HU211330A9 - Phenylimidazolidines having antiandrogenic activity - Google Patents

Description

TECHNICAL STATE

The present application is a continuation of the continuation-in-part of U.S. Patent Application No. 819,910, filed January 9, 1992, where the original application was withdrawn.

Japanese Patent Application No. 48 087 030 discloses 3-phenyl-2-thiohydantoin derivatives, which are described as inhibiting the germination of certain plants. U.S. Patent 4,097,578 discloses imidazolidine derivatives that are different from the present compounds of formula (I) and which possess antiandrogen activity. U.S. Patent Nos. 3,823,240, 4,873,256, 4,407,814, 4,482,739, and 4,234,736 are related to the subject matter of the present invention.

OBJECTIVE OF THE INVENTION

It is an object of the present invention to provide new compounds of formula I, a new process and intermediates for their preparation.

The present invention also relates to novel antiandrogen compositions and to a novel method for inducing antiandrogen activity in warm-blooded animals.

The objects of the invention and the advantages of the invention will be described in detail below.

THE INVENTION

In the compounds of formula I according to the invention

Rj is cyano or nitro. or halogen;

R ₂ is trifluoromethyl or halogen; -AB represents a group of the formula (a) or (b) in which

X is oxygen or sulfur. and R ₃ is

- hydrogen,

alkyl, alkenyl, alkynyl, aryl or arylalkyl groups having up to 12 carbon atoms, optionally substituted with one or more substituents;

hydroxy, halogen, mercapto, cyano, C 17 acyl or acyloxy, aryl, Oaryl, Ο-aralkyl, S-aryl, wherein the aryl groups have up to 12 carbon atoms and optionally aryl and the aralkyl group is substituted by halogen, -CF ₃ , alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alkynyloxy groups, wherein the sulfur atom is optionally oxidized to sulfone or sulfoxide,

- free carboxylic acid, esterified, amide or salt converted.

—NH ₂ , mono- or dialkylamino, and

- a 3-6 membered heterocyclic ring containing at least one heteroatom such as oxygen, sulfur or nitrogen, wherein the alkyl, alkenyl and alkynyl groups are optionally interrupted by at least one oxygen, nitrogen or sulfur atom, wherein the sulfur atom is optionally sulfoxide or is oxidized to sulfone,

- a trialkylsilyl group in which the alkyl group contains from 1 to 6 carbon atoms, and

a C 1-7 acyl or acyloxy group derived from an organic carboxylic acid, and

Y is oxygen or sulfur, or = NH, provided that -AB is not a group of formula (a) wherein X is oxygen and R ₃ is hydrogen, and Y is oxygen or a> NH and R ₂ is halogen or trifluoromethyl; and R 1 is nitro or halogen.

The terms used in the meaning of R ₃ are interpreted as follows.

Examples of alkyl groups having up to 12 carbon atoms are the following: methyl, ethyl, straight or branched propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl or dodecyl.

Preferred alkyl groups include C 1-6, most preferably methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl, tert-butyl, straight or branched pentyl, straight or branched hexyl. .

Alkenyl having up to 12 carbon atoms, preferably 4 carbon atoms, includes vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl.

Most preferred of the alkenyl groups are allyl and chilled.

Alkynyl having up to 12 carbon atoms, and preferably alkynyl having 2 to 4 carbon atoms, means ethynyl, propargyl, butynyl, pentynyl or hexynyl.

Among the alkynyl groups, propargyl is preferably used.

By aryl is meant an aryl group of carbon atoms, such as phenyl or naphthyl, and also a heterocyclic aryl group, wherein the heterocyclic aryl group has 5 to 6 members and contains one or more heteroatoms such as oxygen, sulfur or nitrogen. 5-membered heterocyclic aryl groups include furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl. isoxazolyl.

6-membered heterocyclic aryl groups include pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Examples of fused aryl groups include indolyl, benzofuranyl, benzothienyl and quinolinyl.

Of the aryl groups, phenyl is preferred.

The term aralkyl means a group which is optionally substituted alkyl

It is composed of A9 and optionally substituted aryl, wherein alkyl and aryl have the same meaning as previously defined.

Preferably the aryl group is benzyl, phenylethyl or triphenylmethyl.

Halogen means fluorine, chlorine, bromine or iodine.

Preferably, fluorine, chlorine or bromine are used.

Examples of alkyl substituted with one or more halogen atoms are: monofluoro, chloro, bromo or iodo-methyl, difluoro, dichloro or dibromomethyl, trifluoromethyl.

Substituted aryl or aralkyl groups are those in which the phenyl group is substituted with a fluorine atom, a methoxy group or a trifluoromethyl group.

Acyl is preferably C 1 -C 7 acyl, such as acetyl, propionyl, butyryl or benzoyl; but we can use valeryl, hexane. acryloyl. also a crotonoyl or carbamoyl group; we would also like to mention the formyl group.

The term acyloxy refers to groups wherein the acyl moiety has the same meaning as defined above, such as acetoxy or propionyloxy.

An esterified carboxy group means an alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

Residues of the easy-to-ester ester groups include, for example, methoxymethyl or ethoxymethyl; among the acyloxyalkyl groups are pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl and acetoxyethyl; among the alkyloxycarboyloxyalkyl groups are methoxycarbonyloxymethyl and ethyl groups, isopropyloxycarbonyloxymethyl and ethyl groups.

Similar ester groups are listed in European Patent 0 034 536.

By carboxamide is meant a group of the formula (c) wherein R _e and R ₇ are the same or different hydrogen, C 1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or a tert-butyl group.

Suitably, the radicals of formula (d) are amino, mono- or dimethylamino.

The group of formula (d) may also be a heterocyclic group which may optionally contain an additional heteroatom. These include pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, indolyl, piperidine, morpholino, piperazinyl. Of these groups, piperidino and morpholino are preferred.

By the converted carboxy group is meant salts formed with an equivalent amount of sodium, potassium, lithium, calcium, magnesium or ammonium. Also mentioned are salts with organic bases, such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine.

Preferably, a sodium salt is formed.

Alkylamino means, for example, methylamino, ethylamino, propylamino or straight or branched butylamino. Preferably, C 1 -C 4 alkyl is used wherein the alkyl group may be as defined above.

Examples of dialkylamino groups include dimethylamino, diethylamino, methylethylamino. Suitable alkyl groups include those listed above with 1 to 4 carbon atoms.

Examples of heterocyclic groups containing one or more heteroatoms include saturated monocyclic, heterocyclic groups such as oxiranyl, oxolanyl, dioxolanyl, imidazolinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

Alkyl, alkenyl or alkynyl groups optionally interrupted by a heteroatom, wherein the heteroatom is sulfur, oxygen or nitrogen, contain one or more identical or different atoms as defined above. These heteroatoms naturally cannot be located at the end of the group. Examples of such groups include alkoxyalkyl groups such as methoxymethyl, methoxyethyl, methoxypropyl and methoxybutyl; examples include alkoxyalkoxyalkyl groups such as methoxyethoxymethyl.

Trialkylsilyl, where alkyl has up to 6 carbon atoms, means groups such as trimethylsilyl, triethylsilyl, (1,1-dimethylethyl) dimethylsilyl.

In the case where the compound of formula (I) contains an amino group which may form a salt with an acid, these salts are also within the scope of the invention. Among the salts are those formed with hydrochloric acid and methanesulfonic acid.

Preferably may be prepared according to the invention (I), compounds of formula are prepared in which Y represents an oxygen atom, with the exception of compounds which is -AB group (a) a group of formula wherein X is oxygen and R ₃ represents a hydrogen atom and R ₂ is halogen or trifluoromethyl and R 1 is nitro or halogen.

Particularly preferred among these compounds are those wherein -AB is a group of formula (a) wherein X is sulfur and R ₃ is as defined above.

Particularly preferred are compounds wherein R ₃ is hydrogen or C 1-4 alkyl optionally substituted with hydroxy or methoxy.

Of these compounds, those

A9 wherein R1 is cyano or a halogen atom, preferably chlorine.

A preferred group of compounds of the present invention are those wherein -AB is (e) or (f), wherein R ₃ is optionally substituted alkyl or alkenyl of up to 6 carbon atoms, which may be optionally substituted with one or more optionally oxidized oxygen or sulfur atoms; and wherein R ₃ is an optionally substituted aralkyl or acyl group or a trialkylsilyl group.

Preferred compounds of the invention are those wherein R ₃ is C 1-6 alkyl optionally substituted with halogen, free or esterified hydroxy or carboxy, heterocyclic, O-araHdl or S-aryl. wherein the aryl groups are optionally substituted with one or more halogen or alkoxy groups and wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone group; particularly preferred are those compounds wherein R ₃ is C 2 -C 4 alkyl substituted with a chlorine atom or an ethoxycarbonyl, tert-butoxycarbonyl or cyclopentyloxycarbonyl, 4-fluorophenylthio group, wherein in the latter group the thio group is optionally oxidized to a sulfoxide or sulfone group, and wherein the alkyl group is substituted by morpholino, phenylmethoxy, triphenylmethoxy or methylsulfonyloxy.

Further preferred are compounds wherein R ₃ is acetyl, benzoyl or (1,1-dimethylethyl) dimethylsilyl.

The present invention also relates to compounds of formula (I) wherein R 1, R ₂ and R ₃ are as defined above for formula (I), except for compounds wherein R , is nitro, _R2 is trifluoromethyl, and R ₃ is hydrogen.

Preferred compounds include the following compounds of formula (I):

4- (5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile,

4- (4,4-dimethyl-5-oxo-2-thioxo-1-imidazolyl) -2-trifluoromethylbenzonitrile,

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

3- (3,4-dichlorophenyl) -2-thioxo-1,5,5-trimethyl-4-imidazolidinone, 1- [4-nitro-3- (trifluoromethyl) phenyl] -3,4, 4-trimethyl-2,5imidazolidinon,

4- [4,5-dihydro-4,4-dimethyl-5-oxo-2 - {(phenylmethyl) thio) -1H-imidazol-1-yl] -2- (trifluoromethyl) benzonitrile,

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

4- [4,4-dimethyl-2,5-dioxo-3- (4-hydroxy-DEOXY) -l-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-imidazolidin-butanoic acid.

The compounds of formula (I) and salts of these compounds may be prepared as follows:

(II) a compound of the formula: - wherein R ,, R ₂ and X are as described in Formula (I) is reacted with a compound of formula (IH) of a tertiary base in the presence of the same meanings as R _'3 is R _3' report, with the exception that the optionally reactive function present is optionally protected, provided that when R is nitro or halogen, R ₂ is halogen or trifluoromethyl and X is oxygen, then R ' ₃ is other than hydrogen, and the resulting compound of formula IV, wherein R 1, R ₂ , X and R' ₃ are the same as above - optionally undergo the following reaction:

a) removing the protecting group optionally present in R '₃;

b) hydrolyzing the > C = NH group to a ketone group and optionally converting > C = S group to > C = O group;

c) converting> C = O into> C = S,

d) Compounds of formula IV wherein R ' ₃ is hydrogen and compounds of formula IV obtained after the conversion of> C = NH to a ketone group with a compound of formula HalR ₃ wherein R ₃ is R' ₃ the same, except that it cannot be hydrogen, Hal is halogen, to give compounds of formula (I) wherein the -AB group is of formula (g), or represents a group of formula under the group of formula (b) each of (h), wherein, R ₃ is as defined above, followed, if desired, where R ₃ substituent optionally present protective group is removed, if desired, esterification, amide formation or salt formation is carried out ;

or reacting a compound of formula (II) wherein R 1, R ₂ and X are as defined above with a compound of formula (ΙΙΓ) in the presence of a tertiary base - R ₁₃ is as defined above and Q is a an alkali metal such as sodium or C1-6 alkyl - to provide (IVa) compound is obtained - wherein X, R _b R ₂ and R _'3 are as defined above - and, if desired, the resulting compound in any order one or undergo several of the following reactions:

a) removing the protecting group optionally present in R '₃;

b) converting> C = O to> C = S or, if desired, converting> C = S to> C = O,

c) if desired, R 'is replaced by a hydrogen atom at R ₃

GB 211 330 A9 talmazó (IVa) compounds of the formula is reacted with a Hal-R ₃ compound of the formula: - wherein R ₃ is R 'equal to ₃ meaning as A except that the hydrogen does not mean, and Hal represents a halogen atom - in this way is Compounds of formula (I) are obtained wherein the -AB group is replaced by a compound of formula (g) of formula (a) or a compound of formula (h) of formula (b): wherein R ₃ is as defined above, optionally deprotected or optionally esterified, amidated or salt-formed, or with a reagent of formula Hal-R ₃ wherein Hal and R ₃ are as defined above ) wherein R _b and R ₂ are as defined above and reacting the resulting compound of formula (IV) wherein R 1, R ₂ and R are as defined above, optionally in one or more of the following reactions:

a) deprotection of the optional R ₃ substituent and, if desired, esterification, amidation or salt formation of the compound;

b) converting> C = O present in the compound to> C = S.

The reaction of the compounds of formula (II) with the compounds of formula (III) is conveniently carried out in an organic solvent; as solvent, for example, tetrahydrofuran or dichloroethane, or ethyl ether or isopropyl ether.

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

The reactive group optionally present in R _{3 is} optionally protected in the compounds of formula (III), (IVa) and (IV); these reactive groups may be hydroxy or amino. Generally known protecting groups may be used to protect these groups. Examples of protecting groups for amino include tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, triethyl, formyl, and benzyloxycarbonyl.

Examples of protecting groups for hydroxy include formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert-butyldimethylsilyl.

In addition to the protecting groups listed above, other protecting groups may be used, such as those known in peptide chemistry. Such protecting groups are described in French Patent No. 2,499,995; the disclosure of which is hereby incorporated by reference.

Deprotection may be accomplished as described in the aforementioned U.S. Patent No. 2,499,995. Acid hydrolysis is conveniently employed to remove the protecting groups; hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid or trifluoroacetic acid.

Hydrochloric acid is preferred.

Optionally, the conversion of the > C = NH group to the ketone group can be accomplished by hydrolysis using an acid, for example hydrolysis with aqueous hydrochloric acid, for example under reflux.

In the case of hydrolysis of a group of> C = NH to a ketone by a molecule which also contains a group of> C = S, this group is converted to the group of> C = O during hydrolysis. The free OH group optionally simultaneously present in R ₃ can be converted to a SH group.

The conversion of> C = O into> C = S is the so-called. Lawesson's reagent (the chemical structure of which is represented by Formula (L)) is commercially available, for example, from FLUKA; the use of this reagent is described in detail in Bull. Soc. Chim. Belg. 87, No. 3, p. 229 (1987)].

In the event that two> C = O functional groups are to be converted into two> C = S functional groups, this operation is carried out in the presence of excess Lawesson reagent. This is also the case when starting with a molecule having a> C = S group and a> C = O group and converting the> C = O group to a> C = S group.

Conversely, in the case of two molecules containing > C = O, only one group is desired to be converted to > C = S, the operation is carried out in the presence of a small amount of Lawesson's reagent. In this case, a mixture of three products is obtained; two products having a > C = O and a > C = S, and third, a compound having two > C = S groups. These compounds can be isolated by chromatography.

The reaction of compounds of formula (IV), (IVa) and (IV ') with Hal-R ₃ is carried out in the presence of a strong base; a strong base is sodium or potassium hydride. The operation is carried out in the presence of a phase transfer catalyst and a quaternary ammonium salt; the latter salt being tert-butylammonium.

The protecting group on R ₃ may be one of the groups mentioned above for R ₃ . Deprotection may be carried out as described above.

The removal of the tert-butyldimethylsilyl group with hydrochloric acid is detailed in the following examples.

Optional esterification of the hydroxy group at the R ₃ substituent in the compound of formula (I) may be carried out in conventional manner. An acid or a functional derivative thereof may be used, for example, an acid anhydride such as acetic anhydride in the presence of a base such as pyridine.

The compounds of formula I are R ₃ substituents

The COOH group present in the A9 compound may be optionally esterified or converted to a salt by conventional means.

Amidation of the COOH group in the R ₃ substituent of the compounds of formula (I) is carried out in a conventional manner. For the conversion, a primary or secondary amine is used, and the reaction is carried out with an acid derivative such as a symmetric or mixed anhydride.

