CA1132554A

CA1132554A - 4-aroylimidazol-2-ones

Info

Publication number: CA1132554A
Application number: CA354,197A
Authority: CA
Inventors: Richard A. Schnettler; Richard C. Dage; J. Martin Grisar
Original assignee: Merrell Dow Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1979-06-18
Filing date: 1980-06-17
Publication date: 1982-09-28
Also published as: HK61486A; NO152841B; IE50646B1; DK160269C; IE801162L; NZ193935A; IT8048997A0; SE447107B; DK160269B; FR2459233B1; MY8600709A; NL193752B; NL8003498A; SE8501452D0; NO152841C; AT375349B; AU532783B2; CH646155A5; IT1143922B; HU186736B

Abstract

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

Description

M-964-Cl 1~ J~55~

FIELD OF THE INVENTION

This invention relates to 4-aroylimidazol-2-ones;
their use as antihypertensives, cardiotonics and anti-thrombotics; their pharmaceutical compositions; and their preparation.

DESCRIPTION OF THE PRIOR ART
The closest prior art known to the applicants is found in U S. patents 2~514,380 and 2,441,~33, as well as in R. ~uschinsky and L. A. Dolan, J. Am. C~Qm. soc~ 68, 23~0-55 (1946); ibid. 70, 657-62 (1948); ibid. 67, 2079-84 (1945); and Y. A. Rozin, E. P. Dorienko and Z. V.
Pushkareva, Khim. Geterotsikl. Soed;n., 4(4), 698-701 (1968). These references ~isclose .he preparation and chemical intermediate utility of the following compounds:
4-benzoyl-1,3-dihydro-2H-imidazol-2-onej 4-benzoyl-1,3-dihydro-2H-imidazol-2-one 1,3-diacetate, 4-benzoyl-1~3-dihydro-5-(lo~er alkyl)-2H-imidazol-2-one~
~-benzoyl-1-,3-dihydro-~-methyl-2H-imidâzol-2-one 1,3-diacetate, 1,3-dthydro-~-(3,4-dimethylbenzoyl)-2~-imidazol-2-one 1,~-diacetate, ` ~3255~ M-964-C1 1,3-dihydro-4-(hydroxybenzoyl)-2H-imidazol-2~one;
1,3-dihydro-4-(hydroxybenzoyl)-5-(lower alkyl)-2H-imidazol-

2-one;
1,3-dihydro-4-~3,4-dihydroxybenzoyl)-2H-imidazol-2-one;
1,~-dihydro-4-(4 nitrobenzoyl)-2H-imidazol-2-one;
1,~-dihydro-4-methyl-5-(4-nitrobenzoyl)-2H-imidazol-2-one, 4-(3-aminobenzoyl)-1,~-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl)-1,~-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl)-1J3-dihydro-5-methyl-2H-imidazol-2-one, however, no pharmaceutical utility for the 4-aroylimidazol-2-ones of the present invention has been previously - taught.
SUMMARY OF THE INVENTION
This invention is directed to pharmaceu~ically active 4-aroylimidazol-2-ones of general Formula 1 o R~ ~ A
0 Formula 1 wherein Ar is 2-furyl, ~-thienyl, phenyl, phenyl monosub-stituted at the ortho, meta or para position with X1, or disubstituted phenyl substTtuted at the para position with Xz and at the ortho or meta position with X3; Xl is halogen~ hydroxy, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched ~hain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms, trifluoromethyl, -502N(R2)2, NR3R4, pyrrolidino, piperi-dino, morpholino, piperazino or N'-alkyl-piperazino; X2 and X3 are halogen, hydroxy, a straight or branched chain ~ S~ M-964-C1 lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms or when X3 is at the meta position~ X2 and X3 taken together may be a methylenedioxy optionally substituted by one or two methyl groups; R is hydrogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkylcarbonyl of from 1 to 4 carbon atoms, or a benzoyl group; each of R1, R2, R3 and R4 is hydrogen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms; or a pharmaceuti-cally acceptable salt thereof. These compounds are useful as antihypertensives, cardiotonics and antithrombotics.
This invention is directed, furthermore, to the process of preparing the 4-aroylimidazol-2-ones as well as their pharmaceutical compositions.
DESCRIPT ! ON OF_THE PREFERRED EMBODIMENTS
Illustrative examples of a straight or branched chain lower alkyl of from 1 to 4 carbon atoms as used herein are methyl, ethyl, n-propyl, isopropyl, n-butyl and Tso~utyl.
Illustrative examples of a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms as used herein are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy.
~s used herein, the term halogen is taken to mean fluorine, chlorine, bromine or iodine.
As used herein, the term halide is taken to mean fluoride, chloride, bromide, or iodide.
As used herein, the term a straight or branched chain lower alkylthio of from 1 to ~ carbon atoms is taken to mean a group of the structure, S-alkyl, wherein the alkyl moiety is a straight or branched chain alkyl of from 1 to 4 carbon atoms and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

