DK160269B - METHOD OF ANALOGUE FOR THE PREPARATION OF 4-AROYL-1,3-DIHYDRO-2H-IMIDAZOL-2-ONER OR A PHARMACEUTICAL ACCEPTABLE METAL SALT OR BASIC AMMONIUM SALT THEREOF - Google Patents

Description

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The present invention relates to an analogous process for the preparation of novel 4-aroyl-1,3-dihydro-2H-imidazol-2-ones or pharmaceutically acceptable metal salts or basic ammonium salts thereof.

These compounds have antihypertensive, cardiotonic and antithrombotic properties and therefore find use in pharmaceutical compositions.

The closest prior art is disclosed in U.S. Patent Nos. 2,514,380 and 2,441,933 as well as in R. Du-10 schinsky 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. Pushkareva, Khim. Geterotsikl. Sudin., £ (4), 698-701 (1968). This literature describes the preparation and use as chemical intermediates of the following compounds; 4-benzoyl-1,3-dihydro-2H-imidazol-2-one, 4-benzoyl-1,3-dihydro 2H-imidazol-2-one-1,3-diacetate, 4-benzoyl 1,3-dihydro-2-one 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-imidazole "-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 and 4- (4-aminobenzoyl) -1,3-dihydro-5-methyl 2H-imidazol-2-one.

However, it has not been previously known that 4-aroyl-1,3-dihydrc-2H-imidazol-2-ones are pharmaceutically useful.

The present invention relates to an analogous process for the preparation of pharmaceutically active 4-aroyl-2

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-1,3-dihydro-2H-imidazol-2-ones of general formula IO where Ar represents 2-furyl, 2-thienyl, phenyl, in the ortho, meta or para position with monosubstituted phenyl or in para X 2 ° 9 'position in ortho or meta position with disubstituted phenyl, X 4 represents halogen, hydroxy, straight or branched alkyl of 1-4 carbon atoms, straight or branched alkoxy of 1-4' carbon atoms, straight chain or branched alkylthio of 1-4 carbon atoms, NR 1 R 2, pyrrolidino, piperidino, morpholino, piperazino or Ν'-alkyl * -piperazino of 1-4 alkyl carbon atoms, X 2 and X 3 represent halogen, straight or branched alkoxy of 1- 4 carbon atoms, straight or branched alkyl having 1-4 carbon atoms, however, X 2 does not mean methyl, when X 1 represents methyl, the two R groups which may be the same or different, hydrogen, straight chain or branched alkyl with 1-4 carbon atoms or straight-chain or branched alkylcarbonyl having 1-4 carbon atoms in the alkyl moiety, and Rlf R3 and R 4 each means hydrogen or straight or branched alkyl of 1-4 carbon atoms, however, R 3 and R 4 cannot both be hydrogen, or a pharmaceutically acceptable metal salt or basic ammonium salts thereof. These compounds are valuable as antihypertensive, cardiotonic and antithrombotic agents.

The analogous method of the present invention is characterized by the method of claim 1.

Illustrative examples of straight or branched alkyl of 1-4 carbon atoms, as used herein, are methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

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Illustrative examples of straight or branched alkoxy of 1-4 carbon atoms, as used herein, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy.

As used herein, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.

As used herein, the term "halide" should mean fluoride, chloride, bromide or iodide.

As used herein, the term "straight chain 10 or branched alkythio of 1-4 carbon atoms" means a group of the structure S-alkyl, wherein the alkyl moiety is straight or branched alkyl of 1-4 carbon atoms, and may e.g. be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

As used herein, the term "straight chain or branched alkylcarbonyl of 1-4 carbon atoms" means a group having the structure 0 -C-alkyl 20 wherein the alkyl moiety is straight or branched alkyl of 1-4 carbon atoms and, for example, may be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

As used herein, the term "N'-alkyl-25-piperazino" means a group of the structure -4- N -alkyl / 30 wherein the alkyl moiety is straight or branched alkyl of 1-4 carbon atoms and e.g. may be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

The preferred compounds of this invention are such compounds of formula (I) wherein R is 4

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hydrogen, and Ar means monosubstituted phenyl, where Χχ means piperidino, pyrrolidino, morpholino, piperazino, N'-alkylpiperazino of 1-4 alkyl carbon atoms, straight or branched alkoxy of 1-4 carbon atoms or straight chain 5 or branched alkylthio of 1-4 carbon atoms. Other preferred compounds of this invention are those compounds of formula (I) wherein Ar is unsubstituted phenyl or Ar is disubstituted phenyl, wherein X2 and X3 are straight or branched chain alkoxy of 1-4 carbon atoms.

More preferred of the compounds of this invention are such compounds of formula (I) wherein R 1 is hydrogen or methyl and Ar is monosubstituted phenyl where Χχ is in para position and means pyrrolidino, morpholino, piperazino, N'- alkylpiperazino of 1-4 alkyl carbon atoms, straight or branched chain alkoxy of 1-4 carbon atoms, or straight or branched alkylthio of 1-4 carbon atoms. Other more preferred of the compounds of this invention are those of formula (I) wherein hydrogen or methyl and Ar represents disubstituted phenyl, wherein X3 is in the meta position and wherein X2 and X3 are straight or branched alkoxy of 1- 4 carbon atoms.

The most preferred of the compounds of this invention are such compounds of formula (I) wherein R is hydrogen, is methyl, and Ar is monosubstituted phenyl, which is in para position and means methoxy or methylthio, or where R is hydrogen, R 1 represents methyl, and Ar represents disubstituted phenyl where X 9 is in the meta position and X 2 and X 2 are methoxy.

Examples of compounds of general formula (I) are 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- (4-methoxybenzoyl) -5-methyl-2H-imidazol 2-one, 1,3-dihydro-4- (3,4-dimethoxybenzoyl) -5- methyl 2H-imidazol-2-one, 5

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1,3-dihydro-4- (2-furanoyl) -5-methyl-2H-imidazol-2-one, 1,3-dihydro-4- (2-thienoyl) -2H-imidazol-2-one, 1,3-dihydro-4-one (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-methylpiperazinobenzoyl) J-2E-imidazol-2-one, 1,3-dihydro-4- (4-hydroxybenzoyl) -5-methyl-2H-imidazol-2-one, 1,3-dihydro-4-methyl -5- [beta (methylthio) benzoyl] -2H-imidazol-2-one, 1,3-dihydro-4-ethyl-3- (4-methoxybenzoyl) -2H-imidazol-2-one and 1.3 dihydro-4-ethyl-5- (4- methylthiobenzoyl) -2H-imidazol-2-one.

