DD228260A5 - PROCESS FOR PREPARING NEW OPTICALLY ACTIVE PENEM COMPOUNDS - Google Patents

Abstract

2-Heterocyclyl-6-hydroxy-lower alkyl-2-penem compounds of the formula wherein R 1 is hydroxy substituted or hydroxy-substituted lower alkyl, R 2 is unsaturated azaheterocyclyl linked via a ring nitrogen atom to the penem moiety, and R 3 is carboxyl or functionally-modified carboxyl, optical isomers of Compounds of the formula I, mixtures of these optical isomers, and salts of those compounds of the formula I which have a salt-forming group have antibiotic properties. The compounds are prepared by methods known per se.

Description

4-14723 / 1-3 / +

Process for the preparation of new optically active penem compounds Field of application of the invention

The present invention relates to processes for the preparation of novel 2- (N-azaheterocyclyl) -6-hydroxy-lower alkyl-2-penem compounds and of pharmaceutical preparations containing these compounds.

Characteristic of the Known Technical Solutions Various Penem compounds are known from European Patent Application No. 2210 as well as from German Offenlegungsschrift No. 2950898, which are substituted in the 2-position by a heterocyclyl radical bonded via a ring carbon atom.

Object of the invention

The aim of the invention is to provide processes for the preparation of new, in 6-position by Hydroxiliederalkyl and in position 2 by a via a ring nitrogen atom bound azaheterocyclyl radical-substituted 2-penem-3-carboxylic acids with valuable pharmacological properties and of pharmaceutical preparations, containing such compounds.

Considering the nature of the invention

The object of the present invention is to find, starting from easily accessible starting compounds, novel antibiotically active 2- (N-azaheterocyclyl) -penem compounds and processes for their preparation.

? 8.FE3 / :: 5 * 2.? * 5344

-Ia-

According to the invention, Z-heterocyclyl-δ-hydroxy-lower alkyl-2-penem compounds of the formula

\ A

I i

R ₂ (I),

// 0

^R 3

wherein R ₁ is lower alkyl substituted by hydroxy or protected hydroxy, R represents an unsaturated azaheterocyclyl radical attached to the penem via a ring nitrogen, and R, carboxyl or functionally modified carboxyl, optical isomers of compounds of formula I ₁ mixtures of these optical isomers, and salts of those compounds of the formula which have a salt-forming group and pharmaceutical preparations containing such compounds.

The definitions used hereinbefore and hereinafter preferably have the following meanings in the context of the present description:

An unsaturated azaheterocyclyl radical R "bonded via a ring nitrogen atom to the penem radical is, in particular, a corresponding monocyclic or polycyclic, in particular monocyclic or bicyclic, and also tricyclic, azaheterocyclyl radical, such as an optionally partially saturated monocyclic 5-membered heteroaryl radical having 1 to 4 ring nitrogen atoms, eg a corresponding aza-, diaza-, triaza- or tetraza-cyclic radical of aromatic character or a corresponding dihydro radical, or a corresponding partially saturated monocyclic 6-membered heteroaryl radical having 1 to 3 Ringstipkstoffatomen, such as a corresponding aza-, diaza- or triaza-cyclic radical, eg a corresponding dihydro or tetrahydro radical, furthermore optionally partially saturated benzo, dibenzo, pyrido or pyrimido derivatives of such 5- or 6-membered radicals. Corresponding azaheterocyclyl R are, for example, optionally partially saturated pyrrolyl, diazolyl, triazolyl or tetrazolyl, further partially saturated pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, and optionally in the pyrrolyl, diazolyl or Triazolyltei1 and / or in the benzo, pyrido or Pyrimido part partially saturated benzopyrrolyl, benzodiazolyl, benzotriazolyl, pyridopyrrolyl, pyridodiazolyl, pyridotriazolyl, pyrimidopyrrolyl, pyrimidodiazolyl, pyrimidotriazolyl or dibenzopyrrolyl, furthermore partially saturated in the pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl part and in the benzo, pyrido- or pyrimidoteil optionally partially saturated benzopyridyl, benzopyrimidyl, benzopyridazinyl, benzopyrazinyl, benzotriazinyl, pyridopyridyl, pyridopyrimidyl, pyridopyridazinyl, pyridopyrazinyl, pyridotriazinyl, pyrimidopyridyl, pyrimidopyrimidyl, pyrimidopyridazinyl, pyrimidopyrazinyl, pyrimidotriazinyl, dibenzopyridyl or dibenzopyra zinyl.

Radicals R are unsubstituted or may be replaced by optionally etherified or esterified hydroxy, e.g. Hydroxy, lower alkoxy, lower alkanoyloxy or halogen, optionally etherified mercapto, e.g. Mercapto, lower alkylthio or phenylthio, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, lower alkoxy

lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl, halo-lower alkyl, lower-alkylthio-lower alkyl, optionally N-lower alkylated-amino-lower alkyl, e.g. Amino-lower alkyl, lower-alkyl-amino-lower alkyl or lower-lower alkylamino-lower alkyl, lower alkanoyl-amino-lower alkyl, amino-carboxy-lower alkyl, lower amino-lower alkoxycarbonyl-lower alkyl, lower sulfonated alkyl, optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkylene-amino or acylamino such as lower alkanoylamino, optionally functionally modified carboxyl or sulfo, e.g. Carboxyl, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as carbamoyl or N-mono- or Ν, Ν-diniederalkyliertes carbamoyl, cyano, sulfo or sulfamoyl, optionally substituted by lower alkyl, nitro, lower alkoxy and / or halogen-substituted phenyl, cycloalkyl, nitro , Imino, oxo and / or oxido substituted, in particular mono- or poly-, primarily mono- or disubstituted be. Radicals R "are substituted primarily at the ring carbon atoms, but may also be substituted at the ring nitrogen atoms.

Functionally modified carboxyl R is, in particular, cleavable under physiological conditions, esterified carboxyl or protected carboxyl R '.

A physiologically cleavable esterified carboxyl group R, protects the compounds of formula I from salt formation in the gastrointestinal tract when administered orally, thus preventing premature excretion, and is primarily an acyloxymethoxycarbonyl group in which acyl is e.g. the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone. Such groups are e.g. Lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, 4-crotonolactonyl and 4-butyrolactone-4-yl. Other esterified carboxyl groups R cleavable under physiological conditions are e.g. 5-Indanyloxycar-

carbonyl, phthalodyloxycarbonyl, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl or 2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, which is optionally substituted in the 5-position of the dioxene ring by lower alkyl or phenyl.

In the present specification, the term "lower" used in connection with definitions of groups or compounds means that the corresponding groups or compounds, unless expressly defined otherwise, contain 1 to 7, preferably 1 to 4, carbon atoms.

Hydroxy-substituted lower alkyl R is especially lower α-substituted to the penem ring skeleton by hydroxy-substituted lower alkyl and means e.g. 1-hydroxyprop-1-yl, 2-hydroxyprop-2-yl, 1-hydroxybut-1-yl or 2-hydroxybut-2-yl and in particular hydroxymethyl or 1-hydroxyethyl.

Lower alkoxy is e.g. Methoxy, further ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy, and n-pentyloxy, n-hexyloxy or n-heptyloxy.

Lower alkanoyloxy is e.g. Acetyloxy or propionyloxy. Halogen is e.g. Fluorine, chlorine, bromine or iodine.

Lower alkylthio is e.g. Methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, n-hexyl or n-heptyl.

Hydroxy lower alkyl as a substituent of an azaheterocyclyl radical R is e.g. Hydroxymethyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.

Lower alkanoyloxy lower alkyl is e.g. Acetoxymethyl or 2-acetoxyethyl.

Lower alkoxy lower alkyl is e.g. Methoxymethyl, 2-MeChoxyäthyl, Aethoxymethyl or 2-ethoxyethyl.

Carboxy-lower alkyl is e.g. Carboxymethyl, 1-carboxy, 2-carboxy or 1,2-dicarboxyethyl.

Lower alkoxycarbonyl lower alkyl is e.g. Methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-methoxycarbonylethyl.

Carbamoyl lower alkyl is e.g. Carbamoylmethyl or 2-carbamoylethyl, while carbamoyl-lower alkyl e.g. Carbamoyloxymethyl or 2-carbamoyloxyethyl is.

Halo-lower alkyl is e.g. Chloromethyl, bromomethyl, 2-chloroethyl or 2,2-dichloroethyl.

Lower alkylthio-lower alkyl is e.g. Methylthiomethyl, ethylthiomethyl, n-propylthiomethyl or 2-methylthioethyl.

Amino-lower alkyl is e.g. Aminomethyl or 2-aminoethyl, while lower alkylamino lower alkyl e.g. Methylaminomethyl ,. Ethylaminomethyl, 2-methylaminoethyl or 2-ethylaminoethyl and di-lower alkylamino lower alkyl e.g. Dimethylaminomethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl.

Lower alkanoylamino lower alkyl is e.g. Acetaminomethyl, 2-acetaminoethyl or formylaminomethyl.

Amino-carboxy-lower alkyl is e.g. 2-amino-2-carboxy-ethyl or else 1-amino-1-carboxymethyl, while amino-lower alkoxycarbonyl-lower alkyl e.g. 2-amino-2-methoxy- (or 2-ethoxy) -carbonylethyl.

Sodium lower alkyl is e.g. Sulfomethyl or 2-sulfoethyl.

Lower alkylamino is e.g. Methylaraino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while di-lower alkylamino e.g. Dimethyl amino, diethylamino, di-n-propylamino or diisopropylamino.

Lower alkyleneamino in particular has 4 to 6 carbon chain members and means e.g. Pyrrolidino or piperidino.

Lower alkanoylamino is e.g. Acetylamino or propionylamino. Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl.

N-mono-lower alkylated carbamoyl is e.g. N-methyl, N-ethyl or N-propylcarbamoyl while N, N-di-lower alkylated carbamoyl e.g. N, N-dimethyl or Ν, Ν-diethylcarbamoyl.

Cycloalkyl preferably contains 3 to 8, primarily 5 or 6 ring members and is e.g. Cyclopentyl or cyclohexyl, furthermore cyclopropyl and cycloheptyl.

Lower alkanoyloxymethoxycarbonyl is e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

α-amino lower alkanoyloxymethoxycarbonyl is e.g. Glycyloxymethoxycarbonyl, Valyloxymethoxycarbonyl or Leucyloxymethoxycarbonyl.

L-lower alkoxycarbonyloxy lower alkoxycarbonyl is e.g. Aethoxycarbonyloxymethoxycarbonyl or 1-ethoxycarbonyloxyethoxycarbonyl.

1-lower alkoxy-lower alkoxycarbonyl is e.g. Methoxytnethoxycarbonyl or 1-methoxyethoxycarbonyl.

In a 2-oxo-l, 3-dioxolen-4-ylmethoxy group _I which is substituted in the 5-position of the Dioxolenringes optionally substituted by lower alkyl or phenyl, it is mainly a 5-phenyl and, in the first place to a 5-methyl-2-oxo-l, 3-dioxolen-4-ylmethoxy group.

Corresponding 5-membered optionally partially saturated monocyclic heteroaryl radicals R are e.g. optionally, e.g. lower alkyl or halogen substituted pyrrolyl or dihydropyrrolyl, e.g. 1-pyrrolyl, 3-methyl-1-pyrrolyl, 3,4-dichloro-1-pyrrolyl, furthermore 2,3- or 2,5-dihydro-1-pyrrolyl, optionally e.g. by lower alkyl, lower alkoxy, amino-lower alkyl, N-lower alkylated amino-lower alkyl, lower alkanoyl-lower alkyl, lower-carboxy-lower alkyl, lower-lower alkoxycarbonyl-lower alkyl, lower-oxoxycarbonyl, carbamoyl-lower alkyl, lower carbamoyl, lower alkylanoxy, lower alkanoylamino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, or lower alkynyl Nitro substituted diazolyl, such as imidazolyl or pyrazolyl, for example 1-imidazolyl, 1-pyrazolyl, 4-lower alkyl-1-pyrazolyl, 2-araino, 4-lower-alkoxy, 4-lower-alkyl, 4,5-di-lower alkyl, 2-amino-lower alkyl, 4-amino-lower alkyl, 4-lower alkanoyl-amino-lower alkyl. , 2-hydroxy-lower alkyl, 4-hydroxy-lower alkyl, 4-lower alkanoyloxy-lower alkyl, 2- or 4-amino-carboxy-lower alkyl, 4-carbamoyl-lower alkyl, 4-carbamoyloxy-lower alkyl, 4-halo-lower alkyl, 4-lower-alkylthio-lower alkyl or 2- Nitro-l-imidazolyl, 2-Niederalkylpyrazolio or 3-lower alkylimidazolio, optionally, for example triazolyl substituted by lower alkyl, carboxy-lower alkyl, amino or phenyl, such as IH-I, 2,3-triazol-1-yl, IH-1, 2,3-triazol-2-yl, 1H-1, 2,4-triazole l-yl or IH-I, 3,4-triazol-1-yl, eg the corresponding unsubstituted radicals, 4- or 5-methyl-l, 2,3-triazol-1-yl, 3-methyl or 3-phenyl-1H-l, 2,4-triazol-1-yl or 1 ( 2-methyl or 4-methyl-1H-l, 2,4-triazolio), or optionally, for example tetrazolyl substituted by lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl, di-lower alkylamino-lower alkyl, amino or optionally halogen-substituted phenyl, such as

1H-tetrazol-1-yl or 2H-tetrazol-2-yl, e.g. the corresponding unsubstituted radicals, 5-amino, 5-methyl, 5-carboxymethyl, 5-sulfomethyl, 5- (2-dimethylaminoethyl) - or 5-phenyl-lH-tetrazol-1-yl, or 5-amino , 5-methyl, 5-carboxymethyl, 5-sulfomethyl, 5- (2-dimethylaminoethyl) or 5-phenyl-2H-tetrazol-2-yl.

