JPH0233032B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to aroylimidazolones and their use as cardiotonic agents.

The present invention is based on the general formula 1 Pharmaceutically active 1,3-dihydro-2H-imidazol-2-ones [wherein Q and T are each an oxygen atom or a divalent sulfur atom, R is hydrogen,
Alternatively, it is lower alkanoyl, R ₁ is lower alkyl, and Ar is pyridyl or phenyl optionally optionally substituted with lower alkoxy, provided that when Q and T are both oxygen atoms, Ar is phenyl optionally substituted with lower alkoxy] and acid-base addition salts thereof. These compounds are useful as cardiotonic agents in the treatment of heart failure.

As used herein, the term "lower alkyl" is 1
Includes straight-chain or branched alkyl of ~4 carbon atoms, ie methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary-butyl.

As used herein, the term "lower alkoxy" refers to straight or branched chain alkoxy of 1 to 4 carbon atoms, i.e. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. include.

As used herein, the term "halogen" refers to fluorine,
Includes chlorine or bromine.

The term "lower alkanoyl" embraces straight-chain or branched alkanoyl groups of 1 to 4 carbon atoms, such as acetyl, propionyl, n-butyryl or isobutyryl.

As used herein, the term "phenyl optionally substituted with lower alkoxy" means means the group of In the formula, R ₃ to _{R 6} can be hydrogen or lower alkoxy.

The term "pyridyl" as used herein is 2
-, 3- and 4-pyridyl. The optional substituents on the pyridyl ring of the compounds of the present invention are bonded to any available carbon atom of the pyridine ring. The optional substituents on the pyridyl ring are lower alkyl, halogen, lower alkoxy or lower alkylthio groups.

Formula 1 compounds when R is hydrogen are acidic;
Pharmaceutically active base addition salts of Formula 2 can be formed.

where Ar, Q, T and R ₁ are defined in Formula 1, and M is a pharmaceutically acceptable alkali metal ion such as sodium or potassium ion; an alkaline earth ion such as calcium or magnesium ion. ; transition metal ions such as zinc or iron ions, or main group metal ions such as aluminum ions. Generally pharmaceutically acceptable base addition salts are crystalline materials that are more soluble in water and various hydrophilic solvents and generally exhibit higher melting points than their free acid forms.

Formula 1 compounds where Ar is pyridyl are capable of forming pharmaceutically active acid addition salts with inorganic or organic acids. Examples of suitable salt-forming inorganic acids include hydrochloric, hydrobromic, sulfuric and phosphoric acids, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of suitable salt-forming organic acids include mono-, di-, and tricarboxylic acids. Examples of such acids are e.g. acetic acid, glycolic acid, lactic acid, pyrupic acid, malonic acid, succinic acid,
Glutaric acid, fumaric acid, malic acid, tartaric acid,
Citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenyl acetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. . Such salts may exist in hydrated or substantially anhydrous forms. Generally, the acid addition salts of these compounds are crystalline materials that are soluble in water and various hydrophilic organic solvents, and generally have higher melting points and increased chemical stability compared to their free base forms. show.

From the general formula 1 above, the compounds of the present invention are 1,
3-dihydro-4-nicotinoyl-2H-imidazol-2-one, 1,3-dihydro-4-isonicotinoyl-2H-imidazol-2-one,
It is clear that 1,3-dihydro-4-benzoyl-2H-imidazol-2-one is included.

Preferred compounds of the invention are those of formula 1, where R is hydrogen, Q and T are each an oxygen atom, and Ar is pyridyl.

More preferred compounds of the invention are compounds of formula 1 when R ₁ is methyl or ethyl.

The most preferred compounds of the invention are compounds of formula 1 where Ar is unsubstituted 4-pyridyl.

Examples of compounds of general formula 1 include the following.

1,3-dihydro-4-methyl-5-[4-methoxy(thiobenzoyl)]-2H-imidazole-2-thione, In general, the compounds of the present invention can be prepared using standard procedures analogously known in the art. made by.

