AU648376B2 - 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

P/00/01 1 ReguLation 3.2

AUSTRALIA

PATENTS ACT 1990 64 8 376u COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

2@ 6e~S o.

U

S

*9s0 5FF

S

TO BE COMIwLErm BY APPLICANT :*Na1ne of Applicant

SO

Actual Inventor(s): Address for Service:

ROUSSEL-UCLAF

Martine GAILLARD-KELLY, Francois GOUBET, Daniel PHILIBERT Jean-Georges TEUTSCH CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Invention Title: "NOVEL PHENYLIMIDAZOLIDINES, PROCESS FOR THEI PREPARATION, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING TH-EM" The following statement is a full description of this invention, including the best method of performing it known to me:- Novel phenylimidazolidines. process for their preparation, their use as medicaments and pharmaceutical compositions containing them.

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-2thiohydantoins are described which are shown as inhibiting the germination of certain plants.

In French Patent 2,329,276, imidazolidines are described which are shown as having an anti-androgenic Activity. The products of this patent, however, are different 15 from the products of the present patent application.

S' The present invention therefore relates to the o* products of general formula R N A R Y CH 3

A

25 in which:

R

1 represents a cyano or nitro radical or a halogen atom, R 2 represents a trifluoromethyl radical or a halogen atom, the group is chosen from amongst the radicals 3 and 3 in which X represents an oxygen or sulphur atom and R 3 is 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 2 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, amidated or salified 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, .oo the aryl and aralkyl radicals additionally being optionally substituted by an alkyl, alkenyl or alkynyl, alkoxy, '4 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: q 9 in which X represents an oxygen atom and R 3 represents a 25 hydrogen atom and Y represents an oxygen atom or an NH radical and R 2 represents a halogen atom or a trifluoromethyl radical and R 1 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 mcst 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 dodecyl.

Alkyl 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, 1-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 **go preferably chosen from amongst oxygen, sulphur and nitrogen.

15 Among the heterocyclic aryls having 5 mebers, 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.

25 The phenyl radical is preferred.

Arylalkyl 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 the phenyl radical 4 is substituted in the para position by a fluorine atom or by 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 alkyloxycarbonyl 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 *Opp ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as the methoxycarbonyloxymethyl or -ethyl radicals, or the isopropyloxycarbonyloxymethyl or -ethyl radicals.

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

Amidated carboxyl is understood as meaning radicals of 25 the type /R4 -CON in which identical or different radicals R 4 and R e

R

R

S 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.

/R

4 Among the -N radicals, the amino, mono- or

R

S

dimethylamino radicals are preferred.

S R4 The N radical may also represent a

R

heterocycle which may or may not contain an additional heteroatom. The pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidil, indolyl, piperidino, morpholino and piperazinyl radicals may be mentioned. The piperidino or morpholino radicals are preferred.

Salified carboxyl is understood as meaning the salts formed, for example, with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine may also be mentioned.

The sodium salt is preferred.

Alkylamino radical is understood as meaning the *999 methylamino, ethylamino, propylamino 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 4* 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.

25 Heterocyclic radical containing one or more heteroatoms is understood as meaning, for example, saturated monocyclic heterocyclic radicals such as the oxiranyl, oxolanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, 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 are identical or different in their structure. These heteroatoms can obviously not be situated at the end of the radical. Alkoxyalkyl radicals such as, for example, methoxymethyl or methoxyethyl or else alkoxyalkoxyalkyl radicals such as methoxyethoxymethyl may be mentioned.

When the products of formula 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 as defined above in which Y represents an oxygen atom, with the exception of the products in which: the group represents the radical: 3 in which X represents an oxygen atom and R 3 represents a hydrogen atom and R 2 represents a halogen atom or a trifluoromethyl radical and R 1 represents a nitro radical or a halogen atom.

Among these products, the invention particularly relates to those in which the group represents the radical: S R3 25 in which X represents a sulphur atom and R 3 has the weaning 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 R, represents a cyano radical or a halogen atom and in particular a chlorine atom.

The invention also particularly relates to the products of formula as defined above in which the group A-B- represents a group:

-C-SR

-N 3 or a group: k-N-R 3 in which R 3 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 as defined above and corresponding to the formula 0 R 0 0 represents a hydrogen atom.

Among these products, the present invention also O e 0 06 66, Among these products, the present invention also relates to the products of formula as defined above in foo25 which R 1 represents a nitro radical and R represents an alky 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 as defined above and whose names follow may be mentioned more precisely: 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-4imidazolidirone, 1- (4-nitro-3-(trifluoromethyl) phenyl) 4-trimet',y1- 2, 4-[s[4 ,5-dihydro-4 ,4-dimethyl-5-oxo-2-' (phenylmethyl~thioJ 1H-imidazol-1-yl) -2-(trifluoromethyl) benzonitrile.

The invention also relates to a process for the preparation of the products of general formula as defined above, characterised in that: either a product of formula (II): R2 formul (III) 20 0 *CCH which R 1 ,R aX ha ve the meaing indicated above is hc eaed sinbte resenve fnattertar basei withl a prodct ofd tooti rdc fformula (IV): 0 2 C

H-R'

3in which ha, the eaning indicavethe above foring winh which uits bein udrstood that, if neceprrnt af deired, rdcloe toubtain t an oc o forue ofV) th olwnxeatosi n rder:R 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" 3 in which Y13 has the meanings of R' 3 with the exception of the meaning hydrogen and Hal represents a halogen atom, to obtain products of formula in which the group represents the group

S-R"

3 15 k or S/ 3 in which R" 3 has the meaning indicated above and, if desired, action on these products by an agent eliminating the possible protective groups which R" 3 may carry or, if necessary, action by an esterifying, amidating or salifying agent, S 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 25 0 02

N

N N-H 25

(IV')

F3C to obtain a product of formula 0 0

R

1"

(IV")

3 0 which product of formula 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 R" 3 may carry, and then, if necessary, action by an esterifying, amidating or salifying agent; b) conversion of the >C=O 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 methylethylpyridine.

The possible reactive functions which R 3 may contain S and which are optionally protected in the product of formula (III) or 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, 25 trimethylsilyl and tert-butyldimethylsilyl 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 BY 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 peferred.

The possible hydrolysis of the >C=NH 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 R 3 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 HC

/C

15 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 t from a molecule containing a >C=S function and a >C=O function in which it is wished to convert the said >C=O function to a >C=S function.

25 On the other hand, when starting from a molecule

S

containing two >C=O 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=O function and a >C=S function and the product containing two >C=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-R" 3 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" 3 may carry may be, for example, one of those mentioned above for R 3 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 (I) in which R" 3 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.

*e 15 The optional esterification or salification of the products of formula in which R1 3 represents a COOH group is carried out under the conventional conditions known to the person skilled in the art.

The optional amidation of the products of formula in which R" 3 contains a COOH radical is carried out under ctonventional 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 25 the preparation of the products of formula

A"

R 2 y in which R" 1

R"

2 and have the meanings indicated above for R 1

R

2 and it being understood that when represents a group in which R"' 3 represents a hydrogen atom or a linear or branched alkyl radical having at most 7 carbon atoms and Y represents an oxygen atom, R" 1 represents a cyano radical, this process being characterised in that a product of formula I

(V)

R"2 2 in which and R' 2 have the above meanings and Hal represents a halogen atom, is reacted with a product of formula (VI):

HN

CH (VI) Y CH 3 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 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 S'.I condensation of the product of formula with the product of formula (VI) to give the required product.

The invention more precisely relates to a process such 25 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 a. 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.

The 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 mixture.

