Substituted phenylimidazoline, methods for their preparation and pharmaceutical composition having antiandrogenna activity

 

(57) Abstract:

The invention relates to new substituted phenylimidazoline, to a method for their production and to their use in pharmaceutical compositions. New substituted manifest antiandrogenna activity. 4 C. and 10 C.p. f-crystals, 2 tab.

The present invention applies to new substituted phenylimidazoline, the method of their production, their use as medicaments and to include their pharmaceutical compositions.

In Japanese patent application J 48087030 describes 3-phenyl 2 - thiohydantoin presented as inhibitors of germination of some plants.

In the French patent application N 2329276 describes imidazolidine mentioned that they have antiandrogenna activity. However, the products of the said patent differ from the products of the present patent application.

Thus, the object of the present invention are the products of General formula (I):

< / BR>
in which

R1represents zanily or retrorectal or halogen atom,

R2represents triptoreline radical or a halogen atom,

group-A-B - is selected among radisich radicals:

hydrogen atom,

radicals, such as alkyl, alkanniny, alkynylaryl, aryl or arylalkyl, including not more than 12 carbon atoms, with the ability to replace these radicals one or more substituents selected among these radicals, such as hydroxyl, halogen, mercapto, cyano, acyl or allossery, including not more than 7 carbon atoms, aryl, O-aryl, O-Aracely, S-aryl, in which aryl radical comprising up to 12 carbon atoms that may be substituted, and the sulfur atom may be oxidized to become a sulfoxide or sulfon, carboxyl, free, converted into ester or salt or amide, amine, mono or dialkylamines, or heterocyclic radical comprising 3 to 6 atoms and including one or more heteroatoms, selected from among the atoms of sulfur, oxygen or nitrogen; alkyl, alkanniny or alkynylaryl radicals, which may be, moreover, is interrupted by one or more atoms of oxygen, nitrogen or sulfur, with the possibility of oxidation in becoming sulfoxide or sulfon, with aryl and Aracely radicals can be substituted by a halogen atom, radical, such as alkyl, alkanniny or alkynyl, in which the linear or branched alkyl radical comprises not more than 6 carbon atoms,

acyl or alloxylon radicals containing not more than 7 carbon atoms,

Y represents oxygen atom or sulfur, or a radical =NH,

except for products in which the group-A-B - represents the radical:

< / BR>
in which

X is an oxygen atom, R3is a hydrogen atom, and Y represents an oxygen atom or an NH radical, R2represents a halogen atom or triptorelin radical, and R1is microradian or halogen atom.

To determine R3and used in the following definitions may have the following values:

Under alkyl containing not more than 12 carbon atoms, see, for example, values such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl, linear or branched.

Preference is given to alkyl radicals containing not more than 6 carbon atoms, in particular such radicals as Mitilini sweetlenny, sexily, linear or branched.

Under alkenyl, including not more than 12 and preferably 4 carbon atoms, see, for example, values such as vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl.

Among alkenyl values preference is given to allyl and butenyl.

Under quinil, including not more than 12 and preferably 4 carbon atoms, see, for example, values such as ethinyl, propargyl, butynyl, pentenyl or hexenyl.

Among etkinlik values are preferred propargyl.

Under the aryl understand carbocyclic aryl radicals, such as phenyl or naphthyl, or heterocyclic arily with 5 or 6 atoms, containing one or more heteroatoms selected in the first place, among the atoms of oxygen, sulfur or nitrogen. Among the heterocyclic arrow with 5 atoms include such radicals as purely, thienyl, pyrrolidinyl, diazolidinyl, oxazolidinyl, imidazolidinyl, thiadiazolidine, personilnya, isoxazolidine.

Among the heterocyclic arrow with 6 atoms include such radicals as peredelnyj, pyrimidinyl, pyridazinyl, personilnya.

Among the condensed alny.

Preference is given to phenyl radical.

Under arylalkyl understand radicals, obtained by attaching the above-mentioned alkyl radicals, with the possibility of substitution, and aryl radicals, also listed above, with the possibility of substitution.

Preference is given to benzyl, phenylethylene or triphenylmethyl radicals.

Under the halogen understand, of course, fluorine atoms, chlorine, bromine or iodine.

Preference is given to fluorine atoms, chlorine or bromine.

As specific examples of alkyl radicals, substituted by one or more halogen atoms include such radicals as monitor, chlorine, bromine or iodomethyl, debtor, dichloro or dibromomethyl, trifluoromethyl.

As specific examples of substituted aryl or Uralkalij radicals can be called radicals in which the phenyl radical is substituted by fluorine atom or metaxylene or triptorelin radical.

Under the acyl radical understand, first of all, a radical containing not more than 7 carbon atoms, such as acetyl, propylaniline, bucilly or bentely, but it can also be valelly, hexanoyl, acrylic is colocinni radical see radical, in which the acyl radicals have the abovementioned meaning, and, for example, acetoxyphenyl or propionyloxy radicals.

Under esterified carboxyl radical see, for example, such radicals as allyloxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, botilony or tert-butyloxycarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl or cyclohexyloxycarbonyl.

You can also call the radicals formed from the remnants of easily esters, such as methoxymethyl, ethoxymethyl radicals; aryloxyalkyl radicals, such as pivaloyloxymethyl, pivaloyloxymethyl, acetoxymethyl or acetoxyethyl; allyloxycarbonyl radicals, such as methoxycarbonylmethylene or methoxycarbonylmethylene radicals, isopropoxycarbonyloxymethyl or isopropoxycarbonyloxymethyl radicals.

The list of such ester radicals can be found, for example, in patent application UES ER N 0034536.

Under aminirovanie carboxyl radicals understand radicals , where the radicals R6and R7the same or different, pre, the stylish, sawn, ISO-propyl, boutigny, isobutylene, second - botilony or tert-botilony.

Among the radicals are preferred amino, mono or dimethylamino radicals.

The radical may also be a heterocycle, which may contain or not contain an additional heteroatom. Here include such radicals as pyrrolidinyl, imidazolidinyl, peredelnyj, personilnya, pyrimidinyl, indolinyl, piperidinyl, morpholinyl, piperazinilnom. Preference is given piperidino or morpholino the radical.

Under carboxyl radical, turned into salt, see salt formed, for example, using an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. You can also call the salts obtained by using organic bases, such as methylamine, Propylamine, trimethylamine, diethylamine, triethylamine.

Preference is given to sodium.

Under alkylamine radical realize such radicals as methylamine, ethylamine, Propylamine or boutigny, linear or branched, amine. Preference is given to alkyl radicals containing not more than 4 carbon atoms, and alkyl radicals can€, for example, dimethylamine, diethylamine, methylethylamine radicals. As above, preference is given to alkyl radicals containing not more than 4 carbon atoms, selected from the list above.

Under the heterocyclic radical comprising one or more heteroatoms, see, for example, saturated monocyclic heterocyclic radicals, such as oxiranyl, oxalanilide, DIOXOLANYL, imidazolidinyl, pyrazolidinone, piperidinyl, piperazinilnom or morpholinyl.

Under alkyl, alkenyl or alkynylaryl radicals which may be interrupted by heteroatoms, selected from among the atoms of sulfur, oxygen or nitrogen, understand radicals comprising one or more of these atoms with the same or different structure. These heteroatoms, of course, cannot be placed in the end position of the radical. You can be called, for example, alkoxyalkyl radicals, such as methoxymethyl, methoxyaniline, methoxypropyl and methoxybutyl, or alkoxyalkyl radicals, such as methoxyethoxymethyl.

Under trialkylsilyl radical in which the alkyl radical comprises not more than 6 atoms of carbon is capacity.

When the products of formula (I) include amine radical, turn into salt with the acid, it goes without saying that these acid salts are also subject of the invention. You can call salt, obtained with the help of such acids, such as hydrochloric and methansulfonate.

The object of the present invention are, in particular, the products of formula (I) as defined above in which Y represents an oxygen atom, except for products in which the group-A-B - represents the radical:

< / BR>
in which

X is an oxygen atom, R3is a hydrogen atom, R2represents a halogen atom or triptorelin radical, and R1is microradian or halogen atom.

Among these products the subject of the present invention, in particular, are those products in which the group-A-B represents the radical:

< / BR>
in which

X is a sulfur atom, and R3have the above meaning.

Among these products the subject of the present invention, in particular, are those products in which R3represents a hydrogen atom or an alkyl radical, including the specified products the subject of the present invention, first of all, are those products in which R1represents zanily radical or a halogen atom and in particular a chlorine atom.