Most particularly, imidazol-2-one derivatives of formula 1, where T is an oxygen atom and R is hydrogen, are: prepared by the reaction of an aminodiketone of [wherein R ₁ and Ar are as defined in formula 1] with a suitable dianate or thiocyanate, preferably cyanic acid or sodium or potassium thiocyanate. . This reaction involves adding about 1 molar equivalent of the appropriate aminodiketone to about 1 molar equivalent of the cyanate or thiocyanate.
to about 5 molar equivalents, preferably about 1 molar equivalent, in a suitable solvent. The reaction takes about 50 minutes depending on reactants, solvent and temperature.
The temperature is about 0° to about 100°C, preferably about 80°C. Suitable solvents for this reaction are any non-antique solvents such as water or water-miscible solvents, e.g. organic acids such as acetic acid,
alcohols such as methanol or ethanol,
or an ether such as tetrahydrofuran or p-dioxane. Preferably, the non-aqueous solvent is mixed with water. The preferred solvent is water.

The products of this reaction can be isolated by any procedure known in the art. For example, it is converted to the corresponding sodium or potassium salt and isolated by reprecipitation with carbon dioxide or a mineral acid such as dilute hydrochloric acid.

When Q and T are each an oxygen atom and R is hydrogen, compounds of formula 1 are represented by formula 4 1 of [where R ₁ is defined in formula 1],
It is produced by Friedel-Crafts acylation of 3-dihydro-2H-imidazol-2-one. The acylating agent is an optionally substituted aroyl halide, preferably an optionally substituted aroyl chloride, i.e. an optionally substituted pyridoyl chloride, benzoyl chloride, furanoyl chloride, thienoyl chloride. or pyroyl chloride.

To carry out the Friedel-Crafts reaction of the present invention, one molar equivalent of a suitable imidazol-2-one is mixed with about 1 molar equivalent to about 10 molar equivalents, preferably about 3 to 6 molar equivalents of a Lewis acid catalyst and a suitable solvent. ,
For example petroleum ether; chlorinated hydrocarbons such as carbon tetrachloride, ethylene chloride, 1,1,2,2-tetrachloroethane, methylene chloride or chloroform; 1,2,4-trichlorobenzene or 0-dichlorobenzene. Chlorinated aromatics; carbon disulfide; or premixing in nitrobenzene. A preferred solvent is 1,1,2,2-tetrachloroethane (tetrachloroethane). About 1 molar equivalent to about 10 molar equivalents, preferably about 1 molar equivalent, of a suitable aroyl compound is added to imidazol-2-one,
The mixture of Lewis acid and solvent is preferably added dropwise and the reaction is allowed to proceed for about 0.5 to about 10 hours, preferably about 1 hour to about 5 hours, depending on the reactants, solvent and temperature. The temperature may be about -78° to about 150°C, preferably about 0° to about 100°C, most preferably about 85°C. The resulting aroylimidazol-2-one can be isolated from the reaction mixture by any suitable procedure known in the art, quenching the reaction mixture with ice water or water, and neutralizing with sodium bicarbonate or other weak aqueous base. Preferably, the product is then removed by filtration or by extraction with an organic solvent, typically ethanol, followed by removal of the solvent. Purification is typically by chromatography on silica gel.

Lewis acid catalysts suitable for use in the above Friedel-Crafts reactions are metals such as aluminum, cerium, copper, iron, molybdenum, tungsten or zinc; Bronsted acids, such as phosphoric acid,
sulfuric acid, sulfonic acid, or hydrohaloacids such as hydrochloric acid or hydrobromic acid; halogen-substituted acetic acids such as chloroacetic acid or trifluoroacetic acid; or metal halides such as boron halides, zinc chloride, zinc bromide, beryllium chloride, copper chloride , iron bromide (), iron chloride (), mercury chloride (), mercuric chloride (), antimony bromide, antimony chloride, titanium bromide (), titanium chloride (), titanium chloride (), aluminum bromide or preferably is aluminum chloride.

