CS195689B2 - Method of producing novel derivatives of nitroimidazole - Google Patents

Abstract

Derivs. of formula (I): (where one of R1 and R2 is H or lower alkyl and the other is NO2; R3 is lower alkyl, hydroxyalkyl, alkoxyalkyl, alkyl-sulphonyl-alkyl or aminoalkyl; R4 is O or S; X is CO and R5 is lower alkoxy, NH2 or mono- or di(lower alkyl)-amino or X is CS, SO or SO2 and R5 is lower alkyl, aryl, NH2 or mono- or di-(lower alkyl)-amino; and "alk" is lower alkylene with 2-4 C-atoms in the alkylene chain) (e. g. 1-(methyl-thiocarbamoyl)-2-oxo-3-(1-methyl-5-nitro-2-imidazolyl)-- tetrahydroimidazole) and their salts and N-oxides are new cpds. They may be prepd. e.g. by reacting a cpd. of formula (II) (where Z is a reactive esterified or etherified hydroxy gp., a free or etherified mercapto group, an ammonium gp. or a sulphonyl gp.) with a cpd. of formula (III). (I) are antimicrobial and anthelmintic agents active against bacteria (esp. gram-negative bacteria), protozoa and worms such as trichomonads, schistosomes, coccidia and, especially, amoebae. (I) may thus be used for therapeutic purposes, as animal feed additives, and for protecting organic materials against microbial degradation.

Description

The present invention relates to a process for the preparation of novel nitroimidazole derivatives of the general formula I,

wherein one of the radicals R 1 and R 2 is hydrogen, and the other of the radicals is a nitro group,

R3 represents a lower alkyl radical having 1 to 2 latoms of carbon or a (lower) alkoxy (lower) alkyl radical having at most 4 carbon atoms,

X represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and when X represents a carboinyl group. or a thiocarbonyl group, then

R 5 is benzylamino, piperidino, lower alkylatainoscape, morpholino, pyrrolidino; or a di (lower) alkylamino group, wherein the lower alkyl group always contains 1 to 4 carbon atoms, and if

X is a sulfonyl group, then

195989

R 5 represents a lower alkyl group, a fluorophenyl group. pyrrolidinoscopy, piperidino, lower alkylamino or di (lower) alkylamino; wherein the alkyl group may each contain 1 to 4 carbon atoms, and salts thereof. .

Lower alkoxy (lower) alkyl radicals are, for example, those containing lower radicals. alkyl moieties. in each case up to 4 carbon atoms, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, 1-biphenylmethyl, 2- (n-butoxy) ethyl, 3- (n-propoxy) propyl or in particular 2-methoxyethyl.

Amino (lower alkyl) is, for example, one of the above-defined lower alkyl radicals, which contains an amino group, in particular an alkyl group. di-n-propylate or a dl-n-butylamino group.

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

The novel compounds have valuable pharmacological properties. Thus, they have particular effects against bacteria, in particular against green bacteria, elements (Priotozoa) and worms, such as flagellates (Trichomionaé), bloodworms (Schistosoma) and immunobacteria (Amoebaj), as it is possible to experiment with animals, such as the liver of healthy people. (hamsters that are artificially infected with full-moon vertebrate - (Entamdeib.o, hištolytlca), and when administering a dosage of about - 10 to about 100 iPi ^ / * ι / kg orally. The new imldazoles can therefore be used in particular as - Amoeba, Amyeba, Schidliosoma, Tridhomonae, and bacteria, and the novel imldazoles can be used as starting materials or as intermediates for the production of other, particularly, therapeutically active compounds.

The invention relates in particular to the preparation of compounds of the formula Ia,

wherein R 1 is hydrogen,

R 3, X and R 5 are as defined in formula I and salts thereof.

_{In the} same way (mb also relates to the invention - in particular also to the production of compounds - - of formula Ib,

- lower - -:

Ro is hydrogen,

R 5, - X and - R 5 have the meanings given in vaor cetao Ί and their-SolL

j. invention; refers to the manufacture of those compounds of formula - Ia, - in which - R 1 and R 5 have the meanings indicated - below - of formula Ia, X represents a carhoinyl group and -. R 5 - represents a piperidine, pyrrolidino, morpholino, lower-alkylamino or di (lower) alkylamino group, and lower-alkyl groups having 1 to 4 carbon atoms and their salts. - '.

Furthermore, the invention also relates to the preparation of compounds of formulas Ia-a-1b, wherein R 1 or R 2 and R 5 have the above-mentioned meanings, X is thiocarbonyl and R 5 is henzylamino, lower alkylamino or di (lower). a lower alkyl group having from 1 to 4 carbon atoms and salts thereof.

Of particular interest are compounds of formula Ia and Ib, wherein R 1, optionally. Rj is as shown below by formula -Ia and optionally below-formula; - Ib, -R 5 - represents a lower alkyl radical, for example methyl or ethyl, X - represents a carbonyl group and R 5 represents a morphalino group, a piperidino group (lower alkylamino or di (lower-1-hydroxy), especially methylamino, dithietholbino) or diethylamino; and salts thereof.

Of particular interest are the compounds of the formulas Ia and Ib, in which X is a sulfonyl group, -R 1 and R 2, respectively, have the meaning given by the formulas Ia and Ib, respectively, R 5 is lower alkyl. such as methyl or ethyl, and R 5 is pyrrolidino, piperidino, lower alkyl, such as methyl, lower o-chloro, or C 8 (lower alkylamino), such as methylamino, ethylamino, dimethylamino, diethylamino and their salts. .

Of the following new imidazoles of the formula I, the following must be added in particular:

1- (methylsulfonyl) -2-oxo-3- [l-5-me'tlhyl ... .. - - ^J nitroimiιd02Ol-2-yl] tetrah0ilr'Qimid · azole, lN, N-diethyl'karbamool- 2-oxo-3- [1-methyl-5-nitroimidazol-1-yl] tetrahydroimidazole, 1 N, N-diethylaminoaribainool-2-oxo-3- [1-methyl-5-nitroquinolin-2-yl] tetrahydroimidazole ln-eihylthi (Okarbbmool-2-oxo-3- [l-methyl-1-5-niitroimid and benzimidazol-2 - Y 1] r, and Tet. hydroimidorzol -a .methol ^L lN-thiocarbamoyl-2-oxo-3- [1-Methyl-S-nitro-imidol-1-yl] -etrahydroimidozole, which, in the liver of healthy hamsters, which have been artificially infected with the varicella (Entamiodba histolotico), causes doses of 10 to 100 in the administration. mg / kg - orally - clearly - abscess release such as 1. (methoxysulfonyl) -2-oxo-3- [1-methyl-5-nitroimidozol-J-ol] tetrohodroimidozole causes 45 mg / kg - after x - 2 (2 days] i (lo0 ^'o / o - reducing alpha-N, N-dtetholkar.bomoyl 2-0X0-3- [Ί 5jnltrOímld02ol-methyl-2-yl] tetrohodroimidozol causes at after giving - 50 mg / kg p. d, x '2 (2 days) also - 100% reduction. According to the invention, novel imidozoles are obtained by converting to imidozole of formula II,

wherein: R 1, R 1 -, and R 5 - have the above meaning, and

Z represents - an olcolConol group, wherein the alkyl contains 1- to 2-carbon atoms, acts by a compound of formula III,

О ^υ (т) in which

Ra and X are as defined above.