Corresponding 6-membered partially saturated monocyclic heteroaryl radicals R are e.g. unsubstituted or, in particular, e.g. by oxo and optionally in addition, e.g. halogen substituted dihydro-1-pyridyl, such as 2H-1,2-dihydro- or 4H-1,4-dihydro-1-pyridyl, e.g. 2-OXO-2H-1,2-dihydro-1-pyridyl or 4-oxo-4H-1,4-dihydro-1-pyridyl, optionally, in particular e.g. by oxo and optionally in addition, e.g. lower alkyl, amino, di-lower alkylamino and / or carboxy-substituted dihydro- or tetrahydro-1-pyrimidyl, such as 2H-1,2-dihydro-, 4H-1,4-dihydro- or 1,2,3,4-tetrahydro-1 pyrimidyl, eg 2-oxo-1, 2-dihydro-1-pyrimidyl, 6-methyl, 5-methyl, 5-carboxy or 6-carboxy-2-oxo-1,2-dihydro-1-pyrimidyl, 4-amino 2-oxo-1, 2-dihydro-1-pyrimidyl (cytosyl), 4-oxo-1, 4-dihydro-1-pyrimidyl, 2,4-dioxo-1,2,3,4-tetrahydro-1-one pyrimidyl or 5-methyl-2,4-dioxo-l, 2,3,4-tetrahydro-l-pyrimidyl, or optionally, for example dihydro or tetrahydrotiazinyl substituted by lower alkyl, lower alkoxy, amino and / or up to 2 oxo, such as 2H-1,2-dihydro-1,3,5-triazin-1-yl, 2H-1,2-dihydro-1, 2,4-triazin-1-yl, 1,2,5,6-tetrahydro-1,2,4-triazin-1-yl, or 1,2,3,4-tetrahydro-1,3,6-triazine -l-yl, eg 4-amino-2-oxo-1,2-dihydro-l, 3,5-triazin-1-yl (5-azacytosyl), 4-lower alkyl-1, 4,5,6-tetrahydro-5,6-dioxo -l, 2,4-triazin-1-yl, eg 4-methyl-l, 4,5,6-tetrahydro-5,6-dioxo-l, 2,4-triazin-1-yl, 2,4-dioxo-l, 2,3,4-tetrahydro-1, 3,6-triazin-1-yl (6-azauracyl) or 2,4-dioxo-5-methyl-1,2,3,4-tetrahydro-1,3,6-triazin-1-yl (4-azathymyl ).

Optionally substituted and optionally partially saturated benzo, dibenzo, pyrido and pyrimido derivatives of said monocyclic azaheterocyclyl radicals R are in particular those of the pyrrol-1-yl, imidazol-1-yl and triazol-1-yl radicals, especially indole -1-yl, carbazol-9-yl, benzoimidazol-1-yl, benzotriazol-1-yl,

Pyrido-pyrrol-1-yl, e.g. 1H-pyrrolo (2,3-b) pyrid-1-yl, pyrido-imidazol-1-yl, e.g. 1H-imidazo (4,5-b) pyrid-1-yl, optionally, e.g. pyrimido, dihydropyrimido or tetrahydropyrimido-imidazol-1-yl substituted by amino, imino and / or oxo, e.g. Purin-1-yl, hypoxanthyl, adenyl or guanyl, or optionally, e.g. amino, imino and / or oxo substituted pyrimido, dihydropyrimido or tetrahydropyrimido-1,2,3-triazol-1-yl, e.g. 8-azahypoxanthyl, 8-azaadenyl or 8-azaguanyl.

Preferred radicals R are unsubstituted or e.g. as indicated, substituted pyrrol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl, benzoimidazol-1-yl, indol-1-yl, benzotriazol-1-yl , 1H-pyrrolo (2,3-b) pyrid-1-yl, 1H-imidazo (4,5-b) pyrid-1-yl and purin-1-yl, and especially unsubstituted or eg as indicated, substituted imidazol-1-yl.

Preferred esterified carboxyl groups R cleavable under physiological conditions are e.g. Phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and L-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. l-Aethoxycarbonyloxyäthoxycarbonyl.

The functional groups present in the compounds of the formula I, such as hydroxy-ι carboxy, amino or sulfo groups, in particular the hydroxy group in the radical R and the carboxyl group R-, are optionally protected by protective groups which are present in the penem, penicillin , Cephalosporin and peptide chemistry. Such protecting groups protect the functional groups concerned from undesirable condensation reactions, substitution reactions and the like during the synthesis of the compound of formula I from its precursors.

Such protecting groups are light, i. without unwanted side reactions take place, for example, solvolytic, reductively or under physiological conditions, cleavable.

Protecting groups of this type as well as their introduction and removal are described for example in

J. F. W. McOraie, "Protective Groups in Organic Chemistry," Plenum Press, London, New York, 1973,

T.W. Greene, "Protective Groups in Organic Synthesis," Wiley, New York, 1981,

"The Peptides", Vol. I, Schroeder and Luebke, Academic Press, London, New York, 1965 and

Houben-Weyl, "Methods of Organic Chemistry", Volume 15/1, Georg Thieme Verla'g, Stuttgart, 1974.

In compounds of the formula (I) it is possible for a hydroxy group in the radical R, furthermore a hydroxyl group present in the radical R, to be protected, for example, by acyl radicals. Suitable acyl radicals are, for example, optionally halogen-substituted lower alkanoyl, for example acetyl or trifluoroacetyl, optionally nitro-substituted benzoyl, for example benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally halogen-substituted lower alkoxycarbonyl, for example 2-bromoethoxycarbonyl or 2,2,2 Trichloroethoxycarbonyl, lower alkenyloxycarbonyl, eg allyloxycarbonyl, or optionally nitro-substituted phenyl-lower alkoxycarbonyl, eg 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups include trisubstituted SiIyI ₁ as Triniederalkylsilyl, for example trimethylsilyl or tert-butyl-dimethylsilyl, 2-Halogenniederalkylgruppen, for example, 2-chloro, 2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally substituted by halogen, for example chlorine, lower alkoxy, eg methoxy, and / or nitro substituted phenyl, such as corresponding benzyl. Preferred as hydroxy protecting group is tri-lower alkylsilyl and lower alkenyloxycarbonyl.

A carboxyl group R, as well as a carboxyl group present in the radical R, is usually protected in esterified form, the ester group being protected under mild conditions, e.g. with gently reductive, such as hydrogenolytic, or gently solvolytic, such as acidolytic or especially basic or neutral

hydrolytic conditions, easily cleavable. A protected carboxyl group may further represent an esterified carboxyl group easily converted into another functionally modified carboxyl group such as another esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups primarily in the 1-position branched or in the 1- or 2-position suitably substituted lower alkyl groups. Preferred esterified carboxyl groups include lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl, and (hetero) arylmethoxycarbonyl having 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert-butyl, halogen, e.g. Chloro, and / or nitro mono- or polysubstituiert. Examples of such groups are optionally e.g. As mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as mentioned above, substituted picyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl. Other suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, halo-lower alkoxycarbonyl such as 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or omega-halo-lower alkoxycarbonyl wherein lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, or in the 2-position by lower alkylsulfonyl, cyano or trisubstituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl.

Other esterified carboxy groups present in esterified form are corresponding organic silyloxycarbonyl, further corresponding organic stalyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, in particular methyl or ethyl, furthermore lower alkoxy, e.g. Methoxy, as a substituent. Suitable silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl or dimethyltert.-butylsilyl, or correspondingly substituted stannyl groups, e.g. Tri-n-butylstannyl.

Preferred protected carboxyl groups R 'are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, especially allyloxycarbonyl, and the 2-substituted by lower alkylsulfonyl, cyano or tri-lower alkylsilyl, e.g. Trimethylsilyl or di-n-butylmethylsilyl, substituted ethoxycarbonyl group.

A protected amino group in the radical R "can be present, for example, in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group or as the enamino, nitro or azido group.

In a corresponding acylamino group, for example, acyl is the acyl radical of an organic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or phenyl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2 Trichloroacetyl, optionally substituted benzoyl, eg Benzoyl, halobenzoyl such as 4-chlorobenzoyl, lower alkoxybenzoyl such as 4-methoxybenzoyl, or nitrobenzoyl such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, or lower alkoxycarbonyl optionally substituted in the 1- or 2-position, such as lower alkoxycarbonyl, e.g. Methoxy- or ethoxycarbonyl, given

if substituted benzyloxycarbonyl, e.g. Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted Silyd-ethoxycarbonyl such as 2-tri-lower alkylsilylethoxycarbonyl, eg 2-trirethylethylsilylethoxycarbonyl or 2- (di-n-butylmethyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

For example, in an acylimino group, acyl is the acyl radical of an organic dicarboxylic acid with e.g. up to 12 carbon atoms, especially a corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is primarily phthalimino.

An etherified mercaptoamino group is primarily a phenylthioamino group or a pyridylthioamino group optionally substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and / or nitro. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, wherein the silicon or tin atom is preferably lower alkyl, e.g. Methyl, ethyl, η-butyl or tert-butyl, further lower alkoxy, e.g. Methoxy, as a substituent. Corresponding silyl or stannyl groups are primarily tri-lower alkysilyl, especially trimethylsilyl, furthermore dimethyl-tert-butylsilyl, or appropriately substituted stannyl, e.g. Tri-n-butylstannyl.

Further protected amino groups are e.g. Enaminogruppen containing at the double bond in the 2-position an electron-withdrawing substituent, such as a carbonyl group. Protecting groups of this type are, for example, 1-acyl-lower-alk-1-en-2-yl radicals, in which acyl

e.g. the corresponding residue of a lower alkanecarboxylic acid, e.g. Acetic acid, an optional, e.g. lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halo, such as chloro and / or nitro substituted benzoic acid, or especially a carbonic acid half ester, such as a carbonic acid lower alkyl, e.g. methyl half-ester or ethyl half-ester, and Niederalk-1-en, in particular 1-propene means. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-len-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. 1-ethoxycarbonyl-prop-l-en-2-yl.

Preferred protected amino groups are e.g. Azido, phthalimido, nitro, lower alkenyloxycarbonylamino, e.g. Allyloxycarbonylamino, and optionally nitro-substituted benzyloxycarbonylamino.

A protected sulfo group in R is primarily an esterified one such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, e.g. a lower alkanol, or having a silyl or stannyl radical, such as tri-lower alkysilyl, esterified sulfo group. In a sulfo group, for example, the hydroxy group may be etherified as the hydroxy group in an esterified carboxyl group.

Salts of compounds of the invention are primarily pharmaceutically acceptable non-toxic salts of compounds of formula I. Such salts are exemplified by the acidic groups present in compounds of formula I, e.g. Carboxyl and sulfo groups formed and are primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcia salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-

piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, dibenzylamine or N-benzyl-phenethylamine. Compounds of formula I having a basic group, e.g. with an amino group, acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acid, e.g. Acetic, succinic, fumaric, maleic, tartaric, oxalic, citric, benzoic, mandelic, malic, ascorbic, methanesulfonic or 4-toluenesulfonic acid form. Compounds of formula I having an acidic and a basic group may also be present in the form of internal salts, i. in zwitterionic form.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

The penem compounds of the formula I may have an additional center of chirality in the substituent R ₁ . For example, 1-hydroxyethyl may be present as substituent R in the R, S or racemic R, S configuration. In preferred penem compounds of the formula I, a radical R ₁ which has an asymmetric carbon atom, in particular 1-hydroxyethyl, has the R configuration.