When R is hydrogen in compounds of formula (I), various tautomeric forms of general formula (II) are possible.

25

RlH ^ r_ Rl> = ^ Ar -> Rl ^ Ar (ID

h'n \ ^ n h V h i.

30 ° C

where and Ar has the meaning given in formula (I). These acidic tautomers can form pharmaceutically active salts of the general formula III

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Rl \ Χάτ Riv_A Ar To Ar (III)

H ^ O ^ Λ 'Qs ^^' H

5 'OH 0 6 0' wherein and Ar is as defined in formula (I) and M is a pharmaceutically acceptable alkali metal, such as sodium or potassium, alkaline earth metal such as calcium or magnesium, side group metal such as zinc or iron , major group metal, ammonium or organic ammonium ion, such as a tetramethylammonium ion. Throughout this specification, the term "imidazol-2-one" is to be understood to include any of the tautomers of formula (II), and "a pharmaceutically acceptable salt of an imidazol-2-one" is to be understood to include any tautomer of formula ( III).

4-Aroylimidazole-2-ones of formula (I) wherein R is hydrogen can be prepared by the analogous process of this invention by a Friedel-Crafts acylation of an imidazole-2-one of the general formula

R \ J

25 Λ <iv) l where R 1 has the meaning given above (process variant a). The acylating agent is 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 general formula "Άδ τΛδ-". Αδ '(Va) (Vb) (Vc)

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where Y represents halogen and, X 1 and X 2 have the meaning given above -

The Friedel-Crafts reactions of variant a) can be carried out by approx. 1 mole equivalent of an imidazole-2-5 -one of formula IV is pre-mixed with from ca. 1 molar equivalent to approx. 10 molar equivalents, preferably approx. 2 molar equivalents, of a Lewis acid catalyst in a suitable solvent, e.g. petroleum ether, a chlorinated hydrocarbon such as carbon tetrachloride, ethylene chloride, methylene chloride or chloroform, a chlorinated aromatic compound such as 1,2,4-tetrachlorobenzene or o-dichlorobenzene, carbon disulfide or preferably nitrobenzene. From approx. 1 molar equivalent to approx. 10 molar equivalents, preferably approx. 1.1 molar equivalents of the corresponding aroyl compound are added, preferably dropwise, to the mixture of imidazol-2-one, Lewis acid and solvent, and the reaction is allowed to proceed for about 10 minutes. 1 hour to approx. Depending on the reactants, the solvent and the temperature, which may be from about 1 hour. 0 ° C to approx. 100 ° C, especially approx. 60 ° C. The resulting aroylimidazole 20 -2-one can be isolated from the reaction mixture by any known method, preferably by shaking off the reaction mixture with ice water and subsequent removal of the product by filtration or extraction and solvent removal.

Lewis acid catalysts suitable for use in the Friedel-Crafts reactions described herein are e.g. a metal such as aluminum, cerium, copper, iron, molybdenum, tungsten or zinc, a Brønsted acid such as phosphoric acid, sulfuric acid, sulfonic acid or a hydrohalide acid such as hydrochloric or hydrobromic acid, halogen substituted acetic acids such as chloroacetic acid or the like. trifluoroacetic acid, or a metallic halide such as a boron halide, zinc chloride, zinc bromide, beryllium chloride, copper chloride, iron (III) -bromide, iron (III) chloride, mercury (II) chloride, mercury (I) chloride, antimony bromide, , titanium (IV) bromide, titanium (IV) chloride, titanium (III) chloride, aluminum bromide or preferably aluminum chloride.

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Compounds of formula (I) wherein Ar is monosubstituted phenyl and is in ortho or para position and means pyrrolidino, piperidino, morpholino, piperazino, N'-alkylpiperazino having 1-4 alkylcarbon atoms or NR3R4 may are prepared as described above or they can be prepared from a suitable fluorobenzoylimidazol-2-one of the general formula 10 N- (IV) JT \ yr r ^ Nn / Nvr fi 15 0 20 wherein R and R ^ have the meaning given above. and the fluorine atom is in either ortho or para position (method sub-variant 1). A compound of formula (VI) is allowed to react with from ca. 1 to ea. 10 molar equivalents of amine of formula HNR 3 R 4, pyrrolidine, piperidine, morpholine, piperazine 25 or Ν'-alkylpiperazine having 1-4 alkyl carbon atoms as desired. This reaction is carried out in a suitable solvent, and preferably the amine is both solvent and reactant. Suitable solvents for this reaction are e.g. dimethylformamide, dimethyl sulfoxide, petroleum ether, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulfide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, aromatic solvents such as benzene, toluene or xylene solvents or alcohols . The reaction is allowed to proceed in approx. 1/2 hour 9

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to approx. 48 hours, preferably approx. 24 hours, depending on the reactants, the solvent, and the temperature, which may be from ca. 0 ° C to approx. 150 "C.

Compounds of formula (I) wherein Ar is 5 monosubstituted phenyl and represents an amino group of formula -NR 1 R 2, wherein R 1 and R 4 have the meaning given above, can alternatively be prepared from the corresponding nitrosubstituted benzoylimidazole-2 on the general formula 10 (VII) wherein R and R 2 have the meaning given above (process variant b). The compounds of formula (VII) are either known compounds, or they can be prepared by a Friedel-Crafts-20 acylation of an imidazol-2-one of formula (IV) with a nitrosubstituted benzoyl halide, preferably a nitrosubstituted benzoyl chloride, by methods. which are analogous to those outlined above. The nitro group is reduced to the unsubstituted amino group by any suitable known method, and then the unsubstituted amino group is alkylated by any suitable known method.

