IE53188B1 - 4-piperidinomethyl-1,3-dihydro-2h-imidazole-2-ones - Google Patents

Abstract

A compound of the formula wherein R is hydrogen, C1-4 alkyl, C2-4 alkanoyl or benzoyl; R<1> is hydroxy, C1-4 alkoxy, amino, substituted amino selected from C1-4 alkylamino, di(C1-4alkyl)amino phenylamino, (methylphenyl)amino, (d;methylphenyl)amino and (methoxyphenyl)-amino, C1-4 alkyl, phenyl, substituted phenyl selected from halophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl, dimethoxyphenyl and 3,4- methylenedioxyphenyl, 2 furyl, 2- thienyl or pyridyl; R<2> is hydrogen or C1-4 alkyl; X is hydrogen, halogen, methyl, methoxy or trifluoromethyl; and either Y is hydrogen, hydroxy, cyano, acetyl or (C1-4 alkoxy)carbonyl and Y<1> is hydrogen, or Y and Y<1> together form the second of a carbon- carbon double bond; or a pharmaceutically acceptable acid addition salt thereof. These compounds can have therapeutic utility.

Description

The present invention relates to novel derivatives of imidazole. The novel compounds have the formula wherein R is hydrogen, alkyl, c2-4 alkanoyl or benzoyl; R1 is hydroxy, C^_4 alkoxy, amino, substituted amino selected from Cj__4 alkylamino, di (C^^alkyl)amino, phenylamino, (methylphenyl)amino, (dimethylphenyl) amino and (methoxyphenyl Jamino, cy_4 alkyl, phenyl, substituted phenyl selected from halophenyl,· methylphenyl, methoxyphenyl, methylsulfon10 ylphenyl, dimethylaminophenyl, dimethoxyphenyl and 3,4-meth2 ylenedioxyphenyl, 2-furyl, 2-thienyl or pyridyl; R is hydrogen or Cj_4 alkyl; X is hydrogen, halogen, methyl, methoxy or trifluoromethyl; and either X is hydrogen, hydroxy, cyano, acetyl or (C^4 alkoxy)carbonyl and X1 is hydrogen, or X and X3, together form the second of a carbon-carbon double bond; and include the pharmaceutically acceptable acid addition salts thereof.

Examples of alkyl are methyl, ethyl, propyl, isopropyl and butyl. Examples of cj-4 alkanoyl are acetyl, propionyl and butyryl. Examples of alkoxy are methoxy, ethoxy and propoxy. Examples of halophenyl are fluorophenyl, chlorophenyl and bromophenyl. Examples of halogen are fluorine, chlorine and bromine.

Illustrative pharmaceutically acceptable add addition salts of the compounds of the present invention are salts with inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric or phosphoric acid; with organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, sialic, tartaric, citric, ascorbic, maleic, hydroxymaieic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic or mandelic acid; and with organic sulfonic acids such as methanesulfonic or £-toluenesulfonic acid.

Where R is hydrogen in the compounds of the present invention, several tautomeric forms of the compounds are possible. These form pharmaceutically acceptable salts with a pharmaceutically acceptable alkali metal such as sodium or potassium. Throughout this specification, the various compounds of the invention shall be taken to mean any of the tautomers or tautomer salts.

In general, the term 2-oxo-lH-imidazole may be taken herein to refer to those compounds of the invention, a first preferred group, in which R3 is hydroxy, C1-4 alkoxy, amino or substituted amino as defined above. Again in general,the term imidazol-2-one may be taken to refer to those compounds of the invention, a second preferred group, in which R1 is Cj_4 alkyl, phenyl, substituted phenyl as defined above, 2-furyl, 2-thienyl or pyridyl.

It is preferred that R and R are each hydrogen. It is also preferred that X, Y and Y3 are each hydrogen.

Examples of the first group of compounds defined above are the following: -[[4-(4-chlorophenyl)-1-piperidinyl]-methyl]-2,3-dihydro-2-oxo-lH-imidazole-4-carboxamide.

N-Ethyl-5-([4-(2-methylphenyl)-1-piperidinyl]methyl]2.3- dihydro-2-oxo-lH-imidazole-4-carboxamide.

Ethyl 5-[[4-(4-fluorophenyl)-1-piperidinyl]methyl]3o 2,3- dihydro-2-oxo-lH-imidazole-4-carboxylate.

Ethyl 5-[(4-(2-bromophenyl)-l-piperidinyl]methyl]2.3- dihydro-2-oxo-lH-imidazole-4-carboxylate. -((4-(2-Methylpheny1)-1-piper idinyl]methyl]-2,3dihydro-N-phenyl-2-oxo-l£-imidazole-4-carboxamide. -((4-Phenyl-4-methoxycarbonyl-l-piperidinyl)methyl]-N(4-wethylphenyl)-2,3-dihydro-2-oxo-lH-imidazole-4-carboxamide.

Ethyl 2,3-dihydro-5-[1-(4-(2-methylphenyl)-1-piper idinyl]ethyl]-2-oxo-lH-imidazole-4-carboxylate.

Ethyl 2,3-dihydro-5-[(4-phenyl-l,2,3,6-tettahydro1-pyridinyl)methyl]-2-oxo-lH-imidazole-4-carboxylate.

Ethyl 5-((4-hydroxy-4-phenyl-l-piperidinyl)methyl]2,3-d ihydro-2-oxo-lH-imidazole-4-carboxylate.

Methyl l,3-dipropionyl-2,3-dihydro-5-[[4-(4-chlorophenyl) -1-piperidinyljmethyl]-2-oxo-lH-imidazole-4-carboxylate.

Ethyl l,3-dibenzoyl-2,3-dihydro-5-[[4-(4-chloropheny1)-1-p iper idinyl]me thyl]-2-oxo-lH-imidazole-4-carboxylate.