~ 5 ~

As used herein, the term methylenedioxy optionally substituted by one or two methyl groups is taken to mean methylenedioxy, ethylenedioxy, or isopropylidene-dioxy.
As used herein, the term a benzoyl group is taken to mean a group of the formula -(CO)C6H5.
As used herein, the term a straight or branched chain lower alkylcarbonyl of from 1 to 4 carbon atoms is taken to mean a group of the structure -C-alkyl wherein the alkyl moiety is a straight or branched chain lower alkyl of from 1 to 4 carbon atoms and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
As used hereln, the term N'-alkyl-piperazino is taken to mean a group of the structure -N ~ -alkyl wherein the alkyl moiety is a straight or branched chain lower alkyl of from 1 to 4 carbon atoms and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
The preferred compounds of this invention are those compounds of Formula 1 wherein R is hydrogen and Xl is piperidino, pyrrolidino, morpholino, piperazino, N'-alkyl-piperazino, a straight or branched chain lower alkoxy offrom 1 to 4 carbon atoms3 or a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms. Other pre-ferred compounds of this invention are tbose compounds of Formula 1 wherein Ar is an unsu~stituted ~henyl and where X2 113Z55~

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

~, .

113~255~

1,3-dihydro-4-(2-thienoyl)-2H-imidazol-2-one, 4-benzoyl-1,3-dihydro-2H-imidazol-2-one, 1,3-dihydro-4-(2-furanoyl)-2H-imidazol-2-one, 1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 4-(2-chlorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-(2-hydroxybenzoyl)-5-methyl-2H-imidazol-2-one, 4-(4-chlorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-(4-piperidinobenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-(4-morpholinobenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-(4-pyrrolidinobenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-(4-dimethylaminobenzoyl~-5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-[4-(4-methylpiperazinobenzoyl)]-2H-imi-dazol-2-one, 1,3-dihydro-4-ethyl-5-(4-methoxybenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-ethyl-5-(4-(methylthio)benzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-(4-hydroxybenzoyl)-5-methyl-2H-imidazol-2-one, and 1,3-dihydro-4-methyl-5-[4-(methylthio)benzoyl]-2H-imidazol-2-one, When R is hydrogen in Formula 1 compounds, the several tautomeric forms of general Formula 2 are possible;
1 ~ Ar 1 ~ Ar 1 ~ Ar / N N = H~ ~ N\ = N ~ N\ Formula 2 OH O OH
wherein Rl and Ar are as defined in Formula 1. These acidic tautomers may form pharmaceutically active salts of general Formula 3 M-964-Cl ~1~3;~5~

R1 ~ r R1 ~ Ar Rl Ar R1 Ar H~ ~ ` H' ~ M t M, ~ N~HÇ - ~ `H Formula 3 OM O OM

wherein R1 and Ar are as defined in Formula 1, and M Ts a pharmaceutically acceptable alkall metal, such as sodium or potassium; alkaline earth metal, such as calcium or magnesium; transition metal, such as zinc or iron; main group metal; ammonium or organic ammonium ion, such as tetramethylammonium ion. Throughout this disclosure the term imidazol-2-one shall be taken to mean any of the tautomers of Formula 2 and a pharmaceutically acceptable salt of an imidazol-2-one shall be taken to mean any tautomer of Formula 3.
The 4-aroylimidazol-2-ones of this invention wherein R is hydrogen may be prepared by a Friedel^Crafts acylation of an imidazol-2-one of Formula 4:
R 1~
H' ~ `H Formula 4 wherein Rl is as defined in Formula 1. The acylating agent may be a 2-furanoyl halide~ preferably 2-furanoyl chloride, a 2-thienoyl halide, preferably 2-thienoyl chloride, or a benzoyl halide, preferably a benzoyl chloride, of Formulas 5a, 5b or 5c O O X
yJ~ YJ~Xl YJ~i~

Formula 5a Formula 5b Formula ~c M-964-Cl wherein Y is a halogen and X~, X2 and X3 are as defined in Formula 1 or may additionally be any group which can be converted to the desired X1, X2 or X3 substituent sub-sequent to the Friedel-Crafts reaction such as a blocking group or a nitro group which can be converted, via the diazonium ionJ to a variety of other substituents by chemistry generally known in the art. Furthermore, the Friedel-Crafts reaction may be performed on the free acid or its corresponding acid anhydride instead of the aroyl halides mentioned hereinabove employing essentially identical reaction conditions. These alternate reactions are more fully described in Olah, "Friedel-Crafts and Related Reactions," Vol. III, Part 1, Interscience Publi-cations, John Wily and Sons9 New York, 1964.
The Friedel-Crafts reactions of this invention are performed by premixing about 1 molar equivalent of the appropriate imidazol-2-one with about 1 molar equivalent to about 10 molar equivalents, preferably about 2 molar equivalents, of a Lewis acid catalyst in a suitable solvent, for example, petroleum ethers; a chlorinated hydrocarbon, such as carbon tetrachloride, ethylene chloride, methylene chloride or chloroform; a chlorinated aromatic, such as 1,2,4-trichlorobenzene or o-dichloro-benzene; carbon disulfide; or preferably nitrobenzene.
About 1 molar equivalent to about 10 molar equivalents, preferably about 1.1 molar equivalents of the appropriate aroyl compound is added, preferably dropwise, to the mix-ture of imidazol-2-one, Lewis acid, and solvent and the reaction is allowed to proceed for about 1/2 hour to about 100 hours, preferably from about 1 hour to about 10 hours depending on the reactants, the solvent, and the tempera-ture which can be from about -78 to about 150C, prefera-bly about 0~ to about 100C5 most preferably about 60C.
The resulting aroylimidazol-2-one may be isoiated from the reaction mixture by any su~table art-known procedure, ~ 1 3 ~