This reaction may be carried out in a conventional manner. it is operated in the presence of a basic condensation agent or the compound of formula III is used in the form of its N-metal derivative, such as an N - (alkali metal derivative) obtainable, for example, from the amine, amide, hydride, hydrocarbon derivative or hydroxide Suitable base condensing agents are, for example, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or organic tertiary diesters bases. It is preferable to work with an excess of the compound of formula (III), preferably at elevated temperature or in the presence of an inert solvent, such as a solvent with polar functional groups, such as, for example, tolmefettylamih, triethylamine or pyridine. is, for example, dimethylformamide, dimethylacetate an amide, dimethylsulfoxide, acetonitrile, and cyclic aliphatic ethers such as dioxane and tetrahydrofuran.

In the compounds obtained, substituents can be altered, cleaved or introduced within the definition of the finite substances.

In the compounds obtained in which X is a thiocarbonyl group, the group X can be converted in a conventional manner to a carbonyl group, in particular by known methods of hydrolysis, for example by treatment with an alkaline medium, such as an alkali metal hydroxide, to the obtained Shioxo compounds in the presence of an oxidizing agent. agents, 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 with a suitable solvent).

Compounds of formula I which contain a nitro group in the scope of R2 may be converted to the corresponding 4-nitroimidazoles, e.g. Such compounds of formula I which contain a nitro group as defined by R1. Such a rearrangement is carried out (for example by the action of an alkali metal iodide used, for example, in excess, in particular potassium joidide) in the presence of an inert solvent, preferably a solvent with polar functional groups such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or hexatethyltriamide. phosphoric acid.

The rearrangement of the compounds of formula (I) with a nitro group R 2 and the compounds with the initroscuipinone of R 1 can also be carried out by treatment with an iodide corresponding to the radical R 5, for example by treatment with methyl iodide. group. In this rearrangement, the unsubstituted nitrogen atom of the indazole ring is quaternized. Then the quaternary salt is pyralyzed. This rearrangement is also carried out, for example, in the presence of an inert solvent, preferably one of the above described.

The following conversions may be carried out individually or in combination and in any order. During individual opeirations, it is necessary to ensure that other functional groups are not attacked.

The invention also relates to those process alternatives in which the process is interrupted at any stage, or wherein the starting material is a compound obtained as an intermediate at any stage of the process, or wherein the starting material is formed under the reaction conditions or is optionally used in the form of a salt, and / or a racemate, and / or optical antipodes. Said reactions are carried out in the usual manner in the presence or absence of diluents, condensing agents and / or 'catalytic agents, at room temperature' or at or below room temperature, optionally in a closed vessel. If it is Teaching, work in a larger dilution (dilution principle).

The starting materials are known or can be obtained, if new, by methods known per se. The novel starting materials also form the subject of this invention.

The starting compounds of the formula III can be produced by reacting the compound of the formula z-v o

i.e. imidazolidta-2-one or hexahydropyrimidin-2-one is treated with a compound of the formula

Rs — X — Z, in which

R 5, X and Z have the above extracts.

The nitroimidazoles described herein, which are used as intermediates or as starting materials, have valuable pharmacological properties.

Thus, in particular, they exhibit effects against bacteria, in particular against gram-negative bacteria, protozoa (Brotozoaea, worms such as trtohomonads, stihistosomes, coccidia, and in particular against amoebias, as can be shown by animal experiments such as healthy hamsters that have been artificially fed. (Entamoeba hiStoiyiea), at doses ranging from about 10 to about 100 mg / kg orally, the new imidazoles may also be used, particularly, as anti-amoebic, schistosomic agents. , trichomonadam and bacteria.

Depending on the reaction conditions and starting materials, the reaction products are obtained in the free form or in the form of acid addition salts; which are also within the scope of the invention. Thus, for example, basic, neutral or mixed salts, and optionally also their hemihydrates, monohydrates, acesquihydrates or polybydrates, can be obtained. Acid addition salts (of the novel compounds) can be converted into the free compound in a known manner, for example by treatment with basic alkali or ion exchangers. On the other hand, they can be formed from the organic or organic salts obtained. For the preparation of acid addition salts, in particular, those acids which are suitable for the production of therapeutically useful salts are used, such as, for example: hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, .alpha., .alpha., .alpha., .alpha., .alpha., .alpha.-aromatic or heterocyclic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, Succinic acid, glycolic acid, - Lactic acid, malic acid, tartaric acid, tartaric acid, citric acid, ascorbic acid, acid - ma leino, hydroxymaleinic acid or pyruvic acid, phenylacetic acid, acid. benzoic acid, p-aminobenzoic acid, anthranilic acid, p'-hydroxybenzoic acid, salicyloic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid; halobenzenesulfonic acids, toluenesulfonic acid, naphthalenesulfonic acid or sulfansulfonic acid; methionto, tryptophan, lysine or arginine.

These or other salt compounds, such as picrates, can also serve to purify the obtained free bases by converting the free bases into salts, separating them - and releasing the bases from these salts. As a result of the close relationship between the new compounds in the free form and their salt form, both the preceding and the following are understood to mean the free compounds according to their purpose and purpose and, where appropriate, the respective compounds. Depending on the number of asymmetric carbon atoms and on the chosen starting materials and processes, the novel compounds may be present in -. in the form of mixtures of racemates, in the form of racemates or in the form of optical antipodes. The racemate mixtures can be separated into the pure racemates in a known manner, for example by chromatography and / or fractional crystallization, due to the physical-chemical differences of the individual components. .

Pure racemates can be obtained by known methods, for example, by recrystallization from an optically active solvent, by means of - microorganisms - or by reaction with an optically active acid, - which forms - a - tartaric · - salt compound - salts, for example by virtue of their different solubilities, decompose, into diastereomers, from which the antipodes can be released by treatment with suitable reagents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, acid, e.g. or quinic acid. Preferably ^; isolates more effectively from both antipodes. ... However, according to the invention, reaction products can also be obtained in the form of pure racemates or optical ones. The antipodes are obtained by using starting materials which contain one or more asymmetric carbon atoms in the form of pure racemates, optionally in the form of an optical antipode. ''

In agreement with the antimicrobial. The compounds of formula (I) and their acid addition and quaternary salts can be used for protection - hydrafob? or other high molecular weight organic substances which are subject to degradation by the action of bacteria or other microbes ^; The compounds of the invention are contacted or impregnated with the compounds of the invention. .or they treat them differently. Compounds of the invention. are also used. as additives kite'ré promote growth - animals, and which are added ke- pro- animals feed in a ratio of ¹ 5 to ¹ 500 ° ppm.

The corresponding therapeutic composition consists of an antimlrobial effective proportion of the compounds of formula I - (see above) - or some acid addition or quaternary salts and a pharmacologically usable solid carrier - or of liquid diluents.

The pharmaceutical preparations comprise at least one compound of formula I (see above) as. the active ingredient together with the usual pharmaceutical carrier. The type of carrier valve depends mainly on the region. -application. For external use, for example to disinfect Healthy Skin, - as well as - to disinfect the cavity. oral and cure of dermiatoses - and mucosal affections caused by - bacteria, - especially ointments, - powders, tinctures. The ointment bases may be non-aqueous, for example from a mixture of sheep fat and petrolatum, or they may also be aqueous emulsions in which the charged substance is suspended. Suitable carriers for powders are, for example, starches, such as rice starch, the specific weight of which may be:

If necessary, it is possible to reduce, for example, the addition of highly disperse silicic acid, or it can be increased by adding talc. Tinctures contain at least one active ingredient in aqueous, in particular in 45 to 75% ethanol, to which optionally 10 to 20% glycerin is added. Especially for the disinfection of healthy skin, solutions which are prepared using polyethylene glycol and other conventional co-solvents or emulsifiers are suitable. The active ingredient content of the pharmaceutical preparations for external application is preferably between · 0.1 and 5%.

