CA1039732A - Imidazoles and processes for their production - Google Patents

Abstract

Abstract of Disclosure The present invention relates to processes for the preparation of new imidazoles, especially of 4- or 5-nitro-imidazoles, substituted by tetrahydroimidazoles which may be substituted having the formula

Description

~03973Z
The present invcntion relates to imidazoles and processes for the production thereof. The invention provides new imidazoles of the formula I

' ' ,,L--N~N-X-R5 (1) ;

wherein one of the groups Rl and R2 is a hydrogen or lower alkyl and the other a nitro group, R3 is a lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, lower alkylsulphonylloweralkyl or aminoloweralkyl, X is a carbonyl, thio-carbonyl, sulphinyl or sulphonyl group and R5 when X is a carbonyl group is amino, loweralkylamino or diloweralkylamino group, and when X is a thiocarbonyl, -sulphinyl or sulphonyl, R5 is a lower alkyl, aryl, amino, alkylamino or di-loweralkylamino group, their salts and N-oxides.
The term "lower" as used hereinbefore or hereinbelow in connection with the definition of organic compounds, groups and radicals, signifies that such compounds, groups and radicals contain up to and including 7 carbon atoms preferably up to 4 carbon atoms.
Examples of lower alkyl groups are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, iso-hexyl or n-heptyl groups.
~ydroxyloweralkyl groups have at most 7 carbon atoms, particularly up to 4 carbon atoms, wherein the lower alkyl portion has the above mentioned meaning, like e.g. hydroxymethyl, 3-hydroxy-n-propyl and particularly 2-hydroxyethyl.
Loweralkoxyloweralkyl residues are e.g. those in which the lower part has up to 7 carbon atoms, particularly up to 4 carbon atoms e.g. methoxy-methyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-~n-butoxy)-ethyl, 3-(n-propoxy)-propyl or in particular 2-methoxyethyl.
Loweralkylsulphonylloweralkyl residues are e.g. lower alkyl groups as mentioned above which carry a lower alkyl sulphonyl group such as methyl-D
;

, .. - . . . . . .~ . . .

: - `

sulphonylmethyl, ethylsulphonylmethyl, 2-methylsulphonylethyl, n-propyl- ~
sulphonylmethyl, 2-n-propylsulphonylethyl, 3-n-propylsulphonyl-n-propyl or ~ -ethylsulphonylethyl and in particular 2-ethylsulphonylethyl.
Aminoloweralkyl is e.g. an above mentioned lower alkyl which carries an amino group, in particular a tertiary amino group. A tertiary amino group is e.g. diloweralkylamino, such as dimethylamino, N-methyl-N-ethylamino, diethylamino, di-n-propylamino or di-n-butylamino or loweralkylene-amino in which the lower alkylene part may be interrupted by a hetero atom such as oxaloweralkyleneamino, thialoweralkyleneamino or azaloweralkylene-amino, e.g. pyrrolidino, piperidino, morpholino, thiomorpholino, 2,6-dimethyl-thiomorpholino, piperazino, N'-methylpiperazino, or N'-(~-hydroxyethyl)-piperazino. Aminoloweralkyl is e.g. dimethylaminomethyl, diethylaminomethyl,

2-dimethylaminoethyl, pyrrolidinomethyl, 2-pyrrolidinoethyl, 3-pyrrolidino-n-propyl, piperidinomethyl, morpholino-methyl, 2-morpholino-ethyl, 2-thio-morpholino-ethyl, piperazino-methyl, 2-piperazino-ethyl, N'-methyl-piperazino-methyl, 3-(N-methylpiperazino)-n-propyl and N'-(~-hydroxyethyl)-piperazino-methyl.
The aryl group R5 is an optionally substituted aryl residue e.g.
a phenyl or naphthyl group optionally substituted by one or more than one substituent as well as an optionally substituted 5,6,7,8-tetrahydro-1-or 2-naphthyl residue. Preferred are optionally mono- or di-substituted phenyl or naphthyl radicals, particularly mono-substituted phenyl or naphthyl radicals ~nd especially mono-substituted phenyl radicals.
The aryl residue R5 may be substituted e.g. by the above-defined loweralkyl groups, loweralkoxy groups, halogen atoms such as chlorine, bromine or fluorine or by a trifluoromethyl gro~up.
The new compounds show valuable pharmacological properties. They ~ ~ show, in particular, activity against bacteria, especially against gram ; negative bacteria, protozoa e.g. trichomonads and amoeba and helminths, e.g.
~30 schistosomes and above all amoeba, as shown in experimental animals, e.g. on the liver of hamsters infected with Entamoeba histolytica, at a dose between 10 and 100 mg/kg p.o.. Thus, the new imidazoles are useful against amoeba, - 2 - r ~039'73Z - ~:
schistosomes, trichomonads and bacteria. Further, the new compounds are use-ful as starting materials or intermediates for the preparation of other -compounds, in particular, therapeutically active compounds.
The invention refers particularly to compounds of formula Ia ~ ~ ~Ia) 02N N N ~ N-X-R5 R3 ;~
wherein Rl represents hydrogen or a loweralkyl group, R3 a loweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or aminoloweralkyl group, X and R5 have the earlier defined meanings, their salts and N-oxides.
Furthermore the invention refers particularly to compounds of formula Ib, 02N " ________N

N y N~X~R5 ~Ib) ;~ wherein R2 represents hydrogen or a lower alkyl group, R3 a lower alkyl, ; hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or aminoloweralkyl group, X and R5 have the earlier defined meanings, their ~` ; salts and N-axides. ;

Particularly the invention refers to compounds of formula Ia, wherein Rl and R3 have the meanings as defined under formula Ia, X is a car-bonyl group and R5 represents amino, loweralkylamino or diloweralkylamino ~` 2~ group and to compounds of formula Ib, wherein R2, R3 have the meanings as define~d under formula~Ib, X is a carbonyl group and R5 is a amino, loweralkyl-~- amino or diloweralkylamino group, their salts and N-oxides.
Also of particular interest are compounds of formula Ia and Ib, wherein~Rl or R2, R5, have the me~nings defined above~ X is a thiocarbonyl ~ 3 ~

10397~Z
and R5 a loweralkyl, aryl, amino, loweralkylamino or diloweralkylamino group, their salts and N-oxides.
Of particular interest are compounds of formulae Ia and Ib, wherein Rl or R2, R3 have the meanings defined above and X is a sulphinyl or sulphonyl group and R5 is a lower alkyl, aryl, amino, loweralkylamino or diloweralkylamino group, their salts and N-oxides.
~ e invention concerns primarily of compounds of formulaeIa and Ib, wherein Rl or R2 have the meanings given under formula Ia or Ib, R3 represents lower alkyl as for example methyl, ethyl or hydroxyloweralkyl as for example ~-hydroxymethyl or ~-hydroxypropyl, X is a carbonyl group, and R5 amino, loweralkylamino or diloweralkylamino, their salts and N-oxides.
Of similar interest are compounds of formulae Ia and Ib, wherein X is a thiocarbonyl, sulphinyl or sulphonyl group, Rl or R2 have the meaning given under formulae Ia or Ib, R3 is a lower alkyl group as for example a methyl or ethyl group or lowerhydroxy alkyl, as for example, ~-hydroxyethyl or ~-hydroxypropyl and R5 an amino, loweralkylamino or diloweralkylamino group, their salts and N-oxides.
Among the nitroimidazole compounds which are to be mentioned especially are l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-imidazolyl (2)]-tetrahydroimidazole, 1-N,N-diethylcarbamoyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl(2)]-tetrahydroimidazol and 1-N,N-dimethylcarbamoyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazol, 1-N-ethylthiocarbamoyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl-2]-tetrahydroimidazole, l-N-methylthio-carbamoyl-2-oxo-3-[1-methyl-5-nitroimidazolyl-2]-tetrahydroimidazole whose use result in eradication of abscess on the liver of healthy hamsters infected with Entamoeba histolytica.
These compounds are thus useful as antiamoebic preparations for which purposes doses of 10 to 100 mg/kg p.o. are indicated. '~
The new imidazoles are prepared by methods which are in themselves 3Q known. For example, compound of the formula I may be prepared by the reaction of a compound of the formula II ;~

- 4 - ;
D

103973Z :
Rl N

/~,/\ t wherein Rl, R2 and R3 have the meanings defined earlier and Z is a hydroxy group, esterified with an inorganic or organic acid, a free or etherified ; mercapto group, an ammonium group, a sulphinyl group or a sulphonyl group with a compound of the formula III

