NL8200217A - BICYCLIC COMPOUNDS, METHODS FOR PREPARING THE SAME, AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE BICYCLIC COMPOUNDS. - Google Patents

Description

* * 1 1 / N.0. 30,756 /%

Bicyclic compounds, methods of preparation thereof, as well as pharmaceutical preparations containing these bicyclic compounds.

The present invention relates to bicyclic compounds of the general formula 1, in which one of the substituents R 2 and R 2 is hydrogen and the other hydrogen or an unsubstituted or substituted alkyl group having 1 to k carbon atoms and X an al 5 or not substituted alkanoyloxy group of 1 to 3 carbon atoms, an unsubstituted or substituted cycloalkylthio group of 3 to 7 carbon atoms, alkenylthio group of 2 to 6 carbon atoms or heterocyclic thio group or a substituted alkylthio group of 1 to k carbon atoms or phenylthio esters thereof hydrolyzable , pharmaceutically compatible salts thereof, as well as hydrates of these compounds.

The invention further relates to methods of preparing the above-defined compounds, pharmaceutical preparations based on these compounds and their preparation, as well as the use of these compounds as a medicament, in particular for the treatment and prophylaxis of infectious diseases.

Alkyl radicals of 1 to 1 carbon atoms can be straight or branched. Substituted alkyl radicals of 1 to carbon atoms may contain the following substituents: fluorine, chlorine, bromine; A -S (0) -R residue with n = 0, 1, 2 and 2 '= alkyl with 1 to 3 carbon atoms; a -CO-R * radical with R '= hydroxy, alkoxy with 1 to 3 carbon atoms, alkyl with 1 to 3 carbon atoms, amino, alkyl amino with 1 to 3 carbon atoms or dialkylamino with 1 to 3 carbon atoms per alkyl radical; an amino radical -NR'RH, where R 'and RM 25 represent hydrogen or alkyl of 1 to 3 carbon atoms or an OR' radical with R '= hydrogen, methyl, SO 2, Ï ^ ΟΟΟΕ "(R" = alkyl with 1 to carbon atoms).

1 2

Examples of substituents R / R are: methyl, ethyl, isopropyl, 3-chloropropyl, mesylmethyl, 2- (methoxycarbonyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-1-methyl-ethyl, 3 -fflethoxypropyl, 1-sulfoxyethyl, 1-hydroxy-2,2,2-trifluoro-ethyl, 1- (pivaloyloxy-methoxy) -ethyl, 1-aminoethyl.

As substituents in the remainder X the following are eligible: 35 Alkanoyloxy groups of 1 to 3 carbon atoms can be substituted with 8200217 2 ν / / hydroxy, alkoxy of 1 to 3 carbon atoms, phenyl or alkylthio with 1 to 3 carbon atoms *

Substituted alkylthio radicals having 1 to if carbon atoms may contain one or more substituents R, H being the following -3:

Phenyl, which in turn can be substituted with one or more fluorine, chlorine or bromine atoms, alkyl of 1 to 3 carbon atoms, alkylthio of 1 to k carbon atoms, alkanoyl of 1 to 3 carbon atoms, carboxyl or alkoxycarbonyl of 1 to 3 carbon - 10 atoms: or with a group - (CH) -NRR 'or - (CEL) MCR = NR' or 1 2 n 2 n - (CH.) -N = CR-N (R ') ,, where n 0 , 1, 2 or 3 and R and R '2 n 2 are hydrogen or alkyl of 1 to 3 carbon atoms * fluorine, bromine; an oxime or oxime ether residue = N-OR '(R * = H or alkyl of 1 to 15 carbon atoms) in the syn or anti form; a 3 to 7 atomic monocyclic, saturated, unsaturated or aromatic heterocyclic radical having 1 to if hetero atoms (N, 0, S; which may be substituted with one or more fluorine, chlorine or bromine atoms, alkyl groups having 1 to 3 carbon atoms, 20 alkylthio groups of 1 to if carbon atoms, alkanoyl groups of 1 to 3 carbon atoms, carboxyl groups or alkoxycarbonyl groups of 1 to 3 carbon atoms; or a group - ('CH 1) -NRR' or

w XX

- (CH,) -NH-CR = NR 'or - (CH,) -N = CR-N (R »), where n = 0, 1, 2 or 3 can be 2 n 2 n 2 and R and R H or alkyl of 1 to 3 carbon atoms and also with oxo groups); a cycloalkyl radical of 3 to 6 carbon atoms; a -S (0) -R 'moiety (with n = 1 or 2 and R * alkyl having 1 to 3 n carbon atoms); a -C0R 'radical [with Rf = alkyl of 1 to 3 carbon atoms, phenyl, phenoxy, benzyloxy, cycloalkyl of 3 to 6 carbon atoms or a 3 to 7 atomic heterocyclic ring with 1 to if heteroatoms (N, 0, S ), which may be substituted in the aforementioned manner.

Substituted phenylthio radicals may be substituted with one or more fluorine, chlorine or bromine atoms, one of the groups - (CH,) -NRR ', - (CH,) -NR-CR' = NRM and - (CH,) - N = CR-NR1Rn (with n = 2 n 2 n 2 n 0, 1, 2, 3 and H, R 'and RH H or alkyl with 1 to 3 carbon atoms, alkanoyl with 1 to 3 carbon atoms) or also with alkyl groups with 1 to 3 carbon atoms, alkanoylamino groups with 1 to 3 carbon ifO atoms, hydroxyl groups, alkoxy groups with 1 to if carbon atoms 8200217 3 '* κ or acyloxy groups.

Cycloalkylthio radicals of 3 to 7 carbon atoms may be substituted with one of the groups - (CH ^^ - NRR ', - (0Η2) η-ΝΒ-0Ε, = ΝΗΗ and - (CHj -N = CR-NR * R “(with n = 0, 1, 2, 3 and R, R 'and R "H or alkyl groups with 1 to 3 carbon atoms (alkanoyl groups with 1 to 3 carbon atoms) or with oxo groups, hydroxyl groups" alkyl groups with 1 to b carbon atoms, alkoxy groups with 1 to 4 carbon atoms, carboxyl groups or alkoxycarbonyl groups or with acyl residues of an aliphatic or aromatic carboxylic acid with 1 to 7 carbon atoms.

Alkenylthio radicals of 2 to 6 carbon atoms may contain one or two double bonds and may be substituted with one of the groups “(CJH ^ -NRR», - (CH ^ -NR-CR ^ NR ”and - (CH2VN = GE” NR, 3R "(with n = 0, 1, 2, 3 and R, R 'and B" or alkyl with 1 to 3 carbon atoms, alkanoyl with 1 to 3 carbon atoms) or also with alkyl 13 with 1 to 3 carbon atoms, phenyl, a 3 to 7 atoms saturated, unsaturated or aromatic heterocyclic ring with 1 to b heteroatoms (N, 0, S), cyano, carboxy, alkoxycarbonyl having 1 to 4 carbon atoms, aminocarbonyl or acylamino.

Heterocyclic thio radicals are preferably 4 to 7 atoms containing and monocyclic and may be saturated, unsaturated or aromatic. Preferably they contain 1 to b heteroatoms (N, O, S). They can be singly or multiply substituted with fluoro, chloro or bromo, an oxo or imino group or an alkyl group with 1 to 5 carbon atoms, alkylthio group with 1 to 3 carbon atoms, hydroxyl group, cyano group, N-oxido group, trifluoromethyl group, alkoxy group with 1 to 4 carbon atoms, alkanoyloxy group with 1 to b carbon atoms, phenoxy group, alkanoyl group with 1 to b carbon atoms, phenoxycarbonyl group, pivaloyloxymethoxy-carbonyl group, carbaraoyl group, alkylcarbamoyl group with 1 to 3 carbon atoms in the alkyl group or dialkylcarbamoyl group with 1 to 3 carbon atoms the alkyl group or with - (CH ^^ - NNR *, - (CHJ -NR-GR '= NR "or - (CH.) -N = CR-NR, RM with n = 0, 1, 2, 3 and R , 2 n 2 n R 'ea R "= H, alkyl with 1 to 3 carbon atoms, alkanoyl with 1 to 3 carbon atoms: or with - (CH_) COR' with n = 0, 1, 2 or 3 and B '= 2 zx 35 hydroxy, alkoxy with 1 to 3 carbon atoms, amino or in which m = 2, 3 or 4; or also with - (CH_) OH with n = 0, 1, 2 or 3C * 1

Examples of radicals X are: 2- (acetylamino) -vinylthio, (1-methyl-1H-tetrazol-5-yl) -thio, (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo -as-triazin-3-yl) -thio, (2,5-dihydro-6-hydroxy-2-methyl-bO-5-oxo-as-triazin-3-yl) -thio, (1-ethyl-1, 2-dihydro-2-oxo-4-pyrimidi- 8200217

t I

b / nyl) -thio »(5-methyl-1» 3'-il-thiadiazol-2-yl) -thiotacetoxy.

Easily hydrolysable esters of the compounds of the formula I are understood to be those esters which are cleaved in particular under physiological conditions.

Examples of such esters are the alkanoyloxyalkyl esters with a small number of carbon atoms in the alkyl group, for example the acetoxyraethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyl oxyethyl ester; the alkoxycarbonyloxyalkyl esters with a small number of carbon atoms in the alkyl groups, e.g. the alkoxymethyl esters with a small number of carbon atoms in the alkyl group, for example the methoxymethyl ester and the alkanoylamidomethyl esters with a small number of carbon atoms in the alkyl group, for example the acetamidomethyl ester; the benzyl and cyanomethyl ester, as well as the (2-oxo-1,3- <3ioxol-V-yl) methyl ester.

Examples of salts of the compounds of formula 1 are alkali metal salts, such as the sodium and potassium salt; the ammonium salt; alkaline earth metal salts, such as the calcium salt; salts with organic bases such as salts with amines, for example salts with N-ethylpiperidine, procaxne or N, N * -dibenzylethylene diamine, as well as salts with amino acids, such as salts with arginine or lysine. The salts can be mono, di or tri salts. In addition to the carboxyl group in the 2-position, the salt formation can also take place on a salt group suitable for a substituent.

The compounds of the formula I can further form addition salts with organic or inorganic acids. Examples of such salts are hydrogen halides, eg hydrogen chloride, hydrogen bromide, hydrogen iodide, as well as other salts of inorganic acids, eg sulfates, nitrates, phosphates and the like, alkyl and monoarylsulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like and salts with other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula 1 (including the salts and esters) can finally be hydrated. The hydration can take place during the preparation process or occur gradually as a result of hygroscopic properties of a first anhydrous product.

ifO The compounds of the invention can be prepared, 8200217 5 / * 12

by using a compound of formula 2, wherein R, R and X

as defined in claim 1, R "represents an easily cleavable moiety and R" E "7 and E alkyl of 1 to 6 carbon atoms, phenyl or p-methoxyphenyl, cyclizes, optionally in a substituent protective groups and, if desired, esterifies the ester obtained by converting the residue 3 B into the free acids or converting its salts, and optionally converting a product obtained into a hydrate.

The cyclization of a compound 2 can be carried out in a manner known per se, preferably in an inert organic solvent, for example ethyl acetate, benzene, toluene, xylene, dioxane, at temperatures between about 50 ° C and 150 ° G.

3

By cleaving off the residue R from the ester group in a manner known per se, the corresponding free acids resp. Its salts of formula 1 are obtained. By an easily cleavable residue B B is meant groups which permit an ester cleavage under cautious conditions, in particular by reduction (for example hydrogenolysis) or by hydrolysis (for example enzymatic). Examples of suitable R groups are benzyl (where the phenyl ring may be substituted with halogen, nitro, alkoxy or acyloxy), preferably o- and p-nitrobenzyl or p-methoxybenzyl, benzhydryl, 2,2,2-trichloroethyl, 2 bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, acetonyl or allyl. Residues R 2 also include residues of esters which can be cleaved under physiological conditions, as have already been mentioned above as readily hydrolysable esters.

The conversion of free acids of the formula I or their salts into readily hydrolyzable esters can be carried out in a manner known per se, for example, by reaction with a reactive esterification reagent, such as, for example, a compound X-CH 2 -O-CO-R or a compound of formula 19 or 20, wherein X may be bromine, iodine or another cleavable group, E is a straight or branched chain alkyl radical containing 1 to k carbon atoms and R 'is hydrogen or a conventional substituent.

35 Esterification takes place efficiently via the free acid.

Of course, a substituent of a compound 1 can also be modified in the context of the indicated definitions by means of well-known reactions.

The compounds of the formula I are generally not isolated as K0 free acids, but are obtained directly as their salts and the hydrates of these salts during the preparation and purification process. In addition, salt formation can also take place on a substituent, if appropriate, which is suitable for salt formation, for example a hydroxyl or amino group. It is further possible that a basic group forms in a substituent, for example an araino or an amidino group of an internal salt with an acidic group, for example the carboxyl group in the 2-position. Salinization can take place by techniques known per se at temperatures of preferably 0 to 25 ° C in a solvent such as water, ethanol, methanol, acetone, ethyl acetate or mixtures thereof, whereby the products can be purified by crystallization or chromatography.

Hydrates are usually obtained automatically during the manufacturing process or due to hygroscopic properties of a first anhydrous product. For a specific preparation of a hydrate, a completely or partly anhydrous product can be exposed to a humid atmosphere, for example at about + 10 ° C to + if 0 ° C.

The compounds of the invention are generally mixed with their optical antipodes, ie when 52 / 5S mixtures are obtained. If this is a 1: 1 mixture, the stereochemistry of the products is indicated by the designation rac- (5KS, etc.), for example pivaloyloxymethyl-rac- (5fiS, éRS) -6 - [(BS) -1- hydroxye thy1] -3 - [[(1-me thy1-1H-1e trazol-5-y1) -thio] -25 methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2 -carboxylate. If, on the other hand, exact 1: 1 mixtures are not obtained, as can be the case with products from enantioselective reactions, for example from enzymatic reactions, their stereochemistry is characterized by the designation (5B, etc. and 5S, etc.), for example sodium - (5H, 6S and 5,6R) -6-hydroxymethyl-3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [ 3.2.0] hept-2-an-2-carboxylate «

However, the present invention includes not only these mixtures, but in particular also the pure 5S forms. Cleavage of the 5R / 5-S mixtures into the pure 52 resp. 5S molding can take place by any of the conventional methods, conveniently at a pre-stage. For example, a diastereomeric salt pair of a racemic compound 11 or a pair of diastereomeric derivatives of a compound 8-1 can be separated. The racemic split can also be performed ifO at the steps of compounds 11, 10, 8 or 7 8200217 t * 7 '.

