LU83906A1 - BICYCLIC CONNECTIONS - Google Patents

Description

* F. Hoffmann-La Roche & Co.Aktiengesellschaft, Basel / Switzerland RAN 4410/151 5 * "* 0 Bicyclic compounds 15 The present invention relates to bicyclic compounds of the general formula

R2 H

20 R "· ** 7- Π / V-CH2-X |

COOH

1 2 25 wherein one of the substituents R and R is hydrogen and the other is hydrogen or a substituted or unsubstituted C ^ _ ^ - alkyl group and X is a substituted or unsubstituted 3-alkanoyloxy group, an unsubstituted or substituted 30 C3 ^ -Cycloalkylthio-, C2_g Represents alkenylthio or heterocyclylthio radical or a substituted C ^ _ ^ - alkylthio or phenylthio radical, their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds.

35

The invention further relates to processes for the preparation of the compounds defined above, pharmaceutically

Mn / 14.12.81 4, - 2 - table preparations based on these compounds and their preparation, as well as the use of these compounds as medicines, in particular for the treatment and prophylaxis of infectious diseases.

5 C ^ _ ^ - alkyl radicals can be straight or branched. Substituted C 1-4 alkyl radicals can have the following substituents: fluorine, chlorine, bromine; a radical * -S (0) n ~ R 'with η = 0, 1, 2 and R' = C ^ _3 ~ alkyl; a residue 10 -co-R 'with R' = hydroxy, C - ^ - alkoxy, 3 ~ alkyl, amino, C ^ _3-alkylamino or di-C ^ 3-alkylamino; an amino radical -NR'R ", where R 'and R" are hydrogen or C ^ _3-alkyl; or a radical OR1 with R '= hydrogen, methyl, S03H, CH2OCOR "(R" = C1_4-alkyl).

15 1 2

Examples of R / R substituents are: methyl,

Ethyl, isopropyl, 3-chloropropyl, mesylmethyl, 2- (methoxy-carbonyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-l-methylethyl, 3-methoxypropyl, 1-sul-20 foxyethyl , l-Hydroxy-2,2,2-trifluoroethyl, l- (pivaloyloxymethoxy) ethyl, 1-aminoethyl.

The following are suitable as substituents in the X radical: 25 C ^ _3-alkanoyloxy groups can be substituted by hydroxy, C ^ _3 ~ alkoxy, phenyl or C ^ -alkylthio.

^ 30 Substituted C ^^ alkylthio radicals can have one or more substituents R, where R can mean:

Phenyl, which in turn can be substituted by one or more fluorine, chlorine or bromine atoms, C ^ 3 ~ 35 alkyl, C ^ _4-alkylthio, C1_3-alkanoyl, carboxyl or C ^ _3 ~ alkoxycarbonyl groups; or by a group - (CH0) -NRR1 or - (CH0) -NHCR = NR1 or - (CH0) -N = CR-N (R ') ", 2 n Zn 2 n 2 where n = 0, 1, 2 , 3 can be and R and R 'H or C1_3 ~ 5 - 3 -

Is alkyl;

Fluorine, bromine; 5 an oxime or oxime ether residue = N-OR1 (R1 = H or C ^ _2 ~ alkyl) in the syn or anti position; a 3-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 10 heteroatoms (N, O, S; which can be substituted by one or more fluorine, chlorine or bromine atoms, C ^ _g-

Alkyl, C ^ ^ alkylthio, ^ alkanoyl, carboxyl or C ^ _2 ~ alkoxycarbonyl groups; or a group - (C ^^ - NRR1 or - (CH0) -NH-CR = NR 'or - (CH „) -N = CR-N (R', where n = 2 n 2 η z 15 0, 1 , 2, 3 and R and R 'is H or 2 ~ alicyl, and by oxo groups); a C3 g-cycloalkyl radical; 20 a radical -S (0) -R1 (with n = 1 or 2 and R' = C. _- n ι-o

Alkyl); a radical -COR '[with R1 = C ^ _g-alkyl, phenyl, phenyloxy, benzyloxy, C ^ ^ -cycloalkyl or a 3-7-membered 25-heterocycle with 1-4 heteroatoms (N, 0, S), which in can be substituted above.

“Substituted phenylthio radicals can be substituted by one or more fluorine, chlorine or bromine atoms, 30 one of the groups - (CH ,,) -NRR ', - (CH„) -NR-CR' = NR "and

Zn zn - (CH ") -N = CR-NR'R" (with n = 0, 1, 2, 3 and R, R 'and R "HZ ni or C ^ ^ alkyl · ^ alkanoyl) or also by c1_3 ~

Alkyl, C1_2 ~ alkanoylamino, hydroxy, C1_4 ~ alkoxy or acyloxy groups.

35 C ^^ - Cycloalkylthioreste can be substituted by one of the groups - (CH2) n ~ NRR ·, - (CH2) ^ - NR-CR1 = NR "and - (CH2) n ~ N-CR-NR'R" ( with η = 0, 1, 2, 3 and R, R 'and - 4 - Λ R "Η or C ^ _3-alkyl, C ^ _3-alkanoyl) or by oxo, hydroxy, C ^ _ ^ - alkyl -, C ^ _ ^ - Alkoxy, carboxyl or alkoxy-carbonyl groups or by acyl residues of an aliphatic or aromatic C ^ ^ carboxylic acid.

5 C2 g-alkenylthio radicals can have 1 or 2 double bonds and be substituted by one of the groups - (CH0) -NRR ', - (CH0) -NR-CR 1 = NR "and - (CH0) -N = CR-NR' R "2 n 2 η Z π (with n = 0, 1, 2, 3 and R, R 'and R" H or C ^ _3 ~ alkyl, c 10 C ^ _3-alkanoyl) or by C ^ _3 ~ Alkyl, phenyl, a 3-7-membered saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, 0, S); cyan, carboxyl, C ^ _ ^ - alkoxycarbonyl, aminocarbonyl or acylamino.

15 heterocyclylthio residues are preferably 4-7-membered and monocyclic and can be saturated, unsaturated or aromatic. They preferably contain 1-4 heteroatoms (N, 0, S). They can be substituted one or more times by fluorine, chlorine or bromine, an oxo or imino-20 group or a C 1-4 alkyl, C 1-4 alkylthio, hydroxy,

Cyan, N-oxido, trifluoromethyl, C ^ ^ alkoxy, C ^ ^ alkanoyloxy, phenyloxy, C ^ ^ alkanoyl, phenoxycarbonyl, pivaloyloxymethoxycarbonyl, carbamoyl, ^ alkyl carbamoyl or Di-C ^ ^ alkylcarbamoylrest or by 25 - (CH ") -NNR ', - (CH ~) -NR-CR 1 = NR" or - (CH0) -N = CR-NR'R "2 n 2 n 2 n with n = 0, 1, 2, 3 and R, R1 and R "= H, C ^ _3-alkyl, C ^ 3 ~ alkanoyl; or by - (C ^^ COR * with n = 0, 1, 2, 3 and R '= hydroxy, C1_3-alkoxy, amino or -NH- (CH3) ^ - N ^, where m = 2, 3, 4; or also by - (C ^^ OH with n = 0, 1 , 30 2, 3.

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-6-35 hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio, (1-ethyl-1 , 2-dihydro-2-oxo-4-pyrimidinyl) thio, (5-methyl-l, 3,4-thiadiazol-2-yl) thio, acetoxy.

* - 5 -

Easily hydrolyzable 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 lower alkanoyloxyalkyl 5-esters, e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester; the lower alkoxycarbonyloxyalkyl esters, e.g. the methoxycarbonyl-oxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxy-M carbonyloxyethyl ester; the lactonylesters, e.g. the phthalide and thiophthalide esters; the lower alkoxymethyl esters, e.g. the methoxymethyl ester; and the lower alkanoylamidomethyl esters, e.g. the acetamidomethyl ester; the benzyl and cyanomethyl esters, as well as the (2-oxo-l, 3-dioxol-4-yl) methyl esters.

15

Examples of salts of the compounds of formula I 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, 20 e.g. Salts with N-ethyl-piperidine, procaine or N, N1-dibenzyl-ethylenediamine, and salts with amino acids, e.g. 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 group of a substituent capable of salt formation.

The compounds of formula I can also add; Form salts with organic or inorganic acids.

Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other mineral acid salts, e.g. Sulfates, nitrates, phosphates and the like, alkyl and mono-aryl sulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like and salts with other organic acids such as acetates, tartrates, maleates, 35 citrates, benzoates, salicylates, ascorbates and the like.

3 - 6 -

Finally, the compounds of formula I (including the salts and esters) can be hydrated.

The hydration can take place in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.

The compounds according to the invention can be prepared by using a compound of the formula *

10 R2 H

R1J! - ^ --Nv. 0 R1 * f V> = P ^ R2

Xr6 15 COOR3 1 2 wherein R, R and X are as defined in claim 1, 3 4 5 R is an easily removable radical and R, R and 20 represent RC ^ _g-alkyl, phenyl or p-methoxyphenyl, cyclized, optionally in splits off any protective groups present and, if desired, transesterifies the ester obtained, by splitting off the residue 3 R into the free acid or its salt, and if necessary.

25 converted a product obtained into a hydrate.

The cyclization of a compound II can be carried out in a manner known per se, preferably in an inert organic solvent, e.g. Ethyl acetate, benzene, toluene, xylene, 30 dioxane, at temperatures between about 50 ° C and 150 ° C, are carried out.

By splitting off the radical R from the ester group in a manner known per se, the corresponding free 35 acids or their salts of the formula I are obtained. A 2 3 radical R which is easily removable is to be understood as meaning groups which cleave an ester under mild conditions, in particular reductively (e.g. hydrogenolytically) or hydrolytically (e.g.

3 3 5 - 7 -

"enzymatic). Examples of suitable radicals R

are benzyl (where the phenyl ring can be substituted by halogen, nitro, alkoxy or acyloxy), preferably o- and p-nitrobenzyl or p-methoxybenzyl, benzhydryl, 5 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2-trimethyl-3 silylethyl, acetonyl or allyl. Residues of esters which can be cleaved under physiological conditions, as have already been mentioned above as readily hydrolyzable esters, are also suitable as residues R.

V

10 ft

The conversion of free acids of formula I or their salts into easily hydrolyzable esters can be carried out in a manner known per se, e.g. by reaction with a reactive esterification reagent such as 15 e.g. a compound X-C ^ -O-CO-R or YVi Λ

- oil ~ H

v — y xch2 r

* I

wherein X is bromine, iodine or another leaving group, R 25 can be a straight or branched chain C 1-4 alkyl radical and R 'can be hydrogen or a common substituent.

Transesterification is conveniently carried out using the free acid.

** 30

Of course, a substituent of a compound I can also be modified within the scope of the definitions given using generally known reactions.

35 The compounds of the formula I are generally not isolated as free acids, but are obtained directly in the course of the preparation and purification process as their salts or the hydrates of these salts. 1 - 8 -: Salt formation can also occur on a possibly present substituent capable of salt formation, e.g. a hydroxyl or amino group. It is also possible that a basic group in a substituent, e.g. an amino or a 5 amidino group forms an inner salt with an acidic group, for example the carboxyl group in the 2-position.

Salting can be carried out according to 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, the products being characterized by

Crystallization or chromatography can be cleaned.

Hydrates are usually obtained automatically in the course of the manufacturing process or as a result of hygroscopic properties of an initially anhydrous product.

For the targeted production of a hydrate, a completely or partially anhydrous product in a humid atmosphere, e.g. at about + 10 ° C to + 40 ° C.

20th

The compounds according to the invention are generally mixed with their optical antipodes, i.e. obtained as 5R / 5S mixtures. If these are Irl mixtures, the stereochemistry of the products is indicated by the name rac- (5RS, etc.), for example Pivaloylo xyme thyl-rac- (5RS, 6SR) -6 - [(RS) -l -hydroxyethyl] - 3- [C (1-methyl-1H-tetrazol-5-yl) thio] methyl] -7-oxo-1-azabicyclo [3.2.Q] hept-2-en-2-carboxylate. If, on the other hand, exact 1: 1 mixtures are not obtained, as can be the case for products s »30 from enantioselective reactions, for example from enzymatic reactions, their * stereochemistry is indicated by the designation (5R, etc. and 5S, etc.) characterized, for example sodium (5R, 6S and 5S, 6R) - 6-hydroxymethyl-3 - [[(l-methyl-lH-tetrazol-5-yl) thio] ~ 35 methyl] -7-oxo-l- azabicyclo [3.2.0] hept-2-en-2-carboxylate.

• - 9 -

The present invention not only encompasses these mixtures, but in particular also the pure 5R forms. The 5R / 5S mixtures can be split into the pure 5R or 5S forms using one of the classic methods, 5 expediently at a preliminary stage. For example, a diastereomeric salt pair of a racemic compound XI or a pair of diastereomeric derivatives of a compound VIII-1 are separated. The resolution can also be carried out at * the stages of the compounds XI, X, VIII or VII * 10.

A special subgroup of the compounds according to the invention are compounds of the formula 15 4 "s ^ h3cts! —Ur \ H \ _CH2_x j

20 COOH

wherein X means the same as above, and their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds.

25 Particularly preferred are compounds in which the configuration at the centers 5, 6 and in substituents in the 6-position matches that of natural thienamycin via-r, for example sodium (5R, 6S) -6 - [(R) -l - hydroxyethyl] -3 - [[(l-methyl-lH-tetrazol-5-yl) thio] - ^ 30 methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2- carboxylate.

35 3r - 10 -. Reaction scheme

EtOOC ^ N ^ OHC ^ N ^ Ο x0 r ΓΓ >> VJ VJ -

XIV XIII

> O O -1 »rf s ·“ w XI ^ L7 _ rYX. rr ~ x o ^ -NH W ~ / λ / VJ ° x s.