In particular, the invention relates to compounds of the formula I ₁ in which R. is lower alkyl substituted by hydroxy or protected hydroxy, R is a monocyclic 5-membered heteroaryl radical containing 1-4 ring nitrogen atoms, optionally partially saturated, attached to the penem radical via a ring nitrogen atom a corresponding aza-, diaza-, triaza- or tetraza-cyclic radical of aromatic character or a corresponding dihydroro radical, a corresponding partially saturated monocyclic 6-membered heteroaryl radical having 1-3 ring nitrogen atoms, such as a corresponding aza-, diaza- or triaza- cyclic radical, or a corresponding

optionally partially saturated benzo, dibenzo, pyrido or pyrimido derivative of such a 5- or 6-membered radical, these radicals being unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxy lower alkyl, Lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower-alkoxycarbonyl-lower alkyl, lower alkylthio-lower alkyl, lower N-lower alkylthio-lower alkyl, lower alkanoyl-lower alkyl, lower carboxy-lower alkyl, amino-lower alkoxycarbonyl-lower alkyl, lower sulfonyl, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, lower alkanoylamino, carboxyl, Lower alkoxycarbonyl, carbamoyl, N-rmono- or Ν, Ν-di-lower alkylated carbamoyl, cyano, sulfo, sulfamoyl, optionally substituted by lower alkyl, nitro, lower alkoxy and / or halogen-substituted phenyl, cycloalkyl, nitro, imino, oxo and / or oxido are substituted, R is carboxyl, cleavable under physiological conditions esterified carboxyl or protected carboxyl R ', optical isomers of compounds of formula I ₁ mixtures of these optical isomers and salts. of compounds of the formula I ₁ which have a salt-forming group.

More particularly, the invention relates to compounds of formula I, wherein R ₁ is lower alkyl substituted by hydroxy or tri-lower alkylsilyloxy, R "optionally substituted by lower alkyl or halogen substituted 1-pyrrolyl or dihydro-1-pyrrolyl, optionally lower alkyl, lower alkoxy, amino lower alkyl, N-lower alkylated Amino-lower alkyl, lower alkanoyl-amino-lower alkyl, lower carboxy-lower alkyl, lower-lower alkoxycarbonyl-lower alkyl, lower-alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower carbamoyl-lower alkyl, lower alkylanilo, lower alkylthio-lower alkyl, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or nitro-substituted imidazol-1-yl, optionally substituted by lower alkyl, amino-lower alkyl, amino-carboxy-lower alkyl, amino or nitro-substituted pyrazol-1-yl, optionally lower alkyl,

Carboxy-lower alkyl or phenyl-substituted 1,2,3-, 1,2,4- or 1,3,4-triazol-1-yl, optionally substituted by lower alkyl, carboxy-lower alkyl, lower-sulfo-alkyl, lower di-lower alkyl, amino or optionally substituted by halogen-substituted phenyl. or 2-tetrazolyl, unsubstituted or by oxo and optionally additionally by halogen-substituted dihydro-1-pyridyl, unsubstituted or substituted by oxo and optionally additionally by lower alkyl, amino, di-lower alkylamino and / or carboxy-substituted dihydro- or tetrahydro-1-pyrimidyl, optionally Lower alkyl, lower alkoxy, amino and / or dihydro- or tetrahydro-1,2,4- or -1,3,6-triazin-1-yl substituted up to 2 oxo groups; Indol-1-yl, benzimidazol-1-yl, benzotriazol-1-yl, pyridopyrrol-1-yl, pyrido-imidazol-1-yl, optionally substituted by amino, imino and / or oxo pyrimido-, dihydropyrimido- or tetrahydropyrimido- imidazol-1-yl, or pyrimido-, dihydropyrimido- or tetrahydropyrimido-1,2,3-triazol-1-yl optionally substituted by amino, imino and / or oxo, and R- carboxyl, 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, in 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl-substituted ethoxycarbonyl or a cleavable under physiological conditions esterified carboxy group, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I ₁ which have a salt-forming group ,

More particularly, the invention relates to compounds of formula I ₁ wherein R is α-substituted lower hydroxy by hydroxy, R "is unsubstituted or lower alkyl or halogen substituted pyrrol-1-yl, unsubstituted" or lower alkyl or amino lower alkyl substituted pyrazol-1-yl unsubstituted or imidazol-1-yl substituted by lower alkyl, lower alkoxy, lower aminoalkyl, lower alkanoylamino, lower alkyl, lower alkoxycarbonyl, lower alkyl, lower alkanoyloxy, lower, lower alkylthione, amino or nitro, lower alkoxycarbonyl-lower alkyl, lower alkylcarboxol, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower carbamyl-lower alkyl unsub-

substituted or lower alkyl substituted 1,2,4- or 1,3,4-triazol-1-yl, unsubstituted or lower alkyl, amino or phenyl substituted 1- or 2-tetrazolyl; Indol-1-yl, benzimidazo1-1-yl, benzotriazol-1-yl, 1H-pyrrolo (2,3-b) pyrid-1-yl, 1H-imidazo (4,5-b) pyrid-1-yl or Purin-1-yl, and R. Carboxyl or physiologically cleavable esterified carboxyl, such as lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, means optical isomers of compounds of formula I, mixtures of these optical isomers and salts, especially pharmaceutically acceptable salts of those compounds of the formula I which contain a salt-forming group.

The invention relates primarily to compounds of formula I ₁ wherein R _{1 is} hydroxymethyl or 1-hydroxyethyl, R "pyrrol-1-yl, unsubstituted or substituted by lower alkyl, lower alkoxy, amino or amino lower alkyl imidazol-1-yl, unsubstituted or lower alkyl or amino-lower alkyl substituted pyrazol-1-yl, 1,2,4-triazol-1-yl or unsubstituted or amino-substituted tetrazol-1-yl, and R_carboxyl or physiologically cleavable esterified carboxyl such as lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy lower alkoxycarbonyl, means optical isomers, especially the (IR) isomer of compounds of the formula I ₁ in which R _{1 is} 1-hydroxyethyl, mixtures of these optical isomers and salts, in particular pharmaceutically acceptable salts of compounds of the formula I.

The invention relates mainly to compounds of the formula I in which R _{1 is} hydroxymethyl or (1R) -1-hydroxyethyl, R 10 is unsubstituted or lower-alkyl or amino-lower alkyl-substituted imidazol-1-yl, and R 1 is carboxyl or, under physiological conditions, cleavable esterified carboxyl, such as lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, and salts, especially pharmaceutically acceptable salts of compounds of formula I.

The invention relates in particular to the compounds of the formula I mentioned in the examples and their salts, in particular pharmaceutically acceptable salts.

The compounds of the present invention can be prepared by methods known per se.

The new compounds and pharmaceutical preparations containing such compounds are described e.g. made by

a. an ylide compound of the formula

RS-C-R, \

(II)

// \ θ Θ 0 C-X

^R 3

wherein R ₁ and R have the meanings given under formula I and R 'represents a protected carboxyl group, Z is oxygen or sulfur and X represents either a triply substituted phosphoniogroup or a doubly esterified phosphono group together with a cation, ringschliesst, or

b-, a compound of the formula

(III)

wherein R and R have the meanings given under formula I, Z has the meaning given under formula II and R 'represents a protected carboxyl group, treated with an organic compound of trivalent phosphorus, or

C is a compound of the formula R ₁ S

I I, - * (χ),

/ ΓΛ /

wherein R _{7 has} the meaning given under formula I, R 'represents a protected carboxyl group and Y represents a nucleophilic reaction exchangeable group, with a. Reacting radical R "introducing compound and, if desired or necessary, in a compound of the formula I obtainable a protected hydroxy group in the radical R in the free hydroxy group, and / or, if desired, in a compound of the formula I obtainable a protected carboxyl group R into the free, esterified carboxyl group cleavable under physiological conditions or into another protected carboxyl group R 'or a free carboxyl group R, into a physiologically cleavable esterified carboxyl group or into a protected carboxyl group R', and / or, if desired other protected functional groups contained in the radical R converted into the free functional groups, and / or, if desired in an available compound of formula I, a radical R converted into another radical R, and / or, if desired, a compound obtainable with salt-forming Group in a salt or available s salt is converted to the free compound or other salt, and / or, if desired, an available mixture of isomeric compounds is separated into the individual isomers and / or, if desired, a compound obtainable is made into a pharmaceutical preparation.

In the starting compounds of the formulas II, III and X are functional groups, such as a free hydroxy group in the radical R ₁ and further functional groups containing in the radical R, preferably protected by conventional protecting groups, for example by the above.

a) Cyclization of the compound of the formula II The group X in the starting material of the formula II is one of the commonly used in Wittig condensation reactions phosphonio or phosphono, in particular a triaryl, eg triphenyl, or Triniederalkyl-, eg tri-n-butylphosphoniogruppe, or a phosphono group which has been doubly esterified by lower alkyl, for example ethyl, where the symbol X in the case of the phosphono group additionally comprises the cation of a strong base, in particular a suitable metal such as alkali metal ion, for example the lithium, sodium or potassium ion. Preferred as group X are, on the one hand, triphenylphosphonio and, on the other hand, diethylphosphono together with an alkali metal, eg sodium, ion.

In phosphonio compounds of formula II, the negative charge is neutralized by the positively charged phosphonium group. In phosphono compounds of formula II, the negative charge is neutralized by the cation of a strong base which, depending on the manner of preparation of the phosphono starting material, e.g. an alkali metal, e.g. Sodium, lithium or potassium ion, may be. The phosphono starting materials are therefore used as salts in the reaction.

The ring closure can be spontaneous, i. in the preparation of the starting materials, or by heating, e.g. in a temperature range of about 30 ° C to 160 ° C, preferably from about 50 ° C to about 100 ° C, take place. The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. Methylene chloride, an ether, e.g. Diethyl ether, a cyclic ether, e.g. Dioxane or

Tetrahydrofuran, a carboxamide, for example dimethylformamide, a Diniederalkylsulfoxid, for example dimethyl sulfoxide, or a lower alkanol, for example ethanol, or in a mixture thereof _t and, if necessary, in an inert gas, for example, nitrogen atmosphere performed.

b. Cyclization of the compound of formula III

An organic compound of the trivalent phosphorus is derived e.g. of phosphorous acid and is especially an ester thereof with a lower alkanol, e.g. Methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, e.g. Phenol or catechol, or an amide ester thereof of the formula P (OR) -N (R,) "where R and R independently

a b 2 a Ij °

lower alkyl, e.g. Methyl, or aryl, e.g. Phenyl, mean. Preferred compounds of the trivalent phosphorus are trialkyl phosphites, e.g. Trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. Benzene or toluene, an ether, e.g. Dioxane or tetrahydrofuran, or a halogenated hydrocarbon, e.g. Methylene chloride or chloroform, at a temperature of about 20 ° to 80 ° C, preferably from about 40 ° to about 60 ° C, wherein reacting 1 molar equivalent of a compound of formula III with 2 molar equivalent of the phosphorus compound of formula III in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over an extended period of time, for example over a period of from 2 to 4 hours.

In a preferred embodiment of the process, the starting material of the formula III is prepared as described below and reacted without isolation from the reaction mixture with the organic compound of the trivalent phosphorus, the end products of the formula I being formed.

c. Introduction of the remainder R

In a compound of the formula X, a group Y exchangeable by nucleophilic reaction is, for example, a radical of the formula -S (O) -R ,, in which R is, for example, lower alkyl, for example methyl or ethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, or aralkyl, for example, benzyl, or reactive esterified hydroxy, such as optionally halogen-substituted lower alkanoyloxy, for example acetoxy, lower alkanesulfonyloxy, eg methanesulfonyloxy, optionally substituted by lower alkyl, such as methyl, or halogen, such as bromine, substituted benzenesulfonyloxy, for example benzenesulfonyloxy, p-methyl or p-bromobenzenesulfonyloxy, or a radical of the formula -O-PO (OR _1. ) ", in which R_ is, for example, lower alkyl, such as methyl or ethyl.

Suitable compounds introducing the radical R "are, for example, compounds of the formula R.-H, in which the hydrogen atom is attached to the nitrogen-bonding nitrogen atom of the azaheterocyclyl radical R, or a salt, such as an alkali metal salt, for example the lithium. Sodium or potassium salt thereof, or compounds of the formula R-Si (R ^) ₀₁ wherein R, in particular lower alkyl, for example

ZDJ D

Methyl, stands.

The reaction of the compound of formula X with the radical R "introducing compound is preferably in an inert solvent, for example dimethylformamide, dimethyl sulfoxide, acetonitrile, water or mixtures thereof, at a temperature of about -50 ° C to about +50 ⁰ C, especially at about -2O ⁰ C to about +20 ⁰ C, carried out, wherein in the reaction with compounds of formula R_-H conveniently in the presence of equimolar amounts of a base such as an organic base, for example diisopropylethylamine, triethylamine or pyridine, or a inorganic base ', for example sodium bicarbonate or potassium carbonate.

The starting compounds of the formula X are known or can be prepared by known processes.

Preference is given to using those starting materials of the formulas II, III and X which lead to the compounds of the formula I mentioned at the outset as being particularly preferred.

In one obtainable compound of the formula I ₁ in which one or more functional groups are protected, these, for example protected carboxyl, hydroxyl, amino, and / or sulfo groups, in a conventional manner by solvolysis, in particular hydrolysis, alcoholysis or acidolysis , or by reduction, in particular hydrogenolysis or chemical reduction, optionally be released stepwise or simultaneously.