For disinfection of the oral cavity and the ihrthanum, it is suitable, on the one hand, for water-cleavage or concentrates for the preparation thereof, in particular alcoholic solutions containing from 1 to 5% of active substance to which glycerin and / or flavoring agents may be added. , i. solid dosage forms preferably with a relatively high content of sugar or the like and with a relatively low active ingredient content, for example 0.2 to 20% and also other additives such as binders and flavorings.

I. Disinfection of intestines а. For urinary tract infections, solid dosing devices are particularly suitable. forms, such as tablets, dragees and capsules, which preferably contain between 10 and 90% of the active compound of the formula I (see above), so as to permit the administration of daily doses of between 0.1 and 2.5 g for adult patients or suitably reduced doses for children. For the preparation of tablets and tablets. the dragee cores combine compounds of the formula I with solid, pulverulent carriers such as lactose, sucrose, sorblt, corn starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of lubricants such as magnesium stearate or Calcium stearate or polyethylene glycols of suitable (molecular weight. Dragee cores are coated, for example, with concentrated sugar solutions which contain, for example, gum arabic, talc and / or titanium dioxide or lacquer, which are dissolved in easily volatile organic compounds. dyes, for example to distinguish different doses of the active substance Soft gelatine capsules and others The sealed capsules consist, for example, of a mixture of gelatin and glycerine and may contain, for example, mixtures of a compound of formula I with polyethylene glycol The push-fit capsules contain, for example, a granulate of the active ingredient with solid, powdered carriers such as. for example lactose, sachairose, orbit, mahnitus; starches such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatin, as well as magnesium stearate or stearic acid.

In all dosage forms, the compounds of formula (I) may be present as the only active ingredient or may be combined with other known ingredients. pharmacologically active, in particular antibacterial, and / or antimycotic or otherwise anti-microbial active agents, e.g. to extend application possibilities. Thus, they may be combined with, for example, 5,7 / dichloro-2-methyl-8-halo-ololine or other 8-quinolinol derivatives, sulfameitazine or sulfafurazole or other sulfanl amide derivatives, s-chloramphenicol or tetacyclines or others. antibiotics, with 3,4,5-tribromo-licylaniide or; with other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or with benzoxazolones, with polychlorohydroxydiphenylmethane, with halo-dihydroxy-diphenylsuliphides, with 4,4'-idichloro-2-hydroxydithenyiethylamine or with .2 ', 4, - 4'-Trichloro-2-hydroxyhydroxyphenyl ethers, or other poly-halogenohydroxydiphenyl ethers, or other polyhlaloxyhydroxydiphenyl ethers, or with bacterididine-active quaternary compounds or certain derivatives of di-thiocarbamic acid, such as tetramethylthiuramidis. It is also possible to use carriers which themselves have favorable pharmacological properties, such as sulfur, in the form of powder or zinc stearate, as a component of the ointment bases.

The invention also encompasses a method of protecting organic substances that are built upon. • feeding with bacteria or other microbes, which. The organic substance may be, for example, a natural or synthetic polymeric material, a protein-containing substance, or a carbohydrate, or a natural or synthetic fibrous or textile material made therefrom.

The corresponding animal feed formulation contains a sufficient amount of 5-nitroimidazole of formula I to promote the growth of the animals fed with the formulation.

(The following Examples a) to d) illustrate the preparation of several typical dosage forms, but are by no means the only forms of such formulations.

(a) 250.0 g of the active substance are mixed with 550.0 g of lactose with 292.0 g of potato starch, moistened with an alcoholic solution of 8 g of gelatin and granulated with a sieve. After drying, 60.0 g of potato starch, ΘΟ g of granules, 10.0 g of pinched magnesium and 20.0 g of colloidal silica are admixed to the granulate and compressed to 10,000 tabs. years weighing 125 mg each containing 25 mg of the active substance. The tablets may optionally be scored for finer dose adjustment.

ib] A granulate is prepared from 100.0 g of active ingredient, 379.0 g of 1-actose, and an alcoholic solution of 6.0 g of gelatin, which, after drying, is mixed with 10.0 g of " colloidal silica " 0 g talc, 60.0 g potato

1.9 5 6 88 starch and 5.0 g of magnesium stearate and the mixture is • compressed in 10,000 kDa cores. These dragee cores are then. coated with konpentro; 'weighed' syrup of 533,5 g of crystalline saltharose, 20,0 g of shellac, 7,5 (0 g of Arabic gum, 250,0 g of talc, 20,0 g of colloidal silicon dioxide and 1,5 g of dye and The dragees obtained weigh 1.50 g and contain 10 .mu.g of active ingredient.

(c) 25.0 g of the active ingredient and 1975 g of finely divided base material for the preparation of suppositories (for example cocoa butter) are well understood. mixture and the mixture melts. 1000 grams of 2.0 grams are poured from the melt, which is kept homogeneous by stirring. These suppositories each contain 25 mg of active ingredient.

(d) For the preparation of a syrup containing 0 (25% active substance), 1,5 liters of glycerine, 42 g of p-hydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid n-propyl ester are dissolved in 3 liters of distilled water and 25 g is added. 0 g of active ingredient, 4 liters of 70% sorbitol solution, 1000 g of crystalline sucrose, 3510 g of glucose and flavoring such as 250 g of Orange Peel Sdluble Fluid, manufactured by Élí Lilly and Col, IndianapoliS, or 5 g of natural lemon aroma and 5 g of "Halb un'd. Halb" essence, in both cases Haarmann und Reimer products, Holzminlden (NSR), the solution obtained is filtered and the filtrate is made up to 10 liters with distilled water.

The following examples illustrate the preparation of the novel compounds of the general formula, but in no way limit the scope of the invention.

Example 1

2.4 g of a 50% suspension of sodium hydride in mineral oil are added to a solution of 7.96 g of 1- (methylthiocarbamoyl) -N-oxo-5α-tetrahydrolmidazole in 100 ml of diethylformamide, and the reaction mixture is heated and stirred at 50 ° C. 10.35 g of 1-methyl-2-methylsulphonyl-5-nitrolimidazole are then added and the reaction mixture is stirred for a further 4 hours at 100 DEG C. The reaction mixture is evaporated in vacuo and then concentrated to dryness. The residue is filtered and the residue is washed with water and ether and recrystallized from alcohol to give 1- (methylthiocarbamoyl) -2-O'xo-3 - [: 1-methyl-5]. -n-trimidazol-2-yl] tetrahydroimldiazole of formula

C-NHCH ₃ cH ₃ OS

mp 185-187 ° C. Yield 75%.

1- (Methylthiocarbamoyl) -2-oxo-1,2,3,4,5-tetrahydroimidazole, which, as a starting material, can be produced by the following process:

,. A mixture of 86.0 g of ethylene urea and 73.0 g of methyl isothiocyanate was heated at 10 ° C for 4 hours. stirring. After cooling, the reaction mass is purified using ether and water, filtered and washed with an alcohol / ether mixture. The product was recrystallized from methanol. Mp 168-171 ° C.

Example 2

To a solution of 4.7 g of 1- (benzylthlokaribamoyl) -2-oxo: 2,3,4,5-tetrahydrolmildazole in 50 ml of dimethyifuirmamide was added 0.95 g of a 50% suspension of sodium hydride in mineral oil. The reaction simes were heated at 50 ° C for 30 minutes with stirring. Then added first 4.1 g methyl-2-methylsulfonyl-5-ni.troi.mldazolu · and the mixture is then stirred for a further 4 hours at 100 ^Q C. The reaction mixture was evaporated in vacuo, to the residue was added water and then extracted with chloroform. The chloroform solution was. washed with water, dried over sodium sulphate and evaporated in vacuo. The product obtained as a residue is triturated with ether and recrystallized from a mixture of chloroform and alcohol. There was thus obtained 1- (benzylthiocaramoyl) -2-oxo-3- [1-methyl-5-nitroimldiazol-2-yl] tetrahydrolimidazole which melts at 178-18 [deg.] C. Yield 42.%.

