EP1226111A1

EP1226111A1 - Chiral (s- or r-methylphenylglycine) amino acid crystal and method for preparing same

Info

Publication number: EP1226111A1
Application number: EP00974643A
Authority: EP
Inventors: Isabelle Pelta; Jean-Claude Maret
Original assignee: Aventis CropScience SA
Current assignee: Bayer CropScience SA
Priority date: 1999-11-05
Filing date: 2000-11-03
Publication date: 2002-07-31
Also published as: FR2800734A1; BR0015216A; CA2389373A1; WO2001032603A1; JP2003523322A; FR2800734B1; AU1286901A

Abstract

The invention concerns chiral amino acid, its preparation method, and the use of said chiral amino acid as intermediate for the synthesis of chiral organic compounds.

Description

CHIRAL AMINO ACID CRYSTAL (S- OR R-METHYLPHENYLGLYCIN) AND PROCESS FOR PREPARING THE SAME

FIELD OF THE INVENTION The present invention relates to a chiral α-amino acid in crystalline form, its preparation process, as well as the use of said chiral α-amino acid as an intermediate for the synthesis of chiral organic compounds.

STATE OF THE ART Amino acids are compounds which are very widely used in a very large number of fields. In particular, they are playing an increasingly important role in the synthesis of compounds for pharmaceutical, veterinary and phytopharmaceutical use. In these fields of human, animal and plant health, very active products are constantly sought at low doses. One way to combine these two aspects is to use, in the case of compounds having at least one center of asymmetry, only the optical isomer having the desired activity.

It is therefore necessary to find a simple, economical and effective way to synthesize this active optical isomer. This compound generally has a relatively complex chemical structure, so that the center of chirality is introduced during the synthesis, that is to say that it is provided by a compound with a simpler chemical structure, a synthesis intermediate. for example.

Among the most preferred chiral intermediates, chiral amino acids occupy a prominent place in these areas of human, animal and plant health. The problem that arises is therefore to find methods of synthesizing chiral amino acids which are inexpensive, of easy access from the industrial point of view, and whose yields are high.

Processes for preparing amino acids from hydantoins are known, for example, in patents JP 60224661 and JP 62103049. These processes however lead to racemic amino acids.

[0006] Methods for preparing chiral amino acids are already known in the literature. They are mainly based on methods of solving racemic mixtures by liquid chromatography, resolution using alkaloids or by enzymatic process, as for example in the French patent application not yet published n ° 98 06339. These various methods of resolution or preparation of chiral compounds present the problem of leading to products in mixture in the reaction medium without it being possible to easily isolate the desired product.

An additional problem lies in the fact that the chiral amino acids are of an unsatisfactory degree of purity. Indeed, the synthesis of chemical compounds developed for human, animal and / or plant health uses imposes very high purity synthesis intermediates. It is also well known that the purity of such chiral intermediates is difficult to control; it is notably relatively difficult to find purities acceptable for such syntheses, that is to say purities greater than 99%.

However, it is well known that a means of obtaining high purity consists, for example, in purifying the product in the form of a crystal. Among these techniques, mention may be made, for example, of recrystallization, which makes it possible, by dissolution of the crystal and then slow recrystallization, to obtain a purity close to 100%.

A problem is therefore to be able to separate the desired product from the reaction medium, the product having to have a high chemical and enantiomeric purity To obtain this high purity, it is for example advantageous to be able to have the product in crystalline form. However, it is well known to those skilled in the art that obtaining amino acids in the form of crystals is a difficult operation and not described, for example for the amino acid called 2-methyl-2-phenylglycine from a medium. reaction.

General definition of the invention

A first object of the invention consists in providing a chiral α-amino acid in crystalline form, more particularly (S) - (+) - methylphenylglycine (or (S) - (+) - 2-phenylalanine) or the (7?) - (-) - methylphenylglycine (or

(?) - (-) - 2-phenylalanine) in crystalline form.