In a compound of the formula I obtainable by the process according to the invention in which R represents a protected carboxyl group and / or in which the radical R contains protected carboxyl as substituent, the protected carboxyl group can be liberated in a manner known per se. Thus, tert.-lower alkoxycarbonyl or lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl substituted in the 2-position by a trisubstituted silyl group or in the 1-position by lower alkoxy may be used. by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, into free carboxyl. Optionally substituted benzyloxycarbonyl may be e.g. by means of hydrogenolysis, i. be cleaved by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Further, suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl may also be obtained by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Tin, or metal salt, such as a chromium II salt, e.g. Chromium-II-chloride, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen together with the metal, such as a suitable carboxylic acid, e.g. an optional, e.g. by hydroxy, substituted lower alkanecarboxylic acid, e.g. Acetic, formic or glycolic acid, or an alcohol or thiol,

preferably adding water, convert into free carboxyl. The cleavage of an allyl protecting group can be e.g. by reaction with a compound of palladium, e.g. Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. 2-Aethylhexanoic acid, or a salt thereof. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxyl, while aroylmethoxycarbonyl can also be converted by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, can be cleaved. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetrabutylammonium fluoride are converted into free carboxyl. Carboxylated with an organic silyl or stannyl group, such as tri-lower alkylsilyl or -stannyl, may be solvolytically, e.g. by treatment with water or an alcohol. A lower alkoxycarbonyl group substituted at the 2-position by lower alkylsulfonyl or cyano may be e.g. by treating with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium or potassium hydroxide or sodium or potassium carbonate, are converted into free carboxyl.

On the other hand, compounds of the formula I in which R 1 denotes carboxy can also be converted into compounds of the formula I in which R 1 represents a protected carboxyl group, in particular an esterified carboxyl group, or an esterified carboxyl group which can be cleaved under physiological conditions. Thus, the free carboxyl group can be e.g. by treating with a suitable diazo compound, such as a diazo-lower alkane, e.g. Diazomethane, or one

  - 26 -

Phenyl-diazo-lower alkane, e.g. Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, e.g. Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. Dicyclohexylcarbodiimid, as well as carbonyldiimidazole, esterify. Esters can also be prepared by reacting an optionally in situ prepared salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid. Further, acid halides, such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl ester, such as ethyl chloroformate or isobutyl chloroformate, or with Halogenessigsäurehalogeniden, such as trichloroacetic acid chloride) by reaction with suitable alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group.

In a compound of formula I having an esterified carboxyl group, this may be converted to another esterified carboxyl group, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, e.g. Sodium iodide, in 2-iodoethoxycarbonyl. Further, in compounds of formula I containing an esterified carboxyl group, the carboxyl protecting group can be cleaved as described above and a resulting compound of formula I having a free carboxyl group or a salt thereof by reacting with the reactive ester of a corresponding alcohol in one Convert compound of formula I, wherein R_ is a cleavable esterified carboxyl group under physiological conditions.

In the case of compounds of the formula I obtainable in accordance with the process in which the radical R ₁ and / or optionally the radical R contains protected hydroxyl as substituent, the protected hydroxy group can be converted into the free hydroxy group in a manner known per se.

For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released as a suitably protected amino group (see below), a tri-lower alkylsilyl group e.g. also with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by trisubstituted silylethoxy are not cleaved). A 2-halo-lower alkyl group and an optionally substituted benzyl group are reductively removed.

In a compound of the formula I with a protected amino group which can be obtained according to the invention, it can be prepared in a manner known per se, e.g. depending on the nature of the protecting group, preferably converted by solvolysis or reduction, in the free amino group. For example, 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino may be treated by treatment with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid or catalytically with hydrogen Cleaved presence of a palladium catalyst. Aroylmethoxycarbonylamino may also be obtained by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. Sodium dithionite be cleaved. Optionally substituted benzyloxycarbonylamino may e.g. by means of hydrogenolysis, i. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino by reaction with a compound of palladium, e.g. Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. 2-Aethylhexansäure, or a salt thereof, are cleaved. An amino group protected with an organic silyl or stannyl group may e.g. by hydrolysis or alcoholysis, one represented by 2-halo-lower alkanoyl, e.g. 2-Chloroacetyl, protected amino group by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal

thiolate, the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the resulting condensation product are released. An amino group protected by 2-substituted silylethoxycarbonyl may be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetraäthylammoniumfluorid be converted into the free amino group. An amino group protected in the form of an azido or nitro group is e.g. converted by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid such as acetic acid. A protected in the form of a phthalimido group amino group can be converted by reacting with hydrazine in the free amino group. Furthermore, an arylthioamino group may be converted to amino by treatment with a nucleophilic reagent, such as sulfurous acid.

A protected, in particular esterified, sulfo group is liberated analogously to a protected carboxyl group.

In compounds of the formula I it is also possible to convert a radical R "into another radical R.

Thus, for example, in compounds of formula I in which the radical R is substituted by a carboxyl group, this carboxyl group can be converted into a functionally modified carboxyl group, such as an esterified carboxyl group or optionally substituted carbamoyl, by processes known per se. For example, by reacting a compound of formula I wherein R is carboxyl substituted azaheterocyclyl with an alcohol, especially a lower alkanol, one obtains a compound of formula I wherein R is azaheterocylyl substituted by esterified carboxyl, especially lower alkoxycarbonyl;

preferably in the presence of a suitable condensing agent, e.g. a carbodiimide, or the resulting water removed by azeotropic distillation. On the other hand, carboxyl groups on radicals R can also be converted into reactive functional derivatives such as mixed anhydrides, e.g. Acid halides, or activated esters, and convert them by reaction with an alcohol, e.g. Lower alkanol, ammonia or a primary or secondary amine, e.g. a lower alkyl or di-lower alkylamine, converted into corresponding esterified or amidated carboxyl groups, wherein the use of mixed anhydrides, preferably in the presence of an acid-binding agent, such as an aromatic or tertiary amine or an alkali metal or alkaline earth metal carbonate works.

If a heteroaryl radical R "has a hydroxyl group, it can be etherified in the usual way. The reaction to the corresponding lower alkyl heteroaryl ethers is carried out, for example, in the presence of bases such as alkali metal hydroxides or carbonates, e.g. Sodium hydroxide or potassium carbonate, by means of di-lower alkyl sulfates or lower alkyl halides, or with diazo-lower alkanes, or, in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide, with the aid of lower alkanols. Furthermore, hydroxy can be converted to esterified hydroxy, e.g. Lower alkanoyloxy, for example, by reaction with the reactive derivative of a corresponding lower alkanecarboxylic acid, e.g. Acetic acid, such as an anhydride thereof, e.g. the symmetrical anhydride thereof or a mixed anhydride with a hydrohalic acid, if necessary in the presence of a basic condensing agent such as an alkali metal hydroxides or carbonates, or a nitrogen base, e.g. Pyridine. The conversion of lower alkanoyloxy to hydroxy is carried out, for example, by alcoholysis or, preferably, hydrolysis, e.g. by base catalyzed hydrolysis, e.g. in the presence of sodium hydroxide.

In compounds of formula I wherein R is amino substituted azaheterocylyl, the amino group may be substituted into a substituted amino group, e.g. a lower alkylamino, di-lower alkylamino,

Niederalkylenamino- or Niederalkanoylaminogruppe be transferred. The conversion into a lower alkylamino or di-lower alkylamino group is carried out, for example, by reaction with a reactive esterified lower alkanol, for example a lower alkyl halide or sulfonate, in the presence of a basic condensing agent, such as a hydroxide or carbonate of a. Alkali or alkaline earth metal or a heteroaromatic nitrogen base, e.g. Pyridine. Analogously, amino may be prepared by treating with a lower alkylene dihalide or disulfonate in lower alkylene amino and treating with the reactive functional derivative of a lower alkanecarboxylic acid, e.g. the corresponding carboxylic acid halide, be converted into Niederalkanoylamino. Compounds of the formula I having a substitutable ring nitrogen atom in the radical R can be converted in the same way into compounds of the formula I which contain in the radical R a ring nitrogen atom substituted by an optionally substituted lower alkyl radical. The novel compounds of the formula I which can be prepared with the aid of the abovementioned reactions can therefore be replaced in the radical R "by a correspondingly substituted secondary, tertiary or quaternary, i. contain positively charged, nitrogen atom.

Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of the formula I having a free carboxyl or sulfo group, e.g. by treating with metal compounds such as alkali metal salts of suitable organic carboxylic acid, e.g. the sodium salt of a-ethyl caproic acid, or with inorganic alkalis or alkaline earth metal salts, e.g. Form sodium bicarbonate, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, e.g. by treatment with a suitable acid or a suitable anion exchange reagent. Internal salts of compounds of the formula

I can e.g. by neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.

Salts can be converted to the free compounds in the usual way, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.

Resulting mixtures of isomeric compounds can be separated into the individual isomers by methods known per se. For example, a racemate obtained can be reacted with an optically active auxiliary, the resulting mixture of two diastereomeric compounds can be separated using suitable physicochemical methods (eg fractional crystallization, adsorption chromatography) and the individual diastereomeric compounds then split into the optically active compounds. Particularly suitable racemates for separation into antipodes are those which possess an acidic group, such as, for example, racemates of compounds of the formula I ₁ in which R_ is carboxy. These acidic racemates can be reacted with optically active bases, eg, esters of optically active amino acids, or (-) - brucine, (+) - quinidine, (-) - quinine, (+) - cinchonine, (+) - dehydroabietylamine, (+) - And (-) - ephedrine, (+) - and (-) - l-phenylethylamine or their N-mono- or Ν, Ν-dialkylated derivatives to mixtures consisting of two diastereomeric salts, are reacted.

In carboxyl-containing racemates, this carboxyl group can also be esterified by an optically active alcohol, such as (-) - menthol, (+) - borneol, (+) - or (-O-2-octanol, after which the desired diastereomer has been isolated Carboxyl group is released.

For resolution of the racemate, it is also possible to esterify an existing hydroxy group with optically active acids or their reactive, functional derivatives to form diastereomeric esters.

Examples of such acids are (-) - abietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acids, (+) - and (-) - camphanic acid, (+) - and (-) - Ketopic acid, L (+) - ascorbic acid, (+) - camphoric acid, (O-camphor-10-sulfonic acid C), (+) - or (-) - a-bromocampher-TT-sulfonic acid, D (-) - quinic acid, D (-) - isoascorbic acid, DC -) and L (+) - mandelic acid, (+) - l-menthoxyacetic acid, D (-) - and L (+) - tartaric acid and their di-O-benzoyl and di-Op -Tolylderivate.

By reaction with optically active isocyanates, such as (+) - or (-) - 1-phenylethyl isocyanate, compounds of formula (i) wherein R is protected carboxy and R is hydroxy substituted lower alkyl can be converted to a mixture of diastereomeric urethanes.

Basic racemates, e.g. Compounds of the formula I in which the radical R is substituted by amino can form diastereomeric salts with said optically active acids.

The cleavage of the resolved diastereomers into the optically active compounds of the formula I likewise takes place by customary methods. From the salts are freed the acids or the bases, e.g. by treating with stronger acids or bases than those originally used. From the esters and urethanes, the desired optically active compounds are obtained, for example, after alkaline hydrolysis or after reduction with a complex hydride such as lithium aluminum hydride.

Another method for separating the racemates is the chromatography on optically active adsorption layers, for example on cane sugar.

According to a third method, the racemates can be dissolved in optically active solvents and the less soluble optical antipode crystallized out.

In a fourth method. One uses the different reactivity of the optical antipodes to biological material, such as microorganisms or isolated enzymes.

According to a fifth method, the racemates are dissolved and one of the optical antipodes is crystallized by seeding with a small amount of an optically active product obtained by the above methods.

The separation of the racemates into the optical antipodes may be carried out at any stage of the process, i. e.g. also at the stage of the starting compounds of the formulas II or III or at any stage of the processes described below for the preparation of the starting compounds of the formula II or III.

In all subsequent conversions obtained compounds of formula I are those reactions which take place under alkaline or especially neutral conditions.

The process also includes those embodiments in which intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is stopped at any stage. Furthermore, starting materials may be used in the form of derivatives or prepared in situ, optionally under the reaction conditions.

The starting compounds of the formulas II and III can be prepared as indicated in the following Reaction Scheme I:

Reaction scheme I

\ f

• NH

step

• NH

(V)

Stage level

SCR. ^{2 R} i * ⁵ - r ^R 2

ο I ' (VI)

Level 4 Z

Il

S-C-R "

step

C = O

(III)

SM

O C-X® (II)

(VII)

^R 3

step 1

A thioazetidinone of Formula V is obtained by reacting a compound of the Forme compound.

