CH624953A5 - Process for the preparation of novel 5-nitroimidazoles - Google Patents

Description

The invention relates to a process for the preparation of new nitroimidazolylvinylthiadiazoles which can be used as chemotherapeutic agents for the treatment of microbial infections in humans and animals.

It is known that nitroheterocycles, such as nitrofurans, nitrothiazoles or nitroimidazoles, are effective as agents against bacteria, fungi and protozoa. The minimum inhibitory concentrations of known preparations, for example metronidazole or tinidazole, are in the order of magnitude between 0.1 and 2 ng / ml. However, their effectiveness and tolerability are not always satisfactory. There is therefore a desire to synthesize new substances with increased effectiveness.

It has now been found that compounds of the formula I

in the R1 an alkyl group with 1 to 4 carbon atoms, which can be substituted by hydroxy or alkoxy with 1 to 4 carbon atoms in the alkyl, R2 is hydrogen or methyl and R :! a hydrogen atom, an alkyl radical with 1 to 24 carbon atoms,

an optionally substituted phenyl group or a heteroaryl group, have valuable pharmacological properties.

For the rest of R1, for example, the following are suitable: methyl, ethyl, isopropyl, n-butyl, β-hydroxyethyl, β-methoxyethyl or β-ethoxyethyl.

For the rest R :! come as alkyl radicals with 1 to 24 carbon atoms, for example: methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, iso-butyl, amyl, n-hexyl, n-heptyl , n-octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, cosyl, docosyl, tetradocosyl.

If R "is a phenyl radical, this can be substituted one or more times, preferably once or twice, by radicals which are inert under the production conditions. Inert substituents which may be mentioned in particular are: halogen atoms, such as fluorine, chlorine, bromine, iodine, nitro groups and alkyl groups with 1 to 4 carbon atoms, which in turn can be substituted by one or more halogen atoms, such as trifluoromethyl, alkoxy groups with 1 to 4 carbon atoms, acylated and dialkylated amino groups each with 1 to 4 carbon atoms in the alkyl or acyl radical Examples of substituted phenyl radicals are 2-fluoro, 4-fluoro, 3-chloro, 2-bromo, 3-bromo, 4-iodo, 2,4-dichloro, 3,5-dichloro, 2-methyl,

3-ethyl, 4-i-propyl, 2,4-dimethyl, 3,5-dimethyl, 4-nitro, 3,5-dimethoxy, 4-dimethylamino, 4-trifluoromethyl, 4- Ace-tylamino-phenyl.

As heteroaryl residues for R! For example, pyridyl, furyl, thienyl, oxdiazolyl, thiadiazolyl come into consideration.

For the radicals mentioned, the following are to be mentioned as preferred: for R1 methyl and ethyl and β-hydroxyethyl, β-methoxy-ethyl and β-ethoxymethyl, for R2 hydrogen or methyl and for R; Alkyl radicals with 1 to 13 carbon atoms and particularly preferably alkyl radicals with 1 to 6 carbon atoms and phenyl, and of the heteroaromatic radicals the pyridine radical, which can be linked in the 2-, 3- or 4-position. Preferred substituted phenyl radicals are 2-chloro, 3-chloro,

4-chloro, 2-methyl, 3-methyl, 4-methyl, 4-dimethylamino, 4-nitro-phenol.

Of these, particularly preferred are compounds in which R1 is methyl, R2 is hydrogen or methyl and R: 1 is hydrogen, methyl, ethyl, phenyl or pyridyl.

The process according to the invention is characterized in that 2-substituted 1,3,4-thiadiazoles having the general formula II

in which R2 and R3 have the meanings given above, with a 5-nitro-imidazole-2-carboxaldehyde of the formula III

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624953

o2n

, n ni

■ n '

R1

cho

(in)

in which R1 has the meaning given above, at elevated temperatures and in the presence of an acidic condensation catalyst and a solvent. The aldehydes of the formula III can also be used as acetals or acylals, with particular mention being made of the acetals formed by reaction with methanol and ethanol and the acylal formed by reaction with acetic acid. 15

The reaction can be represented by the following equation:

The 1,3,4-thiadiazoles of the formula II used as starting compounds are known compounds in some cases or they can be readily used, for example, according to the method described by R. Stollé, Ber. dtsch. Ges. 32, 797 (1899). Here, N, N '- diacylhydrazines are used with P2S5 in an aromatic hydrocarbon, such as Xylene, at elevated temperature.

