CH621542A5 - Process for the preparation of isothioureidobenzenes - Google Patents

Description

The present invention relates to new isothio-ureido-benzenes which can be used as anthelmintic and antifungal agents; the scope of the invention also encompasses compositions containing such agents, and it also encompasses methods for the preparation and use of such agents and compositions.

GB patents No. 1307250, US No. 3958008 and NL No. 7401797 describe many thioureas, although none of them has a substituent on sulfur, usable as anthelmintics. German patent No. 2303048 describes 2-acetyl-amino-S-substituted isothio-ureidobenzenes,

usable as anthelmintics. However, no compound has so far been reported comprising both an amino substituent ortho-free on the benzene ring and a sulfur atom substituted in the thio-ureido radical. Among other patents describing anthelmintic compounds, mention may in particular be made of US Pat. Nos. 3865948 and 4005217 and GB patent No. 1350277.

The new 2-ainino-substituted-isothio-ureidobenzenes in question are represented by the following formula (I):

NH

NH-C = N-C-0R

i

SR

in which R is an alkyl radical, for example an alkyl comprising from 1 to 19 carbon atoms (and in particular from 1 to 4.6 or 8 carbon atoms), such as methyl, ethyl, n-propyl, n-butyl, iso-butyl, sec.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and nonadecyl; an alkenyl radical having for example up to 8 carbon atoms and such as a C3 to C8 alkenyl such as allyl, propenyl, 1-methyl-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl; an alkynyl radical which may be a lower alkynyl having up to 8 carbon atoms and such as propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl; a polynuclear aralkyl radical such as naphthylmethyl, naphthylethyl, phenanthrylmethyl; a mononuclear aralkyl radical such as benzyl, phenethyl, phenylpropyl, optionally substituted in the aryl nucleus with from 1 to 3 substituents which can, for example, be chosen from halo, nitro, alkyl and alkoxy radicals, the last two radicals preferably comprising up to 4.6 or 8 carbon atoms; an aryloxyalkyl (Ci-C8) radical, for example aryloxyalkyl (C3-C6), including phenoxypropyl, phenoxybutyl, phenoxypentyl, phenoxyhexyl; a cycloalkylalkyl radical, for example cycloalkyl (C5-C6) alkyl (Ci-C8, or C1-C4. or C6) such as cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclo-hexylethyl; a cyanoalkyl radical (Ci-C8), for example cyanoalkyl (C3-C6) such as cyanopropyl, cyanobutyl, cyano-pentyl, cyanohexyl; a hydroxyalkyl radical (Ci-C8), for example hydroxyalkyl (C3-C8) such as hydroxypropyl, hydroxy-butyl, hydroxypentyl, hydroxyoctyl; an aralkenyl radical, for example poly- and mononuclear aralkenyl having up to 8 carbon atoms in the alkenyl portion, such as phenylpropenyl; an alkoxyalkyl radical, for example (C 1 -C 8) alkoxy (C 1 -C 8) alkyl, such as methoxypropyl, ethoxy-propyl, methoxybutyl, propoxybutyl; an alkoxycarbonylalkyl radical, for example an alkoxycarbonylalkyl radical preferably comprising up to 8 carbon atoms in each of the two alkoxy and alkyl portions and, more advantageously still, comprising from 3 to 6 carbon atoms in the alkyl portion, radical such as methoxycarbonylpropyl , ethoxycarbonyl-butyl, ethoxycarbonylpentyle, propoxycarbonylhexyl;

a carbamoylalkyl radical (Ci-C8) in which the nitrogen atom comprises as a substituent a mononuclear aryl radical optionally itself comprising an alkanoyl-aminoarylthio substituent so as to form an R radical such that N - [(4,4- acetamidophenylthio) phenyl] carbamoylethyl;

a phthalimidoalkyl radical (Ci-C8), preferably phthalimidoalkyl (C3-C6) such as phthalimidobutyl; a phenoxy-carbonylalkyl radical, for example phenoxycarbonylalkyl (Ci-C8), preferably phenoxycarbonylalkyl (C3-C6) such as phenoxy-carbonylpropyl, phenoxycarbonylbutyl, phenoxy-carbonylpentyl, phenoxycarbonylhexyl; R1 is an alkyl radical (Ci-C6) such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, or an alkoxy (Ci-C6) alkyl (Ci- C6) such as methoxyethyl; and X is 1) hydrogen; 2) nitro; 3) halo, such as chloro, bromo or fluoro; 4) alkanoyl (C2-C5) such as acetyl, propionyl, butyryl, pentanoyl; 5) (C1-C4) alkyl such as methyl, ethyl, propyl, n-butyl; 6) thiocyanate; 7) a radical represented by the formula Y — S (0) n— in which Y is alkyl (Ci-C5), alkenyl (C3-C6), alkynyl (C3-C6), cycloalkyl (C3-C7), a heterocycle with 5 or 6 links (for example pyridyl, thienyl, furyl, pyrimidinyl, thioazolyl) or a substituted or unsubstituted aralkyl or mononuclear aryl such as phenyl or benzyl, each optionally substituted with halo, and n is a number from 0 to 3; 8) alkoxycarbonylamino preferably containing up to 4 carbon atoms in the alkoxy radical,

and such as methoxycarbonylamino or isopropylcarbonylamino; 9) a radical represented by the formula O II

Y'C— in which Y 'is mononuclear aryl such as phenyl, a cycloalkyl (C3-C7), a 5 or 6-link heterocycle (for example pyridyl, 2-thienyl or furyl), or 10) is a radical represented by the formula Y "0 - in which Y" is alkyl (C1-C5), mononuclear aryl such as phenyl, alkenyl (C3-C6), mononuclear aralkyl or a heterocycle with 5 or 6 links,

with the condition that the radicals Y, Y 'and Y "specified above may be substituted with one or more substituents which may be identical or different and chosen from a) halogeno, b) cyano, c) alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl , alkylsulfonyl and carboalkoxy, each of the radicals listed under c) containing not more than 8 carbon atoms, preferably not more than 6 carbon atoms, and more advantageously still not more than 4 carbon atoms, d) phenylthio, e) phenylsulfinyl, f) phenylsulfonyl, g) phenoxy, h) halophenoxy, i) benzyloxy and j) trifluoromethyl.

The invention also encompasses, within its scope, addition salts with pharmaceutically and / or agronomically acceptable acids, of compounds having formula (I), for example acid addition salts such as those formed by reaction with acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, benzoic or lactic acids.

The compounds having the formula (I) can exist in various isomeric and stereoisomeric forms; all of the isomers in question and their mixtures and racemates are also included within the scope of the present invention.

Preferred compounds among those included in the scope of the invention are those represented by the formula (IA)

NH,

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in which R3 is alkyl (C1-C4), or R2 is alkyl- (C1-C4), alkenyl (C3-C8), alkynyl (C3-C8), benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl (C5-C6) alkyl (Ci-C4), phenoxyalkyl (C3-C6), cyanoalkyl (C3-C6); alkoxycarbonylalkyl in which the alkoxy portion has from 1 to 5 carbon atoms while the alkyl portion has from 3 to 6 carbon atoms; phthalimidoalkyl (C3-C6); phenylalkenyl (C3-C6) or hydroxyalkyl (C3-C8); and X1 is hydrogen, (Ci-C4) alkyl, alkoxycarbonylamino having up to 4 carbon atoms in the alkoxy, alkoxy (Ci-C5) portion, alkyl (Ci-C4) thio (for example propylthio), alkyl (Ci- C4) sulfinyl (eg propyl-sulfmyl), alkyl (C1-C4) sulfonyl (eg propylsulfonyl), phenylthio, phenylsulfinyl, phenylsulfonyl, (C2-C5) alkyl or benzoyl. These compounds exhibit particularly good anthelmintic and antifungal activity.

The process for the preparation of the compound represented by the formula (I) is characterized in that it consists in treating a compound represented by the formula:

X

NH

NH-CHN-C-OR

11

S

with a base, then in carrying out a treatment with a compound having the formula RX2 in which X2 is a halogen or sulphonate radical, or alternatively, in the case where the desired product is an addition salt with an acid, in reacting a compound having formula (I) with an acid.

Preferably, the compounds having the formula are prepared by treating the corresponding 2-amino-substituted thio-ureidobenzene (formula II above) by the action of a base such as, for example, a base derived from an alkali metal or of an alkaline earth metal and such as sodium hydroxide, potassium hydroxide, or calcium hydroxide, after which it is treated with a sulfonate or organic halide (RX2). The reaction can be carried out at a temperature between 0 and 40 ° C (for example between 10 and 40 ° C) for a time of a duration between a few minutes and about 1 h, the reaction with RX2 being carried out in the same temperature interval and for a period of time between a few minutes and about 3 d. Any solvent in which the reagents are reasonably soluble and which is substantially inert can be used. Mention may in particular be made, among suitable solvents, of dimethylformamide (abbreviated as DMF), acetone and the like. The following chemical equation illustrates this method of preparation:

X

NH

+ base

NH-CNHC-OR

wherein R, R1 and X are as defined above; and X2 is halo (such as chloro, bromo or iodo) or sulfonate.

The compounds having the formula (II) are either known compounds, or else compounds which can be prepared by using known procedures such as those described in the patents GB Nos 1307250 and 1340428 and in the patent NLN No. 7401497 .

A procedure which can be used to prepare the compounds having formula (II) comprises the treatment of a 2-amino-benzene, suitably substituted in position 1 with an amino or nitro radical, with a carboalkoxyisothiocyanate (formula IV below) and, when it is a 1-nitro-substituted compound, the treatment of said nitro compound with a reducing agent in order to arrive at the desired compounds having the formula (II). The following chemical equation illustrates this method of preparation:

X

NH ~ + S = C = NC-OR

(IV)

(III)

Reduction if Compound

* required formula

" (not)

in which R1 and X are as defined above.

The diamines or nitroamines having the above formula (III) are either well known (see, for example, US patents Nos. 3657267, 3929823, 3929824, 3935209, 3993768, 3996368, 3996369, 3984561 and 4002643, patent FR No. 2248037 and German Patent No. 2129960), or else they can be prepared by deacetylating by hydrolysis of the compounds described in patent FR No. 2270861.

Compounds having the formula (I) in which X is a group YS (0) n—, n being other than zero, can be prepared by oxidizing the sulfur atom in the radical YS - by operating in the manner illustrated here- after in examples 48 and 49.

