The present invention is directed to novel substituted thiadiazole compounds, compositions containing said compounds and the use of these compositions as antimicrobial and marine antifouling agents.

EP 0433 616 A2 discloses antimicrobials for the control of bacteria and fungi and teaches the preparation of compounds of the formula :

U.S. Patent 4,094,880 discloses antimicrobials for the control of bacteria and fungi and the preparation and the antimicrobial use of 2,5-bis(chloromethylthιo)-1 ,3,4-thιadiazole and its isomer 3,5-bis(chloromethylthio)-1 ,2,4-thιadiazole of compounds of the formula :

U.S. Patent 3,888,869 discloses the preparation of compounds of the formula :

NCSCH ₂ S S SCH ₂ SCN

which compounds are useful as antimicrobials.

While the above compounds are somewhat active, it is still desirable to identify and/or discover new antimicrobial and/or marine antifoulant agents. Many of the known antimicrobial/maπne antifoulant agents have been found to be of minimal value for several reasons; these include, but are not limited to, the problem created by microbe strains developing resistance to known agents, the occurrence of undesirable interactions of certain known agents with the medium or product in which the agent is used; and the high toxicity of certain known agents to certain non-target organisms, including mammals

The present invention is directed to compounds corresponding to the formula :

N N

wherein R represents -Br, -Cl, -OCH,, -SCN, -OCH SCN, -SCH.SCN, -OCH CH SCN, -SCH CH SCN

Y represents -Br, -Cl, -OCH., -SCN, -OCH.SCN, -SCH.SCN, -OCH CH.SCN or -SCH.CH.SCN; X represents -Br, -Cl, -F, -CH., -OCH ₃ , -COOCH., -NO., -SCH., -SO.CH ₃ or -CF. and n is an integer of from 0-5, with the proviso that at least one of R or Y represents -SCN, OCH.SCN, -SCH.SCN, -OCH CH SCN or -SCH CH SCN and with further proviso that when R is

The present invention is also directed to antimicrobial compositions comprising an inert diluent and an antimicrobially-effective amount of a compound corresponding to Formula 1

The present invention is further directed to a method for inhibiting Q microorganisms in a microbial habitat comprising contacting said microbial habitat with an antimicrobially-effective amount of a compound corresponding to Formula 1

The antimicrobial compositions of the present invention can also be employed to treat surfaces exposed to a marine environment in which marine organisms grow to prevent the growth of said marine organisms on said surfaces 5 The preferred compounds of the present invention include those wherein R represents -Cl, phenyl or -SCN when Y is -SCN; those wherein R represents -Cl, phenyl or -SCH.SCN when Y is -SCH.SCN and those wherein R represents -Cl or -SCH.CH^SCN when Y is

-SCH.CH.SCN

In the present specification and claims, the term "alkali metal" is employed to designate sodium, potassium, lithium or cesium.

In the present specification and claims, the term "halo" is employed to designate bromo, chloro, fluoro or iodo. In the following process schematic formulas, certain specific alkali metals, that is,

Na; halo groups, that is, Cl, and specific solvents are set forth within the depicted reactions. These specific representations are only presented for convenience and are not to be considered as an indication that these specific representations are the only groups or materials which can be employed. The reactions as set forth below and in the specific examples can all be carried out at room temperature in the presence of conventional reaction mediums, such as for example, a 70 percent ethanol/30 percent water mixture.

In the present invention, it is to be noted that all substituent groups are sterically compatible with each other. The term "sterically compatible" is employed to designate substituent groups which are not affected by steric hindrance as this term is defined in "The Condensed Chemical Dictionary", 7th edition, Reinhold Publishing Co., N.Y. page 893 (1966) which definition is as follows:

"steric hindrance. A characteristic of molecular structure in which the molecules have a spatial arrangement of their atoms such that a given reaction with another molecule is prevented or retarded in rate." Sterically compatible may be further defined as reacting compounds having substituents whose physical bulk does not require confinement within volumes insufficient for the exercise of their normal behavior as discussed in Organic Chemistry by D. J. Cram and G. Hammond, 2nd edition, McGraw-Hill Book Company, N Y., page 215 (1964).

The 1 ,2,5-thiadiazole compounds of the present invention, wherein R represents halo and Y represents -SCN or R represents

and Y represents -SCN or -SCH.SCN may be prepared in a two-stage reaction procedure wherein in the first stage or step, a 4-(substituted)-3-halo-1 ,2,5-thiadiazole wherein the substitution set forth hereinafter as R' and which represents Br, -Cl,

is reacted in the presence of a solvent such as dimethylformamide, N-methylpyrroiidone, or

dimethylsulfoxide with an alkali metal sulfide, such as sodium sulfide to produce the corresponding 4-(substituted)-3-mercapto-1, 2, 5-thiadiazole: alkali metal salt.

The reactions are typically carried out at a temperature from 25 to 40°C. The reactants may be added to the reaction mixture in any order of addition; conventionally they are added as a solution in the solvent used for the reaction. The reaction is conveniently allowed to continue over a period from 1 to 24 hours. The reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal sulfide per mole of the 4-(substituted)-3- -halo-1 ,2,5-thiadiazole reactant. To assure the completion of the reaction, an excess of the alkali metal sulfide reactant is normally employed. The general scheme for this first reaction step is as follows:

R 1 — π rt— halo R 1 — r TT— SNa

+ Na _? S '

N N ² _ N N

S S

The above 4-(substituted)-3-(mercapto)-1 ,2,5-thiadiazole: alkali metal salt product is then reacted in situ with a cyanogen halide, such as cyanogen bromide to prepare the desired 4-(substituted)-3-thiocyanato-1,2,5-thiadiazole product or with a halomethylthiocyanate, such as chloromethylthiocyanate to prepare the desired 4-

-(substituted)-3-thiocyanatomethylthio-1,2,5-thiadiazole product. The reaction consumes the reactants in the ratio of one mole equivalent of the cyanogen halide or halomethylthiocyanate per mole of the 4-(substituted)-3-mercapto-1 ,2,5-thiadiazole: alkali metal salt reactant. To assure the completion of the reaction, a slight excess of the cyanogen halide or halomethylthiocyanate reactant is normally employed. The general reaction schemes (A and

B) for this second step is as follows: Reac t ion Scheme A

R ¹ ~ _T. rr SKmx _R ι — r- -1-scN

N N + NCBr N N ** ^•

S

Reaction Scheme B

The above second stage reactions are typically carried out at a temperature from 25 to 40°C The reactants may be added to the reaction mixture in any order of addition, conventionally they are added as a solution in the solvent used for the reaction Subsequent to the addition of the reactants, the reaction is allowed to continue over a period of 1 to 24 hours The reaction product may be isolated by adding a 3 to 10 volume excess of water which will precipitate the desired product Filtration followed by washing and drying yields the desired compounds of the present invention

The bιs(thιocyanato)-1,2,5-thιadιazole compound of the present invention, wherein R and Y both represent -SCN, may be prepared by first reacting in the presence of a solvent an alkali metal sulfide, such as sodium sulfide, with a 4,5-dιhalo-1,2,5-thιadιazole, such as 3,4-dιchloro-1 ,2,5-thιadιazole, to produce a bιs(mercapto)-1 ,2,5-thιadιazole ^* dι(alkalι metal) salt, such as the bis(mercapto)-1 ,2,5-thιadιazole: disodium salt The general scheme for this first reaction step is as follows

Cl — π TT- Cl NaS — r rr— SNa | l

^N ^ ^N + 2 eq Na2S N

S S

The desired bιs(thιocyanato)-1 ,2,5-thιadιazole is then prepared by reacting the thus prepared bιs(mercapto)-1,2,5-thιadιazole dι(alkalι metal) salt with a cyanogen halide, such as cyanogen bromide Two mole equivalents of the cyanogen halide are used per mole of the bιs(mercapto)-1 ,2,5-thιadιazole, dι(alkalι metal) salt to prepare the bιs(thιocyanato)-1 ,2,5-thιadιazole

The general scheme for this second reaction step is as follows

NaS — r ^■ SNa NCS- TT— SCN

_N N + 2 eq BrCN N N s s

The halothιomethyl(or ethyl)thιocyanato-1 ,2,5-thιadιazole compounds of the present invention, wherein, for example, R represents -Cl or -Br and Y represents -SCH ₂ SCN or -SCH.CH.SCN, may be prepared by first preparing a (halomercapto)-1 ,2,5-thιadιazole, alkali metal salt, as described heremabove The halothιomethylthιocyanato-1 ,2,5-thιadιazole is then prepared by reacting the (halomercapto)-l , 2, 5-thιadιazole, alkali metal salt with a halomethyKor ethyl)thιocyanate, such as chloromethylthiocyanate or chloroethylthiocyanate One mole equivalent of the halomethyKor ethyl)thιocyanate is used per mole of

(halomercapto)-1 ,2,5-thiadiazole: alkali metal salt to prepare the halothiomethyKor ethyl)thiocyanato-1 ,2,5-thiadiazole.

