CH646155A5 - 4-AROYLIMIDAZOL-2-ONE. - Google Patents

Description

The invention relates to new 4-aroylimidazol-2-oneJ pharmaceutical preparations containing these compounds and a process for the preparation of the compounds.

The closest prior art are US-PSS 2 514 380 and 2 441 933, also R. Duschinsky and

L.A. Dolan, J. Am. Chem. Soc., 68, 2350-55 (1946); ibid. 70, 657-62 (1948); ibid. 67, 2079-84 (1945) and Y. A. Rozin, E. P. Dorienko and Z. V. Pushkavera, Khim. Heterotics Soedin., 4 (4), 698-701 (1968). From these publications, the production and usability as chemical intermediates of the following compounds are known:

4-benzoyl-l, 3-dihydro-2H-imidazol-2-one, 4-benzoyl-1,3-dihydro-2H-imidazol-2-one-1,3-diacetate, 4-benzoyl-1,3- dihydro-5- (lower alkyl) -2H-imidazol-2-one, 4-benzoyl-1,3-dihydro-5-methyl-2H-imidazol-2-one-1,3-diacetate, 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-one, 1,3-dihydro-4- (3,4-dihydroxybenzoyl) -2H-imidazol-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) - 1,3-dihydro-2H-imidazol-2-one, 4- (4-aminobenzoyl) -1,3-dihydro-2H-imidazol-2-one, 4- (4-aminobenzoyl) -l, 3-dihydro- 5-methyl-2H-imidazol-2-one; however, a pharmaceutical utility of the 4-aroylimidazol-2-ones according to the present invention was not previously known.

The new compounds have the following formula

0

wherein Ar is the 2-furyl or 2-thienyl radical, a phenyl radical monosubstituted in the ortho, meta or para position by Xi or in the para position by X2 and in the ortho or meta position by X3, Xi halogen, one straight-chain or branched alkyl radical with 1 to 4 carbon atoms, a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms, a straight-chain or branched alkyl mercapto radical with 1 to 4 carbon atoms, the trifluoromethyl group, one of the radicals -SChN (R2) 2, -NR3R4, the pyrrolidino -, Piperidino, Morpholino- or Piperazinorest or an N-alkyl-piperazino radical, X2 and X3 halogen, straight-chain or branched alkoxy radicals with 1 to 4 carbon atoms, straight-chain or branched alkyl radicals with 2 to 4 carbon atoms, or, if X3 is in the meta position, X2 and X3 form a methylenedioxy group which is optionally substituted by 1 or 2 methyl radicals, R is hydrogen, a straight-chain or ve rbranched alkyl radical having 1 to 4 carbon atoms, a straight-chain or branched alkylcarbonyl radical having 1 to 4 carbon atoms or the benzoyl radical, and R 1, R 2, R 3 and R 4 denote hydrogen or straight-chain or branched alkyl radicals having 1 to 4 carbon atoms, with the proviso that R 3 and R4 cannot both be hydrogen.

Compounds in which Rs and R4 both represent hydrogen, namely 4- (3-aminobenzoyl) -l, 3-dihydro-2H-imi-dazol-2-one and 4- (4-aminobenzoyl) -l, 3-dihydro- 5-methyl-2H-imidazol-2-one, are already known, as described above.

The new compounds of formula I can also be present as pharmaceutically acceptable salts.

The new compounds of formula I described above, as well as the two known compounds and the pharmaceutically permissible salts of all compounds, can be used as an antihyp?, Cardiotonic and antithrombotic agent!

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Pharmaceutical preparations are characterized in that they contain at least one compound of the formula I described above or a pharmaceutically acceptable salt of the compounds mentioned as the active ingredient component, 4- (3-aminobenzoyl) -l, 3-dihydro-2H-imi-dazol-2 -one and 4- (4-aminobenzoyl) -1,3-dihydro-5-methyl-2H-imidazol-2-one and corresponding salts thereof can also be present as active ingredient components in the preparations according to the invention.

The process according to the invention for the preparation of the new compounds of the formula I is characterized in that a compound of the formula

0.

wherein Ri is defined above, for the introduction of the group -CO-Ar, in which Ar is defined above, is subjected to a Friedels-Crafts acylation and any compounds obtained are converted into the corresponding salts.

Examples of straight-chain or branched alkyl radicals having 1 to 4 carbon atoms are the methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl radical. Examples of straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms are the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy radical.

The term «halogen» includes the elements fluorine, chlorine, bromine and iodine. A halide is understood to mean fluoride, chloride, bromide and iodide.

A straight-chain or branched alkyl mercapto radical with 1 to 4 carbon atoms is understood to mean a radical of the formula S-alkyl, in which the alkyl portion is a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl radical.

A methylenedioxy radical which is optionally substituted by 1 or 2 methyl groups means the methylenedioxy, ethylenedioxy and isopropylidenedioxy radical. The benzoyl radical is understood to mean the radical of the formula - (CO) Cr> H5.

Under a straight-chain or branched alkylcarbonyl radical having 1 to 4 carbon atoms is a radical of the formula

O

II

-C-alkyl understood, wherein the alkyl portion is a straight or branched alkyl radical having 1 to 4 carbon atoms, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl radical.

Under an N'alkyl piperazine residue is a residue of the formula

/ - \

-N ^ ^ -alkyl, in which the alkyl portion is preferably a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl radical.