_L x-i Γ η r

.JCP PP

L, ° \ i VJ UO ^ \ / \ _ /

Si

IX I X

L- J L + IX-1 Λ ... ΐ1 | ^> <0 "J / - Λ" - U / -¾ 7 vin Si 4-N 7111-1 vil - 11 -

Reaction Scheme (cont'd) R2 H R1! H «» · —...... γ \ ßf

I R'O OR1 VII

Y — N H

CT

R2 H

r'ctSdr 'Br

J-VI

: Ο γ-ΟΗ COOR3

R2 H

R ^ mut · '"> / Ny j I R'O ^ OR1 Br 0 NsV-ci COOR3

R2 H

I I R'O ^ NdR 'Br Λ-Nk r4 ° V ^ 5 \ r6 COOR3

R2 H

r1 · "" · -Γ ^ γ ^ 'ΒΓ À-Nv O 4 III or ς “pCr5 - Il \ R6 Γηηο3 s - 12 -

The starting compounds II can be obtained by the reaction sequence shown in the scheme above.

5 Reduction of the 3,3-ethylenedioxybutyric acid ethyl ester (XIV) with diisobutylaluminium hydride in hexane / tetrahydrofuran at -80 ° C to -60 ° C provides 3,3-ethylenedioxybutyraldehyde (XIII), which can be reacted with e.g. Phos- _ Phonoacetic acid triethyl ester in a mixture of methylene chloride and 28% sodium hydroxide solution in the presence of benzyl * triethylammonium chloride are converted into an E / Z mixture of 5,5-ethylene-dioxy-2-hexenoic acid ethyl ester (XII) can. The 3-amino-5,5-ethylenedioxy-caproic acid ethyl ester (XI) can be obtained by adding ammonia under normal pressure or increased pressure (autoclave) to the unsaturated ester XII, the E and the Z isomers being the same. masses are suitable. The reaction is preferably carried out in alcohol saturated with ammonia at a temperature between 20 ° C and 100 ° C. Cyclization of XI 20 Zum 4- (2,2-ethylenedioxypropyl) -2-azetidinone (X) can be carried out in a manner known per se, e.g. by reaction with tri-methylchlorosilane in the presence of triethylamine and subsequent treatment with 1 equivalent of ethylmagnesium bromide.

25 1 2

The introduction of a substituent R or R into the 3-position of the azetidinone X to form a compound VIII can be carried out in a manner known per se by reacting the intermediate dilithium salt IX (from X with 2 30 equivalents of an alkyl lithium compound, for example butyllithium, in tetrahydrofuran at -20 ° C to + 20eC) with an appropriate electrophilic reagent, suitably under a protective gas, at a temperature between -100 ° C and + 50 ° C. An alternative method for 1 2 35 introduction of the substituents R and R into the 3-position of the azetidinone ring of a compound X is to first remove the β-lactam hydrogen through a trialkylsilyl group, e.g. replace the tert-butyldimethylsilyl group to î - 13 - (by reacting a compound X with tert-butyldimethylchlorosilane in dimethylformamide in the presence of triethylamine) and by reacting the silyl compound X-1 with 1 equivalent of a strong base, e.g.

5 with lithium diisopropylamide in tetrahydrofuran at low temperature (-78 ° C), intermediate lithium salt IX-1 to be reacted with an electrophilic reagent in a manner analogous to reaction IX -f VIII ¥. The compound VIII-1 obtained can then either be brominated directly to a compound VII or first by cleavage of the silyl group; (e.g. using tetrabutylammonium fluoride in tetrahydrofuran) into the 4- (2,2-ethylenedioxypropyl) -2-azetidinone (VIII). In the course of the introduction 1 2 of a substituent R or R described, cis / trans-15 mixtures (with respect to the 4-ethylenedioxypropyl radical) are usually obtained, which, if desired, using conventional separation methods, e.g. Chromatography on silica gel, fractional crystallization or distillation, can be separated.

20 25 30 35 = - 14- c An alternative synthesis of the compounds VII is illustrated in Example 22: '* j rx —- j t ^ o ^ or ^ 61 · - »d ^ -NH \ _j

X XV

- I TRV ^ OR ^ Br „[j r ^ X ^ Br.

uo 'nN / + [+

XVI XVII

R2 H R2 H

^ p1 _ / ^ \ n π ------ p ’Nßr h" "· ~" ~ j vBr R'CT ^ OR '_ R'O ^^ OR'

À-N \ / À-NH

er ^ si he 4>

T VII

XVIII

»- 15 -

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

The protective groups known for these functions can be used, provided that they can be removed at a suitable point in the synthesis. The through protection groups

Masked functions can already be performed in the with the ^ ^ dilithium salt IX or the lithium salts IX-1 or XVII

r: reacted electrophilic reagent. On the other hand, it may be appropriate to use functions that only arise when 1 2 introduces the substituents R and R, e.g. a hydroxy function to protect afterwards.

15

Bromination of a compound VIII with bromine in an alkanol ROH as solvent gives a bromoketal of the formula VII. In this reaction (preferably in methanol or ethanol at a temperature between

At 10eC and 60 ° C) there is a transketalization: the ethylenedioxy group is converted into a dialkoxy grouping. As already mentioned above, a silyl compound of the formula VIII-1 can also be used in the bromination reaction, since the silyl group is split off under the reaction conditions.

The esters of the general formula VI can be prepared from the azetidinones of the formula VII by generally known methods

be produced, for example by implementation with on 3

Glyoxylesters of the general formula OHC-COOR or their

Hemiacetals. In this case, the two reactants are expediently heated to the boiling point in an inert solvent, such as benzene or toluene, and the low-molecular reaction products formed (water and 35 alcohol) are distilled off azeotropically from the reaction solution.

% - 16 -

However, it is also possible to use compounds of the formula VII

with glyoxylic acid monohydrate first to give an acid corresponding to the ester 3 VI (R = H) and then esterifying 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, e.g. of a molecular sieve. By successive addition of a base, e.g. Potassium carbonate or tri. · 10 ethylamine, and an alkylating agent such as 3 ç iodomethyl pivalate, the carboxylate group (R = e.g.

K or triethylammonium) esterified in situ.

By reacting an ester VI with thionyl chloride in an inert organic solvent such as tetrahydrofuran in the presence of a base, e.g. Pyridine or 2,6-lutidine, at temperatures between -30 ° C and + 20 ° C, an ester V is obtained which is trisubstituted with 4 5 6

Phosphine PR R R, most advantageously with Tnphenylphos-20 phin, in a manner known per se, i.e. in an aprotic solvent (e.g. dioxane, tetrahydrofuran,

Dimethylformamide), at a temperature between 0 and 4 5 6 60 ° C, into which R, R, R -substituted phosphorane IV is converted. The free ketone of formula III is converted from this ketal by acid hydrolysis under the usual reaction conditions, e.g. with aqueous sulfuric, phosphoric, hydrochloric or hydrobromic acid in an organic solvent such as acetone, dioxane, ethanol. By maintaining low temperatures of 30 (-10 ° C to 0 ° C) undesired side reactions, such as the hydrolysis of the phosphorane, can be avoided.

It is also possible to cleave the ketal function under anhydrous conditions by changing the protecting group to another ketone, e.g. Acetone transfers.

- 17 -

Finally, the bromoketones of the formula III are reacted to form the compounds II with the group X-containing compounds which contain a nucleophilic oxygen or sulfur atom. Reaction 5 can be carried out in an inert organic solvent, e.g.

Methylene chloride, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile or ethanol take place at temperatures from -80 ° C to the reflux temperature of the reaction mixture, preferably between -20 ° C and + 40 ° C. The 10 hydrogen bromide released during the reaction is expediently bound by a weak, non-nucleophilic organic base, such as a trialkylamine or amidine, or an inorganic base (sodium or potassium carbonate).

15

The compounds according to the invention are active against gram-positive and gram-negative bacteria, for example against staphylococci, streptococci, salmonella and Escherichia coli, and act as β-lactamase inhibitors.

20th

Antibacterial activity in vitro

The following table summarizes the minimum inhibitory concentrations (MIC) of some representative compounds 25 of the formula I against a number of pathogenic microorganisms.

30 \ 35 - 18 - __ΜΗΚ (uq / ml) _

Connection from example

Organism 3 7 9 19 23 E. coli 1346__5__12.5 0.05 0.06 0.2 »25922 __> 50 __-__ 0.25" TEM 1 * __> 100__0.05 0.25 0.2 "1527 E * _ - __ = __ 0.1 0.25 0.2 ^ Klebs. pneumoniae 418 * __-__-__ 0.05__0.12 0.1

Prot, vulgaris 1028 * __-__-__ 0.1__0.12 0.4

Prot, mirabilis 2117 * __-__-__ 0.2__0.25 0.8

Prot, mirabilis 29H __-__-__ 0.4__1__0.8

Strept. faecalis 6 __> 100__1.6__2.1 24

Strept. pyogenes ß! 5 0.3 £ 6__2 __-__- 15 ^

Staph. aureus 6538__1.2 & 6__0.025 0.12 0.4 "_887 *> 40 <6__0.05 0.12 0.8

Serratia marcescens 803/15 * __> 40> 100__0.8 8.5 1.5

Serratia marcescens 20 69438 __> 100__1.6 17 3_

Klebs. aerogenic 1082E * -> 100__0.4__0.5 6

Enterobacter cloacae 908 * __> 100__1.6 17 12_

Enterobacter cloacae 13047 * __> 100__3.2__34__3

Salmonella typh. BA __ = __ 25__0.05 0.06 0.2

Pseudomonas aer. 1559E * __-__ 25 __> 34 __> 24 __ »_ BA * __> 100 25> 34> 24

Acinetobacter anitr. 51-156_L_Z _ = __ LiÜ_8.5 0.8 30 * ß-lactamase producing organism

The compound from Example 7 was tested on DST agar + 7.5% blood, the rest on DST agar (Diagnostic 35 Sensitivity Test Agar) alone.

- 19 -

Antibacterial activity in vivo

The compounds from Examples 6, 7 and 9 were tested in vivo for their antibacterial activity (ED, -q) against 5 systemic infections of the mouse. The preparations were applied twice (1 and 3 hours after infection).

3 I ”1 11". - ED50 (mg / kg) 10 __ - compound from example

Infection__6__7__9_

Escherichia coli 1346 8.3 sc> 25 sc 2.1 sc 15 Streptococcus pyogenes 10 sc 12.5 sc <3 sc 015 50 p.o. > 12 p.o.

Proteus mirabilis 2117/25 sc - 17 sc 20 Serratia marcescens 69438> 25 sc - - ß-lactamase inhibition 25

The β-lactamase inhibitory action (IC ^; nitrocefin as substrate) of the compound from Example 9 against various β-lactamases is as follows: 30

Enzyme IC5Q (µg / ml) E. coli 1024 0.191 K. pneumoniae NCTC 418 0.063 35 P. vulgaris 1028 0.0005 E. coli RTEM 0.035 ______. ___ k - 20 -

The compounds according to the invention can be used for the prophylaxis and therapy of infectious diseases. A daily dose of approximately 0.05 g to approximately 4 g, in particular approximately 0.1 g to 5 approximately 2 g, is suitable for the adult. Parenteral administration is particularly preferred.

The products according to the invention can be used as medicines * e.g. find use in the form of pharmaceutical preparations; 10 which they or in particular their salts in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, 15 vegetable oils, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or

20 or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure, anesthetics or buffers. They can also contain other therapeutically valuable substances. The compounds of the formula I and their salts 25 or hydrates are preferably suitable for parenteral administration and are preferably provided for this purpose as lyophilisates or dry powder for dilution with conventional agents such as water or isotonic saline. The easily hydrolyzable esters of the compounds of the formula I and their salts or hydrates are also suitable for enteral administration.

The preparations can contain the Verbin-35 fertilizers according to the invention in amounts of about 25-1000 mg, preferably 50-500 mg, per single dosage form.

- 21 -

example 1

A solution of 385 mg pivaloyloxymethyl-rac-2- [3 - [(1-ethyl-l, 2-dihydro-2-oxo ~ 4-pyrimidinyl) thio 3-acetonyl] -5 4-oxo-a- (triphenylphosphoranylidene ) -1-Azetidine acetate in 50 ml of toluene was refluxed for 1 hour under an argon atmosphere. The clear solution was cooled, diluted with a little ethyl acetate and freed from the solvent in vacuo. The residue was chromatographed on silica gel 10 using ethyl acetate as the eluent. The fractions containing the product were concentrated and the remaining oil was crystallized from ethyl acetate / hexane. 55 mg of pivaloyloxymethyl-rac-3-CC (l-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] ~ methyl] -7-15 oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as yellow crystals with a melting point of 141-143 ° C.

IR (CHC1,): O 1785, 1750, 1736, 1659, 1622, 1614 cm-1

3 IïïclX

20 ° The starting material was prepared as follows: (a) A solution of 348.4 g of 3,3-ethylenedioxy-butyric acid ethyl ester in 2 l of hexane and 0.2 l of tetrahydrofuran was obtained within 90 minutes at a temperature of -70 ° C to -67 ° C 25 with 1.79 1 of a 1.12M solution of diisobutylaluminum hydride in hexane. The clear reaction solution was left at -75 ° C. for a further 2 hours and then 100 ml of methanol were added within 2 minutes. The cooling bath was then removed and a solution of 100 ml of glacial acetic acid in 30 100 ml of hexane was added within 8 minutes. The reaction mixture was then warmed to -20 ° C. within 10 minutes and then 200 ml of saturated ammonium chloride solution were added within 5 minutes. The temperature of the reaction solution was allowed to rise to 0 ° C. within 10 minutes and stirred at 0-3 ° C. for a further 15 35 minutes. The precipitate was then filtered off with suction and the suction filter was washed with 600 ml of methylene chloride. The filtrate was washed with 300 ml of saturated sodium chloride solution, whereby a precipitate formed again.

