SI9500053A - Fungicidal derivatives of 2-imidazoline-5-ones - Google Patents

Abstract

2-imidazoline-5-one derivs. of formula (I), their salts, stereoisomers and enantiomers, partic. the 2 enantiomers of the cpds. with an asymmetric carbon atom in the imidazoline ring carrying R1, are new. R1 = H, vinyl or allyl or 1-3C alkyl or haloalkyl; n = 0 or 1; Y = O or S; R2 = H, haloalkyl or cyclopropyl; R3 = aryl or heteroaryl, phenyl, naphthyl, pyridyl; R4 = H, formyl or aroyl, 2-6C acyl, 2-6C alkoxycarbonyl, aryloxycarbonyl; W = O, S or SO; Ar1 = divalent radical arising from an aryl or heteroaryl gp; Ar2 = 5-10 atom mono- or bi-cyclic gp., aromatic, opt. unsatd., opt. contg. 1-4 heteroatoms (O, S or N); X = -(R'')j-A-(R')k-; j, k = 0 or 1; R'', R' = 1-6C hydrocarbon chain, opt. unsatd.; A = O, S, SO, SO2, CO, CS.

Description

Fungicidal derivatives of 2-imidazolin-5-ones

The present invention relates to novel compounds with a 2-imidazolin-5-one group for phytosanitary use. It also relates to processes for the preparation of these compounds and to products which are useful as intermediates in the preparation processes as appropriate. Finally, it relates to fungicidal preparations based on these compounds and to methods for the control of fungal diseases of cultures using these compounds.

The 2-imidazolin-5-ones for phytosanitary use are known from European patent application EP 0 551048in from international applications WO 93/24467 and WO 94/0110.

It is an object of the present invention to propose novel compounds containing a 2-imidazolin5-one group that have improved properties in the treatment of fungal culture diseases.

Another object of the present invention is to propose compounds that also have an improved spectrum of use in the field of fungal diseases, in particular for the treatment of fungal diseases of rice and for the treatment of brown rust cereals.

We have now found that these goals can be achieved in whole or in part by the products described in the invention described below.

The present invention relates primarily to compounds which are derivatives of 2-imidazolin-5-ones of the general formula (I)

T in which

R [represents a hydrogen atom or a vinyl or allyl group or an alkyl or haloalkyl radical having 1 to 3 carbon atoms each;

or you can R! and Ar ₂ -X-Ar _[ further form the following variant with the carbon to which they are attached on the imidazolinone ring:

in which the dot in the bold print represents the carbon of the imidazolinone ring of formula (I) to which the residues R _t and Ar ₂ -X-Ar _p are attached and m is 2, 3 or 4;

- n is 0 or 1;

- Ύ represents an oxygen or sulfur atom;

- R ₂ represents a hydrogen atom when n is 0 or an alkyl or haloalkyl group of 1 to 3 carbon atoms or a cyclopropyl group;

- R ₃ represents an aryl or heteroaryl residue comprising a phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, benzothiazolyl or methylene dioxyphenyl residue, each of which is a substituent thereof with 1 to 7 groupings, preferably 1 to 3 groupings selected from the meanings R defined below;

- R ₄ represents a hydrogen atom, a formyl or aroyl radical, an acyl radical of 2 to 6 carbon atoms, an alkoxycarbonyl radical of 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulfonyl radical, an alkylsulfonyl radical of 1 to 6 carbon atoms or an alkyloxyalkyl radical or an alkoxyalkyl radical or alkoxyalkyl radical 3 to 6 carbon atoms;

- R ₅ represents a halogen atom or a hydroxy, mercapto, nitro, SF ₅ , cyano, thiocyanato or azido group; or

- alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, alkylsulfinyl, alkylsultonyl, haloalkylsulfinyl or haloalkylsulfonyl radicals having 1 to 6 carbon atoms each; or

- cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkinyloxy, alkenylthio, alkynylthio moieties having 3 to 6 carbon atoms each; or

- an amino residue, optionally mono- or disubstituted by an alkyl or acyl radical of 1 to 6 carbon atoms or an alkoxycarbonyl radical of 2 to 6 atoms

- an alkoxycarbonyl group having 2 to 7 carbon atoms; or

- an N-alkylcarbamoyl group having 2 to 7 carbon atoms; or

- a Ν, dial-dialkylcarbamoyl group of 3 to 13 carbon atoms;

- W represents O, S or SO;

- Arj is a divalent residue derived from an aryl or heteroaryl residue comprising a phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl or methylenedioxyphenyl residue, each of which is incorporated in case substituted with 1 to 6 groupings, preferably 1 to 3 groupings selected from the meanings of R .;

- Ar ₂ represents a mono- or bicyclic system of 5 to 10 atoms which is aromatic, saturated or unsaturated, and which is either a carbocyclic system or a heterocyclic system containing 1 to 4 heteroatoms selected from O, S or N, and which comprises phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl. gasoline, benzene, benzene, benzene, benzyl benzene, benzene, benzene, benzene a naphthyridyl, quinoxazolyl, quinazolyl, cinnolyl or phthalazinyl radical, each of which is optionally substituted by 1 to 7 groups, preferably 1 to 3 groups selected from the meanings of R ₅ ;

- X represents a chain of the general formula in which they are

-j and k, equal or different, 0 or 1;

- R and R ', same or different, represent a hydrocarbon chain, saturated or unsaturated, containing 1 to 6 carbon atoms, optionally substituted by 1 to 12 groups, preferably 1 to 3 groups selected from R _? defined below; and wherein one or more carbon atoms may be replaced by O, S, N ( _Rf1 ), wherein _{Rf1 is} defined below;

- A represents O, S, N (R _fi ), SO, SO ₂ , CO, CS, Si (R _g ) (R ' _s ), N ₂ C (R ₁₀ O) (R' ₁₀ ) or _c = c - t ΐ ⁶ t ί ' ⁿ ' ^R ' ^{R, o} \ _z ^{R |} ° or ^ U _N ^ or

K 10 R 10 'or -C = c - wherein Z represents O, S, C (R _n ) (R' _n ); wherein R _g to R _{n are} defined below;

- represents a hydrogen atom or a cyano, hydroxy, amino, formyl, morpholino, piperidino, pyrrolidino, piperazine group, or

- alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylsulfonyl, haloalkylsulfonyl, cyanoalkylsulfonyl residue, each containing from 1 to 6 carbon atoms, or

a monoalkylamino or dialkylamino residue, or

- cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy radicals having 3 to 6 carbon atoms each;

- or an acyl or alkoxycarbonyl residue having 2 to 6 carbon atoms each; or

- a carbamoyl residue (optionally substituted by one or two alkyl radicals) of 1 to 7 carbon atoms or a sulfamoyl radical of 1 to 6 carbon atoms; or

- an aryl or arylsulfonyl residue; or

- an alkyloxalyl or alkoxyxalyl residue having 3 to 8 carbon atoms each; or

- an oxamyl radical (optionally substituted with one or two alkyl radicals) having 2 to 8 carbon atoms;

- R _? represents a halogen atom, cyano, thiocyanato, hydroxycarbonyl, amino (optionally substituted), hydroxyl, oxo, alkoxy, alkoxycarbonyl, haloalkoxy, alkoxyalkoxy, thiol, alkylthio, haloalkylthio, alkoxyalkylthio, acyloxy, alkyl, haloalkyl, alkyloxy, alkyloxy, alkyloxy, alkyl heteroaroyloxy, aryloxyloxy, cycloalkylcarbonyloxy, acylthio, aroylthio, heteroaroiltio, arylcylthio, cycloalkylcarbonylthio, carbamoyloxy (optionally substituted). carbamoylthio (optionally substituted), thiocarbamoyloxy (optionally substituted), dithiocarbamoyl (optionally substituted), acylamino, cycloalkylcarbonylamino, aroylamino, ureido (optionally substituted), thioureido, alkoxycarbonylamino sulfonamide, aryloxycarbonylamino sulfonylamino sulfonylamino; (optionally substituted), it being understood that, in the present case, substituted radicals are substituted, optionally substituted by 1 or 2 alkyl radicals, each aliphatic hydrocarbon radical having 1 to 4 carbon atoms and containing a cycloalkyl radical 3 up to 7 carbon atoms;

- R _g and R 1 _g , the same or different, represent: an alkyl radical having 1 to 6 carbon atoms; or a cycloalkyl radical having from 3 to 7 carbon atoms; or an alkenyl, alkynyl radical having 2 to 6 carbon atoms; or an arylalkyl radical, preferably benzyl, or an aryl radical, optionally substituted, preferably phenyl, optionally substituted by 1 to 5 groups, preferably 1 to 3 groups selected from the meanings of R ₅ ;

- R ₉ represents a hydrogen atom or a morpholino, piperidino, pyrrolidino, piperazine group; or an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio moiety of 1 to 6 carbon atoms or a dialkylamino containing 2 to 6 carbon atoms;

- R ₁₀ and R ₁₀ are the same or different, representing a hydrogen atom or an alkoxy group of 1 to 6 carbon atoms or R _? ;

- Roar! and R '', the same or different, represent a hydrogen atom or a halogen or alkyl group of 1 to 3 carbon atoms; as well as salt-form compounds and enantiomers and stereoisomers of these compounds, in particular both enantiomers of each of these compounds, corresponding to the asymmetric carbon of the imidazolinone ring bearing Rp, with the exception of compounds to which:

- when (Y) _n -R ₂ represents methylthio, methyl or ethyl, represents an Ar-N-Ar phenoxyphenyl group optionally substituted;

- when (Y) _n -R ₂ represents methoxy, when R _{} is} methyl, when R ₃ represents a phenyl or pyridyl radical optionally substituted by a fluorine atom or a methyl group, when R _{4 is} hydrogen and when W represents an oxygen atom, then Ar ₂ -X-Ar represents either a 4-phenoxyphenyl group optionally substituted on the phenoxy moiety by 1 or 2 fluorine atoms or a 3-phenoxyphenyl group;

and with the exception of the compound of formula

In the present text, the generic terms alkyl, acyl and aroyl have the following meanings:

- alkyl means a straight or branched aliphatic residue;

- acyl means an alkylcarbonyl or haloalkylcarbonyl group; or

- alkoxyalkylcarbonyl or alkylthioalkylcarbonyl group; or

- an alkenylcarbonyl group; or

- an alkynylcarbonyl group; or

- cycloalkylcarbonyl group or halocycloalkylcarbonyl group;

- aroyl means an arylcarbonyl group, the aryl group having the same meanings as those listed as preferred for Ar ₂ , and optionally substituted by R ₅ .

Preferred are compounds of formula (I) wherein

- Ar! represents a divalent radical derived from phenyl, naphthyl, thienyl, pyridyl, benzothienyl, quinolinyl, each of which is optionally substituted by 1 to 3 groupings selected from the meanings of R _s ;

- Ar ₂ represents a phenyl, naphthyl, thienyl, pyridyl, benzothienyl, thiazolyl, benzothiazolyl, pyrimidyl radical, each of which is optionally substituted by 1 to 3 groupings selected from the meanings of R _s .

Particularly preferred are compounds of formula (I), wherein A 1 represents a divalent radical derived from phenyl, thienyl, pyridyl optionally substituted by 1 to 3 groups selected from a halogen atom, an alkyl or haloalkyl radical;

- Ar _? represents a phenyl, naphthyl, pyridyl, benzothiazolyl radical optionally substituted by 1 to 3 groups selected from a halogen atom, an alkyl or haloalkyl radical;

- X represents a chain of the general formula indicated by the yarn in which

-R and R ', the same or different, represent a carbon chain of 1 to 3 carbon atoms, preferably a methylene group, in which one carbon atom is optionally substituted by O or NH and optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxyl group, an oxo group or a C-C alkyl radical;

A is O, S, SO, SO ₂ , CO, C (R ₁₀ ) (R _'10 ),

Rio ^ io 'c = c or

R ιό * · 'io where they are

- R ₁₀ and R ', the same or different, a hydrogen atom, a halogen atom, a hydroxyl atom, a C 1 -C ₃ alkyl group or a C 1 -C ₃ alkoxy radical;

- Z represents O or C (R _n ) (R _'11 ), and R _n or R' _{n are the} same or different, a hydrogen or chlorine atom.

Finally, particularly preferred compounds are obtained by selecting derivatives of formula I, wherein at the same time:

- R ₍ methyl residue;

- R _{2 is a} methyl or ethyl residue;

- R ₃ represents a phenyl or pyridyl radical;

- R ₄ is a hydrogen atom or a formyl radical;

- R. is a halogen atom or a C 1 -C ₃ alkyl or C 1 -C ₃ haloalkyl radical; and

- It's an oxygen atom.

The compounds of formula (I) are prepared by the procedures shown below. All groups which occur in the chemical formulas which follow, and which are already defined in general formula (I), retain the same meaning, unless otherwise defined. In the general description of the processes for the preparation of the compounds of formula (I), the stated conditions are those which are generally used: it must be made clear that conditions other than those indicated may be used, e.g. of the individual reactants used.

The structures of all the products that illustrate these procedures, we have determined by at least one of the following spectral techniques: proton NMR spectrometry, ¹³ C -NMR spectroscopy, IR spectroscopy and mass spectrometry.

