NO771422L - PROCEDURES FOR THE PREPARATION OF TETRAMISOL, LEVAMISOL AND DERIVATIVES THEREOF - Google Patents

Description

The present invention relates to the synthesis of 1,4-disubstituted 4-imidazolin-2-ones, 1,4-disubstituted imidazolidin-2-ones and 1,4-disubstituted imidazolidin-2-thiones with the following formulas:

where R is hydrogen, alkyl-C^-Cg, haloalkyl-C-^-Cg, phenyl, phenyl substituted with up to three groups consisting of alkyl-C-^-Cg, halogen and alkoxy-C^-Cg or a part of formula COR^ where R^ is hydrogen, alkyl-C^-C^, haloalkyl-C^-C^, alkoxy-C-^-C^, phenyl or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C ^-C^, halogen, trifluoromethyl or alkoxy-C-^-Cgj R-^ is hydrogen or a moiety of the formula COR^where R^ is alkyl-C-^-C^, alkoxy<y->C-j^-Cg, phenoxy ,. cycloalkyl-C5-C^O, phenyl or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C^-Cg, alkoxy-C-^-Cg, halogen or trifluoromethyl; R 2 is phenyl, or phenyl substituted with up to two groups consisting of C 1 -C 8 alkyl, C 1 -C 6 alkoxy, halogen and trifluoromethyl; and Z is oxygen or sulfur.

The invention also relates to certain of their 3-acylated derivatives and their subsequent conversion to tetramisole or substituted tetramisoles.

Many methods for the production of

the anthelmintic agent tetramisole in the literature (Raemaekers et al., J. Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J.

Chem. 21, 1557 (1968), T.R. Roy, US Patent 3,855,234, M.E. McMenin,

US Patent 3,845,070). Raemaeker's method includes a reduction step where sodium borohydride, an expensive reducing agent, is used. The method in US patent 3,855,234 suffers from a lack of regioselectivity and also has problems with isolating the intermediate products.

A method for producing tetramisole from 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-thione and thionyl chloride is described in US patent 3,726,894. This compound is prepared by the hydroboration reaction of 1-vinyl-4-phenyl-4-imidazolin-2-thione.

The invention is based on the synthesis of the catalytically reducible, suitably substituted imidazolinone (IV) or derivative as shown in the following scheme.

(R, R-^, R 2 , R 3 » X and Y are as defined above).

A "-substituted ketone of formula I, where X is a group (such as chlorine, fluorine, bromine, iodine and p-toluenesulfonate) which can be displaced by a nucleophilic reagent, is reacted with an amine of formula II or its addition salts, so that the compound of formula III is obtained. This reaction can be carried out using an excess of the compound of formula II, or in the presence of a tertiary amine, e.g. triethylamine, or in the presence of a hydroxide source such as e.g. sodium carbonate, at one temperature from approx. 0 to approx. 50°C in a solvent (such as alcohol or halocarbon) from approx. 30 minutes to approx. 3 hours.

Compound III is dissolved in any suitable organic solvent (such as methanol, chloroform or methylene chloride), heated from approx. 0 to approx. 100°C in the presence of cyanic acid and a suitable hydronium ion source so that the imidazolinone of formula IV is obtained.

Two alternative routes for the preparation of the imidazolidone of formula V can be used. In the first of these two methods, the imidazolidone of formula IV is hydrogenated at approx. 1.05 to 70.3 kg/cm 2 of hydrogen in a suitable solvent (such as alcohol, hydrocarbon, mixed alcohol-hydrocarbon solvent or acetic acid) in the presence of a catalyst (such as palladium or platinum on a suitable, solid support, or a homogeneous catalyst) at a temperature from approx. 0 to approx. 100°C for approx. 30 minutes or more, or reduced with a suitable reducing agent, to give the imidazolidone of formula V. In the second of these two methods, the imidazolinone of formula IV is reacted with an acyl halide or an acyl anhydride of the formula:

where Y is any group (such as halogen) which can be displaced by a nucleophilic reagent, in the presence of a hydroxide ion source while refluxing without or with a hydrocarbon solvent to give the imidazolinone of formula IVa. the imidazolinone of formula IVa is hydrogenated under the same conditions as for IV-^.V to give the imidazolidone of formula ivb. During the hydrogenation of either IV or IVa, any halogen that may be present as part

of R-, R1'-. ', or the R_-• groups, are removed and replaced by hydrogen unless mild hydrogenation conditions or other mild reduction are used. The imidazolidone of formula IVb is hydrolyzed in the presence of

a hydroxide ion source either in water or alcohol at a temperature of from approx. 70 to 100°C so that the imidazolidone of formula V is obtained. It is generally found in the case of ivb with R equal to COR^ that the COR-^ group is also hydrolyzed in this step to give V and. R equals hydrogen.