The nitrobenzoylimidazol-2-ones may conveniently be converted to the corresponding aminobenzoylimidazol-2-ones by reduction with tin, zinc, iron or other suitable active metal in concentrated hydrochloric acid solution. It can be used from approx. 1 molar equivalent to approx. 10 molar equivalents of the metal and the reaction is allowed to proceed from approx.

1/2 hour to approx. 10 hours, preferably approx. 2-3 hours, depending on the reactants and temperature, which may be from about 35 hours. 25 ° C to approx. 150 ° C, preferably approx. 100 ° C. Alternatively,

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For example, the nitrobenzoylimidazole-2-ones can be catalytically reduced with nickel, platinum, palladium or other similar suitable metals and molecular hydrogen. Such reactions are typically carried out in an alcoholic solvent, preferably ethanol, but any non-reactive solvent may be used and the amount of metal catalyst may range from approx.

0.001 molar equivalent to approx. 0.1 molar equivalent. The reaction is allowed to proceed in approx. 1 minute to approx. 1 hour, preferably approx. 10 minutes, depending on the reactants, the solvent and the temperature, which can be from approx. 0 ° C to approx. 100 ° C, preferably about 25 ° C. Alternatively, the nitro-benzoylimidazole-2-ones can be reduced with ammonia tooisulfide (NH 2 SH) in aqueous ammonia. From approx. 1 to approx. 10 molar equivalents, preferably about 3 molar equivalents, of the bisulfide 15 are allowed to react in from ca. 1/2 hour to approx. 10 hours, preferably approx. 2 hours, depending on the reactants and temperature, which can be from approx. 0 ° G to approx. 150 ° C, preferably approx. 50 ° C. Finally, the nitrobenzoylimidazole-2-ones can be reduced to the corresponding amino compounds by any other known method.

The alkylation of the unsubstituted aminobenzo-ylimidazol-2-ones may e.g. is effected by reaction with one or more equivalents of a suitable alkyl halide of formula R 1 X and R 2 X, wherein R 2 and R 2 have the meaning given above and 25 X means halogen. Typically, these reactions are carried out in one solvent, such as petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride, chlorinated aromatic compounds such as 1,2,4-trichlorobenzene, o-dichlorobenzene or chlorobenzene, on carbon disulfide, nitrobenzene, dimethylformamide. , dimethylsulfoxide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, aromatic solvents such as benzene, toluene or xylene, alcohols such as methanol, ethanol or propanol, and aqueous alcohols such as aqueous ethanol. These alkylations are preferably carried out

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in the presence of one or more equivalents of a "proton acceptor" / such as triethylamine, pyridine, sodium hydroxide, calcium hydroxide or potassium hydroxide, to neutralize the hydrogen halide as it is formed. Alternatively, the unsubstituted aminobenzoylimidazole-2-ones can be alkylated by any other suitable known method such as reaction with formic acid and formaldehyde to form a dimethylamine compound.

Compounds of formula (I) wherein Ar is 10 monosubstituted phenyl and X 1 is hydroxy may be prepared as described above or may be prepared from a methoxy-substituted benzoylimidazol-2-one where the alkoxy group sits in the position where the hydroxy substitution desired (method sub-variant 2). The methoxy compound 15 is cleaved to form the corresponding hydroxybenzoylimidazol-2-one by any suitable known method, e.g. as described by R.L. Burwell, "The Cleavage of Ethers," Chem. Rev. 54 / 615-85 (1954), to which reference is made herein.

The substituents, X2 ° <J X3, may be protected as needed to improve the stability of the reactants of formula (Vb) and (Vc) or to allow acylation of the imidazole-2-ring nitrogen nitrogen as described herein without the simultaneous acylation of any reactive X groups. .

When X 1, X 2 or X 3 represent hydroxy, e.g. an amino group of the formula -NHR 3 or -SO 2 NH 2 or a benzyl group is used to block the otherwise reactive hydroxy or amino groups. The benzyl group can later be removed by e.g. hydrogenolysis with hydrogen over a palladium catalyst or with sodium in liquid ammonia.

If desired, one or both of the nitrogen atoms in the imidazole-2-ring can be substituted by an alkyl group by any known method. Such methods include reacting a corresponding N-unsubstituted aroylimidazol-2-one prepared according to the invention with a base and an alkylating agent.

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agent in the presence of a non-reactive solvent. Suitable bases for this reaction may e.g. be a hydride such as sodium hydride or calcium hydride, a carbonate or bicarbonate such as sodium carbonate or sodium bicarbonate, a phenoxide such as sodium phenoxide, an alkoxide such as sodium ethoxide, or preferably a hydroxide such as sodium hydroxide. Suitable alkylating agents for this reaction are e.g. an alkyl halide such as methyl chloride, methyl bromide or methyl iodide, or a dialkyl sulfate such as dimethyl sulfate. Suitable non-reactive solvents are e.g. petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride, chlorinated aromatic compounds such as 1,2., 4-trichlorobenzene, o-dichlorobenzene or chlorobenzene, carbon disulfide, nitrobenzene, ethereal solvents such as diethyl ether, tetrahydrofuran or p. -dioxane, aromatic solvents such as benzene, toluene or xylene, or preferably polar aprotic solvents such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO). The reaction, e.g. allow 20 to run in from approx. 1 minute to approx. 1 hour and the temperature can be from approx. 0 ° C to approx. 100 ° C, preferably approx. 25 ° C.

When it is desired that only one of the imidazole-2-nitrogen nitrogen atoms be substituted with an alkyl group, a corresponding N-unsubstituted imidazol-2-one is reacted with from ca. 1 molar equivalents to approx. 10 molar equivalents of a base, preferably approx.

1 molar equivalent, and with approx. 1 mole equivalent of an alkylating agent. Using this method results in both possible monoalkylated nitrogen isomers. These isomers can be separated by conventional methods such as fractional crystallization, fractional distillation or chromatography. When it is desired that both nitrogen atoms in the imidazole-2-one ring be alkyl substituted, a corresponding imidazol-2-one is reacted with from ca. 2 molar equivalents to approx. 10 molar equivalents of a base, preferably approx. 2 molar equivalents, and from approx. 2 molar equivalents to approx. 10 moles of 35

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13 valents of an alkylating agent / preferably ca. 2 molar equivalents. Finally, any reactive substituents on the aroyl rings, if any, can be alkylated simultaneously. This means that the groups -OH, -NHR 3 and unsubstituted piperazino are alkylated under identical reaction conditions. If desired, the alkylation of the aroyl ring substituents can be avoided using suitable known protecting groups, e.g. may be benzylated as -OH or -NHR 3 and subsequently unblocked by hydrogenolysis.