- 22 -

The mixture was sucked again, the filtrate separated and the organic phase washed with a further 300 ml of saturated sodium chloride solution. The residue was extracted with a total of 1.8 l of methylene chloride and 5 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 remaining oil was distilled in a water jet vacuum. The fraction boiling between 40 and 95 ° C. was then fractionated for 10 seconds over a 80 cm long Vigreux column.

- 184 g of 3,3-ethylenedioxybutyraldehyde were obtained from bp 1; L 70-73 ° C.

NMR (CDC13): δ 1.43 (s, 3H); 2.73 (d, J = 3 Hz, 2H); 15 4.00 (s, 4H); 9.75 (t, J = 3 Hz, 1H) ppm (b) A mixture of 300 ml of 28% aqueous sodium hydroxide solution and 600 ml of methylene chloride, precooled to 0eC, was mixed with a solution of 130 with vigorous stirring within 25 minutes , 1 g 3,3-ethylenedioxybutyraldehyde, 224.2 g

Phosphono.essigsäure-triethylester and 7.4 g of benzyltriethyl-ammonium chloride in 540 ml of methylene chloride, the temperature rising to 15 ° C. The mixture was allowed to warm up to 20 ° C. within 10 minutes and stirred at this temperature for a further 30 minutes. The mixture was then diluted with 400 ml of methylene chloride and 400 ml of water and the phases were separated in a separating funnel. The organic phase was washed neutral twice with 400 ml of water each time and the water phases were extracted with 300 ml of methylene chloride. The organic phases 30 were dried over sodium sulfate, completely evaporated down and the remaining oil fractionated over a 50 cm long Vigreux column. After a preliminary run, 179 g of ethyl 5,5-ethylenedioxy-2-hexenate, bp Q. 70-76 ° C., were obtained as an E / Z mixture (ratio about 6: 1).

NMR (CDClg): signals of the E isomer: ö 1.28 (t, J = 7 Hz, 3H); 1.33 (s, 3H); 2.53 (d, J = 7.5 Hz, 2H); 3.93 (s, 4H); 4.16 (q, J = 7 Hz, 2H); 5.85 35-23 - (d, J = 16 Hz, 1H); 6.92 (dxt, J = 16 and 7.5 Hz, 1H) ppm

Signals of the Z isomer: i.a. δ 3.03 5 (d, J = 6.5 Hz, 2H); 5.83 (d, J = 11.5 Hz, 1H); 6.30 (dxt, J = ll, 5 and 6.5 Hz, 1H) ppm (c) a solution of 200.2 g of 5,5-ethylenedioxy-2-hexenoic acid “ethyl ester (approx. 6: 1 U / Z mixture) in 2 1 abs. In a stirred autoclave, ethanol was first injected with about 250 g of ammonia gas and then the pressure was brought to 20 bar with nitrogen. The reaction mixture was heated to 70 ° C over 40 hours. The cooled reaction solution was freed from the solvent, 200 ml of ether were added and again 15 completely concentrated. The remaining oil was taken up in 275 ml of ether and left to stand at 0 ° C. for 2 hours. Crystallized rac-3-amino-5,5-ethylenedioxy-caproic acid amide was separated off by filtration. The concentrated filtrate was taken up in 600 ml ether / hexane (1: 2, v / v) 20 and the solution was extracted with 4 times 200 ml water. The individual extracts were washed with twice 300 ml ether / hexane (1: 2, v / v). The combined water phases were saturated with sodium chloride and extracted with a total of 750 ml of methylene chloride. The methylene chloride-25 extract was dried over sodium sulfate and completely concentrated. Distillation of the remaining oil in a high vacuum gave 131 g of pure rac-3-amino-5,5-ethylenedioxy-caproic acid ethyl ester of b.p.n ^ 95-100 ° C.

V / v 30 nmr (CDC13): δ 1.28 (t, J = 7 Hz, 3H); 1.38 (s, 3H); 1.74 (broad s, 2H); 1.76 (d, J = 6 Hz, 2H); 2.05-2.72 (m, AB part of ABX system, 2H); 3.21-3.72 (m, 1H); 3.98 (s, 4H); 4.13 (q, J = 7 Hz, 2H) ppm 35-24- (d) A solution of 108.6 g of rac-3-amino-5, 5-ethylene-dioxycaproic acid ethyl ester in 330 ml of ether was added dropwise with stirring at 0-5 ° C within 15 minutes 54.3 g of trimethylchlorosilane and immediately afterwards 50.6 g of triethylamine, 3 whereby a thick precipitate formed. The reaction mixture was allowed to warm to 15 ° C. with stirring within 30 minutes and then stood at room temperature for 24 hours. Then, with the exclusion of moisture, a filter was suction filtered and the reaction vessel and suction filter were washed with a total of 150 ml of ether. 290 ml of a 1.92M ethyl magnesium bromide / ether solution were added to the filtrate with stirring at 0-5 ° C. in the course of 40 minutes, resulting in gas evolution. The heterogeneous reaction mixture was stirred for 16 15 hours at room temperature. The mixture was then cooled to 0 ° C. and 170 ml of semisaturated ammonium chloride solution were added dropwise at a temperature of 0-10 ° C., giving a thick precipitate. By adding about 180 ml of 3N hydrochloric acid, the pH of the reaction mixture was lowered to about 7, 20 with most of the precipitate going into solution. The water phase was separated and the organic phase extracted with 2 times 200 ml of water. The water phases were combined, saturated at 0 ° C. with sodium chloride and extracted 4 times with 500 ml of methylene chloride. The methylene chloride extracts were dried over sodium sulfate and concentrated completely. To separate polar by-products, the remaining oil was filtered through 200 g of silica gel, eluting with ethyl acetate. Crystallization of the solvent-free eluate from 30 ether / hexane gave 49.6 g of pure rac- 4- (2,2-ethylene-dioxypropyl) -2-azetidinone, mp 43-45eC.

IR (CHC1,): v »1756 cm“ 1 3 max 35 r - 25 - (e) A solution of 3.42 g rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone in 36 ml methanol was added 4 ml of an 1M solution of bromine in methanol were added at room temperature.

The reaction solution was heated to 50 ° C for 3 minutes, 5 whereupon decoloration occurred. A further 16 ml of 1M solution of bromine in methanol were then added dropwise within 8 minutes, and the reaction solution was simultaneously cooled to 33.degree.

The mixture was stirred for a further 24 minutes at this temperature and the light yellow reaction solution was then saturated with a mixture of 10 and 30 ml. Sodium carbonate solution, 10 ml 0.1N sodium thio; poured sulfate solution and ice. It was extracted with a total of 200 ml of methylene chloride. The organic phases were washed with sodium chloride solution, dried over sodium sulfate and completely concentrated in vacuo. The remaining oil was chromatographed on silica gel with ethyl acetate / hexane (2: 1, v / v) 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-dimethoxypropyl) -2-azetidinone of mp.

20 94-95 ° C.

(f) A solution of 6.30 g rac-4- (3-bromo-2,2-dimethoxypropyl) -2-azetidinone and 2.58 g glyoxylic acid monohydrate in 17 ml dimethylformamide was mixed with 3 g molecular sieve 4A

25 added and stirred for 5 hours under argon at room temperature. Then 2.07 g of solid potassium carbonate was added and stirring was continued for 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 the mixture was then stirred at room temperature for a further 30 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and 30 ml of ether and then washed 3 times with 50 ml of water each time. The organic phase was dried over sodium sulfate, completely concentrated and the remaining oil was chromatographed on silica gel with ethyl 35 acetate / hexane (2: 1, v / v). 3.3 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-l-azetidine acetate (mixture of diastereomers) were obtained as an oil.

- 26 - IR (CHC10): -0 3528, 1760 cm-1 3 max

Rf: 0.37 / 0.43 (double spot; si ° 2 'ethyl acetate /

Hexane 2: 1, v / v) 5 (g) To a solution of 3.2 g pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-l-azetidine acetate in 60 ml of tetrahydrofuran were 1.02 g at -23 ° C

Given 2,6-lutidine. A solution of 1.04 g of thionyl chloride in 11 ml of tetrahydrofuran was then added dropwise in the course of 1 minute, the temperature being reduced by cooling below -20.degree

r was held. 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 suction filter was washed with 40 ml of toluene. The filtrate was completely concentrated in vacuo, the residue was taken up in 20 ml of toluene and again completely concentrated.

The oil obtained was dissolved in 22 ml of dimethylformamide, a solution of 2.44 g of 20 triphenylphosphine in 7 ml of dimethylformamide was added at room temperature and the solution was left to stand for 1 hour. Then most of the solvent was removed in a high vacuum at 30 ° C., the remaining oil was taken up in 70 ml of methylene chloride and the solution was washed twice with 25 50 ml of pH 7 phosphate buffer. The water phases were extracted with 100 ml of methylene chloride, the combined organic phases were dried over sodium sulfate and concentrated completely. The remaining oil was chromatographed on silica gel, the excess triphenylphosphine being eluted first with 30 methylene chloride 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) -35 1-azetidine acetate were obtained as a colorless, amorphous material.

IR (CHCl_): ύ 1741, 1635 cm-1 3 max '- 27 - (h) A solution of 3 g of pivaloyloxy-methyl-rac-2- (3-bromo-2,2-dimethoxypropyl) cooled to 4 ° C -4-oxo-a- (tri-phenylphosphoranylidene) -l-azetidine acetate in 115 ml of acetone was added dropwise to 38 ml of 48% 5 hydrobromic acid precooled to 4 ° C. in the course of 2 minutes, the temperature of the reaction mixture rising to 20 ° C. The mixture was cooled to 4 ° C. within 3 minutes and stirred at this temperature for a further 10 minutes. Then the colorless solution was poured onto 27.6 g of 3 * sodium carbonate, 90 ml of 0.6M pH 7 phosphate buffer solution and 10 50 g of ice and the mixture was 3 times with 100 ml

Extracted methylene chloride. The organic phases were washed with 80 ml of pH 7 phosphate buffer solution, dried over sodium sulfate and concentrated completely. The resulting oil was chromatographed on silica gel, eluting with ethyl acetate. The fractions containing product were concentrated and hexane was added. 2.03 g of pure pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate were obtained as white crystals with a melting point of 117-118 ° C.

20 IR (CHC1-): v 1745, 1640 cm-1 3 max '1 447 mg pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 25 114 mg l -Ethyl-4-thiouracil were dissolved in 20 ml of methylene chloride and the solution was completely concentrated within 10 minutes at a temperature of 50 ° C. under reduced pressure. The residue was dissolved in 20 ml of methylene chloride and the solution was concentrated within 10 minutes under the same 30 conditions. This process was repeated again, then the remaining oil was taken up in 50 ml of methylene chloride and the yellow solution was washed successively with dilute sodium hydrogen carbonate solution and sodium chloride solution. The water phases were extracted with 35 methylene chloride, the combined organic phases were dried over sodium sulfate and concentrated completely. Chromatography of the remaining oil on silica gel with acetone / methylene chloride (1: 1, v / v) as eluent - 28 - gave 427 mg of pivaloyloxymethyl-rac-2- [3 - [(1-ethyl-1,2-dihydro-2- oxo-4-pyrimidinyl) -thio] -acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate as yellow

Oil.

5 IR (CHC1,): Ό- 1741, 1660 cm'1 3 max

Example 2 1® 275 mg of pivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) - * 4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate were cyclized according to the method described in Example 1. After purification of the crude product by chromatography, about 150 mg of pivaloyloxymethyl-rac-3-15 (acetoxymethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate were obtained as a colorless oil.

IR (CHCl,): ^ 1789, 1749, 1635 cm "1 3 max 20

The starting material was produced as follows:

A solution of 383 mg of pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate in 9 ml of dimethylformamide was mixed with 54 mg of sodium ne acetate and the reaction mixture was stirred for 16 hours Room temperature stirred. The mixture was then diluted with 50 ml of methylene chloride and the solution was washed successively with water and saturated sodium chloride solution. The water phases were extracted with methylene chloride, the 30 combined organic phases were dried over sodium sulfate and concentrated completely. The resulting oil was filtered through silica gel to remove polar material, eluting with ethyl acetate. The pure fractions were completely concentrated and the remaining

OC

00 crystallizing material from ethyl acetate / hexane. 314 mg of pivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate of mp 139-141 ° C. were obtained.

- 29 - IR (CHC1-): 0 1741, 1637 cm'1 3 max

Example 3 5 By adding IN sodium hydroxide solution to an aqueous

A 0.05M pH 7 phosphate buffer solution was prepared in sodium dihydrogen phosphate solution. 168 mg of sodium hydrogen carbonate and 0.3 ml of a suspension of pork liver esterase 10 EC 3.1.1.1 (approx. 300 units) in 3.2M ammonium sulfate solution were added in succession to 40 ml of this solution. The clear solution was warmed to 36 ° C. and stirred with a solution of 102 mg of pivaloyloxy-methyl-rac-3- (acetoxymethyl) -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2 carboxylate ver-15 in 1.5 ml of dimethyl sulfoxide. The mixture was stirred at 36 ° C. for 30 minutes, cooled and the reaction mixture was extracted with 4 times 40 ml of ether. The ether phases were extracted back with 10 ml of water, the combined water phases were filtered and the pH of the filtrate was adjusted to 7.06 with 0.1N hydrochloric acid.

