Note: Descriptions are shown in the official language in which they were submitted.
1043339 MN-26~
DESCRIPI`ION OF l'~E PREFER~ED EM~ODIMENrrS:
The novel 4-oxo-2-imidazolidinylidene ureas of this
invention may be structuraliy represented by the formula:
R4 lR2
3 ~ ~ N-l-NH-Ar
o ~ / (I)
Rl
wherein Rl is a member selected from the group consisting
of hydrogen and loweralkyl, preferably hydrogen; R2 is a
member selected from the group consisting of hydrogen
and loweralkyl, preferably methyl, R3 is a member selected
from the group consisting of hydrogen and aryl, preferably
hydrogen; R4 is a member selected from the group consisting
of hydrogen, aryl, and arylalkyl, preferably hydrogen; and
Ar is aryl; provided that said R3 and said R4 are other
than 2,6-disubstituted aryl. This restriction on the
identity of R3 and R4 is imposed because the s~ic hindrance
occurring if R3 and R4 are not so restricted makes prepara-
tion of such compounds difficult.
As used herein, "loweralkyl" and "loweralkoxy" may be
straight or branch chalned and have from 1 to about 8 carbon
atoms, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, pentyl, octyl, and the like alkyls, and respectively,
the corresponding alkoxys such as methoxy, ethoxy, etc.
The term "halo" is generic to fluoro, bromo, chloro and iodo.
- 2 - ~
I~IN-2~9
1043339
The term "aryl" includes phenyl, nitrophenyl, tri-
fluoromethylphenyl, diloweralkyaminophenyl, and phenyl
substituted with one tc three members selected from the
group consisting of halo, loweralkyl, and loweralkoxy.
The term "arylalkyl" means benzyl, phenethyl, phenpropyl,
and the like arylalkyls, but the preferred arylalkyl is
benzyl.
The compounds of formula (I) wherein either Rl or R2
(or both) are hydrogen may exist in several tautomeric
forms besides that represented by formula (I). These
forms are represented by the following:
H-C-NH-Ar 3 ~ \~ NH-C-NH-Ar
(Ia) Rl (Ib)
wherein Rl, R2, R3, R4, and Ar are as previously defined.
The 4-oxo-2-imidazolidinylidene ureas of formula (I)
are readily obtalned by the reaction of an appropriate
2-imino-imidazolidin-4-one (II) with an appropriate aryl
isocyanate (III). A slight stoichiometric excess of the
former reactant i8 preferred to ensure complete reaction
with the aryl isocyanate. The reaction is preferably
conducted in an anhydrous, polar, inert, aprotic, or-
ganic solvent such as,for example, a polyethereal solvent,e.g. dioxane, tetrahydrofuran (THF), 1,2-dimethoxy-ethane,
the dimethyl ether of diethylene glycol, and the like;
-- 3 --
1~43339 MN-269
N,N-dimethylformamide (DMF), dimethyl sul~`oxide (DMSO)
hexamethylphosphoric acid triamide; and other similar organic
solvents. Any excess 2-imino-1-R-imidazolidin-4-one reactant
(II) is filtered off after the reaction is completed and
the desired product is generally recovered by the addition
of cold water to the reaction mixture. The crude precipitated
product may then be purified by standard recrystallization
techniques from suitable organic solvents. In caseswhere
the purifi~d product is obtained in large crys~alline form,
it may be pharmaceutically advantageous to reduce the size
of the crystals by standard techniques known in the art,
i.e., milling, micronization, reprecipitation, etc. These
techniques are known to result in enhanced absorption and
bioavailability of a given medicament.
R3 ~
R N
Rl
(II) (III) (I)
The subject compounds of formula (I) have been found
to possess useful anti-secretory activity by the following
acute gastric fistula rat test. The anti-secretory activity
of the compound to be tested is studied in femab Sprague-
Dawley rats after intraduodenal (i.d.) injection of the
compound at doses generally ranging from 2.5-40 mg./kg.
body weight. The rats are fasted 24 hours before testing
and are given water ad libidum while being kept in individual
cages. One the day of-testing, the rats are weighed an~ Qr~
1043339 MN-269
selected so that the rats in each test have weights
within a range of +20 g.
