A compound of the formula ##STR1## wherein R.sub.1 is --CN, --NO.sub.2 or halogen, R.sub.2 is --CF.sub.3 or halogen, --A-B-- is of ##STR2## X is --O-- or --S--, R.sub.3 is hydrogen, alkyl, alkenyl or alkynyl of up to 12 carbon atoms, aryl and aralkyl of up to 12 carbon atoms, all optionally substituted by --OH, halogen, --SH, --CN, acyl and acyloxy of up to 7 carbon atoms, --aryl, --O--aryl, --O--aralkyl --S-- aryl of up to 12 carbon atoms the aryl and aralkyl being optionally substituted by halogen, --CF.sub.3, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alkynyloxy with the sulfur being optionally oxidized to sulfone or sulfoxide, free, esterified, amidified or salified carboxy, --NH.sub.2, mono and dialkylamino and heterocyclic of 3 to 6 ring members and containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, the alkyl, alkenyl and alkynyl being optionally interrupted by at least one oxygen, nitrogen or sulfur optionally oxidized to sulfoxide or sulfone, trialkylsilyl with the alkyl having 1 to 6 carbon atoms and acyl and acyloxy of an organic carboxylic acid of 1 to 7 carbon atoms and Y is --O--, --S-- or --NH--, except the compounds wherein --A-B-- is ##STR3## X is oxygen, R.sub.3 is hydrogen and Y is oxygen or --NH--, R.sub.2 is --CF.sub.3 or halogen and R.sub.1 is --NO.sub.2 or halogen and their non-toxic, pharmaceutically acceptable acid addition salts.

Japanese application No J 48087030 describes 3-phenyl-2-thiohydantoins 
useful for inhibiting the germination of certain plants. U.S. Pat. No. 
4,097,578 describes imidazolidines different from formula I having 
antiandrogenic activity. Other pertinent art includes U.S. Pat. Nos. 
3,823,240; No. 4,873,256; No. 4,407,814; No 4,482,739 and No. 4,234,736. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide the novel compounds of formula 
I and a novel process and novel intermediates for their preparation. 
It is another object of the invention to provide novel anti-androgenic 
compositions and a novel method of inducing anti-androgenic activity in 
warm-blooded animals. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel phenylimidazolidines of the invention have the formula 
##STR4## 
wherein R.sub.1 is selected from the group consisting of --CN, --NO.sub.2 
and halogen, R.sub.2 is --CF.sub.3 or halogen, --A-B-- is selected from 
the group consisting of 
##STR5## 
X is --O-- or --S--, R.sub.3 is selected from the group consisting of 
hydrogen, alkyl, alkenyl and alkynyl of up to 12 carbon atoms, aryl and 
aralkyl of up to 12 carbon atoms, all optionally substituted with at least 
one member of the group consisting of --OH, halogen, --SH, --CN, acyl and 
acyloxy of up to 7 carbon atoms, --aryl, --O--aryl, --O--aralkyl --S--aryl 
of up to 12carbon atoms, the aryl and aralkyl being optionally substituted 
with a member of the group consisting of halogen, --CF.sub.3, alkyl, 
alkoxy, alkenyl, alkenyloxy, alkynyl and alkynyloxy with the sulfur being 
optionally oxidized to sulfone or sulfoxide, free, esterified, amidified 
or salified carboxy, --NH.sub.2, mono and dialkylamino and heterocyclic of 
3 to 6 ring members and containing at least one heteroatom selected from 
the group consisting of oxygen, sulfur and nitrogen, the alkyl, alkenyl 
and alkynyl being optionally interrupted with at least one member of the 
group consisting of oxygen, nitrogen and sulfur optionally oxidized to 
sulfoxide or sulfone, trialkylsilyl with the alkyl having 1 to 6 carbon 
atoms and acyl and acyloxy of an organic carboxylic acid of 1 to 7 carbon 
atoms and Y is --O--, --S-- or --NH--, except the compounds wherein 
--A-B-- is 
##STR6## 
X is oxygen, R.sub.3 is hydrogen and Y is oxygen or --NH--, R.sub.2 is 
--CF.sub.3 or halogen and R.sub.1 is --NO.sub.2 or halogen and their 
non-toxic, pharmaceutically acceptable acid addition salts. 
The following examples are given for the values of R.sub.3. Alkyl of up to 
12 carbon atoms includes methyl, ethyl, 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 and dodecyl, branched or linear. Preferred are alkyl 
of 1 to 6 carbon atoms, especially methyl, ethyl, propyl and isopropyl, 
n-butyl, isobutyl, tert-butyl and branched or linear pentyl and hexyl. 
Examples of alkenyl of up to 12 carbon atoms are vinyl, allyl, 1-propenyl, 
butenyl, pentenyl and hexenyl and preferably alkenyl of 2 to 4 carbon 
atoms and especially vinyl, allyl or butenyl. Examples of alkynyl of up to 
12 carbon atoms are ethynyl, propargyl, butynyl, pentynyl and hexynyl and 
preferably 2 to 4 carbon atoms such as ethynyl and propargyl. 
Examples of aryl are carbocyclic aryl such asphenyl and naphthyl, 
heterocyclic aryl of 5 to 6 ring members containing at least one 
heteroatom selected from the group consisting of oxygen, sulfur and 
nitrogen. Examples of 5 ring heteroaryls are furyl, thienyl, pyrrolyl, 
thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl and isoxazolyl. 
Examples of 6 ring heteroaryl are pyridyl, pyrimidinyl, pyridazinyl and 
pyrazinyl. Examples of condensed aryls are indolyl, benzofurannyl, 
benzothienyl and quinoleinyl. The preferred aryl is phenyl. 
Examples of aralkyl include the alkyl recited above substituted with the 
aryl cited above. The preferred aralkyl are triphenylmethyl, phenethyl and 
benzyl. Examples of halogen are fluorine, chlorine, bromine and iodine but 
preferred are fluorine, chlorine and bromine. Examples of alkyl 
substituted with at least one halogen are fluoromethyl, chloromethyl, 
bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl and 
trifluoromethyl. 
Examples of substituents for aryl and aralkyl are phenyl substituted by 
fluorine, --OCH.sub.3 or --CF.sub.3 in the p-position. 
Examples of acyl are preferably those of up to 7 carbon atoms such as 
acetyl, propionyl, butyryl and benzoyl as well as valeryl, hexanoyl, 
acryloyl, crotonoyl, carbamoyl or formyl. The acyloxy may be derived for 
the same acids, especially acetyloxy and propionyloxy. 
The esterified carboxy may be alkoxycarbonyl such as methoxycarbonyl, 
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, 
cyclobutyloxy carbonyl, cyclopentyloxy carbonyl and cyclohexylocy 
carbonyl. 
Examples of easily cleavable esters includes methoxymethyl, ethoxymethyl; 
acyloxyalkyl such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl 
and acetoxyethel; alkoxycarbonyloxyalkyl such as methoxycarbonyloxymethyl, 
methoxycarbonyloxyethyl, isopropoxycarbonyloxymethyl and 
isopropoxycarbonyloxyethyl. Other esters are described in European Patent 
No. 0.034.536. 
The amidified carboxy are of the type 
##STR7## 
wherein R.sub.4 and R.sub.5 are individually selected from the group 
consisting of hydrogen and alkyl of 1 to 4carbon atoms such as methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl. 
Examples of the mono and dialkylamino are methylamino, ethylamino, 
dimethylamino, diethylamino and methylethylamino. The hetero-cyclic of 5 
to 6 ring members optionally containing another heteroatom may be 
pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, indolyl, piperidino, 
morpholino and piperazinyl, preferably piperidino or morpholino. 
Examples of salts of salified carboxy are sodium, potassium, lithium, 
calcium, magnesium, ammonium and organic bases such as methylamine, 
propylamine, trimethylamine, diethylamine and triethylamine. Sodium salt 
is preferred. 
The alkylamino and dialkylamino are preferably alkyl of 1 to 4 carbon atoms 
such as methylamino, ethylamino, propylamino, isopropylamino, 
dimethylamino, diethylamino and ethylmethylamino. 
Examples of the heterocyclics containing at least one heteroatom are 
saturated monocyclics such as oxirannyl, oxolannyl, dioxolannyl, 
imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl. 
The alkyl, alkenyl and alkynyl may be optionally interrupted by one or more 
sulfur, oxygen or nitrogen heteroatoms. Examples are alkoxyalkyl such as 
methoxymethyl, methoxyethyl, methoxypropyl or methoxybutyl or alkoxy 
alkoxyalkyl such as methoxyethoxymethyl. 
Examples of trialkylsilyl groups are trimethylsilyl, triethylsilyl and 
(1,1-dimethylethyl) dimethylsilyl. 
When the products of formula I contain a salifiable amino group, the acid 
addition salts of non-toxic, pharmaceutically acceptable acids may be 
formed. Examples of said acids are inorganic acids such as nitric acid, 
hydrochloric acid, sulfuric acid and phosphoric acid and organic acids 
such as formic acid, acetic acid, propionic acid, benzoic acid and methane 
sulfonic acid. 
Among the preferred compounds of formula I are those wherein Y is oxygen 
except for the compounds wherein --A-B-- is 
##STR8## 
X is oxygen, R.sub.3 is hydrogen, R.sub.2 is --CF.sub.3 or halogen and 
R.sub.1 is --NO.sub.2 or halogen. Other preferred compounds of formula I 
are those wherein --A-B-- is 
##STR9## 
X is sulfur and R.sub.3 has the above definition, those wherein R.sub.3 is 
hydrogen or alkyl of 1 to 4 carbon atoms optionally substituted with --OH 
or methoxy, those wherein R.sub.1 is cyano or halogen, preferably chlorine 
and those wherein --A-B-- is 
##STR10## 
and R.sub.3 is optionally substituted alkyl or alkenyl of up to 6 carbon 
atoms and optionally interrupted by oxygen or optionally oxidized sulfur 
or optionally substituted aralkyl, acyl or trialkylsilyl. 
Other preferred examples of the invention are those in which R.sub.3 is 
alkyl of up to 6 carbon atoms optionally substituted by at least one 
member of the group consisting of halogen, free or esterified hydroxy or 
carboxy, heterocyl, O-aralkyl or S-aryl in which the aryl radical is 
optionally substituted by at least one halogen or alkoxy and the sulfur 
atom is optionally oxidized in the form of the sulfoxide or sulfone and 
quite particularly those in which R.sub.3 is alkyl of 2 to 4 carbon atoms 
substituted by a member of the group consisting of chlorine, 
ethoxycarbonyl, terbutoxycarbonyl, cyclopentyl-oxycarbonyl, 
4-fluorophenylthio optionally oxidized in the form of the sulfoxide or 
sulfone, morpholino, phenylmethoxy, triphenylmethoxy and 
methylsulfonyloxy. 
Other preferred compounds of formula I are those wherein R.sub.3 is acetyl 
or benzoyl or (1,1-dimethylethyl) dimethylsilyl, those wherein R.sub.1 is 
nitro and R.sub.3 is alkyl or alkenyl of up to 4 carbon atoms optionally 
substituted with esterified or salified or free carboxy and those of the 
formula 
##STR11## 
in which R.sub.1, R.sub.2 and R.sub.3 have the above meaning with the 
exception of the products in which R.sub.1 is nitro, R.sub.2 is 
trifluoromethyl and R.sub.3 is hydrogen. 
Examples of specific preferred compounds of formula I are 
4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-(trifluoromethyl)-be 
nzonitrile, 
4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-(trifluoromethyl)-benzo 
nitrile, 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-2,5-imidazolidinedi 
one, 
4-[[4,5-dihydro-4,4-dimethyl-5-oxo-2-benzyl-thio]-1H-imidzao-1-yl]-2-(trif 
luoromethyl) benzonitrile, 4-[4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 
2-thioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 
4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 
2-thioxo 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile and 3-(4-cyano 
3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinebutanoic 
acid. 
The process of the invention for the preparation of a compound of formula I 
comprises either reacting a compound of the formula 
##STR12## 
wherein R.sub.1, R.sub.2 and X have the above definitions with a compound 
of the formula 
##STR13## 
in the presence of a tertiary base wherein R'.sub.3 has the definition of 
R.sub.3 with reactive group optionally protected and if R.sub.1 is 
--NO.sub.2 or halogen, R.sub.2 is halogen or --CF.sub.3 and X is oxygen, 
R'.sub.3 is not hydrogen to obtain a compound of the formula 
##STR14## 
wherein R.sub.1, R.sub.2, X and R'.sub.3 have the above definitions and 
optionally subjecting the latter to one or more of the following reactions 
in any order: 
a) reaction to eliminate the optional protective groups of R'.sub.3 
b) reaction of hydrolysis of C.dbd.NH to a ketone function or 
transformation of C.dbd.S to C.dbd.O 
c) transformation reaction of C.dbd.O to C.dbd.S 
d) and reacting the products of formula IV wherein R'.sub.3 is hydrogen and 
after hydrolysis of C.dbd.NH to a ketone with a compound of the formula 
R".sub.3 -Hal where Hal is a halogen and R".sub.3 is R'.sub.3 except 
hydrogen to obtain a compound of formula I wherein --A-B-- is 
##STR15## 
and optionally reacting the latter to eliminate the protective group of 
R".sub.3 or reacting the same with an esterification, salification or 
amidification agent or reacting a compound of the formula 
##STR16## 
in which R.sub.1, R.sub.2 and X have the above meaning in the presence of 
a tertiary base with a product of the formula 
##STR17## 
in which R'.sub.3 has the above meaning and Q is either an alkali metal 
for example sodium or alkyl of 1 to 6 carbon atoms to obtain a product of 
the formula 
##STR18## 
in which X, R.sub.1, R.sub.2 and R'.sub.3 have the above meaning 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'.sub.3 ; 
b) conversion reaction of the &gt;C.dbd.O group or groups into the &gt;C.dbd.S or 
if appropriate of &gt;C.dbd.S into &gt;C.dbd.O; 
c) the action on the products of formula IVa in which R'.sub.3 is hydrogen 
of a reagent of formula Hal--R".sub.3 in which R".sub.3 has the values of 
R'.sub.3 with the exception of hydrogen and Hal is halogen to obtain the 
products of formula I in which --A-B-- is 
##STR19## 
in which R".sub.3 has the above meaning, then, if desired, the action of 
these products of an elimination agent of the optional protective groups 
that can be carried by R".sub.3 or if appropriate, the action of an 
esterification, amidification or salification agent, or reacting a reagent 
of the formula R".sub.3 --Hal as defined above with a compound of the 
formula 
##STR20## 
to obtain a compound of the formula 
##STR21## 
and optionally subjecting the latter to one or more of the following 
reactions: 
a) elimination reaction of optional protective groups of R".sub.3 and then 
to reaction with an esterification, salification or amidification reagent 
b) reaction of transformation of C.dbd.O to C.dbd.S. 
The reaction of the products of formula II with the products of formula III 
is preferably effected in an organic solvent such as tetrahydrofuran or 
dichloroethane or ethyl ether or isopropyl ether in the presence of a 
tertiary base such as pyridine or methylethyl pyridine. 
The optional reactive functional groups of R.sub.3 which are optionally 
protected in compounds of formula III, IVa or IV" are --OH or amino which 
are protected by the usual protective groups. Examples of such protective 
groups for --NH.sub.2 are tert.-butyl, tert.-amyl, trichloroacetyl, 
chloroacetyl, benzhydryl, trityl, formyl and benzyloxycarbonyl. Examples 
of hydroxy protective groups are formyl, chloroacetyl, tetrahydropyrannyl, 
trimethylsilyl and tert.-butyldimethylsilyl. 
