NO141895B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE NITROIMIDAZOLD DERIVATIVES - Google Patents

Description

The invention relates to an analogue method for the production of therapeutically effective new compounds of formula I

in which one of the radicals R-^ and R2 means hydrogen and the other nitro-

the group, R., means lower alkyl with 1-3 C atoms, lower alkoxy lower-

alkyl with a maximum of 4 C atoms, X means a carbonyl, thiocarbonyl

or sulfonyl group, and if X means a carbonyl group or sulfonyl group, R^ means a piperidino, pyrrolidino, morpholino, lower alkylamino or dilower alkylamino group, and if X means a thiocarbonyl group, R^ means benzylamino, lower alkylamino-

or dilavealkylamino, and if X represents a sulfonyl group,

means R4 a lower alkyl group or optionally halogenated phenyl,

and R 1 means hydrogen or methyl, as well as their salts and N-oxides.

Lower alkyl residues are, for example, methyl, ethyl, n-pro-

pyl or isopropyl, or straight or branched butyl.

Lower alkyl lower alkyl residues are e.g. such as

in the lower alkyl part has up to 4 C atoms, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-(n-butoxy)-ethyl, 3-(n-propoxy)-propyl or especially 2-methyloxyethyl.

Lower alkylamino is e.g. methyl-, ethyl or n-pro-

pylamino and dilavealkylamino are e.g. dimethylamino, N-methyl-N-ethylamino, diethylamino, di-n-propylamino or di-n-butylamino.

The phenyl radical R^ may optionally also be substituted with halogen atoms r.

As halogen atoms, chlorine-

or bromine atoms, especially also fluorine.

The new compounds have valuable pharmacological properties. They particularly show effects against bacteria, especially against gram-negative germs, protozoa and worms, such as trichomonads, schistosomes, and above all amoebae, as can be demonstrated in animal experiments, e.g. on the liver of healthy hamsters artificially infected with Entamoeba histolytica, by administering doses from approx. 10 to approx. 100 mg/kg/p.o. The new imidazoles can therefore be particularly used as agents against amoebae, schistosomes, trichomonads and bacteria. Furthermore, the new imidazoles can serve as starting or intermediate products for the production of other, particularly therapeutically active compounds.

Particular mention of these new imidazoles of formula I are 1-(methylsulfonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)N7-tetrahydroimidazole, 1-N,N-diethylcarbamoyl-2-oxo -3-/l-methyl-5-nitro-imidazolyl-(2)_7~tetrahydroimidazole, 1-N ,N-dimethylcarbamoyl-2-oxo-3~/l-methyl-5-nitro-imidazolyl-(2)_7 -tetrahydroimidazole, 1-N-ethylthiocarbamoyl-2-oxo-3-/l-methyl-5-nitroimidazolyl- (2)_7~tetrahydroimidazole, and 1-N-methylthiocarbamoyl-2-oxo-3-^T-methyl-5 -nitro-imidazolyl-(2)J7-tetrahydroimidazole, which on the liver of healthy hamsters artificially infected with Entamoeba histolytica, at administrations of doses from 10 to 100 mg/kg/p.o. causes a clear absence of abscesses.

The new imidazoles are obtained by methods known per se.

Thus, one can e.g. get the new imidazoles when reacting an imidazole with formula II

wherein R-^, R 2 and R^ have the above meaning, and Z means a reactive esterified hydroxy group, a halogen atom, a reactive etherified hydroxy group, a free or etherified mercapto group, an ammonium group, a sulfinyl group or a sulfonyl group with a compound of formula III

in which Rjj, , X and alk have the above meaning.

A reactive esterified hydroxy group Z is in particular a hydroxyl group esterified with a strong inorganic or organic acid, above all a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or an organic sulphonic acid, such as an aromatic sulphonic acid, e.g. benzenesulfonic acid, p-bromobenzenesulfonic acid or p-toluenesulfonic acid or an aliphatic sulfonic acid, such as an alkanesulfonic acid, e.g. methanesulfone

acid or ethanesulfonic acid. Thus Z means in particular chlorine, bromine or iodine.

A reactive etherified hydroxy group is e.g.

a hydroxyl group etherified with an aromatic or aliphatic, pre-

above all a lower aliphatic alcohol, such as an optionally substituted phenoxy group or an alkoxy group, above all a lower alkoxy group, especially methoxy or ethoxy.

A preferred mercapto group is e.g. an optionally substituted phenyl mercapto or benzyl mercapto group or especially a lower alkyl mercapto group, such as the ethyl or methyl mercapto group.

An ammonium group is in particular a quaternary ammonium group, above all a tri-lower alkylammonium group, e.g. trimethyl-

or the triethylammonium group or the cation of an aromatic nitrogen base, e.g. the pyridinium or quinilinium group.

A sulfinyl or sulfonyl group is especially one of an organic sulfinic or sulfonic acid, especially a sulfinyl or sulfonyl group derived from an aromatic sulfinic or sulfonic acid. Thus, Z means in particular benzenesulfinyl or methylsulfinyl resp. benzenesulfonyl, p-bromobenzenesulfonyl, p-toluenesulfonyl or methylsulfony1.

This turnover can be carried out in the usual way. Preferably, one works in the presence of a basic condensation agent or one uses compounds of formula III in the form of its N-metal derivative, such as its N-alkali metal derivative, which can for example be obtained from the compound of formula II and an amide, hydride, a hydrocarbon compound, a hydroxide or alcoholate of an alkali metal, such as lithium, sodium or potassium and can be used without isolation. Suitable basic condensation agents are e.g. alkali or alkaline earth hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide or organic tertiary nitrogen bases, such as trialkylamines, for example trimethylamine and triethylamine or pyridine. You can also use an excess of the compound of formula III. Preferably, one works at an elevated temperature and/or in the presence of an inert solvent, such as a solvent with polar functional groups, e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or cyclic aliphatic ethers, such as dioxane and tetrahydrofuran.

According to another method, the new imidazoles can be obtained when an imidazole with formula IV is nitrated

in which Rj, R^, R^, X and alk have the above meaning and one of the residues R| and R£ means hydrogen or lower alkyl and the other means hydrogen.

