GB1561529A - 5 - (2 - (5 - nitrolimidazol) - 2 - y)vinyl) - 1,3,4 - thiodiazole derivatives useful as chemotherapeutics - Google Patents

Abstract

Novel compounds of formula I are prepared by reacting a 2-substituted 1,3,4-thiadiazole with 5-nitroimidazole-2-carboxaldehyde. The reaction is carried out at elevated temperatures in the presence of an acid condensation catalyst and of a solvent. Instead of the aldehyde, its acetals or acylals may also be used. The novel compounds of formula I may be used as chemotherapeutics for treatment of microbial infections. <IMAGE>

Description

(54) 5-[2-(5-NITROIMIDAZOL-2-YL)-VINYLl-l,3,4- THIODIAZOLE DERIVATIVES USEFUL AS CHEMO THERAPEUTICS (71) We, BASF AKTIENGESELLSCHAFT, a German Joint Stock Company of 6700 Ludwigshafen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following Statement:- This invention relates to nitroimidazolylvinylthiadiazoles-i.e. 5 [2-(5-nitro- imidazol-2-yl)-vinyl] -1,3,4-thiadiazole derivatives-their production and formulations containing them for use as chemotherapeutics in the treatment of microbial infections in humans and animals.

It is known that nitroheterocycles such as nitrofurans, nitrothiazoles and nitroimidazoles are effective as agents for treating bacteria, fungi and Protozoa. The minimum inhibition concentrations of prior art preparations, for example metronidazole or tinidazole, are of the order of between 0.1 and 2 pg/ml. However, their action and tolerance levels are not always satisfactory. There is therefore a need to synthesize new compounds with increased effectiveness.

We have now found that compounds of formula I

where R1 is alkyl of 1 to 4 carbon atoms optionally substituted by hydroxy or alkoxy of 1 to 4 carbon atoms, R3 is hydrogen or methyl, and R3 is hydrogen, alkyl of 1 to 24 carbon atoms, unsubstituted or substituted phenyl or heteroaryl, have valuable pharmacological properties.

Examples of R1 are methyl, ethyl, isopropyl, n-butyl, fl-hydroxyethyl, ss-methoxy- ethyl or ,B-ethoxyethyL Examples of suitable alkyl radicals of 1 to 24 carbon atoms for R3 are methyl, ethyl, n-propyl, i-propyl, n-butyl, sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, eicosyl, docosyl and tetracosyL When R3 is phenyl, the latter may be substituted one or more times, preferably once or twice, by radicals inert under the conditions of preparation.Special mention should be made of the following as inert substituents: halogen (fluoro- chloro, bromo and iodo), nitro, alkyl of 1 to 4 carbon atoms which in its turn may be substituted by one or more halogen atoms, as in trifluoromethyl, alkoxy of 1 to 4 carbon atoms, and acylated and dialkylated amino groups each with 1 to 4 carbon atoms in the individual alkyl or acyl moieties. Examples of substituted phenyl are 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-iodiphenyl, 2,4-dichlorophenyl, 3 ,5-dichlorophenyl, 2-methylphenyl, 3-ethylphenyl, 4-i-propylphenyl 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4-nitrophenyl, 3,5-dimethoxyphenyl, 4-dimethylaminophenyl, 4-trifluoromethylphenyl and 4-acetvlaminophenyl.

Examples of suitable heteroaryl radicals for R are pyridyl, furyl, thienyl, oxidiazolyl and thiadiazolyl.

Of the radicals mentioned above the following are preferred: for Rl methyl, ethyl, i3-hydroxyethyl, p-methoxyethyl and -ethoxyethyl, for R2 hydrogen and methyl, and for R3 phenyl, alkyl of 1 to 13 carbon atoms, of which alkyl of 1 to 6 carbon atoms are particularly preferred, and from among the hetero-aryl radicals pyridyl, which may be attached in the 2-, 3- or 4-position. Preferred substituted phenyl radicals are 2-chlorophenyl, 3-chlorophenyl, 4-chiorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-dimethylaminophenyl and 4-nitrophenyl.