The above list of protective groups is not intended to be exhaustive and 
any protective group known, for example, in peptide chemistry may be used. 
Other known protective groups are described in French Patent No. 2,499,995 
which is incorporated herein by reference. The optional reactions to 
eliminate groups are indicated in the said patent and the preferred method 
of elimination is acid hydrolysis with hydrochloric acid, benzene sulfonic 
acid, p-toluene sulfonic acid, formic acid or trifluoroacetic acid, 
preferably hydrochloric acid. 
The optional reaction of hydrolysis of C.dbd.NH to C.dbd.O is preferably 
effected with an acid suchas refluxing aqueous hydrochloric acid. When the 
hydrolysis of C.dbd.NH into a C.dbd.O is effected with a molecule also 
containing C.dbd.S, the latter may be transformed in C.dbd.O group. The 
free hydroxy optionally contained in R.sub.3 may also be transformed into 
--SH. 
The transformation of the group C.dbd.O into C.dbd.S is effected with a 
Lawesson reagent of the formula 
##STR22## 
which is a commercial product sold by Fluka for example and is described 
in Bull. Soc. Chim. Belg., Vol 87 No. 3 (1987), p. 229. When two C.dbd.O 
groups are to be changed to C.dbd.S, the reaction is effected in an excess 
of the Lawesson reagent. The same is used also when the molecule contains 
both C.dbd.S and C.dbd.O and it is desired to change the C.dbd.O to 
C.dbd.S. 
On the contrary, when part of the molecule contain two C.dbd.O and it is 
desired to obtain a product with only one C.dbd.S, a deficiency of the 
Lawesson reagent is used to obtain a mixture of 3 products, each of two 
products with a C.dbd.O and C.dbd.S and one containing two C.dbd.S. The 
said products can be separated by known methods such as chromatography. 
The reaction of the compounds of formulae IV, IVA or IV' with a compound of 
the formula R".sub.3 --Hal is effected in the presence of a strong base 
such as sodium hydride or potassium hydride in a phase transfer reaction 
in the presence of quaternary ammonium salts such as tert.-butyl ammonium. 
The protective groups of R".sub.3 may be those discussed above for 
R.sub.3. The reaction to eliminate the protective groups are as discussed 
above. For example, a tert-butyl dimethylsilyl group may be removed by 
hydrochloric acid as described in the examples infra. 
The optional esterification of the compounds of formula I wherein R".sub.3 
is free --OH is effected under the classical conditions using for example 
an acid or a functional derivative thereof such as its anhydride like 
acetic acid anhydride in the presence of a base such as pyridine. The 
optional esterification or salification of the compounds of formula I 
wherein R".sub.3 is --COOH may be effected by known methods. 
The optional amidification of the compounds of formula I wherein R".sub.3 
is --COOH is effected also under classical conditions with primary or 
secondary amine with a functional derivative of --COOH such as a 
symetrical or mixed anhydride thereof. 
The process of the invention to prepare compounds of the formula 
##STR23## 
wherein R".sub.1, R".sub.2 and --A"-B"-- have the definitions of R.sub.1, 
R.sub.2 and --A-B-- except when --A"-B"-- is 
##STR24## 
and R"'.sub.3, is hydrogen or alkyl of 1 to 7 carbon atoms and Y is 
oxygen, R".sub.1 is --CN comprises reacting a compound of the formula 
##STR25## 
wherein R".sub.1 and R".sub.2 have the above definitions and Hal is 
halogen with a compound of the formula 
##STR26## 
wherein --A"-B"-- and Y have the above definitions in the presence of a 
catalyst and optionally a solvent. In the compounds of formula V, the 
halogen is preferably chlorine but may be iodine or bromine. 
The role of the catalyst is obviously to trap the hydrogen halide as it 
forms and to facilitate the condensation reaction of the compounds of 
formulae V and VI to form the desired product. The catalyst is preferably 
a metal in its native form or its oxide or salt form or it may be a base. 
When the catalyst is a metal, it is preferably copper or nickel and the 
metallic salts are preferably the chloride or acetate. When the catalyst 
is a base, it is preferably sodium hydroxide or potassium hydroxide and 
dimethylsulfoxide may be added to the reaction medium. 
The catalyst of the process may be selected from cuprous oxide, cupric 
oxide, metallic copper or a base such as sodium hydroxide or potassium 
hydroxide, preferably cuprous oxide in powdered form. The solvent used 
preferably is a high boiling point ether such as phenyl oxide, diglyme, 
triglyme and dimethylsulfoxide but also useful are high boiling point oils 
such as paraffin or vaseline. Preferably, the process is effected in 
another solvent such as phenyl oxide, diglyme, triglyme or 
dimethylsulfoxide, most preferably in phenyl oxide or triglyme. 
The process may be effected at atmospheric pressure or under pressure at 
temperatures above 100.degree. C., preferably above 150.degree. C. for 
more than two hours. The reaction is preferably effected with cuprous 
oxide in triglyme at temperatures of 200.degree. C. or higher for more 
than three hours. 
The novel anti-androgenic compositions of the invention are comprised of an 
anti-androgenically effective amount of at least one compound of formula I 
and its non-toxic, pharmaceutically acceptable acid addition salts and an 
inert pharmaceutical carrier. The compositions may be in the form of 
tablets, dragees, capsules, syrups, suppositories, creams, pomades, 
lotions or injectable solutions prepared in the usual manner. 
Examples of suitable excipients are aqueous or non-aqueous vehicles, arabic 
gum, lactose, starch, magnesium stearate, cocoa butter, fatty bodies of 
animal or vegetable origin, paraffinic derivatives, glycols, diverse 
wetting agents, dispersants or emulsifiers and preservatives. 
The compositions inhibit the effect of androgens on peripherical receptors 
and have an anti-androgenic activity useful for therapy in adults without 
the certain effects of a chemical castration. The compositions are useful 
for the treatment of adenomas and neoplasies of the prostateas well as 
benign hypertrophia of the prostate as well as the treatment of benign or 
malignant tumors of cells containing androgen receptors. They are 
particularly useful for the treatment of breast, brain, skin and ovarian 
cancer and bladder, lymphatic system, liver and kidney cancers. They are 
equally useful for the treatment of hirsutism, acne, seborrhea, androgenic 
alopecia and hyperpilosity and in the veterinary field. 
The compositions of the invention are useful in dermatology and can contain 
another ingredient such as an antibiotic such as derivatives of retinoids 
for the treatment of acne, or with a 5.alpha.-reductase inhibitor such as 
(5.dbd., 17.beta.)-1,1-dimethylethyl 3-oxo 4-aza-.increment..sup.1 
-androstene-17 carboxamide (or Finasteride Merck, 11th ed.) or azelaic 
acid or a blocking agent of 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 compositions can also 
be used in the veterinary domain and 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 be used. 
The novel method of the invention for inducing anti-androgenic activity in 
warm-blooded animals, including humans, comprises administering to 
warm-blooded animals an anti-androgenically effective amount of at least 
one compound of formula I and its non-toxic, pharmaceutically acceptable 
acid addition salts. The compounds may be administered parenterally, 
buccally, perlingually, rectally or topically and the usual daily dose is 
0.133 to 6.66 mg/kg depending on the condition treated, the specific 
compound and the method of administration. 
The starting compounds of formula II may be prepared by reacting phosgene 
when X is oxygen or thiophosgene when X is sulfur with an amine of the 
formula 
##STR27## 
A product of this type is described in French Patent No. 2,329,276. The 
amines of formula A are described in EP Patent No. 0,002,892 and French 
Patent No. 2,142,804. 
The products of formula III or III' are known or can be prepared from the 
corresponding cyanhydrin by the process of J. Am. Chem. Soc., Vol 75 
(1953), p. 4841. The compounds of formula III wherein R'.sub.3 is other 
than hydrogen may be obtained by reacting a compound of the formula 
R".sub.3 Hal with 2-cyano-2-amino-propane under the conditions described 
above for reacting the said halide with the compounds of formula IV. An 
example is described by Jilek et al, Collect. Czech. Chem. Comm., Vol 
54(8) (1989), p. 2248. The products of formula IV' are described in French 
Patent No. 2,329,276. 
The compounds of formulae V and VI are commercially available known 
compounds and can be prepared by known methods. 
The preparation of the compounds of formula VI are described in the 
following publications: Zhur Preklad Khim., Vol. 28 (1955), p. 969-75 (CA, 
Vol. 50 (1956), p 4881a); Tetrahedron, Vol. 43 (1987), p. 1753; J. Org. 
Chem., Vol. 52 (1987), p. 2407; Zh. Org. Khim., Vol. 21 (1985), p. 2006; 
J. Fluor. Chem., Vol. 17 (1981), p. 345; German Patent No. 637,318, 
European Patent No. 0,130,875 and Japanese Patent No. 81-121,525. 
The products of formula VI which are derivatives of hydantoin are largely 
used and are known in the literature such as J. Pharm. Pharmacal., 67, 
Vol. 19(4) (1967), p. 209-16; J. Chem. Soc., Vol. 74(2) (1972), p. 
219-221; Khim. Farm. Zh., Vol. 67(1)(5), p. 51-2; German Patent No. 
2,217,914; European Patent No. 0,091,596 and J. Chem. Soc. Perkin. Trans. 
1, Vol. 74(2), p. 48 and 219-221. 
The novel intermediates of the invention are the compounds of the formula 
##STR28## 
wherein R.sub.1, R.sub.2 and Y have the above definitions and --Ai-Bi-- is 
##STR29## 
wherein X is oxygen or sulfur and R.sub.3, is R.sub.3 with the reactive 
groups protected among which are --OH or --NH.sub.2 protected as above for 
R.sub.3. 
In the following examples, there are described several preferred 
embodiments to illustrate the invention. However, it should be understood 
that the invention is not intended to be limited to the specific 
embodiments.

EXAMPLE 1 
1-(4-nitro-3-trifluoromethyl-phenyl)-3,4,4-trimethyl-2,5-imidazolidinedione 
A solution of 3.17 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl-imidazoline-2,5-dione 
(French Patent No. 2,329,276) and 32 ml of dimethylformamide were added at 
23.degree. C. to 26.degree. C. to a 50% suspension of 492 mg of sodium 
hydride in oil and 3 ml of dimethylformamide and after stirring for 15 
minutes, a solution of 0.7 ml of methyl iodide in 2 ml of 
dimethylformamide was added. The mixture was stirred for 25 minutes at 
24.degree. C. to 28.degree. C. and was then poured into 200 g of a 1--1 
water-ice mixture. The mixture was extracted with ether and the organic 
phase was washed with saturated aqueous sodium chloride, dried, filtered 
and evaporated to dryness under reduced pressure to obtain 3.6 g of the 
desired product melting at 116.degree. C. An analytical sample was 
crystallized from isopropyl alcohol to obtain 2.73 g of the product 
melting at 116.degree. C. 
______________________________________ 
Analysis: C.sub.13 H.sub.12 F.sub.3 N.sub.3 O.sub.4 ; molecular weight = 
331.25 
% C % H % F % N 
______________________________________ 
Calculated: 47.14 3.65 17.20 
12.68 
Found: 47.0 3.5 17.1 12.5 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1780, 1727 cm.sup.-1 
aromatics 1615, 1596, 1497 cm.sup.-1 
NO.sub.2 1545, 1357 cm.sup.-1 
______________________________________ 
EXAMPLE 2 
5,5-dimethyl-1-ethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-2,4-imidazolidine 
dione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazoline-2,5-dione 
prepared as in French Patent No. 2,329,276 was reacted with 0.37ml of 
ethyl iodide and a 50% suspension of 166 mg of sodium hydride in oil to 
obtain 1.19 g of the desired product melting at 110.degree. C. to 
111.degree. C. which was crystallized from isopropanolto obtain 934 mg of 
the product melting at 110.degree. C. to 111.degree. C. 
______________________________________ 
Analysis: C.sub.14 H.sub.14 F.sub.3 N.sub.3 O.sub.4 ; molecular weight = 
345.28 
% C % H % F % N 
______________________________________ 
Calculated: 48.70 4.09 16.51 
12.17 
Found: 48.6 4.0 16.8 12.1 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1777, 1724 cm.sup.-1 
NO.sub.2 1545, 1356 cm.sup.-1 
aromatics 1614, 1596, 1497 cm.sup.-1 
______________________________________ 
EXAMPLE 3 
5,5-dimethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-1-propyl-2,4-imidazolidin 
edione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazoline-2,5-dione 
was reacted with 0.35 ml of 1-iodopropane and a 50% suspension of 155mg of 
sodium hydride in oil to obtain after chromatography on silica with an 
eluant of acetone-methylene chloride (1-99), 3.087 g of raw product 
melting at 102.degree. C. The product was crystallized from isopropanol to 
obtain 945 mg of the desired product melting at 102.degree. C. 
______________________________________ 
Analysis: C.sub.15 H.sub.16 F.sub.3 N.sub.3 O.sub.4 ; molecular weight = 
359.31 
% C % H % F % N 
______________________________________ 
Calculated: 50.14 4.49 15.86 
11.69 
Found: 50.1 4.4 15.9 11.5 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1778, 1724 cm.sup.-1 
NO.sub.2 1544, 1358 cm.sup.-1 
aromatics 1615, 1596, 1497 cm.sup.-1 
______________________________________ 
EXAMPLE 4 
5,5-dimethyl-1-isopropyl-3-(4-nitor-3-trifluoromethyl-phenyl)-2,4-imidazoli 
dinedione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazoline-2,5-dione 
was reacted with 0.4 ml of 2-iodopropane and a 50% suspension of 166 mg of 
sodium hydride in oil for 18 hours at 50.degree. C. to obtain after 
chromatography over silica (eluant methylene chloride-acetone 99-1), 685 
mg of product melting at 130.degree. C. which after crystallization from 
isopropanol yielded 661 of the desired product melting at 130.degree. C. 
______________________________________ 
Analysis: C.sub.15 H.sub.16 N.sub.3 F.sub.3 O.sub.4 ; molecular weight = 
359.31 
% C % H % F % N 
______________________________________ 
Calculated: 50.14 4.49 15.86 
11.69 
Found: 50.1 4.4 16.2 11.6 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1779, 1771, 1723 cm.sup.-1 
NO.sub.2 1544, 1361 cm.sup.-1 
aromatics 1615, 1596, 1497 cm.sup.-1 
______________________________________ 
EXAMPLE 5 
5,5-dimethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-1-(2-propenyl)-2,4-imidaz 
olidinedione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-(henyl)-4,4-dimethyl imidazoline-2,5-dione 
was reacted with 0.35 ml of allyl bromide and a 50% suspension of 166 mg 
of sodium hydride in oil to obtain after chromatography over silica 
(eluant--methylene chloride-acetone (99-1)) 1.10 g of product which after 
crystallization from isopropanol yielded 1.01 g of the desired product 
melting at 105.degree. C. 
______________________________________ 
Analysis: C.sub.15 H.sub.14 F.sub.3 N.sub.3 O.sub.4 ; molecular weight = 
357.29 
% C % H % F % N 
______________________________________ 
Calculated: 50.42 3.95 15.95 
11.76 
Found: 50.4 3.8 15.8 11.7 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1779, 1724 cm.sup.-1 
NO.sub.2 1545, 1358 cm.sup.-1 
aromatics 1615, 1596, 1497 cm.sup.-1 
CH.dbd.CH.sub.2 1643, 930 cm.sup.-1 
______________________________________ 
EXAMPLE 6 
5,5-dimethyl-3-(3-trifluoromethyl-4-nitro-phenyl)-1-benzyl-2,4-imidazolidin 
edione 
Using the procedure of Example 1, 2 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazolidine-2,5-dione 
was reacted with 0.71 ml of benzyl bromide and a 50% suspension of 332 mg 
of sodium hydride in oil to obtain after chromatography on silica and 
elution with 99-1 methylene chloride-acetone 2.375 g of the desired 
product which as crystallized from isopropanol to obtain 2.165 g of 
product melting at 99.degree. C. 