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 a such as diphenyl ether, diglyme, triglyme or dimethyl «096 sulphoxide.

Boil 4 15 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 25 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 oxLde, in triglyme, at a temperature higher than or equal to 200*C and for more than 3 hours.

The 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 products of general formula 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 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 a a* ovaries but also cancers of the bladder, lymphatic system, 0044 kidney and liver may be mentioned in particular.

46cM S15 The products of general formula of the invention **Stee also find use in the treatment of hirsutism, acne, seborrhea, ieee androgenic alope-ia and hyperpilosity.

*ga* They can also be used in the veterinary fixid.

The invention therefore relates to the administration, by way of medicaments, of the pharmaceutically acceptable products of general formula The invention particularly relates to the administration by way of medicaments of the products whose names follow: 25 4-(5-oxo-2-thioxo-3 ,4,4-trimethyl--imidazolidinyl)-2- (trifluoromethyl)benzonitrile, 4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidi'i,, (trifluoromethyl)benzonitrile, 4-[4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo-1imidazolidinyl]-2-(trifluoromethyl)benzonitr le, 3-(3,4-dichlorophenyl)-2-thioxo-1,5,5-trimethyl-4imidazolidinone, 1-(4-nitro-3-(trifluoromethyl)phenyl)-3,4,4-trimethyl- 4-[[4,5-dihydro-4,4-dimethyl-5-oxo-2-(phenylmethyl)thio]- 1H-imidazol-1-yl]-2-(trifluoromethyl)benzonitrile.

The products can be administered by the parenteral, buccal, perlingual, rectal or topical route.

The invention also relates to pharmaceutical compositions characterised in that they contain, by way of active principle, at least one of the medicaments of general formula 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, g3ycols, various wetting agents, dispersants or emulsifiers and preservatives.

15 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 0 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 R H 2

S

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 are described in European Patent EP 0,002,892 or French Patent BF 2,142,804.

The products of formula are known or can be prepared starting from the corresponding cyanohydrin according to the process described in the publication: J. Am. Chem. Soc.

(1953), 75, 4841.

The products of formula (III) in which R' 3 is other than a hydrogen atom can be obtained by action of a product of formula R" 3 Hal on 2-cyano-2-aminopropane under the conditions stated above for the action of R" 3 Hal on the products of formula 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 are described in French Patent BF 2,329,276.

The starting materials of formulae and on which a process is carried out, to which the invention relates, for obtaining the products of formula are known and commercially available or can be prepared according to methods 'nown to the person skilled in the art.

The preparation of products of formula (VI) is described in particular in the following publications: 15 Zhur. Preklad. Khim. 28, 969-75 (1955) (CA 50A, 4881a, 1956) Tetrahedron 43, 1753 (1987) J. Org. 52, 2407 (1987) Zh. Org. Khim. 21, 2006 (1985) J. Fluor. Chem. 12, 345 (1981) or in the patents: German DRP 637,318 (1935) European EP 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. Pharm. Pharmacol., 67, Vol. 19(4), p. 209-16 (1967) J. Chem. Soc., 74, p. 219-21 (1972) Khim. Farm. Zh., 67, Vol. 1 p. 51-2 German Patent 2,217,914 European Patent 0,091,596 J. Chem. Soc. Perkin. Trans. 1, 74 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 to the products of formula (Xvi): 18 /1

A

(IVi) in which R 1

R

2 and Y have the meanings indicated above and the group: Ai is chosen from amongst the radicals: 3 15 and in which X represents an oxygen or sulphur atom and R 3 i is chosen from amongst the meanings of R 3 containing a protected reactive function.

Amongst the protected reactive functions, the hydroxyl and amino functions may be mentioned. These functions can be protected as indicated above for the substituent R 3 The following examples illustrate the invention without, however, limiting it.

Example 1: 1-(4-nitro-3-(trifluoromethyl)phenyl)-3,4,4- A solution of 3.17 g of 1-(3'-trifluoromethyl-4-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione (obtained according to French Patent 2,329,276) and 32 cm 3 of dimethylformamide are added, at a temperature between 23 and 26*C, to a suspension of 492 mg of 50% sodium hydride in oil and 3 cm 3 of dimethylformamide, the mixture is stirred for 15 minutes and a solution of 0.7 cm 3 of methyl iodide in 2 cm 3 of dimethylformamide is added. The mixture is stirred for 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 0 C, are obtained.

An analytical sample was obtained by recrystallisation in isopropyl alcohol; 2.73 g of the expected product, m.p. 1160C, is thus obtained.

Analysis for C 13

H

12

F

3

N

3 0 4 331.25 calculated: C% 47.14 H% 3.65 F% 17.20 N% 12.68 found: 47.0 3.5 17.1 12.5 IR spectrum (CHCl 3 C=O (1780, 1727 Cm-1) aromatic (1615, 1596, 1497 om-1) N0 2 (1545, 1357 cm- 1 15 Example 2: 5,5-dimethyl-1-ethyl-3--(4-nitro-3-(trifluoromethvl)Dhenyl) lmidazolldine-2 .4-dione The procedure is as in Example 1 starting from 1 g of 1- (3 '-trifluoromethyl-41-nitrophenyl) 4-dimethylimidazolineto :2,5-dione obtained according to French Patent 2,329,276 using 0.33 cm 3 of ethyl iodide and 166 mg of 50% sodium hydride in oil. 1.19 g of the required product, m.p. =110-1116C, are obtained. The producle above is recrystallised in isopropanol.

934 mg of the expected product, m.p. 110-1110C, are obtained.

Analysis for C 14

H

14

F

3

N

3 0 4 345.28 6 calculated: C% 48.70 H% 4.09 F% 16.51 N% 12.17 found: 48.6 4.0 16.8 12.1 IR spectrum (CHCl 3 C=O (1777 cm-1, 1724

NO

2 (1545, 1356 cm- 1 aromatic (1614, 1596, 1497 CM- 1 Zxample 2: 5.5-dimethyl-3- (4-nitro-3- ftrifluorometbhvi)henyli4- I-1ropylimidAzolidine-2 .4-dione The procedure is as in Example 1 starting from 1 g of 1- (3 '-trifluoromethyl-4-nitrophflyl) 4-dimethylimidazoline- (obtained according to French Patent 2,329,276) using 155 mg of 50% sodium hydride in oil and 0.35 cm 3 of 1-iodopropane. After chromatography on silica, eluent acetone/methylene chloride 1:99, 1.087 g of crude product are obtained 102*C). After recrystallisation in isopropanol,, 945 mg of required product are obtained 1020C).

Analysis for C 15

H,

6

F

3

N

3 0 4 359.31 calculated: C% 50.14 H% 4.49 F% 15.86 N% 11.69 found: 50.1 4.4 15.9 11.5 IR spectrum (CHCl 3 C=0 (1778, 1724 cm- 1

NO

2 (1544, 1358 cm- 1 aromatic (1615, 1596, 1497 cm-1) Example 4: 5,5-dimethvl-1- (1-methylethyl) (4-nitro- 3-trifluoromethyl)pihenvl) imidazolidine-2 .4-dione The procedure is as in Example 1 starting from 1 g of 1- -trifluoromethyl-4-nitrophenyl) 4-dimethyJlimidazoline- 2,5-dione (obtained according to French Patent 2,329,276) using 166 mg of 50% sodium hydride in oil and 0.4 cm 3 of 2-iodopropane for 18 hours at 50 0 C. 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, nm.p. 1300C, are obtained.