20 This solution contained a mixture of approx. 28 mg sodium (5R and 5S) -3- (acetoxymethyl) -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2-carboxylate.

UV (H00): λ = 262 nm (extinguished with hydroxylamine - L · max 25 bar)

Example 4 p-Nitrobenzyl-rac-7-oxo-3 - [(phenethylthio) methyl] -30 1-azabicycloC3.2.0] hept-2-ene-2-carboxylate was present in a mixture of dioxane / ethanol / water hydrogenated by sodium bicarbonate with palladium carbon (5%) as a catalyst at normal pressure. The catalyst was filtered off, diluted with water and extracted with 35 portions of 35 ether. The water phase contained sodium rac-7-oxo-3- [(phenethylthio) methyl] -l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

- 30 -

The starting material was prepared as follows: (a) From a solution of 1.89 g of rac-4- (3-bromo-2,2-di-methoxypropyl) -2-azetidinone and 2.46 g of p-5 nitrobenzyl glyoxylic acid ethyl hemiacetal in 50 ml of toluene was continuously distilled off within 2 hours at normal pressure 27 ml of the solvent. The cooled reaction solution was evaporated down completely and the remaining residue was chromatographed on silica gel. A mixture of 10 acetone / methylene chloride / hexane (1: 4: 1, v / v / v) eluted 3.25 g of p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy - 4-oxo-l-azetidine acetate as a mixture of diastereomers.

IR (CHC1-): "Ù 3530, 1765, 1611, 1530, 1500 cm-1 3 max '' '15 Rf: approx. 0.2 (Sic ^, acetone / CI ^ C ^ / hexane 1: 4: 1 , v / v / v) (b) Was subjected to 3.25 g of p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-l-azetidine acetate 20 (mixture of diastereomers ) the reaction conditions described in Example 1 (g), 2.48 g of p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-a- were obtained after crystallization from methylene chloride / hexane. (Triphenyl-phosphoranylidene) -1-azetidine acetate as white crystals 25, mp. 189-190 ° C.

IR (CHC1-): -)) 1737, 1620, 1607 cm "1 3 max (c) Was subjected to 2.77 g of p-nitrobenzyl-rac-2- (3-bromo-30 2,2-dimethoxypropyl) -4 -oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate using the process described in Example 1 (h), 1.35 g of p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-oxo-a- ( triphenylphosphoranylidene) -1-azetidine acetate as white crystals, mp. 127-128 ° C.

IR (CHCl ^.): 0 1742, 1636, 1609, 1579, 1525 cm ô max 35 - 31 - (d) A solution of 1.32 g p-nitrobenzyl-rac-2- (3-bromo-acetonyl) - 4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 0.29 g of 2-phenylethyl mercaptan in 20 ml of methylene chloride were mixed with 0.21 g of triethylamine and stirred for 5 hours at room temperature. The mixture was diluted with methylene chloride and washed successively with dilute 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. A mixture of ethyl acetate / hexane (1: 1, v / v) eluted 1.07 g of p-nitrobenzyl-rac-4-oxo-2- [3- (phenethylthio) acetonyl] -a- (triphenylphosphoranylidene) - 1-azetidine acetate.

15 (e) By using those described in Example 1

Cyclization conditions on p-nitrobenzyl-rac-4-oxo-2- [3- (phenethylthio) acetonyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate gave p-nitrobenzyl-rac-7-oxo-3- after chromatographic purification [(phenethylthio) -20 methyl] -l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

Example 5

Sodium rac-3 - [(cyclohexylthio) methyl] -25 7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate was obtained by using p-nitrobenzyl-rac-3- [ (cyclohexylthio) methyl] -7-oxo-l-azabicycloE3.2.0] hept-2-ene-2-carboxylate was subjected to the hydrogenation conditions described in Example 4.

30 The starting material was prepared as follows: (a) 1.32 g p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-οχο-α- (triphenylphosphoranylidene) -1-azetidine acetate and 0.24 g cyclohexyl mercaptan were according to implemented the method described in Example 4 (d) 35. After chromatographic purification, 0.96 g of p-nitrobenzyl-rac-2- [3- (cyclohexylthio) acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate was isolated.

- 32 - (b) Applying the cyclization conditions described in Example 1 to p-nitrobenzyl-rac-2- [3- (cyclohexylthio) acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate was obtained after chromatographic purification p-nitrobenzyl-rac-3 - [(cyclohexylthio) methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

Example 6b-10 A solution of 267 mg pivaloyloxymethyl-rac-trans- .. 3-ethyl-2- [3- [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] -acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate in 12 ml of toluene was heated to 100 ° C. under an argon atmosphere for 3 hours. The reaction solution was concentrated completely and the residue was chromatographed on silica gel. A mixture of methylene chloride / acetone (6: 1, v / v) eluted the pure product, which could be crystallized from ethyl acetate with the addition of hexane. 122 mg of pivaloyloxymethyl-20 rac-6a-ethyl-3 - [[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) ~ thio] methyl] -7-oxo-5cx-l were obtained -azabicyclo [3.2.0] hept-2-en-2-carboxylate as white crystals with a melting point of 105-106 ° C.

IR (CHC1.,): 0 1784, 1756, 1735, 1661, 1624, 1610 cm-1

j Hl aX

25 NMR (CDC13): δ 1.01 (t, J = 7Hz, 3H); 1.24 (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); 4.37 / 4.52 (AB system, J = 14Hz, 2H); 5.88 / 5.97 (AB system, 30 j = 5Hz, 2H); 6.20 (d, J = 7Hz, 1H); 7.35 (d, J = 7Hz, 1H) ppm

The starting material was prepared as follows: 35 (a) A solution of 0.513 g rac-4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone in 12 ml tetrahydrofuran was 20 ° C with 4 ml of a 1.635M butyllithium / hexane solution and left for 90 minutes in an ice bath in an argon atmosphere. The brown-yellow solution was cooled to -40eC, a solution of 360 mg of ethyl bromide in 0.8 ml of tetrahydrofuran was added and then left to stand in an ice bath for 90 minutes. It was poured onto 5 ice-cold saturated sodium chloride solution and extracted with ethyl acetate. The extracts were washed again with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely. Chromatography of the residue on silica gel with ethyl acetate / 10 hexane (2: 1, v / v) as eluent gave pure rac-trans-3-ethyl-4 - [(2-methyl-l, 3-dioxolane 2-yl) methyl] -2-acetin dinone. Crystallization from ether / hexane gave 122 mg of white crystals with a melting point of 44-45 ° C.

15 IR (CHC1,): t) 3422, 1752 cm “1

J ÏÏlciX

(b) To 4.3 g of rac ~ trans-3-ethyl-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 30 ml of methanol was added about 4 ml of 21.6 ml of an 1M solution of bromine in methanol and 20 heated to 50 ° C. Decolorization occurred after about 3 minutes, after which the rest of the bromine solution was added dropwise within 1 minute. The colorless reaction solution was poured onto a mixture of 30 ml of saturated sodium chloride solution and 20 g of ice, saturated with solid sodium chloride and extracted successively with 50 ml of ether and twice 50 ml of ethyl acetate each time. The organic phases were washed with a mixture of 30 ml saturated sodium bicarbonate and 20 ml IN sodium thiosulfate solution and with 30 ml saturated sodium chloride solution, dried over sodium sulfate · - v 30 and completely concentrated. The remaining oil was chromatographed on silica gel with ethyl acetate as the eluent. 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 35 crystals with a melting point of 77-79 ° C.

3 - 34 - (c) The procedure described in Example 1 (f) - (h) was carried out in an analogous manner to 2.8 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 -ethyl-2-azetidinone applied. After chromatographic purification and crystallization from ethyl acetate / hexane, 0.51 g of pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a- (triphenyl-phosphoranylidene) -l- Azetidine acetate as white crystals with a melting point of 128-129 ° C.

* 10 (d) 333 mg pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) - * 3-ethyl-4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 78 mg l-ethyl-4- thiouracil were reacted according to the procedure described in Example 4 (d). After purification by chromatography, 291 mg of 15 pivaloyloxymethyl-rac-trans-3-ethyl-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] acetonyl] were isolated. -4-oxo-oc- (triphenylphosphoranylidene) -1-azetidine acetate as a white foam.

20 IR (CHC1-): 1745 with shoulder at 1720, 1662, 1627, 3 max.

1580, 1514 crn

Example 7 25 A solution of 151 mg pivaloyloxymethyl-rac-trans-3-ethyl-2- [3 - [(5-methyl-l, 3,4-thiadiazol-2-yl) thio] acetonyl] -4- oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate in 12 ml of toluene was heated at 100 ° C. under an argon atmosphere for 1.5 hours. After chromatographic purification, 30 mg 79 pivaloyloxymethyl-rac-6a-ethyl-3 - [[(5-methyl-l, 3,4-thiadiazol-2-yl) thio] methyl] -7-oxo-5a- were isolated l-az abicyclo [3.2.0] hept-2-en-2-carboxylate as a pale yellow oil.

35 NMR (CDC13): Ö 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 = 6Hz / 2H) ppm

The starting material was prepared as follows: - 35 - 1.33 g pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) - 3-ethyl-4-oxo-a- (triphenylphosphoranylidene) -1-azetidine-5 acetate and 0 , 26 g of 2-mercapto-5-methyl-l, 3,4-thiadiazole were reacted in an analogous manner to the process described in Example 4 (d). After chromatographic purification, 1.24 g of pivaloyloxymethyl-rac-trans- * 3-ethyl-2- [3 - [(5-methyl-l, 3,4-thiadiazol-2-yl) thio] - 10 acetonyl] were isolated -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate as an amorphous powder.

IR (CHC1-): O 1740, 1636 cm "1 3 max 15 Example 8

A solution of 270 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(l-methyl-lH-tetrazol-5-yl) thio] acetonyl] - 4- ΟΧΟ-3 - [(RS ) -1- (trimethylsilyloxy) -ethyl] -a- (phosphor-20 anylidene) -1-azetidine acetate in 32 ml of toluene was heated to 105 ° C. under an argon atmosphere for 1 hour.

The colorless reaction solution was diluted with 50 ml of ethyl acetate and completely concentrated in vacuo. The residue was filtered through silica gel to separate the triphenylphosphine oxide, eluting with ethyl acetate / methylene chloride (1: 1, v / v). 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 the mixture was stirred at room temperature for 40 minutes. It was diluted with 30 ml

Ethyl acetate, completely concentrated in vacuo and chromatographed the residue on silica gel with ethyl acetate / methylene chloride (1: 1, v / v) as the eluent. 60 mg of pivaloyloxymethyl-r ac- (5RS, 6 SR) -6 - [(RS) -1-hydroxyethyl] -35 3- [E (1-methyl-1H-tetrazol-5-yl) thio] were obtained. -methyl] -7-oxo-l-azabicycloC3.2.0] hept-2-en-2-carboxylate as a colorless oil.

IR (CHC1-): ^ 3616, 3446, 1780, 1752, 1732, 1623 cm "1

* 3 ΙΠ B.X

The starting material was prepared as follows: - 36 - (a) To a solution of 34.2 g of rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone and 31.7 g of tert-5, cooled to 0 ° C. Butyldimethylchlorosilane in 160 ml of dimethylformamide was added dropwise 22.2 g of triethylamine within 2 minutes, a precipitate being formed immediately. The mixture was stirred at 0 ° C. for 1 hour, then diluted with 500 ml of ether and 9 - the reaction mixture was washed with 5 times 200 ml of water.

10 The water phases were extracted with 250 ml of ether.

“The organic phases were dried over sodium sulfate, the solvent was removed on a rotary evaporator and the remaining oil was distilled under high vacuum. 53.5 g of rac-l- (tert-butyldimethylsilyl) -4 - [(2-methyl-l, 3-15 dioxolan-2-yl) methyl] -2-azetidinone of bp Q ^ 125- 130 ° C as a colorless oil.

IR (CHC1-): 1728 cm * 1 3 max 20 NMR (CDC13): δ 0.22 (s, 6H); 0.98 (s, 9H); 1.31 (s, 3H); 1.62-2.34 (m, AB part of an ABX system, 2H); 2.70-3.31 (m, AB part of an ABX system, 2H); 3.51-3.85 (m, X part, 1H); 3.85-4.03 (m, 4H) ppm 25 (b) A solution of 3.66 g diisopropylamine in 90 ml tetrahydrofuran was cooled to -78 ° C and within 5 minutes with 24 ml 1.635M butyllithium / hexane -Solution added. The mixture was stirred for 20 minutes at -78 ° C. under an argon atmosphere and then a solution of 8.55 g of rac-1- (tert-butyldimethylsilyl) - 4 - [(2-methyl-l, 3- dioxolan-2-yl) methyl] -2-azetidinone in 90 ml of tetrahydrofuran. After stirring for a further 30 minutes at -78 ° C., 2.22 g of methyl acetate were added to the reaction solution. The mixture was allowed to warm to -35 to 0 ° C. in the course of 5 minutes and stirred at this temperature for a further 20 minutes.

The reaction mixture was poured onto 150 ml of saturated sodium chloride solution and then extracted with a total of 400 ml of ethyl acetate. The organic phase was washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely.

The residue was chromatographed on silica gel with ethyl acetate / hexane (1: 2, v / v) as the eluent and the material 3 of the concentrated pure fractions was distilled under 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 a colorless oil with Sdp.Q 118-120 ° C.