The object of the present invention, in particular, are products of the formula (I) as defined above, in which the group - a-b - represents the group:

< / BR>
or group:

< / BR>
in which

R3represents an alkyl or alkanniny radical containing not more than 6 carbon atoms, with the possibility of substitution and interrupted by one or more oxygen atoms or sulfur, with the possibility of oxidation, or R3represents Uralkaliy radical, with the possibility of substitution, or acyl radical or trialkylsilyl radical.

Among these products the subject of the present invention are, in particular, the products in which R3represents an alkyl radical containing not more than 6 carbon atoms, with the possibility of substitution by a halogen atom, a hydroxyl radical, a carboxyl radical, free or converted into ester, heterocyclic radical, O-Aracely or S-aryl radical, where the aryl radical may be substituted by one or more halogen atamai, first of all, those in which R3represents an alkyl radical comprising from 2 to 4 carbon atoms substituted by a chlorine atom or a radical such as ethoxycarbonyl, tert-butoxycarbonyl or cyclopentanecarbonyl, 4-fortunaltely, with the possibility of oxidation in becoming sulfoxide or sulfon, morpholinyl, phenylmethoxy, triphenylmethyl or methylsulfonyl.

Among these products the subject of the present invention, in particular, are also those products in which R3represents a radical such as acetyl, bentely or (1,1 - dimethylethyl) dimethylsilicone.

The object of the present invention are also the products of formula (I) as defined above corresponding to the formula (I'):

< / BR>
in which

R1, R2and R3have the above significance, with the exception of products in which R1is microradian, R2represents triptoreline radical, and R3is a hydrogen atom.

Among these products the subject of the present invention are also the products of formula (I) as defined above, in which R1Padstow carbon with the possibility of substitution of the carboxyl radical, free, converted into ester or salt.

Among the preferred products of the invention can, in the first place, as the products of formula (I) as defined above, with the following names:

- 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile,

- 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile,

- 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile,

- 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinethione acid.

The object of the present invention is also a method of obtaining the products of General formula (I) as defined above, characterized in that:

or in the presence of tertiary bases conduct the reaction product of the formula (II):

< / BR>
in which

R1, R2and X have the above significance, with a product of formula (III):

< / BR>
in which

R'3has the values specified above for R3where possible functional groups can be protected, and, given the fact that R1is microradian or halogen atom, SUB>3may not be a hydrogen atom, to obtain a product of formula (IV):

< / BR>
in which

R1, R2, X and R'3have the above significance, and, if desired and if necessary, the products of formula (IV) is subjected to one or more of the following reactions, in any order:

a) reaction of a selection of possible protective groups that can be included in R'3;

b) hydrolysis of the group >C=NH with the conversion of the keto group and with the possibility of transforming the group >C=S group >C=O;

C) reactions of transformation groups (groups) >C=O group >C=S;

g) effects on the products of formula (IV) in which R'3represents a hydrogen atom and, after hydrolysis, the group >C=NH with the conversion of the keto group, a reagent of formula Hal-R3in which R3matter R'3with the exception of hydrogen, and Hal is a halogen atom, to obtain products of formula (I), in which the group-A-B - represents the group

< / BR>
in which

R3have the above significance, and, if desired, the impact on these products selector possible protective groups that can be included in R3or, if necessary, the effects of AG is t reaction product of the formula (II):

< / BR>
in which

R1, R2and X have the above significance, with a product of formula (III'):

< / BR>
in which

R'3has the meaning specified above, and Q represents either the alkali metal atom such as sodium or alkyl radical comprising from 1 to 6 carbon atoms, to obtain a product of formula (IVa):

< / BR>
in which

X, R1, R2and R3have the above meaning, and if desired, it is subjected to one or more of the following reactions, in any order:

a) reaction of a selection of possible protective groups that can be included in R'3;

b) reactions of transformation groups (groups) >C=O group >C=S or, if necessary, the group >C=S group >C=O;

C) effects on the products of formula (IVa), in which R'3represents a hydrogen atom, a reagent of formula Hal-R3in which R3matter R'3with the exception of hydrogen, and Hal is a halogen atom, to obtain products of formula (I), in which the group-A-B - represents the group

< / BR>
in which

R3have the above significance, and, if desired, the impact on these products by the selector of possible defenses, the mining or salt formation,

or spend the interaction of the compounds of formula Hal-R3in which Hal and R3have the previously indicated meanings, with the product of formula (IV'):

< / BR>
to obtain a product of formula (IV"):

< / BR>
which is optionally and if necessary subjected to one or more of the following reactions, in any order:

a) reaction of a selection of possible protective groups that can be included in R3and, if necessary, the effects of agent etherification, amination, or salt formation;

b) reactions of transformation groups (groups) >C=O group >C=s

The reaction products of the formula (II) with the products of the formula (III) is produced mainly in an organic solvent, such as tetrahydrofuran or dichloroethane, but you can use also ethyl ester or a simple isopropyl ether.

The operation is performed in the presence of a tertiary base such as triethylamine or pyridine or metiletilpiridin.

Possible functional groups, which may include R3and that can be protected in the product of formula (III), (IVaor (IV) are hydroxyl or amine functional groups. For the protection of these functionby amine radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl.

As a protective group of hydroxyl radical can be called such radicals, such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl, tert-butyldimethylsilyl.

Needless to say that the above list is not exhaustive and that perhaps the use of other protective groups known in the chemistry of peptides. The list of such protective groups may be found, for example, in French patent application BF N 2499995, the contents of which are incorporated into the present application by reference.

Possible reactions allocation protective groups are as described in the referenced patent application BF N 2499995. The preferred method of selection is acidic hydrolysis using acids such as hydrochloric acid, benzosulfimide or paratoluenesulfonyl, formic or triperoxonane acid. Preference is given to hydrochloric acid.

The possible reaction of hydrolysis of the group >C=NH with the formation of the ketone group is also primarily produced using acid such as, for example, aqueous hydrochloric acid when those whom lekule, it also includes group >C=S, this group can be converted into a group >C=o Free OH radical, which may contain R3can be converted in this case, the SH radical.

The reaction of transformation of the group >C=O group >C=S is performed using a reagent, called reagent Laussane and having the following formula:

< / BR>
This product is manufactured, for example, the firm "FLUKE", and its use is described, for example, in the journal Bull. Soc. Chim. Belg., so 87, No. 3 (1987), S. 229.

When you need to change two functional group >C=O in two group >C=S, the operation is performed with an excess amount of reagent Laussane. This applies to the case when there is a molecule that includes one functional group >C=S and one functional group >C=O, and this group >C=O is required to turn in a group >C=s

However, when there is a molecule comprising two functional group >C= O, and you want to receive the product, containing only one functional group, the operation is performed in case of lack of reagent Laussane. In this case, get, usually a mixture of three products: each of the two products, which contains a single functional grout allocated by conventional methods, such as chromatography.

The impact on the products of formula (IV), (IVa) or (IV') with a reagent of formula Hal-R3is performed in the presence of a strong base such as sodium hydride or potassium. This can be the response of the transfer phase in the presence of Quaternary ammonium salts, such as tert-butylamine.

If protecting group, which may include substitute R3that is, for example, one of the groups listed above for R3then the reaction allocation protective groups are made under conditions described above.

An example of allocating tert-butyldimethylsilyloxy group with hydrochloric acid are provided below in the examples.

A possible transformation in the ester products of formula (I) in which R3includes free OH radical, is produced under normal conditions. It is possible to use, for example, an acid or a functional derivative, for example an anhydride, such as acetic anhydride, in the presence of a base, such as pyridine.

Possible conversion into ester or salt of the products of formula (I) in which R3is a group COOH, made in the usual conditions known to experts.

Velovich. You can use primary or secondary amine in the presence of a functional derivative of the acid, for example, a symmetrical or mixed anhydride.

The object of the present invention is also a method of obtaining products of formula (I"):

< / BR>
in which

R1, R2, -A"-B" have the meanings specified above for R1, R2and-A-B-, taking into account the fact that when-A-B - represents the group-CO-N(R"'3)-, in which R"'3represents a hydrogen atom or a linear or branched alkyl radical containing not more than 7 carbon atoms, Y is an oxygen atom, R1represents zanily radical, and this method is characterized by the fact that the product of formula (V):

< / BR>
in which

R1and R2have the above meanings and Hal represents a halogen atom, is introduced into the reaction product of the formula (VI):

< / BR>
in which-A-B - and Y have the above meaning, and this reaction is performed in the presence of a catalyst and possibly solvent.

