IL31074A - 2-amino-5-nitro thiazoles and their preparation - Google Patents

Description

2-Amino-5-nit;ro thiazoles and their preparation.

DR. KARL THOMAE GMBH.

The present invention relates to 2-amino-5-nitro thiazoles having valuable pharmacological properties and processes for the preparation thereof.

According to the present invention there are provided compounds of the general formula or a in which R-^ represents a hydrogen atom} -aft-alk^-l, dialkyl- aminoalkyl or hydroxyalkyl group containing not more than 5 carbon atoms } -ST-¾TT¾i, ,IIA7-r,-gT,aap} R2» ¾'» ¾" and R2IM whlcl1 mav ¾e ΐ1ΐθ same °r different, each represents a hydrogen atom,' an alkyl or hydroxyalkyl group containing 1 to 5 carbon atoms, uv¾ii" ""crikoxycarbOn 1 gruup; X represents an oxygen atom, a sulphur atom or an imino group; and n represents the integer 2 or 3; and acid addition salts thereof. Such acid addition salts may be salts of inorganic or organic acids and for use in pharmaceutical compositions are physiologically acceptable acid addition salts.

The compounds according to the invention may be prepared for example by reacting a compound of the , formulas [in which R4 and R^ which may be the same or different, each represent a halogen atom or a group of the formula -SRg (in which Rg represents an alkyl, aralkyl or alkenyl group) or R4 and R^ together with the adjacent carbon atom form a bis-mercaptoalkylene group having an alkylene residue containing 1,2 or 3 carbon atoms; with a bifunctional nucleophile or the formula [in which Rlt R2, R2', Hg", R2'M ? X and n are as hereinbefore defined] with cyclieation to form the compound of formula I. The reaction is preferably carried out in the presence of a heavy metal oxide, which forms insoluble complexes with mercaptans e.g. in the presence of lead oxide (PbO).

The reaction may for example be effected at an elevated temperature and, if desired, in the presence of a solvent. However, the reaction may also be effected by melting the reactants. Suitable solvents include for example, aqueous or anhydrous aliphatic alcohols or, lower aliphatic ketones. Compounds of the general formula II, in which at least one of the symbols R^ and ^ represents a halogen atom, are preferably reacted in the presence of an anhydrous ether, for example in dioxan. The ' emperature required for the reaction It Is believed that the reaction proceeds via an intermediate compound of the formula t It III in which Rn , R . R0 , R , R„ , X and n are as herein- h a-ofeem? aTd especially if R4 and 5 in formula II are/ before defined. However, in genetfal^this compound can not be isolated, since it readily cyclizes to produce a compound of formula I as hereinbefore defined. Only when reactin a compound of formula III having low reactivity in the process according to the invention, especially those compounds · in which X represents an oxygen atom and at a temperature "below 100°C, may compounds of the general formula IV be isolated,' The compounds of the general formula IV may then be cyclised for example by heating- them to a temperature which is preferably with greater than 100° C or by treating them at room temperature with a base. When a base is used, the base may for example,/be an alkali metal alcoholate or a tertiary amine.

The addition of a heavy metal oxide which forms a slightly soluble complex with mercaptans is advantageous whenever compound of formula III, in which X represents an imino group or an oxygen atom, is reacted. This addition is especially advantageous when R4 and R^ of the compounds of formula II are derivatives of - acceptable acid addition salts thereof "by suitable treatment with an inorganic or organic acid according to conventional methods. Suitable acids which may be used include for example hydrochloric acid, hydrobromic acid, sulphuric acid and acetic acid.

The compounds of the general formula II which are used as starting materials, and in which and each represent a substituted mercapto group, may for example, be produced ■accurdlng -fro— hg~pr -ctbis Qwc i tfd-rn'&erma ·&*θΗ -θ?^4-ε«Η&ΐ- ^-^--Ρΐβ·- §-9¾4-·^ !Storire--! ;p&&e-&e by cam sisee reacting 2-amino-5-nitro-t iazole, which is the compound of the formula in a polar solvent with carbon disulphlde in the presence of a base and converting the salt of 2- (bismercapto-methylenelmino)-5-nitro-thiazole which is formed into a compound of the general formula II, for example, according to known methods, e.g. by reaction with an alkyl-, aralkyl- or alkenyl-halide. If desired, this reaction may also be carried out stepwise.

Compounds of the general formula II, in which one of or represents a halogen atom, are new and may be prepared for example from 2[ (bisalkylmercapto-methylene)-aminoj-5-nit.ro· thiazoles by reacting them with a halogen with warming of the reaction mixture and in the presence of a halogenated solvent, for example carbon tetrachloride When the reaction is com lete the solvent is eva orated If it is desired to substitued the other symbols or in the product of this halogenation' by a second halogen atom, a stronger halogenating agent should be used, for example a phosphorus pentahallde at an elevated temperature.

The following starting materials of formula II have been prepared by these methods : -2-(me hylthiOchloromethyleneimino)-5-nitrothiazole, yellow crystals, m.p. 87 - 90°C{ and 2-(dichloromethyleneimlno)-5-nitrothiazole, b.p. 65-80°C/0.4 mm Hg} m.p. 95-100 C.

The compounds of the general formula III are known from the literature or may be prepared according to known literature methods.