The nitration can be carried out in the manner known in imidazole chemistry, e.g. with nitric acid, with nitric acid and a carboxylic acid, such as e.g. acetic acid, with nitric acid and the anhydride of a carboxylic acid, such as acetic anhydride, with the mixed anhydride of nitric acid and a carboxylic acid, such as of acetic acid, by thermal and/or acid treatment of a nitric acid addition salt of a compound of formula IV, with dinitrogen tetroxide, e.g. dinitrogen tetroxide-boron trifluoride, especially in a suitable solvent, e.g. nitro-hydrocarbons, such as nitroalkanes, e.g. nitromethane or with dinitrogen tetroxide, e.g. in acetonitrile, or with suitable N-nitro compounds.

Suitable N-nitro compounds are e.g. nitramides, such as nitro-urethanes, nitro-guanidines, nitro-biuret and nitrourea, e.g. ethylene dinitrourea (compare J. org. Chem. 1952, 1886-1894) .

During the nitration, acidic agents such as acetic acid, primarily mineral acids, above all sulfuric acid, may be present, for

step by step in concentrated form.

The acid treatment of a nitric acid addition salt

of a compound of formula IV is preferably carried out at an elevated temperature, suitably between 40 and 100°C, e.g. at 60-80°C. The desired product can be isolated according to methods known per se, e.g. by pouring the reaction mixture on ice or in ice water.

According to a third progress myth, a compound of formula I can be obtained by reacting a compound of formula V

wherein R 1 # R 2 , R 3 and R 5 have the above meaning with a compound of formula VI

wherein R^ has the above meaning.

The turnover can be carried out in the usual way. Preferably, one works under the same conditions as was discussed for the reaction of compounds of formula II with compounds of formula III.

In the compounds formed, within the framework of the definition of the final substances, substituents can be introduced, modified or split off.

An imidazole of formula I, which has an N-heterocyclic residue, can be N-oxidized.

The oxidation is carried out in the usual way, e.g. with N-oxidizing agents, such as hydrogen peroxide, ozone, inorganic peracids, e.g. persulfuric acids, such as Caro acid or especially with organic peroxy compounds, above all organic peracids, such as peracetic acid, pertrifluoroacetic acid, perbenzoic acid or phthalmonoperacid, which can also be substituted e.g. with halogen atoms, such as chlorine atoms, for example chlorphthalmonoperic acid or m-chloroper-benzoic acid, or tert. hydroperoxide compounds, such as tert.-butyl or cumene peroxide, optionally in the presence of catalysts such as vanadium^, titanium or molybdenum compounds.

In the compounds formed, in which X means a thiocarbonyl group, X can be converted in the usual way to the carbonyl group, especially according to hydrolysis methods known per se, e.g. by treating the thiocarbonyl compounds formed with an alkaline agent such as an alkali hydroxide in the presence of an oxidizing agent such as hydrogen peroxide. The conversion can also be carried out in the presence of a strong acid, for example a mineral acid such as in the presence of concentrated sulfuric acid in a suitable solvent.

Compounds of formula I which as residue R 2 contain a nitro group can be rearranged in the corresponding 4-nitroimidazoles, i.e. such compounds of formula I, which as residue R 2 contain a nitro group. Such rearrangement takes place, for example, by the action of, e.g., an excess of alkali iodide, especially potassium iodide in the presence of an inert solvent, preferably a solvent with polar functional groups such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or hexamethylphosphoric acid triamide.

The rearrangement of R2 = nitro to = nitro compounds of formula I can optionally take place by the action of an iodide,

which corresponds to the residue R3, R^J which e.g. effect of methyl iodide on compounds of formula I, which as R^-residue contains a methyl group. In this rearrangement, the unsubstituted nitrogen atom of the imidazole ring is quaternized. The quaternary salt is then pyrolysed. This relocation may take place e.g. in the presence of an inert solvent, preferably those mentioned above.

The subsequent transformation can be carried out individually or in combination o in the desired order. During the individual operations, it must be ensured that other functional groups are not attacked.

The starting materials are known, they can, if they are new, be obtained by known methods. New starting materials are likewise an object of the invention.

The starting compounds of formula III which are used in the first method for reaction can be prepared by reacting a compound of formula:

in which R^ has the above-mentioned meaning, i.e. when, for example, re-

puts an imidazolidin-2-one with a compound of formula

wherein , X and Z have the above meaning.

The starting compounds of formula IV, which are reacted in another process, can be prepared by condensing a suitable imidazole derivative of formula II with an exchangeable group Z with a compound of formula III according to the method described in the first process.

Thus, they show special effects on bacteria, especially Gram-negative germs, protozoa and worms, such as Trichomonads, Schistosomes, Coccidia and above all amoebas, as can be demonstrated in animal experiments, e.g. on the liver of healthy hamsters, which are artificially infected with Entamoeba histolytica, by administering doses from approx. 10 to approx. 100 mg/kg/p.o. The new imidazoles can therefore be particularly used as agents against amoebae, schistosomes, trichomonads and bacteria.

Depending on process conditions and starting materials, the final materials are obtained in free form or in the form of their acid addition salts, which are also covered by the invention. Thus, for example, basic, neutral or mixed salts, possibly hemi-, mono-, sesqui- or polyhydrates thereof can be obtained. The acid addition salts of the new compounds can be transferred in a manner known per se into the free compounds, e.g. with basic agents, such as alkalis or ion exchangers. On the other hand, the free bases formed can form salts with organic or inorganic acids.

For the production of acid addition salts, acids which are suitable for the formation of therapeutically applicable salts are used in particular. Examples of such acids should be mentioned: Hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid , citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid; phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as e.g. the picrates can also serve to purify the formed free bases, as one transfers the free bases into salts, separates them and from the salts releases the bases again. Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the following and the preceding, free compounds are understood to also possibly include the corresponding salts.

Depending on the number of asymmetric C atoms and the choice of starting materials and working method, the new compounds can exist as racemate mixtures, as racemates or optical antipodes.