In the tables in which these products are summarized, indicating the meanings of the groups of the general formula, Me, Et, Pr, Py, Pyrim, Ac, Ph and Bn represent methyl, ethyl, propyl, pyridyl, pyrimidinyl, acetyl, phenyl and benzyl residues And PF indicates melting point (PF).

Compounds of formula (I) for which R _{4 is} other than a hydrogen atom are prepared from compounds of formula Ia for reaction with a compound of formula R ₄ L ', in the presence of a base and in a solvent medium according to the following reaction scheme:

In this scheme

- R ₄ represents a formyl radical, an acyl group of 2 to 6 carbon atoms, an aroyl, alkoxycarbonyl group of 2 to 6 carbon atoms, an aryloxycarbonyl, alkylsulfonyl, arylsulfonyl group or an alkyloxalyl radical or an alkoxyxalyl radical of 3 to 6 carbon atoms;

- L 'represents a halogen atom, preferably chlorine, bromine or iodine, a sulfate group, an aryloxy or arylthio moiety, optionally substituted, preferably a phenoxy, alkoxy or dialkylamino moiety, a R ₄ O group when R _{4 is} an acyl or arylsulfonyl or alkylsulfonyl group .

A strong base such as alkali or alkaline earth hydride or hydroxide, alcoholate or tert.amine is used as the base. The reaction is carried out at a temperature between -30 ° C and + 50 ° C. The solvent is selected from cyclic or non-cyclic ethers, dimethylformamide, dimethylsulfoxide, acetonitrile or an aromatic solvent.

The preparation of a compound of formula Ia is described in two embodiments.

We first describe the first method of preparing a compound of formula Ia, in which an imidazolinone moiety is formed from intermediates containing the Ar-X-Ar _{r group.} This first method of preparing the compounds of the invention corresponds to the procedures A, B, C, D described below.

Preparation of Compounds of Formula Ia. where n = 1 and Y = S:

Procedure A:

Compounds of formula (Ia) for which n = 1 and Y = S and W = S or O, in other words compounds of formula II, are prepared by one of the processes described in European patent application EP 0 551 048, in particular by S-alkylation of 2-thiohydantoins of formula (III) wherein W is S or O, in the presence of a base and in a solvent according to the following reaction scheme:

"Base

Rj - L ->

N solvent * ^ 1 '

N.

NH-R '(III) 00 where L represents a group selected from a halogen atom (preferably chlorine, bromine or iodine) or an alkylsulfate, alkylsulfonyloxy or arylsulfonyloxy group. A strong base such as alkali or alkaline earth alkali alcohol (preferably potassium tert-butylate), alkali or alkaline earth hydroxide, alkali or alkaline earth carbonate or tert.amine is used as the base. Cyclic or non-cyclic ether, alkyl ester, acetonitrile, alcohol with 1 to 4 carbon atoms, chlorinated solvent, aromatic solvent are used as the solvent. Tetrahydrofuran (THF) is preferably used as the solvent. The reaction is carried out at a temperature between -5 ° C and + 80 ° C.

This procedure illustrates the following example.

Example CF1: Preparation of (4-R, S) -4-methyl-2-methylthio-1-phenylamino-4- (4- (2-phenylethyl) phenyl) -2-imidazoline-5-thione (Compound No. 14) .

To 5 g (0.012 mol) of (4-R, S) -4-methyl-1-phenylamino-4- (4- (2-phenylethyl) phenyl) imidazolidine-2,5-dition dissolved in 150 ml of THF was added at 0 ° C 1.36 g (0.012 mol) of potassium tert.butylate. After stirring for 15 minutes at this temperature, 1.5 ml (0.024 moles) of methyl iodide were added. The mixture was stirred for 30 minutes at 0 ° C, then after allowing the temperature to rise to room temperature, the medium was hydrolyzed and then extracted with methylene chloride. After washing the organic extracts with saturated sodium chloride solution, decanting, drying and evaporating the solvents, chestnut oil is obtained. This oil was crystallized in a mixture of diisopropylether and pentane. After filtration, 2.7 g (0.006 mol) of (4-R, S) -4-methyl-2-methylthio-1-phenylamino4- (4 (2-phenylethyl) phenyl) -2-imidazoline-5-thione are recovered in the form Chestnut powder, melting at 118 ° C, yield 49%.

We will now describe the preparation of a compound of formula III, wherein W is S (compound of formula lyl) or O (compound of formula Illb).

Preparation of a compound of the formula lilac:

Dithiohydantoins of formula (lila) are obtained from a compound of formula (IV) by a process analogous to that described by T.Yamamoto et Coli in J.Chem. Soc. Perkin Trans I (1990), p. 3003 to 3009, i.e. by reaction:

The following example illustrates the preparation of a compound of formula (lilac):

Example CII: Preparation of (4-R, S) -4-Methyl-1-phenylamino-4- (4- (2-phenylethyl) thienyl) -imidazoline-2,5-dition with the structural formula

To 6.7 ml (toluene) was added to 22.6 g (0.066 mol) of (4-R, S) -4-methyl-4- (4- (2-phenylethyl) phenyl) thiazolidine-2,5-dithione in 100 ml of toluene ( 0.066 moles) of phenylhydrazine. The reaction medium was heated progressively from 60 [deg.] C. to reflux until the gas was stopped. After cooling, the medium was started by hydrolysis followed by extraction with ethyl acetate. After decanting, drying the organic phase and evaporating the solvents, a black oil is obtained. Chromatography on a SiO ₂ column (ethyl acetate / heptane 50/50) gave 11.2 g (0.027 mol) of (4-R, S) -4methyl-1-phenylamino-4- (4- (2-phenylethyl) phenyl) -imidazolidine-2,5-dition as a chestnut powder, melting at 171 ° C, yield 41%.

Thiazolidine 2,5-dithione of formula (IV) is obtained from isothiocyanate of formula (V) by a method analogous to that described by T. Yamamoto et Coli. in J. Chem. Soc. Perkin Trans I (1990), p. 2459 to 2463, by reaction:

The following example illustrates the preparation of a compound of formula (IV):

Example 02: Preparation of (4-R, S) -4-Methyl-4- (4- (2-phenylethyl) phenyl) -thiazolidine-2,5-dition with the structural formula

To a 9.5 g (0.084 mol) of potassium tert.butylate, which was placed in 150 ml of THF at -70 ° C, was added a slow solution of 7 ml (0.11 mol) of carbon disulfide and 20.4 g (0.076 mol) 1- [4- (2-Phenylethyl) phenyl] ethylisothiocyanate in 50 ml THF. After stirring at -70 ° C for 15 minutes, allow the temperature to rise to room temperature. Hydrolysis of the reaction medium with aqueous acetic acid solution, extraction with ethyl acetate, decantation, drying of the organic extracts and evaporation of the solvents yielded 22.6 g (0.065 mol) of (4R, S) -4-methyl-4- (4- (2- phenylethyl) phenyl) -thiazolidine-2,5-ditionate as an oil in a crude yield of 86%.

The isothiocyanate of formula (V) is prepared from an amine of formula (VI), wherein the substituents have the same meaning as in (V), according to one of the procedures set out in Sulfur Report: (1989), Volume 8 (5), p. 327-375, e.g. by reaction:

'/

Ri NH? l \ / ² base / + esci? -: - ►

Ar? —Χ-Arf ~ ^topll ° Ar? —X-Arf (v) (VI) 2

The following example illustrates the preparation of a compound of formula (V):

Example CI3: Preparation of 1- (4- (2-phenylethyl) phenyl) -ethyl isothiocyanate of the structural formula

To a suspension of 20 g (0.076 mol) of 1- (4- (2-phenylethyl) phenyl) ethylamine hydrochloride in 200 ml of toluene at 0 ° C was added 1 equivalent of sodium hydrogen carbonate in aqueous solution. After bringing the reaction medium to room temperature, 2 equivalents of sodium bicarbonate in aqueous solution were added. Then 6.1 ml (0.076 mol) of thiophosgene in solution in 10 ml of toluene are slowly added. At the end of the casting, continue stirring for 15 minutes. After decanting, the organic extracts are washed with water, dried and evaporated. 20.5 g (0.076 mol) of 1- (4- (2-phenylethyl) phenyl) -ethylisothiocyanate are thus obtained in the form of an oil in 100% yield.

Preparation of a compound of formula IUb ·.

2-Thiohydantoins of formula (IUb), compounds of formula (III) wherein W is an oxygen atom, is obtained by the procedure described in European patent application EP 0 551 048, by reaction of cyclization of isothiocyanates of formula (VII) with hydrazines of formula R ₃ -NH-NH ₂ according to the following reaction scheme:

Rj N = C = S

Ar ₂ —X Ar j '

OR e

O + r ₃ -nh -nh ₂ (VII) 'H

θ (Hib), wherein R _e represents a C _t -C alkyl radical.

We can perform cyclization in two ways. After the first, the reagent mixture is heated to a temperature between 110 ° C and 180 ° C in an aromatic solvent such as toluene, xylene, chlorobenzenes or nitrobenzene.

The second method of cyclization is carried out in the presence of a strong base such as alkali or alkaline earth alkali, alkali or alkaline earth hydroxide or tertiamine, at a temperature between -10 ° C and + 80 ° C and in a solvent selected especially from ether, cyclic ether, alcohol, ester, DMF or DMSO.

The following example illustrates the preparation of a compound of formula (Illb).

Example 03 ': Preparation of (5-R, S) -5-methyl-3-phenylamino-5 - ((4-phenylthio) phenyl) -2-thioxoimidazolidin-4-one by the following structural formula, N

8.48 g (0.0258 mol) of methyl (2-R, S) -2-isothiocyanato-2 - ((4-phenylthio) phenyl) -propanoate was dissolved in 250 ml of tetrahydrofuran. 2.78 g (0.0258 moles) of phenylhydrazine were added dropwise. The reaction medium was stirred for 30 minutes at room temperature, poured into water and re-extracted with ether. After drying on magnesium sulfate, the ether was evaporated to give 11.46 g of crystallizing oil. The crude reaction mixture was stirred with ether, filtered and recrystallized to give 3.36 g (0.0082 mol) of (5-R, S) -5methyl-3-phenylamino-5 - ((4-phenylthio) phenyl-2- Thioxo-imidazolidin-4-one as pink crystals, melting at 158 ° C, yield 34%.

α-Isothiocyanato-esters of formula (VII) are prepared from esters of α-amino acids of formula (VIII), wherein said groups have the same meaning as in formula (VII), according to one of the procedures set out in Sulfur Reports (1989), Volume 8 (5), p. 327-375, e.g. after the reaction

The following example illustrates the preparation of a compound of formula (VII):

Example 04: Preparation of methyl (2-R, S) - (4-benzyloxyphenyl) -2-isothiocyanatopropanoate

To a stirred solution of 84.2 g (1.002 mol) of sodium hydrogen carbonate in 800 ml of water was added 143 g (0.501 mol) of methyl (R, S) - (4-benzyloxyphenyl) -methyl-glycinate followed by 800 ml of toluene; then dropwise at room temperature for 1.5 hours while controlling the release of 40 ml (0.526 mol) of thiophosgene. After stirring at room temperature for 2 hours, decanting the aqueous phase, washing with water, drying on magnesium sulfate and concentrating the organic phase, 155.4 g (0.475 mol) of methyl (2, R, S) -2- (4-benzyloxyphenyl) is isolated. 2-isocyanatopropanoate in the form of a very dense oil in 95% yield.

The following compounds of formula (VII) were obtained by analogous operation:

Oh

R ' ^R e ^R 1 profit m.p. (° C) 4-BnO Me Me 62% oil 4-Bn Me Me 50% oil 4-PhS Me Me 96% oil 4-PhSO Me Me 100% oil 4-PhSO ₂ Me Me 85% oil 3 BNO Me Me 80% oil

α-amino-esters of formula (VIII) is obtained by esterification of α-amino acids of formula (IX), wherein the groups have the same meaning as in the formula (VIII) with an alcohol of formula R _£ OH in the presence of thionyl chloride, and the procedure are described in the literature by M. Brenner and W. Huber: Helv. (1953), Vol. 36, p. 1109, according to the scheme:

Rk NH ₂

Ar> —X— Arj '

OH

SOCHI 2 ^R l '

REOH Ar ₂ —X — Arf

NH ₂

OR E

The following example illustrates the preparation of a compound of formula (VIII):

Example CI5: Preparation of methyl (R, S) -2- (4-benzyloxyphenyl) -2-methyl-glycinate

To a stirred suspension of 38.55 g (0.142 mol) of (R, S) -2- (4-benzyloxyphenyl) -2-methyl-glycine in 400 ml of methanol maintained at -20 ° C was added progressively 33.8 g (0.284 moles) of thionyl chloride. At the end of the addition, allow the temperature of the resulting solution to rise to room temperature, then bring it to reflux for 16 hours. After concentration, the residue is taken up in water and the resulting solution is made alkaline with concentrated aqueous sodium hydroxide solution to pH 8. The precipitate is filtered, washed with water, centrifuged and dried in vacuo. After chromatography on 400 g of silica gel, eluting with heptane / ethyl acetate 30/70 and concentration of significant fractions under reduced pressure, 14.7 g (0.0515 mol) of methyl (R, S) -2- (4-benzyloxyphenyl) -2 is isolated. -methyl-glycinate in the form of white powder from the ground. 67 ° C with a yield of 17 pieces of 36%.

