CS201541B2 - Process for preparing 5-//2-nitroimidazolyl/vinyl/-1,3,4-thiadiazoles - Google Patents

Abstract

2-(5-Nitroimidazol-2-ylvinyl)thiadiazoles of formula (I) are new: (where R1 is 1-4C alkyl opt. substd. by OH; or 1-4C alkoxy; R2 is H or Me; R3 is H, 1-24C alkyl, opt. substd. phenyl or heteroaryl). Specif. (I) are 2-methyl-5- 2-(1-methyl-5-nitroimidazol-2-yl)vinyl -1,3,4-thiadia- zole and its i-ethyl analogue. (I) also have bactericidal activity. A typical cpd. 2-methyl-5-2-(1-methyl-5-nitroimidazol-2-yl)vinyl -1,3,4-thiadia- zole is prepd. in 62% yield by heating a mixt. of 2,5-dimethyl-1,3,4-thiadiazole, 1-methyl-5-nitroimidazole-2-carboxaldehyde and ZnCl2 in acetic acid and acetic anhydride.

Description

It is known to be heterocyclic. compounds with nitrogen ring atoms such as nitrofural, nitrothiazole or nitroimidazole are effective against bacteria; fungi 'and aprvokům. Minimum effective concentration of these preparations, for example. metro? midazole or imidazole, moves. v. range. 0.1 to 2 isg / ml. Yet it is not. their. efficiency; a. tolerance. always. enough. satisfactory. It would therefore be necessary. find new substances with higher. effect.

Subject. invention. Yippee . a process for the preparation of 5 - [[2-nitro-imidazinyl] -1,3,4-hiadiazole derivatives. common. of formula I, wherein. means

R2 - atom. hydrogen. or. methyl. and.

R3. hydrogen atom. . alkyl radical. O.' . 1 to 13 atoms. carbon, phenyl, residue,. a chlorophenyl radical or a pyridyl radical, characterized in that it is mentioned. v. 'reaction' 2-substituted. 1,3, 44hiadiazoF of formula II,

(ii) where

R2 a. .R3. have the above meaning, p. 5-nitroimidazole-2-carboxaldehyde. common '. of formula III ^{p 2} - N - N * N - N

I ^CH 3

(III) at a temperature of 50 to 220 ° C, optionally in the presence of. acidic condensation catalyst; and. optionally in the presence of a solvent.

In the case of the radical R @ 3, alkyl radicals having 1 to 13 carbon atoms are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, iso-butyl, amyl, n-hexyl, n-heptyl , n-octyl, 2-ethylhexynyl, decyl, undecyl, dodecyl and tridecyl.

Of the above-mentioned radicals, C1-C6 alkyl radicals, phenyl radicals, pyridine radicals are particularly preferred for R3. Most preferred substituted phenyl radicals are 5- (4-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl).

Especially preferred are compounds in which R2 is hydrogen or methyl and R ^3, methyl, ethyl, phenyl or pyrldyl.

The course of the reaction can be illustrated by the following reaction scheme:

Some of the 1,3,4-thiadiazoles of formula II which are starting materials are known and can be obtained in a manner known per se, for example according to R. Stolle, Her. dtsch. Chem. 32, 797 (1899). This is accomplished by reacting N, N‘-diacylhydrazines with P2S5 in an aromatic hydrocarbon such as xylol at a higher temperature.

The process for the preparation of the compounds according to the invention can conveniently be carried out by reacting a compound of the formula II with a compound of the formula II in a reaction. a temperature of 50 to 220 ° C, preferably in the presence of an acidic condensation catalyst, for example. Lewis acids or inorganic acids or. an acidic ion exchanger, and optionally in the presence of a solvent.

The preferred temperature range is when using a solvent. in the range of 90 to 150 ° C in the absence of solvent at a temperature of 150 to 200 ° C · ^Q

Particularly suitable catalysts are the acidic condensation catalysts known from the condensation of aldehydes and are used in an amount of 0.005 to 1 mol, preferably 0.05 to 0.2 mol, per 1 mol of the starting material of the formula (II). Acidic condensation catalysts are, for example, polyphosphoric acids, boron trifluoride or zinc chloride. The preferred catalyst is zinc chloride.

