SK21595A3 - 2-imidazolin-5-on derivatives, method of their preparation and fungicidal agents containing these derivatives - 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

2-Imidazolin-5-one derivatives, processes for their preparation and fungicidal compositions containing them

Technical field

The invention relates to novel compounds with a 2-imidazolin-5-one group which are useful for phytosanitary application. The invention also relates to a process for the preparation of these compounds and products which may optionally be used as intermediates in these processes. Finally, the invention relates to fungicidal compositions based on these compounds and methods for controlling fungal diseases of crop plants using said compounds.

Previous startechtech

European Patent Application EP 0 551048 and International Patent Applications WO 93/24467 and WO 94 / 014.10 disclose 2-imidazolin-5-ones which are useful for phytosanitary applications.

It is an object of the present invention to provide novel compounds containing a 2-imidazolin-5-one group that have improved properties in the treatment of fungal crop diseases.

Another object of the invention is to provide compounds which also have an improved spectrum of application in the field of fungal diseases and which can be used in particular for combating fungal diseases of rice and combating wheat rust.

It has now been found that said objects can be achieved wholly or at least in part by means of the products according to the invention as defined in the following part of the description.

SUMMARY OF THE INVENTION

In particular, the present invention provides compounds which are 2-imidazolin-5-one derivatives of formula I * 1

ΑΓ2 — X ~ Ar i

In which

R _x represents a hydrogen atom or a vinyl group or an allyl group or an alkyl or haloalkyl group, each containing 1 to 3 carbon atoms, or else

In addition, R _x and Ar _of -X-Ar ₁ may form, with the carbon atom to which they are attached and which is part of the imidazoline ring, a group of the formula

wherein the bold printed dot is the carbon atom of the imidazoline ring of formula I, to which they are attached the group R _x and Ατ -Χ _2-Ατ χ m represents 2, 3 or 4, n is 0 or 1,

Y represents an oxygen atom or a sulfur atom,

R ^ represents a hydrogen atom when n is equal to 0 or an alkyl or haloalkyl group each containing 1 to 3 carbon atoms, or a cyclopropyl group,

R ₃ represents an aryl or heteroaryl group comprising a phenyl group, a naphthyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group, a benzothenyl group, a benzofuryl group, a quinolinyl group, an isoquinolinyl group, a benzothiazolyl group, benzothiazolyl group these groups being optionally substituted with 1 to 7 groups, preferably 1 to 3 groups, selected from the following definitions of the general formula R,

R _a represents a hydrogen atom, a formyl group or an aroyl group, an acyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulfonyl group, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkyloxyxalyl group or up to 6 carbon atoms.

R is

-halogen, hydroxy, mercapto, nitro, SF _a, cyano, thiocyanato ^ ski-pin or azido group or an alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyl, haloalkylsulfinyl or haloalkylsulfonyl, each containing 1 to 6 carbon atoms, or

-cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio, each of which contains 3 to 6 carbon atoms, or -amino, which is optionally mono- or a disubstituted C 1 -C 6 alkyl or acyl group or a C 2 -C 6 alkoxycarbonyl group, or a C 2 -C 7 alkoxycarbonyl group or a C 2 -C 7 -alkylcarbamoyl group, or

-Ν, Ν-dialkylcarbamoyl of 3 to 13 carbon atoms,

W represents an oxygen atom, a sulfur atom or a SO group,

Ατ _χ means a divalent group which is derived from an aryl or heteroaryl group including a phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl or isoquinolinyl group, , each of which is optionally substituted with 1-6 groups, preferably 1 to 3 groups which are selected from the meanings of _R,

Ar ₂ represents a mono- or bicyclic system containing 5 to 10 carbon 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 oxygen, sulfur or nitrogen, wherein: this system includes phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indanyl, indolyl, quinolinyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinoline , pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, benzimidazolyl, indazolyl, benzoxazolyl nu, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, naphthyridyl, quinoxazolyl, quinazolyl, cinnolyl or optionally phthalazinyl groups, each of which is optionally substituted with 1 to 7; preferably 1 to 3 groups which are selected from the meanings of _R,

X is a group of formula

- A - (R ') _x wherein both, which are the same or different, represent 0 or 1,

R and R ', which are the same or different, represent a saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms, which is optionally substituted with 1 to 12, preferably 1 to 3, groups selected from the following definitions of R _? and wherein one or more carbon atoms may be replaced by an oxygen atom, a sulfur atom or an N (R _e ) group, wherein R _e is as defined below,

A means 0, S, N (R), SO, SO, CO, CS, Si, R (R '), N, β 2 S β 2

C (R) (R ') or' 10O '' 10O '

where

Z is O, S, ^C ( ^R 11) ^R 11) ^and

R _a through R are as defined below,

R is

-hydrogen, cyano, hydroxy, amino, formyl, morpholino, piperidino, pyrrolidino, piperazino, or

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

-monoalkylamino or dialkylamino or -cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy each containing 3 to 6 carbon atoms, or

-acyl or alkoxycarbonyl each of 2 to 6 carbon atoms, or -carbamoyl of 1 to 7 carbon atoms optionally substituted by one or two alkyl groups, or sulfamoyl of 1 to 6 carbon atoms, or

-aroyl or arylsulfonyl or -alkyloxalyl or alkoxyoxalyl, each containing 3 to 8 carbon atoms, or -oxamyl having 2 to 8 carbon atoms, optionally substituted by one or two alkyl groups,

R ₇ is halogen, cyano, thiocyanato, hydroxycarbonyl, optionally substituted amino, hydroxyl, oxo, alkoxy, alkoxycarbonyl, haloalkoxy, alkoxyalkoxy, thiol, alkylthio, haloalkylthio, alkoxyalkylthio, acyloxy, alkyl, haloalkyl, alkoxyalkyl, alkylidene, aroyloxy, heteroaroyloxy, arylacyloxy, cycloalkylcarbonyloxy, heteroylthio, aro, thio, arylacylthio, cycloalkylcarbonylthio, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted dithiocarbamoyl, acylamino, cycloalkylcarbonylamino, aroylamino, ureido, optionally substituted, thioureido, aryloxycarbonylamino a group, an alkylsulfonylamino group, an arylsulfonylamino group or an optionally substituted aminosulfonylamino group, where substitution is to be understood as meaning groups optionally substituted by one or two alkyl groups, each aliphatic hydrocarbon group containing 1 to 4 carbon atoms and the cycloalkyl group containing 3 up to 7 carbon atoms,

R _a and R _a , which are the same or different, mean

-alkyl of 1 to 6 carbon atoms or -cycloalkyl of 3 to 7 carbon atoms, or

an alkenyl or alkynyl group each containing 2 to 6 carbon atoms, or

an aralkyl group, preferably a benzyl group, or an optionally substituted aryl group, preferably a phenyl group optionally substituted with 1 to 5, preferably 1 to 3, groups selected from R _s , R is

-hydrogen, morpholino, piperidino, pyrrolidino, piperazino or

-alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, each containing 1 to 6 carbon atoms, or a 2-dialkylamino group up to 6 carbon atoms,

R and R ', which are the same or different, represent a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms or R, ^r

R and R ', which are the same or different, represent a radical of XX XX ⁹ or a halogen atom or an alkyl group containing 1 to 3 carbon atoms, as well as the salts and enantiomers and stereoisomers of these compounds, in particular the 2 enantiomers of each of them the asymmetric carbon of the imidazole ring bearing R, except for compounds to which:

- when (Y) - R ₂ is methylthio, methyl or ethyl, 2 R 5 _and -X-Ar _x is optionally substituted phenoxyphenyl,

-when it represents a methoxy group, when R _x represents a methyl group, when R _a represents a phenyl group or a pyridyl group optionally substituted by a fluorine atom or a methyl group, when R 6 represents a hydrogen atom and when w represents an oxygen atom, then Ατ ₂ -Χ- Ατ _χ means either a 4-phenoxyphenyl group optionally substituted on the phenoxy residue of 1 or 2 fluorine atoms or a 3-phenoxyphenyl group, and with the exception of a compound of the formula

As used herein, generic terms alkyl, acyl, and aroyl have the following meanings:

-alkyl means a linear or branched aliphatic group,

-acyl group means

an alkylcarbonyl or haloalkylcarbonyl group; or

an alkoxyalkylcarbonyl group or an alkylthioalkylcarbonyl group, or

an alkenylcarbonyl group; or

an alkynylcarbonyl group; or

-cycloalkylcarbonyl or halocycloalkylcarbonyl; and

-aroyl means an arylcarbonyl group, wherein the aryl group has the same meanings as indicated for Ar ₂ and is optionally substituted with R 2.

WITH

Preferred compounds of the invention are those compounds of formula I wherein:

Ατ _χ denotes a bivalent group derived from phenyl, naphthyl, thienyl, pyridyl, benzothienyl, quinolinyl, each of which is optionally substituted with 1 to 3 groups selected from ^R _S 'and

Ar ₂ is phenyl, naphthyl, thienyl, pyridyl, benzothienyl, thiazolyl, benzothiazolyl, pyrimidyl, each of which is optionally substituted with 1 to 3 groups selected from the meanings of R _p ·

Particularly important compounds of the invention are those compounds of formula I wherein:

Ατ _χ represents a bivalent group derived from a phenyl group, a thienyl group, a pyridyl group, each of which is preferably substituted by 1 to 3 groups selected from the group consisting of halogen, alkyl and haloalkyl,

Ar ₂ represents a phenyl group, a naphthyl group, a pyridyl group, a benzothienyl group, a benzothiazolyl group, each of which is optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl and haloalkyl,

X represents a group of the above general formula in which

R and R ', which are the same or different, represent a carbon chain of 1 to 3 carbon atoms, preferably a methylene group in which the carbon atom is optionally replaced by an oxygen atom or an NH group and which is optionally substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a hydroxyl group, a οχο group and an alkyl group having 1 to 3 carbon atoms A is O, S, SO, SO ₂ , CO, C (R ₁₀ ) (R ₁₀ ),

K io * 10 ´ —e = c -

where

R _xo and R ', which are the same or different, represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms,

Z is O or C (R _xx) (R _×) t wherein

R and R 'which are the same or different represent a hydrogen atom or a chromium atom.

Particularly preferred compounds of the invention, the end compound of formula I wherein both R _x is methyl,

R _a represents a methyl group or an ethyl group,

R ₃ represents a phenyl group or a pyridyl group, represents a hydrogen atom or a formyl group,

_R is halogen, alkyl of 1 to 3 carbon atoms or haloalkyl having 1 to 3 carbon atoms, and

W represents an oxygen atom.

The compounds of formula I are prepared by the following methods. All groups which are listed in the following chemical formulas and which have already been defined in relation to the general formula (I) retain the same meaning unless expressly stated otherwise. In the general description of the methods for preparing the compounds of formula I, the conditions are generally used: it should be noted that conditions other than those mentioned herein may be used, depending, for example, on the specific reactants used.

The chemical structures of all products illustrating these preparation methods have been verified by at least one of spectral techniques selected from the group consisting of proton nuclear magnetic resonance spectroscopy, ¹³ C-nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.

In the tables that describe these products, the following abbreviations are used for the methyl, ethyl, propyl, pyridyl, pyrimidyl, acetyl, phenyl and benzyl groups to define the meanings of the groups of the formula: Me, ET, Pr, Py, Pyrim, Ac, Ph resp. . Bn.

Compounds of formula I in which they are not hydrogen are prepared from compounds of formula Ia by reaction with a compound of formula R 1 ', in the presence of a base and in a solvent according to the following reaction scheme:

In this reaction scheme

R represents a formyl group, an acyl group having 2 to 4 carbon atoms, an aroyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, an aryloxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group or an alkyloxalyl or alkoxyoxalyl group having 3 to 6 carbon atoms,

L 1 represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, a sulphate group, an optionally substituted aryloxy or arylthio group, preferably a phenoxy group, an alkoxy group or a dialkylamino group, or R ₄₀ when R 6 represents acyl arylsulfonyl or alkylsulfonyl.