A second object of the invention is to propose a process for the preparation of

(S) - (+) - methylphenylglycine or (_ /?) - (-) - methylphenylglycine, in crystalline form from chiral hydantoins. A third object of the present invention is the synthesis of chiral organic compounds prepared from (S) - (+) - methylphenylglycine or

(_ /?) - (-) - methylphenylglycine in crystalline form. Detailed definition of the invention

Thus, a first object of the present invention relates to the crystal of (S) - (+) - 2-methyl-2-phenylglycine and the crystal of (i?) - (-) - 2-methyl-2- phenylglycine (hereinafter called (S) - (+) - methylphenylglycine and (i?) - (-) - methylphenylglycine), characterized in that the single crystal is an orthorhombic crystal system, the mesh parameters of which are a = 5.778 Â, b = 6,692 Â, c = 22,127 Â, of space group P2,2,2 ,, and having four molecules per cell.

More particularly, the present invention relates to the crystal of (S) - (+) - methylphenylglycine and the crystal of (i?) - (-) - methylphenylglycine characterized by the following crystallographic parameters of the single crystal: • Crystal system: orthorhombic ; • Mesh parameters: a = 5.778 À α = 90 ° b = 6.692 Â β = 90 ° c = 22.127 Â γ = 90 °

• Asymmetric unit: 1 molecule;

• Spatial group: P2,2,2,; • Number of molecules per cell: 4;

• Mesh volume: 855.6 Â ³ ;

• Density calculated: 1.282 g / cm ³ ;

• Absorption coefficient μ: 0.91 cm ^"1 (CuKα);

The above parameters are obtained by grinding the product and then analyzed in order to obtain a reference experimental diagram with respect to the resolution of the structure: from this powder is synthesized a single crystal in a solvent or a suitable solvent mixture, for example water, by very slow evaporation; an X-ray diffraction device specially designed for single crystals, all the diffraction lines are analyzed (position, intensity); the crystal parameters are finally obtained using computerized calculation programs.

The crystal defined above also has the following characteristics of not being a solvate, that is to say that the molecule of (S) - (+) - methylphenylglycine or of (_?) - (-) -methylphenylglycine is not linked (chemically and / or physically) to a solvent molecule, and to not contain any solvent in the crystal lattice. It has therefore been discovered the possibility of obtaining (S) - (+) - methylphenylglycine (pure enantiomer) or (_β) - (-) - methylphenylglycine (pure enantiomer) in crystalline form, which has the particular advantage of giving this product great chemical and physical stability over time. In particular, (S) - (+) - methylphenylglycine or (_ /?) - (-) - methylphenylglycine in crystalline form has the advantage of not being hygroscopic, this allowing handling, storage and easy handling and therefore a major advantage when this product enters, as a raw material, in the synthesis of organic compounds.

Another object of the present invention therefore relates to the process for the preparation of (S) - (+) - methylphenylglycine (or of (i?) - (-) - methylphenylglycine) in crystalline form, characterized in that than :

• (S) - (+) - methylphenylglycine (respectively (iî) - (-) - methylphenylglycine) is solubilized, in the form of free amino acid or in salified form, in a zone of pH below about 4, 5 or more than about 9, then

• the pH value is gradually reduced, by adding a base or an acid respectively, to an area greater than approximately 4.5 and less than approximately 9.

The pH value of the reaction medium measured at the start of the crystallization reaction will advantageously be either much less than 4.5, or very much greater than 9, very advantageously, either less than 2 or greater than 12.

In the process described above, it is necessary to add base or acid to a perfectly dissolved reaction medium, that is to say free of any trace of non-soluble compound. Thus, in addition to starting crystallization at pH values which are very acidic or very basic, it may be advantageous to add one or more suitable solvents, making it possible to dissolve the (S) - (+) - methylphenylglycine or the (i ?) - (-) - methylphenylglycine, in the form of a free amino acid or in a salified form. Such solvents are the solvents usually used to dissolve the amino acids, for example water and / or methanol and / or ethanol, etc.

Under the conditions described above, the first crystals appear when the pH reaches values between about 8.5 and 9 or between about 4.5 and 5 pH. These first crystals generally appear without the need initiate crystallization. At this stage of crystallization, the addition of base or acid can advantageously be slowed down or even stopped to allow formation, ripening, optimal growth of the crystals, this having a direct influence on the physical and chemical quality (yield, purity) of the crystals obtained.

The crystallization is then continued by continuing the addition of acid or base until a pH value of between approximately 5 and 7 is obtained, preferably between approximately 5 and 6 in order to transform all of the crystal into crystal. amino acid. The crystallization yield is then optimal.