The general reaction scheme is as follows:

Cl — r ιT- ^SNa Cl — r rt— S ( CH ₂ ) _n SCN

N N + _N CS ( CH ₂ ) _n Cl ^{N N} S ► S

wherein n is 1 or 2. The bιs(thiomethyl(or thioethyl)thiocyanato-1 , 2, 5-thιadiazole compounds of the present invention, wherein, for example, R and Y each represent -SCH ₂ SCN or -SCH .CH.SCN, may be prepared by reacting a halomethyKor ethyl)thiocyanate, such as chloromethylthiocyanate or chloroethylthiocyanate with a bis(mercapto)-1 ,2,5-thιadιazole: alkali metal salt (prepared as described hereinabove) Two mole equivalents of the halomethyKor ethyl)thiocyanate is used per mole of the bis(mercapto)-1 ,2,5-thιadιazole ^* alkali metal salt to prepare the desired bis(thιomethyl(or thιoethyl)-thιocyanato-1 ,2,5-thιadιazole The general reaction scheme is as follows:

NaS — r jT~ ^SNa NCS ( CH ₂ ) _n S— PJ TT— S ( CH ₂ ) _n SCN

N N + 2 NCS ( CH ₂ ) _n Cl _N s ^v s wherein n is 1 or 2

Preferably, the hereinabove depicted reactions are carried out in the presence of an inert solvent such as dimethyiformamide, methanol, ethanol, acetonitπle, acetone, or pyridine Preferably, the reactions are carried out at 0°C under an ambient pressure of inert gas. Subsequent to the addition of the appropriate reaction materials, the reaction mixture is allowed to stir at a temperature between 25°C to 60 ^C C for a period between 2 to 24 hours in order to increase the reaction rate and promote extinction of the limiting reagent Final work-up of the reaction mixture then provides the desired final product.

The thiadiazole compounds of the present invention , wherein R represents -SCN and Y represents -SCH.SCN or -SCH ₂ CH.SCN, may be prepared by first reacting a 4-halo-3- -thιomethyl(or ethyl)thiocyanato-1 ,2,5-thιadιazole, as prepared hereinbefore, an alkali metal sulfide, such as sodium sulfide, followed by reacting the thus formed 4-mercapto-3- -thιomethyl(or ethyl)thiocyanato-1 ,2,5-thιadιazole: alkali metal salt with a cyanogen halide, such as cyanogen bromide to form the desired 3-thιocyanato-4-thιomethyl(or

ethyl)thiocyanato-1 ,2,5-thiadiazole. In the above reactions, equi molar amounts of the reactants are normally employed. The general scheme for this reaction step is as follows:

Cl— π ττ-S ( CH2 ) nSCN NCS— IT ττ- S ( CH2 ) nSCN

N ^ U + ! . _Na2S ^ ^ N

S 2. CNBr S

The thiadiazole compounds of the present invention , wherein R represents -SCH.SCN and Y represents -SCH.CH.SCN, may be prepared by first reacting a 3-halo-4- 10 -mercapto-1,2,5-thiadiazole: alkali metal salt, as prepared hereinbefore, with a dihaloethane such as 1-bromo-2-chloroethane to produce a 4-halo-3-halothioethyl-1,2,5-thiadiazole such as 4-chloro-3-chlorothioethyl-1,2,5-thiadiazole. The general scheme for this reaction step is as follows:

ci — η i ^{" SN} ci — T iT ^" SCH2CH2C1

1.

^N , ^N + BrCH2CH2Cl N N

S _» S

The thus formed 4-halo-3-halothioethyl-1 ,2,5-thiadiazole is then reacted with an 20 alkali metal sulfide, such as sodium sulfide, to produce the corresponding alkali metal salt, such as 4-mercapto-3-halothioethyl-1 ,2,5-thiadiazole: sodium salt. The general scheme for this reaction step is as follows:

Cl — π π— SCH2CH2CI NaS — r rr- SCH2CH2CI

²⁵ N ^ ^ N + Na ₂ S ^N _s ^N

S a* S

This product can, without separation and purification, be reacted with a halomethylthiocyanate, such as chloromethylthiocyanate to form a 3-halothioethyl-4- 0 -thiomethylthiocyanato-1 ,2,5-thiadiazole, such as 3-chlorothioethyl-4-thiomethyl- thiocyanato- 1 ,2,5-thiadiazole. One mole equi alent of the halomethylthiocyanate reactant is used per mole of the 4-mercapto-3-halothιoethyl-1 ,2,5-thiadiazole: alkali metal salt and such equimolar amounts of the reactants are normally employed. The general scheme for this reaction step is as follows:

35

N N

+ CICH2SCN

NCSH2CS- SCH2CH2CI

_^ N

10 s

The above 3-halothioethyl-4-thiomethylthiocyanato-1 ,2,5-thiadiazole product is dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours. The reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such

15 as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired 3-thioethylthiocyanato-4-thiomethylthiocyanatomethyl-1 ,2,5-thiadiazole. The reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25

20 equivalents, of alkali metal thiocyanate is usually provided. The general scheme for this reaction step is as follows:

NCSH2CS- ^• SCH2CH2CI

25 N N

+ KSCN

NCSH2CS- SCH2CH2SCN

30 N N

The halothiocyanatomethyloxo-1,2,5-thιadiazole compounds of the present invention, wherein, for example, R represents -Cl or -Br and Y represents -OCH^SCN, may be ■ _3c prepared by first irradiating a solution of 4-halo-3-methoxy-1 ,2,5-thιadιazole such as 4-

-chloro-3-methoxy-1 ,2,5-thιadιazole in carbon tetrachloπde with a sunlamp while adding a solution of sulfuryl chloride in carbon tetrachloπde. Upon completion of the reaction, the reaction mixture is washed with aqueous sodium bicarbonate and concentrated under reduced

pressure to yield 4-chloro-3-halomethoxy-1 ,2,5-thiadiazole. The general scheme for this first reaction step is as follows:

Cl— r ^, TΓ ^0CH 3 Cl— Π -Γ- OCH- CI

^N s ^N + S0 ₂ C1 ₂ N N

^S ^ ^► S

The above 4-chloro-3-halomethoxy-1 ,2,5-thiadiazole product is dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate _Q and refluxed for a period of about 16 hours. The reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired halothiocyanatomethyloxo-1 ,2,5-thiadiazole. The reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant _ and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided.

The general scheme for this second reaction step is as follows:

Cl fι ττ- 0 ( CH ₂ ⁾ _n Cl _{C 1} — -. τ-0 ( CH ₂ ) _n SCN

N N + KSCN _{N N} S

The bis(thiomethyloxothiocyanato)-1 ,2,5-thiadiazole compounds of the present 5 invention, wherein R and Y both represent -0(CH.) _n SCN and n is 1 or 2, may be prepared by first irradiating a solution of a bis(methoxy)-1 ,2,5-thiadiazole in carbon tetrachloride with a sunlamp while adding a solution of sulfuryl chloride in carbon tetrachloride. The reaction mixture is washed with aqueous sodium bicarbonate and concentrated under reduced pressure to yield bis(chloromethoxy)-1 ,2,5-thiadiazole. The general scheme for this first 0 reaction step is as follows:

5

^CH 3° ^~ n ΓΓ ^OCH 3 + 2 S0 ₂ C1 ₂

N N hv

_^ N

S

The above bis(chloromethoxy)-1,2,5-thiadiazole is dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours. The reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired bis(thiomethyloxothiocyanato)-1 ,2,5-thiadiazole compound. The reaction consumes the reactants in the ratio of two mole equivalents of the alkali metal thiocyanate per mole of the thiadiazole reactant and such amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.2-1.25 equivalents, of alkali metal thiocyanate is usually provided.