The base used is a strong base such as an alkali or alkaline earth metal hydride or hydroxide, an alkoxide or a tertiary amine. The reaction is carried out at a temperature between -30 to 50 C. The solvent is selected from the group consisting of cyclic or non-cyclic ethers, dimethylformamide, dimethylsulfoxide, acetonitrile or an aromatic solvent.

The compounds of formula (Ia) can be prepared in two ways.

First, a first process for the preparation of compounds of formula Ia is described, wherein the imidazolinone ring is formed from intermediates containing the group Ar 1 -X-Ar 1. This first process for the preparation of the compounds of the invention corresponds to processes A, B, C and D described below.

Preparation of compounds of formula Ia in which n = 1 a

Y = S

Method A

Compounds of formula Ia in which n = 1α-SaW = S or O, otherwise referred to as compounds of formula II, are prepared by one of the methods 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

solvent base

(Π) wherein L represents a group selected from the group consisting of a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, or an alkylsulfate, alkylsulfonyloxy or arylsulfonyloxy group. The base used is a strong base such as an alkali metal or alkaline earth metal alkoxide, preferably potassium tert-butoxide, alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate or tertiary amine. The solvent used is a cyclic or non-cyclic ether, an alkyl ester, acetonitrile, an alcohol containing 1 to 4 carbon atoms, a chlorinated solvent or an aromatic solvent. Preferably, tetrahydrofuran is used as the solvent. The reaction is carried out at a temperature between -5 and 80 ° C.

The following example illustrates this method.

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 a solution of 5 g (0.012 mol) of (4-R, S) -4-methyl-1-phenylamino

Of 4- (4- (2-phenylethyl) phenyl) imidazoline-2,5-dithione in 150 ml of tetrahydrofuran at 0 ° C was added 1.36 g (0.012 mol) of potassium tert-butoxide. After stirring at this temperature for 15 minutes, 1.5 ml (0.024 mol) of methyl iodide was added. Stirring is continued at 0 ° C for 30 minutes, then the temperature of the reaction mixture is allowed to rise to ambient temperature and the reaction mixture is hydrolyzed and then extracted with methylene chloride. After washing the organic extracts with saturated sodium chloride solution, decanting, drying and evaporating the solvents, a chestnut-brown oil is obtained. This oil was crystallized from a mixture of diisopropyl ether and pentane. After filtration, 2.7 g (0.006 mol) of (4-5, S) -4-methyl-2-methylthio-1-phenylamino-4- (4- (2-phenylethyl) phenyl) -2-imidazoline-5- is obtained. thion in the form of a chestnut brown powder.

Melting point: 118 ° C, yield: 49%.

The preparation of a compound of formula III in which E is S (compound of formula IIIa) or 0 (compound of formula IIIb) is now described.

Preparation of Compound of Formula IIIa

The dithiohydantoins of formula IIIa are obtained from a compound of formula IV by a procedure analogous to that described by T. Yamamoto et al. in J. Chem. Soc.Perkin Trans I (1990, pp. 3003-3009), i. j. by reaction:

(IV)

The following example illustrates the preparation of the compound of formula IIIa.

Example CI1

Preparation of (4-R, S) -4-methyl-1-phenylamino-4- (4- (2-phenylethyl) phenyl) -2-imidazolidine-2,5-dithione of the structural formula:

Η

To 22.6 g (0.0066 mol) of (4-R, S) -4-methyl-4- (4- (2-phenylethyl) phenyl) thiazolidine-2,5-dithione in 100 ml of toluene is added 6, 7 ml (0.066 mol) of phenylhydrazine. The reaction mixture was gradually heated to 60 ° C and then to reflux until gas evolution ceased. After cooling the reaction mixture, hydrolysis is carried out, followed by extraction with ethyl acetate. After decanting and drying the organic phase, the solvents were evaporated to give a black oil. After chromatography on a silica gel column using a 50:50 mixture of ethyl acetate and heptane, 11.2 g (0.027 mol) of (4-R, S) -4-methyl-1-phenylamino-4- ( 4- (2-Phenylethyl) phenyl) imidazolidine-2,5-dithione as a chestnut-brown powder.

Melting point: 171 ° C, yield: 41%.

The thiazolidine-2,5-dithiones of formula IV are obtained from the isothiocyanate of formula V by a procedure analogous to that described by T. Yamamoto et al. in J. Chem.Soc. Perkin Trans I (1990), p. 2459 to 2463, i. j. by reaction:

The following example illustrates the preparation of a compound of formula IV.

Example CI2

Preparation of (4-R, S) -4-methyl-4- (4- (2-phenylethyl) phenyl) thiazolidine-2,5-dithione of the structural formula:

To 9.5 g (0.084 mol) of potassium tert-butoxide, which was introduced into 150 ml of tetrahydrofuran at -70 ° C. a solution of 7 ml (0.11 mol) of carbon disulfide and 20.4 (0.076 mol) of 1- [4- (2-phenylethyl) phenyl] ethylisothiocyanate in 50 ml of tetrahydrofuran is slowly added. After stirring at -70 ° C for 15 minutes, the mixture was allowed to warm to ambient temperature. Hydrolysis of the reaction mixture with aqueous acetic acid, extraction with ethyl acetate, decantation, drying of the organic extracts and evaporation of the solvents gave 22.6 g (0.065 mol) of (4-R, S) -4-methyl-4- (4- (2- phenylethyl) phenyl) thiazolidine-2,5-dithione as an oil.

Yield of crude product: 86%.

The isothiocyanate of formula (V) is prepared from an amine of formula (VI) in which the substituents have the same meanings as in formula (v) by any of the methods described in Sulfur Reports (1989), vol. 8 (5), p. 327-375, t. j. by reaction:

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

Example CI3

Preparation of 1- [4- (2-phenylethyl) phenyl] ethylisothiocyanate of structural formula

To a suspension of 20 g (0.076 mol) of 1- (4- (2-phenylethyl) phenyl) ethylamine hydrochloride in 200 toluene at 0 ° C was added 1 equivalent of sodium bicarbonate as an aqueous solution. After warming the reaction mixture to ambient temperature, 2 equivalents of sodium bicarbonate are added as an aqueous solution. 6.1 ml (0.076 mol) of thiophosgene in solution in 10 ml of toluene are then slowly added. After the addition was complete, stirring was continued for 15 minutes. After decantation, the organic extracts are washed with water, dried and then evaporated. There was thus obtained 1- [4- (2-phenylethyl) phenyl] ethylisothiocyanate (20.5 g, 0.076 mol) as an oil.

Yield: 100%.

Preparation of Compound of Formula IIIb

The 2-thiohydantoins of formula IIIb, i.e. compounds of formula III in which W represents an oxygen atom, are obtained by the procedure described in European patent application EP 0 551 048, ie by cyclization reaction of isothiocyanates of formula VII with hydrazines of formula R ₃ -NH-NH ₂ according to the following reaction scheme:

wherein R _e represents an alkyl group having 1 to 3 carbon atoms.

This cyclization can be carried out in two ways.

In the first of these methods, the mixture of reactants is heated to a temperature between 110 and 180 ° C in an aromatic solvent such as toluene, xylene, chlorobenzenes or nitrobenzene.

The latter cyclization process is carried out in the presence of a strong base, such as an alkali metal or alkaline earth metal alkoxide, an alkali metal or alkaline earth metal hydroxide or a tertiary amine, at a temperature between -10 and 80 ° C and in a solvent selected in particular from the group consisting of ether, cyclic ether, alcohol, ester, dimethylformamide or dimethylsulfoxide.

The preparation of the compound of formula IIIb is illustrated by the following example.

Example CI3 '

Preparation of (5-R, S) -5-methyl-3-phenylamino-5 - ((4-phenylthio) phenyl)

2-thiooxoimidazolidin-4-one structural formula

H

8.48 g (0.0258 mol) of (2-R, S) -methyl-2-isocyanato-2 - ((4-phenylthio) phenyl) propanoate are dissolved in 250 ml of tetrahydrofuran. 2.78 g (0.0258 mol) of phenylhydrazine are then added dropwise to the obtained solution. The reaction mixture was stirred for 30 minutes at ambient temperature, then poured into water and extracted with ether. After drying over magnesium sulfate, the ether is stripped to give 11.46 g of an oil which crystallizes. The crude reaction product was mixed with ether, filtered and recrystallized to give 3.36 g (0.0082 mol) of (5-R, S) -5-methyl-3-phenylamino-5 ((4-phenylthio) phenyl) -2-thiooxoimidazolidin-4-one in the form of pink crystals.

M.p .: 158 ° C, yield: 34%.

The alpha-isothiocyanatoesters of formula VII are prepared from the alpha-amino acid esters of formula VIII, in which the general groups have the same meanings as in formula VII, according to one of the methods described in Supfur Reports (1989, vol. 8 (5), p. 327-375), ie by reaction:

(VII) (VII)

The following example illustrates the preparation of a compound of formula VII

Example CI4

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

To a stirred solution of sodium bicarbonate (84.2 g, 1.002 mol) in water (800 ml) was added (R, S) methyl (4-benzyloxyphenyl) methylglycinate (143 g, 0.501 mol) followed by toluene (800 ml), then dropwise at RT. ambient temperature and during

Add 1.5 ml (0.526 mol) of thiophosgene for 1.5 hours while controlling gas evolution. After stirring for 2 hours at ambient temperature, decanting the aqueous phase, washing with water, drying over magnesium sulfate and concentrating the organic phase, 155.4 g (0.475 mol) of (2-R, S) -methyl-2- (4-benzyloxyphenyl) - is isolated. 2-isothiocyanatopropanoate in the form of a very dense oil.

Yield: 95%.

By proceeding in an analogous manner, the following compounds of formula VII are obtained

ABOUT

R ' R E R X yield T.t.'C) 4-BnO Me Me 62 honey 4-OBn Me Me 50% honey 4-PhS Me Me 96% honey 4-PhSO Me Me 100% honey 4-PhSO 2 Me Me 85% honey 3-BnO Me Me 80% honey

The alpha-axninoesters of formula VII are obtained by esterifying the alpha-amino acids of formula IX in which the groups have the same meanings as in formula VIII with an alcohol of formula R _E OH in the presence of thionyl chloride according to the literature described by M. Brenner and W. Huber in Helv. (1953), Vol. 36, p. 1109, ie according to the reaction scheme:

Arj —X -

Ar

. 0 (IX)

statue

REOH

(VIII)

The following example illustrates the preparation of compounds of formula VIII

Example CI5

Preparation of (R, S) -methyl 2- (4-benzyloxyphenyl) -2-methylglycinate

To a stirred suspension of (R, S) -2- (4-benzyloxyphenyl) -2-methylglycine (38.55 g, 0.142 mol) in methanol (400 ml) maintained at -20 ° C was added thionyl chloride (33.8 g, 0.284 mol) in succession. Upon completion of the addition, the temperature of the reaction mixture was allowed to rise to ambient temperature and the solution was then heated to reflux for 16 hours. After concentration, the residue is taken up in water and the solution obtained is basified with concentrated aqueous sodium hydroxide solution to a pH of 8. The precipitate is filtered off, washed with water, centrifuged and dried under vacuum. After chromatography on 400 g of silica gel, eluting with a 30:70 mixture of heptane and ethyl acetate and concentrating the product fractions under reduced pressure, the product is isolated.

14.7 g (0.0515 mol) of (R, S) -methyl 2- (4-benzyloxyphenyl) -2-methylglycinate as a white powder.

Melting point: 67 DEG C. Yield: 36%.

The synthesized compounds of formula VIII are summarized in the following table

R ' R 1 R E yield Melting point (° C), n 4-BnO Me Me 36% 68 ° C 4-OBn Me Me 95% 112-116 ° C 4-PhS Me Me 66% 1.6058 3-PhSO Me Me 35% 50 ° C

An alternative preparation of some alpha-aminoesters of formula VIII, namely those in which X is -S (O) _n , and which correspond to formula VIIIb, will now be described.

The alpha-amino esters of formula VIIIb are obtained by oxidation of the alpha-aminoesters of formula VIIIa by the procedures described in Advanced Organic Chemistry, J.March (1985), p. 1089 and 1090, 3rd edition, i. according to the following reaction scheme:

(VlIIa) (VlIIb)

In this reaction scheme, n is equal to 1 or 2 and R _e is as defined in formula VII.