As compounds representative of those represented by formula (I), mention may in particular be made of the following:

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-cyano-phenylthio) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (4-methyl-thiophenylthio) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (3-cyano-phenylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-methyl-thiophenylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-acetyl-phenylthio) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (4-methoxy-carbonylphenylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-cyano-phenylsulfinyl) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -4- (4-acetyl-phenylsulfinyl) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -4- (4-methyl-thiophenylsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-methoxy-carbonylphenylsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-cyano-phenylsulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-acetyl-phenylsulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-propionyl-phenylsulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (4-methoxy-carbonylphenylsulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-acetyl-phenylsulfiny l) aniline;

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2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-methoxy-carbonylphenylIsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (propargylthio) -aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (but-3-en-1-ylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (but-3-en-1-ylsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (but-3-en-1-ylsulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (benzylthio) -aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (benzyl-sulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (thiazol-2-ylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (thiazol-2-ylsulfinyl) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (pyrid-2-ylthio) -aniline;

2- {3-carbomethoxy-S-butylisothio-ureido) -5- (pyrid-2-ylsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (pyrimidin-2-ylthio) anine;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (pyrimidin-2-ylsulfinyl) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (thien-2-ylthio) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (thien-2-ylsulfinyl) -aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (fur-2-ylthio) -aniline;

2- {3-carbomethoxy-S-methylisothio-ureido) -5- (3-chloro-propylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-chloro-propylsulfinyl) ani! Ine;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3-chloroprop-2-en-1 -y lthio) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3-chIoroprop-2-en-1 -ylsulfinyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (2-cyano-ethylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (2-cyano-ethylsulfinyl) aniline;

2- {3-carbomethoxy-S-methylisothio-ureido) -5- (2-benzy Ioxyethoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- [2- {2'-methoxyethoxy) ethoxy] aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (p-chloro-phenoxyethoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (tert.-butoxy ethylthio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- {tert.-butoxyethylsulfiny l) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (benzyl-oxyethylthio) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (phenoxy-butylthio) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (phenoxybutyl-sulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (2-phenyl-thioethylthio) aniline;

2- {3-carbomethoxy-S-benzyIisothio-ureido) -5- [2- (phenyl-sulfinyl) ethylthio] aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- [2- (ethyl-sulfinyl) ethylthio] aniline;

2- {3-carbomethoxy-S-methylisothio-ureido) -5- [2- (phenylthio) -ethoxy] aniline;

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2- (3-carbomethoxy-S-methylisothio-ureido) -4- (cyclopropyl-carbonyl) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -4- {cyclopentyl-carbonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (thénoyl) -aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (phenyl-sulfony loxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-chloro-phenylsulfonyloxy) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (3-chloro-phenylsulfonyloxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- {3,5-dichlorophenylsulfonyloxy) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- {4-methylphenyl-sulfonyloxy) aniline;

2- {3-carbomethoxy-S-benzylisothio-ureido) -5- (3-trifluoro-methylphenylsulfonyloxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-methoxy-phenylsulfonyloxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (phenoxy-sulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-chloro-phenoxysulfonyl) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (3-chloro-phenoxy sulfonyl) aniline;

2- (3-carbomethoxy-S-benzylisothio-ureido) -5- (2-chloro-phenoxysulfonyl) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3,5-dichloro-phenoxysulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-methyl-phenoxysulfony 1) aniline;

2- (3-carbomethoxy-S-isothio-ureido) -5- (4-methoxyphenoxy-sulfonyl) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3-cyanophenoxy-sulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-trifluoro-methylphenoxysulfonyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-chloro-propoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (2-phenyl-ethoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-phenyl-prop-2-en-1 -yloxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (pyrid-2-yloxy) -aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (thiazol-2-yloxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (phenoxy) -aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (4-methyl-phenoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (3-methyl-phenoxy) aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5- (2-methyl-phenoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-chloro-phenoxy) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3-methylthio-phenoxy) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -5- (3-trifluoro-methyl methylphenoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (4-methoxy-phenoxy) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5- (2,3-dichloro-prop-2-en-1-yl-thio) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4-propionyl-aniline;

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2- {3-carbomethoxy-S-propionylisothio-ureido) aniline;

2- {3-carbomethoxy-S-allylisothio-ureido) -4-butyrylaniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -4-valerylaniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5-propoxy-aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5-ethoxyaniline;

2- {3-carbomethoxy-S-allylisothio-ureido) -5-n-butoxyaniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5-isopropoxy-aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4-thiocyanato-aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -5-thiocyanato-aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -5-isopropoxy-carbonylaminoaniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4-isopropoxy-carbonylaminoaniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4-methoxy-carbonylaminoaniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (p-chloro-benzoyl) aniline;

2- (3-carbomethoxy-S-allylisothio-ureido) -4- (p-fluorobenzoyl) -aniline;

2- (3-carbomethoxy-S-butylisothio-ureido) -4- (p-toloyl) -aniline;

2- (3-carbomethoxy-S-benzylisothio-ureido) -4- (p-methoxy-benzoyl) aniline;

2- (3-carbomethoxy-S-methylisothio-ureido) -4- (3-trifluoro-methylbenzoyl) aniline.

2-amino-substituted isothio-ureidobenzenes represented by formula (I) are anthelmintics and have a broad spectrum of activity against animal parasites, especially warm-blooded animals, including against parasitic forms both mature and immature. In particular, the compounds in question show a high activity against various helminthic infestations of the intestinal system of economically important animals, this activity being associated with a low general toxicity for the organism of the host animal.

For example, the compounds are generally effective in killing worms infesting mice intended for laboratory experiments, and in particular the following species of worms: Syphacia obvelata and Aspilcularis tetraptera (worms of mouse needles), the migratory stages of Ascaris suum, Hymenolepsis nana and Nematospiroides dubius.

Compounds having the formula (I) have been shown to be effective against parasitic gastroenteritis in sheep, in particular for combating the following species: Monieza spp, Haemonchus contortus, Ostertagia spp, Trichostrongylus spp, Nematodirus spp, Trichuris ovis, Cooperia spp, Capillaria spp and Strongyloides papillosus. Bunostomum trigonocephalum and Oesophagostomum spp are other important parasites of sheep. The compounds in question are active against pulmonary worms of ruminants, especially against Dictyocaulus filaria in sheep and Dictyocaulus viviparus in cattle. In addition, said compounds are effective against trematodes or liver flukes (Fasciola hepatica) in sheep.

Low-weight animals are treated by administering unit doses of them not more than a few milligrams; on the other hand, the treatment of animals whose body weight is high, which is in particular the case of ruminants, requires the administration of proportionally larger unit doses, which can reach up to several grams. Preferably a single dose is administered for each animal species, based on the weight of an animal of the species in question.

The amount of ingredient administered depends on the weight of the host, but it usually corresponds to a unit dose between about 1 or 5 mg / kg and 125 mg / kg of body weight. Dosage units should be considered,

containing as essentially active ingredient at least one of the compounds having formula (I), orally or by injection, for treating and combating helminthic infestations in domestic animals such as sheep, cattle, horses, dogs, fish, swine and goats.

The compounds represented by the formula (I) are particularly advantageous to use to fight against a helminthic infestation from which suffers a non-human host animal, raised as a domestic animal or companion animal by human beings, and usually on an industrial scale to derive a commercial profit; for example, (a) animals intended to be sacrificed or slaughtered to provide food for humans (or their pets) or to provide other products for human use, such as leather and hides, furs and wool, or b) animals which are the subject of commercial breeding with a view to providing various services desired by human beings, for example for the production of food, for sport, for performances or shows, or view of experimental uses in favor of humans or animals bred by humans to gain commercial gain.

It has further been discovered that the compounds having formula (I) exhibit a broad spectrum of antifungal activity. It is therefore possible to use such compounds, or compositions which contain them as essential active ingredient,

to combat the growth of fungi in or on animals and plants as well as in the products of the paints, wood, textiles, cosmetics, leathers, tobacco, furs, wires and cables, paper, pulp, plastics, fuels, rubber and food products.

With regard to an antifungal application, one can mention a method of combating fungi (that is to say prevention, cessation or slowing down of a fungal attack) on seeds or on plants capable of providing an agronomic harvest. marketable, method which essentially consists in applying to the seeds, to the plants or to the places of their growth or their culture (in particular on or in the grounds) a fungicidally effective proportion of at least one of the compounds having the formula (I).

When used as an anthelmintic agent for the treatment and / or prevention of helminthiasis, the new compounds having formula (I) can be administered orally in a dosage form such as a paste , a powder, a gel, a capsule, a more or less large pill, a tablet or a tablet, or in the form of a liquid potion.

Anthelmintic drugs presented as a dosage unit contain a pharmaceutically acceptable carrier or vehicle; these are medicines presented in the form of separate and distinct doses or dosage units, each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active ingredients. Such doses or portions may, for example, affect the form of a coherent monolithic dose (such as a tablet or tablet or a pill or dragee), or else a dose wrapped or packaged in a suitable manner in for oral administration (e.g. a dose presented as a soluble capsule).

The anthelmintic compounds can be administered orally by dispersing them intimately in a food substance for the animal to be treated or by using them as a seasoning on food, or in the form of pills which can be add to a ready-to-eat food ration.

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Alternatively, they can be administered to animals in a vehicle or liquid carrier by intraruminal, intramuscular or intratracheal injection. The amount of active ingredient necessary to give the best anthelmintic response may depend on the particular compound used, the species of animal to be treated and the type and / or degree of severity of the helminthic infestation. Generally good results are obtained when a total dose of between about 1 and about 125 mg of active ingredient is administered per kilogram of body weight of the animal. Such a total dose can be administered at once or in several times (with submultiples of the dose) distributed over a fairly short period of time such as 1 to 2 days.

When used as antifungal agents, the 2-amino-S-substituted isothio-ureidobenzenes represented by formula (I) can be incorporated into compositions made according to various formulas; these can be solid compositions, including finely divided powders (for example, dusting powders or wettable powders) and granular materials, as well as liquid compositions, such as solutions, emulsions, suspensions, concentrates optionally emulsifiable or in the form of pastes, according to the mode of application envisaged and according to the media desired to establish the formulas of compositions. Compositions in the form of wettable powders, emulsions, emulsifiable concentrates or suspensions can usually contain a surfactant. It should therefore be appreciated that the compounds encompassed within the scope of the invention can be used to establish fungicidally active compositions containing a fungicidally effective proportion of such compounds as an essential active ingredient. Such compositions may also contain finely divided dry or liquid diluents serving as fillers, conditioning agents, excipients, including various diatomaceous earth or clays, talc, etc., or else water and various organic liquids, for example lower alkanols such as ethanol and isopropanol, or kerosene, benzene, toluene and other fractions resulting from petroleum distillation operations, or mixtures of at least two such substances . Ready-to-use compositions can usually contain between about 50 and 800 parts per million (abbreviated: ppm) of active ingredient, and preferably between about 200 and 500 ppm. Of course, it should not be forgotten that any ingredient incorporated into a composition of the genus in question, an ingredient such as a vehicle, a support or a diluent, must be, as the case may be, either pharmaceutically acceptable or agronomically acceptable, in particular with regard to plants intended to provide marketable agronomic crops.