The process according to the invention can conveniently be carried out by reacting a compound of formula II with a compound of formula III or its acetal or acylal at temperatures between 50 and 220 ° C in the presence of an acidic condensation catalyst, e.g. a Lewis acid, a mineral acid or an acidic ion exchanger, and in the presence of a solvent. The preferred temperature range is between 90 and 150 ° C.

Suitable catalysts are the acidic condensation catalysts known per se for aldehyde condensations, which are advantageously used in amounts of 0.005 to 1 mol, preferably 0.05 to 0.2 mol, of catalyst per mol of starting material II. Acidic condensation catalysts are, for example, polyphosphoric acid, boron fluoride or zinc chloride. The preferred catalyst is zinc chloride.

The starting materials are generally used in a stoichiometric ratio, but one of the compounds can also be used in excess. The reaction generally takes place at normal pressure, but overpressure or underpressure can be advantageous in special cases. Lower carboxylic acids such as acetic acid or propionic acid, their anhydrides and mixtures of a lower carboxylic acid and the respective anhydride have proven to be particularly suitable as solvents.

The ratio of the carboxylic acid / carboxylic anhydride mixture is expediently between 9: 1 and 1: 9.

In general, the reaction is complete within a few hours. The workup presents no difficulties; it can be carried out, for example, by adding a precipitant, in particular water or acetone, to the reaction mixture, precipitating the reaction product, filtering off with suction, washing with water and alcohol and recrystallizing from a suitable solvent.

In addition to the compounds described in the examples, the following compounds may also be mentioned:

2-thienyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole 30 2-n-propyl-5- [1-ethyl-2- (1-methyl-5-nitroimidazol-2-yl) - vinyl] -! , 3,4-thiadiazole

2-ethyl-5- [1-methyl-2- (1-ethyl-5-nitroimidazol-2-yl) vinyl] -1, 3,4-thiadiazole

2-methyl-5- [2- (l-ethyl-5-nitroimidazol-2-yl) vinyl] -1, 3,4-35 thiadiazole

2-Thieny 1-5- [1-methyl-2- (1-methyl-5-nitroimidazol-2-yl) - vinyl] -1,3,4-thiadiazole

2-furyl-5- [2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1, 3,4-thiadiazole

40 2-Methyl-5- [2- (l-hydroxyethyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole

2-ethyl-5- [1-methyl-2- (1-hydroxyethyl-5-nitroimidazole - 2-yI) vinylI] -1,3,4-thiadiazole.

45 The compounds produced according to the invention have a good action against microorganisms. They are of primary importance for the treatment of infections by flagella, in particular trichonomades and trypanosomes, and by Entamoeba histolytica in humans and animals.

They can also have a very good antibacterial effect in limit concentrations of <10 ″, for example the compounds of exemplary embodiments 6 and 7.

624953

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TABLE 1

Minimum inhibitory concentrations (MIC) against Trichomonas vaginalis'>

substance

MIC [[ig / ml]

Relative efficacy metronidazole = 1.0

example 1

0.02

5.0

Example 2

0.01

10.0

Example 5

0.01

10.0

Example 10

<0.01

> 10.0

Example 6

<0.01

> 10.0

Example 7

<0.01

> 10.0

Metronidazole

0.1

1.0

Tinidazole

0.1

1.0

2. Trypanosoma gambiense - infections of the mouse methodology as with Trypanosoma brucei

Example I 11x50 mg / kg orally, acute 100% activity,

80% recurrences

Example 2 11X 50 mg / kg orally, no effect

For example, 11x50 mg / kg orally, no effect

Example 10 11x50 mg / kg orally, acute 100% activity,

60% recurrences

Example 6 11x50 mg / kg orally, no effect

Example 7 11X 50 mg / kg orally, no effect

• 5 Suramin 7x50 mg / kg intraperitoneally, acute 50% effect, no recurrences

3. Trypanosoma congolese - infection of the mouse methodology as with Trypanosoma brucei

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11 The experiments were carried out in the tube serial dilution test in vitro according to P. Klein, Bacteriological basis of the chemotherapeutic laboratory practice, Springer-Verlag Berlin - Göttingen - Heidelberg 1957.

It was surprising that by introducing a thiadiazole residue bonded via an ethylene bridge, the effectiveness of known commercial products against Trichomonad infections, e.g. Metronidazole and Tinidazole, at most by more than tenfold.

With regard to their activity against trichomonads, the compounds of Examples 1, 5, 7 and 10 should be emphasized in particular.

