AU670942B2 - New substituted phenylimidazolidines, their preparation process, their use as medicaments and the pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the invention is the products of formula (I): <IMAGE> in which: R1 represents cyano, nitro or halogen, R2 represents trifluoromethyl or halogen, the -A-B- group is chosen from the radicals <IMAGE> in which X represents oxygen or sulphur and R3 is chosen from: - a hydrogen, - alkyl, alkenyl, alkynyl, aryl or arylalkyl, these radicals optionally being substituted, - trialkylsilyl, - acyl or acyloxy, Y represents oxygen or sulphur or NH, with the exception of the products in which: the -A-B- group represents the radical <IMAGE> in which X represents oxygen, R3 represents hydrogen, Y represents oxygen or NH, R2 represents halogen or trifluoromethyl and R1 represents nitro or halogen; the preparation and their application as medicaments, in particular as antiandrogens.

Description

P/00/011 ReguLation 3.2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

e N ~ame of Applicant t t d. idrame of Applicant: i n

I

TO BE COMPLETED BY APPLICANT

ROUSSEL-UCLAF

Martine GAILLARD-KELLY; Frangois GOUBET; and Jean-Georges TEUTSCH Daniel PHILIBERT; CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Invention Title. "NEW SUBSTITUTED PHENYLIMIDAZOLIDINES, THEIR PREPARATION PROCESS, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM" 54 t The following statement is a full description of this invention, including the best method of performing it known to me:i! -1la New substituted phenvlimidazolidines, their preparation process, their use as medicaments and the pharmaceutical compositions containing them.

The present invention relates to new phenylimidazolidines, their preparation process, their use as medicaments and the pharmaceutical compositions containing them.

3-phenyl 2-thiohydantoins are described in the Japanese Application J 48087030 which are presented as inhibiting the germination of certain plants.

Imidazolidines are described in the French Patent 2,329,276 which are presented as having an anti-androgen activity. The products of this Patent are however different from the products of the present Patent Application.

Therefore a subject of the invention is the products of general formula 20 CH R2 Y CH3 in which:

R

1 represents a cyano or nitro radical or a halogen atom,

R

2 represents a trifluoromethyl radical or a halogen atom, the group is chosen from the radicals

X

II

^S-R

-R and in which X represents an oxygen or sulphur atom and R 3 is chosen from the following radicals: a hydrogen atom, alkyl, alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from the 2 following radicals: hydroxy, halogen, mercapto, cyano, acyl or acyloxy having at most 7 carbon atoms, aryl, O-aryl, 0aralkyl, S-aryl in which the aryl radical containing at most 12 carbon atoms is optionally substituted, and the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone, free, esterified, amidified or salified carboxy, amino, mono- or dialkylamino or a heterocyclic radical containing 3 to 6 links and containing one or more heteroatoms chosen from sulphur, oxygen or nitrogen atoms, the alkyl, alkenyl or alkynyl radicals being furthermore optionally interrupted by one or more oxygen, nitrogen or sulphur atoms optionally oxidized in the form of the sulphoxide or sulphone, the aryl and aralkyl radicals furthermore being optionally substituted by a halogen atom, by an alkyl, alkenyl or alkynyl radical, an alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical, the trialkylsilyl radicals in which the linear or branched alkyl radical contains at most 6 carbon atoms, the acyl or acyloxy radicals containing at most 7 carbon atoms, Y represents an oxygen or sulphur atom or a =NH radical, with the exception of the products in which the A-B group represents the radical:

X

N-R

3 in which X represents an oxygen atom and R 3 represents a hydrogen atom and Y represents an oxygen atom or an NH radical and R 2 represents a halogen atom or a trifluoromethyl radical and R 1 represents a nitro radical or a halogen atom.

For the definition of R 3 and in what follows, the definitions used can have the following values.

By alkyl having at most 12 carbon atoms is meant for example the following values: linear or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertoctyl, decyl, undecyl, dodecyl.

Alkyl radicals having at most 6 carbon atoms are preferred, and in particular the following radicals: metlyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, linear or branched pentyl, linear or branched hexyl.

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

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

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

Among the alkynyl values, the propargyl value is preferred.

By aryl is meant carbocyclic aryl radicals such as phenyl or naphthyl or heterocyclic aryls with 5 or 6 links S 20 containing one or more heteroatoms preferably chosen from oxygen, sulphur and nitrogen. Among the heterocyclic aryls with 5 links the following radicals can be mentioned: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tthiadiazolyl, pyrazolyl, isoxazolyl.

Among the heterocyclic aryl radicals with 6 links the pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl radicals can be mentioned.

Among the condensed aryl radicals the indolyl, benzofurannyl, benzothienyl and quinolinyl radicals can be mentioned.

The phenyl radical is preferred.

By arylalkyl is meant the radicals resultirg from the combination of optionally substituted alkyl radicals previously mentioned and the optionally substituted aryl radicals also mentioned above.

The benzyl, phenylethyl or triphenylmethyl radicals are preferred.

By halogen, is of course meant fluorine, chlorine, L~ i L L s--

IL_

s i 4 .9

S.

09 09 9O bromine or iodine atoms.

Fluorine, chlorine or bromine atoms are preferred.

As particular examples of alkyl radicals substituted by one or more halogens, the following radicals can be mentioned: monofluoro, chloro, bromo or iodomethyl, difluoro, dichloro or dibromomethyl, trifluoromethyl.

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

By acyl radical is preferably meant a radical having at most 7 carbon atoms such as the acetyl, propionyl, butyryl or benzoyl radical, but it can also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical: the 15 formyl radical can also be mentioned.

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

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

Radicals formed with the remainders of easily cleavable esters can also be mentioned such as methoxymethyl, ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxy alkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.

A list of such ester radicals can be found for example in the Eu)ropean Patent EP 0 034 536.

By amidified carboxy is meant the radicals of

SI

R6

CON

R7 type in which the Rg and R 7 radicals are identical or different and represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms such as methyl, j o 5: R7 j ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertbutyl radicals.

RR6 Among the -N radicals, the amino, mono- or R7 dimethylamino radicals are preferred.

The N radical can also represent a heterocycle R7 which may or may not contain an additional heteroatom. The following radicals can be mentioned: pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, indolyl, piperidino, morpholino, piperazinyl. The piperidino or morpholino radicals are preferred.

By salified carboxy is meant the salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. There can also be mentioned the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine.

The sodium salt is preferred.

By alkylamino radical is meant the methylamino, ethylamino, propylamino or linear or branched butyl amino radicals. Alkyl radicals having at most 4 carbon atoms are preferred, the alkyl radicals can be chosen from the alkyl 25 radicals mentioned above.

By dialkylamino radical is meant for example the dimethylamino, diethylamino, methylethylainino radicals. As previously the alkyl radicals having at most 4 carbon atoms chosen from the list indicated above are preferred.

By heterocyclic radical containing one or more heteroatoms is meant for example the saturated monocyclic, heterocyclic ralicals such as oxirannyl, oxolannyl, dioxolannyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl radicals.

By alkyl, alkenyl, or alkynyl radicals optionally interrupted by a heteroatom chosen from sulphur, oxygen or nitrogen atoms is meant radicals containing one or more of these atoms, identical or different in their structure.

K 6 These heteroatoms obviously cannot be situated at the end of the radical. There can be mentioned for example alkoxyalkyl radicals such as methoxymethyl, methoxyethyl, methoxypropyl, and methoxybutyl or also alkoxy alkoxyalkyl radicals such as methoxyethoxymethyl.

By trialkylsilyl radical in which the alkyl radical contains at most 6 carbon atoms is meant for example trimehylsilyl, triethysilyl, (1,1-dimethylethyl) dimethylsilyl radicals.

When the products of formula contain an amino radical salifiable by an acid it is well understood that these acid salts also form part of the invention. There can be mentioned the salts produced with hydrochloric or methanesulphonic acids for example.

A particular subject of the invention is the products of formula as defined above in which Y represents an oxygen I t

CCC.

to atom with the exception of the products in which the -A-Bgroup represents th radical: Co

-R

3 in which X represents an oxygen atom and R 3 represents a 25 hydrogen atom and R 2 represents a halogen atom or a trifluoromethyl radical and R 1 represents a nitro radical or a halogen atom.

Among these products, a particular subject of the invention is those in which the group represents the radical: x

II

-aR in which X representr a sulphur atom and R 3 has the meaning indicated previously.

Among these products, a particular subject of the F

I

7 invention is those in which R 3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms optionally substituted by a hydroxy or methoxy radical.

Among these products, a quite particular subject of the invention is those in which R 1 represents a cyano radical or a halogen atom and notably a chlorine atom.

Also a particular subject of the invention is the products of formula as defined above in which the -A-Bgroup represents a group: 0

II

-C-SR3 -N or a group: I li -N-R3 in which R3 represents an optionally substituted alkyl or alkenyl radical having at most 6 carbon atoms and optionally interrupted by one or more optionally oxidized oxygen or Ssulphur atoms, or R3 represents an optionally substituted aralkyl radical, or an acyl radical or a trialkylsilyl radical.

Among these products, a more particular subject of the 25 invention is those in which R 3 represents an alkyl radical containing at most 6 carbon atoms optionally substituted by a halogen atom, a free or esterified hydroxy or carboxy radical, a heLerocycle radical, an O-aralkyl or S-aryl radical in which the aryl radical is optionally substituted by one or more halogen atoms or alkoxy radicals and the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone and quite particularly those in which

R

3 represents an alkyl radical containing 2 to 4 carbon atoms substituted by a chlorine atom or by one of the following radicals: ethoxycarbonyl, terbutoxycarbonyl or cyclopentyloxycarbonyl, 4-fluorophenylthio optionally oxidized in the form of the sulphoxide or sulphone, morpholino, phenylmethoxy, triphenylmethoxy or methylsulphonyloxy.

.i i 8 8 Among these products, a more particular subject of the invention is also those in which R 3 represents an acetyl, benzoyl or (1,1-dimethylethyl) dimethylsilyl radical.

Also a subject of the present invention is the products of formula as defined above and corresponding to formula 0 R1 -R 1

-R

3 R2 0 in which R 1

R

2 and R 3 have the meaning indicated above with the exception of the products in which R 1 represents a nitro j radical, R 2 represents a trifluoromethyl radical and R 3 represents a hydrogen atom.

Among these products, also a subject of the present invention is the products of formula as defined above in which R 1 represents a nitro radical and R 3 represents an alkyl or alkenyl radical having at most 4 carbon atoms optionally substituted by an esterified or salified free carboxy radical.

Among the preferred products of the invention, there can be mentioned more particularly the products of formula as defined above of which the names follow: 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazo- 30 lidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4- I dioxo 1-imidazolidinebutanoic acid.