The imidazolidone of formula V is heated in an inert solvent (such as, for example, toluene, xylene or cyclohexane) at a temperature from approx. 80 to approx. 200°C in the presence of a reagent (such as phosphorus pentasulphide) which can exchange oxygen with sulfur to give the imidazblide ion of formula VI and some of the compound of formula VII (as free base). In the case of compounds of formula V where R is hydrogen, the reaction with phosphorus pentasulphide affects

also the free hydroxyl group and changes it so that it is formed

a sulfur-containing group which may also contain phosphorus.

This altered group can nevertheless undergo cyclization in the final trihne so that compounds of formula VII are formed. In the case of compounds of formula V where R is the COR^ part, it often happens that the COR^ group reacts with the thierating reagent

(e.g. phosphorus pentasulphide) so that a CSR-j group is formed. This does not affect the ability of compounds of formula VI where this change has taken place to be cyclized to the useful compounds of formula VII.

The imidazolidine thione of formula VI is heated with HY, where Y is a pharmaceutically acceptable anion (such as chloride, fluoride, iodide, bisulfate and p-toluenesulfonate) in a solvent at a temperature from approx. 0 to approx. 200°C to give the compound of formula VII. The compound of formula III where R is an acyl group can also be prepared as follows:

The new intermediates according to the invention can be illustrated with the formula:

where R and are as defined above.

The invention is illustrated by the following examples.

Example 1

1-( 2- methoxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Phenacyl bromide (60 g) in 200 ml of methylene chloride is added over 1 hour to 2-methoxyethylamine (52 g) in 100 ml of methylene chloride, and cooled with an ice bath. The mixture is stirred for 2 hours at 0°C. Water (400 ml) is added and the organic layer is separated,

dried over anhydrous sodium sulfate and concentrated under aspirator vacuum (at room temperature). The viscous oil (260 g) is dissolved in • methanol (200 ml), cooled to 0°C and acetic acid (80 ml) and potassium- . cyanate (30g) is added. The mixture is refluxed in . 90 minutes, the solvent is removed under reduced pressure and the residue is taken up in 600 ml of chloroform and washed with saturated sodium bicarbonate solution. The chloroform layer is washed, dried over sodium sulfate and concentrated to a semi-solid. Trituration with ether and filtration gives the title product as yellow crystals, m.p. 152-153°C.

Example 2

1-( 2- methoxyethyl)- 4- phenyl- 4- imidazoline- 2- 6n

Phenacyl bromide (199 g) in 400 ml chloroform is added over 1/2 hour to a mixture of 2-methoxyethylamine (82 g) and triethylamine (152 g) in 200 ml chloroform at 0°C. Water (400 ml) is added and the organic layer is separated and washed with a new 400 ml of water. The chloroform layer is cooled to 0°C with an ice bath and glacial acetic acid (72.g), potassium cyanate (89 g) and methanol (100 ml) are added. The mixture is refluxed for 90 minutes, cool and wash with saturated sodium bicarbonate solution, and the organic layer is dried over anhydrous sodium sulfate and then concentrated to a semi-solid. Trituration with 300 ml of ether and filtration gives the title product as yellow crystals, m.p. 152-154°c.

Example 3

1-(2-Methoxyethyl)-4-phenyl-2-imidazolidone

About 10.9 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 1 g of 10% palladium on carbon in 100 ml of ethanol are hydrogenated in a "Parr Shaker" apparatus at 2.1 kg /cm 2 hydrogen for 45 minutes. The catalyst is filtered off, washed with ethanol and the filtrate is concentrated to give the title compound as a waxy white solid, m.p. 82-83°C.