Of the starting materials, both components are generally used in a stoichiometric ratio, but one of the excess components may also be used. The reaction is carried out at atmospheric pressure, under vacuum or under positive pressure in some cases. The reaction may be carried out in the absence of a solvent. Otherwise, it is necessary as. solvents, in particular lower carboxylic acids, such as acetic or propionic acid, their anhydrides and mixtures of lower carboxylic acids and the corresponding anhydride. In the case of using mixtures of carboxylic acid and carboxylic anhydride, the preferred ratio is between 9: 1 and 1: 9.

The reaction is usually complete in a few hours. Working up of the reaction mixture is not difficult, the resulting product can be precipitated with a suitable precipitating agent, especially water or acetone, the product is filtered off with suction, washed with water or alcohol and recrystallized from a suitable solvent.

In addition to the compounds mentioned in the individual examples, the following substances must be mentioned:

2-thienyl-5- [2- (methyl-5-nitroimidazol-2-yl) -1H-4-yl] -1,4,4-thiadiazole-1,2-n-propyl-5- [ 1-ethyl-2- (1-methyl-b-nitroimidazol-2-yl) -vinyl] -1,3,4-thiadiazole, 2-ethyl-5- [1-methyl-2- (1-ethyl-S) -nitroimidazol-2-yl) -vinyl] -1,3,4-thiadiazole, 2-methyl-5- [2- (1-ethyl-5-nitroimidazol-2-yl) vinyl] -1-1 3,4-thiadiazole-1,2-thienyl-5- [1-methyl-2- [1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole,

2-furyl-5- [2- (1-methyl-5-nitroimidazol-4-yl) vinyl] 11131,4-thi-α-di-1,2-diol, 2-methyl-5- [2] -1- (1-hydroxyethyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-hiadiazole, 2-ethyl-5- [1-methyl] -2- (1-hydroxyethyl-5-nitroimidazol-2-y) 1] vinyl] -1,3,4-thiadiazole.

The compounds of the invention have good activity against microorganisms. They are particularly suitable for the treatment of flagellin infections, in particular Trichomonads and Trypanosoma and Entamoeba in humans and animals.

WITH

These substances also have good antibacterial activity at a concentration of less than 10 ^-5 , which is true, for example, of the compounds of Examples 6 and 7.

Table 1

Minimum inhibitory concentration (MHK) against Trichomonas vaginalis ⁴

Substance MHK [<µg / ml] The relative effectiveness of 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

¹¹ The experiments were performed in vitro series dilution tubes by the method of P. Klein Bakteriologische Grundlagen der chemotherapeutischen, Laboratoriumpraxis, Springer-Verlag Berlin-Gottingen-Heidelberg 1957th

Surprisingly, the introduction of a thiadiazole-linked radical via an ethylene bridge could increase the efficacy of known compounds effective against Trichomonad infections, for example metronidazoles and tinidazoles, more than 10-fold.

Compounds of Examples 1, 5, 7 and 10 are particularly preferred for Trichomonads activity.

Efficacy against Trypanosome and Entamoeba histolytica infections can be demonstrated in NMRI mice as described in Handbuch fur experimentelle Pharmakologie Supplement 16, Erzeugung von Krankheitszustanden durch das Experiment, Vol. 9, pp. 150-292, Springer, Verlag, Berlin — Gottingen-Heidelberg, 1964.

1. Trypanosoma brucei - infection in mice

Various doses of the active substances have been tested. Healing was monitored microscopically and in culture. The animals were monitored 25 days after discontinuation of the drug to monitor for any recurrences.

Example 1. 11 X 50 mg / kg orally, in acute state 100% efficacy, 70% relapse.

Example 2

X 50 mg / kg orally, no effect.

Example 5

X 50 mg / kg orally, no effect.

Example 10

X 25 mg / kg orally, in acute 100% effect, no relapse.