Thiokarba.moyllmldazol which is ^one required as starting material can be prepared as follows: '

A mixture of 8.6 g of ethylene urea and 149 g of benzyl isothiocyanate was stirred at 160 ° C for 6 hours. After cooling, a solid reaction mass is obtained, which is triturated with ether and then with hot alcohol and then filtered off. After the mixture překrysltalování chlořdformu ae tlhanolu afford l- _(Ben zylt.hlpkairbamoyl) -2-oxotetrahýdrolmldazol.

Example 3

To a solution of 5.0 g of 1-methylcarbamoyl) -2-oxo-2,3,4,5-tetrahydropyrimazole in 50 ml of methylformamide was added 1.7 g of a 50% suspension of sodium hydride in mineral oil. The mixtures of the reaction is stirred for for 1 hour at 50 ^Q C. Then a solution of 7.2 g of 1-methyl.-2-methylsulfonyl-5-nitrolmldazolu in 30 ml dlmethyliformamidu r.eakčnf and the resulting mixture was stirred for 3 hours Next- at 100 ° C.

The reaction mixture was evaporated in vacuo and water was added to the residue. The obtained red colored solution was then added. extracted with chloroform · and recovered ^! is an oily product. Purification with methanol and recrystallization three times from methanol gave 1- (methylcarbamoyl) -2-oxo-3- [1-methyl-5-nitroimido] 5 68 9 '.

14 '-S-S-yl] -tetylHydroxyimidazole melting at 176-177 ° C. '

The methylcarbamoylimidazole required as starting material is recovered by heating the mixture for 3 hours with 8.6 g of ethylene urea and 5.7 g of methylsocyanate at 130 DEG C. in a sealed tube. Recrystallization from water followed by recrystallization from chloroform-methanol gave methylcarbamoyl imidazole, m.p. 198-200 ° C.

Example 4

To a solution of 16.4 g of 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetrahydro-pyrimidazole in 120 ml of dimethylformamide was added 4.8 g of a suspension (50%) of sodium hydride in a mineral oil. at 50 3 | U min. Then a solution of 20.5 g of L-2-methyl-5-methylsumonyl nitroimida'zolu in 70 ml of dimethylformamide and the mixture was heated for 1 hour at 100 ^Q C. the reaction mixture was evaporated in The residue was dissolved in water, cooled to give a crystalline residue which was filtered off, and after recrystallization from a mixture of acetone and methanol, 1- (methylsulfonyl) -2-oxo-3- (1-methyl-5-nitiroimidazole) was obtained. 2-yl] -tetrahydroimidazole, melting at 202 DEG-204 DEG C. Yield 77%.

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

A mixture of 86.0 g of ethylene urea and 115 g of methanesuliphonyl chloride was stirred at 120 ° C for 6 hours while a stream of nitrogen was passed through the reaction mixture to remove the resulting hydrogen chloride gas. After cooling, water was added to the reaction mixture, and the mixture was heated on a steam bath until a crystalline precipitate formed. After filtration, the crystals were washed with an alcohol / ether mixture and then recrystallized from methanol. Mp ^192-195 ° C.

Example 5

К solution '8.0 g l- (benzylthiokarbamqyl) -2-oxo-3- [l-5-meiťhyl n.itroimida ^l benzimidazol-2-yl] -2,3,4,5-tetriaJhydiOimida'Zolu 80 5 ml of concentrated sulfuric acid was added to the ml of dimethyl sulfoxide and the solution obtained was heated on a steam bath for 2 days. The residue is diluted with water, the product is filtered off and then dissolved in ethyl acetate. Ether was added to the ethyl acetate solution and recrystallized from ethyl acetate-ether to give 1- (benzylcarbamoyl) -2-oxo-3- [1-methyl-5-nitroimidazol-2-yl] -2, 3,4,5-tetrahydroimidazole, which melts at 113-11 ° C. Yield 40%.

Example 6

К suspension of L _t 5 g of 50% sodium hydride in 10 ml of absolute di'methyi'for, mainidu added under stirring over 15 minutes a solution '5.3 g eithylfihlokanbamoyl LN-2-oxo-tetrahydroiímtdazolu in 20 ml absolute dimedhylformamidu. The reaction mixture is stirred at 50 ° C under nitrogen for 30 minutes, then a solution of 4.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 10 ml of absolute dimethyltormamide is added over 5 minutes and the reaction mixture is heated to 100 ° C. ° C for 4 hours. The reaction mixture is evaporated in vacuo, the residue is triturated with 50 ml of water, extracted with ethylene dichloride and the extract is dried over sodium sulfate. The evaporation residue is chromatographed on silica gel. The fraction was eluted with 2% methanol in chloroform to give 1-N-ethylthiocarbamoyl-2-oxo-3- [14-methyl-1 H -pyrrole] ^. 5-nitro-triazol-2-yl] -tetrahydrimido-dalzole, which melts at 213 ° C after recrystallization from methylene chloride-hexane.

The compound mentioned above as a starting material can be produced as follows:

A mixture of 8.6 g of ethylene urea and 8.7 g of ethyl sulfothiocyanate was heated at 100 ° C for 4 hours. After cooling, the product was recrystallized from a mixture of ethanol and ether. There was thus obtained 1-N-ethylthiocarbamoyl-2-oxotetrahydroimidazole melting at 13-5 ° C-13 ° C.

Example 7

To a suspension of 2.2 g of 50% sodium hydride in 10 ml of absolute dimethylformamide, a solution of 8.7 g of 1- (N, N-dimethylsulfamoyl) -2-oxo-tetrahydroimidazole in 20 ml of absolute dimethylformamide was added over 15 minutes with stirring. . The reaction mixture were stirred under nitrogen for 1 hour at 50 ^Q C and the mixture was then added a solution of 9.25 g dimethyl-2-metjhylisulfonyl-5-nitroimidazole in 20 ml of absolute DMF. The reaction mixture is heated under nitrogen at 95 ° C for 3 hours ... The solution is distilled off in vacuo and the residue is triturated with 4-5 ml of water. The suspension is extracted with ethylene dichloride, dried and evaporated. The residue is washed with hexane and triturated with acetone. Recrystallization from methylene chloride / ether gave 1- (N, N-4-methyl-3 H, amoyl) -2-oxo-3- [1-methyl-5-nitrimimidazol-2-yl] tetrahydroimidazole melting at 217 ° C. Yield 42%.

1- (N, N-Dimethylsulfamoyl) -2-oxotetra-. the hydroimidazole which is needed as a starting material can be prepared as follows:

A mixture of 17.2 grams of ethylene urea and 28.7 g N, N-dimethylsulfamoyl chloride is heated at Loo ^q C for 3 hours. The reaction mixture is cooled and then triturated with 100 ml of methanol. The residue was filtered off, dried, then dissolved in 5% methanol in chloroform and the solution was chromatographed on a 150 g silica gel column. The fractions were eluted with 2% methanol in chloroform, after which the product was recrystallized from methylene chloride / hexane. The product melts at 129 ° C.

'105689

Example 8

A mixture of 34.4 g of ethylene urea and 54.2 g of N, N-tert-butylcarbamoyl chloride under atmosphere. It was heated with nitrogen at 110 ° C for 3 hours. The reaction mixture is cooled and diluted with 200 ml of acetone, then filtered and the filtrate is evaporated. The product is then chromatographed on a 450 g silica gel column. The fraction was eluted with 3% methanol in chloroform. There was thus obtained 1- (N, N-diethylcarbamoyl) -2-O-tetrahydrothiazole as a colorless oil. .