Also a subject of the invention is a preparation process for the products of general formula as defined above characterized in that: either a product of formula (II): i

R

1

-N=C=X

(II)

R

2 in which R 1

R

2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III): HN-R'3 H3C-C-CH3

(III)

CN

in which R' 3 has the values indicated above for R 3 in which the optional reactive functions are optionally protected and it being understood that if R 1 represents a nitro radical or a halogen atom, if R 2 represents a halogen atom or a CF 3 radical and X represents an oxygen atom, R' 3 cannot represent a hydrogen atom, in order to obtain a product of formula

S(IV):

SN N-R'3 C 1 CH (IV) S. 2 HN CH in which R 1

R

2 X and R' 3 have the previous meaning, which products of formula if necessary or if desired, are subjected to any one or more of the following reactions, in any order: a) elimination reaction of the optional protective groups that can be carried by R' 3 b) hydrolysis reaction of the >C=NH group into a ketone function and if appropriate conversion of the >C=S group into a >C=O group; c) conversion reaction of the >C=O group or groups into the following radicals: ./2 g1 10 >C=S group; d) the action on the products of formula (IV) in which R' 3 represents a hydrogen atom, and after hydrolysis of the >C=NH group into a ketone function, of a reagent of formula Hal-R" 3 in which R" 3 has the values of R' 3 with the exception of the hydrogen value and Hal represents a halogen atom, in order to obtain the products of formula in which the group represents the group

S-R"

<3 I s

I)

I b Do o r

I

I

i r I in which R" 3 has the meaning indicated previously, then, if desired, the action on these products of an elimination agent of the optional protective groups that can be carried by R"3 or if appropriate, the action of an esterification, amidification or salification agent, 20 or a product of formula (II):

N=C=X

(II)

r r r

I

1 r riIr j r v. I1 r in which R 1

R

2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III'): HN-R'3 H3C-C-CH 3

COOQ

C00Q

(III')

in which R' 3 has the meaning indicated above and Q represents either an alkali metal atom for example sodium or an alkyl radical containing of 1 to 6 carbon atoms, in order to obtain a product of formula (IVa): s. i jl I 1 .1 1. I I -I Y Y /3 r 4.

~~7FV__ is 4 11 (IVa) S C

*OCC

C'.

C.

in which X, R R 2 and R' 3 have the meaning indicated above, which if desired is subjected to any one or more of the following reactions, in any order: a) elimination reaction of the optional protective groups that can be carried by R' 3 b) conversion reaction of the >C=O group or groups into the >C=S group or if appropriate of the >C=S group into the >C=0 group; c) the action on the products of formula (IVa) in which R' 3 represents a hydrogen atom, of a reagent of formula Hal-R" 3 in which R" 3 has the values of R' 3 with the exception of the hydrogen value and Hal represents a halogen atom, in order to obtain the products of formula in which the group represents the group: 0

S-R"

3 3 or N in which R" 3 has the meaning indicated previously, then, if desired, the action on these products of an elimination agent of the optional protective groups that can be carried by R" 3 or if appropriate, the action of an esterification, amidification or salification agent, or a reagent of formula Hal-R" 3 in which Hal and R"3 have the values indicated previously is reacted on a product of formula

I

Y- i. .f i Lil I Uu I Ui I It;L I Y LJ-- IZ- I ILI I I V j q rl L1: ,F

I

_I a 12 0 R

CH

2

CH

(IV')

in order to obtain a product of formula I I -N

R

0 CH 3

(IV")

S. 5

S

4 4

I

which product of formula if necessary or if desired, is subjected to any one or more of the following reactions in any order: 20 a) elimination reaction of the optional protective groups that can be carried by R" 3 then if appropriate the action of an esterification, amidification or salification agent; b) conversion reaction of the >C=O group or groups into the >C=S groups.

The action of products of formula (II) with the products of formula (III) is preferably carried out in an organic solvent such as tetrahydrofuran or dichloroethane but ethyl ether or isopropyl ether can also be used.

The operation is carried out in the presence of a 30 tertiary base such as triethylamine or also pyridine or methylethylpyridine.

The optional reactive functions which can be contained by R 3 and which are optionally protected in the product of formula (III), (IVa) or are hydroxy or amino functions. The usual protective groups are used to protect these functions. There can be mentioned for example the following protective groups of the amino radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl,

I

C, .I Li i t 13 Sformyl, benzyloxycarbonyl.

As the protective group of the hydroxy radical there can be mentioned the radicals such as formyl, chloroacetyl, tetrahydropyrannyl, trimethylsilyl, tert-butyl dimethylsilyl.

It is well understood that the above list is not limitative and that other protective groups, for example known in the chemistry of the peptides, can be used. A list of such protective groups is found for example in the French Patent BF 2,499,995 the content of which is incorporated here by reference.

The optional elimination reactions of the protective groups are carried out as indicated in said Patent BF 2,499,995. The preferred elimination method is acid hydrolysis using acids chosen from hydrochloric, benzene sulphonic or para toluene sulphonic acids, formic or trifluoroacetic acid. Hydrochloric acid is preferred.

The optional hydrolysis reaction of the >C=NH group into lot the ketone group is also preferably carried out using an acid such as aqueous hydrochloric acid for example under reflux.

When the hydrolysis of the >C=NH group into the ketone group is carried out on a molecule also containing a >C=S group, this can be converted into a >C=0 group. The free OH radical that can optionally be contained by R 3 can then be converted into an SH radical.

The conversion reaction of the >C=O group or groups into the >C=S group is carried out using the so-called Lawesson reagent of formula: s s tti So 30 H3C P P CH

S

which is a product sold for example by the FLUKA firm and the use of which is described for example in the publication: Bull. Soc. Chim. Belg. Vol 87, No. 3, (1987) p. 229.

When it is desired to convert two >C=0 functions into two >C=S functions the operation is carried out in the presence

I

S-

1 14 of an excess of Lawesson reagent. This is also so when starting with a molecule containing a >C=S function and a >C=O function and it is desired to convert said >C=O function into a >C=S function.

On the other hand when starting with a molecule containing two >C=O functions and when it is desired to obtain a product containing a single >C=S function, the operation is carried out in the presence of a deficit of Lawesson reagent. A mixture of three products is then generally obtained: each of the two products containing a >C=O function and a >C=S function and the product containing two >C=S functions. These products can then be separated by the usual methods such as chromatography.

The action on the products of formulae (IVa) or of the reagent of formula Hal-R" 3 is carried out in the presence of a strong base such as sodium or potassium hydride. The operation can be carried out by phase-transfer reaction in the presence of quaternary ammonium salts such as tertbutyl ammonium.

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

25 An example of elimination of the terbutyldimethylsilyl group by means of hydrochloric acid is given hereafter in the examples.

The optional esterification of the products of formula (I) in which R" 3 contains a free OH radical is carried out under S 30 standard conditions. An acid or a functional derivative can for example be used, for example an anhydride such as acetic anhydride in the presence of a base such as pyridine.

The optional esterification or salification of the products of formula in which R" 3 represents a COOH group is carried out under standard conditions known to a man skilled in the art.

The optional amidification of the products of formula (I) in which R" 3 contains a COOH radical is carried out under sUDS1ituLea Dy one or more suostituents cnosen rrom tne standard conditions. A primary or secondary amine can be €R used on a functional derivative of the acid for example a symmetrical or mixed anhydride.

Also a subject of the present invention is a preparation process for products of formula R N B" ,j Hal 2 in which R" 1

R"

2 have the meanings indicated above for R 1

R

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

(V)

R 2 in which R"- 1 and R"2 have the previous meanings and Hal represents a halogen atom, is reacted with a product of i formula (VI): HN' Asf'B )CH 3

(VI)

Y CH 3 in which and Y have the meaning indicated above, the reaction being carried out in the presence of a catalyst and optionally of a solvent.

With regard to the products of formula the term Hal

I-

-16 I4

SC

4 preferably designates the chlorine atom, but can also represent a bromine or iodine atom.

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

A more particular subject of the invention is a process as defined above in which the catalyst is a metal in the native or oxidized form or a base.

The catalyst used can be a metal in native form, in the form of a metal oxide or also in the form of metal salts.

The catalyst can also be a base. When the catalyst used is a metal, this metal can be copper or nickel.

The metal salts can be a chloride or an acetate.

When the catalyst is a base, this base can be for example soda or potash and dimethylsulphoxide can, if desired, be added to the reaction medium.

A more particular subject of the invention is a process as defined above in which the catalyst is chosen from cuprous 20 oxide, cupric oxide, copper in native form and a base such as soda or potash.

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

A particular subject of the invention is a process as defined above in which the catalyst is cuprous oxide.

The solvent used is preferably chosen from ethers with a high boiling point such as, for example, phenyl oxide, diglyme, triglyme and dimethylsulphoxide but can also be, for example, an oil with a high boiling point such as paraffin or vaseline.

A more particular subject of the invention is a process as defined above characterized in that the operation is carried out in the presence of a solvent of ether type such as phenyl oxide, diglyme, triglyme or dimethylsulphoxide.

A quite particular subject of the invention is a process as defined above in which the solvent used is phenyl oxide or triglyme.

The preparation process of the desired product defined S C

J

17 above can be carried out under pressure or at atmospheric pressure, preferably at a high temperature.

Thus a subject of the invention is a process as defined above characterized in that the reaction is carried out at temperature above 100 0 C and preferably above 150 0

C.

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

A very particular subject of the invention is a process as defined above characterized in that the reaction is carried out in the presence of copper oxide, in triglyme, at a temperature greater than or equal to 200 0 C and for more than 3 hours.

The products which are a subject of the present invention are endowed with useful pharmacological properties; i it was observed in particular that they inhibited the effects of androgens on the peripheral receptors.

Tests given in the experimental part illustrate this anti-androgen activity.

Due to this anti-androgen activity, the products of the invention can be used in therapeutics for adults without the fear of certain chemical castration effects.

These properties make the products of general formula of the present invention usable as medicaments for the treatment of adenomas and neoplasias of the prostate as well as for combating benign hypertrophy of the prostate.

These properties make the products of general formula usable also in the treatment of benign or malignant tumours the cells of which contain notably androgen Se 30 receptors. In particular there can be mentioned mainly cancers of the breast, the brain, the skin and the ovaries but also cancers of the bladder, the lymphatic system, the kidney, the liver.A The products of general formula of the invention can also be used in the treatment of hirsutism, acne, seborrhea, androgenic alopecia, hyperpilosity or hirsutism.

