SE464559B - PHARMACEUTICAL COMPOSITION CONTAINING 4-AROYLIMIDAZOLE-2-ONER WITH ANTIHYPERTENSIVE, CARDIOTONE AND ANTITHROMOBOTIC EFFECTS - Google Patents

Description

464 559 2 R 1 Ar R / N * KR I 'wherein Ar represents 2-furyl, 2-thienyl, phenyl, phenyl, monosubstituted in ortho, meta or para position with X1, where X1 represents hydroxy or methoxy or disubstituted phenyl, substituted in the para position with X2 and in the ortho or meta position with X3; X 2 and X 3 represent hydroxy or methyl; R represents hydrogen, a straight or branched lower alkyl group having 1 to 4 carbon atoms, or a benzoyl group, where R 1 represents hydrogen or a straight or branched lower alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof. These compounds are useful as antihypertensive, cardiotone and antithrombotic agents. The invention also relates to a process for the preparation of 4-aroylimidazol-2-ones and their pharmaceutical compositions.

Illustrative examples of a straight or branched alkyl group having 1-4 carbon atoms used in this specification are methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

By the term a benzoyl group is meant a group of the formula - (CO) C 6 H 5.

By the term a straight or branched lower alkyl-carbonyl group having 1-4 carbon atoms is meant a group of the formula O -C-alkyl wherein the alkyl moiety is a straight or branched lower alkyl group having 1-4 carbon atoms and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

The preferred compounds of the invention are those compounds of formula I, wherein R represents hydrogen. The preferred compounds of the invention are those compounds of formula I, wherein R represents hydrogen, R1 represents methyl and X1 is in the para-position and represents methoxy, or wherein R represents hydrogen, R1 represents methyl and X3 is in the meta-position. .

Examples of compounds of general formula I are 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-dimethyl-4-benzoyl-2H-imidazol-2-one, 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H- imidazol-2-one, 4-benzoyl-1,3-dihydro-Semethyl-2H-imidazol-2 * one, 1,3-diacetate, 1,3-dihydro-4- (3,4-dimethoxybenzoyl) -5- methyl 2H-imidazol-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-hydroxybenzoyl) -5-methyl-2H-imidazol-2-one. When R represents hydrogen in compounds of formula 1 are several tautomeric forms of the general formula 2 possible R 1 Ar R 1 Ar R 1 Ar> _ í eJ> _ <<- “_ '>" <2 H / V / NYNNI N \ N \ HYH oH o OH wherein R1 and Ar have the meanings given above: These acidic tautomers can form pharmaceutically active salts with the general formula meln 3 '464 559 4 R 1 Ar R 1 r R 1 Ar R 1 Ar / N \ / N / QN \ / N \ N. N \ HYH TK MMYHYH if oo oM wherein R 1 and Ar have the meanings given above, and M represents a pharmaceutically acceptable alkali metal such as sodium or potassium; alkaline earth metal such as calcium or magnesium; transition metal, such as zinc or iron; main group metal; ammonium or organic ammonium ion, such as tetramethylammonium ion. In this specification, the term imidazol-2-one refers to any of the tautomers of formula 2 and a pharmaceutically acceptable salt of an imidazol-2-one refers to any tautomer of formula 3.

The 4-aroylimidazol-2-ones according to the invention, in which R represents hydrogen, can be prepared by a Friedel-Crafts acylation of an imidazol-2-one of formula 4. wherein R1 has the meaning given for formula I. The acylating agent may be a 2-furanoyl halide, preferably 2-furanoyl chloride, a 2-thienoyl halide, preferably 2-thienoyl chloride or a benzoyl halide, preferably a benzoyl chloride of the formulas Sa, 5b or 5c 5 464 559 OO x Y Y X X y Formula 5b 2 Formula 5c wherein Y represents a halogen and X 1, X 2 and X 3 have the meanings given for formula 1 or may in addition be any group which can be converted into the desired X 1, X 2 or X 3 substituent after Friedel The Crafts reaction, such as a blocking group or a nitro group which can be converted via the diazonium ion to a variety of other substituents with chemistry, is well known. In addition, the Friedel-Crafts reaction can be carried out on the free acid or its corresponding acid anhydride instead of the aoryl halides mentioned above, using essentially identical reaction conditions.

These alternative reactions are described in more detail in Olah, "Friedel-Crafts and Related Reactions" vol. III, part k, Interscience Publications, John Wily and Sönder, New York 1964.