The following examples illustrate the preparation of compounds of Formula IIIb.

Example CI6

Preparation of (R, S) -methyl-2-amino-2 - ((4-phenylsulfinyl) phenyl) propionate Structural Formula

II 0

17.22 g (0.06 mol) of methyl 2-amino-2 - ((4-phenylthio) phenyl) propionate are introduced into 350 ml of dichloromethane and the mixture is cooled to 0 ° C. over a period of about 10 minutes

14.1 g (0.06 mol) of 73% metachloroperbenzoic acid. The reaction mixture was then stirred for 2 hours at 0 ° C. The precipitate is filtered off and the organic phase is washed with normal sodium hydroxide solution and then with water and dried over magnesium sulphate. Evaporation gave 15 g of an oil which was chromatographed on silica gel using ethyl acetate to give 11.3 (0.037 mol) of (R, S) - (methyl-2-amino-2 - (( 4-phenylsulfinyl) phenyl] propionate in the form of a pale yellow oil.

_n = 1.5979 at 25 DEG C., Yield: 62%.

Example CI7

Preparation of (R, S) -methyl-2-amino-2 - ((4-phenylsulfonyl) phenyl) propionate Structural Formula

NH-

21.52 g (0.075 mol) of (R, S) -methyl-2-amino-2 - ((4-phenylthio) phenyl) propionate are introduced into 400 ml of methanol and the resulting mixture is cooled to 0 ° C. and at 0 ° C add 50.12 g (0.163 mol) at 0 ° C.

A 49.5% solution of potassium persulfate in 400 ml of water. The reaction mixture is then stirred for 5 hours at ambient temperature. The remaining oxidizing agent was quenched with 5 ml of 30% sodium bisulfite solution. The pH of the reaction mixture is adjusted to about 8 by addition of 20 g of sodium carbonate, then the solid is filtered off. After stirring the solid in 500 ml of dichloromethane and filtering off the solid residue, the filtrate was dried and the solvent was evaporated to give 16.9 g (0.529 mol) of (R, S) -methyl-2-amino-2 - ((4-phenylsulfonyl)). Phenyl] propionate in the form of white crystals.

Melting point: 124 ° C, yield: 70%.

The alpha-amino acids of formula IX are obtained by hydrolysis of the corresponding hydantoins of formula X in an acidic or basic medium by a method analogous to that described in the Dutch patent NE 69 00349 or in J. Org. (1985) Vol. 50, pp. 1876-1878, i. according to the reaction scheme:

The following example illustrates the preparation of compounds of Formula IX.

Example CI8

Preparation of (4-R, S) -2- (4-benzyloxyphenyl) -2-methylglycine

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-methylhydantoin, and the resulting suspension was it is then heated to reflux for 24 hours. After cooling, the reaction mixture is neutralized with aqueous concentrated hydrochloric acid, then the suspension is diluted with 100 ml of water. The precipitate is filtered off, washed with water and then with acetone, centrifuged and dried under vacuum. 16.2 g of (R, S) -2- (4-benzyloxyphenyl) -2-methylglycine (87 mol%, as determined by nuclear magnetic resonance spectroscopy) are thus isolated in the form of a white powder.

Melting point: greater than 300 C. C.

The synthesized alpha-amino acids of formula IX are summarized in the following table.

R ' R 1 yield MP: (° C) 4- (3-pyridyloxy) Me 96% > 300 ° C 4-BnO Me 42% > 300 ° C 4-OBn Me 100% > 300 ° C 4-PhS Me 100% ≫ 300 ° C 3-BnO Me 100% 270 ° C 3-PhS Me 100% > 300 ° C

The hydantoins of formula X are obtained by the Bucherer-Berg reaction starting from the corresponding acetophenones as described in Chem. Rev. (1950), Vol. 46, p. 422-425 or Chem.Pharm.Bull. (1973), Vol. 21, pp.685-691. These acetophenones can be readily prepared by one skilled in the art.

Method B

According to a preferred embodiment, the compounds according to the invention of formula II in which W represents an oxygen atom, otherwise referred to as compounds of formula IIa, are prepared by successive reaction of a compound of formula VII with a 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 1 L, in which La R _a is as defined above, with the restriction that R ₂ is different from hydrogen. The base is selected from the group consisting of an alkali metal or alkaline earth metal alkoxide, an alkali metal or alkaline earth metal hydroxide, and a tertiary amide. The reaction is carried out at a temperature between -10 and 80 ° C and in a solvent selected in particular from cyclic or non-cyclic ether, alcohol, ester, dimethylformamide, dimethylsulfoxide, acetonitrile and aromatic solvents. The preparation is carried out according to the following reaction scheme:

(Wine

(IIa)

The following example illustrates the preparation of compounds of Formula IIIa.

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 (2-R, S) -methyl 2- (4-phenylthiophenyl) -2-isothiocyanatopropanoate (5 g, 0.015 mol) in anhydrous tetrahydrofuran (120 ml) was added phenylhydrazine (1.62 g, 0.015 mol) under nitrogen. The mixture was allowed to react for one hour at ambient temperature, then cooled to 0 ° C. 1.68 g (0.015 mol) of potassium tert-butoxide are added, the mixture is left to react for 0.25 h, then 2.13 g (0.015 mol) of methyl iodide are added. The temperature of the reaction mixture was allowed to rise to ambient temperature and stirred at this temperature for 3 hours. The reaction mixture is then poured into 100 ml of water and then the product is extracted with ethyl acetate. After washing with water, drying over magnesium sulphate and concentrating the organic phase, 7.4 g of the honey product are isolated, which is dissolved in 30 ml of diisopropyl ether. The product precipitates at 5 ° C, then, after filtration and drying under reduced pressure, 4.8 g (76%) of (4-R, S) -4-methyl-2-methylthio-4- (4-phenylthiophenyl) is obtained. -1-phenylamino-2-imidazolin-5-one (Compound No. 25) in the form of beige crystals. M.p .: 138 ° C.

Preparation of compounds of formula Ia in which n = 1 and Y = 0.

The preparation of compounds of formula Ia in which n = 1 and Y = 0 and W = 0, otherwise referred to as compounds of formula IX, will now be described.

Method C

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

(II)

(xi) wherein R 'is carbon.

represents an alkyl group having 1 to 3 atoms

As a strong base may be used an alkali metal alkoxide R ₂ O "M +, alkali metal, alkaline earth metal hydroxide or organic base. The reaction is preferably carried out in an alcohol R OH is the solvent, the use of the corresponding sodium alkoxide R ₂ O ~ Na + as base. The reaction is carried out at a temperature between 20 and 80 ° C. In one variation of this method, the reaction is carried out in the presence of an oxidizing agent. In particular, sodium or potassium periodate may be used as the oxidizing agent.

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 methoxide in 50 ml of anhydrous methanol was added 2.6 g (0.0062 mol) of (4-R, S) -4- (4-benzyloxyphenyl) under an inert atmosphere. 4-methyl-2-methylthiol-phenylamino-2-imidazolin-5-one and 1.3 g of sodium periodate. The reaction mixture was heated at reflux for 6 hours. After cooling, the reaction mixture was neutralized with acetic acid, then poured into 100 ml of water and extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate and then concentrated under reduced pressure. The crude product thus obtained is purified by chromatography on a silica gel column, eluting with a 50:50 mixture of heptane and ethyl acetate. The purified product is crystallized from diisopropyl ether. After filtration and drying under reduced pressure, 0.8 g (0.002 mol) of (4-R, S) -4- (4- (benzyloxyphenyl) -2-methoxy-4-methyl-1-phenylamino-2-imidazoline-5-) is obtained. Melting point: 127 DEG C., yield: 32%.

Preparation of compounds of formula Ia in which n = 0.

Method D

The preparation of the compounds of formula Ia in which n = 0 and W = 0, otherwise referred to also as compounds of formula XII, will now be described.

These compounds are prepared according to the process described in International Patent Application WO 94/01410, ie by reacting hydrazines of the formula R ₃ -NH-NH ₂ with an azalactone of the formula XIII according to the reaction scheme:

R ₃ NHNH,

CH3COOH

CH3COONa

The reaction is carried out by refluxing the mixture of reactants in acetic acid, 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 structural formula:

g (0.013 mol) of (4-R, S) -2-ethyl-4-methyl-4 - ((4-phenylthio) phenyl) -3-oxazolin-5-one is introduced into 100 ml of acetic acid. 1.4 g (0.013 mol) of phenylhydrazine are then added dropwise to the reaction mixture, then the reaction mixture is heated at reflux for 2 hours and the acetic acid is then removed in vacuo. The residue is mixed with water, neutralized and then re-extracted with dichloromethane. After drying over magnesium sulphate, evaporating the solvent, 4.09 g of an oil is obtained which is chromatographed on silica gel, eluting with a 4: 1 mixture of ethyl acetate and heptane to give 3.41 g (0.0085). mol) (5-R, S) -2-ethyl-5-methyl-3-phenylamino-5 ((4-phenylthio) phenyl) imidazolidin-4-one as an oil, which crystallizes from diisopropyl ether as beige crystals. Melting point: 90 DEG C. Yield: 66%.

The azalactones of formula XIII are obtained by reacting an alpha-amino acid of formula IX with a carboxylic acid anhydride using the procedure described by R. Cotton et al. in Int.J.Peptide Protein Res (1986), Vol. 28, p. 230-244, i. j. according to the reaction scheme:

XII (XIII)

The following example illustrates 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 structural formula

14.2 g (0.052 mol) of (2-R, S) -2-amino-2 - ((4-phenylthio) phenyl) propionic acid are suspended in 200 ml of propionic anhydride. The mixture is then heated at reflux for one hour, then propionic anhydride is removed after the addition of heptane and azeotropic distillation under reduced pressure, which is achieved by vacuum pump. The residue (16 g) was dissolved in 100 ml of ethanol while warm. A white solid crystallized (3.0 g), which was filtered off and discarded. The filtrate was concentrated to give 12.3 g of a brown oil which was chromatographed on silica gel using 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 ol.

Nuclear Magnetic Resonance Spectrum:

(CHC1 _3, 250 MHz, in ppm), 3 (t, 3H), 75 (s, 3H), 2.58 (q, 2H);

7.2-7.6 (m, 9H), yield: 29%.

A second process for preparing the compound of Formula Ia will now be described

This second preparation corresponds to processes E, F, G, H, I, J, K, L and M, which are described in the following section.

Method E

First, the preparation of the compounds of formula Ia is described

(la) wherein X has the same meaning as the group X 'as defined below in the description of process E. Compounds of formula Ia are obtained by condensation of an organometallic imidazolinone derivative of formula XV with an electrophilic group Azr 4 -X' * according to the following reaction scheme :

(XV)

Ar;

- X -

(Y> - Rz

NH-R

W (Ia) wherein Μ _χ is a metal selected from the group consisting of lithium, sodium, magnesium, zinc, titanium, tin, copper, boron and silicon, where Μ _{χ is} preferably lithium, and X 'is such that Ar _and X 'means an electrophilic group provided by a compound selected in particular from the group consisting of

an aralkyl halide or aralkyl sulfate of the formula Ar-R-L in which

R _x2 represents an aliphatic chain of 1 to 6 carbon atoms which is a linear or branched, saturated or unsaturated chain, optionally substituted by halogen or alkoxy or oxo, and

L is as defined above, a -carbonyl compound of formula

N- (R _i2) pCR

II o

wherein p is 0 or 1,

R is as defined above and

R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an alkoxy group, an aryloxy group or a dialkylamino group,

- chloroformate of the general formula

Ar - (R) pC-Cl ^{2 12} II o

wherein R _{x of} pa are as defined above, based isocyanate or isothiocyanate of formula

Ar - (R) -N = C = Q '12' Tp wherein p and R _{x =} have the meanings given above and Q represents an oxygen atom or a sulfur atom, a sulfonyl halide of the formula I '

Ar - (R) pS-Hal ^{2 12} II o

in which R _x2 have the meanings given above and Hal represents a halogen atom, preferably a chlorine atom, and an epoxide of the general formula

K-10 ^Ar Z '/ ^R ' 10.