The above reduction can also be carried out with acetic acid as solvent, and at atmospheric pressure in both solvents.

Example 4

1-(2-Methoxyethyl)-4-phenylimidazolidin-2-thione

About 1 g of 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone. and 0.4 g of phosphorus pentasulphide are refluxed in toluene overnight (16 hours). The toluene is distilled off under reduced pressure and the remaining semi-solid is dissolved in a solution of 50 ml of chloroform and 30 ml of 20% sodium hydroxide. The organic layer is separated, washed, dried and the solvent removed to give 1 g of oil. The oil is dissolved in 3 ml of acetone and anhydrous hydrogen chloride is bubbled in for 2 minutes. The precipitated tetramisole hydrochloride is filtered off and the filtrate is concentrated to dryness. The filtrate is recrystallized from benzene-cyclohexane to give the title compound as a white solid, m.p. 76-78°C.

Example 5

Preparation of tetramisole hydrochloride from 1-(2-methoxyethyl)-4-phenylimidazolidin-2-thione

Approximately 236 mg of 1-(2-methoxyethyl)-4-phenylimidazolidin-2-thione, 5 ml of concentrated hydrochloric acid and 5 ml of acetone are refluxed together for 1 hour. The solution is then concentrated to dryness under reduced pressure and triturated with 2 ml of ethanol. The white solid that precipitates is filtered off to give the title compound.

Example 6

Preparation of tetramisole hydrochloride from 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone

Approximately 4.4 g of 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone and 2 g of phosphorus pentasulphide are refluxed together in 200 ml of toluene for 20 hours. The toluene is distilled off under reduced pressure and the residue is taken up in 100 ml of chloroform and washed with 50 ml of 20% sodium hydroxide solution. The organic layer is washed with water, dried and the solvent is removed, so that a yellow oil is obtained. The oil is refluxed for 1 hour in a solution of 10 ml of concentrated hydrochloric acid and 10 ml of ethanol. The solution is concentrated to dryness, the remaining semi-solid is triturated with ethanol (20 ml), filtered and dried to give the title compound, m.p. 260-262°C.

Example 7

1-( 2- hydroxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Phenacyl bromide (60 g) in methylene chloride (100 ml) is added over 30 minutes to monoethanolamine (41 g) in methylene chloride

(100ml). The solution is cooled to 0°C with an ice bath, stirred for a further 90 minutes at 0-5°C, after which 400 ml of water is added. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure at approximately room

temperature. The residual oil is dissolved in methanol (150 ml), cooled and a solution of sodium cyanate (24 g) in acetic acid (30 ml) is added. The mixture is refluxed for 1 hour and then cooled. The white solid precipitate is filtered off, washed with water, methanol and then dried to give the title product, m.p. 203-205°C.

Example 8

1-(2-Hydroxyethyl)-4-ferryl-2-imidazolidone

A slurry of 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-one (10.2 g) and 10% palladium on carbon (1 g) in ethanol (200 ml) is hydrogenated in a Shaker" apparatus at 2.1 kg/cm<2>hydrogen for 3 hours. The catalyst is then filtered off, washed with

ethanol, and the combined filtrate and washing solutions are concentrated to a colorless oil which solidifies on standing and gives the title compound, m.p. 60-63°C.

Example 9

Preparation of tetramisole hydrochloride from 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone

A mixture of 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone (4.1 g) and phosphorus pentasulfide (1.8 g) in tdlu (25 ml) is refluxed for 20 hours. The toluene is distilled off under reduced pressure and the residue is dissolved in a solution of chloroform (50 ml) and 20% sodium hydroxide (50 ml). The organic layer is separated, washed, dried over sodium sulfate and concentrated to an oil. The oil is refluxed in a solution of ethanol (10ml) and concentrated hydrochloric acid (20ml) for 1 hour. The solution is concentrated

to dryness, triturated with ethanol (20 mL) and filtered to give

the title compound as a white solid, m.p. 260°C.

Example 10

1-(2-acetoxyethyl)-4-phenyl-2-imidazolidone

About 9.2 g of 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone is stirred with acetic anhydride (25 ml) and p-toluenesulfonic acid (200 mg) for 4 hours during which time the imidazolidone is completely dissolved. The solution is poured into a saturated sodium bicarbonate solution (100 ml) from which a white solid precipitates. The solid is extracted with methylene chloride (3 x 100 ml). The organic layer is separated, dried and the solvent removed to give a pale yellow solid. Recrystallization from ether affords the title compound as a white, crystalline solid, m.p. 88-90°C.

