4-AROYLIMIDAZOL-2-ONES

4-AROYLIMIDAZOL-2-ONES

English Abstract

ABSTRACT OF THE DISCLOSURE
Novel 4-aroylimidazol-2-ones of the following general
structure which are useful as antihypertensives, cardio-
tonics and antithrombotics
<IMG>
wherein Ar is 2-furyl, 2-thienyl or phenyl, the latter
of which may optionally be substituted with one or two X
groups; X is halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy,
methylenedioxy, C1-4 alkylthio, CF3, -SO2N(R2)2, NR3R4,
pyrrolidino, piperidino, morpholino, piperazino or
N'-alkyl-piperazino; R is hydrogen, C1-4 alkyl, C1-4
alkylcarbonyl or benzoyl; each of R1, R2, R3 and R4
are hydrogen or C1-4 alkyl; and the pharmaceutically
acceptable salts thereof.

Claims

M-964-C1
-26-
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing an aroylimidazol-2-one of
the formula
<IMG>
wherein Ar is 2-furyl, 2-thienyl, phenyl mono-
substituted at the ortho, meta or para position with X1,
or disubstituted phenyl substituted at the para position
with X2 and at the ortho or meta position with X3; X1
is halogen, a straight or branched chain lower alkyl of
from 1 to 4 carbon atoms, a straight or branched chain
lower alkoxy of from 1 to 4 carbon atoms, a straight or
branched chain lower alkylthio of from 1 to 4 carbon
atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrrolidino,
piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chaln lower
alkoxy or from 1 to 4 carbon atoms, a straight or branched
chain lower alkyl of from 2 to 4 carbon atoms, or when X3
is at the meta position X2 and X3 together may be
methylenedioxy optionally substituted by one or two
methyl groups; R is hydrogen, a straight or branched chain
lower alkyl of from 1 to 4 carbon atoms, a straight or
branched chain lower alkylcarbonyl of from 1 to 4 carbon
atoms, or a benzoyl; each of R1, R2, R3 and R4 are hydro-
gen or a straight or branched chain lower alkyl of from

M-964-C1
27
1 to 4 carbon atoms with the proviso that both R9 and R4
cannot be hydrogen; or a pharmaceutically acceptable salt
thereof which comprises reacting an imidazol-2-one of the
formula
<IMG>
wherein R1 is as defined above with about 1 to
about 10 molar equivalents of a 2-furoyl halide, 2-
thienoyl halide, a benzoyl halide monosubstituted at
the ortho, meta or para position with X1 wherein X1
is as defined above, or a disubstituted benzoyl
halide substituted at the para position with X2 and
at the ortho or meta position with X3 wherein X2 and
X3 are as defined above, in the presence of about 1
to about 10 molar equivalents of a Lewis acid catalyst
in a suitable solvent at a temperature of from about 0°
to about 100°C for about 1 to about 10 hours and when it
is desired that R be other than hydrogen, acylating
or alkylating, as appropriate, the resulting aroylimidazol-
2-one with an appropriate acyl halide or alkylating agent;
alternatively
a) where X1 is pyrrolidino, piperidino, mor-
pholino, piperazino or N'-alkyl-piperazino treating the
thus formed compound wherein X1 is fluorine with from
about 1 to about 10 molar equivalents of pyrrolidine,
piperidino, morpholine, piperazine, or N'-alkyl-piperazine
in a suitable solvent for about 1/2 hour to about 48 hours
at about 0° to about 150°C;
b) where X1 is an amino group of the formula,
NR3R4, reducing a compound of the formula
<IMG>

- 28 -
with tin, zinc or iron metal in concentrated hydrochloric acid
to produce the corresponding aminobenzoylimidazol-2-one which
may then be alkylated by reaction with an appropriate alkyl
halide; and where a pharmaceutically acceptable salt is desired,
reacting the thus formed aroylimidazol-2-one with an appropriate
pharmaceutically acceptable metal or ammonium basic salt.
2. An aroylimidazol-2-one of the formula
<IMG>
wherein Ar is 2-furyl, 2-thienyl, phenyl mono-substituted at
the ortho, meta or para position with X1, or disubstituted
phenyl substituted at the para position with X2 and at the or-
tho or meta position with X3; X1 is halogen, a straight or
branched chain lower alkyl of from 1 to 4 carbon atoms, a
straight or branched chain lower alkoxy of from 1 to 4 carbon
atoms, a straight or branched chain lower alkylthio of from 1
to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrroli-
dino, piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chain lower alkoxy
of from 1 to 4 carbon atoms, a straight or branched chain lower
alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta
position X2 and X3 together may be methylenedioxy optionally
substituted by one or two methyl groups; R is hydrogen, a
straight or branched chain lower alkyl of from 1 to 4 carbon
atoms, a straight or branched chain lower alkylcarbonyl of from
1 to 4 carbon atoms, or a benzoyl; each of R1, R2, R3 and R4
are hydrogen or a straight or branched chain lower alkyl of from
1 to 4 carbon atoms with the proviso that both R3 and R4

- 29 -
cannot be hydrogen; or a pharmaceutically acceptable salt thereof
when prepared by the process of claim 1.
3. The process of claim 1 wherein R is hydrogen and R1
is hydrogen or a straight or branched chain lower alkyl of from
1 to 4 carbon atoms.
4. An aroylimidazol-2-one of the formula as defined in
claim 1 wherein R is hydrogen and R1 is hydrogen or a straight
or branched chain lower alkyl of from 1 to 4 carbon atoms, when
prepared by the process of claim 3.
5. The process of claim 1 wherein R is hydrogen and R1
is hydrogen or a methyl or ethyl group.
6. An aroylimidazol-2-one of the formula as defined in
claim 1 wherein R is hydrogen and R1 is hydrogen or a methyl or
ethyl group, when prepared by the process of claim 5.
7. A process for preparing an aroylimidazol-2-one of
the formula
<IMG>
wherein Ar is 2-furyl, 2-thienyl, phenyl mono-substituted at
the ortho, meta or para position with X1, or disubstituted
phenyl substituted at the para position with X2 and at the
ortho or meta position with X3; X1 is halogen, a straight or
branched chain lower alkyl of from 1 to 4 carbon atoms, a
straight or branched chain lower alkoxy of from 1 to 4 carbon
atoms, a straight or branched chain lower alkylthio of from 1

- 30 -
to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrroli-
dino, piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chain lower alkoxy
of from 1 to 4 carbon atoms, a straight or branched chain lower
alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta
position X2 and X3 together may be methylenedioxy optionally
substituted by one or two methyl groups; R1 is hydrogen or a
methyl or ethyl group; each of R2, R3 and R4 are hydrogen or a
straight or branched chain lower alkyl of from 1 to 4 carbon
atoms with the proviso that both R3 and R4 cannot be hydrogen;
or a pharmaceutically acceptable salt thereof which comprises
reacting an imidazol-2-one of the formula
<IMG>
wherein R1 is as defined above with about 1 to about 10 molar
equivalents of a 2-furoyl halide, 2-thienoyl halide, a benzoyl
halide monosubstituted at the ortho, meta or para position
with X1 wherein X1 is as defined above, or a disubstituted
benzoyl halide substituted at the para position with X2 and at
the ortho or meta position with X3 wherein X2 and X3 are as
defined above, in the presence of about 1 to about 10 molar
equivalents of a Lewis acid catalyst in a suitable solvent at
a temperature of from about 0° to about 100°C for about 1 to
about 10 hours; alternatively
a) where X1 is pyrrolidino, piperidino, morpholino,
piperazino or N'-alkyl-piperazino treating the thus formed com-
pound wherein X1 is fluorine with from about 1 to about 10

