FI62293B - ANALOGIFICATION OF THERMAL NUTROIMIDAZOLDERIVAT - Google Patents

Description

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Switzerland-Switzerland (CH) 13667/73 (71) Ciba-Geigy AG, CH-U002 Basel, Switzerland-Switzerland (CH) (72) Kuppusvamu Nagarajan, Bombay, Vistrwa Prakash Arya, Bombay,

Thomas George, Bombay, India-India (IN) (7U) Oy Jalo Ant-Wuorinen Ab (iU: An alogiamene roll for the preparation of therapeutically active nitroolated sol derivatives - for the preparation of active nitroimidazole derivatives of the formula

jf f I

-X-R * R3 0 wherein one of R1 is hydrogen and the other is nitro, R0 is lower alkyl of 1-3 carbon atoms or lower.

O

coke lower alkyl having up to u carbon atoms, X represents a carbonyl, thiocarbonyl or sulfonyl group, and when X represents a carbonyl group or ^ u: -onyv_i '-yhu- "i-, R., is e; p ^ r-id i ^ o-, pyrrolidine-, morieliv'u- - empi aiv .. vii e-> · - ai J rl "p:.-Ikyvliam: -o ^ group, 2 62293 and when X represents a thiocarbonyl group, is a benzylamino, lower alkylamino or dialkylalkylamino group, and when X represents a sulfonyl group, is a lower alkyl group or optionally halogenated phenyl, and R 1 represents hydrogen or methyl, and for the preparation of their salts or N-oxides.

Lower alkyl radicals are, for example, methyl, ethyl, n-propyl or isopropyl, or straight-chain or branched butyl.

Lower alkoxy lower alkyl radicals are, for example, those having up to 4 carbon atoms in the lower alkyl moieties, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2- (n-butoxy) ethyl, 3- (n-propoxy) propyl or especially 2-methyloxyethyl.

The lower alkylamino is e.g. methyl, ethyl or n-propylamino and the lower alkylamino is e.g. dimethylamino, N-methyl-N-ethylamino, diethylamino, di-n-propylamino or di-n-butylamino.

The phenyl residue R 1 may also be optionally substituted by halogen atoms.

Suitable halogen atoms are chlorine or bromine atoms, in particular fluorine.

The new compounds have valuable pharmacological properties. Thus, they are particularly effective against bacteria, especially gram-negative spores, protozoa and worms such as trichomonads, schistosomes and above all amoebas, as can be demonstrated in animal experiments, e.g., in the liver of healthy hamsters artificially infected with Entamoeba histolytica using Doses of 10 to about 100 mg / kg / po.

The therapeutic properties of the compounds according to the invention will become apparent from the following experimental reports.

3 62293

Test Report No. 1 Test Compounds I. 1-Methanesulfonyl-3- (1-methyl-5-nitroimdazolyl- (2)} - 2-oxo-tetrahydroimidazole (compound of the present invention) II.1-Acetyl-3- (1 -methyl-5-nitroimidazolyl- (2)} - 2-oxo-tetrahydroimidazole (compound according to DE-OS 2 220 235)

Test Methods

Tr ichcmo n i a s i s

For in vivo testing of the compounds against trichomoniasis, Albino mice, a Swiss strain susceptible to both T. fetus and T. vaginalis, were selected as experimental animals.

Albino mice (Swiss strain) weighing between 20 and 25 g were infected with T. fetus or T. vaginalis subcutaneously at the neck with a syringe and needle. The vaccine volume ranged from 0.1 to 0.5 ml per mouse. Both T fetus and T. vaginalis caused lesions in the neck region. When the mice were necropsied on the fifth day after infection, abundant motile Trichomonas organisms were observed under a microscope.

Mice were treated 2-4 hours before infection. Medication continued for the next three days. On the fifth day, the mice were killed. The lesions were examined microscopically for the presence of Tricho-monas organisms.

The absence of Trichomonas organisms in the treated animals was considered an improvement and the percentage improvement was calculated. caecal amoebiasis

to test the compounds against caecal amoebiasis in experimental animals Hamsters were selected. The appendix of the hamsters could be easily infected and amoebic abscesses could be induced in the appendix of the hamster.

Hamsters (weighing 40-110 g) were anesthetized with ether vapor in a small glass vessel. Hamsters, on their left abdomen, underwent a small paramedian incision below the stomach. The appendix was removed and the amoeba vaccine was administered to the appendix with a syringe and needle. Approximately 200,000 amoebas were suspended in 1 ml of buffered saline to form an infectious vaccine.

E. histolytica culture was performed by the usual method in the LES stage, and a 24-hour culture was used for hamster terrain infection.

4 62293

Hamster treatment was started 24 hours after infection and continued for the next 4 days. On the fifth day after infection, the treated animals were sacrificed. The cecum was excised and smear samples were taken and examined under a microscope for the presence of E. histolytica. For further confirmation, caecum was also cultured. The control hamsters had acute infection with abscesses.

The absence of amebas in the treated animals was considered an improvement and the percentage improvement was calculated.

I have an amoebic disease

Hamsters were used for experimental hepatic Entamoeba histolytica infection. Ameba liver abscesses were induced in young kulamamsters (approximately one month old and weighing 45-90 g) by the gelatin-sponge implant method (gelatin-sponge implant; Jarumilinta, 1966). The vaccine for infection was derived from a 24-hour culture of trophosites from the human patient's virulent strain Entamoeba histolytica (SLF1). Small pieces of sterile jelly sponge (spongostan; A / S Ferrosen, Chem.Phams.Fabrik, Copenhagen, Denmark) of about 6.0 x 4.0 x 2.5 mm were used to localize amoebas on the liver surface during infection. The abdominal cavity of hamsters under ether anesthesia was opened with lead in a paramedian incision in the epigastric region. Using forceps, a piece of jelly was placed between the middle and left lobes of the liver just above the gallbladder. 0.1 ml of amoeba suspension vaccine (approximately 30,000-35,000 amoeba) was added to the jelly sponge using a syringe. The gastric ulcer was then closed with Michel forceps. Aseptic precautions were followed during surgery.

Absence of ameboes in treated animals was considered an improvement and the percentage improvement was calculated.