: r ~
HN \ / N-X-R5 (III) .~, ~
' .
;. O
` wherein R5 and X have the meanings defined under formula I.
A reactive esterified hydroxy group Z is, in particular, a hy-droxy group that is esterified with an inorganic or organic acid, above all hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, sulphuric acid or an organic sulphonic acid, such as an aromatic sulphonic acid, e.g. benzenesulphonic, p-bromobenzene sulphonic or p-toluenesulphonic acid, or an aliphatic sulphonic acid, such as an alkanesulphonic acid e.g.
methanesulphonic acid or ethanesulphonic acid.
¦ An etherified mercapto group is e.gu an optionally substituted ~I phenylmercapto or benzyl mercapto group or in particular a lower alkyl mer-i capto group, such as ethyl or methylmercapto group.
; hn ammonium group is, in particular, a quaternary ammonium group, above all a tri-loweralkyl ammonium group e.g. trimethyl or triethylammonium ~20 group or the cation of an aromatic nitrogen base e.g. pyridinium or quino-linium group.
A sulphonyl group is, in particular, that of an organic sulphonic acid, especially an aromatic sulphonic acid residue. The group Z stands pre-ferably for benzenesulphonyl, p-bromobenzenesulphonyl, p-toluenesulphonyl or above all methyl sulphonyl.
The reaction is carried out in the presence of a basic condensing .
D - 5 _ -agent or the compound of formula II is reacted in the form of its N-metal derivatives, such as N-alkali metal derivatives e.g. by the treatment of the compound of formula III with an amide, hydride, an hydroxide or alcoholate of an alkali metal such as lithium, sodium or potassium without isolation of the intermediate, if necessary. Selected basic condensing agents are e.g.
alkali earth hydroxide, such as sodium hydroxide, potassium hydroxide and calcium hydroxide or organic tertiary bases, such as trialkylamine, e.g. tri-methylamine and triethylamine or pyridine. The reaction is carried out, if necessary, at a higher temperature and/or in the presence of an inert solvent, such as those with polar functional groups e.g. dimethylformamide, dimethyl-acetamide, dimethyl-sulphoxide, acetonitrile or a cyclic-aliphatic-ether such as dioxan or tetrahydrofuran.
According to a second process compounds of formula I are prepared by nitration of a compound of the formula IV

~ 11 (IV) R 2 N ~ N ~ N-X-R5 wherein one of the residues Rll and R'2 is a hydrogen atom and the other a hydrogen or a loweralkyl group.
The nitration of a compound of the formula IV is carried out by ; ;!
the usual nitration methods e.g. with nitric acid or a nitrating mixture or a mixture of nitric acid and a carboxylic acid, such as acetic acid, with a mixed anhydride of nitric acid and a carboxylic acid such as acetic acid, by thermal and/or acid treatment of a nitrate salt of the compound IV, with -; dinitrogen tetroxide, e.g. dinitrogen tetroxide/BF3, if necessary, in a suit-able solvent e.g. nitrohydrocarbon, such as nitroalkane e.g. nitromethane or with nitrogen tetroxide eDg. in acetonitrile, or with a N-nitroderivative.

N-nitro compounds are e.g. nitroamides, such as nitrourethanes, nitroguanidine, nitrobiuret and nitro urea e.g. ethylene dinitrourea.
The acid treatment of a nitrate salt of a compound of the formula D ~ .. ~ . .
:
.

1039732 ~ i IV may be carried out at a higher temperature between 40-100, e.g. between 60-80.

Compounds of formula I may be prepared according to a third process which comprises reacting a compound of formula V

Rl N

R2~ ~ N ~ N ~ NH (V) wherein Rl, R2, R3, have the meanings given before with a compound Z-X-R5 (VI) wherein X and R5 have the previously defined meanings and Z is a reactive esterified hydroxy group, a reactive etherified mercapto group, an ammonium group, a sulphinyl group, a sulphonyl group or Z and X together form a cyano 10 group. -l`he reactive esterified hydroxyl group and other reactive groups defined for the group Y are the same as those described earlier for the group ,~ Z under the first process. The reaction is carried out under conditions used for such condensations and described earlier.
According to a four~h process nitroimidazoles of formula I are prepared by reacting a compound of formula VII

.:

R ~ N ~ ~ (Vll) ~, wherein R1J R2, have earlier defined meanings, with a compound of the formula R5-X-MH2 (VIII), wherein R5 and X have the meanings defined earlier.
The reaction of a compound of the formula VII with a compound of the formula R5-X-NH2 (VIII) is preferably carried out with the application of heat, if necessary, in a high boiling inert solvent. It may also be carried out with the aid of suitable dehydrating agents such as phosphorus pentoxide.
Compounds of the general formula I may be converted into one ~''' , , , ~ . .... -;,: ~ . : , : - , - ~ , 1039732 ~:
another by known methods. For example, compounds wherein R3 is a hydroxy-loweralkyl may be converted to loweralkoxy-loweralkyl by alkylation with suitable alkylating agents.
For example, hydroxyloweralkyl substituted derivatives may be reacted with a reactive ester such as an ester of a lower alkanol, preferably in the presence of a basic condensation agent, as for example in the presence of an alkali metal hydroxide or with a diazoloweralkane, such as diazomethane, preferably in the presence of borontrifluoride. However, it is also possible to convert a hydroxy-lower alkyl radical, R3 into an amino-lower alkyl radical in the usual manner. Thus it is possible first to convert a resulting hydroxy-lower alkyl compound into a compound possessing a reactive esterified .
~ hydroxy-lower alkyl radical, a reactive ester being, in particular, an ester . . ,of strong inorganic or organic acids, such as, in particular, hydrogen ~ halide acids, for example hydrochloric acid, hydrobromic acid or hydroiodic .'! acid, toluenesulphonic acids, such as, in particular, arylsulphonic acids, for ~ example benzenesulphonic acid or toluenesulphonic acids, alkylsulphonic acids !j or sulphuric acid. For example, a hydroxy-lower alkyl compound can be con-verted into a halogeno-lower alkyl compound by treatment with halogenating agents, such as thionyl chloride, phosphorus oxychloride or phosphorous penta-~ 20 bromide. In the resulting reactive ester the reactive esterified hydroxyl ¦ group can then be replaced in the usual manner by an amino group, for example by treatment with corresponding amines.
In compounds of the formula I when R3 is an aminolower alkyl group containing at least one replaceable hydrogen atom attached to the nitrogen, this can be substituted. For example, in compounds of the formula I in which R3 is a primary or secondary amino group, such groups may be substituted by i reaction with a reactive ester of an alcohol corresponding to the substituent of the amino group of the aminoloweralkyl radical. ~
, Furthermore it is possible to N-oxidise an imidazole of the ~ -formula I which carries a N-heterocyclic radical.
The oxidation is carried out in the usual manner, for example with N-oxidising agents, such as hydrogen peroxide, ozone, inorganic per-acids, - 8 - ~.
D
:~.

1(~3973Z
for example persulphuric acids, such as Caro's acid, or especially organic peroxy compounds, above all organic per-acids, such as peracetic acid, per-trifluoroacetic acid, perbenzoic acid or monoperphthalic acid, which can also be substituted, for example by halogen atoms, such as chlorine atoms, for instance chloromonoperphthalic acid or m-chloroperbenzoic acid or tertiary hydroperoxide compounds, such as tert.-butyl peroxide or cumene peroxide, optionally in the presence of catalysts such as vanadium, titanium or molyb- `
denum compounds.
Resulting compounds of the formula I, with a N-oxidised N-hetero-cyclic radical, can be converted by reduction into the corresponding compounds of the formula I, with a N-heterocyclic radical.
The reduction is carried out in the usual manner, advantageously ; by the action of phosphorous halides.
Resulting compounds of the formula I, in which X is a sulphinyl group can be oxidised to the S-dioxides (sulphones).
The oxidation to the sulphones can be carried out in a manner which is in itself known, for example by reaction with a S-oxidising agent, such as hydrogen peroxide~ per-acids, especially peracetic acid, perbenzoic , acids or monoperphthalic acids, which can also be substituted, for example by , 20 halogen atoms, l-chlorobenzotriazole, chromic acid, potassium permanganate, hypohalites or nitric acid, nitrous gases and the like, or electrolytically.
In these reactions, whilst on warming and/or using at least 2 mol equivalents ~! of the oxidising agent the sulphones are obtained.
Resulting S-dioxides can be reduced to the corresponding S-oxides of the formula I, for example with a reducing agent, such as a di-light metal hydride, for example with sodium boronhydride, or a light metal hydride such as diborane or a boronhydride-etherate for example BH3-tetrahydrofurane, or above all dichloroborane or, for example, with acetyl chloride, sulphites or hydriodic acid, or especially with triphenylphosphine.
In the above reductions care must be taken, where relevant, that further groups which can be reduced are not attacked. Thus care must in particular be taken, during the reduction9 that any halogen atoms bound to _ g _ .

. . ~ .
-:- - . ~
, - . : , : .