Example 11

Preparation of tetramisole hydrochloride from 1-(2-acetoxyethyl)-4-phenyl-2-imidazolidone,

About 5. g of 1-(2-acetoxyethyl)-4-phenyl-2-imidazolidone and 1.8 g of phosphorus pentasulphide are refluxed in 20 ml of toluene for 20 hours4 The solvent is distilled off under reduced pressure and the residue is dissolved in a solution of chloroform (100 ml) and 20% sodium hydroxide (100 ml). The organic layer is then separated, washed, dried over sodium sulfate treated with charcoal, filtered and concentrated to an oil. The oil is refluxed with a solution of concentrated hydrochloric acid (20 ml) and ethane (10 ml) for 1 hour.

The solution is concentrated to dryness and the residue is triturated with ethanol (20ml) and then filtered to give the title compound with a dark colour, m.p. 2 58-260°C.

Example 12

1-( 2- Acetoxyethyl)- 4- Phenyl-- 4- Imidazolin- 2-one

Approximately 9 g of 2-methyloxazoline and 20 g of phenacyl bromide are refluxed in 100 ml of chloroform for 1 hour. The solvent is concentrated under reduced pressure and acetic acid (10 ml), 9 g of potassium cyanate and 100 ml of methanol are added to the residual oil and the mixture is refluxed for 1 hour. The methanol is removed under reduced pressure and the residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution . The organic layer is dried and concentrated to a semi-solid. Recrystallization from benzene-cyclohexane gives the title compound, m.p. 120-122°C.

Example 13

Reduction of 1-(2-acetoxyethyl)-4-phenyl-4-imidazolin-2-one

About 1 g of 1-(2-acetoxyethyl)-4-phenyl-4-imidazolin-2-one and 250 mg of 10% palladium on carbon in 10 ml of ethanol are stirred in a hydrogen atmosphere. After approx. after three quarters of an hour, the catalyst is filtered off and washed with 20 ml of ethanol. The combined filtrates are concentrated to give the title compound as a white solid, m.p. 86-88°C.

Example 14

1-( 2- methoxyethyl)- 3- acetyl- 4- phenyl- 4- imidazolin- 2- one

Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 120 ml of acetic anhydride are refluxed together for 4 hours. The acetic anhydride is distilled off under reduced pressure. The. remaining semi-solid is recrystallized from ether to give the title compound as a white solid, m.p. 73-75°C.

Example 15

Racemic 1-(2- methoxyethyl)- 3- acetyl- 4- phenyl- 2- imidazolidone Approximately 3.9 g of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one and 400 mg of 10% palladium on carbon in 30 ml of ethanol is hydrogenated in a "Parr Shaker" apparatus at 2.1 kg/cm of hydrogen. After 1 hour, the catalyst is filtered off and washed with 50 ml of ethanol. The combined filtrate is concentrated to give the title compound as a colorless oil.

Example 16

Hydrolysis of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-2-imidazolidone to 1-(2- methoxyethyl)-4-phenyl-2-imidazolidone

About 2.6 g of the 3-acetyl derivative is refluxed in 20 ml of 10% sodium hydroxide for 1 hour. The solution is cooled and then extracted with chloroform (2 x 20ml). The combined chloroform extracts are washed, dried over sodium sulfate and concentrated to the title compound as a solid, m.p. 8l-83°C.

Example 17 1-(2-Methoxyethyl)-3-benzoyl-4-phenyl-4-imidazolin-2-one

About 4.36 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 3 g of triethylamine and 3 g of benzoyl chloride are refluxed together for 3 hours in chloroform. The solution is cooled, washed with water, dried and the solvent removed to give an oil which is the 0-benzoyl ester. The ester is refluxed for 3 hours in 20 ml of xylene. The xylene is removed by reduced pressure. Recrystallization from ether gives the title compound as a pale yellow solid, m.p. 112-117°C.