Surgery is carried out under Jight ether anesthesia.
As soon as the rat is anesthetized its teeth are removed,
using a small pinch pliers. A mid-line incision is made
on the abdomen about 1 2 cm in length and the stomach and
duodenum are exposed. If at this point, the stomach
is filled with food or fecal material, the rat is dis-
carded. Using 4-0 MERSILENE* suture, a purse string ætitch
is placed on the fundic portion of the stomach taking care
not to pierce any blood vessels in the area. A small nick is
made into the stomach in the center of the purse string, and
a cannula, consisting of a small vinyl tube with a flange
on one end, is put into the stomach and the purse string
stitch is closed tightly around the flange. Immediately
following this, the test compound is administered I.D; in a
volume of 0.5 ml per 100 gm rat. Three rats are generally
used for each drug dose tested. Control rats receive the
test vehicle, usually 0.5% aqueous methyl cellulose.
After administration of the test compound, the abdominal
wall and skin are closed simultaneously with 3 to 4 18 mm
wound clips and a collecting tube is placed on the cannula.
Each rat is then placed in a box in which a longitudinal
slit has been made to allow the car.nula to hang freely
* Trademark of Johnson & Johnson or Su~sidiary Co.
- 5 -
1~43339 MN-269
and to allow the rat to move about unencwnbered. After
the rat is allowed to stabilize for 30 minutes, the collec-
tion tube on the carnula is discarded and replaced with a
clean tube to receive the gastric juice. Collections are
made at one hour. At the end of the study, the cannula
is removed and the rat is sacrificed.
The sample of gastric contents collected is drained into a
centrifuge tube and centrifuged to pack down the sediment.
Volumes are read and a 1 ml aliquot of the supernatant is
put into a beaker containing 10 ml distilled H20 andiS titrated
to pH7 using O.OlN NaOH. Results are determined for Volume,
Titratable Acid, and Total Acid Output where Volume = total
ml. of gastric juice minus sediment; Titratable Acid
(milliequivalent~/l)= amount of O.OlN NaOH needed to titrate
the acid to pH7; and Total Acid Output= Titratable Acid x
Volume. Results are reported in % Inhibition vs Controls.
The vast majority of the compounds of the invention
exhlbit useful anti-secretory activity as measured by the
above test, particularly those compounds of formula (I)
wherein Ar i8 other than trisubstituted phenyl.
In addition, the subject compounds of formula (I) also
have been found to possess useful CNS depressant properties
as demonstrated in one or more of the following te6ts indicative
of such activities on laboratory animals.
MN-269
~1)433~9
Test A: An anti-anxiety assay as reported by I.
Geiler in Psychosomatic Medicine, eds. J. H. Nadine and
J. H. Moyer (Lea and Febiger, Phila.) p. 267 ~1962) and
modified by D. I,. Margules and L. Stein in Psychopharmacologia
(Berl.) 13, 74-80 (1968). The anti-anxiety activity of the
compound to be tested is studied in rats daily for 5 days
after intraperitoneal (i.p.) injection of the compound at
doses generally ranging from 5-25 mg/kg body weight and
the effect of the compound is observed on the animal's
bar pressing rate while working for food reinforcement.