The Friedel-Crafts reactions of the invention are carried out by premixing about 1 molar equivalent of a suitable imidazol-2-one with about 1 molar equivalent to about 10 molar equivalents, preferably about 2 molar equivalents of a Lewis acid catalyst in a suitable solvent, e.g. ex. petroleum ethers; a chlorinated hydrocarbon such as carbon tetrachloride, ethylene chloride, methylene chloride or chloroform; a chlorinated aromatic such as 1,2,4-trichlorobenzene or o-dichlorobenzene; carbon disulfide; or preferably nitrobenzene. About 1 molar equivalent to about 10 molar equivalents, preferably about 1.1 molar equivalents of a suitable aroyl compound is preferably added dropwise to the mixture of imidazol-2-one, Lewis acid and solvent, and the reaction is allowed to proceed for about 1/2 hour to about 100 hours, preferably from about 1 hour to about 10 hours depending on the reactants, solvent and temperature, which may be from about -78 to about 1000 ° C, preferably about 0 to about 1000 ° C, most preferably about 600 ° C. C. The resulting aroyl-imidazol-2-one can be isolated from the reaction mixture by any suitable method known in the art, preferably by cooling the reaction mixture with ice water and then removing the product by filtration or extraction and removal of solvent.

Suitable Lewis acid catalysts for use in the Friedel-Crafts reactions described above are e.g. a metal such as aluminum, cerium, copper, iron, molybdenum, tungsten or zinc. A Bronstead acid such as phosphoric acid, sulfuric acid, sulfonic acid or a hydrohalic acid such as hydrochloric or hydrobromic acid; halogen substituted acetic acids, such as chloroacetic or trifluoroacetic acids; a metal halide such as boron halide, zinc chloride, zinc bromide, beryllium chloride, copper chloride, ferric bromide, ferric chloride, mercury chloride, mercury chloride, antimony bromide, antimony chloride, titanium (IV) bromide, titanium (IV) chloride, titanium (III) chloride, aluminum bromide or preferably aluminum chloride.

The compounds of formula I in which X1 or X2 and X3 represent hydroxy may be prepared as described above or may preferably be prepared from a suitable alkoxy, preferably methoxy-substituted benzoylimidazol-2-one, wherein the alkoxy group is in the same position as the desired hydroxy substitution. The alkoxy compound is cleaved to produce the corresponding hydroxybenzoylimidazol-2-one by any suitable method known in the art, as described by RL Burwell, "The Cleavage of Ethers", Chem. Rev. 54, 615 85 (1954). .

The X1, X2 and X3 substituents may, if necessary, be protected to improve the stability of the reactants of formulas Sb and 5c or to enable the acylation of the ring nitrogen atoms in the imidazol-2-one, as described above, without competing acylation of any reactive X groups. When e.g. X 1, X 2 or X 3 is hydroxy, an amino group of the formula -NHR 3 or -SO 2 NH 2, a benzyl group may be used to block the otherwise reactive hydroxy or amino groups. The benzyl group can then be removed e.g. by hydrogenolysis with hydrogen over a palladium catalyst or with sodium in liquid ammonia.

If desired, one or both of the nitrogen atoms in the imidazol-2-one ring can be substituted with an alkyl group by any known method. Such processes include reacting a suitable N-substituted aroylimidazol-2-one of the invention with a base and an alkylating agent in the presence of a non-reactive solvent. Suitable bases for this reaction may e.g. be a hydride such as sodium or calcium hydride; a carbonate or bicarbonate such as sodium carbonate or 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 ethers; chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride; chlorinated aromatics such as 1,2,4-trichlorobenzene, o-dichlorobenzene or chlorobenzene; carbon disulfide; nitrobenzene; ether solvents such as diethyl ether, tetrahydrofuran or p-dioxane; aromatic solvents such as benzene, toluene or xylene; or preferably the polar aprotic solvents such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO). The reaction is allowed to proceed from about 1 minute to about 1 hour, and the temperature may be from about 0 ° C to about 1000 ° C, preferably about 250 ° C. When it is desired that only one of the nitrogen atoms in imidazole-2- the one is to be substituted with an alkyl group, an appropriate imidazol-2-one is reacted with about 1 mole equivalent to about 10 molar equivalents of a base, preferably about 1 molar equivalent and with about 1 molar equivalent of an alkylating agent. Using this procedure, the two possible monoalkylated nitrogen isomers are obtained. These isomers can be separated by conventional known methods such as fractional crystallization, fractional distillation or chromatography. When it is desired that both nitrogen atoms in the imidazol-2-one ring be alkylated, a suitable imidazol-2-one is reacted with about 2 molar equivalents to about 10 molar equivalents of a base, preferably about 2 molar equivalents and from about 2 molar equivalents to about 10 molar equivalents of an alkylating agent, preferably about 2 molar equivalents. Finally, any reactive substituents, if any, on the aroyl rings can be alkylated simultaneously. I.e. the following X groups, X = OH, -NHR 3, SO 2 NH 2 and unsubstituted piperazino are alkylated under identical reaction conditions. If desired, the alkylation of the aroyl ring substituents can be avoided by using suitable protecting groups well known in the art, e.g. for example, X = OH or -NHR 3 can be benzylated and later blocked by hydrogenolysis.