Of these compounds, those in which Rl is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl are especially preferred.

The compounds of the invention may be prepared by reacting a 2-substituted 1,3,4-thiadiazole of the general formula II

where R2 and R3 have the above meanings, with a 5-nitroimidazole-2-carboxaldehyde of the general formula III

where R1 has the above meaning, or an acetal or acylal thereof, at elevated temperature and in the presence or absence of an acid condensation catalyst and in the presence or absence of a solvent The reaction can be carried out in known manner.

Special mention should be made here of the use of acetals of aldehydes of the formula III obtained from reactions with methanol and ethanol and of the use of the acylal obtained from reaction with acetic acid.

The reaction is illustrated by the following equation

Some of the 13P-thiadiazoles of formula II used as starting materials are known compounds or can be easily obtained for example by the process described by R.

Stolle', Ber. dtsch. Chem. Ges. 32, 797 (1899), in which N,N'-diacylhydrazines are reacted at elevated temperature with P2S, in an aromatic hydrocarbon, e.g., xylene.

Compounds within the invention may be advantageously prepared by reacting a compound of formula II with a compound of formula m or its acetal or acylal at a temperature of from 50 to 220or, preferably in the presence of an acid condensation catalyst, e.g. a Lewis acid, a mineral acid or an acid ion exchanger, and, if desired, in the presence of a solvent.

When a solvent is used the preferred temperature range is from 90 to 150 C, and when no solvent is used the preferred range is from 150 to 2000C.

The acid condensation catalysts conventionally used in aldehyde condensation may be employed in this process, suitably in amounts of 0.005 to 1 mole, preferably 0.05 to 0.2 mole, of catalyst per mole of starting material II. Examples of acid condensation catalysts are polyphosphoric add, a borofluoride or zinc chloride. The preferred catalyst is zinc chloride.

The starting materials are generally used in a stoichiometric ratio, although one of the compounds may be used in an excess. The reaction is generally carried out at atmospheric pressure; superarmospheric or subatmospheric pressure may however be an advantage in specific cases. The reaction may be effected in the presence or absence of a solvent. Solvents that have proved particularly suitable are lower carboxylic acids such as acetic acid and propionic acid, their anhydrides and mixtures of a lower carboxylic acid and the particular anhydride. The term "lower" as used in the preceding sentence denotes acids having up to 6 carbon atoms.

In the mixtures of carboxylic acid and carboxylic anhydride the ratio is advan tageously between 9:1 and 1:9.

Generally the reaction is over within a few hours. Working up presents no problems; it can be effected for example by the addition of a precipitating agent, especially water or acetone, to the reaction mixture, precipitation of the reaction product, suction filtration, washing with water and alcohol, and recrystallization from a suitable solvent The following compounds may be mentioned as compounds according to the invention, in addition to those described in the Examples:: 2-thienyl-5- [2-(1-methyl-5-nitroimidazol-2-yl)-vinyl ] -1,3,4-thiadiazole 2-ethyl-5- [1-methyl-2-(1-ethyl-5-nitroimidazol-2-yl)-vinyl] -1,3 ,4-thiadiazole 2-methyl-5- [2-(1-ethyl-5-nitroirnidazol-2-yl)-vinyl] - 1,3,4-thiadiazole 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-2-yl)-] -1,3,4-thiadiazole 2-methyl-5- [2-(1-hydroxyethyl-S-nitroimidazol-2-yl)-vinyl] -1,3,4-thiadiazole 2ethyl-5- [1 -methyl-2-(1-hydroxyethyl-5-nitroimidazol-2-yl)-vinyl] -1,3,4 thiadiazole.

Compounds within the invention exhibit a good action against miaoorganisms.

They are outstandingly effective for the treatment of infections by Flagellata especially Trichomonas and Trypanosoma, and By Entamoaba Itistolytica in humans and animals.

They may also have a very good bacterial action in threshold concentrations of < 10-5, for example the compounds of Working Examples 6 and 7.