When the starting reaction medium has a pH value greater than 9, the acid used in the crystallization reaction described above can be a mineral or organic acid. A mineral type acid is preferred, although an organic acid is also suitable. Mention may be made, by way of nonlimiting example, of acids which can be used hydrochloric acid or sulfuric acid.

When the starting reaction medium has a pH value of less than 4.5, the base used in the crystallization reaction described above can be an inorganic or organic base. A mineral type base is preferred, although an organic base is also suitable. Mention may be made, by way of nonlimiting example, of the bases which can be used, sodium hydroxide or potassium hydroxide.

During crystallization, it may be advantageous to add a compound facilitating the agglomeration of the crystals (for better filterability for example) This compound is advantageously chosen from the range of compounds which are known to facilitate l agglomeration of crystals. These compounds are thus for example chosen from aromatic organic compounds (monochlorobenzene, toluene, etc.).

It is possible to further increase the yields, in quantity of crystals, by operating the crystallization reaction from solutions of (S) - (+) - methylphenylglycine or of (_?) - (+) - methylphenylglycine highly concentrated in amino acid (free or salified). Crystallization will thus advantageously be carried out from solutions whose amino acid concentration is between 4% and 50% by volume. Concentrations below 4% also lead to the formation of crystals, but the yields will be lower. The upper limit of 50% is given as an indication, but it is good it is understood that concentration values greater than 50% are also compatible with the formation of the desired crystals.

It may also be advantageous to dissolve the (S) - (+) - methylphenylglycine or the (i?) - (-) - methylphenylglycine, in salified form, using a solvent, water by example, saturated with salt, for example sodium chloride, sodium sulfate or the like.

In addition, in order to dissolve the entire reaction medium, it may also be advantageous to heat the reaction medium to obtain perfect solubility before proceeding to the crystallization step. This heating step is particularly suitable when the solvent is saturated with salt. The temperature to which the reaction medium is heated must be sufficient to allow the total solubilization of the amino acid salt as well as of all the entities present in the medium. Advantageously, the reaction medium is heated to a temperature between 50 ° C and 100 ° C, preferably between 65 ° C and 85 ° C.

In the case where the reaction medium, containing the dissolved amino acid and to be crystallized, contains other non-soluble entities, it is then possible to add a co-solvent. This co-solvent will have the effect of obtaining a reaction medium free of any insoluble material, which is necessary to start the crystallization reaction. This co-solvent is advantageously chosen from conventional solvents miscible with water, such as for example an alcohol, such as methanol, ethanol, or also solvents such as dimethylformamide or dimethylsulfoxide.

When the crystallization reaction is complete, the reaction medium containing the (S) - (+) - methylphenylglycine (or (?) - (-) - methylphenylglycine) in the form of a crystal in suspension, is then filtered, according to conventional filtration methods, then the crystals are washed and dried. according to conventional techniques known per se. In the case where the crystallization reaction has been carried out hot, it is then advantageous to carry out the hot filtration, at a substantially equivalent temperature.

(S) - (+) - methylphenylglycine or (7?) - (-) - methylphenylglycine (free forms or salified forms) to be crystallized, are themselves obtained according to conventional techniques known to man of the trade and easily accessible in the literature, "Chemical Abstracts", as well as in electronic databases.

For example, the salt of (S) - (+) - methylphenylglycine or (i?) - (-) - methylphenylglycine can be obtained by hydrolysis of phenylhydantoins, as described in the patent application not yet published N ° 9900202 the content of which is included here by reference. Other examples of preparation of (S) - (+) - methylphenylglycine or of (i?) - (-) - methylphenylglycine are those using asymmetric synthesis, splitting, balancing enrichment, catalysis reactions enzymatic, as described for example in French patent application No. 2778671, the content of which is included here by reference. It is understood that the (S) - (+) - methylphenylglycine or the (i?) - (-) - methylphenylglycine which can be used in the process of the present invention can be obtained according to any methods known in the art. skilled in the art.

(S) - (+) - methylphenylglycine or (?) - (-) - methylphenylglycine in crystalline form as described above find a particularly interesting application as intermediates in the synthesis of materials active chirals useful in particular in therapy or in agriculture.