A special subset of the compounds of the invention are compounds of formula Ia, wherein X means the same as above, as well as their readily hydrolyzable esters, pharmaceutically compatible salts thereof, and hydrates of these compounds. Very particularly preferred are compounds in which the configuration at the centers 5-6 and in the substituents of the 6-position corresponds to that of the natural thienamycin, for example sodium- (5R »6S) -6 - [( R) -1-hydroxy-10 ethyl J-3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7 "Oxo-1-aza-bicyclo [3 · 2 · 0] hept-2-an-2-carboxylate.

The starting compounds of formula II can be obtained according to the reaction scheme of fig.

Reduction of the 3 »3-ethylenedioxybutyric acid ethyl ester (1½) with 15 diisobutylaluminum hydride in hexane / tetrahydrofuran at -80 ° C to -60 ° C gives 3,3-ethylenedioxybutyraldehyde (13)» which is converted into, for example, phosphonacetic acid triethyl ester mixture of dichloromethane and 28% sodium hydroxide in the presence of benzyl triethyl ammonium chloride in an E / Z mixture of the 5-20 ethylenedioxy-2-hexenoic acid ethyl ester (12). The 3-amino-5,5-ethylenedioxy-caproic acid ethyl ester (11) can be obtained by adding ammonia under normal or elevated pressure (autoclave) to the unsaturated ester 12, the E and Z isomers being the same be suitable. The reaction is preferably carried out in ammonia-saturated alcohol at a temperature between 20 ° C and 100 ° C. Ring closure of 11 to 1- (2,2-ethylenedioxypropyl) -2-azetidinone (10) can be done in a manner known per se, for example by reaction with trimethylchlorosilane in the presence of triethylamine and subsequent treatment with 1 equivalent of ethyl magnesium bromide. to have.

1 2

The introduction of a substituent R or R in the 3-position of the azetidinone X to form a compound 8 can be done in a manner known per se by reaction of the intermediate dilithium salt 9 (from 10 with 2 equivalents of an alkyl lithium-35 compound , for example, butyl lithium, in tetrahydrofuran at -20 ° C to + 20 ° C) with a corresponding electrophilic reagent, expediently under a protective gas, at a temperature between -100 ° C and + 50 ° C. Another method for introducing the 1 2 substituents R and R at the 3-position of the azetidinone ring of a kO compound 10 consists in the β-lactam hydrogen first passing through an 8200217 δ φ '' trialkylsilyl group, for example tert.bu tyldimethylsilyl group (by reacting a compound 10 with tert-butyldimethylchlorosilane in dimethylformamide in the presence of triethylamine) and by reacting the silyl compound 10-1 with 5 1 equivalent of a strong base, e.g. lithium diisopropylamide in tetrahydrofuran at low temperature (-7 ° 0), intermediate lithium salt 9-1 formed with an electrophilic reagent in a manner analogous to reaction 9 -6. The resulting compound 8-1 can then either be broomed directly to a compound 7 or first by cleavage of the silyl group (for example, by means of tetrabutylammonium fluoride in tetrahydrofuran) into the 4- (2,2-ethylenedioxypropyl) -2-azetidinone (8) are converted. During the described introduction of a substituent R or 2 R, cis / trans mixtures (with respect to the 4-ethylenedioxypropyl residue) are usually obtained, which can optionally be separated by conventional separation methods, for example silica gel chromatography, fractional crystallization or distillation. turn into.

Another synthesis of the compounds 7 is illustrated in Example 20 XXII: (see Figure 2).

It may be expedient to keep functional groups introduced with the sub-1 2 stituents R or R in protected form during further synthesis. Such functional groups may, in particular, be the hydroxyl, the amino or the carboxyl function.

The protecting groups known for these functions can be used as far as their removal from the appropriate site of synthesis is possible. The functions masked by protective groups can already be contained in the dilithium salt 9 resp. the lithium salts 9-1 or 17 converted electrophilic reagent are present.

On the other hand, it may be expedient to subsequently protect functions which arise first when the substituents R and R are introduced, for example a hydroxyl function.

Bromination of a compound 8 with bromine in an alkanol R'OH as solvent gives a bromo-ketal of the formula 7. 35 In this conversion (preferably in methanol or ethanol at a temperature between 10 ° G and 60 ° C) a omketalization takes place: the ethylenedioxy group is converted into a dialkoxy group. As already mentioned above, a silyl compound of the formula 8-1 can also be used in the bromination reaction, because the silyl group is split off under the reaction conditions.

82 0 0 2 1 7 ï i <* 9

The esters of the general formula 6 can be prepared from the azetidinones of the formula 7 by generally known methods, for example, by reaction with glyoxyl esters of the general formula OHC-COOR or its hemiacetals. In this case, the two reaction partners are expediently heated to boiling temperature in an inert solvent, such as benzene or toluene, and the formed low molecular weight reaction products (water and alcohol) are azeotropically distilled from the reaction solution.

It; however, it is also possible to first convert compounds of the formula 7 with 10 glyoxylic acid monohydrate to an acid corresponding to ester 6 (R 3 = H) and then esterify it with a suitable alkylating agent in the presence of a base. The reaction with glyoxylic acid monohydrate takes place, for example, in dimethylformamide at room temperature in the presence of a water binding agent, for example a molecular sieve # By successive addition of a base, for example potassium carbonate or triethylamine, and an alkylating agent, such as pivalic acid iodomethyl ester, the carboxylate group (R ^ = e.g. K or triethylammonium) is then esterified in situ.

An ester 5 is obtained by reacting an ester 6 with thionyl chloride in an inert organic solvent, such as tetrahydrofuran, in the presence of a base, for example pyridine or 2,6-lutidine, at temperatures between -30 ° C and + 20 ° C. , which L 5 5 with a trisubstituted phosphine PR RR, most advantageously with triphenylphosphine, in a manner known per se, i.e. in an aprotic solvent (e.g. dioxane, tetrahydrofuran, dimethylformamide), at a temperature between 0 and 60 ° C is converted into the 11 5 6 R, R, R substituted phosphoran 4 # From this ketal, the free ketone of the formula 3 is converted by acid hydrolysis under the usual reaction conditions, for example, with aqueous sulfuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide. an organic solvent, such as acetone, dioxane, ethanol. By maintaining low temperatures (-10 ° C to 0 ° C), undesired side reactions, such as the hydrolysis of the phosphoran, can be avoided.

It is also possible to split the ketal function under anhydrous conditions by transferring the protecting group to another ketone, for example acetone, in the presence of an acidic catalyst.

* 1-0 Finally, the bromo ketones of the formula III are converted to form compounds of the compounds 2 obtained with the group 10 to form compounds 8200217. containing a nucleophilic oxygen or sulfur atom. The reaction can take place in an inert organic solvent, for example dichloromethane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile or ethanol at temperatures from -8 ° C to the reflux temperature of the reaction mixture, preferably between -20 ° C and +40 ° C. The hydrogen- N released during the reaction.

bromide is conveniently bound by a weak, non-nucleophilic organic base, such as a trialkylamine or amidine, or an inorganic base (sodium or potassium carbonate).

The compounds of the invention are active against gram-positive and gram-negative bacteria, for example against Staphylococci, Streptococci, Salmonelles and Escherichia coli and act as β-lactamase inhibitors.

Anti-bacterial activity in vitro

The following table summarizes the minimum inhibitory concentrations (ΜΞΚ) of some representative compounds of formula 1 against a range of pathogen radiators.

20 8200217 * 11 3 t _____MHK (uq / ml) _,

Connection of example

| Organism__III VII__IXXIX XXIII

E. coli 1346__5 12.5 0.05 0.06 0.2 11 25 922 __> 50 __ = __ 0.25 y 11 TEM 11 __> 100__0.05 0.25 0.2 i "1527 E1__3 __-__ 0J .__ 0.25 0, 2! Klebs.pneumoniae 4181__r__0> 05__0,12 0,1

Prot. vulgaris 10281 __ = __ z__0 / 1 0.12 0.4 I Prot. inirabilis 21171 __-__ ~ _ 0 / 2__0.25 0.8

Prot. mirabilis 29H __- 0.4 ........ 1__0.8

Stripes. faecalis 6 __-> 100__1,6__2,1 24

Stripes. pyocrenes 015__0,3 -6 __-__ z__ ..

Staph, aureus 6538__1.2 -6__0.025 0.12. 0.4 "_8871 __> 40__i_6__0.05__0.12 0.8

Serratia marcescens 803 / 151_> 40> 100 __ <L_8__8.5 1.5

Serratia marcescens 69438 __> 100__1.6 17__3

Klebs. aeroqenes 1082E1 -> 100__0.4 0.5 _ _6_

Enterobacter cloacae 9081 _; __—> 100__1.6 17__12_

Enterobacter cloacae 130471__1100__3,2__34__3

Salmonella typh. BA __-__ 25__0.05__0.06 0.2

Pseudomonas aer. 1559E1__Z__25__134__124 _ »_ BA1 __> 100 25> 34> 24

Acinetobacter anitr. 51-156 _____ Z_Z_1.6 8,510,8_ 8200217 β-lactamase producing organism.

The compound of Example VII was tested for DST agar +? 5% blood, the rest for DST agar (Diagnostic Sensitivity Test Agar) alone.

1 (12

Antibacterial activity in vivo

The compounds of Examples VI, VII and IX were tested in vivo for their antibacterial activity (ED ^ q) against mouse systemic infections. The preparations were applied twice (1 and 3 hours after infection).

ED (mg / kg)

Compound of Example Infection VI VII IX

Escherichia coli 13 ^ 6 δ, 3 sc> 25 sc 2 * 1 sc

Streptococcus pyogenes 10 sc 12.5 sc <3 sc 10 β15 50 p.o.> 12 p.o.

Proteus mirabilis 2117> 25 sc - 17 sc

Serratia marcescens 69 ^ 38> 25 sc g-Dactamase inhibition The β-lactamase inhibition (IC, _0; nitrocefine as substrate) of the compound of Example IX against various β-lactamases is as follows:

Enzyme I ° 50 ^ / Ug / ml) E. coli 102½ 0.191 20 K. pneumoniae NCTC if18 0.063 P. vulgaris 1028 0.0005 E. coli BTEM 0.035

The compounds of the invention can be used for the prophylaxis and therapy of infectious diseases. For adults, a daily dose of from about 0.05 S to about k g, especially from about 0.1 g to about 2 g, is suitable. Parenteral administration is particularly preferred.

The products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations, which these or in particular their salts are mixed with a pharmaceutically, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, for example as 8200217 I * 13 tablets »dragees» suppositories »capsules or in liquid form» for example as solutions »suspensions or emulsions. They may be sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting or emulsifying agents, salts for altering osmotic pressure, anesthetics or buffers · They may also contain other therapeutically valuable substances · The compounds of the formula I and their salts or hydrates preferably for parenteral administration and are preferably provided for this purpose as lyophilisates or dry powders for dilution with conventional agents such as water or isotonic saline solution · The readily hydrolyzable esters of the compounds of formula 1 and their salts or hydrates are also eligible for enteral administration.

The compositions may contain the compounds of the invention in amounts of about 25-1000 mg, preferably 50-500 mg, per individual dosage form.

Example I

A solution of 585 mg of pivaloyloxymethyl-rac-2- [3 - [(1-20 ethyl-1,2-dihydro-2-oxo-if-pyrimidinyl) -thio] -acetonyl] -if-oxo-a- (triphenylphosphoranylides -1-azetidine acetate in 50 ml of toluene was refluxed under an atmosphere of argon for 1 hour. The transparent solution was cooled, diluted with little ethyl acetate and freed from the solvent under reduced pressure. The residue was chromatographed on silica gel with ethyl acetate as eluent. The fractions containing the product were concentrated and the residual oil was crystallized from ethyl acetate / hexane. 55 mg of pivaloyloxymethyl-rac-3 - [[(1-30-ethyl-1,2-dihydro-2-oxo-if-pyrimidinyl) -thio] -methyl] -7-oxo-1-aza-bicyclo [3.2 were obtained] .0] hept-2-an-2-carboxylate as yellow crystals, m.p. 1VI-H 3 ° C IE (CHCl 3: 1785, 1750, 1736, 1659, 1622, 161 cm -1).

The starting material was prepared as follows: 35 (a) To a solution of 3 ^ 8, ½ g of 3,3-ethylidenedioxybutyric acid ethyl ester in 2 liters of hexane and 0.2 liters of tetrahydrofuran was charged at -70 for 90 minutes ° C to -7 ° C 1.79 liters of a 1-12 molar solution of diisobutylaluminum hydride in hexane are added. The transparent reaction solution was kept at -75 ° C for 2 hours more, then 100 ml of methanol 8200217, r 14 was added over 2 minutes. The cooling bath was then removed and a solution of 100 ml glacial acetic acid in 100 ml hexane was added over 8 minutes. The reaction mixture was now heated to -20 ° C for 10 minutes and then 200 ml of saturated ammonium chloride solution 5 was added over 5 minutes. The temperature of the reaction solution was allowed to reach 0 ° C in 10 minutes and stirring was continued at 0-3 ° C for 15 minutes. Precipitation was now effected and the product filtered off was washed with 600 ml of dichloromethane. The filtrate was washed with 300 ml of saturated sodium chloride solution * again yielding a precipitate. The mixture was suctioned again, the filtrate was separated and the organic phase was washed with a further 300 ml of saturated sodium chloride solution. The suction residue was still extracted with a total of 1.8 liters of dichloromethane and the extracts were washed with the sodium chloride solutions. The organic phases were dried over sodium sulfate, the solvent was removed under reduced pressure and the residual oil was generated under a reduced pressure with the water jet pump distilled. The fraction boiling between 40 and 95 ° C was then fractionated on an 80 cm Vigreux column. 184 g of 3'-3-ethylenedioxybutyraldehyde, bp 11 70-73 ° C, were obtained.

NMR (CDCl 3) 1 J + 1.43 (f * - 3H); 2.73 (d, J = 3Hz, 2H); 4.00 (s, 4H); 9.75 (t * j = 3 Hz, 1H) ppm.