When T is desired to be a divalent sulfur atom, the corresponding aroylimidazol-2-one of formula 1 where T is an oxygen atom can be converted to phosphorus pentasulfide P ₂ S ₅ by procedures generally known in the art. react with. This reaction is
About 1 molar equivalent of aroylimidazol-2-one when T is an oxygen atom is mixed with a suitable solvent to about 1
from about 5 molar equivalents, preferably about 1 molar equivalent
Mix _{with P2S5} . The reaction is allowed to proceed for about 1 to about 10 hours, preferably about 5 hours, depending on the reactants, solvent, and temperature, and the temperature is about 25°C to about 125°C.
Preferably it is about 80°C. Suitable solvents for this reaction are any non-reactive solvents, such as tetrahydrofuran, p-dioxane, benzene, toluene or pyridine. A preferred solvent is toluene.

If desired, one or both of the nitrogen atoms of the imidazol-2-one ring can be substituted with an alkyl group by procedures known in the art. Such methods include reacting the appropriate Formula 1 compound, where R is hydrogen, with a base and an alkylating agent in the presence of a non-reactive solvent. A suitable base for this reaction is
For example, it can be a hydride, such as sodium hydride or calcium hydride; an alkoxide, such as sodium ethoxide. Suitable alkylating agents for this reaction are, for example, alkyl halides, such as methyl iodide; or dialkyl sulfates, such as dimethyl sulfate. Suitable non-reactive solvents are, for example, dimethylformamide (DMF) or dimethylsulfoxide (DMSO). Continue the reaction for about 1 minute or
Proceed for 10 hours and the temperature may be between about 0° and about 100°C, preferably about 25°C. When it is desired to substitute only one of the imidazol-2-one nitrogen atoms with an alkyl group, a suitable aroylimidazol-2-one is added in an amount of about 1 molar equivalent to about 10 molar equivalents of a base, preferably about 1 molar equivalent of a base. , and about 1 molar equivalent of an alkylating agent. Utilizing this procedure, both possible monoalkylated nitrogen isomers are generated.
These isomers can be separated by conventional procedures known in the art, such as fractional crystallization, fractional distillation, or chromatography. Imidazole-2
If it is desired to substitute both nitrogen atoms of the -one ring with alkyl substituents, about 2 molar equivalents to about 10 molar equivalents of the appropriate imidazol-2-one, preferably about 2 molar equivalents of base and about 2 molar equivalents to about 10 molar equivalents, React with about 10 molar equivalents, preferably about 2 molar equivalents of alkylating agent.

If desired, the nitrogen atom of the imidazol-2-one ring can be replaced with an alkanoyl or benzoyl group by suitable procedures known in the art. Such a process comprises combining an imidazol-2-one of formula 1, where R is hydrogen, with an acyl halide, preferably an acyl chloride, such as acetyl chloride, n-chloride.
This includes reacting with propanoyl, isopropanoyl chloride or benzoyl chloride. Typically, acylation reactions utilizing acyl halides use an acid sponge such as triethylamine or pyridine to remove any hydrohalide produced. Furthermore, instead of acyl halides, corresponding acid anhydrides can be used. Acylation reactions are generally carried out without addition of solvent, but can be carried out using any non-reactive solvent. For example, petroleum ethers;
Chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; carbon disulfide; ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane; or aromatic solvents such as benzene, toluene or xylene can be used. The reaction is allowed to proceed for about 1 minute to about 20 hours, preferably about 5 hours, at a temperature of about 0° to about 200°C, preferably 135°C.
It is.