Another object of the present invention therefore relates to the process for the preparation of certain 2-imidazoline-5-ones and 2-imidazoline-5-thiones of formula (A) from (S) - (+) - methylphenylglycine or (?) - (-) - methylphenylglycine substantially obtained in crystal form according to the process of the present invention. The compounds of formula (A) defined below are useful in particular as phytosanitary products and are described in particular in patent application EP-A-0 629 616.

These compounds correspond to the general formula (A):

in which : • W represents an oxygen or sulfur atom, or a group S = O;

• M represents an oxygen or sulfur atom, or a CH ₂ radical, optionally halogen;

• p is an integer equal to 0 or 1; • R ₃ represents:

a hydrogen or an optionally halogenated C, -C ₂ alkyl radical, when p equals 0 or (M) _p is a CH ₂ radical,

- an optionally halogenated C, -C ₂ alkyl radical, when (M) _p represents an oxygen or sulfur atom; • R ₄ represents:

- the hydrogen atom, or

- an alkyl radical containing from 1 to 6 carbon atoms, or

- an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl, alkenyl or alkynyl radical containing from 2 to 6 carbon atoms, or a dialkylaminoalkyl, alkoxycarbonylalkyl, or N-alkylcarbamoylalkyl radical containing from 3 to 6 carbon atoms, or - an N radical , N-dialkylcarbamoylalkyl containing from 4 to 8 carbon atoms, or - an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, or methylene dioxyphenyl with 1 to 3 groups chosen from R ₆ , or an arylalkyl, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl radical, the terms aryl and alkyl having the definitions given above;

• R ₅ represents:

- hydrogen, or an alkyl, haloalkyl, alkylsulfonyl, haloalkylsulfonyl radical containing from 1 to 6 carbon atoms or, - an alkoxyalkyl, alkylthioakyl, acyl, alkenyl, alkynyl, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl, cyanoalkyl radical with 6 carbon atoms or an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, cyanoalkoxycarbonyl radical containing from 3 to 6 carbon atoms or, - the formyl radical or a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl, alkynylcarbonyl radical containing from 3 to 6 carbon atoms or . - a cycloalkylcarbonyl radical containing from 4 to 8 carbon atoms or,

- a phenyl radical; arylalkylcarbonyl, in particular phenylacetyl and phenylpropionyl, arylcarbonyl, in particular benzoyl, optionally substituted with 1 to 3 groups among R thienylcarbonyl, furylcarbonyl, pyridylcarbonyl, benzyloxycarbonyl, furfuryloxycarbonyl, tetrahydro-furfuryloxycarbonyl, thiénylméthoxycarbonyle, pyridylméthoxy- carbonyl, phenoxycarbonyl or phénylthiolcarbonyle, the phenyl radical being itself optionally substituted with 1 to 3 groups chosen from R 1, alkylthiolcarbonyl, haloalkylthiolcarbonyl, alkoxyalkylthiolcarbonyl, cyanoalkylthiolcarbonyl, benzylthiolcarbonyl, furfurylthiolcarbonyl, tetrahydrofurfurylthiolcarbonyl, thienylmethylthiolmethylcarbonyl or ethylcarbonylarbonylethylcarbyl

- a carbamoyl radical optionally mono or disubstituted by: - an alkyl or haloalkyl group containing from 1 to 6 carbon atoms,

- a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 carbon atoms,

- an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing from 2 to 6 carbon atoms or, - a phenyl optionally substituted by 1 to 3 group R ^;

- a sulfamoyl group optionally mono or disubstituted by:

- an alkyl or haloalkyl group containing from 1 to 6 carbon atoms,

- a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 carbon atoms,

- an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group of 2 to 6 carbon atoms or

- a phenyl optionally substituted with 1 to 3 group X;

- an alkylthioalkylsulfonyl group containing from 3 to 8 carbon atoms or cycloalkylsulfonyl containing from 3 to 7 carbon atoms;

- R ₄ and R ₅ taken together can also form with the nitrogen atom to which they are attached a pyrrolidino, piperidino, morpholino or piperazino group optionally substituted by an alkyl radical containing from 1 to 3 carbon atoms.

