FR2715402A1 - New substd. phenyl-imidazolidine(s) which fix to androgen receptors - Google Patents

Abstract

Substd. phenylimidazolidines of formula (I), their enantiomers, diastereomers and acid and base addn. salts, are new. Z1, Z2 = cyano, nitro, halo, CF3, carboxy (free, esterified, salified or converted to amide); -A-B- = a gp. -C(:X)-N(R3)- (i) or -C(SR3j)=N- (ii); X = O or S; R3 = H, alkyl, alkenyl, alkynyl, aryl or arylalkyl, max. 12C (opt. substd. by one or more halo, hydroxy (opt. esterified, etherified or protected), alkoxy, hydroxyalkyl, alkenyloxy, alkynyloxy, CF3, mercapto, cyano, acyl, acyloxy, aryl, S-alkyl, S-aryl (opt. substd.) (S is opt. oxidised to sulphoxide or sulphone), carboxy (free, esterified, salified or converted to the amide), amino, mono- or di-alkylamino, 3-6 link cyclic radical (opt. contg. one or more O, S, or N) or -O-C(:O)-R7; R3j = R3 except for H; alkyl, alkenyl, alkynyl are opt. interrupted by one or more O, S (opt. oxidised to the sulphoxide or sulphone) or N (opt. oxidised); aryl and aralkyl are opt. substd. by one alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or CF3; R7 = alkyl, hydroxy, alkoxy, aryl or aryloxy; Y = O, S or NH; R4, R5 = H, 1-12C alkyl (opt. substd. by one or more halo, -O-C(=O)-R7, hydroxyl (opt. esterified, etherified or protected), phenylthio or alkylthio contg. up to 8C (opt. oxidised to sulphoxide or sulphone, and opt. substd. by one or more halo, hydroxyl (opt. esterified, etherified or protected), carboxy (opt. esterified, salified or converted to amide), amino, mono- or di-alkylamino); with the exception of prods. in which: R4, R5 = H or 1-12C alkyl (opt. substd. by halo), or R4 or R5 = methyl and the other hydroxymethyl, Y = O or NH, -A-B- = a gp. -C(:O)-NH (iii), Z1 in position 4 = nitro and Z2 in position 3 = CF3, or Z1 and Z2 = halo; or Z1 or Z2 = halo and one of R4 and R5 = alkyl substd. by -S-CH3, and R3 = H or alkyl.

Description

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

 Japanese application J 48087030 describes 3-phenyl-2-thiohydantoins which are presented as inhibiting the germination of certain plants.

 French Patent 2,329,276 describes imidazolidines which are presented as having an antiandrogenic activity. The products of this patent are however different from the products of the present patent application.

dans laquelle
Z1 et Z2 identiques ou différents représentent un radical cyano, nitro, un atome d'halogène, un radical trifluorométhyle ou un radical carboxy libre estérifié, amidifié ou salifié, le groupement -A-B- est choisi parmi les radicaux

dans lesquels X représente un atome d'oxygène ou de soufre et
R3 est choisi parmi les radicaux suivants - un atome d'hydrogène, - les radicaux alkyle, alkényle, aikynyle, aryle ou aryl alkyle ayant au plus 12 atomes de carbone, ces radicaux étant éventuellement substitués par un ou plusieurs substituants choisis parmi les radicaux hydroxy éventellement estérifié, éthérifié ou protégé, halogène, mercapto, cyano, acyle ou acyloxy ayant au plus 7 atomes de carbone, S-aryle éventuellement substitué, dans lequel l'atome de soufre est éventuellement oxydé sous forme de sulfoxyde ou de sulfone, carboxy libre, estérifié, amidifié ou salifié, amino, mono ou dialkylamino ou un radical cyclique comprenant 3 a 6 charnons et renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes de soufre, d'oxygène ou d'azote, les radicaux alkyle, alkényle ou alkynyle étant de plus éventuellement interrompus par un ou plusieurs atomes d'oxygène, d'azote ou de soufre éventuellement oxydé sous forme de sulfoxyde ou de sulfone, les radicaux aryle et aralkyle étant de plus éventuellement substitués par un radical alkyle, alkényle ou alkynyle, alkoxy, alkényloxy, alkynyloxy ou trifluorométhyle,
Y représente un atome d'oxygène ou de soufre ou un radical
NH,
R4 et R5 identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 12 atomes de carbone éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène, le radical hydroxyle éventuellement estérifié, éthérifié ou protégé, les radicaux phénylthio et alkylthio linéaire ou ramifié renfermant au plus 8 atomes de carbone, les radicaux phénylthio et alkylthio, dans lesquels l'atome de soufre peut être oxydé en sulfoxyde ou sulfone, étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, le radical hydroxyle éventuellement estérifié, éthérifié ou protégé, le radical carboxy libre, estérifié, amidifié ou salifié, amino, mono ou dialkylamino, à l'exception des produits dans lesquels R4 et R5 identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 12 atomes de carbone éventuellement substitué par un ou plusieurs atomes d'halogène et ceux dans lesquels l'un de R4 ou
R5 représente un radical méthyle et l'autre représente un radical hydroxyméthyle, y représente un atome d'oxygène ou un radical NH, le groupement -A-B- représente le radical

dans lequel X représente un atome d'oxygène et R3 représente un atome d'hydrogène, Z1 en position 4 représente un radical nitro et Z2 en position 3 représente un radical trifluorométhyle, b) les produits de formule (Ia)

dans laquelle Z3 représente un radical cyano ou nitro,
R3a représente un atome d'hydrogène ou un radical alkyle linéaire ou ramifié, renfermant au plus 4 atomes de carbone, éventuellement substitué par un atome de fluor ou un radical cyano,
R4a et R5a sont tels que l'un représente un radical méthyle et l'autre représente un radical méthyle substitué par un atome de fluor ou bien R4a et R5a identiques représentent un radical méthyle substitué par un atome de fluor, ou bien R4a et R5a forment avec l'atome de carbone auquel ils sont liés un radical cyclopentyle,
Xa représente un atome de soufre ou d'oxygène, à l'exception du produit dans lequel Z3 représente un radical cyano, Xa représente un atome de soufre, R3a représente un radical méthyle et R4a et R5a forment avec l'atome de carbone auquel ils sont liés un radical cyclopentyle, et c) les produits suivants - 3-(4-cyano 3-(trifluorométhyl) phényl) 5,5-diméthyl 2,4dioxo 1-imidazolidinacétonitrile, - 4-(4,4-diméthyl 2,5-dloxo 3-(2-fluoroéthyl) 1-imidazolidinyl) 2- (trifluorométhyl) benzonitrile, - 4-(4,4-diméthyl 2, 5-dioxo 3-(2,2,2-trifluoroéthyl) l-imidazolidinyl) 2- (trifluorométhyl) benzonitrile, - 4-(4,4-diméthyl 3-(2-fluoroéthyl) 5-oxo 2-thioxo l-imidazolidinyl) 2- (trifluorométhyl) benzonitrile, les dits produits de formules (I) et (Ia) et produits cités ci-dessus étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formules (I) et (Ia) et ci-dessus.The subject of the present invention is therefore a) the products of general formula (I)

in which
Z1 and Z2, which may be identical or different, represent a cyano, nitro radical, a halogen atom, a trifluoromethyl radical or an esterified, amidified or salified free carboxy radical, the -AB- group is chosen from among the radicals

in which X represents an oxygen or sulfur atom and
R 3 is chosen from the following radicals - a hydrogen atom, - alkyl, alkenyl, alkyl, aryl or aryl alkyl radicals having at most 12 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from hydroxyl radicals; optionally esterified, etherified or protected, halogenated, mercapto, cyano, acyl or acyloxy having not more than 7 carbon atoms, optionally substituted S-aryl, in which the sulfur atom is optionally oxidized in the form of sulfoxide or sulfone, free carboxy , esterified, amidated or salified, amino, mono or dialkylamino or a cyclic radical comprising 3 to 6 charnons and optionally containing one or more heteroatoms chosen from sulfur, oxygen or nitrogen atoms, alkyl, alkenyl or alkynyl radicals being further optionally interrupted by one or more oxygen, nitrogen or sulfur atoms optionally oxidized in the form of sulfoxide or lfone, the aryl and aralkyl radicals being further optionally substituted with an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical,
Y represents an oxygen or sulfur atom or a radical
NH,
R4 and R5, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms optionally substituted by one or more substituents chosen from halogen atoms, the hydroxyl radical optionally esterified, etherified or protected, phenylthio and linear or branched alkylthio radicals containing at most 8 carbon atoms, phenylthio and alkylthio radicals, in which the sulfur atom can be oxidized to sulfoxide or sulfone, being optionally substituted by one or more radicals chosen from the atoms of halogen, the optionally esterified, etherified or protected hydroxyl radical, the free carboxy, esterified, amidated or salified, amino, mono or dialkylamino radical, with the exception of products in which R4 and R5, which are identical or different, represent a hydrogen atom; or an alkyl radical having from 1 to 12 carbon atoms optionally substituted by one or more rs halogen atoms and those in which one of R4 or
R5 represents a methyl radical and the other represents a hydroxymethyl radical, y represents an oxygen atom or an NH radical, the -AB- group represents the radical;

in which X represents an oxygen atom and R3 represents a hydrogen atom, Z1 at the 4-position represents a nitro radical and Z2 at the 3-position represents a trifluoromethyl radical, b) the products of formula (Ia)

in which Z3 represents a cyano or nitro radical,
R3a represents a hydrogen atom or a linear or branched alkyl radical, containing at most 4 carbon atoms, optionally substituted by a fluorine atom or a cyano radical,
R4a and R5a are such that one represents a methyl radical and the other represents a methyl radical substituted by a fluorine atom or else R4a and R5a identical represent a methyl radical substituted by a fluorine atom, or else R4a and R5a form with the carbon atom to which they are attached a cyclopentyl radical,
Xa represents a sulfur or oxygen atom, with the exception of the product in which Z3 represents a cyano radical, Xa represents a sulfur atom, R3a represents a methyl radical and R4a and R5a form with the carbon atom to which they are bound cyclopentyl radical, and c) the following products - 3- (4-cyano-3- (trifluoromethyl) phenyl) 5,5-dimethyl-2,4-dioxo-1-imidazolidinacetonitrile, - 4- (4,4-dimethyl-2,5) -dloxo 3- (2-fluoroethyl) 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-2,5-dioxo-3- (2,2,2-trifluoroethyl) -1-imidazolidinyl) 2 - (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, the said products of formulas (I) and (Ia) ) and the products mentioned above being in all the possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic t of said products of formulas (I) and (Ia) and above.

For the definition of the substituents given above and in the following, the definitions used may have the following values:
By alkyl having at most 12 carbon atoms is meant, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neo-pentyl. hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl, linear or branched.

 Alkyl radicals having at most 4 carbon atoms and in particular the methyl, ethyl, propyl and isopropyl radicals are preferred.

 By alkenyl having at most 12 and preferably 4 carbon atoms is meant for example the following values vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl.

 Among the alkenyl values, the allyl or butenyl values are preferred.

 By alkynyl having at most 12 and preferably 4 carbon atoms is meant for example the following values ethynyl, propargyl, butynyl, pentynyl or hexynyl.

 Among the alkynyl values, the propargyl value is preferred.

 Aryl is understood to mean carbocyclic aryl radicals such as phenyl or naphthyl or monocyclic 5 or 6-membered heterocyclic aryls or constituted by condensed rings, comprising one or more heteroatoms chosen preferably from oxygen, sulfur and nitrogen. Among the 5-membered heterocyclic aryls, mention may be made of furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl, isoxazolyl and tetrazolyl radicals.

Among the 6-membered heterocyclic aryls, mention may be made of pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl radicals.

Among the condensed aryl radicals, mention may be made of the indolyl, benzofuranyl, benzothienyl and quinolinyl radicals.

 Phenyl, tetrazolyl and pyridyl radicals are preferred.

 By arylalkyl is meant radicals resulting from the combination of alkyl radicals and aryl radicals mentioned above.

 Benzyl, phenylethyl, pyridylmethyl, pyridylethyl or tetrazolylmethyl radicals are preferred.

 Halogen, of course, means the 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, mention may be made of monofluoro, chloro, bromo or iodomethyl, difluoro, dichloro or dibromomethyl and trifluoromethyl radicals.

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

 The term "acyl radical" preferably means 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: it may also be mentioned formyl radical.

 By acyloxy radical is meant radicals in which the acyl radicals have the meaning indicated above and for example the acetoxy or propionyloxy radicals.

 By esterified carboxy is meant for example radicals such as alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tertbutyloxycarbonyl.

 It is also possible to mention radicals formed with easily cleavable ester residues such as the methoxymethyl and ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.

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

dans lesquels les radicaux R6 et R7 identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 4 atomes de carbone tels que les radicaux méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, secbutyle ou tert-butyle.By carboxy amidated means groups of the type

in which the radicals R6 and R7, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl or tert-butyl radicals.

définis ci-dessus, on préfère ceux dans lesquels le radical

représente le radical amino, mono ou diméthylamino.In groups

defined above, those in which the radical is preferred are preferred.

represents the amino, mono or dimethylamino radical.

peut également représenter un hétérocycle qui peut ou non comporter un hétéroatome supplémentaire. On peut citer les radicaux pyrrolyle, imidazolyle, indolyle, pipéridino, morpholino, pipérazinyle. On préfère les radicaux pipéridino, ou morpholino. The radical

may also represent a heterocycle which may or may not comprise an additional heteroatom. Mention may be made of pyrrolyl, imidazolyl, indolyl, piperidino, morpholino and piperazinyl radicals. Piperidino or morpholino radicals are preferred.

 Salified carboxy means salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine.

 The sodium salt is preferred.

 By alkylamino radical is preferably meant radicals in which the alkyl comprises at most 4 carbon atoms. Mention may be made of methylamino, ethylamino, propylamino or butyl (linear or branched), amino radicals.

 Likewise, dialkylamino radical is preferably understood to mean radicals in which the alkyl comprises at most 4 carbon atoms. Examples that may be mentioned include dimethylamino, diethylamino and methylethylamino radicals.

 By heterocyclic radical containing one or more heteroatoms is meant, for example, monocyclic, saturated heterocyclic radicals such as the oxiranyl, oxolanyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl radicals.