~039'~;~2 aromatic rings which may be present are not replaced by hydrogen.
Very particularly, it is necessary to ensure that the nitro group (Rl or R2) is not reduced. Catalysts which are not affected by sulphur are preferentially to be used, and if necessary the hydrogen absorption should be followed volumetrically and the hydrogenation stopped after the calculated ~ -amount has been absorbed.
Compounds of the formula I which contain a nitro group as the radical R2 can be rearranged to give the corresponding 4-nitroimidazolesJ that is to say compounds of the formula I which contain a nitro group as the radical Rl. Such a rearrangement is effected, for example, by the action of, for instance, an excess of alkali metal iodide, especially potassium iodide, in the presence of an inert solvent, preferably a solvent with polar functional groups, such as dimethylformamide, dimethylacetamide, dimethylsulphoxide, acetonitrile or hexamethylphosphoric acid triamide.
; The rearrangement of R2=nitro compounds into Rl=nitro compounds of the formula I can also be effected by the action of an iodide which corres- ~
ponds to the radical R3, namely R3I, such as for example, the action of methyl -iodide on compounds of the formula I which contain a methyl group as the R
s radical. In this rearrangement, the unsubstituted nitrogen atom of the ; 20 imidazole ring is quaternised. Thereafter, the quaternary salt is pyrolised.
This rearrangement also takes place, for example, in the prosence of an inert solvent, preferably the solvents described above.
The subsequent conversion can be carried out individually or in combination and in optional sequence. Care must be taken in individual operations that other functional groups are not attacked.
The reactions of this invention are carried out in the usual manner, at room temperature or with cooling or heating, under atmospheric or superatmospheric pressure, if necessary, in the presence of diluents, cata-.
lysts and condensing agents, and/ r in the atmosphere of an inert gas, e.g.
nitrogen.
Compounds of the formula III according to the first process are prepared by the action of a compound of the formula IX

D

1~39732 :` :

(IX), HN ~ NH
'` .
:.

i.e. imidazolidin-2-one, with a compound of the formula R5-X-Z, wherein R5, X and Z have the earlier defined meanings.
The compounds of the formula IV according to the second process - are prepared by the reaction of a suitable imidazole derivative carrying a , replaceable group of the type Z of formula II with a compound of the formula III according to the methods described under the first process for such con-:",;
'',i'! densation.
~ Compounds of the formula VII according to the fourth process are -~
~, 10 prepared by the reaction of an imidazole derivative carrying a replaceable ~: group in the 2-position with a compound of the formula X

HN o ( ) 'i`~ 0 `~ namely, oxazolid-2-one.
The new nitro-imidazoles described herein as intermediates and P
starting materials also show valuable pharmacological properties. Thus, ... .
`~ they show, in particular, at a dosage of 10 to 100 mg/kg p.o. action against ;~ bacteria especially gram negative bacteria, protozoa and wor~s, for example, trichomonads, schistosomes, coccidia and, particularly, amoeba as can be shown in animal experiments, for example, from the liver of healthy hamsters . ~ .
~: 20 artificially infected with Entamoeba histolytica. Imidazoles of this inven-tion can, therefore, in particular, be used as agents against amoeba, schistosomes, trichomonads and bacteria.
~-,`~ .
: 1 ~
:i. :

~03973z Depending on the process conditions and the starting substances, the final substances, are obtained in the free form or in the form of their acid addition salts which is also included ~ ¦
in the invention. Thus, for example, basic, neutral or mixed salts and where relevant also hemihydrates, monohydrates, sesquihydrates ~ ;
or polyhydrates thereof can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner which is in itself known, for example with basic agents, such as alkalis or ion exchangers. On the other hand, the resulting free bases can form salts with organic or inorganic acids. The acids - used for the manufacture of acid addition salts are in particular those suitable for forming therapeutically usable salts. As examples t of such acids there may be mentioned: hydrogen halide acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric .,~ . . .
y~ acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid;
phenylacetic acid, benzoic acid, or p-aminobenzoic acid, anthranilic acid, p~hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxy-ethanesulphonic acid and ethylenesulphonic acid; halogenobenzene-`l sulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid of sulphanilic acid; methionine, tryptophane, lysine or arginine.
, .
: '~ .

, ,:, , - 12 -~; .'. ''' ' ., ,. ,~ ~

These or other sal~s of the new compollnds, such as, :Eor example, the picra~es~ can also serve for ~he purification of the ~
resulting free bases, by converting the Lrce bases iTltO salts, ~ ~-isolatillg these and again liberating the bases from the salts.
Because o~ the close relationships between the new compounds in the free form and in the form of their salts, the free compounds are where appropiate also to be understood to include the correspon-ding salts, in the preceding and following text.
'~

The invention also relates to those embodiments of the process in which a process is stopped at any stage Gr in which a compound obtainable as an intermediate product at any stage is used as the starting compound and the missing steps are carried out, or a starting substance is formed under the reaction condi-tions or used, where relevant, in the form of a salt and/or race~
i mate or optical antipode.
,1 ~, ..
, Depending on the number of the asymmetrical C atoms and ;~
, on the choice of the starting substances and procedures, the new .,j compounds can be in the form of racemate mixtures, racemates or ', optical antipodes.
, . . .

;~j Racemate mixtures can be separated into the pure racemateson the basis of the physico-chemical differences of the constituents, ~n a Icnown manner, for example by chromatography and/or fractional crystallisation.
~ .
J Pure racemates can be resolved into the diastereomers according to known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or by reaction with an optically active acid which forms salts with the J~

j~ ' "".~

103973Z ~
racemic compollnd and separation of the salts obtained in this manner, for example on the basis of their different solubilities, and from the diastereomers the antipodes can be liberated by the action of sui~able agel~ts Par~icularly customary optically active acids are, for example, the D- and I.-forms of tartaric acid, di-o--toluyl-tartaric acid, malic acid, mandelic acid, camphor-10-sul-phonic or quinine acid. Resulting salts may be converted into other salts or into the free and optically active bases, and an optically active base may be converted into an acid addition salt by the methods referred to above.
,: :

According to their antimicrobial activity the compounds of formula I, theiE 5-N-oxides and their salts may be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial 7l deterioration by contacting the organic material with, impregnating in or otherwise treating with, the compounds in amo~mts up to about 5 % by weight. The compounds also find application as growth-promoting ;i . .
~ additives to animal feedstuffs, to which they may be added in propor-,.~
~ tion of from 5 to 500 parts per million.

3 :: :
Accordingly, the invention also provides a therapeutic 1 composition comprising an antimicrobially effective proportion of `
i a compound of formula I, or their 5-N-oxides or pharmaceutically ! acceptable salts thereof and a pharmacologically acceptable solid carrier or liquid diluent.

:~ '' : : `
The pharmaceutical compositions according to the invention contain at least one compound of the general formula I, or their 5-N-oxides or a pharmaceutically acceptable salt ` thereof as active substance together with a conventional pharma-;'J D ,~

'' 1 ., ' ' ~

- ~039732 ceutical carrier. The type of carrier actually used depends to a great e~tent on th~ iniended appllcatlon; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and affection~ o-f ~he mucous membranes caused by bacterial or fungi, ointments, powders and tinctures are used ~-in particular. The ointment bases may be anhydrous, for instance -~
they can consist of mixtures of wool fat and soft paraffin, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, for instance, rice starch and other starches; the bulk weight of the carriers may be made lighter, i-E desired, for example by adding highly despersed silicic acid, or may be made heavier by adding talcum. The tinc-tures may contain at least one active ingredient of the formula 1, or 5-N-oxides thereof or a salt thereof in aqueous ethanol, in particular 45 % to 75 % ethanol, to which 10 % to ~0 %
of glycerol may be added, if desired. Solutions prepared from poly-, .
ethylene glycol and other convential solubility promoters, and also, optionally from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions or external application ... .
~ is preferably in the range o from 0,1 % to 5 %.
~ ~ , Gargles or concentrates for their preparation, and tablets for slow dissoluti.on in the mouth, are suitable for the disinfec-tion of the mouth and throat. The former are preferably prepared ;
~ from alcoholic solutions containing 1 % to 5 % of active substance :-~ ~ J~ : .
~ V ' ~ ' :''Z . ~,' .' Z
''~Z ' ' `- '' .. ,~ . .

Z - -:
., , . . :

103973Z ~ :~
t~ .~hich glycerol or flavourings may be added. Lozenges, that is solid dosage units 5 preferably have a relatively high con~ent of s~lgar or similar substances and a relatively low content of active substance, for instance 0,2 to 20 % by weight, as well as the usual ~;~
convential additives such as binding agents and flavourings.
. ' , Solid dosage units, in particular tablets, dragee~s (sugar coated tablets) and capsules, are convenient for use in intestinal disinfectlon. These ~mits preferably contain from 10 % to 90 % of the compound o;f the general formula I, their 5-N oxides .
or a salt thereof to enable the administration of daily doses ~ -of from 0,1 to 2,5 grams to adults, or of suitably reduced doses to children to be made. Tablets and dragee cores are produced by combining the compounds of the general formula I, their 5-N oxides or a pharmaceutically acceptable salt thereof with solid, pulverulent carriers such as lactose, saccharose, sorbitol, :
....
maize starch, potato starch or amylopectin, cellulose derivatives J. or gelatines, preferably with the addition of lubricants such as .1 magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, ~ talcum and/or titanium dioxide, or they may be coated with a lacquer ;~ dissolved in volatile organic solvents or mixtures oE solvents.
,1 . . . ...
'~ Dyestuffs can be added to these coatings, for instance to differen- ~
!l . . ' ~, tiate between varying dosages. Soft gelatine capsules and other ~ closed capsules consist, for example, of a mixture oE gelatines ~ :
;~ and glycerol and may contain, for example, mixtures of the compound `
of formula I, their 5-N oxides or a pharmaceutically acceptable salt thereof with polyethylene glycol. Hard gelatine .~ . .... ..
¦ D c , .. .. . .
.. .,, ... ~

.. i~.. ~ . . . ... .. , .. , . ,.. .... ; . ., .. . . . . ~. . .

cc~ Lles con~ain, for e~campl~, granulates of an active substance with solid pulver~llenl-carriers, for instance lactose, saccharose, sorbitol, mannitoi, starches (such as potato starch, maize starch or amylopectln), cellulose derivatives of gelatines, and magnesium stearate or stearic acic3.