Analysis for C 15 1 1 F N 0 359.31 calculated: C% 50.14 H1% 4.49 F% 15.86 N% 11.69 **found: 50.1 4416.2 11.6 IR spectrum (CHC1 3 C=O (1779t 1771, 1723 crn 1

NO

2 (1544, 1361 cm- 1 aromatics (1615, 1596, 1497 cm" 1 *xmj 5: 5.5-dimethvl-3- (4-nitro-3,-ttrifuoromethvl)hen-yfl.

2-Dropenyli midazolidine-2 .4-dione The procedure is as in Example 1 starting from 1 g of 1- (3 '-trifluoromethyl-4-nitrophenyl) 4-diinethylimidazoline- (obtained according to IPrench Patent 2,329,276) Using 166 mg of 50% sodium hydride in oil and 0.35 cm 3 of allyl bromide. After chromatography on silica# eluent methylene chloride/acetone 99:1, 1.19 g of product are obtained which is recrystallised in isopropatol; 1.01. g of required product, mn.p. w 105*C, are obtained.

Analysis for C, 5

H

14

F

3

N

3 0 4 357.29 calculated: C% 50.42 H% 3.95 F% 15.95 N% 11.76 found: 50.4 3.8 15.8 11.7 IR spectrum (CHC1, 3 C=O (1779, 1724 con-)

NO

2 (1545, 1358 cm- 1 aromatic (1615, 1596, 1497 cm-1)

CH=CH

2 (1643, 930 cm- 1 Example 6: 5.5-dimethvl-3- (4-nitro-3- (trifluoromethyliphenyl)- 1-methv1phenylimidazolidine-2 .4-dione The procedure is as in Example 1 starting from 2 g of 1- (3 '-trifluoromethyl-4-nitrophenyl) 4-dimethylimidazoline- (obtained according to French Patent 2,329,276) 03 .:.-using 332 mg of 5' sodium hydride in oil and 0.71 cm 3 of 000 15 benzyl bromide. After chromatography on silica, eluent 00,00: methylene chloride/acetone 99:1, 2.375 g of product are 0 0 00 obtained which is recrystallised in isopropanol; 2.165 g of *see. the required product, m.p. =990C, are obtained.

Analysis for C 19

H

16

N

3

F

3 0 4 =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=O (1799 cm 1723 cm- 1 aromatic (1608 cm- 1 (1594 cm- 1 (in)) N0 2 (1545 cm 1 (1497 cm-1) fe ExaMRlo 7: 4- (4 .4-dimetbyl-5-iminO-2-oxo-1-imidazliill-2- ~trif1uoromethyjbengzonitrile A solution of 6.6 g of 2-trifluoromethylbenzonitrile- 4-isocyanate, prepared as indicated in the preparation below, in 10 cm 3 of dichloroethane is added at 5*C to a solution of 2.63 g of 2-amino-2-acyariopropane anid 36 Cm 3 of l,2-dichloroethane with 0.9 cm 3 of triethylamine. The mixture is stired 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. 2286C, are obtained.

An analytical sample was prepared by recrystallisation of 300 mg of the above product in isopropanolt 267 mg of required product, m.p. 228 0 C, are obtained.

Analysis for C 3

H

11

F

3

N

4 0 296.25 cilculated: C% 52.71 H% 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 CsN 2240 cm" C=O 1760 cm" 1 C=N 1655 cm" aromatics (1606, 1570, 1502 cm" 1 Preparation: 2-trifluoromethvlbenzonitrile-4-isocyanate 10 g of 4-cyano-3-trifluoromethylaniline (described in 15 European Patent EP 0,002,892) dissolved in 30 cm 3 of ethyl acetate is added in the course of 20 minutes to 33.6 cm 3 of a 1.93 M toluene solution of phosgene kept at 0-5*C. The mixture is stirred for 30 minutes at a temperature between 0 and 0 which is then allowed to rise to 25°C. It is heated until it distils, making up for the volume distilled by toluene, until the distillation temperature reaches 110*C. The condenser is S then put in the reflux position until release of hydrochloric Sacid ceases 4k 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 cm 3 of toluene each time and evaporated to drysiess 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 -N=C=AO 2268 cm" -CN 2233 cm" Example 8: 4-(4,4-dimethyl-.,5-dioxo-l-imidazolidinyl)- 2-trifluoromethyTbenzonitrile A suspension of 2.76 g of the product obtained in Example 7 and 60 cm 3 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 rtquired product, m.p. 210°C, 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 0 C, are obtained.

Analysis for C 13

H

10

F

3

N

3 0 2 297.24 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 3 CEN 2245 cm" 1 C=O (1788, 1722 cm" 1 aromatic (1610, 1572, 1502 cm 1 NH (max) 3340 cm" 1 I Example 9: 3-(4-cyano-3-(trifluoromethyl)phenvl)-5,5-dimethyl- 2,4-dioxo-l-imidazolidinylacetic acid A solution of 600 mg of the product obtained in Example 8 in 6 cm 3 of dimethylformamide is added to a suspension of 210 mg of Sodium hydride (50% in oil) and 3 cm 3 of dimethylformamide, the mixture is stirred for 15 minutes, 290 ng of bromoacetic acid are then added and the mixture is stirrd 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 cm 3 of water and cm 3 of 2 N hydrochloric acid. The mixture is extracted with ether, washed with a saturated solution of sodium chloride, S 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 cm" 1 hydantoin and acid C=0 (1784, 1725, 1710 cm") aromatic (1616, 1580, 1508 cm"1) ultraviolet EtOH HC1 0.1 N max 258 nm epsilon 13300 infl 277 nm epsilon 5000 infl 285 nm epsilon 2600 EtOH NaOH 0.1 N max 287 nm epsilon 19100 max 342 nm epsilon 1900 Example 10: ethyl 3-(4-cyano-3-(trifluoromethvl)phenyl)5,5dimethyl-2,4-dioxo-l-imidazolidinylacetate 600 mg of the product obtained in Example 8 are added in solution in 6 cm 3 of dimethylformamide to a suspension of 100 mg of 50% sodium hdride in oil and 3 cm 3 of dimethylformamide. The mixture is stirred for 15 minutes, then 0.25 cm 3 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 0.5 g of monopotassium phosphate is added and the mixture is extracted with ether. The organic phase is washed with water, dried and 15 evaporated to dryness; 1.1 g of crude product are obtained which is chromatographed on silica (eluent methylene chloride/acetone 709 mg of the expected product, m.p. 152 0 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 0 C, were thus obtained.

Analysis for C 17

H

16

F

3

N

3 0 4 383.33 S 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 3 C=N 2225 cm" imidazolidine (1786, 1729 cm" 1

SCO

2 Et 1751 cm" 1 S aromatics (1616, 1572, 1505 cm 1 Example 11: 4-(5-imino-2-thioxo-3,4,4-trimethyl-1-imidazolidinvl)-2-trifluoromethylbenzonitrile b) Preparation of the isothiocyanate 2.23 g of l-trifluoromethyl-4-aminobenzonitrile (prepared according to EP 0,002,892) is added slowly to a solution of 22 cm 3 of distilled water and 1 cm 3 of thiophosgene, the 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 3 g of the product obtained above is stirred for minutes at reflux with 1.33 cm 3 of 2-methylamino- 2-cyanopropane, 23 cm 3 of tetrahydrofuran and 0.23 cm 3 of triethylamine. The mixture is evaporated to dryness and the residue (3.07 g) is chromatographed on silica (eluent: cyclohexane/ethyl acetate then methylene chloride/acetone 2.83 g of expected product are obtained which is recrystallised in isopropanol to obtain 2.63 g of required product, m.p. 173-174C.