The present invention also relates to the preparation of compounds of formula (I): wherein R 1, R ₂ , -AB- are as defined above for R 1, R ₂ and -AB. provided that when -AB- is a -CO-N (R ' ₃ ) - group in which R' ₃ is hydrogen or C 1-7 straight or branched alkyl and Y is oxygen then R 1 is cyano; this process is carried out by reacting a compound of formula (V) wherein R and R ₂ is as defined above and Hal is a halogen reaction with a compound of formula VI wherein -AB- and Y are as defined above, in the presence of a catalyst and optionally a solvent.

In Formula V, Hal is preferably chlorine, but may also be bromine or iodine.

The catalyst used in the reaction is to bind the liberated hydrogen halide and thus facilitate the condensation reaction between the compounds of formula (V) and (VI) to give the desired product.

In a preferred embodiment of the process according to the invention, the metal is used as a catalyst, in its natural state or in its oxidized form, and a base may be used.

The catalyst may be a metal in its natural state or a metal oxide or a metal salt. The catalyst may also be a base. When used as a catalyst, the metal is preferably copper or nickel.

If a metal salt is used, the salt may be chloride or acetate.

When the base is used as the catalyst, the base may be, for example, sodium or potassium hydroxide, and, if desired, dimethyl sulfoxide may be added.

In a preferred embodiment, the catalysts used in the process of the present invention are divalent copper oxide, trivalent copper oxide, metal copper, and an alkali such as sodium or potassium hydroxide.

Naturally, the metal used as catalyst is preferably in powder form.

A preferred embodiment of the process according to the invention is the use of divalent copper oxide as catalyst.

High-boiling ethers such as phenyl oxide, diglyme are preferably used as solvents. triglyme or dimethylsulfoxide; however, high boiling oils such as paraffin oil or petroleum jelly may also be used.

In a preferred embodiment of the process of the invention, the process is carried out in the presence of an ether-type solvent selected from the group consisting of phenyl oxide, diglyme, triglyme and dimethylsulfoxide.

A very preferred embodiment of the process according to the invention is the use of phenyl oxide or triglyme as a solvent.

The process according to the invention may be carried out under pressure or at atmospheric pressure, preferably at high temperature.

The process according to the invention is conveniently carried out at temperatures above 100 ° C, preferably above 150 ° C. The process of the invention is conveniently carried out as described above, in which case the reaction time is more than 2 hours.

A particular aspect of the process of the present invention is that the operation is carried out in the presence of copper oxide in triglyceride at temperatures above 200 ° C for more than 3 hours.

The pharmaceutical compositions of the present invention contain an effective amount of at least one compound of Formula I, a nontoxic pharmaceutically acceptable salt thereof, and an inert carrier.

The pharmaceutical compositions may be in the form of solutions or suspensions for injection, tablets, coated tablets, capsules, syrups, creams, ointments or solutions. These pharmaceutical compositions may be prepared by conventional means.

The active ingredient is admixed with standard carriers; Suitable carriers include aqueous or non-aqueous vehicles, talc, acacia, lactose, starch, magnesium stearate, cocoa butter, fats such as animal or vegetable fats, paraffin derivatives, glycols, wetting agents, emulsifiers, dispersants.

The compounds of the present invention exhibit favorable pharmacological properties; the compounds of the present invention inhibit the effect of androgens on peripheral receptors without exhibiting the symptoms of chemical castration.

Because of the above properties of the compounds of formula I, they are useful in the treatment of prostate gland tumor and pathological tissue formation, and in the treatment of benign prostatic hyperplasia.

Due to the above properties, the compounds of formula I are useful in the therapeutic treatment of benign or malignant tumorous cells at the androgen receptors. These disorders include breast cancer, brain, skin, ovarian, bladder, lymphatic, and kidney and liver cancers.

The compounds of formula (I) may also be used in the treatment of

EN 211 330 A9 ne, for the treatment of sebaceous gland overgrowth, androgenic hair loss, hyper hair loss, or severe abnormal hair.

The compounds of formula (I) may thus be used in dermatology; these compounds may be used alone or in combination with other substances. These compounds may preferably be used in combination with an antibiotic; these include azelaic acid, fusidic acid, erythromycin, or a derivative of retinoids that may be used to treat acne; the compounds of formula (I) may be combined with a 5-alpha-reductase inhibitor such as (5-alpha, 17-beta) -1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene-17- carboxamide (also known as Finasteride, see Merck '11th Edition); the compounds of the present invention may be used in combination with azelaic acid or an androgen receptor blocking agent in the treatment of acne, hair loss or the treatment of severe abnormal hair; or these compounds may be used in combination with hair growth stimulants such as Minoxidil; this combination can be used to treat hair loss.

The compounds of formula (I) are also useful in veterinary medicine.

In addition, the compounds of formula (I) may also be used as a radioactive product for diagnostic purposes; Thus, in a properly labeled form, they are useful for labeling androgen receptors. In the preparation of a radioactive product, these compounds may be labeled with tritium, carbon 14, or iodine 125.

The present invention also relates to a method of treatment comprising administering to warm-blooded animals, including human patients, an effective amount of at least one compound of formula (I), a non-toxic pharmaceutically acceptable acid addition salt thereof.

The pharmaceutical compositions of this invention may be administered by parenteral, oral, perlingual, rectal or topical routes.

The usual daily dose, depending on the condition of the patient, the route of administration and the disease in question, is in the range of 0.133 mg to 6.66 mg / kg in human patients.

The starting compounds of formula (Π) may be prepared by reacting an amine derivative of formula (A), wherein R 1 and R ₂ are the same as those of formula (I), if the compound of formula (II) X is O or is reacted with thiosgene when X is S.

The preparation of starting compounds is illustrated in the Examples. The preparation of compounds of formula II is also described in French Patent No. 2,329,276.

The preparation of the amine derivatives of the general formula (A) is described in European Patent 0 002 892 and French Patent 2,142,804.

Compounds of formula (III) and (ΠΓ) are known or can be prepared in a known manner from the corresponding cyanohydrin compounds [J. Chem. Soc. 75, 4841 (1953)].

_'3 different hydrogen site (ΠΙ) compounds of formula R can be prepared by reacting 2-cyano-2-amino propane with an R ₃ -Hal compound during the reactions with R ₃ -Hal rotors which described for the compound of formula (IV). This type of preparation is described in Jilek et al., Collect. Czech. Chem. Comm. 54 (8): 2248 (1989). Compounds of formula IV 'are described in French Patent No. 2,329,276.

The starting compounds of the formulas (V) and (VI) are known or can be prepared in a known manner.

The preparation of compounds of formula VI is described in Zhur. Preklad. Khim. 28, 969-75 (1955) (CA 50, 4881a, 1956); Tetrahedron 43: 1753 (1987); J. Org. Chem., 1987, 52, 2407; Zh. Org. Khin. 21, 2006 (1985); J. Flour. Chem., 17, 345 (1981); or the corresponding preparation is disclosed in German Patent Specification DRP 637 318 (1935), European Patent EP 0 130 875, Japanese Patent JP 81 121 524.

The hydantoin derivatives of formula (VI) are widely used and described in the literature, for example, in J. Pharm. Pharmacol., 67, 19 (4), 209-216 (1967); Khim. Farm. Zh., 67, 1 (5), 51-52; German Patent No. 2,217,914; J. Chem. Soc. Perkin. Trans. 1, 219-221 (1974).

For the preparation of compounds of formula (I), intermediates of formula (IV) may be used, wherein R 1, R ₂ and Y are as defined for formula (I) and A 1 -B 1 is either (i) or (I). j) a group of formula wherein, X represents an oxygen atom or a sulfur atom and R _3i are the same meaning as R ₃ above, but a protected functional group.

Among the protected functional groups are hydroxyl and amino. These groups may be protected as described for R ₃ .

The following examples illustrate the present invention.

/. Example 1- 1- [4-Nitro-3- (trifluoromethyl) phenyl] -3,4,4-trimethylimidazolidine-2,5-dione

3.17 g of 1- (3'-trifluoromethyl-4-nitrophenyl) -4,4-dimethylimidazoline-2,5-dione (obtained according to French Patent No. 2 329 276) with 32 cm ^{3 of} dimethylformamide To a 50% suspension of 492 mg of sodium hydride in oil and 3 cm <^{3> of} dimethylformamide at 23 to 26 [deg.] C., the mixture is stirred for 15 minutes and then 0.7 cm <^{3> of} methyl iodide in 2 cm <^{3> of} dimethylformamide are added. formamide solution. The mixture was stirred for 25 minutes

The mixture is stirred at 24 to 28 ° C and then poured into 200 g of a 1: 1 mixture of water and ice. The mixture was extracted with ether and the organic layer was washed with water saturated with sodium chloride, filtered and dried under reduced pressure to give 3.6 g of the title compound.

Melting point: 116 'C.

Recrystallization from isopropanol yielded 2.73 g of the title compound as an analytical sample.

Melting point: 116 ° C

Elemental Formula C _{] 3} H _{] 2} F ₃ N ₃ O ₄ (331.25): calculated:

C 47.14%, H 3.65%, F 17.20%, N 12.68%;

found:

C 47.0%, H 3.5%, F 17.1%, N 12.5%.

IR (CHCl ₃ ): C = O (1780, 1727 cm ^-1 ), aromatic (1615, 1596, 1497 cm ^-1 ), NO ₂ (1545, 1357 cm -1).

Example 2

5,5-dimethyl - / - ethyl-3-l4-3- anhydrous cupric chloride (rrifluor) phenyl] imidazolidine-2,4-dione

The procedure described in Example 1 was applied to 1 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethylimidazoline, 2,5-dione, prepared according to French Patent No. 2,329,276. 0.37 cm ^{3 of} ethyl iodide and 166 mg of a 50% sodium hydride suspension in oil were used. 1.19 g of the expected product are obtained. Melting point: 110-111 ° C.

The product was recrystallized from isopropanol to give 934 mg of the title compound.

Melting point: 110-111 ° C.

Elemental analysis for _{C] I4} H ₄ F ₃ N ₃ O ₄ (345.28) basis: Calcd:

C 48.70%, H 4.09%, F 16.51%, N 12.17%;

found:

C 48.6%, H 4.0%, F 16.8%, N12.1%.

IR (CHCl ₃ ): C = O [1777 cm ^-1 , 1724 (F)],

NO ₂ (1545, 1356 cm ^-1 ), aromatic (1614, 1596,

1497 cm ^-1 ).

Example 3

5,5-Dimethyl-3- [4-nitro-3- (trifluoromethyl) phenyl] -lpropil-imidazolidine-2,4-dione

The procedure described in Example 1 was applied to 1.1 g of a

Starting from 1- (3'-trifluoromethyl-4 -'-nitrophenyl) -4,4-dimethylimidazoline-2,5-dione, prepared according to French Patent 329,276, 0.35 cm ^{3 of} 1-iodine. propane and 155 mg of 50% sodium hydride in oil. After chromatography on silica gel (eluent: acetone / methylene chloride)

1.99) (3.087 g of crude product).

Melting point: 102 ° C.

The product was recrystallized from isopropanol to give 945 mg of the title compound.

Melting point: 102 ° C.

Elemental analysis based on the formula C _I5 H _{) 6} F ₃ N ₃ O ₄ (359.31):

date:

C 50.14%, H 4.49%, F 15.86%, N 11.69%;

found:

C50.1%, H 4.4%, F 15.9%, N11.5%.

IR (CHC1 _3): C = O (1778, 1724 ^cm-1), _NO2 (1544.1358 cm ^- '), aromatic (1615.1596, 1497 cm ^-1).

Example 4

5.5-Dimethyl-1- (1-methylethyl) -3- [4-nitro-3- (trifluoromethyl) phenyl) imidazolidine-2,4-dione

The procedure described in Example 1 is applied to 1.1 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethylimidazoline-2,5, prepared according to French Patent No. 2,329,276. starting from dione, 0.4 ml of 2-iodopropane and 166 mg of a 50% sodium suspension in oil were reacted for 18 hours at 50 ° C. Chromatography on silica gel (eluent: 1:99 acetone / methylene chloride) gave 685 mg of crude product.

Melting point: 130 ° C.

The resulting product was recrystallized from isopropanol to give 661 mg of the title compound.

Melting point: 130 ° C.

Elemental analysis calculated for C ₁₅ H ₁₆ F ₃ N ₃ O ₄ (359.31):

C, 50.14%, H4.49%, F 15.86%, NI 1.69%;

found:

C 50.1%, H4.4%, F 16.2%, NI 1.6%.

IR (CHCl ₃ ): C = O (1779, 1771, 1723 cm ^-1 ),

NO ₂ (1544, 1361 cm ^-1 ), aromatic (1615, 1596,

1497 cm ^-1 ).

Example 5

5.5-Dimethyl-3- [4-nitro-3- (trifluoromethyl) phenyl] -1 (3-propenyl) -imidazolidine-2,4-dione

The procedure described in Example 1 is applied to 1.1 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethylimidazoline-2, prepared according to French Patent No. 2,329,276. Starting with 5-dione, 0.35 ml allyl bromide and 166 mg 50% sodium hydride suspension in oil were used. After chromatography on silica gel (eluent: acetone / methylene chloride 1:99), 1.10 g of crude product are obtained.

The product was recrystallized from isopropanol to give 1.01 g of the title compound.

Melting point: 105 ° C.

Elemental analysis calculated for C ₅ H ₁₄ F ₃ N ₃ O ₄ (357.29):

C 50.42%, H 3.95%, F 15.95%, N 11.76%;

found:

C50.4%, H 3.8%, F 15.8%, NI 1.7%.

IR (CHCl ₃ ): C = O (1779, 1724 cm ^-1 ), NO ₂ (1545, 1358 cm ^-1 ), aromatic (1615, 1596, 1497 cm ^-1 ),

CH = CH _; (1643, 930 cm ^-1 ).

Example 6

5.5-Dimethyl-3- [4-nitro-3- (trifluoromethyl) phenyl]] benzylimidazolidine-2,4-dione

HU 211 330 A9

The procedure described in Example 1 was applied to 1.2 g

Starting from 1.2 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethylimidazoline-2,5-dione, 0.71 ml of benzyl bromide and 332 mg of oil are added. % sodium hydride suspension was used. Chromatography on silica gel (eluent: acetone / methylene chloride = 1:99) gives the crude product (2.375 g).

The product was recrystallized from isopropanol to give 2.165 g of the title compound.

Melting point: 99 'C.

Elemental analysis calculated for C ₁₉ H ₁₆ N ₃ F ₃ O ₄ (407.3):

C 56.02%, H 3.96%, F 10.31%, N 14.00%;

found:

C 56.1%, H 3.8%, F 10.2%, N 13.9%.

IR (CHC1 _3): C = O [1799 cm ^-1 (m), 1723 ^cm-1) (F)], aromatic (1608 ^cm-1)) + [1594 ^cm-1 (m)], NO ₂ [1545 cm ^-1 (F), 1497 cm ^-1 ].

Example 7

4- (4,4-dimethy-5-imino-2-oxo -] - imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

A solution of 6.6 g of 2-trifluoromethylbenzonitrile-4-isocyanate, prepared as described below, in 10 cm ^{3 of} dichloroethane at 5 ° C was treated with 2.63 g of 2-amino-2-cyanopropane and 0.9 cm ^{3 of} triethylamine. cm ^{3 of} 1,2-dichloroethane. The mixture was stirred at room temperature for 16 hours. After evaporation to dryness, the residue (7.7 g) is chromatographed on silica gel, eluting with 85:15 methylene chloride / acetone. 3.54 g of the expected product are obtained.

Melting point: 228 'C.

For analytical analysis, 300 mg of the above product is recrystallized from isopropanol to give 267 mg of the title product.

Melting point: 228 'C.

Elemental analysis calculated for C ₃ H ₃ F ₃ N ₄ O (296.25):

C, 52.71%; H, 3.74%; F, 19.24%; N, 18.91%;

found:

C 52.7%, H 3.6%, F19.1%, N 18.6%.

IR (Nujol): NH / OH (3340, 3290 cm <^-1> ), CsN (2240 cm <^-1> ), C = O (1760 cm <^-1> ), C = N (1655 cm <^-1> ), aromatics, 1606, 1570, 1502 cm ^-1 ).