Example 18

1-( 2- methoxyethyl)- 3- benzoyl- 4- phenyl- 4- imidazolin- 2- one

Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g of benzoyl chloride and 20 g of tri-n-butylamine are refluxed together in 60 ml of xylene for 16 hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml of benzene. The benzene solution is washed with water (2 x 100ml), dried over sodium sulfate and the solvent is removed to give a semi-solid. Recrystallization from ether affords the title compound

as a pale yellow solid, m.p. 114-117°C.

Example 19

Preparation of other 1-(2-methoxyethyl)-3-acyl-4-phenyl-4-imidazolin-2-ones

The following acetyl derivatives are prepared by using procedures identical to that described for the N-benzoyl derivative in example 18: a) 1-(2-methoxyethyl)-3-cyclohexanecarbonyl-4-phenyl-4-imidazolin-2-one j b) 1-(2 -methoxyethyl)-3-p-trifluoromethylbenzoyl-4-phenyl-4-imidazolin-2-one; c) 1-(2-methoxyethyl)-3-(1-adamantanecarbonyl)-4-phenyl-4-imidazolin-2-one; :d). 1-(2-methoxyethyl)-3-o-anisoyl-4-phenyl-4-imidazolin-2-one; e) 1-(2-methoxyethyl)-3-(2-chlorobenzoyl)-4-phenyl-4-imidazolin-2-onejf) 1-(2-methoxyethyl)-3-(2,4-dichlorobenzoyl)-4- phenyl-4-imidazolin-2-one; and g) 1-(2-methoxyethyl)-3-(2-methylbenzoyl)-4-phenyl-4-imidazolin-2-one.

Example 20

Hydrogenations of 3-acyl derivatives of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one [ .

3-acyl-1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 10% palladium on carbon catalyst are taken up in ethanol and hydrogenated x a "Parr Shaker" apparatus at 2,1-3 .5 kg/cm 2 hydrogen from 30 minutes to approx. 6 hours. The catalyst is then filtered and the filtrate

is concentrated to give a 1-(2-methoxyethyl)-3-acyl-2-imidazolidone. The following compounds are prepared in the manner described above:

a) 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-2-imidazolidone; b) 1-(2-methoxyethyl)-3-cyclohexanecarbonyl-4-phenyl-2-imidazolidone; c) 1-(2-methoxyethyl)-3-p-trifluoromethylbenzoyl-4-phenyl-2-imidazolidone; d) 1-(2-methoxyethyl)-3-o-anisoyl-4-phenyl-2-imidazolidone; e) 1-(2-methoxyethyl)-3-(1-adamantanecarbonyl)-4-phenyl-2-imidazolidone; f) 1-(2-methoxyethyl)-3-(2-chlorobenzoyl)-4-phenyl-2-imidazolidone; g) 1-(2-methoxyethyl)-3-(2,4-dichlorobenzoyl)-4-phenyl-2-imidazolidonej and h) 1-(2-methoxyethyl)-3-(2-methylbenzoyl)-4-phenyl- 2-imidazolidone.

Example 21

1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one.

Phenacyl bromide (10 g) in 50 ml of chloroform is added over the course of 20 minutes to a mixture of 2-butoxyethylamine (6 g) and triethylamine (7 g) in 50 ml of chloroform at 0° C. The mixture is stirred for 2 hours. Water (100 ml) is added, the organic layer is separated, cooled to 0°C and glacial acetic acid (5 ml), potassium cyanate (5 g) and methanol (20 ml) are added. The mixture is refluxed for 90 minutes, cooled, washed with saturated sodium bicarbonate-free ning, dried and the solvent removed to give the title product.

Example 22

1-(2-butoxyethyl)-4-phenyl-2-imidazolidone

A solution of 1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one in ethanol with 10% palladium-on-carbon catalyst is reduced in a hydrogen atmosphere. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is concentrated to give the title compound.

Example 23

1-( 2- methoxyethyl)- 4-( 2- chlorophenyl)- 4- imidazolin- 2- one

To 23.4 g of o-chlorophenacyl bromide in 100 ml of chloroform, 20 g of 2-methoxyethylamine in 100 ral of chloroform, which has been cooled with an ice bath, is added over the course of 30 minutes. The mixture is stirred for a further 1 hour at 0°C. 200 ml of water are added and the organic layer is separated, cooled to 0°C with an ice bath and then 8 ml of glacial acetic acid, 9 g of potassium cyanate and methanol are added. The mixture is refluxed for 90 minutes, cooled, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent removed to give the title product.