Activity is also observed after oral administration of
dGses generally ranging from 5-25 mg./kg. body weight by
the ldentical procedure. The method consists of deter-
mining the effect of a test compound on non-punished and
punished responses. Hungry rats are trained to press a
bar for food reinforcement; a dipper full of milk is
delivered to the rat on the average of once every two
minutes (variable interval schedule - V.I. II). Fol-
lowing 12 minutes on this schedule, a tone is presented
for three minutes which signals the rewarding and simul-
taneous punishment of each bar press (a dipper full of
milk is presented and accompanied by a shock, delivered
through the grid floor, with each bar press). The shock
delivered is 0.2 milli-seconds in duration and ranges in
2~ intensity from 0.5 to 3.5 milli-amperes. Each rat is
presented with 4 to 6 alternating pairs of unpunished
periods when milk alone is given and punished periods
when milk and shock are administered. Control responses
are o~tained for each rat after saline intraperitoneal in-
jection daily for five-days. Each rat is evaluated at the
same time of day and in the same test chamber. Responses
10433;~9
are recorded and reinforcements (milk) and punishment
(shock) delivered by means of suitable automated equip-
ment. The activity of the compound to be tested is evaluated
by comparing the number of bar presses after placebo adminis-
tration with the number after administration of the compound
in each rat.
Test B: A muscle-relaxant assay as judged by the
effect of the compound to be tested on strychnine-induced
seizures as described by M.J. Orloff et al., Proc. Soc.
Exp. Biol. and Med. 70, 254 (1949) as modified by G. Chen
and B. Bohner, J. Pharmacol. and Expt. Therap. 117,
142 (1956). The anti-strychnine activity is observed
in mice at oral doses of about 25-500 mg./kg. body weight
by determining the effect of the compound on the seizure
threshold induced by strychnine.
Test C: A mouse behavioral assay as described by
S. Irwin, Gordon Research Conference on Medicinal Chemistry,
1959, p. 133. In this assay, such symptoms as ataxia,
decrease in motor activity and loss of righting reflex
are observed after intraperitoneal (i.p.) administration
in mice of the compound to be treated at doses ranging
from 10-300 mg./kg. body weight.
In view of the foregoing, an effective CNS depressant
amount of a compound of formula (I) intimately admixed with
a pharmaceutically acceptable carrier may be systemically
administered to warm-blooded animals, including humans,
to elicit a CNS depressant response. When administering
the hereinabove described dosage unit forms for such
purpose, amounts of active ingredient ranging about 15-500
mg, and preferably anout 15-250 mg, per dosage unit may be
utilized.
1~43339 MN-269
Among the preferred compounds of the invention are
those wherein Rl = R3 = R4 = hydrogen, ~ is methyl, and
Ar is X
wherein X is a member selected from the group consisting
of hydrogen, halo, methyl, ethyl, methoxy, ethoxy, and
trifluoromethyl. The most preferred compounds are those
wherein Rl = R3 = R4 = hydrogen, ~ is methyl, and Ar is
X
\J
wherein X is a member selected from the group consisting
of hydrogen, methyl, methoxy, chloro, bromo, and trifluoro-
methyl. The~e preferred compounds are especially useful
for their anti-anxiety activity.
Accordingly, thls invention provides a process of
alleviating anxiety which comprises systemically administering
to an anxious individual, for example, one whose anxiety in-
hibits his ability to cope with the various requirements of
his daily life, or one whose anxiety would have an adverse
effect on his physical well-being, an aforementioned compound
as the active ingredient in a concentration adequate to elicit
an effective anti-anxiety response. Preferably, dosage unit
forms containing from about 15 to about 500 mg of such active
ingredient are employed for anti-anxiety purposes. A suitable
_ g _
10433~9
MN-269
human regimen contemplated for the most preferred com-
pounds disclosed above is 15 to ~00 mg orally or parenterally
administered three or four times a day.
For purposes of relaxing skeletal muscle, the pre-
ferred compounds of formula (I) ar~ those wherein Rl =
R3 = R4 = hydrogen, R2 is methyl and Ar is a member
selected from the group consistlng of
E D
~ ~ C and
B , , F
wherein A is a member selected from the group consisting
of halo and loweralkyl; B is a member selected from the
group consisting of halo and loweralkyl; C is a member
selected from the group consisting of halo, loweralkyl,
loweralkoxy, trifluoromethyl and dimethylamino; D is
halo; E i8 loweralkyl; and F is loweralkyl.