Due to the physico-chemical differences of the components, racemate mixtures can be divided into the pure racemates in a known manner, e.g. by chromatography and/or fractional crystallisation.

Pure racemates can be separated according to known methods, for example by recrystallization from an optically active solvent with the help of microorganisms or by reaction with an optically active acid that forms salts with the racemic compound and separation of the salts formed in this way, e.g. because of their different solubilities in the diastereomers, from which the antipodes can be liberated by the action of suitable agents. Particularly common optically active acids are e.g. The D and L form of tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated.

According to the invention, however, the end products can also be obtained in the form of the pure racemates or optical antipodes, using one or more asymmetric C-atom-containing starting materials f are in the form of the pure racemates or optical antipodes.

For intestinal infections and for the oral treatment of infections of the urinary tract, fixed dosage unit forms such as tablets, dragées and capsules, which preferably contain between 10 and 90% of an active substance of the general formula I, are particularly suitable in order to enable administration of daily doses between 0.1 and 2.5 g for adults and suitable reduced doses for children.

The following examples explain the preparation in more detail

of the new compounds of the general formula I,

Example 1.

To a solution of 7.95 g of 1-(methyl-thiocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 100 ml of dimethylformamide are added 2.4 g of a 50/5 suspension of sodium hydride in mineral oil . The reaction mixture is heated and stirred for 30 minutes at 50°C, then 10.25 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole is added and the reaction mixture is stirred for another 4 hours at 100°C. The reaction mixture is evaporated in vacuo and then treated with water. The evaporation residue is filtered off, washed with water and ether. After recrystallization from alcohol, 1-(methyl-thiocarbamoyl)-2-oxo-3-/~1-methyl-5-nitroimidazolyl-(227-tetrahydroimidazole) with the formula

which melts at l85-l87°C.

The 1-(methyl-thiocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole required as starting material can be prepared in the following way: A mixture of 86.0 g of ethylene urea and 73.0 g of methyl isothiocyanate is heated 4 hours at 100°C with stirring. The reaction mass is purified after cooling with ether and water, filtered and washed with an alcohol/ether mixture. It is recrystallized from methanol, melting point 168-171°C.

Example 2.

To a solution of 4.7 g of 1-(benzyl-thiocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethylformamide is added 0.95 r of a 50% suspension of sodium hydride in mineral oil. The reaction mixture is heated for 30 minutes at 50°C with stirring. Then you add. 4.1 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole and then stir for another 4 hours at 100°C. The reaction mixture is evaporated

in vacuo, treated with water and then extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and

evaporated in vacuum. The product formed as a residue is expelled with ether and recrystallized from chloroform/alcohol. One obtains 1-(benzyl-thiocarbamoyl)-2-oxo-3-/, 1-methyl-5-nitroimidazoly 1-(227-tetrahydro-

imidazole, which melts at 178-180°C.

The thiocarbamoylimidazole required as starting material can be prepared in the following way. A mixture of 86.0 g of ethylene urea and 149 g of benzyl isothiocyanate is stirred for 6 hours at 150°C. After cooling, a solid reaction mass is obtained which is expelled with ether and then with hot alcohol and then filtered. After recrystallization from chloroform/ethanol, 1-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole is obtained.

Example 3-

To a solution of 5.0 g of 1-(methyl-carbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethylformamide is added 1.7 g of a 50% suspension of sodium hydride in mineral oil. The reaction mixture is stirred for one hour at 50°C. A solution of 7.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 30 ml of dimethylformamide is then added and the resulting reaction mixture is stirred for a further 3 hours at 100°C.

The reaction mixture is evaporated in vacuo and water is added to the residue formed. The resulting red colored solution is then extracted with chloroform to give an oil. After purification with methanol and after recrystallization three times from methanol, 1-(methyl-carbamoyl)-2-oxo-3-/~1-methyl 1-5-nitro-imidazoly 1-(2_)_7-tetrahydro-imidazole is obtained, which melts at 176-177°C.

The methylcarbamoylimidazole required as starting material is obtained by heating a mixture of 8.6 g of ethylene urea and 5.7 g of methyl isocyanate at 130°C in a fused tube for 3 hours. After recrystallization from water and then from chloroform/methanol, methylcarbamoy1-imidazole with a melting point of 198-200°C is obtained. Example 4.

4.8 g of a 50% suspension of sodium hydride in mineral oil are added to a solution of 16.4 g of 1-(methylsulfonyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 120 ml of dimethylformamide. The mixture is stirred at 50°C for 30 minutes. A solution of 20.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 70 ml of dimethylformamide is added and heated for one hour at 100°C. The reaction mixture is evaporated in vacuo and the residue formed is dissolved in water. After cooling, a crystalline residue is obtained which is then filtered off. After recrystallization from acetone/methanol, 1-(methylsulphonyl)-2-oxo-3-/~1-methyl-5-nitro-imidazolyl-(2_)_/-tetrahydroimidazole is obtained, which melts at 202-204°C.

The 1-(methylsulfonyl)-2-oxo-2,3,4,5-tetrahydroimidazole required as starting material can be prepared as follows: A mixture of 86.0 g of ethylene urea and 115 g of methanesulfonyl chloride is stirred at 120°C for 6 hours and then a stream of nitrogen is introduced into the reaction mixture to remove hydrogen chloride gas formed. After cooling, water is added and the mixture is heated on a steam bath until a crystalline precipitate has formed. After filtration, the crystals are washed with alcohol/ether and recrystallized from methanol, melting point 192-195°C.

Example 5.

To a solution of 8.0 g of 1-(benzyl-thiocarbamoyl)-2-oxo-3-^-1-methyl-5-nitroimidazolyl-(2)7-2,3,4,5-tetrahydroimidazole in 80 ml of dimethylsulfoxide is added to 5 ml of concentrated sulfuric acid and the solution is heated for 2 days on a steam bath. The residue is diluted with water, filtered off and then dissolved in ethyl acetate. Ether is added and after recrystallization from ethyl acetate/ether one obtains l-(benzyl-carbamoyl)-2-oxo-3-^~l-methyl-5-nitroimidazoly1-( 2) 7- 2,3,4,5 -tetrahydro-imidazole, which melts at 113-115°C.