 Alkyl, alkenyl or alkynyl radicals, optionally interrupted by a heteroatom selected from sulfur, oxygen or nitrogen atoms, are understood to mean radicals comprising one or more of these atoms, which are identical or different in their structure, these heteroatoms not being obviously can not be located at the end of the radical. Examples that may be mentioned include alkoxyalkyl radicals such as methoxymethyl or methoxyethyl, or alternatively alkoxyalkoxyalkyl radicals such as methoxyethoxymethyl.

By esterified hydroxyl radical, etherified or protected, the radicals -OC-a1, a2-O-a3 or -OP are respectively understood,
| O formed from a hydroxyl radical -OH, according to the usual methods known to those skilled in the art and in which
P represents a protective group, a2 and a3 represent in particular an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, having at most 12 carbon atoms and optionally substituted as defined above, especially for R3.

 Examples of protecting group P, as well as the formation of the protected hydroxyl radical, are given in particular in the standard book of the specialist: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley Interscience Publishers, John Wiley & Sons.

 The protective group of the hydroxyl radical that may be P may be chosen from the list below, for example formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Mention may also be made of ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, sssssstrichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl and 1-methyl groups. 1-methoxyethyl, phthaloyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl.

ou encore un dérivé du silicium tel que triméthylsilyle.P can in particular represent the radical

or a derivative of silicon such as trimethylsilyl.

 When the products of formulas (I) and (ira) as defined above contain an amino salifiable by an acid it is understood that these acid salts are also part of the invention. There may be mentioned salts formed with hydrochloric or methanesulphonic acid for example.

dans lequel X représente un atome d'oxygène ou de soufre,
R3 représente un atome d'hydrogène, un radical alkyle linéaire ou ramifié, renfermant au plus 6 atomes de carbone, éventuellement interrompu par un ou plusieurs atomes d'oxygène ou de soufre, un radical phényle ou pyridyle, ces radicaux étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, le radical phényle, hydroxyle éventuellement estérifié, éthérifié ou protégé, alkoxy, cyano, trifluorométhyle, hydroxyalkyle, carboxy libre, estérifié, amidifié ou salifié, amino, mono ou dialkylamino, l'atome d'azote du radical pyridyle étant éventuellement oxydé,
R4 et R5 représentent un radical alkyle, linéaire ou ramifié renfermant au plus 6 atomes de carbone, éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux hydroxyle éventuellement estérifié, éthérifié ou protégé, les atomes d'halogène et les radicaux alkylthio et phénylthio eux-mêmes éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle, les dits produits de formule (I) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (I).The subject of the invention is in particular the products of formula (I) as defined above, in which Z1 and
Z2 represent a trifluoromethyl, nitro or cyano radical,
Y represents an oxygen atom or an NH radical, the group -AB- represents the radical

in which X represents an oxygen or sulfur atom,
R3 represents a hydrogen atom, a linear or branched alkyl radical containing at most 6 carbon atoms, optionally interrupted by one or more oxygen or sulfur atoms, a phenyl or pyridyl radical, these radicals being optionally substituted by a or more radicals selected from halogen atoms, phenyl radical, hydroxyl optionally esterified, etherified or protected, alkoxy, cyano, trifluoromethyl, hydroxyalkyl, free carboxy, esterified, amidated or salified, amino, mono or dialkylamino, the atom d nitrogen of the pyridyl radical being optionally oxidized,
R4 and R5 represent a linear or branched alkyl radical containing at most 6 carbon atoms, optionally substituted with one or more radicals chosen from hydroxyl radicals, optionally esterified, etherified or protected, halogen atoms and alkylthio and phenylthio radicals; themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radical, the said products of formula (I) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

dans lequel X représente un atome d'oxygène ou de soufre,
R3 représente un atome d'hydrogène ou un radical alkyle ayant de 1 à 6 atomes de carbone éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle éventuellement estérifié, éthérifié ou protégé, carboxyle libre, estérifié, amidifié ou salifié et cyano, le radical alkyl étant éventuellement interrompu par un ou plusieurs atomes d'oxygène ou de soufre,
R4 et R5 représentent un radical alkyle éventuellement substitué par un ou plusieurs radicaux choisis parmi le radical hydroxyle éventuellement estérifié, éthérifié ou protégé, les atomes d'halogène et les radicaux alkylthio et phénylthio eux-mêmes éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle, les dits produits de formule (I) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (I).Among these products, the subject of the invention is particularly the products of formula (I) as defined above, in which Z1 and Z2 represent a trifluoromethyl, nitro or cyano radical, Y represents an oxygen atom or an NH radical, the grouping -AB- represents the grouping

in which X represents an oxygen or sulfur atom,
R3 represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms optionally substituted with one or more radicals chosen from halogen atoms and the optionally esterified, etherified or protected hydroxyl radical, free carboxyl, esterified, amidated or salified and cyano, the alkyl radical being optionally interrupted by one or more oxygen or sulfur atoms,
R4 and R5 represent an alkyl radical optionally substituted with one or more radicals chosen from the hydroxyl radical, optionally esterified, etherified or protected, the halogen atoms and the alkylthio and phenylthio radicals themselves optionally substituted with one or more radicals chosen from halogen atoms and the hydroxyl radical, the said products of formula (I) being in all the isomeric forms racemic, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases said products of formula (I).

Among these products, the invention more particularly relates to the products of formula (I) as defined above, wherein Y represents an oxygen atom or an NH radical, Z2 in position 3 represents a trifluoromethyl radical and Z1 in position 4 represents a cyano or nitro radical,
X represents an oxygen or sulfur atom,
R3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms, optionally substituted with one or more radicals chosen from halogen atoms or cyano radical,
R4 and R5, which may be identical or different, represent a linear or branched alkyl radical containing at most 4 carbon atoms optionally substituted by a free, esterified, etherified or protected hydroxyl radical, a halogen atom, or a phenylthio radical optionally substituted with a hydrogen atom; halogen or a free hydroxyl radical, esterified, etherified or protected, the said products of formula (I) being in all the isomeric forms racemic, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

 Among the preferred products of the invention, mention may be made more precisely of the products of formula (I) as defined above, whose following names - 2- (trifluoromethyl) 4- (4- (hydroxymethyl) 4-methyl 2, 5-dioxo-1-imidazolidinyl) benzonitrile, 4- (3,4-dimethyl) -4- (hydroxymethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 2- (trifluoromethyl) -4- ( 4- (hydroxymethyl) 3,4-dimethyl-2,5-dioxo-1-imidazolidinyl) benzonitrile, 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydroxymethyl) -4-methyl-1-imidazolidinyl) -2- trifluoromethyl) benzonitrile, 1,5-dimethyl-5- (hydroxymethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) 2,4-imidazolidinedione, the said products of formula (I) being in all racemic isomeric forms, enantiomers and diastereoisomers possible, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

dans laquelle R1, R2 et X ont la signification indiquée cidessus, avec un produit de formule (III)

dans laquelle R4 et R5 ont la signification indiquée cidessus et R'3 a les valeurs indiquées ci-dessus pour R3 dans lequel les éventuelles fonctions réactives sont éventuellement protégées et étant entendu que R4 et R5 ne représentent pas simultanément un radical méthyle et que si R1 représente un radical NO2 en position 4, R2 représente un radical
CF3 en position 3, X représente un atome d'oxygène et R'3 représente un atome d'hydrogène, alors l'un de R4 ou R5 ne représente pas un radical CH3 et l'autre un radical CH2OH, pour obtenir un produit de formule (IV) :

dans laquelle R1, R2, X, R'31 R4 et R5 ont la signification précédente, soit l'on fait agir en présence d'une base tertiaire le produit de formule (II), tel que défini ci-dessus, avec un produit de formule (VII)

dans laquelle W a la signification indiquée ci-dessus pour R5 à l'exception de l'atome d'hydrogène et un radical alkyle substitué par un radical hydroxyle libre, estérifié, éthérifié ou protégé et P représente un groupement protecteur de OH ou un radical tel que -O-P représente un radical hydroxyle éthérifié et R'3 et R4 ont la signification indiquée cidessus, pour obtenir un produit de formule (VIII)

dans laquelle X, R1, R2, R'31 R4, W et P ont la signification indiquée ci-dessus, produit de formule (VIII) dont si nécessaire et si désiré, l'on peut libérer de OP le radical OH que l'on peut alors si nécessaire et si désiré, estérifier ou transformer en radical halogène, produits de formules (IV) et (VIII) que, si nécessaire ou si désiré l'on soumet à l'une quelconque ou plusieurs des réactions suivantes, dans un ordre quelconque a) réaction d'élimination des éventuels groupements protecteurs que peut porter R'3 ; b) réaction d'hydrolyse du groupement > C=NH en fonction carbonyle et le cas échéant transformation du groupement > C=S en groupement > C=O c) réaction de transformation du ou des groupements > C=O en groupement > C=S ; d) action sur les produits de formule (IV) ou (VIII) dans laquelle R'3 représente un atome d'hydrogène, et après hydrolyse du groupement > C=NH en fonction carbonyle d'un réactif de formule Hal-R"3 dans laquelle R"3 a les valeurs de R'3 à l'exception de la valeur hydrogène et Hal représente un atome d'halogène pour obtenir des produits de formules (I), (Ia) et produits cités tels que définis ci-dessus, dans laquelle le groupement -A-B- représente le groupement

dans lesquels R"3 a la signification indiquée précédemment puis, si désiré, action sur ces produits, d'un agent d'élimination des éventuels groupements protecteurs que peut porter
R"3 ou le cas échéant, action d'un agent d'estérification, d'amidification ou de salification, soit l'on fait agir en présence d'une base tertiaire un produit de formule (II) tel que défini ci-dessus, avec un produit de formule (III')

dans laquelle R'3, R4 et R5 ont la signification indiquée cidessus et Q représente soit un atome de métal alcalin ou un radical alkyle renfermant de 1 à 6 atomes de carbone, pour obtenir un produit de formule (IVa)

dans laquelle X, R1, R2, R'31 R4 et R5 ont la signification indiquée ci-dessus, que si désiré l'on soumet à l'une quelconque ou plusieurs des réactions suivantes, dans un ordre quelconque a) réaction d'élimination des éventuels groupements protecteurs que peut porter R'3 ; b) réaction de transformation du ou des groupements > C=O en groupement > C=S ou le cas échéant du groupement > C=S en groupement > C=O c) action sur les produits de formule (IVa) dans laquelle R'3 représente un atome d'hydrogène, d'un réactif de formule
Hal-R"3 dans laquelle R"3 a les valeurs de R'3 a l'exception de la valeur hydrogène et Hal représente un atome d'halogène pour obtenir des produits de formules (I), (Ia) et produits cités tels que définis ci-dessus, dans laquelle le groupement -A-B- représente le groupement

dans lesquels R"3 a la signification indiquée précédemment puis, si désiré, action sur ces produits, d'un agent d'élimination des éventuels groupements protecteurs que peut porter
R"3 ou le cas échéant, action d'un agent d'estérification, d'amidification ou de salification, soit l'on fait agir un réactif de formule Hal-R"3 dans laquelle Hal et R"3 ont les valeurs indiquées précédemment sur un produit de formule (IV')

pour obtenir un produit de formule (1V")

produit de formule (IV") que, si nécessaire ou si désiré l'on soumet a l'une quelconque ou plusieurs des réactions suivantes dans un ordre quelconque a) réaction d'élimination des éventuels groupements protecteurs que peut porter R"3 puis le cas échéant action d'un agent d'estérification, d'amidification ou de salification b) réaction de transformation du ou des groupements > C=O en groupements > C=S.The invention also particularly relates to the products of formula (Ia) as defined above, whose names follow - 4- (4- (fluoromethyl) 3,4-dimethyl) 2,5-dioxo-1-imidazolidinyl 2- (trifluoromethyl) benzonitrile, 4- (3,4-dimethyl) -4- (fluoromethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, -4- (2,5-dioxo) (2-Fluoroethyl) 4- (fluoromethyl) -4-methyl imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) -2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo 1- (2-fluoroethyl) 1,3-diazaspiro (4.4) nonan-3yl) -2- (trifluoromethyl) benzonitrile, -1,5-dimethyl-5- (fluoromethyl) 3 - (4-nitro-3- (trifluoromethyl) phenyl) -2,4-imidazolidinedione, 3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-imidazolidinacetonitrile, 4- (4,4-bis- (fluoromethyl) 3-methyl-5-oxo-2-thioxo-1-imidazolidinyl 2- (trifluoromethyl) benzonitrile, the said products of formula (Ia) etan t in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula
The subject of the invention is also a process for the preparation of the products of formulas (I), (Ia) and products mentioned as defined above, characterized in that either a product or a tertiary base is reacted in the presence of a tertiary base. of formula (II)

in which R1, R2 and X have the meaning indicated above, with a product of formula (III)

in which R4 and R5 have the meaning indicated above and R'3 has the values indicated above for R3 in which the optional reactive functions are optionally protected and it being understood that R4 and R5 do not simultaneously represent a methyl radical and that if R1 represents a radical NO2 in position 4, R2 represents a radical
CF 3 in position 3, X represents an oxygen atom and R '3 represents a hydrogen atom, then one of R4 or R5 does not represent a CH3 radical and the other a CH2OH radical, to obtain a product of formula (IV):

in which R 1, R 2, X, R '31 R 4 and R 5 have the above meaning, or the product of formula (II), as defined above, is reacted in the presence of a tertiary base with a product of formula (VII)

in which W has the meaning indicated above for R5 except for the hydrogen atom and an alkyl radical substituted with a free, esterified, etherified or protected hydroxyl radical and P represents an OH protecting group or a radical such that -OP represents an etherified hydroxyl radical and R'3 and R4 have the meaning indicated above, to obtain a product of formula (VIII)

in which X, R 1, R 2, R '31 R 4, W and P have the meaning indicated above, a product of formula (VIII), of which, if necessary and if desired, the OH radical can be liberated from OP if necessary and if desired, esterify or transform into a halogen radical, products of formulas (IV) and (VIII), if necessary or desired, one or more of the following reactions, in a any order a) elimination reaction of any protective groups that can carry R'3; b) hydrolysis reaction of the group> C = NH in the carbonyl function and, where appropriate, transformation of the group> C = S in group> C = O c) transformation reaction of the group> C = O in group> C = S; d) action on the products of formula (IV) or (VIII) in which R '3 represents a hydrogen atom, and after hydrolysis of the> C = NH carbonyl group of a reagent of formula Hal-R "3 in which R "3 has the values of R'3 with the exception of the hydrogen value and Hal represents a halogen atom to obtain products of formulas (I), (Ia) and products cited as defined above in which the group -AB- represents the grouping

in which R "3 has the meaning indicated above and, if desired, action on these products, an agent for eliminating any protective groups that can carry
R "3 or, as the case may be, the action of an esterification, amidation or salification agent, or a product of formula (II) as defined above is made to act in the presence of a tertiary base; with a product of formula (III ')

in which R'3, R4 and R5 have the meaning indicated above and Q represents either an alkali metal atom or an alkyl radical containing from 1 to 6 carbon atoms, to obtain a product of formula (IVa)

wherein X, R1, R2, R'31 R4 and R5 have the meaning indicated above, if desired subject to any one or more of the following reactions, in any order a) elimination reaction possible protective groups that can carry R'3; b) transformation reaction of the group> C = O in group> C = S or, where appropriate, of the group> C = S in group> C = O c) action on the products of formula (IVa) in which R ' 3 represents a hydrogen atom, a reagent of formula
Hal-R "3 in which R" 3 has the values of R'3 with the exception of the hydrogen value and Hal represents a halogen atom to obtain products of formulas (I), (Ia) and products cited as such defined above, in which the grouping -AB- represents the grouping

in which R "3 has the meaning indicated above and, if desired, action on these products, an agent for eliminating any protective groups that can carry
R "3 or, as the case may be, the action of an esterifying agent, amidation or salification agent, ie a reagent of formula Hal-R" 3 in which Hal and R "3 are used have the values indicated. previously on a product of formula (IV ')

to obtain a product of formula (1V ")

product of formula (IV ") that, if necessary or desired, is subjected to any one or more of the following reactions in any order a) elimination reaction of any protective groups that can carry R" 3 and the if appropriate action of an esterification agent, amidification or salification b) transformation reaction of the group or groups> C = O in groups> C = S.