The general reaction scheme for this reaction is as follows:

Cl ( CH ₂ ) _n 0 — η ΓT— 0 ( CH ₂ ) _n Cl

| l | + 2 eq KSCI^

N N , s

NCS ( CH ₂ ) _n 0 — T TT— 0 ( CH ₂ ) _n SCN

N N

"s ✓

S

The 4-methoxy-3-thiocyanatomethyloxo- 1 ,2,5-thιadiazole compound of the present invention, that is, wherein R represents -OCH ₃ and Y represents -OCH, SCN may be prepared by first irradiating a solution of a bιs(methoxy)-1 ,2,5-thιadιazole in carbon tetrachloride with a sunlamp while adding a solution of sulfuryl chloride in carbon tetrachloride. Upon completion of the reaction, the reaction mixture is washed with aqueous sodium bicarbonate and concentrated unαer reduced pressure to yield 4-methoxy-3- -halomethoxy-1 ,2,5-thiadiazole. This product is then dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period

of about 16 hours. The reaction mixture is filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired 4-methoχy-3- -thiocyanatomethyloxo-1 ,2,5-thiadiazole. The reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided. The general scheme for these reaction steps are as follows:

^H 3 ^C0

H CO -Ti jT-0CH ₂ SCN

N N S

The 4-methoxy-3-thiocyanatoethyloxo- 1, 2, 5-thiadiazole compound of the present invention, that is, wherein R represents -OCH ₃ and Y represents -OCH.CH.SCN may be prepared by treating 4-chloro-3-methoxy-1 , 2, 5-thiadiazole, prepared as set forth hereinbefore, with an alkali metal hydroxide, such as sodium hydroxide, to prepare the corresponding 4-hydroxy-3-methoxy-1 ,2,5-thiadiazole which isthen reacted with a haloethylthiocyanate, such as chloroethylthiocyanate to give the desired 4-methoxy-

-3-thiocyanatoethyloxo-1,2,5-thiadiazole product. The general reaction scheme is as follows:

H CO ^{* ■} Cl H ₃ CO ^{* •} OH

N N NaOH N N

H ₃ CO ' 0CH ₂ CH ₂ SCN

N N

The 3-thiocyanatoethyloxo-4-thiocyanato-methyloxo-1 ,2,5-thiadiazole compound of the present invention, that is, wherein R represents -OCH.SCN and Y represents -OCH.CH.SCN may be prepared by treating a 4-haio-3-thiocyanatomethyloxo- 1 ,2,5- -thiadiazole, such as 4-chloro-3-thiocyanatomethyloxo-1,2,5-thiadiazole, prepared as set forth hereinbefore, with an alkali metal hydroxide, such as sodium hydroxide, to prepare the corresponding 4-hydroxy-3-thiocyanatomethyloxo-1 , 2, 5-thiadiazole which is then reacted with a haloethylthiocyanate, such as chloroethylthiocyanate to give the desired 3- -thiocyanatoethyloxo-4-thiocyanatomethyloxo-1 , 2, 5-thiadiazole product. The general reaction scheme is as follows:

NCSH ₂ C0 ^■ OCH CH SCN

N N

N. S

S

The 3-methoxy-4-thiocyanato-1 ,2,5-thiadiazole compound of the present invention, wherein, R represents -OCH. and Y represents -SCN, may be prepared by reacting a 4-halo-3-methoxy-1,2,5-thiadiazole such as 4-chloro-3-methoxy-1 ,2,5-thiadiazole, prepared as set forth hereinbefore, with an alkali metal sulfide, such as sodium sulfide followed by 5 reacting the thus formed 3-methoxy-4-mercapto-1, 2, 5-thiadiazole; alkali metal salt with a cyanogen halide, such as cyanogen bromide to form the desired 3-methoxy-4-thiocyanato- -1 ,2,5-thiadiazole. The general scheme for this reaction is as follows:

H3CO — T jT-Cl H3CO -Tj rj-SCN

10 v _N N N •

" Ns s + 1 . Na ₂ S *

^S 2. CNBr

The 3-methoxy-4-thiomethyl(or ethyl)-thiocyanato- 1 , 2, 5-thiadiazole compounds of the present invention, wherein, for example, R represents -OCH ₃ represents -SCH.SCN or

^ -SCH.CH.SCN, may be prepared by reacting at room temperature in dimethylformamide a 3- -methoxy-4-mercapto-1 ,2,5-thiadiazole; alkali metal salt, such as 3-methoxy-4-mercapto- -1 ,2,5-thiadiazole; sodium salt, prepared as set forth hereinbefore, with a halomethyKor ethyl)thiocyanate, such as chloromethylthiocyanate or chloroethylthiocyanate. One mole equivalent of the halomethyKor ethyl)thiocyanate is used per mole of the 3-methoxy-4- ^u -mercapto)-1 ,2,5-thiadiazo!e: alkali metal salt to prepare the 3-methoxy-4-thiomethyl(or ethyl)thiocyanato-1,2,5-thiadiazole.

The general reaction scheme is as follows:

H3CO — Tj \ r ^Slia - H3CO — Tj τ-S ( CH ₂ ⁾ _n SCN

N ^ ^ + NCS ( CH ₂ ) _n Cl N N s ^► S ' wherein n is 1 or 2.

The 3-thiocyanatomethyloxo-4-thiocyanato-1,2,5-thiadiazole compound of the

30 present invention, wherein, for example, R represents -OCH.SCN and Y represents -SCN, may be prepared by reacting a 4-chloro-3-halomethoxy-1 ,2,5-thiadiazole such as 4-chloro-3- -chloromethoxy- 1 ,2,5-thiadiazole, prepared as set forth hereinbefore, with 2 equivalents of an alkali metal sulfide, such as sodium sulfide followed by reacting the thus formed 4- -mercaptomethoxy-3-mercapto-1 ,2,5-thiadiazole, dialkali metal salt with 2 equivalents of a

35 cyanogen halide, such as cyanogen bromide to form the desired 3-thiocyanatomethyloxo-4- -thiocyanato-1 ,2,5-thiadιazole. The general scheme for this reaction is as follows:

ⁱ — r. 0CH ₂ C1 NCS" ^• 0CH ₂ SCN

( intermediate structure is not shown)

The 3-thiocyanato-4-thiocyanatoethyloxo-1 , 2, 5-thiadiazole compound of the present invention, wherein, for example, R represents -OCH.CH.SCN and Y represents -SCN, may be prepared by first reacting a 3,4-dihalo-1 ,2,5-thiadιazole, such as 3,4-dichloro- -1 ,2,5-thiadιazole with an alkali metal hydroxide, such as sodium hydroxide and the resulting 3-chloro-4-hydroxy-1 ,2,5-thiadiazole: sodium salt is then reacted at room temperature in dimethylformamide with chloroethyltosylate(Tso-CH.CH.CI). The thus formed 3-chloro-4- -chloroethyloxy-1 ,2,5-thiadiazole is then reacted with an alkali metal sulfide, such as sodium sulfide followed by reacting the thus formed 3-mercapto-4-chloroethyloxy-1 ,2,5-thιadιazole ^* alkali metal salt with 2 equivalents of a cyanogen halide, such as cyanogen bromide to form the desired 3-thιocyanato-4-thiocyanatoethyloxo-1 ,2,5-thιadiazole The general scheme for this reaction is as follows:

i— r, ^* 0Na cr ^* 0CH ₂ CH ₂ C1

N N TSO-CH2CH2CI N N ^s s " ^ s '

— π τp0CH ₂ CH ₂ Cl NCS — π TT— 0CH ₂ CH ₂ SCN

N N + ! . _N a ₂ S N

S 2 . 2 eσ CNBr , - S

(intermediate structure is not shown)

The 3-thiomethyl(or ethyl)cyanato-4-thiocyanatomethyloxo-1 ,2,5-thiadiazole compound of the present invention, wherein, for example, R represents -OCH.SCN and Y represents -S(CH.) _n SCN wherein n is as defined hereinbefore, may be prepared by irradiating a solution of 3-methoxy-4-thiomethyl(or ethyl)thiocyanato1 ,2,5-thiadiazole, prepared as

5 described hereinbefore, in a solvent such as carbon tetrachloride with a sunlamp while adding a solution of a sulfuryl halide such as sulfuryl chloride in a solvent such as carbon tetrachloride The thus formed 3-halomethoxy-4-thiomethyl(or ethyl)thiocyanato-1 ,2,5-thiadiazole product is dissolved in a solvent such as acetone containing an alkali metal thiocyanate such as potassium thiocyanate and refluxed for a period of about 16 hours. The reaction mixture is

10 filtered, and concentrated under reduced pressure and the residue treated by conventional procedures such as, chromatography over silica gel using hexane/ethyl acetate as eluent, to recover the desired above-indicated compound. The reaction consumes the reactants in the ratio of one mole equivalent of the alkali metal thiocyanate per mole of the thiadiazole reactant and such equimolar amounts of the reactants are normally employed. However to