TABLE 1 Minimum inhibition concentrations (MIC) on Trichomonas vaginalis MIC Relative effectiveness Compound [pg/ml] Metronidazole= 1.0 Example 1 0.02 5.0 Example 2 0.01 10.0 Example 5 0.01 10.0 Evample 10 < 0.01 > 10.0 Example 6 < 0.01 > 10.0 Example 7 < 0.01 > 10.0 Metronidazole 0.1 1.0 Trinidazole 0.1 1.0 The tests were carried out in vitro using the quantitative tube-dilution test described by P. Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin-Goettingen-Heidelberg, 1957.

It is surprising that with the introduction of a thiadiazole radical attached via an ethylene bridge it has been possible to exceed the effectiveness of prior art commercial products, e.g., metronidazole and tinidazole, against Trichomonada infections up to more than ten times.

Special mention is made of the compounds of Examples 1, 5, 7 and 10 for their action,on Trichomi,da.

The action against infections caused by Trypanosomas and Entamoeba histolytica can be illustrated on mice (NMRI strains) using methods described in Handbuch fur experimentelle Pharmakologie, Ergânzungswerk 16, Erzeugung von Krankheitszu- stitnden durch das Experiment, Part 9, pages 150 to 292, Springer-Verlag, Berlin Goettingen-Heidelberg, 1964.

1. Trypanosm bnrcedinfections in mice Various dosages were investigated. The curing of the infection was determined microscopically and in a culture. There was also post-observation for 25 days after treatment was discontinued in order to establish whether there was any recidivation.

Example 1 11 X50 mg/kg perorally, acute 100% action, 70% recidivation Example 2 11 X50 mg/kg perorally, no action Example 5 11x50 mg/kg perorally, no action Example 10 11 X 50 ma/kg perorally, acute 100% action, no recidivation Example 6 11 X 50 mg/kg perorally, no action Example 7 11X50mg/kg, acute 100% action, 30% recidivation Suramin, 7 X 50 mg/kg intraperitoneally, acute 80% action, no recidivation Metronidazole 11x50 mg/kg peroralIy, no action Tinidazole 22 X 50 mg/kg percrally, no action 2. Tiypoma gambiense-infection in mice Same method as in the case of Trypanosoma bncei Example 1 llX50 mg/kg perorally, acute 100% action, 80% recidivation Example 2 11 X 50 mg/kg perorally, no action Example 5 11X50 mg/kg perorally, no action Example 10 11 x 50 mg/kg perorally, acute 100% action, 60% recidivation Example 6 llX50 mg/kgperorally, noaction Example 7 11 x 50 mg/kg mg/kg perorally, no action Suramin, 7 X 50mg/kg intraperitoneally, acute 80ç, action, no recidivation 3.Trypanosoma congolense-infection in mice Same method as in the case of Tiypanosoma brucei Example 1 11x50 mg/kgperorally, acute 100% action, 20% no recidivation Example 2 11 X 50 mg,kg perorally, no action Example 5 llX50 mg/kg perorally, no action Example 10 11 x50 mg/kg perorally, acute 100% action, no recidivation Example 6 11 X 50 mg/kg perorally, no action Example 7 11 x 50 mg/kg perorally, no action Suramin 7X50 mg/kg intraperitoneally, acute 70% action, no recidivation 4. Entamoeba histolytica (tube-dilution test) The PN and Q strains were tested.

The minimum inhibition concentrations were as follows: Example 1 < 0.01 Fg/ml Example 2 0.1 Example 5 < 0.01 Example 10 < 0.01 Example 6 < 0.01 Example 7 < 0.01 Menuonidazole 0.1 The experiments were carried out in vitro using the quantitative tube-dilution test described by P. Klein, Bakteriologische Grundlagen der chemitherapeutischen Laboratoriums-praxis, Springer-Verlag, Berlin-Goettingen-Heidelberg, 1957.

The results show that special mention should be made of the compounds of Examples 1 and 10 by virtue of their action and in comparison with Suramin, which is the constituent of the prior art preparations Germanin and Naganol. The action on Entamoeba histolytica in vitro can also be described as very good to good. As can be seen from the Table the action of metronidazole is surpassed by more than 10 times.