As for the products of formula (V), the term Hal denotes, primarily, a chlorine atom, but may also denote a bromine atom, or iodine.

The role of m follows, the condensation reaction product of the formula (V) with the product of formula (VI) to obtain the target product.

The object of the present invention is, in particular, the above-described method in which the catalyst is a metal in pure form or in oxidized form or the basis.

As a catalyst can be used metal in pure form, in the form of metal oxides or in the form of metal salts. The catalyst can also be the basis. When the catalyst is metal, this metal may be copper or Nickel.

The metal salts may be chloride or acetate.

When the catalyst is a base, this base can be, for example, sodium hydroxide or potassium hydroxide, in the reaction medium, if desired, can be added dimethylsulfoxide.

The object of the present invention, in particular, is the above method, in which a catalyst may play an oxide monovalent or divalent copper, copper in its pure form or base, such as sodium hydroxide or potassium hydroxide.

When using as a catalyst a metal of copper, it is preferable to use in the form pouchette of the oxide catalyst is used, containing monovalent copper.

Solvent used is selected in the first place, among the esters high boiling point, such as, for example, diphenyl ether, diglyme, trislim and dimethylsulfoxide, but can be used also, for example, oil with a high boiling point, such as paraffin or vaseline.

The object of the present invention, in particular, is the above method, characterized in that the process takes place in the presence of a solvent of the ether type, such as diphenyl ether, diglyme, trislim and dimethylsulfoxide.

The subject of the invention, first of all, is the above-described method in which the solvent is used diphenyl ether or trislim.

The above-described method of obtaining the target product can flow under pressure or at atmospheric pressure, preferably at an elevated temperature.

Thus, the subject invention is the above method, characterized in that the reaction proceeds at temperatures above 100oC, preferably this temperature is exceeded 150oC.

More specifically, the object of the present invention is described in the invention is the above method, characterized in that the reaction proceeds in the presence of oxide containing monovalent copper, triglyme at a temperature equal to or exceeding 200oC, and for more than 3 hours

The products that are the subject of the present invention have interesting pharmacological properties; it is noted, in particular, they inhibit the action of androgenic hormones on peripheral receptors.

The tests described in the experimental part, illustrate the specified antiandrogenna activity.

In connection with these antiandrogenna properties of the products that are the subject of the present invention can be used in the treatment of adults without the risk of some of the effects of chemical castration.

These properties allow you to use the products of General formula (I) of the present invention as medicaments for the treatment of adenomas and tumors of the prostate, as well as the treatment of benign prostatic hypertrophy.

These properties allow the use of the products of General formula (I) of the present invention in the treatment of benign and malignant tumors whose cells contain, in particular, androgen receptors. It is, in lane is Syria, the lymphatic system, kidneys, liver.

The products of General formula (I) of the present invention can also be used in the treatment of acne, seborrhea, androgenic alopecia, excessive hair or hirsutism.

Thus, the products of formula (I) are used in dermatology, and they can be used both independently and in conjunction with other tools. In particular, they can be combined with an antibiotic, such as derivatives of azelaic acid, guideway acid, erythromycin or derivatives of retinoids to treat acne, or with the inhibitor of 5-reductase, such as ( 5,17 )-1,1 - dimethylethyl 3-oxa-4-Aza-androst-1-EN 17-carboxamid (or Finasteride Merck, 11th ed.) or azelaic acid or agent blocking androgen receptors for the treatment of acne, alopecia or hirsutism, or a stimulator of hair growth, such as Minoxidil to treat hair loss.

The products of formula (I) can also be used in the veterinary field.

The products of formula (I) in the form of radioactive drugs can also be used in diagnosis, as special marks of androgen receptors. As radioactive products can be used, e.g. the Oia is also used in medicines products of General formula (I), acceptable from a pharmaceutical point of view.

The object of the present invention is, in particular, the use of the drug products that have the following names:

- 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile,

- 4-(4,4 - dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile,

- 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile,

- 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinethione acid.

These products can be used orally, parenterally, perlingual, rectal, or local path.

The subject invention are also pharmaceutical compositions characterized in that they include as applicable the beginning of at least one of the compounds of General formula (I).

These compositions can take the form of solutions or suspensions for injection, tablets, simple or draeven, capsules, medicines, suppositories, creams, ointments and lotions; they are produced by conventional methods. The active principle is introduced in the framework commonly used in the manufacture of these compounds, Takei of animal or vegetable origin, derivatives of paraffin, glycols, various moisturizing, dispersion or emulsion agents, preservatives.

Commonly used doses, depending on patient and disease to be from 10 to 500 mg per day for humans by ingestion.

The initial products of the formula (II) of the present invention can be prepared by exposure to phosgene, when X represents an oxygen atom or thiophosgene, when X is a sulfur atom, the corresponding amine of formula (A):

< / BR>
An example of such preparation is given hereafter in the experimental part. The product of this type is described in French patent BF N 2329276.

Amines of the formula (A) described in patent EEC EP N 0002892 and in the French patent BF N 2142804.

The products of formula (III) or (III') are known or can be obtained on the basis of the corresponding cyanhydrin according to the method described in the journal J. Am. Chem. Soc. (1953), 75, 4841.

The products of formula (III) in which R'3is not a hydrogen atom can be obtained by exposure of the product of formula R3-Hal 2-cyano 2-aminopropan in the conditions described above for the impact of R3Hal on the products of formula (IV). The sample prepared with antoszka patent BF N 2329276.

The initial products of formulas (V) and (VI) in respect of which method is used, which is the subject of the invention, to obtain products of formula (l), is known and can be found in the trade network, but can be prepared using generally accepted among experts methods.

Preparation of products of formula (VI) are described, in particular, in the following articles:

- Journal of applied chemistry. 28, 969-75 (1955) (CA 50, 4881 a, 1956 );

- Tetrahedron 43, 1753 (1987);

- Journal J. Org. Chem. 52, 2407 (1987);

- The journal of organic chemistry. 21. 2006 (1985);

- Journal J. Fluor. Chem. 17, 345 (1981);

or in patents:

German patent DRP N 637.318 (1935);

- patent EEC EP N 0130875;

Japanese patent JP N 81121524.

The products of formula (VI), which is derived as widely used and cited in various articles and patents, for example:

- Journal J. Pharm. Pharmacol. 67, vol 19(4), pp. 209-16 (1967);

- Chemical and pharmaceutical journal, 67, I. 1(5), S. 51-2;

German patent N 2217914;

- patent EEC EP N 0091596;

- Journal J. Chem. Soc. Perkin. Trans. 1, c. 219-21 (1974).

The object of the present invention, as new industrial products and, in particular, as new industrial products used as intermediate R> in which

R1, R2and Y have the above values, and the group:

< / BR>
selected from among radicals:

< / BR>
in which

X represents an oxygen atom or sulfur, and R3iselected among the values of R3containing protected functional group.

Among the protected functional groups can be called hydroxyl and amine groups. These functional groups can be protected as described above for replacement of R3.

Example 1. 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile).

a) Condensation.

In the suspension 104 mg of sodium hydride in 0.8 cm3of dimethylformamide add 600 mg of 4- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) -2-(trifluoromethyl)- benzonitrile obtained as in example 8 of the patent application EEC N 0494819, 5 cm3of dimethylformamide, keeping the temperature below +20oC. After 10 minutes of stirring add 445 mg of 4-chloro-tert-butyldimethylsilyloxy and 300 mg of sodium iodide. Then heated for 16 hours at a temperature of +50oC, cooled at room temperature, add 87 mg of sodium hydride and again 400 mg chlorinated ether and 267 mg of sodium hydride and heated DOPOLNITEL mg primary potassium phosphate. Then extracted using ether, the organic phase is washed with water, dried and the solvent evaporated. The residue is subjected to chromatography on silica (eluant : methylene chloride-acetone (99 : 1)) and receive 526 mg of the product used without further processing in the next stage of cleavage.

The above product is mixed with 5 cm3methanol and 1.5 cm32 N. hydrochloric acid. Then shaken for 40 min at room temperature, poured into 30 cm3water is extracted using methylene chloride, the organic phase is washed with water, dried and the solvent evaporated. After chromatography of the residue on silica (eluant : methylene chloride-acetone (9 : 1)) release fraction Rf = 0.15 in, and after recrystallization from simple isopropyl ether to obtain 307 mg of the target product (tPL= 102 - 103oC).

