IE50646B1 - Novel 4-aroylimidazol-2-ones - Google Patents

Abstract

A compound for the alleviation of hypotension or the treatment of cardiac failure, having the formula wherein R is hydrogen, C1-4 alkyl, (C1-4 alkyl) carbonyl or benzoyl; R1 is hydrogen or C1-4 alkyl; and Ar is 2-furyl; 2-thienyl; phenyl; phenyl monosubstituted by halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrrolidino, piperidino, morpholino, piperazino or N'-alkylpiperazino in which R2, R3 and R4 are independently selected from hydrogen and C1-4 alkyl; disubstituted phenyl in which one substituent is at the para position and the substituents are independently selected from halogen, hydroxy, C1-4 alkyl and C1-4 alkoxy; or 3,4-methylenedioxy- phenyl in which the methylene group is optionally substituted by one or two methyl groups; or a pharmaceutically acceptable salt thereof. Many compounds of formula I are novel.

Description

Khim. Geterotsikl. Soedin., £(4), 698-701 (1968) disclose the preparation and chemical intermediate utility of the following compounds; 4-benzoyl-l,3-dihydro-2H-imidazol-2-one; 4-benzoyl-l,3-dihydro-2H-imidazol-2-one 1,3-diacetate; 4-benzoyl-l,3-dihydro-5-(lower alkyl)-2H-imidazol-2-ones; 4-benzoyl-l,3-dihydro-5-methyl-2H-imidazol-2-one 1,3diacetate; 1.3- dihydro-4-(3,4-dimethylbenzoyl)-2H-imidazol-2-one 1.3- diacetate; 1.3- dihydro-4-(hydroxybenzoyl)-2H-imidazol-2-one; 1,3-dihydro-4-(hydroxybenzoyl)-5-(lower alkyl)-2H-imidazol 2-ones; 1.3- dihydro-4-(3,4-dihydroxybenzoyl)-2H-imida2ol-2-one; 1.3- dihydro-4-(4-nitrobenzoyl)-2H-imidazol-2-one; 1.3- dihydro-4-methyl-5-(4-nitrobenzoyl)-2H-imidazol-2-one, 4-(3-aminobenzoyl)-l,3-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl)-l,3-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl)-l,3-dlhydro-5-methyl-2H-imidazol-2-one.

We have now discovered that compounds of formula 1, below, can have antihypertensive, cardiotonic and/or antithrombotic activity. These compounds have the formula 80048 ο 1 wherein R is hydrogen, C1_4 alkyl, (C-^alkyl) carbonyl or benzoyl; is hydrogen or C1-4 alkyl; and Ar is 2-furyl; 2-thienyl; phenyl; phenyl monosubstituted by halogen, hydroxy, C^_4 alkyl, C^_4 alkoxy, C1-4 alkylthio, trifluoromethyl, -SOjNfRj^» NRjR^, pyrrolidino, piperidino, morpholino, piperazino or N'-alkylpiperazino, in which Rj, Rj and R^ are independently selected from hydrogen and Cj_4 alkyl; disubstituted phenyl in which one substituent is at the para position and the substituents are independently selected from halogen, hydroxy, C^_4 alkyl and C·^ alkoxy; or 3,4-methylenedioxyphenyl in which the methylene group is optionally substituted by one or two methyl groups, and include the pharmaceutically acceptable salts thereof.

Those compounds of formula 1 which are novel, particularly those of formula 1 in which Ar is not phenyl, mono- or di-hydroxyphenyl, aminophenyl or dimethylphenyl, form a further aspect of this invention.

A pharmaceutical composition according to the invention comprises a compound of formula 1 in association with a physiologically acceptable excipient (which is a solid or a sterile liquid when the compound is known).

Examples of alkyl are methyl, ethyl, npropyl, isopropyl, n-butyl and isobutyl. Examples of C^_4 alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy and isobutoxy. Examples of C^_4 alkylthio are methylthio etc.

The term halogen means fluorine, chlorine, bromine or iodine, and halide means fluoride, chloride, bromide or iodide.