The following table summarizes the synthesized compounds of formula (VIII):

R ' ^R x R 2 profit m.p. (° C) or nD 4-BnO Me Me 36% 67 ° C 4 -Bn Me Me 95% 112-116 ° C 4-PhS Me Me 66% 1,6058 3 BnO Me Me 35% 50 ° C

We will now describe a variant of the preparation of some α-aminoesters of formula (VIII), those where X represents the group -S (O) _n and which correspond to formula (VHIb).

α-amino esters of formula (VHIb) are obtained by oxidation of α-amino esters of formula (Vlila) according to the procedures described in Advanced Organic Chemistry, J. March (1985), p. 1089 and 1090, 3rd edition, and according to the scheme:

R _k NH

Ar ₂ —S — Ar ORE θ ^ θρ ^ θAr _ž -S (O) n -Ar (

Rt. NH ₂

ORE

Oh

In this scheme, n is 1 or 2, and R _E has the meaning given to the definition of formula (VII).

The following examples illustrate the preparation of compounds of formula (VHIb).

Example 06: Preparation of methyl (R, S) -2-amino-2 - ((4-phenylsulfinyl) phenyl) propionate

17.22 g (0.06 mol) of methyl 2-amino 2 - ((4-phenylthio) phenyl) propionate are added to 350 ml of dichloromethane and cooled to 0 ° C. 14.1 g (0.06 mol) of metachloroperbenzoic acid (73%) was added progressively for about 10 minutes. The reaction medium was stirred for 2 hours at 0 ° C. The precipitate was filtered off and the organic phase was washed with normal soda, then with water and dried on magnesium sulfate. Evaporation gave 15 g of an oil which was chromatographed on SiO ₂ (eluant: ethyl acetate) to give 1.3 g (0.037 mol) of methyl (R, S) -2-amino-2 - ((4-phenylsulfinyl) phenyl) propionate in the form of a slightly yellow oil zn _Q = 1,5979 at 25 ° C in a yield of 62%.

Example 07: Preparation of methyl (R, S) -2-amino-2 - ((4-phenylsulfonyl) phenyl) propionate

21.52 g (0.075 mol) of methyl (R, S) -2-amino - ((4-phenylthio) phenyl) propionate are added to 400 ml of methanol and cooled to 0 ° C. 50.12 g (0.163 mol) of 49.5% persulfate in solution in 400 ml of water were added dropwise at 0 ° C for 1 hour. The reaction medium was stirred for 5 hours at room temperature. The remaining oxidant was decomposed with 5 ml of 30% sodium hydrogen sulphite solution. The pH of the medium was adjusted to about 8 with the addition of 20 g of sodium carbonate and the solid filtered. After mixing the solid in 500 ml of dichloromethane, then filtering the solid residue, the filtrate is dried and the solvent is evaporated to give 16.9 g (0.529 mol) of methyl (R, S) -2-amino-2 - ((4-phenylsulfonyl) phenyl) propionate in the form of white crystals, m.p. 124 C, yield 70%.

α-amino acids of tormula (IX) are obtained by hydrolysis of the corresponding hydantoins (X) in acidic or basic medium according to a procedure analogous to that described in Dutch patent NE 69 00349 or in J. Org. Chem. (1985), Vol. 50, p. 1876 to 1878, e.g. according to the scheme

The following example illustrates the preparation of compounds of formula (IX).

Example CI8: Preparation of (4-R, S) -2- (4-Benzyloxyphenyl) -2-methyl glycine

To a stirred solution of 40 g (1 mol) of sodium hydroxide in 100 ml of water was added 17.2 g (0.0506 mol) of (5-R, S) -5- (4-benzyloxyphenyl) -5-methyl-hydantoin and the resulting suspension bring to reflux within 24 hours. After cooling, neutralize the reaction medium with an aqueous solution of concentrated hydrochloric acid, then dilute the suspension with 100 ml of water. The precipitate was filtered off, washed with water, then with acetone, centrifuged and dried in vacuo. Thus, 16.2 g (87 mol% by NMR) of (R, S) -2- (4-benzyloxyphenyl) -2-methyl-glycine is isolated as a white powder from the ground. above 300 ° C.

The table below summarizes the synthesized α-amino acids of formula (IX).

R '

m.p. ('C) or n _D

96%

4- (3-pyridoxy) Me> 300 '

4-BnO Me 42% > 300 ' 4-Bn Me 100% > 300 ° 4-PhS Me 100% > 300'C 3-BnO Me 100% 270'C 3-PhS Me 100% > 300 '

Hydantoins of formula (X) are obtained by the Bucherer-Berg reaction on the corresponding acetophenones, and the procedure is described in the literature Chem. Rev. (1950), Vol. 46, p. 422425, but Chem. Pharm. Buli. (1973), Vol. 21, p. 685 to 691. These acetophenones are readily available to one skilled in the art.

Procedure B:

According to a preferred embodiment, the compounds of the invention of formula (II) are prepared, wherein W represents oxygen, i.e. compounds of formula (Ha), so that a compound of formula (VII) is reacted successively with hydrazine of formula R ₃ -NH-NH ₂ , then with a base of formula B'M ⁺ , and finally with an alkylating agent of formula R ₂ L, where L and R _{2 are} defined as bounded yarns, R _{2 is} different from a hydrogen atom.

The base is selected from alkali or alkaline earth alkali, alkali or alkaline earth hydroxide or tert.amine. The reaction is carried out at a temperature between -10 ° C and + 80 ° C and in a solvent selected especially from cyclic or non-cyclic ether, alcohol, ester, DMF, DMSO, acetonitrile or an aromatic solvent. The reaction scheme is as follows:

N = c

Ar ₂ —X —Ar j

B-M + _ R ₃ —NH -NH 2->

OR E

O '(VID r ₂ l

(Ha)

The following example illustrates the preparation of compounds of formula (Ha).

Example CF2: Preparation of (4-R, S) -4-methyl-2-methylthio-4- (4-phenylthiophenyl) -1-phenylamino-2-imidazolin-5-one (Compound No. 25):

To a stirred solution of 5 g (0.015 mol) of methyl (2-R, S) -2- (4-phenylthiophenyl) -2-isothiocyanatopropanoate in 120 ml of anhydrous tetrahydrofuran under a nitrogen cap was added 1.62 g (0.015 mol) of phenylhydrazine; allowed to react for 1 hour at room temperature, then cooled the reaction medium to 0 ° C. 1.68 g (0.015 mol) of potassium tert.butylate are added, 0.25 hours are reacted, then 2.13 g (0.015 mol) of methyl iodide are added. Allow the temperature to rise to room temperature and stir for 3 hours. The reaction medium was poured into 100 ml of water, then the product was extracted with ethyl acetate. After washing with water, drying on magnesium sulfate and concentrating the organic phase, 7.4 g of honey is dissolved in 30 ml of diisopropylether. The product was precipitated at 5 ° C; Filtration and drying under reduced pressure yielded 4.8 g (76%) of (4-R, S) -4-methyl-2methylthio-4- (4-phenylthiophenyl) -1-phenylamino-2-imidazolin-5-one ( compound No. 25) in the form of beige crystals from the ground. 138 ° C.

Preparation of Compounds of Formula Ia. where n = 1 and Y = O

We will now describe the preparation of compounds of formula (Ia) wherein n = 1 and Y = O and W = O, i.e. of the compounds of formula (XI).

Procedure C:

These compounds are obtained by reacting in a solvent 2-alkylthio-2-imidazolin-5-ones of formula (II) with an alcohol R ₂ OH in the presence of a strong base according to the scheme:

Ri

Ar *, - X —Ar

N

NH -R ₃

W '(II) .S - ^R ' 2

V ·?

N.

r ₂ oh base

Rl

N ^. ^R 7

N, solvent Ar *, - X — Ar

X

NH —R ₃

W '(XI) wherein R 1 represents an alkyl group of 1 to 3 carbon atoms.

As a strong base, alkali alcoholate R ₂ O'M ⁺ , alkali hydroxide, alkaline earth metal hydroxide or a strong organic base can be used. The reaction is preferably carried out in alcohol R ₂ OH as solvent and using sodium alcohol corresponding to R ₂ O'Na ⁺ as the base. The reaction is carried out at a temperature between 20 and 80 ° C. In one embodiment of the process, the reaction is carried out in the presence of an oxidant. In particular, sodium or potassium periodate may be used as the oxidant.

The following example illustrates the preparation of compounds of formula (XI):

Example CF3: Preparation of (4-R, S) -4- (4-Benzyloxyphenyl) -2-methoxy-4-methyl-1-phenylamino-2-imidazolin-5-one (Compound No. 9):

To a solution of 0.5 g (0.0093 mol) of sodium methylate in 50 ml of anhydrous methanol in an inert atmosphere was added 2.6 g (0.0062 mol) of (4-R, S) -4- (4-benzyloxyphenyl) -4 -methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one and 1.3 g of sodium periodate. Reflux for 6 hours. After cooling the reaction medium, it was neutralized with acetic acid, poured into 100 ml of water and extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate, then concentrated under reduced pressure. The crude product thus obtained was purified by chromatography on SiO ₂ (eluant: heptane / ethyl acetate 50/50). The purified product was crystallized in diisopropylether. Filtration and drying under reduced pressure gave 0.8 g (0.002 mol) of (4-R, S) -4- (4-benzyloxyphenyl) -2-methoxy-4-methyl-1-phenylamino-2-imidazoline-5- it (compound 9) in the form of white crystals from the ground. 127 ° C in 32% yield.

Preparation of Compounds of Formula Ia. where n = 0

Procedure D:

We will now describe the preparation of compounds of formula (Ia) wherein n = 0 and W = 0, i.e. Compounds of Formula (XII):

These compounds are prepared according to the procedure described in international application WO 94/01410, i.e. by allowing hydrazine of formula R ₃ -NH-NH ₂ to be reacted to azalactone of formula (XIII) according to the following reaction scheme:

The reaction is carried out by heating the mixture of the reagents in acetic acid at reflux, optionally in the presence of sodium acetate as a catalyst.

The following example illustrates the preparation of compounds of formula XII.

Example CI8 ': Preparation of (5-R, S) -2-ethyl-5-methyl-3-phenylamino-5 - ((4-phenylthio) phenyl) imidazolidin-4-one by the structural formula:

g (0.013 mol) of (4-R, S) -2-ethyl-4-methyl-4 - ((4-phenylthio) phenyl) -3-oxazolin-5-one was added to 100 ml of acetic acid. 1.4 g (0.013 mol) of phenylhydrazine were added dropwise into the reaction medium. The reaction medium was heated at reflux for 2 hours, then the acetic acid was removed in vacuo. The residue was mixed with water, neutralized, then re-extracted with dichloromethane. After drying on magnesium sulphate by evaporation of the solvent, 4.09 g of an oil was obtained, which was chromatographed on SiO ₂ (eluant: ethyl acetate / heptane 4/1) to give 3.41 g (0.0085 mol) (5-R, S ) -2-ethyl-5-methyl-3-phenylamino-5 - ((4-phenylthio) phenyl) -imidazolidin-4-one in the form of an oil which crystallizes in diisopropylether in the form of beige crystals from the ground. 90 ° C in 66% yield.

Azalactones of formula (XIII) are obtained by reacting the α-amino acids of formula (IX) with the carboxylic acid anhydride according to the procedure described in the literature: R. Cotton and Coli., Int. J. Peptide Protein Res. (1986), Vol. 28, p. 230 to 244, and according to the scheme:

The following example illustrates this process for the preparation of compounds of formula (XIII).

Example CI9: Preparation of (4-R, S) -2-ethyl-4-methyl-4 - ((4-phenylthio) phenyl) -3-oxazolin-5-one of the structural formula:

14.2 g (0.052 mol) of (2-R, S) -2-amino-2 - ((4-phenylthio) phenyl) propionic acid were suspended in 200 ml of propionic anhydride. The medium was heated at reflux for 1 hour, then propionic anhydride was bubbled into the pump by azeotropy using heptane. Dissolve the residue of 16 g hot in 100 ml of ethanol. A white solid (3.0 g) crystallized, which was filtered and removed. The liquids were re-concentrated to give 12.3 g of a brown oil which was chromatographed on SiO ₂ (eluant: ethyl acetate / heptane 4/1) to give 4.76 g (0.0153 mol) (4-R, S) -2 -ethyl-4-methyl-4 - ((4-phenylthio) phenyl) -3-oxazolin-5-one as an oil (NMR 250 MHz - CHCl ₃ in ppm: 1.3 (t, 3H); 1.75 (s , 3H); 2.58 (q, 2H); 7.2 to 7.6 (m, 9H) in 29% yield.

We will now describe another method of preparing a compound of formula Ia according to the invention, by introducing a group Ar, -X to imidazolinone of formula (XIV):

) n —RRi N

Ar

K.

¹ 'NH-R ₃

W (xiv)

This second embodiment corresponds to the procedures E, F, G, H, I, J, K, L, M defined below.

Procedure E:

We will first describe the preparation of compounds of the general formula (Ia):

_R.

Ar ₂

-K-Ar, ⁷ ^ 'nh-r ₃ w

(la) where X has the same meaning as the group X ', which is defined below in the description of process E.