Ethyl 2,3-dihydro-l,3-diethy1-5-((4-(4-chlorophenyl) -1-piperidinyl]methyl]-2-oxo-lH-imidazole-4-carboxy15 late.

- Examples of the second group of compounds defined above are the followings 4- Benzoyl-5-[[4-(4-chlorophenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-one. 4-Propionyl-5-[[4-(2-methylphenyl)-1-piperidinyl]methyl]-1,3-dihydro-2H-imidazol-2-one. - ((4-(4-Fluorophenyl)-1-piper idinyl]methyl]-1,3dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one. -[(4-(2-Bromophenyl)-l-piperidinyl]methyl]-1,325 dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one. 4-(3-Pyridylcarbonyl)-5-[(4-(2-methylphenyl)-1-piper idinyl]methyl]-1,3-dihydro-2H-imidazol-2-one. 4- [(4-Phenyl-4-methoxycarbonyl-l-piperidinyl)methyl]5-(4-fluorobenzoyl)-1,3-d ihydro-2H-imidazol-2-one. l,3-DihydrO-4-(4-methoxybenzoyl)-5-[l-[4-(2-methylphenyl)-1-piperidinyl]ethyl]-2H-imidazol-2-one. 1,3-Dihydro-5-(4-methoxybenzoyl)-4-((4-phenyl-l,2,3,6tetrahydro-l-pyridinyl)methyl]-2H-imidazol-2-one. - (4-Methoxyben2oyl)-4-((4-hydroxy-4-phenyl-l-piperi35 dinyl)methyl]-l,3-dihydro-2H-imidazol-2-one. 1.3- Dipropionyl-l,3-dihydro-4-(4-methoxybenzoyl)-5[[4-(4-chlorophenyl)-1-piperidinyljmethyl]-2H-imidazol-2one. 1.3- Dibenzoyl-l,3-dihydro-4-(4-methoxybenzoyl)-55 [[4- (4-chlorophenyl) -l-piperidinyl]methyl]-2H-imidazol-2one. 1.3- Dihydro-l,3-diethy1-4-(4-methoxybenzoyl)-5-((4(4-chlorophenyl)-1-piper idinyl]methyl ] -2H-imidazol-2-one.

Compounds of the invention may be prepared by a process 10 involving bromination of a 1,3-diacetyl imidazolone such as a compound of the formula R2 , 1! ι Ri-C CHZ 7=\ N ,N CH3COz Xrf'' COCH3 0 wherein Z is hydrogen, to give the corresponding compound wherein Z is Br. The reaction is carried out using N-bromosuccinimide in the presence of a free radical initiator such as benzoyl peroxide, in an appropriate solvent such as carbon tetrachloride.

The specific diacetyl starting materials are obtained from the corresponding 1,3-unsubstituted imidazolones by 10acetylation with acetyl chloride or acetic anhydride. When Η3- is alkoxy, the starting ester is obtained by the procedure described by Duschinsky and Dolan, J. Am. Chem. Soc., 68, 2350 (1946). When R3 contains an amino group, the imidazole-4-carboxamide is obtained from the appropriate 15 N-substituted 2-hydroxyimino-3-oxobutanamide which is reduced to the corresponding 2-amino compound, either catalytically or chemically, depending on the amide involved. The resulting 2-amino compound is then reacted with potassium cyanate to produce the imidazolecarboxamide. When is alkyl, phenyl, substituted phenyl, furyl, thienyl or pyridyl, the unsubstituted imidazolones used may be prepared as described in Belgian Patent Specification No. 883,856 or by the general procedures described in that specification.

The bromo compounds obtained above can be treated with hydrobromic acid in acetic acid to remove one or both of the N-acetyl groups. The resulting imidazolone is then treated with the appropriate amine to give the desired compound of the present invention. The appropriate amine 3188 Is a compound of the formula γΐ wherein X, Y and Y1 are as defined above.

Although the present process has been described using 1,3-unsubstituted imidazolones, it is also possible to use the corresponding 1,3-diacetyl compounds or similarly substituted compounds but, when such compounds are used, the amine will also react with the acyl group to give the deacetylated imidazolone and an N-acyl amine. It is thus necessary to use an excess of the amine to allow for this reaction, and this is therefore not a desirable process when the amine is not readily available and inexpensive.

The compounds in which R represents C2_4 alkanoyl or benzoyl are obtained by reaction of the compounds in which R represents hydrogen with an excess of the appropriate acid anhydride or acid chloride.

The following Examples illustrate the preparation of compounds of the invention. The Preparations relate to starting materials.

PREPARATION 1 A solution of 15.8 g of N,N-dimethyl-2-(hydroxyimino)-3-oxobutanamide in 400 ml of ethanol and 100 ml of 2N hydrochloric acid is hydrogenated over 2 g of 5% palladium on charcoal catalyst in a Parr shaker until one molar equivalent of hydrogen is taken up (3-5 hours). The reaction mixture is then filtered to remove the catalyst and a solution of 16.2 g of potassium cyanate in 80 ml of water is added. The resulting solution is refluxed for 1 hour and then concentrated until solid crystallizes. The solid is separated by filtration and recrystallized from 50% aqueous ethanol to give 2,3-dihydro-N,N,5-trimethyl-2oxo-lH-imidazole-4-carboxamide melting above 300°C.

If the above procedures is repeated using the appropriate substituted 2-(hydroxyimino)-3-oxobutanamide, the following compounds are obtained: 2.3- Dihydro-N,5-dimethyl-2-oxo-lH-imidazole-4-carboxamide melting above 300°C. 2.3- Dihydro-5-methyl-2-oxo-lH-imidazole-4-carboxamide melting above 300°C.

N-(tert-Butyl,-2,3-dihydro-5-methyl-2-oxo-lH-imidazole-4-carboxamide. 2.3- Dihydro-5-ethyl-N,N-dimethyl-2-oxo-lH-imidazole4-carboxamide.