Accordingly, this invention provides a process of
alleviating muscular pain which comprises systemically ad-
ministering to a sub~ect with such pain, such as, for ex-
ample, which may result from muscular spasm or chronlc
lower back pain, an aforementioned compound as the active
ingredient in a concentration adequate to elicit an ef-
fective skeletal muscle relaxant response. Preferably,dosage unit forms containing from abo~t 15 to about 500 mg
- -- 10 --
iO43339
MN-2~9
of such active Ingredient are employed for muscular
relaxation purposes. A suitable human regimen contem-
plated for the preferred compounds disclosed aho~e is
15 to 500 mg ôrally or parenterally administered three
or four times a day.
The followlng examples are intended to illustrate
and not to limit the scope of the present invention.
Unless otherwi-se ætated, all parts are by weight.
~ ' - ' ' -
1043;~39
EXAMPLE I
l-m-Chlorophenyl-3-tl-methyl-4-oxo-2-imidazolidinyl-
idene) urea: To a suspension of creatinine (5.66 g, 0.05 mole)
in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g
(0.05 mole) of m-chlorophenylisocyanate. The mixture is
stirred for two hours and heated on a steam bath for 30
minutes. During this time the solution becomes clear (yellow).
The solution is filtered and the filtrate cooled. Ice and
ice-water are added to the filtrate. A light yellow solid
precipitates and is filtered off. After recrystallizations
from acetone-methanol and tetrahydrofuran-ether, the pure
product, l-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinyl-
idene)urea, is obtained, mp. 180-180.5C.
Analysis: Calcd- for CllHllClN4O2: C, 49-54; H, 4-16%
Found: C, 49.45; H, 4.19%
EXAMPLE II
l-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinyl-
idene)urea hydrate: About 120 g of pure 1-m-chlorophenyl-3-
(l-methyl-4-oxo-2-imidazolidinylidine)urea obtained according
to Example I is dissolved in 400 ml of DMF and poured with
vigorous stirring into about 3.5 liters of water. The
resultant fine crystals of l-m-chlorophenyl-3-(1-methyl-4-
oxo-2-imidazolidinylidene)urea-hydrate are collected by
filtration and washed well with water, dried at room
temperature for 4 days followed by drying (room temperature~
in vacuo at 5.0 mm for 8 hr; yield about 120 g; mp 180.5-
181.5C.
Analysis: Calcd. for CllHllClN4O2-H2O: C, 46.41; H, 4.60;
N, 19.68; H O, 6.33%. Found: C, 46.43, H, 4.62;
N, 19.83; H2O, 6.37, 6.59, 6.41%
-12-
1~1433;~9
EXAMPLE III
1-(2,6-Dichlorophenyl)-3-(1-methyl-4-oxo-2-
imidazolidinylidene)urea: Following the procedure of Example
I, but substituting an equivalent amount of 2,6-dichloro-
phenylisocyanate for the m-chlorophenylisocyanate used
therein, l-(2,6-dichlorophenyl)-3-(1-methyl-4-oxo-2-imidazoli-
dinylidene)urea is obtained; m.p. 211-212C. dec.
Analysis: Calcd. for CllHloC12N4O2
Found: C, 43.55; H, 3.31
EXAMPLE IV
1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-l~-
methoxyphenyl urea: To a stirring suspension of creatinine
(11.88 g, 0.105 mole) in 100 ml. dry DMF, p-methoxyphenyliso-
cyanate (14.91 g, 0.100 mole) is added dropwise over a period
of about 15 minutes with cooling. After stirring for 8 hours
the mixture is poured into about 500 ml of ice water to yield
white crystals of product which are filtered off, washed with
water and purified by recrystallization (twice) from tetra-
hydrofuran-methanol. The crystalline product is reduced to
finer size by adding a solution of the product in minimal DMF
to vigorously stirred water (about 1.1 liters) and filtering
off the resultant crystals which are then dried at room
temperature in vacuo for 24 hours; m.p. 193-5C dec.