Preferred compounds according to the invention are those of the formula I in which R is hydrogen and Xi is the piperidino, pyrrolidino, morpholino, piperazino, an N '- alkylpiperazinorest, a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms or a straight-chain or branched Alkyl mercapto residue with

1 to 4 carbon atoms. Further preferred compounds according to the invention are those of the formula I in which Ar is an unsubstituted phenyl radical and Xz and Xj are straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms.

More preferred compounds according to the invention are those of the formula I in which R 1 is hydrogen or methyl and Xi is in the para position and a pyrrolidino *, morpholino, piperazino, N'alkylpiperazino, a straight-chain or branched alkoxy radical 1 to 4 carbon atoms or straight-chain or branched alkyl mercapto radical having 1 to 4 carbon atoms. Further more preferred compounds according to the invention are those of the formula I in which Ri is hydrogen or methyl, X3 is in the meta position and Xz and X3 are straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms or together, if appropriate by 1 or

Form 2 methyl groups substituted methylenedioxy. Most preferred are compounds of formula I.

wherein R is hydrogen and Ri is methyl and Xi is in the para position and is a methoxy or methylmero radical, or in which R is hydrogen and Ri is methyl, X3 is in the meta position and X2 and X3 are methoxy radicals or together form one Form methylenedioxy radical.

Examples of compounds of the general formula I are:

4-benzoyl-1,3-dihydro-5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5- (2-thienoyl) -2H-imidazol-2-one, 1,1 3-dihydro-4-methyl-5- (3,4-methylenedioxybenzoyl) -2H-imidazol-2-one,

l, 3-dimethyl-4-benzoyl-2H-imidazol-2-one,

1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazole

2-on,

4-benzoyl-l, 3-dihydro-5-methyl-2H-imidazol-2-one-l, 3-di-acetate,

1,3-dihydro-4- (3,4-dimethoxybenzoyl) -5-methyl-2H-imi-dazol-2-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-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-imidazole

2-on,

4- (4-chlorobenzoyl) -1,3-dihydro-5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-methyl-5- (4-piperidinobenzoyl) -2H-imidazole-2- on,

1,3-dihydro-4-methyl-5- (4-morpholinobenzoyl) -2H-imi-dazol-2-one,

1,3-dihydro-4-methyl-5- (4-pyrrolidinobenzoyl) -2H-imi-dazol-2-one,

1,3-dihydro-4- (4-dimethylaminobenzoyl) -5-methyl-2H-imi-dazol-2-one,

1,3-dihydro-4-methyl-5- [4- (4-methylpiperazinobenzoyl)] - 2H-imidazol-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,

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1,3-dihydro-4- (4-hydroxybenzoyl) -5-methyl-2H-imidazol-2-one and 1,3-dihydro-4-methyl-5- [4- (methylthio) benzoyl)] - 2H- imi-dazol-2-one.

RlHAr

H'O

OH

If R in compounds of the formula I is hydrogen, several tautomeric forms of the general formula II are possible:

Formula II

wherein Ri and Ar have the meaning given for formula I. These acidic tautomers can form pharmaceutically active salts of the general formula III

Formula III

wherein Ri and Ar have the meaning given for formula I, while 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, a main group metal, the ammonium or organic ammonium ion such as e.g. represents the tetramethylammonium ion. In the present description, the term imidazol-2-one means any tautomeric form according to formula II, and pharmaceutically acceptable salts of imidazol-2-one mean all tautomers according to formula III.

The 4-aroylimidazol-2-ones according to the invention, in which R is hydrogen, are obtained according to the invention by Friedel-Crafts acylation of an imidazol-2-one of the formula IV

Formula IV

wherein Ri has the meaning given for formula I. The acylating agent can 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 the formulas Va, Vb or Vc

Xi

Formula Vb

Formula Vc in which Y represents a halogen and Xi, X: and X3 have the meanings given for formula I, or represent groups 25 which can be converted into the desired substituents Xi, X2 or Xj after the Friedel-Crafts reaction, e.g. blocking groups or a nitro group which can be converted into various other substituents via the diazonium ion by known methods. 30 Furthermore, the Friedel-Crafts reaction can be carried out with the free acid or the corresponding acid anhydride instead of the aroyl halide, using essentially the same reaction conditions. Such alternatives are described in detail in Olah, Friedel-Crafts and Related 35 Reactions, Vol. III, Part 1, Interscience Publications, John Wily and Sons, New York, 1964.

The Friedel-Crafts reactions according to the invention are preferably carried out by reacting about 1 mol equivalent of the corresponding imidazol-2-one with about 1 to about 40 10 mol equivalents, preferably about 2 mol equivalents, of a Lewis catalyst in a suitable solvent, e.g. in petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride or chloroform, chlorinated aromatics such as 1,2,4-trichloro-45 benzene or o-dichlorobenzene, carbon disulfide or preferably nitrobenzene. About 1 to about 10 molar equivalents, preferably about 1.1 molar equivalents, of the respective aroyl compound are preferably added dropwise to the mixture of imi-dazol-2-one, Lewis acid and solvent, and the reaction is continued for about Vi to about 100 hours. , preferably for about 1 to about 10 hours, depending on the reactants, solvent and temperature, which can be between about -78 and about 150 ° C and preferably between about 0 and about 100 ° C, and more preferably about 60 ° C is. The resulting aroylimidazol-2-one can be isolated from the reaction mixture by any known method, preferably by quenching the mixture with ice water and then filtering or extracting the product and thus removing the solvent.