PREPARATION 2 To a stirred solution of 11.8 g of 2-(hydroxyimino)N-(4-methoxyphenyl)-3-oxobutanamide in 30 ml of acetic acid and 10 ml of acetic anhydride at 20-30°Caxe added 10 g of zinc dust,and the mixture is stirred for 1 hour.

Water (150 ml) is added, the mixture is stirred for 2 hours, and the zinc is removed by filtration. The solvent is evaporated from the filtrate under reduced pressure and the resulting residue is reerystallized from methanol to give 2-acetylamino-N-(4-methoxyphenyl)-3-oxobutanamide.

The product obtained in the preceding paragraph (10.6 g) is dissolved in' 20 ml of 6N hydrochloric acid and the solution is allowed to stand at room temperature for 5 minutes. A solution of 9.7 g of potassium cyanate in 80 ml of water is added and the mixture is stirred at room temperature for 16 hours. The precipitate which forms is separated by filtration and reerystallized twice from 50% aqueous ethanol to give 2,3-dihydro-N-(4-methoxyphenyl)-5methyl-2-oxo-lH-imidazole-4-carboxamide melting at about 299-301°C (dec.).

If the above procedure is repeated using the appro35 priate N-substituted 2-(hydroxyimino)-3-oxobutanamide, the following compounds are obtained: 2.3- Dihydro-5-methyl-2-oxo-N-phenyl-lH-imida2ole4-carboxamide. 2.3- Dihydro-5-methyl-N-(2,4-dimethylphenyl)-2-oxo-lHimidazole-4-carboxamide. 2.3- Dihydro-5-ethyl-2-oxo-N-phenyl-lH-imidazole-4carboxamide.

PREPARATION 3 A mixture of 54.5 g of ethyl 2,3-dihydro-5-methyl2-oxo-lH-imidazole-4-carboxylate and 240 ml of acetic anhydride is refluxed for 13 hours. The mixture is distilled to remove 150 ml of acetic anhydride and acetic acid this is replaced by fresh acetic anhydride and refluxing is resumed. After a total of 22 hours of reflux, excess acetic anhydride is evaporated under reduced pressure and the resulting residue is triturated with cyclohexane and then recrystallized from cyclohexane to give ethyl l,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-lH-imidazole-4-carboxylate melting at about 56-58°C.

If the above procedure is repeated using acetic anhydride and the appropriate substituted 2,3-dihydro-2-oxolH-imidazole-4-carboxylic acid-derivative, the following compounds are obtained: 1.3- Diacetyl-2,3-dihydro-N,N,5-trimethyl-2-oxo-lH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-N,5-dimethyl-2-oxo-lH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-5-methyl-2-oxo-lH-imidazole4-carboxamide. 1.3- Diacetyl-N-(tert-butyl)-2,3-d ihydr o-5-methyl-2oxo-lH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-5-ethyl-N,N-dimethyl-2-oxolH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-N-(4-methoxyphenyl)-5-methyl-2oxo-lH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-5-methyl-2-oxo-N-phenyllE-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-5-methyl-N-(2,4-dimethylphenyl )-2-oxo-lH-imidazole-4-carboxamide. 1.3- Diacetyl-2,3-dihydro-5-ethyl-2-oxo-N-phenyl-lHimidazole-4-carboxamide.

PREBARATION 4 A mixture of 12.7 g (0.050 mole) of ethyl 1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-lH-imidazole-4-carboxylate, 9.3 g (0.052 mole) of N-bromosuccinimide and about 100 mg of benzoyl peroxide in 400 ml of carbon tetrachloride is stirred at reflux temperature for 4 hours.

The mixture is then cooled and filtered to remove the succinimide which formed. The solvent is evaporated from the filtrate to give 5-(bromomethyl)-1,3-diacetyl-2,3-di10 hydro-2-oxo-lH-imidazole-4-carboxylate as an oil.

If the above procedure is repeated using N-bromosuccinimide and the appropriate substituted l,3-diacetyl-2,3dihydro-2-oxo-lH-imidazole-4-carboxylic acid derivative, the following compounds are obtained: -(Bromomethyl)-l,3-diacetyl-2,3-dihydro-N,N-dimethyl-2-oxo-lH-imidazole-4-carboxamide.

- (B romome thy1)-1,3-d iace ty1-2,3-d ihydro-N-me thy1-2oxo-lH-imidazole-4-carboxamide.

-(Bromomethyl)-l,3-diacetyl-2,3-dihydro-2-oxo-lH-imi 20 dazole-4-carboxamide.

-(Bromomethyl)-N-(tert-butyl)-1,3-diacetyl-2,3-dihydro-2-oxo-lH-imidazole-4-carboxamide. -(l-Bromoethyl)-2,3-dihydro-l,3-diacetyl-N,N-dimethyl-2-oxo-lH-imidazole-4-carboxamide.

-(Bromomethyl)-l,3-diacetyl-2,3-dihydro-N-(4-methoxy phenyl)-2-oxo-lB-imidazole-4-carboxamide.

-(Bromomethyl)-l,3-diacetyl-2,3-dihydro-2-oxo-Nphenyl-lH-imidazole-4-carboxamide.

-(Bromomethyl)-1,3-diacetyl-2,3-dihydro-N-(2,4-di30 methylphenyl)-2-oxo-lH-imidazole-4-carboxamide. -(1-Bromoethyl)-l,3-diacetyl-2,3-dihydro-2-oxo-Nphenyl-lH-imidazole-4-carboxamide.

Ethyl 5-(bromomethyl)-2,3-dihydro-l,3-dimethyl-2-oxolH-imidazole-4-carboxylate.

PREPARATION 5 Crude ethyl 5-(bromometnyl)-l,3-diacetyl-2,3-dihydro-2-oxo-lH-imida2ole-4-carboxylate is dissolved in 30% hydrobromic acid in acetic acid and the solution is allowed to stand at room temperature for 4 hours. The solid which precipitates is separated by filtration and dried in vacuo at 80°C over potassium hydroxide to give ethyl 3acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-lH-imidazole-4carboxylate melting at about 193-194°C (dec.).