The compounds according to the invention show interesting pharmacological properties. They exhibit antibacterial activity and in particular they show pronounced activity against trichomonas and schistosomiasis. The activity against trichomonas was tested in male NMRI-laboratory mice which has been infected with trichomonas foetus. A bouillon containing thioglycollate, 10$ of horse serum and a mixture of antibiotics (500 international units of penicillin/ml and 0.2 mg of strepotmycln/ml) at a pH of 7.0 served as nutrient medium for the culture of trichomonas foetus. Trichomonas foetus was incubated in this nutrient medium for 24 hours at a temperature of 37° C.

This incubated broth was sufficiently dilute that at a 320-fold magnification, only 8 to 10 germs could be seen with a microscope, 0.5 ml of this broth were then separately orally over a period of 3 days, twice daily, with a dose of 100 mg/kg or 50 mg/kg of each active substance, the treatment being started.2 hours after infection. The number of surviving animals was determined after 28 days. Untreated control animals died after 4 to 5 days.

/ The acute toxicity of the active substances was determined with groups of 10 male NMRI-laboratory mice per dose level of each active substance. The mice had an average body weight of 18 to 20 g. The - dose, the . administration of which results in the death of 50 of the animals within 7 days - was calculated according to the method of Litchfield and Wilcoxon.

The compounds of the general formula I in general show a good activity against trichomonas, for example the following compounds exhibit a particularly good activity against trichomonas foetus whilst being of only low toxicity:- TABLE I According to a further feature of the invention there are provided pharmaceutical compositions comprising at least one of the compounds of the invention as herein defined' in association with a pharmaceutical carrier or excipient.

The compositions may contain further physiologically active ingredients for example compounds having antibacterial, antiprotozoal and/or anthelmintic activity. The compositions may be presented in a form suitable for oral, rectal or parenteral administration. Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, syrups, emulsions, suspensions or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.

For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 20 to 400 mg, and especially 50 to 250 mg, of active in redient for use in adults. of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients :-Example 1 2-(Oxazolidin-2-ylideneimino)-5-nitrothiazole g (0.04 mol) of 2-[bis-methylthio)-methyleneimino]-5-nitrothiazole were dissolved in 200 ml of n-butanol, 2.4 g (0.04 mol) of ethanolamine were added and the mixture was refluxed for 2 hours „ After evaporation in vacuo, a black, viscous mass remained which was dissolved in ethyl acetate, to yield yellow crystals.

Melting point j 215°C (decomp0); yields 1 g (12 % of theory). Example 2 a) 2-rMethylthio-2-hydroxyethylaminomethyleneimi.no1-5-nitrothiazole g (0,04 mol) of 2-[bis-(methylthio)-methyleneimino]-5-nitrothiazole were dissolved in 300 ml of ethanol, 2,42 g (0,04 mol) of ethanolamine were added and the solution was refluxed for 2 hours. After evaporation, a dark, viscous residue remained. The residue was extracted by ethy] acetate, the solution treated with charcoal, filtered and evaporated. Yellow crystals precipitated. The crystals were recrystal-lized three times from ethyl acetate, M.p. 156 - 158°C; yield: 5,8 g (55$ of theory). b) 2-(0xazolidin-2-ylideneimino)-5-nltrothiazole .3 g (0,02 mol) of 2- (methylthio-^-hydroxyethylamino-methyleneimino^S'-nitrothiazole (Example 2a) were dissolved in 150 ml of ethanol and a solution of 0,46 g of sodium in 50 ml of ethanol was added. The solution was allowed to stand over-night at room temperature. The solution was Example 5 2- *ff-( 2-ftvdrox propyl )-5-methyl-oxazolidin-2-ylidenelmino7-5-nitrothiagole g (0.04 mol) of 2--bisr(rnethylthio) me h lenelmino -5-nitrothiazole were refluxed with 5.32 g (0.04 mol)of di-isopropanolamine in 200 ml of butanol for 2 hours. The crude product was chromatographed on a silica-gel column using methanol as fluting agent. After evaporatio of the methanol an oil remained, which cryotalliaed when triturated with little ethyl acetate* The product was recrystallizfed three times from ethyl acetate* M.p. 139°C, yield 1.5 g (13# of theory).

Example 6 2^/^H-(2-Hydroxyethyl)^oxagolidin-2-ylldeneimlno7^¾-nltro-thiazolo 2.5 g (0*01 mol) of 2-/"bl8-(methylthio) methyleneixaino7-< 5-nitrothiaaole and 1.1 g of diethanolamine (0.01 mol) were refluxed for 2 hours i 50 ml of pro anol. The resulting solution was concentrated, the precipitating product filtered off with suction and recrystalllzed from water using active oharacoal. Yield: 1.8 g (64$ of theory). Sintering above 160°C and decomposition above 260°C.

Example 7 2-/"*N~( 2-Hydroxyethyl)-oxazolidin-2-ylideneimlno7--4--methyl-5-nitrothlazole From diethanolamine and 2- ~bis-(methylthio) methylene-imlno7-5-nitrothiazole according to Example 6'.

Melting point: 192°C (decomp.).