Example 24

1-( 2- methoxyethyl)- 4-( substituted phenyl)- 4- imidazoline-. 2-ones The following 1-(2-methoxyethyl)-4-(substituted phenyl)-4-imidazolin-2-ones are prepared in an identical manner as described in example 23:

a) 1-(2-methoxyethyl)-4-.(2,4-dichlorophenyl)-4-imidazolin-2-one and

b) 1-(2-methoxyethyl)-4-(g-trifluoromethylphenyl)-4-imidazolin-2-one.

Example 25

Preparation of 1-(2-methoxyethyl)-4-(substituted phenyl)-2-imidazolidone

A solution of 1-(2-methoxyethyl)-4-(substituted phenyl)-4-imidazolin-2-one in ethanol with 10% palladium-on-carbon catalyst is reduced by from approx. 1.05 to 70.3 kg/cm<2>hydrogen. After

the theoretical amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is concentrated to give the 1-(2-methoxyethyl)-4-(substituted phenyl)-2-imidazplidones. The following compounds were prepared in the manner described above:

a) 1-(2-methoxyethyl)-4-(m-trifluoromethyl)-2-imidazolidone;.

b.) 1-(2-methoxyethyl)-4-(m-methylphenyl)-2-imidazolidone; c) 1-(2-methoxyethyl)-4-(p-trifluoromethylphenyl)-2-imidazolidone and

d) 1-(2-methoxyethyl)-4-(m-methoxyphenyl)-2-imidazolidone.

Example 26

1-( 2- benzoyloxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Approximately 15 g of 2-phenyloxazoline and 20 g of phenacyl bromide are refluxed in 100 ml of chloroform for 1 hour. The solvent is concentrated under reduced pressure and 10 ml of acetic acid, 9 g of potassium cyanate. and 100 ml of methanol are added and the mixture refluxed for 1 hour. The methanol is removed under reduced pressure and the residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer is dried and concentrated to give the title compound.

Example 2 7

Preparation of other 1-(2-acyloxyethyl)-4-phenyl-4-imidazolin-2-ones

The following 1-(2-acyloxyethyl)-4-phenyl-4-imidazolin-2-ones are prepared using procedures identical to that described for the benzoyloxy derivatives in Example 26:a) 1-[2-(proplonyloxy) )ethyl]-4-phenyl-4-imidazolin-2-one; b) 1-[2-(g-methylbenzoyloxy)ethyl]-4-phenyl-4-imidazolin-2-one; and

c). 1-[2-(p-trifluoromethylbenzoyloxy)ethyl]-4-phenyl-4-imidazoline.

Example 28

Preparation of 1-(2-acyloxyethyl)-4-phenyl-2-imidazolidones The following 1-(2-acyloxyethyl)-4-phenyl-2-imidazolidones are prepared by means of the catalytic reduction of 1-(2-acyloxyethyl) )-4-phenyl-4-imidazoin-2-ones which are identical to that described for the 1-(2-acetoxyethyl) derivatives in example 13: a) 1-[2-benzoyloxyethyl]-4-phenyl-2 -imidazolidone; b) 1-[2-(propyloxy)ethyl]-4-phenyl-2-imidazolidone; c) 1-[2-(p-methylbenzoyloxy)ethyl]-4-phenyl-2-imidazolidone; d) 1-[2-(p-trifluoromethylbenzoyloxy)ethyl]-4-phenyl-2-imidazole 1.done.

Example 29

The following aminoketones of formula A are prepared by the reaction between the corresponding ethanolamines obtained from their acid addition salts, and the corresponding phenacyl bromides, as in the first three sentences of Example 2:

be substituted ethanolamines and their acid addition salts and the phenacyl bromide starting materials are obtained according to known methods from the literature.