Preparation of 2-Trifluoromethyl-benzonitrile-4-isocyanate 4-cyano-3-trifluoromethylaniline (g, described in European Patent 0 001 892) is dissolved in 30 cm ^{3 of} ethyl acetate over a period of 20 minutes.

33.6 cm ^{3 of} a 1.93 M solution of phosgene in toluene at 0 to 5 ° C. The mixture was stirred at 0 to 5 ° C for 30 minutes and then allowed to rise to 25 ° C. The mixture was distilled and toluene was added until the temperature reached 110 ° C. The condenser is then maintained at reflux until the hydrogen chloride emission ceases (about 4.5 hours). After cooling to ambient temperature, the resulting white solid was dried over sodium sulfate under nitrogen, washed three times with 10 cm ^{3 of} toluene each and evaporated to dryness under reduced pressure. After heating to 60 ° C for 1 hour, the solid was placed under an argon atmosphere and the title compound (11.6 g) was used in the next step of the procedure.

IR: -N = C-0 (2268 cm ^-1 ), -CN (2233 cm ^-1 ).

Example 8

4- (4,4-Dimethyl-2,5-dioxo-l-imidazolidinyl) -2-trifluoromethyl-benzonitrile

The product obtained in Example 7 was 2.76 g and 60 cm ³

A solution of 0.5 N hydrochloric acid was refluxed for 35 minutes. The mixture was poured into 100 g of water-ice and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. 2.70 g of the expected product are obtained.

Melting point: 210 'C.

The above product is for analytical testing

Recrystallization of 440 mg in isopropanol gives 383 mg of product.

Melting point: 210-211 ° C.

Elemental analysis calculated for C _{) 3} H |OF ₃ N ₃ 0 ₂ (297.24):

C 52.53%, H 3.39%, F 19.17%, N 14.14%;

found:

C 52.4%, H 3.2%, F 19.4%, N 13.9%.

IR (CHC1 ₃₎ CSN (2245 cm ^-1), aromatic (1610, 1572, 1502 cm ^-1), C = O (1788, 1722 ^cm-1);

NH (max) (3340 cm ^-1 ).

Example 9

3- [4-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidinylacetic acid 600 mg of the product obtained in Example 8 were prepared in 6 cm ^{3 of} dimethylformamide. was added sodium hydride and 3 cm ³ of dimethylformamide, 210 mg (50% in oil), stirred for 15 minutes and then 290 mg of bromoacetic acid was added and the mixture was stirred at room temperature for 16 hours. Thereafter, 105 mg of sodium hydride are added, and after 15 minutes, 145 mg of bromoacetic acid are added. The mixture was stirred for 30 minutes and then poured into a solution of 50 cm ^{3 of} water and 5 cm ^{3 of} 2N hydrochloric acid. The mixture was extracted with ether, washed with brine, dried, filtered and evaporated to dryness. 1.22 g of crude product are obtained, which is chromatographed on silica gel with methylene chloride (methanol) 90: 10: 0.5 as the eluent to give 367 mg of the title product.

IR (CHC1 _3): O (2238 cm ^-1), C = P hydantoin and acid (1784, 1725, 1710 ^cm-1), aromatic (1616, 1580, 1508 ^cm-1).

HU 211 330 A9

UV: EtOH HCl 0.1 n max 258 nm ε = 13 300, infl

277 nm ε = 5000, infl 285 nm ε = 2600.

EtOH NaOH 0.1 n max 287 nm ε = 19 100, max

342 ήπιε = 1900.

Example 10

Ethyl 3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidinyl acetate

A solution of 600 mg of the product obtained in Example 8 in 6 cm ^{3 of} dimethylformamide is added to a suspension of 100 mg of 50% sodium hydride in oil and 3 cm ^{3 of} dimethylformamide. After stirring for 15 minutes, 0.25 cm ^{3 of} ethyl bromoacetic acid is added slowly, without exceeding 30 ° C. The mixture was stirred for 30 minutes, poured into 50 g of a 1: 1 mixture of water and ice, 0.5 g of monopotassium phosphate was added and the mixture was extracted with ether. The organic layer was washed, dried and evaporated to dryness to give 1.1 g of crude product which was chromatographed with 97: 3 methylene chloride / acetone. 709 mg of the expected product are obtained.

Mp 152 ° C.

For analytical analysis, the above product was recrystallized from isopropanol to give 667 mg of the title compound.

Mp 152 ° C.

Elemental Analysis C ₁₇ H | ₆ F ₃ N ₃ O ₄ (383.33) calculated:

C 53.21%, H4.21%, F 14.83%, N 10.96%;

found:

C53.3%, H4.0%, F14.9%, N 10.8%.

IR (CHC1 ₃₎ C = N (2225 ^cm-1), imidazolidine (1786. 1729 ^cm-1). CO ₂ Et (1751 cm ^1), aromatics (1616, 1572, 1505 ^cm-1).

//. example

4- (5-imino-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl) -2-trifluoromethyl-benzonitrile

(a) Preparation of isothiocyanate

1-Trifluoromethyl-4-aminobenzonitrile (2.23 g, prepared according to EP 0 002 892) is added slowly to a solution of 22 cm ^{3 of} distilled water and 1 cm ^{3 of} thiophosgene, and the mixture is stirred for 1 hour and extracted with chloroform. then washed with brine, dried and evaporated to dryness under reduced pressure to give 3 g of product which is used for the preparation of the imine.

b) Preparation of imine

The product (3 g) obtained above was heated at reflux with 1.33 cm ^{3 of} 2-methylamino-2-cyanopropane, 23 cm ^{3 of} tetrahydrofuran and 0.23 cm ^{3 of} triethylamine for 40 minutes. The mixture was evaporated to dryness and the residue (3.07 g) was chromatographed on silica gel with 1: 1 cyclohexane / ethyl acetate as eluent followed by 95: 5 methylene chloride / acetone. 2.83 g of the title compound are obtained, which is recrystallized from isopropanol

2.63 g of the expected product are obtained.

Melting point: 173-174 ° C.

Elemental analysis for C ₁₄ H ₁₃ F ₃ N ₃ S (326.35) calculated:

C 51.53%, H 4.01%, F 17.17%, N 17.46% S 9.82%; found:

C 51.7%, H 3.9%, F 17.2%, N 17.2%, S 9.9%.

IR (CHC1 _3): C = NH (3308, 1678 ^cm-1), C = S + aromatics (1608, 1575, 1505, 1488 ^cm-1), C = N (2230 ^cm-1) CF ₃ (1185 ^cm-1) .

Example 12

4- (5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

2.21 g of the product obtained in Example 11 and 44 cm ^{3 of} 0.5N hydrochloric acid are refluxed for 1 hour with stirring. The reaction mixture was poured into 200 g of a 1: 1 mixture of water and ice, extracted with methylene chloride, washed with water saturated with sodium chloride, then dried and evaporated to dryness. The residue was chromatographed on silica gel with 1: 1 cyclohexane / ethyl acetate to give 2.1 g of product (m.p. 171 ° C), which was recrystallized from isopropanol to give 1.99 g of the title compound.

Melting point: 171 ° C.

Elemental Analysis C ₁₄ H | Calculated as ₂ F ₃ N ₃ OS (327.33):

C 51.37%, H 3.69%, F 12.84%, N 17.41%, S 9.79%; found:

C 51.4%, H 3.5%, F 12.7%, N 17.6%, S 10.79%. IR (CHC1 _3): C = O (1761, 1756 ^cm-1), aromatics (1610, 1578, 1505 ^cm-1), ON (2230 ^cm-1);

CF ₃ (1178 cm ^-1 ).

Example 13

4- (2,5-dithioxo-3,4,4-trimethyl-l-imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

839 mg of the product of Example 12 are refluxed for 24 hours with 518 mg Lawesson's reagent and 4.7 cm ^{3 of} toluene. The mixture was evaporated to dryness under reduced pressure and

1.36 g of product are obtained which is chromatographed on silica gel with methylene chloride / ethyl acetate 99: 1 and then cyclohexane / ethyl acetate 85:15. 783 mg of product are obtained, which is recrystallized from isopropanol to give 690 mg of the title product.

Melting point: 211-212 ° C.

Elemental Analysis C _{) 4} H | ₂ F ₃ N ₃ S ₂ (343.40) calculated:

C 48.97%, H 3.52%, F 16.60%, N 12.24%, S 18.67%; found:

C 49.0%, H 3.4%, F 16.6%, N 12.2%, S18.6%. IR (CHC1 _3): CHN (2230 ^cm-1) + aromatic conjugated system (1612, 1585, 1508 ^cm-1) CF ₃ (1178 cm ^-1).

HU 211 330 A9

Example 14

4- (4,4-Dimethyl-5-imino-2-thioxo-l-imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

To a mixture of 2.54 g of the product obtained in Example 11a), 20 cm ^{3 of} tetrahydrofuran and 0.2 cm ^{3 of} triethylamine, 1 g of 2-amino-2-cyanopropane and 1 cm ^{3 of} tetrahydrofuran are added and the mixture is stirred at room temperature. The mixture is evaporated to dryness and the residue (3.5 g) is chromatographed on silica gel with ethyl acetate / cyclohexane 7: 3 as eluent followed by cyclohexane / ethyl acetate 1: 1. This gives 940 mg of product, 300 mg of which is recrystallized from isopropanol to give 263 mg of product.

Melting point: 296 'C.

Elemental Analysis C _{) 3} H _n F ₃ N ₄ S (312.32) Calculated:

C 50.00%, H 3.55%, F 18.25%, N 17.94%, S 10.27%; found:

C 49.9%, H 3.4%, F18.3%, N 17.6%, S 10.4%. IR (Nujol): OH / NH (3260 cm -1), ON (2230 cm ^-1 ), C = S (1764 cm ^-1 ), aromatic + C = C (1612, 1575, 1530, 1501 cm ^-1). ).

The product was prepared by a novel method by replacing tetrahydrofuran with 1,2-dichloroethane.

The insoluble product precipitated to give the title product in 60% yield.

Example 15

4- (4,4-Dimethyl-5-oxo-2-thioxo-l-imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

635 mg of the product of Example 14 and 14 cm ^{3 of} 0.5N hydrochloric acid are refluxed for 1 hour. After cooling, 100 cm ³ of water was added and extracted with ethyl acetate, the organic layer was washed, dried and evaporated to dryness. This gives 600 mg of product which is chromatographed on silica gel with 95: 5 methylene chloride / acetone to give 590 mg of the title product (m.p. 190-191 ° C), which is recrystallized from isopropanol to give 490 mg of product.

Melting point: 190-191 ° C.

Elemental analysis for C ₁₃ HioF ₃ N ₃ OS (313.30) calculated:

C 49.84%, Η 3.22%, F 18.19%, N 13.41%, S 10.23%; found:

C 49.6%, H 3.1%, F18.4%, N 13.2%, S 10.0%. IR (CHC1 _3): = C-NH (3430 cm ^-1), ON (2230 cm ^-1), C = O (1766 cm ^-1), a conjugated system + aromatics (1612, 1578, 1505 ^cm-1) .

Example 16

5,5-Dimethyl-3- [4-nitro-3- (trifluoromethyl) phenyl] -1-pentylimidazolidine-2,4-dione

Starting from 1.1 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethyl-imidazolin2,5-dione The procedure of Example 1 was used in this 0.47 cm ³ 1- bromopentane and 170 mg of sodium hydride. Chromatography on silica gel (eluent: methylene chloride / cyclohexane 8: 2) gave 1.23 g of crude product.

The product was recrystallized from isopropanol

995 mg of the expected product are obtained.

Melting point: 84 'C.

Anal C7iH ₂₀ F ₃ N ₄ O ₃ Based (387.35): Calcd:

C 52.71%, H5.20%, F 14.71%, N 10.85%;

found:

C 52.8%, H 5.1%, F 14.8%, N 10.7%.

IR (CHCl ₃ ): C = O (1778, 1723 cm ^-1 ), NO ₂ (1544, 1360 cm ^-1 ).

Example 17

5,5-Dimethyl-3- [4-nitro-3- (trifluoromethyl) phenyl] -lnonil-imidazolidine-2,4-dione

The procedure described in Example 1 was applied using 1.1 g of 1- (3'-trifluoromethyl-4'-nitrophenyl) -4,4-dimethylimidazole n-2,5-dione, 0.7 cm ³ -Bromnonan and 170 mg of a 50% sodium hydride suspension in oil were used. Chromatography on silica gel gave 1.08 g of crude product.

Melting point: 63 'C.

Analysis calculated for C _2I H _2g O ₄ F ₃ N ₃ (443.46): Calcd:

C 56.87%, H 6.36%, F 12.85%, N9.48%;

found:

C 57.0%, H 6.5%, F 12.8%, N9.5%.

IR (CHCl 3: C = O (1788, 1723 cm ^-1 ), NO ₂ (1544, 1359 cm ^-1 )).

Example 18

4- (3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl) -2-trifluoromethyl-benzonitrile

Following the procedure of Example 1, starting from 300 mg of the product of Example 8, 275 mg of the title product are obtained.

Melting point: 158 'C.

IR (CHCl ₃ ): C = O (1780, 1727 cm ^-1 ), aromatic (1615, 1574; 1505 cm ^-1 ), ON (2238 cm ^-1 ).

Example 19

4- (5-Thioxo-2-oxo-3,4,4-trimethyl-1-imidazolidinyl) -2-trifluoromethylbenzonitrile (product A)

4- (5-Oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl) -2-trifluoromethylbenzonitrile (product B) 4- (2,5-Dithioxo-3,4,4-trimethyl- 1-imidazolidinyl) -2-trifluoromethylbenzonitrile (product C)

A suspension of 230 mg of the product of Example 18 in 1.4 cm ^{3 of} toluene and 78 mg of Lawesson's reagent was heated at reflux for 9 hours, cooled to room temperature and evaporated to dryness. The product (330 mg) was purified by chromatography on silica gel with methylene chloride / acetone (99: 1).

The following products are obtained in the order of elution:

- 46 mg would C (R _f = 0.63, mp: 21011

HU 211 330 A9

211 ° C), which is identical to the product described in Example 13;

26 mg of product B (R _f = 0.49, m.p. 1 ° C), identical to the product described in Example 12;

42 mg of product A (R _f = 0.34, m.p. 194 ° C). Physical Identification Data for Product A:

IR (CHCl ₃ ): C = O (1760 cm -1), -C = N (2235 cm ^-1 ), aromatic (1615, 1580, 1508 cm ^-1 ). UV spectrum (ethanol): max 228 nm ε = 19,400,256 nm ε = 12 100,298 nm ε = 8600, 390 nm ε = 70.

Example 20

4- [4,5-dihydro-4,4-dimethyl-2- (methylthio) -5-oxo-lH-imidazol-l-yl-trifluoromethyl-benzonitrile

A solution of 626 mg of the product of Example 15 in 6 cm ^{3 of} dimethylformamide was added to a suspension of 108 mg of 50% sodium hydride in oil and 1.8 cm ^{3 of} dimethylformamide. The mixture was washed with 0.3 cm ^{3 of} dimethylformamide and stirred for 10 minutes after the evolution of hydrogen had ceased. Then 0.19 cm ^{3 of} methyl iodide dissolved in 1 cm ^{3 of} dimethylformamide was added dropwise.

After a reaction time of 1 min, the mixture is poured into 50 g of ice / water containing 0.5 g of monopotassium phosphate and extracted four times with ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting product (668 mg) was purified by chromatography on silica gel using 95: 5 CHiCE / AcOEt as eluent.

640 mg of product are obtained, which is chromatographed again on silica gel with 7: 3 cyclohexane / AcOEt as eluant, and then taken up in ether to give 507 mg of the title product.

Melting point: 62 'C.

IR (CHC1 _3): C = O (1747 cm ^-1), C = N and aromatic (1614; 1581, 1569, 1503 ^cm-1).

UV spectrum (EtOH): max 209 nm ε = 26,000, infl

236 nm ε = 11,500, infl 264 nm ε = 8700.

