The use of novel imidazolecarboxylic acid derivatives of the following general structure which are useful as antihypertensives, cardiotonics and antithrombotics ##STR1## wherein Q and T are an oxygen or sulfur atom; R is hydrogen, lower alkyl, lower alkylcarbonyl or benzoyl; R.sub.1 is hydrogen or --CH(R.sub.3)R.sub.4 ; R2 is lower alkoxy, phenoxy or phenoxy substituted at the ortho, meta, or para position with lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, lower alkylthio, lower alkylsulfone, or lower alkylsulfoxide; R.sub.3 is hydrogen or lower alkyl; R.sub.4 is hydrogen, hydroxy, lower alkoxy, lower alkylcarbonyl, --ONO.sub.2 or halogen; and their pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION 
This invention relates to the use of imidazolecarboxylic acid derivatives 
as antihypertensives, cardiotonics and antithrombotics. 
SUMMARY OF THE INVENTION 
This invention is directed to the use of imidazolecarboxylic acid 
derivatives of the general Formula I 
##STR2## 
wherein Q and T are each independently an oxygen atom or a divalent sulfur 
atom; R is hydrogen, lower alkyl, lower alkylcarbonyl or benzoyl; R.sub.1 
is hydrogen or --CH(R.sub.3)R.sub.4 ; R.sub.2 is lower alkoxy, phenoxy or 
phenoxy substituted at the ortho, meta or para position with lower alkyl, 
lower alkoxy, hydroxy, halogen, trifluoromethyl, lower alkylthio, lower 
alkylsulfone, or lower alkylsulfoxide; R.sub.3 is hydrogen or lower alkyl; 
R.sub.4 is hydrogen, hydroxy, lower alkoxy, lower alkylcarbonyloxy, 
--ONO.sub.2 or halogen; and their pharmaceutically acceptable salts 
thereof as antihypertensives, cardiotonics and antithrombotics. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As used herein, the term "lower alkyl" includes straight and branched chain 
alkyl of from 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, 
n-butyl and isobutyl. 
As used herein, the term "lower alkylcarbonyl" is taken to mean a group of 
the structure 
##STR3## 
wherein the alkyl moiety is a straight or branched alkyl of from 1 to 4 
carbon atoms such as methyl, ethyl, isopropyl, n-butyl and isobutyl. 
As used herein, the term "benzoyl" is taken to mean a group of the formula 
--(CO)C.sub.6 H.sub.5. 
As used herein, the term "lower alkoxy" includes straight and branched 
chain alkoxy of from 1 to 4 carbon atoms such as methoxy, ethoxy, 
isopropoxy, n-butoxy and isobutoxy. 
As used herein, the term "lower alkylcarbonyloxy" is taken to mean a group 
of the structure 
##STR4## 
wherein the alkyl moiety is a straight or branched chain alkyl of from 1 
to 4 carbon atoms such as methyl, ethyl, isopropyl, n-butyl and isobutyl. 
As used herein, the term "halogen" includes fluorine, chlorine, bromine or 
iodine. 
As used herein, the term "halide" includes fluoride, chloride, bromide, or 
iodide. 
As used herein, the term "lower alkylthio" includes straight and branched 
chain alkylthio of from 1 to 4 carbon atoms such as methylthio, ethylthio, 
isopropylthio, n-butylthio and isobutylthio. 
As used herein, the term "lower alkylsulfone" is taken to mean a group of 
the structure 
##STR5## 
wherein the alkyl moiety is a straight or branched alkyl of from 1 to 4 
carbon atoms such as methyl, ethyl, isopropyl, n-butyl or isobutyl. 
As used herein, the term "lower alkylsulfoxide" is taken to mean a group of 
the structure 
##STR6## 
wherein the alkyl moiety is a straight or branched alkyl of from 1 to 4 
carbon atoms such as methyl, ethyl, isopropyl, n-butyl or isobutyl. 
The preferred compounds of this invention are those compounds of Formula 1 
wherein Q and T are each oxygen atoms. 