R ₆ represents:

- a halogen atom or - an alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio or alkylsulfonyl radical containing from 1 to 6 carbon atoms or

- a cycloalkyl radical. halocycloalkyle, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio containing from 3 to 6 carbon atoms or

- the nitro or cyano group or

an amino radical optionally mono or disubstituted by an alkyl or acyl radical containing from 1 to 6 carbon atoms or alkoxycarbonyl containing from 2 to 6 carbon atoms,

a phenyl, phenoxy or pyridyloxy radical, these radicals being optionally substituted with 1 to 3 groups, identical or different, chosen from R ₇ , and

R ₇ represents:

- a halogen atom chosen from fluorine, chlorine, bromine, iodine or,

- an alkyl radical containing from 1 to 6 carbon atoms, or

- an alkoxy or alkylthio radical containing from 1 to 6 carbon atoms or,

- a haloalkoxy or haloalkylthio radical containing from 1 to 6 carbon atoms or,

- a nitrile or nitro radical.

The process for preparing the compounds of formula (A) can be represented by the following diagram:

scheme in which the radical R represents the methyl radical. the radical R ₂ represents the phenyl radical, the radicals R ,, R ₄ , R ,, M, p and W are as defined for the compounds of formula (A), R represents a hydroxy, alkoxy radical containing from 1 to 6 carbon atoms, benzyloxy, an amino, alkylamino or dialkylamino radical, an alkylamino radical containing from 1 to 6 carbon atoms, and X represents a leaving group such as a halogen atom, chosen from chlorine, bromine and iodine, or a sulfate radical, or alkylsulfonyloxy or arylsulfonyloxy.

In the previous diagram:

• steps (a), (b), (c) and (d) are described in patent WO-98/03490, the details of which are incorporated here by reference;

• step (e) is described in patent EP-A-0 629 616, the details of which are incorporated here by reference.

A very particularly preferred compound of formula (A) which can be synthesized from the amino acid in crystal form according to the present invention is (4S) -4-methyl-2-methylthio-4-phenyl- l-phenylamino-2-imidazoline-5-one, special case of the compounds of formula (A) for which the asymmetric carbon atom is of configuration S, W represents the oxygen atom, M represents the sulfur atom , p represents 1, R ₃ represents the methyl radical, R ₄ represents the phenyl radical. and R ₅ represents hydrogen.

The following example aims to illustrate the present invention and should in no way be understood as having a limiting nature.

Example: Formation of crystals of (S) - (+) - methylphenyIgIycin

A basic saline solution comprising the sodium salt of (S) - (+) - methylphenylglycine is brought to approximately 70 ° C.

The reaction medium is neutralized with sulfuric acid (95%), with slow stirring (300 revolutions / minute). The addition of sulfuric acid is carried out over a period of approximately 5 hours, in two parts:

(1) about 15% of the total volume of sulfuric acid is added until the pH value of the reaction medium goes from 10 to 8.8. The first crystals then appear. The addition of acid is then stopped in order to allow the crystals to grow. The reaction medium is maintained for one hour at 72 ° C., with stirring, at a pH between 8.8 and 8.6;

(2) the remaining quantity of sulfuric acid is then added over a period of 4 hours, until a stable pH of value 5 to 6 is obtained for at least half an hour. If the pH tends to drop below 5, a small amount 20% sodium hydroxide can be added to maintain the pH in a range of 5 to 7.

The suspension of crystals of (S) - (+) - methylphenylglycine is then filtered hot (around 70 ° C). The crystals obtained are washed once with water (temperature 20 to 25 ° C) to remove the mother liquors, then once with methanol (temperature 20 to 25 ° C) to remove the water. The amino acid in crystalline form is finally dried under reduced pressure (50 mbar) at 100 ° C to be stored.

Claims

01 / 32603REVENDICATIONS

1. Compound which is (S) - (+) - methylphenylglycine in crystalline form, characterized in that the single crystal is an orthorhombic crystal system, the mesh parameters of which are a = 5.778 Â, b = 6.692 Â, c = 22.127 Â, of space group P2,2,2 |, and having four molecules per mesh.

2. Compound which is (i?) - (-) - methylphenylglycine in crystalline form, characterized in that the single crystal is an orthorhombic crystalline system, the mesh parameters of which are a = 5.778 Â, b = 6.692 Â, c = 22.127 Å, of space group P2 ₁ 2.2 _I , and having four molecules per cell.

