IE76143B1 - Novel phenylimidazolidines process for their preparation their use as medicaments and pharmaceutical compositions containing them - Google Patents

Abstract

Products of formula (I): <IMAGE> in which: R1 denotes cyano, nitro or halogen, R2 denotes trifluoromethyl or halogen; the group -A-B- is chosen from the radicals <IMAGE> in which X denotes oxygen or sulphur and R3 is chosen from: - a hydrogen< - alkyl, alkenyl, alkynyl, aryl or arylalkyl, optionally substituted; Y denotes oxygen or sulphur or NH, with the exception of the products in which: the group -A-B- denotes the radical <IMAGE> in which X denotes oxygen, R3 denotes hydrogen, Y denotes oxygen or NH, R2 denotes halogen or trifluoromethyl and R1 denotes nitro or halogen; the preparation, their application as medications and especially antiandrogens.

Description

The present invention relates to novel phenylimidazolidines, a process for their preparation, their use as medicaments and pharmaceutical compositions containing them.

In Japanese Application J 48087030# 3-phenyl-210 thiohydantoins are described which are shown as inhibiting the germination of certain plants. es W2ll as in EP_A_ Qgi 813 In. French Patent 2,, 329,276,/imidasolidin.es are described which are shown as having an anti-androgenic activity. The products of this patent, however, are different from the products of the present patent application.

The present invention therefore relates to the products of general formula (I): in which: represents a cyano or nitro radical or a halogen atom# R2 represents a tri fluoromethyl radical or a halogen atom, the group -A-B- is chosen froa amongst the radicals x in which X represents an oxygen or sulphur atom and R3 is 35 chosen from, amongst the following radicals; - a hydrogen at©»# - alkyl# alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms# these radicals optionally being 761 43 substituted by one or more substituents chosen from amongst hydroxyl, halogen, mercapto, cyano, acyl or acyloxy radicals having at most 7 carbon atoms, optionally substituted S-aryl in which the sulphur atom is optionally oxidised in the form of sulphoxide or of sulphone, free, esterified, amidified oxsal if ied carboxyl, amino, mono- or dialkylamino or a heterocyclic radical comprising 3 to 6 members and containing one or more heteroatoms chosen from amongst sulphur, oxygen or nitrogen atoms, the alkyl, alkenyl or alkynyl radicals additionally being optionally interrupted by one or more oxygen, nitrogen or sulphur atoms optionally oxidised in the form of sulphoxide or of sulphone, the aryl and aralkyl radicals additionally being optionally substituted by an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical, Y represents an oxygen or sulphur atom or an =NH radical, with the exception of the products in which the group -A-Brepresents the radical: x in which X represents an oxygen atom and R., represents a 25 hydrogen atom and Y represents an oxygen atom or an NH radical and represents a halogen atom or a trifluoromethyl radical and Rx represents a nitro radical or a halogen atom.

For the definition of R3 and in that which follows, the definitions used can have the following meanings.

Alkyl having at most 12 carbon atoms is understood, for example, as meaning linear or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl or dodecylAlkyl radicals having at most 4 carbon atoms and in particular methyl, ethyl, propyl and isopropyl radicals are preferred.

Alkenyl having at most 12 carbon atoms is understood as meaning, for example, the following: - vinyl, allyl, l-propenyl, butenyl, pentenyl or hexenyl.

Alkenyl having at most 4 carbon atoms and in particular vinyl or allyl are preferred.

Alkynyl having at most 12 carbon atoms is understood as meaning, for example, the following: - ethynyl, propargyl, butynyl, pentynyl or hexynyl.

Alkynyl having at most 4 carbon atoms and in particular ethynyl and propargyl are preferred meanings.

Aryl is understood as meaning carbocyclic aryl radicals such as phenyl or naphthyl or heterocyclic aryls having 5 or 6 members containing one or more heteroatoms preferably chosen from amongst oxygen, sulphur and nitrogen. Among the heterocyclic aryls having 5 mesabers, the furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl and isoxazolyl radicals may be mentioned.

Among the heterocyclic aryls having 6 members, the pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl radicals may be mentioned.

Among the condensed aryl radicals, the indolyl, benzofuranyl, benzothienyl and quinolinyl radicals may be mentioned.

The phenyl radical is preferred.

Arvlalkyl is understood as meaning the radicals resulting from the combination of the alkyl radicals mentioned above and the aryl radicals also mentioned above.

The benzyl or phenylethyl radicals are preferred.

Halogen is understood, of course, as meaning fluorine, chlorine, bromine or iodine atoms.

Fluorine, chlorine or bromine atoms are preferred.

As particular examples of alkyl radicals substituted by one or more halogens, monofluoro-, chloro-, bromo- or iodomethyl, difluoro-, dichloro- or dibromomethyl, and trifluoromethyl may be mentioned.

As particular examples of substituted aryl or aralkyl radicals, those may be mentioned in which th® phenyl radical is substituted in the para position hy a fluorine atom or hy a methoxy or trifluoromethyl radical.

Acyl radical is preferably understood as meaning a radical having at most 7 carbon atoms such as the acetyl, propionyl, butyryl or benzoyl radical, but may also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical: the formyl radical may also be mentioned.

Acyloxy radical is understood as meaning the radicals in which the acyl radicals have the meaning indicated above and, for example, the acetoxy or propionyloxy radicals.

Esterified carboxyl is understood as meaning, for example, radicals such as the alkyloxvcarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butoxycarbonyl.

Radicals formed with easily cleavable ester residues may also be mentioned, such as the methoxymethyl or ethoxymethyl radicals? acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxvethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as the methoxycarbonyloxymethyl or -ethyl radicals, or the isopropyloxycarhonyloxymethyl or -ethyl radicals.

A list of such ester radicals may be found, for example, in European Patent EP 0,034,536.

Ami di fied carboxyl is understood as meaning radicals of the type -CON in which identical or different radicals R- and R5 Rs represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals. mono- or Among the -N radicals, the amino, \ dimethylamino radicals are preferred.

The radical may also represent a heterocycle which may or may not contain an additional heteroatom. The pyrrolyl, imidazolyl, pyridyl, pvrazinyl, pyrimidil, indolyl, piperidine, morpholino and piperazinyl radicals may he mentioned. The piperidino or morpholine radicals are preferred.

Sal if ied carho2 The sodium salt is preferred.

Alkylamino radical is understood as meaning the methylamino, ethylamino, propylamine or linear or branched butylamino radicals. Alkyl radicals having at most 4 carbon atoms are preferred; the alkyl radicals can be chosen from amongst the alkyl radicals mentioned above.

Dialkylamino radical is understood as meaning, for example, the dimethylamino, diethylamino or methylethylamino radicals. As above, alkyl radicals having at most 4 carbon atoms chosen from the list indicated above are preferred.

Heterocyclic radical containing one or more heteroatoms is understood as meaning, for example, saturated monocyclic heterocyclic radicals such as the oxiranyl, oxolanyl, dioxolanyl, iraidazolidinvl, pvrazolidinyl, piperidyl, piperazinyl or morpholinyl radicals.

Alkyl, alkenyl or alkynyl radicals optionally interrupted by a heteroatom chosen from amongst sulphur, oxygen or nitrogen atoms, are understood as meaning radicals containing one or more of these atoms, which ar® identical or different in their structure™ These heteroatoms can obviously not be situated at the end of th® radical. Alkoxyalkyl radicals such as, for example, methoxymethyl or methoxyethyl or else alkoxyalkoxyalkyl radicals such as »ethoxyethoxy»ethyl may be mentioned.

I* When the products of formula (I) contain an amino radical which can be salified by an acid, it is quite understood that these acid salts are also part of the invention. The salts produced with hydrochloric and methanesulphonic acids may be mentioned for example.

The invention in particular relates to the products of formula (I) as defined above in which ¥ represents an oxygen atom, with the exception of the products in which: the group -A-B- represents th© radical: in which X represents an oxygen atom and R3 represents a hydrogen atom and R2 represents a halogen atom or a trifluoromethyl radical and R, represents a nitro radical or a halogen atom.

Among these products, the invention particularly relates to those in which the group -A-B- represents the radical: in which X represents a sulphur atom and Rg has the meaning indicated above.

Among these products, the invention particularly relates to those in which R represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms and being optionally substituted by a hydroxyl radical.

Among these products, the invention very particularly relates to those in which Rx represents a cyano radical or a halogen atom and in particular a chlorine atom.

The invention also particularly relates to the 35 products of formula (I) as defined above in which the group A-3- represents a croup: \ -C»SR„ < II 3 -N or a group: in which R3 represents an alkyl or alkenyl radical having at most 4 carbon atoms or an optionally substituted aralkyl radical.

The present invention moreover relates to the products of formula (I) as defined above and corresponding to the formula (19) : o in which R^, R3 and R3 have the meaning indicated above with the exception of the products in which represents a nitro radical, R2 represents a trifluoromethyl radical and Rs represents a hydrogen atom.

Among these products, the present invention also relates to the products of formula (I) as defined above in which Rx represents a nitro radical and R3 represents an alkyl or alkenyl radical having at most 4 carbon atoms optionally substituted by a free, esterified or salified carboxyl radical.

Among the preferred products of the invention, the products, of formula (I) as defined above and whose names follow may be mentioned more precisely: 4-(5-oxo-2-thioxo-3,4,4-triaethyl-l-imidazolidinyl)-2(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl-5-oxo-2-thioxo-l-iaidazolidinvl) -2(trifluoromethyl) benzonitrileg 4- [4,, 4 -dimethy 1-3- (2-hydroxyethyl) -5-oxo-2-thioxo-limidazolidinyl]-2-(trifluoromethyl) benzonitrile, 3-(3,4-dichlorophenyl)-2-thioxo-l,5,5-trimethyl-48 imidasolidinone t 1--(4-nitro-3-(trifluoromethyl) phenyl) -3,4,4-trimethyl2,5-imidazolidinedione, 4-[[4,5~dihydro~4,4-dimethyl-5-oxo-2"(phenylmethyl)thio]IH-imidazol-l-yl]-2-(trifluoromethyl)benzonitrile.

