RU2152934C1 - Substituted phenylimidazolidines, methods of their synthesis (variants) and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to substituted phenylimidazolidines of the formula (I)

where Y is O or NH; Z₂ is CF₃; Z₁ is cyano- or nitro-radical; X is O or S; R₃ is H or alkyl possibly substituted with halogen atom or cyano-radical R₄, R₅ is alkyl possibly substituted with hydroxy 1 that can be protected in all possible isomeric, racemic, enentiomeric and diasteriameric forms and acidic or basic salts that show anti-androgenic activity. EFFECT: improved method of synthesis, valuable pharmacological properties. 8 cl, 38 ex

Description

 The invention relates to substituted phenylimidazolidines, to a method for their preparation and to a pharmaceutical composition based on them.

 Japanese application J 48087030 describes 3-phenyl-2-thiohydantoins, which are offered as inhibitors of the germination of certain plants.

 In European patent applications N 0494819 and 0578516 describe imidazolidines, which are offered as compounds with antiandrogen activity. The compounds of this patent are however different from the compounds of this patent application.

 The objective of the invention is to develop new compounds with significant antiandrogenic activity.

в которой Y означает атом кислорода или радикал NH;
Z₂ означает трифторметильный радикал;
Z₁ означает циано- или нитрорадикал;
X означает атом кислорода или серы;
R₃ означает атом водорода или алкильный радикал, содержащий не более 4 атомов углерода, который может быть замещен одним или несколькими радикалами, выбираемыми из атомов галогена или циано-радикала;
R₄ и R₅, одинаковые или различные, означают линейный или разветвленный алкильный радикал, содержащий не более 4 атомов углерода, который может быть замещен гидроксильным радикалом, который может быть защищен или этерифицирован до простого или сложного эфира; атомом галогена или фенилтиорадикалом, который может быть замещен атомом галогена или гидроксильным радикалом, причем продукты формулы (I) находятся во всех возможных изомерных, рацемических, энантиомерных и диастереоизомерных формах, а также соли присоединения неорганических или органических кислот или неорганических или органических оснований продуктов формулы (I).The present invention relates to substituted phenylimidazolidines of the general formula (I):

in which Y represents an oxygen atom or an NH radical;
Z ₂ means trifluoromethyl radical;
Z ₁ means a cyano or nitro radical;
X is an oxygen or sulfur atom;
R ₃ means a hydrogen atom or an alkyl radical containing not more than 4 carbon atoms, which may be substituted by one or more radicals selected from halogen atoms or a cyano radical;
R ₄ and R ₅ , the same or different, mean a linear or branched alkyl radical containing not more than 4 carbon atoms, which may be substituted by a hydroxyl radical, which may be protected or esterified to an ether or ester; a halogen atom or phenylthio radical which may be substituted by a halogen atom or a hydroxyl radical, the products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts of inorganic or organic acids or inorganic or organic bases of products of the formula ( I).

 By halogen is meant fluorine, chlorine, bromine or iodine atoms.

 Fluorine, chlorine or bromine atoms are preferred.

 As examples of alkyl radicals substituted with one or more halogen atoms, mention may be made of monofluoro, chloro, bromo or iodomethyl, difluoro, dichloro or dibromomethyl and trifluoromethyl radicals.

By esterified to an ester or simple hydroxyl radical, respectively, are meant -OC-α ₁ , α ₂ -O-α ₃ or -OP radicals formed from a hydroxyl radical by conventional methods known to the skilled person, and in which P denotes a protective a group;
α ₁ , α ₂ and α ₃ are, in particular, an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical with at most 12 carbon atoms, and optionally substituted in the same manner as indicated above, in particular for R ₃ .

 Examples of the protective group P, as well as methods for protecting the hydroxyl radical, are indicated, in particular, in the well-known specialist book: "Prodective Groups in Organic Synthesis", Theodora W. Greene, Harvard University, 1981, Wiley-Interscience Publishers, John Wiley and Sons.

 The protective group P of the hydroxyl radical can be selected from the following groups: formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Groups such as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, βββ-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclo-propylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl-benzyl, trityl-benzyl methyl-1-methoxyethyl, phthaloyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert. -butylbenzoyl, capryl, acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl.

или производное кремния, такое как триметилсилил.P may denote, in particular, the radical

or a silicon derivative such as trimethylsilyl.

 When the compounds of formula (I), as described above, contain an amino radical forming a salt with an acid, these acid salts also form part of the invention. You can name salts formed, for example, with hydrochloric acid or methane sulfonic acid.

Of the preferred compounds according to the invention, more specifically, compounds of formula (I) can be named, the names of which are as follows:
-2- (trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile;
-4- (3,4-dimethyl-4- (hydroxymethyl) -5-oxo-2-thioxo-1-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) imidazolidine-2,4-dione;
4- (4,4-bis (hydroxymethyl) -2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile;
moreover, the above compounds of formula (I) are in any possible isomeric racemic, enantiomeric and diastereoisomeric forms;
and their addition salts of inorganic or organic acids or addition salts of inorganic or organic bases.

Even more specifically, the invention relates to the following preferred compounds:
-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-3- (2-fluoroethyl) -4- (fluoromethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile;
-1,5-dimethyl-5- (fluoromethyl) -3- (4-nitro-3- (trifluoromethyl) phenyl) imidazolidine-2,4-dione;
-3- (4-cyano-3- (trifluoromethyl) phenyl) -2 4-dioxo-5- (fluoromethyl) -5-methyl-1-imidazolidine acetonitrile;
-4- (4,4-bis- (fluoromethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile;
moreover, the above compounds of formula (I) are in any possible racemic, enantiomeric and diastereoisomeric forms;
and their addition salts of inorganic or organic acids or addition salts of inorganic or organic bases.

 The invention also relates to a method for producing compounds of formula (I) and its variants.

в которой Z₁, Z₂ и X имеют указанные выше значения, в присутствии третичного основания, с соединением формулы (III):

в которой R₄ и R₅ имеют указанное выше значение, и R₃ имеет значения, указанные выше для радикала R₃, в котором возможные реакционноспособные функции при необходимости защищены, для получения соединения формулы (IV):

в которой Z₁, Z₂, X, R₄ и R₅ имеют вышеуказанное значение, которое при желании подвергают одной или нескольким следующим реакциям в любом порядке:
а) реакции удаления защитных групп, которые может нести R₃';
б) реакции гидролиза группы

до карбонильной и при необходимости превращению группы

в группу

в) реакции превращения группы или групп

в группу

г) воздействию на соединение формулы (IV), в которой R₃' означает атом водорода, и после гидролиза группы

до карбонильной, реактивом формулы Гал-R₃'', в которой R₃'' имеет значения R₃' за исключением водорода, а Гал означает атом галогена, для получения продукта формулы (I), затем, при желании, воздействию на полученный продукт агентом удаления возможных защитных групп, которые может нести R₃'', или при желании, агентом этерификации, агентом аминирования или агентом солеобразования, причем полученные соединения формулы (I) находятся во всех возможных изомерных, рацемических, энантиомерных и диастереоизомерных формах.So, substituted phenylimidazolidines of formula (I) can be obtained by reacting a compound of formula (II):

in which Z ₁ , Z ₂ and X have the above meanings, in the presence of a tertiary base, with a compound of formula (III):

in which R ₄ and R ₅ have the above meaning, and R ₃ has the meanings given above for the radical R ₃ , in which possible reactive functions are protected, if necessary, to obtain a compound of formula (IV):

in which Z ₁ , Z ₂ , X, R ₄ and R ₅ have the above meaning, which, if desired, is subjected to one or more of the following reactions in any order:
a) deprotection reactions that R ₃ ′ may carry;
b) hydrolysis reactions of the group

to carbonyl and, if necessary, the transformation of the group

to the group

c) reactions of transformation of a group or groups

to the group

d) acting on a compound of formula (IV) in which R ₃ ′ is a hydrogen atom, and after hydrolysis of the group

to carbonyl, with a reagent of the formula Gal-R ₃ ″, in which R ₃ ″ has the meaning R ₃ ″ except hydrogen, and Gal means a halogen atom, to obtain a product of formula (I), then, if desired, the effect on the resulting product an agent for removing possible protective groups that R ₃ ″ may carry, or, if desired, an esterification agent, an amination agent or a salt formation agent, the compounds of formula (I) being obtained are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms.

 The reaction of compounds of formula (II) with compounds of formula (III) is preferably carried out in an organic solvent such as tetrahydrofuran or dichloroethane, but diethyl ether or diisopropyl ether can also be used.

 Work in the presence of a tertiary base such as triethylamine, or pyridine, or methylethylpyridine.

 As a protective hydroxyl group, radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl, tert.-butyldimethylsilyl can be mentioned. Other protecting groups known from the chemistry of peptides described, for example, in patent FR 2499995 can be used.

 Possible deprotection reactions are carried out as described in the same patent.

 A preferred method of removal is acid hydrolysis with acids selected from the group consisting of hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, formic or trifluoroacetic acid. Prefer hydrochloric acid.

до кетонной группы предпочтительно осуществляют с помощью кислоты, такой как водная соляная кислота, например, при кипячении с обратным холодильником.Possible hydrolysis reaction of the group

to the ketone group, it is preferably carried out with an acid, such as aqueous hydrochloric acid, for example, by heating under reflux.

до карбонильной группы осуществляют в случае молекулы, содержащей также группу

то она также может быть превращена в группу

Свободный OH-радикал, который в случае необходимости может нести R₃, в таком случае может быть превращен в радикал SH.When the hydrolysis of the group

to a carbonyl group is carried out in the case of a molecule also containing a group

then it can also be turned into a group

The free OH radical, which, if necessary, can carry R ₃ , in this case, can be converted into the radical SH.

в группу

осуществляют с помощью так называемого реагента Лавессона формулы:

который является продажным продуктом, выпускаемым, например, фирмой FLUKA и применение которого описывается, например, в публикации: Bull. Soc. Chim. Belg., 87, N 3 (1987), с. 229.The reaction of the transformation of the group or groups

to the group

carried out using the so-called reagent Lawesson formula:

which is a commercial product manufactured, for example, by the company FLUKA and the use of which is described, for example, in the publication: Bull. Soc. Chim. Belg., 87, N 3 (1987), p. 229.

в две функции

то работают в присутствии избытка реагента Лавессона. То же самое имеет место, когда исходят из молекулы, содержащей функцию

и функцию

и хотят превратить вышеуказанную функцию

в функцию

Напротив, когда исходят из молекулы, содержащей две функции

и хотят получить продукт, содержащий только одну функцию

то работают при дефиците реагента Лавессона. В таком случае обычно получают смесь трех продуктов: два продукта, каждый из которых содержит функцию

и функцию

и продукт, содержащий две функции

Эти продукты затем можно разделять обычными способами, такими как хроматография.When they want to turn two functions

in two functions

they work in the presence of an excess of Lawesson's reagent. The same thing happens when you start from a molecule containing a function

and function

and want to turn the above function

in function

On the contrary, when they come from a molecule containing two functions

and want to get a product containing only one function

then they work with a deficiency of Lawesson's reagent. In this case, usually a mixture of three products is obtained: two products, each of which contains a function

and function

and a product containing two functions

These products can then be separated by conventional means, such as chromatography.

The compound of formula (IV) is exposed to a reagent of formula Gal-R ₃ ″ in the presence of a strong base, such as sodium or potassium hydride. You can work using the phase transfer reaction in the presence of quaternary ammonium salts, such as tert.-butylammonium.

 A possible esterification of the compounds of formula (I) having an OH free radical to an ester is carried out under classical conditions. You can use, for example, an acid or a functional derivative thereof, for example an anhydride such as acetic anhydride, in the presence of a base such as pyridine.