Compound of formula IV with the radical -S-C (= Z) -R introducing

In a starting material of the formula IV, W is a nucleofugic radical which can be replaced by the group -S-C (ZZ) -R ". Such radicals W are, for example, acyloxy radicals, sulfonyl radicals R -SO -, in which R is an organic radical, azido or halogen. In an acyloxy radical W, acyl is e.g. the residue of an organic carboxylic acid and represents, for example, lower alkanoyl, e.g. Acetyl or propionyl, optionally substituted benzoyl, e.g. Benzoyl or 2,4-dinitrobenzoyl, or phenyl-lower alkanoyl, e.g. Phenylacetyl. In a sulfonyl radical R -SO - R is, for example, optionally lower-substituted by hydroxy, such as methyl, ethyl, 2-hydroxyethyl, 1-hydroxyprop-2-yl or 1-hydroxy-2-methyl-prop-2-yl, benzyl or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen radical W is e.g. Bromine, iodine or especially chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

A compound introducing the radical -S-C (= Z) -R is, for example, an acid of the formula R -C (= Z) -SH or in particular a salt, e.g. an alkali metal salt such as the sodium or potassium salt thereof. The substitution may be carried out in an organic solvent such as in a lower alkanol, e.g. Methanol or ethanol, a lower alkanone, e.g. Acetone, a lower alkanecarboxylic acid amide, e.g. Dimethylformamide, a cyclic ether, e.g. Tetrahydrofuran or dioxane, or be carried out in a similar inert solvent. The reaction is usually carried out at room temperature, but may also be carried out at elevated or reduced temperature, e.g. at about 0 ° to about 40 ° C. By adding a salt of hydriodic acid or thiocyanic acid, e.g. an alkali metal such as sodium salt, the reaction can be accelerated.

The incoming group -S-C (= Z) -R "is preferably directed from the group R. to the trans position. Therefore, both (3S, 4R) - and (3S, 4RS) -configured starting compounds of formula IV can be used. Although the trans isomers are predominantly formed, occasionally small amounts of the cis isomer may be formed. The separation of the cis isomers, as described above, by conventional methods, in particular by chromatography and / or by crystallization.

Suitable starting compounds of the formula IV are known, for example, from European Patent Application No. 82113, German Offenlegungsschrift No. 3,224,055 or German Offenlegungsschrift 3,013,997, or can be prepared in an analogous manner. They can also be prepared by the methods described in the Examples.

Level 2

A starting compound of formula (III) is obtained by reacting an azetidinone of formula (V) with an acid of formula R'-COOH or, in particular, a reactive derivative such as an ester or acid halide, e.g. the acid chloride, of which at a temperature of 20 ° to 80 ° C, preferably at 40 ° to 60 ° C, in an inert solvent, such as one of the in the implementation of compounds of formula III to compounds of formula I, treated. When using an acid halide it is preferred to work in the presence of an acid binding agent such as a tertiary aliphatic amine, e.g. Triethylamine, an aromatic amine, e.g. Pyridine, or more particularly an alkali metal or alkaline earth metal carbonate or bicarbonate, e.g. Potassium carbonate or calcium carbonate.

level 3

Compounds of the formula VI in which X is a reactive esterified hydroxy group, in particular halogen, e.g. Chlorine or bromine, or organic sulphonyloxy, e.g. Lower alkanesulfonyloxy, such as methanesulfonyloxy, or arenesulfonyloxy, e.g. Benzene or 4-methylbenzenesulfonyloxy, are prepared by reacting a compound of formula V with a glyoxylic acid compound of the formula OHC-Ri or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, e.g. a hemiacetal with a lower alkanol, e.g. Methanol or ethanol, and in an obtained compound of the formula VI in which X is hydroxyl, the hydroxy group is converted into a reactive esterified hydroxy group e11.

The compounds of formula VI are usually obtained as a mixture of the two isomers [[with respect to the grouping -CH (R ') / «^ - X Ί. However, one can also isolate the pure isomers thereof, e.g. by chromatography.

The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound of formula V takes place at room temperature or, if necessary, under heating, e.g. at about 100 ° C, in the absence of an actual condensing agent instead. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is purified by distillation, e.g. azeotrope, or by use of a suitable dehydrating agent, such as a molecular sieve. Preferably, the reaction is carried out in the presence of a suitable solvent, e.g. Dioxane, toluene or dimethylformamide, or solvent mixtures, and if desired or necessary in the atmosphere of an inert gas such as nitrogen.

The conversion of a hydroxy group X into a reactive esterified hydroxy group X in a compound of the formula VI is carried out by treatment with a suitable esterification agent.

leads, for example, with a thionyl halide, for example -chloride, a phosphorus oxyhalide, especially chloride, a Halogenphosphoniumhalogenid such as Triphenylphosphoniumdibromid or dichloride or a suitable organic sulfonic acid halide, such as chloride, preferably in the presence of a basic, primarily organic basic agent such an aliphatic tertiary amine, for example triethylamine or diisopropylamine, or a pyridone-type heterocyclic base, for example pyridine or collidine. Preferably, one works in the presence of a suitable solvent, such as dioxane or tetrahydrofuran, or a solvent mixture, if necessary with cooling, eg at about -30 ° to about 30 ⁰ C, and optionally in the atmosphere of an inert gas such as nitrogen.

Level 4

The starting material of formula (II) is obtained by reacting a compound of formula (VI) with a suitable phosphine compound, such as a tri-lower alkyl phosphine, e.g. Tri-n-butyl-phosphine, or a triarylphosphine, e.g. Triphenylphosphine, or with a suitable phosphite compound such as a tri-lower alkyl phosphite, e.g. Triethyl phosphite, or an alkali metal lower alkyl phosphite, e.g. diethyl phosphite, and in an available compound of the formula (II) the radical R is optionally replaced by another radical R.

The conversion of the compound of formula (VI) into the compound of formula (II) is preferably carried out in the presence of a suitable inert solvent, such as a hydrocarbon, eg cyclohexane or benzene, or an ether, eg dioxane, or a solvent mixture. Depending on the reactivity is carried out under cooling or at elevated temperature, for example between -10 ° and +100 ⁰ C, preferably at about 20 ° to 80 ° C, and / or in the atmosphere of an inert gas such as nitrogen. To prevent oxxdative processes, catalytic amounts of an antioxidant, eg hydroquinone, can be added.

In this case one usually works in the presence of a basic agent, such as an organic base, e.g. an amine such as triethylamine, diisopropylethylamine, pyridine, lutidine, or "polystyrene-Hünigbase", or an inorganic base, e.g. an alkali metal carbonates, e.g. Sodium or potassium carbonate, wherein the primary phosphonium salt of the formula

wherein X 'is a phosphono group or a phosphoniogroup together with an anion, depending on the meaning of the radical X, e.g. Chloride, is converted to the ylide starting material of formula II. However, it is also possible to work in the absence of a base and to isolate a compound of the formula (IIa), in particular a corresponding phosphono compound, and convert it in situ into the starting material of the formula II in the preparation of the end products of the formula (i).

In an available compound of the formula (II), one radical R "can be exchanged for another radical R-. For this purpose, a compound of the formula (II) in which R is an easily exchangeable azaheterocyclyl radical, e.g. optionally substituted imidazol-1-yl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl, 1,2,4-triazole-1-yl, tetrazol-1-yl or Tetrazol-2-yl, with an excess, in particular three to ten times the excess, a compound of the formula R'-H implemented, wherein R 'is a different unsaturated R az of R az "heteroacetyl radical according to the present invention. The reaction is carried out in an inert solvent or solvent mixture, for example in a cyclic ether, e.g.

Dioxane, in acetonitrile or in dimethylformamide, at room temperature or slightly elevated or lowered temperature, e.g. at about 10 ° to about 50 ° C, performed.

Level 5

A compound of formula (II) can be further obtained by treating a mercaptide of formula (VII) wherein M is a metal cation with an acylating agent introducing the radical R -C (= Z).

In the starting material of the formula (VII), the metal cation M is, for example, a cation of the formula M or M / 2, where M

2+ especially for a silver cation and M especially for the divalent cation of a suitable transition metal, e.g. Copper, lead or mercury, stands.

An acylating agent introducing the radical R -C (= Z) - is e.g. the acid R -CC = Z) -OH or, in particular, a reactive functional derivative thereof, such as an acid halide, e.g. Chloride or bromide, azide or anhydride thereof, or a compound of the formula S-C (R ")" in which the azaheterocyclyl radical R "is bonded via a ring nitrogen atom to the thiocarbonyl group.

The acylation takes place when a reactive functional derivative of the acid of the formula R is -C (= Z) -OH, for example the acid chloride, in an inert solvent such as a chlorinated hydrocarbon, for example methylene chloride, or an ether, for example diethyl ether or Dioxane, at room temperature or under heating or cooling, for example in a temperature range of about -50 ° to about +60 ⁰ C _1, in particular at about -30 ° to about + 20 ° C.

The acylation with the aid of the thiocarbonyl compound of the formula S = C (R ") is carried out in an inert solvent, e.g. a halogenated hydrocarbon, such as methylene chloride, a cyclic

Aether, such as tetrahydrofuran, or dimethylformamide, at room temperature or reduced temperature ,. e.g. at about -30 ° to about 30 ° C, especially at about 0 ° to 20 ° C.

The starting compounds of the formula (VII) can be prepared, for example, by reacting an azetidinone of the formula

I I (IV)

• NH

by reacting with an alkali metal salt, e.g. the sodium salt, a thio-lower alkanecarboxylic acid, e.g. Thioacetic acid, or the Triphenylmethylmercaptans in a compound of formula

R, W

I I (VIII)

• NH

wherein W 'is triphenylmethylthio or lower alkanoylthio, e.g. Acetylthio, means this analogous to the process described in the reaction steps and 4 in a compound of the formula

(IX)

transferred and these in the presence of a base, e.g. Pyridine or tri-n-butylamine, in a suitable solvent, e.g. Diethyl ether or methanol, with a salt of the formula MA, wherein M is the above

But in particular stands for a silver cation, and A is a common anion which promotes the solubility of the salt MA in the chosen solvent, e.g. the nitrate, acetate or fluoride anion, is reacted.

Thiocarbonyl compounds of the formula S = C (R ")" in which the radical R is bonded to the thiocarbonyl group via a nitrogen atom are known or can be prepared by reacting a compound of the formula R "-H in which the hydrogen atom is attached to a ring nitrogen of the Restes R is bound, with a strong inorganic base, eg Sodium hydride, in a salt, e.g. into the sodium salt of the formula

Θ Θ Na R, or with a tri-lower alkyl halosilane, e.g. Trimethylchlorosilane, converted in the presence of a base in the Triniederalkylsilyl derivative, and this reacted with thiophosgene.

The ylides of the formula II can be used directly in the cyclization reaction for the preparation of the end products of the formula I. However, it is also possible in compounds of the formula II in which R ₁ is a substituted hydroxy group, for example a hydrolytically readily cleavable protected hydroxy group, such as trisubstituted silyloxy, substituted lower alkyl, first cleave the hydroxy protecting group and then the resulting compound of formula II, wherein R by Hydroxy substituted lower alkyl is used in the cyclization reaction.

When an easily exchangeable radical R. is replaced by an unsymmetrically substituted azaheterocyclyl radical R 'having at least two nitrogen atoms or an unsubstituted azaheterocyclyl radical having at least 3 nitrogen atoms, two of which are adjacent, in a compound of the formula II (see Explanatory Notes to Step 4 of the Reaction Scheme I) or in the introduction of a radical R into a compound of the formula X (cf process c), two isomeric products can be formed. Thus, for example, in the reaction of a compound of the formula II or a compound of the formula X with 4-methylimidazole or a salt thereof, a product having a 4-methyl or a 5-methylimidazol-1-yl radical is formed. The

According to the invention by reacting a corresponding intermediate with an imidazole substituted in the 4-position imidazol-1-yl-penem compounds are homogeneous according to thin-layer chromatogram and probably have due to the spectroscopic data in the 4-position (and not in the 5-position) substituted imidazol-1-yl radical. Steric reasons also favor the preferred formation of the 4-substituted-imidazol-1-ylpenem compounds. Until there is clear structural evidence, e.g. by X-ray structure analysis, but the possibility can not be completely ruled out that said compounds have a substituted in the 5-position imidazol-1-yl radical.

In the compounds of formulas (II) - (VII), existing functional groups can be converted into protected functional groups or existing protected functional groups into the free or otherwise protected groups. Furthermore, in compounds of the formulas (II), (III), (V) and (VI) it is possible to convert a radical R into another radical R. In these conversions, taking into account the other substituents contained in the molecules, the same methods can be used as indicated in the corresponding conversions into the compounds of formula (i).

It is possible to carry out the process described in Reaction Scheme 1 for the preparation of the compounds of the formulas (II), (III) and (V) - (VIl), as well as the stated processes for the preparation of the end products of the formula (i) also with optically inactive compounds, and at any stage of the process, from an obtained diastereomeric mixture or racemate, as described above, to isolate the optically active compounds according to the present invention.