15 ensure completion of the reaction, a slight excess, about 1.0-1.25 equivalents, of alkali metal thiocyanate is usually provided. The general scheme for this reaction is as follows:

H CO- T~ S ( CH ₂ ) _n SCN C1H ₂ C -IT rτ-S ( CH ₂ ) _n SCN

N N so ₂ cι ₂ N N

^~ hv

NCSH ₂ C0 -TJ j-i— S ( CH ₂ ) _n SCN

N N

S

0

5

The 3-thiomethylcyanato-4-thiocyanatoethyloxo-1 ,2,5-thiadiazole compound of the present invention, wherein, for example, R represents -OCH.CH.SCN and Y represents -SCH.SCN, may be prepared by first reacting a 4-halo-3-thiomethylcyanato-1 ,2,5-thiadiazole, such as 4-chloro-3-thiomethylcyanato-1 ,2,5-thiadiazole, prepared as described hereinbefore, with an alkali metal hydroxide, such as sodium hydroxide and the thus formed 4-hydroxy-3- -thiomethylcyanato-1 ,2,5-thiadiazole: sodium salt is then reacted at room temperature in dimethylformamide with a haloethylthiocyanate, such as chloroethylthiocyanate to prepare the desired 3-thiomethylcyanato-4-thiocyanatoethyloxo-1,2,5-thiadiazole. The general scheme for this reaction is as follows:

— Tj τr- S ( CH ₂ ) _n SCN _Na0 — r- -p S ( CH ₂ ) _n SCN

N ^ Ns S N + NaOH ► N N, ^ N s s

NCSH ₂ CH ₂ C0—r rr- S(CH ₂ ) _n SCN

N Ns S N

S wherein n is as hereinbefore defined.

Chloromethylthiocyanate is well known and is described in JP-B-62215561 and JP-B-62215562.

3,4- and 4,5-Dichloro- 1 ,2,5-thiadiazoles are described in U S. Patent 3, 1 15,497

The synthesis of cyanogen bromide is described in Organic Synthesis Collective, Vol. 2, page 150.

The 4-substituted-3-halo-1 ,2,5-thiadiazole reactant corresponding to the formula

N N

S

wherein R is as hereinabove defined are known compounds. The compounds are well known in the literature. The compounds wherein R is phenyl or substituted phenyl are either specifically taught or they can be prepared as described by L. M. Weinstock et al. in the Journal

of Organic Chemistry, Vol. 32, pages 2823-29, (1967); or in U.S. Patent 4,555,521. Other references include Japanese Patents JPO 5,163,257 A2; 5,163,258 A2; and 5,163,259 A2.

The following examples illustrate the present invention and the manner by which it can be practiced but, as such, should not be construed as limitations upon the overall scope of the same.

Since the hereinabove and hereinafter set forth compound preparation procedures employ only standard chemistry practices and it is known that slightly different reactants can require slightly different reaction parameters from those for other reactants, it is to be understood that minor modifications to the reaction parameters set forth such as the use of an excess of one reactant, the use of a catalyst, the use of high temperature and/or high pressure equipment, high speed mixing and other such conventional changes are within the scope of the present invention.

The desired product can be separated from the reaction product of the above preparative procedures employing conventional separatory procedures known to those skilled in the art including steps of solvent extraction, filtration, water washing, column chromatography, neutralization, acidification, crystallization and distillation

The structure identity of all compounds is confirmed by proton nuclear magnetic resonance spectroscopy ('H NMR), recorded at 300 MHz; carbon nuclear magnetic resonance spectroscopy ( ¹³ C NMR) recorded at 75 MHz; infrared spectroscopy (IR) and gas chromatography/mass spectrometry (GC/MS) All of the present reactions were conducted at room temperature unless otherwise stated and under a positive pressure of nitrogen

Example 1 Preparation of 4-Chloro-3-thιocyanato- 1 ,2,5-thιadιazole

N N s S s

A solution of sodium sulfide (3 43 grams (g), 0 044 mole) in 70 percent ethanol/30 percent water (75 mL) was treated at room temperature with 4,5- -dιchloro-1 ,2,5-thιadιazole (6 20 g, 0 04 mole) After stirring for 1 hour, the solution was concentrated to dryness and extracted with ethanol (2 extractions of 30 mL each) Removal of

10 ethanol under reduced pressure gave the sodium salt of the 4-chloro-3- -mercapto-1 ,2,5-thιadιazole The sodium salt was dispersed in dimethylformamide (15 mL) treated with cyanogen bromide (6 36 g, 0 06 mole) and stirred overnight The reaction mixture was diluted with water and extracted with methylene chloride The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated The residue was

15 chromatographed over silica gel with hexane and ethyl acetate as eluent to yield the 4-chloro- -3-thιocyanato-1,2,5-thιadιazole as a yellow solid melting at 63-65°C in a yield of 2 5 g, (35 percent of theoretical) Example 2 Preparation of Bιs(thιocyanato)-1 ,2,5-thιadιazole

N N

X s s

A solution of sodium sulfide (3 12 g, 0 04 mole) in 70 percent ethanol/30 percent , water (75 mL) was treated with 4,5-dιchloro-1 , 2, 5-thιadιazole (3 l O g, 0 02 mole) After stirring for 1 hour the solution was concentrated to dryness and extracted with ethanol (2 extractions of 30 mL each) Removal of ethanol under reduced pressure gave the disodium salt of the bιs(mercapto)-1,2,5-thιadιazole The disodium salt was dispersed in dimethylformamide (15 mL) and treated with cyanogen bromide (4 32 g, 0 04 mole) and stirred overnight The 3 _Q reaction mixture was diluted with water and extracted with methylene chloride The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated The residue was chromatographed over silica gel with methylene chloride as eluent to yield the bιs(thιocyanato)-1 ,2,5-thιadιazole as an oil (1 4 g, 35 percent of theoretical)

35

Example 3: Preparation of 4-chloro-3-thiomethylthiocyanato-1 ,2,5-thiadiazole

A solution of sodium sulfide (3.43 g, 0.044 mole) in 70 percent ethanol/30 percent water (75 mL) was treated with 4,5-dichloro-1 ,2,5-thiadiazole (6.20 g, 0.04 mole). After stirring

10 for 1 hour the solution was treated with chloromethylthiocyanate (6.48 g, 0.06 mole) and stirred overnight. The reaction mixture was concentrated and extracted with methylene chloride. The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated The residue was chromatographed over silica gel with hexane and ethyl acetate as eluent to yield the 4-chloro-3-thιomethylthiocyanato-1 ,2,5-thiadiazole as an oil (3.12 g,

15 35 percent of theoretical).

Example 4: Preparation of Bιs(thiomethylthiocyanato)-1 ,2,5-thιadiazole

NCSH ₂ CS — r j-r— SCH ₂ SCN

N N

20 _S "

A solution of sodium sulfide (3.12 g, 0.04 mole) in 70 percent ethanol/30 percent water (75 mL) was treated wιth 4,5-dichloro-1 ,2,5-thιadiazole (3.10 g, 0.02 mole) After stirring for 1 hour the solution was concentrated to dryness and extracted with ethanol (2 extractions

-_. of 30 mL each). Removal of ethanol under reduced pressure gave the disodium salt of the bis(mercapto)-1,2,5-thιadiazole. The disodium salt was dispersed in dimethylformamide (15 mL) and treated with chloromethylthiocyanate (4.32 g, 0.04 mole) and stirred overnight The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated. The

, _n residue was chromatographed over silica gel with methylene chloride as eluent to yield the bis(thιomethylthiocyanato)-1,2,5-thιadιazole as an oil (1.86 g, 32 percent of theoretical) Example 5: Preparation of Bis(thioethylthιocyanato)-1 ,2,5-thιadiazole

NCS ( H ₂ C ) ₂ S — r ^■ S ( CH ₂ ) ₂ SCN

35 N

X s s

A solution of sodium sulfide (4 42 g, 0 057 mole) in 70 percent ethanol/30 percent water 125 mL) was treated with 4,5-dιchloro- 1 ,2,5-thιadιazole (4 g, 0.026 mole) After stirring for 2 hours the solution was concentrated to dryness and extracted with ethanol (2 extractions of 25 mL each) Removal of ethanol under reduced pressure gave the disodium salt of the bιs(mercapto)-1,2,5-thιadιazole The disodium salt was dispersed in dimethylformamide (30 mL) and treated with chloroethylthiocyanate (6 4 g, 0 0525 mole) and stirred overnight The reaction mixture was diluted with water and extracted with methylene chloride The organic layer was washed with water (3 washings of 40 mL each), dried and concentrated The residue was chromatographed over silica gel with hexane and ethyl acetate as eluent to yield 3 5 g, (42 percent of theoretical) of 3,4-bιs(thιoethylthιocyanato)-1 ,2,5-thιadιazole as a yellow solid melting at 72-74°C Example 6: Preparation of 4-Chloro-3-thιocyanatomethyloxo-1, 2, 5-thιadιazole