в которой W имеет указанное для R₅ значение, за исключением алкильного радикала, замещенного гидроксилом, свободным, этерифицированным до простого или сложного эфира или защищенным, и P означает защитную группу OH-функции или такой радикал, что -O-P означает этерифицированный до простого эфира гидроксил, и R₃ и R₄ имеют значение, указанное выше, для получения продукта формулы (VIII):

в которой X, Z₁, Z₂, R₃', R₄, W и P имеют указанное выше значение, в котором при желании или при необходимости высвобождают из группы OP радикал OH, который при необходимости или при желании этерифицируют до сложного эфира или превращают в галоидный радикал; затем при желании или при необходимости продукт формулы (VIII) подвергают одной или не скольким следующим реакциям в любом порядке:
а) реакции удаления возможных защитных групп, которые может нести радикал R₃';
б) реакции гидролиза группы

до карбонильной группы и, при необходимости, превращения группы

в группу

в) реакции превращения группы или групп

в группу

г) воздействию на продукт формулы (VIII), в которой R₃' означает атом водорода и после гидролиза группы

до карбонильной группы, реактивом формулы Гал-R₃'', в которой R₃'' имеет значения радикала R₃', за исключением водорода, и Гал означает атом галогена, для получения продукта формулы (I') по п. 1 или 2, затем, при желании, воздействию на полученный продукт агентом удаления возможных защитных групп, которые может нести R₃'', или при желании, агентом этерификации, аминирования или солеобразования, причем полученные продукты формулы (I) находятся во всех возможных изомерных, рацемических, энантиомерных или диастереоизомерных формах.Compounds of formula (I) can also be prepared by reacting a compound of formula II as defined above in the presence of a tertiary base with a compound of formula (VII):

in which W has the meaning indicated for R ₅ , with the exception of an alkyl radical substituted with hydroxyl, free, etherified or esterified, or protected, and P is an OH-protecting group or a radical such that —OP is an ether hydroxyl esterified , and R ₃ and R ₄ have the meaning indicated above, to obtain a product of formula (VIII):

in which X, Z ₁ , Z ₂ , R ₃ ', R ₄ , W and P have the above meaning, in which, if desired or if necessary, the OH radical is released from the OP group, which is optionally or optionally esterified to an ester or turn into a halide radical; then, if desired or if necessary, the product of formula (VIII) is subjected to one or more of the following reactions in any order:
a) reactions of removal of possible protective groups that the radical R ₃ ′ may carry;
b) hydrolysis reactions of the group

to a carbonyl group and, if necessary, conversion of the group

to the group

c) reactions of transformation of a group or groups

to the group

g) the impact on the product of formula (VIII), in which R ₃ 'means a hydrogen atom and after hydrolysis of the group

to a carbonyl group, with a reagent of the formula Gal-R ₃ ″, in which R ₃ ″ has the meaning of the radical R ₃ ″, with the exception of hydrogen, and Gal means a halogen atom, to obtain a product of formula (I ') according to claim 1 or 2 then, if desired, by exposing the product obtained to an agent to remove possible protective groups that R ₃ may carry, or if desired, by an esterification, amination or salt formation agent, the products of formula (I) obtained being in all possible isomeric, racemic, enantiomeric or diastereoisomeric forms.

The reaction of a compound of formula (II) above, with a compound of formula (VII) above, to produce a product of formula (VIII) can be carried out, in particular, in the presence of methylene chloride at a temperature of about -30 ^o C.

в которой R₃', R₄ и R₅ имеют значение, указанное выше, и Q означает атом щелочного металла или алкильный радикал, содержащий 1-6 атомов углерода, для получения продукта формулы (IVa):

в которой X, Z₁, Z₂, R₃', R₄ и R₅ имеют вышеуказанное значение, который при желании подвергают одной или нескольким реакциям в любом порядке:
а) реакции удаления возможных защитных групп, которые может нести радикал R₃';
б) реакции превращения группы или групп

в группу

или при желании группы

в группу

в) воздействию на продукт (IVa), в которой R₃' означает атом водорода, реактивом формулы Гал-R₃'', в которой R₃'' имеет значения радикала R₃' за исключением водорода, и Гал означает атом галогена, для получения продукта формулы (I), затем, при желании, воздействию на этот продукт агентом удаления возможных защитных групп, которые может нести радикал R₃'', или при желании, действию агента этерификации, аминирования или солеобразования, причем полученные продукты формулы (I) находятся во всех возможных изомерных, рацемических, энантиомерных и диастереоизомерных формах.Compounds of formula (I) can also be prepared by reacting a compound of formula (II) above in the presence of a tertiary base with a compound of formula (III '):

in which R ₃ ', R ₄ and R ₅ have the meaning indicated above, and Q means an alkali metal atom or an alkyl radical containing 1-6 carbon atoms, to obtain a product of formula (IVa):

in which X, Z ₁ , Z ₂ , R ₃ ', R ₄ and R ₅ have the above meaning, which, if desired, is subjected to one or more reactions in any order:
a) reactions of removal of possible protective groups that the radical R ₃ ′ may carry;
b) reactions of transformation of a group or groups

to the group

or if desired groups

to the group

c) acting on the product (IVa), in which R ₃ ″ means a hydrogen atom, with a reagent of the formula Gal-R ₃ ″, in which R ₃ ″ has the meaning of the radical R ₃ ’except hydrogen, and Gal means a halogen atom, for obtaining a product of formula (I), then, if desired, exposing the product to an agent to remove possible protective groups that the radical R ₃ ″ may carry, or, if desired, the action of an esterification, amination or salt formation agent, the resulting products of formula (I) are found in all possible isomeric, racemic, enantiomeric and diaster oizomernyh forms.

для получения продукта формулы (IV'')

продукт формулы (IV') или (IV''), который может означать или не означать продукт формулы (I), при желании или при необходимости подвергают одной или нескольким следующим реакциям в любом порядке для получения продукта формулы (I):
а) реакции удаления возможных защитных групп, которые может нести радикал R₃'' затем, возможно, действию агента этерификации, аминирования или солеобразования,
б) реакции превращения группы или групп

в группы

причем полученные продукты находятся во всех возможных изомерных, рацемических, энантиомерных или диастереоизомерных формах.Compounds of formula (I) as defined above can also be prepared by reacting a compound of formula Gal-R ₃ ″, wherein Gal and R ₃ ″ are as defined above, with a compound of formula (IV '):

to obtain a product of formula (IV``)

a product of formula (IV ′) or (IV ″), which may or may not mean a product of formula (I), if desired or necessary, is subjected to one or more of the following reactions in any order to obtain a product of formula (I):
a) the reaction of removal of possible protective groups that the radical R ₃ ″ may carry then, possibly, the action of an esterification, amination or salt formation agent,
b) reactions of transformation of a group or groups

in groups

moreover, the resulting products are in all possible isomeric, racemic, enantiomeric or diastereoisomeric forms.

The reaction of a compound of formula (IV), (IVa), (IV ′) or (VII ″) with a reagent of formula Gal-R ₃ ″ is carried out in the presence of a strong base such as sodium or potassium hydride.

 A phase transfer reaction can be carried out in the presence of quaternary ammonium salts such as tert-butylammonium.

The protecting groups that the R ₃ ″ substituent can carry may be, for example, one of the above for R ₃ groups. The removal of protective groups is carried out under the above conditions.

 The examples below provide an example of the removal of a tert-butyldimethylsilyl group with hydrochloric acid.

A possible esterification of the compounds of formula (I) to an ester, where R ₃ ″ carries the free radical OH, is carried out under classical conditions. You can use, for example, an acid or its functional derivative, for example, an anhydride, such as acetic anhydride, in the presence of a base, such as pyridine.

A possible esterification to an ester or a possible conversion to a salt of compounds of formula (I), wherein R ₃ ″ is a COOH group, is carried out under classical conditions known to the skilled person.

A possible amination of the compound of formula (I) and wherein R ₃ ″ contains the radical COOH, is carried out under classical conditions. A primary or secondary amine can be used for a functional derivative of an acid, for example, as a symmetric or mixed anhydride.

в которой R₄ и R₅ имеют вышеуказанное значение; и
Z₁ и Z₂ имеют значения, указанные выше, имея в виду, что когда X = 0, a R₃ обозначает атом водорода или линейный или разветвленный алкильный радикал, содержащий не более 4 атомов углерода, и Y обозначает атом кислорода, а Z₁ означает циано-радикал, могут быть получены также путем взаимодействия соединения (V):

в которой Z₁ и Z₂ имеют указанное выше значение и Гал - атом галогена, с соединением формулы (VI):

в которой R₄, R₅ и Y имеют указанное выше значение, осуществляемого в присутствии катализатора и, при необходимости, растворителя.Compounds of General formula (I '):

in which R ₄ and R ₅ have the above meaning; and
Z ₁ and Z ₂ have the meanings indicated above, bearing in mind that when X = 0, a R ₃ represents a hydrogen atom or a linear or branched alkyl radical containing not more than 4 carbon atoms, and Y represents an oxygen atom, and Z ₁ means a cyano radical, can also be obtained by reacting compound (V):

in which Z ₁ and Z ₂ have the above meaning and Gal is a halogen atom, with a compound of formula (VI):

in which R ₄ , R ₅ and Y have the above meaning, carried out in the presence of a catalyst and, if necessary, a solvent.

 In formula (V), the symbol Gal preferably denotes a chlorine atom, but may also denote a bromine or iodine atom.

 The role of the catalyst, obviously, is to capture hydrogen halide, which is released and thus facilitates the course of the condensation reaction of the compounds of formula (V) with the compound of formula (VI) to obtain the target product.

 The catalyst may be, in particular, a metal in native or oxidized or basic form.

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

 The metal salts may be chloride or acetate.

 When the catalyst is a base, then this base can be, for example, sodium or potassium hydroxide and, if desired, dimethyl sulfoxide can be added to the reaction medium.

 More specifically, the catalyst is selected from the group consisting of copper (I) oxide, copper (II) oxide, native copper and a base such as sodium or potassium hydroxide.

 Copper in native form, used as a catalyst, is preferably in powder form.

 Preferably, the catalyst is copper (I) oxide.

 The solvent used is preferably selected from high boiling ethers, such as, for example, diphenyl ether, diglyme, triglyme and dimethyl sulfoxide, but it is also possible to add, for example, high boiling oil, such as paraffin or petroleum jelly.

 Advantageously they work in the presence of an ether type solvent such as diphenyl ether, diglyme, triglyme or dimethyl sulfoxide.

 In particular, the solvent used is diphenyl ether or triglyme.

 The above method of obtaining the target product can be carried out under pressure or at atmospheric pressure, preferably at elevated temperature.

The reaction can be carried out at a temperature above 100 ^o C and preferably above 150 ^o C.

 More specifically, the reaction is carried out for more than 2 hours.

Even more specifically, the reaction is carried out in the presence of copper oxide (I), in triglyme, at a temperature above or equal to 200 ^° C. and for a period of more than 3 hours.

 The compounds according to the invention have interesting pharmacological properties, in particular, they are fixed on the androgen receptor and they have antiandrogenic activity.

 The tests in the experimental part illustrate these properties.

These properties allow the use of products of the formula (I), such as those indicated above, of the present invention as medicines, especially
- for the treatment of adenomas and neoplasms of the prostate, such as benign prostatic hypertrophy, used individually or in combination with analogues of NRH. They can also be used to treat benign or malignant tumors with androgen receptors, and primarily to treat cancer of the female breast, skin, female genital glands, bladder, lymphatic system, kidneys and liver;
- for the treatment of skin diseases such as acne, hyperseborrhea, alopecia (baldness) or hirsutism. These products, therefore, can be used in dermatology individually or in combination with antibiotics, such as azelaic and fusidic acid derivatives, erythromycin, as well as retinoic acid derivatives or a 5 α-reductase inhibitor such as (5α, 17β) -1,1 dimethylethyl-3-oxo-4-aza-androst-1-ene-17-carboxamide (or finasteride, Merck, 11th edition), for the treatment of acne, alopecia, or hirsutism. They can also be combined with a hair growth promoting product such as minoxidil to treat alopecia.

 The compounds of formula (I) in radioactive form (tritium, carbon 14, iodine 125 or fluorine 18) can still be used as specific markers of androgen receptors. They can also be used in diagnostics for medical imaging.

 The compounds of formula (I) can also be used in the field of veterinary medicine for the treatment of behavioral disorders such as androgen-dependent aggressiveness of a disease state, such as a circum analum in a dog, and tumors including androgen receptors. They can also be used to cause chemical castration in an animal.

The following compounds are preferred as drugs:
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- (trifluoromethyl) benzonitrile;
4- (4,4-dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile;
4- (4,4-dimethyl-2,5-dioxo-3- (2- (2-hydroxyethoxy) ethyl) - 1-imidazolidinyl-2- (trifluoromethyl) benzonitrile.

As medicines, in particular, the use of the following products is possible:
2- (trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile;
4- (3,4-dimethyl-4- (hydroxymethyl) -5-oxo-2-thioxo-1-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) imidazolidine-2,4-dione;
4- (4,4-bis- (hydroxymethyl) -2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile.

More specifically, as medicines, the following products are possible:
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-3- (2-fluoroethyl) -4- (4-fluoromethyl) -4-methyl-1-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) imidazolidine-2,4-dione;
3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-1-imidazolidineacetonitrile;
4- (4,4-bis- (fluoromethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile.

 Products can be administered parenterally, orally, translingually, rectally or topically.

 The subject of the invention is also pharmaceutical compositions, characterized in that they contain, as an active principle, at least one of the pharmaceutical formulas (I), (Ia) and the products cited, such as those mentioned above.