- 31 -
molar equivalents of pyrrolidine, piperidine, morpholine, piper-
azine, or N'-alkyl-piperazine in a suitable solvent for about
1/2 hour to about 48 hours at about 0° to about 150°C;
b) where X1 is an amino group of the formula, NR3R4, re-
ducing a compound of the formula
<IMG>
with tin, zinc or iron metal in concentrated hydrochloric acid
to produce the corresponding aminobenzoylimidazol-2-one which
may then be alkylated by reaction with an appropriate alkyl ha-
lide; and where a pharmaceutically acceptable salt is desired,
reacting the thus formed aroylimidazol-2-one with an appropriate
pharmaceutically acceptable metal or ammonium basic salt.
8. An aroylimidazol-2-one of the formula
<IMG>
wherein Ar is 2-furyl, 2-thienyl, phenyl monosubstituted at the
ortho, meta or para position with X1, or disubstituted phenyl
substituted at the para position with X2 and at the ortho or
meta position with X3; X1 is halogen, a straight or branched
chain lower alkyl of from 1 to 4 carbon atoms, a straight or
branched chain lower alkoxy of from 1 to 4 carbon atoms, a

- 32 -
straight or branched chain lower alkylthio of from 1 to 4 carbon
atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrrolidino, piperi-
dino, morpholino, piperazino or N'-alkyl-piperazino; X2 and X3
are halogen, a straight or branched chain lower alkoxy of from
1 to 4 carbon atoms, a straight or branched chain lower alkyl of
from 2 to 4 carbon atoms, or when X3 is at the meta position X2
and X3 together may be methylenedioxy optionally substituted by
one or two methyl groups; R1 is hydrogen or a methyl or ethyl
group; each of R2, R3 and R4 are hydrogen or a straight or bran-
ched chain lower alkyl of from 1 to 4 carbon atoms with the pro-
viso that both R3 and R4 cannot be hydrogen; or a pharmaceuti-
cally acceptable salt thereof when prepared by the process of
claim 7.
9. A process for preparing 1,3-Dihydro-4-(4-methoxy-
benzoyl)-5-methyl 2H-imidazol-2-one or a pharmaceutically accep-
table salt thereof which comprises reacting an imidazol-2-one
of the formula
<IMG>
with about 1 to about 10 molar equivalents of a 4-methoxy-ben-
zoyl halide in the presence of about 1 to about 10 molar equi-
valents of a Lewis acid catalyst in a suitable solvent at a
temperature of from about 0° to about 100°C for about 1 to
about 10 hours and where a pharmaceutically acceptable salt is
desired, reacting the thus formed aroylimidazol-2-one with an
appropriate metal or ammonium basic salt.

- 33 -
10. The compound 1,3-Dihydro-4-(4-methoxybenzoyl)-5-
methyl-2H-imidazol-2-one or a pharmaceutically acceptable salt
thereof when prepared by the process of claim 9.
11. A process for preparing 1,3-Dihydro-4-(3,4-Dimeth-
oxybenzoyl)-2H-imidazol-2-one or a pharmaceutically acceptable
salt thereof which comprises reacting an imidazol-2-one of the
formula
<IMG>
with about 1 to about 10 molar equivalents of a 3,4-dimethoxy-
benzoyl halide in the presence of about 1 to about 10 molar equi-
valents of a Lewis acid catalyst in a suitable solvent at a
temperature of from about 0° to about 100°C for about 1 to about
10 hours and where a pharmaceutically acceptable salt is desired,
reacting the thus formed aroylimidazol-2-one with an appropriate
metal or ammonium basic salt.
12. The compound 1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-
2H-imidazol-2-one or a pharmaceutically acceptable salt thereof
when prepared by the process of claim 11.
13. A process for preparing 1,3-Dihydro-4[4(methyl-
thio)benzoyl]-5-methyl-2H-imidazol-2-one or a pharmaceutically
acceptable salt thereof which comprises reacting an imidazol-2-
one of the formula
<IMG>

- 34 -
with about 1 to about 10 molar equivalents of a 4-(methylthio)-
benzoyl halide in the presence of about 1 to about 10 molar equi-
valents of a Lewis acid catalyst in a suitable solvent at a
temperature of from about 0° to about 100°C for about 1 to about
10 hours and where a pharmaceutically acceptable salt is desired,
reacting the thus formed aroylimidazol-2-one with an appropriate
metal or ammonium basic salt.
14. The compound 1,3-Dihydro-4[4-(methylthio)benzoyl]-
5-methyl-2H-imidazol-2-one or a pharmaceutically acceptable salt
thereof when prepared by the process of claim 13.

Description

M-964-Cl
1~ J~55~
NOVEL 4-AROYLIMIDAZOL-2-ONES
FIELD OF THE INVENTION
This invention relates to 4-aroylimidazol-2-ones;
their use as antihypertensives, cardiotonics and anti-
thrombotics; their pharmaceutical compositions; and their
preparation.
DESCRIPTION OF THE PRIOR ART
The closest prior art known to the applicants is
found in U S. patents 2~514,380 and 2,441,~33, as well as
in R. ~uschinsky and L. A. Dolan, J. Am. C~Qm. soc~ 68,
23~0-55 (1946); ibid. 70, 657-62 (1948); ibid. 67, 2079-84
(1945); and Y. A. Rozin, E. P. Dorienko and Z. V.
Pushkareva, Khim. Geterotsikl. Soed;n., 4(4), 698-701
(1968). These references ~isclose .he preparation and
chemical intermediate utility of the following compounds:
4-benzoyl-1,3-dihydro-2H-imidazol-2-onej
4-benzoyl-1,3-dihydro-2H-imidazol-2-one 1,3-diacetate,
4-benzoyl-1~3-dihydro-5-(lo~er alkyl)-2H-imidazol-2-one~
~-benzoyl-1-,3-dihydro-~-methyl-2H-imidâzol-2-one 1,3-
diacetate,
1,3-dthydro-~-(3,4-dimethylbenzoyl)-2~-imidazol-2-one
1,~-diacetate,