R. Jarumilinta; Ann.Trop.Med.Parasit. 6j0 (2) 139 (1966).

Test results

Antithrichomonal activity

Compound Strain Dose mg / kg% improved ___p, o, 4 days__ I T.foetus 15 x 2 40 T.vaginalis 15 x 2 40 15 x 3 90 II T.foetus 30 x 2 10 T.vaginalis 30 x 2 10 30 x 3 50 5 62293

Closed-mouth antimatter activity (multiple dose)

Compound Strain Dose mg / kg% improved ___ p.o. 4 days __ I E.histolytica 20 100 II S. histolytica 20 33.3 30 80

Hepatic antimatter activity (single dose) _Compound_Strain_ Dose mg / kg xl% improved I E.histolytica 50 x 1 100 II E.histolytica 50 x 1 42.8

Hepatic antimatter activity (multiple dose)

Compound Strain Daily% improved dose, 2 days ___ mg / kg p.o._ I E.histolytica 20 84.6 10 47.3 II E.histolytica 20 40.9 10 27.2

Summary

The data given in the tables above clearly show the superiority of Compound I in all experiments over Compound II. For example, Compound I has about 4 times better antitrichomonal activity than Compound II; At a dose of 15 x 2 mg / kg, Compound I improved 40% of the animals, while even a double such dose improved only 10%. It is evident that the efficacy is dose-opposite for both compounds, as at a dose of 15 x 3 mg Compound I improved 90% of the animals while at twice such a dose Compound II improved only 50%.

Antiameeba-cecal activity of the compound I is about 3 times more potent than compound II. Compound I is more than twice as potent as Compound II at single doses of hepatic antimeba activity, whereas Compound I is twice as potent as Compound II at multiple doses.

Thus, it is apparent that in all three parameters, Compound I is significantly superior to Compound II.

6 62293

Test report No. 2

The new compounds of the invention were tested for their anti-amoeba properties and compared to a commercial compound, 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole (Flagyl®, U.S. Patent 2,944,061).

Compounds tested: A. 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole (according to this invention), B. 1- (methylthiocarbamoyl) -2- oxo-3- (1-methyl-5-nitroimidazolyl- (2) 1-tetrahydroimidazole (according to this invention), C. 1-N, N-dimethylcarbamoyl-2-oxo-3- (1-methyl- 5-nitroimidazolyl-1- (2)) - tetrahydroimidazole (according to the present invention), D. 1N, N-Diethylcarbamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole (according to the present invention), E. 1-methyl-3- (1-methyl-5-nitro-2-imidazolyl-4-imidazoline-2-thione (according to DE-OS 2 304 508.1), F. 1- ( 2-hydroxyethyl) -2-methyl-5-nitroimidazole (FLAGYL®) (according to U.S. Patent 2,944,061).

The curative effect of test compounds against amoebas in the liver of healthy hamsters artificially infected with Entamoeba hystolytica'11a is (Lit .: Jarumilinta, Rawewn (1966), Ann.Trop.Med.

Parasit. £ 0, 130): j Test substance ED50 p.o. x 2! A 12 (11-15) B 8 (6-10) j C 13 (11-15) D 15 (13-17) E 28 (25-31) F 44 (42-46)

The results obtained show that the new compounds A, B, C and D have a clearly superior effect compared to the known compounds E and F.

») • 62293

The novel imidazoles can thus be used in particular against amoebas, schistosomes, trichomonades and bacteria. The novel iminazoles can also be used as starting materials or intermediates for the preparation of other compounds, in particular therapeutically active compounds.

Among the new imidazoles of the formula I, mention may be made in particular of 1- (methylsulphonyl) -2-oxy-3- (1-methyl-5-nitroimidazolyl- (2)] -tetrahydroimidazole, 1-N, N-diethylcarbamoyl-2- oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole, 1-N, N-dimethylcarbamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl '- (2 )) - tetrahydroimidazole, 1N-ethylthiocarbamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole and 1-N-methylthiocarbamoyl-2-oxo-3- [1-methyl- 5-nitroimidazolyl- (2)) - tetrahydroimidazole, which in the liver of healthy hamsters artificially infected with Entamoeba histolytica'11a at doses of 10-100 mg / kg / po clearly induces the disappearance of abscesses.

The new imidazoles are prepared by methods known per se.

Thus, novel imidazoles can be obtained, e.g., by imidazole of the formula

R -N

Il 11

R -ϋ 1J — Z

* 3 wherein, R2 and R1 are as defined above and Z is 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, is reacted with a compound of the formula

I I III

HN N - X - R

Y

0 8 62293 wherein R 1, R 8 and X are as defined above.

The reactive esterified hydroxy group Z is in particular with a strong inorganic or organic, in particular hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, also sulfuric acid or an organic sulfonic acid, such as aromatic sulfonic acid or alfonic acid, or benzenesulfonic acid, e.g. a hydroxyl group esterified with a phosphatic sulfonic acid such as an alkanesulfonic acid, e.g. methanesulfonic acid or ethanesulfonic acid. Thus, Z in particular means chlorine, bromine or iodine.

The reactive etherified hydroxy group is, for example, a hydroxyl group etherified with an aromatic or aliphatic, in particular lower aliphatic alcohol, such as an optionally substituted phenoxy group or an alkoxy group, in particular a lower alkoxy group, in particular methoxy or ethoxy.

The etherified mercapto group is, for example, an optionally substituted phenyl mercapto or benzyl mercapto group, or in particular a lower alkyl mercapto group, such as an ethyl or methyl mercapto group.

The ammonium group is in particular a quaternary ammonium group, in particular a tri-lower alkylammonium group, e.g. a trimethyl or triethylammonium group, or a cation of an aromatic nitrogen base, e.g. a pyridinium or quinolinium group.

The sulfinyl or sulfonyl group is in particular a sulfinyl or sulfonyl group derived from an organic sulfinic or sulfonic acid, especially an aromatic sulfinic or sulfonic acid. Thus, in particular, Z denotes benzenesulphinyl or methylsulphinyl, i.e. benzenesulphonyl, p-bromobenzenesulphonyl, p-toluenesulphonyl or methylsulphonyl.