The invention also relates to a process for the preparation of the products of general formula (I) as defined above, characterised in that: either a product of formula (II): R N = C = X (II) in which R^, R^ and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III): h3c-c-ch3 (III) in which R3 has the meanings indicated above for R3 in which the possible reactive functions are optionally protected and it being understood that if R, represents a nitro radical or a halogen atom and if R2 represents a halogen atom or a CF3 radical and X represents an oxygen atom, R*3 cannot represent a hydrogen atom, to obtain a product of formula (IV): x (IV) in which R1? R2, X and R*3 have the above meaning, which products of formula (IV), if necessary or if desired, are submitted to any one or more of the following reactions in any order: a) elimination of the possible protective groups which R«3 may carry; b) hydrolysis of the >C=NH group to a ketone function and, if necessary, conversion of the >C=S group to a >C=0 group; c) conversion of the >C=0 group or groups to a >C=S group; d) action on the products of formula (IV) in which R'3 represents a hydrogen, atom, and after hydrolysis of the >C=NH group to the ketone function, a reagent of formula Hal-R^g in which R"3 has the meanings of R3 with the exception of the meaning hydrogen and Hal represents a halogen atom, to obtain products of formula (I) in which the group -A~B- represents the group in which Rli,J3 has the meaning indicated above and, if desired, action on these products by an agent eliminating the possible protective groups which may carry or, if necessary, action tav an esterifying, amidifying or salifying agent, or a reagent of formula Hal-R*«3 in which Hal and R'3 have the meanings indicated above is reacted with a product of formula (IVs): to obtain a product of formula (IV); (IV«) V which product of formula. (IV3!) , if necessary or if desired, is submitted to any one or more of the following reactions in any order: a) elimination of the possible protective groups which may carry, and then, if necessary, action by an esterifying, amidifying , or salifving agent; b) conversion of the >C=0 group or groups to >C=S groups.

The reaction of the products of formula (II) with the products of formula (III) is preferably carried out in an organic solvent such as tetrahydrofuran or dichloroethane, but ethyl ether or isopropyl ether may also be used..

The reaction is carried out in the presence of a tertiary base such as triethylamine or else pyridine or methylethylpvridine.

The possible reactive functions which R3 may contain and which are optionally protected in the product of formula (III) or (IVs) are the hydroxyl or amino functions.

Conventional protective groups are used to protect these functions. The following protective groups for the amino radical may be mentioned as examples: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl or benzyloxycarbonyl.

As a protective group for the hydroxyl radical, radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert-butyldimethylsilyi may be mentioned.

It is quite understood that the above list is not limiting and that other protective groups, for example those known in peptide chemistry, may be used. A list of such protective groups is found, for example, in French Patent 3F 2,499,995, of which the content is incorporated here by way of reference.

The possible elimination of the protective groups are carried out as indicated in the said Patent BF 2,499,995. The preferred mode of. elimination is acid hydrolysis using acids chosen from amongst hydrochloric, benzenesulphonic or paratoluenesulphonic, formic or trifluoroacetic acids. Hydrochloric acid is preferred.

The possible hydrolysis of the >ONH group to a ketone group is also preferably carried out using an acid such as aqueous hydrochloric acid, for example, at reflux.

When the hydrolysis of the >C=NH group to a ketone group is carried out on a molecule also containing a >C=S group, this can be converted to a >C=O group. The free OH radical which may optionally contain R3 may then be converted into an SH radical.

The conversion of the >C=O group or groups to a >C=S group is carried out using the said Lawesson reagent of formula: s s 11/ P \ which is a product marketed, for example, by the company FLUKA and the use of which is described, for example, in the publication: Bull. Soc. Chim. Belg. Vol. 87, No. 3, (1987) p. 229.

When it is wished to convert two >C=O functions to two >C=S functions, the reaction is carried out in the presence of an excess of Lawesson reagent. The same applies when starting from a molecule containing a >C=S function and a >C=0 function in which it is wished to convert the said >C=0 function to a >C=S function.

On the other hand, when starting from a molecule containing two >C-0 functions in which it is wished to obtain a product only containing a single >C~S function the reaction is carried out in the presence of a shortage of Lawesson reagent. A mixture of three products is then generally obtained: each of the two products containing a >C-0 function and a >C-S function and the product containing two >G~S functions. These product can then be separated by the usual methods such as chromatography.

The action on the products of formulae (IV) or (IV) of the reagent of formula Hal-RM3 is carried out in the presence of a strong base such as sodium hydride or potassium hydride. The reaction can be carried out under phase transfer conditions in the presence of quaternary ammonium salts such as the tert-butylammonium salt.

- The protective groups which the substituent R·»^ may carry may be, for example, one of those mentioned above for Rg. The elimination of the protective groups are carried out under the conditions indicated above.

An example of elimination of the tert-butyldimethylsilyl group by means of hydrochloric acid is given below in the examples.

- The possible esterification of the products of formula (1) in which RM3 contains a free OH radical is carried out under conventional conditions. It is possible to use, for example, an acid or a functional derivative, for example an anhydride such as acetic anhydride in the presence of a base such as pyridine.

The optional esterification or salification of the products of formula (I) in which R**3 represents a COOK group is carried out under the conventional conditions known to the person skilled in the art. - of - The optional amidification / products of formula (I) in which R3 contains a COOH radical is carried out under conventional conditions. It is possible to use a primary or secondary amine on a functional derivative of the acid, for example a symmetrical or mixed anhydride.

The present invention also relates to a process for the preparation of the products of formula (I): Ά** N W~ (I") in which R«1?, RM2 and -AM-BM- have the meanings indicated above for iU and -A-B~, At being understood .that when -ΑΜί-ΒΜ- represents a -CO-N(R"’3)- group in which R**'s represents a hydrogen atom or a linear or branched alkyl radical having at most 7 carbon atoms and Y represents an oxygen atom, represents a cyano radical, this process being characterised in that a product of formula (V)ϊ (V) in which and SM2 have the above meanings and Hal represents a halogen atom, is reacted with a product of formula (VI): A H HN \ CH.

(VI) CH in which and Y have the meaning indicated above, the reaction taking place in the presence of a catalyst and, if appropriate, of a solvent.

As far as the products of formula (V) are concerned, the term Hal preferably denotes the chlorine atom, but may also represent a bromine or iodine atom.

The role of the catalyst is probably to trap the hydrogen halide which is evolved and thus to facilitate the condensation of the product of formula (V) with the product of formula (VI) to give the required product.

The invention more precisely relates to a process such as defined above in which the catalyst is a metal in the native or oxidised form or a base.

The catalyst used may be a metal in native form, in the form of metallic oxide or else in the form of metallic salts. The catalyst may also be a base. When the catalyst used is a metal, this metal may be copper or nickel.

Th© metallic salts may be a chloride or an acetate.

When the catalyst is a base, this base may be, for example, soda or potash and it is possible, if desired, to add dimethyl sulphoxide to the reaction exactor©.

The invention more precisely relates to a process such as defined above in which the catalyst is chosen from amongst cuprous oxide, cupric oxide, copper In native form and a base such as soda or potash.

The copper in native form used as a catalyst is preferentially in powder form.

The invention particularly relates to a process such as defined above in which the catalyst is cuprous oxide.

The solvent used is preferentially chosen from amongst high-boiling-point ethers such as, for example, diphenyl ether, diglyme, triglyme and dimethyl sulphoxide, but can also be, for example, a high-boiling-point oil such as paraffin or petroleum jelly.

The invention more particularly relates to a process such as that defined above, characterised in that the reaction is carried out in the presence of a solvent of the ether type such as diphenyl ether, diglyme, triglyme or dimethyl sulphoxide.

The invention very particularly relates to a process such as that defined above in which the solvent used is diphenyl ether or triglyme.

The process for the preparation of the required product defined above can be carried out under pressure or at atmospheric pressure, at a preferentially elevated temperature.

The invention thus relates to a process such as that defined above, characterised in that the reaction is carried out at a temperature higher than 100 *C and preferably higher than 150"C.

The invention more precisely relates to a process such as that defined above, characterised in that the reaction is carried out for more than 2 hours.

The invention very precisely relates to a process such as that defined above, characterised in that the reaction Is carried out in the presence of cuprous oxide, in triglyme, at a temperature higher than or equal to 200’C and for more than 3 hours.

Th© products to which the present invention relates are endowed with interesting pharmacological properties; it has been verified in particular that they inhibit the effects of androgens on the peripheral receptors.

Tests given in the experimental section illustrate this antiandrogenic. activity.

Owing to this antiandrogenic activity, the products of the invention can be used therapeutically with adults without having to fear certain effects of a chemical castration.

These properties make the produets of general formula (I) of the present invention utilisable as medicaments for the treatment of adenomas and neoplasias of the prostate and for combating benign hypertrophy of the prostate.

These properties also make the products of general formula (I) utilisable in the treatment of benign or malignant tumours in which the cells contain, in particular, androgenic receptors. Principally, cancers of the breast, brain, skin and ovaries but also cancers of the bladder, lymphatic system, kidney and liver may be mentioned in particular.

The products of'general formula (I) of the invention also find use in the treatment of hirsutism, acne, seborrhea, androgenic alopecia and hyperpilosity.

They can also be used in the veterinary field.

The invention therefore relates to the administration, by way of medicaments, of the pharmaceutically acceptable products of general formula (I) .

The invention particularly relates to the administration by way of medicaments of the products whose names follow: 4-(5-oxo-2-thioxo-3,4,4~trimethyl~l-imidazolidinyl)-2(trifluoromethyl) benzonitrile, - 4-(4,4-dimethyl-5-oxo-2-thioxo-l-imidazolidinyl)-2(trifluoromethyl)benzonitrile, 4-[4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo-limidazolidinyl]-2-(trifluoromethyl)benzonitrile, 3-(3,4-dichlorophenyl)-2-thioxo-l,5,5-trimethyl-4imidazolidinone, 1-(4-nitro-3-(trifluoromethyl) phenyl)-3,4,4-trimethyl2,5-imidazolidinedione, - 4-((4,5-dihydro-4,4 -dimathy l-5-oaco-2- (phenylmethyl) thio ] IH-iaidasol-l-yl]-2-(trifluoromethyl)benzonitrile.