If desired, the nitrogen atoms in the imidazole-2-one ring may be substituted with an alkylcarbonyl group by any suitable known method. Such processes include reacting the N-unsubstituted aroylimidazole-2-ones of the invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyl chloride, isopropanoyl chloride or butanoyl chloride. Normally, in acylation reactions where acyl halides are used, an acid scavenger such as triethylamine or pyridine is used to remove hydrohalide when it is formed. In addition, the corresponding free acid or acid anhydride can be used instead of the acyl halides. Acylation reactions are generally carried out without added solvent but can be carried out using any non-reactive solvent, e.g. petroleum ethers; chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride; carbon disulfide; ether 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 about 1 minute to about 100 hours, preferably from about 1 hour to about 10 hours; and the temperature may be from about -78 ° C to about 150 ° C, preferably from 0 to 100 ° C. All reactive substituents on the aroyl rings, if present, will eventually be acylated simultaneously. I.e. the following X groups, X = OH, -NHR 3, -SO 2 NH 2 and unsubstituted piperazino groups are acylated under identical reaction conditions. If desired, the acylation of benzoyl ring substituents can be avoided by the use of suitable protecting groups, well known in the art.

For example. For example, X = OH or -NHR 3 can be benzylated and later blocked by hydrogenolysis.

Alkali metal, alkaline earth metal, transition metal, main group metal, ammonium or the organic ammonium salts of the aroylimidazol-2-ones according to the invention can be prepared from a corresponding metal or ammonium basic salt e.g. an alkoxide such as sodium ethoxide 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 performed 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; ether solvents such as diethyl ether, tetrahydrofuran or p-dioxane; and halogenated hydrocarbon solvents such as chloroform, methylene chloride or carbon tetrachloride. The aroylimidazol-2-one and the base are reacted for about 1 minute to about 24 hours depending on the reactants and the temperature, which may be from about -78 to about 15 ° C, preferably from about 11 ° C to about 2 ° C.

The aroyl chlorides or corresponding carboxylic acids required for the Friedel-Crafts acylation of the invention are either generally available in the art or can be prepared by analogous methods. The starting materials imidazolone-2-ones of formula 4 can be prepared as described by or adapted from 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 USP 2,441,933. The compounds of general formula I may be used in the treatment of cardiac defects including congested heart, outflow and outflow defects, left ventricular or right ventricular defects or for the treatment of any other condition. , which requires that cardiac activity be enhanced by a cardiotonic agent. In many respects, these compounds have digitalis-like effects. The compounds of the general formula I can also be used for the treatment of hypertension including primary or essential hypertension, hormonally induced hypertension, renal hypertension and chemically induced hypertension. Finally, the compounds of general formula I can be used as antithrombotic drugs. They affect blood coagulation by preventing platelet aggregation, which plays a dominant role in thrombotic conditions both in the initial stage and in the blocking stage. Arterial thrombosis, especially in the arteries, which feed the heart muscle and brain, is a major cause of death and incapacity.

The compounds can be administered in various ways 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, i.e. intravenously or intramuscularly. The amount of compound administered depends on the severity of the hypertension, the heart defect or blood aggregation and the method of administration. For oral administration, the antihypertensive effective amount of compound is from about 0.1 mg / kg (mg / kg) patient body weight per day to about 500 mg / kg patient body weight per day, and preferably from about 50 mg / kg patient body weight per day. day to about 150 mg / kg patient body weight per day.

