U.S. patent number RE35,956 [Application Number 08/807,760] was granted by the patent office on 1998-11-10 for phenylimidazolidines having antiandrogenic activity.
This patent grant is currently assigned to Roussel Uclaf. Invention is credited to Martine Gaillard-Kelly, Francois Goubet, Daniel Phiibert, Jean-Georges Teutsch.
United States Patent |
RE35,956 |
Gaillard-Kelly , et
al. |
November 10, 1998 |
Phenylimidazolidines having antiandrogenic activity
Abstract
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.
Inventors: |
Gaillard-Kelly; Martine (Paris,
FR), Goubet; Francois (Paris, FR),
Phiibert; Daniel (Laverenne Saint Hiliare, FR),
Teutsch; Jean-Georges (Pantin, FR) |
Assignee: |
Roussel Uclaf
(FR)
|
Family
ID: |
27446787 |
Appl.
No.: |
08/807,760 |
Filed: |
February 27, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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819910 |
Jan 9, 1992 |
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Reissue of: |
064257 |
May 18, 1993 |
05411981 |
May 2, 1995 |
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Foreign Application Priority Data
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Jan 9, 1991 [FR] |
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91 00185 |
Jul 8, 1992 [FR] |
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92 08431 |
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Current U.S.
Class: |
514/386; 514/342;
514/391; 548/311.1; 548/317.1; 548/318.5; 548/320.1; 548/320.5 |
Current CPC
Class: |
C07D
233/84 (20130101); C07D 233/72 (20130101); C07D
233/74 (20130101); C07D 233/76 (20130101); C07D
233/88 (20130101); C07D 233/86 (20130101) |
Current International
Class: |
C07D
233/72 (20060101); C07D 233/88 (20060101); C07D
233/74 (20060101); C07D 233/84 (20060101); C07D
233/76 (20060101); C07D 233/00 (20060101); C07D
233/86 (20060101); A61K 031/415 (); C07D
233/72 () |
Field of
Search: |
;514/386,391,342
;548/311.1,317.1,318.5,320.1,320.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0217893 |
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Jun 1958 |
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AU |
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0017976 |
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Oct 1980 |
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EP |
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2102605 |
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Jul 1971 |
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DE |
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48-87030 |
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Nov 1973 |
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JP |
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Other References
Raynaud et al, J. Steroid Biochem., vol. 11, pp. 93 to 99 (1979).
.
Rao et al, J. Steroid Biochem., vol. 31, pp. 731 to 737
(1988)..
|
Primary Examiner: Higel; Floyd D.
Attorney, Agent or Firm: Bierman, Muserlian and Lucas
Parent Case Text
PRIOR APPLICATION
This application is a continuation-in-part of U.S. Patent
application Ser. No. 819,910, filed Jan. 9, 1992, now abandoned.
Claims
We claim:
1. A compound selected from the group consisting of a compound of
the formula ##STR33## 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 ##STR34## X is --O-- or --S--, R.sub.3 is
selected from the group consisting of a) hydrogen, b) alkyl,
alkenyl and alkynyl of up to 12 carbon atoms, .[.c).]. phenyl and
phenylalkyl unsubstituted or substituted with at least one member
of the group consisting of --OH, halogen, --OCH.sub.3, --CN and
haloalkyl, .[.d).]. acyl of an organic carboxylic acid of up to 7
carbon atoms, .[.e).]. free or salified carboxy, carboxy esterified
with alkyl and amidified carboxy, .[.f).]. amino and mono and
dialkylamino of 1 to 4 carbon atoms and .[.g).]. --S--phenyl
unsubstituted or substituted with at least one member of the group
consisting of--CF.sub.3 and alkyl, alkenyl, alkoxy, alkenyloxy,
alkynyl and alkynyloxy of up to 12 carbon atoms with the sulfur
unoxidized or oxidized to sulfone or sulfoxide, the alkyl, alkenyl
and alkynyl being uninterrupted or interrupted with oxygen, sulfur
or nitrogen and Y is --O--, --S-- or --NH-- with the provisos that
when X is oxygen, R.sub.3 is hydrogen and Y is --O-- or --NH--,
then R.sub.1 is NO.sub.2 or --CN and when X is sulfur and Y is
--O-- then at least one of the following conditions is satisfied,
R.sub.1 is --CN and R.sub.2 is --CF.sub.3 and their non-toxic,
pharmaceutically acceptable acid addition salts.