` ~3255~ M-964-C1
1,3-dihydro-4-(hydroxybenzoyl)-2H-imidazol-2~one;
1,3-dihydro-4-(hydroxybenzoyl)-5-(lower alkyl)-2H-imidazol-
2-one;
1,3-dihydro-4-~3,4-dihydroxybenzoyl)-2H-imidazol-2-one;
1,~-dihydro-4-(4 nitrobenzoyl)-2H-imidazol-2-one;
1,~-dihydro-4-methyl-5-(4-nitrobenzoyl)-2H-imidazol-2-one,
4-(3-aminobenzoyl)-1,~-dihydro-2H-imidazol-2-one,
4-(4-aminobenzoyl)-1,~-dihydro-2H-imidazol-2-one,
4-(4-aminobenzoyl)-1J3-dihydro-5-methyl-2H-imidazol-2-one,
however, no pharmaceutical utility for the 4-aroylimidazol-
2-ones of the present invention has been previously
- taught.
SUMMARY OF THE INVENTION
This invention is directed to pharmaceu~ically active
4-aroylimidazol-2-ones of general Formula 1
o
R~ ~ A
0 Formula 1
wherein Ar is 2-furyl, ~-thienyl, phenyl, phenyl monosub-
stituted at the ortho, meta or para position with X1, or
disubstituted phenyl substTtuted at the para position
with Xz and at the ortho or meta position with X3; Xl is
halogen~ hydroxy, a straight or branched chain lower alkyl
of from 1 to 4 carbon atoms, a straight or branched ~hain
lower alkoxy of from 1 to 4 carbon atoms, a straight or
branched chain lower alkylthio of from 1 to 4 carbon atoms,
trifluoromethyl, -502N(R2)2, NR3R4, pyrrolidino, piperi-
dino, morpholino, piperazino or N'-alkyl-piperazino; X2
and X3 are halogen, hydroxy, a straight or branched chain

~ S~ M-964-C1
lower alkyl of from 1 to 4 carbon atoms, a straight or
branched chain lower alkoxy of from 1 to 4 carbon atoms
or when X3 is at the meta position~ X2 and X3 taken
together may be a methylenedioxy optionally substituted
by one or two methyl groups; R is hydrogen, a straight
or branched chain lower alkyl of from 1 to 4 carbon atoms,
a straight or branched chain lower alkylcarbonyl of from
1 to 4 carbon atoms, or a benzoyl group; each of R1,
R2, R3 and R4 is hydrogen or a straight or branched chain
lower alkyl of from 1 to 4 carbon atoms; or a pharmaceuti-
cally acceptable salt thereof. These compounds are useful
as antihypertensives, cardiotonics and antithrombotics.
This invention is directed, furthermore, to the process
of preparing the 4-aroylimidazol-2-ones as well as their
pharmaceutical compositions.
DESCRIPT ! ON OF_THE PREFERRED EMBODIMENTS
Illustrative examples of a straight or branched chain
lower alkyl of from 1 to 4 carbon atoms as used herein are
methyl, ethyl, n-propyl, isopropyl, n-butyl and Tso~utyl.
Illustrative examples of a straight or branched chain
lower alkoxy of from 1 to 4 carbon atoms as used herein
are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and
isobutoxy.
~s used herein, the term halogen is taken to mean
fluorine, chlorine, bromine or iodine.
As used herein, the term halide is taken to mean
fluoride, chloride, bromide, or iodide.
As used herein, the term a straight or branched chain
lower alkylthio of from 1 to ~ carbon atoms is taken to
mean a group of the structure, S-alkyl, wherein the alkyl
moiety is a straight or branched chain alkyl of from
1 to 4 carbon atoms and may be, for example, methyl,
ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

M-964-C1
~ 5 ~
As used herein, the term methylenedioxy optionally
substituted by one or two methyl groups is taken to
mean methylenedioxy, ethylenedioxy, or isopropylidene-
dioxy.
As used herein, the term a benzoyl group is taken
to mean a group of the formula -(CO)C6H5.
As used herein, the term a straight or branched chain
lower alkylcarbonyl of from 1 to 4 carbon atoms is taken
to mean a group of the structure
-C-alkyl
wherein the alkyl moiety is a straight or branched chain
lower alkyl of from 1 to 4 carbon atoms and may be, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl or
isobutyl.
As used hereln, the term N'-alkyl-piperazino is
taken to mean a group of the structure
-N ~ -alkyl
wherein the alkyl moiety is a straight or branched chain
lower alkyl of from 1 to 4 carbon atoms and may be, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl or
isobutyl.
The preferred compounds of this invention are those
compounds of Formula 1 wherein R is hydrogen and Xl is
piperidino, pyrrolidino, morpholino, piperazino, N'-alkyl-
piperazino, a straight or branched chain lower alkoxy offrom 1 to 4 carbon atoms3 or a straight or branched chain
lower alkylthio of from 1 to 4 carbon atoms. Other pre-
ferred compounds of this invention are tbose compounds of
Formula 1 wherein Ar is an unsu~stituted ~henyl and where X2

M-964-C1
113Z55~
and X3 are a straight or branched chain lower alkoxy of
from 1 to 4 carbon atoms.
The more preferred compounds of this invention are
those compounds of Formula 1 wherein Rl is hydrogen or
methyl and X1 is at the para position and is pyrrolidino,
morpholino, piperazino, N'-alkyl-piperazino, a straight
or branched chain lower alkoxy of from 1 to 4 carbon
atoms, or a straight or branched chain lower alkylthio of
from 1 to 4 carbon atoms. Other more preferred compounds
of this invention are those compounds of Formula 1 where-
in R1 i5 hydrogen or methyl and X~ is at the meta position
and where X2 and X3 are a straight or branched chain lower
~ alkoxy of from 1 to 4 carbon atoms or together are a
methylenedoxy optionally substituted by one or two methyl
groups.
The most preferred compounds o~ this invention are
those compounds of Formula 1 wherein R is hydrogen, R1 is
methyl and X1 is at the para position and is methoxy or
methylthio or wherein R is hydrogen, Rl is methyl and X3
is at the meta position and X2 and X3 are methoxy or
together are a methylenedioxy.
As examples of compounds of general Formula 1 there
may be mentioned the following:
4-benzoyl-1,3-dihydro-5-methyl-2H-imidazol-2-one,
1,3-dihydro-4-methyl-5-(2-thienoyl)-2H-imidazol-2-one,
1,3-dihydro-4-methyl-5-(3,4-methylenedioxybenzoyl)-2H-
imidazol-2-one,
1,3-dimethyl-4-benzoyl-2H-imidazol-2-one,
1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one,
4-benzoyl-1,3-dihydro-~-methyl-2H-imidazol-2-one, 1,3-
diacetate,
1,3-dihydro-4-(~,4-dimethoxybenzoyl)-5-methyl-2H-imidazol-
2-one,
1,3-dihydro-4-(2-furanoyl)-5-methyl-2H-imidazol-2-oneJ
~, .