______________________________________ 
Analysis: C.sub.19 H.sub.16 N.sub.3 F.sub.3 O.sub.4 ; molecular weight = 
407.3 
% C % H % F % N 
______________________________________ 
Calculated: 56.02 3.96 10.31 
14.00 
Found: 56.1 3.8 10.2 13.9 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1799, 1723 cm.sup.-1 
aromatics 1608 cm.sup.-1 
+ 1594 cm.sup.-1 (m) 
NO.sub.2 1545 cm.sup.-1 (F) 
1497 cm.sup.-1 
______________________________________ 
EXAMPLE 7 
4-(4,4-dimethyl-5-imino-2-oxo-1-imidazolidinyl)-2-trifluoromethylbenzonitri 
le 
A solution of 10 g of 4-cyano-3-trifluoromethyl-aniline (described in 
European Paten No. 0,002,892) in 30 ml of ethyl acetate was added at 0 to 
5.degree. C. to 33.6 ml of a toluene solution of 1.93 M/1 of phosgene and 
after stirring at 0 to 5.degree. C. for 30 minutes, the temperature was 
raised to 25.degree. C. The mixture was distilled while introducing fresh 
toluene maintaining to constant level for compensate the distilled volume 
of toluene until a temperature of about 110.degree. C. was reached. The 
mixture was held at reflux until the disengagement of hydrogen chloride 
ceased (4 1/2 hours). The temperature returned to room temperature and the 
white solid was dried over sodium sulfate and was rinsed with toluene 3 
times. The organic phase was evaporated to dryness under reduced pressure, 
heated at60.degree. C. for one hour and then cooled under argon to obtain 
11.6 g of 4-isocyanate of 2-trifluoromethyl-benzonitrile. 
______________________________________ 
IR Spectrum: 
______________________________________ 
--NC.dbd.O 2268 cm.sup.-1 
--CN 2233 cm.sup.-1 
______________________________________ 
A solution of 6.6 g of 4-isocyanate of 2-trifluoromethyl-benzonitrile in 10 
ml of dichloroethane was added at 5.degree. C. to a solution of 2.63 g of 
2-amino-2-cyano-propane and 36 ml of dichloroethane and 0.9 ml of 
triethylamine and after stirring 16hours at room temperature, the mixture 
was evaporated to dryness. The 7.7 g of residue were chromatographed on 
silica and eluted with a 85-15 methylene chloride-acetone mixture to 
obtain 3.54 g of the desired product melting at 228.degree. C. An 
analytical sample was prepared by crystallizing 300 mg from isopropanol to 
obtain 267 mg of the product melting at 228.degree. C. 
______________________________________ 
Analysis: C.sub.13 H.sub.11 F.sub.3 N.sub.4 O; molecular weight = 296.25 
% C % H % F % N 
______________________________________ 
Calculated: 52.71 3.74 19.24 
18.91 
Found: 52.7 3.6 19.1 18.6 
______________________________________ 
______________________________________ 
IR Spectrum (Nujol): 
______________________________________ 
NH/OH 3340, 3290 cm.sup.-1 
CN 2240 cm.sup.-1 
C.dbd.O 1760 cm.sup.-1 
C.dbd.N 1655 cm.sup.-1 
aromatics 1606, 1570, 1502 cm.sup.-1 
______________________________________ 
EXAMPLE 8 
4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethylbenzonitrile 
A solution of 2.76 g of the product of Example 7 and 60 ml of 0.5 
hydrochloric acid was refluxed for 35 minutes and was poured into 100 g of 
water and ice. The mixture was extracted with ethyl acetate and the 
organic phase was washed with water, dried and evaporated to dryness under 
reduced pressure to obtain 2.70 g of the desired product melting at 
210.degree. C. An analytical sample was obtained by crystallizing 440 mg 
of product from isopropanol to obtain 383 mg of product melting at 
210.degree. C. to 211.degree. C. 
______________________________________ 
Analysis: C.sub.13 H.sub.10 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
297.24 
% C % H % F % N 
______________________________________ 
Calculated: 52.53 3.39 19.17 
14.14 
Found: 52.4 3.2 19.4 13.9 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2245 cm.sup.-1 
C.dbd.O 1788, 1722 cm.sup.-1 
aromatics 1610, 1572, 1502 cm.sup.-1 
NH (max) 3340 cm.sup.-1 
______________________________________ 
EXAMPLE 9 
3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidine 
acetic acid 
A solution of 600 mg of the product of Example 8 in 6 ml of 
dimethylformamide was added with stirring over 15 minutes to a suspension 
of a 50% suspension of 210 mg of sodium hydride in oil in 3 ml of 
dimethylformamide and after the addition of 290 mg of bromoacetic acid, 
the mixture was stirred for 16 hours at room temperature. After another 
105 mg of sodium hydride were added, 145 mg of bromoacetic acid were added 
to the mixture which was stirred for 30 minutes and then poured into a 
mixture of 50 ml of water and 5 ml of 2N hydrochloric acid. The mixture 
was extracted with ether and the organic phase was washed with saturated 
aqueous sodium chloride, dried, filtered and evaporated to dryness under 
reduced pressure. The 1.22 g of residue were chromatographed on silica and 
eluted with a 90-10-0.5 methylene chloride-methanol-acetic acid mixture to 
obtain 367 mg of the desired product. 
______________________________________ 
IR Spectrum: 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O hydantoin & acid 
1784, 1725, 1710 cm.sup.-1 
aromatic 1616, 1580, 1508 cm.sup.-1 
______________________________________ 
______________________________________ 
Ultra-violet Spectrum: 
______________________________________ 
ETOH - 0.1N HCl max 258 nm .epsilon. = 13,300 
inflex 277 nm 
.epsilon. = 5,000 
inflex 285 nm 
.epsilon. = 2,600 
ETOH 0.1N NaOH max 287 nm .epsilon. = 19,100 
max 342 nm .epsilon. = 1,900 
______________________________________ 
EXAMPLE 10 
Ethyl3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazol 
idine-acetate 
A solution of 600 mg of the product of Example 8 in6 ml of 
dimethylformamide was added to a 50% suspension of 100 mg of sodium 
hydride in oil and 3 ml of dimethylformamide and after stirring for 15 
minutes, 0.25 ml of ethyl bromoacetate was slowly added at less than 
30.degree. C. The mixture was stirred for 30 minutes and then was poured 
into 50 g of a 1--1 ice-water mixture. 0.5 g of monopotassium phosphate 
was added and the mixture was extracted with ether. The organic phase was 
washed with water, dried and evaporated to dryness to obtain 1.1 g of 
residue which was chromatographed on silica and eluted with 97-3 methylene 
chloride-acetone to obtain 709 mg of the desired product melting at 
152.degree. C. An analytical sample was prepared by crystallization from 
isopropanol to obtain 667 mg of the desired product melting at 152.degree. 
C. 
______________________________________ 
Analysis: C.sub.17 H.sub.16 N.sub.3 F.sub.3 O.sub.4 ; molecular weight = 
383.33 
% C % H % F % N 
______________________________________ 
Calculated: 53.21 4.21 14.83 
10.96 
Found: 53.3 4.0 14.9 10.8 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2225 cm.sup.-1 
imidazolidine 1786, 1729 cm.sup.-1 
COOEt 1751 cm.sup.-1 
aromatics 1616, 1572, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 11 
4-(5-imino-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl-ben 
zonitrile 
2.23 of 1-trifluoromethyl-4-amino-benzonitrile (described in European 
Patent No. 0,002,892)were slowly added to a solution of 22 ml of distilled 
water and 1 ml of thiophosgene and after stirring for one hour, the 
mixture was extracted with chloroform. The organic phase was washed with 
aqueous sodium chloride, dried and evaporated to dryness under reduced 
pressure to obtain 3 g of isocyanate product which as used as is. 
A mixture of the 3 g of product, 1.33 ml of 2-methylamino-2-cyano-propane, 
23 ml of tetrahydrofuran and 0.23 ml of triethylamine was refluxed for 40 
minutes and was evaporated to dryness. The 3.07 g of residue were 
chromatographed on silica and eluted with a 1--1 cyclohexane-ethyl acetate 
mixture and then a 95-5 methylene chloride-acetone mixture to obtain 2.83 
g of product which was crystallized from isopropanol to obtain 2.63 g of 
the desired product melting at 173.degree. C. to 174.degree. C. 
______________________________________ 
Analysis: C.sub.14 H.sub.13 F.sub.3 N.sub.4 S; molecular weight = 326.35 
% C % H % F % N % S 
______________________________________ 
Calculated: 
51.53 4.01 17.17 17.46 
9.82 
Found: 51.7 3.9 17.2 17.2 9.9 
______________________________________ 
______________________________________ 
IR Spectrum: 
______________________________________ 
C.dbd.NH 3308, 1679 cm.sup.-1 
C.dbd.S + aromatics 
1608, 1575, 1505, 1488 cm.sup.-1 
CN 2230 cm.sup.-1 
CF.sub.3 1185 cm.sup.-1 
______________________________________ 
EXAMPLE 12 
4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl-benzo 
nitrile 
A mixture of 2.21 g of the product of Example 11and 44 ml of 0.5 N 
hydrochloric acid was refluxed with stirring for one hour and was then 
poured into 200 g of an ice-water (1--1) mixture. The mixture was 
extracted with methylene chloride and the organic phase was washed with 
saturated aqueous sodium chloride, dried and evaporated to dryness. The 
residue was chromatographed on silica and eluted with a 
1--1cyclohexane-ethyl acetate mixture to obtain 2.1 g of product melting 
at171.degree. C. which was crystallized from isopropanol to obtain 1.99 g 
of the desired product melting at 171.degree. C. 
______________________________________ 
Analysis: C.sub.14 H.sub.12 F.sub.3 N.sub.3 OS; molecular weight = 
327.33 
% C % H % F % N % S 
______________________________________ 
Calculated: 
51.37 3.69 12.84 17.41 
9.79 
Found: 51.4 3.5 12.7 17.6 10.79 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1761, 1756 cm.sup.-1 
aromatics 1610, 1578, 1505 cm.sup.-1 
CN 2230 cm.sup.-1 
CF.sub.3 1178 cm.sup.-1 
______________________________________ 
EXAMPLE 13 
4-(2,5-dithioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl-benzoni 
trile 
A mixture of 839 mg of the product of Example 12, 518 mg of Lawesson 
reagent and 4.7 ml of toluene was refluxed for 24 hours and was then 
evaporated to dryness under reduced pressure. The 1.36 g of residue were 
chromatographed on silica and eluted with a 99-1 methylene chloride-ethyl 
acetate mixture and then an 85-15 cyclohexane-ethylacetate mixture to 
obtain 783 mg of product which was crystallized from isopropanol to obtain 
690 mg of the desired product melting at 211.degree. C. to 212.degree. C. 
______________________________________ 
Analysis: C.sub.14 H.sub.12 F.sub.3 N.sub.3 S.sub.2 ; molecular weight = 
343.40 
% C % H % F % N % S 
______________________________________ 
Calculated: 
48.97 3.52 16.60 12.24 
18.67 
Found: 49.0 3.4 16.6 12.2 18.6 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2230 cm.sup.-1 
aromatics + conjugated system 
1612, 1582, 1508 cm.sup.-1 
CF.sub.3 1178 cm.sup.-1 
______________________________________ 
EXAMPLE 14 
4-(4,4-dimethyl-5-imino-2-thioxo-1-imidazolidinyl)-2-trifluoromethyl-benzon 
itrile 
1 g of 2-amino-2-cyano-propane and 1 ml of tetrahydrofuran were added with 
stirring to a mixture of 2.54 g of the isocyanate product of Example 11, 
20 ml of tetrahydrofuran and 0.2 ml of triethylamine at room temperature 
and was then evaporated to dryness. The 3.5 g of residue were 
chromatographed on silica and eluted with a 7-3 ethyl acetate-cyclohexane 
mixture and then a 1--1 ethyl acetate-cyclohexane mixture to obtain 940 mg 
of the desired product. 300 g were crystallized from isopropanol to obtain 
263 mg of product melting at296.degree. C. 
______________________________________ 
Analysis: C.sub.13 H.sub.11 F.sub.3 N.sub.4 S; molecular weight = 312.32 
% C % H % F % N % S 
______________________________________ 
Calculated: 
50.00 3.55 18.25 17.94 
10.27 
Found: 49.9 3.4 18.3 17.6 10.4 
______________________________________ 
______________________________________ 
IR Spectrum (Nujol): 
______________________________________ 
OH/NH 3260 cm.sup.-1 
CN 2230 cm.sup.-1 
C.dbd.S 1764 cm.sup.-1 
aromatic + C.dbd.C 
1612, 1575, 1530, 1501 cm.sup.-1 
______________________________________ 
A new preparation was effected using 1,2-dichloroethane in place of 
tetrahydrofuran to obtain the product in a 60% yield. 
EXAMPLE 15 
4-(4,4-dimethyl-5-oxo-3-thioxo-1-imidazolidinyl)-1-trifluoromethyl-benzonit 
rile 
A mixture of 635 mg of the product of Example 14 and 14 ml of 0.5 N 
hydrochloric acid was stirred for one hour at reflux and after cooling, 
100 ml of water were added. The mixture was extracted with ethyl acetate 
and the organic phase was washed with aqueous sodium chloride, dried and 
evaporated to dryness. The 600 mg of residue were chromatographed and 
eluted with a 95-5 methylene chloride-acetone mixture to obtain 590 mg of 
product melting at 190.degree. C. to 191.degree. C. The latter was 
crystallized from isopropanol to obtain 490 mg of product melting to 
190.degree. C. to 191.degree. C. 
______________________________________ 
Analysis: C.sub.13 H.sub.10 F.sub.3 N.sub.3 OS; molecular weight = 
313.30 
% C % H % F % N % S 
______________________________________ 
Calculated: 
49.84 3.22 18.19 13.41 
10.23 
Found: 49.6 3.1 18.4 13.2 10.0 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
.dbd.C--NH 3430 cm.sup.-1 
CN 2230 cm.sup.-1 
C.dbd.O 1766 cm.sup.-1 
aromatics and conjugated system 
1612, 1578, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 16 
5,5-dimethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-1-pentyl-2,4-imidazolidin 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazolidien-2,5-dione 
was reacted with 170 mg of sodium hydride and 0.47 ml of 1-bromo-pentane 
to obtain after chromatography on silica and elution with an 8-2 methylene 
chloride-cyclohexane mixture 1.23 g of product which as crystallized from 
isopropanol to obtain 995 mg of the desired product melting at 84.degree. 
C. 
______________________________________ 
Analysis: C.sub.17 H.sub.20 O.sub.4 F.sub.3 N.sub.3 ; molecular weight = 
387.35 
% C % H % F % N 
______________________________________ 
Calculated: 52.71 5.20 14.71 
10.85 
Found: 52.8 5.1 14.8 10.7 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1778, 1723 cm.sup.-1 
NO.sub.2 1544, 1360 cm.sup.-1 
______________________________________ 
EXAMPLE 17 
5,5-dimethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-1-nonyl-2,4-imidazolidine 
dione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazolidine-2,5-dione 
was reacted with a 50% suspension of 170 mg of sodium hydride in oil and 
0.7 ml of 1-bromo-nonane to obtain after chromatography on silica 1.08 g 
of the desired product melting at 63.degree. C. 