The products can b© administered by the parenteral, buccal, perlingual, rectal or topical rout®.

The invention also compositions characterised active principle, at least formula (I). relates to pharmaceutical in that they contain, by way of one of the medicaments of general These compositions can be presented in the form of solutions or Injectable suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams,' ointments and lotions. These pharmaceutical forms are prepared according to the usual, methods. The active principle can be incorporated into excipients usually employed in these compositions, such as aqueous or non-aqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives.

The usual dose, which varies according to the subject treated and the ailment in question, can be, for example, from 10 mg to 500 mg per day in man, by the oral route.

The products of formula (II) used at the start of the invention can be obtained by action of phosgene when X represents an oxygen atom or thiophosgene when X represents a sulphur atom on the corresponding amine of formula (A): An example of such a preparation is given below in the experimental section. A product of this type is also described in French Patent BF 2,329,276.

The amines of formula (A) are described in European Patent EP 0,002,892 or French Patent BF 2,142,804.

The products of formula (III) ar® known or can be prepared starting from the corresponding cyanohydrin according to the process described in the publication: J. Aa. Chen. Soc. (1953), 75, 4841.

The products of formula (III) in which R3 is other than a hydrogen atom can. be obtained by action of a product of formula HM3Hal on 2-cyano-2-aminopropane under the conditions stated, above for the action of R3Hal on the products of formula (IV). An example of preparation of this type is described in the reference: - Jilek et Coll. Collect. Czech. Chem. Comm. 54(8) 2248 (1989).

The products of formula (IV8) are described in French Patent 3F 2,329,276.

The starting materials of formulae (V) and (vi) t on which a process is carried out, to which th® invention relates, for obtaining the products of formula (I), ar® known and commercially available or can be prepared according to methods known to the person skilled in the art.

Th® preparation of products of formula (vi) is described in particular in the following publications: - Zhur. Preklad. Khim. 28, 969=75 (1955) (CA 50, 4881a- 1956) = Tetrahedron 43,, 1753 (1987) = J. Org. 52.., 2407 (1987) - Zh. Org. Khim. 21, 2006 (1985) = J. Fluor. Chem. 17, 345 (1981) or in the patents: - German DRP 637,318 (1935) - European ΞΡ 0,130,875 - Japanese JP 81/121,524.

The products of formula (VI) which are derivatives of hydantoin are widely used and mentioned in the literature as, for example, in the following articles: - J. Pham. Pharmacol., 67, Vol- 19(4), p. 209=16 (1967) - J. Chem. SOC., 74, (2), p. 219=21 (1972) - Shim. Farm. Zh., 67, Vol. 1 (5) p, 51=2 - German Patent 2,217,914 - European Patent 0,091,596 - J. Chem. Soc. Perkin. Trans. 1, 74 (2) p. 48, p. 219-21.

The invention also relates, by way of novel industrial products and in particular by way of novel industrial products utilisable as intermediates for the preparation of the products of general formula (15, to the products of formula (IVi): R, i (IVi) in which R^, R^ and Y have the meanings indicated above and the group: ‘Bi is chosen from amongst the radicals: and in which X represents an oxygen or sulphur atom and R^i is chosen from amongst the meanings of R^ containing a protected reactive function with the exception of the products in which the group -A.-B·represents the radical: in which X represents an oxygen atom and represents a hydrogen atom and Y represents an oxygen atom or an UH radical and R£ represents a halogen atom or a tri fluoromethyl radical and represents a nitro radical or a halogen atom. 18a Amongst the protected reactive functions, the hydroxyl and amino functions may be mentioned. These functions can be protected as indicated above for the substituent R3.

The following examples illustrate the invention without, however, limiting it.

Example l: l- (4-nitro-3~ (trifluoromethyl) phenyl )-3,4,4trimethylimidazolidine-2,5-dione A solution of 3.17 g of l-(3'J-trifluoromethyl-4-nitro10 phenyl)-4,4-dimethylimidasoline-2, 5-dione (obtained according to French Patent 2,329,276) and 32 cm3 of dimethylformamide are added, at a temperature between 23 and 25’C, to a suspension of 492 mg of 50% sodium hydride in oil and 3 cm3 of dimethylformamide, the mixture is stirred for 15 minutes and a solution of 0.7 cm3 of methyl iodide In 2 cm3 of dimethylformamide is added. The mixture is stirred for 25 minutes between 24 and 28’C and then poured onto 200 g of a 1:1 mixture of water and ice. The mixture is extracted with ether, washed with water saturated with sodium chloride, dried, filtered and evaporated to dryness under reduced pressure, and 3.6 g of the required product, m.p. ~ 116*C, are obtained.

An analytical sample was obtained by recrystallisation in isopropyl alcohol; 2.73 g of the eacpected product, m.p. = 116'C, is thus obtained.

Analysis for C23H^2F3N3O^ = 331.25 calculated: C% 47.14 H% 3.65 F% 17.20 N% 12.68 found: 47.0 3.5 17.1 12.5 IR spectrum (CHCl3) C=0 (1780, 1727 cm1) aromatic (1615, 1596, 1497 cm1) N02 (1545, 1357 cm -) Example 2; 5,5-dxmethvl-i-efcfcvl-3-(4-nitro-3-(trifluoromethyl)pheavl)imiaagolidiae-2,4-dione The procedure is as in Example 1 starting from 1 g of 1-(3 '-trifluoromethyl-4 '-nitrophenyl) -4,4-dimethylimidazoline2, 5-dione obtained according to French Patent 2,329,276 using 0.33 cm3 of ethyl iodide and 166 mg of 50% sodium hydride in oil. 1.19 g of the required product, m.p. = 110-lll’C, are obtained. The product above is reerystallised in isopropanol. 934 mg of the expected product, m.p. = HO-llVC, are obtained.

Analysis for C14H14F3N3O4 = 345.28 calculated: C% 48.70 H% 4.09 F% 16.51 N% 12.17 found: 48,6 IR spectrum (CHC13) 1724 (F)) -1 C=0 (1777 cm1, 4.0 16.8 12.1 N02 '(1545, 1356 ra_i) aromatic (1614, 1596, 1497 cm1) Bxaaple 3s 5^5-dimethyl-3~(4-jS3.trar3-itrifluoggmefchTl?bheaylJl-propvlimidasplAaine-g.^4rdigae The procedure is as · in Example 1 starting from 1 g of 1-(3»-trif luoro»ethyl-4-nitrophenyl) -<, 4 -dimethyl inidazoline2,5-dione (obtained according to French Patent 2,329,276) using 155 mg of 50% sodium hydride in oil and 0.35 cm3 of 1-iodopropane. After chromatography on silica, eluent acetone/methylene chloride 1:99, 1.087 g of crude product are obtained (m.p. = 102eC). After recrystallisation in isopropanel, 945 mg of required product are obtained (m.p. = 102*C). Analysis for cxsH16F3MsO4 = 359.31 calculated: C% 50.14 Ji% 4.49 F% 15.86 NS 11.69 found: 50.1 4.4 15.9 11.5 IR spectrum (CHC13) C-0 (1778, 1724 cm1) N0£ (1544, 1358 cm1) aromatic (1615, 1596, 1497 cm1) Example 4 s 5.,S-dimathyl-i- The procedure is as in Example 1 starting from 1 g of 1- (3’-trifluoromethyl-4-nitrophenyl)-4,4-dimethylimidazoline2,5-dione (obtained according to French Patent 2,329,276) using 166 mg of 50% sodium hydride in oil and 0.4 cmJ of 2- iodopropane for 18 hours at 50C. After chromatography on silica (eluent methylene chloride/acetone 99:1), 685 mg of the expected product, m.p. ~ 130’C, are obtained. The product obtained above is recrystallised in isopropanol and 661 mg of required product, m.p. = 130*C, are obtained.

Analysis for Ci5HlgF3N3Oi< - 359.31 calculated: C% 50.14 H% 4.49 F% 15.86 N% 11.69 found: 50.1 4.4 16.2 11.6 IR spectrum (CHC13) C-0 (1779, 1771, 1723 cm"1) N02 (1544, 1361 cm1) aromatics (1615, 1596, 1497 cm1) Bzaanle Ss 5.,_S-dimethyl-3-(4-211^0-3-(trif luprontethvl)pbepyl)l^ja-prooen^ll Imi aassolidlaerg, 4-ai.me The procedure is as In Example 1 starting from l g of 1-(3 *-trifluoro»ethyl-4-nitrophenyl)-4,4-dimethylimidasoline2,5-dione (obtained according to French Patent 2,329,276) using 166 ag of 50% sodium hydride in oil and 0-35 cm3' of allyl bromide. After chromatography on silica, eluent «ethylene chloride/acetone 99 si, 1.19 g of product are obtained which is recrystal Used in isopropanol ,· 1.01 g of required product, m.p. = 105"C, are obtained.

Analysis for C15HX3N3O4 == 357.29 calculated: C% 50.42 H% 3.95 F% 15.95 N% 11.76 found: 50.4 3.3 15.8 11.7 IR spectrum (CHC1S) C=0 (1779, 1724 cm1) KO2 (1545, 1358 cm™1) aromatic (1615, 1596, 1497 cm1) CH~CH2 (1643, 930 cm"1) ggggg&&-£s S.,.S^diagthgl-3^ftrifluoromethvl Ipjaenylj a.-methylpheavlimidagolidine-2., 4-dioae The procedure is as in Example 1 starting from 2 g of 1- (3 ’-trifluoromethyl-4-nitrophenyl)-4,4-dimethylimidazoline2,5-dione (obtained according to French Patent 2,329,276) using 332 mg of 50¾ sodium hydride in oil and 0.71 cm® of benzyl bromide. After chromatography on silica, eluent methylene chloride/aeetone 99:1, 2.375 g of product are obtained which is recrystallised in isopropanol; 2.165 g of the required product, m.p. = 99'C, are obtained.