This reaction can be carried out in a conventional manner. Preferably, work is carried out in the presence of a basic condensing agent, or the compound of formula III is reacted in the form of its N-metal derivative, such as its N-alkali metal derivative, obtained for example from a compound of formula III and an alkali metal, such as lithium, sodium or potassium amide, , a hydrocarbon compound, a hydroxide or an alcoholate, and which can be used without isolation. Suitable basic condensing agents include, for example, alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or organic tertiary nitrogen bases, such as trialkylamines, e.g. trimethylamine and triethylamine, or pyridine. An excess of a compound of formula III may also be used. The work is preferably carried out at elevated temperature and / or in the presence of an inert solvent, such as a solvent containing 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 by nitrating an imidazole of formula I5

V - N | -1 IV

r i j -; - χ - r4

> T

R 30 is wherein R 9, R 2, R 5 and X are as defined above, and the radicals R 2 'and R 7' are as defined above. mean hydrogen.

The nitration can be carried out in a manner known from imidazole chemistry, e.g. a nitric acid addition salt of a compound of formula IV, with nitrous oxide, e.g. nitrous hydroxide boron trifluoride, especially in a suitable solvent, e.g. nitro hydrocarbon such as nitroalkanes, e.g. nitromethane, or nitrous tetroxide, e.g. acetonitrile, e.g. acetonitrile.

Suitable N-nitro compounds include, for example, nitramides, such as nitro-urethanes, nitroguanidines, nitro-biuret, and a nitro-urea, e.g., ethylenedinitrovirus (cf. J.Org.Chem. 1952, 1886-1894).

Acidic substances, such as acetic acid, primarily mineral acids, especially sulfuric acid, may be present in the nitration, preferably in concentrated form.

62293 10

The acid treatment of the nitric acid addition salt of the compound of formula IV is conveniently carried out at an elevated temperature, suitably at i + 0-100 ° C, e.g. at 60-80 ° C. The desired product can be isolated by methods known per se, e.g. by pouring the reaction mixture into ice and ice water.

According to a third method, compounds of formula I are obtained by reacting a compound of formula

Is MTJLn nh v r3 o wherein R 1, R 9 and R 8 are as defined above, to react with a compound of formula

R4 - N = C = 0 VI

where means the same as above.

The reaction can be carried out in a conventional manner. Preferably, the work is carried out under the same conditions described for the reaction of the compounds of formula II with the compounds of formula III.

Substituents can be added to the resulting compounds within the definition of the final products, they can be modified or cleaved.

An imidazole of formula I having an N-heterocyclic residue can be N-oxidized.

The oxidation takes place in the customary manner, e.g. with N-oxidizing agents, such as hydrogen peroxide, ozone, inorganic peracids, e.g. sulfuric acids, such as Caro's acid, or in particular with organic peroxy compounds, such as, in particular, organic peracids, or phthalic monoperacid, which may also be substituted, e.g. in the presence of molybdenum compounds.

In the obtained compounds in which X represents a thiocarbonyl group, X can be converted into a carbonyl group in a conventional manner, in particular by hydrolysis methods known per se, e.g. by treating the obtained thiocarbonyl compounds with an alkaline substance such as alkali hydroxide in the presence of an oxidizing agent such as hydrogen peroxide. The conversion can also take place in the presence of a strong acid, for example a mineral acid, such as concentrated sulfuric acid, in a suitable solvent.

Compounds of formula I which contain a nitro group as a residue can be converted by a rearrangement reaction into the corresponding nitroimidazoles, i.e. compounds of formula I which contain a nitro group as a residue. Such repetition occurs, for example, by reacting an excess of an alkali iodide, especially potassium iodide, in an inert solvent, preferably a solvent containing polar functional groups such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or hexamethylphosphoric phosphorus phosphorus

The conversion of R 1 = nitro compounds of formula I to R 1 = nitro compounds can also take place by reacting an iodide corresponding to the residue R 8, R 9, such as methyl iodide, to react compounds of formula I which contain a methyl group as the R 8 residue. In this rearrangement, the unsubstituted nitrogen atom of the imidazole ring quaternizes. The quaternary salt is then hydrolyzed. This rearrangement also takes place, for example, in the presence of an inert solvent, preferably one of the solvents described above.

Subsequent changes may be made individually or in combination and in any order. In individual procedures, care must be taken not to react to other functional groups.

The starting materials are known or, if they are new, can be prepared by methods known per se. The new starting materials also form part of the invention.

The starting compounds of formula III used in the reaction of the first process can be prepared by reacting a compound of formula 12 62293 with the formula R5

HN NH

wherein R 1 is as defined above, i.e. by reacting, for example, imidazolidin-2-one with a compound of formula R 1 -X-Z, wherein R 1, X and Z are as defined above.

The starting compounds of formula IV used in the second process can be prepared by condensing a suitable imidazole derivative of formula II having a displaceable group Z with a compound of formula III according to the method described in connection with the first process.

Depending on the process conditions and starting materials, the final products are always obtained in free form or also as acid addition salts within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained, possibly also their hemi-, mono-, sesqui- or polyhydrates. The acid addition salts of the novel compounds can be converted into the free compound in a manner known per se, e.g. with basic substances such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In particular, acids suitable for the preparation of therapeutically useful salts are used to form acid addition salts. Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, malic, tartaric, citric, ascorbic, material, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid ·, halobenzenesulfonic, toluenesulfonic, sulphanilic acid; methionine, tryptophan, lysine or arginine.

13 62293

These and other salts of the novel compounds, such as picrates, can also be used to purify the resulting free bases, converting the free bases to salts, separating these, and releasing the bases from the salts again. Since the new compounds in the free form and in the form of their salts are very similar, it is to be understood at the same time and expediently by the free compounds above and below that the corresponding compounds may also be meant to refer to the corresponding salts.

Depending on the number of asymmetric C atoms and the choice of starting materials and the way in which they work, the new compounds can be in the form of racemic mixtures, racemates or optical antipodes.

The racemate mixtures can be separated into the pure racemates in a known manner on the basis of the physicochemical differences between the constituents, e.g. by chromatography and / or fractional crystallization.

Pure racemates can be separated into diastereomers by methods known per se, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction with a racemic compound with a salt-forming optically active acid and separation of the salts thus obtained, e.g. on the basis of their different solubilities. from which the anti-ode can be liberated by suitable agents. Particularly useful optically active acids are, for example, the D and L forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or Chinese acid. Preferably, the more potent is isolated from both antipodes.