 The action 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 it is also possible to use ethyl ether or isopropyl ether.

 It operates in the presence of a tertiary base such as triethylamine or pyridine or methylethylpyridine.

Possible reactive functions that may include
R3 and which are optionally protected, are the hydroxy or amino functions. Protective groups are used to protect these functions. Examples that may be mentioned include the following protective groups of the amino radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl.

 Protective groups of the hydroxyl radical include radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl, tert-butyl dimethylsilyl.

 It is understood that the above list is not limiting and that other protective groups, for example known in the peptide chemistry can be used. A list of such protective groups is found, for example, in French Patent No. 2,499,995, the content of which is incorporated herein by reference.

The possible reactions of removal of the protective groups are carried out as indicated in said patent
BF 2,499,995. The preferred mode of removal is acid hydrolysis using acids selected from hydrochloric acid, benzene sulfonic acid or para toluene sulfonic, formic or trifluoroacetic acid. Hydrochloric acid is preferred.

 The optional hydrolysis reaction of the> C = NH group to the ketone group is also preferably carried out with the aid of an acid such as aqueous hydrochloric acid, for example at reflux.

 When the hydrolysis of the group> C = NH in carbonyl group is carried out on a molecule also comprising a group> C = S, this can be converted into a group> C = O. The free OH radical that may optionally comprise R3 can then be converted into an SH radical.

qui est un produit commercialisé par exemple par la firme
FLUKA et dont l'utilisation est décrite par exemple dans la publication : Bull. Soc. Chim. Belg. vol 87, NO 3, (1987) p.The reaction of transformation of the group> C = O in group> C = S is carried out using the reagent called
Lawesson of formula

which is a product marketed for example by the firm
FLUKA and whose use is described for example in the publication: Bull. Soc. Chim. Belg. 87, No. 3, (1987) p.

229.

 When one wants to transform two functions> C = O into two functions> C = S one operates in the presence of an excess of reagent of Lawesson. It is the same when one starts from a molecule having a function> C = S and a function> C = O and that one wants to transform said function> C = O in function> C = S.

 On the other hand, when one starts from a molecule comprising two functions> C = O and one wants to obtain a product having only one function> C = S. The procedure is carried out in the presence of a Lawesson reagent deficiency. In general, a mixture of three products is obtained: each of the two products having a function> C = O and a function> C = S and the product having two functions> C = S. These products can then be separated by the usual methods such as chromatography.

 The action on the product of formula (IV), (IVa), (IV ') o (VIII) of the reagent of formula Hal-R "3 is carried out in the presence of a strong base such as sodium hydride or It can be carried out by phase transfer reaction in the presence of quaternary ammonium salts such as tertbutyl ammonium.

- The protective groups that can carry the substituent
R "3 may be for example one of those previously mentioned for R 3. The elimination reactions of the protective groups are carried out under the conditions indicated above.

 An example of removal of the terbutyldimethylsilyl group by means of hydrochloric acid is given below in the examples.

The optional esterification of the products of formulas (I), (1a> and as defined above, in which R "3 comprises a free OH radical is carried out under standard conditions. functional derivative, for example an anhydride such as acetic anhydride in the presence of a base such as pyridine.

The esterification or salification, if any, of the products of formulas (I), (1a) and the products cited as defined above, in which R "3 represents a grouping
COOH is carried out under standard conditions known to those skilled in the art.

The optional amidification of the products of formulas (I), (Ia) and as defined above, in which R "3 comprises a COOH radical, is carried out under standard conditions. functional derivative of the acid for example a symmetrical or mixed anhydride.

 The reaction of the product of formula (II) as defined above with the product of formula (VII) as defined above to give the product of formula (VIII) as defined above, can be carried out in particular in presence of methylene chloride at a temperature of about -300C.

dans laquelle R4 et R5 sont définis comme ci-dessus et R''1,
R"2, -A"-B"- ont les significations indiquées ci-dessus pour
R1, R2 et -A-B- étant entendu que lorsque -A"-B"- représente un groupement -CO-N(R"'3)- dans lequel R"'3 représente un atome d'hydrogène ou un radical alkyle linéaire ou ramifié ayant au plus 7 atomes de carbone et Y représente un atome d'oxygène, R''1 représente un radical cyano, procédé caractérisé en ce que l'on fait réagir un produit de formule (V)

dans laquelle R''1 et R"2 ont les significations précédentes et Hal représente un atome d'halogène avec un produit de formule (VI)

dans laquelle -A"-B"-, R4, R5 et Y ont la signification indiquée ci-dessus, la réaction s'effectuant en présence d'un catalyseur et éventuellement d'un solvant.The present invention also relates to a process for the preparation of the products of formula (I):

in which R4 and R5 are defined as above and R''1,
R "2, -A" -B "- have the meanings indicated above for
R1, R2 and -AB- being understood that when -A "-B" - represents a group -CO-N (R "'3) - in which R"' 3 represents a hydrogen atom or a linear alkyl radical or branched having at most 7 carbon atoms and Y represents an oxygen atom, R''1 represents a cyano radical, characterized in that a product of formula (V) is reacted

in which R''1 and R "2 have the above meanings and Hal represents a halogen atom with a product of formula (VI)

wherein -A "-B" -, R4, R5 and Y have the meaning indicated above, the reaction being carried out in the presence of a catalyst and optionally a solvent.

With regard to products of formula (V), the term
Hal preferably denotes the chlorine atom, but may also represent a bromine or iodine atom.

 The role of the catalyst is likely to trap the hydrogen halide that is released and thus facilitate the condensation reaction of the product of formula (V) with the product of formula (VI) to give the desired product.

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

 When the catalyst used is a metal, this metal may be copper or nickel. It may be in native form, in the form of a metal oxide or in the form of metal salts.

 The metal salts can be a chloride or an acetate.

 When the catalyst is a base, this base may be, for example, sodium hydroxide or potassium hydroxide and it is possible, if desired, to add dimethylsulfoxide to the reaction medium.

 The invention more specifically relates to a process as defined above in which the catalyst is selected from cuprous oxide, cupric oxide, copper in native form and a base such as sodium hydroxide or potassium hydroxide.

 The copper in native form used as a catalyst is preferably in the form of a powder.

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

 The solvent used is preferably chosen from high-boiling ethers such as, for example, phenyl ether, diglyme, triglyme and dimethylsulfoxide, but may also be, for example, a high-boiling point oil. boiling such as paraffin or petrolatum.

 The invention more particularly relates to a process as defined above characterized in that one operates in the presence of an ether-type solvent such as phenyl oxide, diglyme, triglyme or dimethylsulfoxide.

 The subject of the invention is particularly a process as defined above in which the solvent used is phenyl ether or triglyme.

 The process for preparing the desired product defined above can be carried out under pressure or at atmospheric pressure, at a temperature which is preferably high.

 The subject of the invention is thus a process as defined above, characterized in that the reaction is carried out at a temperature greater than 100 ° C. and preferably greater than 1500 ° C.

 The subject of the invention is more specifically a process as defined above, characterized in that the reaction is carried out for more than 2 hours.

 The invention specifically relates to a process as defined above characterized in that the reaction is carried out in the presence of cuprous oxide, in triglyme, at a temperature greater than or equal to 2000C and for more than 3 hours.

 The products which are the subject of the present invention possess interesting pharmacological properties, in particular they bind to the androgen receptor and they exhibit an anti-androgenic activity.

 Tests given in the experimental part illustrate these properties.

 These properties make the products of formulas (I), (1a) and products mentioned as defined above, of the present invention usable as medicaments mainly for the treatment of adenomas and neoplasms of the prostate as well as in hypertrophy. benign prostate cancer, alone or in combination with LHRH analogues, and can also be used in the treatment of benign or malignant tumors with androgen receptors, particularly breast, skin, ovarian, the bladder, lymphatic system, kidney and liver, - the treatment of skin conditions such as acne, hyperseborrhea, alopecia or hirsutism.These products can therefore be used in dermatology alone or in combination with antibiotics such as azelaic and fusidic acid derivatives, erythromycin, as well as derivatives of retinoic acid or a 5reductase inhibitor such as that (5a, 17B) -1,1-dimethylethyl-3-oxo-4-azaandrost-1-ene 17-carboxamide (or Finasteride, Merck 11sem ed.) for the treatment of acne, alopecia or hirsutis - me. They can also be combined with a hair growth stimulating product such as Minoxidil for the treatment of alopecia.

 The products of formulas (I), (Ia) and products mentioned as defined above can also be used in the veterinary field.

 The products of formulas (I), (Ia) and products mentioned as defined above, in radioactive form (tritium, carbon 14, iodine 125 or fluorine 18) can still be used as a specific marker for androgen receptors. They can also be used in diagnostics in medical imaging.

 The subject of the invention is therefore the application, as medicaments, of the products of formulas (I) and (Ia) as defined above, which are pharmaceutically acceptable.

 The invention also relates to the application, as medicaments, of the following products - 3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxolimidazolidinacetonitrile 4-dimethyl-2,5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-2,5-dioxo) -2- 2-Trifluoroethyl) 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile.

 The subject of the invention is particularly the application, as medicaments, of the following products: 2- (trifluoromethyl) 4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile; (3,4-Dimethyl) 4- (hydroxymethyl) 5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 2- (trifluoromethyl) -4- (4- (hydroxymethyl) 3,4-dimethyl-2, 5dioxo-1-imidazolidinyl) benzonitrile, 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydroxymethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, -1,5-dimethyl-5- (hydroxymethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) 2,4-imidazolidinedione.

 The invention also particularly relates to the application, as medicaments, of the following products of formula (Ia) - 4- (4- (fluoromethyl) 3,4-dimethyl) 2,5-dioxo-imidazolidinyl) 2 (4- (trifluoromethyl) benzonitrile, 4- (3,4-dimethyl) -4- (fluoromethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (2,5-dioxo) - (- 2-fluoroethyl) 4- (4- (fluoromethyl) -4-methyl-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) 2 - (Trifluoromethyl) benzonitrile - 4- (2,4-dioxo 1- (2-fluoroethyl) 1,3-diazaspiro (4.4) nonan-3yl) -2- (trifluoromethyl) benzonitrile-1,5-dimethyl-5- (fluoromethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) -2,4-imidazolidinedione-3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-imidazolidinacetonitrile-4 (4,4-bis (fluoromethyl) 3-methyl-5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile.

 The products can be administered parenterally, orally, perlingually, rectally or topically.

 The invention also relates to pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs of formulas (I), (1a> and products cited as defined above.

 These compositions may be presented in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions. These pharmaceutical forms are prepared according to the usual methods. The active ingredient can be incorporated into excipients usually used in these compositions, such as aqueous vehicles or not, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats animal or plant origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.

 The usual dose, variable depending on the subject treated and the condition in question, may be, for example, 10 mg to 500 mg per day in humans, orally.

The products of formula (II) used at the start of the invention can be obtained by the action of phosgene when X represents an oxygen atom or thiophosgene when X represents a sulfur atom on the corresponding amine of formula (A)

 An example of such a preparation is given below in the experimental part. A product of this type is also described in French Patent BF 2 329 276.

 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) or (III ') are known or can be prepared from the corresponding cyanohydrin according to the method described in the publications: J. Am.

Chem. Soc. (1953), 75, 4841, BEIL I 4,526 or J. Org. Chem. 2901 (1962).

 The products of formula (III) in which R'3 is different from a hydrogen atom may be obtained by the action of a product of formula R "3 Hal on 2-cyano-2-aminopropane under the conditions set forth herein. above for the action of R "3 Hal on the products of formula (IV). An example preparation of this type is described in the reference - Jilek et al. Collect. Czech. Chem. Comm. 54 (8) 2248 (1989).

 The products of formula (IV ') are described in French Patent BF 2,329,276.

 The products of formulas (V) and (VI), used starting from a process, object of the invention, for obtaining the products of formulas (I), (Ia) and as defined above, are known and commercially available or can be prepared according to methods known to those skilled in the art.

 The 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. Fluorine. Chem. 17, 345 (1981) or in the German patents 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 cited in the literature as for example in the following articles - J. Pharm. Pharmacol., 67, Vol. 19 (4), p. 209-16 (1967) - Khim. 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, p. 219-21 (1974).

dans laquelle R1, R2, R4, R5 et Y ont les significations indiquées ci-dessus et le groupement

est choisi parmi les radicaux

dans lesquels X représente un atome d'oxygène ou de soufre et
R3i est choisi parmi les valeurs de R3 comportant une fonction réactive protégée, à l'exception des produits dans lesquels R4 et R5 identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 12 atomes de carbone éventuellement substitué par un ou plusieurs atomes d'halogène.The subject of the invention is also, as new industrial products and especially as new industrial products usable as intermediates for the preparation of the products of formulas (I), (ira) and products mentioned as defined above, the products of formula (IVi):

in which R1, R2, R4, R5 and Y have the meanings indicated above and the grouping

is chosen from the radicals

in which X represents an oxygen or sulfur atom and
R3i is chosen from the values of R3 comprising a protected reactive function, with the exception of the products in which R4 and R5, which are identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms, optionally substituted with one or more halogen atoms.