113~255~
-- 6 --
1,3-dihydro-4-(2-thienoyl)-2H-imidazol-2-one,
4-benzoyl-1,3-dihydro-2H-imidazol-2-one,
1,3-dihydro-4-(2-furanoyl)-2H-imidazol-2-one,
1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one,
4-(2-chlorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one,
1,3-dihydro-4-(2-hydroxybenzoyl)-5-methyl-2H-imidazol-2-one,
4-(4-chlorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one,
1,3-dihydro-4-methyl-5-(4-piperidinobenzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-methyl-5-(4-morpholinobenzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-methyl-5-(4-pyrrolidinobenzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-(4-dimethylaminobenzoyl~-5-methyl-2H-imidazol-2-
one,
1,3-dihydro-4-methyl-5-[4-(4-methylpiperazinobenzoyl)]-2H-imi-
dazol-2-one,
1,3-dihydro-4-ethyl-5-(4-methoxybenzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-ethyl-5-(4-(methylthio)benzoyl)-2H-imidazol-2-one,
1,3-dihydro-4-(4-hydroxybenzoyl)-5-methyl-2H-imidazol-2-one, and
1,3-dihydro-4-methyl-5-[4-(methylthio)benzoyl]-2H-imidazol-2-
one,
When R is hydrogen in Formula 1 compounds, the several
tautomeric forms of general Formula 2 are possible;
1 ~ Ar 1 ~ Ar 1 ~ Ar
/ N N = H~ ~ N\ = N ~ N\ Formula 2
OH O OH
wherein Rl and Ar are as defined in Formula 1. These acidic
tautomers may form pharmaceutically active salts of general
Formula 3

M-964-Cl
~1~3;~5~
R1 ~ r R1 ~ Ar Rl Ar R1 Ar
H~ ~ ` H' ~ M t M, ~ N~HÇ - ~ `H Formula 3
OM O OM
wherein R1 and Ar are as defined in Formula 1, and M Ts a
pharmaceutically acceptable alkall metal, such as sodium
or potassium; alkaline earth metal, such as calcium or
magnesium; transition metal, such as zinc or iron; main
group metal; ammonium or organic ammonium ion, such as
tetramethylammonium ion. Throughout this disclosure the
term imidazol-2-one shall be taken to mean any of the
tautomers of Formula 2 and a pharmaceutically acceptable
salt of an imidazol-2-one shall be taken to mean any
tautomer of Formula 3.
The 4-aroylimidazol-2-ones of this invention wherein
R is hydrogen may be prepared by a Friedel^Crafts
acylation of an imidazol-2-one of Formula 4:
R 1~
H' ~ `H Formula 4
wherein Rl is as defined in Formula 1. The acylating agent
may be a 2-furanoyl halide~ preferably 2-furanoyl chloride,
a 2-thienoyl halide, preferably 2-thienoyl chloride, or a
benzoyl halide, preferably a benzoyl chloride, of Formulas
5a, 5b or 5c
O O X
yJ~ YJ~Xl YJ~i~
Formula 5a Formula 5b Formula ~c

M-964-Cl
-8-
wherein Y is a halogen and X~, X2 and X3 are as defined
in Formula 1 or may additionally be any group which can
be converted to the desired X1, X2 or X3 substituent sub-
sequent to the Friedel-Crafts reaction such as a blocking
group or a nitro group which can be converted, via the
diazonium ionJ to a variety of other substituents by
chemistry generally known in the art. Furthermore, the
Friedel-Crafts reaction may be performed on the free acid
or its corresponding acid anhydride instead of the
aroyl halides mentioned hereinabove employing essentially
identical reaction conditions. These alternate reactions
are more fully described in Olah, "Friedel-Crafts and
Related Reactions," Vol. III, Part 1, Interscience Publi-
cations, John Wily and Sons9 New York, 1964.
The Friedel-Crafts reactions of this invention are
performed by premixing about 1 molar equivalent of the
appropriate imidazol-2-one with about 1 molar equivalent
to about 10 molar equivalents, preferably about 2 molar
equivalents, of a Lewis acid catalyst in a suitable
solvent, for example, petroleum ethers; a chlorinated
hydrocarbon, such as carbon tetrachloride, ethylene
chloride, methylene chloride or chloroform; a chlorinated
aromatic, such as 1,2,4-trichlorobenzene or o-dichloro-
benzene; carbon disulfide; or preferably nitrobenzene.
About 1 molar equivalent to about 10 molar equivalents,
preferably about 1.1 molar equivalents of the appropriate
aroyl compound is added, preferably dropwise, to the mix-
ture of imidazol-2-one, Lewis acid, and solvent and the
reaction is allowed to proceed for about 1/2 hour to about
100 hours, preferably from about 1 hour to about 10 hours
depending on the reactants, the solvent, and the tempera-
ture which can be from about -78 to about 150C, prefera-
bly about 0~ to about 100C5 most preferably about 60C.
The resulting aroylimidazol-2-one may be isoiated from
the reaction mixture by any su~table art-known procedure,

M-964-C1
~ 1 3 ~
pref~rably by quenching the reaction mixture wlth ice
water and subsequently removing the product by filtra-
tion or extraction and solvent removal.
Lewis acid catalysts suitable for use in the Friedel-
Crafts reactions described herein areI for example, ametal, such as aluminum, cerium, copper, ironJ molybdenum,
tungsten or zinc; a Bronstead acid, such as a phosphoric
acid, sulfuric acid, sulfonic acid, or a hydrohalo acid,
such as hydrochloric or hydrobromic acid; halogen sub-
stituted acetic acids, such as chloroacetic or trifluoro-
acetic acids; or a metallic halide, such as a boron
halidef zinc chloride, zinc bromide, berryl chloride,
copper chloride, iron(III) bromide, iron(III) chloride,
mercury(II) chloride, mercury(I) chloride, antimony
bromide, antimony chloride, titanium(IV) bromide,
titanium(IV) chloride, titanium(III) chloride, aluminum
bromide or preferably aluminum chloride.
The compounds of Formula 1 wherein Xl is at the ortho
or para position and is a pyrrolidino, piperidino, morpho-
lino, piperazino9 N'-alkyl-piperazino and NR3R4 may be pre-
pared as hereinabove described or may be prepared from a
suitable fluorobenzoylimidazol-2-one of Formula 6
R'~,~ ~ F Formula 6
wherein R and R1 are as defined above in Formula 1 and
the fluorine atom is at either the ortho or para
position. The appropriate compound of Formula 6 is
allowed to react with from about l to about 10 molar
equivalents of pyrrolidine, piperidine, morpholine,
piperazine or N'~alkyl-pi?erazine, as appropriate. This
reaction may be performed with or without a solvent, pre-

5S~ M - 96 4- C 1
-10-
ferably~ the amine is the solvent as well as the reactant.
Suitable solvents, if desired, for this reaction are, for
example, dimethylformamide; dimethylsulfoxide; petroleum
ethers; chlorinated hydrocarbons, such as chloroformJ
methylene chloride, or carbon tetrachloride; carbon di-
sulfide; ethereal solvents, such as diethyl ether, tetra-
hydrofuran or p-dioxan; aromatic solvents such as benzene,
toluene or xylene; or alcoholic solvents, such as ethanol.
The reaction is allowed to proceed for about 1/2 hour to
about 48 hours, preferably about 24 hours, depending
on the reactants, the solvent if any, and the temperature
which can be from about 0 to about 150~C.
The compounds of Formula 1 wherein X1 is an amino
group of the formula, -NR3R4, and wherein R~ and R4 are
as defined in Formula 1, may alternatively be prepared
from the corresponding nitro substituted benzoylimidazol-
2-ones of Formula 7
R~ ~ N02 Formula 7
wherein R and Rl are as defined in Formula 1. The com-
pounds of Formula 7 are either known in the prior art or
may be prepared by Friedel-Crafts acylation of an imida-
zol-2-one of Formula 4 with a nitro substituted benzoyl
halide, preferably a nitro substituted benzoyl chloride
by procedures analogous to those outlined above. The
nitro group is reduced to the unsubstituted amino ~roup
by any suitable art-known procedure and subsequently, if
desired, the unsubstituted amino may be alkylated by any
appropriate art known method.