 These compositions may be in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions. These pharmaceutical forms are prepared by conventional methods. The active principle can be included in excipients commonly used in these compositions, such as aqueous or non-pharmaceutical preparations, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, animal or vegetable fatty substances, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 The usual dose, which varies depending on the subject being treated and the cause of the disease, can be, for example, 10-500 mg per day for humans when administered orally.

Пример такого получения приводится ниже в экспериментальной части. Продукт этого типа также описывается в патенте Франции N 2329276.The starting products of the formula (II) used according to the invention can be obtained by exposure to phosgene when X is an oxygen atom, or thiophosgene when X is a sulfur atom, on an amine corresponding to the 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 N 2329276.

 Amines of formula (A) are described in European patent EP 0 002892 or in French patent N 2142804.

 The products of formula (III) or (III ') are known or can be obtained from the corresponding cyanohydrin according to the method described in the publication: J. Am. Chem. Soc. (1953), 75, 4841; Beilstein, 1, 4 526; or J. Org. Chem. 27, 2901 (1962).

Products of formula (III) in which R ₃ ″ is other than a hydrogen atom can be obtained by exposing a product of formula R ₃ ″ Gal to 2-cyano-2-aminopropane under the conditions described above for exposing R ₃ ″ Gal to products formulas (1V). An example of receiving this type is described in the link: Jilek and employees, Collect, Czech. Chem. Comm., 54 (8), 2248 (1989).

 The products of formula (IV ') are described in French patent N 2329276.

 The products of formulas (V) and (VI) used as starting materials in the method of the invention to obtain products of formulas (I), (Ia), such as those mentioned above, are known and commercially available or can be obtained by methods known to the person skilled in the art .

The preparation of products of formula (VI) is particularly described in the following publications:
- Journal of Applied Chemistry, 28, 969-975 (1955); (CA, 50, 4881a, 1956);
- Tetrahedron, 43, 1753 (1987);
- J. Orq. Chem., 52, 2407 (1987);
- Journal of Organic Chemistry (JOC), 21, 2006 (1985);
- J. Fluor. Chem., 17, 345 (1981);
or in patents:
- German patent 637318 (1935);
- European patent 0130875;
- Japan patent 81.121.524.

The products of formula (VI), which are derivatives of hydantoin, are widely used and described in the literature, as, for example, in the following articles:
- J. Pharm. Pharmacol., 67, vol. 19 (4), pp. 209-216 (1967);
- Chemical Pharmaceutical Journal, 67, v. 1 (5), pp. 51-52;
- German patent 2217914;
- European patent 0.091.596;
- J. Chem. Soc. Perkin. Frans., 1, p. 219-221 (1974).

в которой Z₁, Z₂, R₄, R₅ и Y имеют вышеуказанные значения,
а группу

выбирают среди радикалов

в которых X обозначает атом кислорода или серы, и
R_3i выбирают среди указанных для R₃ значений, включающих защищенную реакционноспособную функцию,
за исключением продуктов, в которых R₄ и R₅, одинаковые или разные, обозначают атом водорода или алкильный радикал с 1-12 атомами углерода, в случае необходимости замещенный одним или несколькими атомами галогена.The subject of the invention are also, as new industrial products, and especially as new industrial products used as intermediates for the preparation of products of formulas (I), (Ia) and cited products, such as those mentioned above, products of formula (IVi):

in which Z ₁ , Z ₂ , R ₄ , R ₅ and Y have the above meanings,
and the group

choose among radicals

in which X represents an oxygen or sulfur atom, and
R _{3i is} selected from the values indicated for R ₃ , including a protected reactive function,
with the exception of products in which R ₄ and R ₅ are the same or different, represent a hydrogen atom or an alkyl radical with 1-12 carbon atoms, optionally substituted with one or more halogen atoms.

Of the reactive functions that can be protected, hydroxyl and amino functions can be mentioned. These functions may be protected as described above for the substituent R ₃ .

 The following examples illustrate the invention without limiting in any way its scope of protection.

Example 1. 2- (Trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile
Stage A: / (Tetrahydro-2H-pyran-2-yl) oxy / propan-2-one
Enter (into the flask) 50 g of hydroxyacetone, 100 cm ^{3 of} methylene chloride and 0.5 g of 1% monohydrated para-toluenesulfonic acid. After that, 62.44 g of 3,4-dihydro-2-4-pyran are added over 5 hours and at 20 ^° C. 2.5 hours after the administration, 0.5 g of para-toluenesulfonic acid is added, then it is stirred for 1.5 hours and 100 cm ^{3 of} saturated sodium bicarbonate water are added. Stirred for 5 minutes at an alkaline pH, then decanted and extracted with methylene chloride, then washed with water, dried organic phases, filtered and brought to dryness. Obtain 101.8 g of the target product (pale yellow oil).

Stage B: 2-amino-2-methyl-3 - / (tetrahydro-2H-pyran-2-yl) hydroxy / propannitrile
77.3 g of potassium cyanide, 178.1 g of aluminum oxide and 70 g of ammonium chloride in 1 l of acetonitrile are stirred using ultrasound for 1 hour, maintaining a temperature of 40 ^o C.

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

 It is filtered off, washed with acetonitrile and dried. It is purified on silica (eluting agent: cyclohex / ethyl acetate in a 1: 1 ratio) and the desired product is recovered (yellow oil).

IR (CHCl ₃ ): (C≡N) 2230; (NH) 3393, 3330 cm ^-1 .

Stage B: 2- (Trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile
a). Condensation of 2- (trifluoromethyl) -4- {5-imino-4-methyl-2-oxo-4 - [/ (tetrahydro-2H-pyran-2-yl) oxy / methyl] -1-imidazolidinyl} benzonitrile
At 20 ^° C. ± 2 ^° C., 12.77 g of the product obtained in the above step B is introduced into 127.7 ml of methylene chloride. Then, after about 1.5 hours, with stirring and at a temperature of -30 ^° C ± 3 ^° C, a pre-filtered solution of 11.4 g of the product obtained in Preparation of Example 7 of European Patent Application No. 0494819 in 171 ml of methylene chloride is added and stirred for about 1 hour at -30 ^o C ± 3 ^o C, then the solvent is evaporated under reduced pressure at 40 ^o C. Obtain 24.7 g of the desired condensation product, used as such, for hydrolysis in methanol.

b) Hydrolysis of 2- (trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile
With stirring and at a temperature of 20 ^° C ± 2 ^° C, 21.3 g of the product obtained above in a) is introduced into 213 ml of methanol. Then over 2 minutes add 67 ml of 2 N. of hydrochloric acid. It is refluxed for 1 hour, after which it is allowed to cool with stirring. It is concentrated by distilling off about 100 ml of methanol, the reaction medium is stirred with a magnetic stirrer for about 1 hour at a temperature of 0 ^o C - (+5) ^o C, then suctioned off.

The obtained crystals are purified, 3 volumes of methanol are added, boiled under reflux for 15 minutes, after which they are left to cool with stirring to a temperature of 20-25 ^° C and suctioned off. Obtain 10.7 g of the target product (white crystals). Mp = 218 ^o C.

Microanalysis:
theoretically calculated,%: C 49.85, N 13.4, F 18.9, H 3.22;
product dried at 60 ^° C: C 49.7, N 13.4, F 18.0, H 3.2.

IR spectrum: complex absorption in the OH / NH region; -C≡N 2230 cm ^-1 ; > = O 1780-1735 cm ^-1 ; aromatic 1604-1575-1503 cm ^-1 .

Example 2. 2- (Trifluoromethyl) -4- (4- (hydroxymethyl) -3,4-dimethyl-2,5-dioxo-1-imidazolidinyl) benzonitrile
1). Obtaining tetrahydropyran ether
626 mg of the product of Example 1, 10 ml of tetrahydrofuran, 30 mg of para-toluenesulfonic acid in the form of monohydrate and 2 ml of dihydropyran are introduced (into the flask). After about 30 minutes, the mixture is poured into 10 ml (solution) of sodium bicarbonate and 1 ml of triethylamine and extracted with chloroform. The organic phase is washed with salt water, dried and the solvent is evaporated. Purify on silica (eluting agent: CH ₂ Cl ₂ , methanol). 830 mg of the desired ether are obtained.

2). Nitrogen Methylation
103 mg of 50% sodium hydride are introduced (into the flask) and in about 40 minutes 830 mg of the ether obtained in paragraph 1) of ether are added in 7 ml of dimethylformamide, then, 10 minutes after the end of the evolution of hydrogen (flask with the reaction mixture) ) is placed in a water bath and 0.18 ml of methyl iodide and 0.5 ml of dimethylformamide are added. After the reaction, the mixture is poured into 40 ml of water containing about 0.5 g of monopotassium phosphate for 30 minutes and extracted with ether, then the organic phase is washed with salt water, dried and the solvent is evaporated off under reduced pressure. Purify on silica (eluting agent CH ₂ Cl ₂ -acetone in a ratio of 95: 5). 770 mg of product is obtained, used as it is, in a subsequent step.

3). Hydrolysis of tetrahydropyran ether
770 mg of the N-methylated ether obtained in paragraph 2) above in 10 ml of methanol, 1.5 ml of 2N are introduced. hydrochloric acid and heated at about 40 ^° C. After 30 minutes, it was brought to room temperature, the mixture was poured into 20 ml of sodium bicarbonate (solution), extracted with chloroform, the extract was washed with salt water, dried and the solvent was evaporated under reduced pressure. Purify on silica (eluting agent CH ₂ Cl ₂ -acetone in a ratio of 3: 1). 111 mg of the crude product obtained above are recrystallized from 5 ml of isopropanol with heating, concentrated to about 1 ml and cooled for 16 hours. The obtained crystals are filtered off, dried and 90 mg of the expected product are obtained (white crystals). Mp = 178 -179 ^o C.

Microanalysis:
calculated,%: C 51.38, H 3.70, F 17.41, N 12.84;
Found,%: C 51.5, H 3.7, F 17.5, N 12.8.

IR (CHCl ₃ ): 3620 cm ^-1 (OH); 1781-1728 cm ^-1 (> = O); 2235 cm ^-1 (C≡N) 1615-1576-1505 cm ^-1 (aromatic);
UV spectrum (ethanol): maximum 262 nm ε = 13900;
shoulder (Infl.) 278 nm ε = 7200;
shoulder (Infl.) 286 nm ε = 3800.

Example 3: 4- (2,5-dioxo-3- (2-fluoroethyl) -4- (hydroxymethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
a). Alkylation with 1,2-bromofluoroethane
104 mg of 5% sodium hydride are introduced (into the flask) and 830 mg of the ether obtained in step 1) of Example 2 and 7.5 ml of dimethyl sulfoxide are added dropwise over 30 minutes. About 20 minutes after the cessation of hydrogen evolution, 0.22 ml of 1,2-bromofluoroethane is immediately added. After proceeding for about 1 hour, the mixture was poured into 5 ml of water containing 500 mg of monopotassium phosphate and extracted with ether. The organic phase is washed with water, then with salt water, dried and the solvent is evaporated off under reduced pressure. Purify on silica (eluting agent CH ₂ Cl ₂ -acetone in the ratio of 97.5: 2.5) and get 743 mg of the target product.

b) Hydrolysis of tetrahydropyran ether
743 mg of the product obtained above in item 1) is introduced (into the flask) in 10 ml of methanol, 1.5 ml of 2N. hydrochloric acid and adjusted to 40 ^o C, then, after 45 minutes, the mixture was poured into 20 ml (solution) of potassium bicarbonate and extracted with chloroform. The organic phase is washed with salt water, dried and the solvent is evaporated off under reduced pressure. It is purified on silica (an eluting agent of CH ₂ Cl ₂ -acetone in a 9: 1 ratio), then the obtained crystals are dissolved in 20 ml of isopropanol at 60 ^° C, filtered off, washed and concentrated to about 5 ml, cooled for about 1 hour and sucked off. Obtain 466 mg of the target product (white crystals). T. pl. = 146-147 ^o C.

Microanalysis:
calculated,%: C 50.15, H 3.65, F 21.15, N 11.70;
Found,%: C 50.1, H 3.50, F 20.9, N 11.7.

2235 см^-1 (C≡N).IR (CHCl ₃ ): 3612 cm ^-1 (OH); 1782 (m) -1727 (f) cm ^-1

2235 cm ^-1 (C≡N).

UV spectrum (ethanol): maximum 260 nm ε = 15500;
shoulder 278 nm ε = 6700;
shoulder 286 nm ε = 3300.

Example 4: 4- (3,4-Dimethyl) -4- (hydroxymethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Stage A: (±) -2-Methyl-2- (methylamino-3 - / (tetrahydro-2H-pyran-2-yl) hydroxy / propannitrile
1.54 g of methylamine hydrochloride is introduced (into the flask) as a solution in 10 cm ^{3 of} water and 3.35 g of the ketone obtained in Step A of Example 1, and the resulting suspension is stirred for about 10 minutes.