Analysis for C.4qHxsN3F3O4 = 407.3 calculated: C% 56.02 H% 3.96 N% 10.31 F% 14.00 found: 56.1 3.8 10.2 13.9 IR spectrum C-0 (1799 crn"1 (m) , 1723 cm"1 (F) ) aromatic (1608 cm"1) + (1594 cm"1 (m)) N02 (1545 cm"1 (F) ) (1497 cm1) Example 7: 4-(4/4~dlmgthyl-5-iialao~2-oa:oTlrimidagoIidi.BTlJ^»2^ trifluoromstWlbesaoaicrile A solution of 6,6 g of 2-trifluoromethyIbenzonitrile4-isocyanate, prepared as indicated in the preparation below, in 10 cm3 of dichloroethane is added at 5’C to a solution of 2.63 g of 2-amino-2-cyanopropane and 36 cm3 of 1,2-dichloroethane with 0.9 cm3 of triethylamine. The mixture is stirred at room temperature for 16 hours. It is evaporated to dryness and the residue (7.7 g) is chromatographed on silica, eluent methylene chloride/acetone 85:15? 3.54 g of the expected product, m.p.· ~ 228C, are obtained.

An analytical sample was prepared toy recrystallisation of 300 mg of the above product in isopropanol; 257 mg of required product, m.p. = 228’C, are obtained.

Analysis for cx3S13,F3N4O = 296.25 calculated: C% 52.71 3.74 F% 19.24 N% 18.91 found: 52.7 3.6 19.1 18.6 IR spectrum (Nujol) NH/OH (3340, 3290 cm’1) ON 2240 _!l cm * C—0 1760 cm on 1655 -2, cm aromatics (1606, 1570, 1502 ca’1) EEggarations S-fcrifluorosaethvlbeasonitrile-^-isocyanate g of 4"cyano-3"trifluoromethylaniline (described in European Patent EP 0,002,892) dissolved in 30 cjbP of ethyl acetate is added in the course of 20 minutes to 33.6 cm3 of a 1.93 H toluene solution of phosgene kept at 0 5‘C. The mixture is stirred for 30 minutes at a temperature between 0 and 5’C which is then allowed to rise to 25 G. It is heated until it distils, making up for the volume distilled by toluene, until the distillation temperature reaches 1108C. The condenser is then put in the reflux position until release of hydrochloric acid ceases (i.e. 4¾ hours). The mixture is brought back to ambient temperature, the light, insoluble, white matter is dried under nitrogen on sodium sulphate, washed three times with 10 cm3 of toluene each time and evaporated to dryness under reduced pressure. The process is completed by heating at 60 C for 1 hour, then the solid is returned to an argon atmosphere and 11.6 g of expected product is obtained and used as such In the following stage: Infrared -M»C=O 2268 cm"1 -CN 2233 caT1 gxagBpl© ._S.s A * ,. s-aiozo-x-laidasolMiayD' r A suspension of 2.76 g of the product obtained in Example 7 and 60 cm3 of half-strength hydrochloric acid are heated to reflux for 35 minutes. The mixture is poured onto 100 g of water and ice and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to dryness. 2.70 g of the required product, m.p. — 210C, is obtained.

An analytical sample was obtained by recrystallisation of 440 mg of the product above in isopropanol; 383 mg of expected product, m.p. = 210-211'C, are obtained.

Analysis for = 297.24 calculated: C% 52.53 H% 3.39 F% 19.17 N% 14.14 found: 52.4 3.2 19.4 13.9 IR spectrum (CHC1,) ON 2245 cm1 0=0 (1788, 1722 cm"1) aromatic (1610, 1572, 1502 cm"1) NH (max) 3340 cm"1 Example 9; 3-(4~cyaao~3-{trifluoromethyl)pheavlS-5,5-diaethyl2,,4-diozo-l-imidaaolidinylacetlc acid A solution of 600 mg of the product obtained in Example 8 in 6 cm3 of dimethylformamide is added to a suspension of 210 mg of sodium hydride (50% in oil) and 3 cm3 of dimethylformamide, the mixture Is stirred for 15 minutes, 290 mg of bromoacetic acid are then added and the mixture is stirred at ambient temperature for 16 hours. 105 mg of sodium hydride are again added, then, after 15 minutes, 145 mg of bromoacetic acid. The mixture is stirred for 30 minutes and then poured into a solution composed of 50 cms of water and 5 cm3 of 2 N hydrochloric acid. The mixture is extracted with ether, washed with a saturated solution of sodium chloride, dried, filtered and evaporated to dryness? 1.22 g of crude product are obtained which is chromatographed on silica, eluent methylene chloride/methanol/acetic acid (90:10:0.5). 367 mg of the required product are obtained.

IR spectrum: C»N 2238 cm1 hydantoin and acid C=0 (1784, 1725, 1710 cm"1) aromatic (1616, 1580, 1508 ca1) ultraviolet EtOH HCI 0-1 N max 258 nm epsilon = 13300 infl 277 nm epsilon ~ 5000 infl 285 me epsilon = 2600 EtOH NaOH 0.1 N max 287 nm epsilon = 19100 max 342 nm epsilon = 1900 Eataaple 10 s ethyl 3- £4-gvaaa^3^.gtrlf luQgomethyliphenyl) 5, S~ diae_thvl-2 „ 4-ax20So-i-ialdagolidiaTlacetate 600 mg of the product obtained in Example 8 are added in solution In 6 cm3 of dimethylformamide to a suspension of 100 mg of 50% sodium hydride in oil and 3 cm3 of dimethyl formamide. The mixture Is stirred for 15 minutes, than 0.25 cm2 of ethyl bromoacetate is added slowly without exceeding 30"C. The mixture is stirred for 30 minutes, poured onto 50 g of a mixture of water + ice (1:1), 0.5 g of monopotassium phosphate is added and the mixture is extracted with ether. The organic phase is washed with water, dried and evaporated to dryness; l.l g of crude product are obtained which is chromatographed on silica (eluent methylene chloride/acetone (97:3). 709 mg of th® expected product, m.p. = 152*C, are obtained.

An analytical sample was obtained by recrystallising the above product in isopropanol, and 667 mg of the required product, m.p. = 152°C, were thus obtained.

Analysis for Ci7HX6F3N3°4 = 383 * 33 calculated: C% 53.21 H% 4.21 F% 14.83 N% 10.96 found: 53.3 4.0 14.9 10.8 IR spectrum (CHC1,) C=N 2225 cm1 imidazolidine (1786, 1729 cm1) CO^St 1751 cm1) aromatics (1616, 1572, 1505 cm1) gxample^.lj 4-g5-lmiao-2-thioxo-3,4,4-tglaaethvl-l-imidab> ^reparation of the isothiocyanate 2-23 g of l-trifluoromethyl-4-aminoben«onitrile (prepared according to SP 0,002,892) is added slowly to a solution of 22 c»3 of distilled water and l can3 of thiophosgene, th® mixture is stirred for 1 hour, extracted with chloroform, washed with brine, dried and evaporated to dryness under reduced pressure, and 3 g of product is obtained and used as such for obtaining the imine. b) Obtaining the imine g of the product obtained above is stirred for 40 minutes at reflux with 1.33 cms of 2-methylamino2-cyanopropane, 23 cm3 of tetrahydrofuran and 0.23 cm^ of triethylamine. The mixture is evaporated to dryness and the residue (3.07 g) is chromatographed on silica (eluent: cyclohexane/ethyl acetate (1:3.),. then methylene chloride/acetone (95:5)); 2.83 g of expected product are obtained which is recrystalUsed in isopropanol to obtain 2.63 g of required product, m.p. = 173-174’C.

Analysis for C14H33F3N4S = 326.35 calculated: C% 51.53 H% 4.01 F% 17.17 N% 17.46 S% 9.82 found: 51.7 3.9 17.2 17.2 9.9 IR spectrum C=NH (3308, 1679 ca") C=S + aromatics (1608, 1575, 1505, 1488 cm1) C=N 2230 cm1 CF3 = 1185 cm1 Escamole 12: 4- (S-oao-g-thloxo-S., <, 4-trimethvl-i-iaidazolidxayl I; -S-trifluoromethvlbenzonitrile 2.21 g of the product obtained in Example 11 and 44 cm3 of half-strength hydrochloric acid are stirred at reflux for 1 hour. The reaction mixture is poured onto a mixture of 200 g of water + ice (1:1), extracted with methylene chloride, washed with water saturated with sodium chloride, dried and evaporated to dryness, the residue is chromatographed on silica, eluent cyclohexane/ ethyl acetate 1:1, and 2.1 g of product is obtained (m.p. - X71C) which is recrystallised in isopropanol to obtain 1.99 g of required product, m.p. = 171C.

Analysis for G14H12F3N3OS = 327.33 calculated: C% 51.37 H% 3.69 F% 12.84 N% 17.41 S% 9.79 found: 51.4 3.5 12.7 17.6 10.79 IR spectrum (CSC13) 0=0 (1761, 1756 cm1) aromatics (1610, 1578, 1505 cm1) C^N 2230 cm1 CF3 1178 cm1 Example .AS; 4-i2*5-aitfaiogo-3,4,4-trimethyl-l-imia&golidinyl)2-trifluoromethvlbeazonitrile 839 mg of product obtained in Example 12 is stirred at reflux for 24 hours with 518 mg of Lawesson reagent and 4.7 cm2’ of toluene. The mixture ie evaporated to dryness under reduced pressure and 1.36 g of product are obtained which is chromatographed on silica, eluent methylene chloride/ethyl acetate (99:1), then cyclohexane/ethyl acetate (85:15). 783 mg of product are obtained which are reerystallised in isopropanol; 590 mg of required product, m.p. ~ 211-212'C are obtained.

Analysis for CHHi2?383S2 ~ 343 "40 calculated: CS 48.97 H% 3.52 F% 16.50 N% 12.24 S% 18.67 found: 49.0 3.4 16.5 12.2 18.6 IR spectrum (CHC13) ON 2230 cm1 aromatic + conjugated system (1612, 1582, 1508 cm1) CF3 1178 cm1 Example 14: 4- (4.-«-diaethvl-S-a.iaiuo-S-thioso-l.-imxdagoliaimyl)-2-trif luorometfaylbesasoniferile g of 2-amino-2~cyanopropane and 1 cm3 of tetrahydrofuran ar© added to a mixture of 2.54 g of product obtained as in a) of Example 11 with 20 cm3 of tetrahydrofuran and 0.2 cm3 of triethylamine and th© mixture is stirred at ambient temperature. It is evaporated to dryness and the residue (3.5 g) is chromatographed on silica, eluent ethyl acetate/cyclohexane (7:3), then cyclohexane/ethyl acetate (1:1), and 940 mg of required product is obtained of which 300 mg are reerystallised in isopropanol to obtain 263 ag of product, m.p. = 296’C.