Below are given various examples, of course not limiting, intended to illustrate the compounds included in the scope of the invention, as well as procedures making it possible to prepare and use them. After having read it, as well as the previous description, any specialist can easily imagine and use many other variants and modifications, without thereby departing from the spirit or the scope of the invention. Indeed, all the products represented by the general formula (I) as defined above can also be prepared in an analogous manner using, in place of the raw materials specified in the examples, the appropriate raw materials.

Example 1:

3- (3-Carbomethoxy-S-methylisothio-ureido) -4-amino-

benzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in dimethylformamide (DMF), 5 ml of water is added (used 20 ml DMF). The solution is cooled to ordinary room temperature after the exothermic reaction has ceased. 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added and the solution is stirred for 1 h at ordinary room temperature, then 1.42 g (0.01 mol) of methyl iodide and, within 2 min, the solution is poured into 200 ml of water. A suspension is thus formed which is stirred at ordinary room temperature for 1 h; the solids are then collected by filtration, then washed with ether, with water and again with ether, then dried. 2.84 g are thus collected (yield 82.8%) of 3- (3-carbomethoxy-S-methylisothio-ureido) -4-aminobenzophenone, m.p .: 154 ° C (decomposition).

Elementary analysis for C17H17N3O3S:

Calculated: C 59.46 H 4.99 N 12.24%

Found: C 59.18 H 4.99 N 12.28%

Example 2:

3- (3-Carbomethoxy-S-allylisothio-ureido) -4-aminobenzophenone

To a solution of 6.58 g (0.02 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 75 ml of DMF, 20 ml of water is added. A fine suspension is formed, to which 1.6 g (0.02 mol) of a 50% aqueous sodium hydroxide solution are added; the resulting solution is stirred at ordinary room temperature for 1 h. Then added 2.42 g (0.02 mol) of allyl bromide. The reaction mixture is stirred at room temperature for 18 h, then poured into 500 ml of water. A precipitate is thus formed which is collected by vacuum filtration; the filter cake is washed with ether, then dried. 5 g (69% yield) of 3- (3-carbomethoxy-S-allylisothio-ureido) -4-amino-benzophenone are thus obtained; M.p. 128-131 ° C (decomposition).

Example 3:

3- (3-Carbomethoxy-S-benzylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, cooled to 10 ° C, 5 ml of water is added ( exothermic effect up to 20 ° C). The solution is cooled to 10 ° C and 0.65 g (0.01 mol) of potassium hydroxide pellets are added thereto. After 15 mri of stirring at 10 ° C., a solution is formed to which is then added 3.42 g (0.02 mol) of benzyl bromide. The solution is allowed to warm to ordinary room temperature and, after 10 min, the solids are collected from the suspension which has formed. The filter cake is washed successively with ether,

with water and with ether, then dried; 2.3 g (50% yield) of 3- (3-carbomethoxy-S-benzylisothio-ureido) -4-aminobenzophenone are thus collected; Mp 175 ° C (decomposition).

Elementary analysis for C23H21N3O3S:

Calculated: C 65.85 H 5.05 N 10.02%

Found: C 65.11 H 5.18 N 10.11%

Example 4:

3- (3-Carbo-ethoxy-S-methylisothio-ureido) -4-aminobenzophenone

To a cloudy solution of 1.75 g (0.005 mol) of 3- (3-carbo-ethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF and 5 ml of water, 0.33 g (0.005 mol is added) ) of potassium hydroxide tablets. The reaction mixture is stirred at room temperature for 15 min. About 0.71 g (0.005 mol) of methyl iodide is added thereto, and the reaction mixture is stirred at room temperature for 1 hour. An additional 15 ml of DMF is added, the reaction mixture is further stirred at ordinary room temperature for 30 min,

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then pour it into 300 ml of water. A precipitate is thus formed which is collected by vacuum filtration; the filter cake is then washed with hexane, then dried. 1.15 g are thus obtained (yield 64.4%) of 3- (3-carboethoxy-S-methylisothio-ureido) -4-aminobenzophenone; M.p. 144-146 ° C (decomposition).

Elementary analysis for C18H19N3O3S:

Calculated: C 60.48 H 5.36 N 11.76%

Found: C 60.20 H 5.24 N 11.85%

Example 5:

3- (3-Carbomethoxy-S-n-butylisothio-ureido j-4-aminobenzophenone

To a solution of 3- (3-carbomethoxythio-ureido) -4-amino-benzophenone in 30 ml of DMF, 10 ml of water is added. To the fine suspension thus obtained, 0.8 g (0.01 mol) is added

of a 50% aqueous solution of sodium hydroxide. The solution is stirred at room temperature for 1 h 2 h. Then added 1.84 g (0.01 mol) of butyl iodide, then the reaction mixture is stirred at room temperature for 18 h. The solution is poured into 300 ml of water; a precipitate is thus formed which is collected by vacuum filtration. The filter cake is washed with ether, then dried, which gives 2.5 g (65% yield) of 3- (3-carbo-methoxy-S-n-butylisothio-ureido) -4-aminobenzophenone; M.p. 132 ° C (decomposition).

Elementary analysis for C2oH23N303S:

Calculated: C 62.31 H 6.01 N 10.90%

Found: C 61.81 H 5.97 N 10.90%

Example 6:

3- (3-Carbomethoxy-S-ethylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in 25 ml of DMF, 10 ml of water is added (exothermic reaction). The solution is cooled to room temperature and then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The reaction mixture is stirred at room temperature for 1 hour, and 1.56 g (0.01 mol) of ethyl iodide is added thereto. The reaction mixture is stirred at room temperature for 1 hour; a precipitate is thus formed which is collected by vacuum filtration. The filter cake is washed successively with ether, with water, then again with ether, then the product is dried; 1.45 g (40.6% yield) of 3- (3-carbomethoxy-S-ethylisothio-ureido) -4-aminobenzophenone are thus obtained; M.p. 155-156 ° C (decomposition).

Elementary analysis for C18H19N3O3S (P.M. 357,416):

Calculated: C 60.48 H 5.36 N 11.76%

Found: C 60.38 H 5.44 N 11.75%

Example 7:

3- (3-C arbomethoxy-S-cyclohexylmethylisothio-ureido) -4-aminobenzophenone

To a solution of 3.2 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added. The solution is cooled to ordinary room temperature and then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto; the resulting solution is stirred for 1 h at ordinary room temperature. Then added 1.77 g (0.01 mol) of cyclohexyl bromide, then the solution is stirred at room temperature for 19'A h. The precipitate is collected, washed successively with ether, then with water and finally again with ether,

then we dry it. 1.7 g of 3- (3-carbomethoxy-S-cyclohexylmethylisothio-ureido) -4-aminobenzophenone are thus obtained; M.p. 155-158 ° C (decomposition).

Elementary analysis for C23H27N303S:

Calculated: C 64.91 H 6.40 N 9.87%

Found: C 65.27 H 6.80 N9.96%

Example 8:

3- (3-Carbomethoxy-S-cyanobutylisothio-ureido) -4-

aminobenzophenone

To a solution of 6.5 g (0.02 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to room temperature and 1.6 g (0.02 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 hour, then 3.24 g (0.02 mol) of 5-bromovaleronitrile is added thereto. The solution is stirred at room temperature for 18 h, then poured into 500 ml of water. A suspension is thus formed which is stirred at ordinary room temperature for another 18 h; the solids are collected by filtration, washed with ether, the product is dried and thus 7.35 g (yield 89.5%) of 3- (3-carbomethoxy-S-cyanobutylisothio-ureido) are collected - 4-aminobenzophenone; M.p. 155-160 ° C (decomposition).

Example 9:

3- (3-Carbomethoxy-S-ethoxycarbonylpropylisothio-

ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7.0 ml of water is added. The solution is cooled, and 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. This solution is stirred at ordinary room temperature for 1 h. Then added 1.95 g (0.01 mol) of ethyl 4-bromobutyrate. The solution is stirred at room temperature for 4 days, then poured into excess water. A semi-solid tarry precipitate is thus formed which is collected and triturated with 5 ml of ether. The solid is collected, washed with ether and dried, giving 2.7 g (62% yield) of 3- (3-carbomethoxy-S-ethoxycarbonylpropylisothio-ureido) -4-aminobenzophenone; M.p. 119-120 ° C (decomposition).

Example 10:

3- (3-carbomethoxy-S-phthalimidobutylisothio-ureido) -

4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added. The solution is cooled to room temperature and 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 h, and 2.82 g (0.01 mol) of N- (4-bromobutyl) phthalimide is added thereto. The solution is stirred for 30 min at the end of which a precipitate begins to form; the precipitate is stirred in the solution for a further 30 min, then it is collected by filtration, washed with water and with ether and dried, which gives 2.9 g (yield 54.7 %) of 3- (3-carbomethoxy-S-phthalimidobutylisothio-ureido) -4-aminobenzophenone; M.p. 154-157 ° C (decomposition).

Example 11:

3- (3-Carbomethoxy-S-propargylisothio-nreido) -

4-aminobenzophenone

To a solution of 6.58 g (0.02 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to the temperature

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ordinary room, then add 1.6 g (0.02 mol)

of a 50% aqueous solution of sodium hydroxide, and the solution is stirred at ordinary room temperature for 1 h. 2.38 g (0.02 mol) of propargyl bromide is added and the solution is stirred at room temperature for 3 h, then poured into 500 ml of water. The precipitate is collected by filtration and dried, which gives 5.1 g (yield 69%) of 3- (3-carbomethoxy-S-propargylisothio-ureido) -4- 'aminobenzophenone; M.p. 170 ° C (decomposition).

Example 12:

3- (3-Carbomethoxy-S-hydroxypropylisothio-urèido) -

4-aminobenzophenone

To a solution of 6.58 g (0.02 mol) of 3- (3-carbomethoxythio-ureido J-4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to ordinary room temperature and 1.6 g (0.02 mol) of a 50% aqueous sodium hydroxide solution are added thereto, and the solution is then stirred at ordinary room temperature for 1 hour. g (0.02 mol) of 3-bromopropanol, the reaction mixture is stirred for 48 h, then it is poured into 300 ml of water. After stirring at ordinary room temperature for 5 days, the precipitate is collected by filtration, washed with water and dried, giving 4.65 g (60% yield) of 3- (3-carbomethoxy-S-hydroxypropylisothio-ureido) -4-aminobenzophenone; mp 124 ° C (decomposition ).

Example 13:

3- (3-Carbomethoxy-S-butenylisothio-ureido) -4-aminobenzophenone

To a solution of 6.59 g (0.02 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to room temperature, 1.6 g (0.02 mol) of a 50% aqueous solution of sodium hydroxide is added thereto, and the solution is stirred at room temperature for 1 hr. 2 g (0.02 mol) of 4-bromo-1-butene are added thereto; the solution is stirred at ordinary room temperature for 48 h, then poured into 250 ml of water. The resulting mixture is stirred at room temperature for 3 days; a white precipitate is thus formed which is collected by filtration, which is washed with water and then dried, which gives 6.3 g (82% yield) of 3- (3- carbomethoxy-S-butenylisothio-ureido) -4-aminobenzophenone; M.p. 122 ° C (decomposition).