The more preferred compounds of this invention are those compounds of 
Formula 1 wherein R is hydrogen. Also included among those compounds of 
this invention considered more preferred are those compounds of Formula 1 
wherein R.sub.4 is lower alkoxy or lower alkylcarbonyloxy. 
The most preferred compounds of this invention are those compounds of 
Formula 1 wherein R.sub.2 is methoxy, ethoxy or phenoxy. Also included 
among those compounds of this invention considered most preferred are 
those compounds of Formula 1 wherein R.sub.4 is hydrogen, methyl, hydroxy, 
methoxy, ethoxy or acetyloxy. 
As examples of compounds of Formula 1 there may be mentioned the following: 
Methyl 2-oxo-imidazole-4-carboxylate; 
Phenyl 5-methyl-2-thioxo-imidazole-4-carboxylate; 
(3-methylphenyl) 5-(bromomethyl)-2-oxo-imidazole-4-carboxylate; 
(2-hydroxyphenyl) 5-(1-ethoxyethyl)-2-oxo-imidazole-4-carboxylate; 
(4-methylthiophenyl) 5-ethyl-2-oxo-imidazole-4-carboxylate; 
ethyl 5-acetoxymethyl-2-oxo-imidazole-4-carboxylate; 
(3-chlorophenyl) 5-hydroxymethyl-2-oxo-imidazole-4-carboxylate nitrate 
ester; 
(4-t-butylphenyl) 5-(1-hydroxyethyl)-2-oxo-imidazole-4-thiocarboxylate; 
Propyl 1,3-diacetyl-5-isobutyl-2-oxo-imidazole-4-carboxylate; 
Phenyl 1,3-isopropyl-5-acetoxymethyl-2-oxo-imidazole-4-carboxylate. 
Those compounds of Formula 1 wherein R is hydrogen are acidic and may form 
pharmaceutically active salts of Formula 2 
##STR7## 
wherein Q, T, R.sub.1 and R.sub.2 are as defined in Formula 1, and M is a 
pharmaceutically acceptable alkali metal such as sodium or potassium; 
alkaline earth metal such as calcium or magnesium; transition metal such 
as zinc or iron; or main group metal. 
In general, the compounds of this invention are prepared by standard 
techniques analogously known in the art. 
More specifically, the imidazolecarboxylic acid derivatives of the 
invention wherein T is an oxygen atom and R is hydrogen are well known in 
the prior art and may be prepared by reaction of an aminoketocarboxylate 
of Formula 3 
##STR8## 
wherein R.sub.1 and R.sub.2 are as defined in Formula 1 with a cyanate or 
thiocyanate salt, as appropriate, preferably a sodium or potassium cyanate 
or thiocyanate. This reaction is performed by mixing about 1 molar 
equivalent of the appropriate aminoketocarboxylate with about 1 to about 5 
molar equivalents, preferably about 1 molar equivalent, of a cyanate or 
thiocyanate salt in a suitable solvent. The reaction is allowed to proceed 
for about 5 minutes to about 10 hours depending on the reactants, the 
solvent and the temperature which can be from about -10.degree. to about 
50.degree. C., preferably 0.degree. C. Suitable solvents for this reaction 
are any non-reactive solvent, preferably water miscible solvent, for 
example, an organic acid such as acetic acid; an alcohol such as methanol 
or ethanol; or an ether such as tetrahydrofuran or p-dioxan. Preferably 
the solvent is mixed with water. The preferred solvent is aqueous ethanol. 
The product of this reaction may be isolated by any art-known procedure 
such as by conversion to the corresponding sodium or potassium salt and 
reprecipitation with carbon dioxide or a mineral acid such as dilute 
hydrochloric acid. 