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

According to the invention there is also provided a therapeutic composition comprising an antimicrobially effective amount of a compound of general formula I (cf. above), its 5-N-oxide or acid addition salt, and a pharmacologically acceptable solid carrier or liquid diluent.

The following examples illustrate the preparation of the novel compounds of general formula I. Temperatures are given in degrees Celsius.

62293 14

Example 1:

To a solution of 7.95 g of 1- (methylthiocarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 100 ml of dimethylformamide is added 2.4 g of a 50% mineral oil suspension of sodium hydride. The reaction mixture is heated and stirred at 50 ° for 30 minutes, then 10.25 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole are added and the reaction mixture is stirred for a further 4 hours at 100 °. 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, the alcohol gives 1-methyl-thiocarbamoyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole of the formula »-Ιί I-1 | ii I ^ 0oN-k. > - N N - C - NHCHo 2 Nr | 3! I s CH3 o 15 62293 melting at 185-187 °.

The 1- (methyl-thiocarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole required as a starting material can be prepared as follows: A mixture of 86.0 g of ethylene urea and 73.0 g of methyl isothiocyanate is heated at 100 ° for 4 hours: while confusing. After cooling with ether and water, the reaction mass is purified, filtered and washed with an alcohol / ether mixture. Recrystallized from methanol, m.p. 168-171 °.

Example 2:

To a solution of 4.7 g of 1H-benzyl (thiocarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethylformamide is added 0.95 g of a 50% mineral oil suspension of sodium hydride. The reaction mixture is heated at 50 ° for 30 minutes while stirring. 4.1 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole are then added and the mixture is further stirred for 4 hours at 100 °. 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 vacuo. The residual product is triturated with ether and recrystallized from chloroform / alcohol.

1- (Benzyl-thiocarbamoyl) -2-oxo-3- (1-methyl-5-nitro-imidazolyl- (2)} -tetrahydro-imidazole is obtained, melting at 178-180 °.

The thiocarbamoyl imidazole required as a starting material can be prepared as follows. A mixture of 86.0 g of ethylene urea and 149 g of benzyl isothiocyanate is stirred for 6 hours at 150 °. After cooling, a solid reaction mass is obtained which is triturated 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- (methylcarbamoyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml of dimethylformamide is added 1.7 g of a 50% mineral oil suspension of sodium hydride. The reaction mixture is stirred for 1 hour at 50 °. A solution of 7.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 30 ml of dimethylformamide is then added and the reaction mixture obtained is stirred for a further 3 hours at 100 °.

The reaction mixture is evaporated in vacuo and water is added to the residue obtained. The resulting red-stained solution is then extracted with chloroform to give an oil. After purification with methanol and after triple recrystallization from methanol, 1- (methylcarbamoyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting at 176-177 °.

The methyl carbamoyl imidazole required as a starting material is obtained by heating a mixture of 8.6 g of ethylene urea and 5.7 g of methyl isocyanate at 130 ° in a sealed tube for 3 hours. After recrystallization from water and then from chloroform / methanol, methylcarbamoylimidazole with a melting point of O "128-200 ° is obtained.

Example 4:

To a solution of 16.4 g of 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetrahydroimidazole in 120 ml of dimethylformamide is added 4.8 g of a 5% mineral oil suspension of sodium hydride. The mixture is stirred at 5 ° C for 30 minutes. A solution of 20.5 g of 1-methyl-2-enethylsulfonyl-5-nitroimidazole in 70 ml of dimethylformamide is added and the mixture is heated at 100 [deg.] C. for 1 hour. The reaction mixture is evaporated in vacuo and the residue obtained is dissolved in water. After cooling, a crystalline residue is obtained, which is then filtered. After recrystallization from acetone / methanol, 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting at 202-204 °.

The starting 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetrahydroimidazole can be prepared as follows:

A mixture of 86.0 g of ethylene urea and 115 g of methanesulfonyl chloride is stirred at 120 ° for 6 hours and then a stream of nitrogen is introduced into the reaction mixture to remove the hydrogen chloride gas formed. After cooling, water is added and the mixture is heated on a steam bath until a crystalline precipitate forms. After filtration, the crystals are washed with alcohol / ether and recrystallized from methanol; mp 192-195 °.

17 62293

Example 5:

To a suspension of 1.5 g of 50% sodium hydride in 10 ml of dry dimethylformamide, a solution of 5.3 g of 1-N-ethyl-thiocarbamoyl-2-oxo-tetrahydroimidazole in 20 ml is added with stirring over 15 minutes: in dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50 ° C for 30 minutes and then a solution of 4.5 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 10 ml of dry dimethylformamide is added over 5 minutes and then heated at 100 °. at 4 hours. The reaction mixture is evaporated in vacuo; the residue is triturated with 50 ml of water, extracted with ethylene dichloride and dried over sodium sulfate. The evaporation residue is chromatographed on silica gel. The fraction is eluted with 2% methanol in chloroform to give 1-N-ethyl-thiocarbamoyl-2-oxo-3- (1-methyl-5-nitroimidazole- (2)) -tetrahydroimidazole, which, after recrystallization from a mixture of methylene chloride and hexane, melts at 213 °. :in.

The above-mentioned compound can be prepared as follows.

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

Example 6:

To a suspension of 2.2 g of 50% sodium hydride in 10 ml of dry dimethylformamide is added a solution of 8.7 g of 1- (N, N-dimethylsulfamoyl) -2-oxo-tetrahydroimidazole under stirring over 15 minutes. in ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50 ° for 1 hour and a solution of 9.25 g of 1-methyl-2-methylsulfonyl-5-nitroinidazole in 20 ml of dry dimethylformamide is added in one portion. The reaction mixture is heated under stirring under nitrogen at 95 ° for 3 hours. The solution is distilled in vacuo and the residue is triturated with 45 ml of water. The suspension is extracted with ethylene dichloride, dried and evaporated. The residue obtained is washed with water and triturated with acetone. After recrystallization from methylene chloride / ether, 1- (N, N-dimethylsulfamoyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting in 217 a.