The alkali metal, alkaline earth metal, transition metal, main group metal base addition salts of imidazol-2-ones of the present invention are prepared from the corresponding metal salts, such as alkoxides such as sodium methoxide or potassium ethoxide; Made from hydrides such as calcium hydride. These reactions can be carried out with or without a solvent. Suitable solvents are lower alcohols such as methanol, ethanol, isopropanol, n-propanol or n-propanol.
-butanol; or dimethylformamide (DMF). The imidazol-2-one and the base are reacted for about 1 minute to about 24 hours, preferably for about 1 hour, depending on the reactants and temperature, at a temperature of about -78°C to about 150°C, preferably about 0°C to about 150°C. about
In the range of 25℃.

Acid addition salts of Formula 1 compounds where Ar is pyridyl are made by conventional procedures such as treatment of the Formula 1 compound with a suitable inorganic or organic acid. For example, 1 to 10 molar equivalents of acid to 1 molar equivalent of compound of formula 1 -
Add at 5° to 80°C, typically room temperature, and allow the reaction to proceed.
Allow to proceed for 0.1 to 5 hours. These reactions can be carried out with or without the addition of a solvent. Suitable solvents are, for example, lower alcohols such as methanol, ethanol, isopropanol, n-propanol or n-butanol, or water.

Aminodiketones of formula 3 are of formula 5 [wherein R ₁ and Ar are as defined above in equation 1]
is produced by reduction of a suitable oxime. These oximes are reduced by any suitable method commonly known in the art. With a suitable noble metal catalyst such as palladium on charcoal in an acidic alcoholic medium such as ethanol-hydrochloric acid,
or catalytically reduced by zinc or tin in acetic acid/acetic anhydride.

The oxime of formula 5 is the oxime of formula 6 [wherein R ₁ and Ar are as defined above in equation 1]
by any suitable procedure known in the art, such as nitrosation of the appropriate diketone. A suitable nitrosation reaction is described by O. Theusler (O.
Tousler), Organic Reactions, Vol. 327-
Discussed on page 377.

Formula 4 compounds and aroyl chlorides,
For example, pyridyl, benzoyl, pyroyl, thienoyl and furanyl chlorides are generally known in the art or readily made by similar techniques standard in the art.

Compounds of general formula 1 are useful for the treatment of heart failure, including congestive heart failure, posterior heart failure, anterior heart failure, left ventricular heart failure, or right ventricular heart failure, or for any other condition in which it is necessary to enhance cardiac action with inotropes. Can be used for treatment. In many respects, these compounds act like digitalis.

The usefulness of Formula 1 compounds as cardiotonic agents has been demonstrated by administering the test compound (0.1-10 mg/Kg) in an appropriate vehicle to mongrel dogs (either male or female).
This can be determined by administering intravenously, intracavitally, intraduodenally, or intraduodenally. The test dog is anesthetized, the appropriate artery (e.g. femoral or common carotid artery) and vein (e.g. femoral or lateral jugular vein) are isolated and a polyethylene catheter filled with 0.1% heparin Na is introduced to open each artery. Prepared by recording blood pressure and administering compounds. The chest is opened by separating the sternum along the center line or by making an incision at the left fifth intercostal space. Then, a separation rack around the heart is formed to support the heart. A Walton-Brody strain gauge is sutured to the right or left ventricle to monitor myocardial contractility. An electromagnetic flowmeter is placed around the root of the ascending aorta to measure cardiac output minus coronary blood flow. Heart failure is caused by the addition of sodium pentobarbital (20 to 40
mg/Kg) or propranalol hydrochloride (3 mg/Kg)
Kg). After administration of either of these cardiac depressants, right arterial pressure increases dramatically and cardiac output is significantly suppressed. Reversal of these effects by the test compound is indicative of inotropic effects.

The compounds can be administered in a variety of ways to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the treated patient orally or parenterally, ie, intravenously or intramuscularly. The amount of compound administered will vary depending on the patient, the degree of heart failure and the method of administration.

When administered orally or orally, the inotropically effective amount of the compound is from about 0.01 mg/Kg of patient body weight per day to about
Up to 500 mg/Kg, preferably from about 0.03 mg/Kg to about 200 mg/Kg.

