CA1100521A - 2-imino substituted isothioureidobenzene - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
2-imino substituted isothioureidobenzene products useful as antheimintics and fungicides are disclosed.
The products may be prepared by several different methods including treating a 2-iminothioureidobenzene with a base and either an organic halide, a diester of sulfuric acid or a di-ester of sulfurous acid or treating a 2-aminoisothioureido-benzene with an appropriately substituted aldehyde.

Description

Field of the Invention This invention relates to 2-imino substituted isothioureidobenzenes, to processes for making such compounds, to methods of treating helminth and fungus in~ections and to anthelmintic and antifungal compositions containing them.
Description of the Invention British Pat. Nos. 1,214,415 and 1,307,250; U.S.
Pat. Nos. 3,958,008; 3,860,586 and 3,836,569 and Netherlands Pæt. No. 7,401,787 disclose numerous thio-ureas useful as anthelmintics, though none have a sub-stituent on the sulfur. German Pat. No. 2,303,048 discloses 2-acylated amino-S-substituted isothioureido-benzenes as anthelmintics. However, there are no re~erences disclosing compounds having both an imino substituent on the benzene ring and a substituted sulfur atom in the thioureido group. Other patents disclosing anthelmintic compounds include U. S. Pat. Nos. 3,865,948 and 4,00~,217; also, British Pat. No. 1,350,277.
An ob~ect of this invention is to provide a new class of 2-imino substituted isothioureidobenzenes (I, infra), methods for preparing these compounds, compositions containing said compounds and to their use as anthelmintic and antifungal agents.
The novel 2-imino substituted isothioureidobenzenes (I, infra) of this invention nave the following struct~ral formula:

'~' * - 2 -x ~=CIIR2 o =N-C-OR
SR
I

wllerein R is alkyl, for example, lower alkyl of from l to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl and the like; alkenyl, for example, lower alkenyl of from 3 to 8 carbon atoms such as propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like;
alkynyl, for example, lower alkynyl of from 3 to 8 carbon atoms such as propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like; polynuclear aralkyl su~h as napthylmethyl, napthylethyl, phenanthrenyimethyl and the like; mononuclear aralkyl such as benzyl, phenethyl, phenylpropyl and the like which may be ring-substit~lted with from l to 3 groups such as halo, alkyl, alkoxy, nitro, cyano and the like; mononuclear aryloxy lower alkyl, for example, phenoxy lower alkyl of from 3 to 6 carbon atoms in the a]kyl group including phenoxypropyl, phenoxybutyl, phenoxypentyl, phenoxyhexyl and the like~
cycloalkylalkyl, for example, cycloalkyl lower alkyl of from 5 to 6 nuclea~ carbon atoms su^h as cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and the like; cyano lower alkyl of from 3 to 6 carbon atoms such as cyanopropyl, cyanobutyl, cyanopenlyl, cyanohexyl 110~521 and the like; hydroxy lower alkyl of from 3 to 8 carbon atoms such as hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyoctyl and the like; aralkenyl, for example, poly-and mononuclear aralkenyl such as phen~lpropenyl and the like; alkoxyalkyl, for example, lower alkoxy lower alkyl, such as methoxypropyl, ethoxypropyl, ~ethoxybutyl, propoxy-butyl and the like; alkoxycarbonylalkyl, for example, lower alkoxycarbonyl lower alkyl wherein lower alkyl has 3 to 6 carbon atoms, such as methoxycarbonylpropyl, ethoxycarbonylbutyl, ethoxycarbonylpentyl, propoxycarbonyl-hexyl and the like; phthalimido lower alkyl such as phthalimidobutyl and the like or phenoxycarbonylalkyl, for example, phenoxycarbonyl lower alkyl of from 3 to 6 carbon atoms such as phenoxycarbonyl propyl, phenoxycarbonyl butyl, phenoxycarbonylpentyl, phenoxycarbonylhexyl and the like; R is alkyl, for example, lower alkyl of from 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl and the like or lower alkoxyalkyl such as methoxyethyl ethoxyethyl, propoxyethyl and the like; R2 is alkyl, for example, lower alkyl of from 1 to 6 carbon atoms; substi-tuted or unsubstituted aryl, of from 4 to 6 nuclear carbon atoms, for example, mononuclear aryl of from 4 to 6 nuclear carbon atoms, polynuclear aryl of from 10 to 14 carbon atoms, heteroaryl of from 5 to 6 nuclear atoms containing from 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, examples of aryl include phenyl, naphthyl, thienyl, pyridyl, furyl, furylmethyl, pyrroli-dinyl, pyrrolyl, isothiazolyl, oxadiazolyl, thiadia.zolyl, 3o llQC;~5Z~

imidazolyl,isooxazolyl, N-methylpyrryl, oxazolyl, pyrimidyl, and the like which may be unsubstituted or substituted with from I to 3 radicals selected from halo, such as chloro, bromo and the like, lower alkyl having from I to 5 carbon 110~5~1 atoms, lower alkoxy having from l to 5 carbon atoms;
di-lower alkylamino such as dimethylamino and the like, lower alkanoylamino of from l to 5 carbon atoms; phenoxy, benzyloxy, 3,4-lower alkylenedioxyphenyl, phenylthio lower alkyl, cyano, nitro, alkylthio or arylthio and 'he li'.e;
and X is hydrogen, nitro, halo, such as chloro,iodo, bromo fluoro and the like; lower alkanoyl of from 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl and the like; lower alkyl of from 1 to 4 carbon atoms such as methyl, ethyl, propyl, _-butyl and the like; lower alkoxy, such as methoxy, ethoxy, propoxy, butoxy, pentoxy and the like; thiocyanato, a radical of the formula:
Y-S(O)n wherein Y is lower alkyl of from l to 5 carbon atoms; lower alkenyl (C3-C6), lower alkynyl (C3-C6), cyclo lower alkyl (C3-C7), a 5- or 6-membered heterocycle, such a pyridyl, thienyl, furyl, oyrimidyl, thiazolyl and the like or mononuclear aryl such as ohenyl and n is an integer of O to 3, X is also lower alkylcar~on~llamino, such as methylcarbonylamino ~nd the like, lower (Cl-C~)

2~ alkoxy carbonylamino such as methoxycarbonylarino, isopropoxycarbonylamino and the like, a 5- or 6-membered cycloalkylcarbonylamino such as cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like; a radical of the formula: Y'~- wherein Y' is mononuclear aryl such as phenyl and the like; cyclo lower alkyl (C3-C7), a 5- or 6-membered heterocycle, such as oyridyl, 2-thienyl, furyl and the like or X is also a radical of the formula: Y"O-wherein Y" is lower alkyl (Cl-C5), mononuclear aryl, such as phenyl and the like, lower alkenyl, mononuclear arylkyl or a 5- or 6 membered heterocycle and, when substituted, the substituents on the Y, Y' and Y" are selected from halo, cyano, lower alkyl, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxy, halophenoxy, benzyloxy, trifluoromethyl or carbo lower alkoxy and the nontoxic, pharmaceutically or agronomically acceptable acid addition salts such as those formed with acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, benzoic, lactic and the like and amides of the ester such as amino, mono- and di-lower alkylamino and the like. Representative R2 radicals include chloro-phenyl, bromophenyl, methylphenyl, ethylphenyl, butylphenyl, pentylphenyl; 2,~-dichlorophenyl; 3,4~dichlorophenyl;
methoxyphenyl, ethoxyphenyl, dimethylaminophenyl, acetamido;

3,4-methylenedioxyphenyl, methylthiophenyl, phenylthio- !
phenyl and the like.
When compounds of general Formula I can exist in various isomer and stereoisomer forms, all such isomers and their mixtures and racemates are included within the scope of the present invention.
Preferred Embodiment A preferred embodiment of this invention relates to the 2-imino substituted isothioureidobenzenes (Ia, infra) of the following structural formula:
xl ~5 ~ N=CHR5 ~ O
\NHIC=NC-OR4 I a ~O~S2~

wherein R3 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl of from 5 to 6 nuclear atoms, phenoxy lower alkyl of from 3 ~o 6 carbon atoms, cyano lower alkyl of from 3 to 6 carbon atoms, lower alkoxy carbonyl lower alkyl wherein lower means from 3 to 6 carbon atoms, phthalimido lower alkyl, phenyl lower alkenyl of from 3 to 6 carbon atoms or hydroxy lower alkyl; R4 is lower alkyl; R5 is mononuclear aryl of from 4 to 6 nuclear carbon atoms, poly-nuclear aryl of from lO to 14 nuclear carbon atoms or heteroaryl of from 5 to 6 nuclear atoms containing from 1 to 3 hetero atoms such as o, m, or p-nitrophenyl, o, m or p-dimethylaminophenyl, lower o, m or _-alkoxyphenyl, o, m or _-cyanophenyl, o, m or p-acetamidophenyl, methyene-dioxyphenyl, phenyl, 2-furyl, 5-methyl-2-furyl, 2-thienyl, o, m, or p-halophenyl, lower _, m or _-alkyl phenyl or dihalophenyl and Xl is in the 4 or 5 position of the benzene ring and is selected from hydrogen, lower alkyl carbonylamino, lower alkoxycarbonylamino, lower alkoxy, lower alkanoyl, propylthio, propylsulfinyl, propylsulfonyl, propylsulfonyloxy, propoxysulfonyl, phenylthio, phenyl-sulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy or benzoyl. ~specially preferred are those compounds wherein Xl is hydrogen, 4-benzoyl, 5-propylthio or 5-phenylthio. These compounds exhibit particularly good anthelmintic and antifungal activity.
The produc~s may be prepared by several alter-native processes including treating a 2-imino substituted thioureidobenzene with a base and an organic halide, a diester of sulfuric acid or diester of sulfurous acid or by treating a 2-amino substituted isothioureidobenzene w~h an aldehyde.

5Zl The first method for preparing the 2-imîno sub-stltuted iso~hioureidobenzenes (I, supra ~/

.. ..

ll()~S21 invention comprises treating the corresponding 2-imino substituted thloureidobenzene (II, infra) with a base, for example, an alkali metal or alkaline earth metal base, such as sodium hydride, calcium hydride, sodium hydroxide, pota~sium hydroxide, calcium hydroxide, potassium carbonate and the like followed by treatment with either an organic halide, a diester of sulfuric acid or diester of sulfurous acid. The reaction may be conducted at a temperature in the range of from -10C. to about 60C. for a period of time of from a few minutes to about 24 hours. Any solvent in which the reactants are reasonably soluble and sub-stantially inert may be employed. Suitable solvents include dimethylformamide, acetone, 1,2-dimethoxyethane, dimethyl sul~oxide and the like. The following equation illustrates this process:

N=CHR2 ~ Base ~ ~ ; N=CHR2 01 ~ 11 H-CNHC-ORl or RS04R H-f=NCOR
S SR

II I
wherein R, Rl and X are as defined above and x2 is halo such as chloro, bromo or iodo.
A second method for preparing the compounds of Formula I comprises kreating 2-amino substituted iso-thioureidobenzene with an aldehyde (R2CHQ) in a manner similar to that described below for the .~.' . ~,~,,, 11(3~5~ ~

prepara~ion of the compounds of Formula III. ~he following equation illustrates this process:

~IC=NCOR
SR
IIa wherein R, Rl, R2 and X are as defined above.
The compounds of Formula II are either known compo~nds or may b~e prepared by treating an appropriately substituted l-imin3-2-aminobenzene (III, infra) with a carboalkoxyisothiocyanate (IV, infra), to afford the desired compounds of Formula II. The following equation illustrates this process:

X X

N=CHR2 + S=C=NC-ORl ~ ~N=C,-~o[R2 S
III IV II

wherein Rl, R2 and X are as defined above. This reaction is conveniently conducted in a suitable inert solvent such as diethyl ether, acetone, and the like for a period of time of from ~O minutes 'o 6 ~ours.

76-78l~
ll~CtS~

We have found that the co~pounds of Formula II, supra, wllich have been disclosed as ~nthelmintics are also useful as fungicides.

Compound IIa is prepared by the reaction O
of a thioureidobenzene (V, infra) where Z-C-NHC-ORl with RX2, RS03R or RSO~R under the sa.~e conditions as described in the preparation of Formula I from ~ormula II.
~ he compounds of Formula II and also the compo m ds of Formula IIIa, l-substituted-i~in~-2-substituted aminobenzene, may be prepared by treating thecorrespondingly substituted isothioureidobenzene or substituted 1,2-diaminobenzen~ ~V, infra), respectively, with an aldehyde. The following equation illustrates this ~rocess:

~ N~2 + a2c~o ~ ~ ~I=c~a2 N~-Z' NH-Z' V IIIa wherein R2 and X are as defined above anl Z' is hydrogen or o -C -NHC -O

whereln R is as defined above~ ~his rea^tion is 2 generally conducted at a temperatllre in the range of from about 0C. to about 11C. for a period of time of l~lU~521 from one mi.lute to about 24 hours. ~uitab~ solvenls ~ich can be employed include aceton~, methanol, ethanol, .. .. *
iso-propanol, methylC~llosolve,dimethylformamide, di-met~yl sulfoxide and the like. An acid catalyst such as P-toluene sul~onic acid, sulfuric acid and the like may be employed. L~y water formed dur~ng the reaction may be removed by azeotropic distillation.
When X is the radical Y~, the sulfinyl ~i.e.,Y-~0-) and the sulfonyl product can be prepared by 1~ treating said YS substituted compound with one or two e~uivalents of an oxidizing agent, respectively. ~he oxidizing agen' may be m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium 'nypochlorite and the like.
~he reaction is conducted at a temperat~L~e in the range of from -20C~ to 50C. for a period of time o~ from about 5 minutes ~o 24 houL~s. Any substantially inert solvent in which the reactants are reasonably soluble may be employed including methylene dichloride, chloroform, carbon tetrachloride, banzene,toluene, chlorobenzene, acetone and the like.
The thioureidobenzene of Formula S O
(Z'C-~C ORl) is prepared by t~eatin, a 1,2-diaminobenzene derivative or l-amino-2-nitrobenzene derivative with a carboalkoxy isothiocyanate in the man~er described above and l~hen a nitrobenzene reducing said nitro to an amino ~roup by reduction methods well-known to those skilled in ths art.

*Trademark. Methyl "Cellosolve" i5 ethylene glycol monomethyl ether.