Lewis acid catalysts particularly suitable for use in the Friedel-Crafts reactions are e.g. Metals such as aluminum, cerium, copper, iron, molybdenum, tungsten or zinc, Bronstead acids such as phosphoric acid, sulfuric acid, sulfonic acid or hydrohalic acids such as hydrochloric or hydrobromic acid, halogen-substituted acetic acids such as chloroacetic acid or trifluoroacetic acid, metal halides such as boron halide, zinc chloride,

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Zinc bromide, berrylium 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 the formula I in which Xi is in the ortho or para position and consists of a pyrrolidino, piperidino, morpholino, piperazino or N′-alkylpiperazino radical or an NR3R.4-R. radical be prepared in the above manner or from a fluorobenzoylimi-dazol-2-one of the formula VI

Ri H

wherein R and Ri have the meaning given for formula I and the fluorine atom is in the ortho or para position. The compound of formula VI can be reacted with about 1 to about 10 molar equivalents of pyrrolidine, piperidine, morpholine, piperazine or N'-alkylpiperazine. This reaction can be carried out with or without a solvent, the amine preferably serving both as a reactant and as a solvent. Other preferred solvents for this reaction are e.g. Dimethyl-formamide, dimethyl sulfoxide, petroleum ether, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulfide, ether such as diethyl ether, tetrahydrofuran or p-dioxane, aromatics such as benzene, toluene or xylene and alcohols such as e.g. Ethanol. The reaction is typically allowed to proceed for about Vi to about 48 hours, preferably about 24 hours, depending on the reactants, solvent and temperature, which may be from about 0 to about 150 ° C.

The compounds of the formula I in which Xi is an amino group of the formula -NR3R4, where R3 and R4 have the meaning given for formula I, can also be obtained from the corresponding nitro-substituted benzoylimidazol-2-ones of the formula VII

0

wherein R and Ri have the meaning given for formula I, are prepared. The compounds of the formula VII are either known or can be prepared by Friedel-Crafts acylation of an imidazol-2-one of the formula IV with a nitro-substituted benzoyl halide, preferably a nitro-substituted benzoyl chloride, by working analogously to the processes described above. The nitro group can be reduced to the unsubstituted amino group in a known manner, and the unsubstituted amino group can then optionally be alkylated in a known manner.

The nitrobenzoylimidazol-2-ones are expediently converted into the corresponding aminobenzoylimidazol-2-ones by reduction with tin, zinc, iron or other correspondingly active metals in a concentrated hydrochloric acid solution. About 1 to about 10 molar equivalents of metal are usually used and the reaction is allowed to proceed for about Vi to about 10 hours, and preferably for about 2 to 3 hours, depending on the reactants and the temperature, which is about 25 to about 150 ° C can and is preferably about 100 ° C. The nitrobenzoyimidazol-2-ones can also be reduced catalytically using nickel, platinum, palladium or similar metals and molecular hydrogen. These reactions are typically carried out in alcoholic solvent and preferably in ethanol, but other inert solvents can also be used; the preferred amount of catalyst is from about 0.001 to about 0.1 mole equivalent. The reaction can be allowed to proceed for about 1 minute to about 1 hour, preferably about 10 minutes, depending on the reactants, the solvent and the temperature, which can be from about 0 to about 100 ° C and is preferably about 25 ° C. Furthermore, the nitrobenzoyimidazol-2-ones can be reduced with ammonium bisulfide (NH4SH) in aqueous ammonia. For example, from about 1 to about 10 molar equivalents, and preferably from about 3 molar equivalents, of the bisulfide with the nitro compound from about 1/2 to about 10 hours, and preferably from about 2 hours, depending on the reactants and the temperature, which may be from about 0 to about 150 ° C and is preferably about 50 ° C. Finally, the nitrobenzoylimidazol-2-ones can be reduced to the corresponding amino compounds by any other method known per se.

The preferred alkylation of the unsubstituted amino-benzoylimidazol-2-ones is e.g. by reaction with one or more equivalents of the corresponding alkyl halide of the formula R3X and R4X, in which R3 and R4 have the meaning given for formula I, while X is a halide. These reactions are typically carried out in solvents such as petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride, chlorinated aromatics such as 1,2,4-tri-chlorobenzene, o-dichlorobenzene or chlorobenzene, carbon disulfide, nitrobenzene, dimethylformamide, dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran or p-dioxane, aromatics such as benzene, toluene or xylene, alcohols such as methanol, ethanol or propanol or aqueous alcohols such as aqueous ethanol. These alkylations are usually carried out in the presence of one or more equivalents of a proton receiver such as triethylamine, pyridine, sodium hydroxide, calcium hydroxide or potassium hydroxide in order to neutralize the hydrogen halide formed. The unsubstituted amino-benzoylimidazol-2-ones can also be alkylated by any other known method, e.g. by reaction with formic acid and formaldehyde to form a dimethylamino compound. Furthermore, numerous other substituents such as halogen or the hydroxyl group from the nitro-substituted benzoylimidazol-2-ones of the formula VII can be introduced via the diazonium ion by known processes.