Example 27

4- {4,5-dihydro-4,4-dimethyl-5-oxo-2-l (benzyl) thio] lH-imidazole -} - yl} -2-trifluoromethyl-benzonitrile

4- (4,4-Dimethyl-5-oxo-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile (313 mg) prepared in Example 15 and dissolved in 3 cm <^{3> of} dimethylformamide over 0.5 min. ^cm3 of dimethylformamide suspension of 53 mg of sodium hidrirhez added. After stirring for 10 minutes, benzyl bromide (0.1 cm ³ ) was added and the mixture was stirred continuously for 30 minutes. The reaction mixture was stirred continuously for 30 minutes. The reaction mixture was poured into ice water containing 500 mg of potassium phosphate and extracted with ether, and the organic phase was washed with brine and dried, and then the solvent was evaporated. 450 mg of crude product are obtained, which is chromatographed on silica gel with 97.5: 2.5 methylene chloride / ethyl acetate to give 316 mg of the title product.

R _f = 0.38.

ANALYSIS:

date:

C 59.54%, H 4.0%, F 14.12%, N 10.41%;

found:

C 59.6%, H 4.0%, F 14.1%, N 10.2%.

IR (CHC1 _3): C = O (1746 cm ^-1), C = N (2236 ^cm-1), conjugated system + aromatics (1614, 1580, 1570, 1503, 1499 ^cm-1).

Example 22

4- [4,4-Dimethyl-3- (2-hydroxyethyl) -5-imino-2-dioxolimidazolidinyl] -2-trifluoromethylbenzonitrile All. A solution of 2.11 g of the isothiocyanate prepared in Example 1 is kept at reflux for 30 minutes with 2 - [(2-hydroxyethyl) amino] -2-methylpropionitrile and 2,2-dimethyloxazolidine in 20 cm ^{3 of} tetrahydrofuran. 8: 2 in the presence of 0.5 cm ^{3 of} triethylamine. The solvent was evaporated and the residue was chromatographed on silica gel with 95: 5 methylene chloride / acetone as eluant to give 1.26 g of the crude title compound and 686 mg of N- [4-cyano-2-trifluoromethylphenyl] -2 2-dimethyl-3-oxazolidinecarbothioamide is obtained. 686 mg of this product are dissolved in 10 cm ^{3 of} ethyl acetate, 30 cm ^{3 of} cyclohexane are added, and the mixture is concentrated to 4 cm ³ , blown off and dried to give 518 mg of the title product separately.

Melting point: 181 'C.

ANALYSIS:

date:

C 50.55%, H 4.24%, F 16.00%, N 15.72%, S 9.00%; found:

C 50.4%%, H4.1%, F15.9%, N 15.6%, S 9.0%. IR (CHC1 _3): OH (3630 ^cm-1),> NH (3314,

1677 cm- ¹ ), C = N (2230 cm- ¹ ), aromatic (1611, 1576, 1504 cm- ¹ ).

Preparation of 2- [1- (2-Hydroxyethyl) amino] -2-methylpropionitrile used for Example 22 At 8 ° C to 30 ° C, 8 cm ^{3 of} ethanol amine is added dropwise to 12.3 cm ^{3 of} acetone cyanohydrin. The mixture was stirred for 18 hours and distilled under reduced pressure to give 2.3 g of the title compound and 2,2-dimethyloxazolidine which was used in the next step.

Example 23

4- [4,4-Dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxolimidazolidinyl] -2-trifluoromethylbenzonitrile (Λ product)

4- [4,4-Dimethyl-2,5-dioxo-3- (2-mercaptoethyl) imidazolidmyl] -2-trifluoromethylbenzonitrile (product B) 680 mg of the product of Example 22 for 10 minutes. 7 cm ³ of water, 7 cm ³ of hydrogen chloride in the presence of yarns at reflux, the mixture was cooled to room temperature and extracted with ethyl acetate, the organic layer was washed with brine, dried and the solvent was evaporated. The remaining silica gel was 1: 1

Chromatography EN 211 330 A9 mixture of cyclohexane / ethyl acetate as eluent 119 mg of product B, i.e. 2,5-dioxo3- (2-mercaptoethyl) derivative _(Rf = 0.35) and 569 mg of the product, i.e., 5-oxo-2-thioxo-3- (2-hydroxyethyl) derivative was obtained (R _f = 0.14, mp = 130 ° C;

Elemental analysis calculated for C _{) S} H _{] 4} F ₃ N ₃ O ₂ S (357.36): calculated:

C 50.42%, H 3.95%, F 15.95%, NI 1.7%, S 8.97%; found: (Product)

C50.7%, H4.0%, F 15.7%, N11.5%, S9.1%;

found: (products B)

C50.6%, H 3.8%, F15.9%, N11.6%, S9.1%.

IR (CHCl ₃ ): Product: OH (3636 cm ^-1 ), CsN (2236 cm ^-1 ), C = O (1763 cm ^-1 ), aromatic (1615,

1578, 1504 cm ^-1 ).

Product B: OH (absent), CsN (2228 cm ^-1 ),

C = O (1780, 1726 cm ^-1 ), aromas (1615, 1578,

1505 cm ^-1 ).

1-13. following the examples

A) Using 4- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile prepared according to Example 8 and appropriately substituted reagents, the following compounds were prepared:

Example 24

4- (4,4-Dimethyl-2,5-dioxo-3-ethyl-l-imidazolidinyl) -2-trifluoromethylpropionaldehyde benzonitrile

Melting point: 100-101 ° C.

Elemental analysis based on the formula C ₁₅ H ₁₄ F ₃ N ₃ O ₂ (325.29):

date:

C 55.39%, H 4.34%, F 17.52%, N 12.92%;

found:

C 55.7%, H 4.3%, F 17.6%, N 12.8%.

IR (CHCl ₃ ): ON (2238 cm ^-1 ), C = O (1777,

1724 cm ^-1 ), aromatic (1617, 1575, 1505 cm ^-1 ).

Example 25

4- (4,4-Dimethyl-2,5-dioxo-3- (2-propenyl) -1-imidazolidinyl) -2-trifluoromethylbenzonitrile Melting point: 109-110 ° C.

Elemental analysis for _{C] 6} H ₁₄ F ₃ N ₃ O ₂ (337.35) Calc'd:

date:

C 56.97%, H4.18%, F 16.90%, N 12.46%;

found:

C 57.0%, H4.1%, F 16.2%, N 12.3%.

IR (CHC1 ₃₎ CSN (2238 cm ^-1), C = O (1728,

1725 cm ^-1 ), HC = CH ₂ (1645 cm ^-1 ), aromatic (1616, 1575, 1505 cm ^-1 ).

Example 26

4- [4,4-Dimethyl-2,5-dioxo-3- (phenylmethyl) -] - imidazoUdinilJ-2-trifluoromethyl-benzonitrile

Melting point: 98-99 ° C.

Elemental analysis calculated for C ₂₀ H ₁₆ F ₃ N ₃ O ₂ (387.36):

C 62.01%, H4.16%, F 14.71%, N 10.85%;

found:

C 62.0%, H4.1%, F 14.7%, N 10.8%.

IR (CHCl ₃ ): -C-NH (3430 cm ^-1 ), CsN (2238 cm ^-1 ), C = O (1779, 1724 cm ^-1 ), aromas (1615, 1575, 1504, 1497 cm ^-1). ).

Example 27

4- [4,4-Dimethyl-2,5-dioxo-3-f (4-fluorophenyl) methyl)} - imidazolidinyl] -2-trifluoromethyl-benzonitrile

Melting point: 101-102 ° C.

Elemental analysis for C ₂₀ H | Calculated for ₅ F ₄ N ₃ O ₂ (405.35):

C 59.26%, H 3.73%, F 18.75%, N 10.37%;

found:

C59.1%, H 3.5%, F 18.9%, N 10.3%.

IR (CHCl 3: CsN (2238 cm ^-1 ), C = O (1780,

1724 cm ^-1 ), aromatic (1615, 1612, 1505 cm ^-1 ).

Example 28

4- [4,4-Dimethyl-2,5-dioxo-3 - {(4-methoxyphenyl) methyl} -] imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point: 95-96 ° C.

Elemental Analysis for C ₂₁ H | _{g calculated for} F ₄ N ₃ O ₃ (417.39):

C 60.43%, H4.35%, F 13.65%, N 10.07%;

found:

C59.1%, H 3.5%, F18.9%, N 10.3%.

IR spectrum (CHCl 3: CsN (2238 cm ^-1 ), C = O (1778,

1723 cm ^-1 ), aromas (1615, 1584, 1514,

1505 cm ^-1 ).

Example 29

4- _(4-i 4-Dimethyl-2,5-dioxo-3- [4- (trifluoromethyl) phenyl] methyl] -J-imidazolidinyl / -2-trifluoromethyl-benzonitrile

Melting point: 89-90 ° C.

Elemental analysis for C ₂₁ H ₁₅ F ₆ N ₃ O ₂ (313.30) calculated:

C 55.39%, H 3.32%, F 25.03%, N9.23%;

found:

C 55.2%, H3.2%, F 25.3%, N 9.2%.

IR (CHC1 ₃₎ CSN (2238 cm ^-1), C = O (1615,

1505 cm ^-1 ), aromatic (1615, 1505 cm ^-1 ).

Example 30

4- [4,4-Dimethyl-2,5-dioxo-3- (epoxymethyl) -1-imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point: 112-113 ° C.

Elemental Analysis for C ₁₆ H | According to ₄ F ₃ N ₃ O ₃ (353.30):

date:

C, 54.39%; H, 3.99%; F, 16.13%; N, 11.89%;

found:

C, 54.7%; H, 4.0%; F, 16.1%; N11, 8%.

HU 211 330 A9

IR (CHCl ₃ ): C = (2235 cm ^-1 ), C = O (1781, 1725 cm ^-1 ), aromatic (1615, 1576, 1505 cm ^-1 ).

Example 31

4- (4,4-Dimethyl-2,5-dioxo-3-propyl-lH-imidazolidinyl) -2-trifluoromethyl-benzonitrile

Melting point: 113-114 ° C.

Elemental analysis based on the formula Ci ₆ Hi ₆ F ₃ N ₃ O ₂ (339, 32):

date:

C 56.64%, H 4.75%, F 16.80%, N 12.38%;

found:

C 56.7%, H4.7%, F 16.7%, N 12.2%.

IR (CHCl3: C = N (2236 cm ^-1 ), C = O (1778,

1725 cm ^-1 ), aromatic (1616, 1505 cm ^-1 ).

Example 32

4- (4,4,4-diethyl-2,5-dioxo-3- (1-methylethyl) -1-imidazolidyl) -2-trifluoromethylbenzonitrile Melting point: 138-139 ° C.

Elemental analysis of C | ₆ H ₁₆ F ₃ N ₃ O ₂ (339, 32) calculated for:

C 56.64%, H 4.75%, F 16.80%, N 12.38%;

found:

C 56.5%, H4.7%, F 17.1%, N 12.3%.

IR (CHCl ₃ ): C = N (2236 cm ^-1 ), C = O (1778,

1724 cm ^-1 ), aromatic (1616, 1575, 1505 cm ^-1 ).

B) 4- (4,4-Dimethyl-5-oxo-1-imidazolidinyl) -2-trifluoromethyl-benzonitrile prepared according to Example 15 and the appropriately substituted reagents are prepared in the following examples:

Example 33

4- [4,5-Dihydro-4,4-dimethyl-2-nonyl-thio-5-oxo-1H-imidazyl-1-yl] -2-trifluoromethyl-benzonitrile

R _f = 0.35 (eluent: methylene chloride / ethyl acetate)

97.5: 2.5).

Example 34

4- [4,5-Dihydro-4,4-dimethyl-2 - {(3-hydroxypropyl) thio} -5-oxo-1H-imidazol-1-yl] -2-trifluoromethylbenzonitrile

R _f = 0.17 (eluent: methylene chloride / ethyl acetate 8: 2).

Example 35

Ethyl [N- [4-Cyano-3- (trifluoromethyl) phenyl] -4,5-dihydro-4,4-dimethyl-5-oxo-1H-imidazol-1-yl] thio} acetate

R _f = 0.20 (eluent: cyclohexane / ethyl acetate 65:35).

C) Using the thiocyanate prepared in Example 11 and the appropriately substituted reagents, the following compounds were prepared:

Example 36

4- (4,4-Dimethyl-3-ethyl-5-imino-2-thioxo-l-imidazolidiiiil) -2-trifluoromethyl-benzonitrile

R _f = 0.16 (eluent: methylene chloride / acetone 95: 5).

Example 37

4- (4,4-Dimethyl-5-imine-3-pentyl-2-thioxo-l-imidazolidinyl) -2-trifluoromethyl-benzonitrH

Rf = 0.35 (eluent: ethyl acetate / cyclohexanone 8: 2).

D) 4- (4,4-Dimethyl-3-ethyl-5-imino-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile prepared in Example 36 and 4- (4, 4-dimethylbenzonitrile) prepared in Example 37. Using 4-dimethyl-5-imino-3-pentyl-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile and 1: 1 hydrochloric acid, the following compounds were prepared:

Example 38

4- (4,4-Dimethyl-3-ethyl-5-oxo-2-thioxo-l-imidazolidinyl) -2-trifluoromethyl-benzonitrile

R _f = 0.38 (1: 1 ethyl acetate: cyclohexane).

Example 39

4- (4,4-Dimethyl-5-oxo-3-pentyl-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile Melting point: 78 'C.

R _f = 0.66 (eluent: ethyl acetate / cyclohexane 8: 2).

E) 4- (4,5-Dihydro-4,4-dimethyl-2-methyl-yo-5-oxo-1H-imidazol-1-yl) -2-trifluoromethyl-benzonitrile prepared in Example 20 and 4- [4,5-Dihydro-4,4-dimethyl-5-oxo-2- (phenylmethyl) thio-1H-imidazol-1-yl] -2-trifluoromethylbenzonitrile prepared according to Example 21, and Lawesson using the reagent, the following compounds are prepared:

Example 40

4- [4,5-Dihydro-4,4-dimethyl-2-methyl-thio-5-thioxo-1H-imidazol-1-yl] -2-trifluoromethyl-benzonitrile

R _f = 0.36 (eluent: methylene chloride / ethyl acetate)

97.5: 2.5).

Example 41

4- [4,5-Dihydro-4,4-dimethyl-2- (phenylmethyl) thio} -5-thioxo-1H-imidazol-1-yl] -2-trifluoromethylbenzonitrile

R f = 0.62 (eluent: methylene chloride / ethyl acetate 98: 2).

Example 42

I4-3-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-N-methyl-N - (] - methylethyl) -l-imidazolidine-acetamide

0.1 cm ^{3 of} N-methylmorpholine (235 mg) of 3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidine (Example 9) was prepared. of acetic acid in 4 cm ^{3 of} methylene chloride. The resulting solution was cooled to -10 ° C, treated with 0.1 cm ^{3 of} isobutyl chloroformate dropwise and stirred at -10 ° C for 20 minutes. After adding 0.15 cm ^{3 of} N-methyl-isopropylamine, the mixture was allowed to warm to room temperature over about 40 minutes. A saturated aqueous solution of sodium bicarbonate (5 mL) was added and the mixture was stirred for 30 minutes and then extracted with methylene chloride. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. On silica gel, eluting with 96: 4 methylene chloride / acetone

Chromatography gave 147 mg of the title compound.

IR (CHC1 ₃₎ C = N (2236 cm ^-1) hydantoin

C = O (1738, 1728 cm ^-1 ), amide C = O (1661 cm ^-1 ), aromatic (1615, 1575, 1505 cm ^-1 ).

Example 43

4- [4,4-Dimethyl-2,5-dioxo-3- (2-hydroxyethyl) -l-imidazolidinyl] -2-trifluoromethyl-benzonitrile

a) Condensation

Example 9 was carried out using 900 mg of the product of Example 8 and 1.91 mg of 2-bromoethane tert-butyldimethylsilyl ether. 1 g of the silyloxy ether is obtained. After chromatography on silica gel with 7: 3 cyclohexane / ethyl acetate as eluent, m.p. 86-87 ° C.