4 10 IR (CHC1-): 0 1743, 1712 cm “1’ 3 max 'NMR (CDC13): δ 0.22 (s, 3H); 0.26 (s, 3H); 0.98 (s, 9H); 1.32 (s, 3H); 1.66-2.37 (m, 2H); 2.30 (s, 3H); 3.75-4.00 (m, 4H); 4.00-4.25 (m, 2H) ppm 15 (c) A mixture of 14.3 g rac-trans-3-acetyl-l- (tert-butyldimethylsilyl) -4 - [(2-methyl-l , 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.

20 The catalyst was filtered off, the filtrate was concentrated completely in vacuo and the residue was crystallized from hexane. 12.4 g of a mixture of 2 isomeric alcohols in a ratio of 3: 2 were obtained. Fractional crystallization from ethyl acetate / hexane initially allowed the 25 main components to be isolated in pure form: rac- (3SR, 4RS) - 1- (tert, -butyldimethylsilyl) -3 - [(RS) -1-hydroxyethyl] - 4- [ (2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone, melting point 81-82 ° C.

i SA λ 30 IR (CHC1,): 0 3500, 1735 cm “1 3 ^ max NMR (CDC13): δ 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 35 (d, J = 5H, 1H); 3.54-3.61 (m, lH) j 3.94-4.02 (m, 4H) ppm - 38 -

By repeated crystallization of the mother liquor material from ethyl acetate / hexane, rac- (3SR, 4RS) -1- (tert-butyldimethylsilyl) -3 - [(SR) -1-hydroxyethyl] -4 - [(2-methyl-1,3 -dioxolan-2-yl) -methyl] -2-azetidinone from melting point 5 to 86-88 ° C.

IR (CHC1-): ^ 3630, 3588, 3504, 1728 cm "1 3 max '' 'NMR (CDC13): δ 0.22 (s, 3H); 0.24 (s, 3H); 0.96 ( s, 9H); 10 1.32 (d, J = 6Hz, 3H); 1.36 (s, 3H); 1.78-2.27 s. (m, 2H); 2.46 (d, J = 5Hz, 1H); 3.15 (dxd, J = 5Hz and 2.5Hz, lH); 3.59-3.68 (m, lH); 3.89-4.01 (m, 4H); 4 , 03-4.16 (m, lH) ppm 15 (d) A solution of 79 g rac- (3SR, 4RS) - 1- (tert-butyldimethylsilyl) -3 - [(RS) - cooled to 0 ° C 1-hydroxyethyl] -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone in 720 ml of pyridine was stirred with 63.7 g of 2,2-chloroformic acid, 2-trichloroethyl ester was formed, resulting in 20 lumps which, after some time, dissolved to form a fine precipitate taken on-25, washed with 3 times 600 ml of water and the

Water phases extracted with 1 1 of ethyl acetate. The organic phases were dried over sodium sulfate, the solvent was removed on a roller evaporator and the remaining oil was freed from polar impurities by filtration through silica gel with ethyl V * 9-00 acetate / hexane (1: 1, v / v) as eluent. Concentration of the pure fractions gave 126 g of crude rac- (3SR, 4RS) -l- (tert-butyldimethylsilyl) -3 - [(RS) -l- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -4- [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone 35 as an oil.

IR (CHC1-): v> 1758, 1740 cm "1 3 max / - 39 - (e) A solution of 126 g crude rac- (3SR, 4RS) -1- (tert-butyldimethylsilyl) preheated to 60 ° C -3 - [(RS) -1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-C (2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 700 4 g of bromine were added with stirring to ml of methanol 5. Decoloration occurred after stirring for about 3 minutes at 60 ° C. A further 36 g of bromine were then added dropwise to the reaction solution over the course of 8 minutes, and the reaction temperature was reduced to 40 ° C. in the course of 3 minutes When the addition was complete, the temperature was kept at 40 ° C. for a further 12 minutes, the reaction solution becoming practically colorless, and the mixture was cooled to 10 ° C., neutralized by adding 41 ml of aqueous ammonia (25%), and mixed 8.6 g of ammonium fluoride and stirred for 1 hour at room temperature The yellow solution 1® was concentrated to about half the volume on a rotary evaporator and then taken up in 1.2 l of ethyl acetate / ether (1: 1, v / v) 3 times with 450 ml saturated Na each trium chloride solution and extracted the water phases again with a total of 1.3 1 ethyl acetate. The organic phases were dried over sodium sulfate, the solvent was removed in vacuo and the residue was chromatographed on silica gel. A mixture of ethyl acetate / methylene chloride /

Hexane (1: 1: 1, v / v / v) eluted the pre-cleaned product, which could be crystallized from ethyl acetate with the addition of hexane. 57 g of rac- (3SR, 4RS) -4- (3-bromo-2,2-dimethoxypropyl) -3 - [(RS) -l- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -2- azetidinone as colorless crystals with a melting point of 84-85 ° C.

30 (f) A mixture of 23.58 g rac- (3SR, 4RS) -4- (3-bromo-2,2-dimethoxypropyl) -3 - [(RS) -l- (2,2,2-trichloroethoxycarbo -nyloxy) -ethyl] -2-azetidinone, 4.89 g of glyoxylic acid monohydrate and 15 g of molecular sieve 4A in 25 ml of dimethylformamide was stirred at room temperature for 20 hours. The reaction mixture was cooled to -10 ° C. and 5.25 g of triethylamine were added. After 5 minutes, 13.3 g of iodomethyl pivalate were added, the temperature being kept at 3 ° C. by cooling. The mixture was stirred at 3 ° C. for 15 minutes and at room temperature for a further 20 minutes. It was then decanted from the molecular sieve and simultaneously diluted with 200 ml of ethyl acetate. It was washed 3 times with 100 ml of semi-saturated sodium chloride solution and the 5 water phases were extracted again with 200 ml of ethyl acetate. The organic phases were dried over sodium sulfate and the solvent was removed in vacuo. Chromatography of the residue on silica gel with ethyl acetate / hexane (1: 1, v / v)) gave 15.5 g of pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromo- "^ 2,2-dimethoxypropyl) - 4-oxo-3 - [(RS) -1- (2,2,2-trichloro- = ethoxycarbonyloxy) -ethyl] -a-hydroxy-l-azetidine acetate (mixture of diastereomers) as a colorless oil.

IR (CHCl0): -ύ 3528, 1769 cm “1 3 max 15 NMR (CDC13): u.a. ö 1.23 (s, 9H); 1.50 (d, J = 6Hz, 3H); 2.20-2.60 (m, 2H); 3.05-3.30 (m, 7H); 3.48 (broad s, 2H); 4.73 (s, 2H) ppm (g) To a solution of 15.5 g P ivaloyloxymethyl-rac- (2RS, 3 SR) -2- (3-bromo-2,2-dimethoxypropyl) cooled to -20 ° C ) -4-oxo-3- [(RS) -l- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -a-hydroxy-l-azetidine acetate (mixture of diastereomers) in 200 ml of tetrahydrofuran, 3.50 g of 2.6 -Lutidine given. A solution of 3.74 g of thionyl chloride in 40 ml of tetrahydrofuran was then added dropwise within 1 minute, the temperature being kept below -20 ° C. by cooling.

The reaction mixture was stirred at -20 ° C for 20 minutes and at room temperature for 20 minutes. The precipitate was then filtered off with suction and the filter cake was washed with 360 ml of toluene. The filtrate was completely concentrated in vacuo, the residue was taken up in 150 ml of toluene and again completely concentrated.

The oil thus obtained was taken up in 75 ml of dimethylformamide and a solution of 8 g of triphenylphosphine in 23 ml of dimethylformamide was added. The mixture was left to stand at room temperature for 1 hour and then the major part - 41 - of the solvent was removed in a high vacuum at a temperature of 30 ° C. The residue was taken up in 300 ml of methylene chloride, the solution was washed twice with 240 ml of 1M pH 7 phosphate buffer and the water phases were extracted with 500 ml of methylene-5 chloride. The organic phases were dried over sodium sulfate, the solvent was removed in vacuo and the remaining oil was chromatographed on silica gel. A mixture of ethyl acetate / methylene chloride / hexane (1: 1: 1, v / v / v) first eluted excess triphenyl-10 phosphine and then the product. By completely concentrating the pure fractions, 14.89 g of pivaloyloxy-methyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-3-C (RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate as an amorphous powder.

IR (CHC1-)): V 1747, 1634 cm-1 3 max (h) A solution of 2.66 g pivaloyloxy-20 methyl-rac- (2RS, 3SR) -2- (3- bromo-2,2-dimethoxypropyl) -4-oxo-3 - [(RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate in 75 ml acetone was added Stirring with 75 ml of 48% hydrobromic acid pre-cooled to -10 ° C was added, the temperature rising to 10 ° C. The mixture was cooled to 0 ° C. within 3 minutes, stirred at this temperature for a further 15 minutes and the colorless reaction solution was poured onto a mixture of 17.4 g of sodium carbonate, 150 ml of 1M pH 7 phosphate buffer solution and 150 g of ice. It was extracted with a total of 400 ml of methylene chloride. The organic phase was washed with 50 ml of 1M pH 7 phosphate buffer solution, dried over sodium sulfate and concentrated completely. 2.45 g of crude pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4-oxo-3 - [(RS) -1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] were obtained. -35 a- (triphenylphosphoranylidene) -1-azetidine acetate as a white solid.

\ - 1 IR (CHC10): v> 1750 with shoulder at 1710, 1641 cm 3 max - 42 - (i) A solution of 428 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4 -oxo-3 - [(RS) -l- (2,2,2-trichloro-ethoxycarbonvloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate and 64 mg of 5-mercapto-l-methyl-lH-tetrazole 5 in 10 ml of methylene chloride was mixed with 60 mg of triethylamine and then stirred at room temperature for 2 hours. It was diluted with 10 ml of methylene chloride and washed with 10 ml of saturated sodium bicarbonate and sodium chloride solution. The water phases were extracted with a little 10 methylene chloride, the organic phases 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 were added and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was diluted with 40 ml of methylene chloride and washed successively with 15 ml of saturated sodium carbonate solution and twice 25 ml of water. The water phases were extracted twice with 40 ml methylene chloride each time, the organic phases 20 dried over sodium sulfate and completely concentrated.

The residue was taken up in a mixture of 3 ml of methylene chloride and 1.5 ml of pyridine, and 0.44 g of trimethylchlorosilane was added to the solution. The mixture was stirred at room temperature for 25 hours, diluted with 35 ml of ethyl acetate and washed successively with 15 ml of 5% sodium hydrogen carbonate solution and 25 ml of saturated sodium chloride solution. The water phases were extracted with 60 ml of ethyl acetate, the organic phases were dried over sodium 30 sulfate and completely concentrated. The residue was chromatographed on silica gel with ethyl acetate / hexane (1: 1, v / v) as the eluent. 198 mg of pivaloyloxy-methyl-rac- (2RS, 3SR) -2- [3 - [(l-methyl-lH-tetrazol-5-yl) thio] acetonyl] -4-oxo-3- [( RS) -l- (trimethylsilyloxy) ethyl] -a-35 (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

IR (CHC1-): iJ 1747, 1640 cm “1 o max? - 43 -

Example 9

A 0.05M pH 7-5 phosphate buffer solution was prepared by adding IN sodium hydroxide solution to an aqueous sodium dihydrogen phosphate solution and 1.5 ml of a suspension of pig liver esterase EC 3.1.1.1 (approx. 1500 units) in 3.2M to 150 ml of this solution Ammonium sulfate solution given. A solution of »228 mg pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -l-hydroxy-v Ί0 ethyl] -3 - [[(l-methyl-lH-tetrazole- 5-yl) thio] methyl] -7- “oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate in 3 ml

Methanol too, with a fine precipitate. The mixture was stirred at 23 ° C. for 3.5 hours and the pH of the reaction mixture was kept at 7.1 by adding 0.1N sodium hydroxide solution. The still slightly cloudy solution was extracted 4 times with 50 ml of ether each time and the ether phases were extracted back twice with 50 ml of water each time. The water phases were in a vacuum at a temperature of 0-20 ° C to approx.

30 ml concentrated and chromatographed on RP-18 silica gel (LiChroprep, 20 40-63 µm) with 3% aqueous methanol (v / v). The fractions which contained the product were combined and concentrated, and the solution which had been adjusted to pH 7.1 with 0.1N sodium hydroxide solution was lyophilized. A mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -l-25 hydroxyethyl] -3 - [[(l-methyl-lH-tetrazol-5-yl) - thio] -methyl] - 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as a white, amorphous powder.

UV (Ho0): = 278 nm (can be extinguished with hydroxylamine), see LMax 30 IR (KBr): - £> 1758, 1603, 1400 cm ^

IU8.X

NMR (DMSO-dg): 1.15 (d, J = 6Hz, 3H); 2.66-2.86 (m, 2H); 3.03 (dxd, J = 7Hz and 2.5Hz, 1H); 3.80-3.96 (m, 2H); 35 3.97 (s, 3H); 4.40 / 4.66 (AB system, J = 12Hz, 2H) ppm - 44 -example 10 126 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(5-methyl-1,3 , 4-thiadiazol-2-yl) thio] -acetonyl] -4-oxo-3-5 [(RS) - l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate were added subjected to the cyclization process described in Example 8. After chromatographic purification, 24 mg of pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[(5-methyl-l, 3,4-i "Ό thiadiazole- 2-yl) -thio] -methyl] -7-oxo-l-azabicyclo [3.2.0] - hept-2-ene-2-carboxylate as a colorless oil.