The compounds of the formula I in which Xi or X: and X3 denote the hydroxyl group can be prepared as described above or preferably from the corresponding alkoxy and preferably methoxy-substituted benzoylimidazol-2-ones, the alkoxy group being in the position corresponding to the hydroxyl substitution. The alkoxy compound is generally cleaved by any known method to form the hydroxybenzoylimidazol-2-one, see e.g. R.L. Burwell, "The Cleavage of Ethers," Chem. Rev., 54, 615-85 (1954).

The substituents Xi, X2 and X? can be protected if necessary to ensure the stability of the reactants

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of the formula Vb and Vc or in order to enable the acylation of the ring-shaped nitrogen atom without simultaneous acylation of reactive radicals X. Xi, X2 or X3 hydroxyl groups, an amino group of the formula -NHR3 or -SO2NH2, the benzyl group can be used to block the otherwise reactive hydroxyl or amino groups. The benzyl residue can then be removed, e.g. by hydro-nolysis with hydrogen over a palladium catalyst or with sodium in liquid ammonia.

If desired, one or both nitrogen atoms of the imidazol-2-one ring can be substituted by an alkyl radical in a known manner. The known processes include in particular the reaction of the N-unsubstituted aroylimidazol-2-one according to the invention with a base and an alkylating agent in the presence of an inert solvent. Bases suitable for this preferred implementation are e.g. Hydrides such as sodium hydride or calcium hydride, carbonates or bicarbonates such as sodium carbonate or sodium bicarbonate, phenolates such as sodium phenolate, alkoxides such as sodium ethoxide or preferably hydroxides such as sodium hydroxide. Suitable alkylating agents are e.g. Alkyl halides such as methyl chloride, methyl bromide or methyl iodide or dialkyl sulfates such as dimethyl sulfate. Suitable inert solvents are e.g. Petroleum ether, 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, ethers such as diethyl ether, tetrahydrofuran or p-dioxane, aromatics such as benzene, toluene or Xylene or preferably polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide. The reaction can be allowed to proceed for about 1 minute to about 1 hour, the temperature can be about 0 to about 100 ° C and is preferably about 25 ° C. If only one of the imi-dazol-2-one nitrogen atoms is to be substituted by an alkyl radical, the imidazol-2-one can contain about 1 to about 10 molar equivalents of a base, preferably with about 1 molar equivalent, and with about 1 molar equivalent of an alkyl -rungsmittel be implemented. Using this method usually results in both possible monoalkylated isomers. These isomers can be separated in a conventional manner, e.g. by fractional crystallization, fractional distillation or chromatography. If both nitrogen atoms of the imidazol-2-one ring are to be alkyl-substituted, the imidazol-2-one can be reacted with about 2 to about 10 molar equivalents of a base, preferably about 2 molar equivalents, and about 2 to about 10 molar equivalents of one React alkylating agent, preferably also about 2 molar equivalents. Other reactive substituents on the aroyl rings can be alkylated at the same time. The following radicals X, namely X = OH, -NHR3, -SO2NH2 and the unsubstituted piperazine radical are generally alkylated under the same reaction conditions. Optionally, the alkylation of the substituents on the aroyl ring can be avoided by using known protective groups, where, for example, residues X = OH or -NHR3 can be benzylated and later released by hydrogenolysis.

If desired, the nitrogen atoms of the imidazol-2-one ring can be substituted in any known manner by an alkylcarbonyl radical. The known methods include in particular the reaction of the N-unsubstituted aroylimidazol-2-ones according to the invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyl chloride, isopropionyl chloride or butanoyl chloride. Acylation reactions with acyl halides usually work with an acid scavenger such as

Triethylamine or pyridine to eliminate hydrogen halide when it is formed. The corresponding free acid or its anhydride can also be used instead of the acyl halides. The acylation reactions are generally carried out without the addition of solvents, but can also be carried out in inert solvents, e.g. in petroleum ethers, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulfide, ethers such as diethyl ether, tetrahydrofuran or p-dioxane or in aromatic solvents such as benzene, toluene or xylene. The reactions are typically carried out for about 1 minute to about 100 hours, preferably for about 1 to about 10 hours, at temperatures from about -78 to 150 ° C, and preferably from 0 to 100 ° C. Reactive substituents on the aroyl rings are optionally acylated simultaneously. The following radicals X, namely X = OH, -NHR3, -SO2NH2 and the unsubstituted piperazine ring, are usually acylated under the same conditions. If appropriate, the acylation of the substituents on the benzoyl ring can be avoided by using suitable known protective groups, it being possible, for example, to benzylate the substituents X = OH or -NHR3 and to restore them later by hydrogenolysis.

The alkali metal, alkaline earth metal, transition metal, main group metal, ammonium and organic ammonium salts of the aroylimidazol-2-ones according to the invention can be prepared from a corresponding basic metal or ammonium salt, e.g. 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 bicarbonate. These reactions can be carried out with or without a solvent. Suitable solvents are e.g. lower alcohols such as methanol, ethanol, isopropanol, n-propanol or n-butanol, aromatics such as benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or p-dioxane and halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride. Aroylimidazol-2-one and base can be reacted with each other for about 1 minute to about 24 hours, depending on the reactants and the temperature, which can be from about -78 to about 150 ° C, and preferably at about 0 to about 25 ° C lies.