Analysis for = 312.32 calculated: C% 50.00 H% 3.55 F% 18.25 N% 17.94 S% 10.27 found: 49.9 3.4 18.3 17.6 10-4 IR spectrum (Nujol) OH/KH 3260 C®1 ON 2230 cm1 C-S 1764 cm1 aromatic 4- C=C (1512, 1575, 1530, 1501 cm1) A novel preparation of the product was carried out by replacing the tetrahydrofuran by 1,2-dichloroethane.

The expected product, which is insoluble, precipitates. The required product is thus obtained with a yield of 50%.

Example 15: <- (4,4-dl»ethyl-5-osp-2-thioso-l-iniiaagolidiayl?2r.fegija..UQroae.fchylbengonifcrile 635 mg of the product obtained in Example 14 and 14 cm3 of hydrochloric acid diluted to half strength are stirred for 1 hour at reflux. The mixture is cooled, 100 cm3 of water are added and it is extracted with ethyl acetate, washed with brine, dried and evaporated to dryness; 600 mg of product are obtained which is chromatographed on silica, eluent methylene chloride/acetone (95:5) and 590 mg of expected product (m.p. = 190-191 °C) are obtained which is recrystallised in isopropanol to obtain 490 mg of the required product, m.p. = 190-191C.

Analysis for C13H10F3N^OS = 313.30 calculated: C% 49.84 H% 3.22 F% 18.19 N% 13.41 S% 10.23 found: 49.6 3.1 18.4 13.2 10.0 IR spectrum (CHC13) =C-NH 3430 cm1 C=M 2230 cro'1 C=0 1766 cm1 Conjugated system + aromatics (1612, 1578, 1505 cm1) Example 16; 5, s-dimethvl-S- (<-a,xtro~3- (trif luoromethyl j phenyl)-l-oentvlimxdagolidxae-2,4-dioae The procedure is as in Example 1 starting from 1 g of 1= (3 " -trxfluoromethyl-4-nitrophenyl) -4,4-dimethylimidazoline2,5-dione (obtained according to French Patent 2,329,276) using 170 sag of sodium hydride and 0.47 cm3 of 1-bromopentane, and, after chromatography on silica, eluent methylene chloride/cyclohexane (8:2), 1.23 g of required product are obtained which is crystallised in isopropanol to obtain 995 mg of product, m.p. = 84’C.

Analysis for Ci7H20O4F3N3 - 387.35 calculated: C% 52.71 H% 5.20 F% 14.71 N% 10.85 found: 52.8 5.1 14.8 10.7 IR spectrum (CHCl2) C=0 (1778, 1723 cm"1) N02 (1544, 1360 cm"1) Bacamtle 17: jL^5rfl_iaetWl~3- g*-nitro~3-(trifluoromatby 33 phenyl)~l~noayliada&golidiaer2 , 4-diose The procedure is as in Example 1 starting from 1 g of 1- (3-trifluoromethyl-4-nitrophenyl)-4,4-dimethylimidazoline2,5-dione (obtained according to French Patent 2,329,276) using 170 mg of 50% sodium hydride in oil and 0.7 cm3 of X-bromononane. After chromatography on silica, 1.08 g of the required product, m.p. = 63°C, are obtained.

Analysis for = 443 -46 calculated: C% 56.87 H% 6.36 F% 12.85 N% 9.48 found: 57.0 6.5 12.8 9.5 IR spectrum (CHCl 3) OO (1788, 1723 cm"1) N02 (1544, 1359 cm1) Bxamole 18: 4-(3,4 ^-l.-trimfethyl-S ,5-dxoxo-l-imxdagolxaiayl^-2trifluoromethylbenzonitrile Proceeding as in Example 1, starting from 300 mg of product described in Example 8, 275 mg of expected product are obtained (m.p. = 158’C).

IR spectrum (CHC1S): C=0 (1780, 1727 cm"1) aromatics: (1615, 1574, 1505 cm1) C=N: 2238 cm"1 Example_19: 4- (5^thioxo-2-pxq-3,,4., 4_-tri»et.hylrl-l»idasor lidinylj-2-trAfluoromethyl.beagoaxtri.le _AiAA^^aeh5^zj.=ijBi5aga3^aiayij-jj~tr£Xlsaosgr, ttethylfeengonitrlle. itrcdact 5) A suspension of 230 mg of product obtained An Example 18 is heated to reflux for 9 hours in 1.4 ca3 of toluene and 78 mg of Lawesson reagent, brought back to ambient temperature and then evaporated to dryness. The 330 mg of product obtained are purified by chromatography on silica (eluent methylene chloride/acetone 99:1)» The following are obtained in order of elution: mg of product c (Rf = 0.63, m.p. = 210-211’C) identical to the product described in Example 13; - 26 mg of product 3 (R.* = 0.49, m.p. - 170-171’C) identical to the product described in Example 12; - 42 mg of product A (R^ - 0.34, m.p. = 194*C).

Physical analysis of the product A.

IR spectrum (CHC1-,) : OO: 1760 cm1 -CsN: 2235 cm1 aromatics: (1615, 1580, 1508 cm1) Ultraviolet spectrum (ethanol) max 228 nm epsilon - 19400 256 nm epsilon - 12100 298 nm epsilon — 8600 390 nm epsilon = 70 Example .20; 4- <4, S-dibydro—4 ,r 4-dimethyl--2-· (aethvlfchio) S-axol3-iaidasol-l~yl) 2-fcrifluoroaethvlbengoaitrile A solution' of 626 mg of product from Example 15 in cm3 of dimethylformamide is added to a suspension composed of 108 mg of 50% sodium hydride in oil and 1.8 cm3 of dimethylformamide. Washing is performed with 0.3 cm3 of dimethylformamide and the mixture is stirred for 10 minutes after evolution of hydrogen has ceased. 0.19 cm3 of methyl iodide in 1 cm3 of dimethylformamide is then added dropwise.

After reacting for 45 minutes, the mixture is poured onto 50 g of an ice/water mixture containing 0.5 g of monopotassium phosphate and extracted 4 times with ether. The organic phase is washed with brine, dried on magnesium sulphate and evaporated to dryness. The 668 mg of product obtained are purified by chromatography on silica (eluent CH2Cl2~AcOEt 95:5). 640 mg of product are obtained which are chromatographed again on silica (eluent cyclohexane-AcOEt 7:3) and, after returning to ether, 507 mg of required product, m.p. = 62'C, are obtained.

Infrared spectrum OO: 1747 cm1 1503 cm1) 1569, C—N and aromatic (1614, 1581, Ultraviolet spectrum (EtOH) max 209 nm epsilon = 26000 infl 236 nm epsilon = 11500 infl 264 nm epsilon - 8700 BgsBple.ll: 4- f 4,5-d.ihydre-4,4-dxaethy.lr5-oxo-2-_r(phenylmethyl) thiol -lSrialdagQl-l-yl1H2~tri£luoroBethylbeagQmAtrile 313 mg of 4-(4,4-dimethyl-5~oxo-2-thioxo-l-imidazolidiny1)-2-trifluoromethyIbensonifcrile prepared as in Example 15 and dissolved in 3 cm3 of dimethylformamide are added In the course of 5 minutes to 53 mg of sodium hydride suspended in 0.5 cm3 of dimethylformamide. The mixture is stirred for 10 minutes, 0.1 cm3 of benzyl bromide is added and the mixture is stirred continuously for 30 minutes. The reaction mixture is poured into iced water to which 500 mg of potassium phosphate has been added and extracted with ether, the organic phase is washed with brine and dried and the solvent is evaporated. 450 mg of crude product are obtained which is chromatographed on silica (eluent: methylene chloride/ ethyl acetate 97.5:2.5). 316 mg of expected product are obtained. R^ = 0.38.

Analysis calculated: C% 59.54 H% 4.0 found: 59.6 4.0 F% 14.12 14.1 .2 IR spectrum (CHC1S) c-0: 1746 cm"1 C=N: 2236 cm1 Conjugated system + aromatics: 1499 cm1 1514, 1580, 1570, 1503 Bsaaple 23s 4r.f4,4-aimethyl-3-t2-hy&rogyethvl)-S-iniao2-thiaxo-1- isidagolidiny-¾ -tri f luoroaethy Ibenjspai tril e.

A solution containing 2.11 g of the isothiocyanate prepared in stage a) of Example 11 is heated fo reflux for 30 minutes with 1.18 g of a mixture of 2-[ (2-hydroxyethyl)amino]-2-mefhylpropionitrile and 2,, 2-dimethyloxazolidine (8:2) in 20 cm® of tetrahydrofuran in th© presence of 0.5 cm3 of triethylamine- The solvent is evaporated, the residue is chromatographed on silica (eluent: methylene chloride/acetone 95:5) and 1.26 g of crude expected product and 686 mg of N-[4-cyano-2~(trifluoromethyl)phenyl]2,2-dimethyl-3-oxasolidinecarbothioamide are obtained. The 686 sag of this product are dissolved in 10 cm3 of ethyl acetate, 30 cm3 of cyclohexane are added, and the mixture is concentrated to 4 cm3, drained and dried to obtain 518 mg of extra expected product. The crude product'is dissolved in 20 ca3 of isopropanol, concentrated to 5 cm3, drained and dried. 1.04 g of expected product are obtained. M.p- = 181*c. Analysis calculated: C% 50.55 H% 4.24 F% 16.00 N% 15.72 S% 9.00 found: 50.4 4.1 15.9 15.6 9.0 IR spectrum (CHC13) OH*. 3630 cm2 >—NH: 3314, 1677 cm1 C=N: 2230 cm1 aromatics: 1611, 1576, 1504 cm1 Preparation of 2-[ 2-hy drossy ethyl.amino) -2-methy Ipropxoaitrile used at the start of Example 22 cm3 of ethanolamine are added dropwise at a temperature between 20°C and 30"C to 12.3 cm3 of acetone cyanohydrin- The mixture is stirred for 18 hours, distilled under reduced pressure and 2.3 g of mixture containing the expected product and 2,2-dimethyloxasolidine are obtained and used as such for the following stage.