Analysis for CI 4

H

1 3

F

3

N

4 S 326.35 calculated: C% 51.53 H% 4.01 F% 17.17 N% 17.46 S% 9.82 o found: 51.7 3.9 17.2 17.2 9.9 *ee* 15 IR spectrum C=NH (3308, 1679 cm" 1 C=S aromatics (1608, 1575, 1505, 1488 cl e CaN 2230 cm" 1

CF

3 1185 cm-1 Example 12 4-(5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolidinvl)-2-trifluoromethylbenzonitrile 2.21 g of the product obtained in Example 11 and 44 cm 3 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 extracted with methylene chloride, washed with water saturated with sodium chloride, dried and evaporated tc dryness, the residue is chromatographed on silica, eluent cyclohexane/ ethyl acetate 1:1, and 2.1 g of product is obtained 171°C) which is recrystallised in isopropanol to obtain 1.99 g of required product, m.p. 171°C.

Analysis for C 14

H

12

F

3

N

3 OS 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 (CHC1 3 C=0 (1761, 1755 cm 1 aromatics (1610, 1578, 1505 cm 1 CmN 2230 cm"

CF

3 1178 cm- 1 EX=Pl~e 13: 4- (2 .5-dithioxo-3 .4.4-trimethv1-1-imidazolidinvl)- 2 -tri fluoromethvlbenzonitrile 839 mg of product obtained in Example 12 is stirred at reflux f or 24 hours with 518 mg of Lawesson reagent and 4.7 cm 3 of toluene. The mixture is evaporated to dryness under reduced pressure and 1.36 g of product are obtained which is chromatographed on silica, eluent methylene chloride/ethyl acetate then cyclohexane/ethyl acetate (85:15). 783 mg of product are obtained which are recrystallised in isopropanol; 690 mg of required product, m.p. 211-212 0 C are obtained.

Analysis for C 14

H

12

F

3

N

3

S

2 343.40 a...calculated: C% 48.97 H% 3.52 F% 16.60 N% 12.24 S% 18.67 ~15 found: 49.0 3.4 16.6 12.2 18.6 IR spectrum (CHCl 3 #See CmN 2230 cm-1 aromatic conjugated system (1612, 1582, 1508 cm- 1

CF

3 1178 cm- 1 ExaMple 14: 4- (4 .4-dimethvl-5-imirio-2-thioxo-l-imidazolidinvi) -2-trifluoromethvlbenzonitrile 0* 0 1'g of 2-amino-2-cyanopropane and 1 cm 3 of tetra- A hydrofuran are added to a mixture of 2.54 g of product Go obtained as in a) of Example 11 with 20 cm 3 of tetrahydrofuran and 0.2 cm 3 of triethylamine and the mixtiire is stirred at ambient temperature. It is evaporated to dryness and the residie (3.5 g) is chromatographed on silica, eluent ethyl acetate/cyclohexane then cyclohexane/ethyl acetate and 940 mg of required product is obtained of which 300 mg are recrystallised in isopropanol to obtain 263 mg of product, mopo 296*C.

Analysis for C 13

H

11

F

3

N

4 S 312.32 calculated: C% 50.00 11% 3.55 F% 18.25 N% 17.94 10.27 found: 49.9 3.4 18.3 17.6 10.4 IR spectrum (Nujol) OH/NH 3260 cm- 1 CruN 2230 cm- 1 C=S 1764 cm- 1 aromatic C=C (1612, 1575, 1530, 1501 cm- 1 A novel preparation of the product was carried out by replacing the tetrahydrofuran by 1,2-dichioroethane.

The expected product, which is insoluble, precipitates. The required product is thus obtained with a yield of EXa pie 15: 4- (4 .4-dimethv1-5-oxo-2-thioxo-1-imidazolidinvl)- 2 -tri fluoromethylbenzonitrile 635 mg of the product obtained in Example 14 and 14 cm 3 of hydrochloric acid diluted to half strength are stirred for 1 hour at ref1l2x. The mixture is cooled, 100 cm 3 of water are added and it is extracted with ethyl acetate, washed with brine, driead and evaporated to dryness; 600 mg of product are obtained which is chromatographed on silica, 15 eluent methylene chloride/acetone (95:5) and 590 mg of expected product 190-1910C) are obtained which is too* recrystallised in isopropanol to obtain 490 mg of the required product, m.p. 190-191 0

C.

Analysis for C 13

H

10

F

3

N

3 0S 313.30 calculated: C% 49.84 Ht 3.22 F% 18.19 N% 13.41 S% 10.23 found: 49.6 3.1 18.4 13.2 10.0 IR spectrum (CHCl 3 =C-NH 3430 cm- 1 6CwN 2230 J- C=O 1766 cm- 1 Conjugat'-ed system aromatics (1612, 1578, 1505 cm 1) Exagple 16: 5,5-dimethvl-3- (4-nitro-3- (trifluoromethvil henvi) -l-DentvlimidazolidilO-2 D4-dione The procedure is as in Example 1 starting from 1 g of 1- (3 '-trifluoromethyl-4-nitrophenyl) -4 ,4-dimethylimidazoline- (obtained according to French Patent 2,329,276) using 170 mg of sodium hydride and 0.47 cm 3 of 1-bromopentane, and, after chromatography on silica, eluent methylene chloride/cyclohexane 1.23 g of required product are obtained which is crystallised ink isopropanol to obtain 995 mg of product, m.p. 84*C.

Analysis for C 17

H

20 0 4

F

3

N

3 387.35 calculated: C% 52.71 5.20 F% 14.71 N% 10.85 found: 52.8 5.1 14.8 10.7 IR spectrum (CHC1 3 C=O (1778, 1723 cm- 1 N0 2 (1544, 1360 cm- 1 Example 17: 5.5-dimethvl-3-(4-ni'tro-3-(trifluoromethvl) Dhenvl)-l-nonvlimidazolidine-2 .4-dion The procedure is as in Example 1 starting from 1 g of 1-(3'-trifluoromethyl-4-nitrophenyl)-4,4-dimethylimidazoline- (obtained according to French Patent 2,329,276) using 170 mg of 50% sodium hydride in oil and 0.7 cm 3 of 1-bromononane. After chromatography on silica, 1.08 g of the required product, m.p. 63*C, are obtained.

Analysis for C 21

H

28 0 4

F

3

N

3 443.46 6004 calculated: C% 56.87 H% 6.36 F% 12.85 N% 9.48 16000 15 found: 57.0 6.5 12.8 IR spectrum (CHC1 3 C=O (1788, 1723 cm 1

NO

2 (1544, 1359 cm 1 Example 18: 4-(3,4,4-trimethyv-2.5-dioxo-1-imidamolidinyl)-2trifluoromethvlbenzonitrile Proceeding as in Example 1, starting from 300 mg of product described in Example 8, 275 mg of expected product are obtained 158*C).

IR spectrum (CHCl 3 C=O (1780, 1727 cm- 1 aromatics: (1615, 1574, 1505 cm- 1 C-N: 2238 cm 1 Egmnple 19: 4-(5-thioxo-2-oxo-3.4, 4-trimethv1-1-imidazo-' lidinv1)-2-trifuoromethbenzfonitrile (product A) 2-thioxo-3 .4 .4-trimethv--imidazolidiyl) 2-trifluoromethvybenzonitrile (troduot B) 41-(2,5-dithioro- 3 4,-trimit'hvl-l-imidazo idinyl )-2-rif luoromethlbenzonitrile (pro9 '.AC4 A suspension of 230 mg of product obtained in Example 18 is heated to reflux for 9 hours in 1.4 cm 3 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 I 29 chloride/acetone 99:1).