For parenteral administration, the antihypertensively effective amount of the compound is from about 0.01 mg / kg patient body weight per day to about 150 mg / kg patient body weight per day and preferably from about 1.0 mg / kg patient body weight per day up to about 10.0 mg / kg patient body weight per day. For oral or parenteral administration, the cardiotone effective amount of the compound is from about 0.1 mg / kg patient body weight per day up to about 500 mg / kg patient body weight per day and preferably from about 0.1 mg / kg. patient body weight per day up to gira 10.0 mg / kg patient body weight per day. For oral or parenteral administration, the anticoagulant effective amount of the compound is from about 0.1 mg / kg patient body weight per day up to about 1000 mg / kg patient body weight per day and preferably from about 1 mg / kg patient body weight per day up to about 100 mg. mg / kg patient body weight per day.

For oral administration, a unit dose may be e.g. contain from e.g. 10 - 100 mg of the active ingredient.

For parenteral administration, a unit dose may contain e.g. from 5 to 50 mg of the active ingredient. Repeated daily administration of the compounds may be desirable and will vary with the condition of the patient and the mode of administration.

By the term patient is meant a warm-blooded animal, e.g. birds, such as chickens, turkeys, and mammals, such as primates, humans, sheep, horses, Bovidae cows and bulls, pigs, dogs, cats, rats, and mice.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, round tablets, powders, solutions, suspensions or emulsions. The unit dose for solid forms may be a capsule, which may be of the ordinary gelatin type, containing e.g. lubricants and inert fillers, such as lactose, sucrose and corn starch. In another embodiment, the compounds of general formula I can be made into tablets with common tablet bases such as lactose, sucrose and corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrants such as potato starch or alginic acid and a lubricant such as stearic acid or magnesium stearic acid.

For parenteral administration, the compounds may be administered as injectable doses of a solution or suspension of the compound in a physiologically acceptable excipient with a pharmaceutical carrier, which may be a sterile liquid such as water and oils with or without the addition of 464 559 12 a surfactant and other pharmaceutically acceptable excipients. Examples of oils that can be used in these preparations are petroleum oil, animal, vegetable oil or oil of synthetic origin, e.g. peanut oil, soybean oil and mineral oil. In general, water, common salt, aqueous dextrose and related 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 implanted preparation, which may be formulated to allow prolonged release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. In implants, inert materials can be used such as biodegradable polymers or synthetic silicones, e.g. "Silastic", silicone rubber manufactured by Dow-Corning Corporation.

The following are pharmaceutical formulations which can be used in accordance with the present invention: Preparation of a tablet formulation a) 1,3-dihydro-4- (4-methoxy-benzoyl) -5-methyl per tablet zn-imidazol-z-one 100 mg b) maize starch 15 mg c) lactose 3315 mg d) magnesium stearate 1.5 m9 Preparation of a parenteral formulation a) 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one 1,000 9 b) polyoxyethylene sorbitan monooleate 2,000 9 c) sodium chloride 01128 9 d) water for injection qs ad 20-ÛÛÛ ml Below are examples of the use of the compounds according to the invention as antihypertensive, cardiotone and anticoagulants. 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 substance was administered orally to six spontaneously hypertensive rats. This dose results, on average, in a 40% reduction in blood pressure within 15 minutes of administration.

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

Heart failure is induced in a dog by administering sodium pentobarbitol (20 mg / kg) or propranalol hydrochloride (3 mg / kg) to the blood flowing through the heart.

After administration of either of these cardiac depressants, the right arterial pressure increases dramatically, and the effect of the heart is significantly reduced. Administration of the title compound (1 mg / kg) reverses the error as indicated by the high arterial pressure and cardiac output returning to approximately pre-treatment levels.

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

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

The following specific examples describe the preparation of the compounds used in the present invention.

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

To a melt of 26 g (0.23 mol) of pyridine hydrochloride at 20 DEG-205 DEG C. is added 5.3 g (0.023 mol) of LB-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazole-2 -on, and the mixture- is stirred mechanically for 30 minutes. The reaction mixture is poured onto ice-2NHCl. The resulting precipitate is washed with water and recrystallized from isopropanol-water to give the title substance. Melting point greater than 3000 C.] V (max) (methanol) 320 nn (E. = 13,200). Exemgel 2 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one.

To 19.6 g of 3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene are added dropwise 34.2 g of p-methoxybenzoyl chloride, and the mixture is poured onto 500 ml of 2N- HCl and ice, washed three times with ethyl ether and the resulting solid is recrystallized from isopropanol and water to give the title substance, m.p. 257 DEG-258 DEG C. (dec.).

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

To 7.09,1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one in 100 ml of methanol is added 1.6 g of sodium methoxide. The mixture is heated on a steam bath until homogeneous. , after which it is filtered and evaporated to dryness. The solid residue is recrystallized from isopropanol to give the title substance. melting point 280 - 2a2 ° C (decomposition).