In all forms of administration compounds of the general i formula I, their 5-N oxides or a salt thereof can be present as sole active ingredients or they can also be combined with other known pharmacologically active, and especially anti- -bacterial and/or antimycotically or other antimicrobially active substances, for example to broaden the range of application. They can be combined for example, with 5,7-dichloro-2-methyl-8-quinolinol or other derivatives of 8-quinolinol or other derivatives of 8-quino-linol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other anti-biotics, with 3,4',S-tribromosalicylanilide or other halogenated salicylanilides,with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychloro-hydroxy-diphenyl-~ methanes, with halogen-dihydroxy-diphenyl sulphides, with 4,4'-di- ;~
..
chloro-2-hydroxy-diphenylether or 2,4,~'-trichloro-2-hyclroxydiphenyl-ether or other polyhalogenhydroxydiphenylethers, or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide or with other nitrofurans.
Also, carriers which themselves have favourable pharmacological properties may be used, for instance sulphur as a powder base or zinc stearate as a component of ointment bases.
., ~ . .
'q `~ The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a compound of formula I, their -~ D ,7 ;

5-~ o~ides or an acid addition salt thereof. The organic material may be a natural cr synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fibre or textile material formed therefrom.
.~ ' ." .. ,.. ,.~' The invention also provides an animal feedstuff composition comprising a compound of formula I, their 5-N oxides or a salt there-of in an amount sufficient to promote the growth of the animal fed with the composition.
.. . .

~ Preparation of Tablets .. ' .
100 g of 1-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro~imida-zolyl-(2)]-tetrahydroimidazole are mixed with 60.0 g of maize starch and 35.0 g of lactose, ~he mixture is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium Z stearate. The resulting mixture is pressed into 1,000 tablets, , each containing 100 mg of active substance. If desired, the tablets ;,''ZZ can be grooved for better adaption of the dosage. , J, I _eparation of Dragées ~Z Compositionfor 1,000 draÆées J
I l-tmethylsulphonyl)-2-oxo-3-[1-methyl-5-nitro- :
imidazolyl-(2)]-tetrahydro-~ imidazole 100.0 g `~ Maize starch 27.0 g Gelatine 8.0 g ~ _~_ - :
.~ ,, .
~: .
-~lZ L~
.. Z -:
~ : . .-l.. . ` . ! ' ' . ....... . .: .. ... . ...

Il Glycerol 2.0 g Dis~illed wa~er q-.s. ad 100 ml ~laize starch 10.0 g ; III Talcum 7.0 g Magnesium stearate 1.0_~
155.0 g IV White dragée coating Shellac 2.0 g Sugar 50.0 g Talcum 38.0 g Gum arabic 7.4 g Colloidal silicon dioxide 2.2 g - Titanium dioxide 0.4 g ~ .

:`5~1 Composition I is granulated in the heat with composition II
through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition III and the resulting mixture is pressed 1. .
into 1,00 dragée cores. These are then coated with composition IV ~
and dried. The dragées obtained weigh 255.0 mg and contain 100 mg ~-of active substance.

`i PreParatlon of Syrup "?
ComPosition for 1 liter (methylsulphonyl)-2-oxo--3-[1-methyl-5-nitro-imida-~, zolyl--(2)]-tetrahydroimida-;` zole 100.0 g ;' Colloidal solicone dioxide 13.0 g ,?l p-Hydroxybenzoic acid methyl ester 1.4 g ~ p-Hydroxybenzoic acid propyl `
'~'t, ester ` _ 0.6 ~ ;
t ~ 115.0 g .' ' . ...
~.... .
.~ ., /,9 "'-~1 `

103~73Z -Composition for 1 liter 115.0 g Citric acid 1.0 g Sodium cyclamate 5.0 g ~; Distilled water 610.0 g Glycerol 100.0 g ; Sodium carboxymethyl cellulose 4.0 g Sugar 320.0 g 1155 0 g - The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm mesh diameter (I).
' ,:
; . . . . -The p-hydroxybenzoic acid esters, the citric acid and the sodium cyclamate are dissolved in the given amount of boiling distilled water, the glycerol is then added to this solution (II).
The sodium carboxymethyl cellulose and the sugar are thoroughly $' mixed (III). ~ -,s.~
Composition III is then added at 75C to Solution II under ~; stirring until complete dissolution of III. The viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary, and mixed with composition I. Water ls added to the resultlng mixture up to the prescribed weight of 1,155.0 g and the syrup obtained is homogenized.
.~ , .~ ', '.

,~ Some examples will now begin, all parts and percentages being by weight unless otherwise stated. The temperatures are given in centigrade.

~ .
.~ '' , .' ,' , `l . . :.
,1 1) . ,~o .. ~ , .
.~ .... ,, , ,, .~. , .. , ~.. . .. .. .. . . . .

`" 103973Z
Example 1 .
To a solution of 7.95g 1-(methylthlocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in lO0 ml dimethyl formamide is added 2.4 g of a 50% slurry of sodium hydride in mineral oil The mixLure is heated and stirred at 50 for 30 min.
10.25g of 1-methyl-2-methanesulphonyl-5-nitroimidazole are now added and the mixture stirred at 100 for 4 hrs.The solution is concentrated in vacuo to a small voLume and treated with water. The crystalline precipitate is filtered off, washed with water and ether. It is then recrystallized from alcohol to give l-(methylthiocarbamoyl)-2-oxo-3-[l-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole of . : `
the formula - ' 02N ~ ~ -C-NHCH3 melting at 185-187.
~ I . .
,~ , The starting material l-(methylthiocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole required Eor the above reaction is made as follows: a mixture of 86g ethyleIleurea and 73g methylisothiocyanate is heated at 100 with stirring for

4 hrs.The crystalline mass obtained on cooling is rubbed with ether and water, filtered and washed with alcohol-ether mixture. It is recrystallized from me~hanol; m.p. 168-1~

., . :.

- ~03973Z
Example 2 To a solution of 4.7g 1-(benzyl~ ocarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml dimethyl Eormamide is added 0.95g of a 50% slurry of sodi~n hydride in mineral oil. The mixture is heated and stirred at 50 for 30 min.
4.1g of 1-methyl-2-methanesulpllonyl-5-nitroimidazole are now added and the mixture stirred at 100 for 4 hrs.The .:
solution is concentrated in vacuo to a small volume, ~reated with water and the mixture extracted with chloroform, The chloroform solution is washed with water, dried over sodium i~ sulphate and evaporated in vacuo. Trituration of the residue with ether and crystallization of the resultant solid from ,. . .
chloroform-alcohol affords l-(benzylthiocarbamoyl)-2-oxo-3-[l-methyl-5-nitroimidazolyl-(2)-]-tetrahydroimidazole melting at 178-180.

The starting thiocarbamoylimidazole required for the above reaction is made as follows: 86g ethyleneurea and 149g benzylisothiocyanate are treated togel:her with stirring for 6 hrs.at 150. Upon cooling, a solid mass is obtained, which is triturated with ether and then with hot alcohol and filtered. Recrystallization from chloroform-methanol gives l-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole.

Example 3 To a solution of Sg of l-(methylcarbamoyl)-2-oxo-2,3,4,5-tetrahydroimidazole in 50 ml dimethyl formamide is added 1.7 g of 50% slurry of sodium hydride in mineral oil.
' The mixture is stirred at 50 for 1 hr. A solution of 7,2g . ~ :
`~ D - ~
::
i .
i - ~ - . . . ~ .

103973Z ~ ~
of l~metllyl-2--methanesulphonyl-5 nitrolmidazole in 30 ml dimethyl formamide is now added and the mixtur2 stirred at 100 for 3 hrs.The solvent is then removed in vacuo and water is added to the residue. The resultant red solution is then extracted with chloroform to give an oil, which upon rubbing with methanol affords a solid, recrystallized thrice from methanol to give l-(methylcarbamoyl)-2-oxo-3-[1-methyl-

5-nitroimidazolyl-(2)]-tetrahydromidazole melting at 176-177.