The following are obtained in order of elution: 46 mg of product C (Rf 0.63, m.p. 210-211 0

C)

identical to the product described in Example 13; 26 mg of product B (Rf 0.49, m.p. 170-171°C) identical to the product described in Example 12; 42 mg of product A (Rf 0.34, m.p. 194 0

C).

Physical analysis of the product A.

IR spectrum (CHC13): C=O: 1760 cm'" -CEN: 2235 cm" 1 aromatics: (1615, 1580, 1508 cm 1 Ultraviolet spectrum (ethanol) max 228 nm epsilon 19400 S* 256 nm epsilon 12100 15 298 nm epsilon 8600 *VS 390 nm epsilon Example 20: 4-(4,5-dihvdro-4,4-dimethyme 1H l-imidazol-1-yv-2-trifluoromethylbenzonitrile .A solution' of 626 mg of product from Example 15 in 6 cm 3 of dimethylformamide is added to a suspension composed of 108 mg of 50% sodium hydride in oil and 1.8 cm 3 of dimethylformamide. Washing is performed with 0.3 cm 3 of dimethylformamide and the mixture is stirred for 10 minutes after evolution of hydrogen has ceased. 0.19 cm 3 of methyl iodide in 1 cm 3 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

CH

2 C12-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 prcluct, m.p.

620C, are obtained.

Infrared spectrum C=O: 1747 cm" 1 C=N and aromatic (1614, 1581, 1569, 1503 cm-1) Ultraviolet spectrum (EtOH) max 209 nm epsilon 26000 infl 236 nm epsilon 11500 infl 264 nm epsilon 8700 Example 21: 4-[4.5-dibvdro-4.4-dimethyl-5-oxo-2-r (phenylmethyl)thiol-1H-imidazol-1-yll-2-trifluoromethylbenzonitrile 313 mg of 4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-trifluoromethylbenzonitrile prepared as in Example 15 and dissolved in 3 cm 3 of dimethylformamide are added in the course of 5 minutes to 53 mg of sodium hydride suspended in 0.5 cm 3 of dimethylformamide. The mixture is stirred :or 10 minutes, 0.1 cm 3 of benzyl bromide is added and S. the mixture is stirred continuously for 30 minutes. The lose 15 reaction mixture is poured into iced water to which 500 mg of 0rO6 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. Rf 0.38.

Analysis 0 60 calculated: C% 59.54 H% 4.0 F% 14.12 N% 10.41 found: 59.6 4.0 14.1 10.2 IR spectrum (CHC1 3 1746 cm- CEN: 2236 cm 1 Conjugated system aromatics: 1614, 1580, 1570, 1503, 1499 cm 1 Example 22: 4-[4,4-dimethl-3-(2-hydroxvethyl)-5-imino- 2-thioxo-1-imidAzolidinyl1]-2-trifluoromethylbenzonitrile.

A solution containing 2.11 g of the is)thiocyanate prepared in stage a) of Example 11 is heated to reflux for minutes with 1.18 g of a mixture of 2-((2-hydroxyethyl)amino]-2-methylpropionitrile and 2,2-dimethyloxazolidine in 20 cm 3 of tetrahydrofuran in the presence of 0.5 cm 3 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 636 mg ofi N- E4-cyano-2- (trifluoromethyl) phenyl] 2, 2-dimethyl-3-oxazolidinecarbothioamide are obtained. The 686 mg of this product are dissolved in 10 cm 3 of ethyl acetate, 3U cm 3 of cyclohexane are added, and the mixture is concentreatn 4 cm 3 drained and dried to obtain 518 mg of extra v, ,..ted produzt. The crude product is dissolved in cm-. isopropanol, concentrated to 5 cm drained and dried, g of~ expected product are obtained. M.p. 1810C.

calcubI; 50.55 H1% 4.24 F% 16.00 N% 15.72 S% 9.00 found: 50.4 4.1 15.9 15.6 IR spectrum i:0 C'(t 3 OH: 3630 cm-1 s 3314, 1677 m1 2230 cm- 1 aromatics: 1611, 1576f 1504 cm- 1 Preparation of 2-[2-haydro~nyethylannfo]-2-methylpropioflitrilO rsed at the start of E~xample 22 8 cm 3 of ethanoaamine are added dropwise at a temperature between 20 0 C and 300C to' 12.3 cm 3 of acetone cyanohydrin. The mixture I~s stirrad for 18 hours, distilled under reduced~ pressure and 2.3 g of mixture containing the 0 :25 expected product and 2,2-dimethyloxazolidine are obtained and .e0 used as such for the following stage.

E,amD~Je 23: 4-r44 .I~imet yl-3- (2-lvdroxyethv,) -5-oxO-2-thioxo- *000: 1-M~dzolidinv11 -2-trifiuoromethylbenzonitrile Ci-roduct A) and. -r,4-dimethvl-2 ,S-dioxco-3- C2-merctuptoethv1 Imidiuzolicliiyl1-2-trif uo ometbylbeflzofitrile (productB) 680 mg of product obtained in Example 22 are heated at reflux for 10 minutes in 7 cm 3 of water in the presence of 7 cm 3 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 119 mg of product B iLe. the 2,5-dioxo-3-(2-mercaptoethYl) derivative Rf 0.35 and 569 mg of product A i.e. the 5-oxo-2-thioxo-3-(2hydroxyethyl) derivative Rf 0.14; m.p. 1300C are obtained.

Analysis for C 5

H

1 4

F

3

N

3 0 2 S 357.36 calculated: C% 50.42 H% 3.95 F% 15.95 N% 11.76 S% 8.97 Product A: found: 50.7 4.0 15.7 11.5 9.1 Product B: found: 50.6 3.8 15.9 11.6 9.1 IR spectrum (CHCl 3 Product A: OH 3626 cm 1 CaN 2236 zm 1 C=O 1763 cm 1 aromatics: 1615, 1578, 1504 cm 1 Product B: OH a:sent CNmN 2228 cm- 1 C=O 1780, 1726 cm 1 aromatics 1615, 1578, 1505 cm 1 *000 20 Proceeding as L'icated in Examples 1 to 23: k1) using 4-(4,4-dimethy'l-2,5-dioxo-1-imidazolidinyl)- 2-trifliioromethylbenzonitrile prepared as in Example 8 and the appropriate rea4;oV'nts, the compounds of the following examples were obtained: ]gx ple 24%, 4-(4.4-dimetnvl-2.5-dioXo-3-ethvl-1-imidazCidiv1)-2-trifl'bromethylbenzonitrilo M.p. 100-1010C.

Analysis for CISHI 4

F

3

N

3 0 2 325.29 calculated: C% 55.39 H% 4.34 F% 17.52 N% 12.92 found: 55.7 4.3 17.6 12.8 IR spectrum (CHC1 3 C=N 2238 cm 1 C=O 1777, 1724 cmaromatics 1617, 1575, 1505 cm- 1 Examle 25: A4- 4,,-di ethvl-2.5-d4ioXo-3-(2-proefvsl)-1 imiazolidinvl).-2-trj11iQ tbhvlbelzofhitrile M.p. 109-1106C.

Analysis for C 16

H

14

P

3 0 3

O

2 337.35 calculated: C% 56.97 H% 4.18 F% 16.90 N% 12.46 found: 57.0 4.1 16.2 12.3 IR spectrum (CHC1 3 CeN 2238 cm 1 C=O 1728, 1725 cm- 1

HC=CH

2 1645 cm- 1 aromatics 1616, 1575, 1505 cm- 1 Sample 26: 4-(4 4-dimethyvl-.5-dioxo-3-(Dhonvlmetbyll- 1-imidazolidinyl) ,2-tr3fluoromet3ylbe-nzopitrile M.p. 98-99 0

C.