Example 8 ' 2- N-(2-Hydrox ethyl)-thiazolidln-2-ylideneimlno7-5-nitrothiazole 14.95 & (0.06 mol) of 2- ""bis-(methylthio)-methyleneimino7-5-hitrothiazole were mixed with 100 ml of methanol and 7.27 g (0.06 mol) of 2-(2-hydroxyethylamino) ethane thiol added to the mixture at reflux-temperature. The mixture was re luxed for 2.5 hours. After cooling, 13.6 g (83$ of theory) of a yellow product crystallized.

Melting point: 179 - 180°C from ethanol.

Example 9, 2-(ghlazolidin--2~ylldeneimino )-5-»nitrothiaaole Prom 2-aminoethane thiol and 2-^bia-(methylthio) methyl-enelmiAoJ-S-nitrothiazole according to Example 8 .

Yield: 915¾ o theory; m.p. 26l°e.

Bxample 10 2~(I-nidagolidin--2~.ylideneimino)~5~nitrothiazole 2,5 8 (0.01 mol) of 2-/~bia-(methylthio) methyl©nsimlno7- 5-nitrothiazole and 1 g of ethylenediaiaine were refluxed in cc of ethanol for 10 minutes and the crystals obtained were filtered off with auction after cooling.

Yield: 2 g (94 of theory); m.p. 273°C (decomp.). or a) 4 g (0.01 mol) of 2- ~hi8-(Denzylthio)-ioethyle,neiii)in£7-5-nitrothiazole and 0.6 g (0.01 mol) of ethylenediamine were refluxed in 500 cc of methanol for 1 hour. After cooling, the product was filtered off with suction and recrystalllaed from dime hylformamide.

Yield: 1.2 g ( 56 of theory). or b) 2.5 g (0.01 mol) of 2-(l,3-> dithiolan-2-ylideneimino)-5-nitrothiazole and 0.6 g (0.01 mol) of ethylenedlamine were refluxed in 30 cc of butanol for 30 minutes. After cooling, the product was washed with methanol and then with ether. Yield: 1.7 g (80 of theory).

Example ί& 11 2-ΓN- (2-Hydroxyethyl )-imldazolidin-2-ylideneimino1-5-nitrothiazole — 10 Analogous to Example Ί-5, using monoethanol-ethylene-diamine.

Yield: 76 of theory; m.p. 152 - 153°C Example 11 12 2-rHexahydropyrlmidin-2-ylideneimino1-5-nitrothlazole 2.5 g (0.01 mol) of 2-[bis-(methylthio)methyleneimino]- 5-nltrothiazole and 1 g of propylenediamine in 30 ml of acetone were left to stand over-night at rpom temperature. The acetone was distilled off, the residue triturated with little ethanol and the product filtered off with suction. M.p. 264 - 266° C (deco p.); yield: 1.5 g (67% of theory). Example i8 13 2-( 5"HydrQxymeth.yi-oxazolidin-2^ylideneimino)-5-nltro thiazole 2.5 g (0.01 mol) of 2-[bis-(methylthio)methylene-imino]-5-nitrothiazole and 0.9 g of 3-amino-l, 2-propane .d'iol (0.01 mol) were refluxed for 3 hours in methanol. The precipitated pro-duct was filtered off with suction and recrystal lized from butanol.

° Example l· ^ 14 2-rN-(2-Hydrox.ye hyl)-oxazolidln-2-ylldeneimlno "1-5-nitro- thlazole hydrochloride .8 g of 2-[N~(2-hydroxyethyl)-oxazolidin-2-ylideneimino]- 5-nitrothiazole were dissolved with warming in as little methanol as possible. Methanolic hydrochloric acid was added in excess. The hydrochloride which was formed was subsequently precipitated with' much ether.

Yellow crystals, yield: 23 g (78 of theory), · .M.p. 132 - 133°C Example 2-Q 15 2-rN-(2-Hydroxyethyl)-imidazOlidln-2-ylideneimino1-5- nitrothjazole 2.4 g of 2-(methylthl0chloromethyleneimino)-5-nitro- thiazole were added, in small portion's / whith stirring' to a solution of 2.6 g of 2-(2-hydroxyethylamino) ethylamine in ■ ■ / 50 cc of absolute ethanol. Stirring was continued for minutes. On ice cooling, yellow crystals precipitated, which were recrystallized from ethanol. m.p. 152 - 153°C Example 2&- 16 2-rN-(2-Hydroxyethyl)-thlazolidin-2-ylideneimlmol-5- nltrothiazole Prepared from 2-(methylthiochloromethyleneimino)-5- nitrothiazole and 2-(2-hydroxyethylamino) ethanolthiol according to Example l^. m.p. 178 - 179°C ' Example 2-2- 17 2-f-[ N- ( 2-Hydroxyethyl ) -oxazolidln-2-ylideneimino 1-5- -nitrothiazole' and diethanol-amine a 60-70° C. The crystals sinter above 160°C and decompose above 260°C.