Example 30

. The following imidazolinones of formula B are prepared from aminoketones as in example 29 by reaction with potassium cyanate as in examples 1 and 2:

Example 31

The following 3-substituted imidazolinones of formula C are prepared as in Example 18 using the appropriate carbonyl halides or anhydrides and the corresponding 3-H-imidazolinones:

Example 3 2

The following 3-substituted imidazolidones of formula D are prepared by catalytic hydrogenation of the corresponding 3-substituted imidazolinones using the procedure from Example 13:

If the corresponding compounds of formula C are hydrogenated in the presence of a homogeneous hydrogenation catalyst such as e.g. tristriphenylphosphino-chlororhodium, the following compounds of formula D are obtained:

Example 33

The following imidazolidones of formula E are prepared by hydrogenation of the corresponding 3-unsubstituted imidazolinones according to the method from example 3:

All the above compounds and the following compounds can be prepared by hydrolysis of the corresponding compounds of formula D from example 32.

Example 34

The following imidazolidin-2-thiones of formula F are prepared as in example 4 from the corresponding 3-unsubstituted imidazolidones as in example 4:

Claims (18)

1. Compound, characterized in that it has the formula: where R is hydrogen, alkyl-C^-Cg, haloalkyl-C-^-Cg, phenyl, phenyl substituted with up to three groups, consisting of alkyl-C^-Cg, halogen and alkoxy-C^C^ or a moiety of the formula COR2 where R3 is hydrogen, alkyl-C^-Cg, haloalkyl-C^-Cg, alkoxy-C^-Cg, phenyl, or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C 1 -C 8 , halogen, trifluoromethyl or alkoxy-C 1 -C 6' Rl is ^ lYåxo9ene or a moiety of the formula COR4 where R^ is alkyl-C 1 -C 6 'alko'csy~c£C6' phenoxy, cyclioalk <yl> - <C>5<-> Cl0 , phenyl, phenyl or phenoxy substituted with up to four groups consisting of alkyl-C-^ -Cg/ alkoxy-C^ -Cg, halogen or trifluoromethyl; and R 2 is phenyl, or phenyl substituted with up to two groups consisting of alkyl-C 1 -C 8 , alkoxy-C 1 -C 8 - , halogen or trifluoromethyl; and Z is oxygen or sulfur, provided that when R is hydrogen in the second formula, Z cannot be sulfur. 2. Compound according to claim 1, characterized in that it has the formula: 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 1-(2-acetoxyethyl)-4-phenyl-4-imidazolin- 2-one, 1-(2-methoxyethyl )-4-(3-methoxyphenyl)-4-imidazolin-2-one, 1-(2-methoxyethyl)-4-(3-bromophenyl)-4-imidazolin-2- one, 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one, 1-( 2-methoxyethyl)-3-benzoyl-4^-phenyl-4-imidazolinyl-2- one, 1-(2-methoxyethyl)-3-(2-methoxybenzoyl)-4-phenyl-4-imidazolin-2-one, 1-(2-methoxyethyl)-3-(4-trifluoromethylbenzoyl)-4-phenyl- 4-imidazolin-2-one, 1-(2-methoxyethyl)-3-(1-adamantanecarbonyl)-4-phenyl-4-imidazolin-2-one, 1-(2-methoxyethyl)-3-cyclohexanecarbonyl-4- phenyl-4-imidazolin-2-one, 1-(2-methoxyethyl)-4-(3-trifluoromethyl)-phenyl-4-imidazolin-2-one, 1-(2-butoxyethyl)-4-phenyl-4- imidazolin-2-one, l-(2-methoxyethyl)-4-(3-methyl(phenyl)-4-imidazolin-2-one, l-(2- methoxyethyl)-4-(4-trifluoromethylphenyl)-4- imidazolin-2-one or 1-(2-Benzoyloxyethyl)-4-phenyl)-4-imidazolin-2-one. 3. Compound according to claim 1, characterized in that it has the formula: 1-(1-methoxyethyl)-4-phenyl.1-2-imidazolidone, 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone, 1- (2-acetoxyethyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-methoxyphenyl)-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-bromophenyl)- 2-Imidazolidone, 1-(2-methoxyethyl)-3-acetyl-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl) )-3-(2-methoxy-benzoyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3-(4-trifluoro-methylbenzoyl)-4-phenylr-2-imidazolidone, 1-(2 -methoxyethyl)-3-(1-adamantanecarbonyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3- cyclohexanecarbonyl-4-phenyl-2-imidazolidone, 1-(2-butoxyethyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-trifluoromethyl)phenyl-2-imidazolidone, l- (2-Methoxyethyl)-4-(3-methylphenyl)-2-imidazolidone, 1-(2-Methoxyethyl)-4-(4-trifluoromethyl)phenyl-2-imidazolidone, 1-(2-benzoyloxyethyl)-4-phenyl -2-imidazolidone or 1-(2-butoxyethyl)-3-acetyl-4-phenyl-2-imidazolidone. 