To a suspension of 5.8 g of 50% sodium hydride in 20 ml of absolute dimethylformamide are added under stirring over 15 minutes a solution of 2.2 g of the above mentioned [N, N-dieithylcarbamoyl] -2-oxotetrahydroimidaisole in 40 ml. The reaction mixture was stirred under nitrogen for 1 hour at 50 ° C. A solution of 24.6 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 40 ml of absolute dimethylformamide is then added in one portion to the reaction mixture.

The reaction mixture was further chromatographed as described in Example 6, and the resulting residue (36 g) was chromatographed over О6 g of silica gel. The fraction was eluted with 2.51% methanol in chloroform. Recrystallization from a mixture of methylene chloride and hexane gave 1-N, N-diethylcaryboyl-2-oxo-3- [1-methyl-5-nitroimldazol-2-yl] tetrahydroimidazole, which melts at 133 ° C. Yield 29%. '

Example 9

To a suspension of 24.5 g of 50% sodium hydride in 100 ml of methylenediamide, a solution of 78.5 g of 1 (N, N -dimethylcarbamoyl) -2-oxotetra drotaiidazole in 150 ml of absolute diipethylformamide was added with stirring over 15 minutes. The reaction mixture was stirred under a nitrogen atmosphere at 50 ^and C for 1 hour and a solution of 102.5 g of 1-methyl-2-methylsulfonyl-5-nitroimidazole in 100 ml of absolute dimethylformamide was added over 10 minutes.

. The reaction mixture was heated to 100 ° C under nitrogen for 3 hours. Further work-up is carried out as described in Example 6. After recrystallization of the product from a mixture of methylene chloride and hexane, 1N, N-dimethylcarbamoyl-2-oxo-3- [1-methyl-5-nitro] imidazole is obtained. 2-yl] itetrahydiroitmidazole melting at 190-191 ° C. Yield 35%.

The 1-N, N-dimethylcarbamoyl-2-oxotetriahydroimidazole, which is needed as a starting material, can be prepared as follows:

A mixture of 86 g of ethylene urea and 118 g of N, N-dimethylcarbamoyl chloride in 200 ml of ethylene dichloride was heated under reflux for 3 hours under nitrogen. The reaction simulation was then evaporated and the residue was dissolved in chloroform and the solution was chromatographed over a 1.5 kg column of silica gel. The fraction was eluted with 5% methanol in chloroform and the product was recrystallized from methylene chloride / hexane. The above product melts at 1'3'4 to 136 'Celsius.

Example .10

OF

a) To a suspension of 4.5 g of 50% sodium hydride in 10 ml of absolute dimethylformamide, a solution of 16 g of 1-ethylsulfonyl-2-oxotetrahydroimidazole in 30 ml of absolute dimethylformamide is added over 15 minutes with stirring. Reaction direction? was stirred under nitrogen at 50 ° C for .45 minutes and the mixture was then added a solution of 18.5 g l-Methyl-2-methylsulphonyl-5-nitropyrimidine ^and roimidazolu 30 ml of abs. The reaction mixture was worked up as described in Example 6. The crude product was recrystallized from methylene chloride / hexane. The 1-N-ethylsulfonyl-2-oxo-3- [1-methyl-5-nitro-imidazol-2-yl] -tetrahydro-imidazole thus obtained, melting at 176-177 ° C. Yield 33%.

b) The required starting material is produced as follows:

A mixture of 29.2 g of ethylene urea and 43.7 g of thienyl sulfonyl was heated at 110-6 for 3 hours. The reaction mixture is triturated with 30 ml of methanol and filtered. The filtrate was evaporated and the residue was dissolved in chloroform and this solution was chromatographed on a 750 g silica gel column. The desired fraction was eluted with 5% methanol in chloroform and then the product was recrystallized from methylene chloride / hexane. The thus obtained L-ethylsulfonyl-2-oxo-tetrahydrofuran Rol ^l, iůaje imidazole at 114 to 116 ° C.

Example 11

In an analogous manner to that described in Example 10a), 5.8 g of 1- (4-fluorophenylisulfonyl) -2-oxotetrahyidrolidinazole and 5.0 g of 1-methyl-2-methylsuliphonyl-5-nitroimidazole are obtained. 1-N- (4-fluorophenylsulfonyl) -2-oxo-3-yl-methyl-5-initroimidazol-2-yl ^| ] tetnahyidroimidazole, which melts, e.g., 198-200 ° C.

The starting material referred to above is prepared as follows:

A mixture of 17 g of ethylene urea and 19.5 g of p-fluoro-phenylsulfonyl chloride was heated at 100 ° C for 3 1/2 hours. The residue was recrystallized from a mixture of meithaneblu and water to give 1- (4-fluorophenylsulfonyl) -2. drolmidazole, which melts at 183-185 ° C.

Example 1 and ¹ d 12

To a stirred suspension of 1.3 g of 50% sodium hydride * in mineral oil in 20 ml of anhydrous dimethylformamide was added dropwise a solution of 5.41 g of 1-piperidinocaribonyl-2-oxoteitra195689 17.

of hydrolmldazole in 15 ml of dimethylformanild at. unchanged temperature. The reaction temperature is then adjusted to 50 and stirred for 30 minutes. A solution of 1-methyl-2-methylsulfonyl-S-nitrolimidazole is then added dropwise over ¹ minute to the reaction mixture. 20 ml of dimethylformamide and the temperature is raised to 95 DEG C. and left at this temperature for 1 hour. The reaction mixture is then added. It is evaporated under vacuum and the residue is treated with a mixture of isopropyl alcohol and ether. . (5: 1). The colorless granulate is recrystallized from a mixture of ethyl acetate and hexane. The thus obtained 1-piperidinocarbemyl-2-oxo-3--1-. Methyl-5-nitrole (thiazol-2-yl) -rahydro-thiazolidazole melts at 15-2 ° C. Yield 23%.

• Example 13 ¹ К stirred suspension of 1.92 g., 50% sodium hydride dispersed in mineral oil in '.25 ml of absolute dimethylformamide was added dropwise a solution of 7.96 g ^^^ ^ ot ^ t ^^^^ Tolin 'bb2n] 12-ooo2rt: mhyУdoiιm-da.z21u v. 15 ml of 'absolute' dimethylformamide. Suspension. s тОСА at '50' ° C for 30 minutes. . A solution of 8.2 g is then added over 5 minutes. 1-Methyl-2-methylsulfonyl-15-methyl-imazole v. The reaction temperature was increased to ¹ ml. 95 ° C and maintained. se 'za. stirring for. , 2 hours. The reaction is then carried out. the mixture is evaporated in vacuo and the residue is washed with ether ⁽ and crushed ice is added. 1-morpholinyl-2-oxo-3- (1-methyl) is obtained. 5-nitro-1-imidazol-2-yl] tetrahydroimidazole, which melts at 180 DEG C. after recrystallization from ether. Yield 21%.

• 1-morpholino-carbonyl-2-oxotetrahydr2-.

The mildazole required as starting material is prepared as follows. as follows: · K 'solution. 212.27 g of 1-chlorobenzoyl-2-oxo-methylhydrazole in 80 µl of anhydrous water. sei. a solution of 26.1 g of morpholone in 20 ml was added dropwise with stirring. benzene. The mixture is heated under reflux for 4 'hours. The reaction product is filtered off, then treated with a saturated solution of sodium bicarbonate and filtered. After. recrystallization from isol-1-oxylcarbonyl-2-2X2-tetrahydro-1-alzole having a melting point of 158 ° C.