7~-78 SZl 2-I-mino substituted isothioureidobenzenes of Formula I are anthelmintics and have br3ad spectrum activity against parasites of animals, especially warm blooded animals, including both mature and im~ature parasitic forms. In particular, these compolmds exhibit high ac~ivity against various helmintic infectiors of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
For exanple 7 the disclosed compounds are generally effective in clearing mice of worm infections, for laboratory purposes, including: Syphacia obvelata and As~icularis tetraPtera~ the migratory stages of Ascaris suum, H menole~sis nana and Nematospiroides dubius.
Compounds of Formula I have been demonstrated as efficacious against gastrointestinal parasites in sheep, such as Moniezia spP, Haemonchus contortus, Ost,erta~ sP~, lrichost~on~lus s~p, Nematodirus sPP, Tri^huris ovis, Cooperia spp, Capillaria s~, Stron~Yloids Pa~_llosus, BunostomlIm tri,~oncephalum and 20 OesoPha~3stomum spp. lhe compounds are active against lung wo~ms in ruminants especially Dictyocaullls filaria, in sh~ep and Dict~ocaulus viviparus and in cattle. lhe co~pounds (I) may alsoke used in treating Fasciola ~i~antica in cat51e. In addition, the compounds are 2~ effective against liver flukes (Fasciola ha~atica) in sheep and cattle.
~ nimals of low weigh~ are t~ea5ed with m~t doses ranging no higher than a few milligrams;
whereas, animals of high body weigh5, such as ruminants, ?o-78 i~5 require proportionately lar~er ~nit doses ranging up to several grams. Preferably, a single dose is administered for each anlmal species based on the weight of that species.
The amount of ingredient administered will depend on the weight of the host and will usually be a unit dosage between about 1 mg./kg. and 125 mg./kg.
of body weight. It is ^ontemplated that dosage units containing the compounds of Formula I of this invention as the essential active ingredienl will be administered, 10 orally or by injection, in the treatment and control of helminti^ infections in man and do~estic animals such as sheep, cat~le, horses, dogs, cats, fish, swine and goats.
Further, applicants have found hat the compounds of Formula I and Formula II of this inven'ion 15 display broad spectrum antifungal activity. It is con-templated, therefore, that an.ifungal compositions con-taining these compounds as an essential active ingredient will be employed in controlling the growth of fungi in or on animals and plants as well as in the paint, wood, 20 textile, cosmetic, leather, tobacco, fur, rope, paper, pulp, plastic, fuel, rubber and food industries.
~ en used as an anthelmintic agent for the treatment and/or prevention of helminthiasis, the novel compounds o~ Formula I of this invention may be 25 administered orally, rectally, intranasally, sublingually or topically, in a unit dosage form ,uch as a capsule, bolus, tablet, suppository, paste, gel, spray, powder, ointment, cream or as a liquid drench. ~hey may also be administered orally by intimatel~ dispersing them in an 7~-7 `SZl animal feedstuff or by using them as a top dressing or in the form of pellets which are added to a finished feed. Alternatively, they may be administered to animals in a liquid carrier vehicle by intraruminal, interamuscular and intratracheal injection. In addition, polymeric im-plants providing a controlled release rate can be employed for administration. The quantity of active material re-quired to give the best anthelmintic response will depend upon the particular compound employed, the species of animal to be treated and the type and severity of hel-minth infection. Good results are usually obtained when there is administered a total dose of from about 5 to about 125 mg. of active ingredient per kg. of animal body weight. Such total dose may be given at one time or in divided doses over a short period of time such as 1 to 3 days.
The 2-imino substituted isothioureidobenzenes and acid addition salts and metal salt complexes of the present invention are useful as agricultural fungicides and can be applied to various loci such as the seed, the soil or the foliage. The compounds can be employed in technical or pure form or in solutions or in formulations.
The compounds are usually taken up in an agronomically acceptable carrier or are formulated to render them suitable for use as fungicides. For example, the com-pounds can be formulated as wettable powders, emulsifiable concentrates, dusts, granular formulations, aerosols, or flowable emulsion concentrates. In such formulations, the compounds are usually extended with an agronomically acceptable liquid or solid carrier and, when desired, suitable surfactants are also incorporated.
By the term "agronomically acceptable carrier" is meant any substance which can be utilized to dissolve, disperse, or diffuse the compounds without impairing the effectiveness of the compound and which is environ-mentally acceptable.
It is usually desirable, particularly in the case of foliar spray formulations, to include adjuvants, such as wetting agents, spreading agents, dispersing agents, stickers, adhesives and the like in accordance with the agricultural practices. Such adjuvants commonly used in the art can be found in the John W. McCutcheon, Inc.
publication "Detergents and Emulsifiers, Annual."
In general, the compounds of this invention can be dissolved in organic solvents such as acetone, methanol, ethanol, dime~hylformamide, pyridine, dimethyl sulfoxide and the like and the resulting solutions can be extended with water. The concentrations of the solution can vary from about 1% to about 90% with a preferred range being from about 5% to about 50%.
For the preparation of emulsifiable concentrates, the compound can be dissolved in suitable organic solvents, or a mixture of solvents, together with an emulsifying agent which permits dispersion of the fungicide in water.
The concentration of the active ingredient in emulsifiable concentrates is usually from about lOæ to about 90~ and in flowable emulsion concentratesg can be as high as about 75,0.
Wettable powders suitable for spraying, can be 7~ -7!~A

prepared by admixing the compounds with a finely divided solid, such as clays, inorganic silicates and carbonates, and silicas and incorporating wetting agents, sticking agents, and/or dispersing agents. The concentration of active ingredients in these formulations is usually in the range of from about 20% to about 98%, preferably from about 40% to about 75%. A typical wettable powder is made by blending 50 parts of 1-imino(2-furylmethyl)-2-(3-carbomethoxy-S-buty]isothioureido)benzene~ 45 parts of a synthetic precipitated hydrated silicon dioxide sold under the trademark Hi-Sil ~, and 5 parts of sodium lignosulfonate. In another preparation a kaolin type (Barden) clay is used in place of the Hi-Sil wettable powder, and in another preparation 25% of the Hi-Sil is replaced with a synthetic sodium silico aluminate sold under the trademar~ Zeolex ~ 7.
Dusts are prepared by mixing the compounds with finely divided inert organic or inorganic solids.
Materials useful for this purpose include botanical flours, silicas, silicates, carbonates and clays. One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrates containing from about 20% to about 80% of the active ingredient are commonly made and are subsequently diluted to from about 1% to about 10~ use concentration.
The compounds of this invention can be applied as fungicidal sprays by methods commonly employed, such as conventional high-gallcnage hydraulic sprays, low-gallonage sprays, air-blast sprays, aerial sprays and 7(~- 7 ~

dusts. ~he dilution and rate of application will depend upon the type of equipment employed, the method of appli-cation and diseases to be controlled, but the preferred effective amount is usually from about 0.1 lb. to about 50 lbs. per acre of the active ingredient.
As a seed protectant, the amount of fungicide coated on the seed is usually at a dosage rate of from about 0.1 to about 20 ounces per hundred pounds of seed.
As a soil fungicide the compound can be incorporated in the soil or applied to the surface usually at a rate of from about 0.1 to about 50 lbs. per acre. As a foliar fungicide, the compound is usually applied to growing plants at a rate of from about 0.25 to about 10 lbs. per acre.
Fungicides which can be combined with the fungicides of this invention include:
(a) dithiocarbamate and derivatives such as:
ferric dimethyldithiocarbamate (ferbam), zinc dimethyldithiocarbamate (ziram), manganese ethylenebisdithiocarbamate (maneb) and its coordination product-with zinc ion (mancozeb), zinc ethylenebisdithiocarbamate (zineb), zinc propylenebisdithiocarbamate (propineb), sodium methyldithiocarbamate (metham), tetramethylthiuram disulfide (thiram), the complex of zineb and polyethylene thiuram disulfide, 3,5-dimethyl-1,3,5-2H-tetra-hydrothiadiazine-2-thione (dazomet); and mix-tures of these and mixtures with copper salts;

- ~G-)X

11(J~521 (b) nitrophenol derivatives such as:
dinitro~ methylheptyl)phenyl crotonate (dinocap), 2-sec-butyl-4,6-dinitrophenyl-3,3-dimethylacrylate (binapacryl), and 2-sec-butyl-

4,6-dinitrophenylisopropyl carbonate;
(c) Heterocyclic compounds such as N-trichloro-methylthiotetrahydrophthalimide (captan), N-trichloromethylthiophthalimide (folpet), 2-heptadecyl 2-imidazole acetate (glyodine), 2-octylisothiazol-3-one, 2,4-dichloro-6-(o-chloro-anilino)-s-triazine, diethyl phthalimidophosphoro-thioate, 4-butyl-1,2,4-triazole,5-amino-1-[bis-(dimethylamino)-phosphinyl]-3-phenyl-1,2,4-triazole, 5-ethoxy-3-trichloromethyl 1,2,4-triadiazole, 2,3-dicyano-1,4-dithiaanthraquinone (dithianon), 2-thio-1,3-dithio-[4,5-b] quin-oxaline (thioquinox), methyl l-(butylcarbamoyl)~
2-benzimidazole carbamate (benomyl, 2-(4'-thiazolyl)benzimidazole (thiabendazole), 4-(2-chlorophenylhydrazone)-3-methyl-5-isoxa-zolone, pyridine-2-thio-1-oxide, 8-hydroxy-quinoline sulfate and metal salts thereof; 2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiin-4,4 dioxide-2~3-dihydro-5-carboxanili-do-6-methyl-1,4-oxathiin,~-(phenyl)-~-(2,4-dichloro-phenyl)-5-pyrimidinyl-methanol (triarimol), cis-N-[(1,1,2,2-tetrachloroethyl) thio]-4-cyclohexene-1,2-dicarboxyimide, 3-[2-(3,5-dimethyl-2-oxycyclohexyl-2-hydroxy]-glutarimide 52~

(cycloheximide), dehydroacetic acid, N-(l,l,-2,2-tetrachloroethylthio)-3a,4,7,7a-tetra-hydrophthalimide (captafol), 5-butyl-2-ethyl-amino-4-hydroxy-6-methylpyrimidine(ethirimol), acetate o~ 4-cyclododecyl-2,6-dimethylmorpholine (dodemorph), and 6-methyl-2-oxo-1,3-dithiolo-[4,5-b]quinoxaline (quinomethionate).
(d) miscellaneous halogenated fungicides such as tetrachloro-p-benzoquinone (chloranil), 2,3-dichloro-1,4-naphthoqui.none (dichlone), 2,3-dichloro-2,5-dimethoxybenzene (chloroneb), 3,5,6-trichloro-o-anisic acid (tricamba), 2,4,5,6-tetrachloroisophthalo nitrile (TCPN), 2,6-dichloro-4-nitroaniline (dichloran), 2-chloro-l-nitropropane, polychloronitroben.zenes such as: pentachloronitrobenzene (PCNB) and te~rafluorodichloroacetone;
(e) fungicidal antibiotics such as:
griseofulvin, kasugamycin and streptomycin;
(f) copper~based ~ungicides such as:
cuprous oxide, basic cupric chloride, basic copper carbonate, copper naphthenate and Bordeaux mixture; and (g) miscellaneous fungicides such as:
diphenyl, dodecylguanidine acetate (dodine), phenylmercuric acetate, N-ethylmercuri-1,2,3,6-tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexa-chlorophthalimide, phenylmercuric monoethanol ammonium lactate, p-dimethylaminobenzenediazo `

sodium sulfonate, methyl isothiocyanate~ l-thiocyano-2,4-dinitrobenzene, l-phenylthio-semicarbazide, nickel-containing compounds, calcium cyanamide, lime sulfur, sulfur, and 1~2-bis(3-methoxycarbonyl-2-thioureido) benzene (thiophenatemethyl).
The compounds of this invention can be advantageously employed in various ways. Since these compounds possess broad spectrum fungicidal activity, they can be employed in the storage of cereal grain. These complexes can also be employed as fun.~icides in turf, fruit orchards, vegetables and golf course applications. Other applications o~ the compounds of this invention will suggest themselves to those skilled in the art o~ agriculture and horticulture.
The following examples illustrate the compounds o~
this invention and the methods by which they may be prepared.
However, the examples are illustrative only and it will be apparent to those having ordinary skill in the art that all of the products embraced by Formula I, supra, may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.

- 2~ -...... ~`

76-78l~

~10~52~

EXAMPLE 1 - 3-Imi:~ophenylmethyl-4-(3-carbomethoxy-S-meth~lisothi?ureido)benzophenone_ Sl;e~ A - ~-Iminophen~lmeth~1-4-aminobenzophenone ~o a solution of 3,~-diaminobenzophenone (4.2~ g.; 0.02 mole) in methanol (50 ml.) cooled to O~C. is added benzaldehyde (2.12 g.; 0.02 mole). ~he solution is stirred aL 0C. for one hour. The prscipitate is collected by filtration and dried to yield 3.0 g. of 3-iminophenyl-methyl-4-aminobenzophenone, m.p. 112-116C.
Elemental analysis for c20T~16N20 Calc.: C, 79.97; H, 5.37; N, 9.33 Found: C, 80.11; H, 5.57; N, 9.28 Step B - 3-Iminophenylmethyl-4-(3-carbomethoxy-thioureido~benzophenone ~o a solution of 3-iminophenylmethyl-4-aminobenzophenone (0.5 g.; 0.00166 mole) in diethylether (100 ml.) is added carbomethoxy isothiocyanate (0.19 g.;
0.00166 mole~. ~he solution is stirred at room temper~ture for three hours. lhe precipitate is collected by filtration and dried to yield 0.35 g. of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone, m.p. 194-195~C. (dec.).
Elementa' analysis for C23~19N303S
Calc.: C, 66.17; H, 4.59; N, 10.07 Found: C, 65.81; H, 4.53; N, 9.80 Ste~ C - 3-Iminophenylmethyl-~-(3-carbomethogy-S-methYlisothioureido)benzo~henone _ lo a solution of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone (1.1 g.; 0.0026 mole) in dim~thylformamide (10.0 ml~) is added water (3.0 ml.). Additional dimethylformamide (25.0 ml.) is SZ~

added to dissolve some precipitate and th~3n sodium hydroxide {50% aqueous; 0.21 g.; 0.0026 mole) is added. ~he resulting solution is stirred at room temperature for 1-l/2 hours and then methyl iodide (o.38 g.; 0.0026 mole) is added. ~he solution is stirred for one hour at room temperature and then poured into water (250 ml.). ~he precipitate is collected by filtration and dried to afford 0.95 g. of 3-iminophenylmethyl-~-(3-carbomethoxy-S-methylisothioureido) benzophenone, m.p. 140-1~2C. (dec.).
Elemental analysis for C24X21N303S
Calc.: C, 66.80; H, ~.91; N, 9.7 Found: C, 65068; H, 4.86; N, 10.4~

EXAMPLE 2 - 3-Iminophenylmethyl-~-(3-carbomethoxy-S-methyl-isothioureido)benzoPhenone To a suspension of 3-iminophenylmethyl-~-(3-carbomethoxythioureido)benzophenone (2.09 g.; 0.005 mole) in a mixture of acetone (20 ml.) and water (3.0 ml.) is added aqueous sodium hydroxide solution (50~; 0.4 g.). ~he mixture is stirred for one hour at room temperature. To the solution is added methyl iodide (0.71 g.; 0.005 mole). Within two minutes a thick suspension forms. ~dditional acetone (20 ml.3 and water (3.0 ml.~ is added and stirrin~ is continued for 18 hours. ~he precipitate is collected by filtration and dried to afford 2.05 g. of 3-iminophenylmethyl-~-(3-carbomethoxy-S-methylisothioureido)benzophenone, m,p.
157-158C. (dec.).
Elemental analysis for C2~H21N303S
Calc.: C, 66.80; H, 4.91; N, 9.7~
Found: C, 66.31; H, ~.83; N, 9.95 ~6-78~

5Zl EXAMPLE ~ - 2-Imino(2,5-dichloro)phenylmethyl-4-(3-carbo-methox~-S-meth~lisothioureido)benzophenone ~tep A - 2-Imino-(2,6-dicnloro)phenylmetnyl-4-aminobenzophenone ~o an ice cooled solution of 3,4-diaminobenzophenone (8.48 g.; 0.04 mole) in methanol (100 ml.) is added a solution of 2,6-dichlorobenzaldehyde (7.06 g.; 0.04 mole) in methanol (100 ml.). ~he solution is stirred at 0C. for one hour and at room temperat1~ e over the week-end. The precipitate formed is collected by filtration and dried to afford 11.5 g. of 2-imino-~2,6-dicnloro)phenylmethyl-4-aminobenzophenone, m.p. 141-144C.
Step B - 3-I~ino(2,6-dichloro)phenylmethyl-4~ -carbomethox~thioureido)benzophenone To a solution of 2-imino-~2,6-dichloro)-phenylmethyl-4-aminobenzophenone (2.08 g.; 0.005 mole) in diethyl e-ther (600 ml.) is added carbomethoxy isothiocyanate (0.88 g.; 0.0075 mole). ~he solution is stirred at room temperature for 18 hours. ~he precipitate which forms is collected and dried to yield 1.8 g. of 3-imino(2,6-dichloro) phenylmethyl-4-(3-carbomethoxythioureido)benzophenone, m.p.
197C. (dec.).
Elemental analysis for C23H17C12N303S
Calc.: C, 55.79; H, 3.52; N, 8.64 Found: C, 57.~9; H, 3.66; N, 8.84 Step C - 3-Iminophenylmethyl-4-(3-carbomethoxy-S-metnYl-isothioure_ o)b_nz_Phenon~
~o a solution of 3-imino(2,6-dichloro)-phenylmethyl-4-(3-carbometho~ythioureido)benzophenone (2.43 g.; 0.005 mole) in dimethylformamide (100 ml.) is added water (5.0 ml~) and then sodillm hydroxide (50~ aqueous;
0.4 g.; 0~005 mole). ~he solution is stirred for 1-1/2 h~urs ~ 5 2 1 and then methyl iodide (0.71 g.; 0.005 mole) is added.
T'ne solution is stirred for one-hall hour. ~he pracipitate which formS is collected b-y ~ilt~ation and dried to afford 1.3 g. of 3-imin~phenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 63-68C. (dec.).
Elemental analysis for C2 ~ 1gCl2N303S
Calc.: C, 57.60; H, 3.83; N, 8.40; S, 6.41 Found: C, 55.65; H, 3.8C N, 8.48; S, 5.84 EXAMPLE 4 - 3-Imino-(4-methylphenyl)methyl-4-(3-carbo-ethoxY-S-meth~rlisothioureido)benzo~henone SteP A - 3-Imino-(4-methylphenyl)methyl-4-aminobenzo~henone ~o an ice cooled solution of 3,4-diaminobenzophenone (6.36; 0.03 mole) in methanol (75 ml.) is added ~-tolualdehyde (3.6 g.; 0.03 mole).
~he solution is stirred at 5C. for one hour and at room temperat~re for 18 hours. A precipitate is collected by filtration and dried to a~ford 4.5 g. of 3-imino-(4-methyl)phenylmathyl-~-aminobenzophenone~ m.p~ 136-137C~
~ - 3-~mino-(~-methylp~snyl)methyl-4-(~-carbomethox-~thioureido)benz?~henone ~o a solution of 3-imino-(4-methyl-phe~yl)methyl-4-aminobenzophsnone (4.5 g.; 0.0145 mole) in dimethoxyethane (75 ml.) and diethyl ether (25 ml.) is added carbometho~ isothio-yanate (1.68 g.; 0.0145 mole). ~he solution is stirred at room temperaturefor 10 minutes ~t which time a precipitate begins to form.
Sr,irring is continued at room temperature for one ho~r and the precipitate is collected by filt~ation and dried to afford 3.9 g. of 3-imino-(4-methylphenyl)methyl-4-(3-ca~bometho~Jthioureido)benzophenone, m.p. 201-202C.
(dec.).