The aroyl chlorides of the corresponding carboxylic acids, which are required to carry out the Friedel-Crafts acylation according to the invention, are either known or can be prepared by known processes. The starting materials of formula IV can be prepared as described above or by the method of R. Duschinsky and L.A. Dolan, J. Am. Chem. Soc., 67, 2079 (1945), R. Duschinsky and L.A. Dolan, J. Am. Chem. Soc., 68, 2350 (1945) or according to US Pat. No. 2,441,933.

The compounds of general formula I, including the two known compounds mentioned above, can be used to treat heart failure, including congestion, backward and forward congestion, left or right ventricular failure, or to treat other diseases that enhance cardiac output require a cardiac tonic. The compounds have a digitalis-like effect in various respects. The compounds described can also be used to treat high pressure, including primary or essential hypertension, hormonally caused hypertension, hypertension due to kidney failure and chemically caused hypertension. Finally, the named Verbiad.'igen can be used as antithrombotics. They reduce the coagulation of the blood by

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they prevent platelet aggregation, which plays an essential role in thrombosis, both in the initial stages and in the occlusion of blood vessels. Arterial thrombosis, particularly in the heart muscle and brain arteries, is a major cause of death and serious damage.

The compounds described can be administered in various ways to achieve the desired effects. They can be used alone or in the form of pharmaceutical preparations orally or parenterally, i.e. intravenously or intramuscularly. The amount to be administered depends on the severity of the hypertension, the heart disease or blood clumping and the type of administration. When administered orally, the antihypertensive effective amount is usually from about 0.1 mg / kg body weight per day to about 500 mg / kg body weight per day, and preferably from about 50 to about 150 mg / kg body weight per day.

When administered parenterally, the antihypertensive effective amount is in particular about 0.01 to about 150 mg / kg body weight per day and preferably about 1.0 to about 10.0 mg / kg body weight per day. When administered orally or parenterally, the cardiotonically effective amount is in particular about 0.1 to about 500 mg / kg of body weight per day and preferably about 0.1 to about 10.0 mg / kg of body weight per day. When administered orally or parenterally, the anticoagulant effective amount is usually about 0.1 to about 1000 mg / kg body weight per day, and preferably about 1 to about 100 mg / kg body weight per day.

A unit dose for oral administration may e.g. Contain 10 to 100 mg of active ingredient. A unit dose for parenteral administration contains e.g. 5 to 50 mg of active ingredient. Repeated administration throughout the day may be advisable, depending on the patient's condition and the mode of administration.

Warm-blooded animals, e.g. Birds like chickens and turkeys, mammals like primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice understood.

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 fixed dose unit can e.g.

be a common gelatin capsule containing, for example, lubricants and inert fillers such as lactose, cane sugar and corn starch. According to a further embodiment of the invention, the compounds described can be tableted with conventional tablet bases such as lactose, cane sugar and corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrants such as potato starch or alginic acid and lubricants such as stearic acid or magnesium stearate.

For parenteral administration, the compounds can be given in injectable doses of a solution or suspension in a physiologically acceptable diluent and a pharmaceutical carrier, which can be a sterile liquid such as water or an oil, with the addition of surface active agents and other pharmaceutically acceptable auxiliaries. Examples of suitable oils are petroleum, animal, vegetable or synthetic origin, e.g. Peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose or similar sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions.

The compounds can also be in the form of a depot

Injection or administered as implants that are formulated so that they allow a delayed release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and administered subcutaneously or intramuscularly as a depot injection or implant. Inert materials such as biodegradable polymers or synthetic silicones can be used in implants, e.g. the product "Silastic" (silicone rubber, manufacturer Dow-Corning Corp.).

The following are examples of pharmaceutical preparations which contain the compounds according to the invention:

Tablet mass per tablet a) 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one 100 mg b) corn starch 15 mg c) lactose 35.5 mg d) magnesium stearate 1 , 5 mg

Parenteral preparation a) 1,3-Dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one 1,000 g b) Polyoxyethylene sorbitol monooleate 2,000 g c) Sodium chloride 0.128 g d) Water for injections to 20,000 ml

The use of compounds according to the invention as antihypertensive, cardiotonic and anticoagulant agents is described below:

Example A

Use of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one as an antihypertensive agent.

100 mg / kg of the title compound are administered orally to 6 spontaneously hypertensive rats. This dose leads to a 40% decrease (mean) in blood pressure over the course of 15 minutes after administration.

Example B

Use of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one as a cardiotonic.

Heart failure is caused in a dog by adding sodium pentobar-bitol (20 mg / kg) or propanalol hydrochloride (3 mg / kg) to the blood that perfuses the heart. Afterwards, the pressure in the right atrium increases dramatically and the output of the heart is greatly reduced. Administration of the title compound in an amount of 1 mg / kg causes a reversal, with both the pressure in the right atrium and the heart output returning close to the values before the treatment.

Example C

Use of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one as an antithrombotic.

If adenosine diphosphate is added to human plasma, which is rich in citrated platelets, platelets are typically aggregated. However, if the title compound is added to this plasma in concentrations of 3, 10.30 and 100 (ig / ml before the adenosine diphosphate, the aggregation of the platelets is inhibited by 33.49.82 and 98%, respectively.

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646 155

example 1

1,3-Dihydro-4- (4-fluorobenzoyl) -5-methyl-2H-imidazol-2-one.