When, according to a preferred variant of the invention, Μ _{χ of} formula XV is lithium, the corresponding compounds of formula XV, ie organolithium compounds of formula XVII, are obtained from halogenated derivatives of formula XVI in which Hal is halogen, preferably chlorine or bromine. the metal described by RG Jones and H. Gilman in Organic Reactions (19), Vol. 6, p. 339. The reaction proceeds according to the following equation:

xl --- * t w (XVII)

When Μ _χ in formula XV is not lithium, then the corresponding organometallic compounds of formula XV can be obtained from organo36 lithium compounds of formula XVII by the transmetallation reaction described in Advanced Organic Chemistry, J. March (1985), p. 557, 3rd edition.

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

Example CF4

Preparation of (4-R, S) -4- [4 - ((4-chlorophenyl) hydroxymethyl) phenyl] -4-methyl-3-methylthio-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 is dissolved in 20 ml under an inert atmosphere of anhydrous tetrahydrofuran, then the reaction mixture is cooled to -70 ° C. At this temperature, two equivalents of n-butyllithium (3.2 mL, 1.6 M hexane solution) 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 tetrahydrofuran was added. After 30 minutes, the reaction mixture is hydrolyzed at -70 ° C with saturated ammonium chloride solution. After extraction with ethyl acetate, washing of the organic extracts with saturated sodium chloride solution, drying, evaporation of the solvents and chromatography on a silica gel column of the crude product using a 50:50 mixture of ethyl acetate and heptane, 0.95 g (0.002 mol) is isolated. (4-R, S) -4- [4 - ((4-chlorophenyl) hydroxymethyl) phenyl] -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one.

Melting point: 94 DEG C. Yield: 82%.

2-Imidazolin-5-ones of formula XVI are obtained according to the procedures described in European patent application EP 0 551048 published July 14, 1993, in the case where Y is a sulfur atom and n is 1 by a procedure analogous to procedure C as described above, in the case where n is equal to 1 and Y is an oxygen atom, or in a manner analogous to the above procedure D, in case n is equal to 0.

Method F

The preparation of the compounds of formula (Ib) will now be described

wherein p and Z have the above meanings and R 'is an aliphatic chain having 1 to 6 carbon atoms and having a linear or branched and saturated or unsaturated character.

These compounds are obtained by known procedures by reacting the imidazolinone of formula XVI with a nucleophilic reagent of formula XVIII using a procedure analogous to that described in Comprehensive Heterocyclic Chemistry A. Katrizky, Vol. 2, Part 2A, p. 359, t. j. according to the following reaction scheme:

^{, N} > 1-b. ₃

H

Ar @ 1 - (R @ ₁₂ ) p - ZH (XVUI)

Ar ₂ - (R i ₂₎ p

(Ib)

This reaction is carried out under the conditions customary in carrying out 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-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 64)

To a solution of 1.00 g (2.5 mmol) of 4- (6-chloro-5-nitropyridin-2-yl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in 50 ml of acetone was added. under argon atmosphere and at ambient temperature add 1 g of potassium carbonate and then 0.27 ml (2.5 mol).

4-fluorothiophenol. After two hours at ambient temperature, the reaction mixture is diluted with water, the product is extracted with ethyl acetate, the extracts are dried over magnesium sulphate (anhydrous) and then concentrated under reduced pressure. The product is crystallized from diisopropyl ether after chromatography on silica gel, eluting with a mixture of ethyl acetate and heptane (20:80; v / v). Filtration and drying yielded 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.

Melting point: 171 ° C, yield: 66%.

Method G

The preparation of the compounds of formula Ic will now be described:

(Ic) wherein X 'is as defined above.

Compounds of formula (Ic) are obtained by reacting 4- (hydroxyphenyl) 2-imidazolin-5-one of formula (XIX) with an electrophilic group Ar (X ') according to the following reaction scheme:

HO

Ar; —X · * principle (XIX) · ►

Ατ2 ~ X '

The reaction is carried out under basic conditions under the conditions usually used for the condensation of phenols with various electrophilic groups (these are known procedures described in the literature). In particular, alkali metal carbonates and hydroxides and alkaline earth metal organic bases can be used as the base. The reaction is carried out at a temperature between 20 and 150 C. It is carried out in solvents such as alcohols, ketones, acetonitrile, aliphatic esters, 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- (3-methylbenzyloxy) phenyl) -2-methylthio-1-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-methylthio-1-phenylamino-2-imidazolin-5-one in 50 ml of ethanol 0.92 g (0.0067 mol) of potassium carbonate carbonate, 0.94 g (0.0067 mol) of 3-methylbenzyl chloride and 0.1 g (0.00061 mol) of potassium iodide are added. The reaction mixture was then heated at reflux for 8 hours. The reaction mixture is then poured into 150 ml of water. The precipitate formed is washed with 1N aqueous sodium hydroxide solution and then washed with water until neutral, then centrifuged, washed with diisopropyl ether and dried under reduced pressure. There was thus obtained (4-R, S) -4-methyl- (4- (3-methylbenzyloxy) phenyl) -2-methylthio-1-phenylamino-2-imidazoline-5- (1.94 g, 0.0045 mol). ón. (Compound No. 22) as white crystals.

Melting point: 151 ° C, yield: 75%.

The hydroxylated compounds of formula (XIX) are obtained from the benzyl compounds of formula (Id) by removal of the benzyl group using a so-called debenzylation reaction. Debenzylation is accomplished by conventional methods using oxygen-free acids or catalytic hydrogenation. These methods are described in the literature: G. Buchi and S. M. Weinreb, J. Am. Chem. Soc. (1971), Vol. 93, p. 746 or 0. Th. Schmidt and H. Schmadel, Annalen (1961), Vol. 649, p. 149. The reaction proceeds according to the following reaction scheme:

The following example illustrates 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 structural formula:

To a stirred suspension of 31.2 g (0.075 mol) of (4-R, S) -4- (4-benzyloxyphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazoline-

Of 5-one in 370 ml of acetic acid is added 92 ml of concentrated hydrochloric acid (d = 1.18) and the resulting mixture is heated at 75 ° C for 2 hours. After cooling the reaction mixture to ambient temperature, the reaction mixture was poured into 500 ml of ice water and the mixture was neutralized with concentrated aqueous sodium hydroxide solution. The precipitate formed is stirred for 1 hour at 5 DEG C., then filtered, washed with water, centrifuged and dried under reduced pressure. 22 g (0.067 mol) of (4-R, S) -4- (4-hydroxyphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one are thus obtained in the form of white crystals. Mp .: 206 ° C, yield: 90%.

The following table lists the synthesized imidazolinones of formula XIX.

Location OH Yield (%) M.p. (° C) 3 68 159 4 90 206

4- (Benzyloxyphenyl) -2-imidazolin-5-ones of formula Id are obtained by any of the methods described above.

Method H

The preparation of the compounds of formula Ie will now be described

wherein R and R 'are as defined above and Z' is O, S, or NR _{x 4} , wherein R is H or C 1 -C 6 alkyl.

These compounds are obtained by reacting 4- (carboxyphenyl) -2-imidazolinone derivatives 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, in an inert solvent and then nucleophilic. At a compound of formula ₂ - (R _{i2) e>} -Z'H XVIII in the presence of a base such as an alkali metal or alkaline earth metal or organic base according to the following reaction scheme:

H

The following example illustrates the preparation of compounds of Formula Ie.

Example CF7

Preparation of (4-R, S) -4- (4-chlorophenylaminocarbonyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 45) g (0.0028 mol) ( 4-R, S) -4-Methyl-2-methylthio-1-phenylamino-imidazolin-5-one is dissolved in 20 ml of 1,2-dichloroethane at ambient temperature. At this temperature, 0.5 ml (0.0056 mol) of oxalyl chloride is added followed by a drop of dimethylformamide. After gas evolution had ceased, the solvent was evaporated and the acid chloride was taken up in 20 ml of anhydrous tetrahydrofuran. At ambient temperature, 0.4 ml (0.0028 mol) of triethylamine is added followed by 0.71 g (0.0056 mol) of 4-chloroaniline. After stirring for 1 hour, the reaction mixture is hydrolyzed. After extraction with ethyl acetate, washing of the organic phases with saturated sodium chloride solution, drying, evaporation of the solvents, 1 g of a brown oil is isolated. After crystallization from diisopropyl ether, filtration and drying, 0.85 g (0.0018 mol) of (4-R, S) -4- (4-chlorophenylaminocarbonyl) phenyl) -4-methyl-2-methylthio-1-phenylamino- is isolated. 2-imidazolin-5-one as a beige solid.

Melting point: 210 DEG C. Yield: 65%.

4- (Carboxyphenyl) -2-imidazolin-5-ones of formula XX are prepared by reacting an organolithium compound of formula XVII with carbon dioxide using a procedure analogous to that described in Advanced Organic Chemistry, J. March (1985), p. . 826, 3rd edition, t. j. according to the following reaction scheme:

CO ₂ h ₃ o *

(XX)

The reaction is carried out by bubbling carbon dioxide through a reaction medium containing an organolithium compound.

The following example illustrates 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 structural formula:

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

Melting point: 183 DEG C. Yield: 56%.

Method I

The preparation of the compounds of formula If will now be described

wherein R ', p and Z' are as defined above and R is hydrogen, alkyl, haloalkyl, alkoxyalkyl or alkylidene, each of which contains 1 to 6 carbon atoms. R retains this meaning in the rest of the description.

These compounds are obtained by reacting a nucleophilic compound of formula Ar ₂ - (R 1 _{x 2} ) _p -Z'H of formula XVIII with 4- (chloromethylphenyl) 2-imidazolin-5-one of formula XXIII. The reaction is carried out in the presence of a base under the conditions usually used for the condensation of alcohols with various electrophilic compounds. These conditions are described in Advanced Organic Chemistry, J. March, (1985), p. 342, 3rd edition. The reaction proceeds according to the following reaction scheme:

xchr

(XXIII)

As the base, an alkali or alkaline earth metal carbonate or hydroxide or an organic base may be used. The reaction is carried out at a temperature between 20 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 and N-methylpyrrolidone.

The following example illustrates the preparation of compounds of formula If. Example CF8

Preparation of (4-R, S) -4- (4 - ((2,4-difluorophenoxy) methyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 6). 47)

0.3 g (0.0083 mol) of (4-R, S) -4- (4-chloromethyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in dimethylformamide mixed with 0.11 g (0.0083 mol) of 2,4-difluorophenol, 0.12 g (0.0083 mol) of potassium carbonate and 0.14 g (0.0083 mol) of potassium iodide. Heat the reaction at 80 ° C for 2 hours. After hydrolysis with water, extraction with ethyl acetate, washing of the organic extracts with saturated lithium chloride solution, drying and evaporation of the solvents, the honey-like product obtained is crystallized from diisopropyl ether and then filtered off. There was thus obtained (4-R, S) -4- (4 - ((2,4-difluorophenoxy) methyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazoline (0.250 g, 0.0055 mol). -5-one in the form of a beige precipitate.

Melting point: 152 DEG C. Yield: 66%.

4- (Chloromethylphenyl) -2-imidazolin-5-ones of formula XXIII are obtained by halogenating 4- (hydroxymethylphenyl) -2-imidazolin-5-ones of formula XXII. The halogenation is carried out by methods that are commonly used for this type of reaction using oxygen-free acid or an inorganic acid halide, such as SOC1 _{2, a} PCI, PC1 ₃ and POC1 _3, and which are described in Advanced Organic Chemistry, J. March, (1985) p. 382, 3rd edition, ie according to the following reaction scheme:

Hochries

(XXII) / PX 3 and PX

HX, SOC1 ₇

xchr

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

Example CI12

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

and

To a solution of 0.09 g (0.0026 mol) of (4-R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in 10 ml of toluene is added at ambient temperature to 0.22 ml (0.0026 mol) of pyridine and then 0.2 ml (0.0026 mol) of thionyl chloride in solution in 1 ml of toluene. The reaction mixture is then heated at 60 ° C for three hours, then cooled and hydrolyzed. After extraction with ethyl acetate, washing of the organic extracts with saturated sodium chloride solution, drying and evaporation of the solvents, a honey-like product is obtained. After chromatography on silica gel, eluting with a 50:50 mixture of ethyl acetate and heptane, 0.36 g (0.001 mol) of (4-R, S) -4- (4-chloromethylphenyl) -4-methyl- is isolated. 2-methylthio-1-phenylamino-2-imidazolin-5-one as a yellow powder.