Methylenedioxy optionally substituted by one or two methyl groups means methylenedioxy, ethylenedioxy or isopropylidenedioxy.

The substituent on Ar as monosubstituted phenyl 5 will hereinafter be referred to as X^. The substituents on Ar as disubstituted phenyl (including methylenedioxyphenyl) will hereinafter be referred to as X% 311,3 X3» X2 being at the para position.

Preferred compounds of this invention are those 10 compounds of formula 1 wherein R is hydrogen and X^ is piperidino, pyrrolidino, morpholino, piperazino, N'-alkylpiperazino, C^_4 alkoxy or C^_4 alkylthio. Other preferred compounds of this invention are those wherein Ar is unsubstituted phanyl and where X2 and X3 are C1_4''alkoxy, or (together) methylenedioxy. It is particularly preferred that R^ is hydrogen, methyl or ethyl, especially methyl.

X^ is preferably at the para position, and is most preferably methoxy or methylthio. X3 is preferably at the meta position and is most preferably methoxy.

Particularly preferred compounds of Formula 1 ( are the following: 4-benzoyl-l,3-dihydro-5-methy1-2H-imidazo1-2-one, 1.3- dihydro-4-methyl-5-(2-thienoyl)-2H-imidazol-2-one, 1.3- dihydro-4-methyl-5-(3,4-methylenedioxybenzoyl)-2H25 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-benzoy1-1,3-dihydro-5-methyl-2H-imidazol-2-one, 1,3diacetate, 1,3-dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2H-imidazol2-one, 1.3- dihydro-4-(2-furanoyl)-5-methyl-2H-imidazol-2-one, 1.3- dihydro-4-(2-thienoyl)-2H-imidazol-2-one, 4-benzoyl-l,3-dihydro-2H-imidazol-2-one, 1.3- dihydro-4-(2-f uranoyl)-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)-l,3-dihydro-5-methyl-2H-imidazol-2-one, 1.3- dihydro-4-(2-hydroxybenzoyl)-5-methyl-2H-imidazol-2one, 4-(4-chlorobenzoyl)-l,3-dihydro-5-methyl-2H-imidazol-2-one, 1.3- dihydro-4-methyl-5-(4-piperidinobenzoyl)-2H-imidazol2-one, 1.3- dihydro-4-methyl-5-(4-morpholinobenzoy1)-2H-imidazol2-one, 1.3- dihydro-4-methyl-5-(4-pyrrolidinobenzoyl)-2H-imidazol2-one, 1.3- dihydro-4-(4-dimethylaminobenzoyl)-5-methy1-2Himidazol-2-one, 1.3- dihydro-4-methyl-5-[4-(methylpiperazinobenzoyl)j 2H-imidazol-2-one, 1.3- dihydro-4-ethyl-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 1.3- dihydro-4-ethyl-5-(4-(methylthiobenzoyl)- 2Himidazol-2-one, 1.3- dihydro-4-(4-hydroxybenzoyl)-5-methyl-2H-imidazol-2one, and 1.3- dihydro-4-methyl-5-(4-(methylthiobenzovl)-2Himidazol-2-one, When R is hydrogen in Formula 1 compounds, the several tautomeric forms of general Formula 2 are possible; Formula 2 wherein Ri and Ar are as defined in Formula 1. These acid tautomers may form pharmaceutically active salts of general Formula 3.

Formula J wherein Ri and Ar 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; 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 imidazo!-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 1(-: Ri H Formula 4 wherein R: is as defined in Formula 1. The acylating agent may be a 2-furanoyi 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 Y Y· X: Formula 5a Formula 5b Formula 5c • 50646 wherein Y is a halogen and X^, X? and X^ are substituents on the phenyl as defined in Formula 1 or may additionally be any group which can be converted to the desired Xi, Xa or X3 substituent subsequent to the Friedel-Crafts reaction such as a blocking group or a nitro group which can be converted, via the diazonium ion, 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. Ill, Part 1, Interscience Publications, John Wily and Sons, 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-dichlorobenzene; 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 mixture 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 temperature which can be from about -78’ to about 150°C, preferably about 0° to about 100°C, most preferably about 6o"C.