______________________________________ 
Analysis: C.sub.21 H.sub.28 O.sub.4 F.sub.3 N.sub.3 ; molecular weight = 
443.46 
% C % H % F % N 
______________________________________ 
Calculated: 56.87 6.36 12.85 
9.48 
Found: 57.0 6.5 12.8 9.5 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1788, 1723 cm.sup.-1 
NO.sub.2 1544, 1359 cm.sup.-1 
C.dbd.O 1778, 1723 cm.sup.-1 
NO.sub.2 1544, 1360 cm.sup.-1 
______________________________________ 
EXAMPLE 17 
5,5-dimethyl-3-(4-nitro-3-trifluoromethyl-phenyl)-1-nonyl-2,4-imidazolidine 
dione 
Using the procedure of Example 1, 1 g of 
1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl imidazolidine-2,5-dione 
prepared from a 50% suspension of 170 mg of sodium hydride in oil and 0.7 
ml of 1-bromo-nonane were reacted to obtain after chromatography on silica 
1.08 g of the desired product melting at 63.degree. C. 
______________________________________ 
Analysis: C.sub.21 H.sub.28 O.sub.4 F.sub.3 N.sub.3 ; molecular weight = 
443.46 
% C % H % F % N 
______________________________________ 
Calculated: 56.87 6.36 12.85 
9.48 
Found: 57.0 6.5 12.8 9.5 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1788, 1723 cm.sup.-1 
NO.sub.2 1544, 1359 cm.sup.-1 
______________________________________ 
EXAMPLE 18 
4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethyl-benzonitri 
le 
Using the procedure of Example 1, 300 mg of the product of Example 8 were 
reacted to obtain 275 mg of the desired product melting at 158.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1780, 1727 cm.sup.-1 
aromatics 1615, 1574, 1505 cm.sup.-1 
CN 2238 cm.sup.-1 
______________________________________ 
EXAMPLE 19 
4-(5-thioxo-2-oxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl-benzo 
nitrile (product A), 
4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile (product B) and 
4-(2,5-dithioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-trifluoromethyl-benzon 
itrile (product C) 
A suspension of 230 mg of the product of Example 18, 1.4 ml of toluene and 
78 mg of Lawesson reagent was refluxed for 9 hours and then returned to 
room temperature and evaporated to dryness. The 330 mg of residue was 
chromatographed on silica and eluted with a 99-1 methylenechloride-acetone 
mixture to obtain in the following order of elution 46 mg of product C 
with a melting point of 210.degree. C. to 211.degree. C. and a Rf=0.63 
(identical to the product of Example 13), 26 mg of product B with a 
melting point of 170.degree. C. to 171.degree. C. and a Rf=0.49 (identical 
to the product of Example 12) and 42 mg of product A with a melting point 
of 194.degree. C. and a Rf=0.34. 
______________________________________ 
Analysis for Product A 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1760 cm.sup.-1 
CN 2235 cm.sup.-1 
aromatics 1615, 1580, 1508 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (ethanol): 
______________________________________ 
max 228 nm .epsilon. = 19,400 
256 nm .epsilon. = 12,100 
298 nm .epsilon. = 8,600 
390 nm .epsilon. = 70 
______________________________________ 
EXAMPLE 20 
4-(4,5-dihydro-4,4-dimethyl-2-methylthio-5-oxo-1H-imidazolidin-1-yl)-2-trif 
luoromethyl benzonitrile 
A solution of 626 mg of the product of Example 15 in 6 ml of 
dimethylformamide was added to a 50% suspension of 108 mg of sodium 
hydride in oil and 1.8 ml of dimethylformamide and after rinsing with 0.3 
ml of dimethylformamide, the mixture was stirred for 10 minutes after 
cessation of hydrogen evolution. A mixture of 0.19 ml of methyliodide in 1 
ml of dimethylformamide was added dropwise and after 45 minutes of 
reaction, the mixture was poured into 50 g of an ice-water mixture 
containing 0.5 g of monosodium phosphate. The mixture was extracted4times 
with ether and the combined organic phases were washed with aqueous sodium 
chloride, dried over magnesium sulfate and evaporated to dryness. The 668 
mg of residue were chromatographed on silica and eluted with a 95-5 
dichloromethane-ethyl acetate mixture to obtain 640mg of the desired 
product which chromatographed again on silica. Elution with a 7-3 
cyclohexane-ethyl acetate mixture yielded after taking up in ether 507mg 
of the desired product melting at62.degree. C. 
______________________________________ 
IR Spectrum: 
______________________________________ 
C.dbd.O 1747 cm.sup.-1 
C.dbd.N and aromatics 
1614, 1581, 1563, 1503 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (ethanol): 
______________________________________ 
max 209 nm .epsilon. = 26,000 
inflex. 236 nm .epsilon. = 11,500 
inflex. 264 nm .epsilon. = 8,700 
______________________________________ 
EXAMPLE 21 
4-(4,5-dihydro-4,4-dimethyl-5-oxo-2-benzylthio)-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile 
A solution of 313 mg of 4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile in 3 ml of dimethylformamide were added to 
a suspension of 53 mg of sodium hydride in oil and 0.5 ml of 
dimethylformamide and after stirring for 10 minutes, 0.1 ml of benzyl 
bromide were added. The mixture was stirred for 30 minutes and then poured 
into an ice-water mixture containing 500 mg of monosodium phosphate. The 
mixture was extracted with ether and the organic phase was washed with 
aqueous sodium chloride, dried and evaporated to dryness. The 450 mg of 
residue were chromatographed on silica and eluted with a 97.5-2.5 
methylene chloride-ethyl acetate mixture to obtain 316mg of the desired 
product with a RF=0.38. 
______________________________________ 
Analysis: 
%C %H %F %N 
______________________________________ 
Calculated: 59.54 4.0 14.12 
10.41 
Found: 59.6 4.0 14.1 10.2 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1746 cm.sup.-1 
CN 2236 cm.sup.-1 
aromatics and conjugated system 
1614, 1580, 1570, 1503, 
1499 cm.sup.-1 
______________________________________ 
EXAMPLE 22 
4-(4,4-dimethyl-3-(2-hydroxyethyl)-5-imino-2-thioxo-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile 
8 ml of ethanoline were added dropwise at 20.degree. C. to 30.degree. C. to 
12.3 ml of the cyanhydrin of acetone and after stirring for 18 hours, the 
mixture was distilled to obtain 2.3 g of a mixture of 
2-(2-hydroxyethyl)-amino-2-methyl-propanenitrile and 
2,2-dimethyloxazolidine which was used as is for the next step. 
A mixture of 1.18 g of the said mixture, 2.11 g of the isothiocyanate of 
Example 11 and 20 ml of tetrahydrofuran and 0.5 ml of triethylamine was 
refluxed for 30 minutes and then evaporated to dryness. The residue was 
chromatographed on silica and eluted with a 95-5 methylene 
chloride-acetone mixture to obtain 1.26 g of the desired product and 686 
mg of N-(4-cyano-2-trifluoromethyl-phenyl)-2,2-dimethyl-3-oxazolidine 
carbothioamide. The 686 mg were dissolved in 10 ml of ethyl acetate and 
after the addition of 30 ml of cyclohexane, the mixture was concentrated 
to 4 ml and vacuum filtered and dried to obtain another 518 mg of product. 
The raw product was dissolved in 20 ml of isopropanol and the solution was 
concentrated to 5 ml, vacuum filtered and dried to obtain 1.04 g of the 
desired product melting at 181.degree. C. 
______________________________________ 
Analysis: 
%C %H %F %N %S 
______________________________________ 
Calculated: 
50.55 4.24 16.00 15.72 
9.00 
Found: 50.4 4.1 15.9 15.6 9.0 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
OH 3630 cm.sup.-1 
.dbd.NH 3314, 1677 cm.sup.-1 
CN 2230 cm.sup.-1 
aromatics 1611, 1576, 1504 cm.sup.-1 
______________________________________ 
EXAMPLE 23 
4-(4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile (Product A) and 
4-(4,4-dimethyl-2,5-dioxo-3-(2-mercaptoethyl) 
1-imidazolidinyl)-2-trifluoromethyl-benzonitrile (Product B) 
A mixture of 680 mg of the product of Example 22, 7 ml of water and 7 ml of 
hydrochloric acid was refluxed for 10 minutes and after cooling to room 
temperature, the mixture was extracted with ethyl acetate. The organic 
phase was washed with aqueous sodium chloride, dried and evaporated to 
dryness. The residue was chromatographed on silica and eluted with a 1--1 
cyclohexane-ethyl acetate mixture to obtain 119 mg of product B with a 
Rf=0.35 and 569 mg of product A with a Rf=0.14 and a melting point of 
.apprxeq.130.degree. C. 
______________________________________ 
Analysis: C.sub.15 H.sub.14 F.sub.3 N.sub.3 O.sub.2 S; molecular weight = 
357.36 
%C %H %F %N %S 
______________________________________ 
Calculated: 
50.42 3.95 15.95 11.76 
8.97 
Product A 
Found: 50.7 4.0 15.7 11.5 9.1 
Product B 
Found: 50.6 3.8 15.9 11.6 9.1 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
Product A: 
OH 3626 cm.sup.-1 
CN 2236 cm.sup.-1 
C.dbd.O 1763 cm.sup.-1 
aromatics 1615, 1578, 1504 cm.sup.-1 
Product B: 
Absence of OH 
CN 2228 cm.sup.-1 
C.dbd.O 1780, 1726 cm.sup.-1 
aromatics 1615, 1578, 1505 cm.sup.-1 
______________________________________ 
Using 
4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethyl-benzonitrile 
of Example 8 and the appropriate reactants, the following products were 
prepared. 
EXAMPLE 24 
4-(4,4-dimethyl-2,5-dioxo-3-ethyl-1-imidazolidinyl)-2-trifluoromethyl-benzo 
nitrile with a melting point of 100.degree. C. to 101.degree. C. 
______________________________________ 
Analysis: C.sub.15 H.sub.14 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
325.29 
%C %H %F %N 
______________________________________ 
Calculated: 55.39 4.34 17.52 
12.92 
Found: 55.7 4.3 17.6 12.8 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1777, 1724 cm.sup.-1 
aromatics 1617, 1575, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 25 
4-(4,4-dimethyl-2,5-dioxo-3-(2-propenyl)-1-imidazolidinyl)-2-trifluoromethy 
l-benzonitrile melting at 109.degree. C. to 110.degree. C. 
______________________________________ 
Analysis: C.sub.16 H.sub.14 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
337.35 
%C %H %F %N 
______________________________________ 
Calculated: 56.97 4.18 16.90 
12.46 
Found: 57.0 4.1 16.2 12.3 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1728, 1725 cm.sup.-1 
HC.dbd.CH.sub.2 1645 cm.sup.-1 
aromatics 1616, 1575, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 26 
4-(4,4-dimethyl-2,5-dioxo-3-benzyl-1-imidazolidinyl)-2-trifluoromethyl-benz 
onitrile melting at 98.degree. C. to 99.degree. C. 
______________________________________ 
Analysis: C.sub.20 H.sub.16 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
387.36 
%C %H %F %N 
______________________________________ 
Calculated: 62.01 4.16 14.71 
10.85 
Found: 62.0 4.1 14.7 10.8 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): C--NH: 3430 cm.sup.-1 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1779, 1724 cm.sup.-1 
aromatics 1615, 1605, 1575, 1504, 1497 cm.sup.-1 
______________________________________ 
EXAMPLE 27 
4-(4,4-dimethyl-2,5-dioxo-3-(4-fluorobenzyl)-1-imidazolidinyl-2-trifluorome 
thyl-benzonitrile melting at 101.degree..degree. C. to 102.degree. C. 
______________________________________ 
Analysis: C.sub.20 H.sub.15 F.sub.4 N.sub.3 O.sub.2 ; molecular weight = 
405.35 
%C %H %F %N 
______________________________________ 
Calculated: 59.26 3.73 18.75 
10.37 
Found: 59.1 3.5 18.9 10.3 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1780, 1724 cm.sup.-1 
aromatics 1615, 1612, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 28 
4-(4,4-dimethyl-2,5-dioxo-3-(4-methoxybenzyl)-1-imidazolidinyl-benzonitrile 
melting at 95.degree. C. to 96.degree. C. 
______________________________________ 
Analysis: C.sub.21 H.sub.18 F.sub.3 N.sub.3 O.sub.3 ; molecular weight = 
417.39 
%C %H %F %N 
______________________________________ 
Calculated: 60.43 4.35 13.65 
10.07 
Found: 59.1 3.5 18.9 10.3 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1778, 1723 cm.sup.-1 
aromatics 1615, 1584, 1514, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 29 
4-(4,4-dimethyl-2,5-dioxo-3-(4-trifluoromethyl-benzyl)-1-imidazolidinyl)-2- 
trifluoromethyl benzonitrile melting at .apprxeq.89.degree. C. to 
90.degree. C. 
______________________________________ 
Analysis: C.sub.21 H.sub.15 F.sub.6 N.sub.3 O.sub.2 ; molecular weight = 
313.30 
%C %H %F %N 
______________________________________ 
Calculated: 55.39 3.32 25.03 
9.23 
Found: 55.2 3.2 25.3 9.2 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2238 cm.sup.-1 
C.dbd.O 1615, 1505 cm.sup.-1 
aromatics 1615, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 30 
4-(4,4-dimethyl-2,5-dioxo-3-(2-epoxymethyl)-1-imidazolidinyl 
2-trifluoromethyl-benzonitrile melting at 112.degree. C. to 113.degree. C. 
______________________________________ 
Analysis: C.sub.16 H.sub.14 F.sub.3 N.sub.3 O.sub.3 ; molecular weight = 
353.30 
%C %H %F %N 
______________________________________ 
Calculated: 54.39 3.99 16.13 
11.89 
Found: 54.7 4.0 16.1 11.8 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2235 cm.sup.-1 
C.dbd.O 1781, 1725 cm.sup.-1 
aromatics 1615, 1576, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 31 
4-(4,4-dimethyl-2,5-dioxo-3-propyl-1H-imidazolidinyl)-2-trifluoromethyl 
benzonitrile melting at 113.degree. C. to 114.degree. C. 
______________________________________ 
Analysis: C.sub.16 H.sub.16 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
339.32 
%C %H %F %N 
______________________________________ 
Calculated: 56.64 4.75 16.80 
12.38 
Found: 56.7 4.7 16.7 12.2 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2236 cm.sup.-1 
C.dbd.O 1778, 1725 cm.sup.-1 
aromatics 1616, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 32 
4-(4,4-dimethyl-2,5-dioxo-3-isopropyl-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile melting at 138.degree. C. to 139.degree. C. 
______________________________________ 
Analysis: C.sub.16 H.sub.16 F.sub.3 N.sub.3 O.sub.2 ; molecular weight = 
339.32 
%C %H %F %N 
______________________________________ 
Calculated: 56.64 4.75 16.80 
12.38 
Found: 56.5 4.7 17.1 12.3 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2236 cm.sup.-1 
C.dbd.O 1778, 1724 cm.sup.-1 
aromatics 1616, 1575, 1505 cm.sup.-1 
______________________________________ 
Using 4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile of Example 15 and the appropriate reactants, the following 
compounds were prepared: 
EXAMPLE 33 
4-(4,5-dihydro-4,4-dimethyl-2-nonylthio-5-oxo-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile were a Rf=0.35 (97.5-2.5 methylene 
chloride-ethyl acetate eluant). 