If desired, the nitrogen atoms in the imidazole-2-ring can be substituted with an alkylcarbonyl group by any suitable known method using the corresponding acyl halide as acylating agent. Such methods include reacting the N-unsubstituted aroylimidazol-2-ones prepared according to the invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyl chloride, isopropanoyl chloride or butanoyl chloride. Usually, acylation reactions using acyl halides use an acid binding agent such as triethylamine or pyridine to remove the hydrogen halide as it is formed. In addition, the corresponding free acid or acid anhydride may be used in place of the acyl halides. Acylation reactions are usually conducted without added solvent, but can be carried out using any non-reactive solvent, e.g. petroleum ether, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulfide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, or aromatic solvents such as benzene, toluene or xylene. The reactions are allowed to proceed for approx. 1 minute to approx. 100 hours, preferably from approx. 1 hour to approx. 10 hours and the temperature can be from approx. -78 ° C to approx. 150 ° C, preferably 0-100 ° C. Finally, all reactable substituents on the aroyl rings, if any, will be acylated simultaneously. This means 35

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wherein the Χγ groups -OH, -NHR ^ and unsubstituted piperazino are acylated under identical reaction conditions. If desired, the acylation of the benzoyl ring substituents can be avoided by the use of suitable known protecting groups, e.g.

5, -OH or -NHR3 can be benzylated and subsequently blocked by hydrogenolysis.

The alkali metal, alkaline earth metal, side group number, major group metal, ammonium or organic ammonium salts of the aroylimidazole-2-ones prepared according to the invention can be prepared from a corresponding metal salt or basic 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 hydrogen carbonate. 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, aromatic solvents such as benzene, toluene or xylene, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, and halogenated hydrocarbon solvents such as chloroform, methylene chloride or carbon tetrachloride. The aroylamidazol-2-one and base are allowed to react for approx. 1 minute to approx. 24 hours 25 depending on the reactants and temperature, which may be from approx. -78 ° C to approx. 150 ° C, preferably from ca. 0 ° C to approx.

25 ° C.

The aroyl halides needed for the Friedel-Crafts acylation of the invention are either generally available compounds or can be prepared by analogous methods. The imidazol-2-one starting materials of formula (IV) can be prepared as described by or adapted from R. Duschinsky and L.A. Dolan, J.Am. Chem. Soc. 6 "7, 2079 (1945), R. Duschinsky and L. A. Dolan, J. Am. Chem. Soc.

35 68y 2350 (1945), or U.S. Patent No. 2,441,933.

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The compounds of general formula (I) may be used in the treatment of heart failure, including congestive heart failure, increased filling pressure, decreased stroke volume, left ventricular heart failure, or right sided ventricular heart failure, or in the treatment of any other condition, requiring increase of cardiac effect with a cardiotonic agent. In many respects, these compounds have a digitalis-like effect. The compounds of general formula (I) may also be used in the treatment of hypertension, including primary or essential hypertension, hormone-induced hypertension, renal hypertension, and chemically induced hypertension. Finally, the compounds of general formula (I) can be used as antithrombotic agents. They affect blood coagulation by preventing the aggregation of platelets, which play a dominant role in 15 thrombotic states, both in the initial and occlusive stages. Arterial thrombosis, especially in arteries supplying the heart muscle and brain, is a dominant cause of death and incapacity.

The compounds can be administered in many ways 20 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, ie. intravenously or intramuscularly. The amount of compound administered will vary with the severity of hypertension, heart failure or blood clotting and with the mode of administration. For oral administration, the antihypertensive effective amount of compound from 0.1 mg / kg body weight of the patient per day to approx. 500 mg / kg body weight of the patient per per day and preferably from ca. 50 mg / kg body weight of the patient per day to approx. 150 mg / kg body weight of the patient per day.

For parenteral administration, the antihypertensive effective amount of compound is from ca. 0.01 mg / kg body weight of the patient per day up to approx. 150 mg / kg body weight of the patient per per day and preferably from ca. 1.0 mg / kg le 16

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average weight of the patient per day up to approx. 10.0 mg / kg body weight of the patient per day. For oral or parenteral administration, the cardiotonically effective amount of compound is from ca.

0.1 mg / kg body weight of the patient per day up to approx. 500 5 mg / kg body weight of the patient per per day and preferably from ca. 0.1 mg / kg body weight of the patient per day up to approx.

10.0 mg / kg body weight of the patient per day. For oral or parenteral administration, the anticoagulant effective amount of compound is from ca. 0.1 mg / kg body weight of the patient 10 per day up to approx. 1000 mg / kg body weight of the patient per per day and preferably from ca. 1 mg / kg body weight of the patient per day up to approx. 100 mg / kg body weight of the patient per day.

For oral administration, a dosage unit may e.g.

15 contain from 10 to 100 mg of the active ingredient. For parenteral administration, a dosage unit may e.g. contain from 5 to 50 mg of the active ingredient. The administration of the compounds several times daily may be desired and will vary with the patient's condition and mode of administration.

As used herein, the term "patient" is to be understood as meaning a warm-blooded animal, e.g. birds, such as chickens and turkeys, and mammals such as primates, humans, sheep, horses, cows and bulls, pigs, dogs, cats, rats and mice.

For oral administration, the compounds can be formulated into solid or liquid preparations, such as capsules, pills, tablets, lozenges, powders, solutions, suspensions or emulsions. The solid dosage unit forms may be a capsule which may be of the usual gelatin type containing e.g. lubricants and an inert filler such as lactose, sucrose or corn starch see. In another embodiment, the compounds of general formula (I) may be tableted with conventional tablet matrixes such as lactose, sucrose and corn starch, in combination with binders such as acacia, corn starch or gelatin.