3. Compound according to one of claims 1 or 2, characterized by the following crystallographic parameters of the single crystal:

Crystal system: orthorhombic

Mesh parameters: a = 5.778 Â α = 90 °; b = 6.692 Â β = 90 °; c = 22.127 A γ = 90 °;

Asymmetric unit: 1 molecule;

Spatial group: P2.2.2,;

Number of molecules per cell: 4;

Mesh volume: 855.6 to ³ ;

Calculated density: 1.282 g / cm ³ ;

Absorption coefficient μ: 0.91 cm ^" '(CuKα);

4. Process for the preparation of (S) - (+) - 2-methyl-2-phenylglycine or

(_ /?) - (-) - 2-methyl-2-phenylglycine in crystalline form, characterized in that: • solubilized (S) - (+) - 2-methyl-2-phenylglycine (respectively (i?) - (-) - 2-methyl-2-phenylglycine), in the form of free amino acid or in salified form, in a zone of pH lower than approximately 4.5 or higher than approximately 9, then • one brings back gradually, by adding a base or an acid respectively, the pH value in a zone greater than approximately 4.5 and less than approximately 9.

5. Method according to claim 4, characterized in that the solubilization is carried out in a zone of pH less than 2 or greater than 12.

6. Method according to one of claims 4 or 5, characterized in that the amino acid, in the form of free amino acid or in salified form is dissolved by a solvent.

7. Method according to claim 6, characterized in that the solvent is water and / or methanol and / or ethanol.

8. Method according to claim 7, characterized in that the solvent is saturated with salt.

9. Method according to one of claims 4 to 8, characterized in that, after the appearance of the first crystals, the addition of base or acid is slowed down or even stopped.

10. Method according to one of claims 4 to 9, characterized in that the addition of acid or base is maintained until a pH value of between approximately 5 and 7, preferably between approximately 5, is obtained. and 6.

11. Method according to one of claims 4 to 10, characterized in that the acid used is a mineral or organic acid, preferably a mineral acid, hydrochloric acid or sulfuric acid.

12. Method according to one of claims 4 to 10, characterized in that the base used is a mineral or organic base, preferably a mineral base, sodium hydroxide or potassium hydroxide.

13. Method according to one of claims 4 to 12, characterized in that one adds, during crystallization a compound facilitating the agglomeration of the crystals chosen from aromatic organic compounds.

14. Method according to one of claims 4 to 13, characterized in that the crystallization is carried out from solutions whose amino acid concentration is between 4% and 50% by volume.

15. Method according to one of claims 4 to 14, characterized in that the crystallization is carried out from solutions whose amino acid concentration is between 4% and 50% by volume.

16. Method according to one of claims 4 to 15, characterized in that the reaction medium is heated to a temperature between 50 ° C and 100 ° C, preferably between 65 ° C and 85 ° C.

17. Method according to one of claims 4 to 16. characterized in that a water-miscible co-solvent is added to the reaction medium.

18. Use of the compounds in crystalline form according to one of claims 1 to 3 for the preparation of the compounds of formula (A):

in which :

• W represents an oxygen or sulfur atom, or a group S = O;

• p is an integer equal to 0 or 1; • R ₃ represents:

- the hydrogen atom, or

- an alkyl radical containing from 1 to 6 carbon atoms, or

an alkoxyalkyl, alkylthioalkyl, haloalkyl, cyanoalkyl, thiocyanatoalkyl, alkenyl or alkynyl radical containing from 2 to 6 carbon atoms, or a dialkylaminoalkyl, alkoxycarbonylalkyl, or N-alkylcarbamoylalkyl radical containing from 3 to 6 carbon atoms, or - an N, N-dialkylcarbamoylalkyl radical containing from 4 to 8 carbon atoms, or

an aryl radical, comprising phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, or methylene dioxyphenyl, optionally substituted by 1 to 3 groups chosen from R_, or an arylalkyl radical, aryloxyalkyl, arylthioalkyl or arylsulfonylalkyl, the terms aryl and alkyl having the definitions given above; represented :

hydrogen, or an alkyl, haloalkyl, alkylsulfonyl, haloalkylsulfonyl radical containing from 1 to 6 carbon atoms or,