The action against infections by trypanosomes and Entamoeba histolytica can be determined in the mouse (NMRI strains) by methods such as those described in the manual for experimental pharmacology, supplement 16, generation of disease states by the experiment, part 9, pages 150 to 292, Springer- Verlag, Berlin-Göttingen-Hei-delberg, 1964, are shown.

1. Trypanosoma brucei - infection of the mouse

Different doses were tested. The infection was cured microscopically and culturally. In addition, a follow-up of 25 days after stopping the treatment was carried out in order to be able to identify recurrences.

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example 1

Example 2 25 Example 5 Example 10

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Example 6 Example 7 Suramin

11x50 mg / kg orally, acute 100% effect, 20% no recurrences

11X 50 mg / kg orally, no effect

11x50 mg / kg orally, no effect

11x50 mg / kg orally, acute 100% effect, no recurrences

11x50 mg / kg orally, no effect

11x50 mg / kg orally, no effect

7x50 mg / kg intraperitoneally, acute 70% effect, no recurrences.

35 4. Entamoeba histolytica (serial dilution test) The strains PN and Q were tested. The minimum inhibitory concentrations were:

example 1

40

Example 2 Example 5 Example 10 45 Example 6 Example 7 Metronidazole

<0.01 Hg / ml

0.1 jig / ml <0.01 H.g / ml <0.01 [ig / ml <0.01 ng / ml <0.01 [ig / ml 0.1 [xg / ml

50

Example 1 11X50mg / kg orally, acute 100% activity,

70% recurrences

example

2nd

11X50 mg / kg

example

5

11X50 mg / kg

example

10th

11 X25 mg / kg

example

6

11X50 mg / kg

example

7

11X50 mg / kg no recurrences

30% recurrences

Suramin 7x50 mg / kg intraperitoneally, acute 80% effect, no recurrences

Metronidazole 11X 50 mg / kg orally, no effect

Tinidazole 11X50 mg / kg orally, no effect

The experiments were carried out in the tube serial dilution test in vitro according to P. Klein, bacteriological foundations of the chemotherapeutic laboratory practice, Springer-Verlag Berlin - Göttinger - Heidelberg 1957.

The results show that the compounds of examples 1 and 10 are particularly noteworthy because of their action and in comparison with suramin, which is a component of, for example, the known preparations germanin and naganol. The effectiveness against Entamoeba histolytica can also be described as very good in vitro. As can be seen from gjj in the table, the known metronidazole is more than tenfold exceeded.

5. Trichomonas vaginal - infection of the mouse Different doses were tested. The healing of the 65 infection was determined microscopically and culturally.

Example 1 100% healing at 5x25 mg / kg orally

Example 2 10% healing at 5x50 mg / kg orally

5

624953

Example 5 100% healing at 5x25 mg / kg orally

Example 10 100% healing at 5x25 mg / kg orally

Example 6 50% healing at 5 x50 mg / kg orally

Example 7 100% healing at 5 X 50 mg / kg orally

Metronidazole 100% healing at 5x25 mg / kg orally

Tinidazole 100% healing at 5 X 25 mg / kg orally

The determined toxicity values LD 50 on the mouse, strain NMRJ, when administered orally and in an observation period of one week are above 1500 mg / kg for the compounds of Examples 1, 7 and 10.

The compounds produced according to the invention can consequently be used in humans and animals for therapeutic purposes for the treatment of trichomoniasis, trypanosomiasis and amoebic dysentery. They can also be used to treat leishmaniasis.

The preferred active compounds include:

2-phenyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

2- (4-pyridyl) -5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

2- [2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thia-diazole

2-ethyl-5- [2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole.

The following are also particularly preferred compounds:

2-methyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole and

2-ethyl-5- [1-methyl-2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole.

Chemotherapeutic agents or preparations of compounds of the formula I can be prepared in a conventional manner using customary excipients or diluents and the pharmaceutical-technical auxiliaries usually used, in accordance with the desired type of application, using a metering unit suitable for use.

The preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders or suspensions. Because of the relatively poor solubility of the compounds to be used according to the invention, oral administration is preferred.

Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations. For the treatment of trichomoniasis, pharmaceutical preparations for the vagina, such as vaginal tablets, globules and powder, are also suitable.

The dose to be administered depends on the nature and severity of the diseases. Daily doses up to 5 g can be administered.