pref~rably by quenching the reaction mixture wlth ice water and subsequently removing the product by filtra-tion or extraction and solvent removal.
Lewis acid catalysts suitable for use in the Friedel-Crafts reactions described herein areI for example, ametal, such as aluminum, cerium, copper, ironJ molybdenum, tungsten or zinc; a Bronstead acid, such as a phosphoric acid, sulfuric acid, sulfonic acid, or a hydrohalo acid, such as hydrochloric or hydrobromic acid; halogen sub-stituted acetic acids, such as chloroacetic or trifluoro-acetic acids; or a metallic halide, such as a boron halidef zinc chloride, zinc bromide, berryl chloride, copper chloride, iron(III) bromide, iron(III) chloride, mercury(II) chloride, mercury(I) chloride, antimony bromide, antimony chloride, titanium(IV) bromide, titanium(IV) chloride, titanium(III) chloride, aluminum bromide or preferably aluminum chloride.
The compounds of Formula 1 wherein Xl is at the ortho or para position and is a pyrrolidino, piperidino, morpho-lino, piperazino9 N'-alkyl-piperazino and NR3R4 may be pre-pared as hereinabove described or may be prepared from a suitable fluorobenzoylimidazol-2-one of Formula 6 R'~,~ ~ F Formula 6 wherein R and R1 are as defined above in Formula 1 and the fluorine atom is at either the ortho or para position. The appropriate compound of Formula 6 is allowed to react with from about l to about 10 molar equivalents of pyrrolidine, piperidine, morpholine, piperazine or N'~alkyl-pi?erazine, as appropriate. This reaction may be performed with or without a solvent, pre-5S~ M - 96 4- C 1 ferably~ the amine is the solvent as well as the reactant.
Suitable solvents, if desired, for this reaction are, for example, dimethylformamide; dimethylsulfoxide; petroleum ethers; chlorinated hydrocarbons, such as chloroformJ
methylene chloride, or carbon tetrachloride; carbon di-sulfide; ethereal solvents, such as diethyl ether, tetra-hydrofuran or p-dioxan; aromatic solvents such as benzene, toluene or xylene; or alcoholic solvents, such as ethanol.
The reaction is allowed to proceed for about 1/2 hour to about 48 hours, preferably about 24 hours, depending on the reactants, the solvent if any, and the temperature which can be from about 0 to about 150~C.
The compounds of Formula 1 wherein X1 is an amino group of the formula, -NR3R4, and wherein R~ and R4 are as defined in Formula 1, may alternatively be prepared from the corresponding nitro substituted benzoylimidazol-2-ones of Formula 7 R~ ~ N02 Formula 7 wherein R and Rl are as defined in Formula 1. The com-pounds of Formula 7 are either known in the prior art or may be prepared by Friedel-Crafts acylation of an imida-zol-2-one of Formula 4 with a nitro substituted benzoyl halide, preferably a nitro substituted benzoyl chloride by procedures analogous to those outlined above. The nitro group is reduced to the unsubstituted amino ~roup by any suitable art-known procedure and subsequently, if desired, the unsubstituted amino may be alkylated by any appropriate art known method.

M-964-Cl 5~

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

3 molar equivalents, of the bisulfide is allowed to react for about 1/2 hour to about 10 hours, preferably about 2 hours, dependlng upon the reactants and the temperature which may be from about 0 to about 150C, preferably about 50C. Ftnally, the nitrobenzoylimidazol-2-ones may be reduced to the correspondtng aminG compounds by any other appropriate art-known procedure.
The alkylation of the unsubstituted aminobenzoyl-imidazol-2-ones may be accomplished, for example, by M-964-Cl ~3'~55'-~