The starting 1- (N, N-dimethylsulfamoyl) -2-oxo-tetrahydroimidazole can be prepared as follows:

A mixture of 17.2 g of ethylene urea and 28.7 g of M, N-dimethylsulfamoyl chloride is heated at 100 ° for 3 hours. The reaction mixture is cooled and then triturated with 100 ml of methanol. The residue is filtered, dried, then dissolved in 5% methanol in chloroform and chromatographed through a column containing 150 g of silica gel. The fraction is extracted with 2% methanol in chloroform and then recrystallized from methylene chloride / hexane. The product melts at 129 °.

Example 7;

A mixture of 34 μg of ethylene urea and 54.2 g of '' -N-diethylcarbamoyl chloride is heated in nitrogen gas at 110 °? hours. The reaction mixture is cooled and diluted with 200 ml of acetone, filtered and evaporated. The product is chromatographed on a column of 450 g of silica gel. The fraction is eluted with 3% methanol in chloroform. 1- (N, Ν-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 1- (N, N-diethylcarbamoyl) -2- oxo-tetrahydroimidazole in 40 ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50 ° for 1 hour. To this is added in one portion a solution of 24.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 40 ml of dry dimethylformamide.

The reaction mixture is further worked up as described in Example 6 and the residue obtained (36 g) is chromatographed on a column of 360 g of silica gel. The fraction is eluted with 2.5% methanol in chloroform. After recrystallization from a mixture of methylene chloride-hexane, 1-N, N-diethylcarbamoyl-2-oxo-2-l-62293 (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting at 133 °.

Example 8;

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 150 is added over 15 minutes with stirring. in ml of dry dimethylformamide. The reaction mixture is stirred under nitrogen at 50 ° for 1 hour and a solution of 102.5 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 100 ml of dry dimethylformamide is added over 10 minutes. The reaction mixture is heated in nitrogen gas with stirring at 100 ° for 3 hours. Further processed as described in Example 5. After recrystallization from a mixture of methylene chloride and hexane, 1-N, N-dimethyl-carbamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole is obtained, melting at 190-191 ° C.

The starting 1-N, N-dimethylcarbamoyl-2-oxo-tetrahydroimidazole can be prepared on the following platform:

A mixture of 86 g of ethylene urea and 118 g of N, N-dimethylcarbamoyl chloride in 200 ml of ethylene dichloride is heated under reflux under nitrogen for 3 hours. The reaction mixture is then evaporated and the residue is dissolved in chloroform and chromatographed on a column containing 1.5 kg of silica gel. The fraction is eluted with 5% methanol in chloroform and recrystallized from methylene chloride-hexane. The above product melts at 134-136 °.

Example 9: a) To a suspension of 4.5 g of 50% sodium hydride in 10 ml of dry dimethylformamide is added, within 15 minutes, with 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 ° for 45 minutes and then a solution of 18.5 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 30 ml of dry dimethylformamide is added in one portion and the reaction mixture is heated at 100 ° for 3 hours. :in. It is then further processed as described in Example 5. The crude product is recrystallized from a mixture of methylene chloride and hexane. The 1-ethylsulfonyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole thus obtained melts at 176-177 ° 2.

20 6 2 2 9 3 (b) The required starting material is prepared as follows:

A mixture of 29.2 g of ethylene urea and 43.7 g of ethanesulfonyl chloride is heated at 110 ° for 3 hours. 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 on a column containing 750 g of silica gel. The fraction is eluted with 5% methanol in chloroform and the crystalline material is recrystallized from a mixture of methylene chloride and hexane. The 1-ethylsulfonyl-2-oxo-tetrahydroimidazole thus obtained melts at 11 ° C to 116 ° C.

Example 10:

In a manner similar to that described in Example 9a), 5.8 g of 1- (4-fluorophenylsulfonyl) -2-oxo-tetrahydroimidazole and 5.0 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole 1- (4- fluorophenylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) tetrahydroimidazole, melting at 98-200 °.

The starting material required above is prepared as follows:

A mixture of 17 g of ethylene urea and 19.5 g of p-fluorophenylsulfonyl chloride is heated at 100 ° for 3 1/2 hours. The residue is recrystallized from a mixture of methanol and water; 1- (4-fluorophenylsulfonyl) -2-oxo-tetrahydroimidazole is obtained, melting at 183-185 °.

Example 11:

To a suspension of 0.1 g of 50% sodium hydride in 2 ml of dry dimethylformamide is added dropwise a solution of 0.4 g of 2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole in 8 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for 15 minutes and then a solution of 0.2 g of methyl isocyanate in 2 ml of dry dimethylformamide is added, followed by heating at 100 ° for a further 3 hours. Further processed as described in Example 5.

The residue is chromatographed on a column of 40 g of silica gel. The fraction is eluted with 5% methanol in chloroform. 1-N-methylcarbamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting at 176-177 °.

Example 1 2: To a stirred suspension of 1.3 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide is added dropwise a solution of 5.41 g of 1-piperidinocarbonyl-2-oxo. -tetrahydroimidazole in 15 ml of dimethylformamide at the same temperature. The reaction temperature is adjusted to 50 ° and the 21 62293 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 ° 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 granulate is recrystallized from ethyl acetate / hexane. The 1-piperidino-carbonyl] -N-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole thus obtained melts at 152 °. Example 13; To a stirred suspension of 1.92 g of 50% sodium hydride dispersed in mineral oil in 25 ml of anhydrous dimethylformamide is added dropwise a solution of 7.96 g of 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml. dry dimethylformamide. The suspension is stirred at 50 ° for 30 minutes. A solution of 8.2 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 15 ml of dimethylformamide is then added over a period of 5 minutes. The reaction temperature is raised to 95 ° C and maintained at this temperature 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-nitroimidazolyl- (2)} tetrahydroimidazole is obtained, melting at 180 ° after recrystallization from ether.

The starting 1-morpholino-carbonyl-2-oxo-tetrahydroimidazole is prepared as follows:

To a solution of 22.27 g of 1-chlorocarbonyl-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 at reflux. The reaction product is filtered, treated with saturated sodium bicarbonate solution and filtered. After recrystallization from isopropanol, 1-morpholinecarbonyl-2-oxo-tetrahydroimidazole is obtained, melting at 158 °.