Example 23 18 2-( Imidazolidin-2-ylideneimino) -5-nitrothiazole a) Prepared from 2- (methylthiochloromethyleneimino ) -5-nitrothiazole' and ethylenediamine according to Example .p. 273°C (decomp,). b) 1.9 g (0.01 mol) of 2-(dichloromethyleneimino)-5-nitrothlazole were added ■ in portions with stirring and ice-cooling to a solution of 1.2 g (0.02 mol) of ethylene-diamine in absolute dioxane. The mixture was poured into water and the precipitating crystals were filtered off, dried and were recrystallized from dimethylformamide . m.p. 273°C Example -84 19 2^ (Thiazolidin-2-ylideneimino) -5-nitrothiazole Prepared frorrr 2-mercaptoethylamine and 2-(dichloro-methyleneimino) -5-nitrothiazole in absolute dioxan according 18 to Example -¾ b. m.p. 26l°C.

Example -2-5 20 2- (lmldazolidin-2-ylideneimlno) -5-nitrothiazole 2.6 g (0.01 mol) of (l,3-dithiolan-2-ylideneimino)-5-nitrothiazole were heated in 50 ml of methanol with 0.6 g of ethylenediamine and 3 g of lead oxide. After 30 minutes, the solvent was removed and the residue was recrystallized from dimethylformamide. m.p. 273° C (decomp. ) .

Example 2-6- 21 thiazole and 1 kg of lead-oxide were suspended in 4,5 1 of ethanol. To this suspension was added a solution of 420 g of diethanolamine in 0.5 1 of ethanol and the mixture refluxed for 3 hours. Hot filtratio with suction of the precipitated lead-complex was effected and the residue was washed with some ethanol. The combined filtrates were cooled giving a precipitate of yellow crystals. The crystals sinter above 160° C and melt with decomposition above 260°C.

Example -8? 22 2-fN- ( . -Dimethylaminopropyl)'-imidazolidin-2-ylideneimino "1-5-nitrothiazole 2.5 g (0.01 mol) of 2-[bis-(methylthio)methyleneimiho]-5-nitrothiazole were suspended- in 30 cc of refluxing n-propanol and a solution of 1.5 g (0.01 mol) of N-(3-dimethylaminopropyl)-ethylenediamine in 100 cc of ethanol was added slowly. After 30 minutes then mixture was evaporated on a rotary evaporator and the residue recrystallized from benzene. Yellow crystals precipitated, . which melt above 95°C. The N-(3-dimethyl-amino-propyl) -ethylenediamine used as starting-material was produced from ethylenediamine and 3-chloropropyldimethyl-ammonium chloride in refluxing ethanol. After evaporation of the ethanol the. mixture was diluted with water, the solution was adjusted- with caustic soda to pH 11, saturated with sodium chloride and the mixture stirred with chloroform. A colourless liquid of bp 80-85°C/0.2-0,4 mmHg was isolated from the chloroform.

Example ■£■€ 23 2- fN- ( 2.2-Dimethylaminoe h l ) -imidazolidln-2-ylidenelmino1- · - itr thi . nitrothiazole and N - (.2-dimethylaminoethyl) ethylenediamine 22 according to Example -27% Recrystallisation from n-propanol gave yellow crystals, m.p. 163°C. The N - (.2-dimethylaminoethyl) ethylenediamine was prepared as follows: 300 g of ethylenediamine were heated in 1.2 1 of absolute alcohol with stirring until boiling. A hot solution of 160 g of 2-chloroethyldimethylammonium chloride in 1.2 1 of absolute ethanol was added to this mixture over 3 hours. This mixture was heated for a further 2 hours under reflux.

After evaporation of the alcohol on a rotary evaporator, the mixture was diluted with 300 cc of water, made alkaline with caustic soda (pH 11), saturated with sodium chloride and shaken several times with chloroform. After drying over sodium sulphate, filtration and evaporation of the solvent, the mixture was distilled under an oil pump vacuum.

Colourless liquid of bp 72-80° C/0.2-0.5 mmHg.

Yield: 95 g Example "29 2 2-Γ5-Methyloxazolldin-2-ylideneimino1-5-nitrothlazole g (0.04 mol) of 2-[bis- (methylthio )methyleneimino ]- 5-nitrothiazole were dissolved- in 500 ml of n-propanol, 3 g (0.04 mol) of l-aminopropan-2-ol were added and the solution was heated for 2.5" hours under reflux. After evaporation • in vacuo a viscous ' dark-brown residue' was obtained. The residue was triturated with a small quantity of ethanol and filtered with suction. The crude product was recrystall ised three times from ethanol.

• M.p. 176 - 177°C Yield: 4.6 g (50 of theory). ....2-[bis-(benz^lthio)methyleneimino]-5-nitrothiazole (mp. ·■;'. 141 - 142°C) and also from 2-(allylthiomet y lthiomethylene- imino)-5-nitrothiazole (mp. 85 - 87° C).

Mp. 176-177° C.

Example Q 25 a) N- ( 5-Nitrothlazol-2- yl )- 1- ( 2-hydroxypropyl) -S- methylisothiourea g (0.04 mol) of 2-[bis-(methylthio)methylene- imino]-5-nitrothiazole were dissolved in 500 ml of ethanol and 3 g (0.05 mol) of l-aminopropan-2-ol added. The solution was heated for 2 hours under reflux. After evaporation in vacuo t the residue was triturated with a small quantity of ethanol and filtered with suction. The crude product was recrystallized once from ethanol. M.p. 127 - 128° C; Yield: 9.1 (82 of theory). b) 2-( 5-Methyloxazolidin-2-ylideneimino)-5-nitrothlazole 9.1 g (0.033 mol) erf N-(5-nitrothiazol-2-yl)-N'-(2- 25 hydroxyprOpyl)-S-methylisOthiourea (Example 5-0 a) were dissolved in 200 ml of ethanol and a solution of 0.76 g . of sodium in 50 ml of ethanol added. The solution was kept at room-temperature over-night and then it was evaporated to dryness. The : esidue was dissolved in water and neutralized with acetic acid with cooling.