For oral administration, a unit dose contains, for example, 1.5 to 500 mg of active ingredient, preferably about 10 to 100 mg of active ingredient. For parenteral administration, the unit dose is e.g.
Contains between 50 mg and 50 mg of active ingredient. Repeated administration of the compound per day may be desirable and will vary depending on the patient's condition and the method of administration.

As used herein, patients include warm-blooded animals, such as birds such as chickens and turkeys, and mammals, such as primates, humans, sheep, horses, cows, bulls, pigs,
means dog, cat, mouse, and rat.

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 form can be a capsule. This can be, for example, a conventional gelatin type containing lubricants and inert fillers such as lactose, sucrose, corn starch. In another embodiment, compounds of general formula 1 are combined with conventional tablet bases such as lactose, sucrose and corn starch, binders such as acacia, corn starch or gelatin, disintegrants such as potato starch or alginic acid, and lubricants such as Stearic acid or magnesium stearate can be combined to form tablets.

For parenteral administration, the compound can be administered as an injectable dose of a solution or suspension of the compound in a physiologically acceptable diluent, with a pharmaceutical carrier that can be a sterile liquid, such as water and oils, and a surface-active carrier. The compounds can be administered with or without the addition of agents and other pharmaceutically acceptable auxiliaries. Examples of oils that can be used in these preparations are of petroleum, animal, vegetable or synthetic origin, such as 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 depot injections or implant preparations, which can be formulated in a manner to permit sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant. The implant can be made of inert materials such as biodegradable polymers or synthetic silicones, such as silicone rubber silastic from Dow Corning Corporation.

The following specific examples illustrate the preparation and use of compounds used in the present invention.

Example 1 1,3-dihydro-4-ethyl-isonicotinoyl-2H-imidazol-2-one 1,3-dihydro-4-ethyl-2H-imidazol-2-one in 100 ml of tetrachloroethane
Add 21.3 g (160 mmol) of aluminum chloride to 3.0 g (27 mmol) and 4.74 g (27 mmol) of isonicotinoyl chloride hydrochloride. Mixture at 85℃
Stir for 4 hours and stop with water. Neutralize the solution with sodium bicarbonate and filter the suspension. The residue is washed with ethanol and the combined filtrates are evaporated to dryness. Chromatography on silica gel gives the title compound. Melting point 260-63°.

Follow the above procedure, but instead of isonicotinoyl chloride, use 2-bromoisonicotinoyl chloride, 3-chloroisonicotinoyl chloride,
4-(2-bromoisonicotinoyl)-1,3- using 3-methylisonicotinoyl chloride, 2-ethoxynicotinoyl chloride, 3-furanoyl chloride or 2-(1H-pyroyl) chloride, respectively. dihydro-5-ethyl-
2H-imidazol-2-one, 4-(3-chloroisonicotinoyl)-1,3-dihydro-5-
Ethyl-2H-imidazol-2-one, 1,3
-dihydro-4-ethyl-5-(3-methylisonicotinoyl)-2H-imidazol-2-one,
1,3-dihydro-4-(2-ethoxyisonicotinoyl)-5-ethyl-2H-imidazole-
2-one, 1,3-dihydro-4-ethyl-5-
(3-furanoyl)-2H-imidazol-2-one, or 1,3-dihydro-4-ethyl-5-
[2-(1H-pyroyl)]-2H-imidazole-
2-on occurs.

Following the procedure of Example 1, but using 1,3-dihydro-
1,3-dihydro-2H-imidazole- instead of 4-ethyl-2H-imidazol-2-one
2-one, 1,3-dihydro-4-isobutyl-
1,3-dihydro-4-isonicotinoyl-2H-imidazol-2 using 2H-imidazol-2-one or 1,3-dihydro-4-(n-propyl)-2H-imidazol-2-one, respectively. -one, 1,3-dihydro-4-isobutyl-5-isonicotinoyl-2H-imidazol-2-one or 1,3-dihydro-4-isonicotinoyl-5-(n-propyl-2H-imidazol-2-one) arise.