Example 14:

3- (3-Carbomethoxy-S-phenethylisothio-ureido) -4-aminobenzophenone

To a solution of 6.58 g (0.02 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to room temperature and then 1.6 g (0.02 mol) is added

of a 50% aqueous solution of sodium hydroxide. The solution is stirred at room temperature for 1 h, then 3.9 g (0.02 mol) of phenethyl bromide is added thereto, and the solution is stirred at room temperature for 48 h. The solution is then poured into 250 ml of water, and the mixture is stirred at ordinary room temperature for 3 days. The fine white precipitate is collected by filtration and dried,

which gives 3.7 g of 3- (3-carbomethoxy-S-phenethylisothio-ureido) -4-aminobenzophenone; M.p. 119 ° C (decomposition).

Example 15:

3- (3-Carbomethoxy-S-cinnamylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, the following is added

7 ml of water. The solution is cooled to room temperature, and 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 hour. To this is added 1.97 g (0.01 mol) of cinnamyl bromide, the solution is stirred at ordinary room temperature for 2 h, it is poured into 250 ml of water, and it is further stirred at ordinary room temperature for another 18 h. The above is collected by filtration,

washed with water and dried, giving 4.0 g of 3- (3-carbomethoxy-S-cinnamylisothio-ureido) -4-amino-benzophenone; M.p. 110 ° C (decomposition).

Example 16:

3- [Carbomethoxy-S- (3-methylbutyl) isothio-ureido] -4-aminobenzophenone

To a solution of 6.58 g (0.02 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 50 ml of DMF, 15 ml of water is added. The solution is cooled to room temperature, then 1.6 g (0.02 mol) of a 50% aqueous solution of sodium hydroxide is added thereto, and the solution is stirred for 1 h. 3.02 g (0.02 mol) of 1-bromo-3-methyl-butane is added and the solution is stirred at room temperature for 1 h. A precipitate is thus formed which is collected by filtration, washed with ether, with water and with ether and then dried, which gives 2.3 g (yield 29%) of 3- [carbomethoxy -S- (3-methylbutyl) isothio-ureido] -4-aminobenzophenone; M.p. 142-144 ° C.

Example 17:

3- [3-Carbomethoxy-S- (2,6-dichlorobenzyl) -isothio-ureidoJ-4-aminobenzophenone A solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4 -aminobenzophenone in 25 ml of DMF, 7 ml of water are added. The solution is cooled to room temperature, then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto, and the solution is stirred at room temperature for 1 hour. 2.4 g (0.01 mol) of a-bromo-2,6-dichlorotoluene are added thereto and the solution is stirred at ordinary room temperature for 48 h, then it is poured into 200 ml of water. The precipitate thus formed is collected and dried, which gives 4.5 g of 3- [3-carbomethoxy-S- (2,6-dichlorobenzyl) isothio-ureido] -4-aminobenzophenone; M.p. 80-100 ° C (decomposition).

Example 18:

3- (3-Carbobutoxy-S-methylisothio-ureido) -4-aminobenzophenone

To a solution of 3.71 g (0.01 mol) of 3- (3-carbobutoxythio-ureido) -4-aminobenzophenone in 50 ml of DMF, 10 ml of water is added; 0.8 g (0.01 mol) is added to this mixture

of a 50% aqueous solution of sodium hydroxide, and the resulting solution is stirred at ordinary room temperature for 75 min. Then added 1.42 g (0.01 mol) of methyl iodide, then the reaction mixture was stirred at room temperature for 18 h, and then poured into 300 ml of water. The precipitate thus formed is collected by filtration, washed with ether and then dried, which gives 1.95 g (yield 51%) of 3- (3-carbobutoxy-S-methylisothio-ureido) -4-amino-benzophenone ; M.p. 102 ° C (decomposition).

Example 19:

3- (3-Carbomethoxy-S-phenoxypropylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added. The solution is cooled to ordinary room temperature and 0.8 g (0.01 mol) of a solution is added to it.

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aqueous with 50% sodium hydroxide. The solution is stirred at room temperature for 1 h. 0.01 mol of 3-phenoxypropyl bromide is added thereto, then the solution is left to stand at ordinary room temperature for the duration of the weekend. The solution is then poured into water; the precipitate thus formed is collected, washed with water, with hexane, then dried, which gives 4.3 g (yield 93%) of 3- (3-carbomethoxy-S-phenoxypropylisothio-ureido) - 4-aminobenzophenone; M.p. 62-80 ° C.

Example 20:

Improved preparation of 3- (3-Carbomethoxy-S-

methylisothio-ureido) -4-aminobenzophenone

To a suspension of 6.58 g (0.02 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in 30 ml of acetone and 10 ml of water, 1.76 g ( 0.022 mol) of a 50% aqueous solution of sodium hydroxide. This mixture is stirred at ordinary room temperature for 1 h. The solution is separated by decantation from a small amount of oil. To the solution is then added 3.124 g (0.022 mol) of methyl iodide. A thick suspension is thus formed which is then stirred at ordinary room temperature for 15 min; the solid is then collected by filtration, washed successively with ether, with water and again with ether, then is dried, which gives 4.66 g of 3- (3-carbomethoxy-S- methylisothio-ureido) -4-amino-benzophenone; M.p. 163-164 ° C.

Example 21:

3- (3-Carbopropoxy-S-methylisothio-ureido) -4-

aminobenzophenone

To a suspension of 1.79 g (0.005 mol) of 3- (3-carbopropoxy-thio-ureido) -4-aminobenzophenone in 10 ml of acetone and 5 ml of water, 0.4 g (0.005 mol ) a 50% aqueous solution of sodium hydroxide. The mixture is stirred at room temperature for 1 h, then 0.71 g (0.005 mol) of methyl iodide is added thereto. The resulting suspension is stirred at room temperature for 15 min.

The precipitate thus formed is collected by filtration, washed successively with acetone, water and ether, then is dried, which gives 0.7 g (38% yield) of 3- (3-carbopropoxy -S-methylisothio-ureido) -4-aminobenzophenone; M.p. 128-130 ° C (decomposition).

Example 22:

3-f 3-Carbo-isopropoxy-S-methylisothio-ureido) -

4-aminobenzophenone

To a suspension of 1.79 g (0.005 mol) of 3- (3-carbo-isopropoxythio-ureido) -4-aminobenzophenone in 10 ml of acetone and 5 ml of water, 0.4 g (0.005 mol ) a 50% aqueous solution of sodium hydroxide. The mixture is stirred at ordinary room temperature for 1 h,

then 0.71 g (0.005 mol) of methyl iodide is added thereto. The reaction mixture is stirred at ordinary room temperature for 4 h, then poured into 200 ml of water. The resulting mixture is stirred at room temperature for 18 h. The yellow precipitate is collected by filtration, washed with water and then dried, which gives 1.1 g (yield 59%) of 3- (3-carbo-isopropoxy-S-methylisothio-ureido) -4-aminobenzophenone, Mp 139-142 ° C (decomposition).

Example 23:

3- (3-Carbophenethoxy-S-methylisothio-ureido) -

4-aminobenzophenone Stage A:

Carbophenethoxyisothiocyanate

To a suspension of 9.7 g (0.1 mol) of potassium thiocyanate in 200 ml of ethyl acetate, 18.5 g (0.1 mol) of phenethyl chloroformate are added. The mixture is stirred at ordinary room temperature for 18 h, then filtered under vacuum through Celite. The filtrate is concentrated in vacuo, which gives carbophenethoxyisothiocyanate.

Stage B:

3- (3-Carbophenethoxythio-ureido) -4-aminobenzophenone

To a solution of 2.12 g (0.01 mol) of 3,4-diaminobenzophenone in 200 ml of ether, 2.07 g (0.01 mol) of carbophenethoxyisothiocyanate are added. The mixture is stirred at ordinary room temperature for 2 h, then filtered under vacuum. The filter cake is dried, which gives 3- (3-carbo-phenethoxythio-ureido) -4-aminobenzophenone.

Stage C:

3- (3-Carbophenethoxy-S-methylisothio-ureido) -4-aminobenzophenone

To a mixture of 2.08 g (0.005 mol) of 3- (3-carbophenethoxy-thio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added (exothermic reaction). The mixture is cooled to room temperature and then 0.4 g (0.005 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The mixture is stirred at ordinary room temperature for 1 h, then 0.71 g (0.005 mol) is added to it

methyl iodide. The mixture is stirred at ordinary room temperature for 4 h, then poured into 200 ml of water. A suspension is thus formed which is filtered with the application of a vacuum; the filter cake is then dried, and 3- (3-carbophenethoxy-S-methylisothio-ureido) -4-aminobenzophenone is thus obtained as a product.

Example 24:

3- (3-Carbomethoxy-S-2-methylnaphthylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added (exothermic reaction). The solution is cooled to room temperature and then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 h, then 2.21 g (0.01 mol) of 2-bromomethylnaphthalene is added thereto. The mixture is stirred at ordinary room temperature for 4 h, then poured into 200 ml of water. A suspension is thus formed which is filtered with the application of a vacuum; the filter cake is dried, which gives 3- (3-carbomethoxy-S-methylnaphthylisothio-ureido) -4-aminobenzophenone.

Example 25:

3- (3-Carbomethoxy-S-4-methoxybutylisothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added (exothermic reaction). The solution is cooled to room temperature and then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 hour, then 1.67 g (0.01 mol) of 4-methoxybutyl bromide is added thereto. The mixture is stirred at room temperature for 4 h, then poured into 200 ml of water.

A suspension is thus formed which is subjected to filtration with vacuum application; drying the filter cake thus obtained, which gives the desired product, which is 3- (3-carbomethoxy-S-methoxybutylisothio-ureido) -4-aminobenzophenone.

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Example 26:

3- (3-Carbomethoxy-S-3-carbophenoxypropyl-isothio-ureido) -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added (exothermic reaction). The solution is cooled to room temperature and then 0.8 g is added. (0.01 mol) of a 50% aqueous solution of sodium hydroxide. The solution is stirred at room temperature for 1 hour, then 2.43 g (0.01 mol) of phenyl 3-bromo-butyrate is added thereto. The mixture is stirred for 4 h, then poured into 200 ml of water. A suspension is thus formed which is separated by filtering it with the application of a vacuum; then drying the filter cake gives 3- (3-carbomethoxy-S-

3-carbophenoxypropylisothio-ureido) -4-aminobenzophenone.