5. Trzchomoms vagin1-infection in mice Various dosages were investigated. The curing of the infection was determined microscopically and in a cuture.

Example 1 100% cure with 5 X 25 mg/kg perorally Example 2 10% cure with 5XSO mg/kg perorally Example 5 100% cure with 5X25 mg/kg perorally Example 10 100% cure with 5 X 25 mg/kg perorally Example 6 50% cure with 5 X 50 mg/kg perorally Example 7 100% cure with 5 X 50 mg/kg perorally Metronidazole 100% cure with 5 X25 mg/kg perorally Tinidazole 100% cure with 5 X 25 mg/kg perorally The LD 50 toxicity figures for the compounds of Examples 1, 7 and 10 on mice, NMRI strain, administered orally and with a week's observation period are over 1500 mg/kg.

Compounds within the invention can therefore be administered to humans and animals for therapeutic purposes for the treatment of trichomoniasis, trypanosomiasis and amoebic dysentery. They are also suitable for treating leishmaniasis.

Mention should be made of the following preferred active compounds: 2-phenyl-5- [2-(1-methyl-5-nitroimidazol-2-yl)-vinyl] - 1,3,4-thiadiazole, 2-(4-pyridyl)-5 [2-(1-methyl-s -nitroimidazol-2-yl)-vinyl] - 1,3,4-thiadiazole, 2- [2-(1-methyl-5-nitroimidazol-2-yl)-vinyl] - 1,3,4-thiadiazole and 2-ethyl- 5- [2- 1-methyl-5-nitroimidazol-2-yl-vinyl-1,3,4-thiadiazole, Particularly preferred compounds are 2-methyl-S-[2-1-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.

The present invention accordingly also provides chemotherapeutic compositions for treating microbial infections in humans and animals and comprising a compound of formula I as active ingredient and a carrier or diluent. It also provides a method of treating animals (other than humans) for therapeutic purposes which includes administering such a composition.

The chemotherapeutic compositions may be manufactured in a conventional manner using conventional carriers or diluents and the conventionally used pharmaceutical auxiliaries in accordance with the desired mode of administration in a suitable dosage unit.

The preferred formulations are those intended for oral administration. They may be in the form of example of tablets (such as coated tablets), drawees, capsules, pills, powders or suspensions. On account of the relatively sparing solubility of the compounds of the invention oral administration is preferred.

Naturally, parenteral formulations, such as injection solutions, may also be employed. Suppositories are a further example of formulations that can be used.

For the treatment of trichomoniasis, pharmaceutical formulations for the vagina, such as vaginal tablets, globuli and powders, may be used.

The dose to be administered depends on the nature and the severity of the disorder. Amounts of up to 5 g per day may be administered.

Single doses to be administered several times a day if desired are advantageously 50 to 1000 mg per dose. In the case of Trypanosoma infections the single doses are advantageously from 500 to 1000 mg, in the case of Entamoeba infections from 100 to 500 mg, and in the case of Trichomonada infections from 100 to 300 mg.

As a rule the single doses are administered from two to five daily and generally treatment of Trypanosoma infections lasts from 14 to 20 days, that of Entamoeba infections from 5 to 8 days, and that of Trichomonada infections also from 5 to 8 days.

For use in practise the compounds according to the invention can be processed with the carriers conventionally used in galenical pharmacy.

Tablets can be made for example by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, PVP, calcium carbonate, calcium phosphate and lactose, disintegrants such as Indian corn, starch or alginic acid, binders such as starch or gelatines, lubricants such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxy polymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate.

The tablets may also consist of a plurality of coatings.

Accordingly, drapes may be prepared by coating cores made in the same way as the tablets with agents conventionally used in drawee' coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The shell of the dragee may also consist of a plurality of coatings, and the auxiliaries mentioned above in connection with the tablets may be used.