Example 6.

To a suspension of. 1.5 g of 50% sodium hydride in 10 ml of dry dimethylformamide is added with stirring during 15 minutes a

. solution of 5.3 g of 1-N-ethyl-thiocarbamoyl-2-oxo-tetrahydroimidazole

in 20 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50°C for 30 minutes and a solution of 4.5 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 10 ml of dry dimethylformamide is added during 5 minutes and then heated at 100°C for 4 hours. The reaction mixture is evaporated in vacuo, the residue is expelled with 50 ml of water, extracted with ethylene dichloride and dried over sodium sulphate. The evaporated residue is chromatographed over silica gel. The fraction is eluted with 2% methanol in chloroform and 1-N-ethyl-thiocarbamoyl-2-oxo-3-/~1-methyl-5-nitroimidazole-(227-tetrahydroimidazole) is obtained, which after recrystallization from a mixture of methylene chloride and hexane melts at 213°C.

The compound mentioned above as starting material can

produced in the following way:

A mixture of 8.6 g of ethylene urea and 8.7 g of ethylene isothiocyanate is heated at 100°C for 4 hours. After cooling, the product is recrystallized from ethanol/ether; 1-N-ethyl-thiocarbamoyl-2-oxo-tetrahydroimidazole is obtained, which melts at 135-136°C.

Example 7-

To a suspension of 2.2 g of 50% sodium hydride in 10 ml of dry dimethylformamide, a solution of 8.7 g of 1-(N,N-dimethylsulfamoyl)-2-oxo-tetrahydro-imidazole is added during 15 minutes with stirring in 20 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50° C. for 1 hour and a solution of 9.25 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 20 ml of dry dimethylformamide is added once. The reaction mixture is heated with stirring and under nitrogen at 95°C for 3 hours. The solution is distilled off in a vacuum and the residue is expelled with 45 ml of water. The suspension is extracted with ethylene dichloride, dried and evaporated. The residue formed is washed with hexane and triturated with acetone. After recrystallization from a mixture of methylene chloride/ether, 1-(N,N-dimethyl-sulfamoyl)-2-oxo-3-/-l-methyl-5-nitroimidazolyl-(2_)/-tetrahydroimidazole is obtained, which melts at 217 °C.

The 1-(N,N-dimethyl-sulfamoyl)-2-oxo-tetrahydroimidazole required as starting material can be prepared in the following way: A mixture of 17.2 g of ethylene urea and 28.7 g of N,N-dimethyl-sulfamoyl chloride is heated at 100 °C for 3 hours. The reaction mixture is cooled and then triturated with 100 ml of methanol. The residue is filtered off, dried, then dissolved in 5% methanol in chloroform and chromatographed over a column of 150 g silica gel. The fraction is eluted with 2% methanol in chloroform and then recrystallized from a mixture of methylene chloride/hexane. The product melts at 129°C.

• Example 8.

A mixture of 34.4 g of ethylene urea and 54.2 g of N,N-diethylcarbamoyl chloride is heated under nitrogen at 110°C for 3 hours. The reaction mixture is cooled and diluted with 200 ml of acetone, then filtered and evaporated. The product is chromatographed over a column of 450 g silica gel. The fraction is eluted with 3% methanol in chloroform. 1-(N,N-diethylcarbamoyl)-2-oxo-tetrahydroimidazole is obtained as a colorless oil.

To a suspension of 5.8 g of 50% sodium hydride in 20 ml of dry dimethylformamide, a solution of 22 g of the above-mentioned 1-(N,N-diethy1-carbamoyl)-2-oxo-tetrahydroimidazole is added under stirring during 15 minutes in 40 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50°C for 1 hour. To this is added a solution of 24.6 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 40 ml of dry dimethylformamide all at once.

The reaction mixture is further worked up as indicated in the example. 6. and the resulting residue (36 g) is chromatographed over a column of 360 g silica gel. The fraction is eluted with 2.5% methanol in chloroform. After recrystallization from a mixture of methylene chloride/hexane, 1-N,N-diethy 1-carbamoyl-2-oxo-3-_/—1-methyl-5-nitroimidazolyl-(2_)_/-tetrahydroimidazole is obtained, which melts at 133°C.

Example 9-

To a suspension of 24.5 g of 50% sodium hydride in 100 ml of dry dimethylformamide, a solution of 78.5 g of 1-(N,N-dimethylcarbamoyl)-2-oxo-tetrahydroimidazole is added with stirring over the course of 15 minutes in 150 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50° C. for 1 hour and, within 10 minutes, a solution of 102.5 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 100 ml of dry dimethylformamide is added. The reaction mixture is heated under nitrogen and stirring at 100°C for 3 hours. The further work-up takes place as indicated in example 6. After recrystallization from a mixture of methylene chloride/hexane, 1-N,N-dimethylcarbamoyl-2-oxo-3-(1-methyl-5-nitroimidazolyl-(227-tetrahydroimidazole) is obtained, which melts at 190-191°C.

The 1-N,N-dimethylcarbamoyl-2-oxo-tetrahydroimidazole required as starting material can be prepared as follows: A mixture of 86 g ethylene urea and 118 g N,N-dimethylcarbamoyl chloride in 200 ml ethylene dichloride is heated for 3 hours under nitrogen and backflow. The reaction mixture is then evaporated and. the residue is dissolved in chloroform and chromatographed over a column of 1.5 kg silica gel. The fraction is eluted with 5% methanol in chloroform and recrystallized from a mixture of methylene chloride/hexane. The above product melts at 134-136°C.

Example 10.

a) To a suspension of 4.5 g of 50% sodium hydride in 10 ml of dry dimethylformamide is added during 15 minutes while stirring

a solution of 16 g of 1-ethylsulfonyl-2-oxo-tetrahydroimidazole in 30 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50°C for 45 minutes and then a solution of 18.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 30 ml of dry dimethylformamide is added all at once and the reaction mixture is heated for 3 hours at 100°C . It is then further processed as indicated in example 6. Raw pro-

the duct is recrystallized from a mixture of methylene chloride/hexane.