The resulting aroylimidazol-2-one may be isolated from the reaction mixture by any suitable art-known procedure, preferably by quenching the reaction mixture with ice water and subsequently removing the product by filtration or extraction and solvent removal.

Lewis acid catalysts suitable for use in the Friedel5 Crafts reactions described herein are, for example, a metal, such as aluminum, cerium, copper, iron, 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 sub10 stituted acetic acids, such as chloroacetic or trifluoroacetic acids; or a metallic halide, such as a boron halide, zinc chloride, zinc bromide, berryl chloride, copper chloride, iron(ill) bromide, iron(lll) chloride, mercury(ll) chloride, mercury(l) chloride, antimony bromide, antimony chloride, titanium(IV) bromide, titanium(IV) chloride, titanium(I 11) chloride, aluminum bromide or preferably aluminum chloride.

The compounds of Formula 1 wherein Xi is at the ortho or para position and is a pyrrolidino, piperidino, morpho20 lino, piperazino, N1-alkyl-piperazino and NR3R4 may be prepared as hereinabove described or may be prepared from a suitable fluorobenzoylimidazol-2-one of Formula 6 Formula 6 wherein R and Rt are as defined above in Formula 1 and 25 the fluorine atom is at either the ortho or para position. The appropriate compound of Formula 6 is allowed to react with from 1 to 10 molar equivalents of pyrrolidine, piperidine, morpholine, piperazine or N'-aikyl-piperazine, as appropriate. This reaction may be performed with or without a solvent, pre50646 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 chloroform, methylene chloride, or carbon tetrachloride; carbon disulfide; ethereal solvents, such as diethyl ether, tetrahydrofuran or £-dioxan; aromatic solvents such as benzene, toluene or xylene; or alcoholic solvents, such as ethanol. The reaction is allowed to proceed for 1/2 hour to 48 hours, preferably about 24 hours, depending on the reactants, the solvent if any, and the temperature which can be from 0° to 15O°C.

The compounds of Formula 1 wherein Xi is an amino group of the formula, -NR3R4, and wherein R3 and R4 are as defined in Formula 1, may alternatively be prepared from the corresponding nitro substituted benzoylimidazol2-ones of Formula 7 Formula 7 wherein R and Ri are as defined in Formula 1. The compounds of Formula 7 are either known in the prior art or may be prepared by Friedel-Crafts acylation of an imidazol-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 group by any suitable art-known procedure and subsequently, if desired, the unsubstituted amino may be alkylated by any appropriate art known method.

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 solution. About 1 molar equivalent to about 10 molar equivalents of the metal is used and the reaction is allowed to proceed for 1/2 hour to 10 hours, preferably about 2 or 3 hours depending upon the reactants and the temperature which can be from 25° to 150°C, pre10 ferably about 100°C. Alternatively, the nitrobenzoylimidazol-2-ones may be reduced catalytically with nickel, platinum, palladium, or other similar suitable metals and molecular hydrogen. Such reactions are typically performed in an alcoholic solvent, preferably ethanol, but any nonreactive solvent may be used and the amount of metal catalyst may vary from O.OO1 molar equivalents to 0.1 molar equivalents. The reaction is allowed to proceed for 1 minute to 1 hour, preferably about 10 minutes depending upon the reactants, the solvent and the temperature which can be from 0° to 100°C, preferably about 25°C. And alternatively, the nitrobenzoylimidazol-2-ones may be reduced with ammonium bisulfide (NH4SH) in aqueous ammonia. to 10 molar equivalents, preferably about 3 molar equivalents, of the bisulfide is allowed to react for 1/2 hour to 10 hours, preferably about hours, depending upon the reactants and the temperature which may be from 0° to 15O°C, preferably about 50°C. Finally, the nitrobenzoylimidazol-2-ones may be reduced to the corresponding amino compounds by any other appropriate art-known procedure.