C i — ι ₁ — OCHpSCN

N N

X s s

A solution comprised of 5 g of 60 percent pure 4-chloro-3-methoxy- -1 ,2,5-thιadιazole in 30 mL of carbon tetrachloride was irradiated over a period of 45 minutes at 80°C with a sunlamp while adding a solution comprised of 5 g of sulfuryl chloride in 20 mL of carbon tetrachloride The reaction mixture was then washed with 30 mL of a saturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to yield 4 87 g of 4-chloro-3-chloromethoxy-1 ,2,5-thιadιazole

The -chloro-3-chloromethoxy-1 ,2,5-thιadιazole (4 87 g) was dissolved in 100 mL of acetone containing a 1 2 equivalent excess of potassium thiocvanate and refluxed overnight (aDOut 16 hours) The reaction mixture was filtered, and concentrated under reduced pressure and the residue chromatographed over silica gel with hexane/ethyl acetate as eluent The desired 4-chloro-3-thιocyanatomethyloxo- 1 ,2,5-thιadιazole was recovered as an oil in a yield of 37 percent of theoretical H NMR (CDCI.) 8 5 85 (s, 2H), ^' -C NMR (CDCI.) δ 72 76, 109 78, 133 51 , 156 67, MS (El) m/e 273, 236, 209, 179, 149, 130

Example 7 Preparation of 4-Methoxy-3-thiocyanatomethyloxo-1 ,2,5-thιadιazole

N N X S

S

This compound was prepared following the preparative procedures of Example 6 employing 3,4-dimethoxy-1,2,5-thιadιazole as a starting material. The product was recovered as an oil in a yield of 29 percent of theoretical. 'H NMR (CDCI.) δ 4.16 (s, 3H), 5.85 (s, 2H); ^,3 C NMR (CDCI.) δ 57.94, 72.56, 1 10.57, 148.43, 152.33; MS (El) m/e 203(M + ), 1 5, 130, 90, 72 Example 8: Preparation of 3,4-Bis(thιocyanatomethyloxo)-1 ,2,5-thiadiazole

NCSHpCO — Tl -r— 0CH ₂ SCN

N N

0

This compound was prepared following the preparative procedures of Example 6 employing 3,4-dιmethoxy-1 ,2,5-thιadιazole as a starting material The product was recovered in a yield of 16 percent of theoretical as a light yellow solid melting at 74-75°C. 'H NMR (CDCI.) δ 5.85 (s, 2H); ^,3 C NMR (CDCI.) δ 72.38, 110 03, 148 42; MS (El) m/e 203(M + ), 260, 202, 130, 102, 5 100, 72.

Example 9: Preparation of 4-Phenyl-3-thiocyanato- 1 ,2, 5-thiadiazole

N N 0 ^N _S

To a stirred solution of (3 81 g, 0.05 mole) of sodium sulfide in l OO mL of dimethyl formamide was added 8 g, 0 041 mole) of 4-Phenyl-3-chloro-1 ,2,5-thιadιazole The mixture was stirred overnight (~ 16 hours), and to the resulting dark green solution was added 6 64 g(1 5 molar equivalents) of cyanogen bromide This mixture was stirred for about 14 hours and then diluted with 100 mL of water and extracted with 200 mL of methylene chloride The organic layer was separated and washed with water (2x1 OOmL), dried and concentrated under reduced pressure. The thus recovered crude material was chromatographed on silica gel with a 10 percent EtoAc:90 percent hexane mixture to yield 6 6 g (72 percent of theoretical) as Q an oil which turned to a white solid melting at 49°C upon standing; ¹³ C NMR (75 MHz, CDCI.) δ 159.10, 141.78, 130 59, 129.76, 129 06, 127 88, 105.98; MS (El) m/e 219(M + ), 192, 160, 135, 103 By employing the above preparative procedure of Example 9 employing the appropriate starting materials, the following compounds were prepared

5

Example 10: Preparation of 4-(4-Chlorophenyl)-3-thiocyanato-1,2,5-thiadiazole

N N

This compound was isolated as a white solid which melted at 87-88°C. in a yield of 65 percent of theoretical; ¹ H NMR (300 MHz, CDCI.) δ 7.67 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H); ^,3 C NMR (75 MHz, CDCI.)δ 158.21, 141.66, 137.04, 129.45, 129.31, 128.29, 105.73; MS (El) m/e 255, 253, 194,171,169, 139,137,116,102. Example 11: Preparation of 4-(3-Chlorophenyl)-3-thiocyanato-1,2,5-thiadiazole

This compound was isolated as a white solid which melted at 82-83°C. in a yield of 53 percent of theoretical; 'H NMR (300 MHz, CDCI.) δ 7.72 (s, 1 H), 7.08 (d, J = 6.9 Hz, 1 H), 7.54 (m, 1H),7.48(m, 1H); ^,3 C NM (75 MHz, CDCI.)δ 157.76, 141.83, 135.22,131.40, 130.73,130.34, 128.24, 125.87, 105.59; MS (El) m/e 255, 253, 228, 226, 218, 196,194, 171,169, 139, 137,102. Example 12: Preparation of 4-(2-Chlorophenyl)-3-thιocyanato-1, 2, 5-thiadiazole

This compound was isolated as an oil in a yield of 55 percent of theoretical; ³ C NMR (75 MHz, CDCI.)δ 158.12, 143.88, 131.92, 131.22, 131.12, 130.03, 129.90, 127.75, 106.33; MS (El) m/e 255, 253, 218, 171, 169, 139, 137, 116, 102. Example 13: Preparation of 4-(4-Fluorophenyl)-3-thiocyanato-1,2,5-thiadiazole

N N

X s

This compound was isolated as a white solid which melted at 67-68°C. in a yield of 60 percent of theoretical; 'H NMR (300 MHz, CDCI.) δ 7.70-7.74 (dd, J = 8.3, 5.2 Hz, 2H), 7.24 (t, J = 8.5 Hz, 2H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 165.46, 162.12, 158.31, 142.00, 130.21 , 130.10, 126.05, 1 16.54, 1 16.25, 105.80; MS (El) m/e 237(M + ), 210, 178, 153, 121 , 1 16. Example 14: Preparation of 4-(4-Bromophenyl)-3-thiocyanato-1 ,2,5-thiadiazole

N ^ N

X s

S

This compound was isolated as a yellow solid which melted at 105°C. in a yield of 70 percent of theoretical; 'H NMR (300 MHz, CDCI .) δ 7.68 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H); ¹³ C NMR (75 MHz, CDCI.) δ 158.20, 141.60, 132.35, 129.43, 128.69, 125.36, 105.69; MS (EI) m/e 299, 297, 272, 270, 218, 215, 213, 183, 181 , 160, 1 16. Example 15: Preparation of 4-(3-Methoxyphenyl)-3-thiocyanato-1 ,2,5-thiadiazole

This compound was isolated as a yellow solid which melted at 64-65°C. in a yield of 50 percent of theoretical; 'H NMR (300 MHz, CDCI.) δ 7.45 (d, J = 8.3 Hz, 2H), 7.22 (s, 1 H), 7.07 (dd, J = 8.3, 2.2 Hz, 1 H), 3.88 (s, 3H); ¹ C NMR (75 MHz, CDCI.) δ 159.83, 158.85, 141.98, 130.18, 1 19.90, 1 16.53, 1 13.42, 105.96, 55.47; MS (El) m/e 249(M + ), 222, 190, 175, 159, 147. Example 16: Preparation of 4-(4-Methoxyphenyl)-3-thiocyanato-1 ,2,5-thiadiazole

This compound was isolated as a white solid which melted at 121°C. in a yield of 60 percent of theoretical; H NMR (300 MHz, CDCI.) δ 7 64 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H); "C NMR (75 MHz, CDCI,) δ 161.22, 1 58.93, 141.50, 129.46, 122.27, 1 1 1.50, 106.43, 55.45; MS (El) m/e 249(M + ), 226, 165, 133, 103, 90.