Example 14

A solution of 2.9 g of 1- (methylsulfonyl) -2-oxo-3 '- [1-methyl-5-nitro-imidaz (21-2-yl) -ethoxy] -hyd. roiirnlídajzolu and 1.9 'g ^ethyloxoniu: IůιflU'2r2b2rátu' in '2Q0' chloroform mu 'to' state .ponechá přideplotě 'm ^ i ^^ l ^ i ^ i ^ E ^ THP for 72 hours. a precipitate a viscous oil, The solid residue obtained is filtered off, boiled in acetone and, after filtration, recrystallized from aqueous ethyl acetate to give 1-methyl-2 · [3- (methylsulfanyl) 1- [2- (2-ethoxy) -dazol-1-yl] -3-ethyl-5-nitrol-5-nitrolyl-azulphen-2-ol, orate of formula

having a 'melting point' of 205-267 ° C; . Yield '21%'. ·· '' Example '15'; , .. j '·.

A solution of 3.0 g of 1- (methylsulfonyl-4-oxo-3- [1-methyl-4-nitro-imidiazol-2-yl] -tetrahydro-tolyl) in 30 ml of methylene chloride in which 3.0 g of potassium iodide were added, heated at reflux for 16 hours, the solvent was then removed under vacuum and the residue was treated with water and treated with water. The filtrate is acidified with 2N hydrochloric acid solution, cooled and re-filtered to remove unreacted starting material.

The filtrate is then 'cooled' and the precipitated crystalline residue is filtered off and recrystallized twice from a mixture of acetone and methanol. 1- [1- (methyl) -4-methyl-4'-imidazol-2-yl] -tetr. imldazole melting at 180-181 ° C. Yield = 10%. '. '. -.

'key' 16 ''. ' .. 'и ·. ·· ·. · ·.

A solution of 3.0 g of 1- (methylthlokarbamoyl) -2-. -2xo-3 - ´l-methyl-5-nitr2im.ld'azol-2-y.l] - 'tetrahydroriniidazole' in 25 ml of dimethylformor.m-. amide to which 3.0 g was added. Potassium salt. is warming up. 16 - 'hours to boil' under reflux ''. cooler. Reaction mixture. -`s 'filtered' and. '' The rest of the '-filter is ·' gradually. '' washes' hot '' ethanol and- ·. Methane (piem: 'and then' recrystallizing 'from' a mixture of '' acetone 'and' methaneplu. '), 1- (Methyl-12-cambam-2-yl) -2-oxo-3 is obtained. (1-Methyl-4-nitroimidazol-2-yl) tetrahydrofihidazole, which melts at 239 DEG-241 DEG C. Yield: 20%; . '' h £ · '

Example '' 17 ·. · ··· ·; - / -;

Roz 0,4 · · 9 9 9 9 9 9 9 9 9 9 0,4 9 9 5 5 5 5 5 5 5 5 5 5 5 'ml' dЫěťhyl! · fó'ř'ma 'řnldů'was' mixed 'on' at 50_ ° C for one hour, O, 1I5 'g''50 ^fl / o '· sidného hydride suspension in' mineral oil. To the mixture was added 0.57 g of L-ntóttíýI 2 -. (Me'thylsulfinýl) -5iíl'tro> imidazole and the mixture 'was' stirring, heated for 3 hours and ¹ · to 100 ° C. Solvent. It was stirred in vacuo and water was added. The crystalline precipitate was filtered off. and. recrystallized from ateftonu 'and méthan2lu .. give' L4 (; m'é lhhУsuUfony ^]) ^J-2-2 XO · -3 - l-Methyl-'5-nit.rolmidaz2l 2-yl · ] iétгahydг2imida'zol, which melts' at 202 to 204. ⁰ C and is equal to β

with the product obtained according to Example 4. Yield 30%. _:

(b) The starting material shall be:. as follows: '

Dissolved mixture of 3,4-gmnt-methyl-4-methyl-methyl-methyl-methacrylate and 5 ml of '30% aqueous' solutions' of hydrogen peroxide in 20 ml of methoxyethanol The mixture was refluxed for 6 hours with freshly prepared titanium dioxide at 100 ° C and then diluted with water and filtered. The filtrate was extracted with chloroform and the resulting chloroform layer was evaporated. 2.5 g of an oil are obtained, which solidify slowly on standing, the solid residue obtained is recrystallized from ethanol and from a mixture of chloroform and ether to give 1-methyl-1- (methylsulfiethyl). N-nitroimidazole.

Example 19.

(a) To the obtained suspension of 6.1 g of 50% sodium hydride dispersed in mineral oil in 2 (0 .mu.l of anhydrous dimethylformamide) is added a solution of 30 g. (N, Ν-Diethylsulfamoyl-1) -2-oxotetrahydro-imazole in 50 ml of anhydrous dimethylformamide The reaction mixture is stirred at 50 ° C for 1 hour under nitrogen and then a solution is added. 25.6 g of 1-methyl-2-methylsulphonyl-5-nitrolimidazole in 40 ml of anhydrous dimethylformamide were stirred and stirred at 96 DEG C. for 3 hours under nitrogen. The solvent is removed by vacuum distillation and the residue is digested with 100 ml of water, the suspension obtained is extracted with ethylene chloride, the ethylene chloride extract is dried and evaporated to dryness in vacuo. Silicaigels and in a fraction or eduded with 1% methanol in chloroform precipitate crystals. The precipitate was recrystallized from a mixture of hexylchloride and ether to give 1 N, N -diethyl-8-aminoyl-2-oxo-3- (4-methyl-5-nitrolyl) -azoline. 2-yl) -1,14-tetrahydroimidazole, which melts at 146. to

- 147 ° C; ' ¹ :.' · -.

(B) The starting material is obtained as follows:. -....

A mixture of 51.6 g ethylene urea and 90 g N, N. The ethylsulfamoyl chloride was heated at 110 ° C for 3 hours. The reaction mixture was cooled and digested with 300 ml. The filtrate is filtered in methanol. The vacuum evaporates to the air. - 'The remainder of Jojust' in. 5% methanol in chloroform was chromatographed on a column. Krystalická '. The fraction eluting with 9% methanol in chloroform was recrystallized from methylene chloride / hexane. . Gets. . 2-Oxoethyl-2-oxotetra-4-aminotazole, melting at 90-92 ° C.

Example 1 and d '19

a) To a stirred suspension of 1.6 g. 50% sodium hydride in 'mineral oil' A solution of 5.9 g is added in 30 ml of anhydrous 'dimethylformamide' over 15 minutes. 1-pyrrolidinocarbonyl-2-oxoethyl ether (50 ml) in 15 ml of anhydrous dimethylformamide The reaction mixture was stirred under a nitrogen atmosphere at 50 ° C for 1 hour. and then a solution of 6.6 g of hyo-5-nitroimidazole in 20 ml of anhydrous formamide was added thereto, and the reaction mixture was heated under stirring under nitrogen for 1 hour. 95 DEG C. The solvent is removed by vacuum distillation, the residue is digested with water and extracted with ethyl chloride, the extract is dried and evaporated to dryness and the residue is chromatographed over a silica gel column and the fraction is filtered. 3% in chloroform, provides a crystalline mixture which is recrystallized from methylene chloride / hexane to give the title compound as a pyrrolidine-4-methyl-2-oxo-3- [1-methyl-4-nitro-amino] -2-oxo. Melting point: 156 DEG-156 DEG C. Yield: 20%.

(b) The starting material is prepared as follows:.

Mixture 40. and g. g of 1-pyi ^ i ^ ^people l: iwkarbion. ^ L <chlorides. (b.p. 100 to 104 * 41/600 mbar). that heats up. for .3 hours of temperature. 110 ° C. . The reaction mixture was then cooled and added. 200 ml of chloroform are added. Remove undissolved matter by filtration and filtrate. Evaporate to dryness. The residue is chromatiographed. over a silica column and a fraction eluting with 4% methanol in chloroform, provides a crystalline mixture which is recrystallized. from ethyl acetate. There is thus obtained 11-pyrrolidolido-carbonyl-2-piperidinyl-imidazole which melts at 153-154 ° C.