UV (EtOH): λ = 292 nm max 15 The starting compounds for Examples 10, 12, 13, 14 and 18 were prepared as follows: (a) Pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) - 4-OXO-3-C (RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -20 a- (triphenylphosphoranylidene) -1-azetidine acetate was reacted with in accordance with the process described in Example 8 (i) the difference that instead of 5-mercapto-1-methyl-lH-tetrazole 25 in example 10 5-mercapto-2-methyl-l, 3,4-thiadiazole, in example 12 2-mercapto-pyrimidine, in example 13 4 -Acetamino-thiophenol, in example 14 1,2,3,4-tetrahydro-4-methyl-3-thioxo-as-triazine-5,6-dione, 30 in example 18 methyl-l-methyl-5-mercapto- 1H-1,2,4-triazole-3-carboxylate was used.

35 After chromatographic purification

Example 10: Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] acetonyl] -4-oxo-3-C (RS) -l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranyli- - 45 - den) -l-azetidine acetate as a white foam.

IR (CHC1-): 1749, 1640 cm 3 max ® in Example 12: pivaloyloxymethyl-rac- (2RS, 3SR) -4-oxo-3- [(RS) -1- (trimethylsilyloxy) -ethyl] -2- [ 3- (2-pyrimidinyl-thio) -ace tony1] -a- (tr iphenylpho sphoranyliden) -1-az etidin acet at «as a colorless oil.

* 1® IR (CHC1-): \> 1739 with shoulder at 1715, 1632 cm “1 3 max in Example 13: Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(p-acetaminophenyl) thio ] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl3-a- (triphenylphosphoranylidene) -l-azetidine acetate as an amorphous powder.

IR (CHCl.,): \> 3436, 3322, 1744, 1712, 1636 cm “1 3 max

in Example 14: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3-PO

[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] acetonyl] -4-oxo-3 - [(RS) -l - (tr imethy1s ilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate as a colorless oil.

25 IR (CHCl,): ύ 3394, 1750, 1712, 1616, 1595 cm “1 in Example 18: pivaloyloxymethyl-rac- (2RS, 3SR} -2- [3- [3- (methoxycarbonyl) -l-methyl- lH-l, 2,4-triazol-5-yl] -thiol'ace tonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- ΟΛ (triphenylphosphoranylidene) -1- azetidine acetate as a colorless oil.

IR (CHC10): à 1741, 1715, 1636 cm “1 3 max

Example 11 35 -

Pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -l-hydroxyethyl] -3- [[(5-methyl-l, 3,4-thiadiazol-2-yl) thio] methyl ] - 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate was subjected in an analogous manner to the hydrolysis process described in Example 9. RP-18 silica gel chromatography gave a mixture of sodium (5R, 6S and 5S, 6R) -6 ~ [(R and S) -l-hydroxyethyl] -3 - [[(5-methyl-l, 3,4-thia-5 diazol-2-yl) thio] methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

UV (H „0): λ = 278 nm (with hydroxylamine shift 2 2 max exercise after 287 nm) 10

Example 12 163 mg pivaloyloxymethyl-rac- (2RS, 3SR) -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -2- [3- (2-pyrimidinyl-thio) -15 ace tonyl ] -a- (tr iphenylphosphor anyl iden) -1 - az etidine acetate were subjected to the procedure described in Example 8, with the difference that the reaction time of the cyclization reaction was 3 hours. After chromatographic purification, 42 mg of pivaloyloxymethyl-20 rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -7-oxo-3 - [(2-pyrimidinyl-thio) -methyl] -l- azabicyclo [3.2.0] hept-2-en-2-car-boxylate as a colorless oil.

IR (CHClJ: t> 3618, 3450, 1775, 1753, 1622, 1567, o max a 25 1551 cm

The preparation of the starting material is described in Example 10 (a).

30 Example 13 157 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(p-acetaminophenyl) thio] acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) - ethyl] -a- (triphenylphosphoranylidene) -1-35 azetidine acetate were subjected in an analogous manner to the process described in Example 12. After purification by chromatography, 33 mg of pivaloyloxymethyl-rac- (5RS, 6 SR) -3 - [[(p-acetaminophenyl) thio] methyl] -6 - [(RS) -1- -47-hydroxyethyl] -7 were isolated -oxo-l-azabicyclo [3.2.0] hept-2-en-2-car-boxylate as an amorphous powder.

IR (CHC10): 3618, 3434, 3382, 1778, 1755, 1695, 3 Π13Χ <1 5 1619 cm NMR (CDCl-j): δ 1.22 (s, 9H); 1.31 (d, J = 6Hz, 3H); 1.91 (d, J = 4Hz, 1H); 2.17 (s. 3H); 2.85-3.10 (m, 2H); 3.08 (dxd, J = 6.5Hz and 3Hz, 1H); 3.89 / 4.07. 10 (AB system, J = 13Hz, 2H); 4.07-4.18 (m, 2H); 5.68 / 5.78 (AB system, J = 5.5Hz, 2H); 7.34 (d, J = 8.5 Hz, 2H); 7.36 (s, 1H); 7.44 (d, J = 8.5Hz, 2H) ppm 15 The preparation of the starting material is described in Example 10 (a).

Example 14 20 400 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate were subjected in an analogous manner to process 25 described in Example 8. After chromatographic purification, 31 mg of pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxy-ethyl] -3 - [[(1,4,5,6-tetrahydro-4-methyl- 5,6-dioxo-as-triazin-3-yl) -thiol-methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

30 UV (EtOH): λ = 280 nm (with NHo0H shift according to IQâX Z, 289 nm)

The preparation of the starting material is described in Example 35 10 (a).

- 48 -

Example 15

The product from Example 14 was subjected in an analogous manner to the process described in Example 9.

5 A mixture of sodium (5R, 6S and 5S, 6r) -6 - [(R and S) -l-hydroxyethyl] -3 - [[(1,4,5; 6-tetrahydro-4-methyl -5,6-dioxo-as-triazin-3-yl) thio] methyl] -7-oxo-l-az abicyclo [3.2.0] hept-2-en-2-c arboxylate.

10 uv (HLO): λ v = 283 nm

HLax

Example 16 186 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[2,5-15 dihydro-2-methyl-5-oxo-6 - [(pivaloyloxy) methoxy] -as-triazine 3-yl] -thio] -acetonyl] -4-oxo-3 - [(RS) -l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate were prepared in a manner analogous to that described in Example 8 Procedure implemented. After chromatographic purification, 65 mg of pivaloyloxymethyl-rac- (5RS, 6SR) - 6 - [(RS) -1-hydroxyethyl] -3 - [[[2,5-dihydro-2-methyl-5-oxo -6 - [(pivaloyloxy) methoxy] -as-triazin-3-yl] thio] methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as a colorless oil.

25 IR (CHCln): i> 3692, 3614, 3370, 1775, 1753, 1737, O niclX λ 1670, 1620 cm "1 NMR (CDC13): δ 1.22 (s, 18H); 1.31 (d, J = 6Hz, 3H); 1.80 30 (d, J = 4.5Hz, lH); 2.97-3.23 (m, 2H); 3.18 (dxd, J = 6.5Hz and 2Hz, lH); 3.70 (s, 3H); 4.13-4.28 (m, 2H); 4.40 / 4.54 (AB system, J = 13.5Hz, 2H); 5.88 / 5.97 (AB system, J = 7Hz, 2H); 5.93 (s, 2H) ppm 35

The starting material was prepared as follows: - 49 - (a) To a solution of 858 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4-oxq-3 - [(RS) -l- (2,2,2-tri-chloroethoxycarbonyloxy) ethyl] -a- (triphenylphosphoranylidene) - 1-azetidine acetate and 159 mg 1,2,3,4-tetrahydro-2-methyl-5 3-thioxo-as-triazine 5,6-dione in 10 ml of dimethylformamide, 202 mg of triethylamine were added to 2 ml of methylene chloride and the mixture was then stirred at room temperature for 20 minutes.

The clear solution was cooled to 0 ° C, 242 mg iodomethyl-? pivalat added and stirred for a further 15 minutes at 0 ° C. and 15 minutes at room temperature. The mixture was diluted with ethyl acetate and washed successively with 5% sodium hydrogen carbonate and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, completely concentrated and the residue chromatographed on silica gel with 15 ethyl acetate as the eluent.

The purified product was treated analogously to the process described in Example 8 (i) with zinc in 90% acetic acid and then with trimethylchlorosilane 20. After chromatographic purification, 196 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[2,5-dihydro-2-methyl-5-oxo-6 - [(pivaloyloxy) methoxy] -as- triazin-3-yl] thio] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

Example 17

The product from Example 16 was subjected in an analogous manner 00 to the process described in Example 9.

A mixture of (5R, 6S and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl] -3 - [[2,5-dihydro-6-hydroxy-2-methyl-5-oxo was obtained -as-triazin-3-yl) -thiol-methyl] -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2-carboxylic acid disodium salt.

35 UV (Ho0): λ = 242, 281 nm 2 max

A

IR (KBr): Ί-) 1755, 1602 with shoulder 1650, 1404 cm max - 50 -

Example 18 180 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[3- (methoxycarbonyl) -1-methyl-1H-l, 2,4-triazol-5-yl] thio] -5 acetonyl] -4-oxo-3 - [(RS) -l-trimethylsilyloxy) -ethyl] -a- (tri-phenylphosphoranylidene) -l-azetidine acetate were subjected to the procedure described in Example 8. After chromatographic purification, about 70 mg of pivaloyloxymethyl-r ac- (5 RS, 6 SR) -6 - [(RS) -1-hydr oxye thy 3 - [[[3- (methoxyc ar- ^ 10 bonyl) -l-methyl-lH-l, 2,4-triazol-5-yl] -thio] -methyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as a colorless oil .

IR (CHC1J: <·,> 3680, 3608, 3440, 1780, 1742, 1620 cm "1 3 max 15 NMR (CDC13): ô 1.22 (s, 9H); 1.32 (d, J = 6Hz, 3H); 1.82 (broad -OH signal); 3.03-3.15 (m, 2H); 3.26 (dxd, J = 6.5Hz and 3Hz, lH); 3.89 (s, 3H); 3.98 (s, 3H), 4.10-4.25 (m, 2H); 4.42 / 4.42 20 (degenerate AB system, J = 13.5Hz, 2H); 5, 85 / 5.93 (AB system, J = 5.5Hz, 2H) ppm

The preparation of the starting material is described in Example 10 (a).

25th

Example 19

The product from Example 18 was subjected in an analogous manner to the process described in Example 9.

Λ 30 A mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] -3 - [[[3- (methoxycarbonyl) -l-methyl-lH- 1,2,4-triazol-5-yl] thio] methyl] -7-oxo-l-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylate.

35 UV (Ho0): λ = 278 nm (can be extinguished with NHOH) 2 max 2 IR (KBr): -5 1738 with shoulder 1755, 1591, 1395 cm'1 nmax 7 * - 51 -

Example 20 0.6 g Pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-lH-tetrazol-5-yl) thio] acetonyl] -3- [1-methyl-l- (trimethyl- 5 silyloxy) ethyl] -4-oxo-a- (triphenylphosphoranylidene) -1- azetidine acetate were subjected to the cyclization process described in Example 8, with the difference that in order to remove the trimethylsilyl protective group, the chroma-> tographed cyclization product in 60 ml of methanol was stirred in the presence of 0.6 g of ammonium fluoride for 4 hours at room temperature. After chromatographic purification, 52 mg of pivaloyloxymethyl-rac-6a (1-hydroxy-1-methylethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) thio] methyl] -7-oxo was isolated -5a-l-azabicyclo [3.2.0] hept-2-ene-2-15 carboxylate as a colorless oil.

UV (EtOH): \ = 296 nm (can be extinguished with NHo0H) max z IR (CHC1,): ^ 3690, 3610, 1779, 1752, 1730, 1622 cm "1 3 max 20

The starting material was prepared as follows: (a) A solution of 8.56 g of rac-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 150 ml of tetrahydrofuran became 25 65.5 ml of a 1.6M butyl lithium / hexane solution were added at -30 ° C. within 4 minutes and then left to stand in an ice bath in an argon atmosphere for 90 minutes. The brown-yellow solution was cooled to -30 ° C. and a solution of 3.2 g of acetone in 10 ml of tetrahydrofuran was added.

30 The mixture was stirred at 0 ° C. for a further 30 minutes and the reaction solution was poured onto 50 g of ice. The organic phase was separated and washed with 50 ml of saturated sodium chloride solution. The combined water phases were extracted with a total of 300 ml of methylene chloride. The organic phases 35 were dried over sodium sulfate, concentrated completely under reduced pressure and the remaining oil was chromatographed on silica gel. A mixture of acetone and methylene chloride (1: 8, v / v) initially eluted unused - 52 -

Starting material, then rac-cis-3- (1-hydroxy-l-methylethyl) - 4- [(2-methyl-l, 3-dioxolan-2-yl) methyl] -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.

IR (CHC1-): v 3604, 3424, 1751 cm-1 3 max Λ

Further elution gave rac-trans-3- (Ι-ΙΟ hydroxy-l-methylethyl) -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone, which consists of Ethyl acetate / hexane gave 1.59 g of white crystals with a melting point of 84-86 ° C.

IR (CHC1-): ^ 3604, 3420, 1751 cm "1 3 max 15 (b) The procedures described in Example 8 (a) and (d) - (i) were analogously applied to 4 g rac-trans-3 - (1-Hydroxy-l-methylethyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone was used to obtain 0.96 g of 20 pivaloyloxymethyl-rac-trans -2- [3 - [(1-methyl-lH-tetrazol-5-yl) thio] acetonyl] -3- [1-methyl-l- (trimethylsilyloxy) ethyll-4-οχο-α- (triphenylphosphoranylidene ) -l-azetidine acetate as a colorless oil.

25 IR (CHC10): à 1744, 1635 cm "1 3 max

Example 21

The product from Example 20 was subjected in an analogous manner to the method described in Example 9.