(b) To a mixture of 300 ml of 28% aqueous sodium hydroxide and 600 ml of dichloromethane pre-cooled to 0 ° C, a solution of 130.1 g of 3,3-ethylenedioxybutyraldehyde, 224, was added with vigorous stirring over 25 minutes. 2 g of phosphonacetic acid triethyl ester and 7.4 g of benzyl triethyl ammonium chloride in 540 ml of dichloromethane, the temperature rising to 15 ° C. It was allowed to warm to 20 ° C for 10 minutes and stirred at this temperature for an additional 30 minutes. Thereafter, it was diluted with 400 ml of dichloromethane and 400 ml of water and the phases were separated in the separating funnel. The organic phase was neutral washed twice more with 400 ml of water each time and the water phases were extracted with 300 ml of dichloromethane. The organic phases were dried over sodium sulfate, completely concentrated and the residual oil was fractionated on a 50 cm Vigreux column. After a run, 179 g of 5,5-ethylenedioxy-2-hexenoic acid ethyl ester with b.p. £ 70-76 ° C were obtained as E / Z mixture (ratio about 6: 1).

8200217 15 NMR (CDOl ^): signals of the E isomer: é 1.28 (t, J = 7 Hz, 3H) j 1.33 (s, 3H) j 2.53 (d, J = 7.5 Hz, 2H) j 3.93 (s, itH) 5 4.16 (q, j = 7Hz, 2H); 5.85 (d, J = 16Hz, 1H); 6.92 (dxt, J = 16 and 7.5 Hz, 1H) ppm 3 signals of the Z isomer: e.g. <ζ 3.03 (d, J = 6.5 Hz, 2H); 5.83 (d, J = 11.5 Hz, 1H); 6.30 (dxt, J = 11.5 and 6.5 Hz, 1H) ppm.

(c) With a solution of 200.2 g of 5,5-ethylenedioxy-2-hexenoic acid ethyl ester (approx. 6: 1 E / Z mixture) in 2 liters of abs. ethanol, approximately 250 g of ammonia gas were first added in a stirring autoclave. and then the pressure was brought to 2000 kPa with nitrogen. The reaction medium was heated to 70 ° C for 40 hours. The cooled reaction solution was freed from solvent, 200 ml of ether were added and again fully concentrated. The residual oil was taken up in 275 ml ether and stored at 0 ° C for 2 hours. Crystallized rac-3-amino-5,5-ethylenedioxy-caproic amide was separated by filtration. The concentrated filtrate was taken up in 600 ml ether / hexane (1: 2 by volume) and the solution was extracted four times with 200 ral water. The individual extracts were further washed with two 300 ml ether / hexane (1: 2 by volume). The combined water phases were saturated with sodium chloride and extracted with a total of 750 ml of dichloromethane. The dichloromethane extract was dried over sodium sulfate and completely concentrated. Distillation of the residual oil in a highly reduced pressure gave 131 g of pure rac-3-ami-5,5-ethylenedioxy-caproic acid ethyl ester, boiling point 95-100 ° C.

MR (CDCl 3): 1,2 1.28 Ct, J = 7 Hz, 3H) 1.38 (s, 3H); 1.74 (broad s, 2H); 1.76 (d, J = 6Hz, 2H); 2.05-2.72 (m, AB part 30 of the ABX system, 2H); 3.21-3.72 (m, 1H); 3.98 (s. 4H); 4.13 (q, J = 7Hz, 2H) ppm.

(d) To a solution of 108.6 g of rac-3-amino-5,5-ethylenedioxy-caproic acid ethyl ester in 330 ml of ether, 54.3 g of trimethylchlorosilane were added dropwise with stirring at 0-5 ° C over 15 minutes. 35 and immediately thereafter 50.6 g of triethylamine, resulting in a thick precipitate. The reaction mixture was allowed to stir at 15 C under stirring for 30 minutes and then was allowed to stand at room temperature for 24 hours. Thereafter suction was effected through a filter under exclusion of moisture and the reaction vessel and product 40 were washed with a total of 150 ml of ether. To the filtrate 8200217 16, 290 ml of a 1.92 molar ethylmagnesium bromide / ether solution was added with stirring in 40 minutes at 0-5 ° C, thereby producing gas. The heterogeneous reaction mixture was stirred at room temperature for 16 hours. Then it was cooled to 50 ° C and 170 ml of a semi-saturated ammonium chloride solution were added dropwise at a temperature of 0 - 10 ° C, resulting in a thick precipitate. By adding about 180 ml of 3 N hydrochloric acid, the pH of the reaction mixture was lowered to about 7, with most of the precipitate dissolving. The water phase was separated and the organic phase was extracted with 200 ml of water twice. The water phases were combined, saturated with sodium chloride at 0 ° C and extracted four times with 500 ml of dichloromethane each time. The dichloromethane extracts were dried over sodium sulfate and completely concentrated. For the separation of polar by-products, the residual oil was filtered through 200 g of silica gel, eluting with ethyl acetate. Crystallization of the solvent-free eluate from ether / hexane gave 49.6 g of pure rac-4- (2,2-ethylene-dioxypropyl) -2-azetidinone with m.p. 43 - 45 ° C · 20 IR (C01O-): 1756 cm -1.

5 max (e) To a solution of 3.42 g of rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone in 36 ml of methanol was added 4 ml of a 1 molar solution of bromine in methanol at room temperature. The reaction solution was heated at 50 ° C for 3 minutes, decolorization occurred. Now an additional 16 ml of a 1 molar solution of bromine in methanol was added dropwise over 8 minutes and the reaction solution was simultaneously cooled to 33 ° C. Stirring was continued at this temperature for 24 hours and the light yellow reaction solution was then poured onto a mixture of 30 ml of saturated sodium carbonate solution, 10 ml of 0.1 N sodium thiosulfate solution and ice. It was extracted with a total of 200 ml of dichloromethane. The organic phases were washed with sodium chloride solution, dried over sodium sulfate and completely concentrated under reduced pressure. The residual oil was chromatographed on silica gel with ethyl 35 acetate / hexane (2: 1 by volume) as the eluent. The product-containing fractions were concentrated and the residue was crystallized from ethyl acetate / hexane. 2.03 g of rac-4- (3-bromo-2,2-dimethoxy-propyl) -2-azetidinone were obtained with m.p. 94-95 ° C.

40 (f) To a solution of 6.30 g of rac-4- (3-bromo-2,2-diraethoxy-8200217 f '* 17 propyl) -2-azetidinone and 2.58 g of glyoxylic acid monohydrate in 17 ml of dimethylformamide 3 S molecular sieve was added and stirred at room temperature under argon for 5 hours.

2.07 g of solid potassium carbonate was then added and the mixture was stirred for an additional 30 minutes. The reaction mixture was cooled to 0 ° C, a solution of 6.8 g of iodomethyl pivalate in 6 ml of dimethylformamide was added and then stirred for an additional 1 hour at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate and J> Q ml ether and then washed three times with 50 ml water each time.

The organic phase was dried over sodium sulfate, completely concentrated and the residual oil was chromatographed on silica gel with ethyl acetate / hexane (2: 1 by volume). 3 * 3 g of pivaloyloxy-methyl-rac-2- (3-bromo-2,2-dimethoxy-propyl) -a-hydroxy-if-oxo-1-azeti-15-dinacetate (diastereomer mixture) were obtained as oil.

IE (CHC1,): \? 3528, 1760 cm "1 3 1 max

Rf: 0.37 / 0.1f3 (double spot; SiO4, ethyl acetate / hexane volume ratio 2: 1).

(g) To a solution of 3.2 g of pivaloyloxymethyl-rac-2- (3-bromo-20, 2,2-dimethoxypropyl) -a-hydroxy-if-oxo-1-azetidine acetate in 60 ml of tetrahydrofuran was added at -23 ° C 0.02 g of 2,6-lutidine.

Then, a solution of 1.0 µg of thionyl chloride in 11 ml of tetrahydrofuran was added dropwise over 1 minute, keeping the temperature below -20 ° C by cooling. The reaction mixture was stirred at -20 ° C for 20 minutes and then at room temperature for 20 minutes. The precipitate was then filtered off with suction and the extracted product was further washed with 0 ml of toluene. The filtrate was completely concentrated under reduced pressure, the residue was taken up in 20 rl of toluene and again fully concentrated.

. The resulting oil was dissolved in 22 ml of dimethylformamide, a solution of 2 g of triphenylphosphine in 7 ml of dimethylformamide was added at room temperature and the solution was stored for 1 hour. Thereafter, under a greatly reduced pressure at a temperature of 30 ° C, most of the solvent was removed, the residual oil was taken up in 70 ral dichloromethane and the solution was twice with 50 ml each of a phosphate buffer with a pH of 7 washed. The aqueous phases were further extracted with 100 ml of dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated completely. The residual oil was subjected to a chromatographic treatment with silica gel, eluting the excess triphenylphosphine first with dichloromethane and then the product with ethyl acetate. The fractions containing the product were concentrated. 3.2 g of pivaloyloxymethyl-rac-2- (3 * bromo-2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate were obtained as colorless amorphous material.

IR (CHClJ: V Y 1741, 1635 cm 1).

3 max (h) A solution of 3 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylide a) -1-azetidine acetate in 115 cooled at 4 ° C ml of acetone were added dropwise over 2 minutes to 38 ml of 4% hydrogen bromide pre-cooled at 4 ° C, whereby the temperature of the reaction mixture was brought to 20 ° G. The mixture was cooled to 4 ° C for 3 minutes and stirred at this temperature for an additional 10 minutes. The colorless solution was then poured onto 27.6 g of sodium carbonate, 90 ml of a 0.6 molar phosphate buffer solution containing 7 µl and 50 g of ice and the mixture was extracted three times with 100 ml of dichloromethane each time. The organic phases were washed with 80 ml of phosphate buffer solution with a pH of 7, dried over sodium sulfate and completely concentrated. The resulting oil was subjected to silica gel chromatography, eluting with ethyl acetate. The fractions containing product were concentrated and hexane was added. 2.03 g of pure pivaloyloxymethyl-rac-25 2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate were obtained as white crystals, m.p. 117-118 ° C.

IR (CHClJ: \? 1745? 164 cm) 1.

3 max (i) ifl / 7 mg of pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxO-α- (triphenylphosphoranylidene) -1-azetidine acetate and 114 mg of 1-ethyl-4-thiouracil in 20 ml of dichloromethane dissolved and the solution was completely concentrated at 50 ° C under reduced pressure for 10 minutes. The residue was dissolved in 20 ml of dichloromethane and the solution was concentrated under the same conditions for 10 minutes. This procedure was repeated a further 35, then the residual oil was taken up in 50 ml of dichloromethane and the yellow solution was washed successively with a dilute solution of sodium hydrogen carbonate and sodium chloride. The aqueous phases were post-extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and completely concentrated. Chromatography of the residual oil on silica gel with acetone / dichloromethane (1: 1 volume ratio) as eluent gave 427 mg of pivaloyloxy-methyl-rac-2- [3- [(1-thyl-1,2-dihydro-2- oxo-4-pyriminyl) -thio] -acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -1-azetidin acetate 5 as yellow oil, IE (C 1 -C 1 -): V 1741, 1660 cm -1.

3 max

Example II

275 g of Pivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) -4-oxo-α- (triphenylphosphoranylidene) -1-azetidine acetate were cyclized according to the method described in Example I. After chromatographic purification of the crude product, about 150 mg of pivaloyloxymethyl-rac-3- (acetoxyraethyl) -7-oxo-1-azabicyclo- [3.2.Ο] hept-2-en-2-carboxylate were obtained as a colorless oil.

IE (CHC13): Vmgx 1789, 1749 »1835 cm -1.

15 The starting product was prepared as follows:

To a solution of 383 mg of pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidinacetate in 9 ml of dimethylformamide, 54 mg of sodium acetate were added and the reaction was added for 16 hours at room temperature stirred. Thereafter, it was diluted with 50 ml of dichloromethane and the solution was washed successively with water and a saturated solution of sodium chloride. The aqueous phases were extracted with dichloromethane, the combined organic phases were dried over sodium sulfate and completely concentrated. The resulting oil was filtered through silica gel after removal of polar product, eluting with ethyl acetate. The pure fractions were completely concentrated and the residual product was crystallized from ethyl acetate / hexane. 314 mg of pivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) -4-oxo-a- (triphenyl-30-phosphoranylidene) -1-azetidine acetate were obtained with m.p. Mp 139-141 ° C.

IE (CHClJ: 9 1741 »1637 cm" 1.

p IflcQC

Example III

By adding 1 N sodium hydroxide to an aqueous sodium dihydrogen phosphate solution, a 0.05 molar phosphate buffer solution having a pH of 7 was prepared. To 40 ml of this solution were added successively 168 mg of sodium hydrogen carbonate and 0.3 ml of a suspension of pig liver esterase EC 3 * 1.1.1 (about 300 units) in a 3 2 molar ammonium sulfate solution. The transparent solution was heated to 36 ° G and stirred with a solution of 102 mg of pivaloyloxy-8200217 "20 * methyl-rac-3- (acetoxymethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate in 1.5 ml of dimethyl sulfoxide. The mixture was stirred at 36 ° C for 30 minutes, the reaction mixture was cooled and extracted four times with 40 ml of ether each time. The ether phases 3 were back-extracted with 10 ml of water, the combined water phases were filtered and the filtrate pi was adjusted to 7.06 with 0.1 N hydrochloric acid. This solution contained a mixture of about 28 mg sodium (5R and 5S) -3 * - (acetoxymethyl) -7-oxo-1-aza-bicyclo [3 * 2.o] -hept-2-en-carboxylaato Ί0 UV ( H ^ O): ^ max = 202 nm (erasable with hydroxylamine).

Example IV

p-Nitrobenzyl-rac-7-oxo-3 - [(phenethylthio) -methyl] -1-azabi-cyclo [3 * 2.o] hept-2-en-carboxylate was mixed in a dioxane / ethanol / water mixture at presence of sodium hydrogen carbonate with palladium-on-carbon (5 #) as a catalyst hydrogenated at normal pressure. The catalyst was filtered off, diluted with water and extracted with aliquots of ether. The aqueous phase contained sodium rac-7-oxo-3 - [(phenethylthio) -methyl] -1-azabicyclo- [3.2.0] hept-2-en-2-carboxylate.