(b) Cleavage

380 mg of the product thus obtained, dissolved in 4 cm ^{3 of} methanol and 1 cm ^{3 of} methylene chloride, are added with 1 cm ^{3 of} 2N hydrochloric acid. The mixture was stirred at room temperature for 40 minutes, poured into water (15 cm ³ ), extracted with methylene chloride, washed with water and dried, and then the solvent was evaporated. Silica gel, 7: 3 mixture of methylene chloride / ethyl acetate is purified by chromatography with the eluent _(Rf = 0.9) and crystallized from ether this product in 270 mg of the title compound. After crystallization from isopropanol, the product has a melting point of 109-110 ° C.

ANALYSIS:

date:

C 52.79%, H 4.23%, F 16.70%, N 12.31%;

found:

C 52.5%, H 4.2%, F 16.7%, N 12.1%.

In an analogous manner, the following product is prepared from 2-bromopropanol-tert-butyldimethylsilyl ether:

Example 44

4- [4,4-Dimethyl-2,5-dioxo-3- (3-hydroxypropyl) imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point: 131-132'C.

R _f = 0.13 (eluent: CH ₂ Cl ₂ / AcOEt 75:25).

Example 45

4- [3- {2-Acetylamino-ethyl} -4,4-dimethyl-2,5-dioxo-imidazolidinyl] -2-trifluoromethyl-benzonitrile

215 mg of the product of Example 43, 15 mg

4-Dimethylaminopyridine, 1 cm ^{3 of} pyridine and 0.5 cm ^{3 of} acetic anhydride were stirred for 30 minutes at room temperature. The reaction mixture was poured into 20 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate, stirred for 20 minutes, and then extracted with ethyl acetate; the extract was washed with water and evaporated to dryness. The pyridine and acetic acid residue was removed by distillation, the residue was chromatographed with 65:35 methylene chloride / ethyl acetate, the residue (R _f = 0.35) was taken up in isopropanol, partially concentrated and cooled in ice and filtered under vacuum. The solid was dried to give 210 mg of the title compound.

Melting point: 99-100 ° C.

ANALYSIS:

date:

C 53.27%, H4.21%, F 14.87%, N 10.96%;

found:

C 53.5%, H 4.3%, F 15.2%, N 10.9%.

Following the above examples, the following products were prepared:

Example 46

4- {4,4-Dimethyl-2,5-dioxo-3- (5-hydroxypentyl)] imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point; 101-102 'C.

Example 47

4- [4,4-Dimethyl-2,5-dioxo-3- (2-methoxy-ethyl)] -imidazolidinyl] -2-trifluoromethyl-benzonitrile Melting point: 68-69 ° C.

Example 48

4-1,4,4-Dimethyl-2,5-dioxo-3-cyanomethyl-1-imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point: 186-187 ° C.

Example 49

4- {4,4-Dimethyl-2,5-dioxo-3 - [(L3-dioxolan-2-yl) methyl]] -imidazolidinyl} -2-trifluoromethylbenzonitrile Melting point: 135-136'C.

Example 50

4- [4,4-Dimethyl-2,5-dioxo-3, (3-chloroethyl) -1-imidazolidinyl] -2-trifluoromethylbenzonitrile Melting point: 120-121 ° C.

5 /. Example 1- 1- (3,4-Dichlorophenyl) -5-imino-3,4,4-trimethyl-2-imidazolidinethio

2.4 g of 3,4-dichlorophenyl isocyanate and 1.3 cm ³ of 2-methylamino-2-cyano-propane are heated at reflux for 16 hours in 23 cm ³ of tetrahydrofuran, 0.23 cm ³ of triethyl amine. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with methylene chloride / acetone (96: 4) followed by ethyl acetate / cyclohexane (1: 1). Crystallization from ether gives the title product (2.54 g).

Melting point: 133 'C.

Example 52

3- (3,4-Dichlorophenyl) -2-thioxo -], 5,5-trimethyl-4-imidazolidinone

A solution of 1.88 g of the product prepared in Example 51 in 14 cm ^{3 of} 6N hydrochloric acid is heated at reflux for 45 minutes, then 14 cm ^{3 of} 6N hydrochloric acid is added again and heating is continued for 2 hours. After addition of 4 cm @ ^{3 of} 6N hydrochloric acid and refluxing for 1.5 hours, the mixture was allowed to cool to room temperature. 100 g of ice were added and the mixture was extracted with ethyl acetate. The organic phase is water

Wash, dry and evaporate the solvent. Chromatography on silica gel with 1: 1 cyclohexyl / ethyl acetate as eluant gave the title product (1.84 g). After crystallization from isopropanol, m.p. 129 ° C.

Elemental analysis calculated for C ?? H ?? C ?? N? O (303.21): Calculated:

C 47.54%, H 3.99%, F 23.38%, N 9.24%, S 10.57%; found:

C47.5%, H 3.8%, F23.2%, N 9.3%, S 10.5%. IR (CHCl ₃ ): C = O (1753 cm ^-1 ), C = S and aromatic (1595, 1570, 1496 cm ^-1 ).

Following the above examples, the following compounds were prepared using appropriately substituted compounds and reagents:

Example 53

3- (3,4-Dichlorophenyl) -3,5-dihydro-5,5-dimethyl-2-thio-4H-imidazol ~ ol-4-one

Melting point: 110 ° C.

Example 54 1- (3,4-Dichlorophenyl) -3,4,4-trimethyl-2,5-imidazolidinedione

M.p. = 146 ° C.

Example 55

- [4-Chloro-3- (trifluoromethyl) phenyl] -4,4-dimethyl-2-thioxo-4-imidazolidinone

Melting point: 176 'C.

Example 56 1- [4-Chloro-3- (trifluoromethyl) phenyl] -4,4-dimethyl-5-imino-2-imidazolidinedione

Melting point: 173-174 ° C.

Example 57

3- (3,4-Dichlorophenyl) -3,5-dihydro-5,5-dimethyl-2 - [(phenylmethyl) thio] -4H-imidazol-4-one

IR (CHCl ₃ ): C = O (1736 cm ^-1 ), C = N and aromatic (1576, 1496 cm ^-1 ).

Example 58

4- [4,4-Dimethyl-2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl] -2-trifluoromethylbenzonitrile

a) Condensation

4- (4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile (600 mg) was dissolved in dimethylformamide (5 ml) containing 0.8 ml of sodium hydride (104 mg). is added to a suspension of dimethylformamide while maintaining the temperature below 20 ° C. After stirring for 10 minutes, 445 mg of 4-chloro-tert-butyldimethylsilyl ether and 300 mg of sodium iodide are added. The resulting mixture was heated at 50 ° C for 16 hours and then cooled to room temperature, to which was added 87 mg of sodium hydride, followed by addition of 400 mg of chloroether derivative and 267 mg of sodium hydride; The reaction mixture was heated for a few hours, then cooled to room temperature and poured into 60 ml of an aqueous solution containing 600 mg of monopotassium phosphate.

The mixture is extracted with ethers, the organic phase is washed with water, dried and the solvent is distilled off. The residue was chromatographed on silica (eluent: methylene chloride: acetone = 99: 1); 526 mg of product are obtained, which product is used as is in the following step.

The product thus obtained was mixed with 5 ml of methanol and 1.5 ml of 2N hydrochloric acid. After stirring at room temperature for 40 minutes, the mixture was poured into water (30 mL) and extracted with methylene chloride; the organic phase is washed with water, dried and the solvent is distilled off. The residue is chromatographed on silica, eluting with a 9: 1 mixture of methylene chloride and acetone; isolating the active ingredient in the appropriate fractions, R _f = 0.15; recrystallization from isopropyl ether gave 307 mg of the expected product.

102-103 'C.

Elemental analysis of C | ₇ H | _g calculated using the formula F ₃ N ₃ O ₃ (369.35):

C 55.28%, H4.91%, F 15.43%, N 11.38%;

found:

C 552%, H 4.9%, F 15.3%, N 11.1%.

IR (CHCl ₃ ): OH 3628 cm ^-1 ; ON 2236 cm ^-1 ;

C = O 1778-1724 cm ^-1 ; aromas 1615-1575—

1505 cm ^-1 .

Preparation of 4-chloro-tert-butyldimethylsilyl ether (starting material to be used for Example 58)

9.9 ml of 4-chloro-1-butanol and 24.3 g of imidazole are mixed in 50 ml of tetrahydrofuran with stirring. A solution of tert-butyldimethylsilyl chloride (2.82 g) in tetrahydrofuran (20 ml) was added dropwise at 20 ° C, and the whole was stirred at room temperature for 18 hours, then separated, rinsed with tetrahydrofuran and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (95: 5 cyclohexane: ethyl acetate); 17.5 g of the expected product are obtained.

Example 59

3- (4-Cyano-3- (trifluoromethyl) phenyl-5,5-dimethyl-2,4-dioxo- N -imidazolidineacetic acid [(1,1-dimethyl) ethyl] ester

450 mg of the compound prepared according to Example 8 of European Patent 0 494 819 are dissolved in 4 ml of dimethylformamide and this solution is added to a 50% suspension of 78 mg of sodium hydride in oil and 0.5 ml of dimethylformamide. The mixture was stirred for 15 minutes, ensuring that the temperature did not rise above 30 ° C, and 0.22 ml of bromoacetic acid tert-butyl ester was added slowly. The mixture was stirred for 16 hours. and then poured into a 50: 1 mixture of water and ice (1: 1): 0.5 g of monopotassium phosphate was added and the mixture was extracted with water.

HU 211 330 A9

The organic layer was washed with water, dried, and concentrated to dryness. 1.1 g of product are obtained, which is chromatographed on silica, eluting with a 99: 1 mixture of methylene chloride and acetone. 425 mg of the expected product are obtained.

122-123 'C.

R _f = 0.28 (eluent: 99: 1 methylene chloride / acetone).

IR (CHC1 _3): C = O 1788-1729 cm @ ^-1 (hydantoin) 1745 ^cm-3 (ester), 2235 cm ^-1 CSN, aromatics 1616-1505 cm * ^1st

UV Spectrum (EtOH) λmax 258 nm ε = 16,100, Infl. 277 nm ε = 6000, Infl. 285 nm ε = 3000.

Example 60

3-14-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidine acetic acid cyclopentyl ester 355 mg according to Example 9 of European Patent 0 494 819 Prepared compound (49 mg), 4-dimethylaminopyridine (130 mg), cyclopentanol (130 mg), methylene chloride (6.5 ml) and cooled to -10 ° C were treated with a solution of dicyclohexylcarbodiimide (226 mg) in methylene chloride (2 ml). The resulting mixture was allowed to warm to room temperature, stirred for 25 minutes, and refluxed for 2 hours; The mixture was then distilled to room temperature.

The residue obtained is chromatographed on silica, eluting with a 99: 1 mixture of methylene chloride and acetone; 281 mg of the expected product are obtained.

R _f = 0.25 (99: 1 methylene chloride: acetone).

IR (CHCl,): C = O 1786-1729 cm @ ^-1 (hydantoin) 1748 ^cm-3 (ester), 2235 ^cm-1 CSN, aromatics 1615-1602-1576-1505 cm * ^1st

UV Spectrum (ETOH) λmax 258 nm ε = 16,800, Infl.

276 nm ε = 5800. Infl. 286 nm ε = 3000.

Example 61

3- [4-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidinobutanoic acid ethyl ester The procedure was carried out as in Example 59; The starting material used is the compound prepared according to Example 8 of European Patent 0 494 819, as well as ethyl 4-bromobutyric acid. The title compound is obtained.

Mp: 66-67 ° C.

R f = 0.16 (99: 1 CH 2 Cl 2: acetone).

IR (CHC1 _3): C = O 1770-1726 ^cm-1, C = N 2235 ^cm-1, aromatics 1616-1576-1505 cm * ^1st

UV Spectrum (EtOH): max 260 nm ε = 15,500, Infl.

277 nm ε = 7000, Infl. 286 nm ε =.

Example 62

3- [4-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidinobutanoic acid 1 g of the compound prepared in Example 61 is dissolved in 20 ml of methanol, 2N sodium hydroxide solution was added and the mixture was stirred for 3 hours at room temperature. The mixture was then added to 20 ml of water, acidified to pH 1 with 7 ml of hydrochloric acid solution, extracted with ether, washed with water, dried and evaporated under reduced pressure. 863 mg of crude product are obtained; op. 179-180 ° C; the resulting material was purified by chromatography on silica eluting with methylene chloride chromatography eluting with a 92.5: 7.5 mixture of methylene chloride and methanol. The material was recrystallized from isopropanol; This gives 614 mg of the title compound.

M.p .: 184-185 'C.

R _f = 0.25 (eluent: methylene chloride and acetone)

92.5: 7.5 mixture)

IR (Nujol): C = O 1770-1753-1735-1712-

1690-1645 cm * ¹ , CsN 2235 cm * ¹ , aromas 1613—

1587-1533-1502 cm * ¹ .

Example 63

3- (4-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidinobutanoic acid [(1,1-dimethyl) ethyl] ester

The compound of Example 62 was converted to the ester using tert-butanol; the operation is carried out in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine as described in Example 60; This affords the title compound.

96-97 'C.

R _f = 0.32 (98: 2 methylene chloride: acetone).

IR (CHC1 _3): C = O 1779-1725 ^cm-1, C = N

2235 cm * ¹ , aromas 1616-1576-1505 cm * ¹ . UV Spectrum (EtOH): max 261 nm ε = 15,600, Infl.

276 nm ε = 7800, Infl. 286 nm ε = 3700.

Example 64

3 - ([4-Cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-2,4-dioxo-1-imidazolidine butanoic acid cyclopentyl ester

Example 63 was carried out using cyclopentanol; This affords the title compound.

85-86 'C.

R _f = 0.33 (98: 2 methylene chloride: acetone).

IR (CHC1 _3): C = O 1779-1728 ^cm-1, C = N

2236 cm * ¹ , aromas 1616-1578-1505 cm * ¹ . UV Spectrum (EtOH): max 261 nm ε = 16,000, infl.

277 nm ε = 7600, Infl. 286 nm ε = 3700.

Example 65

4- (4,4-Dimethyl-2,5-dioxo-3- (2 - ((4-fluorophenylthio) ethyl) -1-imidazolidinyl-2- (trifluoromethyl) benzonitrile)

(a) Production of phenolate

4-Fluorothiophenol (0.16 ml) was dissolved in dimethylformamide (1.6 ml) and added to a suspension of 80 mg of sodium hydride in 0.5 ml of dimethylformamide at 28 ° C, followed by stirring for 10 minutes.

HU 211 330 A9

b) Substitution

548 mg of 4- [4,4-dimethyl-2,5-dioxo-3- (2-chloroethyl) -imidazolidinyl] -2-trifluoromethyl-benzonitrile (a compound disclosed in European Patent 0 494 819). Prepared according to Example 50), dissolved in 4 ml of dimethylformamide, added to the solution obtained in a), stirred for 2 hours, then added to 50 ml of water containing 0.5 g of monopotassium phosphate and extracted with ether. . The organic layer was washed with water, dried and the solvent was evaporated. The residue was chromatographed on silica, eluting with 75:25 cyclohexane: ethyl acetate; 570 mg of the title compound are obtained.

M.p. 93-94 'C.

R _f = 0.29 (eluent: cyclohexane and ethyl acetate)

75:25).

IR (CHCl ₃ ): C = O 1780-1726 cm ^-1 , ON

2238 cm ^-1 , aromatic 1616-1579-1506 cm ^-1 , (fluorophenyl) thio 1591-1492 cm ^-1 .

UV Spectrum (EtOH): max 254 nm ε = 18,600.

277 nm ε = 7500, Infl. 286 nm ε = 4200.

Example 66

4- (4,4-Dimethyl-2,5-dioxo-3- (2 - ((4-fluorophenyl) sulphonyl) ethyl] -) - imidazolidinyl 2- (trifluoromethyl pyridylmethyl) -benzonitrile

Methachloroperbenzoic acid (1.21 g) was dissolved in methylene chloride (24 ml) and added dropwise to a solution of the compound prepared in Example 8 (222 mg) in methylene chloride (4.4 ml) at 29 ° C. The mixture was stirred for 30 minutes and then poured into 30 ml of sodium thiosulfate (0.5 mol / liter); the mixture was stirred for 10 minutes, then decanted and extracted with methylene chloride. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and then with water, dried, and then the solvent is evaporated. The residue is chromatographed on silica, eluting with a 1: 1 mixture of cyclohexane and ethyl acetate; 220 mg of the title compound are obtained, which is recrystallized from isopropanol. 196 mg of the title compound are obtained.