The starting methylcarbamoylimidazole for the above experiment is made by heating a mixture of 8.6 g ethylene-urea and 5 7 g methylisocyanate in a sealed tube at 130 or 3 hrs.and crystallizing the solid so obtained first from water and then from chloroform-methanol; m.p. 198-200.
:', .
Example 4 To a solution of 16.4g 1-(methylsulphonyl)-2-oxo-2, 3,4,5-tetrahydroimidazole in 120 ml dimethyl Eormamide is added 4 8 g of a 50% slurry of sodium hydride in mlneral oil, The mixture is stirred at 50 Eor 30 min. A solution oE 20,5g l-methyl-2-methanesulphonyl-5-nitroimidazole in 70 ml dimethyl-formamide is now added and the mixture heated at 100 for 1 hr.
The solvent is then removed in vacuo and the residue dissolved in water. Upon cooling, a crystalline precipitate is obtained, which is filtered off and recrystallized from acetone-methanol to afford l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-D ~3 ~ -, ", :.. : -:: , . . .

~0 39'~3 Z ;
imidazolyl-(2)]-~etrahydroimidazole melting at 202-204.

Tlle starting 1 (methyls-ulphonyl)~2 oxo-2,3,4,5-tetrahydroimidazole for the above reaction is made as follows:
A mixture of 86 g ethyleneurea and 115 g methanesulphonyl chloride is heated for 6 hrS.at 120 with stirring, while a stream of nitrogen is bubbled in to remove hydrogen chloride. After cooling, water is added and the mixture heated on a steam bath till a crystalline powder is formed, ; .
This is filtered off, washed with alcohol-ether and recrystallized `~

~ from methanol; m.p. 192-195~.
.,, . :,.

Example 5 -To 8 g 1-(benzylthiocarbamoyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-2,3,4,5-tetrahydroimidazole in 80 ml dimethylsulphoxide is added 5 ml of concentrated sulphuric acid and the solution is heated on a steam bath for 2 days, It is then diluted with water and the resultant precipitate filtered off. This is dissolved in ethyl acetate and ether added to give a solid. Crystailization from ethylacetate-ether affords l-(benzylcarbamoyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-2,3,4,5-tetrahydroimidazole melting at 113-115. ;~
. . '.
. ~ .
. :. ... . - :~

. i . . , .. ~

.. . . . . . ... . ..

~03973Z :
~ - Ex~mple 6 ~ ,, ~ .
To a suspensioll of l~Sg 50% sodi~l hydride in 10 ml ~;
dry dimethyl formamide is added with s~irring during 15 min~
a solution of 5.. g of 1-N-ethylthiocarbamoyl-2-oxo-tetrahydro-imidazole in 20 ml dry dimethyl formamide. The reaction mixture is stirred under nitrogen at 50 for 30 minO and a solution of 4.5 g of 1-methyl-2-methylsulphonyl-5-nitroimidazole in 10 ml dry dimethyl formamide is added during 5 min., and ' then heated at 100 for 4 hrs.The solvent is evaporated of; under vacuo; residue triturated with 50 ml water and extracted with ~ ethylene dichloride. The ethylene dichloride extract is J dried over anhydrous sodium sulphate and evaporated off to dryness. The residue is chromatographed over silica gel.
The fraction that is eluted with 2% methanol in chloroform ~ affords l-N-ethylthiocarbamoyl-2-oxo~3-[1-methyl-5-nitro~
j imidazolyl-(2)]-tetrahydroimidazole which melts at 213 after recrystallization from a mixture of methylenech]oride and hexane.

~, The starting material requlred for the above xeaction is prepared as follows: A mixture of 3,6 of ethyleneurea and 8,7 g of ethyl isothiocyanate is heated at 100 for 4 hrs.
On cooling, the crystalline product was recrystalliæed from a ;~
mixture of ethanol and ether to afford l-N-ethyl;thio-carbamoyl-2-oxo-tetrahydroimidazole which melts at 135-136, ~: '"'' ' " "

,1 ' : :.. ` ., ' ' ' ~039732 Æxample 7 To a suspension o~ 2.2 g 50% sodium hydride in 10 ml dry dimethyl formamide is added under stirring during 15 minO, a solution of 8 7 g of l-(N~N-dimethylsulphamoyl)-2~oxo-tetrahydroimidazole in 20 ml dry dimethyl formamide. The reaction mixture is stirred under nitrogen at 50 for 1 hr and a solution of 9.25 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazole in 20 ml of dry dimethyl formamide is added all at once. The reaction mixture is heated under stirring and nitrogen at 95 for 3 hrs.The solvent is removed by distillation in vacuo and res;due triturated with 45 ml water. The resulting suspension is extracted with ethylene dichloride, dried and evaporated to dryness. The res-idue is washed with hexane and triturated with acetone to give a crystalline solide. This is recrystallized from a mixture of methylene chloride and ether to afford l-N,N(dimethyl-sulphamoyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole which melts at 217.

The starting material required for the above reaction is prepared as follows: ~ mixture of 17.2g of ethylene urea i and 28.7 g of N,N-dimethyl sulphamoyl chlorid~ is heated at 110 for 3 hours. The reaction mixture is cooled and tri-turated with 100 ml methanol. Some solid material separated ..
which is discarded. The filtrate is evaporated off to dryness and the re~idue is dissolved in 5% methanol in chloroform and chromatographed on a column of 150 g of silica gelO The -_ ' ' :,'.' .
D ~6 .. .
, ~, , ~ 03973Z
fraction which eluted with 2% methanol in chloroform is recrystallised from a mixture of methylenechloride and hexane to give l-(N,N-dimethylsulphamoyl)-2-oxo-tetrahydroimidazole which melts at 129~
.. . .

Example 8 A mixture of 34,4 g ethylene urea and 54,2 g N,N- ;
diethylcarbamyl chloride is heated under nitrogen at 110 for 3 hrs.The reaction mixture is cooled and diluted with 200 ml acetone. It is filtered and the filtrate evaporated off ~j to dryness. The oily product i9 chromatographed on a column ;~ of 450 g of silica gel. The fraction which eluted from 3%
j methanol in chloroform yields l-(N,N-diethylcarbamoyl)-2-oxo-tetrahydroimidazole as a colourless oil.

To a suspension of 5,8 g 50% sodium hydrid in 20 ml -dry dimethyl formamide is added under stirring during 15 min, a solution o 22 g of above mentioned l-(N,N-diethylcarbamoyl)-2-oxo-tetrahydroimidazole in 40 ml oE dry dimethyl form~mide.
`jg The reaction mixture is stirred under nitrogen at 50 for 1 hr and a solution of 24.6 g of l-methyl-2-methylsulphonyl-5-nitroimidazole in 40 ml of dry dimethyl formamide is added all at once.

The reaction mixture is worked up in the manner ~ described under example 6 and the dark oily residue (36 g) ~ ~

:.1 ., . ' ~' ~ 0 39~ 3 Z
is c~ron~l~o3r2plled over a column of 3G0 g of sillca gel.
The flaction that eluted with 2.5% meth~nol in ch]oroorm yields a crystalline substance ~hich is recrystallized from a -mixture of methylene chlorid and hexane to give l-N,N-diethyl ~ -carbamoyl-2-oxo-3-~1-me~hyl-5-nltro-imidazolyl-(2)]-tetrahydroimidazole which melts at 133.

Example 9 .~ ' - ..
To a suspension of 24.5 g of 50% sodium hydride in Z 100 ml dry dimethyl formamide is added under stirring :-j .
during 15 min,-a solution of 78.5 g of l-(N,N-dimethyl carbamoyl)-2-oxo-tetrahydroimidazole in 150 ml of dry dimethyl l formamide. The reaction mixture is stirred under nitrogen '.t~Z at 50 for l hr. and a solution of 102.5 g of l-methyl-2-methyl-sulphonyl-5-nitro~imidazole in 100 ml dry dimethyl formamide is added during 10 min. The reaction mixture Z is heated under stirring and nitrogen at 100 for 3 hours, `J Is is worked up as described under example 6 and tlle residue Z is recrystallised from a mixture of methylene chloride and hexane to afford l-N, N-dimethyl~carbamoyl-2~oxo-3-[l-methyl-5-nitro-imida7.olyl-(2)]-tetrahydroimidazole which ¦ melts at l90-191~
j The starting material required is prepared as follows:
~ . , ~Z A mixture of 86 g of ethylene urea and 118 g of N,N-dimethyl ,'~ ' .
`; D ~ ~:
.,,, . : :
;. .. . . .