The starting product was prepared as follows: (a) From a solution of 1.89 g of ac-4- (3-bromo-2,2-diraethoxy-propyl) -2-azetidinone and 2, if 6 g of glyoxylic acid p- nitrobenzyl ester ethyl hemiacetal in 50 ml toluene was continuously distilled 27 ml of the solvent in 2 minutes at normal pressure. The cooled reaction mixture was completely concentrated and the residual residue was subjected to chromatography with silica gel. A mixture of acetone / dichloromethane / hexane (volume ratio 1: 4: 1) eluted 3 25 g p-nitrobenzyl-raG-2- (3-bromo-2,2-dime thoxypropyl) -α-hydroxy-if-oxo -1-aze tidineaceate 30 as a diastereomer mixture.

IR (CHC1-): 3530, 1765, 1611, 1530, 1500 cm -1 max

Rf: approx. 0.2 (SiO4t acetone / CH2C3 / hexane in the volume ratio 1: 4: 1) (b) 3.25 g of p-nitrobenzyl-rac-2- (3-bromine) were subjected to -2,2-dime-33 thoxypropyl) -a-hydroxy-4-oxo-1-azetidin acetate (diastereomer mixture) under the reaction conditions described in Example I (g), then 2.48 after crystallization from dichloromethane / hexane g p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate as white crystals - 2 * 0 mp 189-190 ° C .

8200217 1 L 21 IR (CHCl 3): "1737, 1620" 1607 cm "1.

3 max (c) 2.77 g of p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate was added to the example In the method described in (h), 5 1 * 35 g of p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-oxo-α- (triphenylphosphoranylidene) -1-acetidine acetate were obtained as white crystals with m.p.

127-128 ° C.

IR (CHCl 3) t 17.5, 1636, 1609, 1579, 1525 cm -1.

3 max (d) To a solution of 1.32 g of p-nitrobenzyl-rac-2- (3-bromo-10-acetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 0.29 g of 2- phenyl ethyl mercaptan in 20 ml of dichloromethane arerd 0.21 g of triethylamine was added and stirred for 1 hour at room temperature. Diluted with dichloromethane and washed successively with a dilute sodium hydrogen carbonate solution and a saturated sodium chloride solution. The organic phase was dried over sodium sulfate, evaporated completely and the residue was subjected to silica gel chromatography. A mixture of ethyl acetate / hexane (1: 1 volume ratio) eluted 1.07 g of p-nitrobenzyl-rac-4-oxo-2- [3- (phenerthylthio) -20 acetonyl] -a- (triphenylphosphoranylide-one) -1- azetidine acetate.

(e) By applying the ring closure conditions described in Example 1 to p-nitrobenzyl-rac-4-oxo-2- [3- (phenyl-thio) -acetonyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate, one obtains after chromatographic purification p-nitrobenzyl-rac-7-oxo-3- [phenethylthio) -methyl] -1-azabicyclo [3, 2 · 0] hept-2-en-2-carboxylate.

Example V

Sodium rac-3 "[(cyclohexylthio) -methyl] -7-oxo-1-azabicyclo [3 * 2.0] hept-2-en-2-carboxylate was obtained by using p-nitro-30 benzyl-rac-3 [[(Cyclohexylthio) -methyl] -7-oxo-1-azabicyclo [3.2.o] hept-2-en-2-carboxylate subjected to the hydrogenation conditions described in Example IV.

The starting product was prepared as follows: (a) 1.32 g p-nitrobenzy1-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 0.24 g cyclohexyl Mercaptan were converted according to the procedure described in Example IV (d). After chromatographic purification, 0.96 g of p-nitrobenzyl-rac-2- [3- (cyclohexylthio) -acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate.

8200217 22 (b) Application of the ring-closure conditions described in Example 1 to p-nitrobenzyl-rac-2- [3- (cyclohexylthio) -acetonyl] -1-oxo-a- (triphenylphosphoranylidene) -1-azatidine acetate gave after chromatographic purification p-nitrobenzyl-rac-5 3 - [(cyclohexylthio) -methyl] -7-oxo-1-azabicyclo [3.2.o] hept-2-en-2-carboxylate.

Example VI

A solution of 267 mg of pivaloyloxymethyl-rac-trans-3-ethyl-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-if-pyrimidinj: 1) -thio] -acetonyl] -10 if-oxo-a- (triphenylphosphoranylidene) -1-azetidin acetate in 12 ml of toluene was heated at 100 ° C under an argon atmosphere for 3 hours. The reaction solution was completely concentrated and the residue was subjected to silica gel chromatography. A mixture of dichloromethane / acetone (volume ratio 6: 1) eluted the pure product, which could be crystallized from ethyl acetate with the addition of hexane. 122 mg of pivaloyloxymethyl-rac-6a-ethyl-3 - [[(1- ethyl 1,2-di-hydro-2-oxo-i-pyrimidinyl) -thio] -methyl] -7-oxo-5a-1-azabicyclo- [3, 2.0] hept-2-en- 2-carboxylate as white crystals with melting-20 point 105-106 ° C IE (CHCl3: V? 17Sif, 1756, 1735, 1661, 162 ^, 1610 cm -1 3 max ME (CDGl ^): ^ 1.01 (t, J = 7Hz, 3H); 1.2i * (s, 9H): 1.38 (t, J = 7Hz, 3H); 1.67-1.95 (m, 2H); 2.90- 3.22 (m, 3H); 3.79-3.96 (m, 3H); 37.72, 52 (AB system, 25 J = 1 * Hz, 2H); 5.38 / 5, 97 (AB system, J = 5Hz, 2H); 6.20 (d, J = 7Hz, 1H); 7.35 (d, J = 7Hz, 1H) ppm.

The starting product was prepared as follows: (a) To a solution of 0.513 g of rac-4 - [(2-raethyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone in 12 ml of tetrahydrofuran was added at 30 -20 ° C of a 1,635 molar butyl lithium / hexane solution was added and it was stored in an ice bath in an argon atmosphere for 90 minutes. · The brownish-yellow solution was cooled to -40 ° C, a solution of 360 mg of ethyl bromide in 0. 8 ml of tetrahydrofuran was added and then kept in the ice bath for 90 minutes. It was poured onto an ice-cold saturated sodium chloride solution and extracted with ethyl acetate. The extracts were washed again with a saturated sodium chloride solution, dried over sodium sulfate and completely concentrated. Chromatography of the residue on silica gel with ethyl acetate / ifO hexane (2: 1 by volume) as an eluent gave pure 8200217 23 rac-trans-3-ethyl-4- [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone. Crystallization from ether / hexane gave 122 white crystals with a melting point of 44 - 45 ° C.

I (CHCl3): ^ max 3k22i 1752 cm "1 * 5 (b) To 4" 3 g rac-trans-3-ethyl-4 ~ [(2-methyl-1,3-dioxolan-2-yl) -methyl -2-azetidinone in 30 ml of methanol, about 4 rals of 21.6 ml of a 1 molar solution of bromine in methanol were added and the mixture was heated to 50 ° C. After about 3 minutes, decolorization started and the rest of the bromine solution was added dropwise in 1 minute. · The colorless reaction solution was poured onto a mixture of 30 ml of a saturated solution of sodium chloride and 20 g of ice, then it was saturated with solid sodium chloride and successively with 50 ml of ether and twice with 50 ml of ethyl acetate each time extracted The organic phases were washed 15 more with a mixture of 30 ml of a saturated sodium hydrogen carbonate solution and 20 ml of 1 N sodium thiosulfate solution as well as with 30 ml of a saturated sodium chloride solution, dried over sodium sulfate and completely concentrated * The residual oil silica gel with ethyl acetate subjected to chromatography as eluent 20. Crystallization of the purified product from ethyl acetate / hexane gave 2.99 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3-ethyl-2-azetidinone as white crystals, mp 77-79 ° C * (c) The method described in Example I (f) - (h) was analyzed in an analogous manner in 2.8 g of rac-trans-4- (3-hromo-2,2-dimethoxy-propyl) - 3-ethyl-2-azetidinone was used. After chromatographic purification and crystallization from ethyl acetate / hexane, 0.51 g of pivaloyl-oxy methyl-rac-tr ans-2- (3-bromaceaton onyl) -3-thyl-4-oxo-ex- (triphenyl- phosphoranylidene) -1-azetidin acetate as white crystals, mp 128-129 ° C.

(d) 333 mg of Pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a "(triphenylphosphoranylidene) -1-azetidine acetate and 78 mg of 1-ethyl-4-thiouracil according to the Example IV (d) described process converted. 291 mg of pivaloyloxymethyl) -rac-trans-3-ethyl-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -acetonyl] was isolated after chromatographic purification. -4-oxo-a- (triphenylphosphoranylidene) -1-azetidin acetate as white foam · IR (CHCl3: 9 1745 with shoulder at 1720, 1662, 1627, 1580, 3 max.

1514 cm ".

8200217 24

Example VII

A solution of 151 mg of pivaloyloxymethyl-rac-trans-3-ethyl-2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acet onylJ-4-οχο-α - (triphenylphosphoranylidene) -1-azetidin acetate in 12 ml toluene was heated to 100 ° G under an argon atmosphere for 90 minutes.

After chromatographic purification, 79 mg of pivaloyloxy-methyl-rac-6a-ethyl-3 - [[(5-methyl-1,3 * 4-thiadiazol-2-yl) -thio] -rae-methyl] -7-oxo were isolated 5a-1-azabicyclo [3 · 2.0] hept-2-an-2-carboxylate as pale yellow oil.

NMR (CDCl 3): δ 1.00 (t, J = 7Hz, 3H); 1.07 (s. 9H); 1.43-2.17 (m. 2H); 2.73 (s, 3H): 2.92-3 * 30 (m, 3H); 3 * 70-4.13 (m, 1H): 4.40 / 4.59 (AB system, J = 14Hz, 2H); 5.86 / 5 * 94 (AB system, J = 612 / 2H) ppm.

The starting product was prepared as follows: 15 1 * 33 g of Pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 0.26 g 2-mercapto-5-methyl-1,3 * 4-thiadiazole were reacted in a manner analogous to the procedure described in Example IV Cd). After chromatographic purification, 1.24 g of pivaloyloxymethyl-20-rac-trans-3-ethyl-2- [3- [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acetonyl was isolated ] -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate as an amorphous powder.

IB (CHCl3: 1740, 1636cm-1.

3 max

Example VIII

A solution of 270 mg of pivaloyloxymethyl-rac- (2KS, 3SR) - 2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-oxo-3 - [( HS) -1- (trimethylsilyloxy) -ethyl] -a- (phosphoranylidene) -1-azetidin acetate in 32 ml of toluene was heated at 105 ° C for 1 hour under an argon atmosphere. The colorless reaction solution was diluted with 50 ml of ethyl acetate and completely concentrated under reduced pressure. The residue was filtered through silica gel after separation of the triphenylphosphine oxide, eluting with ethyl acetate / dichloromethane (1: 1 by volume). The fractions containing the cyclization product were concentrated. The residue was taken up in 17 ml of methanol, 35 mg of ammonium fluoride were added to the solution and stirred at room temperature for 40 minutes. It was diluted with 30 ml ethyl acetate, concentrated completely under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate / dichloroethane (40: 1: 1 volume) as eluent. 60 mg of pivaloyloxy 8200217 was obtained.

methyl-r ac- (5BS, 6SR) -6- [(RS) -1-hydroxyethyl] -3-C [(1-methyl-1H-r-tetrazol-5-yl) -thio] -methyl] -7 oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate as colorless oil.

IR (CHCl 3): 3616, 3446, 1780, 1752, 1732, 1623 cm -1.

3 max 5 The starting product was prepared as follows: (a) To a solution cooled to 0 ° C of 34.2 g of rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone and 31.7 g of t-butyldimethyl- Chlorosilane in 160 ml of dimethyl formamide was 22.2 g in 2 minutes. triethylamine was added dropwise to directly precipitate. It was stirred at 0 ° C for 1 hour, then diluted with 500 ml of ether and the reaction mixture was washed with five times 200 ml of water. The water phases were post-extracted with 250 ml ether. The organic phases were dried over sodium sulfate, freed from solvent on a rotary evaporator, and the residual oil was distilled under a high vacuum. 53.5 g of rac-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3'-dioxolan-2-yl) -methyl] -2-azetidinone were obtained, bp 125-130 ° C C as a colorless oil.

IR (CHCl 3): V 1728 cm -1.

3 'max 20 NMR (CDCl 3): <0.22 (s, 6H); 0.98 (s, 9H); 1.31 (e, 3H) j 1.62-2.34 (m, AS part of an ABX system, 2H); 2.70-3.31 (m, AB part of an ABX system, 2H) j 3.51-3.85 (m, X part, 1H); 3.85-4.03 cm, 4H) ppm.

(b) A solution of. 3.66 g of diisopropylamine in 90 ml of tetrahydrofuran was cooled to -78 ° C and 24 ml of a 1,635 molar butyl lithium / hexane solution was added over 5 minutes. It was stirred at -78 ° C under an atmosphere of argon for 20 minutes and then a solution of 8.55 g of rac-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-30 1) was added dropwise over 5 minutes. , 3-dioxolan-2-yl) -methyl] -2-azetidinone in 90 ml of tetrahydrofuran. After stirring for an additional 30 minutes at -78 ° C, 2.22 g of methyl acetate were added to the reaction solution. It was allowed to reach 0 ° C in 5 minutes and stirred at this temperature for an additional 20 minutes. The reaction mixture was poured into 150 ml of a saturated solution of sodium chloride and then extracted with a total of 400 ml of ethyl acetate. The organic phase was washed neutral with a saturated solution of sodium chloride, dried over sodium sulfate and completely concentrated. The residue was chromatographed on silica gel with ethyl acetate / hexane (volume ratio 1: 2) as the 40 eluant and the product of the concentrated pure fractions was distilled under a high vacuum. 4.49 g of rac-trans-3-acetyl-1- (tert-butyl-dimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone were obtained as colorless oil with bp Q ^^ 5 118 - 120 ° C.

IE (GHC1-): 1743, 1712 at * 1.