Compounds of general formula (Ia) are obtained by condensation of an organometallic imidazolinone derivative of formula (XV) with an electrophilic residue Ar ₂ X ' ⁺ according to the reaction scheme:

(XV)

Ri

Ar ₂ —X —Αη

NH-R ₃

W / (V) ^O - R-2 (1a) wherein it represents a metal selected from lithium, sodium, magnesium, zinc, titanium, tin, copper, boron or silicon, and is preferably lithium, where X 'is such that Ar ₂ -X 'electrophilic residue generated by a compound, especially selected from aralkyl halide or -sulfate of formula Ar ₂ -R ₁₂ -L, where R ₁₂ represents an aliphatic chain of 1 to 6 carbon atoms, straight or branched, saturated or unsaturated optionally substituted by a halogen or alkoxy group or an oxo radical or; and having carbonyl compounds of the formula:

^Ar 2 ^- ( ^R ] 2) P-C- ^{R 13} O where p is 0 or 1;

R _{12 has the} same meaning as above; and

R ₍₃ represents a hydrogen atom, a C 1 -C ₆ alkyl group, halogen, alkoxy, aryloxy or dialkylamino group; chloroformate of the formula

Ar ₂ - (R ₁₂ ) p

O-C-Cl II o where p and R _{12 have the} same meanings as above;

- isocyanates but isothiocyanates of formula

Ar ₂ - (R] ₂ ) P - N = C = Q where p and R _{u have the} same meanings as above and Q represents an oxygen or sulfur atom;

- sulfonyl halides of the formula

Oh

II

Ar ₂ - (R ₁₂ ) p - S - Hal O where R ₁₂ and p have the same meanings as before and Hal represents a halogen atom, preferably a chlorine atom;

- epoxy of formula

Rio

Ar ₂ —R 'O

When, according to a preferred embodiment of the invention, the letter M _t of formula (XV) represents lithium, the corresponding compounds of formula (XV) are obtained, e.g. organolithium compounds of formula (XVII), from halogenated derivatives (XVI), wherein Hal represents a halogen atom, preferably chlorine or bromine, by exchange of metal-halogen (Hal) as described by RG JONES and H. GILMAN, Organic Reactions (19) , vol. 6, p. 339. The reaction is as follows:

W '(XVI)

(XVII)

When the letter Mj of formula (XV) does not represent lithium, the corresponding organometallic compounds of formula (XV) can be obtained from organolithium compounds (XVII) by the transmetallation reaction as described in Advanced organic chemistry, J. March, (1985), p. 557, 3rd edition.

The following example illustrates the preparation of a compound of formula (Ia).

Example CF4: Preparation of (4-R, S) -4- [4 - ((4-chlorophenyl) hydroxymethyl) phenyl] -4-methyl-2methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 30 ):

g (0.0025 mol) of (4-R, S) -4- (4-bromophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one was dissolved in an inert atmosphere in 20 ml of anhydrous THF, the reaction medium is then cooled to -70 ° C. At this temperature, 2 equivalents of n-butyllithium (3.2 ml hexane solution, 1.6 M) were added. After stirring at -70 ° C for 15 minutes, 0.36 g (0.0025 mol) of 4-chlorobenzaldehyde in solution in 3 ml of THF was added. After 30 minutes of the reaction, the reaction medium was hydrolyzed at -70 ° C with saturated ammonium chloride solution. Extraction with ethyl acetate, washing the organic extracts with saturated sodium chloride solution, drying, solvent evaporation, chromatography of the crude product on a SiO ₂ column (ethyl acetate / heptane: 50/50) yielded 0.95 g (0.002 mol) of white solids which is (4-R, S) -4- [4 - ((4-chlorophenyl) hydroxymethyl) phenyl] -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one m.p. 94 ° C in 82% yield.

The 2-imidazolin-5-ones of formula (XVI) are obtained by one of the processes described in European Patent Application EP 0 551048, published July 14, 1993; in the case where Y = S and n = 1; by a method analogous to the method C described above in the case where n = 1 and Y is O; or by a method analogous to method D described for yarns when n is 0.

Procedure F:

We will now describe the preparation of compounds of general formula (Ib):

^R i

At2 ^- (R'i ₂ ) p 2 * Ari

-N.

W

Ob) 'NR ₃

I

H in which p and Z have the same meanings as before and R _'12 represents an aliphatic chain of 1 to 6 carbon atoms, straight or branched, saturated or unsaturated.

These compounds are prepared by known methods by reacting imidazolinone of formula (XVI) with a nucleophile of formula (XVIII) in a manner analogous to that stated in Comprehensive heterocyclic chemistry, A. R. Katritzky, Vol. 2, part 2A, p. 359, e.g. according to the scheme:

The reaction is carried out under conditions commonly used in aromatic substitution reactions.

The following example illustrates the preparation of compounds of formula (Ib).

Example CF5: Preparation of (4-R, S) -4- [6- (4-fluorophenylthio) -5-nitropyridin-2-yl] -4-methyl-229 methylthio-1-phenyl-amino-2-imidazoline-5 -one (Compound No. 64):

K 1.00 g (2.5 mmol) of 4- (6-chloro-5-nitro-pyridin-2-yl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one in a solution in 50 ml of acetone under argon was added at room temperature 1 g of K 2 CO 2 then 0.27 ml (2.5 mmol) of 4-fluorothiophenol. After 2 hours of reaction at room temperature, the medium was diluted with water; the product was extracted with ethyl acetate; the extracts were dried on anhydrous magnesium sulfate, then concentrated under reduced pressure. After chromatographic purification on SiC1 (eluant: ethyl acetate / heptane 20/80), the product was crystallized in diisopropylether. Filtration and drying gave 0.8 g (1.66 mmol) of (4-R, S) -4- [6- (4-fluorophenylthio) -5-nitropyridin-2-yl] -4-methyl-2-methylthio-1 -phenylamino-2-imidazolin-5-one (Compound No. 64) in the form of crystals of m.p. 171 ° C in 66% yield.

Procedure G:

We will now describe the preparation of compounds of formula (Ic):

where X 'has the same meaning as before. Compounds of formula (Ic) are obtained by reaction of 4-hydroxyphenyl) -2-imidazolin-5-one of formula (XIX) with an electrophilic residue Ar ₂ X ' ⁺ according to the reaction scheme

The reaction is carried out in a basic medium under conditions commonly used for condensation between phenols and various electrophilic residues (known procedures in the literature). In particular, alkali or alkaline earth carbonates and hydroxides or organic bases may be used as the base. The reaction is carried out at a temperature between + 20 ° C and +15 () ° C. It is carried out in solvents such as alcohols, ketones, acetonitrile, aliphatic ethers, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone.

The following example illustrates the preparation of compounds of formula (Ic).

Example CF6: Preparation of (4-R, S) -4-methyl-4- (4- (3-methylbenzyloxy) phenyl) -2-methylthio-phenylamino-2-imidazolin-5-one (Compound No. 22).

To a stirred solution of 2 g (0.0061 mol) of (4-R, S) -4- (4-hydroxyphenyl) -4-methyl-2-methylthiol-phenylamino-2-imidazolin-5-one in 50 ml of ethanol was added 0 , 92 g (0.0067 moles) of potassium carbonate., 0.94 g (0.0067 moles) of 3-methylbenzyl chloride and 0.1 g (0.00061 moles) of potassium iodide. The reaction medium is refluxed for 8 hours. Pour this into 150 ml of water. The resulting precipitate was washed with 1N aqueous sodium hydroxide solution, then neutralized with water, centrifuged, washed with diisopropyl ether, then dried under reduced pressure. 1.94 g (0.0045 mol) of (4-R, S) -4-methyl-4- (4- (3-methylbenzyloxy) phenyl) -2-methylthio-1-phenylamino-2-imidazoline-5 are thus obtained -one (compound 22) in the form of white crystals from the ground. 151 ° C in 75% yield.

The hydroxyl compounds of formula (XIX) are obtained from the corresponding benzyl compounds (Id) upon withdrawal of the benzyl group by the debenzylation reaction. Debenzylation is carried out according to commonly used procedures, either with hydrogen acid or catalytic hydrogenation, and are known from the literature: G. Buchi and S. M. Weinreb, J. Am. Chem. Soc. (1971), Vol. 93, p. 746, but O. Th. Schmidt and H. Schmadel, Annalen (1961), Vol. 649, p. 149. The reaction scheme is as follows:

3;

The following example illustrates this process for the preparation of compounds of formula (XIX).

Example CI10: Preparation of (4-R, S) -4- (4-hydroxyphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one of the structural formula

To the stirred suspension, 31.2 g (0.075 mol) of (4-R, S) -4- (4-benzyloxyphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazoline-5 -one in 370 ml of acetic acid was added 92 ml of concentrated hydrochloric acid (d = 1.18) and heated at 75 ° C for 2 hours. After cooling the reaction medium to room temperature, it was poured into 500 ml of ice water, then neutralized with concentrated aqueous sodium hydroxide solution. The resulting precipitate was stirred for 1 hour at 5 ° C, then filtered, washed with water, centrifuged and dried under reduced pressure. There were thus obtained 22 g (0.067 mol) of (4-R, S) -4- (4-hydroxyphenyl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one as white crystals of m.p. 206 ° C in 90% yield.

The table below summarizes the synthesized imidazolinones of formula (XIX):

Position OH Profit m.p. (° C) (%) 3 68 159 4 90 206

4- (Benzyloxyphenyl) -2-imidazolin-5-one (Id) is obtained by one of the methods described above.

Procedure H:

We will now describe the preparation of compounds of formula (Ie):

where p and R ^{'12 have the} same meaning as before and Z' represents an oxygen, sulfur atom or NR ¹⁴ group, where R represents a hydrogen atom or a C _x -C ₆ alkyl group.

These compounds are obtained by reacting the 4- (carboxyphenyl) -2-imidazolin-5-one of formula (XX) with a chlorinating agent such as thionyl chloride, oxalyl chloride or phosgene, optionally in the presence of a catalyst, such as dimethylformamide, and in an inert solvent ; then with a nucleophilic compound of the formula: Ar ₂ - (R ^'12 ) _p ΖΉ (XVIII) in the presence of a base such as alkali or alkaline earth carbonate or organic base, according to the scheme:

The following example illustrates this process for the preparation of compounds of formula (le).

Example CF7: Preparation of (4-R, S) -4- (4- (4-chlorophenylaminocarbonyl) phenyl) -4-methyl2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 45):

g (0.0028 mol) of (4-R, S) -4- (4-carboxyphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is dissolved in 20 ml of dichloro-1,2- ethane at room temperature. At this temperature, 0.5 ml (0.0056 mol) of oxalyl chloride is added, followed by a drop of dimethylformamide. At the end of the gas evolution, the solvent is evaporated and the acid chloride is taken up in 20 ml of anhydrous THF. At room temperature, 0.4 ml (0.0028 moles) of triethylamine are then added, followed by 0.71 g (0.0056 moles) of 4-chloroaniline. After stirring for 1 hour, the medium was hydrolyzed. After extraction with ethyl acetate, washing the organic phases with saturated sodium chloride solution, drying, evaporation of the solvents, 1 g of a brown oil are obtained. After crystallization in diisopropylether, filtration and drying, 0.85 g (0.0018 mol) of (4-R, S) -4- (4- (4-chlorophenylaminocarbonyl) phenyl) -4-methyl-2-methylthio-1- phenylamino-2-imidazolin-5-one as a beige solid from the ground. 210 ° C in 65% yield.

4- (Carboxyphenyl) -2-imidazolin-5-one of formula (XX) is prepared by reacting an organolithium compound of formula (XVII) with carbon dioxide gas in a manner analogous to that specified in Advanced organic chemistry, J. March , (1985), p. 826, 3rd edition, i.e. by reaction:

The reaction is carried out by allowing bubbles of the carbon dioxide gas to pass through in the reaction medium containing the organolithium compound.

The following example illustrates this process for the preparation of compounds of formula (XX).

Example CI11: Preparation of (4-R, S) -4- (4-Carboxyphenyl) -4-methyl-2-methylthio-1-phenylamino 2-imidazolin-5-one of the structural formula

g (0.0025 mol) of (4-R, S) -4- (4-bromophenyl) -4-methyl-2-methylthio-1-phenylamino 2imidazolin-5-one was dissolved in an inert atmosphere in 20 ml of anhydrous tetrahydrofuran. The reaction medium is cooled to -70 ° C. At this temperature, 2 equivalents of n-butyllithium (3.2 ml of hexane solution 1.6 M) were added. After stirring at -70 ° C for 15 minutes, dry carbon dioxide bubbles were allowed to pass. After 30 minutes, the reaction medium was hydrolyzed at -70 ° C. After extraction with ethyl acetate, then washing the organic phase with a saturated solution of potassium carbonate, the aqueous phases are combined, then acidified. Extraction with ethyl acetate, drying and evaporation of the solvents afforded 0.5 g (0.0014 mol) of (4-R, S -) - 4- (4-carboxyphenyl) -4-methyl-2-methylthio-1-phenylamino 2imidazoline -5-one in the form of white powder from the ground. 183 ° C in 56% yield.

Procedure I:

We will now describe the preparation of compounds of the general formula (If)

wherein R ^'12 , p and Z' have the same meaning as before and R represents a hydrogen atom, an alkyl, haloalkyl, alkoxyalkyl or alkylidene residue, each of the alkyl residues containing 1 to 6 carbon atoms. R retains this same definition in the rest of the description.