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

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

M-g64-or p-dioxan; aromatic solvents such as benzene, toluene, or xylene; or preferably the polar aprotic solvents such as dimethylformamide ~DMF) or dimethylsulfoxide (DMSO).
The reaction is allowed to proceed from about 1 minute to about 1 hour and the temperature may be from about O~C to about 100C, preferably about 25C. When it is desired that only one of the imidazol-2-one ni~rogen atoms be substituted with an alkyl group, the appropriate imidazol-2-one is reacted with from about 1 molar equiva-lent to about 10 molar equivalents of a base, preferablyabou~ 1 molar equivalent and with about 1 molar equivalent of an alkylating agent. Utilizing this procedure, both - possible monoalkylated nitrogen isomers result. These isomers are seperable by conventional art-known procedures such as fractional crystallization, fractional distillation, or chromatography. When it is desired that both nitrogen atoms of the imidazol-2-one ring be alkyl substituted, the appropriate imidazol-2-one is reacted with from about 2 molar equivalents to about 10 molar equivalents of a base, preferably about 2 molar equivalents and from about 2 molar equivalents to about 10 molar equivalents of an alkylating agent, preferably about 2 molar equivalents.
Finally, any reactive substituents on the aroyl rings, if present, may become alkylated concurrently. That is, the following X groups, X=OH, -NHR3, SO2NH2 and unsubsti-tuted piperazino, are alkylated under identical reaction conditions. if desired, the alkylation of the aroyl ring substituents may be avoided by the use of suitable pro-tecting groups well-known in the art, for example, ~=OH or -NHR3 may be benzylated and later deblocked by hydrogenoly-s i s .
When desired, the nitrogen atoms of the imidazol-2-one ring may be substituted with an alkylcarbonyl group by any suitable art-known procedure. Such methods include reacting the N-unsu~stttuted aroylimidazol-2-ones of this invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyl chloride, isopropanoyl chloride or butanoyl chloride. Normally, acylation reactions utilizing acyl halides employ an acid sponge such as triethylamine or pyridine to remove any hydrohalide as it is formed. Furthermore, the corres-ponding free acid or acid anhydride may be employed in-stead of the acyl halides. Acylation reactions are generally run without added solvent but may be performed using any nonreactive solvent, for example, petroleum ethers; chlorinated hydrocarbons such as chloroform~
methylene chloride or carbon tetrachloride; carbon disul-find; ethereal solvents, such as diethylether, tetrahydro-furan or p-dioxan or aromatic soivents such as benzene, toluene or xylene. The reactions are allowed to proceed for about 1 minute to about 100 hours, preferably from about 1 hour to about 10 hours and the temperature may be from about -78 to about 150C preferably from 0 to 100C. Finally, any reactive substituents on the aroyl rings, if present, will become acylated concurrently.
That is, the following X groups, X=OH, -NHR3, -SO2NH2 and unsubstituted piperazino, are acylated under identical reaction conditions. If desired, the acylation of the benzoyl ring substituents may be avoided by the use of suitable protecting groups well-known in the art, for example X=OH or -NHR3 may be benzylated and later de-blocked by hydrogenolysis.
The alkali metal, alkaline earth metal, transitionmetal, main group metal, ammonium or organic ammonium salts of the aroylimidazol-2-ones of this invention may be prepared from a corresponding metal or ammonium basic salt for example an alkoxide, such as sodium methoxide or sodium ethoxide, a phenoxide, such as sodium phenoxide;
hydroxides, such as sodium hydroxide or potassium hydrox-ide; or a carbonate/ such as sodium carbonate, potassium carbonate, zinc carbonate, magnesium carbonate or sodium hydrogen carbonate. These reactions may be per~ormed with or without a so1vent. Suitable solvents are, for example, lower alcohols, such as methanol, ethanolJ isopropanol, M-964-Cl n-propanol or n-butanol; aromatic solvents, such as benzene, toluene or xylene; ethereal solvents, such as diethyl ether, tetrahydrofuran or P-dioxan; and halo-genated hydrocarbon solventsJ such as chloroform, methylene chloride or carbon tetrachloride. The aroyl-imidazol-2-one and base are allowed to react for about 1 minute to about 24 hours depending on the reactants and the temperature which can be from about -78 to about 1~0C, preferably from about 0 to about 25C.
The aroyl chlorides or their corresponding carboxylic acids, which are required for the Friedel-Crafts acyla-tion of this invention, are either generally available in the art or may be prepared by analogous procedures.
The imidazol-2-one starting materials of Formula 4 may be prepared as described by or adapted from R. Duschinsky and L. A. Dolan5 J. Am. Chem. Soc. 67, 2079 (19~5), R.
Duschinsky and L. A. Dolan, i. Am. Chem. Soc. 68, 2~50 (1945) or U.S. Patent 2,441,g3~.
The compounds of general Formula 1 may be used in the treatment of cardiac failure including congestive heart failure, backward heart failure, forward heart failure, left ventricular heart failure, or right ventri-cular heart failure or in the treatment of any other con-dition which requires the strengthening of heart action with a cardiotonic. In many respects these compounds possess digitalis-like action. The compounds of general Formula 1 may also be used in the treatment of hyperten-sion including primary or essential hypertension, hormonally induced hypertension, renal hypertension and chemically induced hypertension. Finally, the compounds of general Formula 1 may be used as antithrombotics.
They affect the coagulation of blood by preventing the aggregation of blood platelets, which play a dominant role in thrombotic conditions both in the initial event and at the occlusive stage. Arterial thrombosis, M-96~-Cl 55~