Example 14;

A solution of 2.9 g of 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole and 1.9 g of ethyloxonium fluoroborate in 200 ml of chloroform is allowed to stand at room temperature. at 72 hours.

«62293 This gives a thick-flowing oil which is crystallized by trituration with ethanol. The solid residue obtained is filtered, boiled with acetone and, after filtration, recrystallized from aqueous ethanol. 1-Methyl 2- (3- (methylsulfonyl) -2-oxo-tetrahydroimidazolyl (1)) - 3-ethyl-5-nitroimidazolium fluoroborate of the formula C-H p + / 2 5 - N - is obtained. -------- 1 ^ ---- N N-SO 2 CH 3

OoN ^ I

1 I

CH ~ 0 0 BF4 melting at 265-267 °.

Example 15:

A solution of 3.0 g of 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole in 30 ml of dimethylformamide, to which 3, 0 g of potassium iodide, heated for 16 hours under reflux. The solvent is then removed in vacuo and the residue is treated with water and filtered. The resulting filtrate is acidified with 2N hydrochloric acid, cooled and filtered once more to remove unreacted starting material.

The filtrate is recooled and the separated crystalline residue is filtered and recrystallized twice from acetone / methanol. 1- (methylsulfonyl-2-oxo-3- (1-methyl-4-nitroimidazolyl- (2)) tetrahydroimidazole is obtained, melting at 180-181 °.

A solution of 3.0 g of 1- (methylthiocarbamoyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole in 25 ml of dimethylformamide to which 3.0 g have been added potassium iodide, heated at reflux for 16 hours. The reaction mixture is filtered and the residue is washed successively with hot ethanol and methanol and then recrystallized from a mixture of acetone and methanol.

1- (methylthiocarbamoyl) -2-oxo-3- (1-methyl-4-nitroimidazolyl- (2)) tetrahydroimidazole is obtained, melting at 23 DEG-21 DEG.

23 62293

Example 17: a) A solution of 0.49 g of 1- (methylsulfonyl) -2-oxo-tetrahydroimidazole in 5 ml of dimethylformamide is stirred at 50 ° for one hour with 0.15 g of sodium hydride 50 % suspension in mineral oil. 0.57 g of 1-methyl-2- (methylsulfinyl) -5-nitroimidazole are added to the mixture, and the mixture is heated under stirring at 100 ° for 3 hours. The solvent is evaporated off under vacuum and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from a mixture of acetone and methanol. 1- (Methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained which melts at 202-204 ° and is identical to the compound obtained in Example 4.

b) The starting material is prepared as follows: A solution of a mixture of 3.4 g of 1-methyl-2- (methylmercapto) -5-nitroimidazole and 5 ml of a 30% aqueous solution of hydrogen peroxide in 20 ml of methoxyethanol is heated for 6 hours with freshly prepared titanium dioxide At 100 ° and then diluted with water and filtered. The filtrate is extracted with chloroform, and the resulting chloroform layer is evaporated. 2.5 g of an oil are obtained which, on standing, slowly solidifies. The obtained crystalline residue is crystallized once from ethanol and then from a mixture of chloroform and ether. 1-Methyl-2- (methylsulfinyl) -5-nitroimidazole is obtained.

Example 18: 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 over 15 minutes a solution of 30 g of 1- (N, K-diethylsulfamoyl). ) -2-oxo-tetrahydroimidazole in 50 ml of anhydrous dimethylformamide. The reaction mixture is stirred under a nitrogen atmosphere at 50 ° for 1 hour, then a solution of 25.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 40 ml of anhydrous dimethylformamide is added. The reaction mixture is heated with stirring under a nitrogen atmosphere for 3 hours at 95 °. The solvent is removed by vacuum distillation and the residue is extracted with 100 ml of water. The suspension obtained is extracted with ethylene chloride, the ethylene chloride layer is dried and evaporated to dryness in vacuo. The residue is chromatographed on a silica gel column and in a fraction eluted with 1% methanol-chloroform, a crystalline precipitate separates, which is recrystallized from methylene chloride / ether. 1-N, N-Diethylsulfamoyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole is obtained, melting at 1k6-1u78.

(b) The starting material is prepared as follows:

A mixture of 51.6 g of ethylene urea and 90 g of N, N-diethylsulfamoyl chloride is heated at 110 ° for 3 hours. The reaction mixture is cooled and extracted with 300 ml of methanol, filtered and the suddos is evaporated to dryness in vacuo. The residue is dissolved in 5% methanol / chloroform and chromatographed on a silica gel column. The crystalline fraction eluted with 5% methanol / chloroform is recrystallized from a mixture of methylene chloride and hexane. 1- (N, N-diethylsulfamoyl) -2-oxo-tetrahydroimidazole is obtained, melting at 80-82 °.

Example 19: a) To a stirred suspension of 1.6 g of 50% sodium hydride dispersed in mineral oil in 30 ml of anhydrous dimethylformamide, 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 50 ° for 1 hour and then a solution of 6.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of anhydrous formamide is added. The reaction mixture is heated under stirring under a nitrogen atmosphere at 95 ° for 1 hour. The solvent is removed by vacuum distillation, the residue is extracted with water and ethylene chloride, dried and evaporated to dryness. The residue is chromatographed on a silica gel column and the fraction eluted with 3% methanol / chloroform gives a crystalline mass which is recrystallized from a mixture of methylene chloride and hexane. 1-Pyrrolidinocarbonyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) tetrahydroimidazole is obtained, melting at 155-156 °.

(b) The starting material is prepared as follows:

A mixture of 10 g of ethylene urea and 72 g of 1-pyrrolidinocarbonyl chloride (b.p. 100-104 ° / 4.5 mm Hg) is heated at 110 ° for 3 hours. The reaction mixture is cooled and 20 ml of chloroform are added. The insoluble material is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on a column of silica gel and the fraction eluted with 4% methanol / chloroform gives a crystalline mass which is recrystallized from ethyl acetate. 1-Pyrrolidinocarbonyl-2-oxo-tetrahydroimidazole is obtained, melting at 153-154 °.