EXAMPLE 34 
4-(4,5-dihydro-4,5-dimethyl-2-(3-hydroxypropylthio)-5-oxo-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile with a Rf=0.17 (8-2 methylene 
chloride-ethyl acetate eluant). 
EXAMPLE 35 
Ethyl 
[1-(4-cyano-3-trifluoromethyl-phenyl)-4,5-dihydro-4,4-dimethyl-5-oxo-1H-im 
idazol 2-yl)-thio]-acetate with a Rf=0.20 (65-35 cyclohexane-ethyl acetate 
eluant). 
Using the isocyanate of Example 11 and the appropriate reactants, the 
following compounds were prepared. 
EXAMPLE 36 
4-(4,4-dimethyl-3-ethyl-5-imino-2-thioxo-1-imidazolidinyl)-2-trifluoromethy 
l benzonitrile with a Rf=0.16 (95-5 methylene chloride-acetone eluant). 
EXAMPLE 37 
4-(4,4-dimethyl-5-imino-3-pentyl-2-thioxo-1-imidazolidinyl)-2-trifluorometh 
yl benzonitrile with a RF=0.35 (8-2 ethyl acetate-cyclohexane eluant) 
Using the 
4-(4,4-dimethyl-3-ethyl-5-imino-2-thioxo-1-imidazolidinyl)-2-trifluorometh 
yl benzonitrile of Example 36 and the 
4-(4,4-dimethyl-5-imino-3-pentyl-2-thioxo-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile of Example 37 and 0.5 N hydrochloric acid, 
the following compounds were prepared. 
EXAMPLE 38 
4-(4,4-dimethyl-3-ethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile with a Rf=0.38 (1--1 ethyl acetate-cyclohexane eluant). 
EXAMPLE 39 
4-(4,4-dimethyl-5-oxo-3-pentyl-2-thioxo-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile with a melting point of 78.degree. C. and a Rf=0.66 (8-2 
ethyl acetate-cyclohexane eluant) 
Using 4-(4,5-dihydro-4,4-dimethyl-2-methylthio-5-oxo-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile of Example 20 and 
4-(4,5-dihydro-4,4-dimethyl-5-oxo-2-benzylthio-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile of Example 21 and the Lawesson reagent, the 
following compounds were prepared. 
EXAMPLE 40 
4-(4,5-dihydro-4,4-dimethyl-2-methylthio-5-thioxo-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile with a Rf=0.36 (97.5-2.5 methylene 
chloride-ethyl acetate eluant). 
EXAMPLE 41 
4-(4,5-dihydro-4,4-dimethyl-2-benzylthio-5-thioxo-1H-imidazol-1-yl) 
2-trifluoromethyl-benzonitrile with a Rf=0.62 (98-2 methylene 
chloride-ethyl acetate eluant). 
EXAMPLE 42 
3-(4-cyano-3-trifluoromethyl-penyl)-5,5-dimethyl-2,4-dioxo-N-methyl-N-isopr 
opyl-1-imidazolidine acetamide 
0.1 ml of N-methyl-morpholine was added to a suspension of 
3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-1-acetic acid 
in 4 ml of methylene chloride and after cooling the solution to 
-10.degree. C., 0.1 ml of isobutyl chloroformate was added dropwise. After 
stirring for 25 minutes at -10.degree. C., 0.15 ml of 
N-methyl-N-isopropylamine was added and the mixture was allowed to return 
to room temperature over 40 minutes. 5 ml of an aqueous saturated sodium 
bicarbonate solution were added and after stirring for 30 minutes, the 
mixture was extracted with methylene chloride. The organic phase was 
washed with water, dried and evaporated to dryness under reduced pressure. 
The residue was chromatographed on silica and eluted with a 96-4 methylene 
chloride-acetone mixture to obtain 147 mg of the desired product. 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
CN 2236 cm.sup.-1 
hydantoin C.dbd.O 1783, 1728 cm.sup.-1 
amide C.dbd.O 1661 cm.sup.-1 
aromatics 1615, 1575, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 43 
4-(4,4-dimethyl-2,5-dioxo-3-(2-hydroxyethyl)-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile 
Using the procedure of Example 9, 900 mg of the product of Example 8 and 
1.91 g of 2-bromoethane tert.-butyldimethylsilyl ether were reacted to 
obtain 1 g of the silyloxy ether derivative melting at 86.degree. C. to 
87.degree. C. after chromatography on silica and elution with a 7 g 
cyclohexane-ethyl acetate mixture. 
1 ml of 2 N hydrochloric acid were added to a mixture of 380 mg of the 
silyloxy ether, 4 ml of methanol and 1 ml of methylene chloride and after 
stirring for 40 minutes at room temperature,the mixture was poured into 15 
ml of water and was extracted with methylene chloride. The organic phase 
was washed with water, dried and evaporated to dryness and the residue was 
chromatographed on silica. Elution with a 7-3 methylene chloride-ethyl 
acetate mixture yielded the desired product which after crystallization 
from isopropanol melted at 109.degree. C. to 110.degree. C. and had a 
Rf=0.9. 
______________________________________ 
Analysis: 
%C %H %F %N 
______________________________________ 
Calculated: 52.79 4.23 16.70 
12.31 
Found: 52.5 4.2 16.7 12.1 
______________________________________ 
EXAMPLE 44 
Using the procedure of Example 43, 2-bromopropanol tert.-butyldimethylsilyl 
ether was reacted to obtain 4-(4,4-dimethyl-2,5-dioxo-3-(3-hydroxypropyl) 
1-imidazolidinyl)-2-trifluoromethyl-benzonitrile melting at 131.degree. C. 
to 132.degree. C. and a Rf=0.13 (3-1 methylene chloride-ethyl acetate 
eluant). 
EXAMPLE 45 
4-[3-(2-acetyloxyethyl)-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl]2-trifluoro 
methyl-benzonitrile 
A mixture of 215 mg of the product of Example 43, 15 mg of 
4-dimethylamino-pyridine, 1 ml of pyridine and 0.5 ml of acetic acid 
anhydride was stirred at room temperature for 30 minutes and was then 
poured into 20 ml of a saturated aqueous sodium bicarbonate solution. 
After stirring for 20 minutes, the mixture was extracted with ethyl 
acetate. The organic phase was washed with water and evaporated to dryness 
and the pyridine and residual acetic acid were distilled. The residue was 
chromatographed on silica and eluted with a 65-35 methylene chloride-ethyl 
acetate mixture. The residue with a Rf=0.35 was taken up in isopropanol, 
partially concentrated, iced and vacuum filtered to obtain after drying 
210 mg of the desired product melting at 99.degree. C. to 100.degree. C. 
______________________________________ 
Analysis: 
%C %H %F %N 
______________________________________ 
Calculated: 53.27 4.21 14.87 
10.96 
Found: 53.5 4.3 15.2 10.9 
______________________________________ 
Using the above procedure, the following products were prepared. 
EXAMPLE 46 
4-(4,4-dimethyl-2,5-dioxo-3-(5-hydroxypentyl)-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile melting at 101.degree. C. to 102.degree. C. 
EXAMPLE 47 
4-(4,4-dimethyl-2,5-dioxo-3-(2-methoxyethyl)-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile melting at 68.degree. C. to 69.degree. C. 
EXAMPLE 48 
4-(4,4-dimethyl-2,5-dioxo-3-cyanomethyl-1-imidazolidinyl)-2-trifluoromethyl 
benzonitrile melting at 186.degree. C. to 187.degree. C. 
EXAMPLE 49 
4-(4,4-dimethyl-2,5-dioxo-3-[(1,3-dioxolan-2-yl)-methyl]-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile melting at 135.degree. C. to 136.degree. C. 
EXAMPLE 50 
4-(4,4-dimethyl-2,5-dioxo-3-(2-chloroethyl)-1-imidazolidinyl) 
2-trifluoromethyl-benzonitrile melting at 120.degree. C. to 121.degree. C. 
EXAMPLE 51 
1-(3,4-dichlorophenyl)-5-imino-3,4,4-trimethyl-2-imidazolidine thione 
A mixture of 2.4 g of the isocyanate of 3,4-dichloro-phenyl, 1.3 ml of 
2-methylamino-2-cyano-propane, 23 ml of tetrahydrofuran and 0.23 ml of 
triethylamine was refluxed for 16 hours and then evaporated to dryness 
under reduced pressure. The residue was chromatographed on silica and 
eluted with a 96-4 methylene chloride-acetone mixture to obtain after 
crystallization from ether, 2.54 g of the desired product melting at 
133.degree. C. 
EXAMPLE 52 
3-(3,4-dichlorophenyl)-2-thioxo-1,5,5-trimethyl-1-imidazolidinone 
A suspension of 1.88 g of the product of Example 51 in 14 ml of 6 N 
hydrochloric acid was refluxed for 45 minutes and after the addition of 
another 14 ml of 6 N hydrochloric acid, the mixture was refluxed for 2 
more hours. Another 4 ml of 6 N hydrochloric acid were added and the 
mixture was refluxed for 90 minutes and then returned to room temperature. 
100 g of ice were added and the mixture was extracted with ethyl acetate. 
The organic phase was washed with water, dried and evaporated to dryness. 
The residue was chromatographed on silica and eluted with a 1--1 
cyclohexane-ethyl acetate mixture to obtain 1.84 g of the desired product 
melting at 129.degree. C. after crystallization from isopropanol. 
______________________________________ 
Analysis: C.sub.12 H.sub.12 Cl.sub.2 N.sub.2 OS; molecular weight = 
303.21 
%C %H %Cl %N %S 
______________________________________ 
Calculated: 
47.54 3.99 23.38 9.24 10.57 
Found: 47.5 3.8 23.2 9.3 10.5 
______________________________________ 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1753 cm.sup.-1 
C.dbd.S + aromatics 
1595, 1570, 1496 cm.sup.-1 
______________________________________ 
Using the above procedures, the following compounds were prepared: 
EXAMPLE 53 
3-(3,4-dichlorophenyl)-3,5-dihydro-5,5-dimethyl-2-methylthio-4H-imidazol 
4-one melting at 110.degree. C. 
EXAMPLE 54 
1-(3,4-dichlorophenyl)-3,4-4-trimethyl-2,5-imidazolidine-dithione melting 
at .apprxeq.146.degree. C. 
EXAMPLE 55 
1-(4-chloro-3-trifluoromethyl-phenyl)-4,4-dimethyl-2-thioxo-5-imidazolidino 
ne melting at 176.degree. C. 
EXAMPLE 56 
1-(4-chloro-3-trifluoromethyl-phenyl)-4,4-dimethyl-5-imino-2-imidazolidinet 
hione melting at 173.degree. C. to 174.degree. C. 
EXAMPLE 57 
3-(3,4-dichlorophenyl)-3,5-dihydro-5,5-dimethyl-2-benzylthio 
4H-imidazol-4-one 
______________________________________ 
IR Spectrum (CHCl.sub.3): 
______________________________________ 
C.dbd.O 1736 cm.sup.-1 
CN + aromatics 1578, 1496 cm.sup.-1 
______________________________________ 
EXAMPLE 58 
4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxy butyl) 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
a) Condensation 
600 mg of 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl) 
benzonitrile obtained as in Example 8--in 5 ml of dimethylformamide were 
added to a suspension of 104 mg of sodium hydride in 0.8 ml of 
dimethylformamide, while maintaining the temperature below 20.degree. C. 
After 10 minutes of stirring, 445 mg of 
4-chloro-t-butyl-dimethylsilylether and 300 mg of sodium iodide were 
added. The mixture was heated for 16 hours at 50.degree. C. and then, 
cooled to ambient temperature. 87 mg of sodium hydride were added followed 
by another 400 mg of the chlorinated ether and 267 mg of sodium hydride 
were added. The mixture was heated for another hour and then, returned to 
ambient temperature, and poured into 60 ml of water containing 600 mg of 
monopotassium phosphate. Extraction was carried out with ether and the 
organic phase was washed with water, dried and the solvent was evaporated. 
The residue was chromatographed on silica (eluant: methylene 
chloride--acetone (99-1)) to obtain 526 mg of product which as used as is 
for the stage following the cleavage. 
The said product was mixed in 5 ml of methanol and 1.5 ml of 2 N 
hydrochloric acid and the mixture was stirred for 40 minutes at ambient 
temperature. The mixture was poured into 30 ml of water and was extracted 
with methylene chloride. The organic phase was washed with water, dried 
and the solvent was evaporated. After chromatographing the residue on 
silica (eluant methylene chloride--acetone (9-1), the fractions with a 
Rf=0.15, were recovered, and after crystallization from isopropyl ether, 
307 mg of the expected product melting at 102.degree.-103.degree. C. were 
obtained. 
______________________________________ 
Analysis; C.sub.17 H.sub.18 F.sub.3 N.sub.3 O.sub.3 ; molecular weight = 
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 (CHCl.sub.3); 
______________________________________ 
OH 3628 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
C.dbd.O 1778-1724 cm.sup.-1 
Aromatics 1615-1575-1505 cm.sup.-1 
______________________________________ 
Preparation of the 4-chloro t-buryl dimethylsilylether used at the start of 
Example 58. 
9.9 ml of 4-chloro-1-butanol and 24.3 g of imidazole in 50 ml of 
tetrahydrofuran were stirred and 2.82 g of terbutyldimethylsilyl chloride 
in 20 ml of tetrahydrofuran were added dropwise at a temperature of less 
than 20.degree. C. The mixture was stirred for 18 hours at ambient 
temperature, followed by separating, rinsing with tetrahydrofuran and 
eliminating the solvent under reduced pressure. The residue was purified 
by chromatography on silica (eluant: cyclohexane--ethyl acetate (95-5)) to 
obtain 17.5 g of the expected product. 