A solution of 1.06 g of NaCN in 5 cm ^{3 of} water was poured over 10 minutes, and the mixture was stirred overnight at room temperature.

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

IR (CHCl ₃ ): 3345 cm ^-1 (NH); 2230 cm ^-1 (C≡N).
Stage B: 2- (Trifluoromethyl) -4- {5-imino-3,4-dimethyl-4- [/ (tetrahydro-2H-pyran-2-yl) oxy / methyl] -2-thioxo-1-imidazolidinyl} benzonitrile
2.38 g of aminonitrile are introduced (into the flask) in the form of a solution in 8 cm ^{3 of} 1,2-dichloroethane and 0.5 cm ^{3 of} triethylamine are added, cooled to a temperature of -5 ^o C - 0 ^o C and for 20 minutes at a temperature below A solution of 2.75 g of the isothiocyanate obtained in Preparation of Example 11 of European Patent Application 0494819 is poured at 0 ^° C in 17 cm ^{3 of} 1,2-dichloroethane. The temperature was allowed to rise to room temperature while stirring was maintained for about 2 hours, dried and the solvent was removed under reduced pressure.

After purification on silica (an eluting agent of CH ₂ Cl ₂ acetone in a ratio of 92: 8), 3.31 g of the expected product are obtained.

IR (CHCl ₃ ): 3308 cm ^-1 (> C = NH); 2236 cm ^-1 (C≡N) ;; 1679 cm ^-1 (> C = N); 1614 cm ^-1 (> C = S); 1575, 1505, 1496 cm ^-1 (aromatic).

Stage B: 4- (3,4-Dimethyl) -4- (hydroxymethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
To 3.25 g of the product obtained in the above step B in the form of a solution in 35 cm ^{3 of} methanol, 19 cm ³ 2 N are added dropwise. hydrochloric acid and refluxed for 35 minutes.

It is neutralized with sodium bicarbonate solution, extracted with chloroform, the organic phase is washed with a saturated solution of sodium chloride, dried and the solvent is evaporated off under reduced pressure. After purification on silica (an eluting means of CH ₂ Cl ₂ ethyl acetate in a ratio of 85: 15), then recrystallization from 10 cm ^{3 of} isopropanol gives 1.90 g of the desired product (white crystals). Mp = 167 - 168 ^o C.

Microanalysis:
calculated,%: C 48.98, H 3.52, N 12.24, F 16.60, S 9.34;
Found,%: C 48.9, H 3.6, N 12.1, F 16.7, S 9.1.

IR spectrum (CHCl ₃ ) lack of a band characteristic of C = NH; 3620 cm ^-1 (OH); 1759 cm ^-1 (> C = O); 2238 cm ^-1 (C≡N); 1610-1576-1505-1494 cm ^-1 (aromatic + conjugated system).

Example 5: 1,5-Dimethyl-5- (hydroxymethyl) -3- (4-nitro-3- (trifluoromethyl) phenyl) imidazolidine-2,4-dione
Stage A: The formation of simple tetrahydropyran ether
They proceed according to the procedure of paragraph 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 European patent application 0305270 in 13 ml of tetrahydrofuran using 40 mg of para-toluenesulfonic acid monohydrate and 2.6 ml dihydropyran. After about 15 minutes, the reaction mixture was poured into 10 ml of a saturated solution of sodium bicarbonate and 1 ml of triethylamine and extracted with chloroform. The organic phase is washed with salt water, dried, the solvent is evaporated off under reduced pressure and the residue is purified on silica (eluting with CH ₂ Cl ₂ methanol in a 95: 5 ratio) and the desired product is obtained.

Stage B: Nitrogenation
Do as in paragraph 2) of the above example 2, based on the product obtained above in paragraph 1), and get the target product.

Stage B: Hydrolysis of tetrahydropyran ether
Do as in paragraph 3) of the above example 2, starting from 955 mg of the product obtained in paragraph 2) above, and receive 698 mg of the target product (white crystals). Mp = 153 - 154 ^o C.

Microanalysis:
calculated,%: C 44.96, H 3.48, F 16.41, N 12.10;
Found,%: C 45.0, H 3.50, F 16.3, N 12.1.

IR (CHCl ₃ ): 3620 cm ^-1 (OH); 1782-1727 cm ^-1 (> C = O); 1618-1596-1545-1498 cm ^-1 (aromatic and a strip of NO ₂ ).

UV spectrum (ethanol): shoulder at 214 nm ε = 13000
maximum at 271 nm ε = 6100
shoulder at 320 nm
Example 6: 4- (4- (Fluoromethyl) -3,4-dimethyl-2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
0.2 ml of diethylaminosulfide trifluoride are added to 1 ml of tetrahydrofuran cooled to about -60 ^° C, then a solution of 0.2 g of the product of Example 2 in 6.5 ml of tetrahydrofuran cooled to -60 ^° C is added dropwise.

The temperature is left to rise to room temperature, then heated to 30 ^° C. After 1 hour at this temperature, the mixture is poured into 18 ml of sodium bicarbonate solution and extracted with ether. The organic phase is washed with salt water, dried and the solvents are evaporated off under reduced pressure. The residue is purified on silica (9: 1 CH ₂ Cl ₂ cyclohexane eluting agent), then the resulting crystals are dissolved in 30 ml of isopropanol at 60 ^° C, filtered off, washed with 2 ml of isopropanol, concentrated to a volume of about 5 ml and cool overnight. The crystals are suctioned off, dried and 136 mg of the expected product are obtained (white crystals). Mp = 153 - 154 ^o C.

Microanalysis:
calculated,%: C 51.07, H 3.37, F 23.08, N 12.76;
Found,%: C 50.8, H 3.2, F 25.0, N 12.7.

IR (CHCl ₃ ): 2240 cm ^-1 (C≡N) 1785-1733 cm ^-1 (> C = O); 1616-1575-1505 cm ^-1 (aromatic).

UV spectrum (ethanol): maximum at 259 nm ε = 15200;
shoulder at 278 nm ε = 5800;
shoulder at 286 nm ε = 2900.

Example 7: 4- (3,4-Dimethyl-4- (trifluoromethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
2 cm ^{3 of} anhydrous tetrahydrofuran are cooled to -60 ^° C and 0.88 cm ^{3 of} diethylaminosulfide trifluoride are added dropwise at a temperature between -60 ^° C and (-53) ^° C, then 0.930 g of the product of Example 4 are added in the form solution in 7 cm ³ anhydrous tetrahydrofuran. After returning the temperature to room temperature, it is held for about 30 minutes at a temperature of about 30 ^° C. After this, the reaction mixture is poured into 25 cm ³ of sodium bicarbonate solution with ice. It is extracted with ether, the ether phase is washed with a saturated sodium chloride solution, dried and the solvents are evaporated off under reduced pressure. After purification on silica (an eluting agent of CH ₂ Cl ₂ -cyclohexane in a ratio of 9: 1) and recrystallization from isopropanol, 1.010 g of the expected product (white crystals) are obtained after drying. Mp 163 ^o C.

Microanalysis:
calculated,%: C 48.69, H 3.21, F 22.01, N 12.17, S 9.28;
Found,%: C 48.6, H 3.10, F 22.2, N 12.1, S 9.5.

IR (CHCl ₃ ): lack of a band characteristic of OH; 2238 cm ^-1 (N≡C); 1762 cm ^-1 (> C = O); 1615-1580 cm ^-1 1505-1491 cm ^-1 (conjugated system + aromatic);
UV spectrum (ethanol): maximum at 235 nm ε = 19200;
maximum at 253 nm ε = 23000;
shoulder at 265 nm ε = 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 -50 ^° C and 0.33 ml of diethylaminosulfide trifluoride is added, then 360 mg of the product of Example 3, pre-cooled to about -50 ^° C, are added dropwise in 4 ml of tetrahydrofuran. It is washed with 0.5 ml of tetrahydrofuran and the temperature is allowed to rise to room temperature, then it is brought to about 30 ^° C. Then the mixture is poured into 30 ml of sodium bicarbonate solution with 10 g of ice and extracted with chloroform, the organic phase is then washed with salt water and dried. It is purified on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 99: 1), then the resulting crystals are dissolved in 30 ml of isopropanol at reflux temperature, the resulting solution is washed with 1 ml of isopropanol, concentrated to a volume of about 7 ml and left to stand for 16 hours at 0 ^° C. Suction off, and after drying, 307 mg of the expected product (white crystals) is obtained. Mp = 137 - 138 ^o C.

Microanalysis:
calculated,%: C 49.87, H 3.35, F 26.29, N 11.63;
Found,%: C 49.8, H 3.4, F 26.2, N 11.6.

IR (CHCl ₃ ): 2235 cm ^-1 (C≡N); 1786-1730 cm ^-1 (> = O); 1616-1575-1505 cm ^-1 (aromatic).

UV spectrum (ethanol): maximum at 258 nm ε = 16000;
shoulder at 277 nm ε = 5300;
shoulder at 285 nm ε = 2700.

Example 9: 4- (2,4-dioxo-1,3-diazaspiro (4.4) nonan-3-yl) -2- (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 (into the flask), then they are stirred until they are completely dissolved in an ice bath at a temperature of -8 ^o C. After that, they are added dropwise at a temperature of about -9 ^o C 8 , 8 ml of cyclopentanone, allowed to rise to room temperature and stirred overnight.

After that, the organic phase is decanted, the aqueous phase is extracted with methylene chloride, then the organic phases are washed with salt water and dried. After distillation at 55 ^° C. ± 2 ^° C., 1.2 g of the expected product are obtained.

IR (CHCl ₃ ): 3381-3330 cm ^-1 (NH ₂ ); 2226 cm ^-1 (C≡N); the absence of the band characteristic of C = O.

Stage 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 introduced (into the flask), then adjusted to 0 ^° C. and 3.1 are added over 5 minutes at a temperature of -4 ^° C. ml of the product obtained in Preparation of example 7 of European patent application 0494819, and left to stand until the temperature rises to room temperature.

After the reaction has taken place for about 40 minutes, it is concentrated to dryness, the residue is dissolved in 40 ml of acetone, the solvent is evaporated and the residue is purified on silica (eluting agent CH ₂ Cl ₂ -acetone in a ratio of 90: 10). Obtain 1.24 g of the target product (white crystals). Mp = 212 - 213 ^o C.

IR (vaseline oil): 3350-3280 cm ^-1 (OH / NH); 2240 cm ^-1 (C≡N); 1744 cm ^-1 (> C = O); 1670 cm ^-1 (> = N); 1610-1574-1510 cm ^-1 (aromatic).

Stage B: 4- (2,4-dioxo-1,3-diazaspiro (4,4) nonan-3-yl) - 2- (trifluoromethyl) benzonitrile
Enter (into the flask) 1.17 g of the product obtained in stage B above in 20 ml of methanol, 3 ml of chloroform and 5 ml of 2 N. hydrochloric acid, then heated at a temperature of about 50 ^o C for about 2 hours.

It was brought to room temperature, then the reaction mixture was 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 off under reduced pressure, after which the residue is purified on silica (eluting agent CH ₂ Cl ₂ -acetone in a ratio of 9: 1). Obtain 1.108 g of the target product (white crystals). Mp = 184 - 185 ^o C.

Microanalysis:
calculated,%: C 55.73, H 3.74, F 17.63, N 13.00;
Found,%: C 55.6, H 3.7, F 17.4, N 12.8.

IR (CHCl ₃ ): 3444 cm ^-1 (= C-NH); 2236 cm ^-1 (C≡N); 1786-1731 cm ^-1 (> = O); 1616-1505 cm ^-1 (aromatic).

UV spectrum (ethanol): maximum at 258 nm ε = 15600,
shoulder at 286 nm ε = 3500.

Example 10: 4- (2,4-dioxo-1- (2-fluoroethyl) -1,3-diazaspiro (4,4) nonan-3-yl) -2- (trifluoromethyl) benzonitrile
To 0.050 g of 50% sodium hydride in oil, 0.323 g of the product of Example 9 are added dropwise in about 20 minutes in the form of a solution in 2.5 cm ^{3 of} dimethyl sulfoxide. Stirred for about 1 hour 20 minutes, then 0.09 cm ^{3 of} 1-bromo-2-fluoroethane was added dropwise in the form of a solution in 0.2 cm ^{3 of} dimethyl sulfoxide. After keeping about 2 hours at room temperature, it is heated at 30-35 ^° C for 10 minutes, after which the reaction mixture is poured into 12 cm ^{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. The residue was purified on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 99: 1) and 0.249 mg of the expected product was obtained. Mp = 115 ^o C.