Analysis for C 2 0

H

16

F

3

N

3 0 2 387.36 calculated: C% 62.01 I% 4.16 F% 14.71 N% 10.85 found: 62.0 4.1 14.7 10.8 IR spectrum (CHC1 3 =C-NH 3430 cm1 CN 2238 cm 1 C=O 1779, 1724 cm 1 aromatics 1615, 1605, 1575, 1504, 1497 cmI 20 EXam~le 27: A-E4-ri-dimeth-Vl-2.5-dioxo-3-r (4-fluoro- *to phenv1)methv11--iMidazoldinyl-2-rifluoromthlbGnz-litri1 M.p. 101-1020C4 Analysis for C 20

H

15

F

4

N

3 0 2 405.35 calculated: C% 59.26 H% 3.73 F% 18.75 N% 10.37 St*: 25 found: 59.1 3.5 18.9 )0.3 IR spectrum (CHC1) CwN 2238 cm1 C-O 1780, 1724 cin 1 aromatics 1615, 1612, 1505 cm1 ampale2_q: -4-r4.4-dimothyl-2,5-dioxo-3--r (4-mthox.henxv1wMotbv11-1-iMizoazoiyll'2trifUoromothVlbeflZoflitrile M.p. 95-966C.

Analysis for C 2

H

1 3

N

3 3 417.39 calculated: C% 60.43 H% 4.35 F% 13.65 N% 10.07 found: 59.1 3.5 18.9 10.3 IR spectrum (CHC1 3 CnN 2238 cm-1 C-O 1778, 1723 cm 1 l aromatics 2615, 1584, 1514, 1505 cm 1 Examnle 29: 4-4 4.4-dimethl-2 ,5-Lioxo-3-r 14-(trifluoromethvl)phenlmethvll -1-imidazolidin 1-2-trifluoromethvlbenzonitrile M.p. z 89-900C.

Analysis for C 2

,H

15

FN

3 0 2 313.30 calculated: C% 55.39 H% 3.32 F% 25.03 i% 9.23 found: 55.2 3.2 25,3 9.2 IR spectrum (CHC1 3 CNN 2238 cm-1 C=O 1615, 1505 cm-' aromatics 1615, 1505 cm- 1 EXamI 30: 4-r4e4-dimetbvl-2.5-d.OXO-3-(2-evoxcVmethYl) 1-imi4.Azolidinvl1-2-trifaluoroomethylbenonitrie M.P. 112-1136C.

Analysis for C 16

H

14

F

3

N

3 0 3 353.30 calculatd: C% 54.39 H% 3.99 F% 16.13 N% 11.89 found: 54.7 4.0 16.1 11.8 XR spectrum (CHCl 3 SCmN 2235 cm 1 C-O 1781, 1725 cm"I aromatics 1615, 1576, 1505 cm-' Examp.t2 (4 al: 4-(4.4-dim thyl-2. S-ioxo-3-Drop !l-imdazo" lidinyl)-2-trifluoromethylbenzonitrile M.p. 113-1146C.

25 Analysis for C 16

H

1

F

3

N

3 0 2 3,)9 sea%' calculated: C% 56.64 H% 4.75 F% 16.80 N% 12.38 found: 56.7 4.7 16.7 12.2 0 XR spectrum (CHC1 3 CoN 2236 cm C-O 1778, 1725 cm-1 aromatics 1616, 1505 cm-1 gxa g.-a3: 4-4, .4-dimotBl-g.5-dioxo-3- (-mthletbvl) I-.jimdazo2idinv -2-trIfl uoomthylbgnzgnitgIlq M.p. 138-1391C, Analysis for C, 6

H,

6

F

3

N

3 0 2 u 339.32 calculated: C% 56.64 H% 4.75 'M 16.80 N% 12.38 found: 56.5 4.7 17.1 12.3 XR spectrum

(CHC

3 Cr=N 2236 cm- 1 C=O 1778, 1724 cm- 1 aromatics 1616, 1575, 1505 cm-1 B) Using 4- 4-dimethy1-5-oxo-2-thioxo-i-imidazolidinyl) -2trifluoromethylbenzonitrile prepared as in Example 15 and the appropriate reagents, the following compounds were obtained: Example 33: 4-r4 .5-dihvdro-4.4-dimethyl-2-nonylthio-5-ogco-1Himidazol-1-'vl] -2-trifluoromethvlbenzonitrile Rf =0.35 (eluent: methylene chloride/ethyl acetate 97.5:2.5).

Example 34: 4-r45S-dihydro-4.4-dimethvl-2-r (3-hydroxvpropvl) thiol -5-oxo-1H-imidazol-1-vll -2-trifluoromethylbenzonitrile Rf =0.*17 (eluent: methylene chloride/ethyl acetate 8:2).

Examle 35J: ethyl-r [1--[4-cyano-3- (trifluoromethvyl)Dhenvyl 4jidro-4 .4-iimethvl-5-oxo-lH-imidazol-l-vll -thiol acetate 0.20 (eluent: cyclohexane/ethyl acetate 65:35).

so** C) Using the thiocyanate prepared in Example 11 and the 'logo. appropriate reageints, the following compounds were obtained: ExamRle 36: 4- (4 .4-direthyl-3-thyl-5-imnino-2-thioxo-l- .20 imidazo Iidinyl)-2-tritluoromethylbenzonitrile Rf= 0.1~5 (eluent: mathylene chloride/acetone 95:5).

Examnle 37: 4- (4 .4-dimethvl-5-imino-3-pentyl-2-thioxo- Rf 0.35 (eluent: ethyl acetate/cyclohexane 8:2), D) Using 4-(4,4-dimethyl-3-ethyl-5-imino-2-thiioxo- -imidazol.dinyl)-2-trifluoromethylbenzonitrile prepared as in Example 36 4nd 4-(4 ,4-dimethyl-5-imino-3-pentyl-2-thioxo-1- *@too: imidazolidinyl) -2-trifluoromethylbenzonitrile prepared as in Example 37, respectively, and half- strength hydrochloric acid, the following compounds were obtained: EXample 38: 4-(4.4-dimethvl-3-ethyl-5-oxo-2-thioxo- 1-imidazolidinyl) -2-trifluoromethvlJbenznitriLe_ Rf-0.38 (eluent: ethyl acetate/cyclohexane 1:1).

Example 39: 4- (4 .4-dimethvl-5-oxo-3-Dentvl-2-thioxo-1-imidazolidinVi) -2-trifluoromgthvlbenzonitrile M.P. ft 78'C. Rf 0.66 (eluent: ethyl acetate/cyclohexana E) Using 4- (4 ,5-dihydro-4, 4-dimethyl-2-methylthio-5-oxo-lHimidazol-l-yl) -2-trifluoromethylbenzonitrile prepared as in Example 20 and 4-[4,5-dihydro-4,4-diiethyl-5-oxo-2- [(phenylmethyl)thio-IH-imidazoa-1-yl]-2-trifluoromethylbenzonitrile preparsd as in Example 21. and the Lawesson reagents, the following compounds were obtained: Example 40: 4-r4,5-dibydr -4.4-di m thyvl-2-methilthio-S-thioxo- 1H-imidazol-1-VJ,1 -2-trifluorometh enzonitrile Rf 0.36 (pluelt: methylene chloride/ethyl acetate 97.5:2.5).