M-964-Cl
5~
The nitrobenzoylimidazol-2-ones may suitably be
converted to the corresponding aminobenzoylimidazol~2-ones
by reduction with tin, zinc, iron or other suitable active
metal in concentrated hydrochloric acid solutlon. About
1 molar equivalent to about 10 molar equivalents of the
metal is used and the reaction is allowed to proceed
for about 1~2 hour to about 10 hours, preferably about
2 or 3 hours depending upon the reactants and the tempera-
ture which can be from about 25 to about 150sC, pre-
ferably about 100C. Alternatively, the nitrobenzoyl-
imidazol-2-ones may be reduced catalytically with nickelJ
platinum, pallidium, or other similar suitable metals
and molecular hydrogen. Such reactions are typically per-
formed in an alcoholic solvent, preferably ethanol, but
any nonreactive solvent may be used and the amount of
metal catalyst may vary from about 0.001 molar equiva-
lents to about 0.1 molar equivalents. The reaction is
allowed to proceed for about 1 minute to about 1 hour,
preferably about 10 minutes depending upon the reactants,
the solvent and the temperature which can be from about
0 to about 100C, preferably about 25C. And alterna-
tively, the nitrobenzoyltmtdazol-2-ones may be reduced
with ammonium bisulfide (NH45H) in aqueous ammonia.
About 1 to about 10 molar equivalents, preferably about
3 molar equivalents, of the bisulfide is allowed to react
for about 1/2 hour to about 10 hours, preferably about
2 hours, dependlng upon the reactants and the temperature
which may be from about 0 to about 150C, preferably
about 50C. Ftnally, the nitrobenzoylimidazol-2-ones
may be reduced to the correspondtng aminG compounds by
any other appropriate art-known procedure.
The alkylation of the unsubstituted aminobenzoyl-
imidazol-2-ones may be accomplished, for example, by

M-964-Cl
~3'~55'-~
-12-
reaction with one or more equivalents of an appropriate
alkyl halide of the formulas R9X and R4X wherein R3 and R4
are as defined in Formula 1 and X is a halide. Typically
these reactions are preformed in a solvent such as
5 petroleum ethers; chlorinated hydrocarbons such as carbon
tetrachloride, chloroform or methylene chloride;
chlorinated aromatics such as 1~2,4-trichlorobenzene, o-
dichlorobenzene or chlorobenzene; carbon disulfide;
nitrobenzene; dimethylformamide; dimethylsulfoxide;
ethereal solvents such as diethyl ether, tetrahydrofuran
or p-dioxan; aromatic solvents such as benzene, toluene
or xylene, alcohols such as methanol, ethanol or pro-
- panol; and aqueous alcohols such as aqueous ethanol. These
alkylations are preferably performed in the presence of
one or more e~uivalents of a "proton sponge" such as
triethylamine, pyridine, sodium hydroxide, calcium hydrox-
ide or potasstum hydroxide to neutralize any hydrohalide
as it is formed. Alternatively, the unsubstituted amino-
benzoylimidazol-2-ones may be alkylated by any other appro-
priate art-known procedure such as reaction with formic
acid and formaldehyde to form a dimethylamine compound.
Fur~hermore, a variety of other substituents such as
halogen and hydroxy may be prepared from the nitro sub-
stituted benzoylimidazol-2-ones of Formula 7 via the
diazonium ion by procedures well known in the art.
The compounds of Formula 1 wherein X1 or Xz and X3
are hydroxy may be pr~pared as heretnabove described or
preferably may be prepared from a suitable alkoxy~ pre-
ferably methoxy, substituted benzoylimidazol-2-one
whereTn the alkoxy group is at the position of desired
hydroxy substitution. The alkoxy compound is cleaved to
form the corresponding hydroxybenzoylimidazol-2-one by
any suitable art-known procedure such as are taught by
R. L. Burwell, "The Cleavage of Ethers," Chem. Rev. _4J
615-85 (1954) whose contents are hereby expressly incor-
porated by reference.

~ S~ M-964-C1
-13-
The X1, X2 and X3 substituents may be protected as
necessary in order to improve the stability of the For-
mula 5b and 5c reactants or to allow for the acylation of
the imidazol-2-one ring nitrogen atoms as described
herein without concurrent acylation of any reactive X
groups. For example, where X1, X2 or X3 is hydroxy, an
amino group of the formula -NHR3 or -S02NH2, a benzyl
group may be employed to block the otherwise reactive
hydroxy or amino groups. The benzyl group may be removed
subsequently by, for example, hydrogenolysis with hydro-
gen over a palladium catalyst or with sodium in liquid
- ammonia.
When desired, one or both of the nitrogen atoms of
the imidazol-2-one ring may be substituted with an alkyl
group by any art-known procedure. Such methods include
reac~ing the appropriate N-unsubst7tuted aroylimidazol-
2-one of this invention with a base and an alkylating
agent in presence of an unreactive solvent. Suitable
bases for this reaction can be, for example, a hydride
such as sodium hydride or calcium hydride; a carbonate
or bicarbonate such as sodium carbonate or sodium bi-
carbonate; a phenoxide such as sodium phenoxide; an
alkoxide such as sodium ethoxide; or preferably a hy-
droxide such as sodium hydroxide. Suitable alkylating
agents for this reaction are, for example, an alkyl
halide such as methyl chloride, methyl bromide, or methyl
iodide; or a dialkylsulfate such as dimethylsulfate.
Suitable unreactive solvents are, for example, petroleum
ethers; chlorinated hydrocarbons such as carbon tetra-
chloride, chloroform, or methylene chloride; chlorinatedaromatics such as 1,2,4-trichlorobenzene~ o-dichloro-
benzene, or chlorobenzene; carbon disulfide; nitrobenzene;
ethereal solvents such as diethyl ether, tetrahydrofuran
~ . - .....

M-g64-
-14-
or p-dioxan; aromatic solvents such as benzene, toluene,
or xylene; or preferably the polar aprotic solvents such
as dimethylformamide ~DMF) or dimethylsulfoxide (DMSO).
The reaction is allowed to proceed from about 1 minute
to about 1 hour and the temperature may be from about
O~C to about 100C, preferably about 25C. When it is
desired that only one of the imidazol-2-one ni~rogen
atoms be substituted with an alkyl group, the appropriate
imidazol-2-one is reacted with from about 1 molar equiva-
lent to about 10 molar equivalents of a base, preferablyabou~ 1 molar equivalent and with about 1 molar equivalent
of an alkylating agent. Utilizing this procedure, both
- possible monoalkylated nitrogen isomers result. These
isomers are seperable by conventional art-known procedures
such as fractional crystallization, fractional distillation,
or chromatography. When it is desired that both nitrogen
atoms of the imidazol-2-one ring be alkyl substituted, the
appropriate imidazol-2-one is reacted with from about
2 molar equivalents to about 10 molar equivalents of a
base, preferably about 2 molar equivalents and from about
2 molar equivalents to about 10 molar equivalents of an
alkylating agent, preferably about 2 molar equivalents.
Finally, any reactive substituents on the aroyl rings,
if present, may become alkylated concurrently. That is,
the following X groups, X=OH, -NHR3, SO2NH2 and unsubsti-
tuted piperazino, are alkylated under identical reaction
conditions. if desired, the alkylation of the aroyl ring
substituents may be avoided by the use of suitable pro-
tecting groups well-known in the art, for example, ~=OH or
-NHR3 may be benzylated and later deblocked by hydrogenoly-
s i s .
When desired, the nitrogen atoms of the imidazol-2-
one ring may be substituted with an alkylcarbonyl group
by any suitable art-known procedure. Such methods include
reacting the N-unsu~stttuted aroylimidazol-2-ones of
this invention with an acyl halide, preferably an acyl
chloride such as acetyl chloride, n-propanoyl chloride,