1043339 MN-269
EXAMPLE V
Following the procedure of Example IV, but substituting
equivalent amounts of an appropriate imidazolidin-4-one
and an appropriate arylisocyanate, the following respective
products are obtained:
1-(1-methyl-4-oxo-~-imidazolidinylidene3-3-(3,4-di-
chlorophenyl)urea hemihydrate; m.p. 199-202C. dec.;
l-(l-methyl-4-oxo-2-~midazolidinylidene)-3-m-methoxy-
phenylurea hydrate; m. p. 144C.; ~nd
1-m-chlorophenyl-3-(4-oxo-2-imidazolidinylidene)urea;
m. p. 225-227C. dec.
EXAMPLE VI
Methyl-4-oxo-2-imidazolidinylidene)-3-p-chloro-
~enylurea: To a stirring suspension of creatinine (11.88 g,
0.105 mole) in 100 ml dry DMF, ~-chlorophenylisocyanate (15.3Z ~,
0.100 mole) is added dropwise with cooling. The mixture is
stirred for 16 hours and then poured lnto about 500 ml of iced-
water to yield the crystalline product whlch is flltered off,
washed with water and recrystallized twice from acetone-methanol,
.- . .. . I . .- ..
once from t,etrahydrofuran (THF) and then from DMF-methanol.
The resultant pure l-~l-methyl-4-oxo-2-imidazol~'dinylidene)-3-
~-chlorophenylurea is dried in vacuo for 24 hours; m.p. 190-2C
dec.
- 14 -
i~43339
EXA~LE VI I
~ -Methyl-4-oxo~2-imidazolidinylidene)-3
tolylurea:
To a stirring suspension of creatinine (11.88 g,
0.105 mole) in 100 ml dry DMF, _-tolylisocyanate (13.31 g -
0.100 mole) is added dropwise over a period of about 15
minutes with cooling. After stirring for 3.5 hrs., the
mixture is poured into about 500 ml iced-water to give white
crystals of product which are filtered off and washed with
water. Recrystallization of the product from acetone-
methanol and then from THF-methanol affords the product,
l-(l-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea.
The crystalline particles are reduced to finer size by adding
a solution of the thus-obtained product in minimal DMF to
about 1.1 liters of vigorously stirring water, filtering
off and drying the resultant fine crystals in vacuo for 24
hours; m.p. 198-200C dec.
- 1043339 MN-269
EXAMPLE VIII
Methyl-4-oxo-2-imidazoliainylidene)-3-m-tolylurea
_
is obtained by repeating the procedure of Example VII with
an equivalent amount of m-tolylisocyanate substituted for
the ~-tolylisocyanate used therein; reaction time is six
hours; recrystallization twice from THF-methanol;
m.p. 183-185C.dec.
EXAMPLE IX
- l-(l-Methyl-4-oxo-2-imidazolidinylidene)-3-m-trifluoro-
methyl-phenylurea is obtained by repeating the procedure of
Example VII with an equivalent amount of m-trifluorophenyl-
lo isocyanate substituted for the P-tolyllsocyanate used therein;
reaction time i8 8iX hours; recrystallization from acetone-
methanol; m.p. 197-8C dec.
1C~43339
EXAMPLE X
l-(l-MethYl-4-oxoimidazolidinylidene)-3-(2,6-xylyl)
urea: A suspension of 5.66 g (O.S mole) of creatinine and
7.36 g (0.05 mole) of 2,6-xylyisocyanate in 200 ml of dry
THF is heated under reflux overnight (about 15 hours). The
hot solution is filtered and the filtrate diluted with
ether to about 400 ml total volume, giving the crude product.
Recrystallization from methanol affords pure l-(l-Methyl-4-
oxoimidazolidene)-3-(2,6-xylyl)urea, m.p.> 190C dec.
Analysis: Calcd. for C13H16~4O2 (260.30): C, 59.98; H, 6.20%
Found: C, 60.17; H, 6.24%
EXAMPLE XI
l-(l-Methyl-4-oxo-2-imidazolidinylidene)-3-phenylurea:
The procedure of Example IV is followed except that an
equivalent amount of phenylisocyanate is substituted for the
p-methoxyphenyl-isocyanate used therein to yield as final
product: l-(l-methyl-4-oxo-2-imidazolidinylidene)-3-phenylurea.
m.p. (185) 187-~C.