Example 20: a) To a suspension of 3.5 g of 50% sodium hydride dispersed in mineral oil in 20 ml of dimethylformamide is added over 15 minutes a solution of 15.6 g of 1-pyrrolidinosulfonyl-2-oxo-tetrahydroimidazole 40 in ml of anhydrous dimethylformamide. The reaction mixture is stirred under a nitrogen atmosphere at 50 ° for 1 hour and then a solution of 14.4 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 30 ml of anhydrous dimethylformamide is added. The reaction mixture is heated with stirring and under a nitrogen atmosphere at 95 ° for 1 hour. The solvent is removed by vacuum distillation, the residue is extracted with 50 ml of water to give a crystalline precipitate. The precipitate obtained is filtered off and recrystallized from a mixture of methylene chloride and ether. 1-Pyrrolidino-sulfonyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole is obtained, m.p. 226 °.

(b) The starting material is illuminated as follows:

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

Example 21: a) To a suspension of 1.92 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide is added dropwise at room temperature a solution of 9.3 g of 1-piperidinosulfonyl-2- oxo-tetrahydroimidazole in 15 ml of dimethylformamide. The reaction temperature is raised to 50 ° and further stirred for 30 minutes. A solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 25 ml of dimethylformamide is added and the reaction temperature is maintained at 100 ° for 2 hours. The solvent is removed under reduced pressure and the residue is treated with crushed ice containing water. The aqueous layer is separated 2f 62293 and the residue is treated with a mixture of isopropanol and ether (5: 1). The slightly yellowish precipitate thus obtained is recrystallized from ethyl acetate to give 1-piperidinosulfonyl-2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole, m.p. 192 °.

b) The starting material is prepared as follows: 36 g of piperidinosulfonyl chloride (b.p. 130 ° / 11 mm Hg) are added to 17.4 g of ethylene urea with shaking and the reaction mixture is kept at 100 ° for 3 hours under a nitrogen atmosphere. After cooling, the gummy reaction product is treated with a solvent mixture of methanol and isopropanol (1: 1) -1. 1-Piperidinosulfonyl-2-oxo-tetrahydroimidazole is obtained in the form of a granular product which, after recrystallization from methanol, melts at 201 °.

Example 22: a) To a solution of 8 g of 1- (methylsulfonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole in 30 ml of anhydrous dimethylformamide is added 2.2 g of sodium hydride 50i The mineral oil suspension and mixture are stirred at room temperature for 1 hour.

To this reaction mixture is added a solution of 9.2 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 20 ml of anhydrous dimethylformamide, followed by stirring for a further 3 hours. The solvent is removed in vacuo and the residue is dissolved in water. Cooling of the solution gives a crystalline precipitate which is filtered and recrystallized from a mixture of methylene chloride and ether. 1- (Methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - 4-methyl-tetrahydroimidazole is obtained, melting at 199-200 °.

b) The starting 1- (methylsulfonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole is prepared as follows:

A mixture of 10 g of 4-methyl-2-imidazolidinone and 11.5 g of methylenesulfonyl chloride is heated for 3 hours with stirring at 120 °. At the same time, a stream of nitrogen is introduced to remove the hydrochloric acid gas formed. After cooling, water is added and the mixture is heated in a water bath until ... a crystalline powder forms, which is filtered and, after dissolving in chloroform, chromatographed on a silica gel column. The fraction eluted with a mixture of chloroform and methanol (97: 3) contains 1- (methylsulfonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole, which is recrystallized from a solvent mixture of methylene chloride and hexane and melted 129- 130 ° C.

27 62293

Example 23:

To a solution of 8.2 g of 1- (methylsulfonyl) -2-oxo-2,3, M, 5-tetrahydroimidazole and 60 ml of dimethylformamide is added 2.4 g of a 50% mineral oil suspension of sodium hydride. The mixture is stirred at room temperature. 1 hour. A solution of 12.45 g of 1- (β-methoxyethyl) -2-methylsulfonyl-5-nitroimidazole in 20 ml of dimethylformamide is added and the reaction mixture is stirred at room temperature for 4 1/2 hours. The dimethylformamide is evaporated in vacuo on a steam bath. The residue is treated with 30 g of crushed ice until crystals form. The crystalline residue is filtered and then recrystallized from a mixture of acetone-methanol and ether. There is obtained 1- (methylsulfonyl) -2-oxo-3- (ΐ-β-methoxyethyl-5-nitroimidazolyl- (2)) tetrahydroimidazole of formula I * 1 * '* | JL S-f * .N - SO2CH3 o2, r n ύ o ch2-ch2-och3 sul.p. 126-127 °.

The starting material is prepared as follows: a) g-Methoxy-ethylamino-acetaldehyde-diethyl acetal

A mixture of 170 ml of a 65% aqueous solution of β-methoxyethylamine and 90 g of bromoacetaldehyde diethyl acetal is heated in a steel tube for 16 hours at 120 °. The reaction mixture is treated with 75 g of potassium hydroxide while cooling, filtered and the filtrate is dried over anhydrous potassium carbonate, then distilled at 115-120 ° / 12 mm to give β-methoxyethylaminoacetaldehyde diethyl acetal.

b) 1- (β-methoxyethyl) -2-mercaptoimidazole

A solution of 9.55 g of β-methoxyethylamino-acetaldehyde-diethyl acetal in 50 ml of abs. ethanol, treated successively with 6 g of potassium thiocyanate and 27.5 ml of 2N hydrochloric acid. The reaction mixture is refluxed for 16 hours. 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 obtained 78 62293 is recrystallized from a mixture of acetone and ether.

1- (β-methoxyethyl) -2-mercaptoimidazole, m.p. 92-95 °.

c) 1- (g-Methoxyethyl) -2-methylmercapto-5-nitroimidazole To a cooled solution of 15.8 g of 1- (β-methoxyethyl) -2-mercaptoimidazole in 90 ml of methanol is added in one portion 110 ml. 10N sodium hydroxide while stirring and cooling. The reaction mixture is then treated dropwise with 6.6 ml of methyl iodine for 1 hour. The reaction mixture is further stirred for 2 hours at 10 °, the methanol is removed in vacuo at 93 ° and the residue is diluted with water and extracted with methylene chloride, dried and evaporated to dryness.