"`~

103973Z ~ -carbamoyl-cl~loride in 200 ml ethylene dichloride is heated ~ -under reflux for 3 hr~,under ni~rogen. The solution is evaporated oEf to dryness and the residue dissolved in chloroform and chromatographed on a column of 1.5 kg of silica gel, The fractions that eluted with 5% methanol in chloro-form are comhined and recrystallized from a m ixture of methylene ;-~
chloride and hexane to afford l-N,N-dimethyl-carbamoyl-2-oxo-tetrahydroimidazole which mel~s at 134-136.
i . ::
.. . . ..
~, , , Example 10 ' ~
;~ . ~ ,. .
,.. .
, To a suspension of4.5gof 50% sodium hydride in 10 ml ;j dry dimethyl formamide is added under stirring during 15 min " a solution of 16g of 1-ethyl-sulphonyl-2-oxo-tetrahydroimidazole in 30 ml dry dimethyl formamide. The reaction is stirred under nitrogen at 50 for 45 min. and a solution of 18,5 g of l-methyl-2-methylsulphonyl-5-nitro-imidazole in 30 ml dry dimethyl formamide is added all- at once and the reaction mixture heated at 100 or 3 hrs.
' ' :".
It is worked up in the manner described under example 6 and the residue is recrystallized from a mixture . .. ..
o~ methylene chloride and hexane to afford l-N-ethyl-sulphonyl-2-oxo-3-[1-methyl-S-nitro-imidaæolyl-(2)]-tetrahydroimidazole ~ which melts at 176-177, :~
. . .
~ The starting material required is prepared as follows:
~ . :. . -~ : , ' '. .' :' ~ D
,. .
, . ......

1~ . - . ... ...

A i~Ture of 29.2 g of ethyleneurea and 43,7 g of etllane sulphonyl chloride is h~atecl at 110 for 3 Ixr~ under nitrogen.
The reaction mixture is trituxated with 30 ml methanol and filtered. The filtrate is evaporated off and ~he residue is dissol~ed in chlorofoxm and chromatographed on a column of 75~ g of silica gel. The fraction which eluted with 5%
methanol in chloroform, is recrystallized from a mixture of methylene chloride and hexane to afford l-ethylsulphonyl-2-oxo-tetrahydxoimidazole which melts at 114-116.

. , .
Example 11 ~

,; -To a suspetlsion of 1.2 g of 50% sodium hydride in 10 ml dry dimethyl formamide is added under stirring during 15 minutes, a sol~ition of 5.8 g of 1-(4-fluorophenylsulphonyl)-2-oxo-tetrahydroimidazole in 28 ml dry dimethyl formamide.
The reaction mixture is stirred under nitrogen at room temperature for 1 hr and then at 50 for an other hour. A
solution of 5 g of 1-methyl-2-methylsulphonyl-3-nitroimidazole in 10 ml dry dimethyl formamide ls added all at once. The . :, reaction mixture is heated under stirring and nitrogen at 100 for 3 hrs. and worked up in the manner descrlbed under example 6. The residue is chromatographed on a column of 150 g silica gel, The fractions which eluted with 2.5% methanol ~j in chloroform gives a crystalline substance which is recrystallised from a mixture of methylene chloride and hexane to afford ,; : . ' ~ l-N-(4-fluorophenylsulphonyl)-2-oxo-3-[1-methyl-5-nitro-l~ imidazolyl-(2)]-tetrahydroimidazole which melts at 198-200.

I ~.i ~ ~ 30 .. - ` - . . .
1~ .

~03973Z
. The s~arting.material required is yrepared as follows:
A mixture of 17.2 g o ethyleneurea and 19.5 g of p-f]uorobenzene sulphonyl chloride lS heate~ at 110 Eor 3 1/2 hrS.The residue is recrystallized from a mixture of methanol and water to .;
afford l-(4-fluorophenylsulphonyl)-2-oxo-tetrahydroimidazole which melts at 183-185.
:', ,:
Example 12 - A solution of 0,4 g of 2-oxo~3-[1-methyl-4-nitro-imidazolyl-(2)]-tetrahydroimidazole in 8 ml dry dimethyl : .
formamide is added dropwise to a suspension of 0.1 g of 50% ~j'!"'-'~ ;!:
sodium hydride in 2 ml dry dimethyl formamide. The reaction mixture is stirred at room temperature for 15 minutes and a solution of 0.2 g of methyl isocyanate in 2 ml dry dimethyl .:
formamide is added and the reaction mixture heated for 3 hrs. ~ ~ -at 100 and worked up in the manner described under example 6.
The residue is chromatographed on a column of ~0 g silica gel, The fraction which eluted with 5% methano]. in chloroform aEfords l-N-methyl-carbamoyl-2-oxo-3-[l-methyl-5-nltro-ilnidazolyl-(2)]-tetrahydroimidazole which melts at 176-177. . : . .
!
! Example 13 To a stirred suspension of 1.3 g of 50% sodium hydride :l dispersion in mineral oil.in 20 ml dry dimethyl formamide is added .`.
1 . . . ...
l 3/
1:D -~ ~
;.~ .. . .~ . :.

. .
,; .

lQ3973Z
dropwise a solution of l-piperidinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml dimethylformanide at ambient temperature. The temperature of the reaction is raised to 50 and stirred for 30 min. A solution of 5.12 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole in 20 ml dimethyl formamide is added dropwise in the course of 20 min, the temperature raised to 95 and maintained for 1 hr.
The solvent is removed under reduced pressure~ the residue washed with ether and treated with water containing crushed ice. The residue after removal of aqueous layer is treated with isopropanol ether (5:1). The colourless granular precipitate is recrystallised from ethyl acetate-hexane to afford l-piperidino-carbonyl-2-oxo-3-[1-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole melting at 152.
., Example 14 To a stirred suspension of 1.92 g of 50% sodium hydride dispersion in mineral oil in 25 ml dry dimethyl formamide is added dropwise a solution of 7.96 g of 1-morpholinocarbonyl-2-oxo-tetrahydroimidazole in 15 ml dry di-,~ .
methylformamide at ambient temperature. The above suspension is stirred at50 for 30 min. A solution of 8.2 g of 1-methyl-2-methylsulfonyl-5-nitro-imidazole in 15 ml dimethyl formamide is added in the course of 5 min. The temperature of the reaction is raised to 95 and stirring continued for 2 hrs.
The solvent is removed under reduced pressure, the residue is .1 : .

D ~ :
, .

, ~3.~; .

washed with ether and treated with crushed ice, The solid obtained is filtered to give 1-morpholinocarbonyl-2-oxo-3-[l-methyl-5-nitro-imidazolyl-(2)]-tetrahydroimidazole melting at 180 after crystalliza~ion from ether, l-Morpholinocarbonyl-2-oxo-tetrahydroimidazole used ~ ;-as starting material is prepared as follows: To a s~irred solution of 22.27 g of 1-chloro-carbonyl-2-oxo-tetrahydro imidazole in 80 ml anhydrous benzene is added dropwise a ~ ~;
solution of 26,1 g of morpholine in 20 ml benzene. The mixture is refluxed for 4 hrs,The product is filtered off, ;~
treated with a saturated solution of NaHC03 and filtered, Recrystallization from isopropanol affords l-morpholinocarbonyl- ;
2-oxo-tetrahydroimidazole melting at 158, Example 15 A solution of 2.9 g 1-(methylsulphonyl)--2-oxo-3-[l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazo].e and 1,9 g methyloxonium fluoborate in 200 ml dry chloro~orm is set aside at room temperature for 72 hrs,A thick oil separates out, which crystallizes on treatment with alcohol. The solid is filtered off, boiled with acetone and filtered, The residue is crystalliæed rom aqueous alcohol to give 1-methyl-2-[3-(methyl-sulphonyl)-2-oxo-1,2,3,4-tetrahydroimidazolyl (1)]-3-ethyl-5 ~ ;~
nitroimidazolium fluoborate of the formula ' " ' ~ D ~ -1039~13Z
o~ r~_SO~cll3 C1~3 4 melting at 265-267.

Example 16 A solution of 3.0 g 1-(methylsulphonyl)-2-oxo-3-[l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole in 30 ml dimethylformamide containing 3.0 g potassiumiodide is heated under reflux for 16 hours.The solvent is removed in vacuo and the residue treated with water and filtered. The~ filtrate is ma.de acidic with 2N hydrochloric acid, cooled and filtered to remove unreacted starting material. The filtrate is cooled fur-ther and the crystals that separate are filtered off and recry-stallized twice from acetone-methanol to give l-(methylsulphonyl-3 2-oxo-3-[1-methyl-4-nitroimidazolyl(2)]-tetrahydroimidazole 3 melting at 180-181.

.. . .
~; Example 17 .~ , , .
~ A solution of 3.0g 1-(methylthiocarl)amoyl)~~2~OxO~3~
;~ .
~l-methyl-5-nitroimidazolyl (2)]-tetrahydroimidazole in 25 ml dimethylformamide containing 3.0 g potassium iodide is heated under reflux for 16 hr. The solvent is removed in vacuo and water added to the residue. The mixture is filtered and the precipitate washed sucessively with hot ethanol and methanol and crystallized -D ~y ~:
~3 ; . .
'` :~ ' . ' ' ~ , ~ - ' ''' ' ~03973Z : :
- twice from acetone-methanolto give l-(methylthiocarbamoyl)-2-oxo-3-[1-methyl-4-nitroimidazolyl (2)]-tetrahydroimidazole melting at 239-241~.
; ~
` Example 18 A solution of 0.49 g 1-(methylsulphonyl)-2-oxo-tetra- -hydroimidazole in 5 ml dimethylformamide is stirred with -0.15 g of a 50~/0 suspension of sodium hydride in mineral oil at 50 for 1 hr. It is then treated with 0,57 g of 1-methyl-2-~, (methylsulfinyl)-5-nitroimidazole and the solution heated and stirred at 100 for 3 hours. The solvent is evaporated off in vacuo and the water added to the residue. The crystalline precipitate is filtered off and recrystallized from acetone-methanol to give l-(methylsulphonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl(2)]-tetrahydroimidazole melting at 202-204 and is identical with the , .. .
preparation described in Example 4.