Example 20 .., '·,. . , ..

a) To a suspension of 3.5 g '50% hydride. of sodium salt in a mineral oil in water. 20 ml dt'maťhylfoгm'aml ^, with run. 15 .minutes: adds. solution of 15.6 g of 11-pyrrole-3-sulfonyl-2-oxotetrahydroimidazole in. 40 ml of anhydrous dimetfoylfoirma.midu. The reaction mixture is stirred under nitrogen at room temperature. temperature. 50 ° C for one hour and then. Toztok is added. 14.4 g of 1-ethyl-2- (2-methylsulfonyl-5'-dihydroxybutan). in 30 ml of anhydrous dimethylphenamide. Reaction. the mixture is heated. under stirring under nitrogen atmosphere for 1 hour at 95 ° C. The residue is digested with 50 ml of water to form a crystalline precipitate. The precipitate obtained is filtered off and crystallized. ,. from a mixture of methylene chloride and ether. Se- obtained llpy, rrolid.inosůlfonyl · * 2 l-oxo-3- (6-1lmethyl .'- rittr oimldazol-2-y1) tetrahydrotιmida ^l zol, mp The temperature of 226 ° C. Yield 19%.

(b) The starting material is obtained as follows:

Mixture 30. g ethylene urea and 64.5 g pyrrolidthCll · sulfohyl-chloride (cotton wool temperature)

121 [deg.] 1.6 kPa was heated at 110 [deg.] For 3 hours

Celsius. The reaction mixture is then added. Cool and dissolve in 300 mL of chloroform, filter

The residue was dissolved in 4% methanol in chloroform and chromatographed over a silica gel column. The fraction eluting with 2.5% methanol in chloroform affords 1-pyrrolidolidinesulfonyl-2-oxo-nitrohydro-imidazole which melts at 150 ° C after recrystallization from ethyl acetate.

EXAMPLE 21 In a suspension of 1.92 g of 50% sodium hydride dispersed in mineral oil in 20 ml of anhydrous dimethylformamide, a solution of 9.3 g of 1-piperidinesulfonyl-2-oxophthetrahydroimide in 15 ml of dimethylformamide was added dropwise at room temperature. The reaction temperature was raised to 50 C, ^N, and the reaction mixture was stirred for further 30 minutes. A solution of 8.2 g of 1-methyl-2-methylsulphonyl-5-nitroimidafeol in 25 ml of dimethylformamide is then added and the reaction temperature is maintained at 100 DEG C. for 2 hours. The solvent was removed under reduced pressure and the residue was treated with water containing crushed ice. The residue, after removal of the aqueous layer, was treated with a mixture of isopropyl alcohol and the mixture. and ether {5: 1]. There was thus obtained a pale yellow precipitate which was recrystallized from ethyl acetate to give 1-piperidinesulfonyl-2-nitro-3- [1-methyl-5-nitroimidazol-2-yl] tetrahydroimidazole, m.p. 192 DEG C. Yield 18%.

¹ (b) The starting substance shall be produced by the following procedure:

К 17.4 grams of ethylene urea was added for prptřepáVání 3'6-ahloridu plperidinosulfonyl g (b.p. 130 ^Q C / 1.5 mbar) and the reaction was? maintained at 100 ° C under nitrogen for 3 hours. After cooling, the rubbery reaction product was treated with a mixture of methanol and isopropyl alcohol (1: 1). 1-piperidinosulfonyl-2-oxotetrahydroimidazole is obtained in the form of a granular product which melts at 201 DEG C. after recrystallization from methanol.

Example 22

a) К solution of 8 g of L - () methylsulfonyl) -2-0'XO _4- iethyl ^ ^{J 2,3,4,5;} tetrahydrotmidazolu in '30 ml of dry dimethylformamide was added 2.2 g of 50 ^1% suspension of sodium hydride in mineral oil and the mixture was stirred at míjstnostl, for 1 hour. A solution of 9.2 g of 1-methyl-1-methylsulfonyl-S-nitroimide in 20 ml of absolute dimethylformamide was then added to the reaction mixture, which was then stirred for a further 3 hours. The solvent was removed in vacuo and the residue was dissolved in water. Upon cooling of the solution, a crystalline precipitate is obtained, which is filtered off and recrystallized from a mixture of methylene chloride and ether. 1- (Methylsulphonic acid) -2-oxyl-α- is obtained. 1-Methyl-5-methylimidazol-1-yl-1-methyl-tetralralhydroimidazole, which melts at 199-200 ° C.

b) 1- (methylsulfonyl) -2-oxo-4-methyl-

-2,3,4,5-tetahydroimidoisole used as the starting material; the substance is produced as follows:

A mixture which comprises> 10 g of ^{4-methyl-l-imidazolldlnonu} second and 11.5 g meitihylsulfonýlchlioridu, for 3 hours with stirring and heated to 120 ° C. At the same time, a stream of nitrogen is introduced to remove the resulting hydrogen chloride gas. After cooling, water is added and the mixture is heated on a water bath ¹ until a crystalline powder is formed which is filtered off and, after dissolution in chloroform, chromatographed on a silica gel column. The fraction eluting with a mixture of chloroform and methanol (97: 3) contains lt (methylsuliphonyl) -2-oxo-4-methyl-2,3,4,5-tetrahydroimidazole, which is recrystallized from a mixture of methylene chloride and hexane solvents. and then melts at 129-130 ° C.

Example 1 a d 23

2.4 g of a 501% suspension of sodium hydride in mineral oil are added to a solution of 8.2 g of 1- (methylsulfonyl) -2-oxo-2,3,4,5-tetrahydro-imidazole in 60 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour. A solution of 12.45 g of 1- (p-methoxyethyl) -2-ethylsulfonyl-5-nitroimidazole in 20 ml of dimethylformamide is then added and the reaction mixture is stirred for 4 hours. , 5. hours at room temperature. The dimethylformamide was evaporated in vacuo on a steam bath. The residue was treated with 30 g of crushed ice until crystals formed. The crystalline residue is filtered off and the product is then recrystallized from acetone / methanol / iron. 1- (Methylsulfonyl) -2-oxo-3- [1- p -methoxy-ethyl-5-nitroimidazol-2-yl] -tetrahydroimidazole of formula is obtained.

CH 2 CH ₂ OCH ₃

mp 126-127 ° C.

The starting material is prepared as follows:

and N-methoxyethylamino-acetalide-diethylacetal

A mixture of 170 ml of a 63% aqueous solution of 3-methoxy-ethylamine and 90 g of bromoacetaldehyde diethyl alcetal was heated in a steel tube at 120 ° C for 16 hours. The reaction mixture was then treated with 75 g of potassium hydroxide with cooling; the mixture was filtered and the filtrate was dried over anhydrous potassium carbonate. Thereafter, the mixture is distilled at 1.15-120 mbar to give diethyl acetal / S-methoxyethylaminoacetaldehyde.