Suspensions of the active ingredients according to the invention may also contain flavoring agents such as saccharine, cyclamate and sugar, and for example aromatic such as vanillin or orange extract. They may also contain auxiliaries that promote suspension such as sodium carboxylmethylcellulose, and protective colloids such as p-hydroxybenzoates. Capsules containing active ingredients may be manufactured for example by mixing the active ingredient with an inert carrier such as lactose or sorbitol and encapsulating the mixture in gelatine capsules. Suitable suppositories may be manufactured for example by mixing the active ingredient with the appropriate carriers such as neutral fats or polyethylene glycol or derivatives thereof.

EXAMPLE 1 Preparation of 2-methyl-5-[2-(1-methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole 11A g of 2,5-dimethyl-1,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole-2 carboxyaldehyde with 0.2 g of zinc chloride are heated in a stirred apparatus for 10 hours at reflux temperature in a mixture of 50 ml of glacial acetic acid and 20 ml of acetic anhydride. After cooling, the precipitated solid is washed with glacial acetic acid and recrystallized from dimethylformamide. 15.6 g of colored crystals. melting at 248cm, is obtained, corresponding to 62% of the theory.

EXAMPLE 2 2rphenyl-5- [2-( 1 -methyl-5-nitroimidazol-2-yl)-vinyl j - 1,3,4-thiadiazole 17.6 g of 2-methyl-5-phenyl-l,3,4-thiadiazole, 15.5 g of 1-methyl-5-nitroimidazole2-carboxaldehyde and 0.5 g of ZnCI2 are heated in 100 ml of acetic add and 50 ml of acetic anhydride for 7 hours at reflux temperature. After water has been added to the reaction mixture, the precipitated solid is recrystallized from glacial acetic acid.

17.5 g of a product melting at 257 C is obtained, corresponding to 56'',. -of the theory.

EXAMPLE 3 2 < 2-chlorophenyl)-5- [2-(1-methyl-5-nitroimidazol-2-yl)-vinyl] -1,3,4-thiadiazole 21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and 15.5 g of 1-methyl-S- nitroimidazole-2-carboxaldehyde are heated with 0.5 g of ZnCl2 in a mixture of 100 ml of acetic add and 50 ml of acetic anhydride for 6 hours at refiux temperature.

After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 18.5 g of product is obtained, corresponding to 53 % of the theory. The compound melts at 2390C.

EXAMPLE 4 2-(4-chlorophenyl)-5- [2-(1 -methyl-5 -nitroimidazol-2-yl)-vinyl] - 1,3,4-thiadiazole 21 g of 2-methyl-5-(4-chlorophenyl}1,3,4-thiadiazole and 22.8 g of 1-methyl 5-nitroirnidazol-2-carboxaldehyde are heated with 0.5 g of Zinc12 in a mixture of 100 ml of acetic acid and 50 ml acetic anhydride for 5 hours at reflux temperature. After cooling, diethyl ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 27.5 g of product is obtained, corresponding to 77% of the theory.The compound melts at 2680C EXAMPLE 5 2-(4-pyridyl)-5- [2-(1-rnethyl-S-nitroimidazol-2-yl)-vinyl] - 1,3,4-thiadiazole 8.8 g of 2-methyl-S-(4-pyridyi)-1,3,4-thiadiazole and 7.7 g of 1-methyl-5-nitto- imidazole-2-carboxaldehyde are heated with 0.2 g of ZnCl2 in a mixture of 50 ml of glacial acetic acid and 25 ml of acetic anhydride for 6 hours at reflux temperature.

After cooling, the precipitated solid is suction filtered, washed with concentrated ammonia and recrystallized from dimethylformamide. The melting point of the product obtained is 24e2410C.

EXAMPLE 6 5- [2-(1-methyl-S-nitroimidazol-2-y1)-vinyl] -1,3,4-thiadiazole 0.3 g of zinc chloride is added to 15.5 g of 1-methyl-5-nitroimidazole-2-carbox- aldehyde which has been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride and the whole is dripped into 10 g of 2-methyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride, over a period of 5 hours at reflux temperature. After 24 hours the reaction mixture is freed of the solvent by evaporation and ether is added After the reaction product has been washed with water it is Iecrystallized from xylene, 9.3 g of product corresponding to 39% of the theory, is obtained. The compound melts at 21400.