Example 6

X 50 mg / kg orally, no effect.

Example 7

X 50 mg / kg orally, in an acute state 100% efficacy, 30% relapse.

Suramine - 7 X 50 mg / kg intraperitoneally, in acute 80% effect, no recurrence.

Metronidazole - 11 X 50 mg / kg orally, no effect.

Tinidazole - 11 X 50 mg / kg orally, no effect.

Trypanosoma gambiense - infection in mice

The methodology is the same as for

Trypanosoma brucei.

Example 1

X 50 mg / kg orally in acute state 100% effect, 80% relapse.

Example 2

X 50 mg / kg orally, no effect.

Example 5

X 50 mg / kg orally, no effect.

Example 10

X 50 mg / kg orally, in acute state 100% effect, 60% relapse.

Example 1 a d 6

X 50 mg / kg orally, no effect.

Example 7

X 50 mg / kg orally, no effect.

Suramine - 7 X 50 mg / kg intraperitoneally, acute 50% effect, no recurrence.

3. Trypanosoma congolense - infection in mice

The same methodology as Trypanosomo bru ·, cei.

Example 1

X 50 mg / kg orally, acute 10.0. ·% - effect, .20 -%: relapses.

Example 2

X 50 mg / kg orally, - no recurrence.

Example 5

X 50 mg / kg orally, no effect.

Example 10

- X.50.- mg / kg. orally, in acute. condition 100% - effect, none: · relapse.

Example 1 a d 6

X 50 mg / kg orally, none. effect.

Ex - k1 - ad - 7

X 50 mg / kg orally, no effect.

Suramin - 7 X 50 mg / kg intraperitoneally, in acute. 70% - effect, no recurrence.

4. Entamoeba histolytica (dilution series)

Experiments were performed with PN and Q strains.

Pro - compounds from. The following minimum inhibitory concentrations were found in the examples.

izg / ml

Example 1 <0.01 Example 2 0.1 Example 5 <0.01 Example 10 <0.01 Example 6 <0.01 Example 7 <0.01 Metr.o.n.idazol 0.1

The experiments were carried out in vitro with a dilution series in tubes according to the method of P. Klein, Bakteriologische Grundlagen der - - chemotherap.

From the results. It follows that the compound of Example 1 and the compound of Example 10 are particularly advantageous in comparison. with a suramine which is: a major component, for example, in the known preparations of germariin and neganol. Also the effectiveness of these agents against Entamoeba histolytica in vitro - was - very good. As shown in the table, more than 10X were exceeded: metronidozal activity was exceeded.

5. Tňornornas vaginalis: - infection in mice.

Compounds of the invention. were tested at different concentrations. Healing: infection was monitored microscopically and in culture.

% of healed oral animal dose.

mg / kg

Example-.!, 100 ALIGN! 5 X 25 Example2 < 10 5 X 50 Example 5 100 ALIGN! 5 X 25 Example 10; 100 ALIGN! 5 X 25 Example 6 50 5 X 50 Example 7 100 ALIGN! 5 - X - 50 metronidazole 100 ALIGN! 5 X 25 tin-dazole 100 ALIGN! 5 X 25

Observed - - toxicity values, expressed. as the LD 50 for the mouse, the NMR strain, for peroral administration and the week follow-up, the pro-compounds of Examples 1, 7 and 10 are higher than: 1500 mg / kg.

The compounds of the invention may be used in humans. animals, for - therapeutic purposes, in particular - for the treatment of infections - caused by: Trichomia, Trypanosomami. -. and '- Amoebami. Moreover, these substances fall into consideration in the treatment of Lelshmanias.

Of the particularly effective compounds of the invention, the following should be noted:

2-phenyl-5- (2- (1-methyl-5-nitroimidazol-2-yl) vinyl) -1,3,4'-thiadiazole,

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

1,3,4 - hiadiazole,

2-e.thyl-54 2- (l-.methyl ^J 5-nitro-imidazol-2-yl) -vinyl] -1,3,44hiadiazo.la 2-ethyl-5- (l-nrethyl-2- (l-Methyl -5-nitroimidazol-2-yl) vinyl] -1,3,3-thiadiazole.