These compounds are obtained by reacting a nucleophilic compound of formula Ar ₂ - (R ₁₂ ) _p -Z'H (XVIII) with 4- (chloromethylphenyl) -2-imidazolin-5-one of structure (XXIII).

The reaction is carried out in the presence of a base under conditions commonly used for the condensation between alcohols and various electrophiles and is known from the literature: Advanced organic chemistry, J. March, (1985), p. 342, 3rd edition, i.e. according to the reaction scheme:

Alkali or alkaline earth carbonates and hydroxides or organic bases may be used as the base. The reaction is carried out at a temperature between 20 ° C and 150 ° C. The reaction is carried out in solvents such as alcohols, acetonitrile, aliphatic esters, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, ketones, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone.

The following example illustrates this process for the preparation of compounds of formula (If).

Example CF8: Preparation of (4-R, S) -4- (4 - ((2,4-difluorophenoxy) methyl) phenyl) -4-methyl-2methylthio-1-phenylamino 2-imidazolin-5-one (Compound no. 47)

0.3 g (0.0083 mol) of (4-R, S) -4- (4-chloromethyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2imidazolin-5-one is mixed in DMF with 0 , 11 g (0.0083 moles) of 2,4-difluorophenol, 0.12 g (0.0083 moles) of potassium carbonate and 0.14 g (0.0083 moles) of potassium iodide. The reaction mixture was stored at 80 ° C for 2 hours. After hydrolysis with water, extraction with ethyl acetate, washing the organic extracts with saturated lithium chloride solution, drying and evaporation of the solvents, the resulting honey was crystallized in diisopropylether, then filtered. 0.250 g (0.0055 mol) of (4-R, S) -4- (4 - ((2,4-difluorophenoxy) methyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2- is obtained imidazolin-5-one in the form of a beige precipitate from the ground. 152 ° C in 66% yield.

4- (Chloromethylphenyl) -2-imidazolin-5-one of structure (XXIII) is obtained by halogenation of 4- (hydroxymethylphenyl) -2-imidazolin-5-one of structure (XXII). Halogenation is carried out according to procedures commonly used for this type of reaction, using hydrogen acid or inorganic acid halide, such as SOC1 ₂ , PC1 ₅ , PC1 ₃ , POC1 ₃ , as indicated in Advanced Organic Chemistry, J. March, (1985 ), p. 382, 3rd edition, and according to the reaction scheme:

HOCHR

The following example illustrates this process for the preparation of compounds of structure (XXIII):

Example CU2: Preparation of (4-R, S) -4- (4-chloromethylphenyl) -4-methyl-2-methylthio-1-

To a solution of 0.9 g (0.0026 mol) of (4-R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2-methylthiol-phenylamino-2-imidazolin-5-one in 10 ml of toluene at 0.22 ml (0.0026 moles) of pyridine are then added at room temperature followed by 0.2 ml (0.0026 moles) of thionyl chloride in solution in 1 ml of toluene. The reaction mixture was brought to 60 [deg.] C. for 3 hours, then cooled and hydrolyzed. Extraction with ethyl acetate, washing the organic extracts with saturated sodium chloride solution, drying and evaporation of the solvents gave a yellow honey. Chromatography on a SiO ₂ column (ethyl acetate / heptane: 50/50) gave 0.36 g (0.001 mol) of (4-R, S) -4- (4-chloromethylphenyl) -4-methyl-2-methylthio-1 -phenylamino-2-imidazolin-5-one as a yellow powder from the ground. 130 ° C in 38% yield.

Hydroxymethyl phenyl-2-imidazolin-5-one of formula (XXII) is obtained by reduction of the corresponding carbonyl compounds (XXIV). This reduction can be carried out according to the procedures commonly used for this type of reaction, which are described in Advanced Organic Chemistry, J. March, (1985), p. 1093-6, 3rd edition, and according to the scheme:

The following example illustrates this process for the preparation of compounds of structure (XXII):

Example CII3: Preparation of (4-R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2-methylthio-

A solution of 9 g (0.0026 mol) of (4-R, S) -4- (4-formylphenyl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one in 100 ml abs. of ethanol at 0 ° C was added 1.02 g (0.0026 mol) of NaBH ₄ . After stirring at room temperature for 4 hours, the medium was hydrolyzed and then extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, evaporated and chromatographed on a SiO ₂ column (ethyl acetate / heptane: 50/50). 0.9 g (0.00026 mol) of (4-R, S) -4- (4hydroxymethylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin5-one is obtained as a chestnut brown powder from the ground. 146 ° C in 10% yield.

The table below summarizes the synthesized imidazolinones (XXII):

Position OH X Profit (%) m.p. ('C) 3 S 76 147 4 S 10 146 3 0 76 157

The carbonyl compounds of formula (XXIV) are prepared by reaction with an organolithium compound of formula (XVII) with an electrophilic carbonyl compound, as described in J. IVANS, J. Chem. Soc, (1956), p. 4691, and according to the reaction scheme:

The following example illustrates this process for the preparation of compounds of structure (XXIV):

Example CI14: Preparation of (4-R, S) -4- (4-Formylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one by structural formula

g (0, 0025 mol) of 4- (4-bromophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5one was dissolved in an inert atmosphere in 20 ml of anhydrous THF, then brought to -70 ° C. At this temperature, 2 equivalents of nBuli (3.2 ml; 1.6M) were added. After stirring at -70 ° C for 15 minutes, 0.2 ml (0.0025 mol) of dimethylformamide in solution in 1 ml of THF was added. After 30 minutes, the medium was hydrolyzed at -70 ° C with saturated ammonium chloride solution. Extraction with ethyl acetate, washing the organic phases with saturated sodium chloride solution, drying and evaporating the solvents and chromatography of the crude product on a SiO ₂ column (ethyl acetate / heptane: 50/50) yielded 0.55 g of a yellow clear oil which precipitated in isopropyl ether. 0.35 g (0.001) of (4-R, S) -4- (4formylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is obtained as a white powder from the ground. 181 ° C, e.g. with a gain of 40%.

The table below summarizes the synthesized imidazolinones of formula (XXIV):

Procedure J:

We will now describe the preparation of compounds of formula (Ig):

where X 'has the same meaning as before.

These compounds are obtained by reaction of 4- (aminophenyl) -2-imidazolin-5-one of formula (XXV) with an electrophilic residue of formula Ar, X ' ⁺ , as previously defined, by the reaction scheme:

The reaction is carried out under conditions which are customary for the condensation between anilines and various electrophilic compounds. The reaction is carried out in the presence of a base. Alkali or alkaline earth carbonates, hydroxides, organic bases can be used as the base. The reaction is carried out at a temperature between 20 ° C and 150 ° C and is conducted in a solvent such as alcohols, acetonitrile, aliphatic esters, ethers, cyclic ethers, aromatic solvents, chlorinated solvents, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone.

The following example illustrates this process for the preparation of compounds of formula (Ig).

Example CF9: Preparation of (4-R, S) -4- (4-Benzoylaminophenyl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one (Compound # 1):

To a solution of 2 g (6.1 mmol) of (4-R, S) -4- (4-aminophenyl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one and 0.62 g (6, 1 mmol) of triethylamine in 50 ml of tetrahydrofuran was added 0.86 g (6.1 mmol) of benzoyl chloride. Leave to react for 2 hours at room temperature, filter the precipitate of triethylamine hydrochloride, then concentrate the filtrate under reduced pressure. The crude product is allowed to crystallize in diethyl ether. 2.47 g (5.7 mmol) of (4-R, S) -4- (4-benzoylaminophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No 1) in the state of white solid from the ground. 212 ° C in 94% yield.

4- (Aminophenyl) -2-imidazolin-5-ones of formula (XXV) is prepared by reduction of 4- (nitrophenyl) -2-imidazolin-5-ones of formula (XXVI). The reduction is performed by conventional methods of reducing nitro groups, such as e.g. by catalytic hydrogenation in the presence of a mixture of charcoal and palladium (paladinized charcoal): F. Melani, L. Cecchi, G. Filacchion.

J. Heterocyclic Chem. (1984), Vol. 21, p. 813, according to the scheme:

The following example illustrates this process for the preparation of compounds of formula (XXV).

Example CI15: Preparation of (4-R, S) -4- (4-aminophenyl) -4-methyl-2-methylthio-1-phenylamino-2imidazolin-5-one of the structural formula:

g (39 mmol) (4-R, S) -4- (4-nitrophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one, 100 ml ethyl acetate and 3 g palleted charcoal (10 %) batch into an autoclave with 500 ml. The autoclave was pressurized to 9 bars of hydrogen and heated at 50 ° C for 12 hours. Filtration of the catalyst and concentration under reduced pressure gave a yellow honey which crystallized in ether. Filtration and drying gave 11 g (4-R, S) -4- (4aminophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one as a yellow solid from the ground. 194 ° C, e.g. with a gain of 87%.

Acting analogously, (4-R, S) -4- (3-aminophenyl) -4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one is obtained in 95% yield as a yellow solid from the ground. 100 ° C.

4- (Nitrophenyl) -2-imidazolin-5-one of formula (XXVI) is obtained by one of the processes described in European patent application EP 0 551048, published July 14, 1993, in the case where Y = S and n = l; by a process analogous to the previously described method C in the case where n = 1 and Y = O; or by a process analogous to the method described above, when n is 0.

Procedure K:

We will now describe the preparation of Tormula compounds (Ih):

Ar ₂ - (R 'j ₂ ) p ~ C ^- Z' CHR O

where R ^'12 , p, Z' have the same meaning as before. These compounds are prepared by reacting type (XXVII) derivatives with an electrophilic reagent of formula Ar ₂ - (R ^'12 ) -COC1 in the presence of a base, such as alkali or alkaline earth carbonate or organic base, in an inert solvent according to the scheme:

HZ '-CHR

• R

Ar ₂ - (R _'12 ) PC-C1>-> 0 base, solvent

Ar ₂ - (R _'12 ) P -C-Z'-CHR O

The following example illustrates this process for the preparation of compounds of formula (Ih).

Example CF10: Preparation of (4-R, S) -4- (4- (4-chlorobenzoyloxymethyl) phenyl) -4-methyl-2methylthio-1-phenylamino 2-imidazolin-5-one (Compound No. 94) of the structural formula

To a solution of 1 g (0.0029 mol) of (4-R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2methylthio-1-phenylamino-2-imidazolin-5-one in 20 ml of THF was added at room temperature. 0.42 ml (0.0029 moles) of triethylamine then 0.38 ml (0.0029 moles) of parachlorobenzoyl chloride. After stirring at room temperature for half an hour, the medium was hydrolyzed, then extracted with ethyl acetate. The organic extracts were washed, dried, then evaporated. Mixing with isopropyl ether gives 0.6 g (4-R, S) -4- (4- (4-chlorobenzoyloxymethyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in white powder form from the ground. 129 ° C in 43% yield.

Imidazolinone of formula (XXVII) can be prepared by one of the methods described above, in particular by a method analogous to that used for the preparation of imidazolinone of formula (XXII).

Procedure L:

We will now describe the preparation of compounds of general formula (Ii):

where Ar ² , R ^'12 and Z' have the same meaning as before.

These compounds are obtained by reacting the benzyl derivatives of 2-imidazolin-5-ones of formula (XXVIII) with a nucleotile of formula HZ'R ² , optionally in the presence of a base such as alkali or alkaline earth carbonate or organic base according to the scheme:

W (Ii)

The following example illustrates this process for the preparation of compounds of formula (Ii).

Example CF11. Preparation of (4-R, S) -4- (4-Methoxybenzyl) phenyl) -4-methyl-2-methylthio-1-phenylamino 2-imidazolin-5-one (compound No. 107) of the structural formula

To a solution of 0.37 g (0.007 mol) of sodium methylate in 30 ml of methanol in an inert atmosphere was added 1.5 g (0.0035 mol) of (4-R, S) -4- (4-chlorobenzyl) phenyl) -4- methyl-2methylthio-1-phenylamino-2-imidazolin-5-one. The reaction mixture was heated to 5 () ° C for half an hour. After cooling, the medium was hydrolyzed, then extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, then evaporated. The crude product thus obtained is then chromatographed on a SiO ₂ column (eluant: heptane / ethyl acetate 50/50). 0.7 g of (4-R, S) -4- (4-methoxybenzyl) phenyl) -4-methyl-2methylthio-1-phenylamino-2-imidazolin-5-one is obtained as a white powder from the ground. 161 ° C in 47% yield.

Benzyl derivatives of 2-imidazolin-5-ones of formula (XXVIII) are prepared by one of the methods described above, in particular by a method analogous to that used to prepare a compound of formula (XXIII) from a compound of formula (XXII).

Procedure M:

We will now describe the preparation of compounds of formula (Ij):

where R ^'12 and p have the same meaning as before, Y represents a sulfur atom, X represents a halogen atom, preferably a chlorine atom.