The alkylation of the unsubstituted ami nobenzoylimidazol-2-ones may be accomplished, for example, by reaction with one or more equivalents of an appropriate alkyl halide of the formulas RgX 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 petroleum ethers; chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride; chlorinated aromatics such as 1,2,4-trichlorobenzene, odichlorobenzene or chlorobenzene; carbon disulfide; nitrobenzene; dimethylformamide; dimethylsulfoxide; ethereal solvents such as diethyl ether, tetrahydrofuran or £-dioxan; aromatic solvents such as benzene, toluene or xylene, alcohols such as methanol, ethanol or propanol; and aqueous alcohols such as aqueous ethanol. These alkylations are preferably performed in the presence of one or more equivalents of a proton sponge such as triethylamine, pyridine, sodium hydroxide, calcium hydroxide or potassium hydroxide to neutralize any hydrohalide as it is formed. Alternatively, the unsubstituted aminobenzoyl imidazol -2-ones may be alkylated by any other appropriate art-known procedure such as reaction with formic acid and formaldehyde to form a dimethylamine compound. Furthermore, a variety of other substituents such as halogen and hydroxy may be prepared from the nitro substituted benzoylimidazol-2-ones of Formula 7 via the diazonium ion by procedures well known in the art.

The compounds of Formula 1 wherein Xi or Xa and X3 are hydroxy may be prepared as hereinabove described or preferably may be prepared from a suitable alkoxy, preferably methoxy, substituted benzoy1imidazol-2-one wherein 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. 54. 615-85 (1954) whose contents are hereby expressly incorporated by reference. 646 The Xi, Xs and X3 substituents may be protected as necessary in order to improve the stability of the Formula 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 Xi, XE or X3 is hydroxy, an amino group of the formula -NHR3 or -SOaNHg, 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 hydrogen over a palladium catalyst or with sodium in liquid ammonia.

When desired, one or both of the nitrogen atoms of the imidazoI-2-one ring may be substituted with an alkyl group by any art-known procedure. Such methods include reacting the appropriate N-unsubstituted aroylimidazol2-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 bicarbonate; a phenoxide such as sodium phenoxide; an alkoxide such as sodium ethoxide; or preferably a hydroxide 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 dimethyIsulfate. Suitable unreactive solvents are, for example, 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; ethereal solvents such as diethyl ether, tetrahydrofuran or jp-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 1 minute to 1 hour and the temperature may be from O°C to 1OO°C, preferably about 25°C. When it is desired that only one of the imidazol-2-one nitrogen atoms be substituted with an alkyl group, the appropriate imidazol-2-one is reacted with from 1 molar equivalent to 10 molar equivalents of a base, preferably about 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 2 molar equivalents to 10 molar equivalents of a base, preferably about 2 molar equivalents and from 2 molar equivalents to 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 unsubstituted piperazino, are alkylated under identical reaction conditions. If desired, the alkylation of the aroyl 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 deblocked by hydrogenolysis.

When desired, the nitrogen atoms of the imidazol-2one ring may be substituted with an alkylcarbonyl group by any suitable art-known procedure. Such methods include reacting the N-unsubstituted aroylimidazol-2-ones of this invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyi chloride, .0 6 4 6 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 corres5 ponding free acid or acid anhydride may be employed instead 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 disuifind; ethereal solvents, such as diethylether, tetrahydrofuran or £-dioxan or aromatic solvents such as benzene, toluene or xylene. The reactions are allowed to proceed for 1 minute to 100 hours, preferably from 1 hour to 10 hours and the temperature may be from -78° to 150°C preferably from O° to 100°C. Finally, any reactive substituents on the aroyl rings, if present, will become acylated concurrently.

That is, the following X groups, X=OH, -NHR3, -SOaNHa 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 de25 blocked by hydrogenolysis.

The alkali metal, alkaline earth metal, transition metai, 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 hydroxide; or a carbonate, such as sodium carbonate, potassium carbonate, zinc carbonate, magnesium carbonate or sodium hydrogen carbonate. These reactions may be performed with or without a solvent. Suitable solvents are, for example, lower alcohols, such as methanol, ethanol, isopropanol, £-propanol or .n-butanol; aromatic solvents, such as benzene, toluene or xylene; ethereal solvents, such as diethyl ether, tetrahydrofuran or £-dioxan; and halogenated hydrocarbon solvents, such as chloroform, methylene chloride or carbon tetrachloride. The aroylimidazol-2-one and base are allowed to react for 1 minute to 24 hours depending on the reactants and the temperature which can be from -78°c to 150°C, preferably from about 0° to about 25°C.