Active substances according to. of the invention can be processed into. cHemo-therapeutic - means of treatment. - microbial - infections - both in humans and animals, these preparations contain, in addition to conventional carriers and diluents, a compound of the general formula: I.

The chemotherapeutic agents are manufactured in such a way that the dosage is suitable for. administration. in - appropriate · purity - mixed with. conventional carriers or diluents, and optionally. with other - auxiliary means according to. selected - routes.

Advantageous drug. - forms - contain. a dose suitable for single oral administration. These are in particular tablets, coated tablets, coated tablets, capsules, pills, powders or suspensions. Because of the - relatively - poor solubility of the compounds of the invention, it is -. oral. administration most preferred.

However, it is also possible to administer the compounds of the invention parenterally in addition to injectable solutions. In addition, these substances can be used for the manufacture of suppositories. Also suitable for vaginal administration such as vaginal tablets, globules and powders are contemplated for the treatment of Tri201541 chomoniases.

The appropriate dose will depend on the nature and severity of the disease. Daily doses of up to 5 g are administered.

Single doses, optionally administered several times a day, are 50 to 1000 mg. For Trypanosome infections, the single dose is preferably in the range of 500 to 1000 mg, for Entamoeba infections in the range of 100 to 500 mg, and for Trichomonad infections in the range of 100 to 300 mg.

As a rule, the above single dose is administered 2 to 5 times daily, treatment typically lasts 14 to 20 days for Trypanosoma infections, 5 to 8 days for Entamoeb infections, and 5 to 8 days for Trichomonad infections.

For practical use, the compounds of the invention are formulated with conventional pharmaceutical carriers.

Tablets may be prepared by mixing the active ingredient with known excipients, for example, inert diluents such as dextrose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, with thickening agents such as corn, starch or alginic acid. , with a binder, such as starch or gelatin, with glidants, such as magnesium stearate or talc, and / or with depressants, such as carboxypolymethylene, carboxymethylcellulose, aceeate phthalate cellulose or polyvinyl acetate. The tablets may also consist of several layers.

Correspondingly, dragees can be prepared analogously to tablets and the dragee cores thus produced are then coated in a conventional manner, for example with collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The dragee casing may also consist of several layers, using the excipients mentioned above in the manufacture of tablets.

Suspensions containing the compounds of the invention as active ingredients may contain flavor enhancers such as saccharin, cyclamate or sugar, as well as flavorings such as vanillin or orange extract. In addition, the suspensions may contain substances which make this suspension possible, such as sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoate. The active ingredient capsules can be obtained, for example, by placing a powdered active ingredient mixture, for example a mixture with an inert carrier such as milk sugar or sorbitol, in a gelatin capsule.

Suppositories may be prepared, for example, by mixing the active ingredient with a suitable carrier, such as a neutral fat or polyethylene glycol and derivatives thereof, to form the mixture. then processed in the usual way.

He did

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

In a reaction vessel equipped with a stirrer, 11.4 g of 2,5-dimethyl 1,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.2 g of zinc chloride are heated in admixture with 50 ml of glacial acetic acid and 20 ml of acetic anhydride were refluxed for 10 hours. After cooling, the precipitated solid was washed with glacial acetic acid and recrystallized from dimethylformamide. 15.6 g of color crystals of m.p. 248 DEG C. are obtained in 62% of theory.