These compounds are obtained by halogenating compounds of formula (XXIX). Halogenation is carried out according to procedures commonly used for this type of reaction, using hydrogen acid or inorganic acid halide, such as SOC1 ₂ , PC1 ₅ , PC1 ₃ , POC1 ₃ , as indicated in Advanced Organic Chemistry, J. March, (1985 ), p. 382, 3rd edition, and according to the reaction scheme:

I

Η (lj)

The following example illustrates this process for the preparation of compounds of formula (Ij):

Example CF12: Preparation of (4-R, S) -4- (4-chlorobenzyl) phenyl-4-methyl-2-methylthio-phenylamino-2-imidazolin-5-one (compound no. 106) of the structural formula

To a solution of 6.5 g (0.015 mol) of (4-R, S) -4- (4 - ((phenyl) hydroxymethyl) phenyl) -4methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in 100 ml of methylene chloride was added at 0 ° C to 1.4 ml (0.015 mol) of pyridine followed by 1.15 ml (0.015 mol) of thionyl chloride. The reaction medium was then refluxed for half an hour, then cooled to room temperature, hydrolyzed and extracted with methylene chloride. The organic extracts were washed, dried, then evaporated. Stirring the crude product in diisopropylether gave 4.7 g ((4-R, S) -4- (4- (chlorobenzyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one as a white powder, mp 153 ° C, in 69% yield.

The compound of formula (XXIX) is obtained by one of the methods described above, in particular the process used to prepare the compound of formula (XXII).

The following tables summarize the imidazolinones of formula (I), which also correspond to one of the formulas (Ik) or (funnel above) prepared by one of the methods described above (indicated in the appropriate column).

In these tables, Me, Et, Pr, Py, Pyrim,. Ac, Ph oz. Bn are methyl, ethyl, propyl, pyridyl, pyrimidinyl, acetyl, phenyl or benzyl radicals.

(Ik)

No. W Ar2X (Y) n R2 R3 m.p. ° C Po- hundred- baker 1 0 4- (PhC (O) NH) SMe Ph 212 J 2 0 4- (PhC (O) NH) OMe Ph 150 ^c 3 0 4- (4-Cl-PhC (O) NH) SMe Ph 219 4 0 4- (4-Cl-PhC (O) NH) OMe Ph 182 c 5 0 4- (PhNHC (0) NH) SMe Ph 160 J 6 0 4- (PhNHC (0) NH) OMe Ph 135 c 7 0 4- (PhSO2NH) SMe Ph 185 ¹ 8 0 3-BnO SMe Ph 112 B

⁹ 0 4-BnO OMe Ph 127 C ¹⁰ 0 4-BnNH SMe Ph 114 J j ¹¹ 0 4-Bn OMe Ph 148 C ¹² 0 4-Bn SMe Ph 145 B 13 0 4-BnO SMe 3-F-Ph med B 14 S 4- (2-phenethyl) SMe Ph 118 A 15 0 4- (4-F-BnO) SMe Ph 167 Mr ¹⁶ 0 4- (3-F-BnO) SMe Ph 133 ^Mr 17 0 4- (2-F-BnO) SMe Ph 159 Mr 18 0 4 - [(5-CF ₃ -2-Py) -O] SMe Ph 163 Mr 19 0 4- (4-Me-BnO) SMe Ph 176 Mr 20 0 4- (4-CF ₃ -BnO) SMe Ph 170 Mr 21 0 3- (PhC (O) NH) SMe Ph 130 J 22 0 4- (3-Me-BnO) SMe Ph 151 G j 23 0 4- (2-Me-BnO) SMe Ph 146 G [ 24 0 4- [2,5- (Me) 2-BnO] SMe Ph 149 G j 25 0 4-PhS SMe Ph 138 B 26 0 4-PhS SMe 3-F-Ph 118 B 27 0 4-PhS SMe 3-Cl-Ph 95 B 28 0 4- [Ph (CH ₂ ) 2] SMe Ph 155 B 29 0 3- (BnNH) SMe Ph 72 J 30 0 4- [4-Cl-PhCH (OH)] SMe Ph 94 E 31 0 4- [PhCH ₂ CH (OH)] SMe Ph 83 E 32 0 4- (2-Py-CH2O SMe Ph 139 Mr 33 0 4- [PhCH (CH3) O] SMe Ph 137 Mr 34 0 4- (4-Py-CH2O) SMe Ph 215 Mr

35 0 4- (3-Py-CH2O) SMe Ph 138 Mr 36 0 4- (5-CF ₃ -2-PyO) OMe Ph 88 C 37 0 4- (PhNHC (O) O) SMe Ph 201 ^G I ³⁸ 0 4- [PhS (O)] SMe Ph 132 ^b 1 ³⁹ 0 4- [PhS (O)] SMe 3-Cl-Ph 164 B j ⁴⁰ 0 4- [PhS (O)] SMe 3-F-Ph 115 B 41 0 4- (PhSO2) SMe Ph 80 B 42 0 4- [Ph (CH2) 2l OMe Ph 100 C 43 0 4- (PhCO2) SMe Ph 170 Mr 1 ⁴⁴ 0 PhCOCH2O SMe Ph 163 Mr 1 ⁴⁵ 0 4- [4-Cl-PhNHC (O)] SMe Ph 210 ^h 1 ⁴⁶ 0 4- [PhNHC (O)] SMe Ph 105 ^H I 47 0 4- (2,4-diF-PhOCH2) SMe Ph 152 I ⁴⁸ 0 4- (3-Cl-PhNHCO) S-Me Ph 115 H ⁴⁹ 0 4- (4-Cl-PhCMe (OH)) S-Me Ph 90 E j ⁵⁰ 0 4- (2- (4,6-diMe- Pyrim) O) S-Me Ph 87 G j 51 0 4- (2-Me-PhCH ₂ O) S-Me Ph 129 Mr 52 0 4- (PhSO ₂ ) S-Me 3-Cl-Ph 153 B 53 0 4- (PhSO ₂ ) S-Me 3-F-Ph 188 B 54 0 4- (PhS) Et Ph 85 D 56 0 4- (PhOCH ₂ ) MeS Ph 153 I ⁵⁷ 0 4- (4-Cl-PhOCH ₂ ) MeS Ph 164 I 58 0 4- (3-Cl-PhOCH ₂ ) MeS Ph 149 I 59 0 4- (2-Cl-PhOCH ₂ ) MeS Ph 102 I 60 0 4- (4-F-PhOCH ₂ ) MeS Ph 132 I

61 0 4- (3-F-PhOCH ₂ ) MeS Ph 147 I 62 0 4- (2-MeO-PhOCH ₂ ) MeS Ph 156 I ⁶³ 0 3- (PhCH ₂ O) MeO Ph 56 C 84 0 3- (PhCH ₂ O) OMe Ph 56 C 85 0 4- (2-F-PhOCH ₂ ) SMe Ph 153 I ⁸⁶ 0 4-PhSO Et Ph med ^d 1 1 ⁸⁷ 0 4-PhSO ₂ Et Ph 194 D ⁸⁸ 0 4- (4-F-PhC (O)) SMe Ph 163 E ⁸⁹ 0 4- (4-MeO-Ph) OCH ₂ SMe Ph 151 I ⁹⁰ 0 4- (3-MeO-Ph) OCH ₂ SMe Ph 131 I 1 ⁹¹ 0 4- (4-CF ₃ -Ph) OCH ₂ SMe Ph 173 I 92 0 4- (3-MeO-PhCH ₂ O) SMe Ph 126 Mr ⁹³ 0 4- (2-F-PhOCH ₂ ) OMe Ph 165 C 1 ⁹⁴ 0 4- (4-Cl-PhCO ₂ CH ₂ ) SMe Ph 129 K ⁹⁵ 0 4-PhSO OMe Ph med c ⁹⁶ 0 4- (4-Cl-Ph) CH ₂ O SMe Ph 187 Mr ⁹⁸ 0 4-PhCH (OH) SMe Ph med E ⁹⁹ 0 4- (4-MeO-PhCH ₂ O) SMe Ph 156 Mr 100 0 4- (4-NC-PhCH ₂ O) SMe Ph 209 Mr 101 0 4-PhOCH ₂ OMe Ph 158 C 102 0 4- (3-Cl-PhOCH ₂ ) OMe Ph 147 C 103 0 4- (3-F-PhOCH ₂ ) OMe Ph 179 C 1 ¹⁰⁴ 0 4- (4-F-PhOCH ₂ ) OMe Ph 141 C 1 ¹⁰⁵ 0 4- (4-CF ₃ -PHOCH ₂ ) OMe Ph 143 C 106 0 4-PhCH (Cl) SMe Ph 153 M 107 0 4-PhCH (OMe) SMe Ph 161 L

108 0 4-PhCH (OMe) OMe Ph 136 C 109 - 0 4-PhS SMe 2,5-diF-Ph 104 B 110 0 4-PhCO SMe Ph 162 E ¹¹¹ 0 4- (2-CN-PhCH ₂ O) SMe Ph 174 Mr ¹¹² 0 4-PhCO OMe Ph 83 C 113 0 3- (4-Cl-PhCOOCH ₂ ) SMe Ph 156 K I ¹¹⁴ 0 3- (4-Cl-PhCOOCH ₂ ) OMe Ph 105 ^{c 115} 0 4-PhS SMe 2,3-diF-Ph 113 B 116 0 4- (3-CN-PhCH ₂ O) SMe Ph 171 Mr ¹¹⁷ 0 3- (4-CF3-PhOCH ₂ ) SMe Ph 127 I ¹¹⁸ 0 3- (PhCO) SMe Ph 149 E 119 0 3- (4-Cl-PhCH (OH)) SMe Ph 156 E | 120 0 3- (4-Cl-PhOCH ₂ ) SMe Ph 112 I 1 ¹²¹ 0 3- (4-CF ₅ -PHOCH ₂ ) OMe Ph 102 C j 122 0 3- (PhCH (OMe)) OMe Ph 120 C 123 0 3- (4-Cl-PhCH (OMe)) OMe .Ph 120 c 124 0 3- (4-Cl-PhOCH ₂ ) OMe Ph med C 125 0 3- (4-Me-PhOCH ₂ ) SMe Ph 87 I 126 0 3- (4-F-PhOCH ₂ ) OMe Ph 136 c ¹²⁷ 0 3- (4-F-PhCH (OH)) SMe Ph 128 E 1 ¹²⁸ 0 3- (4-CF ₃ -PhCH (OH)) SMe Ph 145 E 1 ¹²⁹ 0 3- (4-OMe-PhCH (OH)) SMe Ph 114 E 130 0 3- (4-F-PhCH (OMe)) OMe Ph 131 C 131 0 3- (PhCH ₂ O) SMe Ph 132 I 132 0 3- (PhCO) SMe Ph med E 133 0 3- (PhOCH ₂ ) OMe Ph med C

134 0 4- (4-FPhCH ₂ O) OMe Ph 171 Mr 135 ⁰ U - / (2-tenzothiazolylX) / SMe Ph 144 Mr

(Π)

N ° Ar2 R mp x> step 1 64 4-F-Ph no ₂ 171 F | ⁶⁵ Ph no ₂ 148 F | 66 2-F-Ph no ₂ • 115 F | 67 3-F-Ph no ₂ 112 F j 68 4-Cl-Ph no ₂ 146 F 69 3-Cl-Ph no ₂ 103 F 70 2-Cl-Ph no ₂ 93 F j 1 ⁷¹ 2-Naphtyl no ₂ 131 F | 72 2-OH-Ph no ₂ 97 F | 73 4-HOPh no ₂ 145 F J 74 4-MeOPh no ₂ 134 F 75 3-MeOPh no ₂ 165 F

76 4-MePh no ₂ 115 F 77 2-MePh no ₂ 120 F 78 3-MePh no ₂ 113 F 79 Ph cf ₃ 166 F 80 4-Me-Ph cf ₃ 149 F ⁸¹ 4-MeO-Ph cf ₃ 151 F 82 4-Cl-Ph cf ₃ 149 F 83 3-F-Ph cf ₃ 143

The object of the present invention is to provide novel compounds described as yarns as intermediates, i.e., compounds of the formulas lilac, Illb, IV, VII, XIII, XIX, XX, XXII, XXIV and XXVII, wherein the yarn substituents have a defined meaning. As compounds defined by the general formula (I) of the invention, these may exist in one or more isomeric forms according to the number of asymmetric centers of the molecule. The invention therefore also relates to all optical isomers of compounds useful as intermediates, as well as to their racemic mixtures and corresponding diastereoisomers, either separately or in mixture, and in particular enantiomers of compounds containing asymmetric carbon bearing R _p. or diastereoisomers from racemic mixtures can be performed by methods known per se. It is also possible to prepare enantiomers of intermediates containing asymmetric carbon bearing R _p by methods known per se or by the processes described above from chiral feedstocks, in particular chiral α-amino acids of formula (IX), i.e., compounds of formula (IX), where the carbon coupled to R _{r is} asymmetric carbon.

The invention also relates to a method for treating cultivated plants affected by or susceptible to fungal disease, characterized in that an effective dose of a compound of formula (I) is applied to the aerial parts of these plants. Effective dosage means an amount sufficient to allow the control and destruction of the fungi present on these cultivated plants. Useful doses, however, can be varied within wide limits depending on the fungus to be suppressed, the type of culture, the climatic conditions and the compound used.

In practice, it is advantageous to administer the compounds at dosages of 0.02 to 5 kg / ha, preferably from

(), () () 5 to 1 kg / ha.

Fungal diseases are understood to mean diseases caused by phytopathogenic fungi, in particular fungi of the oomycet, ascomycet and bazidiomycetes families.

Among the crops which may be subjected to the tungicidal treatment by the compound of the invention, rice, cereals, in particular wheat and barley, as well as vegetables, may be mentioned. Rice is the preferred culture for the fungicidal treatment with the compound of the invention.