If the above procedure is repeated using the appropriate substituted l,3-diacetyl-2,3-dihydro-2-oxo-lH-imidazole-4-carboxylie acid derivative, the following compounds are obtained: -(Bromomethyl)-2,3-dihydro-N,N-dimethyl-2-oxo-lH-imidazole-4-carboxamide.

-(Bromomethyl)-2,3-dihydro-N-methyl-2-oxo-lH-imidazole-4-carboxamide.

-(Bromomethyl)-2,3-dihydro-2-oxo-lH-imidazole-4carboxamide.

-(Bromomethyl)-N-(tert-butyl)-2,3-dihydro-2-oxolH-imidazole-4-carboxamide. -(1-Bromoethyl)-2,3-dihydro-N,N-dimethyl-2-oxolH-imidazole-4-carboxamide.

-(Bromomethyl)-2,3-dihydro-N-(4-methoxyphenyl)-2oxo-lH-imidazole-4-carboxamide.

-(Bromomethyl)-2,3-dihydro-2-oxo-N-phenyl-lH-imidazole-4-carboxamide.

-(Bromomethyl)-2,3-dihydro-N-(2,4-dimethylphenyl)2oxo-lH-imidazole-4-carboxamide. -(1-Bromoethyl)-2,3-dihydro-2-oxo-N-phenyl-lH-imidazole-4-carboxamide.

EXAMPLE 1 A mixture of 4.4 g (15 mmole) of ethyl 3-acetyl-5(bromomethyl)-2,3-dihydro-2-oxo-lH-imidazole-4-carboxylate 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25°C for 16 hours. Water (100 ml) is added and a precipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added.

The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give ethyl 2,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]2-oxo-lH-imidazole-4-carboxylate hydrochloride melting at about 240-241°C.

If the procedure of Example l is repeated using 45 phenylpiperidine and the appropriate 5-{bromoraethyl)-2,3dihydro-2-oxo-lH-imidazole-4-carboxylic acid derivative of Preparation 4 or 5, the following compounds are obtained: 2.3- Dihydro-5-((4-phenyl-l-piperidinyl)methyl]-2-oxo10 lH-iraidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N-methyl-5-1 (4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N,N-dimethyl-5-[(4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4-carboxamide hydrochloride.

N-(tert-Butyl)-2,3-dihydr0-5-[(4-phenyl-l-piper idinyl)methyl]-2-oxo-lH-imidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N,N-dimethy1-5-[1-(4-phenyl-l-piperidinyl)ethyl]-2-oxo-lH-imidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N-(4-methoxyphenyl)-5-[(4-phenyl-l-piperi2o dinyl)methyl]-2-Oxo-lH-imidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N-phenyl-5-[ (4-phenyl-l-piperidinyl)methyll-2-oxo-lH-imidazole-4-carboxamide hydrochloride. 2.3- Dihydro-N-(4-methylphenyl)-5-[(4-phenyl-l-piperi25 dinyl)methyl]-2-oxo-lH-imidazole-4-carboxaroide hydrochloride. 2.3- Dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-N(2,4-dimethylphenyl)-2-oxo-lH-imidazole-4-carboxamide hydrochloride. 2,3-Dihydro-N-phenyl-5- [l-(4-phenyl-l-piperidinyl)ethyl]-2-oxo-lH-imidazole-4-carboxamide hydrochloride.

Ethyl 2,3-dihydro-l,3-dimethyl-5-((4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4-carboxylate hydrochloride.

EXAMPLE 2 A mixture of 4.1 g (14.2 mmole) of ethyl 3-acetyl-5(bromomethyl)-2,3-dihydro-2-oxo-lH-imidazole-4-carboxy53188 late, 3.0 g (14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25°C. Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated and reerystailized twice from a mixture of 2-propanol and water to give ethyl 5-([4-(4-chlorophenyl)-4-bydroxy-l-piper idinyl]methyl)-2,3-dihydro-2-oxo-lH-imidazole4-carboxylate hydrochloride.

If the procedure of Example 2 is repeated using ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-lH-imidazole-4carboxylate and the appropriate 4-substituted piperidine, the following compounds are obtained: Ethyl 2,3-dihydro-5-[(4-phenyl-l,2,3,6-tetrahydro1-pyridinyl)methyl]-2-oxo-lH-imidazole-4-carboxylate hydrochloride .

Ethyl 5-((4-(4-chlorophenyl)-1,2,3,6-tetrahydro-lpyridinyl]methyl]-2,3-dihydro-2-ox0-lR-imida2ole-4-carboxylate hydrochloride.

Ethyl 5-((4-acetyl-4-phenyl-l-piperidinyl)methyl]2,'3-dihydro-2-oxo-lH-imidazole-4-carboxylate hydrochloride.

Ethyl 5-{(4-cyano-4-phenyl-l-piperidinyl)methyl]-2,3dihydro-2-oxo-lH-imidazole-4-carboxylate hydrochlor ide.

Ethyl 5-((4-ethoxycarbonyl-4-phenyl-l-piperidinyl)methyl]-2,3-dihydro-2-oxo-lH-imidazole-4-carboxylate hydrochloride.

Ethyl 5-[[4-ethoxycarbonyl-4-(4-chlorophenyl)-1piperidinyl]methyl]-2,3-dihydro-2-oxo-lH-imidazole-4carboxylate hydrochloride.

Ethyl 5-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]methyl]-2,3-dihydro-2-oxo-lH-imidazole-4-carboxylate hydrochloride.

Ethyl 5-[[4-hydroxy-4-(3-trifluoromethylphenyl)-lpiperidinyl]methyl]-2,3-dihydro-2-oxo-lH-imidazole-4carboxylate hydrochloride.