To a mixture of 98.1 g (1 mol) l, 3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 mol) anhydrous aluminum chloride and 500 ml nitrobenzene are stirred 158.6 g (1 mol) of p-fluorobenzoyl chloride were added dropwise in the course of 10 min. The mixture is stirred at 60 to 65 ° C. for 6 hours and then poured onto 2 kg of ice. The resulting precipitate is washed with diethyl ether and water and recrystallized from io 1.21 dimethylformamide, giving 131 g of the title compound of mp 289 to 292 ° C.

Example 2

1,3-dihydro-4-methyl-5- [4- (1-piperidinyl) benzoyl] -2H- is imidazol-2-one.

A suspension of 11.0 g (0.05 mol) of 1,3-dihydro-4- (4-fluorobenzoyl) -5-methyl-2H-imidazol-2-one in 30 ml of piperidine is stirred at the reflux temperature for 24 hours. Excess piperidine is evaporated off under reduced pressure and the residue is recrystallized twice from a mixture of isopropanol and water. This gives 11.9 g of the title compound of mp 260 to 263 ° C.

Example 3 25

1,3-Dihydro-4-methyl-5- [4- (4-morpholinyl) benzoyl] -2H-imidazol-2-one.

If the procedure of Example 2 is repeated, but with the piperidine replaced by morpholine, the title compound of mp 283 to 286 ° C. is obtained. 30th

Example 4

1,3-Dihydro-4- [4- (dimethylamino) benzoyl] -5-methyl-2H-imidazol-2-one.

A mixture of 11.0 g (0.05 mol) of 1,3-dihydro-4- (4-fluoro-35 benzoyl) -5-methyl-2H-imidazol-2-one, 100 ml of 30% aqueous Dimethylamine solution and 200 ml of ethanol are heated in a pressure bomb at 130 to 135 ° C. for 22 hours. The mixture is then cooled, the solid is collected and recrystallized from isopropanol / water, giving the title compound, mp> 310 ° C; X (max) (methanol) 364 nm (e = 23,300).

Example 5

1,3-dihydro-4- (4-hydroxybenzoyl) -5-methyl-2H-imi- 45 dazol-2-one.

5.3 g (0.023 mol) are added to a melt of 26 g (0.23 mol) of pyridine hydrochloride at 200 to 250 ° C.

I, 3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one was added and the mixture was stirred mechanically for 30 minutes. Then the reaction mixture is poured onto ice / 2N hydrochloric acid. The resulting precipitate is washed with water and recrystallized from isopropanol / water, giving the title compound of mp> 300 ° C;

X (max) (methanol) 320 nm (e = 13,200). ss

Example 6

1,3-Dihydro-4-methyl-5- [4- (methylthio) benzoyl] -2H-imi-dazoI-2-one.

A solution of 25.0 g of 4- (methylthio) benzoic acid and thus 22 ml of thionyl chloride in 50 ml of benzene is heated under reflux for 4 hours. Excess reagent and solvent are evaporated and the residue is azeotroped three times with benzene to remove all thionyl chloride. Then the residue becomes a mixture of «s

II, 8 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 40.0 g of anhydrous aluminum chloride and 100 ml of nitrobenzene were added dropwise. The resulting mixture is 5 hours at 60 to 65 ° C.

stirred and then poured onto ice, the precipitate that forms is collected, washed with ethyl ether and water and recrystallized from isopropanol / water, giving the title compound of mp 255 to 258 ° C. (dec.).

Example 7

1,3-Dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imi-dazol-2-one.

34.2 g of p-methoxybenzoyl chloride are added dropwise to 19.6 g of l, 3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene, and the mixture is poured into 500 ml of 2N- Poured hydrochloric acid / ice and washed three times with ether. The resulting solid is recrystallized from isopropanol / water, giving the title compound of mp 257 to 258 ° C (dec.).

Example 8

1,3-Dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imi-dazol-2-one sodium salt.

1.6 g of sodium methylate are added to 7.0 g of l, 3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one in 100 ml of methanol. The mixture is heated on a steam bath until it is homogeneous and filtered, and the filtrate is evaporated to dryness. The solid residue is recrystallized from isopropanol, giving the title compound of mp 280 to 282 ° C (dec.).

Example 9

4-benzoyl-1,3-dihydro-5-methylimidazol-2-one.

4.6 g of benzoyl chloride are added dropwise to a solution of 3.0 g of 4-methylimidazoi-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene. The solution is heated to 60 ° C. for 4 hours, poured into ice water and slurried with ether. The resulting solids are filtered off and dried to give the title compound of mp 250 to 254 ° C.

Example 10

1,3-dihydro-4-methyl-5-thienoyl-2H-imidazol-2-one.

12.0 g of 2-thienoyl chloride are added to a solution of 7.3 g of 4-methylimidazol-2-one and 10.8 g of aluminum chloride in 150 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours, cooled and poured into ice water. The organic portion is extracted into ethyl acetate, the extract is dried and freed from the solvent, the title compound of mp 212 to 215 ° C. being obtained.

Example 11

1,3-Dihydro-4- (3,4-dimethoxybenzoyl) -2H-imidazol-2-one.

17.6 g of 3,4-dimethoxybenzoyl chloride are added in portions to a solution of 6.5 g of l, 3-dihydro-4-methyl-2H-imi-dazol-2-one and 14.6 g of aluminum chloride in 65 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours, cooled and poured into ice water. The rubbery solids are filtered off and recrystallized twice from ethyl alcohol / water, giving the title compound of mp 257 to 259 ° C.