M-964-C1
-15-
isopropanoyl chloride or butanoyl chloride. Normally,
acylation reactions utilizing acyl halides employ an
acid sponge such as triethylamine or pyridine to remove
any hydrohalide as it is formed. Furthermore, the corres-
ponding free acid or acid anhydride may be employed in-
stead of the acyl halides. Acylation reactions are
generally run without added solvent but may be performed
using any nonreactive solvent, for example, petroleum
ethers; chlorinated hydrocarbons such as chloroform~
methylene chloride or carbon tetrachloride; carbon disul-
find; ethereal solvents, such as diethylether, tetrahydro-
furan or p-dioxan or aromatic soivents such as benzene,
toluene or xylene. The reactions are allowed to proceed
for about 1 minute to about 100 hours, preferably from
about 1 hour to about 10 hours and the temperature may
be from about -78 to about 150C preferably from 0 to
100C. Finally, any reactive substituents on the aroyl
rings, if present, will become acylated concurrently.
That is, the following X groups, X=OH, -NHR3, -SO2NH2 and
unsubstituted piperazino, are acylated under identical
reaction conditions. If desired, the acylation of the
benzoyl ring substituents may be avoided by the use of
suitable protecting groups well-known in the art, for
example X=OH or -NHR3 may be benzylated and later de-
blocked by hydrogenolysis.
The alkali metal, alkaline earth metal, transitionmetal, main group metal, ammonium or organic ammonium
salts of the aroylimidazol-2-ones of this invention may
be prepared from a corresponding metal or ammonium basic
salt for example an alkoxide, such as sodium methoxide or
sodium ethoxide, a phenoxide, such as sodium phenoxide;
hydroxides, such as sodium hydroxide or potassium hydrox-
ide; or a carbonate/ such as sodium carbonate, potassium
carbonate, zinc carbonate, magnesium carbonate or sodium
hydrogen carbonate. These reactions may be per~ormed with
or without a so1vent. Suitable solvents are, for example,
lower alcohols, such as methanol, ethanolJ isopropanol,

M-964-Cl
-16-
n-propanol or n-butanol; aromatic solvents, such as
benzene, toluene or xylene; ethereal solvents, such as
diethyl ether, tetrahydrofuran or P-dioxan; and halo-
genated hydrocarbon solventsJ such as chloroform,
methylene chloride or carbon tetrachloride. The aroyl-
imidazol-2-one and base are allowed to react for about
1 minute to about 24 hours depending on the reactants and
the temperature which can be from about -78 to about
1~0C, preferably from about 0 to about 25C.
The aroyl chlorides or their corresponding carboxylic
acids, which are required for the Friedel-Crafts acyla-
tion of this invention, are either generally available
in the art or may be prepared by analogous procedures.
The imidazol-2-one starting materials of Formula 4 may
be prepared as described by or adapted from R. Duschinsky
and L. A. Dolan5 J. Am. Chem. Soc. 67, 2079 (19~5), R.
Duschinsky and L. A. Dolan, i. Am. Chem. Soc. 68, 2~50
(1945) or U.S. Patent 2,441,g3~.
The compounds of general Formula 1 may be used in
the treatment of cardiac failure including congestive
heart failure, backward heart failure, forward heart
failure, left ventricular heart failure, or right ventri-
cular heart failure or in the treatment of any other con-
dition which requires the strengthening of heart action
with a cardiotonic. In many respects these compounds
possess digitalis-like action. The compounds of general
Formula 1 may also be used in the treatment of hyperten-
sion including primary or essential hypertension,
hormonally induced hypertension, renal hypertension and
chemically induced hypertension. Finally, the compounds
of general Formula 1 may be used as antithrombotics.
They affect the coagulation of blood by preventing the
aggregation of blood platelets, which play a dominant
role in thrombotic conditions both in the initial event
and at the occlusive stage. Arterial thrombosis,

M-96~-Cl
55~
-17-
particularly in arteries supplying the heart muscle and
brain, is a leading cause of death and disability.
The compounds may be administered in various manners
to achieve the desired effect. The compounds may be
administered alone or in the form of pharmaceutical
preparations to the patient being treated either orally
or parenterally, that is, intravenously or intramuscu-
larly. The amount of compound administered will vary
with the severity of the hypertension, cardiac failure or
blood clotting and the mode of adm;nistration. For oral
administration the antihypertensively effective amount
of compound is from about 0.1 mg/kg (milligrams per
- kilograms) of patient body weight per day to about 500
mg/kg of patient body weight per day and preferably from
about 50 mg/kg of patient body weight per day to about
150 mg/kg of patient body weight per day.
For parenteral administration the antihypertensively
effective amount of compound is from about 0.01 mg/kg
of patient body weight per day up to about 150 mg/kg of
patient body weight per day and preferably from about
1.0 mg/kg of patient body weTght per day up to about 10.0
mg/kg of patient body weight per day. For oral or
parenteral administration the cardiotonically effective
amount of compound is from about 0.1 mg/kg of patient body
weight per day up to about 500 mg/kg of patient body
weight per day and preferably from about 0.1 mg/kg of
patient body weight per day up to about 10.0 ~g/kg of
patient body weight per day. For oral or parenteral
administration the anticoagulant effective amount of com-
pound is from about 0.1 mg/kg of patient body weight perday up to about 1000 mg/kg of patient body weight per day
and preferably from about 1 mg/kg of patient body weisht
per day up to about 100 mg/kg of patient body weight per
day.
- For oral administration a unit dosage may contain~
for example, from 10 to 100 mg of the active ingredient.
For parenteral administration a unit dosage may contain,

~3~ 5 ~ ~ M-964-C1
-18-
for example, from 5 to 50 mg of the active ingredient.
Repetitive daily administration of the compounds may be
desired and will vary with the condition of ~he patient
and the mode of administration.
As used herein the term patient is taken to mean a
warm blooded animalJ for example, birds, such as chickens
and turkeys, and mammals, such as primates, humans, sheep,
horses, bovine cows and bulls, pigs, dogs, cats, rats
and mice.
For oral administration the compounds can be for-
mulated Into solid or liquid preparations such as cap-
sulesJ pills, tablets, troches, powders, solutions, sus-
pensions or emulsions. The solid unit dosage forms can
be a capsule which can be of the ordinary gelative type
containing, for example, lubricants and inert filler,
such as lactosej sucrose, and cornstarch. In another
embodiment the compounds of general Formula 1 can be
tableted with conventional tablet bases such as lactose,
sucrose, and cornstarch in combination with binders,
such as acacia, cornstarch or gelatin, disintegrating
agents such as potato starch or alginic acid, and a lubri-
- cant such as stearic acid or magnesium stearate.
For parenteral administration the compounds may be
administ~red as injectable dosages of a solution or sus-
pension of the compound in a physiologlcally acceptablediluent with a pharmaceutical carrier which can be a
sterile liquid such as water and oils with or without the
addition of a surfactant and other pharmaceutically
acceptable adjuvants. Illustrative of oils which can be
employed in these preparations are those of petroleum,
animal, vegetable, or synthetic origin, for exampleJ
peanut oil, soybean oil, and mineral oil. In general,
water, saline, aqueous dextrose and related sugar 501u-
tions, ethanol and glycols such as propylene glycol or
- 35 polyethylene glycol are preferred liquid carriers,
particularly for injectable solutions.