The thus formed 1-N-ethyl-sulfonyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2_)7-tetrahydroimidazole, which melts at 176-177°C. b) The required starting material is prepared as follows: A mixture of 29.2 g of ethylene urea and 43.7 g of ethane-sulfonyl chloride is heated for 3 hours at 110°C. The reaction mixture is triturated with 30 ml of methanol and filtered. The filtrate is evaporated and the residue is dissolved in chloroform and chromatographed over a column of 750 g silica gel. The fraction is eluted with 5% methanol in chloroform and then the crystalline substance is recrystallized from a mixture of methylene chloride/hexane. The 1-ethyl-sulfonyl-2-oxotetrahydroimidazole thus formed melts at 114-116°C.

Example 11.

In an analogous way as in example 10 a), using 5.8 g of 1-(4-fluorosulfonyl)-2-oxo-tetrahydroimidazole and 5.0 g of 1-methyl-2-methylsulfonyl-1-5-nitroimidazole will be obtained 1-N-(4-fluoro-phenyl-sulfonyl)-2-ox 0-3-/. 1-methyl-5-nitroimidazoly 1-(2_)7-tetrahydroimidazole, which melts at 198-200°C.

The necessary above-mentioned starting material is prepared as follows: A mixture of 17 g of ethylene urea and 19.5 g of p-fluoro-phenyl-sulfonyl chloride is heated for 3 hours at 100°C. The residue is recrystallized from a mixture of methanol/water, 1-(4-fluoro-phenyl-sulfonyl)-2-oxo-tetrahydroimidazole is obtained, which melts at 183-185°C. Example 12.

To a suspension of 0.1 g of 50% sodium hydride in 2 ml of dry dimethylformamide, a solution of 0.4 g of 2-oxo-3-r~ 1-methyl 1-5-nitroimidazoly 1-(2_)_/ -tetrahydroimidazole in 8 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for 15 minutes and a solution of 0.2 g of methyl isocyanate in 2 ml of dry dimethylformamide is added and then heated for a further 3 hours at 100°C. Further processing takes place as indicated under example 6.

The residue is chromatographed over a column of 40 g silica gel. The fraction is eluted with 5% methanol in chloroform. 1-N-methyl-carbamoyl-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2,7-tetrahydroimidazole) is obtained, which melts at 176-177°C.

Example 13.

To a stirred suspension of 1.3 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide, a solution of 5.41 g of 1-piperidino-carbonyl-2-oxo-tetrahydroimidazole in 15 ml of dimethylformamide is added dropwise at a steady temperature. The reaction temperature is set at 50°C and the reaction mixture is stirred for 30 minutes. A solution of 5.12 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of dimethylformamide is added dropwise over 20 minutes and the temperature is raised to 95°C and kept constant for 1 hour. The reaction mixture is then evaporated in vacuo and the residue is treated with isopropanol ether (5:1). The colorless granules are recrystallized from ethyl acetate/hexane. The thus formed 1-piperidino-2-oxo-3-/. 1-methyl-5-nitroimidazolyl-(2_)7-tetrahydroimidazole melts at 152°C.

Example 14.

To a stirred suspension of 1.92 g of 50% sodium hydride dispersed in mineral oil in 25 ml of dewatered dimethylformamide, a solution of 7.96 g of 1-morpholino-carbonyl-2-oxo-tetrahydroimidazole in 15 ml of dry dimethylformamide is added dropwise . The suspension is stirred at 50°C for 30 minutes. Then, a solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole in 15 ml of dimethylformamide is added over the course of 5 minutes. The reaction temperature is increased to 95°C and maintained for 2 hours with stirring. The reaction mixture is then evaporated in vacuo and the residue is washed with ether and treated with crushed ice. After filtration, 1-morpholinocarbonyl-2-oxo-3-/~1-methyl-5-nitro-imidazolyl-(2_)_/-tetrahydroimidazole is obtained, which melts at 180°C after recrystallization from ether.

The 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole required as starting material is prepared as follows: To a solution of 22.27 g of 1-chloro-carbonyl-2-oxo-tetrahydroimidazole in 80 ml of anhydrous benzene is added dropwise with stirring a solution of 26.1 g of morpholine in 20 ml of benzene. The mixture is heated for 4 hours under reflux. The reaction product is filtered off, treated with a saturated solution of NaHCO^ and filtered. After recrystallization from isopropanol, 1-morpholine-carbonyl-2-oxo-tetrahydroimidazole is obtained, which melts at 158°C.

Example 15-

A solution of 2.9 g of 1-(methylsulfonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2j_/_tetrahydroimidazole) and 1.9 g of ethyloxonium fluoborate in 200 ml of chloroform is prepared at room temperature in 72 hours. A viscous oil separates and crystallizes after trituration with methanol. The solid residue formed is filtered off, boiled off with acetone and recrystallized after filtering off from.. aqueous ethanol. One obtains l-methyl-2-/<->3-(methylsulfonyl )-2-oxo-tetrahydroimidazolyl-(1YJ-3-ethyl-5-nitroimidazolium-fluoroborate of formula

which melts at 265-267°C.

Example 16.

A solution of 3.0 g of 1-(methylsulfonyl)-2-oxo-3-/~l-methyl-5-nitroimidazolyl-(2_)7-tetrahydroimidazole in 30 ml of dimethylformamide, to which 3.0 g of potassium iodide has been added , is heated for 16 hours under reflux. The solvent is then removed in vacuo and the residue treated with water and filtered. The resulting filtrate is acidified with 2 N hydrochloric acid, cooled and filtered again, in order to remove unreacted starting material.

The filtrate is further cooled and the crystalline residue which separates is filtered off and recrystallized twice from an acetone/methanol mixture. One obtains 1-(methylsulfonyl-2-oxo-3-[1-methyl-4-nitroimidazolyl-(2_)7-tetrahydroimidazole, which melts at 180-181°C. Example 17.