Example 41: 4-4.5-dihvdro-4 .4-dimethvl-2- (phenylmethvthiol -5-thioxo-1H-imidazol-1-Y.Vl -2-trifluorome,:hvbenzornitrile Rf 0.62 (eluent: methylene chloride/ethyl acetate 98:2).

Example 42: 3- 4-eyano-3-(trifluoromethyl) henyl]- 5,5-dimethyl-2,4-dioxo-N-methyl-N- (-methylethyl)-l-imidazolidine acetamide 0.1 cm 3 of N-methylmorpholine is added to 235 mg of 3- C4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-2,4-dicxo-limidazolidine acetic acid prepared as in Example 9j suspended in 4 cm 3 of methylene chloride. The solution obtained is cooled to -10C, 0.1 cm 3 of isobutyl chloroformate is added dropwise and the mixture is stirred for 20 minutes at -108C.

0.15 Cm 3 of N-methyl-N-isopropylamine is added, the mixture is allowed to return to ambient temperature in the course of approximately 40 minutes, 5 cm 3 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 obtaiied.

IR spectrum (CHC1 3 CmN 2236 cm 1 hydantoin C=O 1783, 1728 cm 1 amide C=O 1661 cm-1 aromatics 1615, 1573, 150 cm-1 E e1e_43: 4-r4.4- dinethv1-2 .5-dioxo-3-(2 -hvdroxvethyv1)- 1-imidazoidinv l-2-trifuoromethbenonitrie a) Condensation.

The procedure is as in Examuple 9 starting from 900 mg of product obtained in Example 8 and 1.91 mg of 2-bromoethanol tert-butyl dimethylsilyl ether. 1 g of the silyloxy ether derivative is obtained. M.p. 86-87°C after chromatography on silica (eluent: cyclohexane/ethyl acetate 7:3).

b) Cleavage: 1 cm 3 of 2 N hydrochloric acid is added to 380 mg of product obtained above dissolved in 4 cm 3 of methanol and 1 cm 3 of methylene chloride. The mixture is stirred for minutes at ambient temperature, poured onto 15 cm 3 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 Rf 0.9, and crystallized in ether, and 270 mg of expected product are obtained. M.p. 109-110°C after crystallization in isopropanol.

Analysis: calculated: C% 52.79 H% 4.23 F% 16.70 N% 12.31 found: 52.5 4.2 16.7 12.1 20 Proceeding in an identical manner, starting with 2-bromopropanol tert-butyl dimethylsilyl ether, the following product was prepared: Example 44: 4-[4.4-dimethyl-2,5-dioxo-3-(3-hydroxypropyl)-limidaqlldinyllv2-trifluoromethvlbenzonitrile 25 M.p. 131-132*C. Rf 0.13 (eluent: CH 2 C12/AcOnt 75:25).

Example 45: 4-r3-[r2-acetyloxvethyvl-4.4-dimetlvl-2,5-dioxo-1imidazolidinyll-2-trifluoomethvlbenzonitrile 215 mg of product obtained in Example 43, 15 mg of 4dimethylaminopyridine, 1 cm 3 of pyridine and 0.5 cm 3 of acetic anhydride are stirred for 30 minutes at ambient temperature.

The reaction mixture is poured into 20 cm 3 of an aqueous solution saturats with Oodium bicarbonate, sti-2ed for 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 (Rf 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 0

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: 4-r4.4-dimethvl-2.5-dioxO-3-(5-hydroM entvl)-1imidazolidinvll-2-trifluoromethvlbenzonitrile M.P. 101-102 0

C.

Examnle 47: 4-r4,4-dimethyl-2.5-dioxO-3-(2-methovethl)-.imidazolidinyl-2-trifluoromethvlbenzonitrile M.P. 68-69 0

C.

Example 48: 4-r4.4-dimethvl-2.5-dioto-3-cvanomethyl- 1-imidazolidinvll -2-trifluoromethvlbenzonitrile M.p. 186-187 0

C.

Example 49: 4-r4.4-dimethyl-2.5-dioxo-3-[(3.3-dioxolan-, '0 0 2-vl)methyl'-1-imidazolidinvl] -2-trifuoromethylbenzonitrile 20 M.p. 135-1360C.

Examle 50: 4-[4.4-dimethvl-2.5-dioxo-3-2-chloroethvl)-limidazolidinyll-2-trifluoromethvlbenzonitrile M.P. 120-1210C.

ExAmple 51: 1-(3.4-dichlorophenyl) -5-imino-3 .4,4-trimethvl-2- 25 imidazoidinethione 00 2.4 g of 3,4-dichiorophenyl isocyanate and 1.3 cm 3 of 2-methylamino-2-cyanopropane are heated to reflux for 16 hours in 23 cm 3 of tetrahydrofuran in the presence of 0.23 cm 3 of triethylamine. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica (eluent: methylene chloride/acetone 96:4 then ethyl acetate/cyclohexane After crystallization in ether, 2.54 g of expectel product are obtained. M.p. 133*C.

Exanle 52: 3-.3,4-dichloroDhenvl)-2-thioxo-1.o5,-trimethvl-4imidazolidinone 1.88 g of product obtained in Example 51 dissolved in 14 cm 3 of 6 N hydrochloric acid are heated to reflux for minutes and then 14 cm 3 of 6 N hydrochloric acid are again added and the heating is continued for 2 hours. After a further addition of 4 cm 3 of 6 N 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. The organic phase is washed with water and dried, and the solvent is evaporated.

After chromatography on silica (eluent: cyclohexane/ethyl acetate 1.84 g of expected product are obtained.

M.p. 129 0 C after crystallization in isopropanol.

Analysis for C 12

H

12 C1 2

N

2 0S 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 IR spectrum (CHCl 3 C=0: 1753 cm-1 C=S and aromatics: 1595, 1570, 1496 cm-1 Proceeding as in the preceding examples using the appropriate products and reagents, the following compounds were prepared: Example 53: 3-(3,4-dichlorophenyl)-3.5-dihydro-5,5-dimethyl- S* 20 2-methylthio-4H-imidazol-4-one M.p. 110°C.

4 Example 54: 1-(3.4-dichlorophenyl)-3,4.4-trimethvl-2,5imidazolidinedithione M.p. z 146 0

C.

o* 25 Example 55: l-r4-chloro-3-(trifluoromethyvl)henYvl- 4.4-dimethvl-2-thioxo-5-imiaidazolidinone M.p. 176°C.

Example 56: -r[4-chloro-3-(trifluoromethvl)phenyll- 4,4-dimethyl-5-imino-2-imidazolidine thione M.p. 173-174C.

0*:9 Example 57: 3-(3,4-dichlorophenvl)-3,5-dihydro-5.5-dimethYl-2r(phenvlmecthvl)thio]-4H-imidazol-4-one IR spectrum (CHC1 3 C=O: 1736 cm" 1 C-N and aromatics: 1578, 1496 cm1 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:

C

3 Y 3 in which Y. represents an oxygen or sulphur atom and RAhas the following meaniings:

*-(CH

2 )nCl

*-(CH

2 )S0 2 -&jF of~

-(CH

2 )n-OH

(CH

2 ),-CO0-alk *-(cH 2 n'CO-N *,ak N aJlc 2

*-CCH

2 )n-C0-alk

(CH

2 n-CH

CH

CH

3 alk, to 4 4.

alk 1 and alk 2 representing an alkyl radical containing up carbon atoms, and n represents an integer between 1 and 41 Example 58: A tablet having the following composition was prepared: 4-(5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolinyl)-2-(trifluoromethyl)benzonitrile.... 100 mg excipient q.s. for a finished tablet 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 Androgenic receptor.