EXAMPLE 59 
(1,1-dimethyl) ethyl 3-(4-cyano 3-trifluoro-methyl-phenyl)5,5-dimethyl 
2,4-dioxo-1-imidazolidine acetate 
450 mg of the product of Example 8--in solution in 4 ml of 
dimethylformamide were added to a suspension of 78 mg of sodium hydride at 
50% in oil and 0.5 ml of dimethylformamide. The mixture was stirred for 15 
minutes and then without exceeding 30.degree. C., 0.22 ml of terbutyl 
bromoacetate were slowly added. The mixture was stirred for 16 hours and 
then, was poured into 50 g of a water and ice mixture (1--1). 0.5 g of 
monopotassium phosphate were added and extraction was carried out with 
ether. The organic phase was washed with water, dried and evaporated to 
dryness. The 1.1 g of crude product was chromatographed on silica (eluant: 
methylene chloride--acetone (99-1)) to obtain 425 mg of the expected 
product melting at 122.degree.-123.degree. C. with a Rf=0.28 (eluant: 
methylene chloride--acetone (99-1)) 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1788-1729 cm.sup.-1 (hydantoin) 1745 cm.sup.-1 
(ester) 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1616-1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 258 nm 
= 16100 
Infl. 277 nm 
= 6000 
Infl. 285 nm 
= 3000 
______________________________________ 
EXAMPLE 60 
cyclopentyl 3-(4-cyano-3-trifluoromethyl phenyl)-5,5-dimethyl 2,4-dioxo 
1-imidazolidine acetate 
A solution of 355 mg of the product of Example 9,--49 mg of 
4-dimethylamino-pyridine 130 mg of cyclopentanol and 6.5 ml of methylene 
chloride was cooled to -10.degree. C. and then 226 mg of 
dicyclohexylcarbodiimide in 2 ml of methylene chloride were added. The 
mixture was allowed to return to ambient temperature, stirred for 25 
minutes, heated at reflux for 2 hours, returned to ambient temperature, 
filtered and the solvent was evaporated. The residue was chromatographed 
on silica (eluant: methylene chloride--acetone (99-1)) to obtain 281 mg of 
the expected product with a Rf=0.25 (eluant: methylene chloride--acetone 
(99-1)) 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1786-1729 cm.sup.-1 (hydantoin) 1748 cm.sup.-1 (ester) 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1615-1602-1576-1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 258 nm 
= 16800 
Infl. 276 nm 
= 5800 
Infl. 286 nm 
= 3000 
______________________________________ 
EXAMPLE 61 
ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo 
1-imidazolidinebutanoate 
Using the procedure of Example 59, the product of Example 8--and ethyl 
4-bromobutyrate were reacted to obtain the expected product melting at 
66.degree.-67.degree. C. with a Rf=0.16 (eluant: methylene 
chloride--acetone (99-1)) 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1770-1726 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1616-1576-1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 260 nm 
= 15500 
Infl. 277 nm 
= 7000 
Infl. 286 nm 
= 3600 
______________________________________ 
EXAMPLE 62 
3-(4-cyano 3-trifluoromethyl-phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidine 
butanoic acid 
1 g of the product of Example 61 in 20 ml of methanol was stirred for 3 
hours at ambient temperature in the presence of 3 ml of 2 N sodium 
hydroxide and the mixture was poured into 20 ml of water and acidified to 
pH=1 using 7 ml of N hydrochloric acid. The mixture was extracted with 
ether and the extracts were washed with water and dried and the solvents 
were eliminated under reduced pressure to obtain 863 mg of crude product 
melting at 179.degree.-180.degree.C. which was purified by chromatography 
on silica (eluant: methylene chloride--methanol (92.5-7.5)). After 
crystallization from isopropanol, 614 mg of the expected product melting 
at 184.degree.-185.degree. C. and with a Rf=0.25 (eluant: methylene 
chloride--methanol (92.5-7.5)) were obtained. 
______________________________________ 
IR Spectrum (nujol); 
______________________________________ 
C.dbd.O 1770-1753-1735-1712-1690-1645 cm.sup.-1 
C.tbd.N 2230 cm.sup.-1 
Aromatics 1613-1587-1533-1502 cm.sup.-1 
______________________________________ 
EXAMPLE 63 
(1,1-dimethyl) ethyl 3-(4-cyano 3-trifluoro-methyl-phenyl)-5,5-dimethyl 
2,4-dioxo-1-imidazolidine-butanoate 
By carrying out the esterification of the product of Example 62, with 
terbutanol in the presence of dicyclohexylcarbodiimide and 
4-dimethylamino-pyridine as in Example 60, the expected product melting at 
96.degree.-97.degree. C. with a Rf=0.32 (eluant: methylene 
chloride--acetone (98-2)) was obtained. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1779-1725 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1616-1576-1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 261 nm 
= 15600 
Infl. 276 nm 
= 7800 
Infl. 286 nm 
= 3700 
______________________________________ 
EXAMPLE 64 
cyclopentyl 3-(4-cyano 3-trifluoromethyl-phenyl) 
5,5-dimethyl-2,4-dioxo-1-imidazolidine butanoate 
Using the procedure of Example 63, cyclopentanol was reacted to obtain the 
expected product melting at 85.degree.-86.degree. C. with a Rf=0.33 
(eluant: methylene chloride--acetone (98-2)). 
______________________________________ 
IR Spectrum (CHCl.sub.3) 
______________________________________ 
C.dbd.O 1779-1728 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1616-1578-1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 261 nm 
= 16000 
Infl. 277 nm 
= 7600 
Infl. 286 nm 
= 3700 
______________________________________ 
EXAMPLE 65 
4-(4,4-dimethyl-2,5-dioxo 3-(2-(4-fluorophenylthio) 
ethyl)-1-imidazolidinyl-2-(trifluoromethyl)-benzonitrile 
a) Formation of the phenolate 
0.16 ml of 4-fluorothiophenol in 1.6 ml of dimethylformamide were added at 
a temperature of less than 28.degree. C. to a suspension of 80 mg of 
sodium hydride in 0.5 ml of dimethylformamide, and the solution was 
stirred for 10 minutes. 
b) Substitition 
548 mg of 4-[4,4-dimethyl-2,5-dioxo-3-(2-chloroethyl) 
1-imidazolidinyl]-2-(trifluoromethyl) benzonitrile (Example 50--in 
solution in 4 ml of dimethylformamide were added to the solution of a) and 
the mixture was stirred for 2 hours, poured into 50 ml of water with 0.5 g 
of monopotassium phosphate. Extraction was carried out with ether and the 
organic phase was washed with water and dried and the solvent was 
evaporated. After chromatographing the residue on silica (eluant: 
cyclohexane--ethyl acetate (75-25)), 570 mg of the expected product 
melting at 93.degree.-94.degree. C. with a Rf=0.29 (eluant: 
cyclohexane--ethyl acetate (75-25)) were obtained. 
______________________________________ 
IR Spectrum (CHCl.sub.3) 
______________________________________ 
C.dbd.O 1780-1726 cm.sup.-1 
C.tbd.N 2238 cm.sup.-1 
Aromatics 1616-1579-1506 cm.sup.-1 
(fluorophenyl) thio 
1591-1492 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 254 nm 
= 18600 
Infl. 277 nm 
= 7500 
Infl. 286 nm 
= 4200 
______________________________________ 
EXAMPLE 66 
4-(4,4-dimethyl-2,5-dioxo-3-(2-(4-fluorophenyl sulfonyl) 
ethyl)-1-imidazolidinyl-2-(trifluoromethyl) benzonitrile 
1.21 g of metachloroperbenzoic acid in 24 ml of methylene chloride were 
added dropwise at a temperature of less than 29.degree. C. to 222 mg of 
the product of Example 65 in 4.4 ml of methylene chloride. After 30 
minutes of stirring, the mixture was poured into 30 ml of sodium 
thiosulfate (0.5 M/1). The mixture was stirred for 10 minutes, followed by 
decanting and extracting with methylene chloride. The organic phase was 
washed with a saturated aqueous solution of sodium bicarbonate, then with 
water, dried, and the solvent was evaporated. After chromatographing the 
residue on silica (eluant: cyclohexane--ethyl acetate (1--1)), 220 mg of 
product were obtained which was crystallized from isopropanol to obtain 
196 mg of the expected product melting at 155.degree.-156.degree. C. with 
a Rf=0.22 (eluant: ethyl acetate--cyclohexane (1--1)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1783-1727 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1615-1593-1505-1497 cm.sup.-1 
SO.sub.2 1314-1150 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 258 nm 
= 16700 
Infl. 286 nm 
______________________________________ 
EXAMPLE 67 
4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) sulfinyl) ethyl) 
1-imidazolidinyl 2-(trifluoromethyl) benzonitrile 
222 mg of the product of Example 65 in 15 ml of methanol were stirred for 
30 minutes at ambient temperature in the presence of 5 ml of an aqueous 
solution of sodium metaperiodate (0.1 M/1). The suspension was heated for 
one hour at 40.degree. C. and 10 ml of methanol and 5 ml of oxidizing 
solution were added. The methanol was evaporated off and after 10 ml of a 
saturated solution of sodium chloride were added, extraction was carried 
out with ethyl acetate. The organic phase was washed with salt water, 
dried, and the solvent was evaporated. After chromatographing the residue 
on silica (eluant: methylene chloride--acetone (9-1)), 205 mg of product 
were obtained which was crystallized from isopropanol to obtain 180 mg of 
the expected product melting at 145.degree.-146.degree. C. with a Rf=0.10 
(eluant: methylene chloride--acetone (9-1)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1782-1727 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1615-1592-1505-1493 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 258 nm .epsilon. = 17600 
Infl. 285 nm 
______________________________________ 
Using the procedure of the preceding examples, 
4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) 2-(trifluoromethyl) 
benzonitrile of Example 8--and the appropriate reagents, the compounds of 
the following examples were obtained: 
EXAMPLE 68 
4-(4,4-dimethyl 2,5-dioxo 3-((3-methoxyphenyl) methyl) 1-imidazolidinyl 
2-(trifluoromethyl) benzonitrile Melting at 88.degree.-89.degree. C. with 
a Rf=0.21 (eluant: cyclohexane--ethyl acetate (7-3)) 
______________________________________ 
IR Spectrum (CHCl.sub.3) 
______________________________________ 
C.dbd.O 1779-1724 cm.sup.-1 
C.tbd.N 2238 cm.sup.-1 
Aromatics 1614-1602-1588-1575-1504-1491 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 260 nm .epsilon. = 16800 
Infl. 210 nm .epsilon. = 28500 
Infl. 280 nm .epsilon. = 8900 
______________________________________ 
EXAMPLE 69 
4-(4,4-dimethyl 2,5-dioxo 3-(2-(4-morpholinyl) ethyl) 1-imidazolidinyl 
2-(trifluoromethyl) benzonitrile with a Rf=0.20 (eluant: methylene 
chloride--acetone (70-30)) 
______________________________________ 
IR Spectrum (CHCl.sub.3) 
______________________________________ 
C.dbd.O 1779-1725 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1616-1576-1505 cm.sup.-1 
morpholinyl 1117 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 261 nm .epsilon. = 14000 
Infl. 277 nm .epsilon. = 6900 
Infl. 286 nm .epsilon. = 3600 
______________________________________ 
EXAMPLE 70 
4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-imino 2-thioxo 1-inidazolidinyl) 
2-(trifluoromethyl)-benzonitrile 
a) Preparation of the isothiocyanate 
2.23 g of 1-trifluoromethyl-4-amino benzonitrile (prepared accord to EP 
0002892) were added slowly to a solution of 22 ml of distilled water and 1 
ml of thiophosgene and the mixture was stirred for one hour and then 
extracted with chloroform. The extracts were washed with salt water, dried 
and evaporated to dryness under reduced pressure to obtain 3 g of product 
which was used as is for obtaining the imine. 
b) Obtaining the imine 
5 g of the said isothiocyanate were mixed with 37 ml of tetrahydrofuran in 
the presence of 1.5 ml of triethylamine and 2.8 g of 2-[(2-hydroxy ethyl) 
amino] 2-methyl propane nitrile (prepared in Example 22)--in solution in 
10 ml of tetrahydrofuran were added all at once. The temperature 
spontaneously increased to 34.degree. C. and the resultant mixture was 
allowed to return to ambient temperature while stirring for one hour. The 
solvent was evaporated off and the residue was chromatographed on silica 
(eluant: methylene chloride--methanol (7-3)) to obtain 5.87 g of the 
expected product melting at 181.degree. C., after crystallization from 
isopropanol. 
EXAMPLE 71 
4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
4.6 g of the product of Example 70 in 65 ml of methanol was refluxed for 
one hour in the presence of 10 ml of 2 N hydrochloric acid. The mixture 
was cooled to ambient temperature and poured into 300 ml of ice-cooled 
water. Extraction was carried out with ethyl acetate and the organic phase 
was washed with salt water, dried, and the solvent was evaporated off. The 
residue was chromatographed on silica (ethyl acetate--cyclohexane (1--1)) 
and the fractions were collected with a Rf=0.14. After crystallization 
from methylene chloride and cyclohexane, 4.37 g of the expected product 
melting at 130.degree. C. were obtained 
______________________________________ 
Analysis; C.sub.15 H.sub.14 F.sub.3 N.sub.3 O.sub.2 S; molecular weight = 
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 (CHCl.sub.3); 
______________________________________ 
OH 3626 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
C.dbd.O 1763 cm.sup.-1 
Aromatics 1615-1578-1504 cm.sup.-1 
______________________________________ 
EXAMPLE 72 
4-(4,4-dimethyl-3-(2-hydroxyethyl)-5-imino-2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl)-5-.sup.3 H-benzonitrile 
a) Preparation of the tritiated benzonitrile 
15 mg of 2-trifluoromethyl 4-amino 5-bromo benzonitrile were mixed with 200 
.mu.l of ethyl acetate in the presence of 6.5 .mu.l of triethylamine and 2 
mg of palladium on activated charcoal and then tritium (1.42 bar) was 
introduced. After filtering, rinsing with ethyl acetate and evaporating to 
dryness at ambient temperature, approximately 66.6 G.Bq (1.8 Ci) of 
product were obtained. 
b) Preparation of the tritiated isothiocyanate 
150 .mu.l of a 10% solution of thiophosgene in chloroform were added to the 
above product, in 150 .mu.l of water and the mixture was stirred for 45 
minutes at ambient temperature. Dilution was carried out with 0.5 ml of 
water and 1 ml of chloroform, followed by extraction with chloroform. The 
solvent was evaporated off under reduced pressure and the residue was 
taken up in toluene to obtain 50.7 G.Bq (1.37 Ci) of the expected product 
which was kept at -80.degree. C. 
c) Preparation of the tritiated imine 
Having eliminated the toluene from the above mixture under reduced 
pressure, 130 .mu.l of tetrahydrofuran with 1% triethylamine were added 
and 13 .mu.l of 2-[(2-hydroxyethyl)-amino] 2-methylpropane-nitrile 
(Example 22)--were added. Then, another 130 .mu.l of tetrahydrofuran with 
1% triethylamine were added and the mixture was stirred for 30 minutes at 
ambient temperature and the solvents were eliminated under reduced 
pressure. 
Preparation of the 2-trifluoromethyl 4-amino 5-bromo benzonitrile used in 
Example 72. 
A solution of 2-trifluoromethyl 4-amino benzonitrile (prepared according to 
EP 0002892) (5 moles) in 25 ml of methanol was cooled to 0.degree. C. and 
bomine was added (5.2 moles). The mixture was allowed to return to ambient 
temperature, stirred for 3 hours, alkalinized with triethylamine and then 
an aqueous solution of sodium thiosulfate was added. The solvents were 
eliminated and extraction was carried out with chloroform. The organic 
phase was washed with water, dried, and the solvent was evaporated to 
obtain the product which was used as is for the following stage. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
NH.sub.2 3612-3408 cm.sup.-1 
C.tbd.N 2230 cm.sup.-1 
Aromatics 1621-1556-1506 cm.sup.-1 
______________________________________ 
EXAMPLE 73 
4-(4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo 
1-imidazolidinyl)-2-(trifluoromethyl) 5-.sup.3 H-benzonitrile 
The product of Example 72 in 180 .mu.l of water was heated to 100.degree. 
C. and 60 .mu.l of 2 N hydrochloric acid was added. The mixture was 
stirred for 5 minutes at reflux and then approximately 600 mg of ice were 
added. Extraction is carried out with ethyl acetate and the extracts were 
washed with salt water and dried to obtain 34.7 G.Bq (937 mCi) of product. 
After chromatography on silica (eluant: cyclohexane--ethyl acetate 
(60-40)), 19 G.Bq (513 mCi) of the expected product were obtained. 