Example 23 s 4- Γ < r 4- 680 mg of product obtained in Example 22 ar® heated at reflux for 10 minutes in 7 cm3 of watex· in the presence of 7 cm3 of hydrochloric acid, the mixture is cooled to ambient temperature and extracted with ethyl acetate, the organic phase is washed with brine and dried and the solvent is evaporated. After chromatography of the residue on silica (eluent: cyclohexane/ethyl acetate 1:1), 119 mg of product B i.e. the 2,5-dioxo-3-(2-mereaptoethyl) derivative Rf = 0.35 and 559 mg of product A i.e. the 5-oxo-2-thioxo-3-(2hydroxyethyl) derivative Rf = 0.14; m.p. ss 130C are obtained.

Analysis for = 357.36 calculated: C% 50.42 H% 3.95 F% 15.95 N% 11.75 S% 8.97 Product A: found: 50.7 4.0 15.7 11,5 9.1 Product 3: found: 50.5 3.8 15.9 11.6 9.1 IR spectrum (CKC13) Product A: OH : 3525 cm1 OsN : 2235 cm1 C=O : 1763 cm1 aromatics: 1515, 1578, 1504 cm1 Product 3: OH absent ON : 2228 cm1 C=0 : 1780, 1726 cm1 aromatics : 1515, 1578, 1505 cm1 Proceeding as indicated in Examples 1 to 23: A) using 4-(4,4-dimethyl-2,5-dioxo~l-imidazolidinyl)·’ 2-trifluoromethylbenzonitrile prepared as in Example 8 and the appropriate reagents, the compounds of the following examples were obtained: Rgaamle 24: 4- (4,4-aimethvl-2, s-aioso-3-ethvl-l-im.idagoli(aiavlX~2-trifluo.g M.p. = 100-101‘C.

Analysis for - 325.29 calculated: C% 55.39 H% 4.34 F% 17.52 N% 12.92 found: 55.7 4.3 17.6 12.8 IR spectrum (CHCl^) (Mi : 2238 cm1 C=0 : 1777, 1724 cm1 aromatics : 1617, 1575, 1505 cm1 g^a^pla,25s 4-(4,.4rdiaefchvl-2dr imidagojiaiasvlj-2-trif luoroaiethylteenzoalf rile M.p, « 109-110C.

Analysis for ci 6^24-3¾¾ = 337.35 calculated: C% 56.97 H% 4.18 F% 16.90 N% 12.46 found: 57.0 4.1 16.2 12.3 IR spectrum (CHC13) CsR : 2238 cm1 C=O : 1728, 1725 cm1 HC=CH2 : 1645 cm1 aromatics : 1616, 1575, 1505 cm1 Bggaaple ,26a 4-,(4 ,<-Mmethyl-Z»5-!a£oso-3- (phenylmethyl! l-imidaggli diwl > -2-trx f Iwrometfeylbeaaeaixrile M.p. = 98-99‘C.

Analysis for C20H16F3W3°2 = 337.36 calculated: C% 62.01 H% 4.16 F% 14.71 N% 10.85 found: 62.0 4.1 14.7 10.8 IR spectrum (CHC13) =C-NH : 3430 cm1 C=N : 2238 cm1 e=o : 1779, 1724 _,-i cm aromatics : 1615, 1605, 1575, 1504, 1497 cm Example 27; 4-(4 T 4-aimethyl-2 > 5-dioa:o-3-Γ (4-fluorophQny.iaaethvlTl-l-iaixdazoliainvl]-2-trifluogonethvlbepgoaitrile M.p. « 101-102’C. Analysis for C2QH15F4N3O2 = 405.35 calculated: C% 59.26 H% 3.73 F% 18.75 N% 10.37 found: 59.1 3.5 18.9 10.3 IR spectrum (CHCl.,) CsN : 2238 cm1 C=0 : 1780, 1724 cm"1 aromatics : 1615, 1612, 1505 cm1 Example 28: 4- T4 .<4-dimetlayl-2, S-dioxo-S-JUrjaethosyp6senvljmethvn-i-ima.dasQlidipyn-2-trif luogoaethTlbegig-QStit,rile· M.p. = 95—96"C.

Analysis for CzAsWs = 417.39 calculated: C% 60.43 H% 4.35 F% 13.65 N% 10.07 found: 59.1 3.5 18.9 10.3 IR spectrum (CHC13) 02$ : 2238 cm1 C=o : 1778, 1723 cm1 aromatics : 1615, 1584, 1514, 1505 cm"1 Example 29; 4- f 4,4-aimefchvl~2., S-djoxo-S- Γ Γ4- gtrif liaoroaefcfayl$ pAejPYlaethyl} -irimidaaolidigiyl ] -2rfcgjf lnoromettoylbeagoaitrile M.p. « 89-90°C, Analysis for 5F^N3O2 - 313.30 calculated: C% 55.39 H% 3.32 F% 25.03 N% 9.23 found: 55.2 3.2 25.3 9.2 IR spectrum (CHC13) ON : 2238 cm1 c=o : 1615, 1505 cm1 aromatics : 1615, 1505 cm1 Esaaiple 30 s 4- Γ4., 4-diaetbvl-2 , S-aioxo-3- t2-eoozvtaethvl) - l-iMidasolidinyll-2-trifliaoroaiethvlbenzonitrile M.p. = 112- 113’C. Analysis for C16H14F3N3O3 = 353.30 calculated: C% 54.39 H% 3.99 F% 16.13 N% 11.89 found: 54.7 4.0 16.1 11.8 IR spectrum (CHC13) ON : 2235 cm1 C=0 : 1781, 1725 cm"1 aromatics : 1615, 1576, 1505 cm1 Sxamnle 31: 4- ί 4., 4-dinetfevl-2,5-dioxo-3-oropvlr ΊΗ-iMidaao· lidinvl)-2- frifluoromethvlbenzonitrile M.p. = 113- 114*C. Analysis for C^H^F.gNgOg = 339.32 calculated: C% 56.64 H% 4.75 F% 16.80 N% 12.38 found: 56.7 4.7 16.7 12.2 IR spectrum (CHC1S) ON : 2236 cm1 c=o : 1778, 1725 cm1 aromatics : 1616, 1505 cm1 Example.. 3¾¾ 4-.i4»4-diaetbylr2 > S-dloxo-S-agi-methglefeteXl l-iaidageiiMByl1-2rtrifljacrcmathyibeaaoaitri3.® M.p. = 138-139’C.

Analysis for CuH16?3!iso2 * 339.32 calculated: C% 56.64 H% 4.75 F% 16.80 N% 12.38 found: 56.5 4.7 17.1 12.3 IR spectrum (CHC1S) CsH : 2236 cm1 C=O : 1778, 1724 cm"1 aromatics : 1616, 1575, 1505 cm1 B) Using 4-(4,4-dimethyl-5-oxo-2-thioxo-l-imidazolidinyl)-2trifluoromethylbenzonitrile prepared as in Example 15 and the appropriate reagents, the following compounds were obtained: Example_33 : 4 - 4 „ Sr.diWtep~4 „ 4_-aiaethyi-2-apa.ylthip~5.rPXOrlH.r ia,idasol-l.-vl 1 -2-ty,i f luoroaethylbenasonitrlle R* = 0.35 (eluent: methylene chloride/ethyl acetate 97.5:2.5). Example _3.4 s 4- [4,s-dlhvdro-4 „4-dimethyl-a- [.gs-frydgfflgyr BrQggl)fcjhi.Oll~5-ogor.lH-iaidazolrl-ylJ-2r-trifmogoaethyA~ bensonitKile - 0.17 (eluent: methylene chloride/ethyl acetate 8:2). Example 35: ethyl Γ [a.-r4~cyano-3~ (trifluoromethyl)phenyl]-4,5dihydro-4,4-dimethyl-5-oxo-lH-imxdagol-l-yl]-thio] acetate Rg == 0.20 (eluent: cyclohexane/ethyl acetate 65:35).

C) Using the thiocyanate prepared in Example 11 and the appropriate reagents, the following compounds were obtained: Example 36s 4- (4, 4-diaiethyl-3-ethyl-5-imino-2-thioxo-limidazolidiavl) -2-trifluoromethylbenzonitrile Rg = 0.16 (eluent: methylene chloride/acetone 95:5).

Sxample 37: 4- (4, 4rjaimethvl-5-imiao-3-peafcyl-2-thioxo.l-imidagolidinyl)-2rtrifluogomethylben2ionitrile Rg ~ 0.35 (eluent: ethyl acetate/cyclohexane 8:2) .

D) Using 4-(4,4-dimethyl-3-ethyl-5-imino-2-thioxo1-imidasolidinyl)-2~trifluoromethylbenzonitrile prepared as in Example 36 and 4-(4,4-dimethyl~5-imino-3-pentyl-2-thioxo-limidazolidinyl)-2-trifluoromethylbenzonitrile prepared as in Example 37, respectively, and half- strength hydrochloric acid, the following compounds were obtained: Example 38: 4- £4,, 4-aiaefchylr3-ethvl.-5-PSo-2-thioxo1-i.Balaasell da,ny 1)-2-tri fltorpaethvlben^oaitgile Rg = 0.38 (eluent: ethyl acetate/cyclohexane 1:1).

Example 39: 4- ¢4, lldxwll.-2-tri£lt'&rometbylbensonitgile M.o. ~ 78 C- R< - 0.66 (eluent: ethyl acetate/cyclohexane 8:2).

E) Using 4-(4,5-dihydro-4,4-dimethyl-2-methylthio-5-oxo-lH36 imidazol-l-yl) -2-trifluoromethylbensonitrile prepared as in Example 20 and 4-[4,5-dihydro-4,4-dimethyl"5-oxo-2~ [(phenylmethyl)thio-lH-imidazol-l-yl]-2-trifluoromethylbenzonitrile prepared as in Example 21 and th® Lawesson reagents, the following compounds were obtained: SSSmlSLdL©: Rj - 0.36 (eluent: methylene chloride/ethyl acetate 97.5:2.5).