180-200 g SPF male Sprague Dawley rats, castrated 24 des hours beforehand, are sacrificed, the prostatea are removed, 0 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, 20 0.1 mM PMSF (phenylmethanesulphonyl fluoride), 20 mM sodium molybdate, HC1 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 25 for 45 minutes at 0°C. Aliquots of the supernatant obtained cytosol) are incubated for 30 minutes and for 24 hours at '0C, with a constant concentration of tritiated testosterone and in the presence of growing concentrations (0 to 2500X10" 9 either of cold testosterone or of products to be tested.

The concentration of bound tritiated testosterone is then measured in each incubate by the adsorption method on carbondextran.

Calculation of the relative binding affinity (RBA).

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 Is=(B/Tmax 42 B/Tmin)/ 2 is determined.

B/Tmax of bound tritiated hormone for an incubation of this tritiated hormone at the concentration B/Tmin c- bound tritiated hormone for an incubation of this tritiated hormone at the concentration in the presence of a large excess of cold hormone (2500X10 9

M).

The intersections of the I50 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 The relative binding affinity (RBA) of the tested product is determined by the equation RBA=100 The following results expressed in RBA are obtained.

Reference product (testosterone): 100 Incubation: Incubation: 30 minutes 24 hours Product of Example 1 27.5 3 Product of Example 2 22 6 o* 20 Product of Example 4 21 Product of Example 11 28 8 5 Product of Example 12 128 92 Product of Example 13 31 39 Product of Example 14 27 7 25 Product of Example 15 69 24 2) Determination of the androqenic or antiandroenic activity of the products of the invention by means of the determination of ornithine 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 the absence of testosterone propionate.

B

e000 o C eg.

C

'see 0 C

S.

o, oL *0 The products to be studied and also the testosterone propionate are administered in a volume of 10 ml/kg.

16 hours after the treatments, the animals are sacrificed, and the kidneys are removed and then homogenised at Q°C by means of a teflon/glass grinder in 10 volumes of mM tris-HCl buffer (pH 7.4) containing 250 gM 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 of 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 15 M) of tritiated putrescine formed/hour/mg of proteins.

20 The following results are obtained: Product of Example 11: antagonism (PO) 3 mg/kg: 83% Product of Example 12: antagonism (PO) 0.1 mg/kg: 12% 0.3 mg/kg: 36% 1 mg/kg: 68% 3 mg/kg: 94% 10 mg/kg: 99% agonism (PO) 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% Conclusion: 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 (11)

1. The products of general formula R LN A (I) m 2 Y CH3 in which: R 1 represents a cyano or nitro radical or a halogen atom, R 2 represents a trifluoromethyl radical or a halogen atom, the group is chosen from amongst the radicals and A 6 in which X represents an oxygen or sulphur atom and R 3 is 20 chosen from amongst the following radicals: S 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 S 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, amidated or salified 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 a =NH radical, with the exception of the products in which the group -A-B- represents the radical: K> 13 in which X represents an oxygen atom and R 3 represents a hydrogen atom and Y represents an oxygen atom or an NH radical and R 2 represents a halogen atom or a trifluoromethyl radical and R 1 represents a nitro radical or a halogen atom.

2. The products of formula as defined in Claim 1 in which Y represents an oxygen atom with the exception of the products in which the group represents the radical: 9 pe S a 2 Sr X 3 in which X represents an oxygen atom and R 3 represents a hydrogen atom, R 2 represents a halogen at n or a tri- fluoromethyl radical and R 1 represents a nitro radical or a halogen atom.

3. The products of formula as defined in Claim 1 or 2 in which the group represents the group: X 3 5S e 0 in which X represents a sulphur atom and R3 has the meaning indicated in Claim 1.

4. The products of formula according to Claim 3 in which R s represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms and being optionally substituted by a hydroxyl radical. The products of formula as defined in any one of Claims 1 to 4, in which formula R 1 represents a cyano radical or a halogen atom.

6. The products of formula according to Claim 5, in which formula R 1 represents a chlprine atom.

7. The products of formula as defined in Claim 1 or 2, in which formula the group represents a group: or a group: in which R 3 represents an alkyl or alkenyl radical having at most 4 carbon atoms or an optionally substituted aralkyl radical.

8. The products of formula as defined in any one of Claims 1 to 5, whose names follow: a. 4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl) -2- 44 'Jo *O(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-l imidazoliinyl]-2-(trifluoromethyl)benzonitrile, 3-(3,4-dichlorophenyl)-2-thioxo-1,5,5-trimethyl-4- 25 imidazolidinone.

9. The products of formula as defined in any one of Claims 1, 2 and 7, whose names follow: l -(4-nitro-3-(trifluoromethyl)phenyl) 4 -trimethyl- 4-[4 ,5-dihydr-4,4-dimethyl-5-oxo-2-(phenylmethyl)thio- 1H-imidazol-1-ylJ -2-(trifluoromethyl)benzonitrile. Process for the preparation of the products of general formula as defined in Claim 1, characterised in that: gi~hera product of formula (II): (I) RI 1 4 47 in which R 1 R 2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III): N-1, 13 H3C-j-CH3 (III) in which RI 3 has the meanings indicated above for R3 in which the possible reactive functions are optionally protected and it being understood that if R 1 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' 3 cannot represent a hydrogen atom, to obtain a product of formula (IV): *4 6 S Sr.. S X SN (IV) /CH 3 2 HN 3 in which R 1 R 2 X and R' 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 R03 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-O group; c) conversion of the >C-O 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 >r NH group to the ketone function, by a reagent of formula Hal-R" 3 in which R"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 in which the group represents the group S-R" w 55 r u*. rr A Crl t^R" 3 Ia in which R" 3 has the meaning indicated above and, if desired, action on these products by an agent tor eliminating the possible protective groups which R" 3 may carry or, if necessary, action by an esterifying, amidating or salifying agent, r 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 0 0 N-H r/ v 7 (V' 1 3 C S to obtain a product of formula too* 0 0 ee 20 02 N (IV") OOlQ r3C 3 c o which product of formula 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" 3 may carry and then, if necessary, action by an esterifying, I amidating or salifying agent; b conversion of the >C-0O group or groups to >c-s groups. S^11. The products of formula as defined in Claims 1 to SQt 7# by way of pharmaceautically acceptable medicaments.

12. The products of formula as defined in Claim 8 or 9f by way of medicaments.

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,

14. The products of formula (XVi)t 49 R A. N).(lvi) in which R3., R 2 and Y have the meanings indicated in claim 1 and the group: is chosen from amongst the radicals: N-3 andN 6990 in which X repressents an oxygen or sulphur atom and R 3 i is chosen from amongst the meanings of R3 containing a protected reactive function,, e=a=oa. 1 6 QMY 0 4QG--EG-M1 6:06 intermediate compound thereof, sub as hereinbefore *uI 0u described, or, t ms when produced by such a process, i il 1 DATED This 8th day of January 1992 4 06 0so ROUSSEL-UCLAF Osseo:by their Patent Attorneys CALLIWAN LAWRIE (67 4 A B ST RA CT The invention concerns the products (1) CH in which: R, represents cyano, nitro or a halogen, R 2 represents trifluoromethyl or halogen, the group is chosen from amongst a 0*OS 0 0000 0 000600 0 0600 S *0* S OSSSS 0S 0 0*~ 50 *ec S 0O S. S S 5 S* 6 0 S. X and in which X represents oxygen or sulphur and R 3 is chosen from amc 4st hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl or arylalky. radicals, their preparation process and their application as medicaments particularly as anti-androgenic medicaments.