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17, such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration, the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable excipients. Illustrative of oils which may be used in these: compositions are those of mineral, animal, vegetable or synthetic origin, e.g. peanut oil, soybean oil and mineral oil. Generally, water, saline, aqueous dextrose and the like sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions.

The compounds may be administered in the form of a depot injection or implant preparation which may be formulated in such a way as to permit a delayed release of the active ingredient. The active ingredient may be compressed into hail or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants can use inert materials such as biodegradable polymers or synthetic silicones, e.g. "Silastic®", a silicone cloth made by Dow-Corning Corporation.

Listed below are pharmaceutical compositions which can be prepared using compounds prepared according to the present invention.

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Preparation of a tablet

Pr. tablet 5 a) 1,3-Dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one 100 mg b) Corn starch 15 mg 10 c) Lactose 33.5 mg d) Magnesium stearate 1, 5 mg

Preparation of a Parenteral Preparation a) 1,3 Dihydro-4- (4-methoxybenzoyl) -5- methyl-2H-imidazole-2-Qn 1,000 g 2Q b) Polyoxyethylene sorbitan monooleate 2,000 gc) Sodium chloride 0.128 gd) Water for injection qs ad 20,000 ml 25

The following examples illustrate the action of the compounds of the invention as antihypertensive, cardiotonic and anticoagulant agents.

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 is administered orally to six spontaneously hypertensive rats. This dose results in an average decrease of 19

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40% in blood pressure within 15 minutes of administration. Example B

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

Heart failure is induced on a dog by intravenous administration of sodium pentobarbitol (20 mg / kg) or propranalol hydrochloride (3 mg / kg) to the blood flowing through the heart. After administration of one of these cardiac depressants, the pressure in the right ventricle drops dramatically and the heart rate decreases sharply. Intravenous administration of the title compound (1 mg / kg) causes insufficiency, as evidenced by pressure in the right ventricle and cardiac output almost reaching the pre-treatment level.

Example C

Use of 1,3-dihydro-4- (4-methoxybenzoyl) -20 -5-methyl-2H-imidazol-2-one as antithrombotic agent.

When adenosine diphosphate is added to citrated platelet-rich human plasma, a typical platelet aggregation occurs. However, if the title compound is added to the citrate-treated, platelet-rich human plasma at concentrations of 3, 10, 30 and 100 µg / ml and then adenosine diphosphate is added, platelet aggregation is inhibited by 33, 49, respectively. 82 and 98%.

30

The compounds 1-32 listed in Table I below have been further tested for biological activity.

35

DK 160269 B

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Example D

Dogs of both sexes weighing 9-23 kg are anesthetized with 35 mg / kg sodium pentobarbital intravenously. The lungs are artificially ventilated with a Bird Mark 7 respirator after tracheal 5 intubation. The left femoral vein is provided with a cannula for administration of test compounds of formula I. A cannula is inserted into the left femoral artery and the cannula is inserted into the thorax aorta to measure the systemic blood pressure recorded with a Statham P23GC pressure transducer. The chest opens at 10th rib spacing and the pericardium is cut to expose the heart. A calibrated Walton-Brodic tension arc is sutured to the left ventricle to measure cardiac contraction force. The pulse is recorded from an ECG with a Grass, 7D tachograph. The dogs are allowed to stabilize for at least 30 15 minutes after the surgical procedure.

The test compounds of formula I are administered intravenously or introduodenally by injection. Each animal is administered only one compound of formula I. If the animals are administered more than one dose of the same compound, there is such a long time between each dose that the variables have returned to baseline level. Equilibrium doses are obtained by extrapolation from dose-response curves. Measurements of heart contraction, heart rate and blood pressure are measured before and after test compound administration for 90-300 minutes at 5-10 minute intervals.

The results of the experiment are shown in Table II, where the numerical values are the doses of each compound of Formula I which increase cardiac contractility by 30%, increase heart rate by 15% and decrease blood pressure by 20%.

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Table II

Effect of 4-aroyl-1,3-dihydro-2H-imidazol-2-ones on cardiac contraction (HHK), heart rate (PH) and blood pressure (BT) in anesthetized dogs.

5

Dosage

Conn. , HKK PH BT No. of dogs 1 0.23 1.55 2.55 1 10 2 0.78 1.85 3.10 1 3 0.16 0.40 0.65 23 4 0.15 0.23 0.62 1 5 0.40 1.05 2.00 1 6 0.18> 3.00 2.35 1 15 7 0.18 4.00 0.29 1 8 0.48 2.20 2.10 1 9 0.70 4.00 2.10 1 10 0.38> 3.00 1.03 3 11 0.25 1.30 2.60 1 20 12 3.28> 10.00 4.50 2 13 0, 50 1.05 pressor 1 14 0.12 1.50 0.55 5 15 0.07 0.54 0.28 5 16 1.13 3.00 2.30 1 25 17> 10.0 8.50 4, 50 1 18> 10.0> 10.0> 10.0 1 19 * 10.0 9.10> 10.0 1 20 1.20> 10.0 6.40 1 21 0.36 2.20 3, 00 1 22 0.72> 10.0 3.70 1 23 0.28 5.40 2.50 5 24 0.41 1.45 1.00 2 25 1.84 4.00 4.20 1 26 1, 05 3.30 0.72 1 35

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Table II (continued)

Dosage

Conn. HKK PH BT Number no a) dogs 5 27 4.70> 10.0 2.60 1 28> 10.0> 10.0> 10.0 1 29 3.00> 10.0 6.50 1 30 1 , 00> 8.00 2.50 1 10 31 0.36> 3.00> 3.00 1 32 2.45> 10.0> 10.0 1 15 a) No. on compound according to Table I.

b) Equivalent effective doses obtained by extrapolation from a dose-response curve obtained by intravenous injection of at least three doses of each compound. The value shown is a geometric mean where more than 20 animals have been tested.