The invention also relates to the new starting compounds and according to the invention e-available new intermediates, such as those of the formulas (II), (III), (V) - (VII) and (IX), and the processes for their preparation. ,

Preferably, such starting compounds are used and the reaction conditions are chosen so as to arrive at the compounds listed above as being particularly preferred.

The compounds of the formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds having valuable pharmacological properties. Compounds of formula I wherein R is lower alkyl substituted by hydroxy, R is as defined for formula I and R represents carboxyl or a cleavable esterified carboxyl group cleavable under physiological conditions, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial activities. For example, they are in vitro against Gram positive and Gram negative cocci, eg Staphylococcus aureus , Streptococcus pyogenes , Streptococcus pneumoniae and Streptococcus faecalis , and against Gram negative rod bacteria, such as Enterobacteriaceae , Haemophilus influenzae and Pseudomonas aeruginosa , and anaerobes, eg Bacteroides sp. , in minimal concentrations of about 0.02 to about 8 μg / ml. In vivo , in the case of systemic infection of the mouse, for example by Staphylococcus aureus , subcutaneous administration of compounds according to the invention results in ED. Values of about 4.5 to about 100 mg / kg.

The new compounds may be administered as orally or parenterally-administrable antibacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations, for the treatment of infections find use.

Compounds of the formula I in which at least one of the functional groups present is in protected form can be used as intermediates for the preparation of the abovementioned pharmacologically active compounds of the formula I.

The pharmacologically useful compounds of the present invention may e.g. be used for the preparation of pharmaceutical preparations containing a therapeutically effective amount of

Active ingredient, taken together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are oral or parenteral, i. intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol having. Tablets also contain binders, e.g. Magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or salts thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, dyes, flavorings or sweeteners.

For parenteral administration are primarily infusion solutions, preferably isotonic aqueous solutions or suspensions, this being e.g. from lyophilized preparations containing the active ingredient alone or together with a carrier material, e.g. Containing mannitol, can be prepared before use. Such preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, for example by means of conventional mixing, solution or lyophilization processes, and contain from about 0.1 "/" to 100 _{° }} especially from about 1 f _o to about 50%, lyophilizates up to 100% of the active substance.

Depending on the nature of the infection and condition of the infected organism, daily doses (oral or parenteral) of from about 100 mg to about 1 g are used to treat warm-blooded animals (humans and animals) weighing about 70 kg.

The following examples serve to illustrate the invention

 Temperatures are given in degrees centigrade.

The following abbreviations are used in the examples: TLC: Thin-layer chromatogram IR: Infrared spectrum UV: Ultraviolet spectrum THF: Tetrahydrofuran

Example 1 : (5R, 6S) -2- (imidazol-1-yl) -6- (tert.butyl! Dimethylsilyl)

oxymethyl) -2-penem-3-carboxylic acid allyl ester

3 g of 2-lb (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(imidazolyl) -thiocarbonylthioJ-2-oxo-azetidin-1-ylj-2-triphenylphosphorany1-idenessigsäure allylester in 500 ml abs. Toluene stirred for 5 hours at reflux temperature and under an argon atmosphere

After cooling, the solvent is distilled off and the residue is chromatographed on silica gel (mobile phase: toluene-ethyl acetate 4: 1); TLC (silica gel ethyl acetate): R _f = 0.4; IR (CHCl): 1790; 1715;

-1 1590 cm.

The starting material can be prepared as follows:

a) (3S, 4R) -3- (tert -butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio -azetidin-2-one

12.5 g of triphenylmethylmercaptan are suspended in 70 ml of methanol at 0 ° and treated in portions with a total of 2.2 g of a 55% strength sodium hydride suspension in 0.1 ml over 10 minutes. Subsequently, an emulsion of 11.1 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one (European Patent Application No. 82113) in 70 ml of acetone and 70 ml of water over 30 minutes dropwise. After 30 minutes stirring at 0 ° and 1 hour at room temperature.

temperature, the reaction mixture is concentrated on a rotary evaporator, treated with methylene chloride, and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulfate. After concentration, the crude title compound is purified by chromatography on silica gel (eluent toluene / ethyl acetate 19: 1) - TLC (toluene-ethyl acetate 19: 1): R _f = 0.64; IR (methylene chloride): 3390; 1761; 1118, 835 cm " ¹ .

b) 2-r (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl-2-hydroxyacetic acid allyl ester 8.4 g (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-azetidin-2-one and 8.23 g of glyoxylic acid allyl ester ethylhemiacetal in 170 ml of abs. Toluene is mixed with 27 g of molecular sieves (4A) and stirred for 10 hours at 55 °. After filtering off and concentrating on a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 95: 5)? TLC (silica gel, toluene / ethyl acetate 10: 1); R _f = 0.37 and 0.27; IR (CH ₂ Cl ₂ ): 3520, 1760, 1745 cm ^-1 .

c) 2-r (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl-2-triphenylphosphoranylideneacetic acid, allyl ester

To a solution of 604 mg of 2-] ~ (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-ylJ-2-hydroxyacetic acid allyl ester in 5 ml of tetrahydrofuran 80 μl of thionyl chloride and 88 μl of pyridine are added in succession with stirring at -15 ° within 5 minutes. The white suspension is stirred for 1 hour at -10 ° and filtered through Hyflo. After washing the residue with toluene is concentrated on a rotary evaporator. The residue is dissolved in 3 ml dioxane, treated with 293 mg triphenylphosphine and 0.13 ml lutidine and stirred for 2 hours at 115 ° bath temperature. The mixture is filtered through Hyflo and this residue is washed with toluene. The combined filtrates are evaporated. Chromatography of the residue on silica gel gives

the pure product (eluent toluene / ethyl acetate 95: 5)? TLC (silica gel, toluene-ethyl acetate 1: 1): R = 0.18; IR (CHCl ₇ ): 1745, 1605

1 ^l

d) 2-f * (3S, 4R) -3- (tert -butyldimethylsilyloxymethyl) -4-mercapto-2-oxoazetidin-1-yl ~] -2-triphenylphosphoranylideneacetic acid allyl ester silver salt

7.5 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl-2-triphenylphosphoranylideneacetic acid allyl ester are initially charged in 87 ml of ether Room temperature with 70 ml of a 0.5 M aqueous silver nitrate solution. Thereafter, a mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is added dropwise, and the reaction mixture is stirred for a further 20 minutes. Then the solid is filtered off with suction and washed with ether, water and ether. The solid is slurried for purification in 40 ml of ether and 40 ml of water, filtered off with suction and dried. IR (CHCl "): 1760, 1620 cm ^-1 .

e) 2-l "(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-f (imidazol-1-yl) -thiocarbonylthio] -2-oxo-azet id in-1-y1-l -2-tr ipheny! Phosphorylanylacetic acid allyl ester

4.27 g of silver salt of 2 - [(3S, 4R) -3- (tert.Butyldimethylsilyloxymethyl) -4-mercapto-2-oxoazetidin-ly 1 ^ -2-tripheny1phosphoranylidenessigsäure-2-allylesters be abs in 40 ml. Dissolved methylene chloride and cooled to 0 ° solution of 2.14 g of 1,1'-thiocarbonyldiimidazole in 40 ml abs. Added methylene chloride. The suspension is stirred for a further 2.5 hours at 0 °, then filtered through Hyflo. The yellow solution is concentrated on a water-jet vacuum and the residue obtained is purified by column chromatography on silica gel (eluent toluene / ethyl acetate 95: 5 to 80:20). TLC (silica gel, toluene / ethyl acetate): R = 0.45; IR (CH ₉ Cl): 1760; 1620;

_i ^r LL

1105 cm ^l .

Example 2 : (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem- 3-carboxylic acid allyl ester

A solution of 105 mg (5R, 6S) -2- (imidazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester in 2.7 ml abs. THF is cooled to -70 ° and treated successively with O ₁ Il ml of acetic acid and dropwise during 10 minutes with 5.9 ml of a 0.1 M tetrabutylammonium fluoride solution in THF. The cooling bath is removed and the reaction mixture is slowly brought to room temperature. After 2.25 hours at room temperature, the reaction mixture is concentrated on a rotary evaporator and taken up in ethyl acetate and aqueous NaHCO 3 solution. The organic phase is separated off, washed with brine, dried over Na 2 SO 4, and concentrated by evaporation. The crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 3: 1 to 1: 3); TLC (silica gel, ethyl acetate): R = 0.14; IR (CH-Cl): 3600; 1790; 1715; 1590

-1 ^{r l L}

Example 3 : (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem- 3-carboxylic acid, sodium salt

0.38 g of (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are dissolved in 16 ml of abs. Dissolved THF, cooled to -10 ° and treated with 40 mg of tetrakis (triphenylphosphine) palladium and 0.4 ml of tributyltin hydride. After stirring for 20 minutes at -10 °, 86 μl of acetic acid are added and the reaction mixture is stirred at -10 ° minutes. After concentration on a rotary evaporator, the residue is taken up in water-ethyl acetate, cooled and basified with NaHC0. The aqueous phase is separated off, washed twice with ethyl acetate and, after concentration on a rotary evaporator, purified on an XAD-2 column (mobile phase: water). The pooled fractions are lyophilized. DC (reverse phase Opti UCP., Ηθ / acetonitrile): R = 0.57; UV (water):

λ = 310 nm

 Max

Example 4 : (5R, 6S) -2- (pyrazol-1-yl) -6- (tert- butyldimethylsilyl oxymethyl) -2-penem-3-carboxylic acid allyl ester

As in Example 1, 84% of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [] (pyrazol-1-yl) thiocarbonylthioJ-2-oxoazetidin-1-lj-2-triphenylphosphoranylideneacetic acid allyl ester are added Title compound implemented. IR "(methylene chloride): 1785; 1705; 1580 cm".

The starting material can be prepared as follows:

Analogously to Example 1 e) 0.21 g of silver salt of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-raercapto-2-oxoazetidin-1-ylj-2-triphenylphosphoranylidenessigsäure allylesters by reaction with 1 , 1'-Thiocarbonyl-dipyrazole reacted to give the title compound. IR (methylene chloride): 1750; 1615 cm ' ¹ .

Example 5 : (5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem- 3-carboxylic acid allyl ester

50 mg of (5R, 6S) -2- (pyrazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 2. IR (methylene chloride): 3600; 1785; 1710; 1580 cm " ¹ .

Example 6 : (5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem-3- carboxylic acid, sodium salt

130 mg of (5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 3. UV (water): λ = 312 nm.

Max

Example 7 : (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester

102 mg of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-] - (1, 2,4-triazol-1-yl) -thiocarbonylthioJ-2-oxo-azetidin-1 are prepared analogously to Example 1. ylJ-2-triphenylphosphoranylidenessigsäure allylester reacted to the title compound. IR (methylene chloride): 1795; 1710; 1585

The starting material can be prepared as follows:

Analogously to Example 1 e) 0.21 g of silver salt of 2 - [(3S, 4R) -3- (tert.Butyldxmethylsilyloxymethyl) -4-mercapto-2-oxoazetidin-l-yl3 ~ 2-triphenylphosphoranylidenessigsäure-2-alIylesters by reaction with 1,1'-thiocarbonyl-di-d, 2,4-triazole) to the title compound. IR (methylene chloride); 1755; 1620 cm " ¹ .

Example 8 : (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6-hydroxymethyl-2- penem-3-carboxylic acid allyl ester

850 mg of (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 2. IR (methylene chloride): 3610; 1790; 1710; 1585 cm " ¹ .

Example 9 : (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6-hydroxymethyl-2- penem-3-carboxylic acid, sodium salt

510 mg of (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 3. UV (water) λ = 310 nm.

Example 10: (5R, 6S) -2- (imidazol-1-yl) -6-r (l'R) -1- (tert-butyl-dimethylsilyloxyethyl) -2-penem-3-carboxylic acid allyl ester.