The aroyl chlorides or their corresponding carboxylic acids, which are required for the Friedel-Crafts acylation 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, Dolan, 2· Δϋ!· Chem. Soc. 67, 2079 (19^5), R. Duschinsky and L. A. Dolan, 2· Am. Chem. Soc. 68, 2350 (1945) or U.S. patent 2,441,933.

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 digitaiis-1 ike action. The compounds of general Formula 1 may also be used in the treatment of hypertension including primary or essentia] 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. Arteriai thrombosis, 646 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 intramuscularly. The amount of compound administered will vary with the severity of the hypertension, cardiac failure or blood clotting and the mode of administration. For oral administration the antihypertensively effective amount of compound is from O.l mg/kg (milligrams per kilograms) of patient body weight per day to 500 mg/kg of patient body weight per day and preferably from 50 mg/kg of patient body weight per day to 150 mg/kg of patient body weight per day.

For parenteral administration the antihypertensively effective amount of compound is from O.Ol mg/kg of patient body weight per day up to 150 mg/kg of patient body weight per day and preferably from 1.0 mg/kg of patient body weight per day up to 10.0 mg/kg of patient body weight per day. For oral or parenteral administration the cardiotonically effective amount of compound is from O.l mg/kg of patient body weight per day up to 500 mg/kg of patient body weight per day and preferably from 0.1 mg/kg of patient body weight per day up to 10.0 mg/kg of patient body weight per day. For oral or parenteral administration the anticoagulant effective amount of compound is from 0.1 mg/kg of patient body weight per day up to 1000 mg/kg of patient body weight per day and preferably from l mg/kg of patient body weight per day up to lOO 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, 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 the patient and the mode of administration.

As used herein the term patient is taken to mean a warm blooded animal, 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 gelative 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. j 50646 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 manu10 factured by the Dow-Corning Corporation.

Following are illustrative pharmaceutical formulations which may be employed in practicing the present i nvent i on: Preparation of a Tablet Formulation Per Tablet a) b) c) d) 1,3-Dihydro-4-(4-methoxybenzoy1)5-methy1-2H-imidazol-2-one Corns ta rch Lactose Magnesium stearate 100 15 33.5 1.5 mg mg mg mg 20 Preparation of a Parenteral Formulation a) 1,3-D ihydro-4-(4-methoxybenzoyl)-5methyl-2H-imidazol-2-one 1.000 9 b) Polyoxyethylene sorbitan monooleate 2.000 9 c) Sodium chloride 0.128 9 25 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, tonics and anticoagulants. cardio- EXAMPLE A 30 Use of 1,3-dihydro-4-( lr-methoxvbenzovl)-5-methvl-2H- imi dazol-2-one as an antihypertensive 100 mg/kg of the title compound is administered orally to six spontaneously hypertensive rats. This dose results in a 40$ decrease, on the average, in the blood pressure within 15 minutes of administration.

EXAMPLE Β Use of l,3-dihydro-4-(4-methoxybenzoyI)-5-methy1-2iiimidazol-2-one as a cardiotonic Heart failure is induced in a dog by administering sodium pentobarbitol (20 mg/kg) or propranalol hydrochloride (j mg/kg) to the blood perfusing the heart. Following administration of either of these cardiac depressants the right atrial pressure increased dramatically and cardiac output is severely depressed. Administration of the title compound (l 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 l,3-dihydro-4-(4-niethoxybenzoy 1)-5-methy 1-2Himidazol-2-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 concentrations of 3, 10, 30 and 100 ug/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 1,3-D jhydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one To a stirred mixture of 98.1 g (l mole) of 1,3dihydro-4-methyl-2H-imldazol-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 (l mole) of £fluorobenzoyl chloride. The mixture is stirred at 6o-65°C for 6 hours, then poured on 2 kg of ice. The resulting precipitate is washed with diethyl ether and water and is recrystallized from 1.2 liters of dimethylformamide to give 131 g of the title compound. M.P. 289-292"C. 0646 EXAMPLE 2 1.5- D ihydro-4-methy1-5-r4-(l-piperi dinyl)benzoyΠ-2Ηimidazol-2-one A suspension of 11.0 g (0.05 mole) of 1,3-dihydro4-(4-fluorobenzoyl)-5-methy1-2H-imidazo1-2-one in 30 ml of piperdine is stirred at reflux temperature for 24 hours. Excess piperdine is evaporated under reduced pressure and the residue is recrystallized twice from a mixture of isopropanol and water to give 11.9 9 of the title compound. M.P. 260-263°C.