particularly in arteries supplying the heart muscle and brain, is a leading cause of death and disability.
The compounds may be administered in various manners to achieve the desired effect. The compounds may be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, that is, intravenously or intramuscu-larly. The amount of compound administered will vary with the severity of the hypertension, cardiac failure or blood clotting and the mode of adm;nistration. For oral administration the antihypertensively effective amount of compound is from about 0.1 mg/kg (milligrams per - kilograms) of patient body weight per day to about 500 mg/kg of patient body weight per day and preferably from about 50 mg/kg of patient body weight per day to about 150 mg/kg of patient body weight per day.
For parenteral administration the antihypertensively effective amount of compound is from about 0.01 mg/kg of patient body weight per day up to about 150 mg/kg of patient body weight per day and preferably from about 1.0 mg/kg of patient body weTght per day up to about 10.0 mg/kg of patient body weight per day. For oral or parenteral administration the cardiotonically effective amount of compound is from about 0.1 mg/kg of patient body weight per day up to about 500 mg/kg of patient body weight per day and preferably from about 0.1 mg/kg of patient body weight per day up to about 10.0 ~g/kg of patient body weight per day. For oral or parenteral administration the anticoagulant effective amount of com-pound is from about 0.1 mg/kg of patient body weight perday up to about 1000 mg/kg of patient body weight per day and preferably from about 1 mg/kg of patient body weisht per day up to about 100 mg/kg of patient body weight per day.
- For oral administration a unit dosage may contain~
for example, from 10 to 100 mg of the active ingredient.
For parenteral administration a unit dosage may contain, ~3~ 5 ~ ~ M-964-C1 for example, from 5 to 50 mg of the active ingredient.
Repetitive daily administration of the compounds may be desired and will vary with the condition of ~he patient and the mode of administration.
As used herein the term patient is taken to mean a warm blooded animalJ for example, birds, such as chickens and turkeys, and mammals, such as primates, humans, sheep, horses, bovine cows and bulls, pigs, dogs, cats, rats and mice.
For oral administration the compounds can be for-mulated Into solid or liquid preparations such as cap-sulesJ pills, tablets, troches, powders, solutions, sus-pensions or emulsions. The solid unit dosage forms can be a capsule which can be of the ordinary gelative type containing, for example, lubricants and inert filler, such as lactosej sucrose, and cornstarch. In another embodiment the compounds of general Formula 1 can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubri-- cant such as stearic acid or magnesium stearate.
For parenteral administration the compounds may be administ~red as injectable dosages of a solution or sus-pension of the compound in a physiologlcally acceptablediluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleum, animal, vegetable, or synthetic origin, for exampleJ
peanut oil, soybean oil, and mineral oil. In general, water, saline, aqueous dextrose and related sugar 501u-tions, ethanol and glycols such as propylene glycol or - 35 polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

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

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

M- 964-c 1 1~3~2~S~

1,3-DihYdro-4-methyl-5-r4-(1-piperidinyl)benzoyll-?H-imidazol-2-one A suspension of 11.0 9 (0.05 mole) of 1, 5-dihydro-

4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of piperdine is stirred at reflux temperature for 24 hours. Excess piperdine is evaporated under reduced pres-sure and the residue is recrystallized twice from a mixture of isopropanol and water to give 11.9 9 of the title compound. M.P. 260-263C.

1.3-DihYdro-4-methYl-5-~4-(4-morDho_Inyl)benzoyll-2H-imidazol-2-one - Following the procedure of Example 2 but substituting morpholine for piperidine, the title compound is obtained.
M.P. 283-286C.

1.3jDihl~dro-4-l4-(dirnethYlamino)benzoYll-~;-methyl-2H-im~ azo -2-one A mixture of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 100 ml of 30 aqueous solution of dimethylamine and 200 ml of ethanol is heated in a pressure bomb at 130-135C for 22 hours.
The mixture is cooled, the solid is collected and recrystallized from isopropanol-water to give the title compound. M.P. >310C. ~-(max)(methanol) 364 nm (~ = 23,300).
EXAMPLE
1,3-Dihydro-4-(4-hYdroxybenzoYl)-~-methYl-2H-imidazol-2-one To a melt of 26 9 (0.23 mole) of pyridine hydro-chloride at 200-205C is added 5.3 9 (0.023 mole) of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one and the mixture is stirred mechanically for 30 minutes.
The reaction mixture is poured on ice-2NHCl. The result-ing precipitate is washed with water and recrystallized from isopropanol-water to give the title compound. M.P.
> 300C. ~(max)(methanol) 320 nm (~ = 13,200).

11~2~S~ M-964-C1 ~,~-DIhydro-4-methyl~5-r4-(methylthio)benzoyll-2H-imidazol-2-one A solution of 25.0 9 of 4-(methylthio)-benzoic acid and 22 ml of thionyl chloride in 50 ml of benzene is refluxed for 4 hours. Excess reagent and solvent is evaporated and the residue is azeotroped 3 times with benzene to remove all thionyl chloride. Th`e residue is added dropwise to a mixture of 11.8 9 of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 40.0 9 of anhydrous aluminum chloride and 100 ml of nitrobenzene. The resulting mix-ture is stirred at 60-65C for 5 hours, poured on ice and the precipitate that forms is collected, washed wi th ethyl ether and water, and recrystallized from isopro-panol-water to give the title compound. M.P. 255-258C.
(dec.).