Example 2

2-Phenyl-5- [2- (1-methyl-4-nitropyridin-2-yl) vinyl] -1,3-1,3,4-thiadiazole

17.6 g of 2-methyl-5-phenyl-1,3,4-thiadiazole,

15.5 g of 1-methyl-5-methylthiazol-2-carboxylate ^, dehydrate and 0.5 g of zinc chloride are heated to reflux in 100 ml of acetic acid and 50 ml of acetic anhydride for 7 hours. After mixing the reaction mixture with water, the precipitated solid is recrystallized from ice. of acetic acid. Yield: 17.5 g (56% of theory);

Example 3

2- [2-Chlorophenyl) -5- [2- (1-methyl-4-nitroimidazol-4-yl) vinyl] -1,3,4-thiadiazole g 2-methlyl-5- (2-thiophenyl) thiazole diazole and 15.5 g l of methyl-5-nitroimidazole-2-carboxaldehyde was heated under reflux with 0.5 g of zinc chloride in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 6 hours. The product was washed with water and recrystallized from dimethylformamide to give 18.5 g (53%) of the title compound, mp 239 ° C.

Example 4

2- (4-СЫог1 enyy) -5- [2- (l-methyl-nitro-imidazole ^ (^] l 2- ^{^,} ^ l) 1 vinyl] thiadiazol-t1,3,4 g of 2- Mephyll-5- (4-chlorophenyl) -4-thiazole diazole and 22.8 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.5 g of zinc chloride in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 5 hours. After cooling, the precipitated solid is filtered off with suction on the filter, washed with concentrated ammonia and recrystallized from dimethylformamide to give the title compound (27.5 g, 77%), m.p. 268 ° C.

Example 5

2- (4-pyridyl) -5- (2- (l-Methyl-5 nltroimidazol ^j-2-yl) -vinyl] -1,3,4-thiadiazole

8.8 g of 2-methyl-5- (4-pyridyl) -1,3,4-thiadiazole and 7.7 g of 1-methyl-5-nitroimidazole-2-carboxaladehyde are heated with 0.2 g of zinc chloride in the mixture 50 ml of glacial acetic acid and 25 ml of acetic anhydride were refluxed for 6 hours. After cooling, the precipitated solid is suction filtered, washed with concentrated ammonia and recrystallized from dimethylformamide.

Example 1 a d 6

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

10 g of 2-methyl-1,3,4-thiadiazole dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride add 15.5 g of 1-methyl dropwise after the addition of 0.3 g of zinc chloride. -5-nitroimidazole-2-carboxaldehyde in a solution of 100 ml of acetic acid and 50 ml of acetic anhydride for 5 hours at reflux temperature. After 24 hours, the solvent was evaporated from the reaction mixture and ether was added. After washing with water, the crude reaction product is recrystallized from xylol to give 9.3 g (39%) of the title compound, m.p. 214 ° C.

Example 1 a d 7

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

12.8 g of 5-ethyl-2-methyl-1,3,4-thiadlazole and 0.5 g of zinc chloride in solution in 100 ml of glacial acetic acid and 50 ml of acetic anhydride are added under heating to reflux. solution of 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde in 50 ml of glacial acetic acid and 25 ml of acetic anhydride over 10 hours. The resulting mixture was refluxed for 20 hours and the solvent was evaporated. The residue is washed with acetone and then purified on a silica gel column (type A from Merck), eluting with a 98/2 mixture of chloroform and ethanol. In this way 5.6 g of analytically pure reaction product are obtained in 21% of theory. mp 165 ° C.

Example 8

2-Methyl-5- [1-methyl-2- (1-methyl-5-nitrolimidazol-2-yl) vinyl] -1,3,4-thiadiazole

The acetone solution of Example 7 is evaporated, the residue is applied to the top of a silica gel column (type A from Merck) and the column is eluted with a 98: 2 mixture of chloroform and methanol. 5.4 g of product having a melting point of 249 DEG C. are obtained. In addition, 3.4 g of a stereoisomeric compound with a melting point of 155 ° C are obtained.

The total yield of Examples 7 and 8 was 54% of theoretical.

Example 9

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

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

Example 10

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

To 17.1 g of 2,5-diethyl-1,3,4-thiadiazole, dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, is added dropwise over 5 hours. at reflux, 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde in solution in 80 ml of glacial acetic acid and 35 ml of acetic anhydride. After 24 hours at reflux, the reaction mixture was evaporated and treated with water. The precipitated reaction product is subjected to sublimation and recrystallization from propanol. 2.9 g of the title compound of melting point 125 DEG C. are obtained in a yield of 35% of theory.