- an alkoxyalkyl, alkylthioakyle radical. acyl, alkenyl, alkynyl, haloacyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkylsulfonyl, cyanoalkylsulfonyl containing from 2 to 6 carbon atoms or an alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, cyanoalkoxycarbonyl containing from 3 to 6 carbon atoms or,

the formyl radical or a cycloalkyl, alkoxyacyl, alkylthioacyl, cyanoacyl, alkenylcarbonyl, alkynylcarbonyl radical containing from 3 to 6 carbon atoms or,

- a cycloalkylcarbonyl radical containing from 4 to 8 carbon atoms or,

- a phenyl radical; arylalkylcarbonyl, in particular phenylacetyl and phenylpropionyl, arylcarbonyl, in particular benzoyl, optionally substituted with 1 to 3 groups from R ₆ , thienylcarbonyl, furylcarbonyl, pyridylcarbonyl, benzyloxycarbonyl, furfuryloxycarbonyl, tetrahydro-carboxycarbonylphenylcarbonoxycarbonylphenylcarbonyl, phenylcarbonyl, phenylcarbonyl, phenylcarbonyl, phenyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropyloxycarbonyl, phenylpropionyl, phenylpropionyl, phenyl propionyl, phenyl propionyl itself being optionally substituted by 1 to 3 groups chosen from R ^ ,. alkylthiolcarbonyl, haloalkylthiolcarbonyl, alkoxyalkylthiolcarbonyl, cyanoalkylthiolcarbonyl, benzylthiolcarbonyl, furfurylthiolcarbonyl, tetrahydrofurfurylthiolcarbonyl, thienylmethylthiolcarbonyl, pyridylmethylthiolcarbonyl, or arylsulfon

- a cycloalkyl group. alkenyl or alkynyl containing from 3 to 6 carbon atoms, an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group containing from 2 to 6 carbon atoms or,

- a phenyl optionally substituted with 1 to 3 group R ^;

a sulfamoyl group optionally mono or disubstituted by: an alkyl or haloalkyl group containing from 1 to 6 carbon atoms,

- a cycloalkyl, alkenyl or alkynyl group containing from 3 to 6 carbon atoms,

- an alkoxyalkyl, alkylthioalkyl or cyanoalkyl group of 2 to 6 carbon atoms or

- a phenyl optionally substituted with 1 to 3 group 1 ^;

• X represents:

- a cycloalkyl, halocycloalkyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio radical containing from 3 to 6 carbon atoms or

- the nitro or cyano group or - an amino radical optionally mono or disubstituted by an alkyl or acyl radical containing from 1 to 6 carbon atoms or alkoxycarbonyl containing from 2 to 6 carbon atoms,

• R ₇ represents:

- a halogen atom chosen from fluorine, chlorine, bromine, iodine or,

- an alkyl radical containing from 1 to 6 carbon atoms, or

- an alkoxy or alkylthio radical containing from 1 to 6 carbon atoms or, - a haloalkoxy or haloalkylthio radical containing from 1 to 6 carbon atoms or,

- a nitrile or nitro radical.

19. Use according to claim 18, characterized in that the compound of formula (A) is (4S) -4-methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one , special case of the compounds of formula (A) for which the asymmetric carbon atom is of configuration S, W represents the oxygen atom, M represents the sulfur atom, p represents 1, R ₃ represents the methyl radical , R ₄ represents the phenyl radical, and R ₅ represents hydrogen.

20. Use according to one of claims 18 or 19, characterized in that the compounds of formula (A) are obtained according to the following scheme:

scheme in which the radical R represents the methyl radical, the radical R ₂ represents the phenyl radical, the radicals R ₃ , R ₄ , R ₅ , M, p and W are as defined for the compounds of formula (A) , R represents a hydroxy, alkoxy radical containing from 1 to 6 carbon atoms, benzyloxy, an amino, alkylamino or dialkylamino radical, an alkylamino radical containing from 1 to 6 carbon atoms, and X represents a leaving group such as an atom of halogen, chosen from chlorine, bromine and iodine, or a sulfate radical, or alkylsulfonyloxy or arylsulfonyloxy.