NL192265C - Penem carboxylic acid compounds and pharmaceutical preparations containing these compounds. - Google Patents

Description

1 192265

Penem carboxylic acid compounds and pharmaceutical preparations containing these compounds

The invention relates to new penem carboxylic acid compounds, i.e. compounds having a 7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-en-2-carboxylic acid as the basic molecule. The fiber bonds, like most known penicillin derivatives, are substituted at the 3 and 6 positions. The penem connections generally have a numbering of the ring atoms which deviates from the systematic nomenclature, which numbering starts with the sulfur atom; said 3 and 6 positions are therein respectively. the 2 and 6 positions.

A large number of penem carboxylic acid compounds are known from European patent application 3,960.

In this, the substituents at the 2 and 6 positions of the penem are very varied. That in the 2 position can be, for example, alkyl, alkylthio, substituted alkylthio or aminoalkyl; according to the general description, the substituent at the 2 position may also have many other meanings, including alkanoyl-thiomethyl and heterocyclyl-thiomethyl, but such compounds are not illustrated. The substituent at the 6 position can be, for example, alkyl, alkoxy or substituted acetoxy; according to the general description, this substituent can also have a wide variety of other meanings, including hydroxyalkyl. however, such connections are not further illustrated. Insofar as penem compounds with ______ are called a hydroxyalkyl group at the 2 position, they do not have a substituted methyl group at the 6 position, and no properties are reported. Also, the compounds of this earlier application are always racemic in terms of the configuration of the C5 ring atom.

A large number of penem carboxylic acid compounds are also known from European patent application 2,210. The substituent at the 6-position of the penem may, in addition to a substituted amine, also be, for example, an α-hydroxyalkyl group. The substituent at the 2 position can vary widely, but is not a substituted methyl group; examples of 2 substituents according to this European patent application 2210 are ethylthio, aminoethylthio and phenylthio.

New penem carboxylic acid compounds of formula 1 have now been found, which, although falling under the broad definitions of the compounds according to the aforementioned European patent application 3960, are of which the specific combination of substituents cannot be derived from that patent application. In addition, the new compounds appear to have an unexpected better action against a number of harmful bacteria, and furthermore have a β-lactamase inhibitory effect.

The novel penem compounds according to the invention are characterized in that they comply with formula 1, in which the C5 atom has the R configuration, and in which further R is a hydrogen atom or an acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1- (ethoxycarbonyloxy) ethyl or C 1 -C 6 alkanoylaminomethyl group, and Z represents a carbamoyloxy, acetoxy, 5-methyl-1,3,4-thiadiazol-2-yl-thio, 1-methyl-1H-tetrazol-5-yl -thio-, 1,2,3-triazol-5-yl-thio or pyrazinylthio group.

The compounds according to the invention in which R represents an acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1- (ethoxycarbonyloxy) ethyl or C6 -alkanoyl-aminomethyl group, ie the respective esters of the penem carboxylic acid, undergo a metabolic reaction in vivo activation and have useful pharmacokinetic properties.

The invention also relates to pharmaceutical preparations containing the above compounds as active substance together with a pharmaceutically acceptable carrier.

Pharmaceutically suitable salts of penem carboxylic acids of the formula 1, such as sodium, potassium, benzathine, procaine and the like salts, which are usually filled with penicillin and cephalosporin, are also within the scope of the invention.

The scheme A of the formula sheet shows the preparation of the compounds of the formula 1.

45 Therein R 1 represents 1-hydroxyethyl. This group can be introduced by the method of Journal of Organic Chemistry 42, 2960 (1977). These compounds of the formula II can also be prepared from suitable esters of penicillanic acid S-oxide as explained in more detail in the examples The substitution at position 6 is directed stereospecifically to the 63 derivatives As is known (see, e.g., DHR Barton et al., J.

Chem. Soc., Chem. Commun. 303-305 (1973)), the ester of penicillanic acid S-oxide (2) (R is alkyl) in 50 an inert solvent, such as benzene or toluene, usually at 70-140 ° C, with a suitable acetylene derivative with the formula X'CsCY, wherein X 'is a group of the formula CH ^', and Z 'is hydrogen, halogen, hydroxy, amino, carbamoyloxy or a group of the formula OR', OCOR 'or NHCOR', and Y is hydrogen , alkyl, cyano or a group of the formula COOR or CH 2 Z ', wherein R and Z' have the meanings shown above are heated. If X 'has a different meaning, it can be converted into a group X by known substitution-55 reactions, where X represents a group of the formula CHgZ, wherein Z has the meaning shown above.