The following examples illustrate the good fungicidal efficacy of the compounds of the invention.

Example BI: An in vivo test for Pyricularia oryzae responsible for rice picriculariosis:

By fine grinding, prepare an aqueous suspension of the active substance to be tested with the following composition:

- active substance 60 mg

- acetone 5 ml

- surfactant (oleate of polyoxyethylated sorbitan derivative) diluted with water to 10% 0,3 ml

- Make up to 60 ml with water.

This aqueous suspension is then diluted with water to obtain the desired concentration of the active substance.

Rice sown in beakers in a mixture of 50/50 enriched peat and puccolane soil is treated at a stage height of approximately 10 cm (corresponding to stage 2-3 leaves) by spraying the upper aqueous suspension.

At the end of 24 hours, the aqueous suspension of Pyricularia oryzae spores obtained from the culture for 15 days was applied to the leaves, which was then put into a suspension of 100,000 units per cm ³ .

The rice plants were incubated for 24 hours (25 ° C, 100% relative humidity), then placed in the observation cell under the same conditions for 5 days.

We evaluate 6 hours after infection.

Under these conditions, a good (at least 75%) or complete protection with the following compounds is observed at a dose of 1 g / l: 9,11, 15, 16, 23, 27 to 29, 31 to 33, 35 to 37, 42, 67, 68 , 84, 92, 94, 95, 96,102, 104,105,108,109,112,114,121.

Example B2: In vivo test for Puccinia reconclita responsible for brown rust of wheat:

By fine grinding, prepare an aqueous suspension of the active substance to be tested with the following composition:

- active substance 60 mg

- acetone 5 ml

- Tvveen 80 surfactant ((oleate polyoxyethylated sorbitan derivative) diluted with water to 10%: 0.3 ml

- Make up to 60 ml with water.

This aqueous suspension is then diluted with water to obtain the desired concentration of the active substance.

Wheat sown on a 50/50 peat-pozzolanic soil substrate in a beaker maintained at 12 ° C is treated at a 10 cm height stage by spraying the upper aqueous suspension.

At the end of 24 hours, an aqueous spore suspension (100,000 spores / cm ³ ) was sprayed onto the wheat; this suspension was obtained from infected plants. The wheat is then placed in an incubation cell at about 20 ° C and 100% relative humidity for 24 hours, then at 60% relative humidity for 7 to 14 days.

Plant condition was monitored between days 8 and 15 after infection by comparison with the untreated control.

Under these conditions, a good (at least 75%) or complete protection with the following compounds is observed at a dose of 1 g / l: 4, 8 to 13, 15 to 18, 20 to 28, 31 to 33, 35, 36, 38, 40 to 43 , 48, 49, 73, 79, 81, 84, 85, 89, 90, 93, 94, 95, 96, 98, 99, 100, 101 to 110, 115 to 117,119 to 121.

Example B3: An in vivo test on Septoria 3 responsible for wheat septoriosis

Aqueous suspension with a concentration of 1 g / l of the active substance tested is obtained by grinding 60 mg of the active substance in the following mixture:

- acetone 5 ml

- surfactant (oleate of polyoxyethylated sorbitan derivative) diluted to 10% 0.3 ml then volume adjusted to 60 ml with water.

This aqueous suspension is then diluted with water to obtain the desired concentration of the active substance.

Wheat plants (Darius version), sown on a 50/50 peat-pozzolanic soil substrate and grown in a greenhouse at 10 to 12 ° C, is treated in stage 1 leaf (approximately 10 cm in size) by spraying the active substance suspension described above.

The plants used as controls were treated by spraying an aqueous solution containing no active substance.

hours after treatment, the plants were infected by spraying an aqueous spore suspension (500,000 spores / ml) harvested on a 7-day-old culture.

After infection, plants are placed at 18 ° C in a humid atmosphere. We evaluate 20 days after infection by comparison with control plants.

Under these conditions, a good (at least 75%) or complete protection with the compounds is observed at a dose of 1 g / l: 9, 15, 21, 23, 32, 36, 49, 73, 88, 89, 90, 93, 94, 95, 98, 104, 105, 108, 112, 114,117,118,120,121.

The subject of the present invention are also preparations useful as fungicides, containing as active substance (s) one or more compounds of formula (I) as previously described, in admixture with solid or liquid carriers that are agriculturally acceptable, and surfactants, which are also agriculturally acceptable. Particularly useful are inert carriers and conventional surfactants.

These compositions may also contain all kinds of other ingredients, such as e.g. protective colloids, adhesives, thickeners, thixotropic agents, penetrating agents, stabilizers, sequestrants, etc. More generally, the compounds used in the invention can be combined with any solid or liquid additives that conform to conventional formulation techniques.

Generally, the compositions of the invention typically contain from about 0.05 to 95% by weight of the compound of the invention (hereinafter the active substance), one or more solid or liquid carriers, and optionally one or more surfactants.

The term carrier in the present specification denotes an organic or mineral, natural or synthetic substance. with which to combine a compound to facilitate its application to the plant, to the grain or to the earth. This carrier, however, is generally inert and must be agriculturally acceptable, especially on the treated plant. The carrier may be solid (clay, natural or synthetic silicates, SiO ₂ , resins, waxes, solid fats, etc.) or liquid (water, alcohols, especially butanol, etc.).

The surfactant may be an emulsifying, dispersing or wetting agent of the ionic or non-ionic type, or a mixture of such surfactants. We can cite e.g. salts of polyacrylic acids, salts of lignosulfonic acids, salts of phenolsulfonic acids or naphthalenesulfonic acids, polycondensates of ethylene oxide to fatty alcohols or fatty acids or fatty amines, substituted phenols (in particular alkylphenols or arylphenols) salts of esters sulfonate phosphorylate, phosphaturate derivatives alcohols or phenols, fatty acid esters and polyols, derivatives of the preceding compounds with sulfate, sulfonate and phosphate functions. The presence of at least one surfactant is generally necessary when the compound and / or inert carrier is insoluble in water and the application vector is water.

Thus, the preparations for agricultural use according to the invention may contain the active substances of the invention within a very wide range from 0.05% to 95% by weight. Their surfactant content is preferably between 5% and 40% by weight.

These compositions of the invention are themselves in many different forms, solid or liquid.

Dust powders (containing up to 100% compound content) and granules, in particular those obtained by extrusion, by compacting, by impregnation of a granular carrier, by powder granulation (the content of the compound in these granules are this last case between 0.5 and 80%), compress or effervescent tablets.

The compounds of formula (I) may also be used in powder form; we can also use a preparation containing 50 g of active substance and 950 g of talc; a preparation containing 20 g of active substance, 10 g of finely divided SiO ₂ , 970 g of talc may also be used; these ingredients are mixed and ground and the mixture is applied by dusting.

The solutions, in particular water-soluble concentrates, emulsifiable concentrates, emulsions, concentrated suspensions, aerosols, wettable powders (or spray powder), pastes, gels, may be mentioned as forms of liquid preparations or forms intended for the preparation of liquid preparations for application.

Emulsifiable or soluble concentrates usually contain 10 to 80% of the active substance, and the emulsions or solutions prepared for administration alone contain 0.001 to 20% of the active substance.

In addition to the solvent, the emulsifiable concentrates may contain, where necessary, 2 to 20% of suitable additives, such as stabilizers, surfactants, penetration agents, corrosion inhibitors, colorants or adhesives, as previously mentioned.

From these concentrates, dilutions with water can provide emulsions of any desired concentration, which are particularly suitable for application to cultures.

As an example, we present the composition of some emulsifiable concentrates:

CE example 1:

- Active substance 400 g / l

- Alkali dodecylbenzenesulfonate 24 g / l

- oxyethylated nonylphenol with 10 ethylene oxide molecules 16 g / l

- cyclohexanone 200 g / l

- aromatic solvent q.s.p. 1 liter

In terms of the second composition of the emulsifiable concentrate, we use:

CE Case 2

- active substance

- epoxidized vegetable oil

a mixture of alkylarylsulfonate and

250 g 25 g polyglycoleter and fatty alcohols

- dimethylformamide

- xylene

100 g 50 g 575 g

Concentrated suspensions, also useful for spraying, are prepared to obtain a liquid, stable, non-settling product and typically contain from 10 to 75% of the active substance, from 0.5 to 15% of surfactants, from 0, 1 to 10% thixotropic agents, 0 to 10% suitable additives such as antifoaming agents and corrosion inhibitors, stabilizers, penetrating agents and adhesives, and as a carrier water or organic liquid in which the active substance is slightly soluble or insoluble: certain organic solids or mineral salts may be dissolved in the vehicle to aid in accelerating sedimentation or be water antigels.

An example is the preparation of a concentrated suspension.

Example SC 1:

- active substance 500 g

- polyethoxylated tristyrylphenolphosphate 50 g

- polyethoxylated alkylphenol 50 g

- sodium polycarboxylate 20 g

- Ethylene glycol 50 g

- Organopolysiloxane oil (antifoam) 1 g

- polysaccharide 1.5 g

-water 316.5 g

Wettable powders (or spray powder) are usually prepared to contain 20 to 95% of the active substance and typically contain, in addition to a solid carrier, from 0 to 30% of a wetting agent, from 3 to 20% of a dispersing agent, and from 0.1 to 10 if necessary. % of one or more stabilizers and / or other additives such as penetrating agents, adhesives or anti - caking agents, colorants, etc.

In order to obtain spray powders or wettable powders, the active substances are thoroughly mixed in suitable mixers with additional substances and milled with mills or other suitable crushers. This produces spray powders with a favorable wettability and ability to form a suspension; they can be suspended with water to any desired concentration, and these suspensions are very advantageous especially for application to vegetable leaves.

Pastes can be used instead of wettable powders. The conditions and methods for making and using these traps are similar to those for wettable powders or spray powders.

For example, various preparations of wettable powders (or spray powders) are cited.

Example PM 1

- active substance 50%

- ethoxylated fatty alcohol (wetting agent) 2,5%

- ethoxylated phenylethylphenol (dispersing agent) 5%

- chalk (inert carrier) 42.5%

Example PM 2:

- active substance 10%

- Synthetic branched-type oxo alcohol, 03 ethoxylated with 8 to 10 ethylene oxides (wetting agent) 0,75%

- calcium calcium lignosulfonate 12% (dispersant)

- calcium carbonate (inert filler) q.s.p. 100%

Example PM 3:

This wettable powder contains the same ingredients as in the previous example in the proportions below:

-active substance 75%

- wetting agent 1.5%

- dispersant 8%

- calcium carbonate (inert filler) q.s.p. 100%

Example PM 4:

- active substance

- ethoxylated fatty alcohol (wetting agent)

- ethoxylated phenylethylphenol (dispersing agent)

90%

4%

6%

Example PM 5:

- active substance

- mixture of anionic and nonionic surfactants (wetting agent)

- sodium lignosulfonate (dispersant)

- kaolin clay (inert carrier)

50%

2.5%

5%

42.5%

Aqueous dispersions and emulsions, e.g. preparations obtained by diluting the wettable powder or emulsifiable concentrate of the invention by means of water are encompassed within the general scope of the present invention. Emulsions can be water-in-oil or oil-inlet types and may have a dense consistency, such as mayonnaise consistency.

The compounds of the invention can be formulated in the form of dispersible granules in water, which is also covered by the invention.

These dispersible granules with a apparent density of generally between about 0.3 and 0.6 have a particle size generally of between about 150 and 2000 and preferably between 300 and 1500 μτη.

The active substance content of these granules is generally between about 1% and 90%, preferably between 25% and 90%.

The remainder of the granule consists essentially of a solid filler and, optionally, of surfactants that confer granularity on the granularity of the dispersibility in water. These granules can be essentially of two different types depending on whether or not the remaining filler is soluble in water. When the filler is soluble in water, it may be mineral or preferably organic. Excellent results were obtained with urea. In the case of insoluble filler, it is preferably a mineral such as e.g. kaolin or bentonite. Therefore, it is advantageously accompanied by surfactants (in an amount of 2 to 20% by weight of the granule), of which e.g. more than half consists of at least one dispersing agent, substantially anionic, such as an alkali or alkaline earth polynaphthalenesulfonate or alkali or alkaline earth alkali sulfonate. however, the remainder being non-ionic or ionic wetting agents, such as alkali or alkaline earth alkyl alkylnaphthalenesulfonate.

Otherwise, while not necessary, other adjuvants may be added as anti-penile agents.

The granules of the invention can be prepared by mixing the necessary ingredients, then granulating by various techniques known per se (irritation, fluidized cushion, spray, extrusion, etc.). We conclude generally by crushing followed by sieving to the particle dimension selected within the limits mentioned above. Granules obtained as before may also be used and then impregnated with a preparation containing the active substance.

They are preferably obtained by extrusion, working as indicated in the following examples.

GDI example: Dispersible granules

In the mixer, 90% by weight of active substance and 10% urea in pearls are mixed. The mixture is then ground in a crusher with plugs. A powder is obtained which is moistened with about 8% water. The wet powder is extruded in an extruder with a perforated cylinder. A granule is obtained which is dry, then crushed and sown so that only granules with a dimension between 150 and 2000 μπι are retained.