Among the reactive functions that can be protected include the hydroxyl and amino functions. These functions can be protected as indicated above for the substituent R3.

The following examples illustrate the invention without limiting it.

Preparation 1: 4-isocyanate 2- (trifluoromethyl) benzonitrile

To 33.6 cm3 of a toluene solution of phosgene at 1.93 ml cooled to 0 / 50C is added in 20 minutes 10 g of 4cyano 3- (trifluoromethyl) aniline (described in European Patent EP 0.002.892) in solution. in 30 cm3 of ethyl acetate. Stirred at this temperature for 30 minutes then allowed to rise to 250C. The mixture is heated until distillation by offsetting the volume distilled with toluene until the distillation temperature reaches 110 ° C. The reflux is maintained until the evolution of hydrochloric acid has ceased (ie 4 hours 30 minutes).

The mixture is cooled to room temperature, the insoluble material is filtered off with sodium sulfate under an inert atmosphere, rinsed with three times 10 cm3 of toluene and evaporated to dryness under reduced pressure. After heating at 600 ° C. for 1 hour, the mixture is returned to ambient temperature under an inert atmosphere and 11.6 g of expected product are obtained.

Infra-red -N = C = O 2268 cm 1 -CN 2233 cm 2 Precartion 2: 4-isothiocyanate 2- (trifluoromethyl) bensonitrile
To a solution of 22 cm3 of distilled water and 1 cm3 of thiophosgene is slowly added 2.23 g of 1-trifluoromethyl-4-aminobenzonitrile (prepared according to EP 0002892), stirred for 1 hour, extracted with chloroform, washed with water salted, dried and evaporated to dryness under reduced pressure. 3 g of expected product are obtained.

EXAMPLE 1 2- (Trifluoromethyl) 4-hydroxymethyl-4-methyl-2,5-dioxo-imidazolidinyl) benzonitrile
Stage A: 1- (tetrahydro-2H-pyran-2-yl) oxy) 2-propanone
50 g of hydroxyacetone, 100 cm3 of methylene chloride and 0.5 g of para-toluenesulphonic acid monohydrate 1% are introduced. 62.44 g of 3,4-dihydro-2-4-pyran are then added over a period of 5 hours at 200 ° C. After 2 h of introduction, 0.5 g of para-toluenesulphonic acid is added, then the mixture is stirred for 1 h 30 and 100 cm3 of water saturated with sodium bicarbonate are added. The mixture is stirred for 5 minutes, at alkaline pH, then decanted and extracted with methylene chloride, then washed with water, the organic phases are dried, filtered and brought to dryness. 101.8 g of expected product (pale yellow oil) are obtained.

Step B: 2-amino-2-methyl-3 - ((tetrahydro-2H-pyran-2-yl) oxy) propanenitrile
After stirring for 1 hour, the temperature is maintained at 400 ° C., 77.3 g of potassium cyanide, 178.1 g of alumina and 70 g of ammonium chloride in 1 l of acetonitrile.

 95 g of the product obtained in Step A) above are then added, then rinsed with 0.2 l of acetonitrile and stirred for about 21 hours.

 It is filtered, rinsed with acetonitrile and dried. Purified on silica (eluent cyclohexane-ethyl acetate 1-1) and recovered 65.5 g of expected product (yellow oil).

IR spectrum: CHCl3
CIN 2230
NH 3393
3330
Stage C: 2- (trifluoromethyl) 4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-imidazolidinyl) benzonitrile a) Condensation 2- (trifluoromethyl) -4-t-imino-4-methyl-2-oxo-4- [t (tetrahydro-2-H-pyran-2-yl) -methylated 1-imidazolidinyl] benzonitrile
12.77 g of the product obtained in Stage B above is introduced at 200 ° C. ± 20 ° C. in 127.7 ml of methylene chloride.

Then, in about 1 hour 30 minutes, with stirring at -300C + 30C, a pre-filtered solution of 11.4 g of the product obtained in Preparation 1 in 171 ml of methylene chloride is added and the mixture is stirred for about 1 hour at -300 ° C. And then evaporating the solvent under reduced pressure at 400C. 24.7 g of the expected condensation product used as such for the methanolic hydrolysis are obtained.

b) Hydrolysis 2- (trifluoromethyl) 4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile
200.3 g of the product obtained above in a, in 213 ml of methanol are introduced with stirring. Then, in 2 minutes, 67 ml of 2N hydrochloric acid are added. Refluxed for 1 h and then allowed to cool with stirring.

It is concentrated while distilling about 100 ml of methanol, the reaction medium is placed under magnetic stirring for about 1 hour at a temperature of 00 / + 50 ° C. and then wrung.

 The crystals obtained are purified, 3 volumes of methanol are added, the mixture is refluxed for 15 minutes, and the mixture is then cooled with stirring to 20-25 and filtered off. 10.7 g of expected product (white crystals) are obtained. Mp 2180 ° C.

Microanalvse
Theory Product dried at 600C
C% 49.85 49.7
N% 13.4 13.4
F% 18.19 18.0 H t 3.22 3.2 IR Absorption complex OH / NH -C region = N - 2230 cm 1> = 0 1780 - 1735 cm
Aromatic 1604 - 1575 - 1503 cm'l
EXAMPLE 2 2- (trifluoromethyl) -4- (4- (hydroxymethyl) 3,4-dimethyl-2,5-dioxo-1-imidazolidinyl) benzonitrile 1) Formation of the tetrahydropyranyl ether
626 mg of the product of Example 1, 10 ml of tetrahydrofuran, 30 mg of para-toluenesulfonic acid, H 2 O and 2 ml of dihydropyran are introduced. After about 30 minutes, poured into 10 ml of sodium bicarbonate and 1 ml of triethylamine and extracted with chloroform. The organic phase is washed with salt water, dried and the solvent evaporated. Purified on silica (eluent CH2Cl2, MeOH). 830 mg of the expected ether are obtained.

2) Nitrogenation
Sodium hydride (103 mg) is introduced at 50 ° C. and 830 mg of the ether obtained above in 1 ml in dimethylformamide (7 ml) are added over approximately 40 minutes, followed by the end of the cessation of the evolution of hydrogen by 10 minutes. placed in a water bath and added 0.18 ml of methyl iodide and 0.5 ml of dimethylformamide. After 30 minutes of reaction, poured into 40 ml of water containing about 0.5 g potassium dihydrogen phosphate and extracted with ether, then the organic phase is washed with brine, dried and the solvent evaporated under reduced pressure. Purified on silica (eluent CH2Cl2-Me2CO (95-5)). 770 mg of product used as such for the next stage are obtained.

3) Hydrolysis of the tetrahydrofranyl ether
770 mg of the N-methyl ether obtained above in 2), in 10 ml of methanol, 1.5 ml of 2N hydrochloric acid and heated to about 400 ° C. are introduced.

 After 30 minutes, it is cooled to room temperature, poured into 20 ml of sodium bicarbonate, extracted with chloroform, washed with brine, dried and the solvent evaporated under reduced pressure. Purified on silica (eluent CH2Cl2-Me2CO (3-1)).

111 mg of the crude product obtained above is recrystallized from 5 ml of hot isopropanol, concentrated to about 1 ml and ice-cream for 16 hours. After filtering, drying and obtaining 90 mg of the expected product (white crystals) F = 178-1790C.

Micro-analvsis
CHFN% calculated 51.38 3.70 17.41 12.84% found 51.5 3.7 17.5 12.8 IS CHCl3
OH 3620 cm 1 1781 1781 - 1728 cm'l cn 2235 cm 1
Aromatic 1615 - 1576 - 1505 cm 1
W EtOH
Max 262 nm g = 13900
Infl 278 nm g = 7200
Infl 286 nm E = 3800
EXAMPLE 3 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydrowymethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile a) Alkylation with 1,2-bromofluoroethane
104 mg of 5% sodium hydride are introduced, and 830 mg of the ether obtained in stage 1) of example 2 and 7.5 ml of dimethylsulfoxide are added dropwise in 30 minutes. About 20 minutes after cessation of the evolution of hydrogen, 0.22 ml of 1,2-bromofluoroethane is added all at once. After about 1 hour of reaction, poured into 5 ml of water containing 500 mg of potassium dihydrogen phosphate and extracted with ether. The organic phase is washed with water and then with salt water, dried and the solvent evaporated under reduced pressure. Purified on silica (eluent CH2Cl2-Me2CO (97.5-2.5)) and obtains 743 mg of expected product.

(b) Hydrolysis of the tetrahydrofranyl ether
743 mg of the product obtained above is introduced into 1) in 10 ml of methanol, 1.5 ml of 2N hydrochloric acid and is heated to 400 ° C. and then after 45 minutes poured into 20 ml of sodium bicarbonate and extracted with chloroform. The organic phase is washed with salt water, dried and the solvent evaporated under reduced pressure. Purified on silica (eluent CH2Cl2
Me2CO (9-1)) then dissolves the crystals obtained in 20 ml of isopropanol at 600C, filtered, rinsed and concentrated to about 5 ml, ice for about 1 hour and filtered. 466 mg of the expected product (white crystals) are obtained. Mp 146-1470 ° C.

Micro-analvsis
CHFN% calculated 50.15 3.65 21.15 11.70% found 50.1 3.50 20.9 11.7
IR CHCl3
OH 3612 cm -1> = 0 1782 (m) - 1727 (f) cm -1 c N 2235 cm 1
W EtOH
Max 260 nm g = 15500
Infl 278 nm g = 6700
Infl 286 nm e = 3300
EXAMPLE 4 4- (3,4-Dimethyl) 4- (hydroxymethyl) 5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
Step A: (+) 2-methyl 2- (methylamino) 3 - [(tetrahydro-2-H pyran-2-yl) oxy] propanenitrile
1.54 g of methylamine hydrochloride dissolved in 10 cm3 of water and 3.35 g of ketone obtained in Stage A of Example 1 are introduced and the suspension obtained is stirred for approximately 10 minutes.

 1.06 g of NaCN in solution in 5 cm3 of water are run in 10 minutes and stirred overnight at room temperature.

 It is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and the solvent evaporated under reduced pressure. 3.72 g of expected product (yellow oil) are obtained, used as it is in the next stage.

IR CHCl3
NH - 3345 cm 1
C - N - 2230 cl 1.

Step B: 2- (Trifluoromethyl) 4- [5-imino-3,4-dimethyl-4 [[(tetrahydro-2-H-pyran-2-yl) oxy) methyl] -2-thioxol-imidazolidinyl] benzonitrile
2.38 g of aminonitrile in solution in 8 cm3 of 1,2-dichloroethane are introduced and 0.5 cm3 of triethylamine is added, cooled to a temperature of -5 to 0 ° C. and sank in 20 minutes at a temperature below 0 ° C. 2.75 g of the isothiocyanate obtained in Preparation II in solution in 17 cm3 of 1,2-dichloroethane. Allowed to warm to room temperature and stir for about 2 hours, dry and evaporate the solvent under reduced pressure.

 After purification on silica (CH 2 Cl 2 -acetone eluent (92-8)), 3.31 g of expected product are obtained.

3308 cm'l 2236 cm-1 1679 cm-1 1614 cm-1
Aromatique 1575 cm-1
1505 cm-1
1496 cm'l
Stade C : 4-(3,4-diméthyl) 4-(hydroxyméthyl) 5-oxo 2-thioxo l-imidazolidinyl) 2-(trifluorométhyl) benzonitrile
A 3,25 g du produit obtenu au stade B ci-dessus, en solution dans 35 cm3 de méthanol, on ajoute goutte à goutte 19 cm3 d'acide chlorhydrique 2N et porte au reflux pendant 35 mn.IB CHCl3

3308 cm -1 2236 cm -1 1679 cm -1 1614 cm -1
Aromatic 1575 cm-1
1505 cm-1
1496 cmL
Stage C: 4- (3,4-dimethyl) 4- (hydroxymethyl) 5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
To 3.25 g of the product obtained in Stage B above, dissolved in 35 cm3 of methanol, is added dropwise 19 cm3 of 2N hydrochloric acid and refluxed for 35 min.

 It is neutralized with a solution of sodium bicarbonate, extracted with chloroform, the organic phase is washed with saturated sodium chloride solution, dried and the solvent is evaporated under reduced pressure. After purification on silica (eluent CH2Cl2-ACOEt (85-15), then recrystallization from 10 cm3 of isopropanol, 1.90 g of expected product (white crystals) are obtained, mp 167 ° -168 ° C.

1759 cm-l
c-N 2238 cm-1
Aromatiques 1610 cm-l
+ 1576 cm-l
Syst. conjugué 1505 cm'l
1494 cm'l
EXEMPLE 5 : 1,5-diméthyl 5-(hydrozyméthyl) 3-(4-nitro 3 (trifluorométhyl) phényl) 2, 4-imidazolidinedione
Stade A : Formation de l'éther tétrahydropyranique
On procède comme en 1) de l'exemple 2 ci-dessus, en remplaçant dans cette préparation le produit de l'exemple 1 par 870 mg du produit obtenu comme à l'exemple 2 de la demande de brevet européen EP 0305270 dans 13 ml de tétrahydrofuranne, 40 mg d'acide paratoluène sulfonique, H2O, 2,6 ml de dihydropyran. Au bout d'environ 15 mn on verse le mélange réactionnel sur 10 ml d'une solution saturée de bicarbonate de sodium et 1 ml de triéthylamine et extrait au chloroforme.Micro-analvsis
CHNFS% calculated 48.98 3.52 12.24 16.60 9.34% found 48.9 3.6 12.1 16.7 9.1
IR CHCl3
Absence of C = NH -OH 3620 cm-1

1759 cm-1
cN 2238 cm-1
Aromatic 1610 cm-l
+ 1576 cm-l
Syst. conjugated 1505 cm'l
1494 cml
EXAMPLE 5 1,5-Dimethyl-5- (hydrozymethyl) -3- (4-nitro-3 (trifluoromethyl) phenyl) -2,4-imidazolidinedione
Stage A: Formation of tetrahydropyranic ether
The procedure is as in 1) of Example 2 above, replacing in this preparation the product of Example 1 with 870 mg of the product obtained as in Example 2 of the European patent application EP 0305270 in 13 ml. of tetrahydrofuran, 40 mg of para-toluenesulfonic acid, H 2 O, 2.6 ml of dihydropyran. After about 15 minutes, the reaction mixture is poured into 10 ml of saturated sodium bicarbonate solution and 1 ml of triethylamine and extracted with chloroform.