The products of formula can therefore be used in dermatology: they can be used alone or in combination. They I i i 1,7 ili~ i: :I-I ;1 I r\ i:

I

18 a Lo can be combined in particular with an antibiotic product such as derivatives of azelaic acid, fusidic acid, erythromycin or with a derivative of the retinoids for the treatment of acne, or with a 5alpha-reductase inhibitor such as (5alpha,17beta)- 1,1-dimethylethyl 3-oxo 4-aza-androst-l-ene 17-carboxamide (or Finasteride Merck, 11th ed.) or azelaic acid or a blocking agent of the androgen receptors for the treatment of acne, alopecia or hirsutism, or with a product stimulating the growth of hair such as Minoxidil for the treatment of alopecia.

The products of formula can also be used in the veterinary domain.

The products of formula in the form of radioactive products, can also be used in diagnostics as specific labels for the androgen receptors. As radioactive products, the products labelled with tritium, with carbon 14 or also with iodine 125 can for example be used.

Therefore a subject of the invention is the use, as medicaments, of the pharmaceutically acceptable products of general formula A particular subject of the invention is the use as medicaments of the products of which the nams follow: 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4- 30 dioxo 1-imidazolidinebutanoic acid.

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

Also a subject of the invention is pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the medicaments of general formula These compositions can be presented in the form of solutions or injectable suspensions, tablets, coated tablets, Irr~tr r .rc cc tr r .c fr

I

19 capsules, syrups, suppositories, creams, ointments and lotions. These pharmaceutical forms are prepared according to the usual methods. The active ingredient can be incorporated with the excipients usually employed in these compositions, such'as aqueous or non-aqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preservatives.

The usual dose, variable according to the patient being treated and the illness in question, can be, for example, mg to 500 mg per day in man, by oral route.

The products of formula (II) used at the start of the invention can be obtained by the action of phosgene when X represents an oxygen atom or thiophosgene when X represents a sulphur atom on the corresponding amine of formula it i e a S. Nrr

NH

2 ct

I

*r rr r i

I

jr r rr i-i I i

I

An example of such a preparation is given hereafter i.i the experimental part. A prodct of this type is also described in the French Pater.t BF 2,329,276.

The amines of formula are described in the European Patent EP 0,002,892 or the French Patent BF 2,142,804.

The products of formula (III) or (III') are known or can be prepared from the corresponding cyanhydrin according to 30 the process described in the publication: J. Am. Chem. Soc.

(1953), 75, 4841.

The products of formula (III) in which R' 3 is different from a hydrogen atom can be obtained by the action of a product of formula R" 3 -Hal on 2-cyano 2-amino propane in the conditions set out above for the action of R" 3 Hal on the products of formula An example of a preparation of this type is described in the reference: Jilek et al. Collect. Czech. Chem. Comm. 54(8) 2248 -1- -Ic 20 (1989), The products of formula are described in the French Patent BF 2,329,276.

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

The preparation of products of formula (VI) is de.cribed notably in the following publications: Zhur. Preklad. Khim. 28, 969-75 (1955) (CA 50, 4881a, ")56) Tetrahedron 43, 1753 (1987) J. Org. Chem. 52, 2407 (1987) Zh. Org. Khin. 21, 2006 (1985) J. Fluor. Chem. 17, 345 (1981) or in the following Patents: German DRP 637,318 (1935) European EP 0,130,875 Japanese JP 81,121,524.

20 The products of formula (VI) which are derivatives of hydantoin are widely used and mentioned in the literature, isch as for example in the following articles: SJ. Pharm. Pharmacol., 67, Vol. 19(4), p. 2C9-16 (1967) Khim. Farm. Zh., 67, Vol. 1 p. 51-2 German Patent 2,217,914 European Patent 0,091,596 J. Chem. Soc. Perkin. Trans. 1, p. 219-21 (1974).

Also a subject of the invention is, as new industrial products and in particular as new industrial products which can be used as intermediates for the preparation of products of general fo.-mula the products of formula (IVi): 4 4 rr

I

t Ir 4 4r

A.

S1\

Y

(IVi) nenyimer-noxy, ripnenyimethoxy or methylsulphonyloxy.

K

I,

21 21in which R R 2 and Y have the meanings indicated above and the group: Ai Bi is chosen from the radicals: S-R3i and N N-R i 3 in which X represents an oxygen or sulphur atom and R3i is chosen from the values of R 3 containing a protected reactive function.

Among the protected reactive functions there can be mentioned the hydroxyl and amino functions. These functions can be protected as indicated above for the R 3 substituent.

EXAMPLE 1: 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxy butyl) 1imidazolidinyl) 2-(trifluorcnethyl) benzonitrile 20 a) Condensation 600 mg of 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2- (trifluoromethyl)-benzonitrile obtained as in Example 8 of the European Patent Application No. 0,494,819 in 5 cm 3 of dimethylformamide is added to a suspension of 104 mg of S 25 sodium hydride in 0.8 cm 3 of dimethylformamide, while maintaining the temperature below 20 0 C. After 10 minutes of agitation, 445 mg of 4-chloro t-butyl dimethylsilylether and 300 mg of sodium iodide are added. The resultant mixture is heated for 16 hours at 50 0 C, cooled down to ambient temperature, 87 mg of sodium hydride is added then another 400 mg of the chlorinated ether and 267 mg of sodium hydride are added, and the whole is heated for another hour. It is returned to ambient temperature, and poured intn 60 cm 3 of water containing 600 mg of monopotassium phosphate.

Extraction is carried out with ether, the organic phase is washed with water, dried and the solvent is evaporated. The residue is chromatographed on silica (eluant: methylene chloride acetone 526 mg of product is collected

L//

f i 22 I C

I

.4 used as it is for the stage following the cleavage.

The product obtained above is mixed in 5 cm 3 of methanol and 1.5 cm 3 of 2N hydrochloric acid. Agitation is carried out for 40 minutes at ambient temperature, the mixture is poured into 30 cm 3 of water, extracted with methylene chloride, the organic phase is washed with water, dried and the solvent is evaporated. After chromatographing the residue on silica (eluant methylene chloride acetone (9-1) the fractions are recovered, rf 0.15, and after recrystallization from isopropyl ether, 307 mg of expected product is obtained. M.p. 102-103 0

C.

Analysis C 17

H

18

F

3

N

3 0 3 369.35 C% H% F% N% Calculated 55.28 4.91 15.43 11.38 Found 55.2 4.9 15.3 11.1 IR Spectrum (CHC1 3 OH 3628 cm-1 C=N 2236 cm- 1 C=O 1778-1724 cm- 1 20 Aromatics 1615-1575-1505 cm- 1 Preparation of the 4-chloro t-butyl dimethylsilylether used at the start of Example 58.

9.9 cm 3 of 4-chloro 1-butanol and 24.3 g of imidazole are mixed under agitation in 50 cm 3 of tetrahydrofuran.

2.82 g of terbutyldimethylsilyl chloride in 20 cm 3 of tetrahydrofuran is added dropwise at a temperature of less than 20 0 C, the whole is agitated for 18 hours at ambient temperature, followed by separating, rinsing with tetrahydrofuran and eliminating the solvent under reduced 30 pressure. The residue is purified by chromatography on silica (eluant: cyclohexane ethyl acetate and 17.5 g of expected product is collected.

EXAMPLE 2: (1,1-dimethyl) ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl 5,5-dimethyl 2,4-dioxo 1-imidazolidineactate 450 mg of the product obtained in Example 8 of the European Patent Application No. 0,494,819 in solution in 4 cm 3 of dimethyl formamide is added to a suspension of 78 mg of sodium hydride at 50% in oil and 0.5 cm 3 of dimethylrr re "i r r r c r

I

UI UV I~UYIIV V~ CLI~ ~U-V ~jLVUf~ VL r~VVL~Y t I 23 Sformamide. Agitation is carried out for 15 minutes then without exceeding 30 0 C, 0.22 cm 3 of terbutyl bromoacetate is slowly added. Agitation is continued for 16 hours, the mixture is poured into 50 g of a water and ice mixture 0.5 g monopotassium phosphate is added and extraction is carried out with ether. The organic phase is washed with water, dried and evaporated to dryness and 1.1 g of crude product is collected which is chromatographed on silica (eluant: methylene chloride acetone 425 mg of expected product is obtained. M.p. 122-123 0 C. Rf 0.28 (eluant: methylene chloride acetone (99-1)) IR Spectrum (CHC1 3 C=O 1788-1729 cm- 1 (hydantoin) 1745 cm 3 (ester) C=N 2235 cm- 1 Aromatics 1616-1505 cm- 1 UV Spectrum (EtOH) Max. 258 nm E 16100 Infl. 277 nm E 6000 S- Infl. 285 nm a 3000 20 EXAMPLE 3: cyclopentyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidineacetate A solution containing 355 mg of the product obtained in Example 9 of the European Patent Application No. 0,494,819, 49 mg of 4-dimethylaminopyridine, 130 mg of cyclopentanol in 25 6.5 cm 3 of methylene chloride is cooled down to -10 0 C then 226 mg of dicyclohexylcarbodiimide in 2 cm 3 of methylene chloride is added. The resultant mixture is allowed to return to ambient temperature, agitated for 25 minutes, heated under reflux for 2 hours, returned to ambient S 30 temperature, filtered and the solvent is evaporated.

The residue is chromatographed on silica (eluant: methylene chloride acetone and 281 mg of expected product is obtained.

Rf 0.25 (eluant: methylene chloride acetone (99-1)) IR Spectrum (CHC1 3 C=O 1786-1729 cm- 1 (hydantoin) 1748 cm 3 (ester) C:N 2235 cm- 1 Aromatics 1615-1602-1576-1505 cm- 1 1 F UJ LU.LIIIU.La .LVCL; 24 I UV Spectrum (EtOH) Max. 258 nm S 16800 Infl. 276 nm E 5800 Infl. 286 nm E 3000 EXAMPLE 4: ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) dimethyl 2,4-dioxo 1-imidazolidinebutanoate The operation is carried out as in Example 2 starting with the product obtained in Example 8 of the European Patent Application No. 0,494,819 and ethyl 4-bromobutyrate. The expected product is obtained. M.p. 66-67 0

C.

Rf 0.16 (eluant: methylene chloride acetone (99-1)) IR Spectrum (CHC1 3 C=O 1770-1726 cm- 1 C-N 2235 cm- 1 Aromatics 1616-1576-1505 cm- 1 UV Spectrum (EtOH) Max. 260 nm f 15500 ct= Infl. 277 nm E 7000 Infl. 286 nm E 3600 20 EXAMPLE 5: 3-(4-cyano 3-(trifluoromethyl) phenyl) dimethyl 2,4-dioxo 1-imidazolidinebutanoic acid 1 g of the product obtained in Example 4 in 20 cm 3 of methanol is agitated for 3 hours at ambient temperature in the presence of 3 cm 3 of 2N soda. The mixture is poured into 25 20 cm 3 of water, acidified to pH 1 using 7 cm 3 of N hydrochloric acid, extracted with ether, the extracts are washed with water and dried and the solvents are eliminated under reduced pressure. 863 mg of crude product is obtained 179-180 0 C) which is purified by chromatography on silica (eluant: methylene chloride methanol After recrystallization from isopropanol, 614 mg of expected product is recovered. M.p. 184-185 0

C.