3 max NMR (CDCl 3): δ 0.22 (s, 3H) y 0.26 (s, 3H); 0.98 (s, 9H) j 1.32 (s, 3H); 1.66-2.37 (m, 2H); 2.30 (s. 3H); 3.75-4.00 (m p); 4.00-1 *, 25 (m, 2H) ppm, 10 (c) A mixture of 14.3 g of rac-trans-3-acetyl-1- (tert-butyldimethylsilyl) -4- [(2 -methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone and 0.78 g of platinum oxide in 70 ml of ethyl acetate were hydrogenated at normal pressure for 8 hours. The catalyst was filtered off, the filtrate was completely concentrated under reduced pressure and the residue crystallized from hexane. 12.4 g of a mixture of 2 isomeric alcohols in the ratio 3 * 2 were obtained. By fractional crystallization from ethyl acetate / hexane, the main component in pure form was first isolated: rac- (3SR, 4HS) -1- (tert-butyldimethylsilyl) -3 - [(ES) -1-hydroxyethyl] -4- [(2-methyl-20-1,3-dioxolan-2-yl) -methyl] -2-azetidinone, mp 81-82 ° C.

IE (CHC13): V> max 3500, 1735 cm ** 1.

NMR (CDCl 3): 0,2 0.22 (s, 3H); 0.24 (s, 3H); 0.96 (s, 9H); 1.34 (d, J = 6Hz, 3H); 1.41 (s, 3H); 1.82-2.27 (m, 2H); 2.96 (dxd, J = 9Hz and 2Hz, 1H); 3.15 (d, J = 5H, 1H); 3.54-3.61 (m, 1H); 3.94-4.02 (m, 4H) ppm.

By repeated crystallization of the mother liquor from ethyl acetate / hexane, rac- (3SR, 4RS) -1- (tert-butyldimethylsilyl) -3 - [(SR) -1-hydroxyethyl] -4 - [(2-methyl-1, 3-dioxolan-2-yl) -methyl] -2-30 azetidinone, mp 86-88 ° C.

IR (CHC13): Ϋ max 3630, 3588, 3504, 1728 cm ** 1.

NMR (CDCl): 6 0.22 (s, 3H); 0.24 (s, 3H); 0.96 (s, 9H) j 1.32 (d, J = 6Hz, 3H); 1.36 (s, 3H); 1.78-2.27 (m, 2H); 2.46 (d, J = 5Hz, 1H); 3.15 (dxd, J = 5Hz and 2.5Hz, 1H); 3.59-3.68 (m, 1H); 3.89-4.01 (m. 4H); 4.03-4.16 (ra, 1H) ppm.

(d) To a 0 0 cooled solution of 79 g of rac- (3SR »4RS) -1- (t erbutyldime thylsilyl) -3 - [(RS) -1-hyd roxye thyl] -4 - [( 2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone in 720 ml pyridine 40 were added with stirring 63.7 g chloroformic acid 2,2,2-trichloroethyl ester 8200217 27. This produced clumps, which after a time dissolved into a fine precipitate. It was stirred at room temperature for 17 hours and then most of the solvent was removed with a rotary evaporator under a high vacuum. The concentrated reaction mixture was taken up in 2 liters of ethyl acetate *, washed three times with 600 ml of water each time, and the water phases were post-extracted with 1 liter of ethyl acetate. The organic phases were dried over sodium sulfate, the solvent was removed on a rotary evaporator, and the residual oil was freed from polar impurities by filtration through silica gel with ethyl acetate / hexane (1: 1 by volume) as an eluent. Concentration of the pure fractions gave 126 g of crude rac- (3SR, 4RS) -1- (tert-butyldimethyl-silyl) -3- [(RS) -1- (2 »2,2-trichloroethoxycarbonyloxy) -ethyl] -1 <-13 [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone as oil.

IR (CHCl 3): 1758.17 * 0 cm ~ 1.

p max (e) To a pre-heated solution of 126 g impure rac- (3SR, 4 RS) -1- (tert.butyldime thylsily1) -3 - [(3SS) -1- (2,2, 2-Tri-chloroethoxycarbonyloxy) -ethyl] -4 - [(2-methyl-1,3-dioxolan-2-yl) -20 methyl] -2-azetidinone in 700 ml of methanol and g of bromine was added with stirring. After stirring at 60 ° C for about 3 minutes, decolorization occurred. Now an additional 36 g of bromine was added dropwise to the reaction solution in 8 minutes and the reaction temperature dropped to 0 ° C in 3 minutes. After completed addition, the temperature was maintained at 40 ° C for another 12 minutes, the reaction solution becoming practically colorless. The mixture was cooled to 10 ° C, neutralized by the addition of 1 ml of aqueous ammonia (25), 8.6 g of ammonium fluoride was added and the mixture was stirred for 1 hour at room temperature. The yellow solution was stirred to about 30 ° C on a rotary evaporator. half the volume concentrated and then taken up in 1.2 liters of ethyl acetate ether (volume ratio 1: 1) The mixture was washed three times with 150 ml each of a saturated sodium chloride solution and the aqueous phases were again extracted with a total of 1.3 liters of ethyl acetate The organic phases were dried over sodium sulfate, freed from solvent under reduced pressure, and the residue was subjected to silica gel chromatography.

A mixture of ethyl acetate / dichloromethane / hexane (1: 1: 1 by volume) eluted the pre-purified product, which could be crystallized from ethyl acetate with the addition of hexane. kO 57 g of rac- (3SR, IIRS) -4- (3-bromo-2,2-dimethoxypropyl) -8200217 28 3 - [(2S) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -2 -azetidinone as colorless crystals with m.p. Mp 84-85 ° C.

(f) A mixture of 23 * 58 g rac- (3SR »42S) -if- (3-bromo-2,2-dimethoxypropyl) -3 - [(RS) -1- (2» 2,2- trichloroethoxycarbonyloxy) -ethyl] - 5 2-azetidinone, g glyoxylic acid monohydrate and 15 g molecular sieve #A in 25 ml dimethylformamide was stirred at room temperature for 20 hours · The reaction mixture was cooled to -10 ° C and 5 * 25 g triethylamine was added · After 5 minutes, 13 * 3 g of iodomethyl pivalate was added, keeping the temperature at 3 ° C by cooling. · It was stirred at 3 ° C for 15 minutes and at room temperature for another 20 minutes. The molecular sieve was then decanted and simultaneously diluted with 200 ml of ethyl acetate. It was washed three times with 100 ml each of a semi-saturated sodium chloride solution and the 15 aqueous phases were extracted again with 200 ml of ethyl acetate. The organic phases were dried over sodium sulfate and freed from the solvent under reduced pressure. Chromatography of the silica gel residue with ethyl acetate / hexane (1: 1 by volume) gave 13.5 g of pivaloyloxy methyl rac (2RS, 3 ^ 3). 2) -2- (3-bromo-2,2-dimethoxypropyl) -20 if-oxo-3- [(RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -e thyl] - <x-hy- droxy-1-azetidine acetate (diastereomer mixture) as colorless oil, IR (CHCl 3): V max 3528, 1769 cm -1.

NMR (CDCl 3): among others, 1.23 (s, 9H); 1.50 (d, J = 6Hz, 3H); 2.20-2.60 (m, 2H); 3.05-3.30 (m, 7H): 3.0 * (broad s, 2H); ij., 73 (s, 2H) ppm.

(g) To a solution of 15 * 5 g of pivaloyloxy-methyl-rac- [2RS, 3SR] -2- (3-bromo-2,2-dimethoxypropyl) -ij.-oxo-3-, cooled to -20 ° C. [(RS) -1- (2 * 2 »2-trichloroethoxycarbonyloxy) -ethyl] -a-hydroxy-1-30 azetidine acetate (diastereomer mixture) in 200 ml tetrahydrofuran, 3 * 50 g 2,6-lutidine was added · Then in A solution of 3-7k g of thionyl chloride in IfO ml of tetrahydrofuran was added dropwise for 1 minute, the temperature being kept below -20 ° C by cooling. The reaction mixture was stirred at -20 ° C for 35 minutes and at room temperature for 20 minutes. The precipitate was then filtered off with suction and the suction product was washed with 360 ml of toluene. The filtrate was completely concentrated under reduced pressure, the residue was taken up in 150 ml of toluene and again completely concentrated.

ifO The oil thus obtained was dissolved in 75 ml of dimethylformamide and a solution of 8 g of triphenylphosphine with 23 ml of dimethylformamide was added. It was allowed to stand at room temperature for 1 hour and then most of the solvent was removed under a highly reduced pressure at a temperature of 30 ° C. The residue 5 was taken up in 300 ml of dichloromethane, the solution was washed twice with 240 ml of a 1 molar phosphate buffer with a pH of 7 each time and the aqueous phases were extracted with 300 ml of dichloromethane. The organic phases were dried over sodium sulfate, freed from solvent under reduced pressure, and the residual oil was subjected to silica gel chromatography. A mixture of ethyl acetate / dichloromethane / hexane (1: 1: 1 by volume) eluted first excess triphenylphosphine and then the product. Concentration of the pure fractions gave 14 * 89 g of pivaloyloxy-15 methyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-3- [(RS) -1- (2,2,2-trichloro-thoxycarb onyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate as an amorphous powder.

IR (CHC15>: y> max 1747, 1634 cm -1).

(h) To a solution cooled to -10 ° C of 2.66 g of pivaloyloxy-20 methyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-3- [(RS) -1- (1,1,1-trichloroethoxycarbonyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate in 75 ml acetone were pre-cooled 48 ml at -10 ° C while stirring 75 ml hydrogen bromide added, bringing the temperature to 10 ° C. The mixture was cooled to 0 ° C in 3 minutes, stirred for an additional 15 minutes at this temperature and the colorless reaction solution was poured onto a mixture of 17 * 4 S sodium carbonate, 150 ml of a 1 molar phosphate buffer solution with a pH of 7 and 150 g of ice. It was extracted with a total of 400 ml of dichloromethane. The organic phase was washed with 50 ml of a 1 molar phosphate buffer solution of pH 7, dried over sodium sulfate and completely concentrated. 2.45 S crude pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bro omacet onyl) -4-oxo-3 - [(RS) -1- (2,2,2-trichloroethoxycarb onyloxy) was obtained ) -e thy1] - <x- (triphenylphosphoranylidene) -1-azetidine acetate as white solid.

55 IR (CHC1-): ^ 1750 with shoulder at 1710, 1641 cm "1.

3 max 0 (i) To a solution of 1 + 28 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -if-oxo-3 - [(RS) -1- (2,2, 2-trichloroethoxy-carbonyloxy) -ethylJ-α- (trxphenylphosphoric anylidene) -1-azetidine acetate and 64 mg 5-mercapto-1-methyl-1H-tetrazole in 10 ml dichloromethane, 60 mg triethylamine were added and then 8200217. Stirred for 2 hours at room temperature. Dilute with 10 ml of dichloromethane and wash with 10 ml each of a saturated solution of sodium hydrogen carbonate and sodium chloride. The water phases were re-extracted with a little dichloromethane, the organic phases were dried over sodium sulfate and completely concentrated *

The residue was dissolved in 3 ml of ice cold 90% acetic acid. 1.5 g of zinc powder was added and stirred at 0 ° C for 20 minutes. The residue was diluted with + 0 ml dichloromethane and washed after 10 with 15 ml of saturated sodium carbonate solution and 25 ml of water twice. * The water phases were extracted twice with 1 * 0 ml of dichloromethane each time * the organic phases were dried over sodium sulfate and completely concentrated .

The residue was taken up in a mixture of 3 l of dichloromethane and 1.5 ml of pyridine and the solution was added 0 l of 4 g of trimethylchlorosilane. It was stirred at room temperature for 1 hour, diluted with 35 ml of ethyl acetate and washed successively with 15 al 5% sodium hydrogen carbonate solution and 25 ml of saturated sodium chloride solution. * The aqueous phases were extracted with 60 ml of ethyl acetate, the organic phases were dried over sodium sulfate and completely concentrated. The residue was chromatographed on silica gel with ethyl acetate / hexane (1: 1 by volume) as eluent. 198 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2-25 [3 - [(1-nonhyl-1] i) were isolated. -tetrazol-5-yl) -thio] -acetonyl] -Voxo-3 - [(RS) - 1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetiodine acetate as colorless oil * IR (CHCl ^): VmaX 1? ^ 7 * l6 ^ ° cm ~ 1 *

Example 9 By adding 1 N sodium hydroxide to an aqueous solution of sodium dihydrogen phosphate, a 0.05 molar phosphate buffer solution with a pH of 7 was prepared and 1.5 ml of a pig liver esterase suspension EG were added to 150 ml of this solution. 3 · 1 · 1 · 1 · (about 1500 units) in a 3.2 molar ammonium sulfate solution. A solution of 228 mg of pivaloyloxymethyl-rac- (5HS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-5-yl)] was then added with stirring. -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate in 3 ml of methanol, yielding a fine precipitate. The mixture was stirred at 23 [deg.] C. for 3.3 hours, while the pH of the reaction mixture was kept 8200217 31 by adding 0.1 N sodium hydroxide to 7 * 1. The still slightly cloudy solution was extracted four times with 50 ml of ether each time and the ether phases were back-extracted two more times with 50 ml of water each time. * The water phases were concentrated under reduced pressure at a temperature of 0-20 ° C to about 30 ml and

R

chromatographically treated with EP-18 silica gel (LiChroprep, 40-63 µm) with 3% aqueous methanol (volume ratio) * The fractions containing the product were combined, concentrated and the solution was dissolved with 0.1 N sodium hydroxide 10 solution adjusted to pH 7.1 was lyophilized * A mixture of sodium (5R »6S and 5S, 6R) _6- [Cb and S) -1-hydroxyethyl J-3 - [[(1- methyl 1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [3 »2.0] hept-2-en-2-carboxylate as white amorphous powder * 15 UV (H ^ O ):) max = 278 (erasable with hydroxylamine).

IE (KBr): 1758, 1603, 1400 cm -1.

* IBcwC

NMB (DMSO-dg): 1.15 Cd, J = 6Hz, 3H); 2.66-2.86 (m, 2H); 3.03 (dxd, J = 7Hz and 2.5Hz, 1H); 3.80-3.96 (m, 2i): 3.97 Cs, 3H); 4.40 / 4.66 (AB system, J = 12Hz, 2H) 20 ppm.

Example X.

126 mg Pivaloyloxymethyl-rac- (2ES, 3SR) -2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acetonyl] -4-oxo-3- [( KS) -1- (trimethylsilyl-oxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate were subjected to the cyclization process described in Example VIII. After chromatographic purification, 24 mg of pivaloyl-oxyethyl-rac- (5RS, 6SB) -6 - [(ES) -1-hydroxyethyl] -3 - [[(5-methyl-1,3,4-thiadiazole-2) were obtained. -Yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2 * 0] hept-2-en-2-carboxylate as colorless oil.