EXAMPLE XII
By repeating the procedure of Example VI, except
that an equivalent amount of an appropriate 2-imino-1-
loweralkylimidazolidin-4-one and an appropriate aryl isocyanate
are utilized as reactants, the following respective products
are obtained:
-17-
1~4~339 MN-~6)
EXAMPLE XII continued
l-(l-ethyl-4-oxo-2-imidazolidinylidene)-3-phenyl urea;
3-m-bromophenyl-1-(1-methyl-4-oxo-2-imidazolidinylidene)
urea, m.p. 183-184C dec;
3-P-ethoxyphenyl-l-(l-n-octyl-4-oxo-2-imida~olidinylidene)
urea;
3-_-ethylphenyl-1-(1-~thyl-4-oxo-2-imidazolidinylidene)
urea;
1-(3,4-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazol-
idinylidene) urea, m.p. 219-221C dec;
1-Ce-trifluoromethylphenyl)-3-(1-methyl-4-oxo-2-
imidazolidinylidene) urea, m.p. 197-200C dec;
1-(e-t-butylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinyl-
idene) urea, m.p. 188-189C ; and
1-(3-n-propylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinyl-
idene) urea, m.p. 167-168C.
EXAMPLE XIII
1_(3_ChloroPhenyl~-3-(1,3-dimeth7~1-4-oxo-2-imidazol-
idinvlidene) urea A mixture of 6.35 g (0.050 mole)
of 1,3-dimethyl-2-iminoimidazolidin-4-one, 7.85 g
(0.050 mole) of 3-chlorophenylisocyanate and 75 ml of
dry tetrahydrofuran is stirred at room temperature for
four hours. The solution is evaporated in vacuo and
''' '
- 18 -
M~-269
1~433~9
EXAMPLE XIII continued
~he residue is crystallized from acetonitrile. Two
recrystallizations from acetonitrile - ether gives
pure product,l-(3-chlorophenyl)-3-(1,3-dimethyl-4-
oxo-2-imidazolidinylidene)urea, m. p. 134-~37C.
E-XAMP~E ~IV
1-(3-Chloro-2~6-dimethYlphenvl)-3-(1-methyl-4-oxo-2-
imidazolidinvlidene) urea. To a stirring suspension of
7.92 g (0.07 mole) of creatinine in 50 ml of dry DMF i~
added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenyl
isocyanate. After stirring for four hours, the reaction
mixture is filtered through a diatomaceous earth pad to
remove unreacted creatinine. Addition of a large excess of
ice water precipitates a gummy semisolid mass which eventusl-
ly crystallizes. After blowing the product to dry it for about
eighteen hours, it is recrystallized from acetone-ether.
Finally the product is taken up in dichloromethane and the
resulting solution i8 filtered through diatomaceous earth.
Concentration and dilution with ether gives pure product,
1-(3-chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazol-
idinylidene) urea; m.p. 140-141.5C.