EXAMPLE 7 2ethyl-S- [2-( 1-methyl-S -nitroimldazol-2-yl)-vinyl] - 1,3 ,4-thiadiazole A solution of 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde in 50 ml of acetic acid and 25 ml of acetic anhydride is added at reflux temperature over a period of 10 hours to 12.8 g of 5ethyl-2-methyl-1,3,4-thiadiazole and 0.5 g of Zna2 which have been dissolved in 100 ml of acetic acid and 50 ml of acetic anhydride.

The mixture is kept at reflux temperature for a further 20 hours and the solvent is then evaporated. The residue is washed with acetone and passed through a readytousle silica gel column (Type A of Messrs. Merck) and eluted with CHOl2/ CII30H=98 :2. 5.6 g of the abovementioned reaction product with a melting point of 16500 is obtained; this corresponds to 21% of the theory.

EXAMPLE 8 2-methyl-S- [1-methyl-2-(1-methyl-5 -nitroimidazol-2-yl)-vinyl 1 -1,3,4-thiadiazole The acetone solution from Example 7 is concentrated, the residue passed through a ready-touse silica gel column (Type A of Messrs Merck) and eluted with CH0l3/CHaOH=98:2. Yield 5.4 g, melting point 2490C. There is also obtained 3.4 g of the stereoisomeric compound with a melting point of 15500.

The total yield from Examples 7 and 8 is 54% of the theory.

EXAMPLE 9 2-n-uidecyl-5- [2-(1-methyl-5-nitroimidazol-2-yl)-vinyl] -1,3,4-thiadiazole 8.45 g of 2-tridecyl-5-methyl-1,3,4-thiadiazolS 4.65 g of 1-methyl-5-niuxF imidazole-2-carboxaldehyde and 0.5 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperature. After the solvent has been removed, the residue is recrystallized from alcohol. 7.1 g of product is obtained, corresponding to 61 " of the theory. The melting point is 91cm.

EXAMPLE 10 2ethyl-S - [1 -methyl-2-( l-methyl-S-nitroimidazol-2-yl)-vinyl] - 1,3 ,4-thiadiazole 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 17.1 g of 2,5diethyl-1,3,4-thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature 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 of product, corresponding to 35 Ó of the theory, is obtained. The compound melts at 1250C.

Other compounds according to the invention may be prepared by methods analogous to those illustrated in Examples 1 to 10.

EXAMPLE 11 Examples of formulations (prepared in conventional manner): 1. Tablet 1. An active ingredient of formula I 120 mg Lactose 200 mg Methylcellulose 1S mg Cornstarch 50 mg Talc 11 mg Magnesium stearate 4 mg 400 mg 2. An active ingredient of formula I 120 mg Lactose 178 mg Avicel (Registered Trade Mark) 80 mg Polywash 6000 20 mg Magnesium stearate 2 mg 400 mg 2. Vaginal tablet 1. An active ingredient of formula I 80 mg Lactic acid 30 mg Glucose 670 nag Lactose 200 mg Hydroypropylmethylcellulose 20 mg 1g 2. An active ingredient of formula I 80 mg Boric acid 30 mg Lactose 890 mg 1g 3. Example of a tablet 1. Compound of Example 1 or Example 10 as active ingredient 200 mg 2.Polyvinylpyrrolidone (mean M.W. 25,000) 20 mg 3. Polyethylene glycol (mean M.W. 4,000) 14 mg 4. Hydroxypropylmethyl cellulose 40 mg 5. Talc 4 mg 6. Magnesium stearate 2 mg 280 mg The active ingredient is moistened with polyvinylpyrrolidone in a 10% aqueous solution, passed through a sieve with 1.0 mm apertures and dried at 500C. This granulated material is mixed with polyethylene glycol (mean M.W. 4,000) hydroxypropylmethylcellulose, talc and magnesium stearate and pressed into tablets à 280 mg.