EXAMPLE 3 Ethyl 2,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4-carboxylate hydrochloride is converted to the free base by standard procedures and then treated with a large excess of refluxing acetic, anhydride for 4 hours. Excess acetic anhydride is evaporated under reduced pressure and the resultant residue is recrystallized twice from a mixture of ethyl acetate and ethanol to give ethyl l,3-diacetyl-2,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4-carboxylate.

PREPARATION- 6 35 The sodium salt of ethyl 2,3-dihydro-5-methyl-2-oxolH-imidazole-4-carboxylate is prepared from 4.9 g of ethyl 2,3-dihydro-5-methyl-2-oxo-lH-imidazole-4-carboxylate in 100 ml of methanol with the addition of 1.6 g of sodium methoxide. A mixture is prepared from 8.0 g of this so20 dium salt, 120 ml of dimethyl sulfoxide and 19.5 g of methyl iodide. This mixture is stirred at room temperature for 60 minutes and then poured into 800 ml of water. The resulting mixture is then extracted with methylene chloride and the solvent is evaporated from the extract to give ethyl 2,3-dihydro-l,3,5-trimethyl-2-oxo-lH-imidazole4-carboxylate.

PREPARATION 7 To a stirred mixture of 98.1 g (1 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 moles) of anhydrous aluninium chloride and 500 ml of nitrobenzene there is added dropwise over 10 minutes, 158.6 g (1 mole) of g-fluorobenzoyl chloride. The mixture is stirred at 60-65°C for 6 hours, then poured onto 2 kg of ice. The precipitate which forms is separated by filtration, washed with diethyl ether and water and recrystallized from dimethylformamide to give l,3-dihydro-4-(4-fluoroben10 zoyl)-5-methyl-2H-imidazol-2-one melting at about 289292°C.

If the above procedure is repeated using 1,3-dihydro4-methyl-2H-imidazol-2-one and the appropriate acid chloride, the following compounds are obtained: l,3-Dihydro-4-methyl-5-[4-(methylsulfonyl)benzoyl] -2Himidazol-2-one. 1.3- Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imida2ol-2-one melting at about 257-258°C (dec.) after recrystallization from isopropanol-water. 4-Benzoyl-l,3-dihydro-5-methylimidazol-2-one melting 5 at about 250-254°C. 1.3- Dihydro-4-methyl-5-(2-thiophenecarbonyl)-2Himidazol-2-one melting at about 212-215°C. In this case, the material obtained after pouring the mixture onto icewater is extracted into ethyl acetate and the ethyl ace10 tate solution is dried and the solvent is evaporated. 1.3- Dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2Himidazol-2-one melting at about 257-259°C after recrystallization twice from ethanol-water. 1.3- Dihydr0-4-(2-furoyl)-5-methyl-2H-imidazol-2-one 15 melting at about 214-216°C after recrystallization twice from methanol. 1.3- Dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl2H-imidazol-2-one melting at about 293-296°C (dec). 1.3- Dihydro-5-ethyl-4-(4-methoxybenzoyl)-2H-imida20 zol-2-one melting at about 132°C (dec). 1.3- Dihydro-5-methyl-4-(4-pyr id inecarbonyl)-2H-imidazol-2-one melting at about 296°C (dec). 4-Acetyl-l,3-dihyro-5-methylimidazol-2-one melting at about 314-316°C.

PREPARATION 6 The sodium salt of 1,3-dihydro-4-(4-methoxybenzoyl)5-methyl-2H-imidazol-2-one is prepared from 7.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 100 ml of methanol with the addition of 1.6 g of sodium methoxide. A mixture is prepared from 8.0 g of this sodium salt, 120 ml of dimethyljsulfoxide, 15.2 g of powdered sodium hydroxide, and 19.5 g of methyl iodide. This mixture is stirred at room temperature for 60 minutes and then poured into 800 ml of water. The resulting mixture is then extracted with methylene chloride and the solvent is evaporated from the extract to give a solid. This is crystallized from ether to give l,3-dihydro-4-(4-methoxyben2oyl)-l,3,5-trimethyl-2H-imidazol-2-one melting at about 109-lll°C.

PREPARATION 9 To 2.0 g of l,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of dimethyl sulfoxide is added 0.29 g of sodium hydride and 1.22 g of methyl iodide. The mixture is stirred at 22°C for 30 minutes, poured in methylene chloride, and washed with water. The methylene chloride solution is dried and the solvent is evaporated to leave an oil which is triturated with chloroform to give a solid. This solid is recrystallized from methanol to give 1,3-dihydro-(1 or 3),5-dimethyl-4-(4methoxybenzoyl)-2H-imidazol-2-one melting at about 22515 228°C.

PREPARATION 10 A mixture of 46.4 g of l,3-dihydro-4-(4-methoxybenzoyl) -5-methyl-2H-imidazol-2-one and 200 ml of acetic ,20 anhydride is refluxed for 2 hours. The mixture is distilled to remove 100 ml of acetic anhydride and acetic acid; this is replaced by fresh acetic anhydride and refluxing is resumed. After a total of 4 hours of reflux, excess acetic anhydride is evaporated under reduced pressure and the resulting residue is crystallized from ethanol to give 1,3-diacetyl-l,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2Himidazol-2-one melting at about 123-125°C.