The individual doses to be administered several times a day are expediently 50 to 1000 mg per dose. In the case of Trypanosoma infections, the individual doses are advantageously in a range from 500 to 1000 mg, in the case of Entamoeba infections in the range from 100 to 500 mg and in the case of Trichomonad infections in the range from 100 to 300 mg.

As a rule, the single doses are administered 2 to 5 times a day and the duration of treatment is generally 14 to 20 days for Trypanosoma infections, 5 to 8 days for Entamoeba infections and 5 to 8 for trichomonad infections 8 days.

For practical use, the compounds prepared according to the invention can be processed with the carriers customary in pharmaceutical pharmacy.

Corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents, such as dextrose, sugar, io sorbitol, mannitol, PVP, calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn, starch or Alginic acid, binders, such as starch or Gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, dragées can be produced by coating cores produced in the same way as the tablets with agents conventionally used in dragée coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The drape shell can also consist of several layers, using the auxiliaries mentioned above for the tablets

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can.

Suspensions with the active substances produced according to the invention can additionally taste-improving agents such as saccarin, cyclamate or sugar and e.g. Aroma-30 substances such as vanillin or orange extract. They can also contain suspending aids, such as sodium carboxymethylcellulose, or protective agents, such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier, such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing them with carriers, such as neutral fats or polyethylene glycol or its derivatives.

example 1

Preparation of 2-methyl-5-] 2- (l-methyl-5-nitroimidazole-2-45 -yl) vinyl [-1, 3,4-thiadiazole

11.4 g of 2,5-dimethyl-l, 3,4-thiadiazole, 15.5 g of l-methyl-5-nitroimidazole-2-carboxaldehyde with 0.2 g of zinc chloride in a mixture of 50 ml are in a stirring apparatus Glacial acetic acid and 20 ml of acetic anhydride heated to the return temperature for 10 hours. After cooling, the precipitated solid is washed with glacial acetic acid and recrystallized from dimethylformamide. 15.6 g of colored crystals with a melting point of mp = 248 ° C. are obtained; this corresponds to 62% of theory. Th.

55

60

Example 2

2-phenyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] -l, 3,4-

thiadiazole

17.6 g of 2-methyl-5-phenyl-l, 3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of ZnCl2 are dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride heated to reflux temperature for 7 hours. After the reaction mixture has been mixed with water, the precipitated solid is recrystallized from glacial acetic acid. 17.5 g of a product are obtained, which melts at 257 ° C .; this corresponds to 56% of theory. Th.

624953

Example 3

2- (2-chlorophenyl) -5- [2- (l-methyl-5-nitroimidazol-2-yl) - vinyl] -l, 3,4-thiadiazole

21 g of 2-methyl-5- (2-chlorophenyl) -l, 3,4-thiadiazole and 15.5 g of l-methyl-5-nitroimidazole-2-carboxaldehyde are mixed with 0.5 g of ZnCl2 in a mixture of 100 ml Acetic acid and 50 ml of acetic anhydride heated to reflux temperature for 6 hours. After cooling, the reaction mixture is mixed with ether, the precipitated solid is washed with water and recrystallized from DMF. 18.5 g, corresponding to 53% of theory, are obtained. Th. The compound melts at 239 ° C.

Example 4

2- (4-chlorophenyl) -5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

21 g of 2-methyl-5- (4-chlorophenyl) -l, 3,4-thiadiazole and 22.8 g of l-methyl-5-nitroimidazole-2-carboxaldehyde are mixed with 0.5 g of ZnCl2 in a mixture of 100 ml Acetic acid and 50 ml of acetic anhydride heated to reflux temperature for 5 hours. After cooling, the reaction mixture is mixed with ether, the precipitated solid is washed with water and recrystallized from DMF. 27.5 g, corresponding to 77% of theory, are obtained. Th. The compound melts at 268 ° C.

Example 5

2- (4-pyridyl) -5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

8.8 g of 2-methyl-5- (4-pyridyl) -l, 3,4-thiadiazole and 7.7 g of l-methyl-5-nitroimidazole-2-carboxaldehyde are mixed with 0.2 g of ZnCl2 in a mixture 50 ml of glacial acetic acid and 25 ml of acetic anhydride heated to the return temperature for 6 hours. After cooling, the precipitated solid is filtered off, washed with concentrated ammonia and recrystallized from DMF. The compound melts at 240 to 241 ° C.