Rf 0.25 (eluant: methylene chloride methanol IR Spectrum (nujol) C 0 1770-1753-1735-1712-1690-1645 cm- 1 C N 2230 cm- 1 Aromatics 1613-1587-1533-1502 cm- 1 EXAMPLE 6: (1,1-dimethyl) ethyl 3-(4-cyano 3-(trifluoroa L C N~g 25

CCC

CC

methyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinebutanoate By carrying out the esterification of the product obtained in Example 5, using terbutanol, in the presence of dicyclohexylcarbodiimide and dimethylamino pyridine, as indicated in Example 3, the expected product is obtained.

M.P. 96 0 -97 0

C.

Rf 0.32 (eluant: methylene chloride acetone IR Spectrum (CHCl 3 C=O 1779-1725 cm- 1 CsNC 2235 cm- 1 Aromatics 1616-1576-1505 cm- 1 UV Spectrum (EtOH) Max. 261 nm S 15600 Infi. 276 nm 7800 Infi. 286 nm 3700 EXAMPLE 7: cyclopentyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 5, 5-dimethyl 2, 4-dioxo 1 -imidazolidinebutanoate By operating as in Example 6, using cyclopentanol, the expected product is obtained. M.p. 85-86 0

C.

Rf 0.33 (eluant: methylene chloride acetone IR Spectrum (CHC1 3 C=O 1779-1728 cm- 1 C-=N 2236 cm- 1 Aromatics 1616-1578-1505 cm- 1 UV Spectrum (EtOH) Max. 261 nm 16000 Infl. 277 nm 6 7600 Infl. 286 nm E 3700 30 EXAMPLE 8: 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) thio) ethyl) 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile a) Formation of the phenolate 0.16 cm 3 of 4-fluorothiophenol in 1.6 cm 3 of dimethylformamide is added at a temperature of less than 28 0

C

to a suspension of 80 mg of sodium hydride in 0.5 cm 3 of dimethylformamide, and the solution is maintained under agitation for 10 minutes.

C* 9 4 0*4 C C C

CC

CC t C 1 p 1-I r .p

AC

or 26 a 1 9r 9 51 4 191 b) Substitution 548 mg of 4-[4,4-dimethyl 2,5-dioxo 3-(2-chloroethyl) 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile obtained as indicated in Example 50 of the European Patent Application No. 0,494,819 in solution in 4 cm 3 of dimethylformamide is added to the solution obtained above, the whole is agitated for 2 hours, poured into 50 cm 3 of water containing 0.5 g of monopotassium phosphate and extraction is carried out with ether. The organic phase is washed with water and dried and the solvent is evaporated. After chromatographing the residue on silica (eluant: cyclohexane ethyl acetate 570 mg of expected product is obtained. M.p. 93- 94 0

C.

rf 0.29 (eluant: cyclohexane ethyl acetate (75-25)).

IR Spectrum (CHC1 3 C=O 1780-1726 cm- 1 C=N 2238 cm- 1 Aromatics 1616-1579-1506 cm- 1 (fluorophenyl) thio 1591-1492 cm- 1 20 UV Spectrum(EtOH) Max. 254 nm E 18600 Infl. 277 nm E 7500 Infl. 286 nm E 4200 EXAMPLE 9: 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) 25 sulphonyl) ethyl) 1-imidazolidinyl 2- (trifiuoromethyl) benzonitrile 1.21 g of metachloroperbenzoic acid in 24 cm 3 of methylene chloride is added dropwise, at a temperature of less than 29 0 C, to 222 mg of the product obtained in Example 8 in 4.4 cm 3 of methylene chloride. After 30 minutes of agitation, the mixture is poured into 30 cm 3 of sodium thiosulphate (0.5 agitation is carried out for minutes, followed by decanting and extracting with methylene chloride. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate then with water, dried, and the solvent is evaporated. After chromatographing the residue on silica (eluant: cyclohexane ethyl acetate 220 mg of product is obtained which is crystallized

I

C L It rrr .V ,,4 rC i-ci.:-'lr r:

I

27

C

*3 I .3.

*i 3 ''It from isopropanol. 196 mg of expected product is recovered.

M.p. 155-156 0 C. Rf 0.22 (eluant: ethyl acetate cyclohexane IR Spectrum (CHC1 3 C=0 1783-1727 cm- 1 C=N 2236 cm- 1 Aromatics 1615-1593-1505-1497 cm- 1 S02 1314-1150 cm- 1 UV Spectrum (EtOH) Max. 258 nm E 16700 Infl. 286 nm EXAMPLE 10: 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) sulphinyl) ethyl) 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile 222 mg of the product obtained in Example 8 in 15 cm 3 of methanol is agitated for 30 minutes at ambient temperature in the presence of 5 cm 3 of an aqueous solution of sodium metaperiodate (0.1 The suspension obtained is heated for one hour at 40 0 C, 10 cm 3 of methanol and 5 cm 3 of oxidizing solution are added.

The methanol is evaporated off, 10 cm 3 of a saturated solution of sodium chloride is added and extraction is carried out with ethyl acetate. The organic phase is washed with salt water, dried, and the solvent is evaporated. After 25 chromatographing the residue on silica (eluant: methylene chloride acetone 205 mg of product is obtained which is crystallized from isopropanol, and 180 mg of expected product is recovered. M.p. 145-146 0

C.

Rf 0.10 (eluant: methylene chloride acetone 30 IR Spectrum (CHC1 3 C=0 1782-1727 cm- 1 CN 2236 cm- 1 Aromatics 1615-1592-1505-1493 cm- 1 UV Spectrum (EtOH) Max. 258 nm E 17600 Infl. 285 nm By operating as indicated in the preceding examples, using 4-(4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2c r 4-

L

L, II

-I

28 *a At A AS (trifluoromethyl) benzonitrile prepared as in Example 8 of the European Patent Application No. 0,494,819 and the appropriate reagents, the compounds of the following examples were obtained: EXAMPLE 11: 4-(4,4--dimethyl 2,5-dioxo 3-((3-methoxyphenyl) methyl) 1 -imidazolidinyl 2- (trifluoromethyl) benzonitrile M.P. 88-89 0

C

rf 0.21 (eluant: cyclohexane ethyl acetate IR Spectrum (CHCl 3 C=O 1779-1724 cm- 1 C EN 2238 cnf 1 Aromatics 1614-1602-1588-1575-1504-1491 UV Spectrum (EtOH) Max. 260 nm 16800 Infl. 210 nm s 28500 Infi. 280 nm e 8900 EXAMPLE 12: 4-(4,4-dimethyl 2,5-dioxo 3-(2-(4-morpholinyl) ethyl) I -imidazolidinyl trifluoromethyl) benzonitrile Rf 0.20 (eluant: methylene chloride -acetone (70-30)) 20 IR Spectrum (CHCl 3 C=O 1779-1725 cm- 1 C=-N 2235 cm- Aromatics 1616-1576-1505 cm 1 morpholinyl 11*17 cm- 1 25 UV Spectrum (EtOH) Max. 261 nm E 14000 Infl. 277 nm SI 6900 Infl. 286 nm C 3600 EXAMPLE 13: 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-iniino 2thioxo 1-imidazolidinyl) 2.--(trifluoromethyl) benzonitrile I a) Preparation of the isothiocyanate 2.23 g of 1-trifluoromethyl-4-amino benzonitrile (prepared according to EP 0002892) is added slowly to a solution of 22 cm 3 of distilled water and 1 cm 3 of thiophosgene, the whole is agitated for one hour, extracted with chloroform, the extracts are washed with salt water, dried and evaporated to dryness under reduced pressure, and 3 g of product is obtained which is used as it is for t t

C~

-29- .obtaining the imine.

b) Obtaining the imine g of the isothiocyanate prepared above is mixed with 37 cm 3 of tetrahydrofuran in the presence of 1.5 cm 3 of triethylamine and 2.8 g of 2-[(2-hydroxy ethyl) amino] 2methyl propane nitrile, prepared as indicated in the preparation given in Example 22 of the European Patent Application No. 0,494,819, in solution in 10 cm 3 of tetrahydrofuran, is added in one lot. The temperature spontaneously increases to 34 0 C. The resultant mixture is allowed to return to ambient temperature while maintaining under agitation for one hour, the solvent is evaporated off and the residue is chromatographed on silica (eluant: methylene chloride methanol 5.87 g of expected product is obtained 181 0

C,

after crystallization from isopropanol).

EXAMPLE 14: 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo S1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile 4.6 g of the product prepared in Example 13 in 65 cm 3 of 20 methanol is heated under reflux for one hour in the presence of 10 cm 3 of 2N hydrochloric acid. The mixture is cooled down to ambient temperature and poured into 300 cm 3 of icecooled water. Extraction is carried out with ethyl acetate, S' the organic phase is washed with salt water, dried, and the solvent is evaporated off. The residue is chromatographed on silica (ethyl acetate cyclohexane the fractions are collected, rf 0.14, and after crystallization from methylene chloride and cyclohexane 4.37 g of expected product is obtained. M.p. 130 0

C.

S 30 Analysis C 15

H

14

F

3

N

3 0 2 S 357.36 C% H% F% N% S% Calculated 50.42 3.95 15.95 11.76 8.97 Found 50.3 3.9 15.9 11.6 8.9 IR Spectrum (CHC1 3 OH 3626 cm- 1 C=N 2236 cm- 1 C=O 1763 cm- 1 Aromatics 1615-1578-1504 cm- 1 .iF i I 30 EXAMPLE 15: 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-imino 2thioxo 1-imidazolidinyl) 2- 1 ifluoromethyl) 5- 3

H

benzonitrile a) Preparation of the tritiated benzonitrile 15 mg of 2-trifluoromethyl 4-amino 5-bromo benzonitrile is mixed with 200 pl of ethyl acetate in the presence of pl of triethylamine and 2 mg of palladium on activated charcoal, then tritium (1.42 bar) is introduced. After filtering, rinsing with ethyl acetate and evaporating to dryness at ambient temperature, approximately 66.6 G.Bq (1.8 Ci) of product is obtained.

b) Preparation of the tritiated isothiocyanate 150 pl of a 10% solution of thiophosgene in chloroform is added to the product obtained above, in 150 pl of water and agitation is carried out for 45 minutes at ambient temperature. Dilution is carried out with 0.5 ml of water and 1 ml of chloroform, followed by extraction with Schloroform, the solvent is evaporated off under reduced pressure, the residue is taken up in toluene and 50.7 G.Bq 20 (1.37 Ci) of expected product is obtained which is kept at ,-800C.