-- 19 --
~-26
1~433;~9
EXAMPLE XV
1-(2~6_dimethylphenyl)_3_(5~5-di~enYl-4-oxo-2-
imidazolidinylidene) urea: A suspention of 6.95 g (0.0306
mole) of 5,5-diphenyl-2-amino-2-imidazoline-4-one in 300 ml
of dry DMF is treated with 4.5 g (0.0306 mole) Gf 2,6-di-
methylphenylisocyanate. The reaction mixture is stirred at
40C for two hours. It is then ~oured into cold water
and the resulting solids are filtered off. To the crude
product is added 30 ml of water with heating; acetone is added
to the heated slurry until all solids go in solution (1.5 liters
of acetone). The solution is then evaporated to a volume of
300 ml., chilled, and the resulting so~ids are filtered off to
give l-(2,6-dimethylphenyl)-3-(S,S-diphenyl-4-oxo-2-
imidazolidinylidene) urea, the pure product; no m.p. up to
350C
lS Analysis: Calcd. for C24H22N402: C, 72.32; H, 5.56%
Found: C, 72.00; H, 5.68%
- 20 -
1~43339
EXAMPLE XVI
1-(1,3-Dimethyl-4-oxo-2-imidazolidinylidene)-
3-(2,6-dimethylphenyl)urea. A mixture of 6.35 g (0.050 mole)
of 1,3-dimethyl-2-iminoimidazolidin-4-one and 7.25 g (0.050 mole)
of 2,6-dimethylphenylisocyanate in 75 ml. of dry tetrahydro-
furan is stirred at room temperature for two hours followed
by refluxing it for thirty minutes. The reaction mixture
is evaporated in vacuo to give a solid, which is crystallized
from tetrahydrofuran-ether. Two more recrystallizations from
the same solvent mixture gives pure product, 1-(1,3-dimethyl-
4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl)urea;
m.p. 115.5-118.5C.
EXAMPLE XVII
Following the procedure of Example XVI, but
substituting equivalent amounts of an appropriate imidazolidin-
4-one and an appropriate arylisocyanate for the 1,3-dimethyl-
2-iminoimidazolidin-4-one and 2,6-dimethylphenylisocyanate
used therein, the following respective products are obtained:
-21-
~ MN-269
1~43339
EXAMPLE XVII continued
1-(3-chlorophenyl)-3-(1-octyl-4-oxo-2-imidazolidinylidene)
urea, m.p. 98-100C;
l-(l-octyl-4-oxo-2-imidazolidinylidene)-3-phenylurea,
m.p. 109.5-110C;
1-(3-chlorophenyl)-3-(1-methyl-4-oxo-5-benzyl-2-
imidazolidinyli~e~n~3urea, m.p.-167-168C; and
l-(l-methyl-4-oxo-5 benzyl-2-imidazolidinylidene)-3-
phenylurea, m.p. 158-160C.
EXAMPLE XVIII
~ Methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl
urea. To a stirred slurry of 12.45 g (O.llmole) of creatinine
in 100 ml of dry DMF is added 16.41 g (0.1 mole) of m-nitro-
phenyl isocyanate (previously recrystallized from benzene-
pentane). After nine hours, ice water is gradually added
until crystallization occurres. A large excess of ice water
precipitates the product as gummy crystals which then
crystallize. The crude product is allowed to air dry for
several days. Recrystallization from THF-H20 followed by
THF gives pure product,l-(1-methyl-4-oxo-2-imidazolidinylidene)-
3-m-nitrophenyl urea; m.p. 182-188C sl. dec.
- 22 -
MN-269
1~33~9
EXAMPLE XIX
Following the procedure of Example XVIII, but sub-
stituting an equivalent amount of an appropriate aryliso-
cyana~e for the 2,6-dimethylphenylisocyanate used therein,
the following respective products are obtained:
1-(1-methyl-4-oxo-2-imidazolidinylide~e)-3-(e-ni~ro-
phenyl)urea, m.p. 220-223C dec; and
1-(e-dimethylaminophenyl)-3-(1-methyl-4-oxo-2-
imidazolidinylidene)urea; m.p. 210-216C dec.
EXAMPLE XX
Following the procedure of Example X, but substituting
equivalent amount~ of an appropriate imidazolidin-4-one
and an appropriate arylisocyanate for the creatinine and
2,6-xylylisocyanate used therein, the following respective
products are obtained:
1-(3-chlorophenyl~-3-(3-methyl-4-oxo-2-imidazolidinylidene)
urea; m.p. 169-171C; and
1-(3-chlorophenyl)-3-(5,5-diphenyl-4-oxo-2-imidazoli-
dinylidene)urea; m.p. 274-277C.
- 23 -
~- 26Y
1~43339
The above examples are intended to illustrate but not to
limit the scope of the present invention,. which is defined
in the following claims.
. - 24 -