Example 4 4-Benzoyl-1,3-dihydro-5-methylimidazol-2-one.

To a solution of 3.0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene is added dropwise 4.6 g of benzyl chloride. The solution is heated at 80 ° C for 4 hours, poured over ice water, slurried with ether and the resulting solid is filtered and dried to give the title compound. melting point 250 - s4 ° c.

Example 5 1,3-Dlynaro-4-methyl-s-thienyl-2n-imiaazol-2-one.

To a solution of 7.3 g of 4-methylimidazol-2-one and (11,10 g of aluminum chloride in 150 ml of nitrobenzene) is added 12.0 g of 2-thienoyl chloride. The mixture is stirred at 60 ° C for 3 hours, cooling 464 559 The organic portion is extracted with ethyl acetate, dried and the organic solvent is evaporated to give the title compound Melting point 212 DEG-215 DEG C.

Example gel Q-1,3-dihydro-4- (2-fuyl-5-methyl-2H-imidazol-2-one.

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 is added 12.9 g of furanoyl chloride dropwise. The mixture is stirred at 600 DEG C. for 3 hours, cooled and poured over ice water. The solid is then filtered and recrystallized twice from methyl alcohol to give the title substance. Melting point 214 - 21 ° C.

Example 7 7,3-Dihydro-4- (2-thienoyl) -2H-imidazol-2-one.

In 50 ml of nitrobenzene are charged 13.3 g of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2-one and 8.1 g of thienoyl chloride.

The mixture is stirred at 60 ° C for 3 hours and poured over ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to give the title compound. melting point 339 - 42 ° C.

Example 8 4-Benzoyl-1,3-dihydro-2H-imidazol-2-one.

To 51 ml of nitrobenzene are added 1.68 g of 1,3-dihydro-2H-imidazol-2-one, 5.3 g of aluminum chloride and 3.1 g of benzoyl chloride.

The mixture is stirred for 3 hours at 60 DEG C. and poured into water.

The solid is filtered, washed with ether and recrystallized twice from methyl alcohol-water to give the title compound. Melting point 329 - 30 ° C.

Example Q 1,3-dihydro-4-furyl-2H-imidazol-2-one.

To 50 ml of nitrobenzene are added 4.2 g of 1,3-dihydro-2H-imidazol-2-one, 13.3 g of aluminum chloride and 7.2 g of furanoyl chloride. The mixture is stirred at 60 ° C for 3 hours and poured over ice water. The solid is filtered, washed with ether and recrystallized twice from ethanolic water to give the title compound. Melting point 318 DEG-321 DEG C. 464 559 16 Example 10 1,3-dihydro-4- (4-methoxybenzoyl) -1,3,5-trimethyl-2H-imidazol-2-one.

In 120 ml of DMSO are charged 15.2 g of powdered potassium hydroxide, 8.0 g, 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 recrystallized from ether. Melting point 109 DEG-111 DEG.

NMR: N-CH 3 (6 protons) at 3.3 ppm.

Example 11 1,3-Dihydro- (1- or 3) -5-dimethyl-4- (4-methoxybenzoyl) -2H-imidazol-2-one.

To 2.0 g of 1,3-dihydro-4- (4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one in 30 ml of DMSO are added 0.288 g of sodium hydride and 1.22 g of methyl iodide. The mixture is stirred at 22 ° C for 30 minutes, poured into methylene chloride and washed with water. The solvent is dried and evaporated to give an oil which, when triturated in chloroform, gives a solid. The solid is crystallized from methanol: mp 225 - 228 ° C.

Analysis calculated for C 12 H 14 N 2 O 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.

Claims (1)

Patented pharmaceutical composition with antihypertensive. cardiotonic and antithrombotic action, characterized in that it contains a compound of the formula wherein Ar represents 2-furyl, 2-thienyl, phenyl, phenyl monosubstituted in ortho-. the meta or para position with X1, where X1 represents hydroxy or methoxy, or disubstituted phenyl substituted in the para position with X2 and in the ortho or meta position with X3. where X 2 and X 3 represent hydroxy or methyl, where R represents hydrogen, a straight or branched lower alkyl group having 1 to 4 carbon atoms. a straight or branched lower alkyl carbonyl group having 1 to 4 carbon atoms or a benzoyl group, where R represents hydrogen or a straight or branched lower alkyl group 1 having 1 to 4 carbon atoms. or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.