When it is desired that T be a divalent sulfur atom, the corresponding 
imidazolecarboxylic acid of Formula 1 wherein T is an oxygen atom is 
reacted with phosphorus pentasulfide, P.sub.2 S.sub.5, by procedures 
generally known in the art. This reaction may be performed by mixing about 
1 molar equivalent of the imidazolecarboxylic acid wherein T is an oxygen 
atom, with about 1 to about 5 molar equivalents, preferably about 1 molar 
equivalent, of P.sub.2 S.sub.5, together with a suitable solvent. This 
reaction is allowed to proceed for about 1 to about 10 hours, preferably 
about 5 hours, depending on the reactant, the solvent and the temperature 
which can be from about 25.degree. C. to about 125.degree. C., preferably 
about 80.degree. C. A suitable solvent for this reaction is any 
non-reactive solvent, for example, tetrahydrofuran, p-dioxan, benzene, 
toluene or pyridine. The preferred solvent is pyridine. 
When desired, one or both of the nitrogen atoms of the imidazole ring may 
be substituted with an alkyl group by any art-known procedure. Such 
methods include reacting the appropriate N-unsubstituted 
imidazolecarboxylic ester of this invention with a base and an alkylating 
agent in the presence of an unreactive solvent. Suitable bases for this 
reaction can be, for example, a hydride such as sodium hydride or calcium 
hydride; or an alkoxide such as sodium ethoxide. Suitable alkylating 
agents for this reaction are, for example, an alkyl halide such as methyl 
iodide; or a dialkylsulfate such as dimethylsulfate. Suitable unreactive 
solvents are, for example, dimethylformamide (DMF) or dimethylsulfoxide 
(DMSO). The reaction is allowed to proceed from about 1 hour to about 10 
hours and the temperature may be from about 0.degree. to about 100.degree. 
C., preferably about 25.degree. C. When it is desired that only one of the 
imidazole ring nitrogen atoms be substituted with an alkyl group, the 
appropriate imidazolecarboxylic ester is reacted with from about 1 molar 
equivalent of an alkylating agent. Utilizing this procedure, both possible 
monoalkylated nitrogen isomers result. These isomers are separable by 
conventional art-known procedures such as fractional crystallization, 
fractional distillation or chromatography. When it is desired that both 
nitrogen atoms of the imidazole ring be alkyl substituted, the appropriate 
imidazolecarboxylic ester 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 equivalent to about 10 molar 
equivalents of an alkylating agent, preferably about 2 molar equivalents. 
Finally, any hydroxy substituents, if present, may become alkylated 
concurrently. That is, when R.sub.4 is hydroxy or when R.sub.2 is a 
phenoxy substituted with hydroxy, such groups are alkylated under 
identical reaction conditions. If desired, the alkylation of these 
substituents may be avoided by the use of suitable protecting groups 
well-known in the art, for example, hydroxy groups may be benzylated and 
later deblocked by hydrogenolysis. 
When desired, the nitrogen atoms of the imidazole ring may be substituted 
with an alkylcarbonyl or benzoyl group by any suitable art-known 
procedure. Such methods include reacting the ring N-unsubstituted 
imidazolecarboxylic ester of this invention with an acid anhydride. The 
reactions are allowed to proceed for about 1 hour to about 20 hours, 
preferably about 5 hours and the temperature may be from about 0.degree. 
to about 200.degree. C. preferably 135.degree. C. Finally, any hydroxy 
substituents, if present, will become acylated or benzoylated 
concurrently. That is, when R.sub.4 is hydroxy or when R.sub.2 is a 
phenoxy substituted with hydroxy, such groups are acylated under identical 
reaction conditions. If desired, the acylation of these substituents may 
be avoided by the use of suitable protecting groups well-known in the art, 
for example hydroxy groups may be benzylated and later deblocked by 
hydrogenolysis. 
The alkali metal, alkaline earth metal, transition metal or main group 
metal, salts of the imidazolecarboxylic esters of this invention may be 
prepared from a corresponding metal alkoxide, such as sodium methoxide or 
potassium ethoxide, or a metal hydride such as calcium hydride. Suitable 
solvents are, for example, lower alcohols, such as methanol, ethanol, 
isopropanol, n-propanol or n-butanol, dimethylformanide or 
dimethylsulfoxide. The imidazolecarboxylic acid derivative and base are 
allowed to react for about 1 minute to about 24 depending on the reactants 
and the temperature which can be from about -78.degree. to about 
150.degree. C., preferably from about 0.degree. to about 25.degree. C. 