Example 27:

1 -Amino-2- (3-carbomethoxy-S-methylisothio-ureido) -4-propylsulfonylbenzene

Stage A:

1 -Amino-2- (3-carbomethoxythio-ureido) -4-propylsulfonylbenzene

To a mixture of 2.14 g of 1,2-diamino-4-propylsulfonyl-benzene (i.e. 0.01 mol of this compound) in 200 ml of chloroform, 1.17 g (0.01 mol) of carbomethoxy is added -isothiocyanate. The mixture is stirred at ordinary room temperature for 4 h, then filtered with the application of vacuum. The filter cake is dried, and thus 1-amino-2- (3-carbomethoxythio-ureido) -4-propylsulfonylbenzene is obtained.

Stage B:

l-amino-2- (3-carbomethoxy-S-methylisothio-ureido) -4-propylsulfonylbenzene

To a mixture of 3.33 g (0.01 mol) of 1-amino-2- (3-carbo-methoxythio-ureido) -4-propylsulfonylbenzene in 25 ml of DMF, 7 ml of water is added (exothermic reaction ). The mixture is cooled to room temperature and then 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The mixture is stirred at room temperature for 1 hour, then 1.42 g (0.01 mol) of methyl iodide is added thereto. The mixture is stirred at room temperature for 4 h, then poured into 200 ml of water.

A suspension is thus formed which is filtered with the application of a vacuum; the filter cake is then dried, which gives 1 -amino-2- (3-carbomethoxy-S-methylisothio-ureido) -

4-propylsulfonylbenzene.

Example 28:

3- (3-carbohexoxy-S-methylisothio-ureido) -4-am inobenzophenone

Stage A:

Carbohexoxyisothiocyanate

To a suspension of 9.7 g (0.1 mol) of potassium thiocyanate in 200 ml of ethyl acetate, 16.5 g (0.1 mol) of n-hexyl chloroformate are added. The mixture is stirred at ordinary room temperature for 18 h, then filtered with the application of a vacuum through celite. The filtrate is concentrated under vacuum, which gives carbohexoxyisothiocyanate.

Stage B:

3- (3-carbohexoxythio-ureido) -4-aminobenzophenone To a solution of 2.12 g (0.01 mol) of 3,4-diaminobenzophenone in 200 ml of ether, 1.87 g (0.01 mol) of carbohexoxyisothiocyanate. The mixture is stirred at ordinary room temperature for 2 h, then filtered with the application of vacuum. The filter cake is dried, and 3- (3-carbohexoxythio-ureido) -4-aminobenzophenone is thus obtained.

Stage C:

3- (3-Carbohexoxy-S-methylisothio-ureido) -4-amino-benzophenone

To a mixture of 2.0 g (0.005 mol) of 3- (3-carbohexoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added (exothermic reaction). The mixture is cooled to room temperature and then 0.4 g (0.005 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The mixture is stirred at room temperature for 1 hour and then 0.71 g (0.005 mol) of methyl iodide is added thereto. The mixture is stirred at room temperature for 4 h, then poured into 200 ml of water. A suspension is thus formed which is filtered with the application of a vacuum. The filter cake is then dried, which gives 3- (3-carbohexoxy-S-methylisothio-ureido) -4-aminobenzophenone.

Example 29:

2- <3-Carbomethoxy-S-methylisothio-ureido) -

4-nitroaniline

Stage A:

2- (3-Carbomethoxythio-ureido) -4-nitroaniline To a solution of 3.83 g (0.0025 mol) of 4-nitro-o-phenylene diamine in 800 ml of ethyl acetate, 2 , 8 g (0.0025 mol) of carbomethoxyisothiocyanate. The solution is stirred at ordinary room temperature for 2 h; the precipitate is collected and dried, which gives 2.5 g of 2- (3-carbomethoxy-thio-ureido) -4-nitroaniline; M.p. 229 ° C (decomposition).

Stage B:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4- nitroaniline To a solution of 2.0 g (0.0074 mol) of 2- (3-carbomethoxy-thio-ureido) -4-nitroaniline in 20 ml of DMF, 4 ml of water are added. The solution heats up slightly, and is cooled to room temperature. 0.59 g (0.0074 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 45 min, then 1.05 g (0.0074 mol) of methyl iodide is added thereto, then the solution is stirred at room temperature for 30 min, and finally pour it into 300 ml of water. The precipitate thus formed is collected, washed with ether, dried, and thus 2- (3-carbomethoxy-S-methylisothio-ureido) -4-nitroaniline is obtained; M.p. 169-171 ° C (decomposition).

Example 30:

2- (3-Carbomethoxy-S-methylisothio-ureido) aniline Stage A:

2- (3-Carbomethoxythio-ureido) aniline

To a solution, cooled to the temperature of ice,

2.75 g (0.025 mol) of o-phenylenediamine in 400 ml of ether, 2.93 g (0.025 mol) of carbomethoxyisothiocyanate are added.

A suspension is immediately formed. The reaction mixture is stirred at 0 ° C for 5 min, then the precipitate is collected by filtration. The product is washed with ether and then dried; 4.25 g of 2- (3-carbomethoxythio-ureido) aniline are thus obtained; M.p. 190-191 ° C (decomposition).

Stage B:

2- (3-Carbomethoxy-S-methylisothio-ureido) aniline To a solution of 2.25 g (0.01 mol) of 2- (3-carbomethoxythio-

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ureido) aniline in 25 ml of DMF, 5 ml of water are added. There is an exothermic reaction; the solution is then cooled to ordinary room temperature. 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide is added thereto, then the reaction mixture is stirred at ordinary room temperature for 1 h. 1.42 g (0.01 mol) of methyl iodide are added thereto, then the reaction mixture is stirred at ordinary room temperature for 3 min, and then it is poured into 200 ml of water. The solution is stirred at ordinary room temperature for 5 min, then the precipitate is collected by filtration and finally dried, which gives 1.6 g of 2- (3-carbomethoxy-S-methylisothio-ureido) aniline.

Example 31:

2- (3-Carbomethoxy-S-methylisothio-ureido J-4-phenylsulfonylaniline

Stage A:

2- (3-Carbomethoxythio-ureido) -4-phenylsulfonylaniline

To a solution of 4.96 g (0.02 mol) of 2-amino-4-phenyl-sulfonylaniline in 200 ml of ether and 150 ml of chloroform, 2.34 g (0.02 mol) of carbomethoxyisothiocyanate is added . The reaction mixture is stirred at ordinary room temperature for 2 h, then the precipitate is collected by filtration, which gives 2.65 g of 2- (3-carbomethoxythio-ureido) -4-phenylsulfonylaniline; M.p. 197 ° C (decomposition).

Elementary analysis for C15H15N3O4S3:

Calculated: C 49.30 H 4.14 N 11.50%

Found: C 49.03 H 4.21 N 11.05%

Stage B:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4-phenylsulfonylaniline

To a solution of 1.0 g (0.0025 mol) of 2- (3-carbomethoxythio-ureido) -4-phenylsulfonylaniline in 15 ml of DMF, 3 ml of water is added. The solution is cooled to room temperature and 0.22 g (0.0027 mol) of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 h, then 0.39 g (0.0027 mol) of methyl iodide is added thereto, after which the solution is stirred at room temperature for 18 h. The solution is then poured into an excess of water; a precipitate is thus formed which is collected by filtration; obtaining 0.75 g of 2- (3-carbomethoxy-S-methylisothio-ureido) -4-phenylsulfonylaniline; M.p. 126-130 ° C (decomposition).

Example 32:

3- (3-Carbomethoxy-S-methylisothio-ureido) -4-aminoacetophenone

Stage A:

3- (3-Carbomethoxythio-ureido) -4-amino-acetophenone

To a solution of 0.85 g (0.0057 mol) of 3,4-diamino-acetophenone in 150 ml of chloroform, 0.66 g (0.0057 mol) of carbomethoxyisothiocyanate is added; the solution is stirred at ordinary room temperature for 2 h. The precipitate formed is collected by filtration, washed with ether and then dried, which gives 0.35 g of 3- (3-carbomethoxythio-ureido) -4-aminoacetophenone; M.p. 200 ° C (decomposition).

Stage B:

3- (3-Carbomethoxy-S-methylisothio-ureido) -4-aminoacetophenone

To a solution of 0.5 g (0.00187 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminoacetophenone in 15 ml of DMF, the following is added

4 ml of water, then 0.15 g (0.00187 mol) of a 50% aqueous solution of sodium hydroxide is added. The solution is stirred at room temperature for 1 hour and then added to it. 0.127 g (0.00187 mol) of methyl iodide and the reaction mixture is stirred at room temperature for 18 h. The reaction mixture is then poured into 100 ml of water and then stirred at room temperature for 1 hr. A precipitate is thus formed which is collected, washed with ether and then dried, which gives 0.25 g of 3- (3-carbomethoxy-S-methylisothio-ureido) - 4-aminoacetophenone; M.p. 165-167 ° C (decomposition).

Example 33:

3- (3-Carbomethoxy-S-nonadecylisothio-ureido) -4-aminobenzophenone

To a suspension of 1.65 g (0.005 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in 15 ml of acetone and 5 ml of water, 0.4 g (0.005 mol ) a 50% aqueous solution of sodium hydroxide. The solution is stirred at room temperature for 30 min, and then 1.97 g (0.005 mol) of 1-iodononadecane in 50 ml of acetone is added thereto. The suspension is stirred at room temperature for 42 h; a precipitate is thus formed which is collected by filtration, washed with acetone, then dried,

which gives 1.05 g of 3- (3-carbomethoxy-S-nonadecylisothio-ureido) -4-aminobenzophenone; M.p. 76-80 ° C (decomposition).

Example 34:

3- [3-Carbo- (2-methoxyethoxy) -S-methylisothio-ureido] -4-aminobenzophenone

Stage A:

2-methoxyethyl chloroformate To an ice-cooled solution of 87 g (0.11 mol) of a benzene solution containing 12.5% phosgene in another 25 ml of benzene, 7.6 g ( 0.1 mol) of Methyl-Cellosolve in 50 ml of benzene. The solution is stirred at 5 ° C for 2 h,

then at ordinary room temperature for 18 h. The solution is then concentrated under vacuum, which gives 15.1 g of 2-methoxyethyl chloroformate in the form of a colorless oil.

Stage B:

Carbo- (2-methoxy) ethoxyisothiocyanate To a suspension of 9.7 g (0.1 mol) of potassium thiocyanate in 150 ml of ethyl acetate, 2-methoxyethyl chloroformate in 25 ml of acetate is added ethyl. The mixture is stirred at room temperature for 1 h, heated to reflux for 1 h, then stirred at room temperature overnight. The mixture is filtered through celite, then the filtrate is concentrated under vacuum at ordinary room temperature, which gives 15 g of carbo- (2-methoxy) ethoxyisothiocyanate in the form of an orange liquid.