S, c) Preparation of the tritiated imine Having eliminated the toluene from the above mixture, under reduced pressure, 130 pl of tetrahydrofuran with 1% 25 triethylamine is added, 13 pl of 2-[(2-hydroxyethyl) amino] 2-methylpropane nitrile prepared as indicated in Example 22 of the European Patent Application No. 0,494,819 is added, then another 130 pl of tetrahydrofuran with 1% triethylamine is added. The whole mixture is agitated for 30 minutes at ambient temperature and the solvents are eliminated under reduced pressure.

Preparation of the 2-trifluoromethyl 4-amino benzonitrile used at the start of Example A solution of 2-trifluoromethyl 4-amino benzonitrile (prepared according to EP 0002892) (5 moles) in 25 cm 3 of methanol is cooled down to 0 0 C and bromine is added.

(5.2 moles). The mixture is allowed to return to ambient j temperature, agitated for 3 hours, alkalinized using 31 Striethylamine then an aqueous solution of sodium thiosulphate is added. The solvents are eliminated, extraction is carried out with chloroform, the organic phase is washed with water, dried, and the solvent is evaporated off in order to obtain the product which is used as it is for the following stage.

IR Spectrum (CHC1 3

NH

2 3612-3408 cm- 1 C=N 2230 cm- 1 Aromatics 1621-1556-1506 cm- 1 EXAMPLE 16: 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) 5- 3 H benzonitrile The product obtained in the previous example in 180 1l of water is heated to 1000C and 60 pi of 2N hydrochloric acid' is added. The mixture is agitated for 5 minutes under reflux then approximately 600 mg of ice is added, extraction is carried out with ethyl acetate, the extracts are washed with salt water, dried, and 34.7 G.Bq (937 mCi) of product is Sobtained. After chromatography on silica (eluant: cyclohexane ethyl acetate 19 G.Bq (513 mCi) of 4 expected product is obtained.

EXAMPLE 17: 4-(4,4-dimethyl 3-(3-hydroxypropyl) 5-imino 2thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile By operating as in Example 22 of the European Patent Application No. 0,494,819 starting with 2 g of the isothiocyanate prepared as indicated in Example 13a) and 1.2 g of the appropriate aminonitrile, 1.70 g of expected product is obtained.

rf 0.25 (methylene chloride acetone (65-35)).

IR Spectrum (CHC1 3 OH 3630 cm- 1 =NH 3314-1676 cm- 1 CSN 2235 cm- 1 Aromatics 1614-1578-1481 cm- 1 EXAMPLE 18: 4-(4,4-dimethyl 3-(3-hydroxypropyl) 5-oxo 2thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile By operating as in Example 14 starting with 240 mg of product obtained in Example 17, 226 mg of expected product is obtained. M.p. 149-150 0

C.

-32 Rf =0.32 (eluant: methylene chloride -acetone (75-25)).

IR Spectrum (CHCl 3 OH 3626 cm- 1 C=O 1763 cm-- 1 C=-N 2236 cm- 1 Aromatics 1 61 5-1 580-1 504-1 483 cm- 1 EXAMPLE 19: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2thioxo 1 -imidazolidinyl) trifluoromethyl) benzonitrile By operating as in Example 22 of the European Patent Application No. 0,494,819, starting with 2 g of isothiocyanate, and 1.38 g of the appropriate aminonitrile, 2.08 g of expected product is obtained.

rIf 0.25 (methylene chloride -acetone (65-35)).

IR Spectrum (CHCl 3 OH 3630 cm- 1 =NH 3314-1675 cm- 1 C 2235 cm- 1 *Aromatics 1614-1577-1504 cm- 1 EXAMPLE 20: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyi) benzonitrile *By operating as in Example 14, starting with 300 mg of the product obtained in Example 19, 236 mg of expected product is obtained. 78-79 0

C.

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

IR Spectrum (CHCl 3 OH 3624 cm- 1 C=O 1762 cm- 1 CSN 2237 cm- 1 Aromatics 1615-1580-1504 cur 1 UV Spectrum (EtOH) Max. 232 nm E 19500 Max. 254 nm 6 24000 Infl. 266 nm EXAMPLE 21: 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-imino 2thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile By operating as in Example 22 of the European Patent Application No. 0,494,819, starting with 2.5 g of isothiocyanate and 1.56 g of the appropriate aminonitrile, -33- 2.36 g of expected product is obtained.

Rf 0.23 (methylene chloride acetone IR Spectrum (CHCl 3 =NH 3314 cm- 1 C=N 2236 cm- 1 Aromatics 1614-1578-1504 cm- 1 CFN 1675 cm- 1 EXAMPLE 22: 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-oxo 2-thioxo 1 -imidazolidinyl) trifluoromethyl) benzonitrile By operating as in Example 14, starting with the product obtained in Example 21, the expected product is obtaine(7, M.p. 98-99 0

C.

Rf 0.32 (eluant: methylene chloride -acetone (99-1)) IR Spectrum (CHCl 3 C=O 1757 cm- 1 C=-N 2236 cm- 1 Aromatics 1615-1580-1504 cm- 1 UV Spectrum (EtOH) Max. 232 nm q- 18200 20 Max. 254 nm E 22400 Infi. 265 nm EXAMPLE 23: 4-(4,4-dimethyl 3-(l-methylethyl) 5-itnino 2thioaxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrilep *By operating as in Example 22 of the Euro~ean Patent Application~ No. 0,494,819, starting with g of the ****isothiocyanate and 1.32 g of the appropriate aminonitrile, 880 mg of expected product is obtained.

rf 0.20 (eluant: methylene chloride -acetone IR Spectrum (CHCl 3 =NH 3310-1675 cm- 1 CmN 2236 cm- 1 Aromatics 1614-1580-1504 cm- 1 EXAMPLE 24: 4-(4,4-diniethyl 3-(1-methylethyl) 5-oxo 2-thioxo 1 -imidazolidinyl) trifluoromethyl) benzonitrile By operating as in Example 14, starting with 880 mg of the product obtained in Example 23 and 35 cm 3 of 6N hydrochloric acid and after extraction with chloroform, 744 mg of expected product is obtained. M.p. =203-204 0

C.

I -34- Rf =0.45 (eluant: cyclcihexane -ethyl acetate. IR Spectrum (CHCl 3 OH 3626 cm- 1 C=O 1753 cm- 1 C=-N 2232 cm- 1 Aromatics 1615-1580-1504 cm- 1 UIV Spectrum (EtOH) Max. 232 rim E= 18900 Max. 235 nm 22500 Infi. 273 nm EXAMPLE 25: 3-(3,4-dichlorophenyl 5,5-dimethyl 1-(3hydroxypropil) 4-imino 1-imidazolidine thione The operation is carried out as in Example 51 of the European Patent Application No. 0,494,819., starting with 24gof 3,4-dichlorophenyl iscaaeand 1.6 g of the (eluant: methylene chloride aceto~ne 2.16 g of expected product is obtained. rf 0.25 IR Spectrum (CHCl 3 OH 3630 cm- 1 essociated C=NH 3294-1676 cm- 1

(F)

Aromatics 1595-1569-1482 cm- 1 *EXAMPLE 26: 3-(3,4--dichlorophenyl 5,5,-dimethyl 1-(3hydroxypropyl) 2-thioxo 4-inidazolidinone 25 The operation is carried out as in Example 52 of the ropean Pe'.ent Application No. 0,494,819, using 0.88 g of iproduct obtained in Example 25 and 35 3 of 61\7 hydrochloric acid. After extraction with chloroform, 0.79 g of expected product is obtained. M.p. =202-203 0

C.

IR Spectrum (CHCl 3 C=O 1753 cnr 1 C=-N 2232 cm- 1 Aromatics '615-1580-1504 cm- 1 UV Spectrum (EtCH) Max. 232 nm E 18900 Max. 235 rim p 22500 Infl. 273 nm I i EXAMPLE 27: 4-(4,4-dimethy. 3-(4-hydroxybutyl) 5-irnino 2- S|i 35 thioxo 1-imidazolidinyl) 2-(trifluoromethyl) (5- 3

H)

benzonitrile a) 4-amino 2-(trifluoromethyl) (5-1H) benzonitrile The following are cooled down to -180 0 C and mixed under an inert t.tosphere: 16 mg of 2-trifluoromethyl 4-amino 5-bromo benzonitrile, 2 mg of palladium on activated charcoal, 200 pl of ethyl acetate, l of triethylamine, then the mixture is left under a tritium atmosphere and taken A" to 200, the pressure is then 1.68 bar.

Agitation is carried out until absorption is complete (p 0.42 bar), followed by cooling down to -180 0 C, the excess tritium is recovered, taken to 200 then filtered, the filtrate is rinsed with ethyl acetate and concentrated at 40 0 C under reduced pressure.

68 G.Bq of expected product is obtained.

b) 4-thioisocyanate 2-(trifluoromethyl) (5- 3 H) benzonitrile The following are mixed under an argon atmosphere: 34 G.Bq of tritiated amino derivative, prepared above, 150 ul of demineralized water, S* 150 pl of 10% thiophosgene solution in chloroform.

The mixture is agitated at 20 0 C for 45 minutes, decanted, reextraction is carried out with chloroform, the 25 extracts are dried over magnesium sulphate, filtered and concentrated under reduced pressure.

The thioisocyanate obtained is used as it is for the following stage.

i c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) (5-3H) benzonitrile The following are mixed under an argon atmosphere with the thioisocyanate prepared in stage b): 350 l of tetrahydrofuran with 1% triethylamine and pl of propanonitrile prepared as indicated below.

Agitation is carried out for 2 hours at 20 0 C followed by concentration at 20 0 C under reduced pressure.

The imine is used as it is for the following stage.

Preparation of the 2--(4-hydroxybutylamino) 2-methylpropano-

I--I

36 nitrile used in stage c) 550 pl of acetone cyanohydrin and 500 yl of 4-amino 1butanol are mixed together, the mixture is agitated for 16 hours at 20 0 C, the product thus obtained is used as it is for the following stage.

EXAMPLE 28: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) (5-3H) benzonitrile 200 )p of 2N hydrochloric acid is added to the imine prepared in Example 27, the mixture is taken to reflux for minutes, returned to 20 0 C, diluted with 1 cm 3 of water, extraction is carried out with ethyl acetate, the extracts are washed with water and concentrated under reduced pressure.