Mp: 155-156 ° C.

R _f = 0.22 (1: 1 ethyl acetate: cyclohexane).

IR (CHCl ₃ ): C = O 1783-1727 cm -1, C = N

2236 cm ^-1 , aromas 1615-1593-1506-1497 cm ¹ ,

SO ₂ 1314-1150 cm ¹ .

UV Spectrum (EtOH): max 258 nmc = 16,700, Infl.

286 nm.

Example 67

4- (4,4-Dimethyl-2,5-dioxo-3- (2 - ((4-fluoro-phenyl) sulfonyl) ethyl) -l-imidazolidinyl 2- (trifluoromethyl) benzonitrile

222 mg of the compound prepared in Example 65 are dissolved in 15 ml of methanol and the solution is stirred at room temperature for 30 minutes in the presence of 5 ml of an aqueous solution of sodium metaperiodate (0.1 M). The resulting slurry was maintained at 40 ° C for 1 hour, and then 10 ml of methanol and 5 ml of oxidizing solution were added.

The methanol was evaporated and to the residue was added 10 ml of saturated sodium chloride solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated. The residue is chromatographed on silica, eluting with a 9: 1 mixture of methylene chloride and acetone; 205 mg of product are obtained which is recrystallized from isopropanol; After recrystallization 180 mg of product are isolated.

M.p .: 145-146'C.

R _f = (9: 1 methylene chloride / acetone).

IR (CHCl ₃ ): C = O 1782-1727 cm ^-1 , C = N

2236 cm ¹ , aromas 1615-1592-1506-1493 cm ¹ . UV spectrum (EtOH): max 258 nm ε = 17,600, Infl.

285 nm.

Proceeding as in the previous examples and starting from 4- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile (Example 8 of European Patent 0 494 819). further prepared using the appropriate reagents, the following examples may be prepared:

Example 68

4- (4,4-Dimethyl-2,5-dioxo-3 - ((3-methoxyphenyl) methyl)] - (imidazolidinyl-2- (trifluoromethyl) benzonitrile, m.p. C.

%.

IR (CHC1 _{3): Rf} = 0.21 (eluent: cyclohexane: ethyl acetate = 7: 3 as eluent).

IR (CHCl3): C = O 1779-1724 cm- ¹ , CsN 2238 cm- ¹ , aromas 1614-1602-1588-15751504-1491 cm- ¹ .

UV Spectrum (EtOH): max 260 nm ε = 16,800, Infl. 210 nm ε = 28,500, Infl. 280 nm ε = 8900.

Example 69

4- (4,4-Dinethyl-2,5-dioxo-3- (2- (4-morpholinyl) ethyl) 1-imidazolidinyl-2- (trifluoromethyl) benzonitrile

R _f = 0.20 (70:30 methylene chloride / acetone).

IR (CHC1 _3): 1779-1725 ^cm-1 C = O, C = N 2235 ^cm-1, aromatics 16-16-1576-1505 ^cm-1, 1117 cm-morpholinyl ^first

UV Spectrum (EtOH): max 261 nm ε = 14,000, Infl. 277 nm ε = 6900, Infl. 286 nm ε = 3600.

Example 70

4- [4,4-Dimethyl-3- (2-hydroxyethyl) -5-imino-2-thioxo] imidazolidinyl] -2- (trifluoromethyl) benzonitrile

(a) Preparation of isothiocyanate

2.23 g of 1-trifluoromethyl-4-aminobenzonitrile (a

(002 892) is slowly added to a solution of 22 ml of distilled water and 1 ml of thiophosgene; the mixture was stirred for 1 hour, then extracted with chloroform, the extract was washed with brine, dried and concentrated to dryness under reduced pressure; 3 g of product are obtained, which product is used as is in the following step.

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b) Preparation of Imin: g of the isothiocyanate prepared in the previous step was treated with 37 ml of tetrahydrofuran in the presence of 1.5 ml of triethylamine and 2.8 g of 2 - [(2-hydroxyethyl) amino] -2-methylpropane- of nitrile (prepared according to Example 22 of EP 0 494 819) in 10 ml of tetrahydrofuran was added in one portion. The temperature of the mixture spontaneously rises to 34 ° C. The mixture was then allowed to cool to room temperature while stirring for 1 hour; the solvent is evaporated and the residue is chromatographed on silica, eluting with a 7: 3 mixture of methylene chloride and methanol.

5.87 g of the title compound are obtained.

181 C after recrystallization from isopropanol.

7 /. example

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

4.6 g of Example 70 are added to 65 ml of methanol and the mixture is refluxed for 1 hour in the presence of 10 ml of 2N hydrochloric acid. The mixture was cooled to room temperature and poured into 300 ml of ice water. After extraction with ethyl acetate, the organic phase is washed with brine, dried and the solvent is evaporated. The residue was chromatographed on silica, eluting with a 1: 1 mixture of ethyl acetate and cyclohexanone; separating the appropriate fractions; _Rf = 0.14; 4.37 g of the title compound are obtained after recrystallization from a mixture of methylene chloride and cyclohexane.

M.p .: 130 'C.

Elemental analysis calculated for C ^ HH ^ FFjN ^OjS (357.36):

C, 50.42%; H, 3.95%. F 15.95%, N 11.76,% S 8.97%; found:

C 50.3%, H 3.9%, F15.9%, N11, 6%, S 8.9%. IR (CHCl ₃ ): OH 3636 cm ^-1 ; Cs2236cm ^_1 ;

C = O 1736 cm ^-1 ; aromas 1615-1578-1504 cm ' ¹ .

Example 72

4- [4,4-Dimethyl-3- (2-hydroxyethyl) -5-imino-2-tioxoJ-imidazolidinyl] -2- (trifluoromethyl) ^{-5-3H-benzonitrile}

a) Preparation of tritium-labeled benzonitrile: mg 2-trifluoromethyl-4-amino-5-bromobenzonitrile was mixed with 200 μΐ of ethyl acetate in the presence of 6.5 μΐ of triethylamine and 2 mg of palladium on activated carbon, Tritium was added at 42 bar. The mixture was filtered, rinsed with ethyl acetate, and concentrated to dryness at room temperature to give about 66.6 G.Bq (1.8 Ci).

b) Preparation of Tricium-labeled isothiocyanate

The product obtained above was dissolved in 150 μΐ of water, 150 μΐ of a 10% solution of thiophosgene in chloroform was added and the mixture was stirred at room temperature for 45 minutes. The mixture was diluted with water (0.5 mL) and chloroform (1 mL) and extracted with chloroform. The solvent was evaporated under reduced pressure and the residue taken up in toluene; This gives 50.7 G.Bq (1.37 Ci) of the title compound which is stored at -80 'C.

c) Preparation of the Trine-labeled imine derivative The toluene was removed from the above mixture under reduced pressure, and the residue was 130 μ tetrah of tetrahydrofuran containing 1% triethylamine followed by 13 μΐ of 2 - [(2-hydroxyethyl) amino] -2 -methylpropanenitrile (prepared according to Example 22 of EP 0 492 819) is added, followed by the addition of 130 μΐ of tetrahydrofuran containing 1% triethylamine. After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure.

Preparation of 2-Trifluoromethyl-4-amino-5-bromobenzonitrile (starting material for Example 72) from mole of 2-trifluoromethyl-4-aminobenzonitrile (a)

A solution of 25 ml of methanol was cooled to 0 ° C and 5.2 moles of bromine were added. The mixture was allowed to warm to room temperature, stirred for 3 hours, basified with triethylamine and then added with an aqueous solution of sodium thiosulfate. The solvent is removed, extracted with chloroform, the organic phase is washed with water, dried and the solvent is evaporated; use the resulting product as is in the next step.

IR (CHCl,): _NH2 3612 to 3408 cm⁻¹. C = N 2230 cm ^-1 , aromas 1621-1556-1506 cm ^-1 .

Example 73

4- [4,4-Dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-imidazolidinyl] -2- (trifluoromethyl) ^{-5-3H-benzonitrile} The compound obtained in the preceding Example Add to 180 μΐ of water, heat to 100 CC and add 60 μΐ of 2N hydrochloric acid. The mixture was refluxed for 5 minutes with stirring, then about 600 mg of ice was added, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried; 34.7 g of Bq (937 mCi) are obtained. The resulting material was chromatographed on silica, eluting with 60:40 cyclohexane: ethyl acetate. 19 g of Bq (513 mCi) are obtained.

Example 74

4- [4,4-Dimethyl-3- (3-hydroxy-phenyl) -5-imino-2-thioxo-1-imidazolidinyl] -2-trifluoromethyl-benzonitrile.

The starting material was 2 g of isothiocyanate (prepared in Example 70 (a)) and 1.2 g of the corresponding aminonitrile. 1.70 g of the title compound are obtained.

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R _f = 0.25 (65:35 methylene chloride / acetone).

IR (CHC1 _3): 3630 ^cm-1 OH, NH 33141676 cm ^-1, 2235 cm ^-1 ON, aromatics 1614-1578- 1481 cm ^1st

Example 75

4-l, 4,4-Dimethyl-3- (3-hydroxy-propyl) -5-oxo-2-thioxo-1-imidazolidinyl] -2- (trifluoromethyl) -benzonitrile Example 72, starting from 240 mg 74. Example 22 was used to obtain 226 mg of the title compound.

Mp 149-150 ° C.

R _f = 0.32 (75:25 methylene chloride: acetone).

IR (CHC1 _3): OH 3626 ^cm-1, C = O 1763 ^cm-1, 2236 ^cm-1 ON, aromatics 1615-1580-1504- 1483 cm ^1st

Example 76

4- [4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-thioxo] -iniodazolidinyl] -2- (trifluoromethyl) -benzonitrile European Patent Application EP 0 494 819 22.

Example 4a; starting material is 2 g of isothiocyanate and 1.38 g of the corresponding aminonitrile; 2.08 g of the title compound are obtained.

R _f = 0.25 (65:35 methylene chloride / acetene).

IR spectrum (CHCl ₃ ): OH 3630 cm ^-1 , = NH 33141675 cm ^-1 , ON 2235 cm ^-1 , aromatics 1614-1577-1504 cm ^-1 .

Example 77

4- [4,4-Dimethyl-3- (4-hydroxybutyl) -5-oxo-2-thioxo-T-imidazolidinyl] -2-trifluoromethyl-benzonitrile Example 71; 300 mg of the compound prepared in Example 76 are used as starting material to give 236 mg of the title compound.

M.p. 78-79 'C.

R _f = 0.31 (75:25 methylene chloride / acetone).

IR spectrum (CHCl ₃ ): OH 3624 cm -1, C = O 1762 cm ^-1 , ON 2237 cm ^-1 , aromatic 1615-1580-1504 cm ^-1 .

UV Spectrum (EtOH): Max 232 nm ε = 19,500, Max 254 nm ε = 24,000, Infl. 266 nm.

Example 78

4- [4,4-Dimethyl-3- (2-methoxy-ethyl) -5-imino-2-dioxo-imidazolidinyl] -2- (trifluoromethyl) -benzonitrile.

following our example; starting material is 2.5 g of isothiocyanate and 1.56 g of the corresponding aminonitrile; 2.36 g of the title compound are obtained.

R _f = 0.23 (92.5: 7.5 methylene chloride: acetone).

IR (CHC1 _3): NH 3314 ^cm-1, 02236 ^cm-1, aromatics 1614-1578-1504 cm ^-1, C = N 1675 ^cm-first

Example 79

4- [4,4-Dimethyl-3- (2-methoxyethyl) -5-oxo-2-thioxo-] imidazolidinyl] -2-trifluoromethylbenzonitrile Example 71; starting from the compound of Example 78; The title compound was obtained.

98-99 ° C.

R _f = 0.32 (99: 1 methylene chloride: acetone).

IR (CHCl ₃ ): C = O 1757 cm ^-1 , ON 2236 cm ^-1 , aromatic 1615-1580-1504 cm ^-1 .

UV Spectrum (EtOH): λ max 232 nm ε = 18 200, λ max 254 nm ε = 22 400, Infl. 265 nm.

Example 80

4- [4,4-Dimethyl-3- (l-methylethyl) -5-imino-2-tio''a-] imidazolidinyl] -2- (trifluoromethyl) benzonitrile

European Patent Application No. 0 494 819 is incorporated herein by reference.

following our example; starting material: 2.5 g of isothiocyanate and 1.32 g of the corresponding aminonitrile; 880 mg of the title compound are obtained.

R _f = 0.20 (96: 4 methylene chloride: acetone).

IR (CHC1 _3): NH = 3310-1675 ^cm-1, 2236 ^cm-1 ON, aromatics 1614-1580-1504 cm ^1st

Example 81

4- [4,4-Dimethyl-3 - (] - methylethyl) -5-oxo-2-thioxo-l-imidazolidinyl] -2- (trifluoromethyl) benzonitrile

Example 71 was followed; Starting with 880 mg of the compound prepared in Example 80 and 35 ml of 6N hydrochloric acid; extraction with chloroform afforded 744 mg of the title compound. Mp: 203-204 "C.

_Rf = 0.45 (eluent: cyclohexane: ethyl acetate 1: 1 as eluent).

IR spectrum (CHCl ₃ ): OH 3626 cm ^-1 , C = O 1753 cm ^-1 , ON 2232 cm ^-1 , aromatic 1615-1580-1504 cm ^-1 .

UV Spectrum (EtOH): λ max 232 nm ε = 18,900, λ max 235 nm ε = 22,500, Infl. 273 nm.

Example 82

3- (3,4-Dichlorophenyl-5.5-dimethyl-1- (3-hydroxypropyl) -4-amino-2-imidazolidinedione

European Patent Specification No. 0 494 819 51.

following our example; starting material 2.4 g

3,4-Dichlorophenyl isocyanate and 1.6 g of the corresponding aminonitrile are used. Chromatography on silica (eluent: methylene chloride: acetone = 6: 4) gave 2.16 g of the title compound.

R _f = 0.25

IR (CHCl?): OH 3630 cm @ ^-1 + associated, C-NH 3294-1676 ^cm-1 = F) ON 2232 cm ^-1, aromatics 1595-1569-1482 cm ^1st

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Example 83

3- (3,4-Dichlorophenyl-5,5-dimethyl-1- (3-hydroxypropyl) -2-thioxo-4-imidazolidinone

Example 52 of EP 0 494 819; 0.88 g of the compound prepared in Example 82 and 35 ml of 6N hydrochloric acid are used as starting material. Extraction with chloroform afforded 0.79 g of the title compound.

'p .: 202-203' C.

_Rf = 0.45 (eluent: cyclohexane: ethyl acetate 1: 1 as eluent).

IR (CHCl ₃ ): C = O 1753 cm ^-1 , Cs 22 32 cm ^-1 , aromatics 1615-1580-1504 cm ^-1 .

UV Spectrum (EtOH): max 232 nm ε = 18 900, Infl.

273 nm.

Example 84

4- [4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) -5- ³ H) -benzonitrile

a) 4-Amino-2- (trifluoromethyl) -5- ^3H) -benzonitrile

The following compounds were cooled to -180 ° C and then added to an inert atmosphere: 16 mg of 2-trifluoromethyl-4-amino-5-bromobenzonitrile, 2 mg of palladium on carbon, 200 μΐ of ethyl acetate, 6.5 μΐ of triethylamine ; the mixture was allowed to stand in a tritium atmosphere and then allowed to warm to 20 ° C, at which time the pressure was

1.68 bar.

The mixture was stirred until the absorption was complete (p = 0.42 bar). The mixture was then cooled to -180 ° C, excess tritium was recovered, the mixture was warmed to 20 ° C, filtered, the filtrate rinsed with ethyl acetate and concentrated under reduced pressure at 40 ° C. 68 G.Bq was obtained.

b) 4-Thioisocyanate-2- (trifluoromethyl) - (5- ³ H) -benzonitrile

Under an argon atmosphere, the following components are mixed together

G.Bq tritium-labeled amino derivative prepared according to the previous example, 150 μΐ demineralized water, 150 μΐ 10% chloroform in thiophosgene solution.