':~'~1 ~!
,~ ., 76-73~\
~ 5 2 1 Eiemental analysis for C24H21N3 3 Calc.: C, 66.80; ~, 4.91; N, 9.74 Found: C, 66.73; H, 4.79; N, 10.18 Ste~ C - 3-Imino-(4-meth~Jlphenyl)methyl-~-(3-carbomethoxy-S-methylisothio-ureido)~benzophenono __ To a solution of 3-imino-(~-methyl-phenyl)methyl-~-(3-carbomethoxythioureido)benzophenone (2.0 g.; 0.00463 mole) in dimethylformamide (100 ml.) and water (5 ml.) is added sodium hydroxide (50~ a¢ueous; 0.37 g.). The solution is stirred at room temperature for one hour at which time methyl iodide (0.66 g.; o. 00463 mole) is added. The solution is stirred at room temperature for 20 minutes and then poured into water (1.0 1.). A
precipitate forms and is collected b~ filtration and dried to afford 2.1 g. of 3-imino-(4-methylphenyl)m3thyl-4 (3-carbomethoxy-S-mQthylisothioureido)banzophenone, m.p.
40-45Co (dec.).
Elemental æalysis for C25E23N303S
~ Calc.: C, 67.39; H~ 5.20; N, 9.43; S, 7.20 Found: C, 66.81; H, 5.22; N, 9.9~; S, 7.23 EXAMPLE ~ - 3-Imino-(4-chlorophenyl)~ethyl-4-(3-carbo-meth,o,x~L-S-meth~lisothioureido)benzoPhenone Step A - 3-Imino ~4-cnlorophenyl)methyl-4-aminobenzophenone To an ice cooled solution of 3,4-dia~inobenzophenone (8.4 g.; 0.04 mole) in methanol (100 ml.) is added ~-chlorobenzaldehyde (5.6 g.; 0.0~ mole).
The solution is stirrad at 0-5C~ for one hour and at room kemperatllre for 18 hours. The precipitate wnich formis is collected and dried to afford 9.2 g. of 3-imino-(4-chlorophenyl)~ethyl-4-aminobenzophenone, m.p. 123-125C.

ll~fL~SZl ~lemental analysis for 5 H ClN 0 Calc.: C, 71.74; H, 4.52; H, 8.37 Found: C, 7.87; H, 4.43; N, 8.60 Ste~ B - 3-Imino-(4-chlorophenyl)methyl-4-(~-carbometho~gthioureido)benzop_en~ne ~o a solution of 3-imino-(4-chlo.o)-phenylmethyl-4 aminobenzophenone (7.9 g.; 0.02 mole) in diethyl ether (700 ml.) is added car~omethoxy isothio-cyanate (2.34 g.; 0.02 mole). ~he solution is stirred at room temperature for 18 hours. ~he precipitate which forms is collected by filtrat-7On and dried to afford 6.6 g. of 3-imino (4-chloro~phenylm~thyl-~-(3 carbomethoxy-thioureido)-benzophenone, ~.p. 212-216C. (dec.).
Elemental analysis for C23H18ClN303S
Calc.: C, 61.12; H, 4.01; N, 9.30 Found: C, 61.37; H, 4.06; N, 9.72 - 3,-I~ino-(4-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothio-ureido)benzophenone ~o a solutlon of 3-imino-(4-chloro-phenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.52 g; 0.01 mole) in dimethylformamide (200 ml~) and water (5.0 ml.) is added aqu~ous sodium hydroxide (50%
aqueous; o.8 g.). ~he solution is stirred at room temperature for one hour and then methyl iodide (1.42 g.;
0.01 mole) is added. ~he solution is stirred at room temperature for 25 minutes and then poured into water (700 ml.). The suspension which forms is then stirred for 5 minutes and the precipitate is collected by filtration and dried to afford 4.3 g. o~ 3-imino-(4-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothio-ureido)benzophenone, m.p. 156-157C. (dec.).

~ 5 Z~

Elemental analysis ~or C24H20ClN303S
Calc.: C, 61.86j H, 4.33; N, 9.02 Found: C, 60.97; H, 4.21; N, 9.51 EXAMPLE 6 - 3-Iminophenylmethyl-4-(3-carbomet'noxy-S-benzYlisothiourQdo)benzo~henone To a solution of 3-iminophenylmethyl-4-(3-carbomethoxy~hioureido)benzophenone ~2.~5 g.; 0.0054 mole) in dimethylformamide (lO0 ml.) and water (10 ml.) there is add~d aqueous sodium hydroxide solution (50~; 0.4~ g.).
~he solution is stirred at room temperatu~ for one hour and then benzyl bromide (0.93 g.; 0.0054 mole~ is added.
~he solution is stir~ed at room temperature ~or 15 minutes and is then poured into 500 ml. of water. ~he suspension which forms is stirred at room temperatuxe for 5 minutes and then collected by filtration and dried to afford 2.45 g. of 3-iminophenylmethyl-~-(3-carbomethoxy-S-benzylisothioureido)benzophenone, m.p. 50-70C. ~dec.).
Elemental anal~s for C30H25N303S
Calc.: C, 70.98; H, 4.96; N, 8.28 Fo~md: C, 69.~4; H, 4.98; N, 8.90 EXAMPLE 7 - 3-Iminophenylmethyl-4-~3-carbomethoxy-S-allvlisothio~reido)benzo~henone _ _ ~o a suspension of 3-iminophen-~lmethyl-~-(3-carbomethoxythioureido)benzophenone (2.09 g.; 0.005 mole~ in acetone (40 ml.) and water (6.0 ml.) is added an aqueous sodium 'nydroxide solution (50~ aqueous; 0.4 g.).
~he suspension is stirred at room temperature for one hour and then allyl bromide (0.6 g.; 0.005 mole) is added and the solution is stirred at room temperature over the week-enA. ~he precipitate which forms is collected by filtration 76-78~
l~rJ~5~1 and then dried to afford 1.3 g. of 3-iminophenylmethyl)-4-(3-carbomethoxy-~-allylisothioureido)ben7Ophen3ne, m.p.
125-127C.
Elemental analysis for C26H23N303S
Calc.: C, 68.25; H, 5.07; N, 9.18 Found: C, 67.93; H, 4.93; N, 8.79 EXAMPLE 8 - 1-(3-Carbomethoxy-S-methylisothioureido)-2-amino~henylmethyl-~-prop~lthiobenzene _ _ Ste~ A - 1-(3-Carbomethoxythioureido)-2-nitro-5-propylthiobenzerle ~ a stirred mixture of 2-nitro-5-propanyl~hioaniline ~1.2 g.; 0.10 mole) in acetonitrile (50 ml.) isadded portionwise carbometh~xy isothiocyanate (11.7 g.; 0.10 mole). ~he reaction mixture is maintained av room temperature and is filtered to remove a small amount of dark colored insoluble material. The clear filtrate was permitted to stand at room temperature for two hours an~ the precipitate which forms is collected by filtration, washed with cold acetonitrile and dried to yield 1-(3-carbom~thoxythioureido~-2-nitro-5-propylthiobenzene (17.9 g.), m~p. 122~-125C.

Ste~ B - 1~(3-Carbomethoxythioureido)-2-amino-~-pro~ylthiobenzene A mixture o~ 1-(3-carbomethoxythio-ureido)-2-nitro-5-propylthiobenzene (~ g.; 0.013~ mole), stannous chloride ~15.2 g.; 0.067 mole), concentrated hydro-chloric acid (25 ml.), methanol (50 ml.) and aceti^ acid (50 ml.) is stirred and refluxed for one half hour. ~he reaction mixture is poured into ice water and basified with 50~ aqueous sodium hydroxide solution. This solution is extracted with dichloro~ethane and the dichloromethane removed to afford 3.8 g. of l-(3 carbomethoxythioureido)-2-amino-5-propylthiobenzene.

3o ~ 5 Z~

Step C - 1-(3-Carb~methoxythioureido)-2-iminophenylmethyl-5-prop~lthio-benzene ~o an ice-cooled solution of 1-(3-carbomethoxythioureido)-2 amino-5-propylthiobenzene (1.0 g.; 0.0033~ mole) in ri'ethanol (100 ml.) is added benzaldehyde (0.35 g.; 0.00334 mole). The solution is stirred at 5C. for an hour and the precipitate which forms is collected by filtration and dried to afford 0.6 g.
of l-(3-carbomethoxythioureido)-2-imin3phenylmethyl-5-pro-pylthiobenzene, m.p. 109-110C.
Elemental analysis for C19H21N302S2 Calc.: C, 58.89; H, 5.~6; N, 10.8`~
Found: C, 58.85; H, 5.46; N, 11.02 Step D - 1-(3-Carbo~ethoxy-S-methylisothio-ureido)-2-iminop~enylmethyl-5-propyl-thiobenzene_ ~o a solution of 1-(3-carbomethoxythio-ureido)-2-iminophenylmethyl-5-propyltAiobenzene (0.5 g~;
0.00129 mole) in acetone (20 ml.) and water (3.0 ml.) is added an aqueous sodium hydroxide solution (50~; 0.103 g.).
The solution is stirred at room temperat~lre for 1-1/2 hours and then msthyl iodide (0.183 g.; 0.00129 mole) is added.
lhe reaction mixture is sl.irred at room temperature for one hourand then poured in water (100 ml.). ~he suspension formed is stirred at room temperature for 1-1/2 hours an~
then the precipitate collected by filtration an~ dried to afford 0.35 g. of 1-(3 carbomethoxy-S-methylisothioureido)-2-iminophenylmethyl-5-propylthiobenzene, m.p. 80-83C.
33 (dec.).
Elem~ntal analysis for C20iI23N303S2 Calc~: C~ 59u82; X, 5.77; N, 10.~6; S, 15.97 Found: C, 59.73; H, 5.88; N, 10.3~; S, 15.89 SZl EXAMPLE 9 - 1-(3-Carbomethoxy-~-methylisothioureido)-2-iminophenylmethyl-4-benzen~r7sulfonylbenzene Ste~ A - 2-I~inophenylmethyl-4-benzenesulfonyl-aniline ~o an ice-cooled solution of 2-ami~o-4-benzenesulfonylaniline ~5.2 g.; 0.021 mole) in methanol (25 ml.) is added benzaldehy~e t2.23 g.; 0.021 mole). ~he solu-tion is stirred at 0C. for 1-1/2 h~urs. A suspension forms which is stirred at room temperature overnight and then the precipitate collected by filtration is ~ashed with methanol and then ether and then dried to afford 6.0 g. of 2-iminophenylmethyl-4-benzenesulfonylaniline, mOp~ 159-160C.
Elemental analysis for CL9Hl6N202s Calc.: C, 67.83; H, 4.79; N, 3.33 Found: C, 67.54; H, 4.90; N, 8.62 ~'ep B ~ 3-Carbomethoxythioureido)-2-imino-~henylmeth~1-4-benæenesulfon.ylb~nzene To a solution of 2-iminophenylmethyl-4-benzenesulfonylaniline (4.5 g.; 0.0134 mole) in acetone (250 ml.) is added carbomethoxy isothiocyan~te (1.57 g.;
0.0134 mole)~ ~he sollltion is stirred at room temperature for two hours a~d the precipitate which forms is collected by filtration, washed with et'ner and dried to afford 2.15 g. of 1-(3-carbomethoxythioureido)-2-iminophenylmethyl-4-benzenesulfonylbenzene, m.p. 207-208C. (decO).
Elemental analysis for C22X19N304S2 Calc.: C, 58.26; H, 4.22; N, 9.27 Found: C, 58032; H, 4.14; N, 9.40 }S21 Step C - 1-(3-Carbomethoxy-S-meth~lisothioureido)-2-iminophen~lmethyl-1+-benzenesulfonyl-benzene ~o a suspension of 1-(3-carbo~ethoxy-thioureido)-2-iminophenylmethyl-1+-benzenesulfonylbenzene (1.0 g.; 0.0022 mole) in acetone (10 ml.) and water (1.0 ml.) there is added an aqueous sodium h-Jdroxide solution (50~;
0.18 g.). This mixture is stirred at room temperature for 2 hours and a fine suspension which forms is removed by filtration. ~o the filtrate is added methyl iodi~e (0.313 g.; 0.0022 mole). The solution is stirred at room temperature ~or 8 days. The reaction mixture is filtered and to the filtrate is added water (300 ml.) and the resultin~ mixture is stirred at room temperature for 3 h~urs. ~he precipitate which forms is collected by filtration and dried to afford 0.3 g. of l-(3-carbomethoxy-S-m3t'nylisothioureido)-2-imino-phenylmethyl-4-benzen~sulfonylbenzene.
Elemental analysis for C23H21N30l+S2 Calc.: C, 59.o8; H, 4.53; N, 8~99 Found: C, 58.67; H, 4.39; N, 8.79 EX~MPLE 10 - 3-Iminophen-~lmet'nyl-4-(3-carbomethox~-S-butyl-isothioureido)benzophenone ~o a suspension of 3-iminophenylmethyl-l+-(3-carbom~thoxythioureido)benzophenone (3.12 g.; 0.0075 mole) in acetone (60 ml.) an1 water (10 ml.) there is added an aqueous solution of sodium hydroxide (50%; 0.6 g.). ~he mixture is stirred at roo~ temperature for 1-1/~+ hours and to the solution form there is added n-butyl iodide (1.38 g.;
0.0075 mole). ~ne solution is stirred at room temperature 3 for 2 hours and the suspension which forms is collected by filtration, washed with ether and dried to afford 1.9 g~