2. A compound of claim 1 wherein Y is oxygen.
3. A compound of claim 1 wherein --A-B-- is ##STR35## and X is
sulfur.
4. A compound of claim 3 wherein R.sub.3 is hydrogen or alkyl of 1
to 4 carbon atoms optionally substituted with a --OH or
methoxy.
5. A compound of claim 1 wherein R.sub.1 is --CN or halogen.
6. A compound of claim 1 wherein R.sub.1 is chlorine.
7. A compound of claim 1 wherein --A-B-- is ##STR36## and R.sub.3
is alkyl or alkenyl of up to 6 carbon atoms unsubstituted or
substituted or uninterrupted or interrupted by oxygen or unoxidized
or oxidized sulfur or unsubstituted or substituted aralkyl or
acyl.[.or trialkylsilyl.]..
8. A compound of claim 7 wherein R.sub.3 is alkyl of 1 to 6 carbon
atoms unsubstituted or substituted by at least one member of the
group consisting of halogen, --OH, --O acyl, carboxy, carboxy
esterified with alkyl, a heterocycle, O-alkyl and unoxidized or
oxidized S-aryl with the aryl unsubstituted or substituted with at
least one member of the group consisting of halogen and alkoxy.
9. A compound of claim 8 wherein R.sub.3 is alkyl of 2 to 4 carbon
atoms substituted by a member selected from the group consisting of
chlorine, ethoxycarbonyl.[., tertbitoxy.]. .Iadd.and tertbutoxy
.Iaddend.carbonyl, .[.cyclopentyloxycarbonyl, unoxidized or
oxidized 4-fluorophenylthio, morpholino, phenylmethoxy,
triphenylmethoxy and methylsulfonyloxy.]..
10. A compound of claim 7 wherein R.sub.3 is acetyl or benzoyl
.[.or (1,1-dimethylethyl)dimethylsilyl.]..
11. A compound of claim 1 selected from the group consisting of
4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-(trifluoromethyl)
benzonitrile, 4-(4,4-dimethyl-5-oxo-2-thioxo
1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile,
4-4,4-dimethyl-3-(2-hydroxyethyl)-5-oxo-2-thioxo-1-imidazolidinyl
2-(trifluoromethyl)-benzonitrile,
3-(3,4-dichlorophenyl)-2-thioxo-1,5,5-trimethyl-4-imidazolidinone,
1-(4-nitro-3-(trifluoromethyl)
phenyl-3,4,4-trimethyl-2,5-imidazolidinedione,
4-4,5-dihydro4,4-dimethyl-5-oxo-2-(phenylmethyl)
thio-1H-imidazol-1-yl-2-(trifluoromethyl) benzonitrile, 4
4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl
2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl
3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl)
2-(trifluoromethyl) benzonitrile, 3-(4-cyano 3-trifluoromethyl)
phenyl) 5,5-dimethyl 2,4-dioxo 1-imidazolidinebutanoic acid and
4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1-imidazolidinyl)
2-(trifluoromethyl benzonitrile.
12. A compound of claim 1 wherein Y is --O-- except the compounds
wherein the --A-B-- group is ##STR37## in which X is oxygen and
R.sub.3 is hydrogen, R.sub.2 is halogen or trifluoromethyl and
R.sub.1 is nitro or halogen.