1,3 Dihydro-4-(4-methoxYbenzoYl)-5-methyl-~-imidazol-2-one To 19.6 9 of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 9 of anhydrous aluminum chloride in 150 ml of nitrobenzene is added dropwise 34.2 9 of P-methoxybenzoyl chloride and the mixture is poured on 500 ml of 2N-HCl and ice, washed ~ times with ethyl ether, the r,osulting solid is recrystallized from isopropanol-water to give the title compound. M .P. 257-258C (dec.).

~-Dihydro-4-(4-methoxYbenzoYl)-5-methYl-?H-imidazol -?-one so ium salt To 7.0 9 of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 100 ml of methanol is added 1.6 9 of sodium methoxide. The mixture is heated on a steam bath until homogeneous, filtered and evaporated to dryness.
The solid residue is recrystallized from isopropanol to ~S5 give the title compound. M.P. 2~0-282CC (dec.).

1~L3~5~ M-964-C1 EXAI~IPLE 4 4-Benzoyl-1,3-dihydro-5-methvlimidazol-2-one To a solution of 3.0 9 of 4-methylim7dazol-2-one and 8.o 9 of aluminum chloride in 50 ml of nitrobenzene is

5 added dropwise 4.o 9 of benzoyl chloride. The solution is warmed at 60C for 4 hours, poured over ice water, slurried with ether and the resulting solids filtered and dried to yield the title compound. M.P. 250-54C.

10 1,3-DihYdro-4-methYl-~-thienoY1-2H-imidazol-2-one To a solution of 7.3 9 of 4-methylimidazol-2-one and 10.8 9 of aluminum chloride in 150 ml of nitrobenzene is added 12.0 9 of 2-thienoyl chloride. The mixture i 5 stirred at 60C for 3 hours, cooled and poured over ice 15 water. The organic portion is extracted into ethyl acetate, dried and the organic solvent evaporated to give the title compound. M.P. 212-215C .

1,3-Dihydro-4-(3,4-dimethoxYbenzoyl~-2H-imidazol-2-one To a solution of 6.5 9 of 1,3 dihydro-4-methyl-2H-imidazol-2-one and 14.6 9 of alurninum chloride in 65 ml of nitrobenzene is added 17.6 9 of 3,4-dimethoxybenzoyl chloride in portions. The mixture is stirred for 3 hours at 60C, cooled and poured over ice water. The gummy solids are filtered and recrystallized twice from ethyl alcohol-water t~ afford the title compound. M.P. 257-259C.

1,3-Dihydro-4-(?-furanoYl)-5-methyl-2H-imidazol-2-one 3o To a slurry of 8.9 9 of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 24.0 9 of aluminum chloride in 135 ml Gf nitrobenzene is added 12.9 9 of furanoyl chloride in a dropwise manner. The mixture is stirred at 60~
for 3 hours, cooled and poured over ice water. The solid 3~ is then filtered and recrystallized twice from methyl alcohol to afford the title compound. ~1.P. 214-216C.

lle3~2554 M-964-C1 EXAMPLE 1~
1,3-Dihvdro-4-(2-thienovl)-2H-im dazol-2-one In 50 ml of nitrobenzene is combined 13.~ 9 of aluminum chloride, 4.2 9 of 1,3-dihydro-2H-imidazol-2-5 one and 8.1 9 of thienoyl chloride. The mixture isstirred at 60C for 3 hours and poured over ice water.
The solids are filtered, washed with ether and recrystal-lized twice from ethanol-water to afford the title compound. M.P. ~i39-42oc.

4-Benzoyl-1,3-dihydro-2H-imidazol-2-one To 51 ml of nitrobenzene is added 1.68 9 of 1,3-dihydro-2H-imidazol-2-one, 5.3 9 o~ aluminum chloride arId 3.1 9 of benzoyl chloride. The mixture is stirred for 3 hours at 60C and poured into ice water. The solids are filtered, washed with ether and recrystallized twice from methyl alcohol-water to afford the title com-pound. M.P. 329-30C.

1,3-Dihydro-4-furanoYl-2H-imidazol-2-one To 50 ml of nitrobenzene is added 4.2 9 of 1,3-dihydro-2H-imidazol-2-one) 13.3 9 of aluminum chloride and 702 9 of furanoyl chloride. The mixture is stirred at 60C for 3 hours and poured over ice water. The solids are flltered, washed with ether and recrystallized twice from ethanol-water to afford the title compounds. M.P.
318-321~C.

EXAMP~E 16 1,3-Dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-one To 5.13 9. of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 7.98 9. of anhydrous aluminum chloride in 80 ml.
of nitrobenzene is added dropwise 10.60 9. of 3,4-methylenedioxybenzoyl chloride and the mixture is poured on 500 ml. of 2N-HCl and ice, washed 3 times with ethyl 11~3ZSS~

ether, the resulting solid is collected to give the title compound. M.p. 293-296C (dec).