Melting point: 130 DEG C. Yield: 38%.

The (hydroxymethyl) phenyl-2-imidazolin-5-ones of formula XXII are obtained by reduction of carbonyl compounds of formula XXIV. This reduction is accomplished using procedures commonly used for this type of reaction and described in Advanced Organic Chemistry, J. March, (1985), p. 1093-6, 3rd edition, t. j. according to the following reaction scheme:

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

Example CI13

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

To a solution of 9 g (0.0026 mol) of (4-R, S) -4- (4-formylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in 100 ml of absolute ethanol, cooled to 0 ° C, 1.02 g (0.0026 mol) of NaBH 4 was added. After stirring at ambient temperature for 4 hours, the reaction mixture is hydrolyzed and then extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, evaporated and chromatographed on a silica gel column using a 50:50 mixture of ethyl acetate and heptane to isolate 0.9 g (0.00026 mol) (4). -R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one as a chestnut brown powder.

Melting point: 146 ° C, yield: 10%.

The synthesized imidazolinones of formula XXII are summarized in the following table

Location OH X Yield (%) MP: (° C) 3 WITH 76 147 4 WITH 10 146 3 0 76 157

Carbonyl compounds of formula XXIV are prepared by reacting an organolithium compound of formula XVII with an electrophilic carbonyl compound using the procedure described by Evans in J. Chem. Soc. (1956), p. 4691, t. j. according to the following reaction scheme:

^R l

Li-Air

M

The preparation of compounds of formula XXIV is illustrated by the following example.

Example CI14

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

g (0.0025 mol) of 4- (4-bromophenyl) -4-methylthio-1-phenylamino-2-imidazolin-5-one is dissolved under an inert atmosphere in 20 ml of tetrahydrofuran (anhydrous) and the solution obtained is cooled to - 70 ° C. At this temperature, 2 equivalents of n-butyllithium (3.2 mL of a 1.6 M solution) were added. After stirring for 15 minutes at -70 ° C, 0.2 ml (0.0025 mol) of dimethylformamide in solution in 1 ml of tetrahydrofuran was added. After 30 minutes, the reaction mixture is hydrolyzed at -70 ° C with saturated ammonium chloride solution. Extraction with ethyl acetate, washing of the organic phase with saturated sodium chloride solution, drying, evaporation of the solvents and silica gel column chromatography using a 50:50 mixture of ethyl acetate and heptane gives a clear yellow oil which precipitates in isopropyl ether. There was thus obtained (4-R, S) -4- (4-formylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (0.35 g, 0.001 mol) as a white powder.

Melting point: 181 ° C, yield: 40%.

The following table summarizes the synthesized imidazolinones of formula XXIV.

Location HCO- Yield (%) MP: ( "C) 3 48 157 4 40 181

Method J

The preparation of the compounds of the general formula Ig will now be described:

wherein X 'is as defined above.

These compounds are obtained by reacting 4- (aminophenyl) -2-imidazolin-5-one of formula XXV with an electrophilic group of formula Ar _and X '*, as defined above, according to the following reaction scheme:

(XXV) '(Ig)

The reaction is carried out under conditions usually used to condense aniline with various electrophilic compounds. The reaction is carried out in the presence of a base. As the base, an alkali or alkaline earth metal carbonate or hydroxide or an organic base may be used. The reaction is carried out at a temperature between 20 and 150 ° C and in a solvent such as an alcohol, acetonitrile, aliphatic ester, ether, cyclic ether, aromatic solvent, chlorinated solvent, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone.

The following example illustrates the preparation of compounds of Formula Ig.

Preparation of (4-R, S) -4- (4-Benzoylaminophenyl) -4-methyl-2-methylthio-1-phenylamino-imidazolin-5-one (Compound No. 1)

To a solution of (4-R, S) -4- (4-aminophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (2 g, 6.1 mmol) 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. The mixture is allowed to react for 2 hours at ambient temperature, then the triethylamine hydrochloride precipitate is filtered off and the filtrate is concentrated under reduced pressure. The crude product is then crystallized from diethyl ether. There was thus obtained (4-R, S) -4- (4-benzoylaminophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (2.47 g, 5.7 mmol). Compound No. 1) as a white solid.

Mp .: 212 ° C, yield: 94%.

4- (Aminophenyl) -2-imidazolin-5-one of formula XXV is prepared by reduction of 4- (nitrophenyl) -2-imidazolin-5-one of formula XXV. This reduction is accomplished using procedures commonly used to reduce nitro groups, for example, by catalytic hydrogenation in the presence of a mixture of coal and palladium (palladium on carbon) described by F. Melani, L. Cecchi and G. Filacchion in J. Heterocyclic Chem . (1984), Vol. 21, p. 813, t. j. according to the following reaction scheme:

(XXVI)

J

-R ₂ , H ₂ , tetalytexr

H ₂ N

(Ύ) η -r ₂

The following example illustrates the preparation of compounds of Formula XXV.

Example CI15

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

g (39 mmol) of (4-R, S) -4- (4-nitrophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one, 100 ml of ethyl acetate and 3 g of 10% palladium The charcoal is introduced into an autoclave containing 500 ml. The autoclave was pressurized with hydrogen to 50 psi and heated at 50 ° C for 12 hours. After filtering off the catalyst and concentrating the filtrate under reduced pressure, a yellow honey-like product is isolated, which crystallizes in ether. After filtration and drying, 11 g of (4-R, S) -4 - (- aminophenyl) 4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is obtained as a yellow solid.

Mp .: 194 ° C, yield: 87%.

Using an analogous procedure gave (4-R, S) -4- (3-aminophenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one as a yellow solid.

Melting point: 100 ° C, yield: 95%.

The 4- (nitrophenyl) -2-imidazolin-5-ones of formula XXVI are obtained according to the procedures described in European Patent Application EP 0 551048 published July 14, 1993, when Y is sulfur and n is 1, , which is analogous to Method C above, when n is equal to 1 and Y is O, or a method analogous to Method D above, if n is 0.

Method K

The preparation of the compounds of formula Ih will now be described:

wherein R ', P and Z' have the above meanings. These compounds are obtained by reacting derivatives of formula XXVII with an electrophile of formula, Ar _and - (R _i) -CO-C1 in the presence of a base such as an alkali metal or alkaline earth metal or organic base, in an inert solvent according to the following reaction scheme :

HZ '

(XXVII)

Ar ₂ ”( ^R ·

ABOUT

The following example illustrates the preparation of compounds of Formula Ih.

Example CF10

Preparation of (4-R, S) -4- (4-chlorobenzoyloxymethyl) phenyl) -4-methylthiol-phenylamino-2-imidazolin-5-one of the structural formula:

about

To a solution of 1 g (0.0029 mol) of (4-R, S) -4- (4-hydroxymethylphenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one in 20 ml of tetrahydrofuran was added. at room temperature, 0.42 ml (0.0029 mol) of triethylamine and then 0.38 ml (0.0029 mol) of parachlorobenzoyl chloride are added. After stirring at room temperature for 30 minutes, the reaction mixture is hydrolyzed and then extracted with ethyl acetate. The organic extracts were washed, dried and then evaporated. After mixing with isopropyl ether, 0.6 g of (4-R, S) -4- (4- (4-chlorobenzoyloxymethyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is isolated in in the form of a white powder.

Melting point: 129 ° C, yield: 43%.

The imidazolinones of formula XXVII may be prepared by the methods described above, in particular by a procedure analogous to that used to prepare the imidazolinone of formula XXII.

Method L

The preparation of the compounds of formula Ii will now be described

Αγ ₂ - (R * ₁₂ ) P - CR

Z'R

in which Ar _a , R 'and Z' have the meanings given above.

These compounds are obtained by reacting 2-imidazolin-5-one-benzyl derivatives of formula XXVIII with a nucleophilic compound of formula HZ'R ² , optionally in the presence of a base such as an alkali or alkaline earth carbonate or an organic base according to the following reaction scheme :

Arz --- K-2 hzr ₂ R | ^FROM VL w principle (XXVM) solvent

(W

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

Example CF11

Preparation of (4-R, S) -4- (4-methoxybenzyl) phenyl) -4-methyl-2-methylthiol-phenylamino-2-imidazolin-5-one (Compound No. 107) of the structural formula:

/ 0

To a solution of 0.37 g (0.007 mol) of sodium methoxide in 30 ml of methanol was added under an inert atmosphere 1.5 g (0.0035 mol) of (4-R, S) -4- (4-chlorobenzyl) phenyl) -4 methyl-2-methylthio-l-phenylamino-2-imidazolin-5-one. The reaction mixture was then heated to 50 ° C for 30 minutes. After cooling, the reaction mixture is hydrolyzed and then extracted with ethyl acetate. The organic extracts were washed with brine, dried and evaporated. The crude product is then chromatographed on a silica gel column, eluting with a 50:50 mixture of heptane and ethyl acetate. 0.7 g of (4-R, S) -4- (4-methoxybenzyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is thus isolated in the form of a white powder.

Melting point: 161 ° C, yield: 47%.

The 2-imidazolin-5-one-benzyl derivatives of formula XXVIII are prepared according to the procedures described above, in particular by a procedure analogous to that used to prepare a compound of formula XXIII from a compound of formula XXII.

Method M

The preparation of the compounds of formula Ij will now be described:

wherein R 'and p are as defined above, Y is a sulfur atom and X is a halogen atom, preferably a chlorine atom.

These compounds are obtained by halogenating compounds of formula XXIX. The halogenation is carried out by methods that are commonly used for this type of reaction, the use of oxygen-free acid or an inorganic acid halide, such as SOC1 _{2, a} PCI, PC1 _3, or POC1 _3, and which are described in Advanced Organic Chemistry, J. March, (1985) p. 382, 3rd ed., Ie according to the following reaction scheme:

dj)

The following example illustrates the preparation of compounds of Formula Ij.

Example CF12

Preparation of (4-R, S) -4- (4-chlorobenzyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 106) of the structural formula:

To a solution of 6.5 g (0.15 mol) of (4-R, S) -4- (4 - ((phenyl) hydroxymethyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazoline- Of 5-one in 100 ml of methylene chloride is added at 0 ° C 1,4 (0,015 mol) pyridine and then 1,15 ml (0,015 mol) thionyl chloride. The reaction mixture is then heated to reflux for 30 minutes, then cooled to ambient temperature. The organic extracts were washed, dried and evaporated. After mixing the crude product with diisopropyl ether, 4.7 g of (4-R, S) -4- (4-chlorobenzyl) phenyl) -4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one is obtained in in the form of a white powder.

Melting point: 153 ° C, yield: 69%.

Compounds of formula XXIX are obtained by the methods described above, in particular by the method used to prepare compounds of formula XXII.

The following tables summarize the imidazolinones of formula (I), which also correspond to any of the above formulas (Ik) or (II), which were prepared by one of the above methods (the method used is shown in the last column of the table).

In these tables, methyl, ethyl, propyl, pyridyl, pyrimidinyl, acetyl, phenyl and benzyl are denoted by the following abbreviations: Me, Et, Pr, Py, Pyrim, Ac, Ph, respectively. Bn.