The compound 3 can be isomerized with a base to the compound 4, which can be converted into the final fat bond 1 in two different 192265 2 ways. According to the first method, the compound 4 on the isopropenyl double bond can be selectively ozonized to give the compound 5 (n = 1), which is converted to the compound 5 (n = 1) using suitable reducing agents, such as phosphorus tribromide or sodium iodide in acetyl chloride. 0) can be reduced, which is then hydrolysed to compound 6 (n = 0) under mild basic conditions or over silica gel. Condensation with a suitable glycolic acid ester yields compound 7 (n = 0), which is mixed with a chlorinating agent, such as thionyl chloride and pyridine, in the chlorine derivative 8 (n = 0) and then in the phosphorane 9 (n = 0) can be converted.

In addition, the same reaction sequence is also performed starting from compound 4 (n = 1), which is stable if Y does not represent a highly cleavable group. In compounds 9 (n = 0), the compound can be selectively ozonized as phosphonium salt under acidic conditions to yield compound 11, which is easily heated by heating in an inert solvent such as toluene at 50-140 ° C to a compound 1 is cycled.

For compounds 11 (n = 1), the compound must be reduced to compound 10 and then selectively ozonized to compound 11 to yield compound 1.

According to the second method, the compound 4 can be reduced under the usual conditions to a compound 12 which is ozonized on both double bonds, whereby compound 13 and after hydrolysis thereof compound 14 is formed. According to the method already shown above, a glyoxylation of the compound 14 yields a compound 15 which can be converted into the chlorine derivative 16 and then into the phosphorane 11, the latter of which is a general intermediate for both methods.

The above series of conversions leading from compound (3) to compound (1) is known per se, for example from German patent application 2,819,655.

Schemes B to FF in the accompanying figures show synthetic methods of compounds of the invention, but omitting the 1-hydroxyethyl group at the 6 position. The reactions are preferably carried out under the protection of the alcohol function of that group.

A series of in vitro experiments were conducted to determine the activities of (5R, 6S) -2-acetoxymethyl-6- (1 (R) -hydroxyethyl!) - 2-penem-3-carboxylic acid (code FCE 21420; R = Η , Z = CH2OCOCH3); (5R, 6S) -2 - [(1-methyl-5-tetrazolyl) thiomethyl] -6- (1 (R) -hydroxyethyl) -2-penem-3-carboxylic acid (code FCE 22055; R = Η, X = -CH2S-CN4CH3); 30 (5R, 6S) -2-carbamoyloxymethyl-6 [1 (R) hydroxyethyl] -2-penem-3-carboxylic acid (code FCE 22101; R = Η, X = -CH2OCONH2) compare with that of a compound according to EP -A-3960, namely 2- (3-aminopropyl) -6-ethyl-2-penem-3-carboxylic acid. The results are shown in Table A below, in the form of minimal inhibitory concentrations (MIC) in pg / ml against a number of bacteria.

35 TABLE A

M.I.C. (pg / ml)

Bacterial strains According to the invention EP-A-3960 FCE 21420 FCE 22055 FCE22101 40 - a) Staphylococcus auereus Smith 0.04 0.01 0.04 0.13 b) Staphylococcus aureus 39/2 * 0.03 0.15 0.03 0.13 c) Diplococcus pneumoniae ATCC6301 0.04 0.06 0.015 0.06 d) Streptococcus pyogenes C 203 0.04 0.015 0.03 0.25 45 e) Streptococcus faecalis ATCC6057 2.8 5.7 2 8 f) Escherichia coli 1507 0.5 0.17 0.5 2 g) Escherichia coli TEM * 0.5 0.17 0.5 2 h) Klebsiella aerogenes 1082 E * 1.4 0.35 0.7 4 i) Klebsiella aerogenes 1522 E 0.5 0.25 0.5 4 j) Enterobacter cloacae P99 * 5.7 2.8 2.8 16 k) Enterobacter cloacae 1321 E 0.5 0.35 0.5 1 l) Salmonella typhi Watson 0 .5 0.125 0.5 4 m) Proteus vulgaris X 20 1 0.125 1 2 n) Proteus mirabilis ATCC 9921 1 0.125 2 4 o) Clostridium perfringens 2886A 0.5 0.25 0.25 p) Bacteroides fragilis ISM 75/42 0 .7 0.25 0.5