Chemical composition C17H18F3N3O3= 369,35.

calculated, %: C 55,28; H 4,91; F 15,43; N 11,38;

received, %: C 55,2; H 4,9; F 15,3; N 11,1.

Infrared spectrum (CHCl3< / BR>
OH - 3628 cm-1< / BR>
CN - 2236 cm-1< / BR>
C=O - 1778-1724 cm-1< / BR>
Aromatic compounds - 1615-1575-1505 cm-1< / BR>
Polowanie mix of 9.9 cm34-chloro-1-butanol and 24.3 g of imidazole with 50 cm3tetrahydrofuran (THF). Then, when the temperature is below +20oC add the drip method 2,82 g of tert - butyldimethylsilyloxy 20 cm3tetrahydrofuran (THF), shaken for 18 hours at room temperature, centrifuged, washed with tetrahydrofuran and remove the solvent under reduced pressure. The residue is purified by chromatography on silica (eluant : cyclohexane-ethyl acetate (95 : 5)) and get 17,5 g of the target product.

Example 2. 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5 - dimethyl 2,4-dioxo 1-imidazolidinyl (1,1-dimethyl) ethyl.

In a suspension of 78 mg of sodium hydride at 50% in oil and 0.5 cm3of dimethylformamide added 450 mg of the product obtained in example 8 of the patent application EEC N 0494819 dissolved in 4 cm3of dimethylformamide. Then shaken for 15 min and added slowly at a temperature not exceeding +30oC and 0.22 cm3tert - butylbromide. Then shaken for 16 h, poured into 50 g of a mixture of water and ice (1 : 1), add 0.5 g of primary potassium phosphate and extracted using ether. The organic phase is washed with water, dried and evaporated to dryness, resulting in a gain of 1.1 g Syrah the way obtain 425 mg of the target product (tPL= 122-123oC, Rf = 0.28 In). Eluant : methylene chloride-acetone (99 : 1).

Infrared spectrum (CHCl3< / BR>
C=O - 1788-1729 cm-1(as) 1745 cm-1(ester)

CN - 2235 cm-1< / BR>
Aromatic compounds - 1616-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 258 N. m = 16100

Pereg. 277 N. m = 6000

Pereg. 285 N. m = 3000

Example 3. 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1 - imidazolidinyl of cyclopentyl.

A solution of 355 mg of the product obtained in example 9 of the patent application EEC N 0494819, 49 mg of 4-dimethylaminopyridine, 130 mg Cyclopentanol 6.5 cm3the methylene chloride is cooled to -10oC, after which it add 226 mg dicyclohexylcarbodiimide 2 cm3of methylene chloride. Then the temperature of the solution is allowed to rise to room, shaken for 25 min, heated for 2 h at boiling point, bring to room temperature, filtered and the solvent evaporated.

After that, the residue is subjected to chromatography on silica (eluant : methylene chloride-acetone (99 : 1)) and obtain 281 mg of the target product.

Rf = 0.25 in (eluant : methylene chloride-acetone (99 : 1)).

Infrared spectrum (CHCl3< / BR>
C=O - 1786-1729 cm-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 258 N. m = 16800

Pereg. 276 N. m = 5800

Pereg. 286 N. m = 3000

Example 4. 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1 - imidazolidinone ethyl.

The operations are carried out as in example 2 using at the initial stage of the product obtained in example 8 of the patent application EEC N 0494819, and ethyl-4-bromobutyrate. The result is the target product (tPL= 66-67oC).

Rf = 0,16 (eluant : methylene chloride-acetone (99 : 1)).

Infrared spectrum (CHCl3< / BR>
C=O - 1770-1726 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1616-1576-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 260 N. m = 15500

Pereg. 277 N. m = 7000

Pereg.286 N. m = 3600

Example 5. 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinethione acid.

For 3 h at room temperature shake 1 g of the product obtained in example 4, 20 cm3methanol in the presence of 3 cm32 N. sodium hydroxide. Then poured into 20 cm3water, acidified with 7 cm31 N. hydrochloric acid to pH 1, extracted using ether, washed with water, dried and remove the solvents under reduced on the Odom chromatography on silica (eluant : methylene chloride-methanol (92,5 : 7,5)). After recrystallization from isopropanol receive 614 mg of the target product (tpl.= 184-185oC).

Rf = 0.25 in (eluant : methylene chloride-methanol (92,5 : 7,5)).

The infrared spectrum - Vaseline oil

C=O - 1770-1753-1735-1712-1690-1645 cm-1< / BR>
CN - 2230 cm-1< / BR>
Aromatic compounds - 1613-1587-1533-1502 cm-1< / BR>
Example 6. (3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinone (1,1-dimethyl) ethyl.

By esterification of the product obtained in example 5 by using tert-butanol, in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine as described in example 3, to obtain the target product (tpl.= 96-97oC).

Rf = 0,32 (eluant : methylene chloride-acetone (98 : 2)).

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1616-1576-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 261 N. m = 15600

Pereg. 276 N. m = 7800

Pereg. 286 N. m = 3700

Example 7. 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4 - dioxo 1-imidazolidinethione of cyclopentyl.

Performing operations as in example 6, using Cyclopentanol, get the target product (tpl.= 85-86oC).

a) the Formation of phenolate

To a suspension of 80 mg of sodium hydride in 0.5 cm3the dimethylformamide was added when the temperature is below +28oC 0,16 cm34-portifino 1.6 cm3of dimethylformamide and incubated solution, with shaking, for 10 minutes

b) Substitution

In the solution obtained in the previous step, add 548 mg of 4-[4,4-dimethyl 2,5-dioxo 3-(2-chloroethyl) 1 - imidazolidinyl] 2-(trifluoromethyl) benzonitrile, obtained as described in example 50 patent applications EEC N 0494819 dissolved in 4 cm3DMF (dimethylformamide), shaken for 2 h, poured into 50 cm3water containing 0.5 g of primary potassium phosphate, and extracted using ether. Then the organic phase is washed with water, dried and the solvent is evaporated. The residue is subjected to chromatography on silica (eluant : cyclohexane-ethyl acetate (75 : 25)) and obtain 570 mg of the target product (tpl.= 93-94o-1< / BR>
CN - 2238 cm-1< / BR>
Aromatic compounds - 1616-1579-1506 cm-1< / BR>
(Forfinal) thio - 1591-1492 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 254 N. m = 18600

Pereg. 277 N. m = 7500

Pereg. 286 N. m = 4200

Example 9. (4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-forfinal) sulfonyl) ethyl) - 1-imidazolidinyl 2- (trifluoromethyl) benzonitrile.

At temperatures below +29oC 1,21 g metacompetencies acid in 24 cm3of methylene chloride add the drip method in 222 mg of the product obtained in example 8, 4.4 cm3of methylene chloride. After 30-minute stirring pour in 30 cm3sodium thiosulfate (0.5 M/l), shaken for 10 min, defend and extracted using methylene chloride. After that, the organic phase is washed with saturated aqueous sodium bicarbonate and then with water, dried and the solvent evaporated. The residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (1 : 1)) and obtain 220 mg of product, which is subjected to crystallization from isopropanol. Thus obtain 196 mg of the target product (tpl.= 155-156oC).

Rf=0,22 (eluant : ethyl acetate-cyclohexane (1 : 1)).

The infrared spectrum -1
< / BR>
SO2- 1314-1150 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 258 N. m = 16700

Pereg. 286 N. m

Example 10. 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-forfinal) sulfinil) ethyl) - 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile.

For 30 min at room temperature, shaken 222 mg of the product obtained in example 8, 15 cm3methanol in the presence of 5 cm3an aqueous solution of metaperiodate sodium (0.1 M/l). Then, the resulting suspension is heated for 1 h at a temperature of +40oC add 10 cm3methanol and 5 cm3oxidizing solution.

Then the methanol is evaporated, add 10 cm3a saturated solution of sodium chloride and extracted using ethyl acetate. Then the organic phase is washed with salt water, dried and the solvent is evaporated. After chromatography of the residue on silica (eluant : methylene chloride-acetone (9 : 1)) to obtain 205 mg of product, which is subjected to crystallization from isopropanol, resulting in a gain 180 mg of the target product (tpl.= 145-146oC).

Rf=0,10 (eluant : methylene chloride-acetone (9 : 1)).

Infrared spectrum (CHCl3< / BR>
C=O - 1782-1727 cm-1< / BR>
CN - 2236 cm-1< / BR>
Aroma is reg. 285 N. m

Performing operations as described in the previous examples, using 4-(4,4-dimethyl 2,5-dioxo 1 - imidazolidinyl) 2-trifluoromethyl) benzonitrile, obtained as described in example 8 of the patent application EEC N 0494819, and related reagents were obtained compounds of the following examples.