A solution of 3.0 g of 1-(methyl-thiocarbamoyl)-2-oxo-3-/~1-methyl-5-nitroimidazolyl-(2_)7-tetrahydroimidazole in 25 ml of dimethylformamide, to which is added 3.0 g potassium iodide, heated for 16 hours under reflux. The reaction mixture is filtered off and the residue is washed successively with hot ethanol and methanol and then recrystallized from a mixture of acetone/methanol. One obtains 1-(methyl-thio-carbamoyl)-2-oxo-3-/~1-methyl-4-nitroimidazoly 1-(2_)7-tetrahydro-imidazole, which melts at 239-241°C. Example 18.

a) A solution of 0.49 g of 1-(methylsulfonyl)-2-oxo-tetrahydroimidazole in 5 ml of dimethylformamide is stirred at a temperature of 50°C for 1 hour with 0.15 g of a suspension of 50% ig sodium hydride in mineral oil. The mixture is mixed with 0.57 g of 1-methyl-2-(methylsulfinyl)-5-nitroimidazole and the solution mixture is heated with stirring for 3 hours at 100°C. The solvent is evaporated in vacuo and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from a mixture of acetone/methanol. One obtains 1-(methylsulfonyl)-2-oxo-3-/~1-methyl-5-nitroimidazolyl-(2_)7-tetrahydro-imidazole, which melts at 202-204°C and is identical to the compound obtained according to example 4.

b) The starting material is obtained in the following way:

A solution mixture of 3.4 g of 1-methyl-2-(methylmercapto)-5-nitro-imidazole and 5 ml of a 30% aqueous hydrogen peroxide solution in 20 ml of methoxyethanol is heated for 6 hours with freshly prepared titanium dioxide at a temperature at 100°C and then diluted with water and filtered off. The filtrate is extracted with chloroform, as the chloroform layer formed is evaporated. You get 2.5 g of an oil, which slowly solidifies on standing. The solid residue formed is recrystallized once from ethanol and then from a mixture of chloroform/ether. 1-Methyl-2-(methylsulfinyl)-5-nitroimidazole is obtained. Example 19.

a) To a stirred suspension of 6.1 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide is added

during 15 minutes a solution of 30 g of 1-(N,N-diethylsulfamoyl)-2-oxo-tetrahydroimidazole in 50 ml of anhydrous dimethylformamide. The reaction mixture is stirred under a nitrogen atmosphere at a temperature of 50°C

for 1 hour and is then mixed with a solution of 25.6 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 40 ml of anhydrous dimethylformamide. The reaction mixture is heated under stirring and nitrogen atmosphere for 3 hours at 95°C. The solvent is removed by vacuum distillation and the residue is digested with 100 ml of water. The resulting suspension is extracted with ethylene chloride, the ethylene chloride layer is dried and evaporated to dryness in vacuo. The residue is chromatographed on a column of silica; gel and in the fraction that is eluted with a methanol-chloroform mixture, a crystalline precipitate separates, which is recrystallized from a mixture of methylene chloride/ether. One obtains 1-N,N-diethyl-1-sulfamoyl-2-oxo-3-/~1-methyl-5-nitroimidazoly1-(227-tetrahydroimidazole), which melts at 146-147°C.

b) The starting material is obtained in the following way:

A mixture of 51.6 g of ethylene urea and 90 g of N,N-diethylsulfamoyl chloride is heated for 3 hours at a temperature of 110°C. The reaction mixture is cooled and digested with 300 ml of methanol, filtered and the filtrate evaporated to dryness in vacuo. The residue is dissolved in a 5% methanol/chloroform mixture and chromatographed on

a column of silica gel. The crystalline fraction eluted with a 5% methanol/chloroform mixture is recrystallized from a mixture of methylene chloride and hexane. 1-(N,N-diethylsulfamoyl)-2-oxo-tetrahydroimidazole is obtained, which melts at 80-82°C.

Example 20.

a) To a stirred suspension of 1.6 g of 50% sodium hydride dispersed in mineral oil in 30 ml of anhydrous dimethylformamide is added

during 15 minutes a solution of 5.9 g of 1-pyrrolidinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml of anhydrous dimethylformamide. The reaction mixture is stirred under a nitrogen atmosphere at a temperature of 50°C for 1 hour and is then mixed with a solution of 6.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of anhydrous formamide. The reaction mixture is heated under stirring and nitrogen atmosphere for 1 hour at a temperature of 95°C. The solvent is removed by vacuum distillation, the residue is digested in water and extracted with ethylene chloride, dried and evaporated to dryness. The residue is chromatographed on a column of silica gel and a fraction that is eluted with a 3% methanol/chloroform mixture gives a crystalline mass, which is recrystallized from a mixture of methylene chloride and hexane. One obtains 1-pyrrolidinocarbonyl-2-oxo-3-/~1-methyl-5-nitroimidazoly 1-(2)7-tetrahydroimidazole, which melts at 155-156°C.

b) The starting material is produced in the following way:

A mixture of 40 g of ethylene urea and 72 g of 1-pyrrolidinocarbonyl chloride (boiling point 100-104°C) 4.5 mm Hg) is heated for 3 hours at a temperature of 110°C. The reaction mixture is cooled and mixed with 200 ml of chloroform. The insoluble part is filtered off by filtration and the filtrate is evaporated to dryness. The residue is chromatographed on a column of silica gel and the fraction eluted with a 4% methanol/chloroform mixture gives a crystalline mass, which is recrystallized from ethyl acetate. One obtains 1-pyrrolidinocarbonyl-2-oxo-tetrahydroimidazole, which melts at 153-154°C.