A mixture of sodium (5R, 6S and 5S, 6R) -6a- (1-hydroxy-l-methylethyl) -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] - was obtained methyl] -7-oxo-5a-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

UV (H „0): λ = 279 nm (can be extinguished with NH0OH) z max z 35 - 53 -

Example 22 230 mg pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-5-yl) thio] acetonyl] -4-oxo-3 - [(trimethyl-5 silyloxy) - methyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate was subjected to the procedure described in Example 8, with the difference that the reaction time of the cyclization reaction was 30 minutes. After chromatographic purification, 66 mg of pivaloyloxymethyl-10 rac-6a- (hydroxymethyl) -3 - [[(l-methyl-lH-tetrazol-5-yl) thio] methyl] -7-oxo-5ct-1- were isolated azabicyclo [3.2.0] hept-2-en-2-carboxylate as a colorless oil.

UV (EtOH): λ = 289 nm (can be extinguished with NH “OH) max 2 15 IR (CHC1-J: à 3440, 1782, 1752, 1619 cm” 1

«3 IUclX

The starting material was prepared as follows: 20 (a) 15.8 g of tert-butyldimethylchlorosilane and 25.2 g of rac-4- (3-bromo-2,2-dimethoxypropyl) -2-azetidinone were successively dissolved in 150 ml of dimethylformamide , the solution was cooled to 0 ° C. and 22.0 g of triethylamine were added with stirring, a precipitate being formed. The mixture was stirred at 0 ° C. for 15 minutes, diluted with 1 l of ether / hexane (1: 1, v / v) and extracted 4 times with 400 ml of water each time. The water phases were extracted back with 500 ml of ether / hexane (1: 1, v / v), the organic phases were dried over sodium sulfate and concentrated completely. The remaining 30 oil was taken up in a little hexane and left at -20 ° C. 31.3 g of rac-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -2-azetidinone were obtained as white crystals with a melting point of 6l-63 ° C.

35 (b) 7.06 g of rac-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -2-azetidinone was subjected to the procedure described in Example 8 (b) in an analogous manner , with the difference that instead of methyl acetate 6.0 g - 54 -

Methyl formate was used. 2.19 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3 were obtained by crystallization of the chromatographically purified product from ether / petroleum ether -formyl-2-azetidinone 5 as white crystals with a melting point of 70-72eC.

(c) A solution of 788 mg rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -l- (tert-butyldimethylsilyl) - cooled to 0 ° C; 3-formyl-2-azetidinone in 12 ml of methanol was mixed with 38 mg of "10 sodium borohydride and the reaction mixture was stirred for 10 minutes. The mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, the organic phase was dried over sodium sulfate and concentrated completely. Crystallization of the residue from ethyl acetate / hexane 15 gave 685 mg of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -l- (tert-butyldimethylsilyl) -3- (hydroxymethyl) -2-azetidinone as white crystals melting point 119-120 ° C.

(d) 7.87 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -l- 20 (tert-butyldimethylsilyl) -3- (hydroxymethyl) -2-azetidinone were added to that in Example 8 ( d) the process described and the crystalline reaction product is 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, 7.66 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 - [(2,2,2-trichloroethoxycarbonyloxy) were obtained. -methyl] -2-azetidinone melting at 108-109 ° C.

00 (e) The reaction sequence described in Example 8 (f) - (i) was analogously carried out on 5.2 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 - [(2, 2,2-trichloroethoxycarbonyloxy) methyl] -2-azetidinone applied. 0.23 g of pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-35 5-yl) thio] acetonyl] -4-oxo-3 - [(trimethylsilyloxy) - methylΊα- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

- 55 -

Example 23

The product from Example 22 was subjected in an analogous manner to the process described in Example 9.

5 A mixture of sodium (5R, 6S and 5S, 6R) -6a- (hydroxymethyl) -3 - [[(l-methyl-lH-tetrazol-5-yl) thio] methyl3-7-oxo was obtained -5a-1-az abicyclo [3.2.0] hept-2-en-2-carboxylate.

* ï- UV (H „0): λ = 277 nm (can be extinguished with NHo0H) 2 JÏIHX / 1 °

Example 24 41 mg of rac-1- (tert-butyldimethylsilyl) -3- (Z) -ethylidene-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone 15 were included 2 ml of ethyl acetate are hydrogenated in the presence of 50 mg of platinum dioxide at normal pressure. A 6: 1 cis / trans isomer mixture was obtained, from which the main component could be obtained in pure form by fractional crystallization of the crude product from hexane: rac-cis-1-20 (tert-butyldimethylsilyl) -3-ethyl-4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone, melting point 80-82 ° C.

The starting material was prepared as follows: 25 To a solution of 330 mg of rac- (3SR, 4RS) -1- (tert-butyldimethylsilyl) -3 - [(SR) -1-hydroxy-ethyl] - cooled to 0 ° C. 4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone and 400 mg triphenylphosphine in 20 ml tetrahydrofuran were added 300 mg diisopropyl azodicarboxylate and the solution was stirred for 1 hour at room temperature . The mixture was then partitioned between water and ethyl acetate, the organic phase was dried over sodium sulfate and concentrated completely. The residue was chromatographed on silica gel using ethyl acetate / methylene chloride / hexane (1: 1: 2, v / v / v) as mobile phase 35 and the purified product was crystallized from hexane. 100 mg of rac-1- (tert-butyldimethylsilyl) -3- (Z) -ethyliden-4 - [(2-methyl-1,3-dioxolan-2- -56-yl) methyl] -2- were obtained. azetidinone as colorless crystals with a melting point of 85-86 ° C.

IR (CHC1-): v 1722 cm "1 3 max 5

Example 25 1.04 g of rac-cis-l- (tert-butyldimethylsilyl) -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl3-3- [1-methyl-l- [ (2,2,2-10 trichloroethoxycarbonyloxy) ethyl] -2-azetidinone were subjected to the process described in Example 8 (e) in an analogous manner, with the difference that the bromination was carried out at a temperature of 45 ° C. After chromatographic purification and crystallization from 15 ethyl acetate / hexane, 0.54 g of rac-cis-4- (3-bromo-2,2-dimethoxypropyl) -3- [1-methyl-l- (2,2, 2-trichloroethoxycarbonyloxy) -ethyl] -2-azetidinone as colorless crystals with a melting point of 104-106 ° C.

20 IR (CHCl-,): nJ 1765 cm "1 3 max

The starting material was prepared as follows: rac-cis-3- (1-hydroxy-l-methylethyl) -4- C (2-methyl-l, 3-25 dioxolan-2-yl) methyl] -2-azetidinone implemented in analogy to the methods described in Example 8 (a) and (d). After crystallization from hexane, rac-cis-l- (tert-butyldimethylsilyl) -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -3- [1-methyl-l- (2,2,2-trichloroethoxycarbonyloxy) -30 ethyl] -2-azetidinone, melting point 89-9 ° C.

Example 26

If (-) - (3S, 4R) -1- (tert-butyldimethylsilyl) -35 3 - [(R) -1-hydroxyethyl] -4 - [(2-methyl-l, 3-dioxolane-2- yl) - methyl] -2-azetidinone as the starting material for the reaction sequence described in Example 8, starting from step (d) and subjecting the product to the process described in Examples 9-57 -, sodium (5R, 6S) is obtained. - 6 - [(R) -l-hydroxyethyl] -3 - [[(l-methyl-lH-tetrazol-5-yl) thio] methyl] -7-oxo-l-azabicyclo [3.2.0] hept -2-en-2-car boxylate.

5 UV (H „0): λ = 278 nm (can be extinguished with NHo0H) 2 max 2

The starting material was prepared as follows: 10 (a) A solution of 19.8 g of rac- (3SR, 4RS) - 1- (tert-butyldimethylsilyl) -3 - [(RS) -1, cooled to 0 ° C. -hydroxyethyl] -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone in 120 ml of pyridine was treated with 18.8 g of (-) - camphanoyl chloride. The mixture was stirred at room temperature for 22 hours.

15 Then the reaction mixture was diluted with 1.2 l of ethyl acetate and washed successively with 360 ml of dilute sodium hydrogen carbonate solution and saturated sodium chloride solution. The water phases were extracted back with 1 1 of ethyl acetate, the combined organic phases were dried over 20 sodium sulfate, completely concentrated and the residue was chromatographed on silica gel. A mixture of ethyl acetate / methylene chloride / hexane (1: 6: 6, v / v / v) initially eluted a (+) - rotating camphanic acid ester, which could be crystallized from ether / hexane. 25 (+) - (3R, 4S) -1- (tert-butyldimethylsilyl) -3 - [(IS) -1-camphanoyloxyethyl] -4 - [(2-methyl-1,3-dioxolane-2- yl) -methyl] - 20 2-azetidinone with melting point 125-127 ° C and [α] β = + 15.0 ° (c = 1, EtOAc). After a few mixed fractions, fractions were obtained which contained a (-) - 30 rotating camphan ester from the main component. This was through

Crystallization from ether / hexane purified. This gave (-) - (3s, 4R) -1- (tert-butyldimethylsilyl) -3- [(IR) -l-camphanoyl-oxyethyl] -4 - [(2-methyl-1,3-dioxolane-2 -yl) -methyl] -2- 2 0 azetidinone with melting point 112-113 ° C and [a] = -19.9 ° 35 (c = 1, EtOAc).

- 58 - (b) A solution of 0.5 g of (-) - (3S, 4R) -l- (tert-butyl-dimethylsilyl) -3 - [(lR) -l-camphanoyloxyethyl] -4 - [( 2-methyl-l, 3-dioxolan-2-yl) -raethyl] -2-azetidinone from stage (a) in 10 ml of toluene was mixed with 4 ml of a 1.12M solution 5 of diisobutylaluminum hydride in hexane at 0 ° C. and the reaction mixture was then stirred at room temperature for 2 hours. The mixture was poured onto saturated sodium chloride solution and extracted with ethyl acetate. The organic / phases were washed again with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely. The remaining oil was chromatographed on silica gel with ethyl acetate / hexane (1: 1, v / v) as the eluent obtained after two crystallizations from hexane (-) - (3S, 4R) -l- (tert-butyldimethylsilyl) -3-15 [(R) -l-hydroxyethyl] -4 - [(2-methyl-l, 3- dioxolan-2-yl) - 20 methyl] -2-azetidinone with melting point 83-84 ° C and [α] ^ = -50.8 ° (c = 1, EtOAc).

Example 27 20

A solution of 10 mg sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl] -3 - [[(1-methyl-tetrazole-1H-5) cooled to 0 ° C -yl) -thio] -methyl] -7-oxo-l-azabicyclo- [3.2.0] hept-2-en-2-carboxylate in 0.2 ml of dimethylformamide 25 was mixed with 7 mg of bromomethyl acetate and then at 1 hour Room temperature stirred. The mixture was diluted with ethyl acetate, washed with 0.05M pH 7 phosphate buffer, dried over sodium sulfate and concentrated completely. Chromatography of the residue on silica gel with ethyl acetate / 30 methylene chloride as the eluent gave 1.8 mg of acetoxymethyl- (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl] -3 - [[(1- methyl-lH-tetrazol-5-yl) thio] methyl] -7-oxo-l-azabicyclo- [3.2.0] hept-2-ene-2-carboxylate as a pale yellow oil.

35 UV (EtOH): λ = 295 nm (can be extinguished with NH_0H) max 2 IR (CHC1,): 1771, 1738 3 max '- 59 - Example 28

The compounds of the formula I listed in Table I 5 can be prepared by appropriate use of the processes described in the preceding examples.

It may be an advantage to change the order of the reaction steps or to use other protective groups in certain cases. The compounds - 28), 30), 43) and 44) are fertilized by reacting the connections 10) 27), 29), 41) and 21) according to generally known methods

Methods, for example with methyl formimidate in aqueous solution at pH 8-8.5, are obtained.

15 20 25 30 35 - 60 - R2 H R1 ·. · ..

6 5 \

/) - CH2-X I

COOH

Table I

Compound R1 R2 χ salt, .—- -.__ i _____ 1) H -CH2CH3 jTj Na

"s I

CH, 2) H -CH2CH3 CH3 N ^ _y'01la 3) H -CH2CH3.

OH

4) -CHCH "CH ^ H

6 A »

—SX N

OH ch3 5) -CHCH “CH_ H λ” λ 2 3 0H CH2COOMa _. Him. / N '___

6) -CHCH "CH_ H ï T

3 -SAA0

OH

Y t N - N

7) -CH-CF H ^ AJ

CH3

OH

0, I II \\

8) -CH-CF 3 H

i - 61 -

Compound R1 r2 χ salt

OH

) CH3V

9, -CH-CP3 Η ^ ΛΛ ° H r \ 10) —CH CH ^ j H -.s' // * S | / <* Sv'cc «ch2ch3 11

! H

11) "" "-B | COOCH2CH3 CH CH,«> "13>" "Well

H

_ / cp3 / u 14) "- Aj

S - N

15) ·· "CH3 16>“ "_ÂX., N / CH3 17)" "X \ - ~ s S 'coONa n_ / CH3, 18)". J \ S “' COOCH2CH3

19) ».. JO

w »S 13

ί I

- 62 -

Connection R1 | R2 X salt

OH

j ^ CH2CH2QH

20) -ch-ch3 h Na -s ^ S ^ ch3! / CH CH.NH, -. ..! _Â <, i; j 22> "": I well

! 'ch3 I

23) ".; I.

I; 5; CH3 \ j

2 · »-": _, AV

1 0 CONH2 i; CH3 \!