EXAMPLE 74 
4-(4,4-dimethyl-3-hydroxypropyl)-5-imino-2-thioxo-1-imidazolidinyl) 
2-(trifluoromethyl)-benzonitrile 
Using the procedure of Example 22--2 g of the isothio-cyanate of Example 70 
(a) and 1.2 g of the appropriate aminonitrile were reacted to obtain 1.70 
g of the expected product with a Rf=0.25 (methylene chloride--acetone 
(65-35)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3630 cm.sup.-1 
.dbd.NH 3314-1676 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
______________________________________ 
EXAMPLE 75 
4-(4,4-dimethyl-3-(3-hydroxypropyl)-5-oxo-2-thioxo-1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 71, 240 mg of the product of Example 74 were 
reacted to obtain 226 mg of the expected product melting at 
149.degree.-150.degree. C. with a Rf=0.32 (eluant; methylene 
chloride--acetone (75-25)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3626 cm.sup.-1 
C.dbd.O 1763 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1615-1580-1504-1483 cm.sup.-1 
______________________________________ 
EXAMPLE 76 
4-(4,4-dimethyl 3-(4-hydroxybutyl)-5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 22,--2 g of isothio-cyanate and 1.38 g of 
the appropriate aminoitrile were reacted to obtain 2.08 g of the expected 
product with a Rf=0.25 (methylene chloride--acetone (65-35)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3630 cm.sup.-1 
.dbd.NH 3314-1675 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1614-1577-1504 cm.sup.-1 
______________________________________ 
EXAMPLE 77 
4-(4,4-dimethyl 3-(4-hydroxybutyl)-5-oxo 2-thioxo-1-imidazolidinyl) 
2-(trifluoromethyl) benzonitile 
Using the procedure of Example 71, 300 mg of the product of Example 76 were 
reacted to obtain 236 mg of the expected product melting at 
78.degree.-79.degree. C. with a Rf=0.31 (eluant: methylene 
chloride--acetone (75-25)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3624 cm.sup.-1 
C.dbd.O 1762 cm.sup.-1 
C.tbd.N 2237 cm.sup.-1 
Aromatics 1615-1580-1504 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 232 nm .epsilon. = 19500 
Max. 254 nm .epsilon. = 24000 
Infl. 266 nm 
______________________________________ 
EXAMPLE 78 
4-(4,4-dimethyl 3-(2-methoxyethyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 22,--2.5 g of isothiocyanate and 1.56 g of 
the appropriate aminoitrile were reacted to obtain 2.36 g of the expected 
product with a Rf=0.23 (methylene chloride--acetone (92.5-7.5)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
.dbd.NH 3314 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1614-1578-1504 cm.sup.-1 
C.dbd.N 1675 cm.sup.-1 
______________________________________ 
EXAMPLE 79 
4-(4,4-dimethyl 3-(2-methoxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 71, the product of Example 78 was reacted to 
obtain the expected product melting at 98.degree.-99.degree. C. with a 
Rf=0.32 (eluant: methylene chloride--acetone (99-1)) 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1757 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1615-1580-1504 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 232 nm .epsilon. = 18200 
Max. 254 nm .epsilon. = 22400 
Infl. 265 nm 
______________________________________ 
EXAMPLE 80 
4-(4,4-dimethyl 3-(1-methylethyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 22,--2.5 g of the isothiocyanate and 1.32 g 
of the appropriate aminonitrile were reacted to obtain 880 mg of the 
expected product with a Rf=0.20 (eluant: methylene chloride--acetone 
(96-4)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
.dbd.NH 3310-1675 cm.sup.-1 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1614-1580-1504 cm.sup.-1 
______________________________________ 
EXAMPLE 81 
4-(4,4-dimethyl 3-(1-methylethyl) 5-oxo 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 71, 880 mg of the product of Example 80 and 
35 ml of 6 N hydrochloric acid were reacted to obtain after extraction 
with chloroform, 744 mg of the expected product melting at 
203.degree.-204.degree. C. with a Rf=0.45 (eluant: cyclohexane--ethyl 
acetate (1--1)). 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3626 cm.sup.-1 
C.dbd.O 1753 cm.sup.-1 
C.tbd.N 2232 cm.sup.-1 
Aromatics 1615-1580-1504 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 232 nm .epsilon. = 18900 
Max. 235 nm .epsilon. = 22500 
Infl. 273 nm 
______________________________________ 
EXAMPLE 82 
3-(3,4-dichlorophenyl 5,5-dimethyl 1-(3-hydroxypropyl) 4-imino 
2-imidazolidine thione 
Using the procedure of Example 51,--2.4 g of 3,4-dichlorophenyl isocyanate 
and 1.6 g of the appropriate aminonitrile were reacted to obtain, after 
chromatography on silica (eluant: methylene chloride--acetone (6-4)), 2.16 
g of expected product with a Rf=0.25 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
OH 3630 cm.sup.-1 + associated 
C.dbd.NH 3294-1676 cm.sup.-1 (F) 
Aromatics 1595-1569-1482 cm.sup.-1 
______________________________________ 
EXAMPLE 83 
3-(3,4-dichlorophenyl 5,5-dimethyl 1-(3-hydroxypropyl) 2-thioxo 
4-imidazolidinone 
Using the procedure of Example 52,--0.88 g of the product of Example 82 
and 35 ml of 6 N hydrochloric acid were reacted to obtain, after 
extraction with chloroform, 0.79 g of the expected product melting at 
202.degree.-203.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1753 cm.sup.-1 
C.tbd.N 2232 cm.sup.-1 
Aromatics 1615-1580-1504 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
Max. 232 nm .epsilon. = 18900 
Max. 235 nm .epsilon. = 22500 
Infl. 273 nm 
______________________________________ 
EXAMPLE 84 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
a) 4-amino 2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
The following were cooled to -180.degree. C. and mixed under an inert 
atmosphere: 16 mg of 2-trifluoromethyl 4-amino 5-bromo benzonitrile, 2 mg 
of palladium on activated charcoal, 200 .mu.l of ethyl acetate and 6.5 
.mu.l of triethylamine. Then the mixture was left under a tritium 
atmosphere and taken to 20.degree. C. and the pressure was then 1.68 bar. 
The mixture was stirred until absorption was complete (p=0.42 bar), 
followed by cooling to -180.degree. C. The excess tritium was recovered, 
taken to 20.degree. C. and then filtered. The filtrate was rinsed with 
ethyl acetate and concentrated at 40.degree. C. under reduced pressure to 
obtain 68 G.Bq of the expected product. 
b) 4-thioisocyanate 2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
The following were mixed under an argon atmosphere: 34 G.Bq of the above 
tritiated amino derivate, 150 .mu.l of demineralized water and 150 .mu.l 
of 10% thiophosgene solution in chloroform. The mixture was stirred at 
20.degree. C. for 45 minutes, decanted and reextraction was carried out 
with chloroform. The extracts were dried over magnesium sulfate, filtered 
and concentrated under reduced pressure. The thioisocyanate obtained was 
used as is for the following stage. 
c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
The following were mixed under an argon atmosphere with the thioisocyanate 
of stage b): 350 .mu.l of tetrahydrofuran with 1% triethylamine and 20 
.mu.l of propanonitrile prepared as indicated below. The mixture was 
stirred for 2 hours at 20.degree. C., followed by concentration at 
20.degree. C. under reduced pressure. The imine was used as is for the 
following stage. Preparation of the 2-(4-hydroxybutylamino) 
2-methylpropano-nitrile used in stage c) 
550 .mu.l of acetone cyanohydrin and 500 .mu.l of 4-amino 1-butanol were 
mixed together and the mixture was stirred for 16 hours at 20.degree. C. 
to obtain the desired product which was used as is for the following 
stage. 
EXAMPLE 85 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
200 .mu.l of 2 N hydrochloric acid were added to the imine of Example 84 
and the mixture was refluxed for 5 minutes, then returned to 20.degree. C. 
and diluted with 1 ml of water. Extaction was carried out with ethyl 
acetate and the extracts were washed with water and concentrated under 
reduced pressure. The crude product was purified by chromatography on 
silica (eluant: cyclohexane--ethyl acetate (6-4)) to obtain 2.8 G.Bq of 
the expected product. 
EXAMPLE 86 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
a) 4-amino 2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
377 mg of cuprous cyanide .sup.14 C (9 G.Bq) and 1.0732 g of 4-bromo 
3-(trifluoromethyl) benzenamine were mixed together under a nitrogen 
atmosphere in 8 ml of dimethylformamide and the mixture was refluxed for 4 
hours, then cooled to 0.degree. C. and diluted with 20 ml of acetone. The 
insoluble part was filtered off and the filtrate was concentrated at 
70.degree. C. under reduced pressure. The residue was taken up in 
methylene chloride, filtered and the filtrate was concentrated under 
reduced pressure. The benzonitrile (.sup.14 C) was purified by 
chromatography on silica (eluant: methylene chloride--cyclohexane (70-30)) 
to obtain 0.558 g (6.62 G.Bq) of the expected product. 
b) 4-thioisocyanate 2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
The following were mixed under a nitrogen atmosphere: 189 mg of 
benzonitrile (.sup.14 C) of stage a), 2.7 ml of water and 85 .mu.l of 
thiophosgene. The mixture was agitated vigorously stirred for 5 minutes, 
and after 30 .mu.l of thiophosgene were added, stirring was continued for 
one hour at 20.degree. C. Then extraction was carried out with chloroform 
and the extracts were washed with water, dried and concentrated under 
reduced pressure. The thioisocyanate obtained was used as is for the 
following stage. 
c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
2 ml of tetrahydrofuran, the propanonitrile prepared below in solution in 
1.5 ml of methylene chloride and 150 .mu.l of triethylamine were added 
under a nitrogen atmosphere to the thioisocyanate of stage b). The mixture 
was heated for 30 minutes under reflux and concentrated under reduced 
pressure to obtain the imine which was used as is for the following stage. 
Preparation of the 2-(4-hydroxybutylamino) 2-methylpropano-nitrile of stage 
c 
220 .mu.l of acetone cyanohydrin and 200 .mu.l of 4-amino 1-butanol were 
mixed together with stirring for 16 hours at 20.degree. C. and then was 
diluted with 2 ml of methylene chloride, dried, filtered and the filtrate 
was concentrated under reduced pressure to obtain the propanonitrile which 
was used as is for the following stage. 
EXAMPLE 87 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
6 ml of methanol and 1.6 ml of 2 N hydrochloric acid were added to the 
imine of Example 86 and the mixture was refluxed for 45 minutes, cooled to 
20.degree. C. and diluted with 10 ml of water. Extraction was carried out 
with methylene chloride and the extracts were washed with water and 
concentrated under reduced pressure. The crude product was purified by 
chromatography on silica (eluant: ether--acetonitrile--cyclohexane 
(50-15-35)) to obtain 328 mg of the expected product. 
EXAMPLE 88 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
a) 4-amino 2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
Using the procedure of stage a) of Example 84, 16 mg of 4-amino 5-bromo 
2-trifluoromethyl benzonitrile, 2 mg of palladium on activated charcoal, 
200 .mu.l of ethyl acetate and 6.5 .mu.l of triethylamine were reacted to 
obtain 68 G.Bq of the expected product. 
b) 4-isocyanate 2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
34 G.Bq of tritiated amino derivate of step a) and 100 .mu.l of 20% 
phosgene in toluene were mixed together under an argon atmosphere and the 
mixture was taken to 80.degree. C. for one hour. A further 100 .mu.l of 
phosgene were added and the mixture heated for one hour at 80.degree. C. 
This operation was repeated one more time, then concentration was carried 
out at 20.degree. C. under reduced pressure to obtain the isocyanate which 
was used as is for the following stage. 
c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
The following were added under an argon atmosphere to the isocyanate of 
stage b): 200 .mu.l of methylene chloride, 50 .mu.l of the propanonitrile 
chloromethylene solution prepared as below and 20 .mu.l of triethylamine 
and the mixture was stirred for 30 minutes. A further 50 .mu.l of the 
propanonitrile solution were added and stirring was continued for 30 
minutes followed by concentration at 20.degree. C. under reduced pressure. 
The imine was used as is for the following stage. Preparation of the 
2-(4-hydroxybutylamino) 2-methyl propano-nitrile, of stage c) 
220 .mu.l of acetone cyanohydrin and 200 .mu.l of 4-amino 1-butanol were 
mixed together and the mixture was stirred for 16 hours at 20.degree. C., 
then diluted with 3 ml of methylene chloride and dried over magnesium 
sulfate. The decanted solution was used as is for the following stage. 
EXAMPLE 89 
4-(4,4-dimethyl2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 
2-(trifluoromethyl) (5-.sup.3 H) benzonitrile 
200 .mu.l of methanol and 50 .mu.l of 2 N hydrochloric acid were added to 
the imine of Example 88 and the mixture was refluxed for 45 minutes, then 
returned to 20.degree. C. and diluted with 1 ml of water. Extraction was 
carried out with methylene chloride and the extracts were washed with 
water and concentrated at 20.degree. C. under reduced pressure. The crude 
product was purified by chromatography on silica (eluant: methylene 
chloride--ethyl acetate (7-3 then 5--5)) to obtain 16 G.Bq of the expected 
product. 
EXAMPLE 90 
4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
a) 4-amino 2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
Using the procedure of Example 86, stage a), 377 mg of cuprous cyanide 
.sup.14 C, 1.0732 g of 4-bromo 3-trifluoromethyl benzenamine and 8 ml of 
dimethylformamide were reacted to obtain 0.558 g (6.62 G.Bq) of the 
expected product. 
b) 4-isocyanato 2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
182.4 mg of benzonitrile (.sup.14 C) (0.97 mmole), 2 ml of dioxane and 1 ml 
of 20% phosgene in toluene were mixed together under a nitrogen atmosphere 
and the solution was heated at 60.degree. C. for 22 hours, then 
concentrated at 60.degree. C. under reduced pressure. The isocyanate was 
used as is for the following stage. 
c) 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
1.5 ml of methylene chloride (on siliporite NK 30), the propanonitrile of 
Example 88 in solution in 1.5 ml of methylene chloride, and 150 .mu.l of 
triethylamine were added under a nitrogen atmosphere to the isocyanate of 
stage b). The mixture was stirred for one hour at 20.degree. C. and 
concentrated under reduced pressure. The imine was used as is for the 
following stage. 
EXAMPLE 91 
4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl) 
2-(trifluoromethyl) benzo (.sup.14 C) nitrile 
5 ml of methanol and 1.2 ml of 1 N hydrochloric acid were added to the 
imine of Example 90 and the mixture was refluxed for 40 minutes, then 
returned to 20.degree. C. and diluted with 10 ml of water. Extraction was 
carried out with methylene chloride and the extracts were washed with 
water and concentrated under reduced pressure. The crude product was 
purified by chromatography on silica (eluant: 
ether--acetonitrile--cyclohexane (50-15-35)) to obtain 289 mg (1.26 G.Bq) 
of the expected product. 