Example 2 1,3-dihydro-4-isonicotinoyl-5
-Methyl-2H-imidazol-2-one 1,3-dihydro-4-methyl-2H-imidazol-2-one in 80 ml of tetrachloroethane
Add 3.87 g (39.5 mmol) and 7 g (39.5 mmol) of isonicotinoyl chloride hydrochloride. Aluminum chloride (26 g, 194 mmol) is added and the mixture is stirred at 85° C. for 3 hours. Tetrachloroethane is decanted from the reaction mixture and the residue is quenched with water and neutralized with sodium bicarbonate. The suspension is filtered and the filtrate is evaporated to dryness. Chromatography on silica gel yields the title compound. melting point
295~96°.

Analysis C ₁₀ H ₉ N ₃ O ₂ Calculated value: C, 59.10; H, 4.46; N, 20.68 Measured value: C, 59.00; H, 4.45; N, 20.32 Example 3 1,3-dihydro-4-ethyl- 5-Nicotinoyl-2H-imidazole-2-one 8.85 g (50 mmol) of nicotinoyl chloride hydrochloride and 1,3-dihydro-4-ethyl-2H-imidazole-2- in 100 ml of tetrachloroethane.
Add 22 g (164 mmol) of aluminum chloride to a well-stirred mixture of 5.6 g (50 mmol) of aluminum. The mixture is heated at 85° C. for 2 hours and treated with water. Neutralize the solution with sodium bicarbonate, filter and dry. Chromatography on silica gel gives the title compound. Melting point 219-21°C Analysis C ₁₁ H ₁₁ N ₃ O ₂ Calculated: C, 60.81; H, 5.10; N, 19.34 Measured: C, 60.50; H, 5.19; N, 19.47 Using the procedure of Example 3 However, instead of nicotinoyl chloride, 2-chloronicotinoyl chloride, 4-bromonicotinoyl chloride, 5
-Fluoronicotinoyl chloride, 2-ethylnicotinoyl chloride, 4-isobutylnicotinoyl chloride, 5-methylnicotinoyl chloride, 6-methoxynicotinoyl chloride,
Picolinoyl chloride, 4-bromopicolinoyl chloride, 6-fluoropicolinoyl chloride, 3-methylpicolinoyl chloride, 5-
(n-butyl)picolinoyl chloride, 4-isopropoxypicolinoyl chloride, or 3-
using furanoyl chloride, respectively 4-
(2-chloronicotinoyl)-1,3-dihydro-5-ethyl-2H-imidazol-2-one,
4-(4-bromonicotinoyl)-1,3-dihydro-5-ethyl-2H-imidazol-2-one, 1,3-dihydro-4-ethyl-5-(5-
Fluoronicotinoyl)-2H-imidazole-
2-one, 1,3-dihydro-4-ethyl-5-
(2-ethylnicotinoyl)-2H-imidazol-2-one, 1,3-dihydro-4-ethyl-5
-(4-isobutylnicotinoyl)-2H-imizol-2-one, 1,3-dihydro-4-ethyl-5-(5-methylnicotinoyl)-2H-imidazol-2-one, 1,3-dihydro -4-
Ethyl-5-(6-methoxynicotinoyl)-
2H-imidazol-2-one, 1,3-dihydro-4-ethyl-5-picolinoyl-2H-imidazol-2-one, 4-(4-bromopicolinoyl)-1,3-dihydro-5-ethyl- 2H―
imidazol-2-one, 1,3-dihydro-4
-Ethyl-5-(6-fluoropicolinoyl)-
2H-imidazol-2-one, 1,3-dihydro-4-ethyl-5-(3-methylpicolinoyl)-2H-imidazol-2-one, 4-[5
-(n-butyl)-picolinoyl]-1,3-dihydro-5-ethyl-2H-imidazole-2-
on, 1,3-dihydro-4-ethyl-5-(4
-isopropoxypicolinoyl)-2H-imidazol-2-one, or 1,3-dihydro-4-
Ethyl-5-(3-furanoyl)-2H-imidazol-2-one is formed.