Example 17: Preparation of 4-(4-Methylthιophenyl)-3-thιocyanato-1 , 2, 5-thιadιazole

This compound was isolated as a yellow solid which melted at 80-82°C in a yield of 46 percent of theoretical; 'H NMR (300 MHz, CDCI.) δ 7 62 (d, J = 8 7 Hz, 2H), 7 35 (d, J = 8 7 Hz, 2H), 2 53 (s, 3H); ¹³ C NMR (75 MHz, CDCI,) δ 158 86, 142 76, 141 63, 128 62, 128 13, 125 88, 125 56, 105 98, 15 13; MS (EI) m/e 265(M + ), 205, 192, 181 , 149, 1 16 Example 18: Preparation of 4-(4-Trιfluoromethylphenyl)-3-thιocyanato-1, 2, 5-thιadιazole

N N

This compound was isolated as a white solid which melted at 76°C in a yield of 65 percent of theoretical, 'H NMR (300 MHz, CDCI,) 67 87 (d, J = 8 4 Hz, 2H), 7 81 (d, J = 8 4 Hz, 2H); ^,3 C NMR (75 MHz, CDCI,) δ 158 94, 142 06, 133 33, 132 85, 132 42, 128 65, 128 38, 126 26, 121 72, 105 69, MS (El) m/e 287(M + ), 260, 203, 1 16 Example 19 Preparation of 4-(4-Methylsulfonylphenyl)-3-thιocyanato-1 ,2,5-thιadιazole

N N

This compound was isolated as a tan solid which melted at 158-160°C in a yield of 66 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 8 13 (d, J = 8 1 Hz, 2H), 7 96 (d, J = 8 2 Hz, 2H), 3 13 (s, 3H), ¹³ C MR (75 MHz, CDCI,) δ 157 43, 142 24, 134 80, 129 35, 129 05, 128 18, 105 39, 44 45

Example 20: Preparation of 4-(4-Carboxymethylphenyl)-3-thiocyanato-1 ,2,5-thiadiazole

N N

This compound was isolated as a yellow solid which melted at 135°C. in a yield of 48 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 8.21 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H), 3.97 (s, 3H); ^,3 C NMR (75 MHz, CDCI.) δ 165.64, 158.17, 141.97, 133.73, 131.90, 130.19, 127.99, 105.58, 52.54; MS (El) m/e 278(M + ), 246, 130, 102. Example 21 : Preparation of 4-(4-Nitrophenyl)-thiocyanato-1 , 2, 5-thiadiazole

N N

This compound was isolated as a yellow solid which melted at 1 17°C. in a yield of 48 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 8.42 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H); ^,3 C NMR (75 MHz, CDCI,) δ 157.06, 148.56, 141.93, 135.47, 129.10, 124.19, 105.27; MS (El) m/e 264(M + ), 218. Example 22: Preparation of 4-(2-Thiophene)-3-thiocyanato-1,2,5-thiadiazole

N N

X s s

This compound was isolated as a white solid which melted at 70-7 C. in a yield of 48 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 7.62 (d, J = 3.5 Hz, 1 H), 7.57 (d, J = 5 Hz, 1 H), 7.19 (dd, J = 3.5, 5.0 Hz, 1 H); ^, C NMR (75 MHz, CDCI,) δ 153.33, 140.01 , 132.10, 130.04,

128.20, 128.12, 105.63; MS (El) m/e 225(M + ), 198, 180, 141 , 1 16.

Example 23: Preparation of 4-(3-Pyridyl)-3-thiocyanato-1,2,5-thiadiazole

N N

This compound was isolated as a yellow solid which melted at 120°C in a yield of 45 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 8.97 (s, 1 H), 7.58 (d, J = 3.8 Hz, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.48 (m, 1 H); ¹³ C NMR (75 MHz, CDCI,) δ 156.74, 151.34, 148.48, 141.77,

10 135.33, 126.16, 123.64, 105.48; MS (EI) m/e 220(M + ), 194, 156, 136, 130, 116. Example 24: Preparation of 4-Phenyl-3-thiocyanatomethylthio-1,2,5-thiadiazole

15 N N

To a stirred solution of (3.81 g, 0.05 mole) of sodium sulfide in lOO mL of dimethylformamide was added 8 g (0.041 mole) of 4-Phenyl-3-chloro-1,2,5-thιadiazole. The mixture was stirred ~ 18 hours and to this mixture was added 6.68 g(1.5 molar equivalents) of

^2u chloromethylthiocyanate. This mixture was stirred for -~14 hours and then diluted with 100 mL of water and extracted with 200 mL of methylene chloride. The organic layer was separated and washed with water (2x100mL), dried and concentrated under reduced pressure. The thus recovered crude material was chromatographed on silica gel with a 10 percent EtoAc:90 percent hexane mixture to yield 8.99 g (83 percent of theoretical) as an oil. Upon

²⁵ crystallization, a light yellow solid melting at 58-60°C. was recovered in a yield of 69 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 4.77 (s, 2H), 7.49 (m, 3H), 7.82 (m, 2H); ^,3 C NMR (75 MHz, CDCI,) δ 38.28, 11 1.46, 127.97, 128.78, 130.06, 151.77, 157.93; MS (El) m/e 265(M + ), 207, 148, 1 16.

^■ * ^υ By employing the above preparative procedures of Example 24 employing the appropriate starting materials, the following compounds were prepared.

35

Example 25: Preparation of 4-(4-Bromophenyl)-3-thiocyanatomethylthio-1 ,2,5-thiadiazole

N N

This compound was isolated as a tan solid which melted at 67-68°C. in a yield of 65 percent of theoretical; ¹ H NMR (300 MHz, CDCI.) δ 4.79 (s, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.30 (d,

J = 8.4 Hz, 2H); ¹³ C NMR (75 MHz, CDCI ) δ 38.31, 111.32, 129.48, 129.78, 132.01, 151.62, 156.75; ³

MS (El) m/e 345, 343, 287, 285, 206.

Example 26: Preparation of 4-(4-Chlorophenyl)-3-thiocyanatomethylthio-1 ,2,5-thiadiazole

N N

This compound was isolated as a white solid which melted at 62-63°C. in a yield of 60 percent of theoretical; 'H NMR (300 MHz, CDCI.) δ 4.80 (s. 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H); ' ³ C NMR (75 MHz, CDCI.) δ 38.33, 11 1.32, 129.09, 129.32, 136.28, 151.66, 156.75; MS (El) m/e 301(M + + 1), 299, 243, 241 , 182, 150. Example 27: Preparation of 4-(3-Chlorophenyl)-3-thiocyanatomethylthio-1 ,2,5-thiadiazole

This compound was isolated as a white solid which melted at 67°C. in a yield of 52 percent of theoretical; Η NMR (300 MHz, CDCI,) 54.80 (s, 2H), 7.72 (m, 1 H), 7.83 (s, 1 H); ¹³ C NMR (75 MHz, CDCI,) 538.30, 1 1 1.23, 125.90, 128.18, 129.99, 130.09, 132.44, 134.83, 151.75, 156.35; MS (El) m/e 301(M + + 1), 299. 243, 241 , 202, 182.

Example 28: Preparation of 4-(2-Chlorophenyl)-3-thiocyanatomethylthio-1 ,2,5-thiadiazole

This compound was isolated as an oil in a yield of 52 percent of theoretical; ^* H NMR (300 MHz, CDCI.) δ 4.74 (s, 2H), 7.41-7.52 (m, 4H); ^,3 C NM (75 MHz, CDCI,) δ 38.08,1 1 1.15, 126.90, 129.81, 130.15, 130.86, 131.32, 133.32, 153.64, 156.34; MS (El) m/e 301 (M + + 1), 299, 205,184, 182, 150. Example 29: Preparation of 4-(4-Fluorophenyl)-3-thiocyanatomethylthio-1,2,5-thiadiazole

SCH2SCN

N N

This compound was isolated as a clear oil in a yield of 65 percent of theoretical; 'H NMR (300 MHz, CDCI ) δ 4.80 (s, 2H), 7.20 (t, J = 8.5 Hz, 2H), 7.84 (m, 2H); ¹³ C NMR (75 MHz,

CDCI,) 638.32, 1 1.36, 115.85, 1 16.44, 127.15, 130.04, 130.16, 151.51 , 156.51, 161.79, 165.12.

Example 30: Preparation of 4-(3-Methoxyphenyl)-3-thiocyanatomethylthio-1 ,2,5-thiadiazole

This compound was isolated as a yellow oil with a yield of 70 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 3.87 (s, 3H), 4.79 (s, 2H), 7.05 (m, 1 H), 7.42 (m, 3H); ^,3 C NMR (75 MHz, CDCI,) 638.36, 55.47, 1 11.39, 113.23, 116.20, 120.17, 129.84, 132.03, 151.81, 157.73, 159.60; MS (El) m/e 295(M + ), 237, 178, 146.