25) "· j r \ I H

CH3 \

N * ~ N

26) "" '„* —s' ch2oh CHv 27)" »% -«

Λ K

“~ S CH NH, 2 2 ch3 n 28)" <· r \\ A x “• —s ^ n

; V CH2-NH-CH = NH

CH3 \

N ~ N

29) "" _, AX

ch2-ch2-nh2 CHjn N “N,

30) "λ 'V

-s / x CHjCHjNH-CH-NH

i / ,.

- 63 - A i o '| 1

Connection R j_RZ x salt

OH

31) -CH-CH ^ H \ -N | N / A

_AA

CH3 y "

N-N

32) · ch3 s •. 331 "_χχ ^ 5 CONHCH2CH2NH2 CH3CH ^ / CONH2 _AÎ

H2N

35) · '· / -¾ _SA / h2n V / nh-nh2 36) - .. _sA / N = C v> 3H - 3 ’) ·' JX $ 38)» .. J)

—-S · ^ N

NH2 39) .. J'j

COOCH3 N -N

40) "* '..

CH2-COONa N - N

41) »- X> '^ c / N - CH2CH2NH2 î

I I

; ! - 64 - I T "ô ~ ~ ---— '

Compound R Rz χ salt 0H // "5

42) -CH-CH-j H -s I

J / CH3 ch9ch9-n ^ λ ^ ch3

H —N

«)" .. nA, i

CHjCHj-NH-CH-NH __ / CH CH NH-CH-NK

44) "·· J-ζ ~ * s s N" ch3 0

451 "" _SEA

0 .c.

6) "^ AJ

X '"3 47)" »| JJ-: o 48) "..;

-, AJ

0

· ”· A

* “S N CH3 CH3 50)" ··

! I.

j -SA '\! Λ; ^ s ^ n ^ -o

! I.

I H

i! 1 i I i - 65 -

Connection R1 R2 x salt

OH

, n / ^ cû ° ch2ch3 52) -CH-CH3 H _SA / X Na —s N ^ nh2 0 _ ^ ° CH_CH, CH, CH,

53) "· 'Il I

i - NHNH2 * 54) "» fil

, _s> ^ N

0 55> '· "-SÂJ Well

H

O

561 "" 1 11

H

^ N-îs

571 "" xX

-S ^ N ^ NHCH3

58) "» _SÀA

NH2.

59) "» _SA „A

S N ^ NH2

OH

N <K ^ CH3 60) "» I p-CH3 "-N v

H

"'SS *

î 61) »M

62) ».. ~ 5 ^ Ύ COONa - 66 - - - - ___ .——-

Connection RR X salt

?H

63) -CH-CH3 H -s ^ ÿ "conhch2ch2nh2 nh2 64) ··“ Y ™ Na —rS ^^ N ^

. 65) »H _sXX

5 N OH

1.0

A

66) ".. -sA„ ß OCH2CH2CH3 ch3

67) "» N M

CN

®3S, -N ^ OCH

68) "« · Ϊ T

__SANA0

69) ·· ·. | fS

0 70) "" -0-C-CH3 fH ch3 jtj

71) H -C <CH

CH3

_aX

N —N

73) ».. M $ V"

I _, CH

CH, CH, N * 2 2''CH3 i_______________ «- 67 -Example 29

Manufacture of dry ampoules for intramuscular administration: 5

A lyophilisate of 500 mg of sodium (5R, 6S) -6 - [(R) -l-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-5-yl) thio] -methyl] -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2-carboxylate and filled into an ampoule 10. Before the administration, 2.5 ml of a 2% aqueous lidocaine hydrochloride solution are added to the lyophilisate.

Example 30 15

A gelatin capsule of the following composition is produced in the usual way:

Pivaloyloxymethyl- (5R, 6S) -3 - [[(1-ethyl-l, 2-20 dihydro-2-oxo-4-pyrimidinyl) thio] methyl3- 6 - [(R) -l-hydroxyethyl] - 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate 500 mg

Luviskol (water soluble polyvinylpyrrolidone) 20 mg

Mannitol 20 mg 25 talc 15 mg

Magnesium stearate 2 mg 557 mg ^ 30 35 «- 68 - Example 31

A tablet of the following composition is produced in the usual way: 5

Pivaloyloxymethyl- (5R, 6S) -3 - [[(l-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl] - 6 - [(R) -l-hydroxyethyl] - 7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 250 mg 10 lactose 70 mg

Corn starch 65 mg

Polyvinyl pyrrolidone 10 mg

Magnesium stearate 5 mg 400 mg 15

With the active ingredient, lactose, polyvinylpyrrolidone and 40 parts by weight of corn starch, granules are produced in the usual way. This is mixed with the remaining 25 parts by weight of corn starch and 5 parts by weight of 20 magnesium stearate and pressed into tablets.

25 v 30 35

Claims (29)

69. DS 4410/151 1. Bicyclic compounds of the general formula 5 R2 H f_ | 1 2 3 Λ — CH ^ —X | ✓ COOH 10 · '---- 1 2 wherein one of the substituents R and R is hydrogen and the other is hydrogen or a substituted or unsubstituted C ^ _ ^ - alkyl group and X is a -jg substituted or unsubstituted C ^ _3-alkanoyloxy group, represents an unsubstituted or substituted C3_7 ~ cycloalkylthio, C2 g-alkenylthio or hetero-cyclylthio radical or a substituted C1_4-alkylthio or phenylthio radical, 20 their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds. 2. Compounds according to claim 1, characterized in that one of the substituents R and R is hydrogen, and the other is hydrogen, alkyl or C 1-4 alkyl substituted by fluorine, chlorine, bromine; a radical -S (0) n-R 'with n = 0, 1, 2 and R' = C ^ _3-alkyl; a radical "-CO-R 'with R1 = hydroxy, C ^ _3 ~ alkoxy, C ^ _3-alkyl, amino, C1_3-alkylamino or di-C ^ _3 ~ alkylamino; an amino radical 30 -NR'R ", where R 'and R" are hydrogen or C 1-4 alkyl; or a radical OR 'with R' = hydrogen, methyl, r SO3H, CH2OCOR "(R" = C1_4-alkyl). Compounds according to claim 2, characterized in that one of the substituents R and R is hydrogen and the other is hydrogen, ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, l-hydroxy-2,2,2- is trifluoro-ethyl or 1-hydroxy-l-methylethyl. Λ 70. DS 4410/151 4. Compounds according to any one of claims 1-3, characterized in that X 3 ~ alkanoyloxy or C ^ _3-alkanoyloxy substituted by hydroxy, C ^ _3 ~ alkoxy, phenyl or ^ -alkylthio. 5 5. Compounds according to any one of claims 1-3, characterized in that X ^ alkylthio substituted by a 10 phenyl, which can be substituted by one or; several fluorine, chlorine or bromine atoms, ^ alkyl, ^ - alkylthio, C ^^ - alkanoyl, carboxyl or 3 ~ alkoxycarbonyl groups; or by a group - (CI ^^ - NRR 'or - (CH0) -NHCR = NR1 or - (CH0) -N = CR-N (R') ", where n = 0, 1, Zn Zn Z 15 2 , 3 and R and R 'is H or C ^ _3 ~ alkyl; fluorine, bromine; an oxime or oxime ether radical = N-OR' (R1 = H or 20 C ^ _3 ~ alkyl) in syn or anti Position; a 3-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, 0, S; which can be substituted by a 25 or more fluorine, chlorine or bromine atoms, 3 ~ alkyl , ^ -Alkylthio-, C ^ _3-alkanoyl, carboxyl or C ^ _3 ~ alkoxycarbonyl groups; or by a group - (C ^) n ~ NRR1 or - (CH0) -NH-CR = NR1 or - ( CH0) -N = CR-N (R ') ", where n = 0, Zn Zn Z can be 1, 2, 3 and R and R' is H or C ^^ - alkyl, and ^ 30 by oxo groups); r is a C3_g-cycloalkyl radical; a radical -S (O) -R1 (with n = 1 or 2 and R '= n 35 C1_3 alkyl); a residue -COR '[with R' = C ^ _3-alkyl, phenyl, phenyloxy, benzyloxy, C3_g-cycloalkyl or a 3-7-glie- 71. DS 4410/151 ë third heterocycle with 1-4 heteroatoms (N, O, S), which can be substituted in the above manner. 5 6. Compounds according to any one of claims 1-3, characterized in that X phenylthio substituted by one or more fluorine, chlorine or bromine atoms, one - - of the groups - (CH,) - NRR1, - (CH0) -NR- CR '= NR "and 2 n' 2 n. 10 - (CH0) -N = CR-NR'R" (with n = 0, 1, 2, 3 and R, R 'and R "H * 2 n' 0 or C ^ 3 ~ alkyl, C ^ _3 ~ alkanoyl) or by C ^ ^ alkyl, C ^ _3 alkanoylamino, hydroxy, C ^ ^ alkoxy or acyloxy groups means. 7. Compounds according to any one of claims 1-3, characterized in that XC ^^ - cycloalkylthio or C3 7 ~ cycl ° a ^^ ylthio substituted by one or more oxo, hydroxy, C ^ _ ^ - alkyl, C ^ ^ Alkoxy, carboxyl or alkoxycarbonyl groups or through one of the groups 20 - (CH,) -NRR ', - (CH,) -NR-CR1 = NR "and - (CH,) -N = CR-NR' R "2 n 2 n 2 n (with η = 0, 1, 2, 3 and R, R 'and R" H or 3 ~ alkyl, C ^ 3-alkanoyl) or by one or more acyl radicals of an aliphatic or aromatic 7 ~ Carboxylic acid means 25 8. Compounds according to any one of claims 1-3, characterized in that X C_C-alkenylthio or C2_g-alkenylthio substituted by one of the groups - (CH,) -NRR ', - (CH,) -NR-CR' = NR "and - (CH,) -N = CR-NR'R" 2 n 2 n 2 ri 30 (with n = 0, 1, 2, 3 and R, R 'and R "H or C ^ _3-alkyl, C ^ _3 ~ alkanoyl) or also by C ^ _3 ~ alkyl, phenyl, a 3-7-membered saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (nitrogen, oxygen, sulfur), cyan, carboxyl, C ^ ^ - Alkoxycarbonyl, amino-35 carbonyl or acylamino means. 72. DS 4410/151 Λ 9. Compounds according to any one of claims 1-3, characterized in that X represents a 4-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, 0, S), 5 which can be substituted by fluorine, chlorine, bromine, oxo, imino, [.-alkyl, 3 ~ alkylthio, hydroxy, cyan, N-oxido, trifluoromethyl, C ^ _4-alkoxy, C ^ _ ^ - alkanoyloxy, phenyloxy, C ^ _ ^ - Alkanoyl, phenoxycarbonyl, pivaloyloxy- "" methoxycarbonyl, carbamoyl, C ^ 3-alkylcarbamoyl and / or J Ί0 ^ -alkylcarbamoyl or by - (C ^^ NRR ', ~ ^ CH2 ^ n_ NR-CR' = NR "or - ( CH2) nN = CR-NR'R "with n = 0, 1, 2, 3 and R, R 'and R" = H, C ^ ^ alkyl, C ^ _3alkanoyl; or by "^ CH2 ^ nC0R' m '' Lt n = 0, ^ · 2 # 3 and R '= hydroxy, C ^ _3 ~ alkoxy, amino or -NH- (CH2) m-NH2, where m = 2, 3, 4; or - | 5 too by - (CH2) nOH with η = 0, 1, 2, 3 means. 10. Compounds according to any one of claims 1-3, characterized in that X 2- (acetylamino) vinylthio, (l-methyl-lH-tetrazol-5-yl) thio, (1,4,5,6-tetrahydro -4-20 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-pyrimidinyl) -thio, (5-methyl-l, 3,4-thiadiazol-2-yl) -thio or acetoxy. 11. Compounds according to any one of claims 1-10, as defined as end products in one of Examples 1-3. in the 12. Compounds according to any one of claims 1-10, as 30 defined as end products in one of Examples 4-28 ^. 35 73. DS 44Î0 / 151 * 13. Compounds according to any one of claims 1-10 of the general formula,? Hh h <R> 1 | V 5. j I}) - CH ^ ’X Iä COOH * and their easily hydrolyzable esters, pharmaceutically ^’ 10 compatible salts and hydrates of these compounds. 14. Compounds of the general formula R2 H R1 LK -x 15 R, "" \ - 1 1-N \ 0 R4 * * ^ FiS COOR3 20 12 3 4 5 6 wherein R, R, R, R, R, R and X have the meaning given in claim 19, where X can also mean bromine. 15. Compounds according to any one of claims 1-13 as active pharmaceutical ingredients. 16. Compounds according to any one of claims 1-13 as = active pharmaceutical ingredients for the treatment and prophylaxis 30 of infectious diseases. 5 * 17. Pharmaceutical preparations, characterized by a content of a compound according to any one of claims 1-13. 35 * 4 74. DS 4410/151 18. Pharmaceutical preparations for the treatment and prophylaxis of infectious diseases, characterized by a content of a compound according to one of the claims. talk 1-13. 5 19. A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula ^ 2 ^ t R1 1 ^ ch2 — x 2 \ —Nn. 0 r4 ^ </ 1 = p ^ r5 \ r6 COOR3 15 1 2 wherein R, R and X are as defined in claim 1, R ^ is an easily removable radical and R ^, R ^ and R ^ C ^ _g-alkyl Represent, phenyl or p-methoxyphenyl, cyclized, optionally cleaving off the protective group present in a substituent and, if desired, transesterifying the ester obtained, if necessary converting the 3 R radical into the free acid or its salt and, if necessary, a product obtained converted into a hydrate. 20. The method according to claim 19, characterized in that 4 5 6 that R, R and R each represent a phenyl radical. 21. Use of a compound according to any one of claims 1-13 in the treatment or prophylaxis of infectious diseases. S'k'k'k 35