Stage C:

3- [3-Carbo- (2-methoxy) ethoxythio-ureido ~ \ -4-amino-benzophenone

To a solution of 4.24 g (0.02 mol) of 3,4-diamino-benzophenone in 500 ml of ether, 3.22 g (0.02 mol) of carbo- (2-methoxy) ethoxyisothiocyanate is added . The solution is stirred for 1 h; the precipitate which has formed is collected by filtration and is dried, which gives 2.85 g of 3- [3-carbo- (2-methoxy) ethoxythio-ureido] -4-amino-benzophenone; M.p. 147-151 ° C (decomposition).

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Elementary analysis for C18H19N3O4S:

Calculated: C 57.86 H 5.13 N 11.29%

Found: C 57.89 H 5.82 N 10.77%

Stage D:

3- [3-Carbo- (2-methoxy) ethoxy-S-methyl-isothio-ureido] -4-aminobenzophenone

To a solution of 1.87 g (0.005 mol) of 3- [3-carbo- (2-methoxy) -ethoxythio-ureido] -4-aminobenzophenone in 15 ml of DMF, 3 ml of water is added. To the solution thus obtained, 0.4 g of a 50% aqueous solution of sodium hydroxide is added,

and the solution is stirred at room temperature for 1 hour. 0.71 g (0.005 mol) of methyl iodide is then added thereto, and the solution is stirred at room temperature for 18 h. The solution is poured into 200 ml of water, which causes the formation of a precipitate which is collected by filtration, which is washed with water and which is dried, which gives 1, 1 g of 3- [3-carbo- (2-methoxy) ethoxy-S-methylisothio-ureido] -4-aminobenzophenone.

Elementary analysis for C19H21N3O4S:

Calculated: C 58.90 H 5.46 N 10.85%

Found: C 58.31 H 5.34 N 11.05%

Example 35:

3-Amino-4- (3-carbomethoxy-S-methylisothio-ureido Jbenzophenone

Stage A:

3-nitro-4- (3-carbomethoxythio-ureido) -benzophenone

Stirred and heated to reflux for 17 h, a mixture of 9.9 g (0.041 mol) of 3-nitro-4-aminobenzophenone,

4.8 g (0.041 mol) of carbomethoxyisothiocyanate in 25 ml of acetonitrile. The reaction mixture is then cooled; the precipitate which is formed therein is collected by filtration, washed with acetonitrile, then dried, which gives 8.7 g of 3-nitro-4- (3-carbomethoxythio-ureido) benzophenone; M.p. 178-183 ° C (decomposition).

Stage B:

3-Amino-4- (3-carbomethoxythio-ureido) benzophenone

The mixture is heated while stirring, until reflux, a mixture of 3.6 g (0.01 mol) of 3-nitro-4- (3-carbomethoxythio-ureido) -benzophenone, 11.3 g (0.05 mol ) stannous chloride, 20 ml of concentrated hydrochloric acid, 40 ml of methanol and 40 ml of acetic acid. After 10 min most of the solid matter has dissolved. The reaction mixture is heated to reflux for a total of 35 minutes, then filtered to remove a small amount of colored substance. The filtrate is added to 600 ml of water while stirring; a precipitate is thus formed which is collected by filtration, which gives 3.5 g of 3-amino-4- (3-carbomethoxy-thio-ureido) benzophenone; M.p. 187 ° C (decomposition).

Stage C:

3-Amino-4- (3-carbomethoxy-S-methylisothio-ureido Jbenzophenone

To a stirred suspension of 2.5 g (0.0076 mol) of 3-amino-4- (3-carbomethoxythio-ureido) benzophenone in 20 ml of DMF, 0.61 g (0.0076 mol) of a 50% aqueous solution of sodium hydroxide in deionized water. The clear orange-red solution which forms is cooled to 4 ° C.

after which 1.1 g (0.0076 mol) of methyl iodide are added thereto. The temperature rises to 7 ° C (pH 7.8). After 3 mins,

the reaction mixture is added to 200 ml of deionized water, while stirring. A precipitate is formed which is collected, which gives 1.8 g of 3-amino-4- (3-carbomethoxy-S-methyl-isothio-ureido) benzophenone.

Elementary analysis for C17H17N3O3S:

Calculated: C 59.45 H 5.00 N 12.24 S 9.34%

Found: C 59.48 H 5.11 N 12.59 S 8.90%

Example 36:

3- [3-Carbomethoxy-S- (2-nitro) benzylisothio-ureido ~] -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF, 7 ml of water is added. The solution is cooled to ordinary room temperature, then 0.8 g of a 50% aqueous solution of sodium hydroxide is added thereto. The solution is stirred at room temperature for 1 hour. 2.1 g (0.01 mol) of o-nitrobenzyl bromide in 20 ml of DMF are then added thereto. The solution is stirred at room temperature for 24 h, then poured into 300 ml of water. A suspension is formed which is stirred at ordinary room temperature for 18 h, after which the solid is collected by filtration and dried, which gives 4.25 g of 3- [3-carbomethoxy-S- ( 2-nitro) -benzylisothio-ureido] -4-aminobenzophenone; M.p. 75-85 ° C (decomposition).

Elementary analysis for C23H20N4O5S:

Calculated: C 59.47 H 4.34 N 12.06%

Found: C 57.91 H 4.20 N 12.98%

Example 37:

3- [3-Carbomethoxy-S- (p-nitro) benzylisothio-ureido ~ \ -4-aminobenzophenone

To a solution of 3.29 g (0.01 mol) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone in 25 ml of DMF,

7 ml of water are added. The solution is cooled to room temperature and 0.8 g of a 50% aqueous sodium hydroxide solution is added thereto. The solution is stirred at room temperature for 1 hour, and 2.11 g (0.01 mol) of p-nitrobenzyl bromide in 20 ml of DMF is added thereto. The solution is stirred at room temperature for 24 h, then poured into 300 ml of water. A suspension is thus formed which is stirred at ordinary room temperature for 18 h, after which the precipitate is collected by filtration and dried, which gives 4.25 g of 3- [3-carbomethoxy-S- (p-nitro) benzylisothio-ureido] -4-aminobenzophenone; M.p. 100-105 ° C (decomposition).

Elementary analysis for C23H2oN405S:

Calculated: C 59.47 H 4.34 N 12.06%

Found: C 57.91 H 4.29 N 11.89%

By operating in a manner analogous to that described above in Example 37, with the exception of the use in place of p-nitrobenzyl bromide, an equimolar amount of each of the following organic halides: p-methylbenzyl bromide, m-methylbenzyl bromide, p-chlorobenzyl chloride, crotyl chloride and 3-chloro-2-methyl-propene, and by following substantially the same procedure as that described in the above example 37, we obtains, respectively, the following compounds:

(Table at the top of the next page)

Example 43:

3- (3-Carbomethoxy-S-2- [4- (4-acetamidophenylthio) -phenylcarbamyl \ ethylisothio-ureido) -4-aminobenzo-phenone

Stage A:

4- (3-Bromopropionamido) -4'-nitrodiphenylsulfide

To a suspension of 7.4 g (0.03 mol) of 4-amino-4'-nitro-

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Example Elementary analysis

No. Compound prepared P.F.

(° C) Calculated Found

38 3- [3-Carbomethoxy-S- (4- 157-159 methyl) benzylisothio-ureido] -4-aminobenzophenone

39 3- [3-Carbomethoxy-S- (3- 143-145 methyl) benzylisothio-ureido] -4-aminobenzophenone

40 3- [3-Carbomethoxy-S- (p- 153-155 chloro) benzylisothio-ureido] -4-aminobenzophenone

41 3- [3-Carbomethoxy-S- 156-157 (buten-2-yl) isothio-ureido] -4-aminobenzophenone

42 3- [3-Carbomethoxy-S- 110-112 (2-methyl) propen-2-yl-isothio-ureido] -4-amino-benzophenone for C24H23N3O3S: C 66.49 C 65.93 H 5.35 H 5.42 N 9.69 N 10.09

for C24H23N3O3S: C 66.49 C 65.85 H 5.35 H 5.33 N 9.69 N 9.89

for C23H20CIN3O3S: C 60.85 C 61.04 H 4.44 H 4.43 N 9.26 N 9.40

for C2oH2iN303S: C 62.64 C 63.24 H 5.52 H 5.49 N 10.96 N 12.11

for C2oH2iN303S: C 62.64 C 61.78 H 5.52 H 5.35 N 10.96 N 11.65

diphenylsulfide in 200 ml of toluene, 5.14 g (0.03 mol) of 3-bromopropionyl chloride are added. The mixture is heated to reflux and stirred for 3 h, then stirred overnight at ordinary room temperature. The precipitate which has thus formed is collected by filtration, washed with hexane, then dried, which gives 10.1 g of 4- (3-bromopropionamido) -4'-nitrodiphenylsulfide; M.p. 136-138 ° C (decomposition).

Stage B:

4- (3-Bromopropionamido) -4'-aminodiphenylsulfide

To a suspension of 4 g (0.0105 mol) of 4- (3-bromopropion-amido) -4'-nitrodiphenylsulfide in 250 ml of ethanol, 0.2 g of 5% palladium on carbon is added. The mixture is shaken on a Parr hydrogenator for 5 h, then allowed to stand overnight at ordinary room temperature. There was no hydrogen capture. A stream of nitrogen gas is passed through the mixture and 1 g of Raney nickel is added. The mixture is shaken on a Parr hydrogenator (initial pressure 3.5 bar) for 5 h. After 5 h, there was a hydrogen uptake corresponding to 0.07 bar. The reaction mixture is kept under pressure for 18 h, at the end of which the total hydrogen uptake corresponds to 0.14 bar. The mixture is filtered, and the filtrate is concentrated in vacuo. 2.7 g of 4- (3-bromo-propionamido) -4'-aminodiphenylsulfide are thus obtained; M.p. 141-148 ° C (decomposition).

Stage C:

4- (3-Bromopropionamido) -4'-acetamidodiphenylsulfide

To a suspension of 2 g (0.0057 mol) of 4- (3-bromopropion-amido) -4'-aminodiphenylsulfide in 150 ml of toluene, 0.58 g (0.0057 mol) of acetic anhydride is added. The suspension is heated to reflux and stirred for 3 h, then allowed to stand overnight at ordinary room temperature. A precipitate has thus formed which is collected by filtration,

after which it is washed with hexane and dried. 1.4 g of 4- (3-bromopropionamido) -4'-acetamido-diphenylsulfide are thus obtained; M.p. 189-193 ° C (decomposition).