Example 31 : Preparation of 4-(4-Methoxyphenyl)-3-thiocyanatomethylthio-1,2,5-thiadiazol e

N N

This compound was isolated as a white solid which melted at 79-80°C. in a yield of 69 percent of theoretical; Η NMR (300 MHz, CDCI,) δ 3.87 (s, 3H), 4.78 (s, 2H), 7.02 (d, J = 8.52 Hz, 2H), 7.79 (d, J = 8.52 Hz, 2H); ¹³ C NMR (75 MHz, CDCI,) δ 38.41, 55.41, 1 1.52, 1 14.17, 123.54, 129.18, 151.23, 157.68, 160.79; MS (El) m/e 295, 237, 178, 146. Example 32: Preparation of 4-(4-Methylthiophenyl)-3-thiocyanatomethylthio-

-1 ,2,5-thiadiazole

N N

This compound was isolated as a white solid which melted at 79-80 ^c C. in a yield of 64 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 2.53 (s, 3H), 4.78 (s, 2H), 7.34 (d, J = 8.71 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H); ¹³ C NMR (75 MHz, CDCI,) δ 15.26, 38.38, 1 1 1.36, 125.73, 127.22, 128.17, 141.72, 151.44, 157.36; MS (El) m/e 31 1 (M + ), 253, 206. Example 33: Preparation of 4-(4-Methylsulfonylphenyl)-3-thiocyanatomethylthio- -1 ,2,5-thiadiazole

N N

This compound was isolated as a white sol id which melted at 120-121°C. in a yield of 54 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 3.13 (s, 3H), 4.84 (s, 2H), 8.09 (q, 4H); ¹³ C NMR (75 MHz, ^" CDCI,) 6 38.21 , 44.48, 11 1.12, 127.86, 128.95, 135.81 , 141.48, 152.08, 155.80.

Example 34: Preparation of 4-(4-Trifluoromethylphenyl)-3-thiocyanatomethylthio- -1,2,5-thiadiazole

N N

This compound was isolated as a white solid which melted at 79-80°C in a yield of 74 percent of theoretical ; ¹ H NMR (300 MHz, CDCI,) 64.81 (s, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7,98 (d, J = 8.2 Hz, 2H); ¹³ C NMR (75 MHz, CDCI,) δ 138.26, 1 11.19, 121.73, 125.33, 125.78, 125.82, 128.43. 131,61 , 132.04, 134.18, 151.96, 156,42; MS (El) m/e 333(M + )■ 275, 216, 184. Example 35: Preparation of 4-(4-Methylphenyl)-3-thiocyanatomethylthio- 1 ,2, 5-thiadiazole

N N

This compound was isolated as a yellow oil in a yield of.42 percent of theoretical; Η NMR (300 MHz, CDCI,) δ 2.42 (s, 3H), 4.76 (s, 2H), 7.29 (d, J = 7.7 Hz, 1 H), 7.38 (t, J = 7.6 Hz,

1 H), 7.60 (m. 2H); ¹³ C NMR (75 MHz, CDCI,) δ 21.40, 38.26 1 1 1.49, 125.03, 128.70 130.92, 138.73,

151.92, 158.25.

Example 36: Preparation of 4-(4-Carboxymethylphenyl)-3-thiocyanatomethylthio-

-1 ,2,5-thiadiazole

N N

This compound was isolated as a white solid which melted at 1 19-120°C. in a yield of 65 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 3.96 (s, 3H), 4.81 (s, 2H), 7.93 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 8.3 Hz, 2H); ^,3 C NMR (75 MHz, CDCI,) 638.31 , 52.44, 1 1 1.21 , 127.97, 129.93, 131.28, 134.82, 152.01, 156.76, 165.90; MS (El) m/e 323(M + ), 265, 221 , 205 162, 130.

Example 37: Preparation of 4-(4-Nitrophenyl)-3-thiocyanatomethylthio-1,2,5-thiadiazole

N N

This compound was isolated as a yellow solid which melted at 78°C. in a yield of 56 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 4.86 (s, 2H), 8.06 (d, J = 8.8 Hz, 2H), 8.36 (d, J = 8.8 Hz, 2H); ³ C NMR (75 MHz, CDCI,) δ 38.32, 1 1 1.13, 123.98, 129.02, 136.60, 148.19, 152.22, 155.43; MS (El) m/e 310(M + ), 252, 206. Example 38: Preparation of 4-(2-Thiophene)-3-thiocyanatomethylthio-1 , 2, 5-thiadiazole

N N

This compound was isolated as a tan solid which melted at 120-122°C. in a yield of 67 percent of theoretical; 'H NMR (300 MHz, CDCI,) δ 7.16 (dd, J = 4.8, 3.6 Hz, 1 H), 7.71 (d, J = 3.6 Hz, 1 H); ' ³ C NMR (75 MHz, CDCI,) 638.23, 1 1 1.30, 127.56, 126.63, 129.14, 133.53, 150.44, 151.93; MS (El) m/e 271 (M + ), 213, 180, 154, 122. Example 39: Preparation of 4-(3-Pyridyl)-3-thiocyanatomethylthio-1,2,5-thiadiazole

N N

This compound was isolated as a yellow solid which melted at 88-90°C. in a yield of 77 percent of theoretical; ^* H NMR (300 MHz, CDCI,) 64.84 (s, 2H), 7.46 (dd, J = 4.7, 7.9 Hz, 1 H), 8.17 (d, J = 7.9 Hz, 1 H), 8.73 (d, J = 7.9Hz, 1 H), 9.10 (s, 1 H); ^,3 C NMR (75 MHz, CDCI,) δ 38.24, 1 1 1.08, 123.39, 127.1 1, 135.1 1 , 148.75, 150.73, 151.93, 155.08; MS (El) m/e 266(M -. ), 208, 149, 1 18.

The compounds of this invention are useful as antimicrobial additives, and they can be added to industrial products such as paints, inks, adhesives, soaps, cutting oils, textiles, paper pigment slurries and styrene-butadiene latexes used for paper coatings to provide needed antimicrobial properties. The compounds are also used as antimicrobial additives in such personal care products as hand creams, lotions, shampoos and hand soaps. A further advantage in the use of the compounds of this invention is their cost-effectiveness for applications which need to have an antimicrobial continuously replenished, such as in cooling towers and pulp and paper mills.

As appreciated by those skilled in the art, each of the compounds disclosed herein are not necessarily active at the same concentrations or against the same microbial species. There may be some compound-to-compound variation in antimicrobial potency and spectrum of antimicrobial activity.

The antimicrobial compounds of the present invention may be added to formulations susceptible to microbial growth. They may be added either undiluted or dissolved in inert diluents such as organic solvents such as glycols, alcohols or acetone They may also be added alone or in combination with other preservatives

As used herein, the term "microorganism" is meant to refer to bacteria, fungi, viruses, algae, subviral agents and protozoa.

As used herein, the term "antimicrobially-effective amount" refers to that amount of one or a mixture of the compounds, or of a composition comprising such compound or compounds, of this invention needed to exhibit inhibition of selected microorganisms Typically, this amount varies from providing 1 part per million (ppm) to 5,000 ppm by weight of the compound to a microbial habitat being contacted with the compound Such amounts typically vary depending upon the particular compound tested and microorganism treated Additionally, the exact concentration of the compounds to be added in the treatment of industrial and consumer formulations may vary within a product type depending upon the components of the formulation. A preferred effective amount of the compound is from 1 ppm to 500 ppm, more preferably from 1 ppm to 50 ppm by weight, of a microbial habitat.

The term "habitat" refers to a place or site where a microorganism naturally or normally lives or grows Typically, such a habitat will be an area that provides a moisture source, nutrient source, and/or an oxygen source such as, for example, a cooling water tower or an air washing system.

The terms "inhibition", "inhibit" or "inhibiting" refer to the suppression, stasis, kill, or any other interference with the normal life processes of microorganisms that is adverse to such microorganisms, so as to destroy or irreversibly inactivate existing microorganisms and/or prevent or control their future growth and reproduction

The antimicrobial activity of the compounds of the present invention is set forth as the minimum inhibitory concentration (MIC) for the active compounds and is determined

for nine (9) bacteria, using nutrient agar, and seven (7) yeast and fungi, using malt yeast agar. This determination is conducted using a one percent solution of the test compound prepared in a mixture of acetone and water.