13. A compound of the formula ##STR38## wherein R.sub.1, R.sub.2
and Y have the definitions of claim 1, --A--.sub.i --B.sub.1 is
##STR39## Y is oxygen or sulfur and R'.sub.3 is R.sub.3 with any
reactive functions protected.
14. An anti-androgenic composition comprising an
anti-androgenically effective amount of at least one compound of
claim 1 and an inert pharmaceutical carrier.
15. A composition of claim 14 wherein the active compound is
selected from the group consisting of
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)-benzoitrile,
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-imidazolidinedio
ne,
4-4,5-dihydro4,4-dimethyl-5-oxo-2-(phenylmethyl)thio-1H-imidazol
1-yl)2-(trifluoromethyl) benzonitrile-4,4,4-dimethyl
3-(2-hydroxyethyl) 5-oxo 2-thioxo 1-imidazolidinyl
2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl
3-(4-hydroxybutyl) 5-oxo 2-thioxo 1-imidazolidinyl)
2-(trifluoromethyl) benzonitrile-3-(4-cyano 3-trifluoromethyl)
phenyl) 5,5-dimethyl 2,4-dioxo 1-dioxo 3-(4-hydroxybutyl) 1-
imidazolidinyl) 2-(trifluoromethyl) benzonitrile.
16. A method of inducing anti-androgenic activity in warm-blooded
animals comprising administering to warm-blooded animals an
anti-androgenically effective amount of at least one compound of
claim 1.
17. A method of claim 16 wherein Y is oxygen.
18. A method of claim 16 wherein R.sub.1 is --CN or halogen.
19. A method of claim 16 wherein R.sub.1 is chlorine.
20. A method of claim 14 wherein the active compound is selected
from the group consisting of
4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)
2-(trifluoromethyl)-benzonitrile, 4-(4,4-dimethyl-5-oxo-2-thioxo
1-imidazolidinyl)-2-(trifluoromethyl)-benzoitrile,
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-imidazolidinedio
ne,
4-4,5-dihydro4,4-dimethyl-5-oxo-2-(phenylmethyl)-thio-1H-imidazol-1-yl-2-(
trifluoromethyl) benzonitrile-4,4,4-dimethyl 3-(2-hydroxyethyl)
5-oxo 2-thioxo 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile,
-4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo
1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile-3-(4-cyano
3-trifluoromethyl) phenyl) 5,5-dimethyl 2,4-dioxo
1-imidazolidinebutanoic and acid and 4-(4,4-dimethyl 2,5-dioxo
3-(4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl)
benzonitrile.
Description
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, cyclopentyloxycarbonyl, 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-trifl
uoromethyl) 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 >C.dbd.O group or groups into the
>C.dbd.S or if appropriate of >C.dbd.S into >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-.DELTA..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-nitrophenyl)-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-trifluoromethylphenyl)-2,4-imidazolidined
ione
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-trifluoromethylphenyl)-2,4-imidazolid
inedione
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 or 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.degree. to 5.degree. C. to 33.6 ml of a toluene solution
of 1.93 M/l 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.3 O.sub.4 : molecular weight = 296.25 % C % H % F % N
______________________________________ Calculated: 52.71 3.74 19.24
18.91 Found: 52.7 2.6 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.4 : 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 (CHCl.sub.3):
______________________________________ 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.12 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 (CHCl.sub.3):
______________________________________ 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 = 313.50 % 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-bromononane 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-bromononane 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, 1506 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 9.2 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 or 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-trifuoromethyl-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
______________________________________ IR Spectrum (CHCl.sub.3):
______________________________________ 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-dichlorophenyl, 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
______________________________________
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.dbd.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.dbd.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 or 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 or 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.-
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/l). 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/l). 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.dbd.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 or 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 isothiocyanate 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) benzonitrile
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.dbd.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.dbd.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-(4hydroxybutylamino) 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-dimethylaminopyridine, 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.dbd.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.dbd.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 C N
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
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
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 subcutaneous 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.
* * * * *