Example 11. (4-(4,4-dimethyl 2,5-dioxo 3-((3-methoxyphenyl) methyl) 1 - imidazolidinyl 2-(trifluoromethyl) benzonitrile.

tpl.. = 88-89oC

Rf=0.21 in (eluant: cyclohexane-ethyl acetate (7: 3)),

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1724 cm-1< / BR>
CN - 2238 cm-1< / BR>
Aromatic compounds - 1614-1602-1588-1575 - 1504-1491 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 260 N. m = 16800

Pereg. 210 N. m = 28500

Pereg. 280 N. m = 8900

Example 12. 4-(4,4-dimethyl 2,5-dioxo 3-(2-(4-morpholinyl) ethyl) - 1 - imidazolidinyl 2-(trifluoromethyl) benzonitrile.

Rf = 0,20 (eluant : methylene chloride-acetone (70 : 30)).

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1616 - 1576-1505 cm-1< / BR>
Morpholinyl - 1117 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 261 N. m = 14000

Pereg. 277 N. m = 6900

Pereg. 286 N. m = 3600

Example 13. 4-(4,4-dim suicient

Into a solution of 22 cm3distilled water and 1 cm3thiophosgene slowly add of 2.23 g of 1 - trifluoromethyl-4-aminobenzonitrile (obtained as described in the patent EEC N 0002892), shaken for 1 h, extracted using chloroform, washed with salt water, dried and evaporated to dryness under reduced pressure. The result is 3 g of the product used without further processing to produce imine.

b) Receiving imine

At room temperature, mix 5 g of isothiocyanate obtained in the previous step, with 37 cm3tetrahydrofuran (THF) in the presence of 1.5 cm3of triethylamine and add one dose of 2.8 g of 2-[(2-hydroxyethyl) amino] 2-methylpropionitrile, obtained as described in preparation of example 22 the patent application EEC N 0494819 dissolved in 10 cm3tetrahydrofuran (THF). The temperature spontaneously rises to +34oC. Then the solution is cooled to room temperature, shaking it within 1 h, the solvent is evaporated and chromatographic the residue on silica (eluant : methylene chloride-methanol (7 : 3)).

Thus, after crystallization from isopropanol get by 5.87 g of the target product (tpl.= 181oC).

For 1 h at boiling point heat of 4.6 g of the product obtained in example 13, 65 cm3methanol in the presence of 10 cm32 N. hydrochloric acid. Then cooled at room temperature and poured into 300 cm3ice water. Then extracted using ethyl acetate, the organic phase is washed with salt water, dried and the solvent is evaporated. After chromatography of the residue on silica (eluant : ethyl acetate-cyclohexane (1 : 1)) to collect the fraction Rf = 0.14 and after crystallization from methylene chloride and cyclohexane get 4,37 g of the target product (tpl.= 130oC).

Chemical composition: C15H14F3N3O2S = 357,36.

calculated % C 50,42; H 3,95; F 15,95; N 11,76; S 8,97;

received % C 50,3; H 3,9; F 15,6; 11,6 N; S 8,9.

Infrared spectrum (CHCl3< / BR>
OH - 3626 cm-1< / BR>
CN - 2236 cm-1< / BR>
C=O - 1763 cm-1< / BR>
Aromatic compounds - 1615-1578-1504 cm-1< / BR>
Example 15. 4-(4,4-dimethyl 3- (2-hydroxyethyl) 5-imino-2 thioxo 1-imidazolidinyl) 2-(trifluoromethyl) 5-3Mr. benzonitrile.

a) Obtaining titiraupenga benzonitrile

At room temperature, mix 15 mg of 2-trifluoromethyl 4-amino 5 - bromobenzoic who W ill result tritium (1,42 bar). Then filtered, rinsed with ethyl acetate and evaporated to dryness at room temperature, resulting in a gain of approximately 6,66 GBq (1,8 S) of the product.

b) Receiving titiraupenga isothiocyanate

150 μl of a 10% aqueous solution of thiophosgene in chloroform is added to the product obtained in the previous step, dissolved in 150 μl of water, and shaken for 45 min at room temperature. Then the solution is diluted with 0.5 ml water and 1 ml of chloroform, extracted using chloroform, the solvent is evaporated under reduced pressure, toluene take and get 50,7 GBq (1,37 S) of the target product, which is maintained at -80oC.

C) Obtaining titiraupenga imine

After removal under reduced pressure, toluene of the above mixture in it add 130 μl of tetrahydrofuran with 1% content of triethylamine, then add 13 ál of 2-[(2-hydroxyethyl) amino] 2-methylpropionitrile, prepared as described in example 22 the patent application EEC N 0494819, and again add 130 μl of tetrahydrofuran with 1% content of triethylamine. Then shaken for 30 min at room temperature and remove the solvent under reduced pressure.

Getting 2-trifluoromethyl 4-openconffile (obtained as described in the patent EEC N 0002892) (5 mol) in 25 cm3methanol is cooled to 0oC and add bromine (5.2 mol). Then the temperature of the solution is allowed to rise to room, shaken for 3 h, alkalinized by triethylamine and added an aqueous solution of sodium thiosulfate. After removing the solvent, extracted using chloroform, the organic phase is washed with water, dried and the solvent is evaporated, which allows to obtain a product used in the next step without additional processing.

Infrared spectrum (CHCl3< / BR>
NH2- 3612-3408 cm-1< / BR>
CN - 2230 cm-1< / BR>
Aromatic compounds - 1621-1556-1506 cm-1< / BR>
Example 16. 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5 - oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) 5-3Mr. benzonitrile.

The product obtained in the previous example, dissolved in 180 μl of water, heated to +100oC and add 60 ál of 2 N. hydrochloric acid. Then shaken for 5 min at boiling point and add about 600 mg of ice, and then extracted using ethyl acetate, washed with salt water, dried and receive 34,7 GBq (937 MCI) of product. After chromatography on silica (eluant : cyclohexane-ethyl acetate (60 : 40)) get 19 GBq is l) 2-(trifluoromethyl) benzonitrile.

Operations are as in example 22 the patent application EEC N 0494819 using at the initial stage 2 g isothiocyanate, obtained as described in example 13A, and 1.2 g of the corresponding aminonitriles. The result is 1.70 g of the target product.

Rf=0.25 in (eluant : methylene chloride-acetone (65 : 35)).

Infrared spectrum (CHCl3< / BR>
OH - 3630 cm-1< / BR>
=NH - 3314-1676 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1614-1578-1481 cm-1< / BR>
Example 18. 4- (4,4-dimethyl 3-(3-hydroxypropyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile.

The operations are carried out as in example 14 on the basis of 240 mg of the product obtained as described in example 17, resulting in a gain of 226 mg of the target product (tpl.= 149-150oC).

Rf=0,32 (eluant : methylene chloride-acetone (75 : 25)).

Infrared spectrum (CHCl3< / BR>
OH - 3626 cm-1< / BR>
C=O - 1763 cm-1< / BR>
CN - 2236 cm-1< / BR>
Aromatic compounds - 1615-1580-1504-1483 cm-1< / BR>
Example 19. 4-(4,4-dimethyl 3-(4 - hydroxybutyl) 5-imino-2 thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

Operations are as in example 22 the patent application EEC N 0494819 using at the initial stage 2 the ptx2">

Rf=0.25 in (eluant : methylene chloride-acetone (65 : 35)).

Infrared spectrum (CHCl3< / BR>
OH - 3630 cm-1< / BR>
=NH - 3314-1675 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1614-1577-1504 cm-1< / BR>
Example 20. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 14 on the basis of 300 mg of the product obtained as described in example 19, resulting in a gain of 236 mg of the target product (tpl.= 78-79oC).

Rf=0.31 in (eluant : methylene chloride-acetone (75 : 25)).

Infrared spectrum (CHCl3< / BR>
OH - 3624 cm-1< / BR>
C=O - 1762 cm-1< / BR>
CN - 2237 cm-1< / BR>
Aromatic compounds - 1615-1580-1504 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 232 N. m = 19500

Max. 232 N. m = 24000

Pereg. 266 N. m

Example 21. 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-imino-2 thioxo 1 - imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

Operations are as in example 22 the patent application EEC N 0494819 using at the initial stage 2.5 g of isothiocyanate and 1.56 g of the corresponding aminonitriles, resulting in a gain of 2.36 g of the target product.