Notes: a-e and o: Gram-positive bacteria; f-n and p: Gram-negative bacteria; o and p; anaerobic bacteria * = ($ -lactamase formers 3 192265

Preparation method 1

Methyl 6a- (1-hydroxyethyl) penicillanate S-oxide (Scheme GG).

A solution of 2.3 g of methylpenicillanate S-oxide in 50 ml of anhydrous tetrahydrofuran was cooled to -78 ° C. Lithium dfisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6 M 5 butyl-Li solution in hexane dissolved in anhydrous tetrahydrofuran was added, this mixture was stored at -78 ° C for 10 min. (5 ml) was added slowly and the whole was stirred for 15 min. Then the reaction mixture was quenched with a saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, washed twice with water and dried with sodium sulfate. After distilling off the solvent, the residue was purified briefly by column chromatography over silica gel eluting with 10 dichloromethane / ethyl acetate (1: 1) Yield 1.5 g The title compound consisted of a 2: 3 mixture of epimers of the carbon atom with the hydroxyl group determined by NMR, wherein the new C6-C8 bond was only α-position due to the stereospecificity of the reaction under the conditions used.

15 Preparation method 2

To a solution of 2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium dFisopropylamide was added at -78 ° C under nitrogen. An excess of acetaldehyde was added dropwise, the mixture was stirred for 5 min, quenched with a trace of acetic acid, poured into water and extracted with methylene chloride. The organic layers dried with sodium sulfate and evaporated in vacuo gave 0.8 g of the title compound.

Preparation method 3

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate (scheme JJ-PNB therein means 25 p-nitrobenzyl-).

1.2 g of methyl 6- (1-hydroxyethyl) -3-penicillanate was dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with an equivalent of butyl lithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to this mixture. After standing at -78 ° C for 30 min, the reaction mixture was stored at room temperature for 60 min, poured into water and extracted with methylene chloride. After drying with sodium sulfate and evaporation, 1.4 g of the title compound were obtained.

Preparation method 4

Methy 1-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate S-oxide (scheme KK).

1.8 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate was dissolved in 50 ml of methylene chloride and treated with 1.5 equivalents of m-chloroperbenzoic acid at 0 ° C. The organic phase was shaken with saturated NaHCO 3 solution, extracted with Na 2 SO 4 and evaporated. 1.4 g of sulfoxide were thus obtained.

Preparation method 5 40 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidine-2-on-S oxide (scheme LL).

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide and 2.4 g of butyndiol diacetate in 50 ml of toluene was boiled for 24 hours. The addition compound was then purified by column chromatography, eluting with 9: 1 dichloromethane / ethyl acetate. Thus, 1.1 g of 45 title compound were obtained.

Preparation method 6 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrober »zyloxycarbonyloxy-ethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-on-S- oxide (schedule MM).

50 1.3 g 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2-methyl-2-propenyl) -azetidine-2-on-S-oxide was dissolved in 80 cm3 of dichloromethane. 0.3 ml triethylamine was added and this mixture was kept at room temperature for 2 hours. The pure title compound was obtained in a quantitative yield by distilling off the solvent.

55 Preparation Method 7 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one-S-oxide (Scheme NN).

192 265 4

A solution of 1,1 4 | 3-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidine-2- on-S-oxide in 100 ml of dichloromethane was cooled to -78 ° C. Ozone in oxygen was purged until blue coloring occurred. This solution was shaken with an aqueous sodium bisulfite solution and dried with sodium sulfate. After evaporation, 0.5 g of the title compound were obtained.

Preparation Method 8 4 {1-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one (Scheme OO).