The organic phase is washed with brine, 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
In 1 ml of tetrahydrofuran, cooled to about -600 ° C., 0.2 ml of diethylaminosulfide trifluoride is added, then the solution cooled to -600 ° C. of 0.2 g of the product of Example 2 and 6.5 ml of tetrahydrofuran is added dropwise. .

 It is allowed to rise to room temperature and then heated to 300C. After 1 h, poured into 18 ml of sodium bicarbonate and extracted with ether. The organic phase is washed with salt water, dried and the solvents are evaporated off under reduced pressure. Purified on silica (eluent CH2Cl2-cyclohexane (9-1)) and the crystals obtained are dissolved in 30 ml of isopropanol at 600C, filtered, rinsed with 2 ml of isopropanol, concentrated to about 5 ml and ice overnight. The mixture is drained and dried, and 136 mg of expected product (white crystals) is obtained.

Mp 153-1540 ° C.

1785 - 1733 cm'l
Aromatique 1616 - 1575 - 1505 cm'l
W EtOH
Max 259 nm e = 15200
Infl 278 nm E = 5800
Infl 286 nm e = 2900
EXEMPLE 7 : 4-(3.4-diméthvl) 4-(fluorométhvl) 5-oxo 2-thioxo l-imidazolidinvl) 2-(trifluorométhvl) benzonitrile
On refroidit 2 cm3 de tétrahydrofuranne anhydre, à -600C et coule goutte à goutte en environ 15 mn à une température comprise entre -60 C et -530C, 0,88 cm3 de diéthylaminosulfure trifluorure puis 0,930 g du produit de l'exemple 4 en solution dans 7 cm3 de tétrahydrofuranne anhydre. Après retour à température ambiante, on maintient environ 30 mn à environ 300C. On verse alors sur 25 cm3 de solution de bicarbonate de sodium + glace. On extrait à l'éther, lave la phase éthérée avec une solution saturée de chlorure de sodium, sèche et évapore les solvants sous pression réduite. Après purification sur silice (éluant CH2C12-cyclohexane (9-1)) et recristallisation dans l'isopropanol, on obtient après séchage, 1,010 g de produit attendu (cristaux blancs). F = 1630C.Micro-analvsis
CHFN% calculated 51.07 3.37 23.08 12.76% found 50.8 3.2 25.0 12.7 EB CHCl3 C - N 2240 cm 1

1785 - 1733 cm'l
Aromatic 1616 - 1575 - 1505 cm'l
W EtOH
Max 259 nm e = 15200
Infl 278 nm E = 5800
Infl 286 nm e = 2900
EXAMPLE 7 4- (3,4-dimethyl) 4- (fluoromethyl) 5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
2 cm3 of anhydrous tetrahydrofuran are cooled down to -600 ° C. and poured dropwise over approximately 15 minutes at a temperature of between -60 ° C. and -5 ° C., 0.88 cm 3 of diethylaminosulfide trifluoride and then 0.930 g of the product of Example 4 in solution in 7 cm3 of anhydrous tetrahydrofuran. After returning to ambient temperature, it is maintained for approximately 30 minutes at approximately 300 ° C. Then poured over 25 cm3 of sodium bicarbonate solution + ice. Extracted with ether, the ether phase is washed with a saturated solution of sodium chloride, dried and the solvents evaporated under reduced pressure. After purification on silica (CH 2 Cl 2 -cyclohexane eluent (9-1)) and recrystallization from isopropanol, 1.010 g of expected product (white crystals) are obtained after drying. F = 1630C.

1762 cm-l
Syst. conjugué + 1615 - 1580 cm-l
Aromatique 1505 - 1491 cm 1
UV EtOH
Max 235 nm e = 19200
Max 253 nm e = 23000
Infl 265 nm g = 18300
EXEMPLE 8 : 4-(2.5-dioxo 3-(2-fluoroéthvl) 4-(fluorométhvl) 4-méthvl l-imidazolidinvl) 2-(trifluorométhvl benzonitrile
On refroidit 1 ml de tétrahydrofuranne, à -500C et ajoute 0,33 ml de diéthylaminosulfure trifluorure puis goutte à goutte une solution préalablement refroidie à environ -500C de 360 mg du produit de l'exemple 3 et 4 ml de tétrahydrofu- ranne. On rince avec 0,5 ml de tétrahydrofuranne et laisse remonter à température ambiante puis porte à environ 300C. On verse alors sur 30 ml de bicarbonate de sodium + 10 g de glace et extrait au chloroforme puis lave la phase organique à l'eau salée et sèche. On purifie sur silice (éluant CH2C12acétate d'éthyle (99-1)) puis dissout les cristaux obtenus dans 30 ml d'isopropanol à reflux, filtre, rince avec 1 ml d'isopropanol, concentre à environ 7 ml et laisse reposer 16 heures à OOC. On essore et obtient après séchage 307 mg de produit attendu (cristaux blancs) F = 137-1380C.Micro-analvsis
CHFNS% calculated 48.69 3.21 22.01 12.17 9.28% found 48.6 3.10 22.2 12.1 9.5
IR CHCl3
Absence of OH
NC - 2238 cm'l

1762 cm-1
Syst. conjugate + 1615 - 1580 cm-l
Aromatic 1505 - 1491 cm 1
UV EtOH
Max 235 nm e = 19200
Max 253 nm e = 23000
Infl 265 nm g = 18300
EXAMPLE 8 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (fluoromethyl) -4-methyl-1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
1 ml of tetrahydrofuran is cooled to -500 ° C. and 0.33 ml of diethylaminosulfide trifluoride is added and then a solution previously cooled to about 500 ° C. of 360 mg of the product of Example 3 and 4 ml of tetrahydrofuran is added dropwise. Rinsed with 0.5 ml of tetrahydrofuran and allowed to rise to room temperature and then brought to about 300C. Then poured over 30 ml of sodium bicarbonate + 10 g of ice and extracted with chloroform and the organic phase is washed with salt water and dried. It is purified on silica (eluent CH 2 Cl 2 ethyl acetate (99-1)) and then the crystals obtained are dissolved in 30 ml of isopropanol at reflux, filtered, rinsed with 1 ml of isopropanol, concentrated to approximately 7 ml and allowed to stand for 16 hours. at OOC. After draining, 307 mg of expected product (white crystals) are obtained, mp = 137 ° -1380 ° C.

1786 - 1730 cm'l
Aromatique 1616 - 1575 - 1505 cm
W EtOH
Max 258 nm e = 16000
Infl 277 nm t = 5300
Infl 285 nm e = 2700
EXEMPLE 9 : 4-f2.4-dioxo 1,3-diazaspiro (4.4)nonan 3-vl) 2 (trifluorométhvl0 benzonitrile
Stade A : l-amino cyclopentanecarbonitrile
On introduit 40 ml d'ammoniaque, 7,9 g de chlorure d'ammonium et 6,14 g de cyanure de sodium puis agite jusqu'à dissolution totale au bain de glace à une température de -80C. On ajoute alors goutte à goutte à une température d'environ -90C, 8,8 ml de cyclopentanone, laisse remonter à température ambiante et agite une nuit.Micro-analvsis
CHFN% calculated 49.87 3.35 26.29 11.63% found 49.8 3.4 26.2 11.6 lE CHCl3 cN 2235 cm 1

1786 - 1730 cm'l
Aromatic 1616 - 1575 - 1505 cm
W EtOH
Max 258 nm e = 16000
Infl 277 nm t = 5300
Infl 285 nm e = 2700
EXAMPLE 9 4-Al 2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) (trifluoromethyl) benzonitrile
Stage A: 1-amino cyclopentanecarbonitrile
40 ml of ammonia, 7.9 g of ammonium chloride and 6.14 g of sodium cyanide are introduced and then stirred until complete dissolution in an ice bath at a temperature of -80 ° C. 8.8 ml of cyclopentanone are then added dropwise at a temperature of about -90.degree. C., the mixture is left to rise to ambient temperature and the mixture is stirred overnight.

 The organic phase is then decanted, the aqueous phase is extracted with methylene chloride and the organic phases are washed with salt water and dried. After distillation at 550C + 20C, 1.2 g of expected product are obtained.

IR CHCl 3 NH 2 3381-3330 cm 1 cN 2226 cm -1
Absence C = O
Step B: 2- (trifluoromethyl) 4- [4-imino-2-oxo-1,3-diazaspiro [4.4] nonan-3-yl] benzonitrile
550 ml of the product obtained in Step A above, 4 ml of 1,2-dichloroethane and 0.2 ml of triethylamine are then introduced and brought to 0 ° C. and the mixture is added at a temperature of -40 ° C. for 5 minutes. in preparation 1, and allowed to rise to room temperature.

 It is concentrated to dryness after about 40 minutes of reaction, the residue is dissolved in 40 ml of acetone, the solvent is evaporated off and the residue is purified on silica (CH 2 Cl 2 -Me 2 CO (90-10) eluent). 1.24 g of expected product (white crystals) are obtained. Mp 212-213.

1670 cm'l
Aromatique 1610-1574-1510 cm 1
Stade C : 4-(2,4-dioxo 1,3-diazaspiro (4,4)nonan 3-yl) 2 (trifluorométhyl) benzonitrile
On introduit 1,17 g du produit obtenu au stade B cidessus dans 20 ml de méthanol, 3 ml de chloroforme et 5 ml d'acide chlorhydrique 2N puis porte à environ 500C pendant environ 2 h.IR nujol
OH / NH 3350-3280 cm-1 cN 2240 cm 1
C = O 1744 cm -1

1670 cm'l
Aromatic 1610-1574-1510 cm 1
Stage C: 4- (2,4-dioxo-1,3-diazaspiro (4,4) nonan-3-yl) 2 (trifluoromethyl) benzonitrile
1.17 g of the product obtained in Stage B above is introduced into 20 ml of methanol, 3 ml of chloroform and 5 ml of 2N hydrochloric acid and then brought to approximately 500 ° C. for approximately 2 hours.

The mixture is cooled to room temperature, poured into 40 ml of water and extracted 3 times with methylene chloride. The organic phase is washed with salt water, dried and the solvent is evaporated under reduced pressure and then purified on silica (eluent
CH2Cl2-Me2CO (9-1)). 1.108 g of expected product (white crystals) is obtained. M.p. 184-185 ° C.

1786 - 1731 cm'l
Aromatique 1616 - 1505 cm-l
UV EtOH
Max 258 nm e = 15600
Infl 286 nm e = 3500
EXEMPLE 10 : 4-(2.4-dioxo 1-(2-fluoroéthyl) 1.3-diazaspiro(4.4)nonan-3-yl) 2-(trifluorométhyl) benzonitrile
Dans 0,050 g d'hydrure de sodium à 50 % dans l'huile on coule goutte à goute en environ 20 minutes, 0,323 g du produit de l'exemple 9 en solution dans 2,5 cm3 de diméthylsul- foxyde. On agite environ 1 h 20 puis coule goutte à goutte 0,09 cm3 de l-bromo 2-fluoroéthane en solution dans 0,2 cm3 de diméthylsulfoxyde. Après environ 2 h à température ambiante, on chauffe 10 mn entre 30C et 350C, puis verse sur 12 cm3 d'eau contenant 0,2 g de phosphate monosodique et extrait à l'éther. La phase éthérée est lavée avec une solution saturée de chlorure de sodium, séchée et évaporée à sec.Microanalysis
CHFN% calculated 55.73 3.74 17.63 13.00% found 55.6 3.7 17.4 12.8 IR CHCl3 = C-NH 3444 cm 1 C # N 2236 cm 1

1786 - 1731 cm'l
Aromatic 1616 - 1505 cm-l
UV EtOH
Max 258 nm e = 15600
Infl 286 nm e = 3500
EXAMPLE 10 4- (2,4-dioxo-1- (2-fluoroethyl) -1,3-diazaspiro (4.4) nonan-3-yl) 2- (trifluoromethyl) benzonitrile
In 0.050 g of 50% sodium hydride in the oil, 0.323 g of the product of Example 9 dissolved in 2.5 cm3 of dimethylsulfoxide are run dropwise over approximately 20 minutes. The mixture is stirred for about 1 hour and then dripped 0.09 cm3 of 1-bromo-2-fluoroethane dissolved in 0.2 cm3 of dimethylsulfoxide. After approximately 2 hours at room temperature, the mixture is heated for 10 minutes at 30.degree. C. to 350.degree. C. and then poured into 12 cm.sup.3 of water containing 0.2 g of monosodium phosphate and extracted with ether. The ether phase is washed with a saturated solution of sodium chloride, dried and evaporated to dryness.

Purified on silica (eluent CH2Cl2-ethyl acetate (99-1)) and 0.249 g of expected product. F = 1150C.

Microanalysis
CHFN% calculated 55.29 4.09 20.58 11.38% found 55.3 4.1 20.25 11.3
IR CHCl 3 - cN 2238 cm -1 -C = O 1776 - 1723 cm -1
Aromatic 1616 - 1575 - 1505 cm 1
UV EtOH
Max 260 nm g = 15600
Infl 287 nm
EXAMPLE 11: 1,5-Dimethyl-5- (fluoromethyl) 3- (4-nitro-3 (trifluoromethyl) -Dhenyl-2,4-imidazolidinedione
1 ml of tetrahydrofuran is introduced, cooled to about -600 ° C., 0.09 ml of diethylaminosulfide trifluoride is added and a solution cooled to about -600 ° C. of 210 mg of the product of Example 5 and 2.5 ml of tetrahydrofuran is added dropwise. . Rinsed with 0.5 ml of tetrahydrofuran, allowed to rise to room temperature, brought to a temperature of about -600C and added 0.1 ml of diethylamino-sulfide trifluoride.

 After 1 h 20, poured into 8 ml of sodium bicarbonate and extracted with ether. The organic phase is washed with brine, dried, the solvent is evaporated under reduced pressure and purified on silica eluting with CH 2 Cl 2 -Me 2 CO (99-1).

152 mg of expected product (white crystals) are obtained.

Mp 118-1190 ° C.