Microanalysis:
calculated,%: C 55.29, H 4.09, F 20.58, N 11.38;
Found,%: C 55.3, H 4.1, F 20.25, N 11.3.

IR (CHCl ₃ ): 2238 cm ^-1 (-C≡N); 1776-1723 cm ^-1 (-C = O); 1616-1575-1505 cm ^-1 (aromatic).

UV spectrum (ethanol): maximum at 260 nm ε = 15600;
shoulder at 287 nm
Example 11: 1,5-Dimethyl-5- (fluoromethyl) -3- (4-nitro-3- (trifluoromethyl) -phenyl) imide-azolidine-2,4-dione
Administered (in a flask) 1 ml of tetrahydrofuran, cooled to about -60 ^o C, is added 0.09 ml dietilaminosulfid trifluoride was added dropwise and cooled to about -60 ^o C solution of 210 mg of Example 5 in 2.5 ml of tetrahydrofuran. The mixture was washed with 0.5 ml of tetrahydrofuran, the temperature was allowed to rise to room temperature, the temperature was adjusted to about -60 ^° C and 0.1 ml of diethylaminosulfide trifluoride was added.

After 1 hour 20 minutes, the reaction mixture was poured into 8 ml of sodium bicarbonate solution and extracted with ether. The organic phase is washed with salt water, dried, the solvent is evaporated off under reduced pressure and the residue is purified on silica using CH ₂ Cl ₂ -acetone (99: 1) as an eluting agent. 152 mg of the expected product is obtained (white crystals). Mp = 118-119 ^o C.

Microanalysis:
calculated,%: C 44.71, H 3.17, F 21.76, N 12.03;
Found,%: C 44.9, H 3.1, F 21.42, N 11.9.

; 1618-1597-1546-1498 см^-1 (ароматические).IR (CHCl ₃ ): 1786-1732 cm ^-1

; 1618-1597-1546-1498 cm ^-1 (aromatic).

UV spectrum (ethanol): shoulder at 214 nm ε = 13400
maximum at 267 nm ε = 6200
shoulder at 320 nm
Example 12: 4- (4,4-Dimethyl-2,5-dioxo-3- (2- (2-hydroxyethoxy) ethyl) -1-imidazolidinyl-2- (trifluoromethyl) benzonitrile
Stage 1: 4- (4,4-dimethyl-2,5-dioxo-3- / 2 - (/ (1,1-dimethylethyl) dimethylsilyl / oxy) ethoxy / ethyl-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile
0.101 g of 50% sodium hydride in oil is introduced (into the flask) and a solution of 0.594 g of the product of Example 8 of European Patent 0494819 in 4.5 ml of dimethyl sulfoxide is added dropwise and stirred for 30 minutes after the hydrogen evolution ceases.

 A solution of 0.594 g of (2- / 2-bromoethoxy / ethoxy) dimethyl- (1,1-dimethylsilyl) silane in 1 ml of dimethyl sulfoxide is added dropwise over 5 minutes.

It is stirred for one hour at room temperature, then 0.056 g of (2- / 2-bromoethoxy / ethoxy) -dimethyl- (1,1-dimethylethyl) silane is added and incubated for 2.5 hours at a temperature of 30-40 ^o C.

 The reaction mixture was poured into a solution of 0.6 g of monosodium phosphate in 30 ml of ice water and extracted with ether. The ether phase was washed with a NaCl solution, dried and the solvent was evaporated. After chromatography on silica (eluting agent: methylene chloride / ethyl acetate in a ratio of 99: 1), 0.776 g of the expected product (oil) is isolated.

1616-1577-1505 (ароматические).IR spectrum (CHCl ₃ ), cm ^-1 : lack of a band characteristic of = C-NH; 2235 (-CN); 1778-1724 (> C = O); 838

1616-1577-1505 (aromatic).

Stage 2: 4- (4,4-Dimethyl-2,5-dioxo-3- (2- / 2-hydroxyethoxy / ethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
0.759 g of the product obtained in stage 1 above, dissolved in 7.5 ml of methanol, is introduced (into the flask) and 2 ml of 2 N are added dropwise. of hydrochloric acid.

It is stirred for 40 minutes at room temperature, poured into ice water and extracted with chloroform. The organic phase is washed with sodium chloride solution and dried; the solvent is evaporated, the residue is chromatographed on silica (9: 1 methylene chloride / acetone elution), 0.549 g of the expected product is isolated. Mp <60 ^o C.

IR (CHCl ₃ ) cm ^-1 ; about 3610-3620 (complex-OH); 2235 (-CN); 1779-1725 (> C = O); 1616-1575-1505 (aromatic).

Example 13: 4- (4,4-Dimethyl) -2,5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
104 ml of 50% sodium hydride are introduced (into the flask), a solution of 600 mg of the product of example 8 of European patent application 0494819 in 5 ml of dimethylformamide is added dropwise in about 20 minutes. It is washed with 0.5 ml of dimethylformamide and after stopping the evolution of hydrogen, 0.16 ml of 1-bromo-2-fluoroethane is added. Then add 98 ml of 50% sodium hydride, then, after about 10 minutes, add 0.1 ml of 1-bromo-2-fluoroethane and heat at 50 ^o C. The reaction mixture is brought to room temperature, poured into 20 ml of water, containing 200 mg of monopotassium phosphate, and extracted with ether. The organic phase is washed with water, then with salt water, dried, the solvent is evaporated off under reduced pressure, the residue is dissolved in 20 ml of acetone and purified on silica (eluting agent CH ₂ Cl ₂ ethyl acetate in a ratio of 99: 1). Get 200 mg of the target product (white crystals). Mp = 108-109 ^o C.

Microanalysis:
calculated,%: C 52.48, H 3.82, F 22.14, N 12.24;
Found,%: C 52.4, H 3.7, F 22.0, N 12.4.

IR (CHCl ₃ ), cm ^-1 : 2236 (C≡N); 1780-1728 (> C = O); (1618-1580-1504 (aromatic).

Example 14: 4- (4,4-Dimethyl-2,5-dioxo-3- (2,2,2 trifluoroethyl) - 1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Introduce (into the flask) 0.125 g of 50% sodium hydride in oil and within 20 minutes a solution of 0.742 g of the product of example 8 of European patent application 0494819 in 7.5 cm ^{3 of} dimethyl sulfoxide and washed with 1 cm ^{3 of} dimethyl sulfoxide. At the end of the evolution of hydrogen, they are kept under stirring for about 20 minutes and 0.5 cm ^{3 of} iodotrifluoromethane are added and 0.5 cm ^{3 of} ether 15-crown-5 is added. It is kept for 16 hours at 60 ^° C. After adding 0.25 cm ^{3 of} iodotrifluoromethane, heating is continued for approximately 19 hours at 80 ^° C. After this, the mixture is poured into 30 ml of water containing 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. The residue was purified on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 99: 1), then recrystallized from 10 cm ^{3 of} isopropanol and 0.262 g of the expected product was obtained (white crystals). Mp = 110 ^o C.

Microanalysis:
calculated,%: C 47.5, H 2.92, F 30.05, N 11.08;
found,%. C 47.3, H 2.8, F 30.0, N 11.0.

IR spectrum (CHCl ₃ ), cm ^-1 : lack of a band characteristic of NH; 1790-1732 (> C = O); 1616-1578-1505 (aromatic); 2235 (C≡N);
UV spectrum (ethanol): maximum at 255 nm ε = 16400
shoulder at 276 nm ε = 4400
shoulder at 285 nm ε = 2400
Example 15: 4- (4,4-Dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxo-3-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Stage 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-methyl-propannitrile and 0.55 cm ^{3 of} triethylamine in 12 cm ^{3 of} 1,2-dichloroethane are added. The mixture is cooled to 0 ^o C and for about 25 minutes at about 0 ^o C solution was poured 2.97 g of the isothiocyanate prepared as described in Preparation Example 11 of European Patent Application 0,494,819, in 22 cm ³ of 1,2-dichloroethane. Stirring was continued for 7 hours at room temperature, then the solvent was evaporated under reduced pressure. The residue was purified on silica (eluting with CH ₂ Cl ₂ acetone in a ratio of 95: 5, then 97: 3), treated with several cm ^{3 of} ether, suctioned off, dried, and 1.84 g of the expected product was obtained. T. pl. = 160 ^o C.

IR (CHCl ₃ ), cm ^-1 : 3308 (C = NH); 2236 (C≡N); 1677 and 1604 + 1576-1504 (conjugated system + aromatic).

Stage B: 4- (4,4-Dimethyl-3- (2-fluoroethyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
6.9 cm ³ of 2N are added dropwise to a solution of 1.65 g of the product obtained in stage A above in 60 cm ^{3 of} methanol. of hydrochloric acid. After about 1.5 hours at 50 ^° C., the reaction mixture was neutralized with sodium bicarbonate and the methanol was distilled off. It is treated with water, extracted with ether, the ether phase is washed with a solution of sodium chloride and dried. After purification on silica with CH ₂ Cl ₂ as an eluting agent and recrystallization from 15 cm ^{3 of} isopropanol, 2.99 g of the expected product are obtained (white crystals). Mp = 135 ^o C.

Microanalysis:
calculated,%: C 50.14, H 3.65, F 21.15, N 11.69, S 8.92;
Found,%: C 50.1, H 3.60, F 21.0, N 11.7, S 9.2.

1610 и 1576 + 1504 (конъюгированная система + ароматические).IR spectrum (CHCl ₃ ), cm ^-1 : lack of a band characteristic of = C-NH; 1758 (> C = O); 2236

1610 and 1576 + 1504 (conjugated system + aromatic).

UV spectrum (ethanol): maximum at 233 nm ε = 17700
maximum at 253 nm ε = 21600
Example 16: 3- (4-Cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (hydroxymethyl) -5-methyl-1-imidazolidine-acetonitrile
Do as in example 2, starting from the product of example 1, but replacing in paragraph 2) of example 2 methyl iodide with cyanomethyl bromide, and thus obtain the target product. Mp = 171 ^o C.

Example 17: 3- (4-Cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-1- imidazolidine-acetonitrile
They proceed according to the preparation procedure of Example 6, replacing the product of Example 2 with the product of Example 16 there, and thus the desired product is obtained. Mp = 175 ^o C.

Example 18: (±) -4- {2-oxo-5-imino - / [(4-fluorophenyl) thio] methyl / -4-methyl-1-imidazolidinyl} -2- (trifluoromethyl) benzonitrile
Stage A: (±) -3 - / (4-fluorophenyl) thio / -2-amino-2-methyl-propannitrile
A solution of 4.81 g of ammonium chloride in 12 ml of water and 24.6 ml of ammonia (25 ^° Bome) is successively added to 2.21 g of sodium cyanide in 45 ml of water, then a solution of 8.32 g of 1- (4-fluorophenylthio) propane -2-one, obtained as described in patent 8246399 E, in 21 ml of 96.2% ethanol. Incubated at 60 ^o C and stirred for about 22 hours. It is cooled to a temperature of 0 ^° C. to 4 ^° C., washed with ethanol, distilled, decanted, the aqueous phase is extracted with CH ₂ Cl ₂ , the extract is washed with saturated sodium chloride solution, dried and the solvent is evaporated off under reduced pressure. The residue was purified by chromatography on silica using a mixture of cyclohexane and ethyl acetate (50:50) as an eluting agent to obtain 14.50 g of the expected product.

IR (CHCl ₃ ), cm ^-1 : 3382-3327 (NM absorption); 1591-1491 (aromatic); 2228 (-C≡N).
Stage B: (±) 4- {2-Oxo-5-imino [/ (4-fluorophenyl) thio / methyl] -4-methyl-1-imidazolidinyl} - 2- (trifluoromethyl) benzonitrile
Introduce (into the flask) 9.8 g of the product obtained in stage A above, 35 ml of 1,2-dichloroethane and add 0.2 ml of triethylamine. It is cooled to 5 ^° C. and a solution of 7.7 g of the product obtained in Preparation of Example 7 of European Patent Application 0494819 in 40 ml of 1,2-dichloroethane is added for 12 minutes at a temperature of 5-10 ^° C. Washed with 5 ml of dichloroethane and left at room temperature for 16 hours. The solvent is evaporated under reduced pressure, the residue is purified on silica (eluting with CH ₂ Cl ₂ -acetone in a ratio of 93: 7), then dissolved in 100 ml of isopropanol at about 60 ^° C, filtered off, washed with 20 ml of heated isopropanol, concentrated , cooled for about 3 hours, suctioned off, washed with cold isopropanol and dried. Obtain 2.815 g of the target product (white crystals). Mp = 150 ^o C.