4. Example of a dragée 1. Compound of Example 1 or Example 10 as active ingredient 150 mg 2. Lactose 60 mg 4. Cornstarch 30 mg 4. Polyvinylpyrrolidone 4 mg 5. Magnesium stearate 1 mg 245 mg The mixture of active ingredient with lactose and cornstarch is granulated through a 1.5 mm sieve dried at 50 C and then passed through a 1.0 mm sieve. The granulated material thus obtained is mixed with magnesium stearate and pressed into dragee cores. The latter are then covered in conventional manner with a coating consisting essentially of sugar and talc 5.Example of a suppository 1 suppository contains Active ingredient 250 mg Suppository composition (e.g., Witepsol H 19-Witepsol is a Registered Trade Mark) 1500 mg 1750 The suppository composition is melted. At 380C the finely pulverized ingredient is dispersed homogeneously in the melt It is then poured into precooled suppository molds at 35 C WHAT WE CLAIM IS: 1. A nitroimidazolylvinylthiadiazole compound of the general formula I: -

in which Rt is alkyl of 1 to 4 carbon atoms optionally substituted by hydroxy or alkoxy of 1 to 4 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, alkyl of 1 to 24 carbon atoms, unsubstituted or substituted phenyl or heteroaryL 2.A compound as claimed in claim 1 wherein R1 is methyl, ethyl, isopropyl, n-butyl, ss-hydroxyethyl, ,,B-methoxyethyl or ss-ethoxyethyl.

3. A compound as claimed in claim 1 or 2 wherein R3 is hydrogen, methyl, ethyl, n-propy, i-propyl, n-butyl, sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, eicosyl, doco syl, tetracosyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl" 3 -bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3 -ethylphenyl, 4-i-propylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4nitrophenyl, 3,5 -dimethoxyphenyl, 4Aimethylarinopbenyl, 4-trifluoromethylphenyl or 4-acetylaminophenyL 4. A compound as claimed in claim 1 or 2 wherein R3 is methyl, ethyl, hydrogen, n-tridecyl, phenyl, chlorophenyl or pyridyL 5. A compound as claimed in claim 1 wherein R' is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl.

6. A compound as claimed in claim 1 and hereinbefore individually named.

7. 2 - Methyl - 5 - [2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) - vinyl] 1,3,4 - thiadiazole.

8. 2 - Ethyl - S - [2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) - vinyli - 1,3,4 thiadiazole.

9. 2 - Ethyl - 5 - [1 - methyl - 2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) vinyli - 2,3,4 - thiadiazole.

10. A process for the production of a compound as claimed in claim 1 which process comprises reacting a 2-substituted 1,3,4-thiadiazole of the general formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (1)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   granulated material is mixed with polyethylene glycol (mean M.W. 4,000) hydroxypropylmethylcellulose, talc and magnesium stearate and pressed into tablets à 280 mg.

   4. Example of a dragée

   1. Compound of Example 1 or Example 10 as active ingredient 150 mg

   2. Lactose 60 mg

   4. Cornstarch 30 mg

   4. Polyvinylpyrrolidone 4 mg

   5. Magnesium stearate 1 mg 245 mg The mixture of active ingredient with lactose and cornstarch is granulated through a 1.5 mm sieve dried at 50 C and then passed through a 1.0 mm sieve. The granulated material thus obtained is mixed with magnesium stearate and pressed into dragee cores. The latter are then covered in conventional manner with a coating consisting essentially of sugar and talc 5.Example of a suppository 1 suppository contains Active ingredient 250 mg Suppository composition (e.g., Witepsol H 19-Witepsol is a Registered Trade Mark) 1500 mg 1750 The suppository composition is melted. At 380C the finely pulverized ingredient is dispersed homogeneously in the melt It is then poured into precooled suppository molds at 35 C WHAT WE CLAIM IS:

   1. A nitroimidazolylvinylthiadiazole compound of the general formula I: -

   in which Rt is alkyl of 1 to 4 carbon atoms optionally substituted by hydroxy or alkoxy of 1 to 4 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, alkyl of 1 to 24 carbon atoms, unsubstituted or substituted phenyl or heteroaryL 2.A compound as claimed in claim 1 wherein R1 is methyl, ethyl, isopropyl, n-butyl, ss-hydroxyethyl, ,,B-methoxyethyl or ss-ethoxyethyl.