Micro-analvsis
CHFN% calculated 44.71 3.17 21.76 12.03% found 44.9 3.1 21.42 11.9
IR CHCl 3 -C = O 1786 - 1732 cm -1
Aromatic and 1618 - 1597 - 1546 - 1498 cm 1 EtOH
Influx 214 nm e = 13400
Max 267 nm t = 6200
Infl 320 nm
EXAMPLE 12 3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidinacetonitrile
78 mg of 50% sodium hydride and 0.5 ml of dimethylformamide are introduced and then 450 mg of the product of Example 8 of the European patent application EP 0494819 and 3.5 ml are added dropwise at -260 ° C. of dimethylformamide. Rinsed with 0.5 ml of dimethylformamide and after the end of evolution of hydrogen, added in one portion 0.11 ml of bromoacetonitrile
After 40 minutes, poured into 30 ml of ice water containing about 0.5 g potassium dihydrogen phosphate and extracted with ether.

It is washed with water and then with salt water, dried, the solvent is evaporated off under reduced pressure and the residue is taken up in 15 ml of ethyl acetate. Purified on silica with eluent CH2Cl2
Me 2 CO (98-2) then dissolves the crude product obtained in 60 ml of isopropanol at 700 ° C., rinsed with isopropanol and concentrated to approximately 15 ml. It is chilled for 1 hour, drained and dried to obtain 355 mg of expected product (white crystals). Mp 186-1870 ° C.

Micro-analvsis
CHFN% calculated 53.57 3.30 16.95 16.66% found 53.7 3.1 17.00 16.7
IR CHCl3
C = O 1790 - 1733 cm -1
Aromatic 1615 - 1575 - 1505 cm'l
CN 2238 cm 1
W EtOH
Max 254 nm e = 17200
Infl 276 nm e = 4600
Infl 284 nm e = 2500
EXAMPLE 13 4- (4,4-Dimethyl-2,5-dioxo-3- (2-fluoroethyl) imidazolidinyl) -2- (trifluoromethyl) benzonitrile
104 ml of 50% sodium hydride are introduced, the solution of 600 mg of the product of Example 8 of the European patent application is added dropwise over approximately 20 minutes.
EP 0494819 and 5 ml of dimethylformamide. Rinsed with 0.5 ml of dimethylformamide and after ceasing the evolution of hydrogen, adds 0.16 ml of 1-bromo-2-fluoroethane. Then 98 ml of sodium hydride 50% and then after about 10 minutes, 0.1 ml of 1-bromo-2-fluoroethane and heated to 500C. It is cooled to room temperature, poured into 20 ml of water containing 200 mg monopotassium phosphate and extracted with ether. Wash with water and brine, dry, evaporate the solvent under reduced pressure, dissolved in 20 ml Me 2 CO and purified on silica (eluent CH 2 Cl 2 -acetate (99-1)). 200 mg of expected product (white crystals) are obtained.

Mp 108-1090 ° C.

Micro-analvsis
CHFN% calculated 52.48 3.82 22.14 12.24% found 52.4 3.7 22.00 12.4 IR CHCl3 cN 2236 cm 1 C = O 1780 - 1728 cm-1
Aromatic 1618 - 1580 - 1504 cm 1
EXAMPLE 14 4- (4,4-Dimethyl-2,5-dioxo-3- (2,2,2-trifluoroethyl) -imidazolidinyl) -2- (trifluoromethyl) benzonitrile
0.125 g of 50% sodium hydride in oil is introduced and flows in 20 minutes, 0.742 g of the product of Example 8 of the European patent application EP 0494819 in solution in 7.5 cm 3 of dimethylsulfoxide and rinses with 1 cm3 of dimethylsulfoxide. After the end of the evolution of hydrogen, stirring is maintained for about 20 minutes and 0.5 cm3 of iodotrifluoromethane and 0.5 cm3 of 15-crown-5 ether are added. It is kept at 600C for 16 hours. After addition of 0.25 cc of iodotrifluoromethane, heating was continued for about 19 hours at 800C. Then poured over 30 cm3 of water + 0.5 g of monosodium phosphate and extracted with ether.

 The ether phase is washed with a saturated solution of sodium chloride, dried and evaporated to dryness. Purified on silica (eluent CH2Cl2-ethyl acetate (99-1)), then recrystallized in 10 cm3 of isopropanol and 0.262 g of expected product (white crystals). F = 1100C.

1790 - 1732 cm'l
Aromatique 1616 - 1578 - 1505 cm-1 c-N 2235 cm-1
W EtOH
Max 255 nm E = 16400
Infl 276 nm e = 4400
Infl 285 nm e = 2400
EXEMPLE 15 : 4-(4,4-diméthyl 3-(2-fluoroéthyl) 5-oxo 2-thioxo l-imidazolidinyl) 2-(trifluorométhyl) benzonitrile
Stade A : 4-[3-(2-fluoroéthyl) 5-imino 4,4-diméthyl 2-thioxo 1-imidazolidinyl] 2-(trifluorométhyl) benzonitrile
On introduit 1,86 g de 2-[(2-fluoroéthyl) amino] 2méthyl propanenitrile et 0,55 cm3 de triéthylamine dans 12 cm3 de 1,2-dichloroéthane. On refroidit à 0 C et coule en environ 25 mn à une température d'environ OOC, 2,97 g de l'isothiocyanate obtenu comme à la préparation 2 en solution dans 22 cm3 de l,2-dichloroéthane. On poursuit l'agitation pendant 7 h à la température ambiante puis évapore le solvant sous pression réduite. On purifie sur silice (éluant CH2C12- acétone (95-5) puis (97-3)), reprend avec quelques cm3 d'éther, essore, sèche et obtient 1,84 g de produit attendu.Microanalysis
CHFN% calculated 47.5 2.92 30.05 11.08% found 47.3 2.8 30.0 11.0 IR CHCl3
Absence of NH

1790 - 1732 cm'l
Aromatic 1616 - 1578 - 1505 cm-1 cN 2235 cm-1
W EtOH
Max 255 nm E = 16400
Infl 276 nm e = 4400
Infl 285 nm e = 2400
EXAMPLE 15 4- (4,4-Dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Step A: 4- [3- (2-Fluoroethyl) 5-imino-4,4-dimethyl-2-thioxo-1-imidazolidinyl] 2- (trifluoromethyl) benzonitrile
1.86 g of 2 - [(2-fluoroethyl) amino] -2-methylpropanenitrile and 0.55 cm3 of triethylamine are introduced into 12 cm3 of 1,2-dichloroethane. Cooled to 0 ° C. and poured in approximately 25 minutes at a temperature of approximately OOC, 2.97 g of the isothiocyanate obtained as in Preparation 2 in solution in 22 cm.sup.3 of 1,2-dichloroethane. Stirring is continued for 7 h at room temperature and then the solvent is evaporated off under reduced pressure. Purified on silica (eluent CH2Cl2-acetone (95-5) and then (97-3)), taken up with a few cm3 of ether, drained, dried and obtained 1.84 g of expected product.

 F = 1600C.

1758 cm'l
N-C 2236 cm-1
Syst. conjugué 1610 cm'l
+ 1576 cm'l
Aromatique 1504 cm-1
W EtOH
Max 233 nm e = 17700
Max 253 nm e = 21600
EXEMPLE 16 : 3-(4-cyano 3-(trifluoromethyl) phényle 2,4-dioxo 5-(hydroxymethyl) 5-méthyl 1-imidazolidinacétonitrile
On procède comme à l'exemple 2, à partir du produit de l'exemple 1, en remplacant au 2) de l'exemple 2 le iodométhyle par du bromocyanométhyle et obtient ainsi le produit attendu. F = 1710C.IR CHCl3
C = NH 3308 cm-1
C - N 2236 cm -1
Conjugated system 1677 cm'l
+ 1604 cm-l aromatic 1576 - 1504 cm'l
Step B: 4- (4,4-Dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxoimidazolidinyl) 2- (trifluoromethyl) benzonitrile
To 1.65 g of the product obtained in Stage A above, dissolved in 60 cm3 of methanol, 6.9 cm3 of 2N hydrochloric acid are added dropwise. After about 1 h 30 to 500C, neutralized with sodium bicarbonate and distilled methanol. It is taken up in water and extracted with ether, the ethereal phase is washed with sodium chloride solution and dried. After purification on silica eluting with CH 2 Cl 2 and recrystallization from 15 cm 3 of isopropanol, 2.99 g of expected product (white crystals) are obtained. F = 1350C
Micro-analvsis
CHFNS% calculated 50.14 3.65 21.15 11.69 9.92% found 50.1 3.60 21.0 11.7 9.2 IR CHCl3
Absence of = C-NH

1758 cm -1
NC 2236 cm-1
Syst. conjugated 1610 cm'l
+ 1576 cm'l
Aromatic 1504 cm-1
W EtOH
Max 233 nm e = 17700
Max 253 nm e = 21600
EXAMPLE 16 3- (4-cyano-3- (trifluoromethyl) phenyl 2,4-dioxo-5- (hydroxymethyl) -5-methyl-1-imidazolidinacetonitrile
The procedure is as in Example 2, starting from the product of Example 1, substituting in 2) of Example 2 iodomethyl with bromocyanomethyl and thus obtaining the expected product. F = 1710C.

EXAMPLE 17 3- (4-cyano-3- (trifluoromethyl) phenyl 2,4-dioxo-5- (fluoromethyl) -5-methyl-imidazolidinacetonitrile
The procedure is as for the preparation of Example 6, replacing the product of Example 2 with the product of Example 16 and thus obtaining the expected product. F = 1750C.

EXAMPLE 18: (+) 4- (2-oxo-5-imino [[(4-fluorophenyl) thiol methyl] -4-methyl-imidazolidinyl 2-trifluoromethyl benzonitrile
Step A: (t) 3 - [(4-fluorophenyl) thio] 2-amino-2-methyl propane nitrile
2.21 g of sodium cyanide in 45 ml of water are successively added a solution of 4.81 g of ammonium chloride in 12 ml of water and 24.6 ml of 250 B ammonia and then a solution of 8.32 g of 1- [4-fluorophenylthio] 2propanone prepared as indicated in patent 82 46399 E, in 21 ml of 96.2% ethanol. It is maintained at 600 ° C. and stirred for about 22 hours. Cooled to 00C / + 40C, rinsed with methanol, distilled, decanted, the aqueous phase extracted with CH2Cl2, washed with saturated sodium chloride, dried and the solvent evaporated under reduced pressure.

Purified by chromatography on silica eluting with cyclohexane-ethyl acetate (50-50) and 14.50 g of expected product.

IR CHC13
Absorption NM 3382 - 3327 cm 1
Aromatic 1591 - 1491 cm 1 -C - N 2228 cm 1
Step B: (t) 4- [2-oxo-5-imino [[(4-fluorophenyl) thio] methyl] -4-methyl-imidazolidinyl 2-trilfluoromethyl benzonitrile
9.8 g of the product obtained in Stage A above, 35 ml of 1,2-dichloroethane, and 0.2 ml of triethylamine are introduced. The solution of 7.7 g of the product obtained in Preparation 1 and 40 ml of 1,2-dichloroethane is cooled to 50 ° C. and introduced at 12 ° C. for 12 minutes at a temperature of between 5 ° C. and 100 ° C.

 Rinsed with 5 ml of dichloroethane and left for 16 hours at room temperature. The solvent is evaporated off under reduced pressure, purified on silica (eluent CH 2 Cl 2 -Me 2 CO (93-7)), then dissolved in 100 ml of isopropanol at approximately 600 ° C., filtered, rinsed with 20 ml of hot isopropanol, concentrated, ice-cold about 3 hours, drained, rinsed with iced isopropanol and dried. 2.815 g of expected product (white crystals) are obtained, mp = 1500 ° C.

Micro-analvsis
CHFNS% calculated 54.03 3.34 17.99 13.26 7.59% found 54.1 3.30 17.9 13.1 7.7
IR CHCl3 C = O 1756 cm -1
C = N 1669 cm -1
NH 3444 cm-1
Aromatic 1614 - 1591 - 1505 - 1491 cm'l cN exists
EXAMPLE 19 4-t 2,5-dioxo 4 - [[(4-fluorophenyl) thio] methyl] -4-methyl-imidazolidinyl] 2-trifluoromethyl benzonitrile
3.95 g of the product obtained in Example 18, 14 ml of 220B hydrochloric acid and 14 ml of water are introduced and the suspension is refluxed.

 After about 1 hour 30 minutes, the mixture is cooled to room temperature, poured onto ice + water (100 g, 1-1) and extracted with ethyl acetate. The organic phase is washed with water, then with saturated sodium bicarbonate, finally with saturated sodium chloride and the solvent is evaporated.

Purify by chromatography on silica (CH 2 Cl 2 eluent
Me2CO (95-5)). It is taken up in 50 ml of ethanol (100 ° C. to 500 ° C.), filtered, rinsed with 5 ml of hot ethanol, concentrated and left for 16 hours in the refrigerator at about 0 ° to + 40 ° C.

 It is drained, rinsed with iced ethanol and dried. 3.55 g of expected product (white crystals) are obtained. F = 1530C.

Microanalysis
CHFNS% calculated 53.9 3.09 17.95 9.92 7.57% found 53.9 3.1 18.3 9.8 7.8
IR CHCl3
C = O 1791 - 1734 cm -1
NH 3439 cm-1
C = N 2236 cm 1
Aromatic 1615 - 1591 - 1505 - 1492 cm-1
EXAMPLE 20 4- (2,5-Dioxo-3- (2-fluoroethyl) -4 - ((4-fluorophenylthiomethyl) -4-methyl-imidazolidinyl 2- (trifluoromethyl) benzonitrile
To 0.031 g of 50% sodium hydride in oil is poured in about 10 minutes dropwise the solution of 0.254 g of the product obtained as in Example 19 in 2.2 cm3 of dimethylsulfoxide. Stirring is maintained for about 40 minutes. Then the solution of 0.54 cm3 of 1-bromo-2-fluoroethane in 0.7 cm3 of dimethylsulfoxide is added dropwise in about 5 minutes.

 After stirring for 30 minutes, the mixture is poured onto 0.4 g of monosodium phosphate, water + ice. Extracted with ether, the organic phase washed with saturated sodium chloride solution, dried and the solvent evaporated under reduced pressure. After purification on silica (eluent CH2Cl2-ethyl acetate (100 0.5)) and then recrystallization from 15 cm3 of isopropanol, 0.175 g of expected product (white crystals) is obtained.

F = 1550C.