195889 ²³ • b). 1- (β-Methoxyethyl) -2-mercaptoimidazole. - _:;

To a solution of 9.55 g. [Eta] &lt; 3 &gt; -ethoxyethanol ^, n.acet: α'lddhVdu 'at '50. ml of absolute ethanol use is gradually treated with 6 g of potassium thiocyanate and 27.5 ml of 2N hydrochloric acid solution. The reaction mixture was then refluxed for 16 hours. The solvent was evaporated in a steam bath in vacuo and the residue was extracted with acetone. The extract is concentrated to a small volume and ether is added. The residue obtained is recrystallized from a mixture of acetone and ether. There was obtained 1- (3-aminodoyl-ethyl) -2-mercaptoimidazole of m.p. 92-95 ° C.

cj 1-piperidin-2-ylmethyl-2-methylhexapto-5-nitroimidazole

To the cooled solution 15.8 g. 1 - ([.eta. @ 3 - (3-methoxyphenyl) -2-dimethoxymethyl] azole in 90 ml of methanol is added in one portion to 110 ml of 1N sodium hydroxide solution with stirring and cooling. The reaction mixture was stirred for an additional 2 hours at 10 ° C, the methanol was removed in vacuo at 50 ° C, and the residue was diluted with water and extracted with ethyl acetate. The methylene chloride extract was dried and evaporated to dryness.

The compound (15.3 g) obtained above was collected

-. 24 is added dropwise. 82 ml of concentrated nitric acid under a nitrogen atmosphere. The reaction mixture was then slowly warmed with stirring and maintained at a temperature of 100 ° C for 40 minutes. After cooling to room temperature, the reaction mixture was heated to room temperature. The residue is poured onto 50 g of ground ice, the mixture is neutralized with 50% sodium hydroxide solution and then extracted with methylene chloride. And the extract evaporated to dryness. The residue was recrystallized slowly from hexane to give the product obtained above, m.p. 44-45 ° C.

d] 1- [5-methoxyphthyl] -2Z-methylsulfonyl-S-nitroimidazole.

To a solution of 26 g of 1 - (((R) - ((4-thoxyethyl) -2,2-methylmercapto-5-nitrimidinol) v. 80 ml of methylene chloride) was added dropwise 550 ml of 0.48 molar. · monoperftalov.é acid solution and treated for 6 hours · · at · 10 to '16 ^e C. After this time the reaction mixture was stirred '^ · h at room temperature, boiled for 1 hour under reflux · · · · and cooled condenser The filtrate is washed successively with sodium bicarbonate solution and water, then dried and evaporated to dryness. A crystalline residue which is recrystallized from a mixture of diethyl ether and hexane to give 1-methyl-methoxyethyl) -2-methylsulfoilyl-5-nitro-imidazole. Mp 92-93 ° C.

Claims (14)

1. A method for producing derivatives of an imidazole compound according to the formula I, xr ₅ O (n 'in which one of the radicals R 1' and R 2 'represents · hydrogen · and the other one represents n-thro-cup, R 1 is a lowered lower alkyl radical having from 1 to 2 2 carbon atoms or a (lower) alkoxy (&quot; lower) alkyl group having up to 4 carbon atoms, &quot; X represents a carbonyl group, a carbonyl group or a sulfonyl group, and if X represents a carbonyl group or a thiocarbonyl group, then. R 5 denotes benzylamino group. morpholino, pyrrolidino, piperidinoctipine, lower alkyl amine, or lower [lower] alkylamino. a lower alkyl group always contains. 1 to 4 carbon atoms, and when X is a sulfonyl group, R 5 is a fluorophenyl group, a pyrrole-3-group, a piperidino group, a. lower alkyl having 1 to 4 carbon atoms, lower alkyl having 1 to 4 carbon atoms, or di (lower) amino, C1-4 alkyl, C1-4 alkyl or C1-4 alkylamino groups; us 1 to '4' · carbon atoms. - in alkyl residues and its acid addition salts and quaternary salts, characterized in that:. That the 'imidiazole' of the general formula II is:. in 'which' R1, R2 and R1 3. Have · sihtora Z is an alkylsulfoinyl group wherein the alkyl contains 1 to 2 carbon atoms and is a compound of formula III; ^θ ^ -X-Rs Ύ '·' ⁰ (lil). 198669 v n tož R 5 and X are as defined above, whereupon any compound of formula I in which R 2 is nitro is converted to the corresponding 4-nitro derivative of formula I by treatment with an alkali metal iodide or by an alkyl iodide of formula R 3J in which R 3 is an alkyl group and / or the compound of formula (I) in which X is known thiocarbonyl. is converted to compounds of formula I wherein X is a carbonyl group by reacting thiocarbonyl derivatives with an alkali metal hydroxide in the presence of an oxidizing agent, or in the presence of a strong acid, and / or separating the resulting racemate mixture into pure racemates; or the obtained racemates are separated into optical antipodes, and / or the salts obtained are converted into the free compounds or other salts or the obtained free compounds are converted into their salts. '2. The process according to claim 1, characterized in that the starting jiako' substance of the formula II wherein Z is, metlhylsuUfonylolvOu ^one group that Ri, Rz and RSMA 'meaning. under the formula! AND. • 3. 1. A method according to claim 1 or 2, wherein one of R1 and R2 is hydrogen and the other is n-nitro, R3 is methyl or ethyl and Z is methylsulfonyl is treated with a compound of formula II. III in which X represents a carbonyl group or thlokarbones a left group and R 5 represents a full-length group, a morpholino group, a pyrrolldino group, a methylamino group, a dimethylamino group or a dlethylamino group. 4. The method of item 1. or 2, characterized in that the compound of formula ž in which one of R 1 and R 2 is hydrogen and the other is ntro, R 3 is methoxyethyl, methyl or ethyl, and Z is meithylsulfonyl is treated with a compound of formula Ш. wherein X is a sulfonyl group and R5 is a pyrrolidino group, a plperi diamino group, a methyl group, an ethyl group, a fluoro-phenyl group, a methylamino group, an ethylaminoiminocipine, a dimethyliamino group or a diethylamino group. 5. The method of item 1 or. 2. The method of claim 1 wherein the 1-methyl-2-methylsulfonyl-5-nitroimidazole is treated with 1- (methylthiocarbamoyl) -2-oxo-2,3,4,5-tetrahydroimldazole. 6 .. A method according .bodu 1 or 2 .Vyznačující in that the L-meehyl-2-methylsulfonyl-5-l-operates nitrolimiidiazol fíměthylkarbamoyl) ^j -2-oxo-2,3,4,5-tetrahydroimidazol. 7. A method according to claim 1 or 2, wherein the 1- (methylsulphonyl-5-nitroimidazole) is treated with 1- (methylsulphonyl) -2-oxo-2-ol. 3,4,5-itetrahydr'1''midazole. 8. A process according to claim 1 or 2, wherein the 1-methyl-2-methylisulfonyl-S-nitrolimidazole is treated with 1-N-ethylthiocarbamoyl-4-oxotetrahydrotmlidazole. 9. The method of claim 1, wherein the 1-methyl-2-ethylsulfonyl-5-nitrolimidazole is treated with 1 '(N, N-dimethylsulfonyloyl) -2-oxoteitrahydrimidazole. 10. A process according to claim 1 or 2, characterized in that 1-methyl-4-methylsulfonyl-5-nitroimidazole is treated with 1- (N, N-diethylcarbaimoyl) -Z-oxothenethyhydrolmiidiazole. 11. The method of claim 1 or 2, wherein the lanethyl-2-methylsulfonyl-5-nitrolimidazole is treated with 1- (N, N-dimethylcarbamoyl) -2-oxotetrahydroimidazole. ' 12. The method of claim 1 or 2, wherein: 1-methyl-2-methylhulfohyl-5-nitroimidazole; is treated with 1-plperamino-aribonyl-2-oxotetrahydrimidazole. 13. A method according to claim 1 or 2, characterized in that 1-methyl-2-methylsulfonyl-5-nitroimidazole is treated with 1-methylphenylcarbonyl-2-oxotetrahydrolmidiaisoleim. 14. The process of claim V or 2, wherein 1-methyl-2-methylisuliphonyl-5-nitroimidazole is treated with 1- (N, N-diethylsulfamoyl) -2-oxo-tetrahydroimidimidazole.