UV (EtOH):) = 292 nm.

'max

The starting compounds for Examples X, XII, XIII, XIV and XVIII were prepared as follows: (a) Pivaloyloxymethyl-rac- (2BS, 3SR) -2- (3-bromoacetonyl) -4-oxo-3 - [(ES) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -a- (triphenyl-35-phosphoranylidene) -1-azetidine acetate was reacted according to the process described in Example VIII (i) with the difference that instead of 5- mercapto-1-methyl-1H-tetrazole in example X 5-mercapto-2-methyl-1,3,4-thiadiazole, in example XII 2-mercaptopyrimidine, 40 in example XIII 4-acetamino-thiophenol, 8200217 • # 32 in example XIV 1,2,3 * - - tetrahydro-if-methyl-3-thioxo-as-triazin-5,6-dione, in example XVIII methyl-1-methyl-5-mercapto-1H-1,2 »if -triazole- 3-carboxylate. » 5 was used.

After chromatographic purification in Example X, pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(5-methyl-1,3-if-thiadiazol-2-yl) -thio] -acetonyl] -2f was obtained -oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate as white foam · 10 IR (CHOI,): a 17 * f9 »looO cm" 1.

y DlcOC

in example XII: pivaloyloxyrae thy1-rac- (2R, 3SR) -if-oxo-3- [(RS) -1- (trimethylsilyloxy) -ethyl] -2- [3- (2-pyrimidinyl-thio) acetonyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate as a colorless oil. IR (CIC1-): V 1739 with shoulder at 1715 * 1632 cm ”1» 15 in example XIII: pivaloyloxyraethyl-rac- (2RS, 3SR) -2- [3 - [(para-arainophenyl) -thio] - acetonyl] -if-oxo-3- [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranyiidene) -1-azetidine acetate as amorphous powder.

IR (CHCl 3): ^ max 3 ^ 36, 3322, 17Ml, 1712, 1636 cm -1.

In Example XIV: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(1 * f, 5,6-tetrahydro-4-methyl-5i6-dioxo-as-triazin-3-yl) - thio] -acetonyl] -if-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate as colorless oil.

IR (CHCl 3): fflax 339 ^f * 1750, 1712, 1616, 1595cm -1.

In Example XVIII: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3- [3- (methoxycarbonyl) -1-methyl-1H-1,2, if-triazol-5-yl] -thi 0 ] -ace tonyl] -if-oxo-3 - [(RS) -1- (trime thylsilyloxy) -e thy 1] -a- (tr if eny If os f or anyli-deen) -1-azetidine acetate as colorless oil.

IR (CHCl 3): max 1741, 1715, 1636 cm -1.

Example XI

Pivaloyloxyraethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3- [[(5-methyl-1,3, if-thiadiazol-2-yl) -thio] -methyl ] -7-oxo-1-aza-bicyclo [3.2.0] hept-2-en-2-carboxylate was analogously subjected to the hydrolysis procedure described in example. A mixture of sodium (5R, 6s and 5S, RR) -6 - [(R and S) -1-hydroxyethyl] -3 - [[(5-methyl-1, 3,4-thiadiazol-2-yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

UV (IL, 0):? Imax = 278 nm (with hydroxylamine shift to kO 278 nm).

8200217 Η 33 *

Example XII

1β3 mS Pivaloyloxymethyl-rac- (2RS, 3SB) -4-oxo-3 - [(BS) -1- (tri-methylsilyloxy) -ethyl] -2- [3- (2-pyrimidinyl-thio) -acetonyl] - α- (triT phenylphosphoranylidene) -1-azetidine acetate was subjected to the procedure described in Example 5 VIII with the difference that the reaction time of the cyclization reaction was 3 hours. After chromatographic purification, 42 mg of pivaloyloxymethyl-rac- (5 & S, 6SR) -6- [(RS) -1-hydroxyethyl] -7-oxo-3 - [(2-pyrimidinyl-thio) -methyl] -1-azabicyclo were isolated [3 * 2.0] hept-2-an-2-carboxylate as a colorless oil.

IR (CHCl 3): Vmav 3618, 3430, 1775, 1753, 1622, 1567, 1331cm -1.

2 melX

The preparation of the starting product is described in Example X (a).

Example XIII

157 mg Pivaloyloxymethyl-rac- (2RS, 3SB) -2- [3 - [(p-acetamino-phenyl) -thio] -acetonyl] -4-oxo-3 - [(BS) -1- (trimethylsilyloxy) - ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate are subjected analogously to the procedure described in Example XII.

After chromatographic purification, 33 mg of pivaloyloxy-20-methyl-rac- (5BS, 6SR) -3 - [[(p-acetaminophenyl) -thio] -methyl] -6 - [(RS) - 1-hydroxyethyl] -7- was isolated oxo-1-azabicyclo [3 * 2.0] hept-2-en-2-carboxylate as an amorphous powder.

IR (GHCl 3): Vaax 3618, 3434, 3382, 1778, 1755, 1695, 1619 at “1.

NMR (CDCl 3): δ 1.22 (s, 9H); 1.31 (d, J = 6Hz, 3H); 1.91 (d, 25 J = 4Hz, 1H) 2.17 (s, 3H) j 2.85-3.10 (m, 2H); 3.08 (dxd, J = 6.5Hz and 3Hz, 1H) j 3.89 / 4.07 (AB system, J = 13Hz, 2H); 4.07-4.18 (m, 2H); 5.68 / 5.78 (AB system, J = 5.5Hz, 2H) j 7.34 (d, J = 8.5Hz, 2H); 7.36 (s. 1H); 7.44 (d, 30 J = 8.5 Hz, 2H) ppm.

The preparation of the starting product is described in Example X (a).

Example XIV

400 mg Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3- [0, 4,5,6-tetra-35-hydro-4-methyl-5,6-dioxo-as-triazin-3-yl) - thio] -acetonyl] -4-oxo-3 - [(BS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate were analogously subjected to the procedure described in Example VIII. After chromatographic purification, 31 mg of pivaloyloxymethyl-rac- (5ES, 6SB) -6 - [(RS) -1-hydroxy-40-ethyl] -3 - [[(1,4,5,6-tetrahydro-4-ethyl) 5,6-dioxo-as-triazin-3-yl-8200217-3k thio-methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

UV (EtOH): ^ = 280 nm (with NH-OH shift to 289 nm).

max d

The preparation of the starting product is described in Example X (a).

Example XV

The product of Example XIV was subjected in an analogous manner to the procedure described in Example IX. A mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] - 3- was obtained. [[(1, ^ »3» ö-tetrahydro-if-methyl-5,6-dioxo-as-triazin-3-yl) -thio] -10 methyl] -7-oxo-1-azabi cyclo [3 2.0 Jhept-2-e and-2-carboxylate.

UV (H-0): = 283 nm, 2 'max

Example XVI

186 mg Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[2,5- <3ihydro-2-methyl-5-oxo-6 - [(pivaloyloxy) -methoxy] -as-triazin-3- yl] -thio] -13 acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate were analogous to the described in Example VIII. After chromatographic purification, 65 mg of pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[[2,5- <5ihydro-2-methyl-5-oxo-6 - [(piva-20 loyloxy) -methoxy] -as-triazin-3-yl] -thio] -methyl] -7-oxo-1-azabicy-clo [3 * 2.0] hept-2-ene-2-carboxylate as colorless oil.

IR (CHCl 3): 3692, 361-13370, 1775, 1753, 1737, 1670, 1610 cm-1.

NMR (CDCl 3): 1,2 1.22 (s, 18H); 1.31 (d, J = 6Hz, 3H); 1.80 (d, 25 J = »5Hz, 1H); 2.97-3 * 23 (m, 2H); 3.18 (dxd, J = 6.5Hz and 2Hz, 1H); 3 * 70 (s, 3H); **, 13-1 *, 28 (m, 2H); 1 *, lf0 / ki5k (AB system, J »13.5Hz, 2H); 5.88 / 5.97 (AB system, J = 7Hz, 2H); 5.93 (2.2H), ppm.

The starting product was prepared as follows: (a) To a solution of 858 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -it-oxo-3 - [(RS) -1- (2 2,2-trichloroethoxycarbonyl-oxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate and 159 mg 1,2,3,4-tetrahydro-2-methyl-3-thioxo-as-triazin-5,6 -dione in 10 ml of dimethylformamide, 202 mg of triethylamine in 2 ml of dichloromethane were added and then stirred at room temperature for 20 minutes. The transparent solution was cooled to 0 ° C, 21 * 2 mg of iodomethyl pivalate was added and 15 minutes more stirred at 0 ° C and 15 minutes at room temperature. 1 * 0 was diluted with ethyl acetate and washed successively with 5% 8200217 35% sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate »completely concentrated and the residue was chromatographed on silica gel with ethyl acetate as the running liquid *

The purified product was analogous to that in Example VIII

(i) described process with zinc in 90% acetic acid and then treated with trimethylchlorosilane * 196 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2-10 [3-C [2 »5- <3ihydro] were obtained after chromatographic purification -2-methyl-5-oxo-6- [(pi-valoyloxy) -methoxy] -as-triazin-3-yl] -thio] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy ) -e thyl] -a- (triphenylphos foranylidene) -1-azetid inac e tate as colorless oil *

Example XVII

The product of Example XVI was analogously subjected to the procedure described in Example IX. A mixture of (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] -3- was obtained. [[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -7-oxo-1-azabicyclo [3 * 2.0] -hept-2-ene -2-carboxylic acid disodium salt20 µV (H, 0): ^ = 22 * 2,281 nm.

£ * iosx ^ IR (KBr): V 1755 »1602 with shoulder 1650, 1404 cm 1.

v max

Example XVIII

180 mg Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 "[[3- (methoxy-carbonyl) -1-methyl-1H-1,2,4-triazol-5-yl] -thio] -acetonyl ] -4-oxo-25 3 - [(RS) -1-trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylide e) -1-azetidine acetate was subjected to the procedure described in Example VIII. After chromatographic purification, about 70 mg of pivaloyloxymathyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[[3- (methoxycarbonyl) -1-methyl-1H-1 j2 »4- * triazole, 5-yl] -30 thio] -methyl] -7-oxo-1-azabicyclo [3 * 2.0] hept-2-en-2-carboxylate as colorless oil.

IR (ClCl 3): Vmax 3680, 3608, 3440, 1780, 1742, 1620cm -1.

NMR (CDCl 3) j 1.22 (s, 9H) j 1.32 (d, J = 6Hz, 3H) j 1.82 (broad -OH signal); 3 »03-3» 15 (m, 2H); 3.26 (dxdj 35 J = 6.5 Hz and 3 Hz, 1H); 3.89 (a, 3H); 3, 9δ (s, 3H); 4.10-4.25 (m. 2H); 4.42 / 4 * 42 (degenerate AB system, J »13.5Hz; 2H); 5.85 / 5.93 (AB system, J = 5 »5Hz, 2H) ppm *

The preparation of the starting product is described in Example X (a) 40.

8200217 36

Example XIX

The product of Example XVIII was analogously subjected to the procedure described in Example IX. A mixture of sodium (5R »6S and 5S, 6S) -6 - [(E and S) -1-hydroxyethyl] - 5 was obtained. 3 - [[[3- (methoxycarbonyl) -1-methyl-1H-1,2, k-triazol-5-yl] -thio] -methyl] -7-oxo-azabicyclo [3 · 2.0] hept-2 -a-2-carboxylate.

HV (HoO): = 278 nm (erasable with NH-QH).

(L ’max (L λ IE (KBr): 1738 with shoulder 1753 * 1591» 1395 cm ”max

Example XX

0.6 g of Pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -3- [1-methyl-1- (triraethylsilyloxy) ) -ethyl] -ij.-oxo-α- (triphenylphosphoranylidene) -1-azetidine acetate was subjected to the cyclization process described in Example 8, except that to remove the trimethylsilyl protecting group, the cyclization product in 60 ml of methanol in the presence of 0.6 g of ammonium fluoride was stirred at room temperature for k hours * Chromatographic purification isolated 52 mg of pivaloyloxymethyl-rac-6a- (1-hydroxy-1-methyl-ethyl) -3 ~ [[(1-methyl- 20 1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-5a-1-azabicyclo [3 »2.0] -hept-2-ene-2-carboxylate as colorless oil · UV (EtOH): λ = 296 nm (erasable with EE.QH).

max d ^ IE (CHCl 3): Ϋ a 3690, 3610, 1779 »1752, 1730, 1622 cm”. y max

The starting product was prepared as follows: (a) To a solution of 8.56 g of rac-if- [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone in 150 ml of tetrahydrofuran 65.5 ml of a 1.6 molar butyl lithium / hexane solution were added at -30 ° C in k minutes and then stored in an ice bath in an atmosphere of argon for 90 minutes. The brownish-yellow solution was cooled to -30 ° C and a solution of 3.2 g of acetone in 10 ml of tetrahydrofuran was added. The mixture was stirred for another 30 minutes at 0 ° C and the reaction solution was poured onto 50 g of ice. The organic phase was separated and washed with 50 ml of a saturated solution of sodium chloride. The combined aqueous phases were still extracted with a total of 300 ml of dichloromethane. The organic phases were dried over sodium sulfate, completely concentrated under reduced pressure and the residual oil was subjected to silica gel chromatography

A mixture of acetone and dichloromethane (volume ratio 1: 8) eluted first unused starting product, then rac-cis-3- 8200217 37 (1-hydroxy-1-methyl-ethyl) -4- [(2-methyl-1,3- di oxolan-2-yl) -methyl 1] -2-azetidinone, which after crystallization from ethyl acetate / hexane was obtained as 0.80 g of white crystals with a melting point of 134-135 ° C · 5 IR (CHCl):] / aax 3604, 3424 * 1751 cm "1.