1780 - 1727 cm'l
Aromatiques 1616 - 1591 - 1505 - 1492 cm 1
W EtOH
Max 255 nm e = 18600
Infl 278 nm g = 8000
Infl 287 nm e = 4400
EXEMPLE 21 : 4-(4,4-bis(hydroxyméthyl) 3-méthyl 5-oxo 2thioxo 1-imidazolidinyl) 2-(trifluorométhyl) benzonitrile
Stade A : 2-(méthylamino) 2-[[(tétrahydro 2-H-pyranl 2-yl) oxy) méthyl] 3-[(tétrahydro 2H-pyran 2-yl) oxy propanenitrile
On introduit 2,7 g de 1,3-bis[(tétrahydro 2H-pyran-2-yl) oxy] 2-propanone obtenu ainsi qu'il est ci-dessous, 5 ml d'eau et 0,77 g de méthylamine chlorhydrate puis ajoute en 5 mn, 503 mg de cyanure de sodium et 3 ml d'eau. Après 2 heures et demie de réaction, on extrait au chlorure de méthylène, lave la phase organique à l'eau salée, évapore le solvant sous pression réduite. On obtient 3,3 g de produit attendu, utilisé tel quel pour le stade suivant.Micro-analvsis
CHFNS% calculated 53.73 3.43 20.23 8.95 6.83% found 53.5 3.2 20.5 9.0 7.1 iB CHCl3
Absence of = C-NH CN - 2235 cm 1

1780 - 1727 cm'l
Aromatic 1616 - 1591 - 1505 - 1492 cm 1
W EtOH
Max 255 nm e = 18600
Infl 278 nm g = 8000
Infl 287 nm e = 4400
EXAMPLE 21 4- (4,4-bis (hydroxymethyl) 3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
Step A: 2- (methylamino) 2 - [[(tetrahydro-2-H-pyran-2-yl) oxy) methyl] 3 - [(tetrahydro-2H-pyran-2-yl) oxypropanenitrile
2.7 g of 1,3-bis [(tetrahydro-2H-pyran-2-yl) oxy] -2-propanone obtained as follows, 5 ml of water and 0.77 g of methylamine are introduced. hydrochloride then added in 5 minutes, 503 mg of sodium cyanide and 3 ml of water. After 2 hours and a half of reaction, the mixture is extracted with methylene chloride, the organic phase is washed with salt water and the solvent is evaporated under reduced pressure. 3.3 g of expected product is obtained, used as such for the next stage.

IR CHCl3
NH 3346 cm 1
C - N 2230 cm 1
C = O 1732 cm -1
Preparation of 1,3-bis - [(tetrahydro-2H-pyran-2-yl) oxy] -2-propanone used starting from Example 21
At 700 ° C., 9 g of 1,3-dihydroxyacetone dimer are suspended in 60 ml of dioxane and brought to room temperature. 20 ml of 3,4-dihydro-2,4-pyran and then 300 mg of para-toluenesulphonic acid, H 2 O are added keeping the temperature below 400 ° C. The mixture is stirred for 16 hours, poured into 300 ml of saturated sodium bicarbonate solution, the organic phase is washed with brine, dried and the solvent is evaporated off under reduced pressure. After chromatography of the residue on silica (eluent ethyl cyclohexaneacetate-triethylamine (8-2-0.5), 17 g of expected product are obtained, RF = 0.2.

Step B: 2- (Trifluoromethyl) -4-14-4-bis - [[(tetrahydro-2-Hpyran-2-yl) oxy] methyl] -5-imino-3-methyl-2-thioxo-1-imidazolidinyl] benzonitrile
2.39 g of the isothiocyanate obtained in Preparation 2 and 10 ml of 1,2-dichloroethane are introduced. Then, to the solution cooled to + 50 ° C., 3.2 g of the product obtained in Stage A above, 0.4 ml of triethylamine and 10 ml of 1,2-dichloroethane are added dropwise. After about 1 h of heating the solvent is evaporated and purified on silica (eluent ethyl acetate 7 cyclohexane 3). 3.82 g of the expected product are obtained.

3314 cm~l C-N 2230 cm'l
C=N 1678 - 1670 - 1876
C=S 1505 - 1495 cm'l
Aromatiques
Stade C : 4-(4,4-bis(hyaroxyméthyl) 3-méthyl 5-oxo 2-thioxo l-imidazolidinyl) 2- (trifluorométhyl) benzonitrile
On introduit 3,8 g du produit obtenu au stade B cidessus dans 38 ml de méthanol et 19 ml d'acide chlorhydrique 2N, puis chauffe à reflux. Au bout d'environ 2 h, on verse sur 200 ml d'eau et extrait à l'éther puis à l'acétate d'éthyle. On joint les phases organiques et les lave à l'eau salée puis évapore le solvant. On purifie sur silice (éluant
CH2C12-MeOH (95-5)) puis dissout dans 30 ml d'éther isopropylique au reflux, filtre et concentre partiellement. On glace pendant environ 1 h et essore. On obtient 282 mg de produit attendu (cristaux jaunes). F = 169-1700C.IR CHCl3

3314 cm ~ l CN 2230 cm'l
C = N 1678 - 1670 - 1876
C = S 1505 - 1495 cm -1
aromatic
Stage C: 4- (4,4-bis (hyaroxymethyl) 3-methyl-5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
3.8 g of the product obtained in Stage B above are introduced into 38 ml of methanol and 19 ml of 2N hydrochloric acid, and then heated under reflux. After about 2 hours, poured into 200 ml of water and extracted with ether and then with ethyl acetate. The organic phases are combined and washed with salt water and then the solvent is evaporated off. Purify on silica (eluent
CH 2 Cl 2 -MeOH (95-5)) and then dissolved in 30 ml of isopropyl ether under reflux, filtered and partially concentrated. It is iced for about 1 hour and squeezed. 282 mg of expected product (yellow crystals) are obtained. Mp 169-1700 ° C.

Micro-analvsis
CHFNS% calculated 46.80 3.37 15.86 11.69 8.92% found 46.8 3.3 15.9 11.5 9.0 IR Nujol
OH / NH 3410 - 3385 cm 1 C # N 2240 cm -1 C = O 1720 cm -1
Aromatic 1608 - 1580 - 1568 cm 1
W EtOH
Max 234 nm e = 17600
Max 256 nm e = 23200
EXAMPLE 22: 4,4-bis (1-oxopropoxy) methyl 3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
200 mg of the product of Example 21 are introduced into 2 ml of pyridine and 25 mg of 4-dimethylamino pyridine and then 16 ml of propionic anhydride are added. After 25 minutes of reaction, poured into 20 ml of sodium bicarbonate and extracted with methylene chloride, the organic phase washed with brine, dried, evaporated the solvent and distilled 3 times with 30 ml of toluene. Purified on silica (eluent CH2Cl2), then crystallized in ether and 239 mg of expected product (white crystals). M.p. 117-1180 ° C.

1755 - 1762 cm'l c-N 2235 cm-1
Aromatiques et C=S 1615 - 1580 - 1504 - 1488 cm-1
UV EtOH
Infl 236 nm e = 18800
Max 253 nm g = 22600
Infl 265 nm e = 18200
EXEMPLE 23 : 4-(4,4-bis(fluorométhyl) 3-méthyl 5-oxo 2-thioxo l-imidazolidinyl) 2- (trifluorométhyl) benzonitrile
On refroidit 1 ml de tétrahydrofuranne à -500C et ajoute 0,66 ml de diéthylaminosulfure trifluorure puis goutte à goutte la solution refroidie à une température d'environ -500C de 360 mg du produit de l'exemple 21 dans 4 ml de tétrahydrofuranne. On chauffe à une température d'environ 300C.* Micro-analvsis
CHFNS% calculated 50.95 4.27 12.09 8.91 6.80% found 51.2 4.5 12.1 8.8 6.9
IR CHCl3

1755 - 1762 cm -1 C 2235 cm -1
Aromatic and C = S 1615 - 1580 - 1504 - 1488 cm-1
UV EtOH
Infl 236 nm e = 18800
Max 253 nm g = 22600
Infl 265 nm e = 18200
EXAMPLE 23 4- (4,4-bis (fluoromethyl) -3-methyl-5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile
1 ml of tetrahydrofuran is cooled to -500 ° C. and 0.66 ml of diethylaminosulfide trifluoride are added, followed by dropwise addition of the cooled solution at a temperature of about -500 ° C. of 360 mg of the product of Example 21 in 4 ml of tetrahydrofuran. It is heated to a temperature of approximately 300 ° C.

 After about 30 minutes, it is poured dropwise over 50 ml of a saturated aqueous solution of sodium bicarbonate extracted with chloroform, the organic phase washed with salt water and the solvent evaporated. It is purified on silica eluting with CH 2 Cl 2 -cyclohexane (9-1) and then dissolved in 20 ml of isopropanol at a temperature of approximately 600 ° C. The mixture is filtered, rinsed with 1 ml of isopropanol and concentrated, ice 1 hour and filtered. 314 mg of expected product (white crystals) are obtained. Mp: 1221230C.

Micro-analvsis
Saturated aqueous sodium bicarbonate and 1 ml triethylamine, extracted with chloroform, washed with brine, dried and evaporated the solvent.

 Purified on silica (eluent CH2Cl2-MeOH (93-7)) and obtains 600 mg of expected product, used as such for the next stage.

2) Passage to the Hydroentoin
600 mg of the diether obtained in 1) in 4 ml of dimethylformamide and added 55 mg of sodium hydride at 50%, and after discontinuation of hydrogen, 0.09 ml of methyl iodide. About 40 minutes later, 110 mg of 50% sodium hydride are successively added, then 10 minutes after 0.18 ml of methyl iodide. The reaction mixture is poured into 10 ml of iced water containing 1.3 g of potassium dihydrogen phosphate and extracted with ether. The organic phase is washed with salt water, dried and the solvent evaporated. Purified on silica (eluent CH2Cl2-ethyl acetate (92.5-7.5)) and 370 mg of expected product, used as such for the next stage.

3) Deprotection of Dvraniaues ethers
370 mg of the product obtained above in 2) are introduced into 4 ml of methanol and 2 ml of 2N hydrochloric acid and the solution is then brought to 600 ° C. for approximately 2 hours.

 It is then poured into 15 ml of salt water, dried, the solvent is evaporated and then the residue is dissolved in 20 ml of acetone and evaporated to dryness. It is purified on silica (CH 2 Cl 2 -MeOH eluent (92.57.5)) and then recrystallized from acetone to give 197 mg of expected product (white crystals) mp = 217-2180C.

W EtOH
Max 263 nm e = 14600
Infl 237, 278, 287 nm
EXAMPLE 25 4- (4,4-bis (hydroxymethyl) 3-methyl-5-imino-2-oxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
The procedure is as in Example 21 and gives in Step C of the preparation of Example 21, 421 mg of expected product.

IR CN 2230 cm 1
C = N, C = S 1680 - 1614 - 1580 - 1510 cm -1
aromatic
EXAMPLE 26
Tablets having the following composition were prepared: - Product of Example 3 ............................. 100 mg - Excipient qs for a tablet finished at .......... 300 mg (Detail of the excipient: lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION 1) Study of the affinity of the products of the invention for the androgenic newer
Androgenic receptor.

Male Sprague Dawley EOPS rats 180-200 g, castrated 24 hours, are sacrificed, the prostates removed, weighed and homogenized at 00C using a glass-glass potter, in a buffered solution (10mM Tris, sucrose 0.25M, PMSF (phenylmethanesulfonylfluoride) 0.1mM, 20mM sodium molybdate, HCl pH 7.4, to which 2mM of
DTT (DL dithiothreitol), at a rate of 1 g of tissue per 8 ml of buffer.

 The homogenate is then ultracentrifuged to OOC for 30 minutes at 209,000 g. Aliquots of the obtained supernatant (= cytosol) are incubated for 30 minutes and 24 hours at OOC, with a constant concentration (T) of tritiated testosterone and in the presence of increasing concentrations (0 to 2500 × 10 -9 M), either of cold testosterone or products to test. The bound tritiated Testosterone concentration (B) is then measured in each incubate by the carbon-dextran adsorption method.

Calculation of the relative binding affinity (ARL).

 The following 2 curves are plotted: the percentage of bound tritiated hormone B / T as a function of the logarithm of the concentration of the cold reference hormone and B / T as a function of the logarithm of the concentration of the cold product tested. The equation line I50 = (B / Tmax + B / Tmin) / 2 is determined.

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

B / T min =% of bound tritiated hormone for incubation of this tritiated hormone at the concentration (T) in the presence of a large excess of cold hormone (2500.10 9M>.

 The intersections of the I50 line and the curves allow to evaluate the concentrations of the cold reference hormone (CH) and the cold product tested (CX) which inhibit the binding of the tritiated hormone on the receptor by 50%. The relative binding affinity (ARL) of the test product is determined by the equation ARL = 100 (CH) / (CX).

The following results are obtained in ARL.

Reference product (Testosterone): 100

<tb> Product <SEP> of <SEP> examples <SEP> | <SEP> Incubation <SEP>: <SEP> 24 <SEP> hours
<tb><SEP> 3 <SEP> 6
<tb><SEP> 6 <SEP> 16
<tb> 2) Determination of the Androgenic or Anti-Androgenic Activity of the Products of the Invention Using the Ornithine Decarboxylase (ODC) Dosaae.

- Treatment protocol
SWISS male mice, 6 weeks old, and castrated for 24 hours, receive orally or percutaneously the products to be studied (suspension in methyl cellulose at 0.5% or in solution in ethanol), simultaneously with a subcutaneous injection. Dermal Testosterone Propionate 3 mg / kg (solution in corn oil) to determine antiandrogenic activity. Agonist activity is determined in the absence of testosterone propionate.

 Testosterone Propionate is administered in a volume of 10 ml / kg.

 20 hours after the treatments, the animals are sacrificed, the kidneys removed, then homogenized with OOC, using a teflon-glass grinder in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4) containing 250 μM pyridoxal phosphate, 0.1 mM EDTA, and 5 mM dithiothreitol. The homogenate is then centrifuged at 209,000 g for 30 minutes.

- Principle of dosage
At 370C, ornithine decarboxylase renal transforms an isotopic mixture of cold ornithine and tritiated ornithine into cold putrescine and tritiated putrescine.

 Putrescine is then collected on selective papers, ion exchangers. After drying, the excess of untransformed tritiated and cold ornithine is removed, by washing with 3 M ammonia, 3 times. The papers are dried, then the radioactivity is counted after addition of scintillating Aqualite.