The crude product is purified by chromatography on silica (eluant: cyclohexane ethyl acetate S2.8 G.Bq of expected product is obtained.

t t EXAMPLE 29: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo 14

C)

nitrile 20 a) 4-amino 2-(trifluoromethyl) benzo 14 C) nitrile 377 mg of cuprous cyanide 14 C (9 G.Bq) and 1.0732 g of 4-bromo 3-(trifluoromethyl) benzenamine are mixed together under a nitrogen atmosphere in 8 cm 3 of dimethylformamide.

The mixture is heated for 4 hours under reflux, then cooled down to 0°C, diluted with 20 cm 3 of acetone and the insoluble part is filtered off. The filtrate is concentrated at 70 0 C under reduced pressure. The residue is taken up in methylene chloride, filtered and the filtrate is concentrated under reduced pressure.

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

0.558 g (6.62 G.Bq) of expected product is obtained.

b) 4-thioisocyanate 2-(trifluoromethyl) benzo 14 C) nitrile The following are mixed under a nitrogen atmosphere: 189 mg of benzonitrile 14 C) prepared in stage a) 2.7 cm 3 of water and 1l of thiophosgene.

t i{ 37 The mixture is agitated vigorously for 5 minutes, 30 pl of thiophosgene is added and agitation is continued for one hour at 20 0 C, then extraction is carried out with chloroform, the extracts are washed with water, dried and concentrated under reduced pressure.

The thioisocyanate obtained is used as it is for the following stage.

c) 4-(4,4--dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1imidazolidlinyl) 2-(trifluoromethyl) benzo 14 C) nitrile 2 cm 3 of tetrahydrofuran, the propanonitrile prepared as indicated below in solution in 1.5 cm 3 of methylene chloride and 150 pl of triethylamine are added under a nitrogen atmosphere to the thioisocyanate obtained in stage b).

The mixture is heated for 30 minutes under reflux and concentrated under reduced pressure.

The imine obtained is used as it is for the following stage.

Preparation of the 2-(4-hydroxybutylamino) 2-methylpropanonitrile used in stage c 220 1l of acetone cyanohydrin and 200 pl of 4-amino 1butanol are mixed together, the mixture is agitated for 16 hours at 20 0 C, diluted with 2 cm 3 of methylene chloride, dried, filtered and the filtrate is concentrated under reduced pressure.

25 The propanonitrile obtained is used as it is for the following stage.

EXAMPLE 30: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo 14 C) nitrile 6 cm 3 of methanol and 1.6 cm 3 of 2N hydrochloric acid are added to the imine obtained in Example 29.

The mixture is taken to reflux for 45 minutes, cooled down to 20 0 C, diluted with 10 cm 3 of water, extraction is carried out with methylene chloride, the extracts are washed with water and concentrated under reduced pressure.

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

J!

328 mg of expected product is obtained.

jR 1.

Sj.

1 3 38 EXAMPLE 31: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile a) 4-amino 2-(trifluoromethyl) (5- 3 H) benzonitrile The operation is carried out as in stage a) of Example 27 using: 16 mg of 4-amino 5-bromo 2-trifluoromethyl benzonitrile, 2 mg of palladium on activated charcoal, 200 pl of ethyl acetate, pl of triethylamine.

68 G.Bq of expected product is obtained.

b) 4-isocyanate 2-(trifluoromethyl) (5-3H) benzonitrile 34 G.Bq of tritiated amino derivative, prepared above and 100 pl of 20% phosgene in toluene are mixed together under an argon atmosphere.

The mixture is taken to 80 0 C for one hour, a further 100 pl of phosgene is added and the whole is heated for one hour at 80 0 C, this operation is repeated one more time then concentration is carried out at 20 0 C, under reduced pressure.

The isocyanate obtained is used as it is for the following stage.

c: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile The following are added under an argon atmosphere to the isocyanate obtained in stage b): 25 200 ul of methylene chloride, )l of the propanonitrile chloromethylene solution prepared as indicated below and 20 pl of triethylamine.

The mixture is agitated for 30 minutes, a further 50 l of the propanonitrile solution is added, agitation is continued for 30 minutes followed by concentration at 20 0

C

under reduced pressure.

The imine is used as it is for the following stage.

Preparation of the 2-(4-hydroxybutylamino) 2-methyl propanonitrile, used in stage c) 220 pl of acetone cyanohydrin and 200 pl of 4-amino 1butanol are mixed together, the mixture is agitated for 16 hours at 20°C, diluted with 3 cm 3 of methylene chloride and L JL__T 39 dried over magnesium sulphate.

The decanted solution thus obtained is used as it is for the following stage.

EXAMPLE 32: 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile 200 pl of methanol and 50 pl of 2N hydrochloric acid are added to the imine obtained in Example 31, the mixture is taken to reflux for 45 minutes, returned to 20 0 C, diluted with 1 cm 3 of water, extraction is carried out with methylene chloride, the extracts are washed with water and concentrated at 20 0 C under reduced pressure.

The crude product is purified by chromatography on silica (eluant: methylene chloride ethyl acetate (7-3 then 16 G.Bq of expected product is obtained.

EXAMPLE 33: 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5--imino 2-oxo S1-imidazolidinyl) 2-(trifluoromethyl) benzo 14 C) nitrile a) 4-amino 2-(trifluoromethyl) benzo (14C) nitrile The operation is carried out as in Example 29, stage using 377 mg of cuprous cyanide 14 C, 1.0732 g of 4-bromo 3-trifluoromethyl benzenamine and 8 cm 3 of dimethylformamide.

0.558 g (6.62 G.Bq) of expected product is obtained.

b) 4-isocyanato 2-(trifluoromethyl) benzo 14 C) nitrile 182.4 mg of benzonitrile 14 C) (0.97 mmole), 2 cm 3 of dioxane and 1 cm 3 of 20% phosgene in toluene are mixed together under a nitrogen atmosphere.

The solution obtained is taken to 60 0 C for 22 hours, then concentrated at 60 0 C under reduced pressure.

The isocyanate obtained is used as it is for the following stage.

c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1imidazolidinyl) 2-(trifluoromethyl) benzo 14 C) nitrile cm 3 of methylene chloride (on siliporite NK 30), the propanonitrile prepared as in Example 31, in solution in 1.5 cm 3 of methylene chloride, and 150 pl of triethylamine are added under a nitrogen atmosphere to the isocyanate prepared in stage b).

The mixture is agitated for one hour at 20 0 C and _I l 40 CE (C CCt

C(

CC C

I

It

C

concentrated under reduced pressure.

The imine is used as it is for the following stage.

EXAMPLE 34: 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) benzo 14 C) nitrile 5 cm 3 of methanol and 1.2 cm 3 of 1N hydrochloric acid are added to the imine obtained in Example 33, the mixture is taken to reflux for 40 minutes, returned to 20 0 C, diluted with 10 cm 3 of water, extraction is carried out with methylene chloride, the extracts are washed with water and concentrated under reduced pressure.

The crude product is purified by chromatography on silica (eluant: ether acetonitrile cyclohexane (50-15- 289 mg (1.26 G.Bq) of expected product is obtained.

EXAMPLE 35: 4-(2,5-dioxo 4,4-dimethyl 3-(4-triphenylmethoxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile 370 mg of the product obtained in Example 1, 307 mg of trityl chloride in the presence of 10 mg of 4-dimethylaminopyridine, 0.25 cm 3 of triethylamine and 4 cm 3 of dimethylformamide are agitated at ambient temperature for 16 hours. The mixture is heated to 40 0 C for 4 hours, poured into water, extraction is carried out with ether, the extracts are washed with water, dried, the solvent is eliminated under reduced pressure, the residue is chromato- 25 graphed on silica (eluant: cyclohexane ethyl acetate 75-25) and 467 mg of expected product is collected. rf 0.25.

IR Spectrum (CHC1 3 C=O 1778, 1725 cm- 1

(F)

C=N 2235 cm- 1 Aromatics 1615, 1597, 1505, 1490 cm- 1 EXAMPLE 36: 4-(2,5-dioxo 4,4-dimethyl 3-(4-phenylmethoxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile 48 mg of sodium hydride is added in several lots to 370 mg of the product obtained in Example 1 in solution in 4 cm 3 of dimethylformamide, agitation is carried out for minutes, then 0.12 cm 3 of benzyl bromide and 40 mg of tetrabutylammonium iodide are added. After one hour minutes of reaction, the same quantity of each reagent is V §g 41 added, agitation is continued for one hour, the reaction medium is poured into an ice-cooled aqueous solution of monopotassium phosphate and extraction is carried out with ether, the extracts are washed with water, dried, the solvent is eliminated under reduced pressure, the residue is chromatographed on silica (eluant: methylene chloride acetone 99-1) and 140 mg of expected product is obtained.

M.p. 75-76 0

C.

IR Spectrum (CHC1 3 C=O 1779, 1725 cm 1 CSN 2235 cm-1 Aromatics 1615, 1580, 1505, 1497 cm-1 EXAMPLE 37: 4-[4,4-dimethyl 2,5-dioxo 3-(4-methoxybutyl) 1imidazolidinyl] 2-(trifluoromethyl)-benzonitrile 50 mg of sodium hydride is added in several lots to 370 mg of the product obtained in Example 1 in solution in 3 cm of dimethylformamide, agitation is carried out for minutes, 0.06 cm 3 of methyl iodide is added, agitation is continued for one hour, a further 50 mg of sodium hydride is 20 added then after 20 minutes 0.06 cm 3 of methyl iodide is added. The reaction medium is poured into water, extracted with ether, the extracts are washed with water, dried, the Ssolvent is evaporated, the residue is chromatographed on silica (eluant: methylene chloride acetone 98-2) and 25 135 mg of expected product is obtained. M.p. 80-81 0

C.

IR Spectrum (CHC1 3 C=O 1779, 1725 cm- 1

(F)

CN 2234 cm- 1 Aromatics 1616, 1576, 1505 cm-1

OCH

3 approx. 2830 cm 1 EXAMPLE 38: 4-[3-(4-chlorobutyl) 4,4-dimethyl 2,5-dioxo 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile The operation is carried out as in Example 2 starting with 600 mg of the product obtained in Example 8 of the European Patent Application No. 0,494,819 and 660 mg of 1chloro 4-iodobutane in solution in 1 cm 3 of dimethylformamide cooled down to +5 0 C. 604 mg of expected product is obtained.

M.p. 80-81 0

C.