   3. A compound as claimed in claim 1 or 2 wherein R3 is hydrogen, methyl, ethyl, n-propy, i-propyl, n-butyl, sec. butyl, isobutyl, amyl, n-hexyl, n-heptyl, n-octyl, 2ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, octadecyl, eicosyl, doco syl, tetracosyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2-bromophenyl" 3 -bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3 -ethylphenyl, 4-i-propylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4nitrophenyl, 3,5 -dimethoxyphenyl, 4Aimethylarinopbenyl, 4-trifluoromethylphenyl or 4-acetylaminophenyL 4. A compound as claimed in claim 1 or 2 wherein R3 is methyl, ethyl, hydrogen, n-tridecyl, phenyl, chlorophenyl or pyridyL

   5. A compound as claimed in claim 1 wherein R' is methyl, R2 is hydrogen or methyl and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl.

   6. A compound as claimed in claim 1 and hereinbefore individually named.

   7. 2 - Methyl - 5 - [2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) - vinyl] 1,3,4 - thiadiazole.

   8. 2 - Ethyl - S - [2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) - vinyli - 1,3,4 thiadiazole.

   9. 2 - Ethyl - 5 - [1 - methyl - 2 - (1 - methyl - 5 - nitroimidazol - 2 - yl) vinyli - 2,3,4 - thiadiazole.

   10. A process for the production of a compound as claimed in claim 1 which process comprises reacting a 2-substituted 1,3,4-thiadiazole of the general formula:

   in which R2 and R3 are each as defined in claim 1, with a 5-nitro-imidazole-2-carbox- aldehyde or acetal or acylal thereof, the carboxaldehyde having the general formula:

   in which Rl is as defined in claim 1, the reaction being carried out at elevated temperature.

   11. A process as claimed in claim 10 wherein the reaction is carried out in the presence of an acid condensation catalyst.

   12. A process as claimed in claim 10 or 11 wherein the reaction is carried out in the presence of a solvent.

   13. A process as claimed in claim 10 and substantially as described in any of rhe foregoing Examples 1 to 10.

   14. A compound as claimed in claim 1 when obtained by a process as claimed in any of claims 10 to 13.

   15. A chemotherapeutic composition comprising a compound as claimed in any of claims 1 to 9 and 14, as active ingredient, together with a carrier or diluent.

   16. A composition as claimed in claim 15 containing as active ingredient a compound of formula I in which R1 is methyl, R2 is hydrogen or methyl, and R3 is hydrogen, methyl, ethyl, phenyl or pyridyl.

   17. A composition as claimed in claim 15 or 16 containing 2-methyl-5-[2-(1 methyl-5-nitroimidazol-2-yl)-vinylj -1,3,4-thiadiazole as active ingredient.

   18. A composition as daimed in claim 15 or 16 containing 2ethyl-5-[1-methyl- 2-(1-methyl-5-nitroirnidazol-2-flvinyl] -1,3,4-thiadiazole as active ingredient

   19. A composition as claimed in claim 15 or 16 containing 2ethyl-5-[2-(1- methyl-5-nitroimidazol-2-yl)-vinyl]-1,3,4-thiadiazole as active ingredient.

   20. A composition as claimed in any of claims 15 to 19 which is in unit dosage or multiple unit dosage form and which contains from 50 to 1000 mg of active ingredient per unit dose.

   21. A composition as claimed in claim 15 and substantially as hereinbefore described in any one of parts (1) to (5) of Example 11.

   22. A method of treating animals other than humans for therapeutic purposes which includes administering a chemotherapeutic composition as claimed in any of claims 15 to 21.