The starting l-methyl-2-(methylsulfinyl)-5-nitroimidazole for the above reaction is made as ~ollows:

A solution of 3.4 g 1-methyl-2-(methylmercapto)-5-7 nitroimidazole and 5 ml 30% aqueous hydrogen peroxide in i 20 ml methoxyethanol is heated at 100 with freshly prepared j~ titanium dioxide for 6 hrs.It is then diluted with water and filtered. The filtrate is extracted with chloroform 1~ and the chloroform layer evaporated to give 2.5 g of an oil ,,. ~ which solidifies slowly upon standing. The solid is crystalllzed ~
~: . :' ,'-' ,t -D 3~

.: . .

1039'73Z
once from ethanol and then from chlorofor~ether to give l-methyl-2-(methylsulfinyl)-5-nitroimidazole.
' . ' . .
Example 19 To a suspension of 6,1 g 50% sodium hydride in 20 ml dry dimethyl formamide is added under stirring during 15 min.
a solution of 30 g 1-(N,N-diethylsulphamoyl)-2-oxo-tetrahydro-imidazole in 50 ml dry dimethyl formamide, The reaction mixture is stirred under nitrogen at 50 for 1 hour and a solution of 25.6 g of 1-methyl-2-methylsulphonyl-5-nitro-imidazole in 40 ml of dry dimethyl formamide is added all at once, The reaction is heated under stirring and nitrogen at 95 for 3 hours, The solvent is removed by distillation in vacuo and the residue triturated with 100 ml water, The resulting suspension is extracted with ethylene dichloride, dried and evaporated to dryness, The residue is chromatographed on a column of silica gel and the fraction that elutes with 1% methanol in chloroform afords a crystalline mass, This is recrystallized from a mixture of methy-"
~;' lene chloride and ether to afford l-N,N-diethyl sulphamoyl-2-oxo-3-[1-methyl-5-nitroimidazolyl-(2)]tetrahydroimidazole which melts at 14~-147, The starting material required for the above reaction is prepared as follows:

- , - . .
'~ , ' .' .
, ~. 3C . :-.. . . .
,~ ..

.~' , ~'''~' .. . . . . . ~ . . . . . .

~39732 A mixture of 51. 6 g of ethylene urea and 90 g of N,N-diethyl-sulphamoyl-chloride is heated at 110 for 3 hours. The reaction mixture is cooled and triturated with 300 ml of methanol, filtered and the filtrate evaporated off to dryness and the residue -~
dissolved in 5% methanol in chlorofonn and chromatographed on a ;~
column of silica gel. That fraction which elutes with 5% methanol ~ -.. .::
in chloroform is recrystallized fro~ a mixture of methylenechlorid and hexane to give l-(N,N-diethylsulphamoyl ~ -2-oxo-tetrahydroimida-zole which melts at 80-82.

.,~. ~ .. ~.

Example 20 To a stirred suspension of 1,6 g of 50~b sodium hydride dispersion in mineral oil in 30 ml dry dimethyl formamide is added during 15 min. a solution of 5.9 g of l-pyrrolidino-carbonyl-2-oxo-tetrahydroimidazole in 15 ml dry dimethyl forma-mide. The reaction is stirred under nitrogen at 50 for 1 hour .: .. . ..
and a solution of 6.6 g of 1-methyl-2-methyl-sulphonyl-5-nitro-imidazole in 20 ml dry dimethyl formamide is added ~11 at once, The mixture is heated under stirring and nitrogen at 95 for 1 hour, The solvent is removed by distillation in vacuo and the ~ ,' residue is trituxated with water and extracted with ethylene , dichloride, dried and evaporated to dryness. The residue is chro-matographed over silica gel and that fraction which elutes with 3% , methanol in chloroform affords a crystalline mass. This is re-. . ~ ,.
~ crystallised from a mixture of methylene chloride and hexane to ~
., . ~

~;affoFd l-pyrrolidino-carbonyl-2-oxo-3~[1-methyl-5-nitro-imidazolyl . .
:~D ~7 ~ 03973Z
(2)]-tetrahydroimidazole which melts at 155-156.

The starti~g material required for the above reaction is prepared as follows:

A mixture of 40 g ethylene urea and 72 g of l-pyrrolidino-car~onyl chloride (b.p. 100-104/4.5 mm Hg.) is heated at 110 ~ -for 3 hours. The reaction mixture is cooled, 200 ml of chloroform added, the insoluble material filtered off and the filtrate evaporated to dryness. It is chromatographed on a column of silica gel. That fraction which elutes with 4%
of methanol in chloroform is recrystallised from ethylacetate to give l-pyrrolidino-carbonyl-2-oxo-tetrahydroimidazole which melts at 153-154.
' ~ .
- Example 21 To a suspension of 3.5 g of 50% sodium hydride in 20 ml dimethyl formamide is added under stirring during 15 minu-tes, a solution of 15.6 g of 1-pyrrolidino-sulphonyl-2-oxo-tetrahydroimidazole in 40 ml dry dimethyl formamide, The reaction mixture is stirred under nitrogen at 50 or 1 hour, ~ ~
and a solution of 14,4 g of 1-methyl-2-methyl-sulphonyl-5- ;
nitroimidazole in 30 ml dry dimethyl formamide is added all at once, The reaction mixture is heated under stirring and ni- -~
trogen at 95 for 3 hours, The solvent is removed by distillation in vacuo and the residue is triturated with 50 ml of water when a crystalline precipitate is formed, This is filtered and recrystallised from a mixture of methylene chloride and ether to afford l-pyrro-lidino-sulphonyl-2-oxo-3-[1-methyl-5 nitro~imidazolyl-(2)]-~;D

., ~ . . ~ . -.

~()3973Z -~ :
tetrahydroimidazole which melts at 226 -;
,:
The starting material required for the above reaction is prepared as follows: ~ -A mixture of 30 g of ethyleneurea and 64,5 g of pyrroli-......... -dino~l-sulphonylchloride (b.p. 120/11 mm Hg.) is heated at 110 for 3 hours. The reaction mixture is cooled, dissoved in 300 ml chloroform, filtered, the filtrate evaporated off and the residue is redissolved in 2.5% methanol in chloroform and chromatographed on a column of silicagel. That fraction which elutes with ~
2,5% methanol in chloroform affords 1-pyrrolidino-sulphonyl-2-oxo- ;
tetrahydroimidazole which is recrystallized from ethylacetate, m.p, 150, :

Example 22 .: .
. ., :;.
To a stirred suspension of 1.92 g of 50% sodium hydride dispersion in mineral oil in 20 ml dry dimethyl formamide is added dropwise a solution of 9,3 g of 1-piperidino-sulfonyl-2-oxo-tetrahydroimidazole in 15 ml dimethyl formamide at amblent temperature. The temperature of the reaction is raised to 50 and stirred for 30 min. A solution of 8,2 g of 1-methyl-2-methyl- ;~
sulfonyl-5-nitroimidazole in 25 ml of dimethyl formamide is added ... ... .
in one lot and the temperature of the reaction is maintained for 2 hrs.
at 100. The solvent is removed under reduced pressure and the ;
residue treated with water containing crushed ice, The redsidue ~ ~
', "' ~.
~D~
-~46 -'.
.
. .

1039'73Z
after removal of the aqueous layer is treated with isopropanol-ether (5:1). The pale yellow precipitate so obtained is recry-stallised from ethyl acetate to afford l-piperidino-sulfonyl-2-oxo-3-[l methyl-5-nitroimidazolyl-(2)]-tetrahydroimidazole melting at 192, The starting material is prepared as follows:

To 17.4 of ethyleneurea is added with shaking 36 g of piperidinosulfonyl chloride (b.p 130/llmm) and the mixture kept under nitrogen at 100 for 3 hrs.The mixture is cooled and the gummy material treated with methanol-isopropanol (1:1) to give a granular product of l-piperidinosulfonyl-2-oxo-tetrahy-droimidazole which melts at 201 on recrystallization from -~
methanol.