Rf=0,23 (eluant : methylene chloride-acetone (92,5 : 7,5)).

-1< / BR>
C=N - 1675 cm-1< / BR>
Example 22. 4-(4,4-dimethyl 3-(2 - methoxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 14 on the basis of the product obtained as described in example 21, resulting in a gain target product (tpl.= 98-99oC).

Rf=0,32 (eluant : methylene chloride-acetone (99 : 1)).

Infrared spectrum (CHCl3< / BR>
C=O - 1757 cm-1< / BR>
CN - 2236 cm-1< / BR>
Aromatic compounds - 1615 - 1580-1504 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 232 N. m = 18200

Max. 254 N. m = 22400

Pereg. 265 N. m

Example 23. 4-(4,4-dimethyl 3-(1-methylethyl) 5-imino-2 thioxo 1 - imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

Operations are as in example 22 the patent application EEC N 0494819 using at the initial stage 2.5 g of isothiocyanate and of 1.32 g of the corresponding aminonitriles, resulting in a gain 880 mg of the target product.

Rf=0,20 (eluant : methylene chloride-acetone (96 : 4)).

Infrared spectrum (CHCl3< / BR>
=NH - 3310-1675 cm-1< / BR>
CN - 2236 cm-1< / BR>
Aromatic compounds - 1614-1580-1504 cm-1< / BR>
Example 24. 4-(4,4-dimethyl 3-(1-methylethyl) 5-oxo 2-thioxo 1-imidazolylidene as described in example 23, and 35 cm36 N. hydrochloric acid, then extracted using chloroform, resulting in a gain 744 mg of the target product (tpl.=203-204oC).

Rf=0.45 in (eluant : cyclohexane-ethyl acetate (1 : 1)).

Infrared spectrum (CHCl3< / BR>
OH - 3626 cm-1< / BR>
C=O - 1753 cm-1< / BR>
CN - 2232 cm-1< / BR>
Aromatic compounds - 1615-1580-1504 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 232 N. m = 18900

Max. 235 N. m = 22500

Pereg. 273 N. m

Example 25. 3-(3,4-dichlorophenyl 5,5-dimethyl 1-(3-hydroxypropyl) 4-imino 2-imidazolidinethione.

The operations are carried out as in example 51 patent application EEC N 0494819 using 2.4 g of isocyanate 3,4-dichlorophenyl and 1.6 g of the corresponding aminonitriles. After chromatography on silica (eluant : methylene chloride-acetone (6 : 4)) to obtain 2.16 g of the target product.

Rf=0.25 in.

Infrared spectrum (CHCl3< / BR>
OH - 3630 cm-1+ associerad.

C=NH - 3294-1676 cm-1(F)

Aromatic compounds - 1595-1569-1482 cm-1< / BR>
Example 26. 3-(3,4 - dichlorophenyl 5,5-dimethyl 1-(3-hydroxypropyl) 2-thioxo 4 imidazolidinone.

The operations are carried out as in example 52 patent applications EEC N 0494819 the BL is by using chloroform gain of 0.79 g of the target product (tpl.= 202-203oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1753 cm-1< / BR>
CN - 2232 cm-1< / BR>
Aromatic compounds - 1615-1580-1504 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 232 N. m = 18900

Max. 235 N. m = 22500

Pereg. 273 N. m

Example 27. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino-2 thioxo 1 - imidazolidinyl) 2-(trifluoromethyl) (5-3N) benzonitrile.

a) 4-amino 2-(trifluoromethyl) (5-3N) benzonitrile.

16 mg of 2-trifluoromethyl 4-amino 5 - bromobenzonitrile, 2 mg of palladium on charcoal, 200 μl of ethyl acetate and 6.5 μl of triethylamine is cooled to -180oC and mixed in an inert atmosphere, after which survive in the environment, tritium, allowing the temperature to rise to +20oC; pressure is 1,68 bar.

Then shaken to ensure absorption (R = 0,42 bar), cooled to -180oC, remove the excess tritium, allow the temperature to rise to +20oC, and then filtered, rinsed with ethyl acetate and concentrating the filtrate at a temperature of +40oC, under reduced pressure.

The result is 68 GBq target product.

b) 4-diisocyanate 2-(trifluoromethyl) (5-3N) benzonitrile.

In argon mix or of thiophosgene in chloroform.

Then shaken for 45 min at a temperature of +20oC, defend, re-extracted using chloroform, dried on magnesium sulfate, filtered and concentrated under reduced pressure.

Received diisocyanate used in the next step without additional processing.

b) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino-2 thioxo 1 - imidazolidinyl) 2-(trifluoromethyl) (5-3N) benzonitrile.

In thioisocyanate obtained in stage b), mix in argon 350 μl of tetrahydrofuran with 1% content of triethylamine and 20 ml of propanenitrile obtained as described above.

Then shaken for 2 h at a temperature of +20oC and concentrate at +20oC, under reduced pressure.

Imin used in the next step without additional processing.

Obtaining 2-(4-hydroxyethylamino) 2-methylpropionitrile used on stage).

Mix 550 μl of cyanhydrin of acetone and 500 μl of 4-amino - 1-butanol, shaken for 16 hours at a temperature of +20oC and use the thus obtained product in the next step without additional processing.

Example 28. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-CTI the keys 200 μl of 2 N. hydrochloric acid, boil for 5 min to boiling point, cooled to +20oC, diluted 1 cm3water, extracted using ethyl acetate, washed with water and concentrated under reduced pressure.

The crude product is purified by chromatography on silica (eluant : cyclohexane-ethyl acetate (6 : 4)).

The result of 2.8 GBq target product.

Example 29. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino-2 thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

a) 4-amino 2-(trifluoromethyl) benzo (14C) nitrile.

In a nitrogen atmosphere, mixed 377 mg cyanide copper (14C) (9 GBq) and 1,0732 g of 4-bromo 3- (trifluoromethyl) benzenamine 8 cm3of dimethylformamide.

Then heated for 4 hours at boiling temperature, then cooled to 0oC, diluted with 20 cm3acetone and filtered off the insoluble fraction, the filtrate is concentrated at +70oC under reduced pressure. The residue is taken with methylene chloride, filtered, and the filtrate concentrated under reduced pressure.

The resulting benzonitrile (14C) purified by chromatography on silica (eluant : methylene chloride-cyclohexane (70 : 30)).

14C) nitrile.

In a nitrogen atmosphere, mixed 189 mg benzonitrile (14C) obtained in step a), 2.7 cm3water and 85 μl of thiophosgene.

Then vigorously shaken for 5 min, add 30 ál of thiophosgene and shaken for 1 h at a temperature of +20oC, and then extracted using chloroform, washed with water, dried and concentrated under reduced pressure.

Thus obtained diisocyanate used in the next step without additional processing.

b) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino-2 thioxo 1 - imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

In thioisocyanate obtained in stage b), add in a nitrogen atmosphere, 2 cm3tetrahydrofuran (THF), propanenitrile obtained as indicated below, dissolved in 1.5 cm3of methylene chloride, and 150 μl of triethylamine.

Then heated for 30 minutes at boiling temperature and concentrate under reduced pressure.

Thus obtained Imin used in the next step without additional processing.

Obtaining 2-(4-hydroxyethylamino) 5 - methylpropionitrile used on stage).

Mix 220 ál cyanhydrin acetone is chloride, dry, filter and concentrate the filtrate under reduced pressure.

Thus obtained propanenitrile used in the next step without additional processing.

Example 30. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2 - thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

To imine obtained in example 29, add 6 cm3methanol and 1.6 cm32 N. hydrochloric acid.

Then cook for 45 minutes to boiling point, cooled to +20oC, diluted with 10 cm3water is extracted using methylene chloride, washed with water and concentrated under reduced pressure.

The crude product is purified by chromatography on silica (eluant : ether-acetonitrile-cyclohexane(50 : 15 : 35)).

As a result, 328 mg of the target product.

Example 31. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 2-(trifluoromethyl) (5-3N) benzonitrile.

a) 4 - amino 2-(trifluoromethyl) (5-3N) benzonitrile.

The operations are carried out as in stage a) of example 27 using 16 mg of 4-amino 5-bromo - 2 triftormetilfosfinov, 2 mg of palladium on charcoal, 200 μl of ethyl acetate, and 6.5 μl of ethyl) (5-3N) benzonitrile.

In argon mix 34 GBq obtained above titiraupenga amino, 100 μl of a 20% solution of phosgene in toluene.