The following are the mixtures from which the pharmaceutical preparations can be prepared in the usual way:

1. Tablets

1. an active ingredient of the formula I 120 mg lactose 200 mg methylcellulose 15 mg cornstarch 50 mg talc 11 mg magnesium stearate 4 mg

400 mg

2. an active ingredient of the formula I 120 · mg lactose 178 mg Avicel 80 mg Polywachs 6000 20 mg magnesium stearate 2 mg

400 mg average molecular weight 4000, hydroxypropyl methylcellulose, talc and magnesium stearate and compressed into tablets weighing 280 mg.

4. Method of producing dragees

2. Vaginal tablets

The dragees weighing 245 mg can be made from the following mixture:

1. Active substance of the formula I 80 mg lactic acid 30 mg glucose 670 mg lactose 200 mg hydroxypropyl methylcellulose 20 mg g

2. active ingredient of the formula I 80mg boric acid 30mg lactose 890mg g

3. A method of making tablets

Tablets weighing 280 mg can be made with the following mixtures:

compound of Example 1 or 10 200 mg polyvinylpyrrolidone with a molecular weight of 250,000 20 mg polyethylene glycol with a molecular weight of 4000 14mg hydroxypropylmethylcellulose 40mg talc 4mg magnesium stearate 2mg

280 mg

The active ingredient is moistened with polyvinylpyrrolidone as a 10% aqueous solution and passed through a 1.0 mm sieve and dried at 50 ° C. The resulting granulate is mixed with polyethylene glycol

the active ingredient of Example 1 or 10 150 mg lactose 60 mg cornstarch 30 mg polyvinylpyrrolidone 4 mg magnesium stearate 1 mg

245 mg

The active ingredient / lactose / corn starch mixture is moistened with an 8% aqueous solution of polyvinylpyrrolidone and passed through a 1.5 mm sieve, dried at 50 ° C and passed through a 1.0 mm sieve. The granulate thus obtained is mixed with magnesium stearate and pressed into dragee cores. The cores obtained are coated in a conventional manner with a shell consisting essentially of sugar and talc.

5. A method of making suppositories of suppositories comprises:

active substance 550 mg matrix (for example

Witepsol H 19) 1500 mg

1750 mg

The matrix is melted and the powdered active substance is dispersed in the melt at a temperature of 38 ° C. The mixture was poured at 35 ° C into pre-cooled molds.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of 5 - [(2-nitroimidazolyl) -vinyl] -1,3,4-thiadiazole derivatives of the general formula I, R * where ^R2 and R3 are as defined above, with 5-nitro-2-carboxaldehyde of formula III wherein R R2 is hydrogen or methyl; R3 is a hydrogen atom, an alkyl radical of 1 to 13 carbon atoms, a phenyl radical, a chlorophenyl radical or a pyridyl radical, characterized in that a 2-substituted 1,3-thiadiazole of the formula n, (III) is reacted at 50 to 220 ° C, optionally in the presence of an acidic condensation catalyst, and optionally in the presence of a solvent. 2. A process according to claim 1, wherein R @ ² is hydrogen or methyl and R @ ³ is hydrogen, methyl, ethyl, phenyl or pyridyl. 3. A process according to claim 1, which comprises reacting 2,5-dimethyl-1,3,4-thiadiazole with 1-methyl-5-nitroimidazole-2-carboxaldehyde to form 2-methyl-5- [ 2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole. 4. The process of claim 1, wherein 5-ethyl-2-methyl-1,3,4-thiadiazole is reacted with 1-methyl-5-nitroimidazole-2-carboxaldehyde to form 2-ethyl-5. - [2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole. 5. The process of claim 1, wherein 2,5-diethyl-1,3,4-thiadiazole is reacted with 1-methyl-5-nitroimidazolecarboxaldehyde to give 2-ethyl-5- [1-methyl- 2- (1-methyl-5-nitroimidazol-2-yl) vinyl] -1,3,4-thiadiazole.