1,3-Dihydro-4-(4-m thoxybenzoyl)-1,3,5-trimethyl-2H-imidazol-2-one In 120 ml of DMS0 ts placed 15.2 9 of powdered potassium hydroxide, 8.o 9 of 1,3-dihydro-4-(4-methoxy-benzoyl)-5-methyl-2H-imidazol-2-one, sodium salt and 19.5 9 of methyl iodide. The mixture is stirred at room temperature for 60 minutes and poured into 800 ml of water. Extraction with methylene chloride gives a solid, which is crystallized from ether. M.p. 109-111C.
NMR: N-CH3 (6 protons) at 3.3 ppm.

1,3-Dihydro-~1 or 3),5-dimethyl-4-(4-methoxybenzoyl) 2H-imidazol 2-one -To 2.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of DMS0 is added o.288 9 of sodium hydride and 1.22 9 of methyl iodide.
The mixture is stirred at 22C for 30 minutes, poured into methylene chloride and washed with water. The solvent is dried and evaporated to give an oil which when triturated with chloroform gives a solid. The solid is crystallized from methanol; m.p. 225-228C.
25 Anal. calcd. for Cl2H14N203: C, 63.40; H, 5.73; N, 11.39.;
Found: C, 63.~4; H, 5.85, N, 11.21.;
NMR: N-Methyl; Singlet at 3.2 ppm.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing an aroylimidazol-2-one of the formula wherein Ar is 2-furyl, 2-thienyl, phenyl mono-substituted at the ortho, meta or para position with X1, or disubstituted phenyl substituted at the para position with X2 and at the ortho or meta position with X3; X1 is halogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrrolidino, piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chaln lower alkoxy or from 1 to 4 carbon atoms, a straight or branched chain lower alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta position X2 and X3 together may be methylenedioxy optionally substituted by one or two methyl groups; R is hydrogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkylcarbonyl of from 1 to 4 carbon atoms, or a benzoyl; each of R1, R2, R3 and R4 are hydro-gen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms with the proviso that both R9 and R4 cannot be hydrogen; or a pharmaceutically acceptable salt thereof which comprises reacting an imidazol-2-one of the formula wherein R1 is as defined above with about 1 to about 10 molar equivalents of a 2-furoyl halide, 2-thienoyl halide, a benzoyl halide monosubstituted at the ortho, meta or para position with X1 wherein X1 is as defined above, or a disubstituted benzoyl halide substituted at the para position with X2 and at the ortho or meta position with X3 wherein X2 and X3 are as defined above, in the presence of about 1 to about 10 molar equivalents of a Lewis acid catalyst in a suitable solvent at a temperature of from about 0°
to about 100°C for about 1 to about 10 hours and when it is desired that R be other than hydrogen, acylating or alkylating, as appropriate, the resulting aroylimidazol-2-one with an appropriate acyl halide or alkylating agent;
alternatively a) where X1 is pyrrolidino, piperidino, mor-pholino, piperazino or N'-alkyl-piperazino treating the thus formed compound wherein X1 is fluorine with from about 1 to about 10 molar equivalents of pyrrolidine, piperidino, morpholine, piperazine, or N'-alkyl-piperazine in a suitable solvent for about 1/2 hour to about 48 hours at about 0° to about 150°C;
b) where X1 is an amino group of the formula, NR3R4, reducing a compound of the formula with tin, zinc or iron metal in concentrated hydrochloric acid to produce the corresponding aminobenzoylimidazol-2-one which may then be alkylated by reaction with an appropriate alkyl halide; and where a pharmaceutically acceptable salt is desired, reacting the thus formed aroylimidazol-2-one with an appropriate pharmaceutically acceptable metal or ammonium basic salt.

2. An aroylimidazol-2-one of the formula wherein Ar is 2-furyl, 2-thienyl, phenyl mono-substituted at the ortho, meta or para position with X1, or disubstituted phenyl substituted at the para position with X2 and at the or-tho or meta position with X3; X1 is halogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrroli-dino, piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta position X2 and X3 together may be methylenedioxy optionally substituted by one or two methyl groups; R is hydrogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkylcarbonyl of from 1 to 4 carbon atoms, or a benzoyl; each of R1, R2, R3 and R4 are hydrogen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms with the proviso that both R3 and R4 cannot be hydrogen; or a pharmaceutically acceptable salt thereof when prepared by the process of claim 1.

3. The process of claim 1 wherein R is hydrogen and R1 is hydrogen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms.

4. An aroylimidazol-2-one of the formula as defined in claim 1 wherein R is hydrogen and R1 is hydrogen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, when prepared by the process of claim 3.

5. The process of claim 1 wherein R is hydrogen and R1 is hydrogen or a methyl or ethyl group.

6. An aroylimidazol-2-one of the formula as defined in claim 1 wherein R is hydrogen and R1 is hydrogen or a methyl or ethyl group, when prepared by the process of claim 5.