Then heated for 1 h to a temperature of +80oC, again add 100 ál of phosgene and heated for 1 h at +80oC, repeat this operation once more and concentrate at a temperature of +20oC, under reduced pressure.

The resulting isocyanate is used in the next step without additional processing.

b) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1 - imidazolidinyl) 2-(trifluoromethyl) (5-3N) benzonitrile.

In the isocyanate obtained in stage b), mix in argon 200 μl of methylene chloride, 50 μl chlormethiazole solution propanenitrile obtained as indicated below, and 20 μl of triethylamine.

Then shaken for 30 min, again add 50 ál of solution propanenitrile and shaken for another 30 min at a temperature of +20oC, under reduced pressure.

Imin used in the next step without additional processing.

Obtaining 2-(4-hydroxyethylamino) 2-methylpropionitrile used on stage).

Mix 220 ál cyanhydrin of acetone and 200 MCD and dried on magnesium sulfate.

Settled thus the solution is used in the next step without additional processing.

Example 32. 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) (5-3N) benzonitrile.

To imine obtained in example 31, add 200 ál of methanol, 50 μl of 2 N. hydrochloric acid, boil for 45 minutes to boiling point, cooled to +20oC, diluted 1 cm3water is extracted using methylene chloride, washed with water and concentrated at a temperature of +20oC, under reduced pressure.

The crude product is purified by chromatography on silica (eluant : methylene chloride-ethyl acetate (7 : 3), and then (5 : 5)).

The result is 16 GBq target product.

Example 33. 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

a) 4-amino 2-(trifluoromethyl) benzo (14C) nitrile.

The operations are carried out as in stage a) of example 29 using 377 mg cyanide copper (14C), 1,0732 g of 4-bromo 3-triftorperasin and 8 cm3of dimethylformamide.

The result 0,558 g (6,62 GBq) of the target product.

b) 4-isocyanate 2-(trif, cm3dioxane and 1 cm320% solution of phosgene in toluene.

Then the resulting solution was heated for 22 hours at a temperature of +60oC and concentrate at +60oC, under reduced pressure.

Thus obtained isocyanate used in the next step without additional processing.

b) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1 - imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

In the isocyanate obtained in stage b), add in a nitrogen atmosphere, 1.5 cm3of methylene chloride (siliporite NK 30), propanenitrile obtained as in example 31, dissolved in 1.5 cm3of methylene chloride, 150 μl of triethylamine.

Then shaken for 1 h at a temperature of +20oC, then concentrated under reduced pressure.

Imin used in the next step without additional processing.

Example 34. 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile.

To imine obtained in example 33, add 5 cm3methanol and 1.2 cm31 N. hydrochloric acid, and then bring over 40 min to boiling point and then cooled to +20oC, diluted with 10 cm3

The crude product is purified by chromatography on silica (eluant : ether-acetonitrile-cyclohexane(50 : 15 : 35)).

As a result, 289 mg (1.26 in GBq) of the target product.

Example 35. 4-(2,5-dioxo 4,4-dimethyl 3-(4-triphenylmethyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

For 16 h at room temperature, shaken 370 mg of the product obtained in example 1, 307 mg of triphenylmethylchloride in the presence of 10 mg of 4 - dimethylaminopyridine, 0.25 cm3of triethylamine and 4 cm3of dimethylformamide. Then heated for 4 hours at a temperature of +40oC, poured into water, extracted using ether, washed with water, dried, remove the solvent under reduced pressure and the residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (75:25)). The result of 467 mg of the target product

(Rf= 0.25 in).

Infrared spectrum (CHCl3< / BR>
C=O - 1778-1725 cm-1(F)

CN - 2235 cm-1< / BR>
Aromatic compounds - 1615-1597-1505-1490 cm-1< / BR>
Example 36. 4-(2,5-dioxo 4,4-dimethyl 3-(4-phenylmethoxy) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

To 370 mg of the product obtained in example 1 dissolved in 4 cm33
brombenzene and 40 mg iodotope tetrabutylammonium. After half reactions add an identical amount of each of the reagents, shaken for 1 h, poured into ice-cold aqueous solution of primary potassium phosphate and extracted using ether, washed with water, dried, remove the solvent under reduced pressure and the residue is subjected to chromatography on silica (eluant : methylene chloride-acetone (99 : 1)). The result is 140 mg of the target product (tpl.= 75 - 76oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1615-1580-1505-1497 cm-1< / BR>
Example 37. 4-[4,4-dimethyl 2,5-dioxo 3-(4-methoxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

To 370 mg of the product obtained in example 1 dissolved in 3 cm3of dimethylformamide, add a few tricks of 50 mg of sodium hydride, shake for 20 minutes, add 0,06 cm3under the conditions, shake for 1 h, the newly added 50 mg of sodium hydride, and then, after 20 min 0,06 cm3under the conditions. After this reaction medium was poured into water, extracted using ether, washed with water, dried, the solvent is evaporated and Podoroga product (tpl.= 80-81oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1(F)

CN - 2234 cm-1< / BR>
Aromatic compounds - 1616-1576-1505 cm-1.

OCH3- 2830 cm-1< / BR>
Example 38. 4-[3-(4-chlorobutyl) 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 2 using at the initial stage 600 mg of the product obtained in example 8 of the patent application EEC N 0494819, and 660 mg of 1-chloro 4-iodobutane dissolved in 1 cm3of dimethylformamide, cooled to +5oC. the result 604 mg of the target product (tpl.= 80-81oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1(F)

CN - 2238 cm-1< / BR>
Aromatic compounds - 1616-1575 - 1505 cm-1< / BR>
Example 39. 4-[3-[4-[(methylsulphonyl) oxy] butyl] 4,4 - dimethyl 2,5-dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile.

to 0.17 cm3methanesulfonanilide add to 740 mg of the product obtained in example 1 dissolved in 7.4 cm3pyridine, and 24 mg of 4 - dimethylaminopyridine. Then shaken for 1 h, poured into ice water, extracted using methylene chloride, washed with water, is removed by distillation OST is ltate get what 771 mg of the target product.

Infrared spectrum (CHCl3< / BR>
C=O - 1779-1725 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1615-1575-1505 cm-1< / BR>
- 1361-1175 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 261 N. m = 14900

Pereg. 279-297 N. m

Example 40. 4-(3-acetyl-4,4-dimethyl 2,5 - dioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 2 using at the initial stage 420 mg of the product obtained in example 8 of the patent application EEC N 0494819, and double-0.1 cm3acetylchloride. After chromatography on silica (eluant : methylene chloride-ethyl acetate (98 : 2)) receive 334 mg of the target product (tpl.= 129-130oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1800-1740-1717 cm-1< / BR>
CN - 2240 cm-1< / BR>
Aromatic compounds - 1616-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 250 N. m = 12000

Pereg. 274-284 N. m

Example 41. 4-(3-benzoyl 4,4 - dimethyl 2,5-dioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 2 using at the initial stage 300 mg of the product obtained in example 8 of the patent application EEC N 0494819, and double-0,12 cm3of benzoyl chloride, dissolved in 0.5 cm3digitiform is the product (tpl.= 179-180oC).

Infrared spectrum (CHCl3< / BR>
C=O - 1800-1780-1746-1699 cm-1< / BR>
CN - 2235 cm-1< / BR>
Aromatic compounds - 1617-1600-1580-1504 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 250 N. m = 28500

Pereg. 275 N. m = 6500

Pereg. 263 N. m = 3850

Example 42. 4-[3-[dimethyl (1,1-dimethylethyl) silyl] 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile.

The operations are carried out as in example 2 using at the initial stage 450 mg of the product obtained in example 8 of the patent application EEC 0494819, and 300 mg of dimethyl-tert-butylchloride 2 cm3of dimethylformamide. After chromatography on silica (eluant : methylene chloride-acetone (99 : 1)) receive 527 mg of the target product (tpl.= 147-148oC).

Infrared spectrum (CHCl3< / BR>
CN - 2236 cm-1< / BR>
Aromatic compounds - 1615-1579-1505 cm-1< / BR>
Ultraviolet spectrum - EtOH

Max. 258 N. m = 17000

Pereg. 275-285 N. m

In addition to the above products in the framework of the present invention can be obtained the following products of formula:

< / BR>
in which YArepresents an oxygen atom or sulfur, and R3Ahas the following values:

SUB>)nCN

in which

alk, alk1and alk2represent an alkyl radical with up to 4 carbon atoms, and n takes an integer value from 1 to 4.

Example 43.