 The results are expressed in fmoles (10'15 M) of tritiated putrescine formed / hour / mg of protein.

 The results are expressed in% inhibition of the ODC of the controls receiving only testosterone propionate.

Test: the products are administered percutaneously to 1.5 mg / kg under a volume of 10 il.

<Tb>

Products <SEP> of <SEP> examples <SEP> Test
<tb><SEP> 3 <SEP> 47
<tb><SEP> 6 <SEP> 84
<Tb>
Conclusion: The tests indicated above show that the products of the invention tested have a strong anti-androgenic activity.

Claims (13)

REVENDICATION8 1) a) The products of general formula (I):

 in which Z1 and Z2, which may be identical or different, represent a cyano, nitro, a halogen atom, a trifluoromethyl radical or a free esterified amidified or salified carboxy radical, the -A-B- group is chosen from among the radicals

 in which X represents an oxygen or sulfur atom and R3 is chosen from the following radicals - a hydrogen atom, - alkyl, alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from hydroxy radicals, optionally esterified, etherified or protected, halogenated, mercapto, cyano, acyl or acyloxy having at most 7 carbon atoms, optionally substituted S-aryl, in which the sulfur atom is optionally oxidized in the form of sulfoxide or sulfone, free carboxy , esterified, amidated or salified, amino, mono or dialkylamino or a cyclic radical comprising 3 to 6 members and optionally containing one or more heteroatoms chosen from sulfur, oxygen or nitrogen atoms, alkyl, alkenyl or alkynyl radicals; being further optionally interrupted by one or more oxygen, nitrogen or sulfur atoms optionally oxidized in the form of sulfoxide or sulfone, the aryl and aralkyl radicals being further optionally substituted with an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical, Y represents an oxygen or sulfur atom or a radical NH, R4 and R5, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms optionally substituted by one or more substituents chosen from halogen atoms, the hydroxyl radical optionally esterified, etherified or protected, phenylthio and linear or branched alkylthio radicals containing at most 8 carbon atoms, phenylthio and alkylthio radicals, in which the sulfur atom can be oxidized to sulfoxide or sulfone, being optionally substituted by one or more radicals chosen from the atoms of halogen, the optionally esterified, etherified or protected hydroxyl radical, the free carboxy, esterified, amidated or salified, amino, mono or dialkylamino radical, with the exception of products in which R4 and R5, which are identical or different, represent a hydrogen atom; or an alkyl radical having from 1 to 12 carbon atoms optionally substituted by one or more rs halogen atoms and those in which one of R4 or R5 represents a methyl radical and the other represents a hydroxymethyl radical, Y represents an oxygen atom or an NH radical, the -A-B- radical represents the radical

 in which X represents an oxygen atom and R3 represents a hydrogen atom, Z1 at the 4-position represents a nitro radical and Z2 at the 3-position represents a trifluoromethyl radical, b) the products of formula (ira):

 in which Z3 represents a cyano or nitro radical, R3a represents a hydrogen atom or a linear or branched alkyl radical, containing at most 4 carbon atoms, optionally substituted by a fluorine atom or a cyano radical, R4a and R5a are such that one represents a methyl radical and the other represents a methyl radical substituted by a fluorine atom or else R4a and R5a identical represent a methyl radical substituted by a fluorine atom, or else R4a and R5a form with the carbon atom to which they are attached a cyclopentyl radical, Xa represents a sulfur or oxygen atom, with the exception of the product in which Z3 represents a cyano radical, Xa represents a sulfur atom, R3a represents a methyl radical and R4a and R5a form with the carbon atom to which they are bound cyclopentyl, and c) the following products - 3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidinacetonitrile, - 4- (4,4-dimethyl-2,5) 3- (2-Fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, -4- (4,4-dimethyl-2,5-dioxo-3- (2,2,2-trifluoroethyl) -1-imidazolidinyl) -2- 2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (2-fluoroethyl) 5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, the said products of formulas (I> and (Ia) and the products mentioned above being in all the racemic isomeric forms, enantiomers and diastereoisomers possible, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formulas (I) and (Ia) and above. 2) The products of formula (I) as defined in claim 1, wherein Z1 and Z2 represent a trifluoromethyl, nitro or cyano radical, Y represents an oxygen atom or an NH radical, the -AB- group represents the radical

 in which X represents an oxygen or sulfur atom, R3 represents a hydrogen atom, a linear or branched alkyl radical containing at most 6 carbon atoms, optionally interrupted by one or more oxygen or sulfur atoms, a phenyl or pyridyl radical, these radicals being optionally substituted by a or more radicals selected from halogen atoms, phenyl radical, hydroxyl optionally esterified, etherified or protected, alkoxy, cyano, trifluoromethyl, hydroxyalkyl, free carboxy, esterified, amidated or salified, amino, mono or dialkylamino, the atom d nitrogen of the pyridyl radical being optionally oxidized, R4 and R5 represent a linear or branched alkyl radical containing at most 6 carbon atoms, optionally substituted with one or more radicals chosen from hydroxyl radicals, optionally esterified, etherified or protected, halogen atoms and alkylthio and phenylthio radicals; themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl radical, the said products of formula (I) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible, as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 3) The products of formula (I) as defined in claim 1 or 2 wherein Z1 and Z2 represent a trifluoromethyl, nitro or cyano radical, Y represents an oxygen atom or an NH radical, the -AB- group represents grouping

 in which X represents an oxygen or sulfur atom, R3 represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms optionally substituted with one or more radicals chosen from halogen atoms and optionally esterified, etherified or protected hydroxyl radicals, free carboxyl, esterified, amidated or salified and cyano, the alkyl radical being optionally interrupted by one or more oxygen or sulfur atoms, R4 and R5 represent an alkyl radical optionally substituted with one or more radicals chosen from the hydroxyl radical, optionally esterified, etherified or protected, the halogen atoms and the alkylthio and phenylthio radicals themselves optionally substituted with one or more radicals chosen from halogen atoms and the hydroxyl radical, the said products of formula (I) being in all the isomeric forms racemic, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases said products of formula (I). 4) The products of formula (I) as defined in claim 3, wherein Y represents an oxygen atom or an NH radical, Z2 in position 3 represents a trifluoromethyl radical and Z1 in position 4 represents a cyano or nitro radical; , X represents an oxygen or sulfur atom, R3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms, optionally substituted with one or more radicals chosen from halogen atoms or cyano radical, R4 and R5, which may be identical or different, represent a linear or branched alkyl radical containing at most 4 carbon atoms optionally substituted with an optionally esterified, etherified or protected hydroxyl radical, a halogen atom, or a phenylthio radical optionally substituted by an atom of halogen or a free hydroxyl radical, esterified, etherified or protected, the said products of formula (I) being in all the isomeric forms racemic, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 5) The products of formula (I) as defined in any one of claims 1 to 4, whose names follow - 2- (trifluoromethyl) 4- (4- (hydroxymethyl) -4-methyl 2,5-dioxo imidazolidinyl) benzonitrile, 4- (3,4-dimethyl) -4- (hydroxymethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 2- (trifluoromethyl) -4- (4- (trifluoromethyl) benzonitrile) (hydroxymethyl) 3,4-dimethyl-2,5-dioxo-imidazolidinyl) benzonitrile, 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydroxymethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 1,5-dimethyl-5- (hydroxymethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) 2,4-imidazolidinedione, the said products of formula (I) being in all isomeric forms racemic, enantiomers and possible diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 6) The products of formula (Ia) as defined in claim 1, whose names follow - 4- (4- (fluoromethyl) 3,4-dimethyl) 2,5-dioxo-imidazol dinyl) 2- 2- (Trifluoromethyl) benzonitrile, 4- (3,4-dimethyl) -4- (fluoromethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (2,5-dioxo) - (2-Fluoroethyl) 4- (fluoromethyl) -4-methyl imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) -2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo-1-fluoroethyl) 1,3-diazaspiro (4.4) nonan-3yl) -2- (trifluoromethyl) benzonitrile, -1,5-dimethyl-5- (Fluoromethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) -2,4-imidazolidinedione, 3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoro-methyl) -5- methyl 1-imidazolidinacetonitrile, 4- (4,4-bis- (fluoromethyl) 3-methyl-5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile, the said products of formula (Ia) being in all the forms i racemic esters, enantiomers and diastereoisomers possible, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (ira) 7) Process for the preparation of the products of formulas (I) and those as defined in claim 1, characterized in that either a product of formula (II) is reacted in the presence of a tertiary base

 in which R1, R2 and X have the meaning indicated above, with a product of formula (III)

  in which R4 and R5 have the meaning indicated above and R'3 has the values indicated above for R3 in which the optional reactive functions are optionally protected and it being understood that R4 and R5 do not simultaneously represent a methyl radical and that if R1 represents a radical NO2 in position 4, R2 represents a radical CF 3 in position 3, X represents an oxygen atom and R '3 represents a hydrogen atom, then one of R4 or R5 does not represent a CH3 radical and the other a CH2OH radical, to obtain a product of formula (IV)

 in which R 1, R 2, X, R '3, R 4 and R 5 have the above meaning, or the product of formula (II) as defined above is made to act in the presence of a tertiary base with a product of formula (VII)

 in which W has the meaning indicated in claim 1 for R5 except for the hydrogen atom and an alkyl radical substituted by an optionally esterified, etherified or protected hydroxyl radical and P represents an OH protecting group or a radical such that -OP represents an etherified hydroxyl radical and R'3 and R4 have the meaning indicated above, to obtain a product of formula (VIII):

 in which X, R 1, R 2, R '3, R 4, W and P have the meaning indicated above, a product of formula (VIII), of which, if necessary and if desired, the OH radical can be liberated from OH then, if necessary and if desired, esterify or transform into a halogen radical, products of formulas (IV) and (VIII) that, if necessary or desired, are subjected to any one or more of the following reactions, in any order a) elimination reaction of any protective groups that can carry R'3; b) hydrolysis reaction of the group> C = NH in the carbonyl function and, where appropriate, transformation of the group> C = S in group> C = O c) transformation reaction of the group> C = O in group> C = S; d) action on the products of formula (IV) or (VIII) in which R '3 represents a hydrogen atom, and after hydrolysis of the> C = NH carbonyl group of a reagent of formula Hal-R "3 in which R "3 has the values of R'3 with the exception of the hydrogen value and Hal represents a halogen atom to obtain products of formulas (I) and (I,) and as defined in claim 1 in which the group -AB- represents the grouping

  in which R "3 has the meaning indicated above and, if desired, action on these products, an agent for eliminating any protective groups that can carry R "3 or, as the case may be, the action of an esterification, amidation or salification agent, or a product of formula (II) as defined above is made to act in the presence of a tertiary base; with a product of formula (III ')

 in which R'3, R4 and R5 have the meaning indicated above and Q represents either an alkali metal atom or an alkyl radical containing from 1 to 6 carbon atoms, to obtain a product of formula (IVa):

 wherein X, R1, R2, R'3, R4 and R5 have the meaning indicated above, if desired subject to any one or more of the following reactions, in any order a) reaction of elimination of any protective groups that R'3 can carry; b) transformation reaction of the group> C = O in group> C = S or, where appropriate, of the group> C = S in group> C = O c) action on the products of formula (IVa) in which R ' 3 represents a hydrogen atom, a reagent of formula Hal-R "3 in which R" 3 has the values of R'3 with the exception of the hydrogen value and Hal represents a halogen atom to obtain products of formula (I) in which the group -AB- represents grouping

 in which R "3 has the meaning indicated above and, if desired, action on these products, an agent for eliminating any protective groups that can carry R "3 or, as the case may be, the action of an esterifying agent, amidation or salification agent, ie a reagent of formula Hal-R" 3 in which Hal and R "3 are used have the values indicated. previously on a product of formula (IV ')

 to obtain a product of formula (IV "):

 product of formula (IV ") that, if necessary or if desired is subjected to any one or more of the following reactions in any order a) reaction elimination of any protective groups that can carry R'23 then the if appropriate action of an esterification agent, amidification or salification b) transformation reaction of the group or groups> C = O in groups> C = S. 8) As medicaments, the products of formulas (I) and (ira) as defined in claims 1 to 6, pharmaceutically acceptable. 9) As medicaments, the following products - 3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidinacetonitrile, 4- (4,4-dimethyl-2,5-dioxo) 3- (2-Fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-2,5-dioxo-3- (2,2,2-trifluoroethyl) -1-imidazolidinyl) -2- (4-trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxol-imidazolidinyl) -2-trifluoromethyl-benzonitrile. 10) As medicaments, the following products of formula (I) - 2- (trifluoromethyl) 4- (4- (hydroxymethyl) -4-methyl 2,5-dioxo-imidazolidinyl) benzonitrile, - 4- (3,4) dimethyl) 4- (hydroxymethyl) -5-oxo-2-thioxol-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 2- (trifluoromethyl) -4- (4- (hydroxymethyl) 3,4-dimethyl-2,5-dioxo) imidazolidinyl) benzonitrile, 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydroxymethyl) -4-methyl-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, -1,5-dimethyl-5- (hydroxymethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) 2,4-imidazolidinedione. 11) As medicaments, the following products of formula (Ia) - 4- (4- (fluoromethyl) 3,4-dimethyl) 2,5-dioxo-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, - 4 (3,4-dimethyl) 4- (fluoromethyl) -5-oxo-2-thioxol-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4- (2,5-dioxo-3- (2-fluoroethyl) -4- - (4- (Fluoro-methyl) -4-methyl-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) -2- (trifluoromethyl) ) benzonitrile-4- (2,4-dioxo-1- (2-fluoroethyl) 1,3-diazaspiro (4.4) nonan-3-yl) -2- (trifluoromethyl) benzonitrile-1,5-dimethyl-5- (fluoromethyl) 3- (4-nitro-3- (trifluoromethyl) phenyl) -2,4-imidazolidinedione-3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-imidazolidinacetonitrile-4 (4,4-bis- (fluoromethyl) 3-methyl-5-oxo-2-thioxol-imidazolidinyl-2- (trifluoromethyl) benzonitrile. 12) Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in any one of claims 8 to 11. 13) As new industrial products, the products of formula (IVi)

 in which R1, R2, R4, R5 and Y have the meanings indicated in claim 1 and the grouping

 is chosen from the radicals

  in which X represents an oxygen or sulfur atom and R3i is selected from the values of R3 having a protected reactive function.