Example GD2: Dispersible granules

The following ingredients are mixed in the blender:

- active substance 75%

- wetting agent (sodium alkylnaphthalene sulfonate) 2%

- dispersant (sodium polynaphthalenesulfonate) 8%

- inert filler insoluble in water (kaolin) 15%

This mixture was granulated in a fluidized bed in the presence of water, then dried, crushed and sieved to give granules with a dimension between 0.15 and 0.80, um.

These granules can be used alone, in solution or dispersion in water, to obtain the desired dose. They can also be used to prepare combinations with other active substances, in particular fungicides, the latter being in the form of wettable powders or granules or aqueous suspensions.

As for preparations adapted for storage and transport, they preferably contain from 0.5 to 95% by weight of the active substance.

Claims (10)

Claims 1. Compounds which are derivatives of 2-midazolin-5-ones, of the general formula (I) in which it represents a hydrogen atom or a vinyl or allyl group or an alkyl or haloalkyl radical of 1 to 3 carbon atoms; or R _t and Ar ₂ -X-Ar _{1 may} further form the following variant with the carbon to which they are attached on the imidazolinone ring: in which the dot in the bold print represents the carbon of the imidazolinone ring of formula (I) to which the residues R _t and Ar are -X-Ar _v and m is 2, 3 or 4; is not 0 or 1; - Y represents an oxygen or sulfur atom; - R ₂ represents a hydrogen atom when n is 0 or an alkyl or haloalkyl group of 1 to 3 carbon atoms or a cyclopropyl group; - R ₃ represents an aryl or heteroaryl radical comprising a phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiazolyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, benzothiazolyl or methylene dioxytenyl residue, each of which is substituted by a substituent thereof. with 1 to 7 groups, preferably 1 to 3 groups selected from the meanings of R ₅ defined below; - R ₄ represents a hydrogen atom, a formyl or aroyl radical, an acyl radical of 2 to 6 carbon atoms, an alkoxycarbonyl radical of 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulfonyl radical, an alkylsulfonyl radical of 1 to 6 carbon atoms or an alkyloxyalkyl radical or an alkoxyalkyl radical or alkoxyalkyl radical 3 to 6 carbon atoms; - R ₅ represents a halogen atom or a hydroxy, mercapto, nitro, SF, cyano, thiocyanato or azido group; or - alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl or haloalkylsulfonyl radicals having 1 to 6 carbon atoms each; or - cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkinyloxy, alkenylthio, alkynylthio moieties having 3 to 6 carbon atoms each; or - an amino moiety optionally mono- or disubstituted by an alkyl or acyl radical having 1 to 6 carbon atoms or an alkoxycarbonyl radical having 2 to 6 carbon atoms; or - an alkoxycarbonyl group having 2 to 7 carbon atoms; or - an N-alkylcarbamoyl group having 2 to 7 carbon atoms; or - a Ν, dial-dialkylcarbamoyl group of 3 to 13 carbon atoms; - W represents O, S or SO; - Arj is a divalent moiety derived from an aryl or heteroaryl moiety comprising a phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl or methylenedioxyphenyl moiety, each of which is present in these case substituted with 1 to 6 groupings, preferably 1 to 3 groupings selected from the meanings of R _s ; - Ar ₂ represents a mono- or bicyclic system of 5 to 10 atoms which is aromatic, saturated or unsaturated, and which is either a carbocyclic system or a heterocyclic system containing 1 to 4 heteroatoms selected from O, S or N, and which comprises phenyl, naphthyl, tetrahydro-naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, indolyl, isoquinolinyl, methylenedioxyphenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxazolyl, oxazolyl , indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, naphthyridyl, quinoxazolyl, quinazolyl, cinnolyl or phthalazinyl residues, each of these residues being preferably 1 group with, if desired, substituents with 1, optionally substituted up to 3 groupings selected from the meanings of R ₅ ; - X represents a chain of the general formula (R) _f -A --- (R ') _k in which they are -j and k, equal or different, 0 or 1; - R and R ', same or different, represent a saturated or unsaturated hydrocarbon chain containing 1 to 6 carbon atoms, optionally substituted by 1 to 12 groups, preferably 1 to 3 groups selected from R defined below; and wherein one or more carbon atoms can be replaced by O, S, N (R ₆ ), wherein R _{6 is} defined below; - A represents O, S, N (R ₆ ), SO, SO ₂ , CO, CS, Si (R _g ) (R ' _s ), N ₂ C (R _W ) (R' _1O ), or Rio Rio 'or C = C wherein Z represents O, S, C (R ₁₁ ) (R' ₁₁ j; wherein R _g to R _{n are} defined below; - R ₆ represents a hydrogen atom or a cyano, hydroxy, amino, formyl, morpholino, piperidino, pyrrolidino, piperazine group, or - alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylsulfonyl, haloalkylsulfonyl, cyanoalkylsultonyl residue, each containing from 1 to 6 carbon atoms, or a monoalkylamino or dialkylamino residue, or - cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkinyloxy residues of 3 to 6 carbon atoms each; - or an acyl or alkoxycarbonyl residue having 2 to 6 carbon atoms each; or - a carbamoyl residue (optionally substituted by one or two alkyl radicals) of 1 to 7 carbon atoms or a sulfamoyl radical of 1 to 6 carbon atoms; or - an aryl or arylsulfonyl residue; or - an alkyloxalyl or alkoxyxalyl residue having 3 to 8 carbon atoms each; or - an oxamyl radical (optionally substituted with one or two alkyl radicals) having 2 to 8 carbon atoms; - R _? represents a halogen atom, cyano, thiocyanato, hydroxycarbonyl, amino (optionally substituted), hydroxyl, oxo, alkoxy, alkoxycarbonyl, haloalkoxy, alkoxyalkoxy, thiol, alkylthio, haloalkylthio, alkoxyalkylthio, acyloxy, alkyl, haloalkyl, alkyloxy, alkyloxy, alkyl heteroaroyloxy, aryloxyloxy, cycloalkylcarbonyloxy, acylthio, aroylthio, heteroaroiltio, arylcylthio, cycloalkylcarbonylthio, carbamoyloxy (optionally substituted), carbamoylthio (optionally substituted), thiocarbamoyloxy (optionally substituted, acylamino, substituted, optionally substituted, acylthiocarbamoyloxy (optionally substituted) cycloalkylcarbonylamino, aroylamino, ureido (optionally substituted), thioureido, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, aminosulfonylamino group (optionally substituted), being understood to be substituted by mice, optionally substituted substituted with 1 or 2 alkyl o stance, each aliphatic hydrocarbon moiety has from 1 to 4 carbon atoms and contains a cycloalkyl moiety from 3 to 7 carbon atoms; - R _K and R ' _K , the same or different, represent: an alkyl radical having 1 to 6 carbon atoms; or a cycloalkyl radical having from 3 to 7 carbon atoms; or an alkenyl, alkynyl radical having 2 to 6 carbon atoms; or an arylalkyl radical, preferably benzyl, or an aryl radical, optionally substituted, preferably phenyl, optionally substituted by 1 to 5 groups, preferably 1 to 3 groups selected from the meanings of R .; - R _y represents a hydrogen atom or a morpholino, piperidino, pyrrolidino, piperazine group; or an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio moiety of 1 to 6 carbon atoms or a dialkylamino containing 2 to 6 carbon atoms; - R ₁₀ and R ' _w , the same or different, represent a hydrogen atom or an alkoxy group of 1 to 6 carbon atoms or R _? ; - R _n and R ', the same or different, represent a hydrogen atom or a halogen or alkyl group of 1 to 3 carbon atoms; as well as salt-form compounds and enantiomers and stereoisomers of these compounds, in particular both enantiomers of each of these compounds, corresponding to the asymmetric carbon of the imidazolinone ring bearing R1, with the exception of compounds to which: - when (Y) -R represents methylthio, methyl or ethyl, the Ar ₂ -X-Ar 1 phenoxyphenyl group optionally substituted; - when (Y) _n -R ₂ represents methoxy, when R _{t is} methyl, when R ₃ represents a phenyl or pyridyl radical optionally substituted by a fluorine atom or a methyl group, when R _{4 is} hydrogen and when W represents an oxygen atom, then Ατ ^ Χ-Αη represents either a 4-phenoxyphenyl group optionally substituted on the phenoxy moiety by 1 or 2 fluorine atoms or a 3-phenoxyphenyl group; and with the exception of the compound of formula CH-> 0 ' Compounds according to claim 1, characterized in that - Ar _(represents a divalent radical derived from phenyl, Natta, thienyl, pyridyl, benzothienyl, quinolinyl, wherein each of these moieties are optionally substituted with 1 to 3 is a group selected from the meanings of R _$; - Ar ₂ represents a phenyl, naphthyl, thienyl, pyridyl, benzothienyl, thiazolyl, benzothiazolyl, pyrimidyl radical, each of which is optionally substituted by 1 to 3 groupings selected from the meanings of R _y Compounds according to one of claims 1 or 2, characterized in that Ar represents a divalent radical derived from phenyl, thienyl, pyridyl which is optionally substituted by 1 to 3 groups selected from a halogen atom, an alkyl or haloalkyl radical; - Ar ₂ represents a phenyl, naphthyl, pyridyl, benzothiazolyl residue optionally substituted by 1 to 3 groups selected from a halogen atom, an alkyl or haloalkyl radical; - X represents a chain of the general formula (R) _r -A- (R ') _k · in which -R and R ', the same or different, represent a carbon chain of 1 to 3 carbon atoms, preferably a methylene group, in which one carbon atom is optionally substituted by O or NH and optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxyl group, an oxo group or a C 1 -C alkyl radical; - A is O, S, SO, SO ?, CO, C (Rio) (R'io)> ^R ic ^R io or wherein - R ₁₀ and R ₁₀ is the same or different hydrogen atom, halogen atom, hydroxyl, C 1 -C ₆ alkyl or C 1 -C ₃ alkoxy radical; ΰ - Z represents O or C (R ₁₁ ) (R ' _[[] ), and R _u and R' _{H are the} same or different, a hydrogen or chlorine atom. Compounds according to one of claims 1 to 3, characterized in that they correspond to the formula I, wherein at the same time - R [methyl residue; - R _{2 is a} methyl or ethyl residue; - R ₃ represents a phenyl or pyridyl radical; - R ₄ is a hydrogen atom or a formyl radical; - R ₅ is a halogen atom or a C 1 -C ₃ alkyl or C 1 -C ₃ haloalkyl residue; and - W is an oxygen atom. A process for the preparation of compounds of formula (I) according to claim 1, wherein R _{4 is} other than a hydrogen atom, characterized in that the compounds of formula (Ia) are reacted with a compound of formula R ₄ L 'in the presence of a base and a solvent medium according to the scheme Arj-X “ΑΓ] where - R ₄ represents a formyl radical, an acyl group of 2 to 6 carbon atoms, an aroyl, alkoxycarbonyl group of 2 to 6 carbon atoms, an aryloxycarbonyl, alkylsulfonyl, arylsulfonyl group or an alkyloxalyl radical or an alkoxyxalyl radical of 3 to 6 carbon atoms; - L 'represents a halogen atom, preferably chlorine, bromine or iodine, a sulfate group, an aryloxy or arylthio moiety, optionally substituted, preferably a phenoxy, alkoxy or dialkylamino moiety, a R ₄ O group when R _{4 is} an acyl or arylsulfonyl or alkylsulfonyl group . 6. The method of claim 5, characterized in that a strong base is used as the base. as an alkali or alkaline earth hydride or hydroxide, alcoholate or tert.amine, the reaction being carried out at a temperature between -30 ° C and + 50 ° C, and the solvent is selected from cyclic or non-cyclic ethers, dimethylformamide, dimethylsulfoxide, acetonitrile or an aromatic solvent. A process for the preparation of compounds of formula (II), characterized in that S-alkylates 2-thiohydantoins of formula (III) in the presence of a base and in a solvent according to the scheme: Rj-L '(III) base solvent Ri. N Ar j — X— Ar N, 'NH - R ₃ V / '(II) S - R Where R _p R ₂ , R ₃ , Ar _p Ar ₂ , X is as defined in claim 1, W represents S or O and L represents a group selected from a halogen atom (preferably chlorine, bromine or iodine) or sulfate, alkylsulfonyloxy or arylsulfonyloxy groups. A process for the preparation of compounds of formula (Ha), characterized in that it is allowed to react sequentially in the presence of a solvent of a compound of formula (VII) with hydrazine of formula R ₃ -NH-NH ₂ , then with a base of formula B * M ⁺ and finally with an alkylating agent of the formula R ₂ L according to the scheme: o * (Ha) where R ,, R ,, R _r Ar ,, Ar ₂ , X are defined as in claim 1, with the restriction that R _{2 is} other than a hydrogen atom, R ₍₇ represents C 1 -C ₃ alkyl the residue and L is a halogen atom or an alkylsulfate, alkylsulfonyloxy or arylsulfonyloxy group. Process according to claim 8, characterized in that the base is selected from alkali or alkaline earth alkali, alkali or alkaline earth hydroxide or tert.amine and the reaction is carried out at a temperature of -10 ° C to + 80 ° C and in a solvent selected especially from cyclic or non-cyclic ether, alcohol, ester, DMF, DMSO, acetonitrile or aromatic solvent. A process for the preparation of compounds of formula (XI), characterized in that 2-alkylthio-2-imidazolin-5-ones of formula (II) are reacted with a R ₂ OH alcohol in the presence of a strong base and in a solvent according to the invention. scheme