Example 6

2- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] -1, 3,4-thiadiazole

After adding 0.3 g of zinc chloride, 15.5 l-methyl-5-nitroimidazole is added dropwise to 10 g of 2-methyl-l, 3,4-thiadiazole, which are dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride -2-carboxaldehyde, which is dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride, for 5 hours at reflux temperature. After 24 hours, the reaction mixture is freed from the solvent by concentration and mixed with ether. After washing with water, the crude reaction product is recrystallized from xylene. 9.3 g, corresponding to 39% of theory, are obtained. Th. The compound melts at 214 ° C.

Example 7

2-ethyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] -1, 3,4-thiadiazole

A solution of 15 is added to 12.8 g of 5-ethyl-2-methyl-l, 3,4-thiadiazoi and 0.5 g of ZnCl2, which are dissolved in 100 ml of glacial acetic acid and 50 ml of acetic anhydride, at the reflux temperature for 10 hours , 5 g of l-methyl-5-nitro-imidazole-2-carboxaldehyde in 50 ml of glacial acetic acid and 25 ml of acetic anhydride. The mixture is kept at the reflux temperature for a further 20 hours and the solvent is then evaporated off. The residue is washed out with acetone and purified on a silica gel column (type A from Merck); elute with CHCI3 / CH3OH = 98: 2. 5.6 g of the above are obtained. Reaction product with a melting point mp 165 ° C; this corresponds to 21% of theory. Th.

Example 8

2-methyl-5- [l-methyl-2- (l-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole

The acetone solution from Example 7 is concentrated, the residue is added to a silica gel column (type A from Merck) and eluted with CHCl3 / CH3OH = 98: 2. Yield 5.4 g, melting point 249 ° C. In addition, 3.4 g of the stereoisomeric compound with a melting point of 155 ° C.

The overall yield from Examples 7 and 8 is 54% of theory. Th.

Example 9

2-n-T ridecyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

8.45 g of 2-tridecyl-5-methyl-l, 3,4-thiadiazole, 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of zinc chloride are dissolved in 40 ml of acetic acid and 15 ml of acetic anhydride heated to reflux temperature for 24 hours. After removing the solvent, the residue is recrystallized from alcohol. 7.1 g, corresponding to 61% of theory, are obtained. Th. The melting point is 91 ° C.

Example 10

2-ethyl-5- [l-methyl-2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole

To 17.1 g of 2,5-diethyl-l, 3,4-thiadiazole, which are dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, 4.65 g of l-methyl 5-nitroimidazole-2-carboxaldehyde, which is dissolved in 80 ml of glacial acetic acid and 35 ml of acetic anhydride, is added dropwise at the reflux temperature for 5 hours. After heating to the reflux temperature for 24 hours, the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then subjected to sublimation and recrystallized from propanol. 2.9 g, corresponding to 35% of theory, are obtained. Th. The compound melts at 125 ° C.

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Claims (6)

624953 PATENT CLAIMS , 1 Î? (II> r3 CH2 with a 5-nitroimidazole-2-carboxaldehyde of the formula III JOk OoN ,, CHO ^ RA or its acetal or acylal, in which R1 has the meanings given above, at elevated temperatures in the presence of an acidic condensation catalyst and a solvent. 1. Process for the preparation of new nitroimidazolyl-vinylthiadiazoles of the formula I. R1 in which R1 is an alkyl group with 1 to 4 carbon atoms, which can be substituted by hydroxy or alkoxy with 1 to 4 carbon atoms in the alkyl, R2 is hydrogen or methyl and R: 1 is a hydrogen atom, an alkyl radical with 1 to 24 carbon atoms Atoms, is an optionally substituted phenyl group or a He-teroaryl group, characterized in that a 2-substituted 1,3,4-thiadiazole of the formula II N N 2 2. The method according to claim 1, characterized in that compounds of the formula I are prepared in which R1 is methyl, R2 is hydrogen or methyl and R :: is hydrogen, methyl, ethyl, phenyl or pyridyl. 3. The method according to claim 1, characterized in that 2-methyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) - vinylj-l, 3,4-thiadiazole. 4. The method according to claim 1, characterized in that 2-ethyl-5- [2- (l-methyl-5-nitroimidazol-2-yl) vinyl] - 1,3,4-thiadiazole. 5. The method according to claim 1, characterized in that 2-ethyl-5- [l-methyl-2- (l-methyl-5-nitroimidazol - 2-yl) vinyl] -l, 3,4-thiadiazole manufactures. 6. Compounds of formula I, prepared by the process according to claim 1.