Example 21.

a) To a suspension of 3.5 g of 50#-ig sodium hydride dispersed in mineral oil in 20 ml of dimethylformamide is added within 15 minutes

a solution of 15.6 g of 1-pyrrolidino-sulfonyl-2-oxo-tetrahydro-

imidazole in 40 ml of anhydrous dimethylformamide. The reaction mixture is stirred under a nitrogen atmosphere at a temperature of 50°C for 1 hour and is then mixed with a solution of 14.4 g of 1-methyl-2-methyl-sulfonyl-5-nitroimidazole in 30 ml of anhydrous dimethylformamide. The reaction mixture is heated under stirring and nitrogen atmosphere for 1 hour at a temperature of 95°C. The solvent is removed by vacuum distillation, the residue is digested with 50 ml of water, forming a crystalline precipitate. The precipitate formed is filtered off and recrystallized from a mixture of methylene chloride/ether. One obtains 1-pyrrolidino-sulfonyl 1-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2,7-tetrahydroimidazole), melting point 226°C.

b) The starting material is produced in the following way:

A mixture of 30 g of ethylene urea and 64.5 g of pyrrolidino-l-sulfonyl chloride (boiling point 120°C/11 mm Hg) is heated for 3 hours at 110°C. The reaction mixture is cooled and dissolved in 300 ml of chloroform, filtered; the filtrate formed is evaporated in vacuo and the residue is dissolved in a 4% methanol/chloroform mixture and chromatographed on a column of silica gel. The fraction that is eluted with a 2.5% methanol/chloroform mixture gives 1-pyrrolidino-sulphonyl-2-oxo-tetrahydroimidazole, which after recrystallization from ethyl acetate melts at 150°C.

Example 22.

a) To a suspension of 1.92 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide, mix

dropwise with a solution of 9j3 g of 1-piperidinosulfonyl-2-oxo-tetrahydroimidazole in 15 ml of dimethylformamide at room temperature. The reaction temperature is increased to 50°C and stirred for a further 30 minutes. A solution of 8.2 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 25 ml of dimethylformamide is added and the reaction temperature is maintained for 2 hours at 100°C. The solvent is removed under reduced pressure and the residue is treated with water containing crushed ice. The residue is treated after removal of the aqueous layer with a solution; middle mixture isopropanol/ether (5:1). The slightly yellow precipitate thus formed is recrystallized from ethyl acetate and 1-piperidinosulfonyl-2-oxo-3-/.~1-methyl-5-nitroimidazoly 1-(2_)7-tetrahydroimidazole is obtained, melting point 192°C.

b) The starting material is produced in the following way:

To 17.4 g of ethylene urea add, while shaking, 36 g

piperidinosulfonyl chloride (boiling point 130°C711 mm Hg) and reaction mixture

none is kept under a nitrogen atmosphere for 3 hours at 100°C. After cooling, the rubbery reaction product is treated with a solvent mixture of methanol/isopropanol (1:1). 1-piperidinosulfony1-2-oxo-tetrahydroimidazole is obtained as a granular product, which after recrystallization from methanol melts at 201°C.

Example 23-

a) To a solution of 8 g of 1-(methylsulfonyl)-2-oxo-4-methyl-2,3,4,5-betrahydroimidazole in 30 ml of dewatered dimethylformamide

2.2 g of a 50# suspension of sodium hydride in mineral oil is added and the mixture is stirred at room temperature for 1 hour. A solution of 9.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of dewatered dimethylformamide is added to this reaction mixture and stirred for 3 hours. The solvent is removed in vacuo and the residue is dissolved in water. When the solution is cooled, a crystalline precipitate is obtained which is filtered off and recrystallized from a mixture of methylene chloride/ether. One obtains 1-(methylsulfonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2_)7-4-methyl-tetrahydroimidazole, which melts at 199-200°C.

b) The 1-(methylsulfonyl)-2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole used as starting material is prepared in the following way

manner:

A mixture of 10 g of 4-methyl-2-imidazolidinone and 11.5 g of methylsulfonyl chloride was heated for 3 hours with stirring at a temperature of 120°C. At the same time, a stream of nitrogen is introduced to remove formed hydrochloric acid gas. After cooling, water is added and the mixture is heated in a water bath until a crystalline powder forms which is filtered off and, after dissolution in chloroform, chromatographed on a silica gel column. The fraction eluted with a mixture of chloroform/methanol (97:3) contains ^(methyl-sulfonyl)-2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole, which is recrystallized from a solvent mixture of methylene chloride /hexane and melts at 129-130°C.

Example 24.

To a solution of 8.2 g of 1-(methylsulfonyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 60 ml of dimethylformamide is added 2.4 g of a 50% suspension of sodium hydride in mineral oil. The mixture is stirred for 1 hour at room temperature. A solution of 12.45 g of 1-(3-methoxyethyl)-2-methylsulfonyl-5-nitroimidazole in 20 ml of dimethylformamide is added and the reaction mixture is stirred at room temperature for 4| hour. The dimethylformamide is evaporated in vacuum on a steam bath. The residue is treated with 30 g of crushed ice until crystals form.

The crystalline residue is filtered off and then recrystallized

. ,. from a mixture of acetone/methanol and ether. One obtains 1-(methylsulfonyl)-2-oxo-3-[1-6-methoxyethyl-5-nitro-imidazolyl-(2)-]-tetrahydroimidazole

Melting point 126-127°C.

The starting material is produced in the following way:

a) g- methoxy- ethylamino- acetaldehyde- diethyl acetal.

A mixture of 170 ml of 65/S-ig aqueous solution of 3~

methoxyethylamine and 90 g of bromoacetaldehyde-diethyl acetal are heated in a steel tube for 16 hours at 120°C. The reaction mixture is treated with 75 g of potassium hydroxide on cooling, filtered and the filtrate is dried

over anhydrous potassium carbonate, then distilled at 115-120°/

12 mm and you get B-methoxyethylamino-acetaldehyde-diethylacetal.

b) 1-(3-Methoxyethyl)-2-mercaptoimidazole.

A solution of 9.55 g of 6-methoxyethylamino-acetaldehyde-diethyl acetal in 50 ml of absolute ethanol is treated sequentially with 6 g of potassium thiocyanate and 27.5 ml of 2 N hydrochloric acid. The reaction mixture is boiled for 16 hours under reflux. The solvent is removed in vacuo on a steam bath and the residue is extracted with acetone. The extract is concentrated to a small volume and treated with ether. The residue formed is recrystallized from a mixture of acetone/ether. 1-(3-methoxyethyl)-2-mercaptoimidazole is obtained, melting point 92-95<3C.

c) 1-(6-Methoxyethyl)-2-methylmercapto-5-nitroimidazole.