76-78l-~

~ 2 ~

of 3-iminophenylmethyl-4-(3-carbomethoxy-S-n-butylisothio-ureido)benzophenone, m.p. 105-107C. (dec.).
Elemental analysis for C27X27N303S
Calc.: C, 68.47; H, 5.75; N, 8~87 Found: C, 67.56; H, 5.77; N, 8~52 EXAMPLE 11 - 3-Iminophenylmethyl-~-[3-carbomethoxy-S-(2,6-dichlorophen"vl)isothiol~reido3benzophenon~
~o a suspension of 3-iminophenylmethyl-4-(3-carbometho~Jthioureido)benzophenone (3.12 g.; 0~0075 mole) in acetone (60 ml.) a;~d water (10 ml.) is added an aqueous solution of sodium hydroxide (50~; o.6 g.). ~he mixture is stirred at room temperature for 2 hours and then ~-bromo-2,6-dichlorotoluene (1.3 g.; 0.0075 mole) is added. ~his solution is stirred at room temperaturefor one half hour. ~he precipitate which forms is collected by filtration, washed with ether and dried to afford 2.5 g. of 3-iminophenJlmethyl-4-[3-carbomethoxy-S-(2,6-di-chlorophen~rl)isothioureido]benzophenone, m~p. 148-150C.
(dec.).
Elementa' analysis for C3~H23C12N
Calc.: C, 62.50; H, 4.02; N, 7.29 Found: C, 61.64; H, 3.95; N, 7.21 EXAMPLE 12 - 3-(Imino-(4-nitrophenyl)methyl-4-(3-carbo-meth?x-~-S~methvlisothioureido)benzo~henone S'.e~ A - 3-Imino-(4-nitrophenyl)methyl-4-aminobenzopheno,ne_ ~o a solution of 3,4-diaminobenzo-phenone {8~48 g.; 0.04 mole) in methanol (100 ml.) is added P-nitrobenzaldehyde (6.o4 g.; 0.04 mole). ~he re-action mixture is stirred for 5 days and the precipitate is collected by filtration and dried to afford 12.45 g.
of 3-imino-(4-nitrophenyl)methyl 4-a~inobenzophenone, m.p. 161-163C. (dec.)~

~ 34 ~

76-78l~\

~ 5 21 Ste~ B - 3-Imino-(4-nitro~henylmeth-yl)-~-(3-carbomethox~thioireido)benzoPhenone To a solution of 3-imino-~4-nitro-phenylmethyl-4 aminobenzophenone (6.9 g.; 0.02 mole) in acetone (225 ml.) there is added carbomethoxy isothio-cyanate (2.3~ g.; 0.02 mole). ~he solution is stirred at room temperature for 18 hours. ~he precipitate which forms is collected by filtration and then dried to afford 7.35 g. of 3-imino-(4 nitrophenylmethyl)-~-(3-carbomethoxythio~lreido~benzophenone, m.p. 229-230C.
(dec.).
Ste~ C - 3-Imino-(~-nitrophenyl)methyl-4-(3-carbomethoxy S-methylisothio-ureido)benzo-~henone To a suspension of 3 imino-(~-nitro-phen~Jlmethyl)-4 (3 carbomethoxythioureido)benzophenone (4.62 g.; 0.01 mo'e) in acetone (160 m'.) and water (24 ml.)there is added an aqueous solution of sodium hydroxide (50~; o.8 g.). ~he solution is stirred at room temperature for one hour at which tlme methyl iodide (1.42 g.; 0.01 mole) is added. ~he Sllspension forms and the reaction mixture is stirred for 30 minutes. lhe precipitate is collected by filtration, washed with ether and dried to afford 2.55 g. of 3-imino-(4-nitrophen-~l)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p.
180-182C. (dec.).
Elemental analysis for C24~2oN405S
Calc.: C, 60.49; H, 4.23; N, 11.76 Found: C, 60.90; H, L.33; N, 11.87 ~ 5 21 EXAMPLE l~ - 3-Imino-(2~ap~hylmethy~-4 (3-carbometho~y-Step A - 3~Imino-(2-naphthy ~ thyl )-4-amino-benzoPhenone ~o an ice cooled solution of 3,4-diaminobenzop'nenone ~10.6 g.; 0.05 mole) in-methanol (120 ml.) is added 2-sphthy ~ thyl (7.8 g.; 0.05 mole).
The solution is stirred at 5C. for 2 hours at room temperature overnight. Sulfuric acid (5 drops) is added 10 and the solution st~ red an additional 5 days at room tem-perat~re. ~he ~re~ipitate is collected by fil~ration and dried to afford 5.25 g. of 3-imino-(4-nitrophenyl)methyl-~-aminoben20phenone, m.p. 141-143C. (dec.).
Elemental analysis for C24H18N20 Calc.: C, 82.26; H, 5.18; N, 8.00 Found: C, 81.53; ~, 4.98; N, 7.19 SteP B - 3-Imino-(2-~a~hthylmethy~ (3-ca~bomethox~It -oureido)benzo~henone ~o a solution of 3-imino-(2-naphthyl) 20 4-(aminobenzophenone) (4.0 g.; 0. OllL~ mole) in acetone (50 ml.) is add~d carbomethox~ isothiocyanate (1.34 g.; 0.0114 mole). A suspension forms within 5 minutes and stirring is continued at room temperature for 18 hours. ~hs pre-cipitate is collected by filtration, washed successively 25 with acetone and ether and then dried to af~ord 3.1 g. of 3-imino-(2-naPhthY ~ ~Y~ 3-carbomethoxythioureido~-benzophenone, m.p. 207-209C. (dec.~.
Elemental analysis for C27H2~M303S
Calc.: C, 69.36; H, 4.53; N, 8.99 Found: C, 69~37; H, 4.58; N, 8.83 ; 36

5~ ' Ste~ C - 3-Imino-~2-r~phthyllrethy~ (3-carbomel;ho~y-S-msthylisothioureido)-ben~.o~henone ,.. .
'rO a suspension of 3-imino-(2-naphthyl-methyl)-~-(3-carbomethoxythioureido)benzophenone (2.5 g.; r 0.0535 mole) in acetone (25 ml.) and water ~3 ml.) there is added an aqueous sodium hydroxide solution (50~; 0.43 g.).
The mixture is stirred at room temperature ~or 18 hours and then filtered. To the filtrate is added methyl iodide (0.76 g~; 0.00535 mole). The precipitate for~rs within 5 minutes. ~he suspension is stirred at room temperature for 30 min~ltes arld the precipitate is collected by filtration, washed with ether and dried to af~ord o.8 g. of 3-imino-(2- naphthyl methyl)-4-(3-carbomet~ox-y-s-methylisothioureido) benzopheilone, m.p. 147-149.5C. (dec.).
EleD;ental analysis for C28~I23N303S
Calc.: ~, 69.83; ~I, 4.81; N, 8.73 Found: C, 69.28; H, 4.82; N, 8.50 EXAMPLE lL~ - 3-Imino-(4~methoxyphenylmethyl) 4-(3 carbo-methoxy-S-methylisothioureido~benzophenone Ste~ A - 3-Imino-~4-methoxyphenylmethyl~
aminobenzo~hsnone ~o an ice-cooled solution OI 3,4-diaminobenzophenone (10.6 g.; 0.05 mole) in methanol (120 ml.) is added ~-anisaldehyde (6.8 g.; 0.05 mole). ~he solution is stirred at 5C~ for 2 hours and at room tempe~ature for 18 hours. Sulfuric acid (5 drops) is added to the solution and it is stirred an additional 9 days at room temperaturQ.
~he precipitate is collected by filtration, washed with ether and then dried to afford 4.2 g. o~ 3-amino-(4~ethoxyphenyl-methyl)-4-aminobenzophenone, m.p. 129-131~. ~dec.).

h~-~
, ~ , 76-78l~
~lU~;2~

Step B - 3-Imino-(4-methoxyphen~lmethyl)-~-~-carbomethoxvthioureido)benzoPheno~e To a soluti~n ~f 3-imino-(~-metho~J-phenylmetnyl)-~-aminobenzophenone (4.29 g.; 0.0127 mole) in aceto~e (75 ml.) is added carbomethoxy isothiocyanate (1.49 g.; 0.027 mole). ~he solution is stirred a', room temperature for 18 hours (a precipitate forms within 3 minutes). ~ke precipitate is collected by filtration, washed with ether an~ then dried to afford 3.3 g. of 3-imino-(~-methoxyphenylmeth-~1)-4-(3-carbomethoxythio-ureido)benzophenone, m.p. 182-18~C. (dec.).
Step C - 3-Imino-(4-met~yphenylmethyl) 4-(3-carbomethoxy-S-methylisothioureido)-benzo~hen,~ne __ _ To a suspension of 3-imino-(4-methoxy-phenylmethyl)-~-(3-carbomethoxythioureido)benzophenone (2.5 g.; 0.0056 mole) in acetone (20 ml.) and water (~ ml.) there is added an aqueous solution of sodium ~ydroxide (50%; 0.45 g.). Ths reaction ~ixture is stirred at room temperature for two hours. A solid which forms is removed by filtra-tion and to the clear filtrate is added methyl iodide (0.79 g.; 0.0056 mole). A precipitate forms within 5 minutes~ ~he suspension is stirred a' room temperature for 30 minutes and the precipitate is collected by filtra-tion, washed with ether and dried to afford 1.1 g~ of 3-imino-(4-m-thoxyphenylmethyl)-~(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 136-13~3C. (dec.).
Elemental analysis for C25'H23N30,~S
Calc.: C, 65.06; H, 5.02; N, 9.10 Found: C~ 6~.87. H, 5.0~; N, 8.87 76-78l~
~ 21 ,, EXAMPLE 15 - 3-Imino-(2-nitrophenylmethyl)-4-(3-carbo-meth~x~--S-methylisothioureido~benzo henone Ste~ A - 3-Imino-(2-nitrophenylmethyl)-4-aminobenzophenone ~o an ice-cooled solution of 3,4 diaminobenzophenone (8.48 g.; 0.04 mole) in methanol (100 m .) there is added o-nitrobenzaldehyde (6.04 g.;
0.04 mole). The mixture is stirred a'~ 5C~ for one hour and at room temperature for 18 hours. Sulfuric acid (3 drops) is added to the solution and then within one hour a suspension forms. ~he suspension is stirred at room temperature for 18 hours and a precipitate collected by filtration, washed with et'ner and dried to afford 10.85 g.
of 3-imino-(2 nitrophenylmethyl)-4 aminobenzophenone, m.p. 140-142C. ~dec.). This material is used in the next step without further purification.
Step B - 3-Imi;o-(2-nitroph3nylmethyl)-4-(3-carbomethox~thioureido)benzo~,henone ~o a solution of 3 imino-(2-nitro-phenù71meth~1)-4-aminobenzophenone (10.0 g.; 0.029 mole) in acetone (100 ml.) is added carbomethoxy isothiocyanats (3.4 g,; 0.029 ~ole). ~he solution is stirred at room temperature for 3 hours and the precipitate coll~cted by filtration and dried to afford 7.3 g. of 3-imino-(2-nitro-phenylmethyl)-4-(3-carbomethoxythioureido)benzophenone, m.p. 215-217C. (dec.).
Element,al analysis for C23H18N~05S
Calc.: C, 59.73; H, 3.92; N, 12.12 Found: C, 59.65; H, 3.98; N, 12.28 76-7~i~

Step C - 3-Imino-t2-nitrophenylmethyl)-4-(3-carbomethoxy-S-methylisothioureido)-benzophenone ~o a suspension of 3-imino-(2-nitro-phenylmethyl)-4-(3-carbomethoxythioureido)benzophen~ne (4.62 g.; 0.01 mole) in acetone ~160 ml.) and water (24 ml.) is added an aqueous solution of sodium hydroxide (50%;
0.8 g.). ~he mixture is stirred at room temperature for one hour anl a fine precipitate which forms is removed by filtration. lo the filtrate is added methyl iodide (1.42 g.; 0.01 mole~ and the solution stirred at room temperature for 45 minutss. Ihe precipitate which forms is collected by filtration and dried to afford 2.65 g.
of 3-imino-(2-nitrophenylmethyl~-4-(3-carbometh~xy-S-methylisothioureido)benzophenone, m.p. 167-168.5C. (dec.).
Elemental analysis for C24H20N405S
Calc.: C, 60.49; ~, 4.23; N, 11.76 Found: C, 60.55; X, 4.26; N, 11.65 EXAMPLE 16 - 3-Imino-(3,4-dichlorophenylmethyl)-4-(3-carbomethox~-S-meth~liso'.hioureido)benzophenone Ste~ A - 3-Imino-(3,4-dichlorophenylmethyl)-~-aminobenzoPhenorle To a solution of 3,4-diaminobonzo-phenone (6.15 g.; 0.029 mole) in methanol (103 ml.~, cooled to 5C., is added 3,4-dichlorobenzaldehyde (5.08 g.;
0.029 mole). ~he mixture is stirred at 5C. for one hour and at room temperalure for 18 hours. ~he precipitate which forms is collected by filtration and dried to afford 7.96 g. of 3-imino-(3,4-dichlorophenylmethyl)-4-amino-benzophen~ne, m.p. 147-148C.

76 -78,~

Elemental analysis for C20EI14C12N20 Calc.: C, 65.05; H, 3.82; N, 7.59 Found: C, 64.60; H, 3.79; N1 7.49 Step_B - 3-Imino-(3,4-dichlorophenylmeth~J1)-~-(~-carbomethox~thioureido)benzophenone ~o a solution o~ 3-imino-~3,~-dichlorophenylmethyl)-~-a~inobenzophenone (7.0 g.; 0.019 mole) in acetone t200 ml.) there is added carbomethoxy isothiocyanate (2.22 g.; 0.019 mole). A precipitate forms within five minutes. The mixture is stirred at room temperature for 1-1/2 hours and the precipitate which forms is collected by filtration, washed with acetone and then ether and then dried to afford 6.9 g. of 3-imino-~3,4-dichlorophenylmethyl)-~-(3-carbomethoxythioureido)benzo-phenone, m.p. 214-126~C. (dec.).
Elemental analysis for C23X17C12r~303S
Calc.: C, 56.79; H, 3052; N, 8.6 Found: C~ 56.76; H, 3.53; N, 8.43 Ste~ C - 3-Im no-(3,~-dichlorophenylmethyl~-4-(3-carbomethoxy-S-methylisothioureido)-benzoPhenone To a solution of 3-imino-(3,4-dichloro-phenylmethyl~-~-(3-carbomethoxythioureido)benzophenone (3.0 g.; 0.0062 mole) in dimethylformamide ~225 ml.) and water (10 ml.) there is added an aqueous sodium hydroxide solution (50%; 0.49 g.). The solution is stirred at room temperature ~or one hour and then methyl iodide (0.88 g.;
0.0062 mole) is added. ~he solution is stirred at room 'emperature for 20 minut~s and then poured into water (1.0 1.). The susp~nsion is filtsred to collect the precipitate and then dried to afford 2.55 g. of 3-imino-(3,4-dichlorophenylmethyl)-~-~3-carbomethoxy-S-methyliso-thioureido)benzophenone, ~.p. 168-174C. (dec.).

76-78~.