Further elution gave rac-trans-3- (1-b-hydroxy-1-methyl-ethyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone, which from ethyl acetate / hexane gave 1.59 g of white crystals with a melting point of 84 -6 ° C, 10 IR (CHCl 3): v 3604, 3420, 1731 cm -1.

p max (b) The methods described in Example VIII (a) and (d) - (i) were analogously prepared on 4 g of rac-trans-3- (1-hydroxy-1-methyl-ethyl) -4- [ (2-Methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone used · 0.96 g of pivaloyloxymethyl-rac-trans-2- [3 - [(1-me-15-thyl-) were obtained 1H-Tetrazol-5-yl) -thio] -acetonyl] -3- [1-methyl-1- (trimethyl-silyloxy) -ethyl] -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate as colorless oil · IR (CHCl 3); VMAV 1744, 1635 cm "1.

p max

Example XXI

The product of Example XX was subjected in an analogous manner to the method described in Example IX. A mixture of sodium- (5R-6S and 5Si6R) -6x- (1-hydroxy-1-methyl-ethyl) -3- [[ (1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-5a-1-azabicyclo [3 · 2.0] hept-2-en-2-carboxylate.

UV (H-0): 1? = 279 µm (with ΝΗ-0Η erasable).

2 r max 2

Example XXII

230 mg of Pivaloyloxymethyl-rac-1-trans-2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-oxo-3 - [(trimethylsilyloxy) -methyl] - α- (triphenylphosphoranylidene) -1-azetidine acetate are subjected to the method described in Example VIII, except that the reaction time of the cyclization reaction was 30 minutes. After chromatographic purification, 66 mg of pivaloyloxy-methyl-rac-6a- (hydroxymethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-5a- 1-azabicyclo [3.2.0] hept-2-en-2-carboxylate 35 as colorless oil, UV (StOH): /) = 289 nm (with ΝΞ-0Η erasable).

Π13Χ & IR (CHCl-): V3440, 1782, 1752, 1619 cm -1.

p ulcLX

The starting product was prepared as follows; (a) 15.8 g of t-butyldimethylchlorosilane and 25.2 g of rac-4- (3- 40 bromo-2,2-dimethoxypropyl) -2-azetidinone were successively dissolved in 8200217 38 150 ml of dimethylformamide, the solution was added to 0 Cooled to 0 ° C and, with stirring, 22.0 g of triethylamine were added to form a precipitate. It was stirred at 0 ° C for 15 minutes, diluted with 1 liter of ether / hexane (volume ratio 1: 1) and ex-5 extracted four times with 400 ml of water each time. The aqueous phases were back-extracted with 500 ml ether / hexane (1: 1 volume ratio), the organic phases were dried over sodium sulfate and completely concentrated. The residual oil was taken up in little hexane and stored at -20 ° C. 31 g of rac-10 4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -2-azeididinone were obtained as white crystals, mp 61-63 ° C.

(b) 7 06 g of rac-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -2-azetidinone were analogous to the procedure described in Example VIII (b) subject to the difference that 6.0 g of methyl formate were used instead of methyl acetate. 2.19 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3-formyl-2--2-formyl-2-yl-crystallization of the product purified by chromatography from ether / petroleum ether were obtained. azetidinone as white crystals with a melting point of 70 - 72 ° C.

(C) To a solution of 788 mg of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3-formyl-2-azetidinone in 12 cooled to 0 ° C ml of methanol, 38 mg of sodium borohydride were added and the reaction mixture was stirred for 10 minutes. It was diluted with ethyl acetate, washed with a saturated sodium chloride solution, the organic phase was dried over sodium sulfate and concentrated completely. Crystallization of the residue from ethyl acetate / hexane gave 685 mg of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3- (hydroxymethyl) -2-azetidinone as white crystals a melting point of 119-120 ° C.

(D) 7187 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyl dimethylsilyl) -3- (hydroxymethyl) -2-azetidinone were added to the Example VIII ( d) the method described and the crystalline reaction product was then stirred in 240 ml of methanol in the presence of 0.70 g of ammonium fluoride for 20 minutes at room temperature. After aqueous work-up and crystallization of the crude product from ethyl acetate / hexane, 7 g of 6 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 - [(2,2,2-trichloro) were obtained. thoxy-carbonyloxy-methyl] -2-azetidinone, mp 108-109 ° C.

(e) The reaction sequence described in Example VIII (f) - (i) was analogous to 512 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) - 8200217 39. 3- [(2,2,2-trichloroethoxycarbonyloxy) -methyl] -2-azetidinone used. 0.23 g of pivaloyloxymethyl-rac-trans-2- [3- [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-oxo-3 - [(trimethylsilyloxy) were obtained -methyl] -a- (triphenylphosphoranylidene) -1-azetidin acetate 5 as colorless oil

Example XXIII

The product of Example XXII was subjected analogously to the method described in Example IX. A mixture of sodium (52,6S and 5S, 6R) -6a- (hydroxymethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] - was obtained. 7 - oxo-5a-1-azabicyclo- [3,2% 0] hept-2-en-2-carboxylate.

UV (H_0): 277 µm (erasable with NH_0H).

2 'max 2

Example XXIV

41 mg of rac-1- (tert-butyldimethylsilyl) -3- (Z) -ethylidene-1-5 4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone in 2 ml of ethyl acetate in the presence of 50 mg of platinum dioxide hydrogenated at normal pressure. A 6: 1 cis / trans isomer mixture was obtained, from which the main component could be obtained by fractional crystallization of the crude product from hexane in pure form: rac-cis-1- (tert-butyldimethylsilyl) -3-ethyl-4- [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone, mp 80-82 ° C.

The starting product was prepared as follows:

To a solution of 330 mg of rac- (3SR, 4Ss) -25 l - (tert-butyldimethylsilyl) -3 - [(SR) -1-hydroxyethyl] -4 - [(2-methyl-1, -), cooled to 0 ° C. 3-dioxolan-2-yl) -methyl] -2-azetidinone and 400 mg of triphenylphosphine in 20 ml of tetrahydrofuran, 300 mg of azodicarboxylic acid diisopropyl ester were added and the solution was stirred at room temperature for 1 hour. Then partitioned between water and ethyl acetate, the organic phase was dried over sodium sulfate and completely concentrated. The residue was chromatographed on silica gel with ethyl acetate / dichloromethane / hexane (1: 1: 2 by volume) as the running liquid and the purified product was recrystallized from hexane. 100 rag rac-1- (tert-butyldimethylsilyl) -3- (Z) -ethylidene-4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone was obtained as colorless crystals with a melting point of 85 - 86 ° C.

IR (CHC1-): I? 1722 cm "1.

3 v max

Example XXV

40 1.04 g of rac-cis-1- (tert-butyldiraethylsilyl) -4 - [(2-methyl-1,3-8200217]. * ¥ 3 dioxolan-2-yl) -methyl] -3- [1 -raethyl-1 - [(2,2,2-trichloroethoxy-carbonyloxy) -ethyl] -2-azetidinone were analogously subjected to the procedure described in Example VIII (e), except that the bromination at a temperature of 45 ° G was carried out · After chromatographic purification and crystallization from ethyl acetate / hexane 0.5 µg of rac-cis-ii .- (3-bromo-2,2-dimetho-xypropyl) -3- [isolated 1-methyl-1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -2-azetidinone as colorless crystals, mp 104 ° C.

IH (GHC1): \ max 1765 onf1.

10 The starting product was prepared as follows:

rac-cis-3- (1-hydroxy-1-methyl-ethyl) -if - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone was used in analogy to Example VIII (a) and (d) described method converted. After crystallization from hexane, rac-cis-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -3- [1-methyl- 1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -2-azetidinone, mp 89 - 91 ° G * Example XXVI

Do you use (-) - (3S, 4E) -1- (tert-butyldimethylsilyl) -3 - [(E) -1-hydroxy-thyl] -if - [(2-methyl-1,3- <iioxolan-2) -yl) -methyl] -2-azetidinone 20 as starting material for the reaction sequence described in Example VIII starting from step (d) and subjecting the product to the method described in Example IX, sodium (5R) is obtained. 6S) -6 - [(E) -1-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [ 3 «2.0] hept-2-an-2-25 carboxylate.

IV (H-0): λ = 278 nm (erasable with NH0H).

2 max d

The starting product was prepared as follows: (a) To a solution of 19.8 g of rac- (3SR, 4RS) -1- (tert-butyldimethylsilyl) -3 - [(HS) -1-hydroxyethyl] - cooled to 0 ° C - ¥ - [(2-methyl-30-1,3-clioxolan-2-yl) -methyl] -2-azetidinone in 120 ml of pyridine, 18.8 g of (-O-camphanoic acid chloride were added. Stirred at room temperature for 22 hours The reaction mixture was then diluted with 1.2 liters of ethyl acetate and washed successively with 360 ml each of a dilute sodium hydrogen carbonate solution and a saturated sodium chloride solution The water phases were back extracted with 1 liter of ethyl acetate, the combined organic phases were dried over sodium sulfate, completely concentrated and the residue was subjected to chromatographic treatment on silica gel A mixture of ethyl acetate / dichloromethane / hexane 40 (volume ratio 1: 6: 6) first eluted a (+) rotary 8200217 I if 41 camphanic acid ester, which could be crystallized from ether / hexane One obtained (+) - (3R » 4S) ~ 1- (tert-butyldimethylsilyl) -3 ~ [(iS) -1-camfanoyloxyethyl] -! * - [(2-methyl ~ 1,3-dioxolan-2-yl) -methyl] -2-azetidinone mp 125-127 ° C and [α] PO = + 1510 ° (c = 1 * 5 EtOAc). After a few mixing fractions, fractions were obtained which, as the main component, contained a (-) - rotating camphane ester. This was purified by crystallization from ether / hexane. (-) - (3S, 4R) -1-tert-butyldimethylsilyl) -3 - [(IR) -1-camfanoyloxy-ethyl,] - 4- [(2-methyl-1,3-dioxolan-2-) was obtained yl) -methyl] -2-azetidinone with melting point 112-113 ° C and [α] 25 = -19 * 9 ° (c = 1, EtOAc).

(b) To a solution of 0.5 g (") - (3S, 4R) -1- (tert-butyldimethylsilyl) -3 - [(1H) -1-camfanoyloxyethyl] -4 - [(2-methyl -1,3-dioxolan-2-yl) -methyl] -2-azetidinone from step (a) in 10 ml of toluene at 0 ° C, 4 ml of a 1.12 molar solution of diisobutylaluminium hydride in hexane were added and the reaction mixture was then stirred at room temperature for 2 hours. It was poured onto a saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were again washed with saturated sodium chloride solution, dried over sodium sulfate and completely concentrated. The residual oil was chromatographed on silica gel with ethyl acetate / hexane (1: 1 by volume) as the eluent.

Twice crystallization from hexane gave (-) - (3S, 4R) -1- (tert-butyldimethylsilyl) -3 - [(R) -1-hydroxyethyl] -4 - [(2-methyl-25 1,3-) dioxolan-2-yl) -methyl] -2-azetidinone, mp 83-84 ° C and [α] 25 = -50.8 ° (c = 1, EtOAc).

Example XXVII

To a solution of 10 mg sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] -3 - [[(1-methyl-tetrazole-1H-) cooled to 0 ° C 5-30 yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate in 0.2 ml dimethylformamide, 7 mg bromomethyl acetate was added and then 1 stirred at room temperature for an hour.

It was diluted with ethyl acetate, washed with a 0.05 molar phosphate buffer with a pH of 7i, dried over sodium sulfate and concentrated completely. Chromatography of the silica gel residue with ethyl acetate / dichloromethane as eluent gave 1.8 mg of acetoxy-methyl- (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] -3 - [[( 1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-carboxylate as pale yellow oil.

40 UV (EtOH): λ = 295 am (erasable with NIL.OH).

max & 8200217 42 IR (CHC1): ^ max 17711 1738.

Example XXVIII

By meaningfully using the methods described in the previous examples, the compounds of formula 1 shown in Table A can be prepared. In this context, it may be advantageous under certain circumstances to change the order of the reaction steps or in certain cases to add other protecting groups. to suit. The compounds 28), J> 0) »43) resp. 44) are obtained by reacting compounds 27) »29)» 41) or · 21) by generally known methods »for example with raethylformimidate in aqueous solution at a pH of 8-8» 5.

8200217 - b3 - R2 Η.

rU

| 6 15 \

I I yV — CHg — X I

/? -

COOH

ƒ fr

Table ^ e- "!

Compound R1 R2 X salt

H * N

1) H -CH 2 CH 3 ^ Na

“S I

ch3 “jv.

H.

2) H -CH2 CH, AN'X

2 3 - S / N ^ COOCHj 3) H -CH2CH3 —s ^ h ^ o "

OH

4) —CHCH0CH0 H l ~ * \ 2 3 Λ »* S i CH.

OH 3 5} -CHCHOCH-, H // "J" 2 3 CHlCOOHa

OH

I CH3> s / NX / ® * 6) -CHCH2CH3 H jf T "—S '^ VsNX ^%' 0

OH

I 1! 7) -CH-CF, H ./A·3

3 ”I

ch3

OH N ~ * N

% i Jf i

8-CHr-CF H

3 Cyl3 i i 8200217 - kk - - 2 * 1 'Ί

Compound R R X salt

OH

J CH3 ~ v / H ^ Wi 9) -CH-CF3 H ΛΑ Na OH / -¾

10) -CH-CH 3; H

H

11) “, _, A \ —s | COOCHCHCH | 12). "- 13) ··" Na

H

i n 14) "" S * »'·"

mmS 'N

s - u 15) "" -G '/ ^ N> ^ Sca "” * 3.

S —s 16) ""

17) "» XX

-S s' coONa

^ CHJ

18) "" t -— S ^ s ^ COOCHCHCH 19) "" AX) • S 5 i i i ί 8200217 - 45 - 14 * R I R X salt

OH

J CH 2 CH 2 OH

20) -CH-CH 3 h Ji \ Na

-S ^ CH

1 · 3 ί ✓ CH-CH.NH,

! jK

2D "" I

I »

"I

22) ""; 3 After ί 'CH-j

i A. I

23) ""; An A | »; "Λ _ j 24)" ": AA *! "i CONH," 2 [i! 25) "·· ί r \ - _sAAC0ONa ch3n

i N — N

26) "·· -" n 27) "" 7 · - «.