Yellow crystals were obtained which were filtered off with suction and recrystallized twice from ethanol.

' M.p. 176 - 177°C; Yield: 5.6 g (74 % of theory).

. Example J- 26 2- -Meth loxazolidin-2- lideneimino - -nitrothiazole M.p, 176 - 177°C; Yields 5.5 g (60 of theory).

Example £2 27 2- (5-Methyloxazolidin-2-ylideneimino) -5-nitrothiazole 9.9 g (0.04 mol) of 2-(1, 3-dithiolan-2-ylid?eneii;mino)- 5-nitrothiazole and 13.5 g (0.06 mol) of lead^oxide (PbO) were suspended in 500 ml of ethanol, 3 g.of l-aminopr.opahr.2- ol were added to this suspension and the mixture refluxed for; 3 hours with efficient stirring. The mixture was filtered off with suction- from the" first "formed lead-salt of the 1, 2-ethylenedithiol. The- filtrate was treated with charcoal, filtered' and evaporated in vacuo. The crude product was recrystallized from ethanol.

•M.p. 176-177°C; Yield: 4.2 g (46 of theory).

Example ■¾ 28 2-(5-Meth.yloxazolidin-2-ylldeneimino)-5-nltrothiazole 6.15 g (0.03 mol) of 2-(methylthiochloromethyleneimino) 5-nitrothiazole were dissolved in 30 ml of anhydrous dioxan and 4.56 g (0.03, mol) of l-aminopropan-2-ol were added with ice-cooling. The brown-reddish solution was kept at room- temperature over night and heated for 20 minutes on a boiling water-bath. After evaporation in vacuo, a brown-reddish grease was obtained which partly crystallized on trituration with -a small amount of e thyl acetate. The crystals were filtered off with suction and recrystallized three times from ethanol.

M.p, 175°C.

Example ¾r 29 1-Aminopropan-2-ol, dissolved in dioxan, was added while cooling with ice. The solution was brought to room-temperature and' then heated for 20 minutes to 50 - 60°C.

During the evaporation of the solution a crude product was obtained, which was recrystallized three times.

M.p. 175°C.

Example 30 2- ( 5-Ethyloxazolldln--2-ylldenelmlnO)-5-nltrothlazole g (0.04 mol) of 2-[bis- (methylthio)methyleneimino]-5-nitrothiazole were suspended in 300 ml of n-butanol and 3.6 g (0.04 mol) of l-aminobutan-2-ol were added. The mixture was heated" under reflux and- after 0.5 hours, with the formation of methylmercaptan,- a dark-brown solution was obtained. The solution was refluxed for a further 2.5 hours. After evaporation of the "solution in vacuo, the residue was recrystallized three times from ethyl acetate and once from ethanol.

M.p. 183 - 185°C; Yield: 3.9 g (40 of theory).

Example 3-6- 31 2-(4-Ethyloxazolidln-2-ylldeneimlno)-5-nltrothiazole g (0.04 mol) of 2-[b.is-(methylthio)methyleneimino]-5-nitrothlazole were suspended in 300 ml of n-butanol and 3.6 g (0.04 mol) of 2-amiriobutan-l-ol were added. The mixture was heated for 2.5 hours under reflux. On cooling, crystals precipi'tated-from the dark-brown solution.

Evaporation of the mother liquors gave more of the crude product as a precipitate. The crude product was re-crystallised twice from ethanol.

Example 32 2~( B ~I)lmethyloxazolldln-2-ylldenelmlno)-5-nltrothlazole g (0.04 mol) of 2-[bis-(methylthio)methyleneimino]-5 nitrothiazole were suspended in 300 ml of n-butanol and 3.6 g (0.04 mol) of 2-amino-2-methylpropan-l-ol were added. The mixture was refluxed for 2.5 hours. The solution obtained was evaporated in vacuo and the residue recrystalllz twice from ethyl acetate, .p. 246 - 247°C; Yield 4.2 g (43.5$ of theory). 24 26 In the same way as described in Examples ■&$ to Jrt 32 and 5-'to 3-7- the following compounds were produced: Example SS" 33 2-( 5-n-Propyloxazolidin-2-ylldeneimlno)-5-nitrothiazole Prepared from 2-[bis-(methylthio)methyleneimino]-5-nitrothiazole and l-aminopentan-2-ol.

M.p. 175°C} Yield: 42 Example y 34 2-( ~lso-Propyloxazolidln-2-ylideneimino)-5~nltrothlazole Prepared from' 2-[bis- (methylthio)methyleneimlnO ]-5-n trothiazole and l-amino-3-methylbutan-2-ol .