If the above procedure is repeated using acetic anhydride and the appropriate substituted 1,3-dihydro-2H30 imidazol-2-one, the following compounds are obtained: 4-Benzoyl-l,3-diacetyl-1,3-dihydro-5-methyl-2H-imidazol-2-one melting at about 120-122°C. 1.3- Diacetyl-l,3-dihydro-4 - (4-fluorobenzoyl)-5methyl-2H-imidazol-2-one melting at about 102-103°C. 1,3-Diacetyl-l,3-dihydro-4-(4-dimethylaminobenzoyl)5-methyl-2H-imidazol-2-one melting at about 183-184°C. 1.3- Dihydro-l,3,4-triacetyl-5-methyl-2H-imidazol-2-one melting at about 73-75°C. 1.3- Diacetyl-l,3-dihydro-4-(3,4-dimethoxybenzoyl)5-methyl-2H-imidazol-2-one. 1.3- Diacetyl-J,3-dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-one. l,3-Diacetyl-l,3-dihydro-4-(4-methylsulfonylbenzoyl)5-methyl-2H-imidazol-2-one. 1.3- Diacetyl-l,3-dihydro-4-(2-furoyl)-5-methyl-2Himidazol-2-one. 1.3- Diacetyl-l,3-dihydro-4-(2-thiophenecarbonyl)10 5-methyl-2H-imidazol-2-one. 1.3- Diacetyl-l,3-dihydro-5-methyl-4-(4-pyridinecarbony1)-2H-imidazol-2-one. 1.3- Diacetyl-l,3-dihydro-5-ethyl-4-(4-methoxybenzoyl)2H-imidazol-2-one.

PREPARATION 11 A mixture of 55.5 g (0.176 mole) of 1,3-diacetyl-l,3dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one, 37.4 g (0.210 mole) of N-bromosuccinimide and about 100 mg of benzoyl peroxide in 500 ml of carbon tetrachloride is stirred at reflux temperature for 4 hours. The mixture is then cooled and filtered to remove the succinimide which formed. The solvent is evaporated from the filtrate and the resulting residue is crystallized from a mixture of 300 ml of ethyl acetate and 300 ml of hexane to give 525 (bromomethyl)-1,3-diacetyl-l,3-dihydro-4-(4-methoxybenzoyl) -2H-imidazol-2-one melting at about 135-136°C.

If the above procedure is repeated using N-bromosuccinimide and the appropriate substituted 1,3-diacetyll,3-dihydro-2H-imidazol-2-one, the following compounds are obtained: -(Bromomethyl)-1,3-diacetyl-l,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-one melting at about 113-120°C.

-(Bromomethyl)-1,3-dihydro-l,3,4-triacetyl-2H-imidazol-2-one melting at about 88-90°C. 4-Benzoyl-5-(bromomethyl)-1,3-diacetyl-l,3-dihydro-2Hiwidazol-2-one.

- (Bromomethyl )-1,3-diacetyl-l, 3-dihydro-4 - (3,4-dime thoxybenzoy1)-2H-imidazol-2-one.

-(Bromomethy1)-1,3-diacetyl-1,3-dihydro-4- (3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

-{Bromomethyl)-1,3-diacetyl-l,3-dihydro-4- (4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

-(Bromomethyl)-1,3-diacetyl-l,3-dihydro-4-(4-dimethylaminobenzoyl)-2H-imidazol-2-one.

-(Bromomethyl)-1,3-diacetyl-l,3-dihydro-4-(2-furoyl)2H-imidazol-2-one.

-(Bromomethyl)-l,3-diacetyl-l,3-dihydro-4-(2-thiophenecarbonyl )-2H-imidazol-2-one.

-(Bromomethyl)-1,3-diacetyl-l,3-dihydro-4-(4-pyridinecarbonyl) -2H-imidazol-2-one. -(1-Bromoethyl)-1,3-diacetyl-l, 3-d ihydr0-4-(4-methoxybenzoyl )-2H-imidazol-2-one.

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

-(Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-(1 or 3)-methyl-2H-imidazol-2-one.

PREPARATION 12 A mixture of 50 g of 5-(bromomethyl)-1,3-diacetyl1,3- dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one in 75 ml of 30% hydrobromic acid in acetic acid and 150 ml of acetic acid is heated to 80°C on a steam bath and allowed to stand for 2 hours. The mixture is then evaporated to dryness under reduced pressure and the residue is crystallized from acetic acid and then dried in vacuo at 80°C over potassium hydroxide. This gives 5-(bromomethyl)-1,3dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about 205-207°C with decomposition.

If the above procedure is repeated using the appropriate 5-(bromomethyl)-1,3-diacetyl-l, 3-dihydro-2H-imidazol-2-one, the,following products are obtained: -(Bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2Himidazol-2-one melting at greater than 300°C with decomposition. 4-Benzoyl-5-(bromomethyl)-l,3-dihydro-2B-imidazol-2one.

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

-(Bromomethyl)-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

-(Bromomethyl)-1,3-d ihydro-4-{4-methylsulfonylbenzoy1) 2H-imidazol-2-one.

-(Bromomethyl)-1,3-dihydro-4-(4-dimethylaminobenzoyl)2H-imidazol-2-one.

-(Bromomethyl)-1,3-dihydro-4-(2-furoyl)-2H-imidazol10 2-one.

-(Bromomethyl)-l,3-dihydro-4-(2-thiophenecarbonyl)2H-imidazol-2-one. 4- Acetyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2one.

-(Bromomethyl)-1,3-dihydro-4-(4-pyridinecarbonyl)-2Himidazol-2-one. - (1-Bromoethyl)-l,3-dihydro-4-(4-methoxybenzoyl)-2Himidazol-2-one.

EXAMPLE 4 A mixture of 4.7 g (15 mmole) of 5-(bromomethyl)l,3-dihydro-4-(4-methoxybenzoyl)-2B-imidazol-2-one, 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25°C for 16 hours. Water (100 ml) is added and a pre25 cipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added.

The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give l,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-lpiperidinyljmethyl]-2H-imidazol-2-one hydrochloride melting at about 230°C with decomposition.