0.76 g of 2 - [(3S, 4R) -3 - [(1'R) -1-tert-butyldimethylsilyloxyethyl] -J-4- (imidazol-1-yl-thiocarbonylthio) -2-oxoazetidine-1 are prepared analogously to Example 1. yl-2-triphenylphosphoranylideneacetic acid allyl ester to give the title compound. TLC (silica gel, ethyl acetate): R _f = 0.74; IR I ₂ ): 1790; 1715; 1587 cm " ¹

- 52 The starting material can be prepared as follows:

a). Np-Methoxybenzyl-N-tert-butylthiomethylammonium chloride A solution of 10.69 g (23.9 mmol) of 1,3,5-tris (p-methoxybenzyl) -hexahydro-1,3,5-triazine, which is analogous to the instructions in German Offenlegungsschrift DE-A-2,431,862 can be prepared in 170 ml of acetonitrile at room temperature successively with a solution of 2.88 g (78.8 mmol) of hydrogen chloride in 20 ml of acetonitrile and 6.45 g (71.66 mmol ) tert-butylmercaptan. The mixture is stirred for 22 hours. Undissolved material is filtered off and the filtrate is concentrated under reduced pressure. A crystalline residue is obtained, which is stirred with ether and filtered with suction. F. 142 °.

b). (2S, 3R) -Np-methoxybenzyl-N-tert.butylthiomethyl-2-bromo-3-hydroxyfautyramid

A solution of 1.83 g (10 mmol) of (2S, 3R) -2-bromo-3-hydroxybutyric acid, prepared analogously according to a protocol of Shimohigashi Y. et al., Bull. Chem. Soc. Japan _5_2, 949 (1979) is charged successively with 2.76 g (10 mmol) of Np-methoxybenzyl-N-tert-butylthiomethylammonium chloride, 2.06 g (10 mmol) of dicyclohexylcarbodiimide dropwise with 1.40 ml (10 mmol ) Triethylamine. The resulting reaction mixture is stirred at room temperature for two hours. The precipitated dicyclohexylurea is filtered off with suction, the filtrate is diluted with methylene chloride and washed with water and phosphate buffer solution of pH 8. The organic phase is dried over sodium sulfate, evaporated and the oily residue is chromatographed on silica gel with toluene-ethyl acetate. The title compound is obtained as a colorless, viscous oil. Rf (toluene-ethyl acetate 1: 1): 0.55; IR (in methylene chloride): 3550-3200, 2950-2850, 1632, 1608, 1508, 1457, 1438, 1407, 1360, 1242, 1202, 1175, 1150, 1028.

c). (2S, 3R) -Np-methoxybenzyl-N-tert-butylsulfonylmethyl-2-bromo-3-hydroxybutyramide .

A solution of 1.97 g (4.89 mmol) of (2S, 3R) -Np-methoxybenzyl-N-tert-butylthiomethyl-2-bromo-3-hydroxybutyramide in 50 ml of methylene chloride is stirred at -14 ° while stirring with 2 , 06 g (about 2.2 equivalents) of 90% m-chloroperbenzoic acid. The reaction mixture is stirred at 0 ° for 80 minutes. The precipitated m-chlorobenzoic acid is filtered off, the filtrate is diluted with methylene chloride and shaken this successively with 3 iger aqueous sodium hydrogen sulfite and 8 iger aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate, evaporated under reduced pressure and the residue chromatographed on silica gel with toluene-ethyl acetate (7: 1) and (6: 1). The title compound is obtained as a colorless, viscous oil. Rf (toluene-ethyl acetate 1: 1): 0.43; [α] = + 88 _ + 1 ° (1.01 % in chloroform). The ¹ H NMR spectrum (400 MHz in CDCl ,,) indicates the existence of two rotamers in the ratio of 1.3: 1.

d). Np -methoxybenzyl-N-tert-butylsulfonylmethyl- (2R, 3R) -2,3-epoxybutyramide

To a solution of 486 mg (1.1 mmol) of (2S, 3R) -Np-methoxybenzyl-N-tert-butylsulfonylmethyl-bromo-S-hydroxybutyramide in 8 ml of tetrahydrofuran at -14 ° and exclusion of moisture, 340 ml of 1.5 -Diazabicyclo] _5.4.0Jundec-5-ene in 1 ml of tetrahydrofuran. The solution is stirred for 75 minutes at room temperature. After addition of methylene chloride, the organic phase is extracted by shaking with 15% strength aqueous citric acid solution and 8% strength aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue on silica gel with toluene-ethyl acetate (4: 1) gives the title compound as a colorless, viscous oil. Rf (toluene-ethyl acetate 1: 1): 0.29; [α] = + 45 _ + Γ (1.065 % in CHCl ₃ ). The ^ -NMR spectrum (400 MHz in CDCl ₃ ) indicates the presence of two rotamers in a ratio of 1: 2.8.

e). (3S, 4R) -p -methoxybenzyl-3-r (l'R) -1-hydroxyethyl "-4-tert-butylsulfonyl -2-azetidinone

A solution of 398 mg (1.12 mmol) of Np-methoxybenzyl-N-tert-butylsulfonylmethyl (2R, 3R) -2,3-epoxybutyramide in 2.5 ml of tetrahydrofuran is added dropwise at 0 "with stirring and exclusion of moisture with 7 ml a solution of dehydrated tetra-n-butylammonium fluoride in THF ₁ prepared by dehydrating 5 g of tetra-n-butylammonium fluoride trihydrate at 55 ° and 0.1 torr and filling with 20 ml with tetrahydrofuran, added to the reaction mixture with activated molecular sieve 4 A and stirred for two hours, the molecular sieves are filtered off with suction, washed four times with 20 ml of methylene chloride each time, and each filtrate is treated separately with 5 parts of diethyl ether and washed successively with aqueous phosphate buffer solution of pH 8. The combined organic Phases over magnesium sulfate and evaporated under reduced pressure, and the residue is chromatographed on 20 g of silica gel with toluene-ethyl acetate (3: 1) to obtain the crystalline title compound ind. F. 112 ° -113 ° (Kofier, from methylene chloride, diethyl ether, pentane); Rf (toluene-ethyl acetate 1: 1): 0.27? [a] = + 9 _ + 1 ° (1.105 ^ in chloroform); ^ -NMR spectrum (400 MHz in CDCl ₃ ): δ = 4.65 for proton (a) at the 4 (R) -C atom, δ = 3.61 for proton (b) at 3 (S) -C Atom and δ = 4.09 for proton (c) at the 1 '(R) -C atom of the hydroxyethyl group; J down: about 2, J bc: about 7.

f). (3S, 4R) -3-r (l'R) -1-hydroxyethyl-4-tert-butylsulfonyne-1, 2-azetidinone

A solution of 71 mg (0.2 mmol) of (3S, 4R) -LP-methoxybenzyl 3 - [(l ¹ R) -l-hydroxyäthylJ-4-tert.butylsulfonyl-2-azetidinone in 4 ml of acetonitrile is added to a heated to 65 °, well stirred solution of 428 mg (1.8 mmol) of sodium peroxodisulfate, 174 mg (1 mmol) of dipotassium hydrogen phosphate, 1 mg of iron (II) sulfate heptahydrate and 2 mg of copper (II) acetate hydrate in 4 ml of water , The reaction mixture is stirred for 2 hours at 65 °. The organic solvent is distilled off under reduced pressure and the aqueous residue is extracted with ethyl acetate. After concentration of the organic

Phase in vacuo, the residue is crystallized from methylene chloride-diethyl ether to give the title compound. F. 194 °; Rf (ethyl acetate): [of] = + 13 ^ 1 ° (0.75 % in methanol); ^ -NMR spectrum (400 MHz in CD ₃ OD): δ = 5.04 for proton (a) at 4 (R) -C-AtOm, δ = 3.58 for proton (b) at 3 (S) - C atom and δ = 4.18 for proton (c) on the l '(R) -C atom of the hydroxyethyl group, · J; about 2, J bc: about 4.5.

G). -4-tert-butylsulfonyl-2-azetidinone (3S, 4R) -3-f (l R) -I- (tert.Butyldimethylsilyloxyäthyl) ~]

135 mg (0.574 mmol) of (3S, 4R) -3 - [(l'R) -1-hydroxyethyl] -4-tert-butylsulfonyl-2-azetidinone are mixed with 173 mg (1.15 mmol) of t-butyldimethylchlorosilane and 78 Mg (1.15 mmol) imidazole in 3 ml of dimethylformamide for two hours at room temperature. The reaction mixture is evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 8 iger aqueous sodium bicarbonate solution. After drying the organic phase over sodium sulfate and evaporation under reduced pressure, the title compound is obtained as a crystalline residue. Chromatography on silica gel with toluene-ethyl acetate (4: 1) frees it from traces of imidazole and gives white crystals. F. 196 °; Rf (toluene-ethyl acetate 1: 1): 0.48; [α] = + Ujt 1 °.

h) (3S, 4R) -3-r (l'R) -1- (tert-butyldimethylsilyloxyethyl) "] - 4-triphenylmethylthio-azetidin-2-one

Analogously to Example 1a), 6.99 g of (3S, 4R) -3 - [(1'R) -1- (tert-butyldimethylsilyloxyethyl) J-4-tert-butylsulphonylazetidin-2-one are converted into the title compound. TLC (toluene / ethyl acetate 4: 1) R _f = 0.57, IR (CH ₂ Cl) 3400, · 1765 cm ^-1 .

i) 2 -] "(3S, 4R) -3-r (l * R) -1- (tert-butyldimethylsilyloxyethyl) -4-triphenylmethylthio-2-oxoazetidl-nyl-2-hydroxyacetic acid allyl · Ester Analogously to Example Ib) are 9,55'g (3S, 4R) -3 - [(l'R) -1- (tert.Butyldimethylsilyloxyäthyl) _] - 4-triphenylmethylthio-azet idin-2-one in the TLC (toluene-ethyl acetate 19: 1) R _f = 0.32 and 0.2, IR (CH ₂ CL ₂ ) 3520, 1765, 1750 cm ^-1 .

j) 2-f * (3S, 4R) -3-r (l 'R) -IC tert. Butyldimethylsilyoxyethyl) ~] -4-tr iphenylmethylthio-2-oxo-azetidin-1-yl ~] -2-triphenyl phosphoric idenessigsäure allylester.

Analogously to Example 1c), 12.5 g of 2 - [(3S, 4R) -3 - [(1'R) -1- (tert-butyldimethylsilyloxyethyl)] - (4-triphenylmethylthio-2-oxo-azetidin-1-yl) Allyl 2-hydroxyacetate is converted into the title compound. TLC (toluene / ethyl acetate 4: 1) R = 0.38, IR (CH Cl) 1740;

-1 til

1615 cm.

k) 2-] ~ (3S, 4R) -3-f ~ (l ¹ R) IC tert. Butyldimethylsilylxyethyl firmer c apto ^ oxo-azetidin-l-ll ^ -tr ipheny! Phosphor any! idenessigsäure-allylester, silver salt

Analogously to Example ld), 8.47 g of 2 - [(3S, 4R) -3 - [(1'-R) -1- (tert-butyldimethylsilyloxyethyl)] - 4-triphenylmethylthio-2-oxo-azetidin-1-yl-1 -2-triphenylphosphoranylidenessigsäure allylester converted into the title compound. IR CCH Cl) 1760; 1615 cm ".

1) 2-rC3S, 4R) -3-r (l'R) -1- (tert-butyldimethylsilyloxyethyl) ~ | -4- (imidazol-1-yl-thiocarbonylthio) -2-oxoazetidin-1-yl-I 2-tripheny! Phosphor any! idenessigsäure-al Iy! ester

Analogously to Example le), 5.09 g of the silver salt of 2 - [(3S, 4R) -3-ε (1'R) -1- (tert-butyldimethyl isilyloxyethyl) -4-tercapto-2-oxoazetidin-1-yl4 are obtained -2-triphenylphosphoranylidenessigsäure allylesters reacted with 2.5 g thiocarbonyldiimidazole. After purification by column chromatography (eluent toluene-ethyl acetate 1: 1) to give the title compound. TLC (silica gel, ethyl acetate): R = 0.42; IR (CHCl): 1755; 1620; 1110 cm-1.

Example 11: (5R, 6S) -2- (imidazol-1-yl) -6-f (1'R) -1-hydroxyethyl ~ -

2-penem-3-carboxylic acid aliy! Ester.

Analogously to Example 2, 0.33 g of (5R, 6S) -2- (imidazol-1-yl) -6 - [(lR) -1-tert-butyldimethylsilyloxyethyl-2-penem-3-carboxylic acid allyl ester are incorporated in the Title compound transferred. TLC (silica gel, ethyl acetate): R _f = 0.13; IR (CH ₂ Cl ₂ ) 3600; 1790; 1715; 1587 cm ~ ^l .

Example 12: (5R, 6S) -2- (imidazol-1-yl) -6-f "(1'R) -1-hydroxyethyl" 1-2-

penem-3-carboxylic acid, sodium salt.

132 mg (5R, 6S) -2- (imidazol-1-yl) -6 - [(lR) -l-hydroxyethyl J-2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 3. DC (reverse phase Opti UCP ₁₉ , water): R _f = 0.14; UV (phosphate buffer pH 7.4): λ = 309.5 mn.

ΓΠ3Χ.

Example 13 : (5R, 6S) -2- (pyrro-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester.

5.4 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(pyrrolyl) -thiocarbonylthioj-azetidin-2-one are dissolved in 60 ml of abs. CH "C1" dissolved and successively with 6 g of CaCO3. and at + 10 ° with 2,7 allyloxalyl chloride. After dropwise addition of 5.3 ml of Hünig's base in 10 ml of methylene chloride over 5 minutes, the mixture is stirred for a further 30 minutes at 10 °.