Microanalysis:
calculated,%: C 54.03, H 3.34, F 17.99, N 13.26, S 7.59;
Found,%: C 54.1, H 3.30, F 17.9, N 13.1, S 7.7.

IR (CHCl ₃ ), cm ^-1 : 1756 (> C = O); 1669 (C = N); 3444 (NH); 1614-1591-1505-1491 (aromatic); C≡N is present.

Example 19: 4- {2,5-dioxo-4 - [/ (4-fluorophenyl) thio / methyl] -4-methyl-1-imidazolidinyl} -2-trifluoromethyl-benzonitrile
3.95 g of the product obtained in Example 18 are introduced (into a flask), 14 ml of hydrochloric acid (22 ^° Bome) and 14 ml of water, and the suspension is refluxed.

After 1.5 hours, the reaction mixture was returned to room temperature, poured onto ice with water in an amount of 100 g (1: 1) and extracted with ethyl acetate. The organic phase is washed with water, then with a saturated sodium bicarbonate solution, finally with a saturated sodium chloride solution, and the solvent is evaporated. The residue was purified by chromatography on silica (eluting with CH ₂ Cl ₂ acetone in a ratio of 95: 5). It is treated with 50 ml of 100% ethanol at a temperature of 50 ^o C, filtered off, washed with 5 ml of heated ethanol, concentrated and left for 16 hours in a refrigerator at a temperature of about 0 ^o C - 4 ^o C. Then it is suctioned off, washed with chilled ethanol and dried. Obtain 3.55 g of the target product (white crystals). Mp = 153 ^o C.

Microanalysis:
calculated,%: C 53.9, H 3.09, F 17.95, N 9.92, S 7.57;
Found,%: C 53.9, H 3.1, F 18.3, N 9.8, S 7.8.

IR (CHCl ₃ ), cm ^-1 : 1791-1734 (C = O); 3439 (NH); 2236 (C = N); 1615-1591-1505-1492 (aromatic).

Example 20: 4- (2,5-dioxo-3- (2-fluoroethyl) -4 - / (4-fluorophenyl) thiomethyl / -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
To 0.031 g of a 50% strength sodium hydride oil, a solution of 0.254 g of the product obtained as in Example 19 in 2.2 cm ^{3 of} dimethyl sulfoxide is added dropwise. Stirring is maintained for approximately 40 minutes. Then, a solution of 0.54 cm ^{3 of} 1-bromo-2-fluoroethane in 0.7 cm ^{3 of} dimethyl sulfoxide is added dropwise in about 5 minutes.

After stirring for 30 minutes, the mixture was poured into a mixture of ice water containing 0.4 g of monosodium phosphate. It is extracted with ether, the organic phase is washed with a saturated solution of sodium chloride, dried and the solvent is evaporated off under reduced pressure. After purification on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 100: 0.5), then recrystallization from 15 cm ^{3 of} isopropanol gives 0.175 g of the expected product (white crystals). Mp = 155 ^o C.

Microanalysis:
calculated,%: C 53.73, H 3.43, F 20.23, N 8.95, S 6.83;
found,%; C 53.5, H 3.2, F 20.5, N 9.0, S 7.1.

IR spectrum (CHCl ₃ ), cm ^-1 : lack of a band characteristic of = C-NH; 2235 (C≡N); 1780-1727 (> C = O); 1616-1591-1505-1492 (aromatic).

UV spectrum (ethanol): maximum at 255 nm ε = 18600
shoulder at 278 nm ε = 8000
shoulder at 287 nm ε = 4400
Example 21: 4- (4,4-Bis (hydroxymethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Stage A: 2- (Methylamino) -2 - [/ (tetrahydro-2H-pyran-2-yl) oxy / - methyl] -3 - / (tetrahydro-2H-pyran-2-yl) oxy / propanenitrile
Enter (into the flask) 2.7 g of 1,3-bis / (tetrahydro-2H-pyran-2-yl) oxy / propan-2-one, prepared as follows, 5 ml of water and 0.77 g of methylamine hydrochloride, then 503 mg of sodium cyanide and 3 ml of water are added over 5 minutes. After 2.5 hours of the reaction time, it is extracted with methylene chloride, the organic phase is washed with salt water, the solvent is evaporated off under reduced pressure. Obtain 3.3 g of the target product, used as it is, in the next stage.

IR (CHCl ₃ ), cm ^-1 : 3346 (NH); 2230 (Χ≡N); 1732 (> C = O).

 Preparation of 1,3-bis - / (tetrahydro-2H-pyran-2-yl) oxy / -2-propan-2-one, used as starting material of Example 21.

At 70 ^° C., 9 g of dimeric 1,3-dihydroxyacetone are heated in suspension in 60 ml of dioxane and brought to room temperature. Add 20 ml of 3,4-dihydro-2,4-pyran, then 300 mg of p-toluenesulfonic acid monohydrate, keeping the temperature below 40 ^o C. Hold for 16 hours with stirring, pour into 300 ml of saturated sodium bicarbonate solution, wash the organic phase salt water, dried and the solvent was evaporated under reduced pressure. After chromatography of the residue on silica (eluent cyclohexane-ethyl acetate-triethylamine in a ratio of 8: 2: 0.5), 17 g of the expected product are obtained. R _f = 0.2.

Stage B: 2- (Trifluoromethyl) -4- {4,4-bis [/ (tetrahydro-2H-pyran-2-yl) oxy / methyl] -5-imino-3-methyl-2-thioxo-2-imidazolidinyl } -benzonitrile
2.39 g of the isothiocyanate obtained in the Preparation of Example 11 of European Patent Application 0494819 and 10 ml of 1,2-dichloroethane are introduced (into the flask). Then, to a solution cooled to +5 ^° C, a solution of 3.2 g of the product obtained in Step A above, 0.4 ml of triethylamine and 10 ml of 1,2-dichloroethane is added dropwise. After about 1 hour and 20 minutes of heating, the solvent is evaporated and the residue is purified on silica (eluting means ethyl acetate-cyclohexane in a ratio of 7: 3). 3.82 g of the expected product is obtained.

IR (CHCl ₃ ), cm ^-1 : 3314 (> C = NH); 2230 (C≡N); 1678-1670-1876 (C = N); 1505-1495 (C = S; aromatic).

Stage B: 4- (4,4-Bis (hydroxymethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
3.8 g of the product obtained in step B above are introduced into 38 ml of methanol and 19 ml of 2N. hydrochloric acid, then refluxed. After about 2 hours, the reaction mixture was poured into 200 ml of water and extracted with ether, then ethyl acetate. The organic phases are combined and washed with water containing sodium chloride, then the solvent is evaporated. The residue was purified on silica (an eluting agent of CH ₂ Cl ₂ methanol in a 95: 5 ratio), then dissolved in 30 ml of diisopropyl ether at reflux temperature, filtered and partially concentrated. It is cooled for about 1 hour and the product is sucked off. Obtain 282 mg of the target product (white crystals). Mp = 169-170 ^o C.

Microanalysis:
calculated,%: C 46.80, H 3.37, F 15.86, N 11.69, S 8.92,
Found,%: C 46.8, H 3.3, F 15.9, N 11.5, S 9.0.

IR (vaseline oil), cm ^-1 : 3410-3385 (OH / NH); 2240 (C≡N); 1720 (C = O); 1608-1580-1568 (aromatic).

UV spectrum (ethanol): maximum at 234 nm ε = 17600
maximum at 256 nm ε = 23200
Example 22: 4- (4,4-Bis (1-oxo-propoxymethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
200 mg of the product of Example 21 are introduced in 2 ml of pyridine and 25 mg of 4-dimethylamino-pyridine, then 16 ml of propionic anhydride are added. After reacting for 25 minutes, the reaction mixture was poured into 20 ml of sodium bicarbonate solution and extracted with methylene chloride, the organic phase was washed with salt water (an aqueous solution of sodium chloride), dried, the solvent was evaporated and the residue was distilled 3 times with 30 ml of toluene. Purify on silica (eluting agent CH ₂ Cl ₂ ), then crystallize from ether and obtain 239 mg of the desired product (white crystals). Mp = 117-118 ^o C.

Microanalysis:
calculated,%: C 50.95, H 4.27, F 12.09, N 8.91, S 6.80,
found,%; C 51.2, H 4.5, F 12.1, N 8.8, S 6.9.

IR (CHCl ₃ ), cm ^-1 : 1755-1762 (> C = O); 2235 (C≡N); 1615-1580-1504-1488 (aromatic and C = S).

UV spectrum (ethanol): shoulder at 236 nm ε = 18800
maximum at 253 nm ε = 22600
shoulder at 265 nm ε = 18200
Example 23: 4- (4,4-Bis (fluoromethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
1 ml of tetrahydrofuran is cooled to -50 ^° C and 0.66 ml of diethylamine sulfide trifluoride is added, then a solution of 360 mg of the product of Example 21 in 4 ml of tetrahydrofuran cooled to a temperature of about -50 ^° C is added dropwise. Heated at a temperature of about 30 ^o C.

After about 30 minutes, the reaction mixture was poured dropwise into 50 ml of an aqueous saturated sodium bicarbonate solution, extracted with chloroform, the organic phase was washed with salt water (an aqueous solution of sodium chloride) and the solvent was evaporated. The residue was purified on silica using a mixture of CH ₂ Cl ₂ with cyclohexane (9: 1) as an eluting agent, then dissolved in 20 ml of isopropanol at a temperature of about 60 ^o C. It was filtered off, washed with 1 ml of isopropanol and concentrated, cooled in within 1 hour and the product is sucked off. Obtain 314 mg of the target product (white crystals). Mp = 122-123 ^o C.

Microanalysis:
calculated,%: C 46.28, H 2.77, F 26.15, N 11.56, S 8.82,
Found,%: C 46.3, H 2.7, F 25.7, N 11.25, S 8.8.

IR (CHCl ₃ ), cm ^-1 : 2236 (C≡N); 1763 (C = O); 1615-1580-1504-1487 (aromatic).

UV spectrum (ethanol): shoulder at 247 nm ε = 20300
maximum at 250 nm ε = 22000
shoulder at 266 nm ε = 17100
Example 24: 4- (4,4-Bis (hydroxymethyl) -3-methyl-2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
1) The formation of simple tetrahydropyran ethers
360 mg of the product of Example 21 are introduced (into the flask) in 5 ml of tetrahydrofuran, 1 ml of 3,4-dihydro-2H-pyran and 15 mg of p-toluenesulfonic acid monohydrate. After about 40 minutes, 10 ml of an aqueous saturated sodium bicarbonate solution and 1 ml of triethylamine are poured, extracted with chloroform, washed with salt water, dried and the solvent is evaporated.

The residue was purified on silica (an eluting agent of CH ₂ Cl ₂ methanol in a ratio of 93: 7) to obtain 600 mg of the expected product, which is used as such in the next step.

2) Transition to hydantoin
600 mg of diester obtained in paragraph 1) are introduced into 4 ml of dimethylformamide and 55 mg of 50% sodium hydride are added, then, after the evolution of hydrogen has ceased, 0.09 ml of methyl iodide. After about 40 minutes, 110 mg of 50% sodium hydride are successively added, then, after 10 minutes, 0.18 ml of methyl iodide. The reaction mixture was poured into 10 ml of cold water containing 1.3 g of monopotassium phosphate and extracted with ether. The organic phase is washed with an aqueous solution of sodium chloride, dried and the solvent is evaporated. The residue was purified on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 92.5: 7.5) to obtain 370 mg of the expected product, which is used as such in the next step.

3). Removal of protecting groups from pyran ethers
370 mg of the product obtained above in item 2) is introduced into 4 ml of methanol and 2 ml of 2 N. hydrochloric acid, then the solution is kept at 60 ^o C for about 2 hours.

Then it is poured into 15 ml of an aqueous solution of sodium chloride, dried, the solvent is evaporated, then the residue is dissolved in 20 ml of acetone and evaporated to dryness. The residue was purified on silica (eluting with CH ₂ Cl ₂ methanol in a ratio of 92.5: 7.5), then recrystallized from acetone to give 197 mg of the expected product (white crystals). Mp = 217-218 ^o C.

UV spectrum (ethanol): maximum at 263 nm ε = 14600
shoulder at 237, 278, 287 nm
Example 25: 4- (4,4-Bis- (hydroxymethyl) -3-methyl-5-imino-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Do as in example 21 and in stage b. Preparation of example 21 receive 421 mg of the target product.

IR spectrum, cm ^-1 : 2230 (C≡N); 1680-1614-1580-1510 (C = N, C = S, aromatic).