M.p. 232°C (decomp. ) Yield: 59 °/o Example 40- 35 2-( -n-Pentyloxazolldln-2-ylidenelmino)-5-nitrothiazole Prepared from 2-[biB-(methylthio)methyleneimino]-5-nitrothiazole and l-aminoheptan-2-ol.

M.p. 144 - 146° C Yield: 22 M.p. 212-214°C (decomp.) Yield: 46 # Example 2 3 2-(5.5-Dimethyloxaa;olidiii-2-ylideneimino)-5-nltrothlazole Prepared from 2-[bis-(methylthiO)methyleneimino]-5-·■*<' nitrothiazole and r-amino-2-methylpropan-2-ol.

M.p. 144 - 146° C.

Example ? 38 2-(5~Ethyl-5~methyloxazolidln--2-ylidenelmlno)-5-nltro:fehlazole Prepared from 2-[bis-(methylthio)methyleneimino]-5-nitrothiazole and l-amino-2-methylbutan-2-ol.

M.p. 186 - 188° C.

Yield: 50 Example frfr 39 2~(5-n-Hexyloxazolidin-2-ylldeneimlno)-5~nitrothlazole Prepared' from 2-[bis- (me hylthio) methyleneimino]-5-nitrothiazole and l-amin0octan-2-ol.

M.p. 148 - 150°C.

Yield: 35 ^ Example 4-5- 40 2- (4.5-Pimethyloxazolidin-2-ylldeneimino)-5-nltrothlazole Prepared from 2-[bls-(methylthio)methyleneimino]-5-nitrothiazole and 3-aminobutan-2-ol.

M.p. 180 - 182° C.

Example 4-6- 41 2- (4-Ethyl-5-methyloxazolidln-2-ylldeneimino)-5-nitro-thlazole Prepared from 2-[bis-(methylthio)methyleneimino]-5-nltrothiazole and 3-aminopentan-2-ol.

M.p. 159°C Yield: 49 f° Example 4? 42 2- (5-Ethyl-4-methyloxazolldin-2-ylidenelmino)-5-nltrothiazole Prepared from-2-[bis- (methylthio )me yleneimino ]-5-nitrothiazole and 2-aminopentan-3-ol.

M.p. 158°C Yield: 30 % Example 40- · 43 2-r4-Meth'yl-5-pentyloxazolidln-2-ylldeneimino1-5-nltro-thlazole Prepared from 2-[bis-(methylthio)methyleneimino]-5-nitrothiazole and 2-aminooctan-3-ol.

M.p. 156 - 157°C Yield: 27 Example 43. 44 2- (4.4. .5-Tetrame hyloxazolidln-2-ylideneimino) -5-nltrothiazole Prepared from- 2-[biB-(methylthio)methyleneimino-5-nitrothiazole and ;3-amino-2,3-dimethylbutan-2-ol.

M.p. 206 - 209°C Yield: 26 Example Q 45 2-(4-Hydroxymethyl-4-methylOxazolldin-2-ylidenelmlno)-5- nitrothlazole and 2-amlno~2-methylpropan-lf 3-diol.

M.p. 230°C Yields 46°/0 Example -51 46 2-(4-Methyl-5-isopropyloxazolldln-2-ylldenelmino)-5-nltrothiazole Prepared from 2-[bis- (methylthio)methyleneimino]-5-nitrothiazole and 2-amino-4-methylpentan-3-ol.

M.p. 197 - 199°C.

Example "52 47 . 2- (4~Methyl~5--n~propyloxazolldln~2--ylidenelmino)-5-nitro--thiazole.

Prepared from 2-[bis-(methylthio)methyleneimino]-5-nitrothia^ole and 2-aminohexan-3-ol.

M.p. 198 - 199°C Example ■¾ 48 Tablets with 100 mg of 2-Γ N-(2"hydroxyeth,yl)~oxazolidin-2-ylldenelmlnol-5-nltrothiazole or 2-(5-methyloxazolldln-2-ylideneimlno)-5-nltrothiazole Compositions 1 tablet contains s 2-[ N-(2-hydroxyethyl)-oxazolidin-2~ ylideneimino]-5-nitro hiazole or 2- ( 5-methyloxazolidin-2-ylideneimino )-5-nltrothiazole 100.0 mg lactose 50.0 mg potato starch 42.0 mg polyvinylpyrrolidone 6.0 mg cellulose miorocr stalline 20 0 m Preparation; The active ingredient is mixed with the lactose and potato starch and granulated with a 12.5% ethanolic solution of the polyvinylpyrrolidone through a .5 mm mesh screen, dried at 40° C and triturated once more through 1,0 mm mesh The granulate thus obtained is pressed into tablets with cellulose and magnesium stearate.

Weight of tablet: 220,0 mg Punch: 9 mm Example -54 49 Dragees containing 100 mg of 2-rN-(2-hydroxyethyl)-oxazolidin-2-ylideneimino1-5-nitrothiazole or 2- (5-methyloxazolidin-2- The tablets produced according to Example Jt.'are with a shell according to a known process. The shell consists essentially of talcum and- sugar. The finished dragees are polished with beeswax.

Weight of dragee: 300,0 mg.