I 1 ~I 30OH prx.23 m 1 1 442 42 IR Spectrum

(CHCI

3 C=O 1779, 1725 cm 1

(F)

CSN 2238 cm 1 Aromatics 1616, 1575, 1505 cm 1 EXAMPLE 39: 4-[3-[4-[(methylsulphonyl) oxy] butyl] 4,4dimethyl 2,5-dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile 0.17 cm 3 of methanesulphonyl chloride is added to 740 mg of the product obtained in Example 1 in solution in 7.4 cm 3 of pyridine and 24 mg of 4-dimethylaminopyridine. Agitation is carried out for one hour, the mixture is poured into icecooled water, extraction is carried out with methylene chloride, the extracts are washed with water, the residual pyridine is eliminated by distillation, the residue is chromatographed on silica (eluant: methylene chloride ethyl c acetate 8-2) and 771 mg of expected product is obtained.

IR Spectrum (CHCl 3 C=O 1779, 1725 cm 1 CsN 2235 cm 1 Aromatics 1615, 1575, 1505 cm 1 0 -OS- 1361, 1175 cm 1 UV Spectrum (EtOH) max. 261 nm 14900 infl. 279-297 nm EXAMPLE 40: 4-(3-acetyl 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile SThe operation is carried out as in Example 2 starting i 30 with 420 mg of the product prepared in Example 8 of the European Patent Application No. 0,494,819 and two lots of 0.1 cm 3 of acetyl chloride. After chromatography on silica (eluant: methylene chloride ethyl acetate 98-2), 334 mg of expected product is obtained. M.p. 129-130 0

C.

IR Spectrum (CHCl 3 C=0 1800, 1740, 1717 cm 1 CEN 2240 cm- 1 Aromatics 1616, 1505 cm 1 I 4 43 UV Spectrum (EtOH) max. 250 nm E 12000 infl. 274--284 nm EXAMPLE 41: 4-(3-benzoyl 4,4-dimethyl 2,5-dioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile The operation is carried out as in Example 2 starting with 300 mg of the product prepared in Example 8 of the European Patent Application No. 0,494,819 and two lots of 0.12 cm 3 of benzoyl chloride in solution in 0.5 cm 3 of dimethylformamide. After chromatography on silica (eluant: cyclohexane ethyl acetate 285 mg of expected product is obtained. M.p. 179-180 0

C.

IR Spectrum (CHC1 3 C=O 1800, 1780, 1746, 1699 cm- 1 C=N 2235 cm- 1 SAromatics 1617, 1600, 1580, 1504 cm- 1 UV Spectrum (EtOH) max. 250 nm E 28500 infl. 275 nm E 6500 20 infl. 263 nm E 3850 EXAMPLE 42: 4-[3-[dimethyl (1,1-dimethylethyl) silyl] 4,4dimethyl 2,5-dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile The operation is carried out as in Example 2 starting with 450 mg of the product prepared in Example 8 of the European Patent Application No. 0,494,819 and 300 mg of dimethyl t-butylsilyl chloride in 2 cm 3 of dimethylformamide.

After chromatography on silica (eluant: methylene chloride acetone 99-1), 527 mg of expected product is obtained.

M.p. 147-148 0

C.

IR Spectrum (CHC1 3 C=N 2236 cm- 1 Aromatics 1615, 1579, 1505 cm- 1 UV Spectrum (EtOH) max. 258 nm E 17000 infl. 275-285 nm In addition to the products described above, the following products constitute products which can be obtained i p s

I

19 44 within the scope of the present invention, namely the products of formula: in which YA represents an oxygen or sulphur atom and R3A has the following values: 4, 4t St S 4,55 S 5455 St C 5t4 5 C S I 45 51

C

44 55 I C ''Sc

S..

IS

4 4 445 4444 St

S

55

S

S S

*-(CH

2 )nSY&-F

*-(CH

2 )nSO 2

~F

CH

3 -CH2)n-OH .(CH2)n-COO-alk -(CH2)nCOI< lk "Ialk 2

-(CH

2 )n-COalk -CH2)n-CHI-I'

H

CH

3 alk, alkl and alk 2 representing an alkyl radical containing S 4 45 up to 4 carbon atoms and n representing an integer between 1 and 4.

EXAMPLE 43: Tablets were prepared having the following composition: 4-(5-oxo-2-thioxo-3,4,4-trimethyl 1-imidazolinyl) -2-(trifluoromethyl) benzonitrile 100 mg Excipient sufficient quantity for a tablet completed at 300 mg (Detail of the excipient: lactose, starch, talc, magnesium stearate).

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION 1) Study of the affinity of the products of the invention for the androgen receptor Androgen receptor.

Male Sprague Dawley EOPS rats weighing 180-200 g, castrated 24 hours previously, are killed, the prostates are removed, weighed and homogenized at 0°C using a Potter glass flask, 20 in a buffer solution (10mM Tris, 0.25M saccharose, 0.1mM PMSF (phenylmethanesulphonylfluoride), 20mM sodium molybdate, HC1 pH to which 2mM of DTT (DL dithiothreitol) is added extemporaneously, at a rate of 1 g of tissue per 8 ml of buffer solution.

25 The homogenate is then ultracentrifuged at 0°C, for minutes at 209,000 g. Aliquots of the supernatant obtained (=cytosol), are incubated for 30 minutes and 24 hours at o0C, with a constant concentration of tritiated Testosterone and in the presence of increasing concentrations (0 to 2500.10-9M), either of unlabelled testosterone, or the products being tested. The concentration of bound tritiated Testostrone is then measured in each incubate by the method of adsorption on carbon dextran.

Calculation of the relative bond affinity (RBA).

The following 2 curves are drawn: the percentage of the bound tritiated hormone B/T as a function of the logarithm of the concentration of the unlabelled reference hormone and B/T as a function of the logarithm of the concentration of the _1_ 46 unlabelled product being tested. The straight line of the equation I50 (B/Tmax B/Tmin)/2 is determined.

B/T max of the bound tritiated hormone for an incubation of this tritiated hormone at the concentration B/T min of the bound tritiated hormone for an incubation of this tritiated hormone at the concentration in the presence of a large excess of unlabelled hormone (2500.10-9M).

The intersections of the straight line I50 and the curves allow the evaluation of the concentrations of unlabelled reference hormone (CH) and the unlabelled product being tested (CX) which inhibit by 50% the binding of the tritiated hormone on the receptor.

The relative bond affinity (RBA) of the tested product is determined by the equation RBA 100 The following results are obtained, expressed in RBA.

Reference product (Testosterone): 100 Product of examples Incubation 24 hours e 1 31 14 163 i 20 300 22 81 i24 28 30 2) Determination of the androgen or anti-androgen activity of the products of the invention by dosage with ornithine decarboxylase.

Treatment protocol SWISS 6-week old male mice, castrated 24 hours previously, receive, by oral or percutaneous route, the products being studied suspension in methyl cellulose or in solution in ethanol), simultaneously with a subcutaneous injection of testosterone propionate 3 mg/kg ;i6 slP -L 47 (solution in corn oil) in order to determine the antiandrogen activity. The agonistic activity is determined in the absence of testosterone propionate.

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

hours after the treatments, the animals are killed, the kidneys are removed, then homogenized at 0oC, using a teflon-glass grinder in 10 volumes of 50mM Tris-HC1 (pH 7.4) buffer solution containing 250 M of pyridoxal phosphate, 0.1 mM EDTA, and 5 mM of dithiothreitol. The homogenate is then centrifuged at 209,000 g for 30 minutes.

Principle of dosage At 37 0 C, renal ornithine decarboxylase converts an isotopic mixture of unlabelled ornithine and tritiated ornithine into unlabelled putrescine and tritiat .d putrescine.

The putrescine is then collected on ion-exchange selective papers, After drying, the excess tritiated and Sunlabelled unconverted ornithine is eliminated, by washing 3 times with 0.1M ammonium hydroxide. The papers are dried, It then the radioactivity is counted after the addition of scintillating Aqualite. i SThe results are expressed in fmoles (10 15 M) of tritiated putrescine formed/hour/mg of proteins.

The results are expressed in of inhib 'ion of the ODL tthe samples receiving only the testosterone rropionat i Test A the products are administered by percutaneous route at 1,5 mg/kg under a volume of 10 l.

Test B the products are administered by orale route at 30 1 mg/kg.

Test C the products are administered by orale route at 3 mg/kg.

J 47 a Products of ODTJ example Test A Test B Test C 1 40 36 14 32 67 18 41 78 22 62 24 26 58 Conclusion: The tests indicated above show that the products 15 of the invention tested possess a strong anti-androgen activity and have no agonistic activity.

4.

41<44 4~ CC CtCe tt C C at''

I

4C$$

IC

C 4

A

Claims (3)