Example. 41s 4-.(4 „5-dxhydro-4.,4'^diaefhTl-arFlpheaylmetWlS thialrS-thioso-lH-im&aazol-l-yl?j-2-trlfluorom,ethylbeaaoaitylle Rj = 0.62 (eluent: methylene chloride/ethyl acetate 98:2). Bgaanple 42 s 3- r4-cve.ao-3- (trifluoromethyl? phenyl ]| S, S-diaethyl-2 , 4-dioxe-S-»ethyl-2Sf- (l-aethylethyl S -l-iaidasolidise acetamide 0.1 cm3 of N-methylmorpholine is added to 235 mg of 3[4-cvano-3-(trifluoromethyl)phenyl]-5,5"dimethyl-2,4-dioxo-limidazolidine acetic acid prepared as in Example 9, suspended in 4 cm.3 of methylene chloride. The solution obtained is cooled to -10’C, 0.1 cm3 of isobutyl chloroformate is added dropwise and the mixture is stirred for 20 minutes at -10C. 0.15 cm3 of N-methyl-N-isopropylamine is added, the mixture is allowed to return to ambient temperature in the course of approximately 40 minutes, 5 car' of an aqueous solution saturated with sodium bicarbonate is added, the mixture is stirred for 30 minutes and extracted with methylene chloride, the organic phase is washed with water and dried, and the solvent is evaporated under reduced pressure. After chromatography on silica (eluent: methylene chloride/acetone 96:4), 147 mg of expected product are obtained.

IR spectrum (CHC1S) C®N : 2236 cm"1 hydantoin C=0 ; 1783, 1728 cm"1 amide C-0 : 1661 cm1 aromatics : 1615, 1575, 1503 cm1 Example 43 s 4- ( 4,4rdiaetWl-2^S-aioxar iiaidagoXidlnYl1,r2-trlfluc a) Condensation.

The procedure is as in Example 9 starting from 900 mg of product obtained in Example 8 and 1.91 mg of 2bromoethanol tert-butyl dimethylsilyl ether. 1 g of the silyloxy ether derivative is obtained.., M.p. = 85-87*C after chromatography on silica (eluent: cyclohexane/ethyl acetate 7:3). b) Cleavage: cm3 of 2 N hydrochloric acid is added to 380 mg of product obtained above dissolved In 4 cm3 of methanol and 1 cm3 of methylene chloride. The mixture Is stirred for 40 minutes at ambient temperature, poured onto 15 cm3 of water and extracted with methylene chloride, the extract is washed with water and dried, and the solvent is evaporated. The residue is purified by chromatography on silica (eluent: methylene chloride/ethyl acetate 7:3), R^ = 0.9, and crystallized in ether, and 270 mg of expected product are obtained. M.p. - 109-110’C after crystallization in xsopropanol.

Analysis: calculated: C% 52.79 H% 4.23 F% 16.70 N% 12.31 found; 52.5 4.2 16.7 12.1 Proceeding in an identical manner, starting with 2-bromopropanol tert-butyl dimethylsilyl ether, the following product was prepared: Example 4 M.p. = 131-132OC. Rf = 0.13 (eluent: CH2Cl2/AcOEt 75:25).

Example,45; <-Γ3-ίS-acefvloxvQthylT,4-dimethyl-2,5-dioxo-lr imidasolidiavlT-Z-fcrifluoromethvlbensoatitrile 215 mg of product obtained in Example 43, 15 mg of 4dimethylaminopyridine, 1 cm3, of pyridine and 0.5 cm3 of acetic anhydride are stirred for 30 minutes at ambient temperature. The reaction mixture is poured info 20 cm3 of an aqueous solution saturated with sodium bicarbonate, stirred for 20 minutes and extracted with ethyl acetate, and the extract is washed with water and evaporated to dryness- The residual pyridine and acetic acid are removed by distillation, the residue is purified by chromatography on silica (eluent: methylene chloride/ethyl acetate 65:35), the residue (R^ = 0.35) is returned to isopropanol, partially concentrated and ice-cooled, the solid is dried and 210 mg of expected product are obtained after drying.

M.p. = 99-100°C.

Analysis: calculated: C% 53.27 H% 4.21 F% 14.87 N% 10.96 found: 53.5 4.3 15.2 10.9 Proceeding as in the preceding examples, the examples of the following products were prepared; Example,. 46; f 4rdimethslr2^ (5-hvaroxvpentvl) -3.10 imidssolidjaylT-g-triflupromethvlbensonltrile M.p. = 101-102aC.

Example 47¾ .4-ff4,4-aiaetfrrl-2,,s-dioso-3-r2-aethosyethvl)-ximidazolidinvli-2-trifluoromethvlbeazonitrile M.p. = 58-69-0.

Example ,48: 4- Γ4 , 4-dintetfayl-2 , s-dioxo-3-cvaaoaefc’av.l. .l-iaidagolidinyli-2-trif luoromethvlbenzonitrile M.p. = 186-187’C.

Example. 49: 4.-r4,4-aittethvl-_2,5-dioso-3-f (1,3-dioxolan2-ν1ΐ methyl]-i-imidazolidinvl] -2-trifluoromethvlbengonitrile M.p. = 135-136'C.

Example 50: 4- IT4,4-dimethvl-2 .,S-dioxo-3- (2-chloroethyl)-limidagolidinylW-fcrifluoromethvlbenzonitrile M.p. = 120-121*C.

Example 51 i Arl3U-dichlorophenyn -5-imino-3, 4,4-fcriaethyl-225 imidasolidinethioae 2.4 g of 3,4-dichlorophenyl isocyanate and 1.3 ca3 of 2-methylamino-2-cyanopropane are heated to reflux for 15 hours in 23 cm3 of tetrahydrofuran in the presence of 0.23 cm3 of triethylamine. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica (eluent: methylene chloride/acetone 95:4 then ethyl acetate/cyclohexane 1:1). After crystallization in ether, 2.54 g of expected product are obtained. M.p. = 133C.

Example ,S2a 3-<3,4-diohlorspheagllrJgrtbipgorA^S-trimethyl-435 imiaagclidisjose 1.88 g of product obtained in Example 51 dissolved in 14 cm3 of 6 'W hydrochloric acid are heated to reflux for 45 minutes and then 14 cm3 of 6 N hydrochloric acid are again added and the heating is continued for 2 hours. After a further addition of 4 ca2 of 5 K hydrochloric acid and heating to reflux for 1 and a half hours, the mixture is allowed to return to ambient temperature, 100 g of ice are added and the mixture is extracted with ethyl acetate. Th® organic phase is washed with water and dried, and the solvent is evaporated. After chromatography on silica (eluent: cyclohexane/ethyl acetate 1:1), 1.84 g of expected product ar© obtained.

M.p. = 129'C after crystallization in isopropanol.

Analysis for C12H12C12N2OS - 303.21 calculated: C% 47.54 H% 3.99 F% 23.38 N% 9.24 S% 10.57 found: 47.5 3.8 23.2 9.3 10.5 IS spectrum (CHC13) 0=0: 1753 cm1 OS and aromatics: 1595, 1570, 1496 cm1 Proceeding as in the preceding examples using the appropriate products and reagents, the following compounds were prepared: Example S3: 3-(3,4-dicfeloroohenyl 1 -3,S-dihydro-S,5-dxmethyl2-m©thylthxo-4B:-imxaazol—<-oae M.p. = 110’C.

Example .54: 1-(3,4-di.chlorophepyl) »3,4., 4->triaethyl-2,5i»idagoli.dinedithione M.p. ss 146-0.

Example 5,5s I- Γ4~chlorp~3~ (trif luoraBethyX.)jPtenylT 4,4-aimethyl-2»fchlpgo-5~xmi M.p. = 176-C.

Example 56s l-.£4-chloro-3-CtrifluoroaethylJphenyl)4,. 4~dis©tb2’l-5~iaisc"2-xmidasolidine throne M.p. - 173-174'CExample S7 s 3- (3,4-dighloraphenyli -3, S.-dihydro-S,, S-dlmethyl-SrCphesylaethyl? thiol -4H-i»id.agol-4-oae IB, spectrum (CHC13) 0=0: 1736 cm1 C=H and aromatics: 1578, 1496 ca1 In addition to the products described above, the following products constitute products which can be obtained in the context of the present invention, that is to say the products of formula: in which represents an oxygen or sulphur atom and has the following meanings: ~(CK2)aCi F ~(CH2)a-OH (CH2)s~COO~alk alk.

-(CH2)a-CO~N alk£ . ~(CH2)a-CO-alk . -(CH2)a-CH<^ CH, CH.

. (CH2)E-CmN alk, alkx and alk2 representing an alkyl radical containing up to 4 carbon atoms, and n represents an integer between 1 and 4 .

Example 58 s A tablet having the following composition was prepared: 4—(5—oxo-2-thioxo—3,4,4—trimathyi—l~imidaso— linyl)-2-(trifluoromethyl)benzonitrile.... 100 mg excipient q.s. for a finished tablet containing................................ 300 mg (Make-up of the excipient: lactose,, starch, talc and magnesium stearate).

Pharmacological .study of the products of the invention 1) Study of the affinity of the products of the invention, for the androgenic receptor Sbadrogeaie receptor. 180-200 g SPF male Sprague Dawley rats, castrated 24 hours beforehand, are sacrificed, the prostates are removed, weighed and homogenised at 0’C with the aid of a glass/glass Potter, in a buffered solution (10 mM tris), 0.25 M sucrose, 0.1 mM PMSF (phenyImethanesulphonyl fluoride), 20 mM sodium molybdate, HCI pH 7.4; to which is added for immediate use 2 mmol of DTT (DL-dithiothreitol), in a ratio of 1 g of tissue per 8 ml of buffer.

The homogenate is then ultracentrifuged at 105,000 g for 45 minutes at 0’C. Aliquots of the supernatant obtained (= cytosol) are incubated for 30 minutes and for 24 hours at 0’C, with a constant concentration (T) of tritiated testosterone and in the presence of growing concentrations (0 to 2500x10" ® Μ) , either of cold testosterone or of products to be tested. The concentration of bound tritiated testosterone (B) is then measured in each incubate by the adsorption method on carbondextran.