Example 26: 4- (4,4-Bis- (hydroxymethyl) -2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Stage 1: 1,3-Bis - / (tetrahydro-2H-pyran-2-yl) oxy / propan-2-one
9 g of 2,5-dihydroxy-1,4-dioxane-2,5-dimethanol in 60 ml of dioxane are introduced and the suspension is heated for 15 minutes at 70 ^° C, then brought to room temperature. After that, 20 ml of 3,4-dihydro-2H-pyran and 300 mg of p-toluenesulfonic acid monohydrate are added and the temperature is maintained at about 40 ^° C., then left at room temperature for 16 hours.

 Then the reaction mixture was poured into a mixture of 300 ml of a saturated solution of sodium bicarbonate + 10 ml of triethylamine and extracted with methylene chloride. The organic phase is washed with salt water, dried and the solvent is evaporated. After chromatography on silica (an eluting means of ethyl acetate-triethylamine in a ratio of 8: 2), 17 g of the expected product (pale yellow syrup) are obtained.

IR spectrum (CHCl ₃ ), cm ^-1 : lack of a band characteristic of OH; 1736 (O = C).

Stage 2: 2-amino-3 - / (tetrahydro-2H-pyran-2-yl) oxy / -2- [/ (tetrahydro-2H-pyran-2-yl) oxy / methyl] propannitrile
5.6 g of the product obtained in stage 1 above is introduced into 8 ml of ammonia, adjusted to a temperature of about -5 ^° and 1.58 g of ammonium chloride and 1.23 g of sodium cyanide are added successively and the temperature is left to rise to room temperature over about 40 minutes , then heated for 16 hours and with stirring at a temperature of 40 ^o C ± 5 ^o C the organic phase is washed with salt water, dried and the solvent is evaporated.

 After chromatography on silica (eluting with ethyl acetate-triethylamine 3: 7), 4.41 g of the expected product (pale yellow syrup) are obtained.

IR (CHCl ₃ ) cm ^-1 : 2235 (-CN); 3390-3317 (NH ₂ ).

Stage 3: 4- (5-Imino-2-oxo-4,4-bis - [/ (tetrahydro-2H-pyran-2-yl) oxy / methyl] -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
570 mg of the product obtained in stage 2 above, is introduced into 5 ml of diisopropyl ether and 0.28 ml of triethylamine and brought to a temperature of -30 ^o C, then 2.32 g of an 18.4% solution of the product obtained are added over an hour. in the Preparation of example 7 of European patent application 0494819, in 1,2-dichloroethane.

 4 ml of methylene chloride are added, then the temperature is allowed to rise to room temperature, maintained for about 2 hours and the solvent is evaporated. After purification on silica (eluting agent methylene chloride-acetone in a ratio of 9: 1), 700 mg of the expected product are obtained.

IR (CHCl ₃ ): cm ^-1 : 3442-3317 (NH); 2235 (-CN), 1757 (C = O); 1670 (C = N); 1614-1575-1505 (aromatic).

Stage 4: 4- (4,4-Bis- (hydroxymethyl) -2,5-dioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
300 mg of the product obtained in stage 3 above, is introduced into 3 ml of methanol and 1.5 ml of 2 N. hydrochloric acid and refluxed for 1.5 hours. The temperature was brought to room temperature, poured into an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, then washed with an aqueous solution of sodium chloride, dried and the solvent was evaporated. 5 ml of methanol is added and purified on silica (methylene chloride-methanol eluting agent in a 9: 1 ratio).

It is treated in 20 ml of isopropanol at the boiling temperature under reflux, then concentrated and 225 mg of the expected product are obtained (white crystals). Mp = 207-208 ^o C.

IR (vaseline oil), cm ^-1 : 3525-3365-3250 (OH / NH); 2240 (CN); 1778-1738 (C = O); 1618-1578-1506 (aromatic).

Example 27: 4- (4,4-Bis- (fluoromethyl) -2,5-dioxo-3-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Proceed according to the procedure of example 23, using 120 mg of the product obtained in example 24. After chromatography on silica (an eluting agent of CH ₂ Cl ₂ ethyl acetate in a ratio of 99: 1), 111 mg of the expected product is obtained. Mp = 137-138 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2235 (C≡N); 1790-1735 (C = O); 1617-1580-1505 (aromatic).

Example 28: 4- (2,5-dioxo-3-ethyl-4- (hydroxymethyl) -4-methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Proceed according to the procedure of example 2, stages 2 and 3, using 1.033 g of tetrahydropyran ether prepared in stage 1 and 0.24 ml of ethyl iodide. After chromatography on silica (eluting with methylene chloride-ethyl acetate), 0.796 g of the expected product is obtained, which is recrystallized from isopropanol. Mp = 138 ^o C.

IR (CHCl ₃ ), cm ^-1 : 3616 (OH); 2236 (C≡N); 1779 (m) -1725 (F) (C = O); 1617-1506 (aromatic).

Example 29: 3- (2,5-dioxo-3-ethyl-4-methyl-4- (2-methyl-1-oxopropoxy) methyl-1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
Do as in example 22, using 280 mg of the product obtained in example 28, 2.5 ml of pyridine, 23 mg of dimethylaminopyridine and 0.16 ml of isobutyric anhydride. After extraction with ether, removal of solvents and chromatography on silica (eluting means methylene chloride-ethyl acetate in a ratio of 100: 1), 321 mg of the expected product are obtained. Mp = 85 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2235 (C≡N); 1781 (m) -1728 (F) (C = O); 1615-1575-1505 (aromatic).

Example 30: Methyl- and 1-methylethyl- (1- (4-cyano-3- (trifluoromethyl) phenyl) - 2,5-dioxo-3-ethyl-4-methyl-4-imidazolidinyl) carbonate
Do as in example 22, using 376 mg of the product obtained in example 28, 3.8 ml of pyridine, 25 mg of dimethylaminopyridine, 2.2 ml of isopropylchloroformate toluene solution (1 mol / l) is added at 0 ^° C. After stirring for 30 minutes at 0 ^° C., then for 3 hours at room temperature, 0.4 ml of isopropyl chloroformate solution was added and stirring was continued at room temperature for 2.5 hours. It is poured into 20 g of cold (ice) water, extracted with ether, the organic solution is washed with salt water, dried and the solvents are removed under reduced pressure. It is treated with toluene, concentrated to dryness, the resulting oil is allowed to crystallize and 422 mg of crude product are obtained, which is chromatographed on silica (eluting with methylene chloride-ethyl acetate in a ratio of 100: 2). 270 mg of expected product is obtained. Mp = 123 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2235 (C≡N); 1782-1744-1729 (C = O); 1616-1578-1505 (aromatic).

Example 31: 4- (4,4-Bis- (hydroxymethyl) -2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
1). The formation of tetrahydropyran ethers
Do as in example 24, stage 1, using 331 mg obtained in example 26 product. Extracted with methylene chloride, washed with salt water, the solvent is evaporated and obtained after chromatography on silica (elution means CHCl _3- methanol in a ratio of 9: 1), 500 mg of the target product, used as it is, in the next step.

2). Hydroxyalkylation
456 mg of the above-obtained diester in 3 ml of dimethyl sulfoxide are added dropwise to 52 mg of sodium hydride over 20 minutes, then, 20 minutes after the cessation of hydrogen evolution, 374 mg of trimethylsilyl-4-iodobutanol is added. After proceeding for 40 minutes, the reaction mixture was poured into 20 ml of water, extracted with ether, the organic phase was washed with salt water, dried and the solvent was evaporated. 650 mg of crude product are obtained, which product is used as it is in the next step.

3). Hydrolysis of Protecting Groups
650 mg of the product obtained above are introduced into 7 ml of methanol and 3 ml of 2 N. hydrochloric acid, then for about 40 minutes the solution was kept at 40 ^o C. The mixture was poured into 20 ml of an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with salt water, dried, the solvent was evaporated. The residue is purified on silica (an eluting agent of CH ₂ Cl ₂ methanol in a ratio of 9: 1) and 950 mg of the expected product is obtained.

UV spectrum (ethanol): maximum at 237 nm ε = 8600
maximum at 263 nm ε = 14000
shoulder at 278 nm ε = 8400
shoulder at 287 nm ε = 4200
Example 32: 4- (4,4-Bis- (hydroxymethyl) -2,5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
1). Fluoroalkylation
Do as in example 3, stage a), using as the starting compound 5 g of a simple tetrahydropyran diester obtained as described in example 31, stage 1), and 1.1 ml of 2-bromo-1-fluoroethane. 5.31 g of the expected product is obtained.

2). Hydrolysis of tetrahydropyran ether
Do as in example 3, stage b), using as starting material 550 mg of the product obtained above, 6 ml of methanol and 2 ml of 2 N. of hydrochloric acid. After chromatography on silica (an eluting agent of CH ₂ Cl ₂ acetone in a ratio of 8: 2), 351 mg of the expected product are obtained. Mp = 138-139 ^o C.

IR (vaseline oil), cm ^-1 : 3580-3505 (OH / NH); 2245 (C≡N); 1778-1716 (C = O); 1616-1580-1512 (aromatic).

UV spectrum (ethanol): maximum at 260 nm ε = 15300
shoulder at 280 nm ε = 3400
Example 33: 4- (4,4-Bis- (fluoromethyl) -2,5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
1 ml of tetrahydrofuran in an inert atmosphere is cooled to -50 ^° C and 0.66 ml of diethylaminosulfide trifluoride is added dropwise, then 375 ml of the product obtained in Example 32 are added in 4 ml of tetrahydrofuran. The temperature is allowed to rise to room temperature, kept under stirring for an hour, poured into an aqueous cold sodium bicarbonate solution, extracted with chloroform, the organic phase is washed with salt water, dried, the solvent is evaporated and the residue is chromatographed on silica (eluting with CH ₂ Cl ₂ -cyclohexane 9: 1 ratio) and 337 mg of the expected product are obtained. Mp = 136-137 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2235 (C≡N); 1787-1736 (C = O); 1617-1577-1505 (aromatic).

Example 34: 4- (4,4-Bis- (2-methyl-1-hydroxypropoxymethyl) -2,5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile
0.5 ml of isobutyric anhydride in an inert atmosphere is added to a solution containing 375 mg of the product obtained in Example 32, 4 ml of pyridine and 122 mg of dimethylaminopyridine. Stirred for 30 minutes, poured into 20 ml of a 50% aqueous sodium bicarbonate solution, dried and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica (eluting with CH ₂ Cl ₂ ethyl acetate in a 95: 5 ratio) to give 457 mg of the expected product. Mp = 71-72 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2236 (C≡N); 1789-1733 (C = O); 1616-1505 (aromatic).

UV spectrum (ethanol): maximum at 257 nm ε = 17000
shoulder at 285 nm ε = 2600
Example 35: Bis- (1-methylethyl) - and bis- (methylene) - (3- (4-cyano- 3- (trifluoromethyl) phenyl) -2,4-dioxo-1- (2-fluoroethyl) -5- imidazolidinyl) - carbonate and (±)-racemic methyl- and 1-methylethyl- (3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-1- (2-fluoroethyl) -5- ( hydroxymethyl) -5-imidazolidinyl) carbonate
Under argon atmosphere, 375 mg of the product obtained in Example 32 in 4 ml of pyridine and 122 mg of 4-dimethylaminopyridine are cooled to -4 ^° C. At -4 ^° C, 550 mg of isopropyl chloroformate are added dropwise. The temperature is allowed to rise to room temperature, stirring is continued for 2 hours. Since the reaction was not complete, add 122 mg of dimethylaminopyridine and 2 ml of isopropyl chloroformate and heat for 18 hours at 50 ^o C.

The temperature is brought to room temperature, poured into salt water, extracted with ethyl acetate, the extract is dried, the solvents are removed and 570 mg of crude product are obtained, which is purified by chromatography on silica (eluting with CH ₂ Cl ₂ - ethyl acetate in a ratio of 95: 5) to obtain 275 mg of dicarbonate (mp = 122-123 ^o C), then (eluting agent CH ₂ Cl ₂ -acetone in a ratio of 9: 1) to obtain 156 mg of monocarbonate (mp = 154-155 ^o C).

Analyzes
Dicarbonate
IR (CHCl ₃ ), cm ^-1 : 2238 (C≡N); 1789-1749-1734 (C = O); 1615-1578-1505 (aromatic).

UV spectrum (ethanol): maximum at 256 nm ε = 15400
shoulder at 285 nm ε = 2500
Monocarbonate
IR (vaseline oil), cm ^-1 : 3450 (OH / NH); 2250 (C≡N); 1789-1736 (C = O); 1616-1576-1506 (aromatic).