Example -5-5 50 Wa er-capsules with 200 mg of 2-rN-(2-hydroxyethyl)-thiazol-idin-2-ylideneimino "1-5-nitrothiazole or 2-( -methyloxazol-ideneimino)-5-ni rothiazole 1 wafer-capsule contains: 2- [N- ( 2-hydroxye thyl )-thiazolidin-2-ylidene-imino]-5-nitrothiazole or 2-(5-methyloxazol-idin-2-ylideneimino)-5-nitrothiazole 200,0 mg corn starch 50.0 mg 250,0 mg Preparation Example 5& 51 Dragees containing 150 mg of 2-[N-(2-hydroxyethyl)-thiazol-idln-2-ylideneimino "1-5-nitrothiazole or 2-(5-methyloxazolidin 2-ylideneimino )-5-nitrothiazole 1 dragee core contains 2-[N-(2-hydroxyethyl)-thiazolidin-2-ylidenelmino ]-5-nitrothiazole or 2-(5-methyloxazolidin-2-ylideneimino)-5-nitrothiazole 150.0 mg corn starch 60.0 mg gelatin 4.0 mg carboxymethylcellulose 4.0 mg high viscosity magnesium stearate 2.0 mg 220.0 mg Pre aration: A mixture of active ingredient and corn starch is granulated with a 10$ aqueous gelatin-solution through a 1.5 mm mesh screen, dried at 45° C and pressed once more through a 1.0 mm mesh screen. The granulate is mixed with the carboxymethylcellulose and the magnesium stearate and the mixture is pressed into dragee cores.

Weight of core: 220.0 mg. Die: 9 mm, arched.

The dragee cores thus prepared are coated with a Bheli according to a known process, the shell consisting essentially of talcum and sugar. The finished dragees are polished with beeswax.

Weight of dragee: 300.0 mg.

Example . ? 52 · Composition: 1 gelatin-capsule contains: 2-[N-(2-hydroxyethyl)-imidazolidin-2-ylideneimino]-5-nitrothiazole or 2- ( 5-methyloxazolidin-2-ylideneimino) - 5-nitrothiazole 100.0 mg Aerosil R 972 1.0 mg 101.0 mg Preparation The active ingredient is intimately mixed with the Aerosil and filled into gelatin-capsules of a suitable size..

Filling of capsule: 101.0 mg.

Example -5β· 53 Tablets with 200 mg of 2-fN- (2-hydroxyethyl)-imidazolidin- 2-ylidenelmlno1-5-nitrothiazole or 2-(5-methyloxazolidin- 2-ylideneimino) -5-nitrothiazole Composition: 1 tablet contains: 2-[N-(2-hydroxyethyl)-imidazolidin-2-ylideneimino]-5-nitrothiazole or 2-(5-methyloxazolidin-2-ylideneimino) -5-nitrothiazole 200.0 mg. lactose 110.0 mg. potato starch 70,0 mg. polyvinylpyrrolidone 10.0 mg.

Aerosil 5.0 mg.

Magnesium stearate . 5.0 mg. 400.0 mg Preparation: The active ingredient mixed with lactose and potato starch is granulated with a 10% ethanolic solution of the polyvinylpyrrolidone through a 1.5 mm mesh screen dried at 45°C and pressed once more through the above screen. The granulate thus obtained is mixed with Aerosil and magnesium stearate. The mixture is pressed into tablets. Weight of tablet: 400.0 mg.

Die: 11 mm, flat.

Claims (9)

1. Compounds of the general formula or a in which R-^ represents a .hydr.ogen atom; 'a^^¾£--b, dialkyl- aminoalkyl or .hyd ox alky.L..group containing not more than. 5 carbon atoms; R2» R2 ' > ¾" R2"' > which may. be the ..same...or different, each represent: a hydrogen atom, an alky1...or hydr.oxyalkyl. group containing. 1 to 5 carbon -g3?

2. , Compounds as claimed...in claim .1...in which R-^ repr.e.s.ent s a benzyl ,.2-hydroxy.ethyl., 2-hydroxypropyl, ., 3-hydroxypropyl 2-( N, .-dimethylamino) ethyl or a 3-(N,N- dimethylamino) propyl group...

3. Compounds as claimed in claim 1 or claim 2 in which R2» 2'» ^2" and ' wnicil may be ΐηθ same or different each represents a methyl, ethyl, propyl, pentyl, hexyl., hydroxymethyl or. methoxy.carbonyl group.

4. 2-( 5-Methyloxazolidin-2-ylideneimino' -5-nitrothizo.l.e.. · - - - e - -nitr thia le 6. 2- [IT- ( 2-Hydroxypropyl ) -oxazolidln-2-ylideneimino ] -5-nitrothiazole. 7. 2- 2-HydroxyprOpyl)-5-methyloxazolidin-2-yl.id.ene iraino ]-5~ni.trothiazole . 8. 2- [N-( 3-Hydroxy.propyl)-.oxazolidin-2-ylideneimino]-5 -nltrothiazole . 9. 2- ( 4-Ethyl-5-methyloxazolidin-2-ylideneimino ) -5 -nltrothiazole. 10. 2-(4-Ethyloxazolidin-,2.-yli.dene.iniino.)-5--iitrothiazole.. 11. 2-(5-Ethyloxazolidin-2-ylid,eneiiiiino)-5-nltrothiaz.ole... 12. 2-( 4 > 5-Dimethy1oxaz.o1idin-.. -ylideneimino ) -5-nitrothlazole. 13. 2-[N-(2--'.H.ydroxyethy1 )-oxazo1idin-2-y.l1deneimino] -5-nitrothiazole . 1 . 2- [N- ( 2-Hydroxyethyl)-thiazolidin-2-y.lid.eneimino] -5-nitrothiazole. 1