No. W Ar2X (Y) n R 2 R3 MP: ° C Way to reindeer 1 0 4- (PhC (0) NH) SMe ph 212 J 2 0 4- (PhC (0) NH) OMe ph 150 C J 0 4- (4-Cl-PhC (O) NH) SMe ph 219 J 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 J 8 0 3-BnO SMe ph 112 B

9 0 4-BnO OMe ph 127 C 10 0 4-BnNH SMe ph 114 J 11 0 4-OBn OMe ph 148 C 12 0 4-OBn SMe ph 145 B 13 0 4-BnO SMe 3-F-Ph honey B 14 with 4- (2-yl Phene ±) SMe ph 118 A 15 0 4- (4-F-BnO) SMe ph 167 G 16 0 4- (3-F-BnO) SMe ph 133 G 17 0 4- (2-F-BnO) SMe ph 159 G 18 0 4 - [(5-CF ₃ -2-Py) O] SMe ph 163 G 1 19 0 4- (4-Me-BuO) SMe Ph. 176 G. 20 0 4- (4-CF ₃ -BnO) SMe ph 170 G 21 0 3- (PhC (O) NH) SMe ph 130 J 22 0 4- (3-Me-BnO) SMe ph 151 G 23 0 4- (2-Me-BnO) SMe ph 146 G 24 0 4- [2,5- (Me) 2-BnO] SMe • Ph 149 G 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 í 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) J SMe ph 94 E ä 31 0 4- [PhCH ₂ CH (OH)] SMe ph 83 E 32 0 4- (2-Py-CH 2 O SMe ph 139 G j 33 0 4- [PhCH (CH 3) O] SMe ph 137 G 34 0 4 (4-Py-CH 2 O) SMe ph 215 G

35 0 4- (3-Py-CH 2 O) SMe ph 138 G 36 0 4- (5-CFj-2-pyo) OMe ph 88 C 37 0 4- (PhNHC (O) O) SMe ph 201 G 38 0 4- [PhS (O)] SMe ph 132 B 39 0 4- [PhS (O)] SMe 3-Cl-Ph 164 B 40 0 4- [PhS (O)] SMe 3-F-Ph 115 B 41 0 4- (PhSO2) SMe ph 80 B 42 0 4- [Ph (CH ₂₎ 21 OMe ph 100 C 43 0 4- (PhCO2) SMe ph 170 G 44 0 PhC0CH2O SMe ph 163 G 45 0 4- [4-Cl-PhNHC (O)] SMe ph 210 H 46 0 4- (PhNHC (O)] SMe ph 105 H 47 0 4- (2,4-Difluoro-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 50 0 4- (2- (4,6-diMePyrim) O) S-Me ph 87 G 51 0 4- (2-Me-PhCH ₂ O) S-Me ph 129 G 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-CI-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 honey D 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-Ph CH ₂ O) SMe ph 126 G! 93 0 4- (2-F-PhOCH ₂ ) OMe ph 165 c! 94 0 4- (4-Cl-PhCO ₂ CH ₂ ) SMe ph 129 ^The 95 0 4-PhSO OMe ph honey C 96 0 4- (4-Cl-Ph) CH ₂ O SMe ph 187 G | 98 0 4-PhCH (OH) SMe ph honey E 99 0 4- (4-MeO-Ph CH ₂ O) SMe ph 156 G 100 0 4- _(4-NO: PhCH ₂ O) SMe ph 209 G 101 0 4-PhOCH ₂ OMe ph 158 c 1 102 0 4- (3-Cl-PhOCH ₂ ) OMe ph 147 c ^J 103 0 4- (3-F-PhOCH ₂ ) OMe ph 179 C 104 0 4- (4-F-PhOCH ₂ ) OMe ph 141 C i 105 0 4- (4-CF ₃ -PhOCH ₂ ) OMe ph 143 C 106 0 4-PhCH (CI) 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-difluoro-Ph 104 B 110 0 4-PhCO SMe ph 162 E 111 0 4- (2-CN-PhCH ₂ O) SMe ph 174 θ 112 0 4-PhCO OMe ph 83 C! 113 0 3- (4-CI-PhCOOCH ₂ ) SMe ph 156 The 114 0 . 3- (4-Cl-PhCOOCH ₂ ) OMe ph 105 c i 115 0 4-PhS SMe 2,3-difluoro-Ph 113 B 116 0 4- (3-CN-PhCH ₂ O) SMe ph 171 G | 117 0 3- (4-CF 3 -PhOCH ₂ ) SMe ph 127 I 118 0 3- (PhCO) SMe ph 149 E i 119 0 3- (4-Cl-PhCH (OH)) SMe ph 156 E 1 120 0 3- (4-CI-PhOCH ₂ ) SMe ph 1.12 I | 121 0 3- (4-CF ₅ -PhOCH ₂ ) OMe ph 1.2 C 122 0 3- (PhCH (OMe)) OMe ph 1.20 c! 123 0 3- (4-Cl-PhCH (OMe)) OMe .ph 1.20 C 124 0 3- (4-Cl-PhOCH ₂ ) OMe ph honey C I 125 0 3- (4-Me-PhOCH ₂ ) SMe ph 87 I i 126 0 3- (4-F-PhOCH ₂ ) OMe ph 136 C 127 0 3- (4-F-PhCH (OH)) SMe ph 12S E 128 0 3- (4-CFj-PhCH (OH)) SMe ph 145 E 129 0 3- (4-OMe-Ph CH (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 honey E 133 0 3- (PhOCH ₂ ) OMe ph honey C

134 0 4- (4-FPhCH ₂ ) OMe ph 171 G 135 0 4 - [(2-benzothiazolyl) 0] SMe ph 144 G

FROM

No. r2 R T.tľC Method j 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 68 4-Cl-Ph no ₂ 146 F 69 3-Cl-Ph no ₂ 103 F 70 2-Cl-Ph no ₂ 93 F 71 2-Naphthyl no ₂ 131 F 72 2-OH-Ph no ₂ 97 F 73 4-HOPh no ₂ 145 F 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 CFs 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 í 83 3-F-Ph cf ₃ 143 F

The invention also relates to some novel compounds which have been described in the preceding section as intermediates, ie compounds of formulas IIa, IIb, IV, VII, XIII, XIX, XX, XXII, XXIV and XXVII, wherein the general substituents have the meanings given above. Like the compounds of the formula I according to the invention, they can exist in one or more isomeric forms, depending on the number of asymmetric centers in the molecule. The invention thus encompasses all optical isomers of the compounds which are useful as intermediates, as well as their racemic mixtures and the corresponding diastereoisomers, whether separated or in admixture, and in particular the enantiomers of the compounds containing an asymmetric carbon bearing R. The separation of optical isomers and / or diastereoisomers from racemic mixtures can be carried out by methods known per se. Enantiomers of asymmetric carbon-containing intermediates carrying R _x may also be prepared by methods known per se or as described above from chiral starting materials and in particular from chiral alpha-amino acids of formula IX, i.e. from compounds of formula IX in which the carbon atom attached to R _{x is} asymmetric carbon atom.

The invention also relates to a method for the treatment of crop plants which are infected with or susceptible to fungal diseases, characterized in that an effective dose of a compound of the formula I according to the invention is applied to the above-ground part of the crop. means a quantity sufficient to control and destroy the fungi present on these crops. However, the application rates may vary within wide limits, depending on the fungus to be destroyed, the type of crop, the climatic conditions and the particular compound used.

In practice, the compounds are preferably applied at doses of from 0.002 to 5 kg / ha, preferably from 0.005 to 1 kg / ha.

Fungal diseases are diseases caused by phytopathogenic fungi, in particular fungi of the family oomycetes, ascomycetes and basidiomycetes.

Among the crop plants which can be treated fungicidally with the compound according to the invention, mention may be made of rice, cereals, in particular wheat and barley. Rice is a preferred crop for fungicidal treatment using a compound of the invention.

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

Example BI

In vivo test for Pyricularia oryzae causing rice piricullariosis

Using fine grinding, an aqueous suspension of the test compound is prepared having the following composition:

- active substance: 60 mg,

- acetone: 5 ml,

surfactant (polyoxyethylene sorbitan derivative oleate): 0.3 ml, and

- make up the volume of the suspension to 60 ml with water.

The aqueous suspension is then diluted with water to obtain the desired concentration of active ingredient.

The rice sown in 50:50 enriched peat / pozzolanic dishes is treated at a height of about 10 cm (corresponding to a 2-3 leaf stage) by spraying the above suspension. After 24 hours, an aqueous spore suspension of Pyricularia oryzae, obtained from a 15-day culture, is applied to the leaves of the plants and then suspended to reach 100,000 units / cm ³ . The rice plants are then incubated for 24 hours at 25 ° C and 100% relative humidity, then stored in an observation chamber for 5 days under the same conditions. The counting of the plant condition is performed 6 days after infection.

Under these conditions, it was found that at a dose of 1 g / l, good (at least 75%) or total protection was obtained for the following compounds: 9, 11, 15, 16, 23, 27-29, 31-31

33, 35-37, 42, 67, 68, 84, 92, 94, 95, 96, 102, 104, 105,

108, 109, 112, 114 and 121.

Example B2

In vivo test for Puccinia recondita causing wheat rust.

Using fine grinding, an aqueous suspension of the test compound is prepared having the following composition:

- active substance: 60 mg,

- acetone: 5 ml,

- Tween 80 surfactant (polyoxyethylene sorbitan oleate) diluted to 10% with water: 0,3 ml, and

- make up the volume of the suspension to 60 ml with water.

The aqueous suspension is then diluted with water to obtain the desired concentration of active ingredient.

Wheat sown in a 50:50 mixture of peat soil and pozzolan, filled into a bowl and maintained at 12 ° C, is treated at the height of 10 cm by spraying the above aqueous suspension. After 24 hours, the wheat plants are sprayed with an aqueous spore suspension (100,000 spores / cm ³ ). This suspension was obtained from infected plants. The wheat is then stored for 24 hours in an incubation chamber in which a temperature of about 20 ° C and 100% relative humidity is maintained, after which the wheat is kept at 60% relative humidity for 7-14 days. Plant health control is performed on days 8 and 15 post contamination by comparison with control plants.

Under these conditions, it was found that at a dose of 1 g / l, good (at least 75%) or total protection of the following compounds was obtained: 4, 8 to 13, 15 to 18, 20 to 28, 31 to 33, 35, 36, 38 , 40-43, 48, 49, 73, 79, 81, 84, 85, 89, 90, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 , 108, 109

110, 115, 116, 117, 119, 120, 121

Example B3

In vivo test for Septoria tritici causing septoriosis of wheat

Using fine grinding, an aqueous suspension of the active substance to be tested is prepared at a concentration of 1 g / l, with 60 mg of said active substance being ground in a mixture having the following composition:

- acetone: 5 ml,

- surfactant (polyoxyethylene sorbitan derivative oleate): diluted to 10%: 0,3 ml, and

- make up to 60 ml with water.

The resulting aqueous suspension is then diluted with water to obtain the desired concentration of active ingredient.

Wheat plants (Darius variety) sown in a 50:50 peat / pozzolan mixture and cultivated in a greenhouse at 10-12 ° C are treated at the first leaf stage (corresponding to a crop height of about 10 cm) by spraying the above aqueous suspension of the active ingredient. Control plants are treated by spraying with an aqueous solution containing no active ingredient. 24 hours after this treatment, the plants are infected by spraying an aqueous spore suspension (500,000 spores / ml) obtained by harvesting from a 7-day culture. After infection, the plants are kept in a humid atmosphere at 18 ° C. The counting of the plant state is performed 20 days after infection by comparison with that of the control plants.

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

The present invention also provides compositions useful as fungicidal agents, which contain, as the active ingredient (s), one or more of the compounds of formula (I) described above, and which are present in the composition in combination with an agriculturally acceptable surfactant. In particular, inert and customary carriers and customary surfactants are used.

These compositions may also contain any other ingredients such as protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, stabilizers and sequestering agents. Even more generally, the compounds of the invention may be combined with any solid or liquid additives which correspond to conventional formulation methods.

In general, the compositions of the invention usually contain from 0.05 to 95% by weight of a compound of the invention (hereinafter referred to as the active ingredient) one or more solid or liquid carriers and optionally one or more surfactants.

As used herein, the term carrier means a natural or synthetic, organic or mineral substance with which the active substance is combined to facilitate its application to the plant, grain or soil. Thus, this carrier is generally inert and must be an agriculturally acceptable substance, especially for the treated plants. The carrier must be solid (clays, natural or artificial silicates, silicas, resins, waxes, solid fertilizers and the like) or liquid (water, alcohols, especially butanol and the like).