From Table II, it will be seen that exchange of Ar = phenyl (Compound 1) with Ar = 2-thienyl (Compounds 22 25 and 23) increases the potency and inotropic selectivity, while Ar = furyl (Compounds 25 and 26) is less effective. In this regard. Furthermore, it will be seen that = CH 2 (compounds 3, 14, 23 and 26) are correspondingly stronger inotropic compounds than their corresponding demethyl compounds (R 2 = H, 30 compounds 2, 13, 22 and 25), as is a change to R1 = ^ 2 ^ 5 ^ certain cases (compounds 4, 6 and 15) further increase the inotropic potency, although this is not always the case (compound 23). Compound 16 (R 2 = i-C 3 H 7) shows that the strength begins to decrease again. Alkylation of one or both of the ring nitrogen atoms (compounds 27 and 28) results in

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in a sharp decrease in activity, however, which is not the case with acylation (Compounds 29-32). This may be due to desacylation in vivo, so that it is possible that free NH groups in the ring are of importance for the inotropic activity.

Example E

Compounds 3, 14 and 15 (Table I), which are among the most potent in Example D, have been investigated in more detail. Thus, the strongest compound (no. 15) at doses of 0.1, 0.3 and 1.0 mg / kg intravenously has been found to give dose-dependent increases in HKK in anesthetized dogs. These increases last from 39 to 86 minutes. There are relatively small increases in PH and BT. Corresponding but less pronounced increases are seen with the other two compounds.

Compound # 3 gives intravenous or intraduodenal doses of 0.3-10 mg / kg the same effects in anesthetized dogs. These effects are not altered by a dose of 20 propranolol which appreciably inhibits an equivocal dose of isoproterenol, suggesting that a stimulation of / Sveller-adrenergic receptors is not involved in the mechanism of action.

Example F

It has been investigated whether compound 3 (Table I) could improve cardiac pumping function in the normal and failing hearts. For this, pulmonary heart preparation is used in the method of Somani and Bachand, Am. Heart j.

74, 222 (1967).

Bastard dogs of both sexes (weight 11-19 kg) are anesthetized and prepared for recording HKK, PH and BT as described in Example D, however, HKK is measured on the right ventricle. Furthermore, the left atrial blood pressure (VABT) is measured via a cannula 35 inserted into the left atrium. Aortic blood flow is measured outside

26 DK 160269 B

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the body with a flow meter (Biotronex, model BL 610). Cardiac output (HY) is calculated as aortic blood flow, which does not include cardiac inflow from arteries. Stroke volume (SV) is calculated as the quotient between HY and PH, and heart rate 5 is calculated according to the formula

BT - WEAPON 0.0136 EN

where BT and VABT are mm Hg and SV is ml.

In the trial, the heart and lungs are isolated from the blood vessel system and flow in situ from an extracorporeal circulation, the blood from the heart being pumped into the outer circulation via a cannula in the aorta and returned to the heart via a cannula in the upper vein. cava. The outer circulation comprises a blood reservoir of 800 ml of blood and the height of blood 15 in the right atrium reservoir determines the venous return flow (VR) and is kept constant. The total volume of blood outside the body is approx. 1200 ml.

At the start of the experiment, BP is set to 75-90 mm Hg when adjusting the resistance in the aorta, HY is adjusted by adjusting the VR to approx. 2/3 of that expected based on animal weight (100 ml / kg). Under these conditions, the blood height in the reservoir is 18-25 cm above the right atrium. The measurements are recorded continuously on a polygraph (Grass, model 7B). All test compounds are added to the reservoir.

The test compounds are dissolved in normal saline or 1N NaOH and normal saline. Isoproterenol is dissolved in normal saline solution containing 0.01% ascorbic acid.

The results of the experiment are shown in Table III.

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From Table III, it will be seen that compound 3 at doses of 0.3, 1 and 3 mg / kg gives significant increase in HKK, PH, HY, while there is a decrease in SV and VABT ^ Since the heart - lung preparation not affected by nerves or hormones, these effects are the result of a \ direct effect on the heart. The decrease in SV, which is observed despite the increase in HKK, is undoubtedly the result of the PH increase, which reduces the diastolic filling time. The increase in HY and the decrease in VABT show an increase of 10 heart pump function. Finally, the relatively greater decrease in VABT relative to SV, especially at a dose of 0.3: mg / kg, indicates a true cardiotonic effect of: compound 3.

Example G.

It is well known that cardiotonic agents, such as cardiac glycosides, are more effective in failing hearts than in normal hearts. To determine if compound 3 also has this effect in cardiac glycosides, 20 cardiac failures have been induced in cardiac lung preparations by adding a myocardial depressant dose of pentobarbital (20 mg / kg) to the reservoir. This dose significantly lowers HKK, PH, HY and SV and increases VABT, as shown in * Table IV below. Addition of 1 mg / kg of compound 25 3 to the venous blood reservoir 10 minutes after the pentobarbital addition reverses the lowering effects of pentobarbital. The increases in HY and SV, together with the decrease in VABT, show a noticeable increase in the heart's pumping function and alleviate the pentobarbital-induced heart failure. ' 30 35

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DK 160269 B

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The following examples illustrate the process of the invention.

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

To a stirred mixture of 98.1 g (1 mole) of 1,3-di-hydro-4-methyl-2H-imidazol-2-One, 266.7 g (2 moles) of anhydrous aluminum chloride and 500 ml of nitrobenzene are added. 158.6 g (1 mole) of 10β-fluorobenzoyl chloride dropwise over 10 minutes. The mixture is stirred at 60-65 ° 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 1.2 liters of dimethyl formamide to give 131 g of the title compound, m.p. 289-292 ° C.

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

A suspension of 11.0 g (0.05 mole) of 1,3-dihydro-4- (4-fluorobenzoyl) -5-methyl-2H-imidazol-2-one in 30 ml (0.3 mole) of piperidine The excess piperidine is evaporated at reduced pressure and the residue is recrystallized twice from a mixture of isopropanol and water to give 11.9 g of the title compound, m.p. 260-263 ° C.

Example 3 1,3-Dihydro-4-methyl-5- [4- (4-morpholinyl) -benzoyl] -2H-imidazole-2-n

Proceeding as described in Example 2 but using morpholine instead of piperidine, the title compound, m.p. 283-286 C.