Example 36: Bis- (2-methylpropyl) - and bis- (methylene) - (3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-1- (2-fluoroethyl) -5- imidazolidinyl) carbonate
Under argon atmosphere, 375 mg of the product obtained in Example 32 in 4 ml of pyridine and 122 mg of 4-dimethylaminopyridine are cooled to -4 ^° C. At -4 ^° C, 50 mg of isobutyl chloroformate is added dropwise. Leave the temperature to rise to room temperature. After 40 minutes, the reaction medium was poured into water, washed with an aqueous solution of sodium chloride, dried and the solvents were removed, the residue was chromatographed on silica (eluting with CH ₂ Cl ₂ ethyl acetate in a ratio of 92.5: 7.5) to obtain 476 mg of the expected product . Mp = 109-110 ^o C.

IR (CHCl ₃ ), cm ^-1 : 2236 (C≡N); 1790-1754-1734 (C = O); 1615-1578-1505 (aromatic).

UV spectrum (ethanol): maximum at 256 nm ε = 15500
shoulder at 285 nm ε = 2700
Example 37

Get tablets having the following composition:
product of example 3 - 100 mg
excipient, sufficient amount for the final weight of the tablet is 300 mg
(List of excipients: lactose, starch, talc, magnesium stearate).

 Example 38

Get tablets having the following composition:
product of example 26 - 100 mg
excipient, sufficient amount for the final weight of the tablet is 300 mg
(List of excipients: lactose, starch, talc, magnesium stearate).

Pharmacological study of the products of the invention
1). The study of the affinity of the products of the invention to the androgen receptor
Male Sprague Dawley EOPS rats weighing 180-200 g, castrated in 24 hours, are sacrificed, prostates are removed, weighed and homogenized at 0 ^° C using a glass homogenizer (un potte verre - verre), in buffer solution (TRIS, 10 mmol; sucrose , 0.25 mol; phenylmethanesulfonyl fluoride (PMSF), 0.1 mol; sodium molybdate, 20 mmol; HCl to pH 7.4), 2 mmol of DL-dithiotrenthol (DTT) prepared just before use is added to them; 1 g of tissue per 8 ml of buffer.

The homogenizate is then ultracentrifuged at 0 ^° C. for 30 minutes at 209,000 q. Aliquots of the obtained supernatant (= cytosol) are incubated for 30 minutes and 24 hours at 0 ^o C with a constant concentration (T) of tritium-containing testosterone and in the presence of increasing concentrations (0-2500 • 10 ^-9 mol) or “cold” (non-radioactive ) testosterone, or test products. The concentration of the bound, containing tritium testosterone (B) is then measured in each incubate using the adsorption method in a combination of coal-dextran.

The calculation of the relative affinity for binding (ARL):
The following curves are plotted 2: the percentage of bound, containing tritium, H / T hormone depending on the logarithm of the concentration of the “cold” standard hormone and W / T depending on the logarithm of the concentration of the test “cold” product. The direct equation is determined:
I ₅₀ = (W / T _max + V / T _min ) / 2,
where B / T _max =% tritium-containing hormone associated through incubation of this tritium-containing hormone with a concentration (T);
W / T _min =% tritium-containing hormone associated with incubation of this tritium-containing hormone with a concentration (T) in the presence of a large excess of “cold” hormone (2500 • 10 ^-9 mol).

The intersections of the straight line I ₅₀ with the curves make it possible to evaluate the concentrations of the standard cold hormone (CH) and the test cold product (CX), which inhibit 50% of the binding of tritium-containing hormone to the receptor. The relative binding affinity (ARL) of the test product is determined by the equation:
ARL = 100 (CH) / (CX)
The following results are expressed in ARL:
Standard Product (Testosterone): 100
Product Examples - Incubation 24 hours
3 - 6
6 - 16
26 - 4
2. Determination of androgenic or antiandrogenic activity of the products of the invention by quantitative determination of ornithine decarboxylase (ODC)
Processing protocol
Male SWISS mice at 6 weeks of age and castrated in 24 hours receive test products orally or subcutaneously (0.5% suspension in methylcellulose or as a solution in ethanol) simultaneously with subcutaneous injection of testosterone propionate in an amount of 3 mg / kg (solution in corn oil) to determine antiandrogenic activity. Agonistic activity is determined in the absence of testosterone propionate.

 Testosterone propionate is administered in a volume of 10 mg / kg.

20 hours after the treatments, the animals were sacrificed, their kidneys were removed, then homogenized at 0 ^° C using a Teflon-glass crusher in 10 volumes of 50 mmol TRIS-HCl buffer (pH 7.4) containing 250 uM pyridoxalphosphate, 0.1 mmol EDTA and 5 mmol of dithiothreitol. The homogenizer is then centrifuged for 30 minutes at 209,000 q.

Principle of quantification
At 37 ^° C., real ornithine decarboxylase converts an isotopic mixture of “cold” ornithine and tritium-containing ornithine to “cold” putrescine and tritium-containing putrescine.

 Putrescin is then collected on selective, ion-exchange papers. After drying, excess tritium-containing ornithine and cold, unconverted ornithine are removed by 3 washes with 0.1 M ammonia solution. The papers are dried, then, after the addition of scintillating Aqualit, the radioactivity is calculated.

The results are expressed in f moles (10 ^-15 mol) of the resulting tritiated putrescine per hour and per mg of protein.

 The results are expressed as% inhibition of ODC of control animals receiving only testosterone propionate.

 Test: the products are administered subcutaneously at a concentration of 1.5 mg / kg in a volume of 10 μl.

Products examples - Test
3 - 47
6 - 84
Conclusion: The above tests (tests) show that the tested products of the invention have strong antiandrogenic activity.

Claims (8)

1. Substituted phenylimidazolidines of the formula I

in which Y represents an oxygen atom or an NH radical;
Z ₂ trifluoromethyl radical;
Z ₁ is a cyano or nitro radical;
X is an oxygen or sulfur atom;
R ₃ is a hydrogen atom or an alkyl radical containing not more than 4 carbon atoms, which may be substituted by one or more radicals selected from halogen atoms or a cyano radical;
R ₄ and R _{5 are} such that either one means methyl and the other is selected from the values of R ₄ and R ₅ , or R ₄ and R ₅ , the same or different, mean a linear or branched alkyl radical containing not more than 4 carbon atoms, which may be substituted by a hydroxyl radical, which may be protected or esterified to an ether or ester; a halogen atom or a phenylthio radical which may be substituted by a halogen atom or a hydroxyl radical,
moreover, the products of formula I are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts of inorganic or organic acids or inorganic or organic bases of the products of formula I. 2. Substituted phenylimidazolidines of the formula I according to claim 1, characterized in that they are the following compounds:
2- (trifluoromethyl) -4- (4- (hydroxymethyl) -4-methyl-2,5-dioxo-1-imidazolidinyl) benzonitrile;
4- [3,4- (dimethyl) -4- (hydroxymethyl) -5-oxo-2-thioxo-1-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) imidazolidine-2,4-dione;
4- [4,4-bis (hydroxymethyl) -2,5-dioxo-1-imidazolidinyl] -2- (trifluoromethyl) benzonitrile;
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-3- (2-fluoroethyl) -4- (fluoromethyl) -4-methyl-1-imidazolidinyl] -2- (trifluoromethyl) benzonitrile;
1,5-dimethyl-5- (fluoromethyl) -3- (4-nitro-3- (trifluoromethyl) phenyl) imidazolidine-2,4-dione;
3- (4-cyano-3- (trifluoromethyl) phenyl) -2,4-dioxo-5- (fluoromethyl) -5-methyl-1-imidazolidine-acetonitrile;
4- [4,4-bis (fluoromethyl) -3-methyl-5-oxo-2-thioxo-1-imidazolidinyl] -2- (trifluoromethyl) benzonitrile,
moreover, these products are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts of inorganic or organic acids or inorganic or organic bases of the products of formula I.  3. Substituted phenylimidazolidines of the formula I according to claim 1 or 2, having antiandrogenic activity. 4. The method of obtaining substituted phenylimidazolidines of formula I according to claim 1 or 2, characterized in that the compound of formula II

in which Z ₁ , Z ₂ and X have the meanings indicated in claim 1,
in the presence of a tertiary base is reacted with a product of formula III

in which R ₄ and R ₅ have the meaning indicated in claim 1;
R ₃ 'has the meanings indicated in claim 1 for the radical R ₃ , in which possible reactive functions are protected, if necessary,
to obtain the compounds of formula IV

in which Z ₁ , Z ₂ , X, R ₃ ', R ₄ and R ₅ have the above meanings,
which, if desired or necessary, is subjected to one or more of the following reactions in any order: a) deprotection reactions that R ₃ ′ may carry; b) hydrolysis reactions of the group

to carbonyl and, if necessary, the transformation of the group

to the group

c) reactions of transformation of a group or groups

to the group

g) acting on a compound of formula IV in which R ' ₃ is a hydrogen atom, and after hydrolysis of the group

to carbonyl, with a reagent of the formula Gal-R ″ ₃ , in which R ″ ₃ has the meaning R ″ ₃ , with the exception of hydrogen, and Gal means a halogen atom, to obtain a product of formula I, then, if desired, by applying an agent to the obtained product removal of the possible protective groups that R ″ ₃ can carry, or, if desired, an esterification agent, an amination agent or a salt formation agent, the resulting compounds of formula I being in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms. 5. The method of obtaining substituted phenylimidazolidines of formula I according to claim 1 or 2, characterized in that the compound of formula II above, in the presence of a tertiary base is reacted with a compound of formula VII

in which W has the meaning indicated for R ₅ , with the exception of an alkyl radical substituted with hydroxyl, free, esterified to ether or complex, or protected;
and P denotes a protective group of OH function or a radical such that —O — P denotes an esterified hydroxyl;
R ' ₃ and R ₄ have the meanings indicated above,
to obtain a product of formula VIII

in which X, Z ₁ , Z ₂ , R ' ₃ , R ₄ , W and P have the above meaning, in which, if desired or necessary, the OH radical is released from the group OP, which, if necessary or if desired, is esterified to ester or converted into a halide radical, then, if desired or if necessary, the product of formula VIII is subjected to one or more of the following reactions in any order: a) the reaction of removal of the possible protective groups that the radical R ' ₃ may carry; b) hydrolysis reactions of the group

to a carbonyl group and, if necessary, conversion of the group

to the group

c) reactions of transformation of a group or groups

to the group

g) the impact on the product of formula VIII, in which R ' ₃ means a hydrogen atom and after hydrolysis of the group

to a carbonyl group, with a reagent of the formula Gal-R ″ ₃ , in which R ″ ₃ has the meaning of the radical R ″ ₃ , with the exception of hydrogen, and Gal is a halogen atom, to obtain a product of formula I according to claim 1 or 2, then optionally, acting on the product obtained with an agent to remove possible protective groups that R ″ ₃ can carry, or, if desired, an esterification, amination or salt formation agent, and the resulting products of formula I are in all possible isomeric, racemic, enantiomeric or diastereoisomeric forms . 6. A method of producing substituted phenylimidazolidines of formula I according to claim 1 or 2, characterized in that the compound of formula II above, in the presence of a tertiary base, is reacted with a compound of formula III '

in which R ' ₃ , R ₄ and R ₅ have the meaning indicated above;
Q means an alkali metal atom or an alkyl radical containing 1 to 6 carbon atoms,
to obtain the product of formula IVa:

in which X, Z ₁ , Z ₂ , R ' ₃ , R ₄ and R ₅ have the above meanings,
which, if desired, is subjected to one or more reactions in any order: a) the reaction of removal of possible protective groups that the radical R ' ₃ may carry; b) reactions of transformation of a group or groups

to the group

or, if desired, groups

to the group

c) exposed to the product of the formula IVa, wherein R _'3 represents a hydrogen atom, a reagent of formula Hal-R'_'3 in which R'_'3 has the values of the radical R' _3, except hydrogen, and Hal represents a halogen atom, for the preparation of a product of formula I, then, if desired, and if necessary, the agent acts on the product to remove possible protective groups that the radical R ″ ₃ can carry, or if desired, by the action of an esterification, amination or salt formation agent, the resulting products of formula I being in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms. 7. A method of producing substituted phenylimidazolidines of formula I according to claim 1 or 2, characterized in that the compound of formula Gal-R ″ ₃ , in which Gal and R ″ ₃ have the above meanings, are reacted with a compound of formula IV ′

to obtain the compounds of formula IV ″:

a compound of formula IV 'or IV'', which may or may not mean a product of formula I, if desired or necessary, is subjected to one or more of the following reactions in any order to obtain a product of formula I': a) a reaction to remove possible protective groups which may carry the radical R ″ ₃ , then, possibly, the action of an esterification agent, amination or salt formation, b) the reaction of the transformation of the group or groups

in groups

moreover, the resulting products are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms.  8. A pharmaceutical composition having antiandrogenic activity, comprising an active principle and an excipient, characterized in that as an active principle it contains at least one of the compounds according to any one of claims 1 and 2.