Example 4 1,3-diacetyl-1,3-dihydro-4-
Ethyl-5-[2-methoxy(thiobenzoyl)]-2H-imidazol-2-one 1,3-diacetyl-1,
3-dihydro-4-ethyl-55-(2-methoxybenzoyl)-2H-imidazol-2-one 10g
and suspend 20 g of phosphorus pentasulfide. The mixture is refluxed for 6 hours and the solvent is evaporated to yield the title compound.

Utilizing the procedure of Example 4, but using 1,3-diacetyl-1,3-dihydro-4-ethyl-5-(2
-Methoxybenzoyl)-2H-imidazole-
1,3-dihydro-4- instead of 2-one
(4-fluorobenzoyl)-5-methyl-2H-
imidazol-2-one, 1,3-dihydro-4
-Methyl-5-[4-(methylthio)benzoyl]-2H-imidazol-2-one or 1,3
1,3-dihydro-4-[4-fluoro(thiobenzoyl)]-5-methyl- using dihydro-4-isopropyl-5-(2-thienoyl)-2H-imidazol-2-one, respectively. 2H―
imidazol-2-one, 1,3-dihydro-4
-Methyl-5-[4-methylthio(thiobenzoyl)]-2H-imidazol-2-one, or 1,
3-dihydro-4-isopropyl-5-(thienylthiocarbonyl)-2H-imidazole-2-
On occurs.

Example 5 1,3-dihydro-4-methyl-5-benzoyl-2H-imidazole-2-thione To 9.8 g of 2-amino-1-phenyl-1,3-butadione in 200 ml of 1N HCl, 14.5 g of potassium thiocyanate added. The solution was warmed on a steam bath for 30 minutes and cooled. The solid title compound was recrystallized from alcohol. Melting point 268-69°.

By a similar method, but instead of 2-amino-1-phenyl-1,3-butadione in the above example, 2-amino-1-(2,3-methylenedioxyphenylene)-1,3-pentadione , 2-amino-4-methyl-1-[2-(1H-pyryl)]-
1,3-pentadione or 2-amino-1-(4
-pyridyl)-1,3-hexadione, respectively 1,3-dihydro-4-ethyl-5
-(2,3-methylenedioxybenzoyl)-
2H-imidazole-2-thione, 1,3-dihydro-4-isopropyl-5-[2-(1H-pyrrolyl)]-2H-imidazole-2-thione, or 1,3-dihydro-4-propyl-5 -Isonicotinoyl-2H-imidazole-2-thione is produced.

Example 6 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazole-2
-Thion 1.66 g of potassium thiocyanate was added to 1.77 g of 2-amino-1-(4-methoxyphenyl)-1,3-butadione in 100 ml of 1N HC. The solution was heated on a steam bath for 30 minutes and cooled. The title compound was isolated as a solid material. Melting point 200℃.

Reference example 7 1,3-dihydro-4-ethyl-5-[3,4
-Difluoro(thiobenzoyl)]-2H-imidazole-2-thione 1,3-dihydro-4-ethyl in toluene-
5-(3,4-difluorobenzoyl)-2H-
10 g of imidazole-2-thione and phosphorus pentasulfide were heated at reflux temperature for 5 hours. Evaporation of the solvent yields the title compound.