4. Compound according to claim 1, characterized in that it has the formula: 1-(2-methoxyethyl)-4-phenylimidazolidon-2-thione, 1-(2-butoxyethyl)-4-phenylimidazolidin-2-thione or 1-(2 -phenoxyethyl)-4-phenylimidazolidin-2-thione. 5. Compound according to claim 1, characterized in that it has the formula: where R and R2 are as defined above. 6. Procedure for the preparation of a compound of the formula: where , R 2 and R are as defined above, characterized in that an α-(2-substituted) amino ketone with the formula: where R and R2 are as defined above are dissolved in an organic solvent, heated from approx. 0 to 100°C in the presence of cyanic acid and a hydronium ion source so that a substituted imidazolinone with the formula is obtained: where R and R2 are as defined above, after which said imidazolinone is reacted with an acyl halide or acyl anhydride with the formulas: where R^ is. as defined above and Y is any group which can be displaced by a nucleophilic reagent, in the presence of a base under reflux treatment with or without a hydrocarbon solvent. 7. Process for the preparation of a compound of formula: where R, R^ and R2 are as defined above, characterized in that an imidazolinone with the formula: where R, R^ and R are as defined above, is reduced by hydrogenation in the presence of a catalyst at from approx. 25 to approx. 80°C in a suitable solvent.. 8. Method according to claim 7, characterized in that palladium, platinum, nickel, rhodium, iridium, ruthenium or cobalt are used as catalyst. 9. Method according to claim 7, characterized in that 10% palladium on carbon is used as catalyst. 10. Method according to claim 7, characterized in that when Z is oxygen, it is converted to sulfur by reflux treatment of said imidazolidone with a reagent that can replace oxygen with sulfur in a suitable solvent at a temperature of from approx. 80 to 200°C. 11. Method according to claim 10, characterized in that phosphorus pentasulphide or hydrogen sulphide is used as said reagent. 12. Method according to claim 10, characterized in that phosphorus pentasulphide is used as the aforementioned reagent which can replace oxygen with sulphur. 13. Procedure for preparing a compound of the formula: where R and R2 are as defined above, characterized in that an α-substituted ketone with the formula: where R2 is as defined above and X is a group that can be displaced by a nucleophilic reagent, reacted with an amine or its acid addition salt with the formula: where R is as defined above, in an excess of said amine, or in the presence of a tertiary amine, or in the presence of a hydroxide source, at a temperature from approx. 0 to approx. 50°C for approx. 30 minutes or more. 14.Procedure for the preparation of a compound with the formula: where R2 is as defined above and Y is a pharmaceutically acceptable anion, characterized in that a substituted imidazolidinion with the formula: where R and R2 are as defined above, is heated with HY, where HY is as defined above, in a suitable solvent at a temperature from approx. o to approx. 200°C whereby the substituted 2,3,5,6-tetrahydroimidazo [2,1-b]-thiazolic acid addition salt of the free base is obtained. 15. Process according to claim 13, characterized in that said acid addition site is neutralized to give the free base. 16. Procedure for preparing a compound of the formula: where R2 and R^ are as defined above, characterized in that a compound with the formula: where R2 is as defined above and X is a group which can be displaced by means of a nucleophilic reagent, reacted with a compound of the formula: where R _ is as defined above, in a suitable solvent at a temperature from approx. 25 to approx. 65°C, so the solution is reacted with potassium cyanate and acetic acid. 17. Method according to claim 16, characterized in that chlorine, fluorine, bromine, iodine or p-toluenesulphonate is used as X. 18. Method according to claim 16, characterized in that chlorinated hydrocarbons, C 1 -C 2 -alcohols, diethyl ether or tetrahydrofuran are used as suitable solvents.