24 wherein the compound is incorporated in the range of 0.1 to 10,000 parts per million.

31. A process for preparing a compound of the formula which comprises reacting a compound of the formula with a compound of the formula RI¾=C=X wherein R, R"'", R^ and X are as defined in Claim 7. For the Applicants DR. REINHOLD v