The aminoketocarboxylate of Formula 3 may be prepared by reduction of the 
appropriate oxime of Formula 4 
##STR9## 
wherein R.sub.1 and R.sub.2 are as defined above in Formula 1. These 
oximes are reduced by any suitable method generally known in the art such 
as catalytically in acidic alcoholic medium such as ethanol hydrochloric 
acid over an appropriate noble metal catalyst such as palladium on 
charcoal or with zinc or tin in acetic acid/acetic anhydride solution. 
The oximes of Formula 4 may be prepared by any suitable art-known procedure 
such as nitrosation of the appropriate .beta.-ketoesters of Formula 5 
##STR10## 
wherein R.sub.1 and R.sub.2 are as defined above in Formula 1. Suitable 
nitrosation reactions are reviewed by O. Tousler in "Organic Reactions," 
volume VII, pp. 327-377. 
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 
ventricular heart failure or in the treatment of any other condition 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 hypertension 
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, particularly in arteries supplying the heart muscle and brain, 
is a leading cause of death and disability. 
The utility of Formula 1 compounds as antihypertensives may be determined 
by administering the test compound (50 mg/5 kg p.o.) to six spontaneously 
hypertensive rats (having a systolic blood pressure greater than 150 mm 
Hg) at 50 mg/5 ml/kg using 0.5% methylcellulose. Caudal artery blood 
pressure is recorded via a photocell transducer placed over the tail just 
behind the pressure cuff. Three readings of approximately 2 minutes are 
made 1, 2, 3, 4 and 24 hours after dosing. A compound in this test is 
considered active if the mean fall in blood pressure is significantly 
(p&lt;0.05) greater than control for at least one of the 1, 2, 3, 4, or 24 
hours post-drug treatment time periods. 
The utility of Formula 1 compounds as cardiotonics may be determined by 
administering the test compound (0.1-10 mg/kg) intravenously, 
intraperitoneally, intraduodenally or intragastrically in a suitable 
vehicle to a mongrel dog (either sex). The test dogs are anesthetized and 
prepared by isolating a suitable artery (e.g. femoral or common carotid) 
and vein (e.g., femoral or external jugular); introducing polyethylene 
catheters filled with 0.1% Heparin-Na to record arterial blood pressure 
and administer compounds, respectively. The chest is opened by splitting 
the sternum at the midline or by an incision at the left fifth intercostal 
space, and a pericardial cradle is formed to support the heart. A 
Walton-Brodie strain gage is sutured to the right or left ventricle to 
measure myocardial contractile force. An electromagnetic flow probe may be 
placed around the root of the ascending aorta for measuring cardiac output 
less coronary blood flow. The aorta and vena cava may be connected to 
measure the venous return to the heart. Alternatively the heart and the 
lungs may be vascularly isolated from the rest of the circulatory system. 
Heart failure is induced by administering sodium pentobarbital (20-40 
mg/kg injection followed by a constant infusion of 0.25 mg/kg/min), by 
administering propranalol hydrochloride (4 mg/kg injection followed by a 
constant infusion of 0.18 mg/kg/min) intravenously, or by administering 
sodium pentobarbital (0.15 mg/ml) into the blood perfusing the heart. 
Following administration of any of these cardiac depressants, the right 
atrial pressure dramatically increases and cardiac output is severely 
depressed. Reversal of these effects by the test compound indicates 
cardiotonic activity. 
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 intramuscularly. The amount of 
compound administered will vary with the severity of the cardiac failure 
and the mode of administration. 
For oral or parenteral administration the cardiotonically effective amount 
of compound is from about 0.01 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 50.0 mg/kg of patient 
body weight per day. 
For oral administration a unit dosage may contain, for example, from 1 to 
500 mg of the active ingredient. For parenteral administration a unit 
dosage may contain, for example, from 1 to 50 mg of the active ingredient. 
Repetitive daily administration of the compounds may be desired and will 
vary with the condition of the patient and the mode of administration. 