Elemental analysis for C2~H19C12N303S
Calc.: C, 57.60; H, 3~83; N, 8.40 Found: C, 57.22; H, 3.79; N, 8.24 E~ PLE 17 - 3-Imino-(2-chlorophenylmethyl)-4-(3-carbo-methoxy-S-methylisothioureido)benzophenone Step A - 3-Imino-(2-chlo,ophenylmethyl)-4-aminobenzo~henone To an ice-cooled solution of 3,4-diaminobenzophenone (16.96 g.; 0.08 mole) in methanol (200 ml.) is added o-chlorobenzaldehyde (11.2 g.; 0. o8 mole). The solution is stirred at room temperature for 30 minutes and the precipitate which separates is collected by filtration and dried to afford 20.5 g. of 3-imino-(2-chlorophenylmethyl~-4-aminobenzophenone, m.p.
112C. ~dec.).
Step B - 3-Imino-(2-chlorophenylmethyl)-~-(~-carbomethoxythioureido~benzophenone To a solution of 3-i~ino-(2-chloro-phenylmethyl)-4-aminobenzophenone (11.85 g., 0.03 mole) in acetone (100 ml.) is added carbomethoxy isothiocyanate (3.51 g.; 0.03 mole). It is necessary to add another portion of acetone (100 ml.) to the thick suspension which forms. The reaction mixture is stirred for an additional 30 minutes and the precipitate collected by filtration and dried to afford 9O0 g. of 3-imino-~2-chlorophenylmethyl~-4-~3-carbomethoxythioureido)benzophenone, m.p. 204-205C.
(dec.).
Elemental analysis for C23H18ClN303S
Calc.: C, 61.12; H, ~.01; N, 9.30 Found: C, 60.93; H, 4.00j N, 9.19 76-78 It Ste~ C - 3-Imino-(2-chlorophenylmethyl)-4-(3-carbomethoxy-S-methylisothio-ureido~benzop_enone ~o asuspension of 3-imino-(2 chloro-phenylmethyl)-4-(3-carbomethoxythioureido~benzop~enone ~3.0 g.; 0.0066 mole) in acetone (50 ml.) and water (10 ml.~ is added an aqueous solution of sodium hydroxide (50~; 0.53 g.~. ~he mixture is stirr~d at room temperature for one hour and then methyl iodide (0.94 g.; 0.0066 ~ole) is added. ~he solution is stirred at room temperature o~er the week-end and the precipitate -~Thich forms is collected by filtration and dried to afford 0.9 g. of 3-imino-(2-chlorophenylmethyl)-4-(3~carbomethoxy-S-methyl-isothioureido)benzop'nenone, rn.p. 140-142C. (dec.).
Elemental analysis for ~,24H20ClN303S
Calc.: C, 61.86; H, 4.33; N, 9.02 Found: C, 61.76; H, 4~40; N, 8.80 EXL~IPLE 18 - 3-I~nino-(4-dimethylaminop~enylmethyl)-4-(3-carbomethoxs-S-meth~Ilisothioureido)benzo~henone Ste~ A - 3-Imino-(4-dimethylaminophenylmethyl)-4-aminobenzophenone ~o an ice-cooled solution of 3,4-diaminobenzophenone (8.48 g.; 0.04 mole) in methanol (100 ml.) is added p-N,N-dimethylaminobenzaldehyde (6.0 g.; 0.04 mole). ~he mixture is stirred at 5C. for on~ hour and at room temperature for 18 hours. Sulfuric acid (3 drops) is added to the reaction mixtu-^e and within one hour a thick suspen;,ion forms. ~he reaction mixture is stirred at room te~peralul~e for an additional 8 hours and the precipitate 3o is collected and dried to afford 10.2 g. of 3-imino-(4-dimethylaminophenylmethyl)-4-aminobenzophenone, m.p.
171-173C. (dec.).

76-781~
S2~

El?mental analysis for C~2E21N30 Calc.: C, 7O.94; H, 6.16; N, 12.24 Found: C, 76.08; H, 6.17; N, 12.03 Step,B - 3-Imino-(4-dimethylaminophenylmethyl~-4-(3-carbomethoxythioureido)benzo-phenone To a solution of 3-imino-(~-dimethyl-aminophenylmethyl~-4-aminob~nzophenone (9.6 g.; 0.0262 mole) in acetone (2 1.) there is added carbomethoxy isothiocyanate (3.0 g.; 0.0262 mole). ~he solution is stirred at room temperature for 10 days and the acetone removed under vacuum. The residue is slurried in 100 ml. of acetone and filtered and washed with ether and then dried to afford 8.o g. of 3-imino-(4-dimethylaminophenylmethyl)-4-(3-carbomethoxythiollreido)benzophenone, m.p. 199C. (dec.).
Elemental analysis for C25H2~N403S
Calc.: C, 65.20; H, 5.25; N, 12.17 Found: C, 65.05; H, 5.25; N, 11.98 Step C, - 3-Imino-(4-dimethylaminophenylmethyl)-4-(3-ca:^bomethoxy-S-methylisothio-ureilo)benzo~henone ~o a suspension of 3-imino-(4-dimethyl-aminophenylmethyl)-~-(3-carbomethoxythioureido)benzophenone (3.0 g.; 0.0065 mole) in acetone (50 ml.) and water (10 ml.) there is added an aqueous solution of sodium hydroxide (50~; 0.52 g.). ~he mixture is stirred at room temperature for one hour and then methyl iodide (0.93 g.) is added. ~he solution is stirred at room temperature for one hollr (a precipitate begins to form after 15 minutes). ~he pre-cipitate which forms is collected by filtration and driedto afford 0.6 g. of 3-i~ino-(4-dimethylaminophen,rlmeth-vrl)-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 143-14~C. (dec.)~

76-7sr~

Elemental analysis for C22H21N30 Calc.: C, 76.94; H, 6.16; N, 12.24 Found: C, 76.08; H, 6.17; N, 12.03 EXAMPLE 19 - 1-Imino~ -chlorophenyl)methyl-2-(3-car~o-methoxy-S-methylisothioureido)-4-propylthio-benzene Step A - l-Imino-(~-chlorophenyl)methyl-2-(3-carbomethoxythioureido)-4-propyl-thiobenzene l~o an ice-cooled solution of 1-amino-2-(3-carbomethoxythioureido~-4-propylthiobenzene (3.0 g.~ in absolute methanel (100 ml.) there is added finely divided ~-chlorobenzaldehyde (1.4 g.). ~he yellow solution formed is stirred at 5C. for one hour (precipitate forms after 10 minutes~. The precipitate is collected by filtration. 'rhe yellow solid is dried to afford 1.2 g. of 1-imino-(p-chlorophenyl)methyl-2-(3-carbometho~ythioureido)-4-propylthiobenzene, m.p. 170-172C. (dec.~.
Elemental anal~Jsis for C19H20ClN302S2 Calc.: C, 54.08; H, 4.78; N, 9.9~
Found: C, 54.0~; H, 4.80; N, 9.89 SteP B - l-Imino~ chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-PropYlthiobenzene ~o a suspension of l-imino-(P-chlorophenyl)methyl-2-(3-carbomethoxyisothioureido~-4-propylthiobenzene (1.2 g.~ in acetone (30 ml.) and water ~10 ml.) is added sodium hydroxide (0.23 g.; 50~ aqueous ).
~he mixture is stirred at room temperature ~or one hour and to the solution formed there is added methyl iodide (0.4 g.).
A precipitate forms immediately and the suspension is ~ 45 -76-78 !
~S21 stirred at room temperature for 30 minutes. ~he p-ecipitate is collected by filtration, washad with ether and dried to afford 1.05 g. of 1-imi~o-(~-chlorophenyl)methyl-2-(3-carbomethoxy-~-methylisothioureido)-4-p~opylthiobenzene, ~.p. 139-1~0C.
Elemental analysis for C20H22ClN302S2 Calc.: C, 55.09; X, 5.09; N, 9.64 Fownd: C, 54.28; H, 5.06; N, 9.29 EXAMPLE 20 - 1-Imino-(2-thienyl)methyl-2-(3-carbomethoxy-~~ S-m~th~lisothioureido)-4-~ro~ylthiobenzene Step A - l-Imino-(2-thienyl)methyl-2-(3-carbomethoxythioureido)-4-thiobenzene To an ice-cooled solution of 1-amino-2-(3-carbomethoxythioureido)-4-propylthiobenzen~
(3.0 g.) in methanol (75 ml.) there is added 2-thio-phenecarboxaldehyde (1.12 g.). The solution immediately cnanges to a yellow color and within 15 mi.~utes a precipitate forms. The suspension is stirred at 5C.
for one hour and at roo~ temperature for 24 hours. The solid is collected by filtration and dried l;o afford 1.05 g. of l-imino-(2-thienyl)met:~yl-2-(3-carbomethoxy-S-meth~Jlisothioureido)-~-propylthiobenzene, m.p. 123-124C.
Elemental analysis for C17H19N302S3 Calc.: C, 51.88; H, 4.87; N, 10.68 Found: C, 51.52; H, 4.92; ~, 10.63 ~ 5 2~

S-5e~ B - l-Imino-(2-thienyl)methyl-2-(3-carbom~thoxy-~-methylisothioureido)-lt-proT)~ll I;hiobenzene ~o a ~ixture of l-im~no-(2-thien71)-methyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1.0 g.) in acetone (20 ml.` an~ water (7 ml.), there is added a 50~ aqueous sodium hydroxide solution (0.203 g.).
The mixture is stirred at room temperature for one h~ur.
A solution forms after 15 minutes and to it is added methyl iodide to.36 g.~. The sollltion is stirred at room temperature for two hours and the precipitate formed is collected by filtration and dried to afford 0.55 g. of l-imino-(2-thienyl~methyl-2-(3-carbomethoxy-S-methyliso-thioureido)-4-propylthiobenzene, m.p. 95C. (dec.).
EXAMPLE 21 - 1-Imino-(~-cnlorophenyl)methyl-2-(3-carbo-methoxy-S-methylisothioureido)-4 phenyl-thiobenzene Step A - l-Imino-(P-cnlorophenyl)methyl-2-(3-carbomethoxythioureido)-~-~hen~lthiobenzene To an ice-cooled solution ~f l-amine-2-(3-carbomethoxythiourei~10)-4-phenylthiobenzene (3.33 g.) in anhydrous methanol (300 ml.) is added finely powdered ~-chlorobenzaldehyde (1.~ g.). ~he sollltion is stirred at 5C. for one ho~lr (a precipitate b~gins to form after 15 minutes). ~he solid formed is collected by filtration and dried to afford 2.6 g. of l-imino-(~-chlorophenyl)-methyl-2-(3-carbomethoxythioureid~)-4-phenylthiobenzene, m.p. 170-172C.
- l-Imino-(~-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothio-ureido ? -4-~henYlthiobenzene To a suspension of l-imino-( -chlorophenyl)methyl-2-(3-carbomethoxythioureido)-~-76-78~

phenylthio~enzene (1.6 g.;.00351 mole) in aceton~ (30 ml.) and water (10 ml.) is added sodium llydroxide ~50~ aqueous;
0.28 g.). ~he mixture is stirred at room temperature for one hour and to the solution formed there is added methyl iodide (0.5 g.). A precipitale ~orms within ~ive minutes and the suspension is stirred at room temperature for 30 minutes. ~he precipitate is collectsd and dried toafford 1.02 g~ of 1-imino-(P-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothioureido)-L~-phenylthiobenzene, m.p. 135-136~.
Elemental analysis for C23E20ClN302S2 Calc.: C, 58.77; H, 4.29; N, 8.9~
Found: C, 57.90; H, ~.20; N, 8.77 EXAMPLE 22 - 3-Imino-(2 thienyl)methyl-~-(3-carbomethoxy-S-meth~lisothioureido)benzo~heno~e A mixture of 3-imino-(2-thienyl)methyl-~-(3-carbomethoxythioureido)benzophenone (1.0 g.; 0.062~ mole) in acetone (L2 ml.) and water (4 ml.) containing aqueous sodium hydroxide (0.22 g.; 0.002~ mole; 50~) is stirred at room temperature for one hour and methyl iodide (0.4 g.) is added. A precipitate forms almos'. i~mediately, filtered and the solid washed with water and drisd to afford 0.7 g.
of 3-imino-(2-thienyl)methyl-~-(3-carbomethoxy-S-methyliso-thioureido)benzophenone, m.p. 168-170~. (dec.); 67% yield.

EXAMPLE 2~ Iminophen~lmethyl-2-(3-carbomethoxy-S-all~l-isothioureido)-~-~ro2~1thiobenzene ~o a suspension of l-iminophenyl~ethyl-2-(3-carbometh~xythiourei~o)-~-propylthiobenzene (1.0 g.~ in acetone (30 ml.) and water (10 ml.) there is added aqueous sodium hydroxide (0~21 g.). ~he mixture is stirred at room temperature for one hour (a solution forms 20 minutes after the addition of sodium hydroxide) and to it there is added -48 ~

76-78~

allyl bromide (0.36 g.). The solution is stirred at room temperature for two hours and is then poured into water (300 ~1.). ~he mixture is stirred at room temperature for 24 hours and is vacuum filtered. The tacky yellow solid is stirred in hexane (50 ml.) and is filtered to yield 0.35 g. of 1-iminohexylmethyl-2-(3-carbomethoxy-~-isothioureido)-~-propylthiobenzene, m.p. 70~-72C.

In a manner similar to that described in the written examples, all of the 2-imino substituted thio-L0 ureidobenzenes (I) of this invenlion may be prepared bybeginning with an appropriately substituted l,2-diamino-benzene co~pound and following substantially the procedures described herein. The following equation illustrates the various reactions which maJ be employed and taken together with Iable I, infra, depict the starting materials, inter-mediates and final products ob=airled.

7 ~-78,~
'52 ~2 O / Va S-C=NCORl / \ R2CHO
IV
1~ ~
X

~NH2 ~J-CTC[R2 NHCINFICO 2Rl N~12 Base \ R2cHo ~ S=C=N~OR
~3 or or ~ X
RS04R ~ =C.~2 II S
~) -Ba s e 3-R -Ha l or X
RZC~IO ~_CHR2 irH=NC02R.' ~HC,-NC02R
SR . SR
IIa ~ ~n -76 -78~ -llOC}S21 TABLE I
E:x.R Rl R2 X
N3.-- O

25-C3H7 -C2H5 ~ Cl ~

26-C4H9 -n-C3H7 C~ "

275 11 -iso-C3E7 ~53 28C6H13 -n-C4H9 _~

29-C7E15 _iso-CL~E9 _~

30C8H17 -tert-C,.Hg ~ 3 31~ (C~2) 2C~I CH2 c~clo-c5H9 ~ 3 "

32 -(CH2)3CE=cH2 Cvcl-c6H~

33 -(CH2)4CH=C~2 -GH3 ~C2H5 "

34 - (CH2) 5CX=CH2 -CH3 _~C2X5 C2~5 3 5 - (CH2 ) 6CX=CX2 -CH3 ot~
110~521 ~ABLE I (cont.) Ex. R Rl R2 X
No. O
36 -CH2C--CH -CH3 ~ (5)-C

37 -(CH2)2c-cH -CH3 ~ "

O
38 ( 2 3 -CH3 ~ (5)-CCH3 o 39 -(C~2)4C-CH -CH3 ~ (5)-cc2H5 -(CH2)sc-cE -C~3 ~ (5)-CC3H7 41 (CH2)6C-CH -C:~3 ~ o ~5)-CC4H9 42 CX ~ -C~X_ ~ NO2 (5)-oCH3 43 -CH2CE2 ~ C2H5 ~ (4)-oc2x5 44 -CF2 ~ -CX3 ~ (4)-OC3H7 -CH2 ~ -C3H7 ~ ~ (4)-Oc4H9 46 -CH2CH2 ~ -CE3 ~ ~ N (4)-oc5~9 47 -CH2CH2CH2 ~ -tert ~4H9 ~ (5)-SCN

76-78~\
110~52~

TABLE I (cont.) Ex. R Rl R2 X

~8 CH ~ Cl -tert-C~H9 ~ -OCH3 (5) -SO

~9 -C~2 ~ C~3 -C'~3 ~ OC~3 ~5~-So2 -CH2CH2 ~ OC~3 -CH3 ~ (4)-SO

51 -(CH2)3-0 ~ -CT~3 ~ (5~--S2 52 -(CX2)4-0 ~ 3 ~ ~ (4)-~CH3 53 (CH2)5 ~ c~clo-c5H9 ~ F (~ C3H7 (CH2)6 ~ c~c10-~5H9 ~ CH (5)-SOC3H7 -CX2 ~ -n-C3H7 ~ C~ (5)-so2cH3 56 ( 2)2{~ -a-C3H7 -n-C3~7 0 57 -CH2{) -CH3 -n-C4H9 (4)-NHCCH3 58 (CH2) 2~ -C2H5 -n-C5Hll ( 5) -NHC{~

59 -(CH2)3CN -CH3 ~ 5 11 (4)-NHC~

76-78 ~' S~:l ~ABLE I (cont. ) No. R Rl R2 X

~ (CH2)4GN CH ~ Cl (4~ -NHc-oc2H5 61 ~ ( CH2 ) 5C~ -CH3 ~ ( 5~ -NHRC -O -CH/ 3 Il 62 - (C-d2 ) 6CN - CH3 ( 4 ) -NHC -OC4H9 63 -(CX2)30H " ~ ( ) ii~;9 64 - (CH2)40H `' Cl ( 4 ~_ S4 ~ (CH2) 5~ ~ (5) _ (CH2 ) 8 (5) ~ ; 2 ~