If the procedure of Example 4 is repeated using 4phenylpiperidine and the appropriate 4-substituted 535 (bromomethyl)-l,3-dihydro-2H-imidazol-2-one, the following compounds are obtained: 4-Benzoyl-l,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-2H-imida2ol-2-one hydrochloride. 1.3- Dihydro-4-(3,4-dimethoxybenzoyl)-5-((4-phenyll-piperidinyl ) methyl]-2H-imidazol-2-one hydrochlor ide. 1.3- Dihydro-4-(3,4-methylenedioxybenzoyl)-5-[(4phenyl-l-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride. 1.3- Dihydro-4- [4- (methylsulfonyl)bemoyl] -5- [ (4-phenyl1- piper idinyl) methyl] -2H-imidazol-2-one hydrochloride. 1.3- Dihydro-4-(4-methoxybenzoyl,-1,3-dimethyl-5[(4-phenyl-l-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride. 1.3- Dihydro-4-(2-furoyl)-5-[(4-phenyl-l-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride. 1.3- Dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-4(2-thiophenecarbonyl)-2H-imidazol-2-one hydrochloride. 4-Acetyl-l,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride. 1.3- Dihydro-5-[(4-phenyl-l-piperidinyl)methyl]-4(4-pyridinecarbonyl)-2H-imidazol-2-one hydrochloride. 1.3- Dihydro-4-(4-methoxybenzoyl)-5-(1-(4-phenyl-lpiper idinyl) ethyl] -2H-imidazol-2-one hydrochloride.

EXAMPLE 5 A mixture of 4.3 g (14.2 mmole) of 5-(bromomethyl)1,3-dihydr0-4-(4-fluorobenzoyl)-2H-imidazol-2-one, 3.0 g (14.2 mmole, of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25°c.

Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2- propanol and 1 equivalent of hydrogen chloride in 2propanol is added. The resulting solid is separated and recrystallized twice from a mixture of 2-propanol and water to give 4-[[4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl]methyl]-5-(4-fluoroben2oyl)-l,3-dihydro-2H-imidazol2-one hydrochloride melting at about 235-236°C with decomposition.

If the procedure of Example 5 is repeated using 5(bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol2-one and the appropriate 4-substituted piperidine, the following compounds are obtained: 5-(4-Fluorobenzoyl)-4-[(4-phenyl-l,2,3,6-tetrahydrοΙ -pyr idinyl)methyl]-1,3-dihydro-2H-imidazol-2-one hydrochloride. -(4-F1uorobenzoy1)-4-((4-(4-chlorophenyl)-1,2,3,6tetrahydro-l-pyridinyl]methyl]-l,3-dihydro-2H-imidazol-210 one hydrochloride. 4-[(4-Acetyl-4-phenyl-l-piperidinyl)methyl]-5-(4fluorobenzoyl)-l,3-dihydro-2H-imidazoI-2-one hydrochloride . 4-[(4-Cyano-4-phenyl-l-piperidinyl)methyl]-5-(4-fluoro15 benzoyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride. 4-[(4-Ethoxycarbonyl-4-phenyl-1-piperidinyl )methylJ 5-(4-fluoroben2oyl)-l,3-dihydro-2H-imidazol-2-one hydrochloride. 4- [[4-Ethoxyearbonyl-4-(4-chlorophenyl)-1-piperidinyl]20 methyl] -5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride. - (4-Fluorobenzoyl)-4-([4-hydroxy-4-(4-methylphenyl)1-piperidinyl]methyl]-l,3-dihydro-2H-imidazol-2-one hydrochloride. -(4-Fluorobenzoyl)-4-[[4-hydroxy-4-(3-trifluoromethylphenyl )-1-piper idinyl]methyl]-1,3-dihydro-2H-imidazol-2one hydrochloride.

EXAMPLE 6 1,3-Dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-l30 piperidinyl)methyl]-2H-imidazol-2-one hydrochloride is converted to the free base by standard procedures and then treated with a large excess of refluxing acetic anhydride for 4 hours. Excess acetic anhydride is evaporated under reduced pressure and the resultant residue is recrystal35 lized twice from a mixture of ethyl acetate and ethanol to give 1,3-diacetyl-l,3-dihydro-4-(4-methoxybenzoyl)-5[(4-phenyl-1-piperidinyl)methyl]-2H-imida2ol-2-one.

A pharmaceutical composition according to the present invention comprises a compound of the invention in association with a physiologically acceptable excipient.

Compounds of the present Invention can have utility in 5 the treatment of cardiac failure, including congestive heart failure, backward heart failure, forward heart failure, left or right ventricular heart failure, or in the treatment of any other condition which requires the strengthening of heart action with a cardiotonic. In many respects, these compounds possess digitalis-like action. The compounds of the present invention can also have utility in the treatment of hypertension, including primary or essential hypertension, hormonally-induced hypertension, renal hypertension and chemically-induced hypertension. The compounds of the present invention can additionally have utility as anti-thrombotics. They affect the coagulation of blood by preventing the aggregation of blood platelets, which play a dominant role in thrombotic conditions both in the initial event and at the occlusive stage. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death and disability.

Antihypertensive activity for the present compounds 5 was demonstrated using groups of 12 spontaneously hypertensive rats. Blood pressure was measured by a pressure cuff occluder around the base of the tails of the rats.

The blood pressure was determined in the animals, test compound was administered orally in a vehicle -at a dose of 50 mg/kg and blood pressure was measured again at 1, 2, 3, and 24 hours after administration of the test compound. The difference in blood pressure observed was analyzed to establish if it was statistically significant. The vehicle used in administering the test compound did not have a significant effect on blood pressure when used alone.

Cardiotonic activity for the present compounds was demonstrated by the following procedure. A Walton-Brodie strain gage arch was surgically implanted on the heart of anesthetized dogs to measure cardiac contractile force.

After the vital signs of the animal were stable for 10 minutes, test compound was administered intravenously starting at a dose of 0.3 mg/kg and continuing with higher doses of 1, 3 and 10 mg/kg if no effect is observed. Active compounds, such as compounds of the present inven25 tion, which increase cardiac contractile force measured in this way exert a true positive inotropic effect, or a cardiotonic effect.