1. 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxy butyl) 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile (1,1-dimethyl) ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl 1 5 2,4-dioxo 1 -imid azo lid ineactate ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1 -imidazolidinebutanoate 'Olt 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinebutanoic acid 0 o (1,1-dimnethyl) ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 44 ~2,4-dioxo 1 -imidazolidinebutanoate 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl)thio) ethyl) 1 -imidazolidinyl 2-(trifluoromethyl) benzonitrile 4-(4,4-dirnethyl 2,5-dioxo 3-(2-((4-fluorophenyl) sulphonyl) ethyl) 1-imidazolidinyl 2- (trifluoromethyl) benzonitrile 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) sulphinyl) ethyl) 4 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile 4-(4,4-dimethyl 2,5-dioxo 3-((3-methoxyphenyl) methyl) 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile IZ- B LI, 1/SI/6VSAP7G75.SPJ!,48 49a 4-(4,4-dimethyl 2, 5-dioxo 3-(2-(4-morpholinyl) ethyl) 1 -imidazolindinyl 2-(tifluoromethyl) benzonitrile 4-(4,4-dirnethyl 3-(2-hydroxyethyl) 5.-imino 2-thioxo 1 -imidazolidinyl) 2-(trifluoromethyl) benzonitrile 4-(4,4-dimethyl 3-(2-hydroxvethyl) 5-oxo 2-,thioxo 1-imidazolidinyl) 2-(tifluorornethyl) benzonitrile 4-(4,4-dlimethyl 3-(2-hydroxyethyl) 5-imino 2-thioxo 1-imidazolidinyl) 2-(trifluoromethl 5- 3 H benzonitrile 4- (4,4-d im ethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 1 0 2-(trifluoromethyl) 5_ 3 H benzonitrile 4-(4,4-dlinethyl 3-(3-hydroxypropyl) 5-imino 2-thioxo 1-imidlazolidliny!) 2-(tifluoromethyl) benzonitrile 4-(4,4-dirnethyl 3-(3-hydroxpropyi) 5-oxo 2-thioxo 1-imidazolidinyl') 2-(tifluoromethyi) benzonitrile 4-(4,4-dlimethyl 3-(4-hydroxybutyi) 5-imino 2-thioxo 1-imidazolidinyl) 2-(trifluorornethyl) benzonitrile 4-(4,4-dirn ethyl 3-(4-hydroxbutyl) 5-oxo 2-thioxo 1-imidazolidinyl) S 2-(trifluorornethyl) benzonitrile 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-imino 2-thioxo 1-imidazolidinyl) 2a 2-(trif luorom ethyl) benzonitrile 2-(trifluormethyl) benzonitrile 4- (4,4-d im ethyl 3-(l1-methylethyl) 5-imino 2-thioxo 1 -imidazolidinyl) -(trifluoronethyl 3enzonit leth 5-oxo 2-thioxo 1-imidazolidinyl) 2-(trifluororneth yl) benzonitrile 3-(3,4-dichlorophenyl 5,5-dimethyl 1 -(3-hydroxypropyl) -imino 2-imidazolidine thione 3-(3,4-diclilorophenyl 5, 5-dimethyl 1 -(3-hydlrox/propyl) 2-thioxo 4-imidazolidinone 15/5/96VSAIP7075.SPE,48 49b 4-(4,4-dimethyl 3-(4-hydroxybutyl) 2-(tifluaromethyl) (5_ 3 H) benzonitrile 4-(4,4-dimethyl 3-(4-hydroxybutyl) 2-(tifluoromethyl) benzonitrile 4-(4,4-dimethyl 3-(4-hydrcxybutyl) 2-(tifluoromethyl) benzo (14C0) nitrile 4-(4,4-dimethyl 3-(4-hydroxybutyl) 2-(trifluorornethyl) benzo (140) nitrile 4- (4,4-ci im ethyl 3-(4-hydroxybutyl) 1 0 2-(tifluoromethyl) benzonitrile
2. 5-imino 2-thioxo 1-imidazolidinyl) 5-oxo 2-thioxo 1-imidazolidinyl) 5-imino 2-thioxo 1-imidazolidinyl) 5-oxo 2-thioxo 1-imidazolidinyl) 5-imino 2-oxo 1-imidazolidinyl) .4 41 4 44 4 ii I., 44 4 44 4~ .4 14 1- £4 4" 4- (4,4-d im ethyl 2,5-dioxo 3-(40hydroxybutyl) 1-imidazolidinyl) 2-(tifluoroinedhyl) (5_ 3 H) benzonitrile 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 2-(trifluoromethyl) benzo (140 nitrile 4-(4,4-dimnethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluorom-ethyl) benzo (140 nitrile 4-14,4-dirnethyl 2,5-diana 3-(4-methoxybutyl) 1-imidazolidinyll 14 2-(trifluorornetlhyl)-benzonitrile 4-[3-(4-chlorobutyl) 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl] C E 2,5 2-(trif luororn ethyl) benzonitrile 4- 4-1(methylsulphonyl) oxy] butyl] 4,4-dimethyl '1 -imidlazolidiiiyll 2-(trifluoromethyl) benzonitrile V2) The products of formula as defined in claim 1, in which Y ~25 represents an oxygen atom, with the exception of the products in which the group represents the radical: in which X represents an oxygen atom and R 3 represents a hydrogen atom, R 2 15/5/96VSAP'7075. SPE,48 49c represents a halogen atom or a trifluoromethyl radical and R, represents a nitro radical or a halogen atom. 3) The products of formula as defined in claim 1 or 2 in which the group represents the group: in which X represents a sulphur atom and R 3 has the meaning t tI 4t n* T 50 indicated in claim 1. 4) The products of formula according to claim 3, in which R 3 represents n an alkyl radical having at most 4 carbon atoms optionally substituted by a hydroxy or methoxy radical. The products of formula as defined in any one of claims 1 to 4, in which R 1 represents a cyano radical or a halogen atom. 6) The products of formula according to claim 5, in which R 1 represents a chlorine atom. 7) The products of formula as defined in claim 1 or 2, in which the group represents a group: -C-SR 3 S. 15 -N or a group: 0 -N-R 3 in which R 3 represents an alkyl or alkenyl radical having at most 6 carbon atoms .7 ionally siu. i e optionally interrupted by one or more optionally oxidized oxygen or 25 sulphur atoms, or R 3 represents an plit ally ubnl i.lnl. H aralkyl radical, or an acyl radical or trialkylsilyl radical. I 8) The products of formula as defined in claim 7, in which R3 represents an alkyl radical containing at most 6 carbon atoms substituted by a halogen atom, a free or esterified hydroxy or carboxy radical, a heterocycle radical, an 0-aralkyl or S-aryl radical in which the aryl radical is optionally substituted by one or more halogen atoms or alkoxy radicals and the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone. h 35 9) The products of formula according to claim 8, in which R 3 represents an alkyl radical containing 2 to 4 carbon I atoms substituted by a chlorine atom or by one of the s n, following radicals: ethoxycarbonyl, tertbutoxycarbonyl or L- 1 51 cyclopentyloxycarbonyl, 4-fluorophenylthio optionally oxidized in the form of the sulphoxide or sulphone, morpholino, phenylmethoxy, triphenylmethoxy or methyl- sulphonyloxy. 10) The products of formula according to claim 7, in which R 3 represents an acetyl, benzoyl or (1,1-dimethylethyl) dimethylsilyl radical. 11) The products of formula as defined in any one of claims 1 to 5, of which the names follow: 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1- imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1- imidazolidinyl) 2-(trifluoromethyl) benzonitrile. 12) The products of formula as defined in any one of 15 claims 1, 2, 7, 8 and 9, of which the names follow: 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4- dioxo 1-imidazolidinebutanoic acid, 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1- imidazolidinyl) 2-(trifluoromethyl) benzonitrile. 13) Preparation process for the products of general formula as defined in claim 1, characterized in that: either a product of formula (II): N=C=X (II) i in which R 1 R 2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III): HN-R'3 H3C- -CH3 (III) CN in which R' 3 has the values indicated above for R 3 in which the optional reactive functions are optionally protected r 52 and it being understood that if R 1 represents a nitro radical or a halogen atom, if R 2 represents a halogen atom or a CF 3 radical and X represents an oxygen atom, R' 3 cannot represent a hydrogen atom, in order to obtain a product of formula (IV): X 1 N N-R' 7 3-c (IV) HN CH in which R 1 R 2 X and R' 3 have the previous meaning, which products of formula if necessary or if desired, are 15 subjected to any one or more of the following reactions, in any order: elimination reaction of the optional protective groups that can be carried by R' 3 b) hydrolysis reaction of the >C=NH group into a ketone function and if appropriate conversion of the >C=S group into a >C=O group; c) conversion reaction of the >C=O group or groups into the >C=S group; d) the action on the products of formula (IV) in which R' 3 25 represents a hydrogen atom, and after hydrolysis of the >C=NH group into a ketone function, of a reagent of formula Hal-R" 3 in which R" 3 has the values of R' 3 with the exception of the hydrogen value and Hal represents a halogen atom, in order to obtain the products of formula in which the group represents the group 0 S R -R" 3 or N in which R" 3 has the meaning indicated previously, then, if desired, the action on these products of an elimination agent L .J a j 53 of the optional protective groups that can be carried by R" 3 or if appropriate, the action of an esterification, amidification or salification agent, or a product of formula (II): R N=C X (II) R 2 in which R 1 R 2 and X have the meaning indicated above, is reacted in the presence of a tertiary base with a product of formula (III'): 15 HN-R'3 H 3 C-C-CH 3 (III') COOQ in which R' 3 has the meaning indicated above and Q represents either an alkali metal atom for example sodium or an alkyl radical containing of 1 to 6 carbon atoms, in order to obtain a product of formula (IVa): x 25 25 R- N N-R i *is CH 3 (IVa) 2 C 3 30I in which X, R 1 R 2 and R' 3 have the meaning indicated above, which if desired is subjected to any one or more of the following reactions, in any order: a) elimination reaction of the optional protective groups that can be carried by R' 3 b) conversion reaction of the >C=0 group or groups into the >C=S group or if appropriate of the >C=S group into the >C=0 group; L 54 c) the action on the products of formula (IVa) in which R' 3 represents a hydrogen atom, of a reagent of formula Hal-R" 3 in which R" 3 has the values of R' 3 with the exception of the hydrogen value and Hal represents a halogen atom, in order to obtain the products of formula in which the group represents the group: 0 S-R" N-R" or N 3 in which R" 3 has the meaning indicated previously, then, if desired, the action on these products of an elimination agent of the optional protective groups that can be carried by R" 3 or if appropriate, the action of an esterification, amidification or salification agent, or a reagent of formula Hal-R"3 in which Hal and R" 3 have the values indicated previously is reacted on a product of formula 0 N-H i; R (IV') CH 3 2 CH in order to obtain a product of formula R 1 j C-H 3 (Iv") 3 2 0 CH 3 which product of formula if necessary or if desired, is subjected to any one or more of the following reactions in any order: I a) elimination reaction of the optional protective groups that can be carried by R" 3 then if appropriate the action of an esterification, amidification or salification agent; b) conversion reaction of the >C=O group or groups into the >C=S groups 14) A pharmaceutical composition containing, as active ingredient, at least one of the compounds as defined in any one of claims 1 to 12 ooeter w 0 c prPrvuoc oreceip'coce. cmrrner or ck^-i. A method of treatment of a human or animal patient in need thereof comprising administering to said patient a compound as defined in any one of claims 1 to 12 or a composition according to claim 14. 16) As new industrial products, the products of formula (IVi): N 8i (IVi) R 2 Y in which RH, H 2 and Y have the meanings indicated in claim 1 and the group: A i *r S Is S S+ S S 04 5)445 is chosen from the radicals: x N-R, i /i S-R. 3 and in which X represents an oxygen or sulphur atom and R 3 i is chosen from the values of Ri containing a protected reactive function. 15/5/96VSA17075.SPE,48 I .i 56 17) A compound according to Claimi substantially as hereinbefore described withi reference to any one of the examples. 18) A ocess according to claim 13 substntially as hereinbefore described with reference to any one of the examples. DATED this day of
3. 1996. R Ous sEL-UCLA F By their Patent Attorneys: CALLINAN LAWRIE 4. 4* 4 4* 4 .4,444 .4 .4 4 444 4 #4 4 4 4 4 4 44 44*e o 44 4' #4 44 4 4 4 4 .4 4. 4 49 4 4.4' 44 44 44 44 I 4 15/519MVAP7075.8PP,48 ABSTRACT The invention relates to a preparation process for compounds 49Z N(I) (3 2. in which R is hy ogen or an ester or ether remainder, R' is C methyl or -CH,OR", R" i an ester or ether remainder and A and B represent a steroid remainder of free or blocked 3-keto or ooo 3-keto A4 type, consisting of converting a A9(11) compound into the corresponding halohydrin and characterized in that the said halohydrin is rearranged in the presence of an alcohol then treated with an acid. The compounds are knr:n therapeutically-active compounds or intermediates. o I