As used herein the term patients is taken to mean warm blooded animals, 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 formulated into solid or 
liquid preparations such as capsules, pills, tablets, troches, powders, 
solutions, suspensions or emulsions. The solid unit dosage forms can be a 
capsule which can be of the ordinary gelatin type containing, for example, 
lubricants and inert filler, such as lactose, 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 
lubricant such as stearic acid or magnesium stearate. 
For parenteral administration the compounds may be administered as 
injectable dosages of a solution or suspension of the compound in a 
physiologically acceptable diluent 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 example, peanut 
oil, soybean oil and mineral oil. In general, water, saline, aqueous 
dextrose and related sugar solutions, ethanol and glycols such as 
propylene glycol or polyethylene glycol are preferred liquid carriers, 
particularly for injectable solutions. 
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 sustained release 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 manufactured by the Dow-Corning 
Corporation. 
The following are illustrative examples of the preparation and use of the 
compounds of this invention.

EXAMPLE 1 
1,1-Dimethylethyl 2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate 
To a solution of 31.6 g (0.2 ml) of tert-butyl acetoacetate in 30 ml of 
acetic acid, stirred and cooled in an ice-methanol bath, is added dropwise 
over 70 minutes a solution of 15.2 g (0.22 ml) of sodium nitrite in 50 ml 
of water. The mixture is stirred for 2 hours at 0.degree. C., and 500 ml 
of ethyl ether is added. The ethereal solution is washed with water, 
sodium bicarbonate solution, sodium chloride solution, and is dried over 
magnesium sulfate. The solvent is evaporated leaving 36.4 g of an oil that 
is tert-butyl 2-(oximino)-3-oxobutanoate. 
The oil is dissolved in 300 ml of ethanol and 200 ml of 2 N hydrochloric 
acid. 2.0 g of 10% palladium on charcoal is added and the mixture is 
shaken under hydrogen gas in a Parr shaker until 2 molar equivalents of 
hydrogen are consumed (about 2 hours). The catalyst is removed by 
filtration to given an acidic solution of tert-butyl 
2-amino-3-oxo-butanoate, which is divided into 2 equal portions. 
To one half of the above solution is added 16.2 g (0.2 ml) of potassium 
cyanate and the mixture is heated on a steam bath for 1 hour. The 
solution, which becomes neutral, is acidified with 2 N hydrochloric acid 
and the product crystallizes on cooling. Recrystallization from a mixture 
of ethanol and water gives the title compound, m.p. 225.degree. C. (dec.). 
EXAMPLE 2 
Ethyl 2,3-Dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate 
This compound was prepared in the manner described in example 1, m.p. 
217.degree.-220.degree. C. Synthesis of this compound was first described 
by Gabriel and Posner, Ber., 27, 1144 (1894). 
EXAMPLE 3 
Ethyl 5-Ethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 
This compound was prepared in the manner described in example 1, m.p. 
186.degree.-189.degree. C. Synthesis of this compound was first described 
by Duschinsky and Dolan, J. Am. Chem. Soc., 68, 2350 (1946). 
EXAMPLE 4 
Ethyl 1,3-Diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidzole-4-carboxylate 
A mixture of 54.5 g (0.32 ml) of ethyl 
2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate and 240 ml of acetic 
anhydride is stirred at reflux temperature for 13 hours. Acetic anhydride 
and the acetic acid that forms is distilled off (150 ml) and is replaced 
by fresh acetic anhydride. After another 9 hours of reflux the mixture is 
evaporated under reduced pressure and the oily residue is triturated with 
cyclohexane. The resulting crystalline material is dissolved in 600 ml of 
boiling cyclohexane, a small amount of insoluble material is removed by 
decantation, the solution is decolorized by treatment with charcoal (which 
is filtered off), 400 ml of hexane is added and the solution is allowed to 
cool (-20.degree. C.). The crystalline product is collected, 48.4 g (56%), 
m.p. 56.degree.-58.degree. C. (dec.). 