Antithrombotic activity for the present compounds is demonstrated by the following procedure. When adenosine diphosphate is added to citrated platelet rich human plasma, a typical aggregation of blood platelets occurs. Antithrombotic activity is determined by adding a test compound to the citrated platelet rich human plasma in concentrations of 3, 10, 30 and 100 pg/ml and subsequently adding adenosine diphosphate and observing the extent of inhibition of aggregation of blood platelets.

The compounds may be administered in various manners to achieve the desired effect. The compounds may be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, that is, intravenously or intramuscularly. The amount of compound administered will vary with the severity of the hypertension, cardiac failure or blood clotting and the mode of administration. For oral administration the antihypertensively effective amount of compound is from about 0.1 mg/kg (milligrams per kilograms) of patient body weight per day to about 50 mg/kg of patient body weight per day and preferably from about 5 mg/kg of patient body weight per day to about 30 mg/kg of patient body weight per day.

For parenteral administration the antihypertensively effective amount of compound is from about 0.01 mg/kg of patient body weight per day up to about 50 mg/kg of patient body weight per day and preferably from about 0.1 mg/kg of patient body weight per day up to about 20.0 mg/kg of patient body weight per day. For oral or parenteral administration the cardiotonically effective amount of compound is from about 0.1 mg/kg of patient body weight per day up to about 50 mg/kg of patient body weight per day and preferably from about 0.1 mg/kg of patient body weight per day up to about 20.0 mg/kg of patient body weight per day. For oral or parenteral administration the anticoagulant effective amount of compound is from about 0.1 mg/kg of patient body weight per day up to about 100 mg/kg of patient body weight per day and preferably from about 0.1 mg/kg of patient body weight per day up to about 50 mg/kg of patient body weight per day.

For oral administration a unit dosage may contain, for example, from Ito 100 mg of the active ingredient.

For parenteral' administration a unit dosage may contain, for example, from 0.5 to 50 mg of the active ingredient. Repetitive daily administration of the compounds may be desired and will vary with the condition of the patient and the mode of administration.

As used herein the term patient is taken to mean a warm blooded animal, for example, birds, such as chickens and turkeys, and mammals, such as primates, humans, sheep, horses, bovine cows and bulls, pigs, dogs, cats, rats and mice.

For oral administration the compounds can be formu5 lated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The solid unit dosage forms can be a capsule which can be of the ordinary gelatin type containing, for example, lubricants and inert filler, such as lactose, sucrose and cornstarch. In another embodiment the compounds of the invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders, such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleum, ani25 mal, vegetable or synthetic origin, for example, peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol can be used as liquid carriers for injec30 table solutions. Particularly preferred are combinations of the above carriers such as aqueous ethanol or propylene glycol-aqueous ethanol at alkaline pH.

The compounds can be administered in the form of a depot injection or implant preparation which may be formu35 lated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or Implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, e.g. a silicone rubber such as Silastic (registered Trade Mark).

By way of illustration, a tablet formulation of the invention may comprise, per tablet, 100 mg of the active Ingredient, 15 mg of cornstarch, 33.5 mg of lactose and 1.5 mg of magnesium stearate. A parenteral formulation may comprise, for example, 100 mg of active ingredient, 25 mg of sodium hydroxide, 1.516 g of ethanol, 8.264 g of propylene glycol, and sufficient water for injection to a total volume of 20 ml. The active ingredient may be ethyl 2,3-dihydro5-[(4-phenyl-l-piperidinyl)methyl]-2-oxo-lH-imidazole-4carboxylate or l,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyll-piperidinyl)methyl]-2H-imidazol-2-one (the latter compound may be in the hydrochloride form in the tablet formulation).

Claims (11)

1. A compound of the formula O R 2 O X γΐ wherein R is hydrogen, C^_ 4 alkyl, C^_ 4 alkanoyl or benzoyl; r1 is hydroxy, C^_ 4 alkoxy, amino, substituted amino selected from C 1-4 alkylamino, dl(C^_ 4 alkyl) amino, phenylamino, (methylphenyl)amino, (dimethylphenyl)amino and (methoxyphenyl)-amino, Cj_ 4 alkyl, phenyl, substituted phenyl selected from halophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl, dimethoxyphenyl and 3,4-meth2 ylenedioxyphenyl, 2—furyl, 2-thienyl or pyridyl; R is hydrogen or Cj_ 4 alkyl; X Is hydrogen, halogen, methyl, methoxy or trifluoromethyl; and either Y is hydrogen, hydroxy, cyano, acetyl or ( c j_ 4 alkoxy)carbonyl and Y^ is hydrogen, or Y and Y^ together form the second of a carbon-carbon double bond; or a pharmaceutically -acceptable acid addition salt thereof.

2. A compound as claimed in claim 1, wherein R^ is hydroxy, alkoxy, amino or substituted amino as defined in claim 1.

3. A compound as claimed in claim 1, wherein R 3 is C^_ 4 alkyl, phenyl, substituted phenyl as defined in claim 1, 2-furyl, 2-thienyl or pyridyl.

4. A compound as claimed in any preceding claim, wherein R and R 2 are each hydrogen.

5. A compound as claimed in any preceding claim, wherein X, Y and Υ 3 · are each hydrogen.

6. Ethyl 2,3-dihydro-5-[(4-phenyl-l-piperidinyl)methyl]2-oxo-lH-imidazole-4-carboxylate

7. Ethyl 5-[[4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl]methyl]-2,3-dihydro-2-oxo-lH-imidazole-4-carboxylate.

8. 1,3-Dihydro—4-(4-methoxybenzoyl)-5-[(4-phenyl-lpiperidinyl) -methyl]-2H-imidazol-2-one.

9. 4-[[4-(4-Chlorophenyl)-4-hydroxy-l-piperidinyl]methyl] 5-(4-fluorobenzoyl)-l,3-dihydro-2H-imida2ol-2-one. 5

10. A compound as claimed in claim 1, substantially as decribed in any of the Examples.

11. A pharmaceutical composition comprising a compound as claimed in any preceding claim, in association with a physiologically acceptable excipient.