There were prepared tablets that meet the following formula:

- 4-(5-oxo-2-dioxo-3,4,4-trimethyl 1-imidazolidinyl)

- 2-(trifluoromethyl) benzonitrile 100 mg

The basis for the finished tablets 300 mg

(Detailing the basics : lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

1. The study of the impact of the products of the invention on the androgen receptor.

Androgen receptor

Male rats Sprague-Dawley EOPS (weighing 180 to 200 g), castrated within 24 h, wordplays, after which they cut prostate, weighed and homogenized at a temperature of 0oC using tubular grinder glass-glass in buffered solution (Tris 10 mmol, sucrose 0.25 mol, PMSF (phenylmethanesulfonyl) 0.1 mmol, sodium molybdate 20 mmol, HCl pH 7,4, to which add 2 mmol DTT (DL dithiothreitol) at the rate of 1 g of tissue in 8 ml of buffer solution.

Then the homogenate was subjected to ultracentrifugation (209 000 g for 30 min) at temperatures for 24 h at a temperature of 0oC at a constant concentration (T) titiraupenga testosterone, and in the presence of increasing concentrations (from 0 to 250010-9mol) or cold testosterone or of the products tested. The concentration associated titiraupenga testosterone (In) is measured and then each incubate by adsorption by charcoal-dextran.

The calculation of the relative binding effects (ARL).

Draw two curves: the percentage associated titiraupenga hormone a/T depending on the logarithm of the concentration of cold control hormone and a/T depending on the logarithm of the concentration of cold tested product. Then determine the direct equation I50= (B/Tmax+ B/Tminutes)/2,

in which a/Tmax= % associated titiraupenga hormone for an incubation of this titiraupenga hormone at a concentration So

A/Tminutes= % associated titiraupenga hormone for an incubation of this titiraupenga hormone at a concentration of T in the presence of a large excess of cold hormone (250010-9mol).

The intersection of the line I50and curves allow us to calculate the concentration of cold control hormone (CH) and cold test product (CX) which donkey the product is determined using equation ARL = 100 (CH) / (CX).

You get the following results, expressed in ARL (see tab. 1).

2. The definition of androgenic or antiandrogenna activity of products of the invention with the dosage of ornithine - decarboxylase.

The Protocol of the experiment

Six-week and castrated within 24 h of the male mice was hanging entering through the mouth or subcutaneously investigational products (0,5% suspension in methylcellulose or solution in ethanol), while subcutaneous injection of testosterone propionate at the rate of 3 mg/kg (solution in corn oil) to determine antiandrogenna activity. Agonistic activity determined in the absence of testosterone propionate.

The testosterone propionate is injected at a rate of 10 ml/kg.

After 20 h after entering the drug animals wordplays, then they cut out the kidneys and homogenized at a temperature of 0oC using the shredder Teflon-glass in 10 volumes of buffer Tris - HCl 50 mmol (pH 7,4) containing 250 µmol of phosphate pyridoxal, 0.1 mm EDTA and 5 mmol of dithiothreitol. Then the homogenate was centrifuged (209 000 g for 30 min).

The principle of dosage

At a temperature of +37oC renal ornithine-decarboxylase converts the mixture holh">

Then putrescine collect on selective ion exchange paper. After drying the excess untransformed tretirovanie and cold ornithine is removed by three washes with ammonia molar concentration of 1 mol/L. the Paper is dried, after which the radioactivity is determined by adding the scintillator equality.

The results are expressed in moles (10-15mol) formed titiraupenga of putrescine / h / mg protein.

The results are expressed in % inhibition ODL control hormones affected only one propionate testosterone (see table.2).

Test A : the Products are injected subcutaneously at the rate of 1.5 mg/kg at a volume of 10 µl.

Test B : the Products are introduced through the mouth at a rate of 1 mg/kg

Test : Products are introduced through the mouth at the rate of 3 mg/kg

The above tests show that the tested products of the invention possess high antiandrogenna activity and devoid of agonistic activity.

1. Substituted phenylimidazoline General formula I

< / BR>
in which R1is cyano or halogen;

R2- triptoreline radical or halogen;

-A - b - is selected from the group

< / BR>
how many radicals, selected from hydroxyl, halogen, phenyl, or-S-phenyl, where the phenyl radical may be substituted with halogen or alkoxygroup, carboxylation, free or esterified, morpholino, and alkalemia radicals, in addition, may be interrupted by one or more oxygen atoms or sulfur, and all sulfur atoms, if necessary, can be oxidized to a sulfoxide or sulfone, trialkyl acyl;

Y is an oxygen atom or a radical = NH.

2. Connection on p. 1 of the formula I in which Y is an oxygen atom, except for products in which the group-a-b - radical

< / BR>
in which X is an oxygen atom;

R3is a hydrogen atom;

R2is a halogen atom or trifluoromethyl;

R1is a halogen atom.

3. Connection PP.1 and 2 of the formula I in which the group-a-b - radical

< / BR>
in which X is a sulfur atom;

R3has the meaning specified in paragraph 1.

4. Connection on p. 3 of the formula I, in which R3is a hydrogen atom or an alkyl radical containing not more than 4 carbon atoms, with the possibility of substitution of the hydroxyl radical.

5. Connection on p. 1 of the formula I, in which R1the chlorine atom.

6. Connection PP.1 and 2 of the formula I, in which the group And the s carbon with the ability to replace and terminate one or more oxygen atoms or sulfur, with the possibility of oxidation of the sulfur atom.

7. Connection on p. 6 of the formula I, in which R3is an alkyl radical comprising 2 to 4 carbon atoms substituted by a chlorine atom or a radical such as 4-fortunaltely, with the possibility of oxidation of sulfur in becoming sulfoxide or sulfon.

8. Connection on p. 1 of formula I, which are the following connections:

-4-[4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo-1-imidazolidinyl] -2-(trifluoromethyl)benzonitrile;

-4-[4,4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl] -2-(trifluoromethyl)benzonitrile.

9. Connection on p. 1 of formula I, which are the following connections:

-3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidinethione acid;

-4-(4,4-dimethyl, 2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile.

10. The method of obtaining compounds of General formula I on p. 1, characterized in that in the presence of a tertiary base spend the interaction of the compounds of formula II

< / BR>
in which R1, R2and X have the above values,

connection formwalt to be protected, and R1- microradian or halogen atom, if R2the halogen atom or the radical CF3and X is an oxygen atom, can not be a hydrogen atom, to obtain the compounds of formula IV

< / BR>
in which R1, R2, X and a have the above meanings, and, if desired, the compound of formula IV remove possible protective group radical, or is subjected to hydrolysis group with the conversion of the keto group, or make a group in the group or make a group in the group or treated with the compounds of formula IV, in which the hydrogen atom, the compound of the formula in which matter except hydrogen, and Hal is a halogen atom, to obtain the compounds of formula I in which the group-a-b - group

< / BR>
which has the specified values,

if desired, followed by removal of the protective groups of the radical with the separation of the target product in the form of an ether, amine or salt.

11. The method of obtaining compounds of General formula I on p. 1, characterized in that in the presence of tertiary bases interact the compounds of formula II

< / BR>
in which R1, R2and X have the above values,

with the compound of the formula III

< / BR>
which has the value specified EOD,

to obtain a product of formula IV

< / BR>
in which X, R1, R2and have the specified values,

and, if desired, removing the possible protective group radical, or make a group in the group or, if necessary, the group in the group or treated with the compounds of formula IV, in which the hydrogen atom, the compound of the formula in which matter except hydrogen, and Hal is a halogen atom, to obtain the compounds of formula I, in which the group-a-b - group

< / BR>
which has a specified value,

followed, if desired, removing the protective groups of the radical with the separation of the target product in the form of an ether, amine or salt.

12. The method of obtaining compounds of formula I on p. 1, wherein interact compounds of the formula

< / BR>
in which Hal and have the specified values,

with the compound of the formula IV

< / BR>
where R1, R2have the specified values,

to obtain the compounds of formula IV

< / BR>
where R1, R2have the specified values,

and, if desired, the resulting compound to remove the possible protective group radical, or turn the group into a group, followed, if necessary, the allocation of target UB> and Y have the above values,

and group

< / BR>
selected from among radicals

< / BR>
in which X is an oxygen atom or sulfur,

and selected among the values of R3containing protected functional group as intermediate products.

14. Pharmaceutical composition having antiandrogenna activity, containing a derivative of phenylimidazoline as the active agent and a base, characterized in that as a derivative of phenylimidazoline it contains a compound of formula I under item 1 as an effective dose.

 

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