The mixture was stirred at 20 ° C for 45 minutes, then decanted, re-extracted with chloroform, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

The resulting thioisocyanate is used as is in the next step.

c) 4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-ynino-2-thioxo] imidazolidinyl) -2- (trifluoromethyl) - (5- ³ H) -benzonitrile

The thioisocyanate obtained in step b) is mixed under argon with the following components:

350 μΐ tetrahydrofuran containing 1% triethylamine and 20 μΐ propanonitrile, prepared as follows.

The mixture was stirred at 20 ° C for 2 hours and then concentrated under reduced pressure at 20 ° C.

The resulting imine derivative is used as is in the next step.

Preparation of 2- (4-hydroxybutylamino) -2-methylpropanonitrile (used in step c))

550 μΐ of acetocyanohydrin and 500 μΐ of 4-amino-1-butanol were added and the mixture was stirred for 16 hours at 20 ° C to give the product as used in the next step.

Example 85

4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-oxo-2-thioxo-] imidazolidinyl) -2-trifluoromethyl) - (5- ³ H) -benzonitrile 200 μΐ 2N hydrochloric acid to the imine compound prepared in Example 84, reflux for 5 minutes, cool again to 20 ° C, dilute with water (1 mL) and extract with ethyl acetate; the extracts were washed with water and concentrated under reduced pressure.

The crude product was purified by chromatography on silica eluting with a 6: 4 mixture of cyclohexane and ethyl acetate.

2.8 g of the title compound are obtained.

Example 86

4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-thioxo-1-imidazolidinyl) -2- (trifluoromethyl) benzo ( ¹ C) -nitrile;

a) 4-Amino-2- (trifluoromethyl) -benzo ( ¹⁴ C) -nitrile

A mixture of 377 g of copper cyanide ¹⁴ C (9 G.Bq) and 1.0732 g of 4-bromo-3-trifluoromethylbenzolamine is stirred under 8 ml of nitrogen in dimethylformamide.

The mixture was refluxed for 4 hours, cooled to 0 ° C, diluted with acetone (20 mL), and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure at 70 ° C. The residue was taken up in methylene chloride, filtered, and the filtrate was concentrated under reduced pressure.

The resulting benzonitrile ( ¹⁴ C) was purified by chromatography on silica eluting with a 70:30 mixture of methylene chloride and cyclohexane.

0.588 g (6.62 G.Bq) of the title compound are obtained.

b) 4-thioisocyanate-2- (trifluoromethyl) benzo (C ⁱ⁴⁾ nitrile

In a nitrogen atmosphere, the following components are added:

189 mg benzonitrile ( ¹⁴ C); prepared in step a), 2.7 mL of water and 85 μΐ of thiophosgene.

After stirring vigorously for 5 minutes, 30 μΐ of thiophosgene was added, stirring continued at 20 ° C for 1 hour, followed by extraction with chloroform, the extracts washed with water, dried and concentrated under reduced pressure.

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The resulting thioisocyanate is used as is in the next step.

c) 4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-thioxo-l-imidazolidinyl) -2- (trfluor-methyl) benzo (C ⁱ⁴⁾ nitrile ml tetrahydrofuran, a solution of propanonitrile (prepared as follows) in methylene chloride (1.5 mL) and triethylamine (150 mL) under nitrogen were added to the thioisocyanate obtained in step b).

The mixture was refluxed for 30 minutes and then concentrated under reduced pressure.

The resulting imine derivative is used as is in the next step.

Preparation of 2- (4-hydroxybutylamino) -2-methylpropanonitrile (used in step c)

Acetocyanohydrin (220 µL) and 4-amino-1-butanol (200 µL) were added, the mixture was stirred at 20 ° C for 16 h, diluted with methylene chloride (2 mL), dried, filtered and the filtrate concentrated under reduced pressure.

The resulting propanonitrile is used as is in the next step.

Example 87

4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-oxo-2-thioxo-imidazolidinyl) -2- (trfluor-methyl) benzo (C ⁱ⁴⁾ nitrite in 6 ml of methanol and 1.6 ml of 2N hydrochloric acid solution are added

Example 86 for the imine derivative prepared according to Example 86.

The mixture was refluxed for 45 minutes, cooled to 20 ° C, diluted with water (10 mL); extracted with methylene chloride, the extract was washed with water and concentrated under reduced pressure.

The crude product obtained is purified by chromatography on silica, eluting with 50:15:35 ether: acetonitrile: cyclohexane.

328 mg of the title compound are obtained.

Example 88

4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-oxo-imidazolidinyl) -2- (trifluoromethyl) - (5- ⁱ H) -benzonitrile

a) 4-Amino-2- (trifluoromethyl) - (5- ³ H) -benzonitrile

The procedure is carried out as in Example 84, step a, using the following components:

mg 4-amino-5-bromo-2-trifluoromethylbenzonitrile, 2 mg palladium on carbon, 200 μ 200 ethyl acetate, 6.5 L triethylamine.

G.Bq is obtained.

b) 4-Isocyanate-2- (trifluoromethyl) - (5- ³ H) -benzonitrile

G.Bq tritium-labeled amino derivative (prepared as above) and 100 μΐ of 20% toluene in phosgene were combined under argon.

The mixture was heated at 80 ° C for 1 hour, then another 100 μ 100 of phosgene was added and the mixture was heated at 80 ° C for 1 hour; this operation was repeated once more and the mixture was concentrated under reduced pressure at 0 ° C.

The resulting isocyanate is used as is in the next step.

c) 4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-oxo-1-imidazolidinyl) -2- (trifluoromethyl) - (5- ³ H) -benzonitrile

To the isocyanate obtained in step b) under argon atmosphere are added the following components:

μΐ methylene chloride, 50 μΐ propanonitrile in chloromethylene (prepared as below) and 20 μΐ triethylamine.

The mixture was stirred for 30 minutes, 50 μΐ propanonitrile was added, stirring continued for 30 minutes, and the mixture was concentrated at 20 ° C under reduced pressure. The resulting imine derivative is used as is in the next step.

Preparation of 2- (4-Hydroxybutylamino) -2-methylpropanonitrile (used in step c)

Acetocyanohydrin (220 μΐ) and 4-amino-1-butanol (200 μΐ) were added, the mixture was stirred at 20 16 C for 16 h, then diluted with methylene chloride (3 mL) and dried over magnesium sulfate.

The decanted solution is used as is in the next step.

Example 89

4- (4,4-Dimethyl-2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl) -2- (trifluoromethyl) - (5- ³ H) -benzonitrile Example 88 imine derivative

200 μΐ of methanol and 50 μΐ of 2N hydrochloric acid were added, the mixture was refluxed for 45 minutes, cooled to 20 ° C, diluted with 1 ml of water; extracted with methylene chloride, the extract was washed with water and then concentrated under reduced pressure at 20 ° C.

The crude product was purified by chromatography on silica eluting with methylene chloride / ethyl acetate 7: 3 then 5: 5. 16 g of the title compound were obtained.

Example 90

4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-oxo-imidazolidinyl) -2- (trfluor-methyl) benzo ⁽ⁱ⁴ C] nitrile

a) 4-Amino-2- (trifluoromethyl) -benzo ( ^} 4C) -nitrile

Example 86 was the same as in step a), starting from 377 mg of copper cyanide ( ¹⁴ C), 1.0732 g of 4-bromo-3-trifluoromethylbenzolamine and 8 ml of dimethylformamide.

0.558 g (6.62 g.Bq) of the title compound are obtained.

b) 4-Isocyanate-2- (trifluoromethyl) -benzo ( ^} 4C) -nitrile

182.4 mg of benzonitrile ( ¹⁴ C) (0.97 mmol), 2 mL of dioxane and 1 mL of a 20% solution of phosgene in toluene are added under nitrogen.

The resulting solution was heated at 60 ° C for 22 hours

The reaction mixture was concentrated under reduced pressure at 60 ° C.

The resulting isocyanate is used as is in the next step.

c) 4- (4,4-Dimethyl-3- (4-hydroxybutyl) -5-imino-2-oxo -] - imidazolidinyl) -2- (trifluoromethyl) benzo ^(l4 C) nitrile

1.5 ml of methylene chloride (siliporytone NK 30) is added to a solution of the propanonitrile prepared in Example 88 in 1.5 ml of methylene chloride and 150 μΐ of triethylamine under nitrogen atmosphere to the isocyanate prepared in step b).

The mixture was stirred at 20 ° C for 1 hour and then concentrated under reduced pressure. The resulting imine derivative is used as is in the next step.

Example 91

4- (4,4-Dimethyl-2,5-dioxo-3- (4-hydroxybutyl)] - imidazolidinyl) -2- (trifluoromethyl) -benzo (14C) -nitrile Add 2 ml of n hydrochloric acid to a solution of 90 ml.

the mixture was heated to reflux for 40 minutes and then cooled to 20 ° C and diluted with 10 ml of water; extracted with methylene chloride, the extract was washed with water and then concentrated under reduced pressure.

The crude product obtained was purified by silica chromatography (eluent: 50:15:35 ether: acetonitrile: cyclohexane).

289 mg (1.26 G.Bg) of the title compound are obtained.

Example 92

4- (2,5-Dioxo-4,4-dimethyl-3- (4-triphenylmethoxy-butyl) -1-imidazolidinyl) -2-trifluoromethyl-benzonitrile 370 mg of the compound prepared in Example 58, m.p. Trityl chloride (10 mg) was combined with 10 mg of 4-dimethylaminopyridine, 0.25 ml of triethylamine and 4 ml of dimethylformamide, and the mixture was stirred at room temperature for 16 hours. After 4 hours at 40 ° C, the reaction mixture was poured into water, extracted with ether, the extract was washed with water, dried, the solvent removed under reduced pressure and the residue chromatographed on silica, eluting with 75:25 cyclohexane / ethyl acetate. . 467 mg of the title compound are obtained.

Rf = 0.25;

IR (CHC1 ₃₎

C = O 1778, 1725 cm ^-1 (F)

C = 2235 cm ^-1

Aromatics 1615, 1597, 1505, 1490 ^cm-1

Example 93

4- (2,5-Dioxo-4,4-dimethyl-3- (4-phenylmethoxy-butyl) -1-imidazolidinyl) -2-trifluoromethyl-benzonitrile 370 mg of the compound prepared in Example 58 in 4 ml. Dissolve in dimethylformamide, add 48 mg of sodium hydride in portions, stir for 30 minutes, then add 0.12 ml of benzyl bromide and 40 mg of tert-butylammonium iodide. The reaction mixture is allowed to react for 1.5 hours and the above reagent amount is added again to the reaction mixture. The reaction mixture was stirred for an additional hour and then cooled in ice-cooled monopotassium phosphate. solution; extract with ether, wash the extract with water, dry, remove the solvent under reduced pressure, and chromatograph the residue on silica, eluting with a 99: 1 mixture of methylene chloride and acetone; 140 mg of the title compound are obtained.

Mp: 75-76 ° C.

IR (CHCl ₃ ): C = O 1779, 1725 cm ^-1 , C = N

2235 cm ^-1 , aromas 1615, 1580, 1505, 1497 cm ^-1 .

Example 94

4- {4,4-Dimethyl-2,5-dioxo-3- (4-methoxybutyl) -1-imidazolidinyl] -2-trifluoromethylbenzonitrile mg of sodium hydride was added in several portions.

To a solution of 370 mg of the compound prepared in Example 58 in 3 ml of dimethylformamide was stirred for 20 minutes, 0.06 ml of methyl iodide was added, stirring was continued for a further 1 hour, and then 50 mg of sodium hydride was added. and after 20 minutes, 0.06 ml of methyl iodide was added. The reaction mixture is poured into water, extracted with ether, the extract is washed with water, dried, the solvent is evaporated off and the residue is chromatographed on silica, eluting with a 98: 2 mixture of methylene chloride and acetone. 135 mg of the title compound are obtained.

Mp: 80-81 ° C.

IR (CHCl ₃ ): C = O 1779, 1725 cm ^-1 , C = N

2234 cm ¹ , aromas 1615, 1576, 1505 cm ¹ ,

OCH ₃ about 2830 cm ¹ .

Example 95

4- [3- (4-Chloro-butyl) -4,4-dimethyl-2,5-dioxo-1-imidazolidinyl] -2- (trifluoromethyl) -benzonitrile

Example 59 is carried out using 600 mg of the compound prepared in Example 8 of EP 0 494 819 and 660 mg of 1-chloro-4-iodobutane in 1 ml of dimethylformamide; the solution was cooled to 5 ° C. 604 mg of the title compound are obtained.

Mp: 80-81 ° C.

IR (CHCl ₃ ): C = O 1779, 1725 cm ^-1 , C = N

2238 cm ^-1 , aromas 1616, 1575, 1505 cm ¹ .

Example 96

4- [3- [4 - [(methylsulfonyl) oxy] butyl] -4,4-dimetil2,5-dioxo-l-imidazolidinyl] -2- (trifluoromethyl) benzonitrile

Methanesulfonyl chloride (0.17 mL) was added to a solution of the compound prepared in Example 58 (740 mg) in pyridine (7.4 mL) and 4-dimethylamidopyridine (24 mg). The mixture was stirred for 1 hour and then to ice water

HU 211 330 A9 is poured; The extract was washed with water, the residual pyridine was removed by distillation, and the residue was chromatographed on silica, eluting with a 8: 2 mixture of methylene chloride and ethyl acetate. 771 mg of the title compound are obtained.

IR (CHCl ₃ ): C = O 1779, 1725 cm ^-1 , C = N

2235 cm ' ¹ , Aromas 1616, 1575, 1505 cm ^-1 ,

SHE

I

-OS- 1361, 1175 cm * ¹ .

I o

UV Spectrum (EtOH): max 261 nm ε = 14 900, Infl.

279-297 nm.

Example 97

4- (3-Acetyl-4,4-dimethyl-2,5-dioxo-l-imidazolidinyl) 2- (trifluoromethyl) benzonitrile

In the same manner as in Example 59, 420 mg of the compound prepared according to Example 8 of European Patent 0 494 819 and two portions of 0.1 ml of acetyl chloride are used as starting material. Chromatography on silica (eluent: 98: 2 methylene chloride: ethyl acetate) gave the title compound (334 mg).

M.p .: 129-130'C.

IR (CHCl ₃ ): C = O 1800, 1740, 1717 cm -1;

CeN 2240 cm ^-1 , aromas 1616, 1505 cm ^-1 . UV Spectrum (EtOH): max 250 nm ε = 12,000, Infl.

274-284 nm.

Example 98

4- (3-benzoyl-4,4-dimethyl-2,5-dioxo-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile

In the same manner as in Example 59, 300 mg of the compound prepared in Example 8 of European Patent 0 494 819 and two portions of 0.12 ml of benzoyl chloride in 0.5 ml of dimethylformamide are used as starting material. Chromatography on silica (eluent: cyclohexane: ethyl acetate = 8: 2) gave the title compound (285 mg).

Mp: 179-180 ° C.

IR (CHCl ₃ ): C = O 1800, 1780, 1746;

1699 cm ^-1 . ON 2235 cm ^-1 , aromas 1617, 1600, 1580, 1504 cm ^-1 .

UV Spectrum (EtOH): max 250 nm ε = 28,500, Infl.

275 nm ε = 6500, Infl. 263 nm ε = 3850.

Example 99

4- [3- [Dimethyl- (1,1-dimethylethyl) silyl] -4,4-dimethyl-2 ',' - dioxo] imidazolidinyl] -2- (trifluoromethyl) -benzonitrile

The procedure was carried out as described in Example 59; 450 mg of the compound prepared in Example 8 of EP 0 494 819 and 300 mg of dimethyl tert-butylsilyl chloride in 2 ml of dimethylformamide are used as starting material. Chromatography on silica (eluting with a 99: 1 mixture of methylene chloride and acetone) afforded 527 mg of the title compound.

Mp 147-148 ° C.

IR (CHCl ₃ ): C = N 2236 cm ^-1 , aromatic

1615, 1579, 1505 cm ^-1 .

UV Spectrum (EtOH): max 258 nm ε = 17,000, Infl.

275-285 nm.

In the same manner as described above, compounds of formula (X) of formula (I) can be prepared wherein Y _A is oxygen or sulfur and R _3A is:

a group of formula (k), a group of formula (I), a group of formula (m),

- (CH ₂ ) - OH (n), (CH ₂ ) _n -COO-alk (o) - (p),

- (CH ₂ ) _n -CO-alk (r), (s),

- (CH ₂ ) n - C = N (t);

alk, alky, and alk _{2 in} the formulas are C 1 -C 4 alkyl and n is an integer of 1 to 4.