67 -CH=CHCH24~ " " (5)-C4~-CL

68 -(CX2)30C~'13 1~ " (5)-C~30C-~

69 ( 2 3 2 5 " (5) -C~c~3 (C 2)L~ 3 -C~13 0 71 ~ (CH2)~0c3H7 -C3H7 " (5) -C~-CF3 7 2 ~ ( CX2 ) 3C -O CH3 C 2H5 ( 5 ) -C

~ABLE I (cont.) Ex.
No. R R R2 X
O O
73-(C~2)4C~C2~5 C2H5 ~ C. (5)-C ~

74-(C'~'I2)5cc2~5 " " (~-SO ~ CN

O ' O
75-(CH2~5C-OC3H7 -C3H7 ~ ~ 3 ,0 76-(CH2)4- ~ ~ -C~3 " (~-S2 ~ CN

77-(CH2)3c- ~ ~ ( 4) S2 ~ -CCE3 78(CX2)~C-0 ~ " (4)-S ~ CN

2 5 ~

30-(CH2)6C-O ~ " ,t ( ~C~Hg-n 81 -C4Hg " ~ H
N ~ g 82 -C3H7 -C2H5 ~ (4) -C-83 -C2H5 -C3H7 ~ "

84 -CH3 -C4Hg ~ ,N

85 -C4Hg -C3H7 N~ N

110~21 Ex. 2 No. R Rl R X
86 -C3H7 -C2H5 ~ (5) -C-N

87 -C2H5 -CH3 ~ N H

88 -CH3 -CH3 ~ H

89 -C4Hg -C2H5 ~ H
~CH3 -C4Hg n-C4Hg ~ H

91 -C3H7 tert-C4Hg ~ 1~ (5)-C3H7 92 -CH3 tert-C4Hg ~ ~ (4)-C4Hg 93 -C4Hg tert-C4Hg ~ (4)-C2Hs - 5~ -76-78~

110~

EXAMPLE 94 - 1-Imino(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureide)benzene To 100.0 g (0.33 mole) of imino(2-furylmethyl)-2-(3-carbomethoxythiOureido) benzene and 50.0 g. (0.395 mole) of benzyl chloride in 275 ml. of dimethyl sul~oxide is slowly added 15.0 ~ (0.375 mole) of sodium hydroxide in 260 g. of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate is separated by filtration and recrystallized from 800 ml of methylene chloride-hexane (1:1) to give 91.1 g (70.1%) of 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)-benzene m.p. 112-114C.
Elemental Analysis for C21H19MOS:
Calc: C,64.10; H,4.87; N,10.68; 0,12.20; S,8.15 Found: C,64.22; H,4.83; N,ll.11; 0,12.29; S,8.24 EXAMPLE 95 - 1-Imino)2-furylmethyl)-2-(3-carbomethoxy-S-butylisothioureido)benzene To 5.0 g (0.0165 mole) of 1-imino(2-furylmethyl)-2-(3-carbomethoxythioureido)benzene and 3.6 g (0.01975 mole) of iodobutane in 80 ml. of N,N-dimethylformamide is added 0.7 g (0.0175 mole) of sodium hydroxide in 20 ml of water.
The resulting mixture is stirred for 1/2 hour and the yellow precipitate that formed is separated by filtration, washed with 50 ml of water and dried to give 3.4 g of crude product, m.p. 86-7C. Recrystallization from ether-hexane affords l-imino(2-furylmethyl)-2-(3-carbo~
methoxy-S-butylisothioureido)benzene m.p. 84-85C.
Elemental Analysis for C18H21N3O3S:
Calc.: C,60.15; H,5.89; N,11.69; 0,13.35; s,8.g2 Found: C,59.98; H,5.93; N,11.77; 0,13.83; S,8.90 ?SZ~

EXAMPLE 96 - 1-Imino(2-furylmethyl~2-(3-carbomethoxy-S-methylisothioureido)benzene _ .
A mixture of 3.03 g ~.01 mole) 1-imino(2-furyl- !
methyl)-2-(3-carbomethoxythioureido)benzene, 1.38 g (.01 mole) of potassium carbonate, and 1.42 g (.01 mole) of methyl iodide in 50 ml of acetone is refluxed and stirred for 1 hour. The suspension is allowed to stand at room temperature for 24 hours and is vacuum filtered. The filtrate is concentrated in vacuo and the residue orange semi-solid is slurried in 50 ml of ether and allowed to stand at room temperature for 24 hours. The suspension formed is vacuum filtered and the filter cake of gold needles is dried to afford 2.45 g (77% yield) of product, m.p. 97-105C.
A sample of the product recrystallized from ether affords l-imino(2-furylmethyl)2-(3-carbomethoxy-S-methyl-isothioureido)benzene as a fluffy yellow solid, m.p. 94-97C.
Elemental Analysis for C15H15N33S: Calc: C,56.77; H,4.76; N,13.24; S,10.10 Found: C,57.22; H,4.84; N,13.60; S,10.43 - 58 - .

5Z1 76-78~

EXAMPLE ~7 - 1-Imino-(p-chlorophenyl)methyl-2-(~-carbo-methoxy-S-methylisothioureido)-4-propylthio-benzens To a mixture o~ l-imino-(p-chlorophsnyl)-methyl-2-(3-carbo~ethoxythioureido)-4-propylthiobsnzens (4.22 g.;
.01 mol) in acetone (25 ~1.) and water (1O ml.) there is added 50~ aqueous sodium hydroxide (0.8 g.; .01 mol). The mixture is stirred at room temparature for one hour and to it there is added dimethyl sulfate (1.26 ~.; ,01 mol). The reaction mixture is stirred at room temperature for one hour and the precipitate collected and dried to afford l-imino-tp-chlorophenyl)methyl-2-(3-carbomethoxy-S-methyli~othio-ureido)-4-propylthiobenzene.
EXAMPLE ~98- 1-Iminophenylmethyl-2-(3-carbomethoxy-$-methyl-isothioureido)-4-propylthiobenzene To a solution of l-iminophenylmethyl-2-(3-carbo-methoxythioureido)-4-propylth~obenzens (3.88 g.; .01 mol) in acetone (40 ml.) and water (10 ml.) there is added calcium hydroxide (0.74 g.; .01 mol). The mixture is stirred at room temperature for 4 hours and then is added methy~ iodide (1.42 g.; .01 mol). The .mixture is stirred at room tempera-ture for 4 hours and the precipitate collected and dried to afford l-iminophenylmethyl-2-(3-carbomethoxy-~-met hyli s ot hi o-ureido)-4-propylthiobenzene.
EXAMPLE 99- 1-Iminophenylmethyl-2-(3-carbomethoxy-S-methyl-isothi~lr- ~ -propylthiobenzere To a solut,ion of l-iminophenylm~thyl-2-(3-carbo-methoxythiourei.do~-4-propylthiobenzene (3.88 g.; .01 mol) in dimethylformamide (40 ml.) and water (10 ml.) there is added 3o calcium hydroxide (0.74 g.; .01 mol). The mixture is stirred at room temperature for four hours and to it there i~ added dimethy~sulfate (1.26 g.). The mixture is stirred at rGom 76-78 l~

temperature for four hours and the precipitate collected and dried to afford l-iminophenylmethyl-2-~3-carbomethoxy-S-methylisothioureido~-4-propylthiobenz~e.

EXAMPLE ~OC- l-Imino-(o-chlorophenyl)methyl-2~(3-carbo-methoxy-S-methylisothioureido)-4-propylthio-benzene To a mixture of l-imino-(o-chlorophenyl)methyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.22 g.;
.Ol mol) in acetone (25 ml.) and water (lO ml.) there is lO added 50~ aqueous sodium hydroxide (o.8 g.; .ol mol). The mixture is stirred at room temparature for one hour and there is then added dimethy~ sulfi~ (l.l g.; .Ol mol). The mixture is stirred at room temperature for 3 hours and the precipi-tate collected and dried to af~ord l-imino-(o-chlorophenyl)-15 methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthio-benzene.
EXAMPLE l~l- l-Iminophenylmethyl-2-(3-carbomethoxy-S-methyl-isothioureido)-5-benzoylbenzene To a solution of l-iminophen~lmethyl-2-(3-carbo-20 methoxythioureido)-5-benzoylbenzene (4.33 g.; .Ol mol) in di-methylformamide (50 ml.) and water (5 ml.) there is added calcium hydroxide (0.74 g.; .Ol mol). The mixture i3 stirred at 30C. for 2 hours and to it there is added dimethyl sulfite (1.1 g.; .01 mol). The mixture is stirred at room te~perature 25 for 3 hours and the precipitate c~llected and dried to af~ord l-iminophenylmethyl 2-(3-carbomethoxy-S-methylisothioureido)-5-benzoylbenzene, EXAMPLE 102- l-Imino-(p-chlorophenyl)methyl-2-(3-carbo-~~ methoxy-S-methylisothioureido)-4-phenylthio-~0 benzene J
To a mixture of l-imino-(p-chlorophenyl)-methyl-2-(3-carbomethoxythioureido)-4-phenylthiobenzene (4~56 ~.;
.Ol mol) in ~cetone (35 ml.) there is added 57%

~ 60 -76-78 I`
110~5Zl sodium 'nydride (0.42 g.; oOl mol) (oil dispersion).
The mixture is stirred at room temperature for one hour and there is then added methyl iodide (1.42 g.; .01 mol).
The mixture is stirred at room temperature for one hour and is poured into an excess of water. ~he suspension is filtered and the precipitate dried to a~ford l-imino-~p-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothio-ureido)-4-phenylthiobenzene.
EXAMPLE 1,~3- 3-Imino-(o-chlorophenyl)methyl-4-(3-carbo-methox~-S-meth.-Ylisothioureido)benzoPhenone To a mixture of 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.52 g.; .01 mol) in 1,2-dimethoxyethane (50 ml.) there is added ~7~ sodium hydride (0.42 g.; .01 mol) (oil dispersion). Tne mixture is stirred at room temperature for one hour and there is then added dimethyl sulfate (1.26 g.; .01 mol). The mix-ture is stirred at room temperature for one hour and is poured into an excess o~ water. The suspens-on is filtered and the filter cake dried to afford 3-imino-(o-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido~
~enzophenone.
EXAMPLE lQ4- 3-Imino-(o-n~trophenyl)methyl-4-(3-carbome~hoxy-S-methYlisothio~ureido)benzo~henone To a mixture of 3-imino-(o-nitrophenyl)methJl-4-(3-carbomethoxythioureido)benzophenonQ (4.62 g.; .01 mol) in dimQthyl formamide (40 ml.) there is added 57~ sodium hydride (0.42 g.; .01 mol) (oil dispersion). The mix.ure is stirred at room temperature ~or one hour and to it there is added dimethyl sulfite(l.l g.; .01 mol). The 3o mixture is stirred at room temperature for l-1/2 hours and is poured into an excess o~ water. The suspension 76--78~ !

formed is vacu~m filtered and the filter caked dried to afford 3-imino-(o-nitronhenyl)metnyl-4-(3-carbo~ethoxy-S-methylisothioureido)benzophenone.
EXAMPLE 1~5- 3-Imino-(3,4-dichlorophenyl)methyl-4-(3-carbomethoxy-S-msth~lisothioureido)benzophenone To a mixture of 3-imino-(3,4-dichlorophenyl)-methyl-4-(3-carbomethoxythioureido)benzophenone (4.86 g.;
.01 mol) in acetone (50 ml.) there is added calcium hydride (0.42 g.; .01 mol). ~he mixture i3 r~fluxed for one hour and then cooled to room temperature. To the mixtllre is added methyl iodide (1.~2 g.; .01 mol).
The mixture is stirred at room temperature for one hour and is poured into an excess of ice water. The suspension formed is filtered and the filter cake dried to afford 3-imino-(3,4-dichlorophenyl)methyl-~-(3-carbome~hoxy-S-methylisothioureido)benzophenone.
EX~MPLE lO~- 3-Imino-(4-methoxyphenyl)metnyl-4-(3-carbomethox~ -meth~lisothioureido)benzoPhenone To a mixture of 3-imino-(4 methoxyphenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.47 g.; .01 mol) in 1,2-dimethoxyethane (50 ml.) there is added calcium hydride (0.42 g.; .01 mol). The mixture is refluxed for one hour and is cooled to room temperature. To the mixture there is added dimethylsulfate (1.26 g.; oOl mol). The mixture is stirred at room temperature for one hour and is poured into an excess of ice water. The suspension formed is filtered and the filter cake dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methyliso-thioureido)benzophenone.

76-78~-\

I

E ~PLE ~07- 3-Imino-(4-nitrophenyl)methyl-4-(3-carbo-methox~-S-methvlisothioureido)benzophenone To a mixture of 3-imino-(4-nitrophenyl)-methyl-4-(3-carbomethoxythioureido)benzophenone (4.62 g.;
.01 mol) in acetone (50 ml.) there is added calcium hydride (0.42 g.; .01 mol). ~he mixture is refluxed for one hour and is cooled to room temperature. ~o the mixture there is added dimethylslllfite (1~1 g.; .01 mol). The mix-ture is stirred at room temperature for one hour and is poured into an excess of ice water. The suspension fo-med is filtered an~ the filter cake dried to afford 3-imino-(4-nitrophenyl)methyl-~-(3-carbomethoxy-S metnylisothio-ureido)benzophenone.

3X~LE1~8 - 1-Iminophenylmethyl-2-(3-carbomethoxy-S-meth~lisothioureido~-4-PropYlthiobenzene To a mixt~lre of 2-(3-carbomethoxy-S-methyl-isothioureido)-~-propylthioaniline (3.13 g.; .01 mol) in methanol (25 ml.), cooled to 5C., there is added benz-aldehyde (1.06 g.; 0.1 mol). ~he mixture is stirred at room temperature for one hour and is filtered. The filter cake is dried to afford l-iminophenylmethyl-2-(3-carbo-methoxy-S-methylisothioureido)-4-propylthiobenzene.

EXAMPLE ~109- 1-Imino-(~-chlorophenyl)methyl-2-t3-carbo-methoxy-S-methylisothioureido)-~-phenylthio-aniline To a mixture of 2-(3-carbomethoxy-S-methyliso-thioureido)-~-phenylthioaniline (~.5~ g.; .01 mol) in methanol (25 ml.), cooled to 5C., is added p-chlorobenz-aldehyde (1.4 g.; .01 mol) followed by concentrated sulfuric acid (3 drops). The mixture is stirred at 5C. for one hour and is then vacuum filtered. The filter cake is dried to afford l-imino-(4-chlorophenyl)methyl-2-(3-carko-methoxy-S-methylisothioureido)-4-pllen~lthioaniline.

~ 5 21 EXAMPLE 110- 3-Imino-(4-nitrophenyl)~nethyl-4-(3-carbo-mgthox~-~-methylisothioureido)benzophenone To a mixture of 3-amino-4-(3-carbometho~y-S-methylisothioureido)benzophenone (3.43 g.; .01 mol) in be~zene (lO0 ml.) there i a added 4-nitrobenzaldehyde (1.5 g.; .01 mol). The mixture is re~luxed and stirred for 3 hours. Water of the reaction is rem~ved by a Dean-Sta~k distillation receiver. ~he mixture is poured into an excess of hexane ana the suspension formed is vacuum filtered. The filter cake is dried to afford 3-imino-(4-nitrophenyl)methyl-4-(3-carbomsthoxy-S-methylisothio-ureido)benzophenone.

EXAMPLE 111- 3-Imino (4-methoxyphenyl)meth 1-~-(3-carbo-methoxY-S-methylisothioureido~bsnzophenone_ To a mixture o~ 3-amino-4-(3-carbomethoxy-S-mathylisothioureido)benzophenone (3.~3 g.; .01 mol) in benzene (100 ml.) -there is added P-methoxybenzaldehyde (1.36 g.; .01 mol~ and p-toluenes-ul~niC acid mono-hydrate (0.1 g.). The mixture is refluxed and stirred for 3 hours. The water reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is filtered.
~he ~ilter cake is dried to afford 3-imino-(4-methoxy-phenyl)methyl-4-(3 carbomethoxy-S-methyli~thioureido)-benzophenone.