The surfactant may be an emulsifying, dispersing or wetting agent of the ionic or non-ionic type or a mixture of such surfactants. For example, polyacrylic acid salts, lignosulfonic acid salts, phenolsulfonic acid salts or naphthalenesulfonic acid salts, polycondensates of ethylene oxide and fatty alcohols, fatty acids or fatty amines, substituted phenols (especially alkylphenols or arylphenols), esters of sulfosuccinic acid esters, in particular sulfosuccinic acid derivatives , esters of phosphoric acid and alcohols or polyoxyethylated phenols, esters of fatty acids and polyols, sulphate derivatives, sulphonates and phosphates of the foregoing compounds. The presence of at least one surfactant is generally necessary when the active compound and / or the inert carrier is not water-soluble and the carrier medium is water.

Ί4

The compositions for agricultural use according to the invention can thus contain the active compounds according to the invention in very wide ranges, from 0.05 to 95% by weight. These compositions preferably contain 5 to 40% of a surfactant.

The compositions according to the invention themselves have various solid or liquid forms.

Solid forms of these compositions include powders for dusting (up to 100% active ingredient) and granules, in particular granules obtained by extrusion, compression, granular carrier impregnation and powder granulation (up to 0.5% to 80% active ingredient for the last time). of these forms) as well as effervescent tablets.

The compounds of formula I can still be used in the form of powders for dusting. Compositions containing 50 g of active ingredient and 950 g of talc, 10 g of finely divided silica and 970 g of talc may also be used. The ingredients are mixed and ground and the resulting mixture is applied by powdering.

Liquid form preparations or forms which are intended to form liquid formulations immediately prior to application include solutions, in particular concentrated solutions in water, emulsifiable concentrates, emulsions, concentrated suspensions, aerosols, wetting powders (or sprayable powders), pastes and gels.

Emulsifiable or soluble concentrates usually contain from 10 to 80% active ingredient and emulsions or solutions ready for application contain from 0.001 to 20% active ingredient.

Emulsifiable concentrates may contain, in addition to the solvent, if necessary, 2 to 20% of appropriate additives, such as stabilizers, surfactants, penetrating agents, corrosion inhibitors, colorants or even the aforementioned additives.

Emulsions of any desired concentration which specifically correspond to the application to crop plants can be obtained from said concentrates by dilution with water.

In the following, some examples of emulsifiable concentrates are given.

Example CE1

- active substance 400 g / l - alkali metal dodecylbenzenesulfonate 24 g / l - nonylphenol oxyethylated with 10 molecules ethylene oxide 16 g / l - cyclohexanone 200 g / l - add aromatic solvent to 1 liter.

In another emulsifiable concentrate formulation:

Example CE2

- active ingredient 250 g * - epoxidized vegetable oil 25 g

- mixture of alkylarylsulphonate and polyglycol ether 'and fatty alcohol 100g

- dimethylformamide 50g

- xylene 575g.

Suspension concentrates can also be applied by spraying, and these concentrates are prepared to provide a stable, sediment-free liquid. These concentrates generally contain 10 to 75% of active ingredient, 0.5 to 15% of surfactants, 0.1 to 10% of thixotropic agents, 0 to 10% of appropriate additives such as defoamers, corrosion inhibitors, stabilizing agents, penetrating agents and adhesives, and as a carrier water or an organic liquid in which the active ingredient is poorly soluble or insoluble.

Certain solid organic substances or mineral salts may be dissolved in such a carrier to aid in the elimination of sedimentation or as antifreeze agents.

The following is an example of a suspension concentrate formulation.

Example SC 1

- active ingredient 500g

- polyethoxylated tristyrylphenol phosphate 50g

- Polyethoxylated alkylphenol 50g

- sodium polycarboxylate 20g

- ethylene glycol 50g

- organopolysiloxane oil (antifoam) 1g

- polysaccharide 1.5 g

- water 316.5 g.

The soaking powders (or sprayable powders) are usually prepared to contain 20 to 95% of the active ingredient, in addition to a solid carrier usually containing 0 to 30% of a wetting agent, 3 to 20% of a dispersing agent and 0.1 to 10% of one or several stabilizers, or other additives such as penetrating agents, adhesives, anti-caking agents, colorants and the like.

In order to obtain sprayable powders or wettable powders, the active ingredients are intimately mixed with the ingredients in a suitable mixer and the resulting mixture is ground in a mill or other disintegrator. In this way, sprayable powders are obtained which have advantageous wettability and suspensibility. These powders may be suspended in water at any desired concentration, such suspensions being very advantageously used for application to the foliage of plants.

Pastes can be prepared instead of soaking powders. The conditions of preparation and application of these pastes are analogous to those used for soaking powders or sprayable powders.

The following are some examples of wetting powder (or sprayable powder) compositions.

Example PM 1%

2.5%%

42.5%.

- active substance

- ethoxylated fatty alcohol (soaking agent)

- ethoxylated phenylethylphenol (dispersing agent)

- chalk (inert carrier)

Example of PM 2

- active substance

- branched-type synthetic oxo-alcohol ethoxylated to C8 and 10 with ethylene oxide molecules (soaking agent)

- neutral calcium lignosulfonate (dispersing agent)

- calcium carbonate (inert filler) up to%

0,75%%

100%.

Example of PM 3

This soaking powder contains the same ingredients as in the previous example, but is used in the following amounts:

- active substance 75%

- soaking agent 1,50%

- dispersing agent 8%

- calcium carbonate (inert filler) up to 100%.

Example of PM 4

- active substance 90%

- ethoxylated fatty alcohol (soak) 4%

- ethoxylated phenylethylphenol (dispersant) 6%.

Example of PM 5

- active substance 50%

- mixture of anionic and non-ionic surfactants (soaking agent) 2,5%

- sodium lignosulfonate (dispersing agent) 5%

- kaolin clay (inert carrier) 42.5%.

Also included within the general scope of the invention are aqueous dispersions and emulsions, for example, compositions obtained by diluting the soaking powder or emulsifiable concentrate of the invention. The emulsions may be water-in-oil or oil-in-water emulsions and may have a dense consistency like mayonnaise.

The compounds of the invention may be formulated in the form of granules which are dispersible in water and such granules are also within the scope of the invention. These dispersible granules having a bulk density generally between about 0.3 and 0.6 are in the form of particles generally having a size between about 150 and 2000 and preferably between 300 and 1500 microns. The active ingredient content of these granules is generally about 1 to 90%, preferably 25 to 90%.

The remainder of the granules essentially consist of a solid filler and, optionally, a surfactant, which imparts the dispersibility in water of the granules. These granules may be essentially granules of two different types depending on whether the filler is water-soluble or insoluble. If the filler is water soluble, it may have a mineral or substantially organic nature. Excellent results were obtained using urea. In the case of an insoluble filler, the filler is preferably a mineral such as kaolin or bentonite. In this case, it is preferably accompanied by surfactants (in an amount of 2 to 20%, based on the weight of the granule), more than half of which are, for example, at least one dispersing substantially anionic agent such as an alkali metal or alkaline earth metal polynaphthal metal or alkaline earth metal, the remainder being nonionic or anionic wetting agents such as alkali metal or alkaline earth metal alkylnaphthalenesulfonates.

Otherwise, although not necessary, other additives, for example antifoams, may be used.

The granules according to the invention can be prepared by mixing the necessary ingredients and then granulating according to techniques known per se (coating apparatus, fluidized beds, spraying, extrusion and the like). The preparation of the granules is usually terminated by grinding and subsequent sieving to obtain a fraction of particles of the desired size range. It is also possible to use the granules obtained by the above process and subsequently impregnating the formulations containing the active ingredient.

The granules are preferably obtained by extrusion using the procedure described in the following examples.

Example GR 1

Dispersible granules

90% by weight of the active ingredient and 10% bead urea are mixed in a blender. The resulting mixture is then ground in a spindle mill. A powder is obtained which is moistened with about 8% by weight of water. The wet powder is extruded in an extruder with a perforated exit disc. Granules are obtained which are dried, crushed and screened to obtain granules between 150 and 2000 microns in size.

Example GD 2

The following components are mixed in the mixer:

- active substance 75%

- soaking agent (sodium alkylnaphthalenesulfonate) 2%

- dispersing agent (sodium polynaphthalenesulfonate) 8%

- inert filler insoluble in water (kaolin) 15%

The mixture is granulated in a fluidized bed in the presence of water, then dried, crushed and screened to sieve granules between 0.15 and 0.80 mm in size.

These granules can be used as such or in solution or dispersion in water, the ratio of granules to water being chosen to obtain the desired dosage. These granules can also be used for the preparation of compositions with other active substances, in particular fungicides, the latter being in the form of wetting powders or granules or aqueous suspensions.

For compositions intended and adapted for storage and transport, these compositions preferably contain from 0.5 to 95% by weight of the active ingredient.

Claims (5)