l:~L3Z55~ M-964-Cl
- 1 9 -
The compounds can be administered in the form of a
depot injection or implant preparation which may be
formulated in such a manner as to permit a susta7ned re-
lease of the active ingredient. The active ingredient
can be compressed into pellets or small cylinders and
implanted subcutaneously or intramuscularly as depot
injections or implants. Implants may employ inert
materials such as biodegradable polymers or synthetic
silicones, for example, Silastic, silicone rubber manu-
factured by the Dow-Corning Corporation.
Following are illustrative pharmaceutical formu-
lations which may be employed in practicing the present
invention:
Preparation of a Tablet Formulation
Per Tablet
a) 1,3-Dihydro-4-(4-methoxybenzoyl)- 100 mg
~-methyl-2H-imidazol-2-one
b) Cornstarch 15 mg
c) Lactose 33.5 mg
d) Magnesium stearate 1.5 mg
Preparation of a Parenteral Formulation
a) 1,3-Dihydro-4-(4-methoxybenzoyl)-5- 1.000 g
methyl-2H-imidazol-2-one
b) Polyoxyethylene sorbitan monooleate2.000 g
c) Sodium chloride 0.128 9
d) Water for injection qs ad 20.000 ml
The following are examples of the use of the com-
pounds of this invention as antihypertensives, cardio-
tonics and anticoagulants.
EXAMPLE A
Use of 1,3-dihYdro-4-(4-methoxYbenzoYl)-~-methYl-2H
imidazol-2-one as an antihYpertensive
100 mg/kg of the title compound is administered orally
to s7x spontaneously hypertensive rats. This dose results
in a 40% decrease, on the average, in the blood pressure
wlthln 15 minutes of administration.

~3ZSS4 M-g64-cl
-20-
EXAMPLE B
Use of 1,3-dihYdro-4-(4-methoxYbenzoyl)-5-methvl-2H-
imidazol-?-one as a cardiotonic
Heart failure is induced in a dog by administering
sodium pentobarbitol (20 mg/kg) or propranalol hydro-
chloride (3 mg/kg) to the blood perfusing the heart.
Following administration of either of these cardiac depres-
sants the right atrial pressure increased dramatical1y
and cardiac output is severely depressed. Administration
of the title compound (1 mg/kg) reverses the failure as
indicated by reversal of the right atrial pressure and
cardiac output to near pretreatment levels.
EXAMPLE C
Use_of 1,~-dihydro-_-(4-methoxybenzoyl)-5-methyl-2H-
imidazol-?-one as an antithrombotic
When adenosine diphosphate is added to citrated
platelet rich human plasma a typical aggregation of blood
platelets occurs. However, if the title compound is
added to the citrated platelet rich human plasma in concen-
trations of 3, lQ, 30 and 100 ~g/ml and subsequently
adenosine diphosphate is added, the aggregation of blood
platelets is inhibited 33~ 49, 82 and 98%, respectively.
The following specific examples further illustrate
the preparation of compounds employed in the instant
invention.
EXAMPLE
1.3-DihYdro-4-(4-fluorobenzoYl)-5-methyl-2H-imida2ol-2-one
To a stirred mixture of g8.l 9 (1 mole) of 1,3-
dihydro-4-methyl-2H-imidazol-2-one, 266.7 9 (2 mole) of
anhydrous aluminum chloride and 500 ml of nitrobenzene is
added dropwise over 10 minutes, 158.6 g (1 mole) of p-
fluorobenzoyl chloride. The mixture is stirred at 60-6sC
for 6 hours, then poured on 2 kg of ice. The r~sulting
precipitate is washed with diethyl ether and water and
3~ is recrystallized from 1.2 liters of dimethylformamide
to give 131 g of the title compound. M.P. 289-292C.

M- 964-c 1
1~3~2~S~
-21-
EXAMPLE 2
1,3-DihYdro-4-methyl-5-r4-(1-piperidinyl)benzoyll-?H-
imidazol-2-one
A suspension of 11.0 9 (0.05 mole) of 1, 5-dihydro-
4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml
of piperdine is stirred at reflux temperature for 24
hours. Excess piperdine is evaporated under reduced pres-
sure and the residue is recrystallized twice from a mixture
of isopropanol and water to give 11.9 9 of the title
compound. M.P. 260-263C.
EXAMPLE 3
1.3-DihYdro-4-methYl-5-~4-(4-morDho_Inyl)benzoyll-2H-
imidazol-2-one
- Following the procedure of Example 2 but substituting
morpholine for piperidine, the title compound is obtained.
M.P. 283-286C.
EXAMPLE 4
1.3jDihl~dro-4-l4-(dirnethYlamino)benzoYll-~;-methyl-2H-
im~ azo -2-one
A mixture of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-
fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 100 ml of 30
aqueous solution of dimethylamine and 200 ml of ethanol
is heated in a pressure bomb at 130-135C for 22 hours.
The mixture is cooled, the solid is collected and
recrystallized from isopropanol-water to give the title
compound. M.P. >310C. ~-(max)(methanol) 364 nm
(~ = 23,300).
EXAMPLE
1,3-Dihydro-4-(4-hYdroxybenzoYl)-~-methYl-2H-imidazol-2-one
To a melt of 26 9 (0.23 mole) of pyridine hydro-
chloride at 200-205C is added 5.3 9 (0.023 mole) of 1,3-
dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one
and the mixture is stirred mechanically for 30 minutes.
The reaction mixture is poured on ice-2NHCl. The result-
ing precipitate is washed with water and recrystallized
from isopropanol-water to give the title compound. M.P.
> 300C. ~(max)(methanol) 320 nm (~ = 13,200).