A solution of 0.8 g of 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was added at -20 ° C cooled and 0.6 cc of phosphorus tribromide was added. This reaction mixture was diluted with ethyl acetate after 10 min and washed twice with sodium bicarbonate solution. The organic phase dried and evaporated with sodium sulfate gave 0.4 g of the reduced compound.

Preparation Method 9______________________ 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidine-2-one (schedule PP).

1.2 g of 4p-vinylthio- (1,2-diacetoxy-methyl-1) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one were dissolved in methanol and 2 g of silica gel was added thereto. After 60 minutes, the insoluble material was filtered off and the organic phase evaporated. A short column chromatography gave 0.4 g of the title compound.

Preparation Method 10 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-25-1-hydroxymethyl) -azetidine-2-one (Scheme QQ).

0.6 g of 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one, dissolved in 30 ml of benzene and 0.6 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethylfuma) -rate) was refluxed. The reaction ended after 2 hours. The condensation product could be used for the next step without further purification.

30

Preparation Method 11 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidine-2-one (Scheme RR).

0.5 g of 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyl-35-oxycarbonyl-1-hydroxymethyl) -azetidin-2-one were added in 12 ml anhydrous tetrahydrofuran dissolved and cooled to 0 ° C. 1.1 equivalent of pyridine and 1.1 equivalent of thionyl chloride were added. This mixture was stirred for 10 min. The insoluble material was filtered off and the solution evaporated at room temperature to yield the title compound in substantially quantitative yield. This product could be used for the next step without further purification.

40

Preparation Method 12 4p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (acetoxymethyloxycaibonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (Scheme SS).

A solution of 0.760 g of 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitnobenzyloxycarbonyloxyethyl) -1- (1 -45 acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidine-2-one in 10 cm 3 of tetrahydrofuran and 10 cm 3 of dioxane was stirred with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine at 50 ° C overnight. The phosphorane was purified by a silica gel column chromatography, eluting with 7: 3 dichloromethane / ethyl acetate. 480 g of the title compound were obtained.

50 Preparation Method 13 4p-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one (Scheme TT).

0.45 g of 4p-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one was dissolved in 50 ml dichloromethane and dissolved in 55 Cooled to -20 ° C. 30 ml of a solution of trifluoroacetic acid in dichloromethane was added. After a few minutes, ozone in oxygen was purged until a light blue coloration occurred. This reaction was stopped and a few drops of trimethyl phosphite were added. The organic phase was washed with a saturated sodium bicarbonate solution and dried with sodium sulfate. Thus, 260 mg of the title compound were obtained.

Preparation Method 14 5p-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one (Scheme UU).

1.5 g of vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidine-2-on-S-oxide was added in 10 cm3 of anhydrous dimethylforamide dissolved and cooled to -20 ° C. 0.8 ml of phosphorus tribromide was added, this mixture was stirred for 10 min, diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate solution. The organic layer dried and evaporated with sodium sulfate gave 1.1 g of the title compound.

Preparation Method 15 4-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one (Scheme W).

1.4 1.4 [} - vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (methoxycarbonyl-2 ______ methyl-1-propenyl) -azetidin-2-one in 120 cm3 dichloromethane was cooled to -78 ° C. Ozone in oxygen was purged until blue coloration occurred. This solution was shaken with an aqueous sodium bisulfite solution and dried with sodium sulfate. After evaporation, 0.8 g of the title compound were collected.

Preparation Method 16 4p-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one (scheme WW).

0.800 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxalyl-azetidin-2-one were dissolved in 50 ml of methanol and several grams of silica gel were added. The mixture was kept at room temperature for 60 min, the insoluble material was filtered off and the filtrate yielded 0.3 g of the title compound on evaporation.

Preparation Method 17 4p-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidine-2on (Scheme XX).

0.5 g of 4p-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidine-2-one and 0.5 g acetoxymethylglyoxylate in 30 ml of benzene were boiled until response was over (2 hours). The title compound obtained could be used for the next step without further purification.

Preparation Method 18 4p-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one (Scheme YY).

0.35 g of 4p-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidine-2-one was dissolved in 10 ml anhydrous tetrahydrofuran at 0 ° C. 1.1 equivalent 40 pyridine and 1.1 equivalent thionyl chloride were added. This mixture was stirred for 10 min. The precipitate was filtered off and the filtrate, after evaporation, gave the title compound in a quantitative yield. This crude product was used as such for the next step.