EXAMPLE 1l2- 1-Iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-~-_-propylsulfinyl-benzene , To a solution of l-iminophenylmethyl-2-(3-3o carbomethoxy-S-methylisothioureido)-4-n-propylthiobenzene (4.02 g.; .01 mol) in methylene chloride (50 ml.), cooled to -5C., is added o5% of _-chloroperoxybenzoic acid _ f~LI _ 76-78~\
~ 5 21 (2.02 g.; .01 mol). The mixture is st.irred at -5C. for 30 minutes and is washed with aqueous sodium bicarbonate solution~ The methylene dichloride is evaporated from the organic solution to afford l-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-~-n-propylsulfinyl-benzene.

EXAMPLE 113- l-Iminophenylmethyl-2-(3-carbomethoxy-S-- methylisothioureido~-4-_-prcpylsulfonylbe~zene lo a solution of l-iminophenylmethyl-2-(3-carbomethoxy-S-meth~Jlisothioureido)-~-jn-propylthiobenzene ~4.02 g.; .01 mol) in methylene chloride (50 ml. ), cooled to -5C~, is added _-chloroperoxybenzoic acid (4.04 g.;
.02 mol). The mixture is stirred at room temperature for 2 hours and is washed with aqueous sodium bicarbonate solution. The methylens dichloride is evaporated from the organic mixture to afford l-iminophenylmethyl-2-(3 carbo-methoxy-S-methylisothioureido)-~-n-propylsulfonylbenzene.
EXAMPLE ~14- l-Iminopropyl-2-(3-Carbomethoxy-S-methylisothioureido)-~-~ro~ylthiobenzene Step A- l-Iminopropyl-2-(3-carbomethoxy-thioureido~-4-Propvlthiobenzene To a suspension of 2-(3-carbomethoxy-thioureido)-~-propylthioaniline (2.99 g.; .01 mole) in methanol (50 ml.), cooled to 5C., there is added propion-aldehyde (0.6~ g.; .01 mole). The mixture is stirred at 5G. for 2 hours and the solution formed is stirred at ~oom temperatllre for l week. The s-~spension that forms is vacuum filtered and the filter cake is washed with ether and dried tc afford l-iminopropyl-2-(3-carbomethoxy-3o thioureido)-~-propylthiobenzene (1.3 g.; 38.3%), m.p.
163-168 C. (dec.).

~ 5 2 ~

Elemental analysis for C15H21N302S2 Calc.~ C, 53.07; H, 6.24; ~J, 12.38 Foun~: C, 52.72; H, 6.32; N, 12.38 Step B - l-Iminopropyl-2-(3-carbomethoxy-S-methylisothioureido)-~-propJlthio-benzene To a suspenslo~ o~ l-imino~ropyl-2-(3-carbomethoxythioureido)-~-propylthiobe~zene ~1 g.;
.00295 mole~ in acetone (30 ml.) and water (L5 ml.) there is added 50.8% aoueous sodium hydroxide (0.23 g.; ~00295 mole). The solution that forms is stirred at room temperature f~r one hour and to it there is added met;~yl iodide (0.~2 g.; .0029~ mole). The turbid solution formed is stirred at room temperature for 30 minutes and is poured in.o wa'er (500 ml.). The suspension for~ed is s~irred at ro~m temperature ~or one hour an~is vacullm filtered. The ~ilter cake is dried to afford l-imino-propyl-2-(3-carbomethoxy-S-methylisothioureido)-~-propylthiobenzene (0.85 g.; 81.5%) ? m.p 85-go~ ec.).

Elemental analysis for C16H23N302S2 Calc.: C, 5~.36; H, 6.56; N, 11.89 Fou~d: C, 53.96; H, 6.60; N, lL.63 EXAMPLE 115 - 1 Imino (4-methyl)phenylmethyl-2-(3carbo-methoxy-S-methylisothioureido)-4-propyl-thioben~ene Step A - l-Imino(4-methyl)phenylmethyl-2-(3 carbo-methoxythioureido-4-~ropylthiobenzene To a suspension of 2-(3-carbomethoxythioureido)-4-propylthioaniline (9.0 g; .03 mole) in methanol (100 ml), cooled to 10C, there is added _-methylbenzaldehyde (3.6 g;
.03 mole). The mixture is stirred at lO~C for 1 hr. and llQ~S21 at room temperature for 18 hrs. The suspension that forms is vacuum filtered and the filter cake is air dried to afford l-imino(4-methyl)phenylmethyl-2-(3-carbomethoxy-thioureido)-4-propylthiobenzene (10.75g; 89%), m.p. 135-141C.
Elemental AnalysiS for C20H23N302S2 Calc: C, 59.82; H, 5.77; N, 10.46 Found: C, 59.32; H, 5.87; N, 10.75 Ste~ B - 1-Imino(4-methyl)phenylmethyl-2-(3~carbo-~ methoxy-S-methylisothioureido)-4-propyl-thiobenzene To a suspension of l-imino(4-methyl)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.02 g;
.01 mole) in acetone (60 ml) and water (20 ml) there is added 50% aqueous sodium hydroxide (0.8 g; .01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; .01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered.
The filter cake is air dried to afford l-imino(4-methyl)-; phenylmethyl-2-(3-carbomethoxy~S-methyl isothioureido)-4-propylthiobenzene (3.6 g; 86.6%), m.p. 113-115C.
Elemental analysis for C21H25N32S2 Calc: 5, 60.69; H, 6.o6; N, 10.11 Found: C, 60.75; H, 6.29; N, 10.47 EXAMPLE 116 - 1-Imino-(4-methoxy)phenylmethyl-2-(3-carbo-methoxy-S-methylisothioureido)-4-propylthio-benzene Ste~ A - l-Imino-(4-methoxy)phenylmethyl-2-(3-3 carbomethox~lthioureido)-~-~ro~vl~hiobenzene To a suspension of 2-(3-carbomethoxy thioureido)-4-propylthioaniline (9.0 g; .03 mole) in methanol (100 ml) llU~521 cooled to 10C, there is added _=anisaldehyde (4.o8 ~;
.03 mole). The mixture is stirred at 10C for 1 hr. and at room temperature for 18 hrs. The suspension that forms is vacuum filtered and the filter cake air dried to afford 1-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (9.9 g,;79%), m.p. 141-144C.
Elemental analysis for C20H23N303S2 Calc: C, 57.53; H, 5.55; N, 10.06 Found: C, 57.19; H, 5.67; N, 10.25 Step B - l-Imino-(4-methoxy)phenylmethyl-2-(3-carbo-methoxy-S-methylisothioureido)-4-propyl-thiobenzene To a suspension of l-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.18 g;
.01 mole) in acetone (60 ml) and water (20 ml) there is added 50~ aqueous sodium hydroxide (.38 g; .01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; .01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is air dried to af~ord l-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxy-S-methylisothio-ureido)-4-propylthiobenzene (2.3 g; 53%), m.p. 90-92.
Elemental analysis for C21H25N303S2 Calc: C, 58.44; H, 5.84; N, g.74 Found: C~ 58.38; H, 5.94; N, 9.91 EXAMPLE 117 - 1-Imino(4-nitro)phenylmethyl-2-(3-carbo-methoxy-S-methylisothioureido)-4-propylthio-benzene Step A - l-Imino-(4-nitro)phenylmethyl-2-(3-carbo-methoxythioureido)-4-~ro~vlthioben~ene .
To a suspension of 2-(3-carbometho~ythioureido)-4-propylthioaniline (4.0 g; .013 mole) in methanol (35 ml) 76-7~A

l~U~521 there is added a solution of ~-nitrobenzaldehyde (2.0 g;
.013 mole) in methanol (35 ml). The mixture is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is washed with methanol and dried to afford 1-imino(4-nitro)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (5.3 g; 94%), m.p. 198-200C.
Elemental anal~sis for Cl9H20N44S2 Calc: C, 52.76; H, 4.66; N, 12.95; S, 14.83 Found: C, 52.85; H, 4.79; N, 13.39, S, 14.84 Step B - l-Imino-(4-nitro)phenylmethyl-2-(3-carbo-methoxy-S-methylisothioureido)-4-propyl-t,hio~nzene ... ........ ~
A mixture of l-imino-(4-nitro)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.3 g; .01 mole) acetone (50 ml), water (25 ml) and 50% aqueous sodium hydroxide (o.8 g; .01 mole) is stirred at room temperature for 15 min. and is cooled to 12C. To the mixture there is added methyl iodide (1.4 g; .01 mole) and it is stirred at 13C to 20C for 2 hrs. The suspension that forms is vacuum filtered and the filter cake is washed with acetone and dried to afford l-imino(4-nitro)phenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (3.5 g; 78%), m.p. 135-137C dec.
Elemental analysis for C20H22N404S2 Calc: C, 53.79; H, 4.97; N, 12.55; S, 14.36 Found: C, 53.39; H, 4.97; N, 12.60; S, 14.69 EXAMPLE 118 - 1-Imino-(2-furylmethyl)-2-(3-carbomethoxy-S-methyl~sothioureido)-4-propylthiobenzene Step A - l-lmino-(2-furylmethyl)-2-(3-carbomethoxy-thioureido)-4-~rop~lthiobenzene To a suspension of 2-(3-carbomethoxythioureido)-4-propylthioaniline (6~0 g; .02 mole) in methanol (200 ml), SZl cooled to 10C there is added 2-furfuraldehyde (1.92 g, .02 mole). The mixture is stirred at 10C for 1 hr. and at room temperature for 18 hrs. The suspension formed is vacuum filtered and the filter cake is air dried to afford 1-imino(2~furylmethyl)-2-(3-carbomethoxythiouriedo)-4-propyl-thioaniline (5.6 ~; 74%), m.p. 131-,33C.
Elemental analysis for C17H19N303S2 Calc: C, 54.09; H, 5.07; N, 11.13 Found: C, 53.68; H, 5.11; N, 11.13 Step B - l-Imino-(2-furylmethyl)-2-(3-carbomethoxy-S-meth,ylisothioureido)-4-propylthiobenzene To a suspension of l-imino-(2-furylmethyl)-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.77 g, .01 mole) in acetone (45 ml) and water (15 ml) there is added 5% aqueous sodium hydroxide (0.79 g; .01 mole). ~ithin 15 min. after addition a solution forms and is stirred at room temperature for 30 min. To the solution there is added methyl iodide (1.42 g; .01 mole). The mixture is stirred at room temperature for 1-3/4 hrs. and the sus-pension that forms is vacuum filtered. The filter cake is air dried to afford l-imino-(3-furylmethyl)-2-(3-carbo-methoxy-S-methylisothioureido)-4-propylthiobenzene (2.65 g;
67.7~), m.p. 96-98C.
Elemental analysis for 518H21N33S2 Calc: C, 55.22; H, 5.41; N, 10.73 Found: C, 54.71; H, 5.39; N, 10.51 --- - - . .

5Z~

.

.. . . . .. . ... . . . . . .. . . . . .. . .. . ...

When the procedures o~ the above examples are ~ollowed and by employin~ known starting diamine precursors, the following products may be ob~ained:
3-iminophenylmethyl-4-(3-carboethoxy-S-methylisothioureido)-benzophenone;
3-imino(p-chloro)phenylmethyl-4-(3-carbopropoxy-S-methyl-isothioureido)benzophenone;
l-iminophenylmethyl-2-(3-carbo-isopropoxy-S-methylisothio-ureido)-4-propylthiobenzene;
l-iminophenylmethyl-2-(3-carbobutoxy-S-allylisothioureido)-4-phenylthiobenzene;
3-iminophenylmethyl-4-[3-carbo-(2-methoxy)ethoxy-S-methyl-isothioureido]benzophenone;
l-iminophenylmethyl-2-[3-carbo-(2-methoxy)ethoxy-S-methyl-10 i30thioureido]-4-propylthiobenzene;
3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)-4'-chlorobenzophenone;
3-imino-(~-chlorophenyl)methyl-4-(3-carbomethoxy-S-allyl-isothioureido)-4'-fluorobenzophenone;
.... . ~ . . ..

.. . . ... .. ..
3-iminophenylmethyl-4-(3-carbomethoxy-S-butylisothioureido)-4'-methylbenzophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-benzylisothioureido)-4'-methoxybenzophenone;
3-imino-(o-chloro)phenylmethyl-4-(3-carbomethoxy-S-methyl-15 isothioureido)-3'-trifluoromethylbenzophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothio-ureido)propiophenone;
3-iminophenylmethyl-4-(3-carbomethoxy-S-allylisothioureido)-butyrophenone;
3-imino-p-nitrophenylmethyl-4-(3-carbomethoxy-S-butylisothio-ureido)valerophenone;
l-cyclopropylcarbonyl-3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzene;
1-cyclopentylcarbonyl-3-imino-(~-chloro)phenylmethyl-4-(3-carbomethoxy-S-butylisothioureido)benzene;

.. _ , . . . . . . . .. . . . . .

1106~521 1-(2-thienyl) -3-im no-~-msthylphenyl~ethyl-4-(3-carbo-methoxy-S-methylisothioureido)benzene;
l-imin~ henylmethyl-2-(3-carbomethoxy-S-methylisothio-ureido~-4-(4-cyanophenylthio)benzene;
1-imino~henylmethyl-2-(3-carbomethoxy-S-butylisothio-ureido)-4-(3-cyanophenJlthio~benzene;
l-imino~henylmethyl-2-(3-carbomethoxy-S-butylisothio-ureido)-4-(4-methylthiophenylthio)benzene;
l-iminophenylmethyl-2-(3-carbometho~y-S-m3thylisothio-ureido~-4-(3-methylthiophenylthio)benzene;
l-imino-(~-c~lorophenyl)meth~1-2-~3-carbomethoxy-S-methyl-isothioureido~-4-(4-acetylphenyl~hio)benzens;
l-imino-(p-chlorophenyl)methyl-2-(3-carbomethoxy-S-allyl-isothioureido)-4-(4-metho~ycarbonylphenylthio)benzene;
1-iminophenylmet~yl-2-(3-carbomethoxy-S-methylisothio-ureido~-4-(4-acetylaminophenyl~benzene;
l-imino henylmsthyl-2-(3-carbometh~xy-S-butylisothio-ureido~-4-(4-phen~xyphenylthio~benzene;
l-imino henylmethyl-2-(3-carbometh~xy-S-methylisothio-ureido~-~-t4-cyanophenylsulfin~Jl)benzene;
l-imino-~-chlorophenyl)~ethyl-2-(3-carbomethoxy-S-butyl-isothioureido)-4-(4-acetylphenylsulfinyl)benzene;
l-iminophenylm_thyl-2-(3-carbomethoxy-S-methylisothio-ureido~-~-(4-cyanophsnylsulfonyl)benzene;
1-imino-(~-chlorophenyl)m~thyl-2-(3-carbomethox-r-S-methyl-isothioureido)-4-(4-acetylphenylsulfonyl)benzene;
-imino-(P-chlorophenyl)methyl-2-(3-carbomethoxy-s-moth~
isot.hioureido)-4 (phenylsulfinyl)benzene;
l-imino-(p-cnloro~henyl~msthyl-2-(3-caLbomethoxy-s-meth isothioureilo)-~ (phenylsulfo.~yl)benzene;
l-imino-(~-chlorophenyl)~ethyl-2 (3-carbomethoxy-S-methrl-isothioureido)-5-(4-acetylphenylsulfonyl)benzene;
l-imino-(o-chloro~henyl)methyl-2-(3-carbomethoxy-S-methyl-isothioureido 5-~4-cyanophenylsulfonyl)benzene;
1-imino~hen~Jlmethyl-2-(3-carbomethoxy-S-methylisothio-ureido)-5-~4-acetylphenylsulfinyl)benzene;
l-imin~ henylmethyl-2-(3-carbomethoxy-S-methylisothio-ureido~-5-(4-cyanophenylsulfinyl)benzen^;