7. A process for preparing an aroylimidazol-2-one of the formula wherein Ar is 2-furyl, 2-thienyl, phenyl mono-substituted at the ortho, meta or para position with X1, or disubstituted phenyl substituted at the para position with X2 and at the ortho or meta position with X3; X1 is halogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrroli-dino, piperidino, morpholino, piperazino or N'-alkyl-piperazino;
X2 and X3 are halogen, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta position X2 and X3 together may be methylenedioxy optionally substituted by one or two methyl groups; R1 is hydrogen or a methyl or ethyl group; each of R2, R3 and R4 are hydrogen or a straight or branched chain lower alkyl of from 1 to 4 carbon atoms with the proviso that both R3 and R4 cannot be hydrogen;
or a pharmaceutically acceptable salt thereof which comprises reacting an imidazol-2-one of the formula wherein R1 is as defined above with about 1 to about 10 molar equivalents of a 2-furoyl halide, 2-thienoyl halide, a benzoyl halide monosubstituted at the ortho, meta or para position with X1 wherein X1 is as defined above, or a disubstituted benzoyl halide substituted at the para position with X2 and at the ortho or meta position with X3 wherein X2 and X3 are as defined above, in the presence of about 1 to about 10 molar equivalents of a Lewis acid catalyst in a suitable solvent at a temperature of from about 0° to about 100°C for about 1 to about 10 hours; alternatively a) where X1 is pyrrolidino, piperidino, morpholino, piperazino or N'-alkyl-piperazino treating the thus formed com-pound wherein X1 is fluorine with from about 1 to about 10 molar equivalents of pyrrolidine, piperidine, morpholine, piper-azine, or N'-alkyl-piperazine in a suitable solvent for about 1/2 hour to about 48 hours at about 0° to about 150°C;
b) where X1 is an amino group of the formula, NR3R4, re-ducing a compound of the formula with tin, zinc or iron metal in concentrated hydrochloric acid to produce the corresponding aminobenzoylimidazol-2-one which may then be alkylated by reaction with an appropriate alkyl ha-lide; and where a pharmaceutically acceptable salt is desired, reacting the thus formed aroylimidazol-2-one with an appropriate pharmaceutically acceptable metal or ammonium basic salt.

8. An aroylimidazol-2-one of the formula wherein Ar is 2-furyl, 2-thienyl, phenyl monosubstituted at the ortho, meta or para position with X1, or disubstituted phenyl substituted at the para position with X2 and at the ortho or meta position with X3; X1 is halogen, a straight or branched chain lower alkyl of from 1 to 4 carbon atoms, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkylthio of from 1 to 4 carbon atoms, trifluoromethyl, -SO2N(R2)2, NR3R4, pyrrolidino, piperi-dino, morpholino, piperazino or N'-alkyl-piperazino; X2 and X3 are halogen, a straight or branched chain lower alkoxy of from 1 to 4 carbon atoms, a straight or branched chain lower alkyl of from 2 to 4 carbon atoms, or when X3 is at the meta position X2 and X3 together may be methylenedioxy optionally substituted by one or two methyl groups; R1 is hydrogen or a methyl or ethyl group; each of R2, R3 and R4 are hydrogen or a straight or bran-ched chain lower alkyl of from 1 to 4 carbon atoms with the pro-viso that both R3 and R4 cannot be hydrogen; or a pharmaceuti-cally acceptable salt thereof when prepared by the process of claim 7.

9. A process for preparing 1,3-Dihydro-4-(4-methoxy-benzoyl)-5-methyl 2H-imidazol-2-one or a pharmaceutically accep-table salt thereof which comprises reacting an imidazol-2-one of the formula with about 1 to about 10 molar equivalents of a 4-methoxy-ben-zoyl halide in the presence of about 1 to about 10 molar equi-valents of a Lewis acid catalyst in a suitable solvent at a temperature of from about 0° to about 100°C for about 1 to about 10 hours and where a pharmaceutically acceptable salt is desired, reacting the thus formed aroylimidazol-2-one with an appropriate metal or ammonium basic salt.

10. The compound 1,3-Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one or a pharmaceutically acceptable salt thereof when prepared by the process of claim 9.

11. A process for preparing 1,3-Dihydro-4-(3,4-Dimeth-oxybenzoyl)-2H-imidazol-2-one or a pharmaceutically acceptable salt thereof which comprises reacting an imidazol-2-one of the formula with about 1 to about 10 molar equivalents of a 3,4-dimethoxy-benzoyl halide in the presence of about 1 to about 10 molar equi-valents of a Lewis acid catalyst in a suitable solvent at a temperature of from about 0° to about 100°C for about 1 to about 10 hours and where a pharmaceutically acceptable salt is desired, reacting the thus formed aroylimidazol-2-one with an appropriate metal or ammonium basic salt.

12. The compound 1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one or a pharmaceutically acceptable salt thereof when prepared by the process of claim 11.

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

14. The compound 1,3-Dihydro-4[4-(methylthio)benzoyl]-5-methyl-2H-imidazol-2-one or a pharmaceutically acceptable salt thereof when prepared by the process of claim 13.