Elementary analysis for Ci7Hi7BrN202S:

Calculated: C 51.97 H 4.36 N 7.12%

Found: C 52.70 H 4.50 N 7.43%

Stage D:

40 3- (3-Carbomethoxy-S-2- [4- (4-acetamido-

phenylthio) phenylcarbamyï \ ethylisothio-ureido) -4-aminobenzophenone

To a solution of 0.84 g (0.00254 mol) of 3- (3-carbomethoxy-thio-ureido) -4-aminobenzophenone in 10 ml of DMF and 2 ml of water, 0.2 g of d is added. '' a 50% aqueous solution of sodium hydroxide. The solution is stirred at room temperature for 1 hour, then 1 g of 4- (3-bromo-propionamido) -4'-acetamidodiphenylsulfide and 5 ml of DMF are added thereto. The solution is stirred at ordinary room temperature so for 18 h, then poured into 300 ml of water. The mixture is stirred for 30 min, after which the precipitate which has thus formed is collected by filtration, then dried, which gives 1.45 g of 3- (3-carbomethoxy-S-2- [4- (4 -acetamidophenylthio) -phenylcarbamyl] ethylisothio-ureido) -4-aminobenzophenone; ss m.p. 120 ° C with decomposition at 162-166 ° C.

Elementary analysis for C33H31N5O5S2:

Calculated: C 61.76 H 4.87 N 10.91%

Found: C 61.14 H 4.91 N 11.57%

60 Example 44:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4-phenoxysulfonylaniline

Stage A:

65

2- (3-Carbomethoxythio-ureido) -4-phenoxysulfonyl-aniline

To a solution of 5.28 g (0.02 mol) of 2-amino-5-phenoxy-

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sulfonylaniline in 350 ml of ether, 2.34 g (0.02 mol) of carbomethoxyisothiocyanate are added. The solution is stirred. ordinary room temperature for 1 h; the precipitate which thus forms is collected by filtration, washed with ether and then dried, which gives 5.65 g of 2- (3-carbomethoxythio-ureido) -4-phenoxysulfonylaniline; Mp 185-186 ° C (decomposition).

Elementary analysis for Ci 5Hi 5N3O5S2:

Calculated: C 47.23 H 3.96 N 11.02%

Found: C 47.83 H 4.13 N 10.66%

Stage B:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4-phenoxysulfonylaniline

0.84 g of a solution is added to a solution of 4.0 g (0.0105 mol) of 2- (3-carbomethoxythio-ureido) -4-phenoxysulfonylaniline in 25 ml of DMF and 5 ml of water aqueous with 50% sodium hydroxide. The solution is stirred at room temperature for 1 h, then 1.49 g of methyl iodide are added thereto. The solution is stirred at room temperature for 30 min, then poured into 500 ml of water. A precipitate is thus formed which is collected by filtration and dried, which gives 3.4 g of 2- (3-carbomethoxy-S-methylisothio-ureido) -4-phenoxysulfonylaniline; M.p. 108-113 ° C.

Elementary analysis for C16H17N3O5S2:

Calculated: C 48.59 H 4.33 N 10.63 S 16.22%

Found: C 48.20 H 4.41 N 10.74 S 15.89%

Example 45:

2- (3-Carbomethoxy-S-methylisothio-ureido) -5-butyl-aniline

Stage A:

2- (3-Carbomethoxythio-ureido) -5-n-butylaniline

To a solution of 5.0 g (0.0305 mol) of 4-n-butyl-o-phenylene diamine in 250 ml of ether, 3.57 g (0.0305 mol) of carbomethoxyisothiocyanate is added. The solution is stirred at ordinary room temperature for 2 h (a precipitate in very fine particles begins to form). The mixture is continued to stir at ordinary room temperature for the entire weekend, after which the precipitate is collected by filtration and dried, giving 1.15 g of 2- (3-carbomethoxy-thio-ureido) -5-n-butylaniline; M.p. 162-165 ° C (decomposition).

Stage B:

2- (3-Carbomethoxy-S-methylisothio-ureido) -5-butylaniline

To a solution of 1 g (0.00355 mol) of 2- (3-carbomethoxythio-ureido) -5-n-butylaniline in 15 ml of DMF, 5 ml of water is added. The solution is cooled to room temperature and then 0.284 mol of sodium hydroxide is added thereto in the form of a 50% aqueous solution. The solution is stirred at room temperature for 1 hour, then 0.505 g of methyl iodide is added thereto. The solution is stirred at ordinary room temperature for 10 min, then poured into 200 ml of water. The suspension is stirred at ordinary room temperature for 10 min, and the precipitate which has thus formed is collected by filtration and dried, which gives 0.8 g of 2- (3-carbo-methoxy-S-methylisothio- ureido) -5-butylaniline.

Elementary analysis for Ci4.H2iN302S:

Calculated: C 56.92 H 7.17 N 14.22 S 10.86%

Found: C 57.15 H 7.11 N 14.47 S 10.48%

By using, in place of 4-n-butyl-o-phenylenediamine of Stage A of Example 45, 3,4-diaminopropylthiobenzene, and by following substantially the same procedure as that described therein, 2- (3-carbomethoxythio-ureido) -5-propylthioaniline is obtained; M.p. 167-168 ° C (decomposition),

and this product, when it is treated with methyl iodide by operating in the manner described for stage B of Example 45, allows finally to obtain 2- (3-carbomethoxy-S-methyliso-thio -ureido) -5-propylthioaniline.

Elementary analysis for C13H19N3O2S2:

Calculated: C 49.81 H 6.12 N 13.41 S 20.45%

Found: C 49.17 H 6.02 N 13.53 S 20.58%

Example 46:

2- (3-Carbomethoxy-S-methylisothio-ureido j-4-propylthioaniline

Stage A:

2- (3-Carbomethoxythio-ureido) -4-propyl-thionitrobenzene

A mixture of 5.4 g (0.026 mol) of 2-nitro-5-propylthioaniline, 3.1 g (0.026 mol) of carbomethoxyisothiocyanate and 10 ml of acetonitrile is stirred and refluxed for 1 h. The reaction mixture is cooled; ether is added thereto, then the mixture is filtered; 6.3 g of 2- (3-carbomethoxythio-ureido) -4-propylthionitrobenzene are thus obtained; M.p. 123-125 ° C.

Stage B:

2- (3-Carbomethoxythio-ureido) -4-propylthioaniline

Stir and reflux for 30 min a mixture of 8.8 g (0.027 mol) of 2- (3-carbomethoxythio-ureido) -4-propylthionitrobenzene, 30.2 g (0.135 mol) of stannous chloride, 30 ml concentrated hydrochloric acid, 60 ml of acetic acid and 60 ml of methanol; then pour it into water.

A precipitate is thus formed which is collected by filtration, stirred with an aqueous solution of sodium bicarbonate, then filtered, which gives 6.7 g of 2- (3-carbomethoxythio-ureido) -4-propylthioaniline; M.p. 127-135 ° C (decomposition).

Stage C:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4-propylthioaniline

By substantially following the procedure of stage B of Example 45, 2- (3-carbomethoxythio-ureido) -4-propylthioaniline is reacted with methyl iodide in order to obtain 2- ( 3-carbomethoxy-S-methylisothio-ureido) -4-propylthioaniline.

Elementary analysis for C13H19N3S2O2:

Calculated: C 49.81 H 6.12 N 13.41 S 20.45%

Found: C 49.89 H 6.16 N 13.39 S 20.26%

Using, in place of 2-nitro-5-propylthioaniline of stage A of example 46, an equimolar amount of 2-nitro-5-phenylthioaniline and substantially following the procedures described in stages A to C of 1 Example 46, 2- (3-carbomethoxy-S-methylisothio-ureido) -4-phenylthioaniline is finally obtained; M.p. 126-128 ° C (decomposition).

Example 47:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4- (p-chloro) benzylthioaniline

Stage A:

2-Nitro-5- (p-chloro) benzylthioaniline 3.1 g (0.018 mol) of 5-chloro-2-nitroaniline are dissolved in 30 ml of DMF. 2.85 g (0.018 mol) of 4-chlorobenzyl-mercaptan and 4 g (0.03 mol) of potassium carbonate are added, then

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another 10 ml of DMF are added. The suspension is stirred and heated at 76 ° C for 8 h. It is poured into 200 ml of cold water. A yellow solid is formed which is isolated by filtration with the application of a vacuum, then washed with water and dried; 4.9 g (93% yield) of 2-nitro-5- (p-chloro) benzylthioaniline are thus obtained; M.p. 160-163 ° C (decomposition).

Stage B:

1- (p-Chloro) benzylthio-3- (3-carbomethoxythio-ureido) -4-nitrobenzene

To a solution of 3.6 g of 2-nitro-5- (p-chloro) benzylthio-aniline (i.e. 0.013 mol of this product) in 75 ml of acetone, 1.5 g (0.013 mol) of carbomethoxyisothiocyanate are added in

10 ml of acetone. The reaction mixture is heated until boiling for 1 h. Five drops of triethylamine are added, and stirring is continued over the weekend at ordinary room temperature. A precipitate is thus formed which is collected by filtration, washed with acetonitrile, then dried, which finally gives 2.3 g of l- (p-chloro) benzylthio-3- (3-carbomethoxythio-ureido) - 4-nitrobenzene; M.p. 180-190 ° C (decomposition).

Elementary analysis for C16H14CIN3S2O2:

Calculated: C 46.65 H 3.43 N 10.20 S 15.57 Cl 8.61% Found: C 46.48 H 3.38 NI 1.27 S 14.73 Cl 8.36%

Stage C:

2- (3-Carbomethoxythio-ureido) -4- (p-chloro) -benzylthioaniline

Stirred and heated to reflux for 30 min a mixture of 1.8 g of 1- (p-chloro) benzylthio-3- (3-carbomethoxythio-ureido) -4-nitrobenzene, 10 ml of concentrated hydrochloric acid , 20 ml of methanol, 20 ml of acetic acid and 5.1 g (0.0226 mol) of stannous chloride. The mixture is filtered to remove a small amount of insoluble substance. The filtrate is poured into 500 ml of water while stirring. A precipitate is thus formed which is collected by filtration, washed with water and then dried, which gives 1.4 g of 2- (3-carbomethoxythio-ureido) -4- (p-chloro) -benzylthioaniline; M.p. 161-162 ° C.

Stage D:

2- (3-Carbomethoxy-S-methylisothio-ureido) -4- (p-chloro Jbenzylthioaniline

A mixture of 0.9 g of 2- (3-carbo-methoxythio-ureido) -4- (p-chloro) benzylthioaniline and an aqueous solution of 0.0976 g of hydroxide is cooled to 5 ° C. sodium in 10 ml of DMF. A solution of 0.4 g of methyl iodide in 1 ml of DMF is added thereto, with stirring. The temperature rises to 10aC. The reaction mixture is stirred in an ice bath for 5 min, it is poured into 400 ml of a mixture of ice and water, while stirring. The aqueous phase is extracted with ether, then the ether is removed and 3.0 g of product are thus obtained.