EXAMPLE 3 1.3- D ihydro-4-methyl-5-r4-(4-morPho1i nyl)benzoyI1-2Himidazol-2-one Following the procedure of Example 2 but substituting morpholine for piperidine, the title compound is obtained.

M.P. 283-286°C.

EXAMPLE 4 1.5- Dihydro-4-(4-( dimethy1 ami no)benzoyl!-5-methyl-2Himidazol-2-one A mixture of 11.0 g (0.05 mole) of l,3-dihydro-4-(4fluorobenzoyl)-5-methy1-2H-imidazol-2-one, 100 ml of 3θ$ aqueous solution of dimethylamine and 200 ml of ethanol is heated in a pressure bomb at 130-135"C for 22 hours.

The mixture is cooled, the solid is collected and recrystallized from isopropanoi-water to give the title compound. M.P. >310°C. λ(max)(methanol) 364 nm (e = 23,300).

EXAMPLE 5 1.3- P ihydro-4-(4-hydroxybenzoy1)-5-methy1-2H-imidazol-2-one To a melt of 26 g (0.23 mole) of pyridine hydrochloride at 200-205°C is added 5,5 g (0.023 mole) of 1,3di hydro-4-(4-methoxybenzoy 1)-5-methy I-2H-imidazol-2-one and the mixture is stirred mechanically for 30 minutes.

The reaction mixture is poured on ice-2,NHCl. The resulting precipitate is washed with water and recrystaiiized from isopropanoi-water to give the title compound. M.P. > 300°C. X(max)(methanol) 320 nm (e = 13,200).

EXAMPLE 6 1.5- D i hydro-4-methyI-5-Γ4-(methy1th io)benzoyl1-2Himidazol-2-one A solution of 25-0 g of 4-(methy1thio)-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 5 times with benzene to remove all thionyl chloride. The residue is added dropwise to a mixture of 11.8 g of l,3-dihydro-4methy1-2H-imidazol-2-one, 40.0 g of anhydrous aluminum chloride and 100 ml of nitrobenzene. The resulting mixture fs stirred at 6o-65°C for 5 hours, poured on ice and the precipitate that forms is collected, washed with ethyl ether and water, and recrystallized from Isopropanol-water to give the title compound. M.P. 255*258eC. (dec.).

EXAMPLE 7 1.5- Dihydro-4-(4-methoxybenzoyl)-5-methy1-2H-imidazol-2one To 19.6 g of l,3-dihydro-4-methyl-2H-imidazol-2-one and 55.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene is added dropwise 34.2 g of £-methoxybenzoyl chloride and the mixture is poured on 500 ml of 2N-HC1 and ice, washed 3 times with ethyl ether, the resulting solid is recrystallized from Isopropanol-water to give the title compound. M.P. 257-258°C (dec.), EXAMPLE 8 1,3-D I hydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2one, sodium salt To 7-0 g of l,3-dihydro-4-(4-methoxybenzoyl)~5-methyl2H-imidazol-2-one in 100 ml of methanol Is added 1.6 g 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 give the title compound. M.P. 2S0-282°C (dec.).

EXAMPLE 9 A-Benzoy1-1,3-dihydro-5-methylimidazol-2-one To a solution of 3-0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g of benzoyl chloride. The solution is warmed at 60°C for 4 hours, poured over ice water, slurried with ether and the resulting solids filtered and dried to yield the title compound. M.P. 250-54eC.