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Example 4 1.3-Dihydro-4- [4- (dimethylamino) -benzoyl] -5-methyl-2H-imidazol-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 are heated in a pressure bomb to 130-135 ° C for 22 hours. The mixture is cooled and the solid is collected and recrystallized from isopropanol-10 water to produce the title compound, m.p. > 310 ° C, Λ (max) (methanol) 364 nm (λ = 23,300).

Example 5 1.3-Dihydro 4- (4-hydroxybenzoyl) -5-methyl-2H-15-imidazol-2-one

To a melt of 26 g (0.23 mole) of pyridine hydrochloride at 200-205 ° C is added 5.3 g (0.023 mole) of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl -2H-imidazole-2 "one, and the mixture is stirred mechanically for 30 minutes. The reaction mixture is poured onto ice-2N HCl. The resulting precipitate is washed with water and recrystallized from isopropanol-water to give the title compound, m.p. > 300 ° C, λ (max) (methanol) 320 nm (? = 13,200).

25

Example 6 1.3-Dihydro-4-methyl-5- [4- (methylthio) -benzoyl-2H-imidazol-2-one

A solution of 25.0 g (0.15 mol) 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 are evaporated and the residue azeotroped 3 times with benzene to remove all thionyl chloride. The residue is added dropwise to a mixture of 11.8 g (0.12 mol) of 1,3-dihydro 32

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dro-4-methyl-2H-imidazol-2-one, 40.0 g (0.3 mole) of anhydrous aluminum chloride and 100 ml of nitrobenzene. The resulting mixture is stirred at 60-65 ° C for 5 hours, poured on ice, and the precipitate which is formed is collected, washed with ethyl ether and water and recrystallized from isopropanol-water to give the title compound, m.p. 255-258 ° C (dec.).

Example 7 1,3-Dihydro 4- (4-methoxybenzoyl) -5-methyl-2H- -imidazol-2-one

To 19.6 g (0.2 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g (0.4 mole) of anhydrous aluminum chloride 15 in 150 ml of nitrobenzene are added dropwise 34 , 2 g (0.2 mol) of p-methoxybenzoyl chloride and the mixture is poured after 1 hour at room temperature on 500 ml of 2N HCl and ice, washed 3 times with ethyl ether and the resulting solid is recrystallized from isopropanol-water to prepare of the compound mentioned in heading 20, m.p. 257-258 ° C (dec.).

Example 8 1,3-Dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one sodium salt

To 7.0 g of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one in 100 ml of methanol are added 1.6 g of sodium methoxide. The mixture is heated on a steam bath until it is homogeneous, filtered and evaporated to dryness. The solid residue is recrystallized from isopropanol to give the title compound, m.p. 280-282 ° C (dec.).

35

Example 9

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33 DK 160269 B

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

To a solution of 3.0 g (0.03 mole) of 4-methyl-imidazol-2-one and 8.0 g (0.06 mole) of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g (0.03 mole) benzoyl chloride. The solution is heated to 60 ° C for 4 hours, poured over ice water, slurried with ether, and the resulting solid filtered and dried to give the title compound, m.p. 250-254 ° C.

Example 10 1.3-Dihydro-4-methyl-5-thienoyl-2H-imidazol-2-one

To a solution of 7.3 g (0.077 mol) of 4-methyl-imidazol-2-one and 10.8 g (0.081 mol) of aluminum chloride in 150 ml of nitrobenzene is added 12.0 g (0.082 mol) of 2-thienoyl chloride. The mixture is stirred at 60 ° C for 3 hours, cooled and poured out 2Q over ice water. The organic portion is extracted into ethyl acetate, dried, and the organic solvent is evaporated to give the title compound, m.p.

212-215 ° C.

Example 11 1,3-Dihydro-4- (3,4-dimethoxybenzoyl) -2H-imidazol-2-one

To a solution of 6.5 g (0.065 mol) of 1,3-di-hydro-4-methyl-2H-imidazol-2-one and 14.6 g (0.11 mol) of aluminum chloride in 65 ml of nitrobenzene is added. , 6 g (0.088 mol) of 3,4-dimethoxybenzoyl chloride in portions. The mixture is stirred for 3 hours at 60 ° C, cooled and poured over ice water. Rubber-like solids are filtered off and recrystallized two 35 times from ethyl alcohol-water to produce the title compound, m.p. 257 ^ 259 ° C.

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Example 12 1.3- Dihydro-4- (2-furanoyl) -5-methyl-2H-imidazol-2-one For a slurry of 8.9 g (0.09 mol) of 1,3-dihydro-2 4-methyl-2H-imidazol-2-one and 24.0 g (0.18 mole) of aluminum chloride in 135 ml of nitrobenzene are added dropwise 12.9 g (0.1 mole) of furanoyl chloride. The mixture is stirred at 60 ° C for 3 hours, cooled and poured over ice water. The solid is then filtered off and recrystallized twice from methyl alcohol to give the title compound, m.p. 214-216 ° C.

Example 13 1,3-Dihydro-4- (2-thienoyl) -2H-imidazol-2-one In 50 ml of nitrobenzene, 13.3 g (0.1 mole) of aluminum chloride, 4.2 g (0.081 mole) are combined. , 3-dihydro-2H-imidazol-2-one and 8.1 g (0.055 mol) of thienoyl chloride. The mixture is stirred at 60 ° C for 3 hours and poured over ice water. The solids are filtered off, washed with ether and recrystallized twice from ethanol-water to give the title compound, m.p. 339-342 ° C.

Example 14 1.3-Dihydro-4-furanoyl-2H-imidazol-2-one

To 50 ml of nitrobenzene was added 4.2 g (0.051 mole) of 1,3-dihydro-2H-imidazol-2-one, 13.3 g (0.1 mole) of aluminum chloride and 7.2 g (0.056 mole). furanoylchlorid. The mixture is stirred at 60 ° C for 3 hours and poured over ice water. The solids are filtered off, washed with ether and recrystallized twice from ethanol-water to give the title compound, m.p. 318-321 ° C.