PATENT CLAIMS First 2-Imidazolin-5-one derivatives of the general formula I (I) in which R _x represents a hydrogen atom or a vinyl group or an allyl group or an alkyl or haloalkyl group, each containing 1 to 3 carbon atoms, or else In addition, R _x and Ar 1 -X-Ar 1 may form, with the carbon atom to which they are attached and which is part of the imidazoline ring, a group of the formula (CH 2) Ar ₂ X in which the bold dot represents the carbon atom of the imidazoline ring of formula I to which R _x groups are attached and Ar 1 -X-Ar 1 and m is 2, 3 or 4, n is Ο or 1, Y represents an oxygen atom or a sulfur atom, R ₂ is hydrogen, if n is 0, or an alkyl or haloalkyl, each having 1 to 3 carbon atoms, or cyclopropyl, R ₃ represents an aryl or heteroaryl group comprising a phenyl group, a naphthyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group, a benzothenyl group, a benzofuryl group, a quinolinyl group, an isoquinolinyl group, a benzothiazolyl group, benzothiazolyl group which is optionally substituted by 1 to 7 groups, preferably 1 to 3 groups selected from the below-defined meanings of _R, R represents a hydrogen atom, a formyl group or an aroyl group, an acyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an aryloxycarbonyl or arylsulfonyl group, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkyloxalyl group or alkoxyxalyl 6 carbon atoms. R is -halogen, hydroxy, mercapto, nitro, SF, cyano, thiocyanato or azido or -alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy , alkylthio, haloalkylthio, cyanoalkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyl, haloalkylsulfinyl or haloalkylsulfonyl, each containing 1 to 6 carbon atoms, or -cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio, each of which contains 3 to 6 carbon atoms, or -amino, which is optionally mono - or a disubstituted alkyl or acyl group having 1 to 6 carbon atoms or an alkoxycarbonyl group 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 -N, N-dialkylcarbamoyl of 3 to 13 carbon atoms, W represents an oxygen atom, a sulfur atom or a SO group, Ατ _χ means a divalent group which is derived from an aryl or heteroaryl group including a phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl or isoquinolinyl group, , each of which is optionally substituted with 1-6 groups, preferably 1 to 3 groups which are selected from the meanings of _R, Ar ₂ represents a mono- or bicyclic system containing 5 to 10 carbon 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 oxygen, sulfur or nitrogen, wherein: this system includes phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, thienyl, furyl, pyrrolyl, pyridyl, benzothienyl, benzofuryl, indanyl, indolyl, quinolinyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinolyl, iminoquinoline , pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, benzimidazolyl, inda84 zolyl, benzoxazolyl group pis, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, naphthyridyl, quinoxazolyl, quinazolyl, cinnolyl or optionally phthalazinyl, each of which is 1, phthalazinyl, or phthalazinyl; preferably 1 to 3 groups which are selected from the meanings of _R, X is a group of formula - (R). And in which both, which are the same or different, mean 0 or 1, R and R ', which are the same or different, represent a saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms, which is optionally substituted with 1 to 12, preferably 1 to 3, groups selected from the following definitions of R _? and wherein one or more carbon atoms may be replaced by an oxygen atom, a sulfur atom or an N (R _e ) group, wherein R _e is as defined below, A represents O, S, N (R _a ), SO, SO _a , CO, CS, Si (R _a ) (R _a ), N _a , C (R) (R a) or 'xo''XO ⁷ where * 10 * 10 * or --C = CR, Z is O, S, C (R _1, J R 1) ^and R _e to R are as defined below, R is e -hydrogen, cyano, hydroxy, amino, formyl, morpholino, piperidino, pyrrolidino, piperazino, or -alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylsulfonyl, haloalkylsulfonyl, cyanoalkylsulfonyl, each containing 1 to 6 carbon atoms, or -monoalkylamino or dialkylamino or -cycloalkyl, halocycloalkyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy each of 3 to 6 carbon atoms, or -acyl or alkoxycarbonyl each of 2 to 6 carbon atoms, or -carbamoyl of 1 to 7 carbon atoms optionally substituted by one or two alkyl groups, or sulfamoyl of 1 to 6 carbon atoms, or -aroylovú group or arylsulfonyl group, or a -alkyloxalylovú or alkoxyoxalylovú radical, each containing 3 to 8 carbon atoms, or -oxamylovú of 2 to 8 carbon atoms which is optionally substituted by one or two alkyl groups, _R? is halogen, cyano, thiocyanato, hydroxycarbonyl, optionally substituted amino, hydroxyl, oxo, alkoxy, alkoxycarbonyl, haloalkoxy, alkoxyalkoxy, thiol, alkylthio, haloalkylthio; a group, alkoxyalkythio, acyloxy, alkyl, haloalkyl, alkoxy xyalkyl, alkylidene, aroyloxy, heteroaroyloxy, arylacyloxy, cycloalkylcarbonyloxy, acylthio, aroylthio, heteroarylthio, heteroaroylthio, -cycloalkylcarbonylthio, optionally substituted cardamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted dithiocarbamoyl, acylamino, cycloalkylcarbonylamino, aroylamino, ureido, which is optionally substituted, thiycreido, alkoxy aryloxycarbonylamino a group, an alkylsulfonylamino group, an arylsulfonylamino group or an optionally substituted aminosulfonylamino group, where substitution is to be understood as meaning groups optionally substituted by one or two alkyl groups, each aliphatic hydrocarbon group containing 1 to 4 carbon atoms and the cycloalkyl group containing 3 up to 7 carbon atoms, R _e and R ', which are the same or different, mean -alkyl of 1 to 6 carbon atoms or -cycloalkyl of 3 to 7 carbon atoms, or an alkenyl or alkynyl group each containing 2 to 6 carbon atoms, or -aralkyl radical, preferably a benzyl group, or an optionally substituted aryl, preferably phenyl optionally substituted by 1 to 5, preferably 1 to 3 groups selected from the meanings of R @ _g, R @ -hydrogen, morpholino, piperidino, pyrrolidino, piperazino or -alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, cyanoalkoxy, alkylthio, haloalkylthio, cyanoalkylthio, each containing 1 to 6 carbon atoms, or a dialkylamino group 2 to 6 carbon atoms, R and R _y are the same or different, represent a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms, or R R and R ' _xx , which are the same or different, represent a hydrogen atom or a halogen atom or an alkyl group containing 1 to 3 carbon atoms, as well as the salts and enantiomers and stereoisomers of these compounds, in particular the 2 enantiomers of each of the compounds corresponding to asymmetric carbon imidazole ring bearing R _x , with the exception of compounds for which: -when (Y) -R is methylthio, methyl or ethyl, Ar ₂ -W-Ar _x is optionally substituted phenoxyphenyl, - when (Y) -R represents a methoxy group, when R _x represents a methyl group, when R _a represents a phenyl group or a pyridyl group optionally substituted by a fluorine atom or a methyl group, when R 6 represents a hydrogen atom and when W represents an oxygen atom, Ar ₂ -X-Ar _x represents either a 4-phenoxyphenyl group optionally substituted at the phenoxy residue of 1 or 2 fluorine atoms or a 3-phenoxyphenyl group, and with the exception of a compound of the formula Compounds according to claim 1 of the general formula I, in which Ar 2 represents a bivalent group derived from phenyl, naphthyl, thienyl, pyridyl, benzothienyl, quinolinyl, each of which is optionally substituted with 1 to 3 groups selected from ^R s' and Ar _a represents a phenyl group, a naphthyl group, a thienyl group, a pyridyl group, a benzothienyl group, a thiazolyl group, a benzothiazolyl group, a pyrimidyl group, each of which is optionally substituted with 1 to 3 groups selected from R _s . Compounds according to claim 1 or 2 of the general formula I, in which Ατ _χ represents a bivalent group derived from a phenyl group, a thienyl group, a pyridyl group, each of which is preferably substituted by 1 to 3 groups selected from the group consisting of halogen, alkyl and haloalkyl, Ar ₂ represents a phenyl group, a naphthyl group, a pyridyl group, a benzothienyl group, a benzothiazolyl group, each of which is optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl and haloalkyl, X represents a group of the formula - (R) -A- (R ') - in which R and R ', which are the same or different, represent a carbon chain of 1 to 3 carbon atoms, preferably a methylene group in which the carbon atom is optionally replaced by an oxygen atom or an NH group and which is optionally substituted by 1 to 3 groups selected from the group consisting of group, oxo group and alkylo3 carbon ^{atom (R} XOH ^R xo) ^'R io C "10 M R x R 2 • R 3 R 4 R with W 5th a halogen atom, a hydroxyl group containing 1 to A is O, S, SO, SO ₂ , CO, R io R io - C = C - allet From where R and R _o are the same or different, are hydrogen, halogen, hydroxy, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms, Z is O or C (R) (R '), wherein R _xx and R 'r, which are the same or different, represent a hydrogen atom or a chlorine atom. Compounds according to any one of claims 1 to 3, in which at the same time it is a methyl group, a methyl group or an ethyl group, a phenyl group or a pyridyl group, a hydrogen atom or a formyl group, a halogen atom, an alkyl group containing 1 C 3 to C 3 or a haloalkyl group having 1 to 3 carbon atoms, and is an oxygen atom. A process for the preparation of compounds according to claim 1 of the general formula I, wherein R ₄ is different from a hydrogen atom, characterized in that the compounds of formula Ia are reacted with a compound of formula R 1 'in the presence of a base and in a solvent environment according to the reaction scheme S, in which it represents a formyl group, an acyl group containing 2 to 5 carbon atoms; 6 carbon atoms, aroyl, 2-6C alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, or 3-6C alkyloxyxalyl or alkoxyoxalyl, L 'represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, a sulphate group, an aryloxy or an arylthio group which is optionally substituted, preferably a phenoxy group, an alkoxy group or a dialkylamino group, R 4 O when R ??? represents an acyl group, an arylsulfonyl group or an alkylsulfonyl group. Process according to Claim 5, characterized in that a strong base such as an alkali or alkaline earth metal hydride or hydroxide, an alkoxide or a tertiary amine is used as the base, that the reaction is carried out at a temperature between -30 to 50 ° C and using a solvent selected from cyclic or non-cyclic ethers, dimethylformamide, dimethylsulfoxide, acetonitrile or an aromatic solvent. 7. A process for the preparation of compounds of formula II, characterized in that the 2-thiohydantoins of formula III, the S-alkylated in the presence of a base and in a solvent according to the reaction scheme wherein R, R _2, R _{3, Ατ} χ, Ar ₂ and X are as defined in of claim 1, W represents a sulfur atom or an oxygen atom and L represents a group selected from a halogen atom, preferably a chlorine atom, a bromine atom and an iodine atom, a sulfate group, an alkylsulfonyloxy group and an arylsulfonyloxy group. 8. A process for the preparation of compounds of formula IIa, characterized in that a compound of formula VII is treated sequentially in a solvent with a 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 according to the reaction scheme wherein R, R _a , R ₃ , τ _χ , Ar _a and X have the meanings given in claim 1 with the limitation that R _a is different from hydrogen, R _e is an alkyl group containing And 1-3 represents a halogen atom or an alkyl sulfate group, an alkylsulfonyloxy group or an arylsulfonyloxy group. 9. The process of claim 8 wherein the base is selected from the group consisting of an alkali metal or alkaline earth metal alkoxide, an alkali metal or alkaline earth metal hydroxide, and a tertiary amine, and wherein the reaction is carried out at a temperature between -10 and 80 ° C. which is selected from the group consisting, in particular, of cyclic and non-cyclic ethers, alcohol, ester, dimethylformamide, dimethylsulfoxide, acetonitrile and an aromatic solvent. 10. A process for the preparation of compounds of formula XI, characterized in that the 2-alkylthio-2-imidazolin-5-ones of formula II are reacted in a solvent with an alcohol R @ 1, OH in the presence of a strong base and a solvent according to is alkyl of 1 to 3 carbon 'atoms and the ^two other groups are as defined in claim 1. Process according to claim 10, characterized in that the reaction is carried out in a solvent which forms an alcohol of formula R ₂ OH, that the base is sodium alkoxide R ₂ O-Na * and that the reaction is carried out at a temperature between 20 and 80 C. Process for the preparation of compounds of formula XII, characterized in that hydrazine of formula R ₃ -NH-NH ₂ is reacted with an azalactone of formula XIII according to the reaction scheme R3NHNH 2 CH3COOH CH3COONa * 1 Ar) -X-Ar R Θ (XII) wherein R, R _a, R _{a, Ατ} χ, Ar _and X are as defined in claim 1, wherein the mixture of reactants is heated in acetic acid at reflux in the presence of sodium acetate catalyst. A process for the preparation of compounds of formula Ia ri Ar? X-At [w (Ia) characterized in that the organometallic derivative of the formula XV is condensed with an electrophilic group Ar 1 -X 1 'according to the following reaction scheme o, N-R; VJ!) Αγί-Χ “t ^{Ar, /} y ⁿ 'n-r, v ** ¹ * ^w M (XV) Ari-X- (V) n-Rz NH-Rj (Ia) wherein R, R, R, Y, Ar, Ar, W, and n have the meanings given in claim 2 3 X 2 to 1, Χ _χ means a metal selected from the group consisting of lithium, sodium, magnesium, zinc, titanium, tin, copper, boron and silicon, preferably lithium, Ar ₂ -X 'represents an electrophilic group provided by a compound selected in particular from the group consisting of an aralkyl halide or aralkyl sulfate of the formula Ar 1 -R 1 -L in which R _it is an aliphatic chain of 1 to 6 carbon atoms that is linear or branched, saturated or unsaturated chain, optionally substituted by halogen or alkoxy group or an oxo-group, and L is as defined in Step 7, a 7-carbonyl compound of formula Ar- (R) pCR-12 ^{/ r} || 13 wherein p is 0 or 1, and R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an alkoxy group, an aryloxy group or a dialkylamino group, - chloroformate of the general formula Ar - (R) p -O-C-Cl an isocyanate or isothiocyanate of the general formula Ar _and - (R _ia ) pN = C = Q wherein Q represents an oxygen atom or a sulfur atom, a sulfonyl halide of the formula Ο II Ar - (R) pS-Hal ² x ₂ ']] wherein Hal represents a halogen atom, preferably a chlorine atom, and an epoxide of formula A ^f 2 in which R and R ' _x0 have the meanings given in the claim has the same meaning as X'. Compounds particularly useful as intermediates in the preparation of the compounds of claim 1 and corresponding to formulas IIIa, IIIb, IV, VII, XIII, XIX, XX, XXII, XXIV and XXVII (IHb) S (IV) (VII) >. , ϊ (XXIV) (XXVII) in which R _e is as defined in claim 8, Z 'represents an oxygen atom, a sulfur atom or a NR group in which R represents a hydrogen atom or a C 1 -C 6 alkyl group and other groups as defined in claim 1 and the optical isomers of these compounds, in particular the enantiomers of asymmetric compounds carbon bearing R. Fungicidal composition, characterized in that it contains, as the active substance or substances, one or more compounds according to any one of claims 1 to 4 in admixture with agriculturally acceptable solid or liquid carriers and agriculturally acceptable surfactants. 16. Fungicidal compositions according to claim 15, characterized in that they contain from 0.05 to 95% by weight of active substances. A method of treating crop plants which are infected with or susceptible to fungal diseases, characterized in that an effective dose of a compound according to any one of claims 1 to 4 is applied to the above-ground part of the plants. Treatment method according to claim 17, characterized in that the active substance is 0.002 to 10% 5 kg / ha, preferably 0.005 S up to 1 kg / ha.