EXAMPLE 10 1,3-D ihydro-4-methvl-5-thienovl-2H-imidazol-2-one To a solution of 7·3 g of 4-methylimidazol-2-one and 10.8 g of aluminum chloride in 150 ml of nitrobenzene is added 12.0 g of 2-thienoyl chloride. The mixture is stirred at 60°C for 3 hours, cooled and poured over ice water. The organic portion is extracted into ethyl acetate, dried and the organic solvent evaporated to give the title compound. M.P. 212-215°C.

EXAMPLE 11 1,3 -D i hyd ro-4- f 3,4-d ? methoxybenzoyl) -2jj- i mi dazol -2-one To a solution of 6.5 g of l,3-dihydro-4-methyl-2Himidazol-2-one and 14.6 g of aluminum chloride in 65 ml of nitrobenzene is added 17.6 g of 3,4-dimethoxybenzoyl chloride in portions. The mixture is stirred for 3 hours at 6o°C, cooled and poured over ice water. The gummy solids are filtered and recrystallized twice from ethyl alcohol-water to afford the title compound. M.P. 257259°C.

EXAMPLE 12 1,3-P ihydro-4-(2-furanoyl)-5-methyl-211-imidazol-2-one To a slurry of 8.9 g of l,3-dihydro-4-methy1-2Himidazol-2-one and 24.0 g of aluminum chloride in 135 ml of nitrobenzene is added 12.9 g of furanoyl chloride in a dropwise manner. The mixture is stirred at 6o’C for 3 hours, cooled and poured over ice water. The solid is then filtered and recrystallized twice from methyl alcohol to afford the title compound. M.P. 2l4-2l6eC.

EXAMPLE 13 1.3- Dihydro-4-(2-thienoyl)-2(1-imidazol-2-one In 50 nil of nitrobenzene is combined 13-5 9 of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2one and 8.1 g of thienoyl chloride. The mixture is stirred at 60°C for 3 hours and poured over ice water.

The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compound. M.P. 359-^2°C.

EXAMPLE 14 4-Benzoy1-1,3-dihydro-2H-imidazol-2-one To 51 ml of nitrobenzene is added 1.68 g of 1,3dihydro-2H-imldazol-2-one, 5.5 g of aluminum chloride and 3.1 g of benzoyl chloride. The mixture is stirred for 3 hours at 60°C and poured into ice water. The solids are filtered, washed with ether and recrystallized twice from methyl alcohol-water to afford the title compound. M.P. 329-50°C.

EXAMPLE 15 1.3- D i hydro-4-furanoyl-211-imidazol-2-one To 50 ml of nitrobenzene Is added 4.2 g of 1,3dihydro-2H-imidazol-2-one, 13-5 9 of aluminum chloride and 7.2 g of furanoyl chloride. The mixture is stirred at 60°C for 3 hours and poured over Ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compounds. M.P. 318-321’C.

EXAMPLE 16 l,3-0ihydro-4-(5.4-methylenedioxvbenzoyI)-5-methyl-2Himidazoi-2-one To 5.15 9. of l,3-dihydro-4-methyl-2H-imidazo1-2-one and 7·9θ 9· of anhydrous aluminum chloride in 80 ml. of nitrobenzene is added dropwise 10.60 g. of 3,4methylenedioxybenzoyl chloride and the mixture is poured on 500 mi. of 2N-HC1 and ice, washed 3 times with ethyl ether, the resulting solid is collected to give the title compound. M.p. 293-296’C (dec).

EXAMPLE 17 1,3-D ihydro-4-(4-methoxybenzoyl)-1,3,5-tr imethy1-2H5 imidazol-2-one In 120 ml of DMSO is placed 15.2 g of powdered potassium hydroxide, 8.0 g of l,3-dihydro-*-(*-methoxybenzoy I)-5-methy 1-2fl-imidazoI-2-one, sodium salt and 19.5 g 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-llleC. 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-methoxybenzoy1)-5* methy1-2H-imidazol-2-one in 30 ml of DMSO is added 0.288 g of sodium hydride and 1.22 g of methyl iodide.