Calculation of the relative binding affinity ., The following 2 curves are plotted: the percentage of bound tritiated hormone B/T as a function of the logarithm of the concentration of cold reference hormone and B/T as a function of the logarithm of the concentration of the cold tested product. The line of the equation (B/Tg?5, 442 3/T-i-)/2 is determined.

B/Taax = % of bound tritiated hormone for an incubation of this tritiated hormone at the concentration (T).

B/Tqjg, = % of bound tritiated hormone for an incubation of this tritiated hormone at the concentration (T) in the presence of a large excess of cold hormone (2500x10® M).

The intersections of the Iso line and of the curves allow elevation of the concentrations of the cold reference hormone (CH) and of the cold tested product (CX) which inhibit the binding of the tritiated hormone to the receptor by 50%. The relative binding affinity (MBA) of the tested product is determined by the equation MBA-100 (CH)/(CX).

The following results expressed in MBA are obtained. Reference product (testosterone): 100 Incubation: 30 minutes Incubation: 24 hours Product of Example 1 27.5 3 Product of Example 2 22 6 Product of Example 4 21 5 Product of Example 11 28 8 Product of Example 12 128 92 Product of Example 13 31 39 Produet of Example 14 27 7 Product of Example 15 69 24 21-Determination of the andi^genic, or, antlandrocenic activity of the products of the invention _by means of the determination of ornithina. decarboxylase.

- Treatment protocol Male SWISS mice aged 6 weeks and castrated 24 hours beforehand receive the products to be studied by the oral route (suspension in 0.5% methylcellulose), simultaneously with a subcutaneous injection of testosterone propionate 3 mg/kg (solution in sesame oil, containing 5% of benzyl alcohol) to determine the antiandrogenic activity. The agonistic activity is determined in th® absence of testosterone propionate.

The products to be studied and also the testosterone propionate are administered in a volume of 10 ml/kg. hours after the treatments, the animals are sacrificed, and the kidneys are removed and then homogenised at 0C by means of a teflon/glass grinder in 10 volumes of 50 mM tris-HCl buffer (pH 7.4) containing 250 μΜ pyridoxal phosphate, 0.1 mM EDTA, and 5 mmol of dithiothreitol. The homogenate is then centrifuged at 105,000 g for 45 min.

- Principle of determination At 37"C, renal ornithine decarboxylase converts an isotopic mixture of cold ornithine and tritiated ornithine into cold putrescine and tritiated putrescine.

The putrescine is then collected on selective ion exchange papers. After drying, the excess ox tritiated and cold unconverted ornithine is eliminated by 3 0.1 M ammonia washings. The papers are dried, then the radioactivity is counted after addition of Aqualite scintillant.

The results are expressed in fmoles (10"ls M) of tritiated putrescine formed/hour/mg of proteins.

The following results are obtained: Product of Example 11: antagonism (PG) 3 mg/kg: 83% Product of Example 12: antagonism (PG) 0.1 mg/kg: 12% 0.3 mg/kg: 36% 1 mg/kg: 68% • 3 mg/kg: 94% 10 mg/kg: 99% : agonism (PG) 10 mg/kg: 0% Product of Example 14: antagonism (PO) 3 mg/kg: 87% Product of Example 15: antagonism (PO) 0.3 mg/kg: 4% 1 mg/kg: 82% ConeItsions The tests Indicated above show that the products of the invention tested have a strong anti-androgenic activity and are devoid of agonistic activity.

Claims (13)

1. The products of general formula (X); R (I) 10 in which: represents a cyano or nitro radical or a halogen atom, ϊ? 2 represents a trifluoromethyl radical or a halogen atom, the group -A-B- is chosen from amongst the radicals in which X represents an oxygen or sulphur atom and R 3 is 20 chosen from amongst the following radicals: - a hydrogen atom, - alkyl, alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms, these radicals optionally being substituted by one or more substituents chosen from amongst 25 hydroxyl, halogen, mercapto, cyano, acyl or acyloxy radicals having at most 7 carbon atoms, optionally substituted S-aryl in which the sulphur atom is optionally oxidised in the form of sulphoxide or of sulphone, free, esterified, amidified or salified carboxyl, amino, mono- or dialkylamino or a 30 heterocyclic radical comprising 3 to 6 links and containing one or more heteroatoms chosen from amongst sulphur, oxygen or nitrogen atoms, the alkyl, alkenyl or alkynyl radicals additionally being optionally interrupted by one or more oxygen, nitrogen or 35 sulphur atoms optionally oxidised in the form of sulphoxide or of sulphone, the aryl and aralkyl radicals additionally being optionally substituted by an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxv or trifluoromethyl radical, ¥ represents an oxygen or sulphur atom or an =NH radical, with the exception of the products in which the group -A-Brepresents the radical: x in which X represents an oxygen atom and R 3 represents a hydrogen atom and ¥ represents an oxygen atom or an NH radical and R 2 represents a halogen atom or a trifluoromethvl radical and R^ represents a nitro radical or a halogen atom.

2. The products of formula (I) as defined in Claim 1 in which ¥ represents an oxygen atom with the exception of the products in which the group -A-B- represents the radical: x in which X represents an oxygen atom and R 3 represents a hydrogen atom, R ; ~. represents a halogen atom or a trifluoromethyl radical and R^ represents a nitro radical or a halogen atom.

3. The products of formula (I) as defined in Claim 1 or 2 in which the group -A-B- represents the group: X II in which X represents a sulphur atom and R 3 has the meaning indicated in Claim 1.

4. The products of formula (I) according to Claim 3 in which R 3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms and being optionally substituted by a hydroxyl radical.

5. The products of formula (I) as defined in any one of Claims 1 to 4,- in which formula R x represents a cyano radical or a halogen atom46 δ. which 7. The products of formula (I) according to Claim 5, in formula represents a chlorine atom. The products of formula (I) as defined in Claim 1 or 2, in which formula the group -A-Β- represents a group: (C~SRg y or a group: in which represents an alkyl or alkenyl radical having at most 4 carbon atoms or an optionally substituted aralkyl radical.

6. 8. The products of formula (I) as defined in any one of Claims 1 to 5 f whose names follow: 4- (5-oxo-2-thioxo-3,4 ,4-trimethyl-l-imidazolidinyl)-2(trifluoromethyl)benzonitrile, 4-(4,4-'dimethyl-’5-oxo-2“thioxo“limidasolidinyl)-2(trifluoromethyl)benzonitrile, 4-[4,4-dimethyl-3-(2-hydroxyethvl)-5-oxo-2~thioxo-limidazolidinyl]-2~(trifluoromethyl)benzonitrile, 3- (3,4-dichlorophenyl)-2-thioxo-l,5,5-trimethyl~4imidazolidinone.

7. 9. The products of formula (I) as defined in any one of Claims 1, 2 and 7, whose names follow: - 1- (4-nitro-3- (trifluoi’omethyl)phenyl) -3,4,4-trimethyl2,5-imidazolidinedione, 4- [[4,5-dihydro-4,4-dimethyl-5-oxo-2-(phenylmethyl) thio]IH-imidazol-l-yl]-2-(trifluoromethyl)benzonitrile. XO. process for the preparation of the products of general formula (I) as defined in Claim 1, characterised in that: either a product of formula (II): (II) (XII) in which R 2 , R 2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III)x HN-R' ·, I H,C-C-CH, An in which R» 3 has the meanings indicated above for R 3 in which

8. 10 the possible reactive functions are optionally protected and it being understood that if represents a nitro radical or a halogen atom and if R 2 represents a halogen atom or a CF 3 radical and X represents an oxygen atom, R lll 3 cannot represent a hydrogen atom, 15 to obtain a product of formula (IV)ξ (IV) in which R 2 , R 2 , X and R ,f 3 have the above meaning, products of formula (IV) which, if necessary or if desired, are submitted to any one or more of the following reactions in any order: a) elimination of the possible protective groups which R’ 3 may 25 carry; b) hydrolysis of the >C=NH group to a ketone function and, if necessary, conversion of the >C=S group to a >C=0 group; c) conversion of the >G-0 group or groups to a >C=S group; d) action on the products of formula (IV) in which R’ 3 30 represents a hydrogen atom, and after hydrolysis of the >C=NH group to the ketone function, by a reagent of formula Hal-R” 3 in which R M 3 has the meanings of R* 3 with the exception of the meaning hydrogen and Hal represents a halogen atom, to obtain products of formula (I) in which the group -A-B- represents 35 the group 8-a 09 or / in which R” J 3 has the meaning indicated above and, if desired, action on these products by an agent for eliminating the possible protective groups which R M 3 may carry or, if necessary, action by an esterifying, amidifying or salifying 5 agent, or a reagent of formula Hal-R” 3 in which Hal and R 3 have the meanings indicated above is reacted with a product of formula (IV): (IV) to obtain a product of formula (1V’ S ) : o (IV«) which product of formula (IV”) , if necessary or if desired, is 25 submitted to any one or more of the following reactions in any order: a) elimination of the possible protective groups which R M 3 may carry and then, if necessary, action by an esterifying, amidifying or salifying agent; 30 b) conversion of the >G=O group or groups to >C~S groups.

9. 11. The products of formula (I) as defined in Claims 1 to 7, by way of pharmaceutically acceptable medicaments.

10. 12. The products of formula (I) as defined in Claim 8 or 9, by way of medicaments35

11. 13. The pharmaceutical compositions containing, by way of active principle, at least one of the medicaments as defined in either of Claims 11 and 12.

12. 14. The products of formula (ivi): (IVi) in which R^, R 2 and Y have the meanings indicated in Claim 1 and the groun: I is chosen from amongst the radicals: S-R„i f J A / and N k/ in which X represents an oxygen or sulphur atom and R 3 i is chosen iroxn amongst the meanings of Rg containing a protected reactive function · - with the exception of the products in which the group represents the radical: in which X represents an oxygen atom and R·^ represents a hydrogen atom and Y represents an oxygen atom or an NH radical and R£ represents a halogen atom or a trifluoromethyl radical and Rj represents a nitro radical or a halogen atom.

13. 15, A compound of general formula (I) as defined in Claim 1 whenever prepared by a process as claimed in Claim 10«,