Example 100

Preparation of tablets

The following components may be used to make tablets by conventional means:

4- (5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolinyl) -2- (trifluoromethyl) -benzonitrile 100 mg excipient 300 mg (Excipients lactose, starch, talc, magnesium stearate acid.)

Pharmacological examination of the product according to the invention

1) Testing the affinity of the products of the present invention for androgen receptors

Male SPF Sprague Dawley rats weighing 180-200 g, previously spayed an androgen receptor hour, were sacrificed, weight removed and homogenized at 0 ° C in 8 ml of buffer solution (10 mM Tris) for 1 g tissue / glass. in 0.25 molar sucrose, 0.1 mmol PMSF (phenylmethanesulfonyl fluoride), 20 mmol sodium molybdate, adjusted to pH 7.4 with hydrochloric acid, to which 2 mmol of DTT was added immediately before use. (DL-dithiothreitol) was added.

The homogenate is then ultracentrifuged at 105,000 g for 45 minutes at 0 ° C. Aliquots of the resulting supernatant (cytosol) were incubated at 0 ° C for 30 minutes and 24 hours, respectively, with constant concentration of T-tritiated testosterone and with increasing concentrations of cold testosterone or test compound between 0 and 2500 x 10 ⁹ moles.

HU 211 330 A9

The concentration of bound tritiated-labeled testosterone (B) was then determined in each incubated sample by the carbon dextran method.

Calculation of relative binding affinity (RBA)

The following two curves are plotted:

Percent B / T of bound tritiated hormone as a function of logarithm of cold reference hormone concentration and B / T as a function of log concentration of cold test compound. Determine the line corresponding to I ₅₀ = (B / T ^ + B / T ^ ,,) ^.

B / T _{max is} the percentage of bound tritiated hormone when incubated with this tritiated hormone (T).

B / T _{m, n} represents the percentage of bound tritiated hormone at a concentration value in case of incubation of cold hormone large excess (2500xl0 ^-9 M) is of appearance of this tritiated hormone (T).

The line _I50 and the curves allow the intersections of unlabelled reference hormone (CH) and unlabeled test compound (CX) to define the concentration which inhibit the binding of tritiated hormone receptor by 50%. The relative binding affinity (RBA) of the test compound is determined by the RBA = 100 (CH) / (CX) equation. The following results, expressed in RBA, were obtained during our investigations.

Reference substance (testosterone): 100.

2) Testing the affinity of the compounds of this invention for adrogen receptors

Androgen receptor

Male Sprague Dawley EOPS rats weighing 180-200 g were castrated 24 hours prior to the study. then the animals are sacrificed and the prostate removed, weighed and homogenized in a Potter glass jar at 0 ° C; buffer (100 mmol Tris, 0.25 M sucrose, 0.1 mmol PMSF (phenylmethanesulfonyl fluoride), 20 mL sodium molybdate, hydrochloric acid, pH 7.4); 2 mmol of DTT (DL-dithiothreitol) was added to 1 g of tissue per 8 ml of buffer.

The homogenate is then ultracentrifuged at 0 ° C for 30 minutes (209,000 g). Aliquots (cytosol) were removed from the supernatant, incubated for 30 minutes and kept at constant concentration for 24 hours at 0 ° C, tritium-treated testosterone was added to the samples at increasing concentrations (0-2500x1 CT ⁹ mol) or unlabeled testosterone. or the test compound is added to an aliquot of the supernatant. The concentration of bound, labeled testosterone (B) in each sample is then measured and adsorbed on carbon dextran.

Calculation of relative binding affinity (RBA)

Two curves are plotted: percentage of bound labeled hormone (B / T) versus logarithm of the concentration of unlabeled reference hormone; and B / T relative to the logarithm of the concentration of unlabeled test compound. From the straight line of the equation, determine 1¾ = (B / T _max + B / T _mlr ) / 2.

B / Tmax represents the percentage of bound labeled hormone at T concentration

B / Tmin represents the percentage of bound labeled hormone at T concentration in the presence of a large amount of unlabeled hormone (25,000 x 10 ~ ⁹ moles).

From the Al ₅ o straight section and the curve, determine the concentration of unlabeled reference hormone (CH) and the concentration of unlabeled test substance (CX) that inhibits binding of the labeled hormone to the receptor by 50%.

The relative affinity (RBA) of the test compounds was determined using the RBA equation;

RBA = 100 (CH) / (CX).

The results, expressed in RBA values, are summarized in the table below.

The testosterone used as a reference is taken as 100

The RBA of the test compounds

Example number of compounds prepared After 24 hours of incubation 59th 31 71st 163 77th 300 79th 81 81st 28

3) Determination of Androgen or Antiandrogen Activity of the Compounds of the Invention by Determination of Omitin Decarboxylase

One hour before treatment, six-week-old male SWISS male mice were dosed orally (as a suspension in 0.5% methylcellulose) with 3 mg / kg testosterone propionate subcutaneously (in a solution of 5% benzyl alcohol in sesame oil). to determine antiandrogen activity. Agonist activity was detected in the absence of testosterone propionate.

Test compounds and testosterone propionate were administered in a volume of 10 ml / kg. 16 hours after treatment, the animals were sacrificed, the kidneys removed, and homogenized at 0 ° C in a Teflon / glass grinder in 10 volumes of 50 mM Tris-HCl buffer, pH 7.4 containing 250 pmoles of pyridoxal phosphate, 0, It contained 1 mmol EDTA and 5 mmol dithiothreitol. The homogenate was centrifuged at 105,000 g for 45 minutes.

The principle of determination at temperature 'C is renal omitin decarboxylase a

A9 Converts a mixture of cold omitin and tritium-labeled ornithine to cold putrescine and tritium-labeled putrescine.

The putrescine is then collected on a selective ion exchange paper. After drying, the excess tritiated and cold unconverted ornithine is removed by washing three times with 0.1 M ammonia. The papers were dried and radioactivity was determined after adding Aqualite scintillation material. Results are expressed in units of 10 to ¹⁵ moles of tritium-labeled putrescin produced per hour of protein.

The results of our tests were as follows:

Example 11 Product: antagonism (PO) Product of Example 12: 3 mg / kg: 83% antagonism (PO) Product of Example 12: Antagonism: 0.1 mg / kg: 12% 0.3 mg / kg: 36% 1 mg / kg: 68% 3 mg / kg: 94% antagonism (PO) 10 mg / kg: 99% agonism (PO) Example 14 product: 10 mg / kg: 0% antagonism (PO) Example 15 Product: 3 mg / kg: 87% antagonism (PO) 0.3 mg / kg: 4% 1 mg / kg: 82%.

Következtelés

The above test results show that the compounds of the present invention exhibit strong anti-androgen activity and are devoid of agonist activity.

4) The androgenic or anti-adrogenic activity of the compounds of the present invention in the presence of ornithine decarboxylase

Procedure of investigation

Six-week-old SWISS mice are castrated 24 hours prior to the test and the test compounds (in suspension in 0.5% methylcellulose or in ethanol solution) are administered orally or percutaneously with 3 mg / kg testosterone propionate (dissolved in corn germ oil). animals to determine the anti-androgenic effect. Agonist activity was determined in the absence of testosterone propionate.

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

one hour after treatment, the animals were sacrificed, the kidneys removed and homogenized at 0 ° C using a Teflon glass mill and 10 volumes of 50 mM Tris-HCl buffer solution (pH 7.4), buffer solution 250 mM pyridoxal phosphate, It contains 0.1 mmol EDTA and 5 mmol dithiothreitol. The homogenate is then centrifuged at 209,000 g for 30 minutes.

Assay Procedure At-C, the renal-derived ornithine decarboxylase converts a mixture of unlabelled ornithine and labeled omitin to unlabelled and labeled puterescin.

The putrescine is then captured on an ion exchange selective paper; After drying, the unconverted labeled and unlabeled ornithine is removed by washing the paper three times with 0.1M ammonium hydroxide solution, the paper is then dried, and the amount of radioactivity is added after adding scintillation aqualite.

Results are expressed as mol / h / mg of labeled putrescine formed ( ^10-15 moles).

Inhibition is expressed as a percentage, based on the ODL of samples containing testosterone propionate alone.

Assay: Test compounds are administered percutaneously;

1.5 mg / kg in a volume of 10 μΐ.

Test B: Test compounds are administered orally at 1 mg / kg.

Test C: Test compounds are administered orally at 3 mg / kg.

Example number of test compound The examination ODL B test Study C 58th 40 36 67 71st 32 75th 41 78th 78 80th 62 81st 35 83rd 58

Evaluation:

The test results show that the compounds of the present invention show potent anti-androgen activity without agonist activity.

The compounds and methods of the invention may be varied without departing from the spirit or scope of the invention.

Claims (20)

PATENT CLAIMS Compounds of formula (I), and non-toxic pharmaceutically acceptable acid addition salts thereof, wherein: R | is cyano or nitro, or halogen; R ₂ is trifluoromethyl or halogen; -AB represents a group of the formula (a) or (b) in which X is oxygen or sulfur, and R ₃ is one of the following: a) a hydrogen atom, b) alkyl. an alkenyl or alkynyl group containing up to 12 carbon atoms, c) phenyl or phenylalkyl optionally substituted with at least one halogen, hydroxy, HU 211 330 A9 -OCH ₃ -, cyano or haloalkyl (d) an acyl group derived from a C 1 -C 7 organic carboxylic acid, e) a free or salted carboxyl group, a carboxyl group converted to an ester by an alkyl group, or a carboxyl group converted to an amide; f) an amino group or a mono- or dialkyl derivative thereof, wherein the alkyl groups have from 1 to 4 carbon atoms, g) -S-Phenyl optionally substituted with at least one of the following groups: -CF ₃ , alkyl, alkenyl, alkoxy, alkenyloxy, alkynyl or alkynyloxy groups having up to 12 moieties; and wherein the sulfur atom is optionally oxidized to a sulfone or sulfoxy group, and wherein the alkyl, alkenyl, and alkynyl groups are optionally interrupted by an oxygen atom, a nitrogen atom, or a sulfur atom, Y is oxygen or sulfur or = NH, provided that when X is oxygen, R ₃ is hydrogen and Y is oxygen or NH, then R 1 is NO _; or cyano, and in addition, when X is sulfur and Y is oxygen atom, then at least one of the following conditions is met, R is cyano and _R2 is _CF3. Compounds according to claim 1, wherein Y is oxygen. Compounds according to claim 1, wherein -A-B is a group of formula (a) and X is sulfur. Compounds according to claim 3, wherein R ₃ is hydrogen or C 1-4 alkyl optionally substituted by hydroxy or methoxy. Compounds according to claim 1, wherein R 1 is cyano or halogen. Compounds according to claim 1, wherein R 1 is chlorine. Compounds according to claim 1, wherein -A-B is (b) or (g), and R ₃ is C 1-6 alkyl or alkenyl, optionally substituted or optionally substituted with oxygen or optionally interrupted by an oxidized or non-oxidized sulfur atom or an optionally substituted or unsubstituted aralkyl or acyl or trialkylsilyl group. Compounds according to claim 7, wherein R ₃ is C 1 -C 6 alkyl optionally substituted with at least one of the following substituents: halogen, -OH, -O-acyl, carboxyl, alkyl-esterified carboxyl, heterocyclic, -O-alkyl or optionally oxidized S-aryl, wherein the aryl optionally has at least one halogen or alkoxy substituent. The compound of claim 8, wherein R ₃ is C 2 -C 4 alkyl which is chloro, ethoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, optionally oxidized 4-fluoro, phenylthio, morpholino, phenylmethoxy, triphenylmethoxy or methylsulfonyloxy. Compounds according to claim 7, wherein R ₃ is acetyl or benzyl or (1,1-dimethylethyl) dimethylsilyl. 11. The method of claim 1 4- (5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-5-oxo-2-thioxo-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4-4,4-dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile, 3- (3,4-dichlorophenyl) -2-thioxo-1,5,5-trimethyl-4-imidazolidinone, 1- (4-nitro-3- (trifluoromethyl) phenyl) -3,4, 4-trimethyl-2,5imidazolidin-dione, 4- 4,5-dihydro-4,4-dimethyl-5-oxo-2- (phenylmethyl) thio) 1H-imidazol-1-yl-2- (trifluoromethyl) benzonitrile, 4-4.4-dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-l-imidazolidinyl 2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (4-hydroxybutyl) -5-oxo-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile, 3- (4-Cyano-3-trifluoromethyl) phenyl-5,5-dimethyl-2,4-dioxo-1-imidazolidine butanoic acid and 4- (4,4-Dimethyl-2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl) -2- (trifluoromethyl) benzonitrile. Compounds according to claim 1, wherein Y is oxygen, except those compounds wherein -AB- is a group of formula (X) wherein X is oxygen and R ₃ is hydrogen, R ₂ is halogen or trifluoromethyl; and R 1 is nitro or halogen. A compound of formula (I) wherein R 1, R ₂ and Y are as defined in claim 1 and -AB- is a group of formula (a) or (b) wherein Y is oxygen or sulfur. and R ' ₃ has the same meaning as R ₃ , but the reactive functional groups in the groups carry a protecting group. 14. An antiandrogen-containing pharmaceutical composition, comprising an effective amount of at least one compound according to claim 1 and an inert pharmaceutically acceptable excipient and carrier. 15. A composition according to claim 14 wherein the active ingredient is 4- (5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl) -2-trifluoromethylbenzonitrile. 4- (4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl) -2-trifluoromethylbenzonitrile, 4-4.4-dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-l-imidazolidinyl 2- (trifluoromethyl) benzonitrile, 3- (3,4-dichlorophenyl) -2-thioxo-1,5,5-trimethyl-4-imidazolidinone, HU 211 330 A9 1- (4-Nitro-3- (trifluoromethyl) phenyl) -3,4,4-trimethyl-2,5-imidazolidinedione; 4-4,5-dihydro-4,4-dimethyl-5-oxo-2- (phenylmethyl) thio} 1H-imidazol-1-yl-2- (trifluoromethyl) benzonitrile, 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-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 3- (4-Cyano-3-trifluoromethyl) phenyl-5,5-dimethyl-2,4-dioxo-1-imidazolidinobutanoic acid and Contains 4- (4,4-dimethyl-2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl) -2-trifluoromethylbenzonitrile. 16. A method of inducing antiandrogen activity in warm-blooded animals comprising administering to the warm-blooded animals an effective amount of at least one antiandrogen compound according to claim 1. 17. The method of claim 16, wherein the treatment comprises using a compound wherein Y is oxygen. 18. The method of claim 16, wherein the treatment is a compound wherein R1 is cyano or halogen. 19. The method of claim 16, wherein the treatment comprises a compound wherein R 1 is chlorine. 20. The method of claim 14 wherein the active ingredient is one of the following: 4- (5-oxo-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-5-oxo-2-thioxo-1-imidazoldinyl) -2-trifluoromethylbenzonitrile, 4-4.4-dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-l-imidazolidinyl 2- (trifluoromethyl) benzonitrile, 3- (3,4-Dichlorophenyl) -2-thioxo-1,5,5-trimethyl-4-imidazolidinone, 1- (4-nitro-3- (trifluoromethyl) phenyl-3,4,4 trimethylammonium 2,5imidazolidin-dione, 4- 4,5-Dihydro-4,4-dimethyl-5-oxo-2- (phenylmethyl) thio-1H-imidazol-1-yl-2- (trifluoromethyl) benzonitrile, 4-4,4- dimethyl-3- (2-hydroxyethyl) -5-oxo-2-thioxo-1-imidazolidinyl-2- (trifluoromethyl) benzonitrile, 4- (4,4-dimethyl-3- (4-hydroxy) butyl) -5-oxo-2-thioxo-l-imidazolidinyl) -2- (trifluoromethyl) benzonitrile, 3- (4-Cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-2,4-dioxo-1-imidazolidine bulanoic acid and 4- (4,4-Dimethyl-2,5-dioxo-3- (4-hydroxybutyl) -1-imidazolidinyl) -2- (trifluoromethyl) -benzonitrile.