Preparation Method 19 45 4p-Acetylglycolylthio-3- (1-nitrobenzyloxycarbonyloxyethyl) -1 - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidine-2-one (Scheme ZZ).

0.400 g of 4p-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl) -1-chloromethyl) -azetidin-2-one was dissolved in 20 ml of a 1: 1 mixture of tetrahydrofuran and dioxane .

2 equivalents of triphenylphosphine 1.1 equivalent of pyridine were added and this mixture was stirred at 50 ° C overnight. The title compound was purified by column chromatography over silica gel eluting with 7: 3 dichloromethane / ethyl acetate. 0.280 g of the formed phosphorane was thus obtained.

Preparation Method 20 (5R) -Acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate (Scheme 55 AB).

0.210 g of 4p-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl-azetidin-2-one) was dissolved in 7 ml of toluene and this solution was dissolved for 2 hours

Claims (3)

192 265 6 cooked. Purification via a short column chromatography eluting with 95: 5 dichloromethane-ethyl acetate gave 50 mg of the title compound. Vborbee / d I 5 (5R) -Acetoxymethyl-6- (1-hydroxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate (scheme AC). 0.060 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-caiboxylate was poured into a mixture of water, ethanol and K2HPO4 and hydrogenated with 10% Pd / C. Rapid cleaning by silica gel column chromatography gave 0.015 g of the title fiber bond. Example II (5R) -6- (1-Hydroxyethyl) -2- (1-methyltetrazol-5-ylthiomethyl) -2-penem-3-carboxylic acid (FCE 22055). Methyl-6- [1- (p-nitrobenzyloxycarbonyloxy) ethyl] -4-oxo-3-penicillanate (Preparation Example 4) was sequentially reacted with propargyla alcohol (V), isomerized (W) according to Schemes V through EE and AC , reacted with phosphorus tribromide (X), sodium 1-methyl-5-tetrazole thiolate (Y), ozone (Z), silica gel / ethyl acetate / methanol (AA), acetoxymethyl glyoxylate (BB), thionyl chloride (CC) and triphenylphosphine ( DD), ________heated (EE). and treated with hydrogen at Pd / C (AC), where after column chromatographic purification (5R) -acetoxymethyl-6- (1-hydroxyethyl) -2- (1-methyltetrazol-5-ylthiomethyl) -2-penem-3-carboxylate obtained. This was then converted into the title compound. Alternatively, the title compound was prepared by hydrogenolysis of the p-nitrobenzyl ester (Scheme FF), which was prepared according to Scheme (BB), but with p-nitrobenzyl glyoxylate instead of acetoxymethyl glyoxylate. Analogously, using the sodium salt of resp. 5-methyl-2-mercapto-1,3,4-thiadiazole, 5-mercapto-1,2,3-triazole and pyrazinethiol instead of sodium 1-methyl-5-tetrazole thiolate the active compounds (5R) -6- (1-hydroxyethyl) -2- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -2-penem-3-25 carboxylic acid, (5R) -6- (1-hydroxyethyl) -2- ( 1,2,3-Triazol-5-ylthiomethyl) -2-penem-3-carboxylic acid and (5R) -6- (1-hydroxyethyl) -2- (pyrazinylthiomethyl) -2-penem-3-carboxylic acid. 30 Penemic carboxylic acid compounds or pharmaceutically acceptable salts thereof, characterized in that the compounds are of formula 1, wherein the C5 atom has the R configuration and wherein R further comprises a hydrogen atom or an acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1- (ethoxycarbonyloxy) ethyl or C 1 -C 6 alkanoylaminomethyl group, and Z represents a carbamoyloxy, acetoxy, 5-methyl-1,3,4-thiadiazol-2-yl-thio, 35 1 -methyl-1 H -tetrazol-5-yl-thio, 1,2,3-triazol-5-yl-thio or pyrazinylthio group. Penemic carboxylic acid compounds according to claim 1, characterized in that R represents a hydrogen atom. Pharmaceutical preparation containing a penem compound as active substance in a pharmaceutically acceptable carrier, characterized in that the penem compound is a compound according to claim 1 or 2. Hereby 10 sheets drawing