Example 12

1,3-Dihydro-4- (2-furanoyl) -5-methyl-2H-imidazol-2-one.

12.9 g of furanoyl chloride are added dropwise to a slurry of 8.9 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 24.0 g of aluminum chloride in 135 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours, cooled and poured into ice water. The solid is then filtered off and recrystallized twice from methyl alcohol, giving the title compound of mp 214 to 216 ° C.

646155

10th

Example 13

1,3-Dihydro-4- (2-thienoyl) -2H-imidazol-2-one.

13.3 g of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2-one and 8.1 g of thienoyl chloride are combined in 50 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours and then poured into ice water. The solids are filtered off, washed with ether and recrystallized twice from ethanol / water, giving the title compound of mp 339 to 342 ° C.

Example 14

4-benzoyl-1,3-dihydro-2H-imidazol-2-one.

1.68 g of l, 3-dihydro-2H-imi-dazol-2-one, 5.3 g of aluminum chloride and 3.1 g of benzoyl chloride are added to 51 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours and then poured into ice water. The solids are filtered off, washed with ether and recrystallized twice from methyl alcohol / water, giving the title compound of mp 329 to 330 ° C.

Example 15

1,3-dihydro-4-furanoyl-2H-imidazol-2-one.

4.2 g of l, 3-dihydro-2H-imi-dazoI-2-one, 13.3 g of aluminum chloride and 7.2 g of furanoyl chloride are added to 50 ml of nitrobenzene. The mixture is stirred at 60 ° C. for 3 hours and then poured into ice water. The solids are filtered off, washed with ether and recrystallized twice from ethanol / water, giving the title compound of melting point 318 to 321 ° C.

Example 16

1,3-Dihydro-4- (3,4-methylenedioxybenzoyl) -5-methyl-2H-imidazol-2-one.

To 5.13 g of l, 3-dihydro-4-methyl-2H-imidazol-2-one and

7.98 g of anhydrous aluminum chloride in 80 ml of nitrobenzene, 10.60 g of 3,4-methylenedioxybenzoyl chloride are added dropwise and the mixture is poured onto 500 ml of 2N hydrochloric acid / ice and then washed three times with ethyl ether. The resulting solid is collected and gives the title compound of mp 293-296 ° C (dec.).

Example 17

1,3-dihydro-4- (4-methoxybenzoyl) -l, 3,5-trimethyl-2H-10 imidazol-2-one.

15.2 g of potassium hydroxide powder, 8.0 g of 3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one (sodium salt) and 19.5 g of methyl are placed in 120 ml of dimethyl sulfoxide -iodide combined. The mixture is stirred at room temperature for 60 min and then poured into 800 ml of water. After extraction with methylene chloride, a solid is obtained which is recrystallized from ether: mp 109 to 111 ° C; NMR: N-CH3 (6 protons) at 3.3 ppm.

20 Example 18

1,3-dihydro- (1 or 3), 5-dimethyl-4- (4-methoxybenzoyl) -2H-imidazol-2-one.

0.288 g of 25 sodium hydride and 1.22 g of methyl iodide are added to 2.0 g of l, 3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one in 30 ml of dimethyl sulfoxide. The mixture is stirred at 22 ° C for 30 min and poured into methylene chloride, the resulting mixture is washed with water. Then it is dried and concentrated to an oil which, when triturated with chloroform, gives a solid 30. The solid is crystallized from methanol, mp 225 to 228 ° C.

Anal .: Ber. for C12H14N2O3: C: 63.40; H: 5.73; N: 11.39; Found: C: 63.34; H: 5.85; N: 11.21.

35 NMR: N-methyl; Singlet at 3.2 ppm.

B

Claims (27)