11~2~S~ M-964-C1
EXAMPLE 6
~,~-DIhydro-4-methyl~5-r4-(methylthio)benzoyll-2H-
imidazol-2-one
A solution of 25.0 9 of 4-(methylthio)-benzoic acid
and 22 ml of thionyl chloride in 50 ml of benzene is
refluxed for 4 hours. Excess reagent and solvent is
evaporated and the residue is azeotroped 3 times with
benzene to remove all thionyl chloride. Th`e residue is
added dropwise to a mixture of 11.8 9 of 1,3-dihydro-4-
methyl-2H-imidazol-2-one, 40.0 9 of anhydrous aluminum
chloride and 100 ml of nitrobenzene. The resulting mix-
ture is stirred at 60-65C for 5 hours, poured on ice
and the precipitate that forms is collected, washed wi th
ethyl ether and water, and recrystallized from isopro-
panol-water to give the title compound. M.P. 255-258C.
(dec.).
EXAMPLE 7
1,3 Dihydro-4-(4-methoxYbenzoYl)-5-methyl-~-imidazol-2-
one
To 19.6 9 of 1,3-dihydro-4-methyl-2H-imidazol-2-one
and 53.2 9 of anhydrous aluminum chloride in 150 ml of
nitrobenzene is added dropwise 34.2 9 of P-methoxybenzoyl
chloride and the mixture is poured on 500 ml of 2N-HCl
and ice, washed ~ times with ethyl ether, the r,osulting
solid is recrystallized from isopropanol-water to give
the title compound. M .P. 257-258C (dec.).
EXAMPLE 8
~-Dihydro-4-(4-methoxYbenzoYl)-5-methYl-?H-imidazol -?-
one so ium salt
To 7.0 9 of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-
2H-imidazol-2-one in 100 ml of methanol is added 1.6 9 of
sodium methoxide. The mixture is heated on a steam bath
until homogeneous, filtered and evaporated to dryness.
The solid residue is recrystallized from isopropanol to
~S5 give the title compound. M.P. 2~0-282CC (dec.).

1~L3~5~ M-964-C1
-23-
EXAI~IPLE 4
4-Benzoyl-1,3-dihydro-5-methvlimidazol-2-one
To a solution of 3.0 9 of 4-methylim7dazol-2-one and
8.o 9 of aluminum chloride in 50 ml of nitrobenzene is
5 added dropwise 4.o 9 of benzoyl chloride. The solution
is warmed at 60C for 4 hours, poured over ice water,
slurried with ether and the resulting solids filtered
and dried to yield the title compound. M.P. 250-54C.
EXAMPLE 10
10 1,3-DihYdro-4-methYl-~-thienoY1-2H-imidazol-2-one
To a solution of 7.3 9 of 4-methylimidazol-2-one
and 10.8 9 of aluminum chloride in 150 ml of nitrobenzene
is added 12.0 9 of 2-thienoyl chloride. The mixture i 5
stirred at 60C for 3 hours, cooled and poured over ice
15 water. The organic portion is extracted into ethyl
acetate, dried and the organic solvent evaporated to give
the title compound. M.P. 212-215C .
EXAMPLE 11
1,3-Dihydro-4-(3,4-dimethoxYbenzoyl~-2H-imidazol-2-one
To a solution of 6.5 9 of 1,3 dihydro-4-methyl-2H-
imidazol-2-one and 14.6 9 of alurninum chloride in 65 ml
of nitrobenzene is added 17.6 9 of 3,4-dimethoxybenzoyl
chloride in portions. The mixture is stirred for 3 hours
at 60C, cooled and poured over ice water. The gummy
solids are filtered and recrystallized twice from ethyl
alcohol-water t~ afford the title compound. M.P. 257-
259C.
EXAMPLE 12
1,3-Dihydro-4-(?-furanoYl)-5-methyl-2H-imidazol-2-one
3o To a slurry of 8.9 9 of 1,3-dihydro-4-methyl-2H-
imidazol-2-one and 24.0 9 of aluminum chloride in 135 ml
Gf nitrobenzene is added 12.9 9 of furanoyl chloride
in a dropwise manner. The mixture is stirred at 60~
for 3 hours, cooled and poured over ice water. The solid
3~ is then filtered and recrystallized twice from methyl
alcohol to afford the title compound. ~1.P. 214-216C.

lle3~2554 M-964-C1
-24-
EXAMPLE 1~
1,3-Dihvdro-4-(2-thienovl)-2H-im dazol-2-one
In 50 ml of nitrobenzene is combined 13.~ 9 of
aluminum chloride, 4.2 9 of 1,3-dihydro-2H-imidazol-2-
5 one and 8.1 9 of thienoyl chloride. The mixture isstirred at 60C for 3 hours and poured over ice water.
The solids are filtered, washed with ether and recrystal-
lized twice from ethanol-water to afford the title
compound. M.P. ~i39-42oc.
EXAMPLE 14
4-Benzoyl-1,3-dihydro-2H-imidazol-2-one
To 51 ml of nitrobenzene is added 1.68 9 of 1,3-
dihydro-2H-imidazol-2-one, 5.3 9 o~ aluminum chloride
arId 3.1 9 of benzoyl chloride. The mixture is stirred
for 3 hours at 60C and poured into ice water. The
solids are filtered, washed with ether and recrystallized
twice from methyl alcohol-water to afford the title com-
pound. M.P. 329-30C.
EXAMPLE 15
1,3-Dihydro-4-furanoYl-2H-imidazol-2-one
To 50 ml of nitrobenzene is added 4.2 9 of 1,3-
dihydro-2H-imidazol-2-one) 13.3 9 of aluminum chloride
and 702 9 of furanoyl chloride. The mixture is stirred
at 60C for 3 hours and poured over ice water. The solids
are flltered, washed with ether and recrystallized twice
from ethanol-water to afford the title compounds. M.P.
318-321~C.
EXAMP~E 16
1,3-Dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-
imidazol-2-one
To 5.13 9. of 1,3-dihydro-4-methyl-2H-imidazol-2-one
and 7.98 9. of anhydrous aluminum chloride in 80 ml.
of nitrobenzene is added dropwise 10.60 9. of 3,4-
methylenedioxybenzoyl chloride and the mixture is poured
on 500 ml. of 2N-HCl and ice, washed 3 times with ethyl

M-964-C1
11~3ZSS~
-25-
ether, the resulting solid is collected to give the title
compound. M.p. 293-296C (dec).
EXAMPLE 17
1,3-Dihydro-4-(4-m thoxybenzoyl)-1,3,5-trimethyl-2H-
imidazol-2-one
In 120 ml of DMS0 ts placed 15.2 9 of powdered
potassium hydroxide, 8.o 9 of 1,3-dihydro-4-(4-methoxy-
benzoyl)-5-methyl-2H-imidazol-2-one, sodium salt and
19.5 9 of methyl iodide. The mixture is stirred at
room temperature for 60 minutes and poured into 800 ml
of water. Extraction with methylene chloride gives a
solid, which is crystallized from ether. M.p. 109-111C.
NMR: N-CH3 (6 protons) at 3.3 ppm.
EXAMPLE 18
1,3-Dihydro-~1 or 3),5-dimethyl-4-(4-methoxybenzoyl)
2H-imidazol 2-one
-
To 2.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-
methyl-2H-imidazol-2-one in 30 ml of DMS0 is added
o.288 9 of sodium hydride and 1.22 9 of methyl iodide.
The mixture is stirred at 22C for 30 minutes, poured
into methylene chloride and washed with water. The
solvent is dried and evaporated to give an oil which
when triturated with chloroform gives a solid. The solid
is crystallized from methanol; m.p. 225-228C.
25 Anal. calcd. for Cl2H14N203: C, 63.40; H, 5.73; N, 11.39.;
Found: C, 63.~4; H, 5.85, N, 11.21.;
NMR: N-Methyl; Singlet at 3.2 ppm.