The mixture is stirred at 22°C 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. 225-228°C.

Anal . calcd. for CiaHmNaOa: C, 63.40; H, 5-73; N, 11.39 Found: C, 63.3*; H, 5.85; N, 11.21.; NMR: N-Methyl; Singlet at 3-2 ppm.

Claims (18)

1. CLAIMS :1. A pharmaceutical composition for use in the alleviation of hypertension or the treatment of cardiac failure, containing wherein R is hydrogen, C^_ 4 alkyl, (Cj_ 4 alkyl)carbonyl or benzoyl; R^ is hydrogen or Cj_ 4 alkyl; and Ar is 2-furyl; 2-thienyl; phenyl; phenyl monosubstituted 10 by halogen, hydroxy, alkyl, Cj_ 4 alkoxy, C^_ 4 alkylthio, trifluoromethyl, -SO 2 N(R 2 ) 2 , NR^R^, pyrrolidino, piperidino,morpholino, piperazino or Ν'-alkylpiperazino, in which R 2 , R 3 and R^ are independently selected from hydrogen and C^_ 4 alkyl; disubstituted phenyl in which one 15 substituent is at the para position and the substituents are independently selected from halogen, hydroxy, alkyl and C^_ 4 alkoxy; or 3,4-methylenedioxyphenyl in which the methylene group is optionally substituted by one or two Methyl groups; or a pharmaceutically acceptable salt thereof, in association 20 with a physiologically acceptable excipient or diluent therefor.

2. A pharmaceutical composition as claimed in claim 1 wherein Ar is phenyl.

3. A pharmaceutical composition as claimed in claim 1 25 wherein Ar is monosubstituted phenyl.

4. . A pharmaceutical conposition as claimed in claim 3 wherein the substituent is C^_ 4 alkoxy or C^_ 4 alkylthio.

5. . A pharmaceutical conposition as claimed in claim 3 wherein the· substituent is methoxy. 5

6. . A pharmaceutical composition as claimed in claim 3 wherein the substituent is methylthio.

7. . A pharmaceutical composition as claimed in any of claims 3 to 6 wherein the substituent is at the para position.

8. . A pharmaceutical conposition as claimed in claim 1 wherein 10 Ar is disubstituted phenyl.

9. . A pharmaaeutical composition as clained in claim 8 wherein the substituents are each C^_ 4 alkoxy.

10. . A pharmaceutical composition as clained in claim 9 wherein the substituents are each methoxy. 15

11. . A pharmaceutical conposition as clained in any of cl aims 8 to 10 wherein the substituents are at the meta and para positions.

12. . A pharmaceutical conposition as claimed in claim 1 wherein Ar is 3,4-methylenedioxyphenyl in which the methylene group is optionally substituted by one or two methyl 20 groups.

13. . A pharmaceutical composition as claimed in any preceding claim wherein R is hydrogen and R^ is hydrogen or C^_ 4 alkyl.

14. . A pharmaoeutioal conposition as claimed in ary preceding claim wherein is hydrogen, methyl or ethyl. 25

15. A pharmaceutical composition as claimed in claim 14 wherein R^ is methyl. 16. A pharmaceutical composition comprising a compound having the formula defined in claim 1 in association with a physiologically acceptable excipient which is a solid or a sterile liquid. 5 17. A compound having the formula defined in claim 1, with the provisos that Ar is not phenyl, mono- or dihydroxyphenyl, aminophenyl or dimethylphenyl. 18. A compound according to claim 17, wherein Ar is as defined in any one of claims 3 to 12. 10 19. A compound according to claim 18, wherein R is hydrogen and R^ is as defined in any one of claims 13 to

16. 20. 1,3-Dihydro-4-methyl-5-[4-(methylthio)benzoyl]-2Himidazol-2-one or a pharmaceutically acceptable salt thereof. 15

17. 21. A composition according to claim 1 substantially as herein described.

18. 22. A compound as claimed in claim 17 which is any one of those specifically hereinbefore mentioned.