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Example 15 35

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1.3-Dihydro-4- (4-methoxybenzoyl) -1,3,5-trimethyl-2H-imidazol-2-one In 120 ml of DMSO, 15.2 g of powdered potassium hydroxide, 8.0 g of 1.3 dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one sodium salt and 19.5 g of methyl iodide. The mixture is stirred at room temperature for 60 minutes and poured into. 800 ml of water. Extraction with methylene chloride gives a solid which is crystallized from ether, m.p. 109-111 ° C, NMR: N-CH3 (6 protons) at 3.3 ppm.

Example 16 1.3-Dihydro- (1 and 3), 5-dimethyl-4- (4-methoxy-benzoyl) -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 DMSO are added 0.288 g of sodium hydride and 1.22 g of methyl iodide. The mixture is stirred at 22 ° C for 20 minutes, poured into methylene chloride and washed with water.

The solvent is dried and evaporated to give an oil which gives a solid when triturated with chloroform.

The solid is crystallized from methanol, m.p. 225-228 ° C.

Analysis: Calculated for C₂ 2H- ]N₂O 3: C = 63.40%, H = 5.73%, N = 11.39% <

Found: C = 63.34%, H = 5.85%, N = 11.21%.

NMR: N methyl, singlet at 3.2 ppm.

30 35

Claims (12)

An analogous process for the preparation of 4-aroyl-1,3-dihydro-2H-imidazol-2-ones of the general formula 510 wherein Ar is 2-furyl, 2-thienyl, phenyl, in ortho, meta or para position with Χγ monosubstituted phenyl or in para position with X2 and in ortho or meta position with X ^ disubstituted phenyl, X ^ means halogen, hydroxy, straight or branched alkyl of 1-4 carbon atoms, straight chain or branched alkoxy of 1-4 carbon atoms, straight-chain or branched alkylthio of 1-4 carbon atoms, NR 1 R 2, pyrrolidino, piperidino, morpholino, piperazino or N'-alkylpiperazino of 1-4 alkyl carbon atoms, X 2 and X halogen, straight or branched alkoxy of 1-4 carbon atoms or straight or branched alkyl · of 1-4 carbon atoms, however, X2 does not mean methyl, when X1 means methyl, the two R groups which may be the same or different, means hydrogen, straight chain or branched alkyl of 1-4 carbon atoms or straight chain or branched alkylcarbonyl having from 1 to 4 carbon atoms in the alkyl moiety and R 1, R 2 and R 2 each represent hydrogen or straight or branched alkyl of 1 to 4 carbon atoms, however, R 3 and R 2 cannot both be hydrogen or a pharmaceutically acceptable metal salt or basic ammonium salt thereof, characterized in that a) a compound of the general formula R, H> (<+) 0, having the meaning given above, is subjected to a Friedel-Crafts acylation of from ca. 1 to approx. 10 molar equivalents of a 2-furoyl halide, 2-thienoyl halide, a benzoyl halide, one in ortho, meta or para position 5 having monosubstituted benzoyl halide having the above meaning, or one in para position with X 2 and in ortho or meta position with X 2 disubstituted benzoyl halide, wherein X 2 and X 3 have the meaning given above, in the presence of from 1 to approx. 10 molar equivalents 10 of a Lewis acid catalyst in a suitable solvent at a temperature of approx. 0 ° C to approx. 100 ° C for approx. 1 to approx. 10 hours, whereupon the compound of formula I *, if R is hydrogen, is optionally acylated or alkylated with a corresponding acylating agent or alkylating agent to form a compound of formula I wherein R is alkyl or alkoxycarbonyl (both, or b) a compound of formula 0 25 wherein R and having the meaning set forth above is reduced to form the corresponding aminobenzoylimidazol-2-one, which is then alkylated to form a compound of general formula I wherein Ar represents NR 3 R 4 -substituted phenyl, wherein R3 and R4 have the meaning given above, wherein the alkylations under a) and b) can be carried out separately or simultaneously, if necessary using protective groups for R, Xj, X2 or x3, which are eventually removed and if desired 1. A compound thus formed, wherein Ar represents ortho- or para-fluorosubstituted phenyl, is treated with from ca. 1 to approx. 10 molar equivalents of amine of the formula HNR3R4, pyrrolidine, piperidine, morpholine, piperazine or 5 N'-alkylpiperazine having 1-4 alkylcarbon atoms in a suitable solvent for from ca. 1/2 hour to approx. 48 hours from approx. 0 ° C to approx. 150 ° C to form a compound of formula I wherein Ar is with ortho- or para-substituted phenyl, wherein X 1 is NR 3 R 4, pyrrolidino, piperidino, morpholino, piperazino or Ν'-alkylpiperazino (C 1-4 alkyl), or 2. a compound thus formed, wherein Ar represents methoxy-substituted phenyl, is cleaved to form a compound of formula I wherein Ar represents hydroxy-substituted phenyl and the aroylimidazol-2-one of formula I thus formed, if desired. pharmaceutically acceptable salt, reacted with a suitable metal salt or basic ammonium salt. Process according to claim 1, characterized in that a compound wherein R is hydrogen and R-j is hydrogen or straight or branched or branched alkyl of 1-4 carbon atoms, preferably methyl or ethyl. Process according to claim 2, characterized in that a compound wherein Ar is phenyl which is monosubstituted with X 1 is prepared. A process according to claim 3, characterized in that a compound is prepared wherein X 1 represents straight-chain or branched alkoxy of 1-4 carbon atoms or straight-chain or branched alkylthio of 1-4 carbon atoms. Process according to claim 4, characterized in that a compound is prepared in which X 1 stands at 35 para position. Process according to claim 5, characterized in that a compound is prepared wherein X 1 is methoxy or methylthio and R 2 is methyl. DK 160269 B Process according to claim 2, characterized in that a compound is prepared in which Ar is disubstituted phenyl, which is substituted by X 2 / and which is substituted with ortho or meta position. Method according to claim 7, characterized in that a compound is prepared in which X 1 is in the meta position. A process according to claim 8, characterized in that a compound is prepared wherein X 2 and X 2 represent straight or branched chain alkoxy of 1-4 carbon atoms. Process according to claim 9, characterized in that a compound is prepared wherein R 1 is methyl and X 2 and X 3 are methoxy. 20 25 30 35