The compound obtained above (15.3 g) is treated dropwise with 82 ml of concentrated nitric acid under a nitrogen atmosphere. The reaction mixture is heated slowly, with stirring, and kept at 100 ° for 40 minutes. After cooling to room temperature, the residue is poured into 50 g of crushed ice, neutralized with 50% sodium hydroxide solution and extracted with methylene chloride and. evaporated to dryness. The residue is slowly recrystallized from hexane to give the above product, m.p. 44-45 °.

d) 1- (g-methoxyethyl) -2-methylsulfonyl-5-nitroimidazole

A solution of 26 g of 1- (β-methoxyethyl) -2-methylmercapto-5-nitroimidazole in 80 ml of methylene chloride is treated dropwise with 50 ml of a 0.48 molar solution of monoperphthalic acid for 6 hours at 1 ° C-15 °. The reaction mixture is stirred for 20 hours at room temperature, refluxed for 1 hour and cooled to room temperature and filtered. The filtrate is washed successively with sodium bicarbonate solution and water, dried and evaporated to dryness. A crystalline residue is obtained which is recrystallized from a mixture of methylene chloride and hexane. 1- (β-methoxyethyl) -2-methylsulfonyl-5-nitroimidazole, m.p. 92-93 °.

29 62293

Example 24:

A solution of 0.4 g of 3- (1-methyl-5-nitroimidazolyl- (2)) - 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 solution 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 ° for 3 hours, then evaporated, triturated with 1N hydrochloric acid, extracted with methyl chloride to give 1- (methylcarbamoyl) -2-oxo -3- (1-methyl-5-nitroimidazolyl- (2)) -tetrahydroimidazole, melting at 176-177 °. Example 25:

To a solution of 0.4 ml of conc. nitric acid and 4 drops conc. sulfuric acid, 68 mg of 1- (methylsulfonyl) -2-oxo-3- (1-methylimidazolyl- (2)) - tetrahydroimidazole are added, and the reaction mixture is heated at 110-115 ° for 2 hours. The reaction solution is poured onto ice, neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract is dried over Na2SO4 and evaporated. The evaporation residue is chromatographed on silica gel. 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitroimidazolyl- (2)) - tetrahydroimidazole is obtained, melting at 202-204 °.

The starting material is prepared as follows:

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

To a solution of 500 mg of 1- (methylimidazolyl- (2)) - imidazolidin-2-one in 5 ml of dimethylformamide and 30 ml of dioxane, which is cooled to 10 °, is added 0.16 g of sodium hydride. (50% dispersion in oil) and the reaction solution is stirred for 30 minutes. Methanesulfonyl chloride (0.6 g) is added dropwise and the solution is stirred in an ice bath for 1 hour and kept at ambient temperature for 3 hours. The residue is filtered, the filtrate is evaporated to dryness to give 0.6 g of an oily residue which is chromatographed on silica gel. The fraction is eluted with chloroform, crystallized from isopropanol ether to give 1- (methylsulfonyl) -2-oxo-3- (1-methylimidazolyl- (2)) -tetrahydroimidazole, melting at 171-172 °.

Claims (2)

62293 Claim: An analogous process for the preparation of therapeutically active nitroimidazole derivatives of the formula R 5: wherein one of the radicals and R 3 represents hydrogen and the other represents a nitro group, R 1 represents lower alkyl having 1 to 3 carbon atoms or lower alkoxy-lower alkyl having up to 4 carbon atoms, X represents a carbonyl-thiocarbonyl or sulfonyl group, and when X represents a carbonyl group or a sulfonyl group, R 4 is a piperidino, pyrrolidino, morpholino, lower alkylamino or dialkylalkylamino group; X represents a thiocarbonyl group, R 1 is a benzylamino, lower alkylamino or dialkylalkylamino group, and when X represents a sulfonyl group, R 1 is a lower alkyl group or optionally halogenated phenyl, and R 1 represents hydrogen or methyl, and for the preparation of their salts and N-oxides, that either a) an imidazole of the formula R--N 1. iz 11 »3 wherein R1, R2 and R3 have the same meaning a as above and Z is a reactive esterified hydroxy group, a halogen atom, a reactive etherified hydroxy group, a free or etherified mercapto group, an ammonium group or a sulfinyl or sulfonyl group, is reacted with a compound of formula 31 62293 R5 I III HN2. N - X - R 4 wherein R 4, R 5 and X are as defined above; or b) an imidazole of the formula R5 R ·! —- N I 1. m I IV Ri_J J-N .N - X - R, r V r3 · 0 wherein R ^ f R4 / and X have the same meaning as above and the radicals R | and RJ, are hydrogen, nitrated; or c) imidazole of the formula R5 R, -r-n - i jf I v / S, N / 1-N \ / NH R "'T R 3 O wherein R 1, R 3, R 3 and R 2 are as defined above is reacted with a compound of formula R 4 - N = C = O VI wherein R 4 is as defined above, or in the resulting compound of general formula I wherein X represents a thiocarbonyl group, this group can be converted into a carbonyl group, and / or the obtained 5-nitro compound of formula I is converted into a 4-nitro compound, and / or the salts obtained are converted into free compounds or other salts or the resulting free compounds are converted into salts. Claim. 32 62293 Analogous fate for the formulation of a therapeutic agent nitroinidazole with formula R5 r N | JD II_N N - X - R, R — Y 4 * 3 i are selected from the group consisting of 1 and 3 carbon atoms, R3 from 1 to 3 carbon atoms or from 4 carbon atoms and X carbon atoms , thiocarbonyl or sulfonyl, and X is a carbonyl or sulfonyl, R1 is piperidino, pyrrolidino, morpholino, pendalkylamino or dilalkylamino, and X is a thiocarbonyl group, R4 is benzylamino, lgalkylamino- or dilägalkylamino, och dä X avser en sulfonylgroup, är R4 en lgalkylgroup or optionally halogenated phenyl, and R, - a hydrogen -ated or N-oxider group, känneteck-n at därav, att a) enidaz the R1-N 11 form of R 1, R 2 and R 2 is selected from the group consisting of a hydroxyl group, a halogen atom, a reactive hydroxy group, a free or a mercapto group, an ammonium group or a sulfinyl group sulfonyl group, having the same meaning as R5 -1 111 HN N - X - R. V "O