EXAMPLE 5 
Ethyl 
1,3-Diacetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 
A mixture of 12.7 g (0.05 ml) of ethyl 
1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate 
(example 3), 9.3 g (0.052 ml) of N-bromosuccinimide and about 100 mg of 
benzoyl peroxide in 400 ml of carbon tetrachloride is refluxed for 4 hours 
with stirring. The mixture is cooled in ice, the precipitated succinimide 
is removed by filtration, and the filtrate is evaporated to give 28.8 g of 
an oil. An NMR spectrum (in CDCl.sub.3) shows this to be the title 
compound. 
EXAMPLE 6 
Ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 
Crude ethyl 
5-(bromomethyl)-1,3-diacetyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 
is dissolved in 30% hydrobromic acid in acetic acid and the solution is 
allowed to stand at room temperature for 4 hours. The product 
precipitates, is collected and dried in vacuo at 80.degree. C. over KOH, 
m.p. 193.degree.-194.degree. C. (dec.). 
EXAMPLE 7 
Ethyl 
3-acetyl-5-[(acetyloxy)methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylat 
e 
To a solution of compound of Example 1 (2.9 g) 60 ml of acetic acid is 
added 1.7 g of silver acetate and the mixture is stirred at 25.degree. C. 
for 6 hours. Silver salts are removed by filtration and the filtrate is 
evaporated to dryness. The residue is recrystallized twice from ethyl 
acetate/hexane (1:1) to give the title compound, m.p. 
138.degree.-139.degree. C. 
EXAMPLE 8 
Ethyl 
1,3-Diacetyl-2,3-dihydro-5-(hydroxmethyl)-2-oxo-1H-imidazole-4-carboxylate 
nitrate ester 
To a cold (0.degree. C.) solution of 8.5 g (0.05 ml) of silver nitrate in 
100 ml of dry acetonitrile is added dropwise over 30 minutes a solution of 
8.3 g (approximately 0.025 ml) of crude ethyl 
1,3-diacetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate 
(example 4) in 40 ml of acetonitrile. The mixture is stirred for 45 
minutes at 0.degree. C. The precipitated silver bromide is removed by 
filtration and the filtrate is evaporated to dryness. The residue is 
partitioned between ethyl acetate and water, the ethyl acetate solution is 
washed with water and dried over magnesium sulfate, and the solvent is 
evaporated. The resulting oil is crystallized from a mixture of ethyl 
acetate and hexane, and recrystallized from ethyl acetate to give the 
title compound, m.p. 84.degree.-85.degree. C. 
EXAMPLE 9 
Cardiotonic Activity of 5-Alkyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic 
Acid Esters 
Mongrel dogs of 1-3 kg body weight were anesthethized with 35 mg/kg iv of 
pentobarbital sodium. Their chests were opened surgically and a 
pericardial cradle was formed to support the heart. A Brodie-Walton strain 
gage was sutured to the left ventrical to monitor myocardial contractile 
force. Devices to monitor heart rate and arterial blood pressure were also 
attached. 
Test compounds were weighted and dissolved in dimethylacetamide and diluted 
with water to known concentrations and the solutions were infused 
intravenously through polyethylene catheters filled with 0.1% Heparin 
sodium. The amount of test compound infused was adjusted to give 0.3, 1 
and 3 mg per kg of body weight of the animal. 
The increase of myrocardial contractile force following administration of 
test compound at each concentration was measured. From these measurements 
the effective dose, that is the dose that causes an increase of 
contractile force of 30% for a duration of at least 20 minutes, was 
calculated. 
The following results were obtained: 
______________________________________ 
Effective Dose 
Compound mg/kg/IV 
______________________________________ 
1 0.45 
2 0.44 
3 0.51 
______________________________________ 
Compound 1: Ethyl 5methyl-2-oxo-1H-imidazole-4-carboxylate 
Compound 2: 1,1Dimethylethyl 5methyl-2-oxo-1H-imidazole-4-carboxylate 
Compound 3: Ethyl 5ethyl-2-oxo-1H-imidazole-4-carboxylate