A new amount of precipitate is formed in the aqueous layer; this additional precipitate is collected by filtration and dried, which gives another 0.2 g of product. The two jets of substance are mixed and the overall product thus obtained is subjected to analysis.

Elementary analysis for Ci7Hi6ClN3S202:

Calculated: C 51.56 H 4.61 N 10.78 S 15.27 Cl 9.00%

Found: C 51.01 H 4.59 N 10.61 S 16.10 Cl 8.95%

Example 48:

2- (3-Carbomethoxy-S-methylisothio-ureido) -5-propylsulfinylaniline

To a stirred suspension of 1.7 g (0.0542 mol) of 2- (3-carbomethoxy-S-methylisothio-ureido) -5-propylthio-

aniline in 50 ml of ether, 1.1 g (0.0053 mol) of 85% m-chloroperoxybenzoic acid in 20 ml of ether are added. The mixture is stirred at ordinary room temperature for 20 min, then 50 ml of a 5% aqueous solution of sodium bicarbonate are added. We separate the layers. The organic layer is washed with two other portions of 5% aqueous sodium bicarbonate solution, dried (over MgSO 4), then concentrated, which gives 0.5 g of crude product which is purified by Chromatography (silica gel column which is developed using ethyl acetate)

and which is crystallized from ether; 2- (3-carbomethoxy-S-methylisothio-ureido) -5-propyl-sulfinylaniline is thus obtained; M.p. 131-132 ° C (decomposition).

Elementary analysis for Ci3Hi9N303S2:

Calculated: C 47.39 H 5.83 N 12.76 S 19.81%

Found: C 47.48 H 5.98 N 12.75 S 19.46%

Example 49:

2- (3-Carbomethoxy-S-methylisothio-ureido) -

4-phenylsulfinylaniline

A mixture of 6.0 g (0.0173 mol) of 2- (3-carbomethoxy-S-methylisothio-ureido) -4-phenylthio-aniline and 200 ml of methylene chloride is cooled to -15 ° C. then we filter it through celite. To the filtrate (at 0 ° C.), 3.6 g (0.0177 mol) of 85% m-chloroperoxybenzoic acid are added. The mixture is stirred at 0 ° C + 10 ° C for 20 min, then washed with four 75 ml portions of a 5% aqueous solution of sodium bicarbonate. The organic layer is dried (over MgSO4), then concentrated. To the residue, ethyl acetate is added and the insoluble impurities are removed by filtration. The filtrate is concentrated again, and the residue is recrystallized from ether, which gives 3.5 g (yield 56%) of 2- (3-carbomethoxy-S-methylisothio-ureido) -4- phenylsulfinylaniline; M.p. 126-128 ° C (decomposition).

Elementary analysis for C16H17N3O3S2:

Calculated: C 52.89 H 4.72 N 11.56 S 17.66%

Found: C 52.46 H 4.73 N 11.64 S 18.16%

The following describes, by way of illustration, preparations of raw materials which can be used for the preparation of compounds having formula (I).

Preparation A:

3- (3-Carbomethoxythio-ureido) -4-aminobenzophenone

52.6 g (0.45 mol) of carbomethoxyisothiocyanate are added dropwise to a solution of 63.6 g (0.3 mol) of 3,4-diaminobenzophenone in 1.5 l of chloroform period of 5 min. The temperature of the reaction mixture rises from 25 ° C to 30 ° C. A suspension forms, and the reaction mixture is stirred at room temperature for 30 min, after which the precipitate is collected by filtration. The product thus collected is washed with chloroform, triturated in 500 ml of ether, collected and dried, which gives 79.8 g (yield 80.9%) of 3- (3-carbomethoxythio-ureido) -4-aminobenzophenone ; M.p. 192 ° C (decomposition).

Preparation B:

3- (Carboethoxythio-ureido) -4-aminobenzophenone

To a solution of 4.24 g (0.02 mol) of 3,4-diaminobenzo-phenone in 600 ml of ether, 2.62 g (0.02 mol) of carboethoxyisothiocyanate are added. A suspension is thus formed which is stirred at ordinary room temperature for 45 min; by filtration, the precipitate is then collected, and 3.1 g (yield 45%) of 3- (carboethoxythio-ureido) -4-aminobenzophenone in the form of a yellow powder are thus obtained; M.p. 200 ° C (decomposition).

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By replacing, during the preparation of preparation B, the carboethoxyisothiocyanate by an equimolar amount of carbo-n-propoxyisothiocyanate, carbo-isopropoxy-isothiocyanate, carbo-n-butoxyisothiocyanate and

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according to substantially the same procedure which is described above for said preparation B, 3- (carbo-n-propoxy) -4-aminobenzophenone and 3- (carbo-isopropoxy) -4-aminobenzophenone are obtained respectively and 5 3- (carbo-n-butoxy) -4-aminobenzophenone.

Claims (11)

621,542 2 1. Process for the preparation of a compound represented by the formula: X NH SR in which R is an alkyl, alkenyl, alkynyl, polynuclear aralkyl radical, mononuclear aralkyl optionally substituted in the aryl nucleus with from 1 to 3 substituents, aryloxy (mono-nuclear) alkyl (C i -C8), cycloalkylalkyl, cyanoalkyl -C8), hydroxyalkyl (Ci-C8), aralkenyl, alkoxyalkyl, alkoxycarbonyl-alkyl, phthalimidoalkyl (Ci-C8), phenoxycarbonylalkyl- (Ci-C8) or carbamoylalkyl (Ci-Cg) in which the nitrogen atom contains as substituent a mononuclear aryl radical itself optionally comprising an alkanoyl-aminoarylthio substituent; Rl is an alkyl radical (-C 6) or alkoxy (C1-C6) -alkyl (C 1 -C 6); X is 1) hydrogen, 2) nitro, 3) halo, 4) alkanoyl (C2-C5), 5) alkyl ^ -C4), 6) thiocyanato, 7) Y — S (0) n— in which Y is alkyl (Ci-C5), alkenyl (C3-C6), alkynyl (C3-C6), cycloalkyl (C3-C7), a 5- or 6-link heterocycle or a substituted or unsubstituted aryl or aralkyl and n is a number of 0 to 3, 8) alkoxycarbonylamino, O 11 9) Y'C— in which Y 'is mononuclear aryl, cycloalkyl (C3-C7) or a heterocycle with 5 or 6 links, or 10) Y "0— in which Y" is alkyl (Ci-C5), mononuclear aryl, alkenyl- (C3-C6), mononuclear aralkyl or heterocycle with 5 or 6 links; with the condition that the radicals Y, Y ′ or Y "defined above may be substituted with one or more substituents chosen from a) halo, b) cyano, c) alkyl, alkoxy, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl and carboalkoxy , each of these radicals listed under c) containing not more than 8 carbon atoms, d) phenylthio, e) phenylsulfinyl, f) phenyl-sulfonyl, g) phenoxy, h) halophenoxy, i) benzyloxy and j) trifluoromethyl; or else an addition salt, with a pharmaceutically or agronomically acceptable acid, of a compound having the formula (I), characterized in that it constitutes in treating a compound represented by the formula: X NH NH-CHN-C-OR II S with a base, then to carry out a treatment with a compound having the formula RX2, in which X2 is a halogen or sulfonate radical, or alternatively, in the case where the desired product is an addition salt with an acid, to react a compound having formula (I) with an acid. 2. Method according to claim 1, characterized in that it is implemented in solution at a temperature between 0 and 40 ° C. 3. Method according to claims 1 and 2, characterized in that it is implemented at a temperature between 10 and 40 ° C. 4. Method according to claim 1, characterized in that it is applied to the preparation of a compound of formula (I) in which R is an alkyl, alkenyl, alkynyl, polynuclear aralkyl, mononuclear aralkyl, aryfoxy radical (mono- nuclear) alkyl (C3-C6), cycloalkylalkyl, cyanoalkyl- (C3-C6), hydroxyalkyl (C3-C8), aralkenyl, alkoxyalkyl, alkoxycarbonylalkyl, phthalimidoalkyl (C3-Cg) or phenoxy-carbonylalkyl; R1 is an alkyl radical (C1-C6); X is hydrogen, nitro, halo, alkanoyl (C2-C5), alkoxy (Cx-C5), alkyl (Ci-C4), thiocyanato, alkyl (Ci-C4) S (0) n where n is a number from 0 to 2, alkoxycarbonylamino, benzoyl, phenylthio, phenylsulfinyl or phenylsulfonyl; an addition salt, with a pharmaceutically or agronomically acceptable acid, of a compound as defined above. 5. Method according to claim 1, characterized in that it is used to prepare a compound represented by the formula: NH, NH-C = NC-0R ' 1 X in which R3 is an alkyl radical (Ci-C4); R2 is an alkyl radical (Ci-C4), alkenyl (C3-C8), alkynyl (C3-C8), benzyl, 2,6-dichlorobenzyl, phenethyl, cycloalkyl (C5-C6) alkyl- (C1-C4.), phenoxyalkyl (C3-C6), cyanoalkyl (C5-C6), alkoxycarbonylalkyl in which the alkoxy portion has from 1 to 5 carbon atoms and the alkyl portion has from 3 to 6 carbon atoms; phthalimidoalkyl (C3-C6), phenylalkenyl (C3-C6) or hydroxyalkyl (C3-C8); and X1 is hydrogen, alkyl (Cj-C4), alkoxycarbonylamino having up to 4 carbon atoms in the alkoxy portion, alkoxy (Ci-C5), alkyl (Ci-C4) thio, alkyl (Cj-C4) sulfinyl, alkylI (Ci-C4) -sulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl, alkanoyl (C2-C5) or benzoyl; an addition salt, with a pharmaceutically or agronomically acceptable acid, of a compound as defined above. 6. Method according to claims 1 and 5, characterized in that X1 is a 5-benzoyl radical. 7. Method according to claims 1 and 5, characterized in that it is implemented to prepare 3- (3-carbomethoxy-S-methylisothio-ureido) -4-aminobenzophenone, or a salt of such substance. 8. Method according to claims 1 and 5, characterized in that it is implemented to prepare 2- (3-carbomethoxy-S-methylisothio-ureido) -5-propylthioaniline, or a salt of such substance. 9. Method according to claims 1 and 5, characterized in that it is implemented to prepare 2- (3-carboxymethoxy-S-methylisothio-ureido) -4-phenylthioaniline, or a salt of such substance. 10. Process according to claims 1 and 5, characterized in that it is used to prepare 2- (3-carbomethoxy-S-methylisothio-ureido) -4-phenylsulfinylaniline, or else a salt of such a substance. 11. Method according to claims 1 and 5, characterized in that it is used to prepare 3- (3-carbomethoxy-S-hydroxypropylisothio-ureido) -4-aminobenzophenone, or else a salt of such a substance. 5 10 15 20 25 30 35 40 45 50 55 60 65 3 621,542