5. 2-[N-( 2-Hydroxyethyl)r-imi.idaz.olidin-2-ylid,eneimino] -5-nitrothiazole. 1

6. 2-(Thiazolidin-T2-ylidene.imino)-5-nitr.othiazole. 1

7. .Compounds as claimed... in. any of claims 4 to 16. in the. form1 of th ir ...acid....addition, salts . ;1

8. Compounds as claimed in any of the preceding claims, in which the said, acid . addition...salts, are .salts with hydrochloric, hydro¾romic, sulfuric, or acetic acids.. 1

9. Compounds as claimed, in. claim .1. as herein..specifically described, being other than as...claimed in .any of claims . 4 to 16. 20. A process for the preparation of compounds of the general formula I, as defined in ..claim 1, in which a compound of the formula in which R^ and R^ , which may be the same, or different, each represent a halogen...atom .or a gr.oup. of the formula -SRg (in which Rg represents an. alk 1, aralkyl or. alkenyl. group) o R^ and R^ together, ith... the adjacent carbon. atom form a bis-mercaptoaikylene group, having an alkylene residue containing 1, 2 or 3 carbon atoms is reacted with a bifunctional nucleophile of the formula [in which ^> 2> ' X n are as de:f,:i-ned in claim l] with cy.cli.sation to .f.orm the .compound,. of formula I.. 21. Λ process as claimed in claim .2.0 in which the. reaction is effected in the. presence of..a heavy metal oxide capable of 22. A process as claimed in claim .21 in which the said heavy met l oxide comprises ...lead- oxide... 23. A process as claimed in. any of claims 20 to 22 which the reaction is effected at an elevated temperature. 24. A process as claimed in claim.23. in which the . said temperature is between.6.0 and 20.Q°C, 25. A process as claimed in .any of claims 20 to 24 in which the reaction is effected. as a melt of. a mixture of reactants. 26. A process as claimed in any. of..claims 20 to 24 in which the reaction, is effected.. in., a solvent..- 27. A process, as claimed., in cl.aim..,.2.6 in which the said solvent comprises, an..aqueous .or .anhydrous aliphatic alcohol, a lower aliphatic ketone or a ether. 28. A process as claimed, in .claim 2.7 in which the said solvent comprises dioxan. 29. A process as claimed, in any of claims 20 to 28 in which an intermediate of formula in which R^, R2> R2 ' > ¾"'» X and n. are as defined in claim 1 and ^ is as defined., in claim..20., is formed and is subsequentl cy.cli.se..d to form...the., compound of formula I by further heating ..on the .addition of a base. 30. A process as claimed in claim 29 in which the intermediate is a compound of formula IV when X represents an oxygen atom, the said . intermediate is isolated after formation and is, subsequently .cyc.li.aed... o form the compound of formula I by further heating or by the addition of a base. •31. A process as claimed in claim 30 in. which the reaction to form the said intermediate is effected at a tempereture below 100°C. 32. A process . as claimed in claim 30 or claim 31 in which the subsequent cyclisation step..la effected at a temperature above 100°C. 33. A process as claimed in any of claim's 29 to 32 in which the subsequent cyclisation is effected by addition of an alkali metal alcoholate or a tertiary amine. 34. A process as claimed in any of claims.20 to 33 in .'■which- the compound of. formula- I is converted . into an .acid addition salt thereof... .35. A process as claimed in claim 20 substantially as herein described. 36. A process for the preparation of compounds as claimed in claim 1, substantially as ..herein ..described in. any of 47. ■ Examples 1-5-2-. 37. Compounds as claimed in..claim .1., . when prepared by a process as claimed. in any of claims 20 to 36. 38. Pharmaceutical compositions, .comprising at least one- of the compounds of the invention., as claimed in claim 1, in association with, a pharmaceutical carrier or excipient. 39. Compositions as claimed in claim 38 comprising further physiologically active ingredients. 31074/2 40. Compositions as claimed in. claim 39 in which the .said further physiologically active ingredients comprise antibacterial, antiprotozoal and/or. ■ anthelmintic. 'agents. 41. Compositions as claimed in .any of., claims 38, to 40 in a form suitable for oral, rectal or parenteral administration. 42. Compositions as claimed in.. claim.41. in. the farm..,of. granules, tablets, coated tablets capsules , syrups., emulsions, suspensions or .drops. 43.. Compositions as claimed in any o.f ..claims 38 to 42 in the form of dosage- units. .44.· Compositions as claimed...in., claim .43. in which ..each, dosage unit comprises 20 to 400...mg .of .active ingredient for use in adults. ' 45. Compositions as claimed* in claim 44 in which each dosage unit comprises 50 to.250 mg of active ingredient. 46.^ vPharmaceutical compositions, .as claimed., in. claim.38 substantially as herein described. 47. Pharmaceutical compositions .substantially as. herein described in any of Examples .53^5^ . 48-53. For thrf MpUctnt!,