EXAMPLE 92 
4-(2,5-dioxo 4,4-dimethyl 3-(4-triphenylmethoxy-butyl) 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
370 mg of the product of Example 58, 307 mg of trityl chloride in the 
presence of 10 mg of 4-dimethylamino-pyridine, 0.25 ml of triethylamine 
and 4 ml of dimethylformamide were stirred at ambient temperature for 16 
hours. The mixture was heated to 40.degree. C. for 4 hours, poured into 
water and extraction was carried out with ether. The extracts were washed 
with water and dried and the solvent was eliminated under reduced 
pressure. The residue was chromatographed on silica (eluant: 
cyclohexane--ethyl acetate 75-25) to obtain 467 mg of the expected product 
with a Rf=0.25. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1778, 1725 cm.sup.-1 (F) 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1615, 1597, 1505, 1490 cm.sup.-1 
______________________________________ 
EXAMPLE 93 
4-(2,5-dioxo 4,4-dimethyl 3-(4-phenylmethoxy-butyl) 1-imidazolidinyl) 
2-(trifluoromethyl) benzonitrile 
48 mg of sodium hydride were added in several lots to 370 mg of the product 
of Example 58 in solution in 4 ml of dimethylformamide and the mixture was 
stirred for 30 minutes. Then, 0.12 ml of benzyl bromide and 40 mg of 
tetrabutylammonium iodide were added and after 90 minutes of reaction, the 
same amount of each reagent was added. The mixture was stirred for one 
hour and the reaction medium was poured into an ice-cooled aqueous 
solution of monopotassium phosphate. Extraction was carried out with ether 
and the extracts were washed with water and dried. The solvent was 
eliminated under reduced pressure and the residue was chromatographed on 
silica (eluant: methylene chloride--acetone 99-1) to obtain 140 mg of the 
expected product melting at 75.degree.-76.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1779, 1725 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1615, 1580, 1505, 1497 cm.sup.-1 
______________________________________ 
EXAMPLE 94 
4-[4,4-dimethyl 2,5-dioxo 3-(4-methoxybutyl) 1-imidazolidinyl] 
2-(trifluoromethyl)-benzonitrile 
50 mg of sodium hydride were added in several lots to 370 mg of the product 
of Example 58 in solution in 3 ml of dimethylformamide and the mixture was 
stirred for 20 minutes. 0.06 ml of methyl iodide were added and the 
mixture was stirred for one hour. A further 50 mg of sodium hydride were 
added and then after 20 minutes, 0.06 ml of methyl iodide were added. The 
reaction medium was poured into water and extracted with ether. The 
extracts were washed with water, dried and the solvent was evaporated. The 
residue was chromatographed on silica (eluant: methylene chloride--acetone 
98-2) to obtain 135 mg of the expected product melting at 
80.degree.-81.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1779, 1725 cm.sup.-1 (F) 
C.tbd.N 2234 cm.sup.-1 
Aromatics 1616, 1576, 1505 cm.sup.-1 
OCH.sub.3 approx. 2830 cm.sup.-1 
______________________________________ 
EXAMPLE 95 
4-[3-(4-chlorobutyl) 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl] 
2-(trifluoromethyl) benzonitrile 
Using the procedure of Example 59, 600 mg of the product of Example 8--and 
660 mg of 1-chloro 4-iodobutane in solution in 1 ml of dimethylformamide 
cooled down to +5.degree. C. were reacted to obtain 604 mg of the expected 
product melting at 80.degree.-81.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1779, 1725 cm.sup.-1 (F) 
C.tbd.N 2238 cm.sup.-1 
Aromatics 1616, 1575, 1505 cm.sup.-1 
______________________________________ 
EXAMPLE 96 
4-[3-[4-[(methylsulphoneyl) oxyl] butyl] 4,4-dimethyl 2,5-dioxo 
1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile 
0.17 ml of methanesulfonyl chloride were added to 740 mg of the product of 
Example 58 in solution in 7.4 ml of pyridine and 24 mg of 
4-dimethylamino-pyridine and the mixture was stirred for one hour. The 
mixture was poured into ice-cooled water and extraction was carried out 
with methylene chloride. The extracts were washed with water and the 
residual pyridine was eliminated by distillation. The residue was 
chromatographed on silica (eluant: methylene chloride--ethyl acetate 8-2) 
to obtain 771 mg of the expected product. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
CO 1779, 1725 cm.sup.-1 
CN 2235 cm.sup.-1 
Aromatics 1615, 1575, 1505 cm.sup.-1 
##STR30## 1361, 1175 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
max. 261 nm .epsilon. = 14900 
infl. 279-297 nm 
______________________________________ 
EXAMPLE 97 
4-(3-acetyl 4,4-dimethyl 2,5-dioxo 1-imidazo-lidinyl) 2-(trifluoromethyl) 
benzonitrile 
Using the procedure of Example 59, 420 mg of the product of Example 8--and 
two lots of 0.1 ml of acetyl chloride were reacted to obtain after 
chromatography on silica (eluant: methylene chloride--ethyl acetate 98-2), 
334 mg of the expected product melting at 129.degree.-130.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1800, 1740, 1717 cm.sup.-1 
C.tbd.N 2240 cm.sup.-1 
Aromatics 1616, 1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
max 250 nm .epsilon. = 12000 
infl. 274-284 nm 
______________________________________ 
EXAMPLE 98 
4-(3-benzoyl 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2-(trifluoromethyl) 
benzonitrile 
Using the procedure of Example 59, 300 mg of the product of Example 8--and 
two lots of 0.12 ml of benzoyl chloride in solution in 0.5 ml of 
dimethylformamide were reacted to obtain after chromatography on silica 
(eluant: cyclohexane--ethyl acetate 8-2), 285 mg of the expected product 
melting at 179.degree.-180.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.dbd.O 1800, 1780, 1746, 1699 cm.sup.-1 
C.tbd.N 2235 cm.sup.-1 
Aromatics 1617, 1600, 1580, 1504 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
max. 250 nm .epsilon. = 28500 
infl. 275 nm .epsilon. = 6500 
infl. 263 nm .epsilon. = 3850 
______________________________________ 
EXAMPLE 99 
4-[3-[dimethyl (1,1-dimethylethyl) silyl] 4,4-dimethyl 2,5-dioxo 
1-imidazolidinyl] 2-(trifluoromethyl) benzonitrle 
Using the procedure of Example 59, 450 mg of the product of Example 8--and 
300 mg of dimethyl t-butylsilyl chloride in 2 ml of dimethylformamide were 
reacted to obtain after chromatography on silica (eluant: methylene 
chloride--acetone 99-1), 527 mg of the expected product melting at 
147.degree.-148.degree. C. 
______________________________________ 
IR Spectrum (CHCl.sub.3); 
______________________________________ 
C.tbd.N 2236 cm.sup.-1 
Aromatics 1615, 1579, 1505 cm.sup.-1 
______________________________________ 
______________________________________ 
UV Spectrum (EtOH) 
______________________________________ 
max. 258 nm .epsilon. = 17000 
infl. 275-285 nm 
______________________________________ 
In addition to the products described above, the following products are 
products which can be obtained within the scope of the present invention, 
namely the products of the formula: 
##STR31## 
in which Y.sub.A is oxygen or sulfur and R.sub.3A has the following 
values: 
##STR32## 
alk, alk.sub.1 and alk.sub.2 are alkyl of 1 to 4 carbon atoms and n is an 
integer between 1 and 4. 
EXAMPLE 100 
Tablets were prepared with a composition of 100 mg of 
4-(5-oxo-2-thioxo-3,4,4-trimethyl 
1-imidazolinyl)-2-trifluoromethyl-benzonitrile and sufficient excipient of 
lactose, starch, talc and magnesium stearate for a final tablet weight of 
300 mg. 
PHARMACOLOGICAL DATA 
Study of the affinity of the products of the invention for the androgenic 
receptor. 
1) Androgenic receptor 
Male rats of the Sprague Dawley EOPS strain weighing 180 to 200 g, 
castrated 24 hours previously, were killed and the prostrate was removed, 
weighed and homogenized at 0.degree. C. with a potter glass in a buffered 
solution (Tris 10 mM, saccharose 0.25 M, PMSF (phenyl methane sulfonyl 
fluoride) 0.1 mM, sodium molybdate 20 mM, HCl pH 7.4 into which was added 
extemporaneously 2 M of DTT (DL dithiothreitol) at a rate of 1 g of tissue 
per 8 ml of buffer solution. The homogenate was then ultracentrifuged at 
0.degree. C. for 45 minutes at 105,000 g and the aliquots of supernatant 
(=cytosol) were incubated for 30 minutes and 24 hours with a concentration 
(T) of tritiated testosterone and in the presence of increasing 
concentrations (0 to 2500.10.sup.-9 M) of cold testosterone or the test 
products. The concentration of bound tritiated Testostrone (B) was then 
measured for each incubate by adsorption method of carbon-dextran. The 
relative affinity of bonding (RBA) was calculated. 
The following two curves were graphed: the percentage of the bound 
tritiated hormone B/T as a logarithm function of the concentration of the 
cold hormone and B/T as a logarithm function of the concentration of the 
tested cold product. The line of the equation 
##EQU1## 
was determined. B/T max=% of the bound tritiated hormone for an incubation 
of this tritiated hormone at the concentration (T). B/T min=% of the bound 
tritiated hormone for an incubation of this tritiated hormone at the 
concentration (T) in the presence of a large excess of cold hormone 
(2,500.times.10.sup.-9 M). 
The intersections of the straight line I.sub.50 and the curves permit an 
evaluation of the concentrations of the cold reference hormones (CH) and 
the cold test product (CX) which inhibit by 50% the bonding of the 
tritiated hormone on the receptor. The RBA 9of the test product was 
determined by the equation 
EQU RBA=(CH)/(CX) 
and the following results expressed in ARL were obtained with 
testosterone=100. 
______________________________________ 
Incubation 
Incubation 
30 minutes 
24 hours 
______________________________________ 
Product Example 1 
27.5 3 
Product Example 2 
22 6 
Product Example 4 
21 5 
Product Example 11 
28 8 
Product Example 12 
128 92 
Product Example 13 
31 39 
Product Example 14 
27 7 
Product Example 15 
69 24 
______________________________________ 
2) Study of the affinity of the products of the invention for the androgen 
receptor. 
Male rats of the Sprague Dawley EOPS strain weighing 180 to 200 g, 
castrated 24 hours previously, were killed and the prostate was removed, 
weighed and homogenized at 0.degree. C. with a potter glass in a buffered 
solution (Tris 10 mM, saccharose 0.25 M, PMSF (phenyl methane sulfonyl 
fluoride) 0.1 mM, sodium molybdate 20 mM, HCl pH 7.4 into which was added 
extemporaneously 2 mM of DTT (DL dithiothreitol) at a rate of 1 g of 
tissue per 8 ml of buffer solution. The homogenate was then 
ultracentrifuged at 0.degree. C. for 30 minutes at 209,000 g and the 
aliquots of supernatant (=cytosol) were incubated for 30 minutes and 24 
hours with a concentration (T) of tritiated testosterone and in the 
presence of increasing concentrations (0 to 2500.10.sup.-9 M) of cold 
testosterone or the test products. The concentration of bound tritiated 
Testostrone (B) was then measured for each incubate by adsorption method 
of carbon-dextran. The relative affinity of bonding (RBA) was calculated. 
The following two curves were graphed: the percentage of the bound 
tritiated hormone B/T as a logarithm function of the concentration of the 
cold hormone and B/T as a logarithm function of the concentration of the 
tested cold product. The line of the equation 
##EQU2## 
was determined. B/T max=% of the bound tritiated hormone for an incubation 
of this tritiated hormone at the concentration (T). B/T min=% of the bound 
tritiated hormone for an incubation of this tritiated hormone at the 
concentration (T) in the presence of a large excess of cold hormone 
(2,500.times.10.sup.-9 M). 
The intersections of the straight line I.sub.50 and the curves permit an 
evaluation of the concentrations of the cold reference hormones (CH) and 
the cold test product (CX) which inhibit by 50% the bonding of the 
tritiated hormone on the receptor. The RBA of the test product was 
determined by the equation 
EQU RBA=100(CH)/(CX) 
and the following results expressed in RBA were obtained with 
testosterone=100. 
______________________________________ 
Incubation 
24 hours 
______________________________________ 
Example 59 31 
Example 71 163 
Example 77 300 
Example 79 81 
Example 81 28 
______________________________________ 
3) Determination of the androgen or anti-androgen activity by the dosage of 
ornithine carboxylase. 
Six week old male Swiss mice castrated 24 hours receive oral does of the 
test products as a 0.5% suspension in methyl cellulose simultaneously with 
a sub-cutaneous injection of 3 mg/kg of testosterone propionate in 
solution in sesame oil containing 5% of benzyl alcohol to determine the 
anti-androgen activity. Active agonists were determined in the absence of 
testosterone propionate. The test compounds as well as testosterone were 
administered in a volume of 10 ml/kg. 16 hours after the treatments, the 
animals were killed, the kidneys were removed and then homogenized at 
0.degree. C. with a teflon-glass grinding apparatus in 10 volumes of 
buffer Tris-HCl 50 mM at a pH 7.4 containing 250 mM of pyridoxal 
phosphate, 0.1 mM EDTA and 5 mM of dithiothreitol. The homogenate was 
centrifuged at 105,000 g for 45 minutes. 
At 37.degree. C., renal ornithine decarboxylase transforms an isotropic 
mixture of cold ornithine and tritiated ornithine in cold putrescine and 
tritiated putrescine. The putrescine was then collected on selective 
ion-exchange papers. After drying, excess non-transformed cold and 
tritiated ornithine were eliminated by washing 3 times with 0.1 M ammonium 
hydroxide. The papers were dried and the radioactivity was determined 
after addition of an Aqualite sample. The results expressed in fmoles 
(10.sup.-15 M) of tritiated putrescine formed per hour mg of protein are 
reported in the following Table 
______________________________________ 
PRODUCT 
OF EXAMPLE ANTAGONISM IN MG/KG PERCENT 
______________________________________ 
11 3 83 
12 0.1 12 
0.3 36 
1 68 
3 94 
10 99 
12 (Agonism) 10 0 
14 Antagonism 3 87 
15 0.3 4 
1 82 
______________________________________ 
4) Determination of the androgen or anti-androgen activity by the dosage of 
ornithine carboxylase. 
Swiss six week old male mice castrated24 hours received oralor percutaneous 
doses of the test products as a 0.5% suspension in methyl cellulose or in 
ethanol simultaneously with a sub-cutaneous injection of 3 mg/kg of 
testosterone propionate in solution in corn oil to determine the 
anti-androgen activity. Active agonists were determined in the absence of 
testosterone propionate. The test compounds as well as testosterone were 
administered in a volume of 10 ml/kg. 20 hours after the treatments, the 
animals were killed, the kidneys were removed and then homogenized at 
0.degree. C. with a teflon-glass grinding apparatus in 10 volumes of 
buffer Tris-HCl 50 mM at a pH 7.4 containing 250 mM of pyridoxal 
phosphate, 0.1 mM EDTA and 5 mM of dithiothreitol. The homogenate was 
centrifuged at 209,000 g for 45 minutes. 
Principle of dosage 
At 37.degree. C., renal ornithine decarboxylase transforms an isotopic 
mixture of cold ornithine and tritiated ornithine in cold putrescine and 
tritiated putrescine. The putrescine was then collected on selective 
ion-exchange papers. After drying, excess non-transformed cold and 
tritiated ornithine were eliminated by washing 3 times with 0.1 M ammonium 
hydroxide. The papers were dried and the radioactivity was determined 
after addition of an Aqualite sample. The results expressed in fmoles 
(10.sup.-15 M) of tritiated putrescine formed per hour/mg of protein are 
reported in the following Table. 
The same test were repeated with the following changes: 
Test A: the products were administered percutaneously at 1.5 mg/kg at a 
volume of 10 .mu.l. 
Test B: the products were administered orally at 1 mg/kg. 
Test C: the products are administered orally at 3 mg/kg. The results are in 
the following Table. 
The results are expressed in % of inhibition of the ODL the samples 
receiving only the testosterone propionate: 
______________________________________ 
Products of 
ODL 
example Test A Test B Test C 
______________________________________ 
58 40 36 
71 32 67 
75 41 
78 78 
80 62 
81 35 
83 58 
______________________________________ 
CONCLUSION 
The tests show that the tested compounds of the invention possess a strong 
anti-androgen activity and do not have agonist activity. 
Various modifications of the compounds and method of the invention may be 
made without departing from the spirit or scope thereof and it is to be 
understood that the invention is intended to be limited only as defined in 
the appended claims.