,,,~', 0 ~; :

Claims (37)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the production of compounds having the general formula I

(I) where one of the groups R1 and R2 is a hydrogen or lower alkyl and the other a nitro group, R3 is a lower alkyl, hydroxylower alkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or aminoloweralkyl, X is a carbonyl, thiocarbonyl, sulphinyl or sulphonyl group and R5 when X is a carbonyl group is a amino, loweralkylamino or diloweralkylamino group, and when X is a thiocarbonyl, sulphinyl or sulphonyl, R5 is a lower alkyl, aryl, amino, alkylamino or diloweralkylamino group, their salts and N-oxides selected from a) reacting a cornpound of forrnula II

(II) wherein R1, R2 and R3 have the meanings defined above and Z is a reactive esterified hydroxy group, a free or etherified mercapto group, an ammonium group or a sulphonyl group wlth a compound of formula III

(III) wherein R5 and X have the meanings defined under formula I, or b) by nitrating a compound of formula IV

(IV) wherein one of the residues R? and R? is a hydrogen atom and the other a hydrogen atom or a lower-alkyl group, or c) reacting a compound of formula V

(V) wherein R1, R2 and R3 have the above defined meaning, with a compound of formula VI
Z - X - R5 (VI) wherein X and R5 have the previously defined meanings and Z is a reactive esterified hydroxy group, a reactive etherified morcapto group, an ammonium group, a sulphinyl, a sulphonyl group or Z and X together form a cyano-group;or d) reacting a compound of formula VII
(VII) wherein R1, R2, and R3 have the above defined meanings, with a compound of formula VIII

H2N - X - R5 (VIII) wherein R5 and X have the meanings defined earlier and if desired, resulting salts are converted into the free compounds or other salts, or resulting free compounds are converted into their salts.

2. Process according to claim 1 wherein a compound of formula I, an N-oxide thereof or a salt thereof is converted into a pharmaceutically acceptable salt thereof.

3. Process as defined in claim 1 for the production of a compound having the formula I as defined in claim 1 which comprises reacting the cor-responding compound having the formula II as illustrated in claim 1 with a reagent having the formula III as defined in claim 1.

4. Process according to claim 3, characterised that a reactive esterified hydroxy group Z in compounds of formula II is an hydroxy group esterified with a strong inorganic or organic acid.

5. Process according to claim 4, characterised that a reactive esterified hydroxy group Z in compounds of formula II is an hydroxy group esterified by a benzenesulfonic or an methanesulphonlc acid.

6. Process according to claim 3, characterised that a reactive esterified hydroxy group Z in compounds of formula II is a halogen atom.

7. Process according to claim 6, characterised that a reactive esterified hydroxy group Z in compounds of formula II is a chlorine atom.

8. Process according to claim 4, characterised that Z in compounds of formula II as a reactive esterified hydroxy group is a sulphonyl group de-rived from an organic sulphonic acid.

9. Process as defined in claim 1 for the production of a compound having the formula I as defined in claim 1 which comprises nitrating a compound of formula IV as illustrated in claim 1.

10. Process according to claims 1 and 9 that the nitration of compounds of formula IV is carried out with nitric acid.

11. Process according to claims 1 and 9 that the nitration of com-pounds of formula IV is carried out with a mixture of nitric acid and carboxylic acid.

12. Process according to claims 1 and 9 that the nitration of com-pounds of formula IV is carried out with a mixture of nitric acid and an anhydride of a carboxylic acid.

13. Process according to claims 1 and 9 that the nitration of com-pounds of formula IV is carried out with a mixed anhydride of nitric acid and a carboxylic acid.

14. Process according to claims 1 and 9 that the nitration of com-pounds of formula IV is carried out by thermal and/or acid treatment of a nitrate salt of a compound of formula IV.

15. Process according to claims 1 and 9 that the nitration of com-pounds of formula IV is carried out with dinitrogen tetroxide or with a suitable N-nitro derivative.

16. Process as defined in claim 1 for the production of a compound having the formula I as defined in claim 1 which comprises reacting the cor-responding compound having the formula V as illustrated in claim 1 with a reagent having the formula VI as defined in claim 1.

17. Process according to claim 16, characterised that a reactive hydroxy group Z in compounds of formula VI is an hydroxy group esterified with a strong inorganic or organic acid.

18. Process according to claims 1 and 16, characterised that a reactive esterified hydroxy group Z in compounds of formula VI is an hydroxy group esterified by a benzenesulphonic or methanesulphonic acid.

19. Process according to claim 16, characterised that a reactive esterified hydroxy group Z in compounds of formula VI is a halogen atom.

20. Process according to claim 19, characterised that a reactive esterified hydroxy group Z in compounds of formula VI is a chlorine atom.

21. Process according to claim 17, characterised that Z in compounds of formula VI as a reactive esterified hydroxy group is a sulphonyl group de-rived from an organic sulphonic acid.

22. Process as defined in claim 1 for the production of a compound having the formula I as defined in claim 1 which comprises reacting a compound of formula VII as illustrated in claim 1 with a reagent having the formula VIII as defined in claim 1.

23. Process according to claim 22, characterised that the reaction of a compound of formula VII with a compound of formula VIII is carried out at elevated temperature in the presence of a high boiling inert solvent.

24. Process according to claim 23, characterised that the reaction of a compound of formula VII with a compound of formula VIII is carried out with the aid of a dehydrating agent.

25. Process for the production of compounds having the formula Ia (Ia) wherein R1 represents hydrogen or a lower-alkyl group, R3 a lower-alkyl, hydroxy lower-alkyl, loweralkoxy-loweralkyl, loweralkylsulphonylloweralkyl or aminoloweralkyl group, and X and R5 have the meanings defined in claim 1, their salts, and N-oxides, which comprises reacting a compound of the formula II

(II) wherein R1, R2 and R3 have the meanings defined under formula Ia and Z is a reactive esterified hydroxy group, a free or etherified mercapto group, an ammonium group, a sulphinyl group or a sulphonyl group with a compound of the formula III

wherein R5, and X have the meanings defined under formula Ia and if desired converting resulting compounds of formula Ia into their N-oxides and/or resulting salts into the free compounds or other salts, or resulting free compounds into their salts.

26. Process for the production of compounds of formula Ia as defined in claim 25, characterised by reacting a compound of formula V

(V) wherein R1, R2, and R3 have the meanings defined in claim 25, with a compound of formula VI
Z - X - R5 (VI) wherein X and R5 have the previously defined meanings and Z is a reactive esterified hydroxy group, a reactive etherified mercapto group, an ammonium group, a sulphinyl, a sulphonyl group or Z and X together represent a cyano group, and if desired converting resulting compounds of formula Ia into their N-oxides and/or resulting salts into the free compounds or other salts, or resulting free compounds into their salts.

27. Process for the production of compounds having the formula Ib (Ib) wherein R2 represents hydrogen or a lower alkyl group, R3 a lower alkyl, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkylsulphonylloweralkyl or aminoloweralkyl group, and X and R5 have the earlier defined meanings, their salts and N-oxides, characterised by reacting a compound of the formula II

(II) wherein R1, R2 and R3 have the meanings defined under formula Ib and Z is a reactive esterified hydroxy group, a free or etherified mercapto group, an ammonium group, a sulphinyl group or a sulphonyl group with a compound of the formula III

(III) wherein R5, and X have the meanings defined under formula Ib and if desired converting resulting compounds of formula Ib into their N-oxides and/or resulting salts into the free compounds or other salts, or resulting free compounds into their salts.

28. Process for the production of compounds of formula Ib as defined in claim 27, characterised by reacting a compound of formula V

(V) wherein R1, R2, and R3 have the meanings defined in claim 27, with a compound of formula VI

Z - X - R5 (VI) wherein X and R5 have the previously defined meanings and Z is a reactive esterified hydroxy group, a reactive etherified mercapto group, an ammonium group, a sulphinyl, a sulphonyl or Z and X together form a cyano group, and if desired converting resulting compounds of formula Ib into their N-oxides and/or resulting salts into the free com-pounds into their salts.

29. Processes according to claims 25 and 26 wherein a compound of formula Ia, an N-oxide or a salt thus obtained is con-verted into a pharmaceutically acceptable acid addition salt thereof.

30. Processes according to claims 27 and 28 wherein a compound of formula Ib, an N-oxide or a salt thus obtained is converted into a pharmacutically acceptable acid addition salt thereof,

31. A compound having the formula I whenever prepared by a process as claimed in claim 1 or by an obvious chemical equivalent.

32. A compound having the formula Ia whenever prepared by a process as claimed in claim 25 or by an obvious chemical equivalent thereof.

33. A compound having the formula Ia whenever prepared by a process as claimed in claim 26 or by an obvious chemical equivalent thereof.

34. A compound having the formula Ib whenever prepared by a process as claimed in claim 27 or by an obvious chemical equivalent thereof.

35. A compound having the formula Ib whenever prepared by a process as claimed in claim 28 or by an obvious chemical equivalent thereof.

36. Process according to claim 25 for the production of 1-(methylsulphonyl-2-oxo-3-[1-methyl-5-nitroimidazolyl(2)]-tetrahydroimidazole which comprises reacting 1-(methylsulphonyl)-2-oxo-2,3,4,5-tetrahydroimidazole and 1-methyl-2-methylsulphonyl-5-nitroimidazole.

37. 1-(Methylsulphonyl)-2-oxo-3-[1-methyl-5-nitroimidazolyl(2)]-tetrahydroimidazole whenever prepared by a process as claimed in claim 36 or by an obvious chemical equivalent thereof.