Nutrient agar is prepared at pH 6.8, representing a neutral medium, and at pH 8.2, representing an alkaline medium. The nutrient agars are prepared by adding 23 g of nutrient agar to one-liter of deionized water. In addition, the alkaline medium is prepared by adjusting a 0.04 M solution of N-(tris-(hydroxymethyl)methyl)glycine buffered deionized water with concentrated sodium hydroxide to a pH of 8.5.

Malt yeast agar is prepared by adding 3 g yeast extract and 45 g malt agar per liter of deionized water. The specific agar is dispensed in 30 mL aliquots into 25 x 200 mm test tubes, capped and autoclaved for 15 minutes at 1 15°C.

The test tubes containing the agar are cooled in a water bath until the temperature of the agar is 48°C. Then, an appropriate amount of the one percent solution of the test compound is added (except in the controls where no compound is added) to the respective test tubes so that the final concentrations are 500, 250, 100, 50, 25, 10, 5, 2.5, 1.0 and zero parts per million of the test compound in the agar, thus having a known concentration of test compound dispersed therein. The contents of the test tubes are then transferred to respective petri plates. After drying for 24 hours, the petri plates containing nutrient agar are inoculated with bacteria and those containing malt yeast agar are inoculated with yeast and ^fun 9'-

The inoculation with bacteria is accomplished by using the following procedure.

Twenty- four hour-cultures of each of the bacteria are prepared by incubating the respective bacteria in tubes containing nutrient broth for 24 hours at 30 ^β C in a shaker. Dilutions of each of the 24 hour-cultures are made so that nine separate suspensions (one for each of the nine test bacteria) are made, each containing 10 ^B colony forming units (CFU) per mL of suspension of a particular bacteria. Aliquots of 0.3 mL of each of the bacterial suspensions are used to fill the individual wells of Steer's Replicator. For each microbial suspension, 0.3 mL was used to fill three wells (that is, three wells of 0.3 mL each) so that for the nine different bacteria, 27 wells are filled. The Steer's Replicator is then used to inoculate both the neutral and alkaline pH nutrient agar petri plates.

The inoculated petri plates are incubated at 30°C for 48 hours and then read to determine if the test compound which is incorporated into the agar prevented growth of the respective bacteria.

The inoculation with the yeast and fungi is accomplished as follows. Cultures of yeast and fungi are incubated for seven days on malt yeast agar at 30°C. These cultures are used to prepare suspensions by the following procedure. A suspension of each organism is prepared by adding 10 mL of sterile saline and 10 microliters of octylphenoxy polyethoxy ethanol to the agar slant of yeast or fungi. The sterile saline/octylphenoxy polyethoxy ethanol

solution is then agitated with a sterile swab to suspend the microorganism grown on the slant. Each resulting suspension is diluted into sterile saline (1 part suspension: 9 parts sterile saline). Aliquots of these dilutions are placed in individual wells of Steer's Replicator and petri plates inoculated as previously described. The petri plates are incubated at 30°C and read after 48 hours for yeast and 72 hours for fungi.

Table I lists the bacteria, yeast and fungi used in the MIC test described above along with their respective American Type Culture Collection (ATCC) identification numbers.

TABLE I

Organisms Used in the Minimum Inhibitory Concentration Test

In Tables II and III, the MIC values of the compounds of the present invention as compared to the MIC of a standard commercial preservative (with 1-(3-chloroallyl)-3,5,7-triaza- -1-azoniaadamantane chloride as the active agent and referred to in Tables III and IV as "STANDARD I") are set forth for the bacteria organisms and yeast/fungi organisms which are listed in Table I.

TABLE II

Minimum Inhibitory Concentrations for Test Compounds in Bacteria Species (in ppm)

I

(jϋ σ- i

TABLE II CONTINUATION

I

-ci l

I oo I

I

I

I

-tr O I

TABLE III

Minimum Inhibitory Concentrations for Test Compounds in Yeast/Fungi Species (in ppm) at pH 5.5

35

0

The present invention is also directed to a method for inhibiting marine organisms The term "marine organisms" is meant to include marine animals, such as barnacles, serpu d, bryozoa, oysters and hydroids, and marine plants, such as green algae and brown algae The method for inhibiting marine organisms comprises contacting a surface ς exposed to a marine environment in which marine organisms grow with a marine antifou ng effective amount of the compound of this invention

As appreciated by those skilled in the art, not all of the compounds disclosed herein are active at the same concentrations or against the same marine organism species

That is, there may be some compound-to-compound variation in marine antifouhng potency and spectrum of marine antifouhng activity Furthermore, a compound's marine antifouhng 0 activity may be dependent on the specific materials with which the compound is formulated to form a marine antifouhng composition

As used herein, the term "marine antifouhng effective amount" refers to that amount of one or a mixture of two or more of the compounds of this invention needed to exhibit inhibition of selected marine organisms Typically, this amount varies from providing 1 5 weight percent to 30 weight percent of the compound to a marine antifouhng composition which is used to treat a surface exposed to a marine environment in which marine organisms live or grow Such amounts vary depending upon the particular compound tested and marine

organism to be treated. Also, the exact concentration of the compounds to be added in the preparation of industrial and consumer formulations may vary within a product type depending upon the components of the formulation.

A composition comprising a marine antifouhng effective amount of the compound will also comprise an inert diluent which may be, for example, in the form of a paint. Particularly preferred are those paints having a vinyl resin binder such as, for example, a plasticized polyvinyl chloride or a polyvinyl chloride-polyvinyl acetate type. Preferably, the binders are formulated as latexes or emulsions. In a paint composition, the compound of the present invention is preferably used in an amount from 1 to 30 weight percent and, most preferably, from 10 to 25 weight percent. In addition to vinyl resin binder paints, epoxy and polyurethane binder paints containing the compound may also be useful. Coatings and films prepared from paints comprising the compound of the present invention typically remain substantially free from build-up of marine organisms for periods ranging from 3 to 12 months, depending upon the concentration of the compound and the thickness of the applied coating or film.

The term "a surface exposed to a marine environment" refers to a surface where a marine organism naturally or normally lives or grows. Typically, such a surface will be an area that is in continual or periodic contact with a marine environment such as an ocean or other body of water. Typical surfaces include, for example, a ship hull. The marine antifouhng activity of the compounds of the present invention is demonstrated by the following techniques.

Test panels are prepared from clear, rigid polyvinyl chloride film that is 0.381 x 10 ^'3 m thick and has one textured surface. The test panels are 0.1524 m by 0.1524 m squares that have 0.00635 m holes punched at corners on 0.127 m centers. A 0.102 square template, with a 0.067 m diameter hole at the center, is attached to the center of the textured surface of the test panels.

A candidate marine antifoulant compound (1.0 g) is stirred into a resinous latex binder (9.0 g). A portion of the compound/binder mixture (1.5 g) is added to the center of the test panel and uniformly spread over the circular area inside the template. Water is added dropwise as needed to properly spread the compound/binder mixture. The template prevents the compound/binder mixture from spreading beyond the uncovered area. The test panel is allowed to sit for between 10 to 30 minutes until the edge of the spread compound/binder mixture has dried. The template is then removed. The test panel is then allowed to dry for 8 to 12 hours at room temperature. Two test panels are prepared for each candidate marine antifoulant compound.

Two control test panels are also prepared by only treating with the resinous latex binder. One test panel of each candidate marine surfactant compound is attached over a white background to the topside of an exposure support apparatus. The second test panel is attached over a

black background to the underside of the exposure support apparatus. The exposure support apparatus is placed horizontally 0.0254 m under a marine surface with the white background topside facing up. The exposure support apparatus is exposed to the mari e environment for both 3 and 6 weeks during which time the control test panels become substantially covered with mature marine organism growth on both the topside and underside exposures.

After being removed from the exposure support apparatus, each test panel is inspected and rated for marine organism growth on both the treated and untreated areas of the test panel. The marine organisms present on the treated and untreated areas are noted. The presence of algae spores and bacterial slime are noted but not included in rating each test panel. The test panels are rated on a scale from 10 (representing completely free of marine organism growth) to 0 (representing completely covered with marine organism growth).

In Table IV, the marine antifouhng rating values for some of the compounds listed in Table I are set forth, as well as the ratings for control panels (with no marine antifouhng compound and referred to in Table IV as "Control"). In addition, test panels were prepared using tributyl tin oxide, a known marine antifouhng compound. One set of such panels used the tributyl tin oxide in a commercially available ship-hull paint (referred to in Table IV as "STANDARD II") which was employed in the same manner as the resinous latex binder used on the other test panels. A second set of such panels used the tributyl tin oxide at a 10 percent concentration in the resinous latex binder (referred to in Table IV as "STANDARD III").

TABLE IV

Marine Antifouling Rating for Test Compounds