Example 7 1,3-dihydro-4-methyl-5-isonicotinoyl-2H-imidazol-2-one (RMI 19,214), 1,3-dihydro-4-ethyl-5-isonicotinoyl-2H-imidazol-2 -On (RMI 19205) and 1,3-
dihydro-4-ethyl-5-nicotinoyl-
2H-imidazol-2-one (RMI 19198)
Cardiovascular effects of dogs treated with sodium pentobarbital (35mg/
Kg, intravenously) and give artificial respiration. Cannulae are introduced into the femoral artery and vein for systemic blood pressure measurement and drug infusion, respectively. make an incision in the chest,
To measure cardiac contractility, the arch of the Walton-Brody-strainmeter is sutured to the left ventricle. Measure heart rate from the Lead electrocardiogram. All measurements are recorded continuously on the polygraph. RMI19198, RMI19205 and
RMI19214 is administered by intravenous injection, all of which increase cardiac contractility, heart rate, and decrease systemic blood pressure. Of these effects, increased cardiac contractility is the most potent effect of each drug. RMI19198, RMI19205 and
The intravenous dose of RMI19214 is 0.16mg/each.
Kg, 0.04 mg/Kg and 0.13 mg/Kg. For comparison, the doses of these compounds that increase heart rate by 15% are 3.5mg/Kg, 1.5mg/Kg and 6mg/Kg, respectively.
It is. RMI19198 (3mg/Kg,
intravenous), RMI19205 (1mg/Kg, intravenous) and
RMI19214 (1 mg/Kg, iv) lowers systemic blood pressure by only 11%, 10% and 4%, respectively.

Claims (1)

[Claims] 1 [Q and T are each an oxygen atom or a divalent sulfur atom, R is hydrogen or lower alkanoyl, R1 is lower alkyl, Ar is pyridyl,
or phenyl which may be optionally substituted with lower alkoxy, provided that when both Q and T are oxygen atoms, Ar cannot be phenyl which may be optionally substituted with lower alkoxy; Provided that when R ₁ is methyl, Ar cannot be 3-pyridyl. ] or a pharmaceutically acceptable acid-base addition salt. 2. The compound according to claim 1, wherein R is hydrogen, and Q and T are each oxygen atoms. 3. The compound of claim 2, wherein 3 Ar is 2- or 4-pyridyl. 4. The compound of claim 3, wherein R ₁ is methyl or ethyl. 3. The compound of claim 2, wherein 5 Ar is 4-pyridyl. 6. The compound of claim 5, wherein R ₁ is methyl or ethyl. 7 The compound of claim 1, where Ar is 4-pyridyl, R is hydrogen, and R ₁ is methyl, that is, 1,3-dihydro-4-isonicotinoyl-
5-Methyl-2H-imidazol-2-one. 8 The compound of claim 1, ie 1,3-dihydro-4-ethyl-5-isonicotinoyl-2H-imidazol-2-one, where Ar is 4-pyridyl, R is hydrogen and R ₁ is ethyl. 9 [In the formula, Q and T are each an oxygen atom or a divalent sulfur atom, R is hydrogen or lower alkanoyl, R ₁ is lower alkyl, and Ar is pyridyl or optionally substituted with lower alkoxy. provided that when both Q and T are oxygen atoms, Ar cannot be phenyl which may be optionally substituted with lower alkoxy. A therapeutic agent for heart failure, comprising a cardiotonic effective amount of an acid-base addition salt thereof that is acceptable to the public. 10. The therapeutic agent according to claim 9, wherein R is hydrogen, and Q and T are each oxygen atoms. 11. The therapeutic agent of claim 10, wherein 11 Ar is 2- or 4-pyridyl. 12. The therapeutic agent of claim 11, wherein 12 R ₁ is methyl or ethyl. 11. The therapeutic agent of claim 10, wherein 13 Ar is 4-pyridyl. 14. The therapeutic agent of claim 13, wherein R ₁ is methyl or ethyl. Claim 9 in which 15 Ar is 4-pyridyl, R is hydrogen and R ₁ is methyl, that is, 1,3-dihydro-4-isonicotinoyl-5-methyl-2H-imidazol-2-one therapeutic agent. 16 Claim 9 when Ar is 4-pyridyl, R is hydrogen and R ₁ is ethyl, that is, 1,3-dihydro-4-ethyl-5-isonicotinoyl-2H-imidazol-2-one therapeutic agent.