To a cooled solution of 15.8 g of 1-(3-methoxyethyl)-2-mercaptoimidazole in 90 ml of methanol, 110 ml of 10 M sodium hydroxide are added at once while stirring and cooling. The reaction mixture is then treated dropwise with 6.6 ml of methyl iodide over the course of 1 hour. The reaction mixture is stirred for a further 2 hours at 10°C, the methanol is removed in vacuo at 50°C and the residue is diluted with water and extracted with methyl chloride, dried and evaporated to dryness.

The compound formed above (15.3 g) is treated dropwise with 82 ml of concentrated hydrochloric acid under a nitrogen atmosphere. The reaction mixture is slowly heated with stirring and held for 40 minutes at 100°C. After cooling to room temperature, the residue is poured onto 50 g of crushed ice, neutralized with 50/5 sodium hydroxide solution and extracted with methylene chloride and evaporated to dryness. The residue is slowly recrystallized from hexane and the above-mentioned product is obtained, melting point 44-45°C.

d) 1-(g-Methoxyethyl)-2-methylsulphonyl-5-nitroimidazole.

A solution of 26 g of 1-(f5-methoxyethyl)-2-methylmercapto-5-nitroimidazole in 80 ml of methylene chloride is treated dropwise with 550 ml of a 0.48 molar solution of monoperphthalic acid for 6 hours at 10-15°C. The reaction mixture is stirred for 20 hours at room temperature, boiled for 1 hour under reflux and cooled to room temperature and filtered. The filtrate is washed successively with sodium bicarbonate solution and water, then dried and evaporated to dryness. A crystalline residue is obtained, which is recrystallized from a mixture of methylene chloride and hexane. 1-(6-Methoxyethyl)-2-methylsulfonyl-5-nitroimidazole is obtained, melting point 92-93°C.

Example 25

A solution of 0.4 g of 3-/1-methyl-5-nitroimidazolyl (2)-7-2-oxo-tetrahydroimidazole in 8 ml of dimethylformamide is added to a suspension of 0.1 g of sodium hydride in dimethylformamide, and the reaction mixture is stirred at room temperature for 25 minutes. A mixture of 0.2 g of methyl isocyanate and 2 ml of dimethylformamide is added and then heated at 100°C for three hours, then evaporated, crushed with IN hydrochloric acid, extracted with methyl chloride, 1-(methyl-carbamoyl)-2-oxo- 3-/1-methyl-5-nitroimidazolyl-(2)_7~tetrahydro-imidazole, which melts at 176-177°C.

Example 26

To a solution of 0.4 ml conc. nitric acid and

4 drops of concentrated sulfuric acid are added to 68 g of 1-(methylsulfonyl)-2-oxo-3-(1-methylimidazolyl-(2).7-tetrahydroimidazole) and the reaction mixture is heated for 2 hours at 110-115°C. The reaction mixture is poured onto ice, neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract is dried over ^280^ and then evaporated. The evaporation residue is chromatographed over silica gel. One obtains 1-(methyl-sulfonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl (2}_7-tetrahydroimidazole, which melts at 202-204°C.

The starting material is produced as follows:

To a solution of 16 g of 2-amino-1-methylimidazole in 165 ml of acetonitrile, a solution of 31 g of chloroethyl isocyanate in 80 ml of acetonitrile is added dropwise over 30 minutes with stirring at room temperature and then heated under reflux for 10 hours. The solution is cooled and the residue is recrystallized. The free base 1-(1-ethyl-imidazolyl-(2)J-imidazolidinone is separated with potassium carbonate and crystallized from chloroform ether, it melts at 136-137°C.

0.16 g of sodium hydride (50% dispersion in oil) and the reaction mixture is stirred for 30 minutes. Methanesulfonyl chloride (0.6 g) is added dropwise and the solution is stirred in an ice-base for one hour and kept at ambient temperature for 3 hours. The residue is filtered, the filtrate is evaporated to dryness, 0.6 g of an oily residue is obtained, which is chromatographed over silica gel. The fraction is eluted with chloroform, crystallized from isopropanol ether and 1-(methylsulfonyl)-2-oxo-3-(1-methylimidazolyl-(2)-7-tetrahydro-imidazole is obtained, which melts at 171-172°C.

Claims (1)

Analogy method for the preparation of therapeutic active nitroimidazole derivatives of formula I in which one of the residues R, and R2 means hydrogen and the other nitro group, R3 means lower alkyl of 1-3 C atoms or lower alkoxy lower alkyl of at most 4 C atoms, X means a carbonyl, thiocarbonyl or sulfonyl group, and if X means a carbonyl group or sulfonyl group, R^ means a piperidino, pyrrolidino- , morpholino, lower alkylamino or dilower alkylamino group, and if X means a thiocarbonyl group, R^ means a benzylamino, lower alkylamino or dilower alkylamino group, and if X means a sulfonyl group, means R^ a lower alkyl group or optionally halogenated phenyl, and R5 means hydrogen or methyl, as well as their salts and N-oxides, characterized in that either a) an imidazole of formula II wherein R^, R2 and R^ have the above meaning and Z means a reactive esterified hydroxy group, a halogen atom, a reactive etherified hydroxy group, a free or etherified marcapto group, an ammonium group or sulfinyl or sulfonyl group, is reacted with a compound of formula III wherein , R(-, X and alk) have the above meaning, or b) an imidazole of formula IV in which R^, R^, R g and X have the above meaning, and the residues R^ and R 2 ' mean hydrogen, are nitrated, or c) an imidazole of formula V in which R 1 , R 2 , R 3 and R 3 have the above meaning is reacted with a compound of formula VI wherein R^ has the above meaning, or in a formed compound of the general formula I, wherein X means a thiocarbonyl group, this can be converted into the carbonyl group and/or a formed 5-nitro compound of formula I can be converted into a 4-nitro compound and/or formed salts are converted into the free compounds or other salts or formed free compounds in their salts.