,.1~ ~
. x~ , 1 10 ~ 5 21 l-iminophenylmethyl-2-(3-carbometho~y-S-methylisothio-ureido)-5-phenoxysul~onylbenzene;
l-(imino-p-chlorophenylmethyl)-2-(3-carbomethoxy-~-methylisothioureido)-5-(~-cnlorophenox~sulfonyl)benzene;
1-(imino-p-chlorophenylmethyl)-2-(3-carbomethoxy-s-but isothioureido-5-(3-chlorophenoxysulfonyl~benzene;
l-iminophenylmethyl-2-(3-carbomei,hoxy-S-benzylisothio-ureido-5-(2 chlorophenoxysulfonyl)benzene;
l-~imino-o-chlorophenylmethyl)-2-(3-carbomethoxy-S-allyl-isothioureido)- 5-(3,5-dichlorophenoxysulfonyl)benzene;
l~~imino-P-nitrophenylmet'nyl)-2-(3 carbomethoxy-S-methyl-isothiourei~o)-5-(4-methoxyphenoxysul~onyl)benzene;
l-(imino-~-methoxyphenyl)-2-(3-carbomethoxy-S-methyliso-thiourei~o)-5-(3-cyanophenoxysulfonyl~benzene;
1-iminophenyl-2-(3-carbomethoxy-S-methylisothiourei~o)-5-(3-trifluoromethylphenoxysulfonyl~benzene;
l-i~inophenylmethyl-2-(3-~arbomethoxy-S-methylisothio-ureido~-5-phenylsulfonyloxybenzene;
l-imino-(~-chlorophenyl)methyl-2-(3-carbomethoxy-S-allyl-isothioureido)-5-(4-chlorophenyl)sulfonyloxybenzene;
l-imino-(o-chlorophenyl)methyl-2-(3-carbo~ethoxy-S-b~tyl-isothiourei.~o)-5-(3-chlorophenyl)sulfonyloxybenzene;
l-iminophenylmethyl-2-(3-carbomethoxy-S-butylisothio-ureido)-5-(3,5-dichlorophenyl)sulfonyloxybenzene;
1-imino-(~-nitrophenyl)methyl-2-(3-carbomethoxy-S-benzyl-isothioureido)-5- (4-methylphenyl~sulfonyloxybenzene;
-imino-(P-methoxyphenyl~methyl-2-(3-carbomethoxy-s-a isothioureido)-5- (3-trifluorophenyl)sulfonyloxybenzene;
l-iminophenylmethyl-2-t3-carbomethoxy-S-methylisothio-ureido)-5-(4-methoxyphenyl)sulfonyloxybenzene.
Examples of other X substituents on known diamines ~nclude 4-and 5-propoxy; 4- and 5-phenoxy; 4-and 5-(pyrid-2-yloxy); 4-(~-chlorophenoxy); 4-(trifluoro-methylphenoxy); 5- (3-chloropropoxy); 5-(2-phenylethoxy);
5- (3-phenylprop-2-en-l-yloxy); 5- (4-methylphenoxy); 5-(3-methylphenoxy); 5- (2-methylphenoxy); 5-(3-methylthio-phenoxy); 5- (propargylthio); 5-(but-3-en-1-yl-thio);

~o-~ol l l~OQSZl 5-(but-3-en-1-yl-sulfinyl); 5-(but-3-en-1-yl-sulfonyl);
5-(b3nzylthio); 5-(benz~Jlsulfin~Jl); 5-(thiazol-2-yl-thio); 5-(pyrid-2-yl-thio~; 4-pyrimidin-2-yl-thio);
5-(thien-2-yl-thio); 5-(fur-2-yl-t~io); 5-(3-c;~loro-propylthio); 4-(3-chloropropylthio); 4-(3-chloroprop-2-en-l-yl-th o); 4-(2-cyanoethylthio); 5-(2,3-dichloro-propyl-2-en-1-yl-thio) and the like.
These diamine precursors can be found in U. S. Pat. Nos. 3,657,267; 3,929,823; 3,929,824; 3,935,209;
3,98~,561; 3,993,768; 3,996,368; 3,996,369; ~,002,640;
French Pat. Nos. 2,248,037; 2,270,861 and Netherlands Pat.
No. 4,701,797.

- ,..~

Claims (28)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing the compound of the formula:

I

wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cyclo-alkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is lower alkyl or lower alkoxyalkyl;
R2 is alkyl substituted or unsubstituted aryl;and X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, lower alkoxy, thio-cyanato, a radical of the formula: Y-S(O)n wherein Y is lower alkyl, lower alkenyl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or mononuclear aryl, and n is an integer of 0 to 3, X is also lower alkyl carbonylamino, lower alkoxy carbonylamino, cycloalkylcarbonylamino, a radical of the formula: Y'?- wherein Y' is mononuclear aryl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl; or a radical of the formula Y"O wherein Y" is lower alkyl, lower alkenyl, mononuclear aralkyl, or pyridyl, thienyl, furyl, pyrimidyl or thiazolyl; and the nontoxic, pharmaceutically acceptable acid addition salts and amides thereof, which comprises (a) treating a compound of the formula:

wherein R1, R2 and X are as defined above, with a base, followed by treating with a compound selected from RSO3R, RSO4R, and RX2 wherein R is as defined above and X2 is halo; or (b) treating a compound of the formula wherein R, R1 and X are as defined above, with an aldehyde of the formula: R2CHO wherein R2 is as defined above;
and where desired, forming a nontoxic pharmaceutically acceptable acid addition salt or amide of the compound of formula I so prepared.

2. A process for preparing the compound of the formula:

I

wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cyclo-alkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is lower alkyl or lower alkoxyalkyl;
R2 is alkyl substituted or unsubstituted aryl;and X is hydrogen, nitro, halo, lower alkanoyl, lower alkyl, lower alkoxy, thio-cyanato, a radical of the formula: Y-S(O)n wherein Y is lower alkyl, lower alkenyl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or mononuclear aryl, and n is an integer of 0 to 3, X is also lower alkyl carbonylamino, lower alkoxy carbonylamino, cycloalkylcarbonylamino, a radical of the formula:
Y'?- wherein Y' is mononuclear aryl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, a radical of the formula: Y"O wherein Y" is lower alkyl, lower alkenyl, mononuclear aryl, mononuclear aralkyl or pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or a radical of the formula: Y"O wherein Y" is lower alkyl, lower alkenyl, mononuclear aryl, mononuclear aralkyl or pyridyl, thienyl, furyl, pyrimidyl or thiazolyl,and the nontoxic pharmaceutically acceptable acid addition salts and amides thereof, which comprises treating a compound of the formula:

wherein R1, R2 and X are as defined above, with a base, followed by treating with a compound selected from RSO3R, RSO4R or RX2 wherein R is as defined above and X2 is halo;
and where desired, forming a nontoxic pharmaceutically acceptable acid addition salt or amide of the compound of formula I so prepared.

3. A process for preparing a compound of the formula:

I

wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cyclo-alkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is lower alkyl or lower alkoxyalkyl;
R2 is alkyl or substituted or unsubstituted aryl; and X is hydrogen, nitro, halo, lower alkoxy, lower alkanoyl, lower alkyl, thiocyanato, a radical of the formula: Y-S(O)n wherein Y is lower alkyl, lower alkenyl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or mononuclear aryl, and n is an integer of 0 to 3, X is also lower alkyl carbonyl-amino, lower alkoxy carbonylamino, cycloalkylcarbonylamino, a radical of the formula:
Y'?- wherein Y' is mononuclear aryl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or a radical of the formula: Y"O wherein Y" is lower alkyl, lower alkenyl, mononuclear aralkyl,or pyridyl, thienyl, furyl, pyrimidyl or thiazolyl; and the nontoxic, pharmaceutically acceptable acid addition salts and amides thereof, which comprises treating a compound of the formula:

wherein R, R1 and X are as defined above, with an aldehyde of the formula: R2CHO wherein R2 is as defined above; and where desired, forming a nontoxic pharmaceutically acceptable acid addition salt or amide of the compound of formula I so prepared.

4. The process of Claim 2 for preparing a compound of the formula:

wherein R4 is lower alkyl or lower alkoxy alkyl, R3 is lower alkyl lower alkenyl, lower alkynyl, benzyl, 2,4-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl; R5 is mononuclear aryl of from 4 to 6 nuclear carbon atoms, polynuclear aryl of from 10 to 14 nuclear carbon atoms, or heteroaryl of from 5 to 6 nuclear atoms containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, and X1 is hydrogen, lower alkyl carbonylamino, lower alkoxycarbonylamino, lower alkoxy, propyl thio, propylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, lower alkanoyl or benzoyl, which comprises treating the compound of the formula:

wherein X1, R4 and R5 are as defined above, with a base, followed by treatment with a compound of the formula:
R3SO3R3, R3SO4R3 or R3X2 wherein R3 is as defined above, and X2 is halo.

5. A process according to Claim 3 for preparing a compound of the formula:

wherein R3 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl; R4 is lower alkyl; R5 is mononuclear aryl of from 4 to 6 nuclear carbon atoms, polynuclear aryl of from 10 to 14 nuclear carbon atoms,or heteroaryl of from 5 to 6 nuclear atoms containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, and X1 is hydrogen, lower alkyl carbonylamino, lower alkoxy carbonylamino, lower alkoxy, propylthio, propoxysulfonyl, propylsulfonyloxy, propylsulfinyl, propylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyloxy, lower alkanoyl or benzoyl, which comprises treating a compound of the formula:

wherein R3, R4 and X1 are as defined above, with an aldehyde of the formula: R5CHO, wherein R5 is as defined above.

6. The process of Claim 4 wherein R5 is nitrophenyl, dimethylaminophenyl, lower alkoxyphenyl, cyanophenyl, acetamidophenyl, methylenedioxyphenyl, phenyl, halophenyl, furyl, thienyl, lower alkylphenyl or dihalophenyl.

7. The process of Claim 6 wherein X1 is hydrogen, 4-benzoyl, 5-propylthio or 5-phenylthio.

8. A process according to Claim 6 for pre-paring 3-iminophenylmethyl-4-(3-carbomethoxy-S- methyl-isothioureido)-benzophenone which comprises treating 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone with aqueous sodium hydroxide and methyl iodide.

9. A process according to Claim 6 for pre-paring 3-imino-(4-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone which comprises treating 3-imino-(4-chlorophenyl)methyl-4-(3-carbomethoxy-S-thioureido)benzophenone with aqueous sodium hydroxide and methyl iodide.

10. A process according to Claim 6 for preparing 1-iminophenylmethyl-2-(3-carbomethoxy-S-methyl-isothioureido)-4-propylthiobenzene with aqueous sodium hydroxide and methyl iodide.

11. A process according to Claim 6 for pre-paring 1-imino(p-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthiobenzene which comprises treating 1-imino-(p-chlorophenyl)methyl-2-(3-carbomethoxy-thioureido)-4-phenylthiobenzene with aqueous sodium hydroxide and methyl iodide.

12. A process according to Claim 6 for pre-paring 1-imino-(p-chlorophenylmethyl)-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene which comprises treating 1-imino-(p-chlorophenylmethyl)-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene with aqueous sodium hydroxide and methyl iodide.

13. A process according to Claim 6 for pre-paring 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-butyl-isothioureido)benzene which comprises treating 1-imino-(2-furylmethyl)-2-(3-carbomethoxythioureido)benzene with aqueous sodium hydroxide and iodobutane.

14. A process according to Claim 6 for preparing 1-imino -(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)benzene which comprises treating 1-imino-(2-furylmethyl)-2-(3-carbomethoxythioureido)-benzene with aqueous sodium hydroxide and benzyl chloride.

15. A process according to Claim 6 for preparing 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-methylisothioureido)benzene which comprises treating 1-imino-(2-furylmethyl)-2-(3-carbomethoxythioureido)-benzene with potassium carbonate and methyl iodide.

16. A compound of the formula:

I

wherein R is alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, mononuclear aryloxy lower alkyl, cycloalkylalkyl, cyano lower alkyl, hydroxy lower alkyl, aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimido lower alkyl or phenoxycarbonylalkyl; R1 is alkyl or lower alkoxyalkyl; R2 is alkyl or substituted or unsub-stituted aryl;and X is hydrogen, nitro, halo, lower alkoxy, lower alkanoyl, lower alkyl, thiocyanato, a radical of the formula: Y-S(O)n wherein Y is lower alkyl, lower alkenyl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or mononuclear aryl, and n is an integer of 0 to 3, X is also lower alkyl carbonylamino, lower alkoxy carbonylamino, cycloalkylcarbonylamino, a radical of the formula:
Y"?- wherein Y' is mononuclear aryl, cyclo lower alkyl, pyridyl, thienyl, furyl, pyrimidyl or thiazolyl, or a radical of the formula:
Y"O wherein Y" is lower alkyl, lower alkenyl, mononuclear aralkyl or pyridyl, thienyl, furyl, pyrimidyl or thiazolyl; and the non-toxic pharmaceutically acceptable acid addition salts and amides thereof; when prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.

17. A compound of the formula:

wherein R3 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl; R4 is lower alkyl; R5 is mononuclear aryl of from 4 to 6 nuclear carbon atoms, polynuclear aryl of from 10 to 14 nuclear carbon atoms or heteroaryl of from 5 to 6 nuclear atoms and containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, and X1 is hydrogen, lower alkyl carbonylamino, lower alkoxy carbonylamino, lower alkoxy, propylthio, propoxysulfonyl, propylsulfonyl-oxy, propylsulfinyl, propylsulfonyl, phenylthio, phenyl-sulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyl-oxy, lower alkanoyl or benzoyl, when prepared by the process of claim 4, or by an obvious chemical equivalent thereof.

18. The compound of Claim 16 wherein R5 is nitrophenyl, dimethylaminophenyl, lower alkoxyphenyl, cyanophenyl, acetamidophenyl, methylenedioxyphenyl, phenyl, halophenyl, furyl, thienyl, lower alkyl phenyl or dihalophenyl, when prepared by the process of Claim 6 or by an obvious chemical equivalent thereof.

19. The compound of Claim 17 wherein X1 is hydrogen, 4-benzoyl, 5-propylthio or 5-phenylthio, when prepared by the process of Claim 7 or by an obvious chemical equivalent thereof.

20. The compound named 3-imino-phenylmethyl-4-(3-carbo-methoxy-S-methylisothioureido)benzophenone, when prepared by the process of Claim 8 or by an obvious chemical equivalent thereof.

21. The compound named 3-imino-(4-chlorophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone when pre-pared by the process of Claim 9 or by an obvious chemical equivalent thereof.

22. The compound named 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene, when prepared by the process of claim 10 or an obvious chemical equivalent thereof.

23. The compound named 1-imino-(p-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-phenylthiobenzene, when prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

24. The compound named 1-imino-(p-chlorophenyl)methyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene, when prepared by the process of Claim 12 or by an obvious chemical equivalent thereof.

25. The compound named 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-butylisothioureido)-benzene, when prepared by the process of Claim 13 or by an obvious chemical equivalent thereof.

26. The compound named 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)-benzene, when prepared by the process of Claim 14 or by an obvious chemical equivalent thereof.

27. The compound named 1-imino-(2-furylmethyl)2-(3-carbomethoxy-S-methylisothioureido)-benzene, when prepared by the process of Claim 15 or by an obvious chemical equivalent thereof.

28. A compound according to Claim 16 of the formula wherein R3 is lower alkyl, lower alkenyl, lower alkynyl, benzyl, 2,6-dichiorobenzyl, phenethyl, cycloalkyl lower alkyl, phenoxy lower alkyl, cyano lower alkyl, lower alkoxy carbonyl lower alkyl, phthalimido lower alkyl, phenyl lower alkenyl or hydroxy lower alkyl; R4 is lower alkyl; R5 is mononuclear aryl of from 4 to 6 nuclear carbon atoms, polynuclear aryl of from 10 to 14 nuclear carbon atoms or heteroaryl of from 5 to 6 nuclear atoms and containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, and X1 is hydrogen, lower alkyl carbonylamino, lower alkoxy carbonylamino, lower alkoxy, propylthio, propoxysulfonyl, propylsulfonyl-oxy, propylsulfinyl, propylsulfonyl, phenylthio, phenyl-sulfinyl, phenylsulfonyl, phenoxysulfonyl, phenylsulfonyl-oxy, lower alkanoyl or benzoyl, when prepared by the process or claim 5 or by an obvious chemical equivalent thereof.