C "3N

28) "·· Γ \\ _

CH2-NH-CH * NH

CH3 \ n "" n

29) "" __SAA

CHj-CH2-NH2®3 S, N * ”N. _

30) i "A

J -CHNCHCHNH-CH-NH

! ί lil I 1 8200217 i j - Ifé -

Connection j

. I OH

'H »

31) -CH-CH-1H

_A.K

ch3

• i -n / H

I 32) ·· "fj - i —S * • i - i 'CT3 \:;. 331" ΛΚ “' s CONHCH2CH2HH2 CH3CHiS / ***% 34)" / -¾ H2N \ 35) "" _SA / H2M \ V HH-NH2] ~ ζ

36) "" "syVN

^ γγ0 ** * 37) "33) ··" Χί

NH2 N - N

39) "" yAj

S I

COOCHj

N —N

// 40) "" "./A-21

CH2-COONa N —N

41) "" I yA ")»

"I

CH2CH2NH2 I i I i! ! I I 1 i 8200217 _______ ί * - i ν <· - ί> ί ί; 47; 2 1

Connection R R X

N —N

? H _A *. 42) -CK-CH Η I yen, ^ * ^ ch3 M - N // * 43) "”

i I

\ CH 2 CH 2 -NH-CH »NH

f ych2ch2nh-ch «nh 44)" "" - —SS ^ CH3 0 45) "» X) 0 N fT 2 3 46) · Λ 47) "" \ ji ^ C "3; 0 48)" * · ' 0

49) - - A

- S ^ N ^ ch1 3 f CH3; 50) "" Λ. Nv

NX

51) "" I nA

Ι _, αλ,

«I

I H

ι \ i I 1 i 1 ι 8200217 i I i - 48 - * ί.

- -, ο Γ-

Compound R j R X salt ° H n ^ y'Co ° chjch3 52) -CH-CH H I A Na -3 —s ^ 'n' ^ Nh2 o 531 _ΑΛ NHNH2

54) "" jfS

0 Λ 55) ”" -.AJ Na

H

O

56) ·· .. Λ · ··

—S ^ H

- H

571 "Λ, λ —S N HHCHj" rf "** 58)" "_.Λλ« nh2 59) "- _SAN ^ ~“ s ** ^ NH2

OH

60) "" I P-chj "

> S KN

__g '^ N ^ Λ 61) "" "n 62)" "COONa 1 8200217 - 49 - __

Compound R R X salt, 'H J0

63) -CH-CH 3 H

conhch2ch2nh2 nk2 64) "" ιΓί "Na

_SAA

65) "H -SO4 / OH

0 Λ 66) "" "CHAPTER 673 67)" "». R5] "

_ AA

CH

xN ^ s ^ -OCHy

68 "AA

69) "" (Γί. "0 70)" "-0-C-CH3"? / CH3 -X \

711 H -C <CH8 -I

Y CH3 CH3 · ^ ^ N ^> / 0 Na

72} "" AA

N - N

73) "" At

- 'H

- Ιηγη, ν '· ™ 3 2 2v'CK3 j _! _! ___ 8200217

Λ I

50

Example XXIX

Preparation of dry ampoules for intrarauscular administration.

In a conventional manner, a lyophilisate of 500 mg 5 of sodium- (5R »6S) -6 - [(B) -1-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [5.2.0] hept-2-en-2-carboxylate prepared and filled in an ampoule. Before administration, 2.5 ml of a 2% aqueous solution of lidocaine hydrochloride is added to the lyophilisate.

10 Example XXX

A gelatin capsule of the following composition was prepared in the usual manner:

Pivaloyloxymethyl- (5R, 6S) -3 - [[(1-ethyl-1,2-dihydro-2-oxo-1-pyrimidinyl) -thio] -methyl] -15 6 - [(E) -1-hydroxyethyl ] -7-oxo-1-azabicyclo- [3.2.0] hept-2-en-2-carboxylate 500 mg

Luviskol (water-soluble polyvinylpyrrolidone) 20 mg

Mannitol 20 mg

Talc 15 mg 20 Magnesium stearate 2 mg 557 mg

Example XXXI

A tablet of the following composition was prepared in the following manner: Pivaloyloxymethyl- (5E, 6S) -3 - [[(1-ethyl-1,2-dihydro-2-oxo-it-pynmidinyl) -thio] -methyl ] - 6- [(E) -1-hydroxyethyl] -7-oxo-1-azabicyclo- [3 * 2.0] hept-2-ene-2-carboxylate 250 mg

Lactose 70 mg 30 Corn Starch 65 mg

Polyvinylpyrrolidone 10 mg

Magnesium Stearate 5mg 1) .00mg

A granulate is prepared in the usual manner with the active substance, the lactose, the polyvinylpyrrolidone and 35 1 + 0 parts by weight of the corn starch. This is mixed with the remaining 25 parts of corn starch and 5 parts of magnesium stearate and pressed into tablets.

8200217

Claims (18)

Bicyclic compounds of the general formula 1, wherein 1 2 of the substituents R and R is hydrogen and the other hydrogen or an unsubstituted or substituted alkyl group with 1 to 4 carbon-5 atoms and X an unsubstituted or substituted alkanoyloxy group with 1 up to 3 carbon atoms, a substituted or unsubstituted cycloalkyl-thio group of 3 to 7 carbon atoms, alkenyltio group of 2 to 6 carbon atoms or heterocyclic thio group or a substituted alkylthio group of 1 to 4 carbon atoms or phenylthio group, its readily hydrolysable esters, pharmaceutically compatible salts thereof, as well as hydrates of these compounds. Compounds according to claim 1, characterized in that one of the substituents R and R is hydrogen and the other hydrogen, alkyl of 1 to 4 carbon atoms or alkyl of 15 to 4 carbon atoms substituted with fluorine, chlorine, bromine ; a -S (0) -R 'having n = 0, 1, 2 and R' = alkyl having 1 to 3 carbon n atoms; a -C0 -R 'radical with R' = hydroxy, alkoxy with 1 to 3 carbon atoms, alkyl with 1 to 3 carbon atoms, amino, alkylamino with 1 to 3 carbon atoms or dialkylamino with 1 to 3 carbon-20 atoms in the alkyl group; an amino radical -NR'R ", wherein R 'and RH represent hydrogen or alkyl of 1 to 3 carbon atoms or an OR' radical with R '= hydrogen, methyl, SO 2, CH 2 OCOR" (r "= alkyl with 1 up to 4 carbon atoms). Compounds according to claim 2, characterized in that one of the substituents R and R is hydrogen and the other hydrogen, ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-propyl, 1-hydroxy-2, 2,2-trifluoroethyl or 1-hydroxy-1-methyl ethyl. 4. Compounds according to any one of claims 1-3, characterized in that X alkanoyloxy with 1 to 3 carbon atoms or alkanoyloxy with 1 to 3 carbon atoms substituted with hydroxy, alkoxy with 1 to 3 carbon atoms, phenyl or alkylthio with 1 to 3 represents carbon atoms. Compounds according to any one of claims 1 to 3, characterized in that X alkylthio with 1 to 4 carbon atoms substituted with phenyl, which may be substituted with one or more fluorine, chlorine or scalding atoms, alkyl groups with 1 to 3 carbon aroms, alkylthio groups of 1 to 4 carbon atoms, alkanoyl groups of 40 1 to 3 carbon atoms, carboxyl groups or alkoxycarbonyl groups 8200217 *, 52 of 1 to 3 carbon atoms; or with a - (CH ^^ - NRR1 - (CH_) -NHCR = NR »or - (OH.) -N = CR-N (R ') _ group, where η = 0, 1, du du d 2 or 3 and R and B 'is hydrogen or alkyl of 1 to 3 carbon atoms; 5 fluorine, bromine; an oxime or oxime ether radical = N-QR' (R * = η or alkyl of 1 to 3 carbon atoms) in syn- or anti-form; a 3-7 atomic monocyclic, saturated, unsaturated or aromatic heterocyclic ring with 1-4 hetero-10 atoms (N, O, S;) which may be substituted with one or more fluorine, chlorine or bromine atoms, alkyl groups of 1 to 3 carbon atoms, alkylthio groups of 1 to 4 carbon atoms, alkanoyl groups of 1 to 3 carbon atoms, carboxyl groups or alkoxycarbonyl groups of 1 to 3 carbon atoms; or with a - (CH2) -NRR ' or 15 - (CH_) -NH-CR = NR »or - (CH.) -N = CR-N (R *) 0 group, where n = 0, 1, dU dU d can be 2 or 3 and R and R 'is hydrogen or alkyl of 1 to 3 carbon atoms, as well as by oxo groups); a cycloalkyl radical of 3 to 6 carbon atoms; a -S (0) -R' radical (with n = 1 or 2 and R '= alkyl of 1 to 3 n 20 carbon atoms); a -COR1 radical [with R '= alkyl of 1 to 3 carbon atoms, phenyl, phenoxy, benzyloxy, cycloalkyl of 3 to 6 carbon atoms or a 3-7 atomic heterocyclic group with 1-4 hetero atoms (N, 0, S), which may be substituted in the aforementioned manner, represents · 6. Compounds according to any one of claims 1 to 3, characterized in that X phenylthio substituted with one or more fluorine, chlorine or bromine atoms, one of the groups 30 - (CHn) -NRR ', - (CH_) - NR ~ CR '= NR "and - (CH_) -N = CR-NR'R" (with n = 2 n 2 n 2 n 0, 1, 2, 3 and fi, E' and E1 'H or alkyl with 1 to 3 carbon atoms, alkanoyl of 1 to 3 carbon atoms) or also having alkyl groups of 1-3 carbon atoms, alkanoylamino groups of 1-3 carbon atoms, hydroxyl groups, alkoxy groups of 1-4 carbon atoms or acyloxy-35 groups. Compounds according to any one of claims 1 to 3, characterized in that X cycloalkylthio with 3 to 7 carbon atoms or cycloalkylthio with 3 to 7 carbon atoms substituted with one or more oxo groups, hydroxyl groups, alkyl groups with 1 to 40 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, carb- 8200217 'V * oxyl groups or alkoxycarbonyl groups or with one of the groups - (CHJ -NES', - (CH_) -NR-CR ^ NE »and - (CH,) -IfcCR-NR1R” ( with n = 2 n 2 a 2 a 0, 1j 2j 3 and R, R 'and R "H or alkyl of 1-3 carbon atoms, alkanoyl of 1-3 carbon atoms) or with one or more acyl radicals of an aliphatic or aromatic carboxylic acid with 1-7 carbon atoms. Compounds according to any one of claims 1 to 3, characterized in that X is alkenylthio of 2-6 carbon atoms or alkenylthio of 2-6 carbon atoms substituted with one of the 10 groups - (CH 2) -NRR '- (CHJ -NR-CR '= NR "and - (CH_) -NzzCR-NR'R" dn dn £ n (with n = 0, 1, 2, 3 and fi, R' and Htt H or alkyl of 1-3 carbon atoms Alkanoyl of 1-3 carbon atoms) or also of alkyl of 1-3 carbon atoms phenyl, a saturated, unsaturated or aromatic heterocyclic radical of 1 to 4 heteroatoms (nitrogen, oxygen, sulfur), cyano, carboxy consisting of 3 to 7 atoms alkoxy carbonyl having 1 to 4 carbon atoms, aminocarbonyl or acylamino. 9. Compounds according to any one of claims 1-3, characterized in that X is a 4-7 atomic monocyclic, saturated, unsaturated or aromatic heterocyclic ring with 1-4 heteroatoms (N, O, S) which may be substituted with fluorine, chlorine, bromine, oxo, imino, alkyl of 1 to 5 carbon atoms, alkylthio of 1-3 carbon atoms, hydroxy, cyano, N-oxido, trifluoromethyl, alkoxy of 1-4 carbon-25 atoms , alkanoyloxy of 1-4 carbon atoms, phenoxy, alkanoyl of 1-4 carbon atoms, phenoxycarbonyl, pivaloyloxymethoxycarbonyl »carbamoyl, alkylcarbamoyl having 1-3 carbon atoms in the alkyl group and / or dialkylcarbamoyl having 1-3 carbon atoms in the alkyl groups or with - (CH ^ i ^ NER *, - (CH ^^ - NR-CR1 = NR "or 30 - (CH") -NsCR-NR'R "with n = Ö, 1, 2, 3 and R, R ' and R "= H, alkyl dn of 1-3 carbon atoms, alkanoyl of 1-3 carbon atoms, or with - (CH-) -COR1 with n = 0, 1, 2, 3 and S '= hydroxy, alkoxy with dn 1 -3 carbon atoms, amino or -NH- (CH-) -NEL, where m = 2.3, 4; d m d or also represents - (CH_) OH with n = 0, 1, 2, 3. d n Compounds according to any one of claims 1 to 3, characterized in that X is 2- (acetylamino) -vinylthio, (1-methyl-1H-tetrazol-5-yl) -thio, (1,4,5,6 -tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio, (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl ) -thio, (1-ethyl-1,2-dihydro-2-oxo-4-pyrimi-40-dinyl) -thio, (5-methyl-1,3,4-thiadiazol-2-yl) -thio or acetoxy 8200217 '' 5k represents. Compounds according to any one of claims 1 to 10j as defined as end products in any of Examples I-III. Compounds according to any one of claims 1 to 10j as defined as end products in any of Examples IV-XXVIII. Compounds according to any one of claims 1-10, having the general formula 1a, as well as their readily hydrolysable esters, pharmaceutically compatible salts thereof, and hydrates of these compounds. Compounds of the general formula 2, wherein R 1, R 2, R 3, R 3, R 3, R 3, and X have the meaning as defined in claim 19, wherein X may also represent bromine. Compounds according to any one of claims 1 to 13 as pharmaceutically active substances. Compounds according to any one of claims 1 to 13 as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. Pharmaceutical preparations, characterized by a content of a compound according to any one of claims 1 to 13 Pharmaceutical preparations for the treatment and prophylaxis of infectious diseases, characterized by a content of a compound according to any one of claims 1 to 13 19. Process for preparing a compound according to claim 1, characterized in that a compound 12 of formula 2, in which R, R and X as defined in claim 1 are defined, R is an easily cleavable moiety and R, R and R 1 alkyl of 1-6 carbon atoms, phenyl or p-methoxyphenyl, ring-closes, optionally cleaves the protecting group present in a substituent and optionally transesterifies the ester 3 obtained, optionally by cleavage of the residue R in the free acid resp. converts a salt thereof and optionally converts a product obtained into a hydrate. A method according to claim 19, characterized in that R, R 7 and R 0 each represent a phenyl residue. Use of a compound according to any one of claims 1 to 13 in the treatment or. prophylaxis of infectious diseases. ***** 8200217