646 155 2. A compound according to claim 1, characterized in that R is hydrogen and Ri is hydrogen or a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. 2nd PATENT CLAIMS 1. Compound of the formula 0 in which Ar is the 2-furyl or 2-thienyl radical, a phenyl radical monosubstituted in the ortho, meta or para position by Xi or in the para position by X: and in the ortho or meta position by X 'disubstituted phenyl radical, Xi halogen, a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms, a straight-chain or branched alkyl mercapto radical with 1 to 4 carbon atoms, the trifluoromethyl group, one of the radicals -SChN (R2) 2, -NR3R4 , the pyrrolidino, piperidino, morpholino or piperazinorest or an N'-alkyl-piperazi-norest, X2 and X3 halogen, straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms, straight-chain or branched alkyl radicals having 2 to 4 carbon atoms , or, if X3 is in the meta position, X2 and X3 form a methylenedioxy group which is optionally substituted by 1 or 2 methyl radicals, R is hydrogen, a straight-chain or v branched alkyl radical having 1 to 4 carbon atoms, a straight-chain or branched alkylcarbonyl radical having 1 to 4 carbon atoms or the benzoyl radical, and R 1, R 2, R 3 and R 4 are hydrogen or straight-chain or branched alkyl radicals having 1 to 4 carbon atoms, with the proviso that R 3 and R4 cannot both be hydrogen, and their pharmaceutically acceptable salts. 3rd 646 155 3. A compound according to claim 2, characterized in that R is hydrogen and Ri is hydrogen, the methyl or ethyl group. 4. A compound according to claim 3, characterized in that Ar is a phenyl radical monosubstituted by Xi. 5 5. A compound according to claim 4, characterized in that Xi is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms or a straight-chain or branched alkyl mercapto radical having 1 to 4 carbon atoms. 6. Connection according to claim 5, characterized in that Xi is in the para position. 7. A compound according to claim 6, characterized in that Xi is the methoxy group and Ri is the methyl group. 8. A compound according to claim 6, characterized in that Xi is the methyl mercapto group and Ri is the methyl group. 9. A compound according to claim 3, characterized in that Ar is a phenyl radical disubstituted in the para position by X2 and in the ortho position or meta position by X3. 10th 10. A compound according to claim 9, characterized in that X3 is in the meta position. 11. A compound according to claim 10, characterized in that X2 and X3 represent straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms or together a methylenedioxy radical which is optionally substituted by 1 or 2 methyl groups. 12. A compound according to claim 11, characterized in that Ri is the methyl group and X2 and X3 are methoxy groups. 13. A compound according to claim 11, characterized in that Ri is the methyl group and X2 and X3 together are the methylenedioxy group. 14. Pharmaceutical preparation containing at least one compound of the formula as active ingredient R '> = Ar (IA) r "nYNsR 0 in which Ar is the 2-furyl, 2-thienyl or phenyl radical or a phenyl radical monosubstituted in the ortho, meta or para position by Xi or in the para position by X2 and in the ortho position or meta position by X3, Xi halogen, the hydroxyl group, a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms, a straight-chain or branched alkyl mercapto radical with 1 to 4 carbon atoms, the trifluoromethyl group, one of the radicals -S02N (R2) 2, -NR3R4, the pyrrolidino, piperidino, morpholino or piperazinorest or an N '-alkyl-piperazinorest, X2 and X3 halogen, the hydroxyl group, straight-chain or branched alkyl radicals with 1 to 4 carbon atoms or straight-chain or branched alkoxy radicals with 1 to 4 carbon atoms or, if X3 is in the meta position, X2 and X3 together represent an M optionally substituted by 1 or 2 methyl groups are ethylenedioxy radical, in which R furthermore represents hydrogen, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, a straight-chain or branched alkylcarbonyl radical having 1 to 4 carbon atoms or the benzoyl radical and R 1, R 2, R 3 and R 4 in each case hydrogen or straight-chain or branched alkyl radicals having 1 to 4 4 carbon atoms, or a pharmaceutically acceptable salt thereof. 15 15. Preparation according to claim 14, characterized in that R is hydrogen and Ri is hydrogen, the methyl or ethyl group. 16. Preparation according to claim 15, characterized in that Ar is the phenyl radical. 17. Preparation according to claim 15, characterized in that Ar is a phenyl radical monosubstituted by Xi. 18. Preparation according to claim 17, characterized in that Xi is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms or a straight-chain or branched alkyl mercapto radical having 1 to 4 carbon atoms. 19. Preparation according to claim 18, characterized in that Xi is in the para position. 20th 20. Preparation according to claim 19, characterized in that Xi is the methoxy group and Ri is the methyl group. 21. Preparation according to claim 19, characterized in that Xi is the methyl mercapto group and Ri is the methyl group. 22. Preparation according to claim 15, characterized in that Ar is a phenyl radical disubstituted in the para position by X2 and in the ortho position or meta position by Xs. 23. Preparation according to claim 22, characterized in that Xj is in the meta position. 24. Preparation according to claim 23, characterized in that X: and Xj represent straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms or together a methylenedioxy radical which is optionally substituted by 1 or 2 methyl groups. 25. Preparation according to claim 24, characterized in that Ri is the methyl group and X2 and X3 are methoxy groups. 25th 30th 35 40 45 50 55 60 65 26. Preparation according to claim 24, characterized in that Ri is the methyl group and X2 and X3 are the methylenedioxy radical. 27. Process for the preparation of aroylimidazol-2-ones of the formula 0 R H wherein Ar is the 2-furyl or 2-thienyl radical, one monosubstituted in the ortho, meta or para position by Xi or in the para position by X: and in the ortho or meta position by X? disubstituted phenyl radical, Xi halogen, a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms, a straight-chain or branched alkyl mercapto radical with 1 to 4 carbon atoms, the trifluoromethyl group, one of the radicals -SO: N ( R2) :, -NR3R4, the pyrrolidino, piperidino, morpholino or piperazino radical or an N-alkylpiperazino radical, X: and X3 halogen, straight-chain or branched alkoxy radicals having 1 to 4 carbon atoms, straight-chain or branched alkyl radicals represent with 2 to 4 carbon atoms, or, if X3 is in the meta position, X2 and X3 form a methylenedioxy group which is optionally substituted by 1 or 2 methyl radicals, and R 1, R 2, R 3 and R 4 are hydrogen or straight-chain or branched alkyl radicals 1 to 4 carbon atoms mean, provided that R3 and R4 cannot both be hydrogen, and their pharmaceutically acceptable S alze, characterized in that compounds of the formula RXH (IV) 0 wherein Ri is defined above, for the introduction of the group -CO-Ar, in which Ar is defined above, is subjected to a Friedel-Crafts acylation and any compounds obtained are converted into the corresponding salts.