The reaction mixture is diluted with chloroform (abs.), Washed twice with ice water, dried over Na 2 SO 4, filtered and concentrated to a volume of 25 ml. After dilution with 400 ml of abs. Chloroform, the bath temperature is raised to 70 °, and the mixture is added over 2.5 hours with a total of 6 ml of triethyl phosphite in 100 ml of chloroform. The reaction mixture is kept at gentle reflux for 3.25 hours, cooled and concentrated. The crude product was purified by chromatography on silica gel (eluent toluene and toluene-ethyl acetate 97.5: 2.5). TLC (silica gel, toluene-ethyl acetate 4: 1) R = 0.67; IR (CHCl) 1790; 1710; 1575 cm

The starting material can be prepared as follows:

(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-j "(pyrrol-l-yl) -thiocarbonylthio | azetidin-2-one.

11.72 g of (3S, 4R) -3-tert-butyldimethylsilyloxymethyl-4-methylsulfonylazetidin-2-one (European Patent Application No. 82113) are dissolved in 150 ml of abs. Dissolved ethanol and dropwise with a solution of

10.88 g of potassium N-pyrrole dithiocarboxylate ^ preparation see RD Bereman, D. Nalewajek, Inorganic Chemistry JJ ^, 2687 (1977)] in 150 ml abs. Ethanol added. After one hour of stirring at room temperature, the reaction mixture is concentrated on a rotary evaporator and the residue is partitioned between ethyl acetate and water. After washing the organic phase with brine and drying it over sodium sulfate, the solvent is removed in vacuo. The crude product is purified by chromatography on silica gel. TLC (silica gel; toluene / ethyl acetate; 4: 1) R = 0.5 IR (CH ₂ Cl ₂ ) 3410; 1780; 1310; 1110 cm " ¹ .

Example 14; (5R, 6S) -2- (pyrrol-l-yl) -6-hydroxymethyl-2-penem-3-

carboxylate.

Analogously to Example 2, 1.1 g of (5R, 6S) -2- (pyrrol-1-yl) -6-tert-butyldimethylsilyloxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound. TLC (ethyl acetate) R _f = 0.5; IR (CH "C1) 3600; 1785; 1705; 1575 cm " ¹ .

Example 15: (5R, 6S) -2- (pyrrol-1-yl) -6-hydroxymethyl-2-penem-3

carboxylic acid sodium salt

Analogously to Example 3, 0.36 g of (5R, 6S) -2- (pyrrol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound. UV (water) λ = 310 nm.

Max

Example 16: 2-j "(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-

f (pyrazol-1-yl) -thiocarbonylthio'Ί-2-oxo-azetidin-1-yl-2-triphenylphospho-anylideneacetic acid allyl ester. 108 mg of 2 - [(3S, 4R) -3-tert-butyldimethylsilyloxymethyl) -4 - [(imidazol-1-yl) -thiocarbonylthioJ-2-oxo-azetidin-1-ylJ-2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 0, 6 ml abs. Dissolved dimethylformamide and treated with 51 mg of pyrazole. After stirring for 6 hours at 40 °, the reaction mixture is poured into ice-water. The precipitate is filtered off and washed with water. The residue is taken up in ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered and concentrated. The crude product is chromatographed

phie on silica gel (eluent toluene to toluene / ethyl acetate 85:15). IR (methylene chloride) 1750; 1615 cm " ¹ } TLC (toluene / ethyl acetate l / l) R _f = 0.55.

The product is identical to that described in Example 4.

Example 17: (5R, 6S) -2- (4-methyl-pyrazol-1-yl) -6- (tert -butyl-di-

methylsilyoxymethyl) -2-penem-3-carboxylic acid allyl ester Analogously to Example 1, 1.15 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [[(4-methyl-pyrazole-1-one] yl) -thiocarbonylthioJ-2-oxoazetidin-1-yl ^] - 2-triphenylphosphoranylidenessigsäure allylester converted into the title compound. IR (CH Cl): 1780, 1700, 1590; 1565 cm " ¹ .

The starting material can be prepared as follows:

2-j ~ (3S, 4R) -3- (tert -butyldimethylsilyloxymethyl) -4-j "- (4-methylpyrazol-1-yl) -thiocarbonylthio ^ -2-oxo-azetidin-1-yl.-2-triphenylphosphoranylideneacetic acid -allylester.

Analogously to Example 16, 1.43 g of allyl 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - {(imidazol-1-yl) thiocarbonylthioj-2-oxoazetidin-1-yl] -2-triphenylphosphoranylideneacetate are obtained in 10 ml abs. DMF with 0.49 ml of 4-methylpyrazole at room temperature for 18.5 hours to give the title compound. TLC (toluene-ethyl acetate 1: 1) R = 0.48; IR (CHCl) 1750; 1615 cm " ¹ .

Example 18: (5R.6S) -2- (4-methylpyrazol-1-yl) -6- (hydroxy

methyl-Z-penem-ß-carboxylic acid aHylester

Analogously to Example 2, 0.44 g of (5R, 6S) -2- (4-methyl-pyrazol-1-yl) -6- (tert-butyl-dimethyl-silyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound. IR (CH Cl.): 3600; 1785; 1705; 1590; 1570 cm " ¹ .

Example 19: (5R, 6S) -2- (4-methyl-pyrazol-1-yl) -6-hydroxymethyl

2-penem-3-carboxylic acid, sodium salt.

Analogously to Example 3, 0.19 g of (5R, 6S) -2- (4-methyl-pyrazol-1-yl) -6-hydroxy-ethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound. UV (water) λ = 318 nm

Max

Example 20: (5R, 6S) -2- (4-methyl-imidazol-1-yl) -6- (tert-butyl)

dimethylsilyloxymethyQ ^ penem-O-carboxylate.

Analogously to Example 1, 2.4 g of 2 - {] (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (4-methylimidazol-1-yl) thiocarbonylthio] -2-ozoazetidin-1-one yl ^] - 2-triphenylphosphoranylideneacetic acid allyl ester is converted to the title compound, IR (CHCl-): 1790; 1710; 1585 cm " ¹ .

The starting material can be prepared as follows:

2- ["(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [" (4-methylimidazol-1-yl) -thiocarbonylthio "1- (2-oxoazetidin-1-yl)] - 2- triphenylphosphoranylidenessigsäure allyl ester.

Analogously to Example 3, 2.5 g of allyl ester of 2-l (3S, 4R) -3-tert-butyldimethylsilyloxymethyl-4 -] ^ (imidazol-1-yl) thiocarbonylthio]] - 2-oxoazetidin-1-yl-3-yl-triphenylphosphoranylidenessigsäureallylester in 18 ml abs. DMF with 1.44 g of 4-methylimidazole at room temperature for 1.5 hours to the title compound. TLC (acetone-hexane l / l) R _f = 0.5; IR (CH ₂ Cl ₂ ): 1750, 1615 cm ^-1 .

Example 21: (5R, 6S) -2- (4-methyl-imidazol-1-yl) -6-hydroxymethyl

2-penem-3-carboxylic acid aliy! Ester

Analogously to Example 2, 0.75 g of (5R, 6S) -2- (4-methylimidazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound. IR (CH Cl): 3600; 1790, 1710; 1590 cm " ¹ .

Example 22: (5R, 6S) -2- (4-methyl-imidazo 1-1-yD-6-hydroxy

methyl-2-penem-3-carboxylic acid, sodium saline

Analogously to Example 3, 0.36 g of (5R, 6S) -2- (4-methylimidazole-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound. UV (water) λ = 310 nm.

Example 23: (5R, 6S) -2- (3-ethyl-imidazolio) -6- (tert-butyldimethylsilyloxymethyl) -penem-S -carboxylic allyl ester tetrafluoroborate

a) Method A:

2.0 g of 2 - [(3S ₁ 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (imidazol-1-yl-thiocarbonylthio) -2-oxoazetidin-1-yl] -2-triphenylphosphoranyl 1-idenessigsäure allylester be in 50 ml abs. Dissolved ethylene chloride and treated at 0 ° with 0.533 g of triethyloxonium tetrafluoroborate. Then remove the cooling bath and stir at room temperature for 21 hours. After addition of a further 50 mg of triethyloxonium tetraflouroborate, the reaction mixture is stirred for 3 hours at 40 °. The mixture is then washed twice with water, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (mobile phase ethyl acetate to ethyl acetate / acetone 2: 1). TLC (silica gel, ethyl acetate / acetone 4: 1) R = 0.23, IR (methylene chloride): 1800; 1715; 1600 cm ".

b) Method B:

21 mg (5R ", 6S) -2- (imidazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are dissolved in 1 ml of absolute methylene chloride, to -10 After addition of 9.5 mg of triethyloxonium tetrafluoroborate, the reaction mixture is then stirred for a further 1.75 hours at 0 ° C. The reaction mixture is then diluted with methylene chloride, washed with water, dried and concentrated, and the crude product is purified as in process a) (Methylene chloride) as above.

Example 24: (5R, 6S) -2- (3-ethylimidazolio) -6-r (1'R) -1- (t: 1-butyldimethylsilyloxyethyl) ~ [-2-penem-3-carboxylic acid allyl ester tetrafluoroborate

Analogously to Example 23 b), 0.6 g of (5R, 6S) -2- (imidazol-1-yl) -6- (1'R) -1-tert-butyldimethylsilyloxyethyl} -penem-S-carboxylic acid allyl ester is converted into the title compound transferred. IR (methylene chloride): 1800; 1718; 1600 cm " ¹ .

Example 25: (5R, 6S) -2- (3-ethylimidazolio) -6-hydroxymethyl-2-peneme

3-carboxylic acid alIylester tetrafluoroborate

Analogously to Example 2, 0.1 g of (5R, 6S) -2- (3-ethylimidazolio) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester tetrafluoroborate is converted into the title compound. IR (methylene chloride): 3600; 1800; 1715; 1600 cm " ¹ .

Example 26: (5R, 6S) -2- (3-ethyl-imidazolio) -6-r (l'R) -l-hydroxy- * ethyl-2-penem-3-carboxylic acid lysed ester met luoroborate

Analogously to Example 2, 0.15 g of (5R, 6S) -2- (3-ethyl-imidazolio) -6-J (l-R) -I- (tert-butyldimethylsilyloxyethyl) J-2-penem-3-carboxylic acid allyl ester tetrafluoroborate are obtained transferred the title compound. IR (methylene chloride): 3600; 1800; 1718; 1600 cm " ¹ .

Example 27: (5R, 6S) -2- (3-ethylimidazolio) -6-hydroxymethyl-2-

penem-3-carboxylate

80 mg of (5R, 6s) -2- (3-ethylimidazolio) -6-hydroxymethyl-2-penem-3-carboxylic acid all-ester tetrafluoroborate are converted into the title compound analogously to Example 3, which is purified by chromatography on antecels (OPTI UPC ₁₀ ) , UV (phosphate buffer pH 7.4): λ

12 r r r

Example 28: (5R, 6S) -2- (3-ethylimidazo! Ω) -6- [~ (1'R) -1-hydroxyethyl [-2-

237 mg (5R ₁ 6S) -2- (3-ethylimidazolio) -6- [( 1'R) -1-hydroxyethyl J-2-penem-3-carboxylic acid allyl ester tetrafluoroborate are converted into the title compound analogously to Example 3. UV (phosphate buffer pH 7.4):

λ = 319 μm. ' max ^r

Example 29: (5R, 6S) -2- (4,5-Dimethylimidazol-1-yl) -6- (tert-butyl-dimethylsilyloxymethyl) -butem-S-carboxylic acid allyl ester

0.15 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (4,5-dimethyimidazol-1-yl) -thiocarbonylthio] -2-oxoazetidin-1-yl] 2-triphenylphosphoranylidenessigsäure allylester converted into the title compound. IR (CHCl) 1790; 1715; 1590 cm " ¹ .

The starting material 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(4,5-dimethylimidazol-1-yl) thiocarbonylthioJ-2-oxoazetidin-1-yl-2-triphenylphosphoranylideneacetic acid Allyl ester can be prepared as follows:

Analogously to Example 16, 3 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [(imidazol-1-yl) thiocarbonylthio] -2-oxoazetidin-1-yl) -2-triphenylphosphoranylideneacetic acid Alllester in 20 ml of DMF with 2.1 g of 4,5-dimethylimidazole at room temperature for 6 hours to the title compound. TLC (toluene / ethyl acetate 1: 1) R _f = 0.2.IR l ₂ ): 1750, x 1615 cm ^-1 .

Example 30: (5R, 6S) -2- (4,5-dimethylimidazol-1-yl) -6-hydroxymethyl-

2-penem-3-carboxylic acid allyl ester

Analogously to Example 2, 90 mg of (5R, 6S) -2- (4,5-dimethylimidazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound. IR (CH Cl): 3590; 1790; 1710; 1590 cm " ¹ .

Example 31; (5R, 6S) -2- (4,5-Dimethylimidazo1-1-y1) -6-hydroxy

methyl-2-penem-3-carboxylic acid, sodium salt

Analogously to Example 3, 0.43 g of (5R, 6S) -2- (4,5-dimethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound. UV (water) λ = 312 nm.

Max

Example 32: (5R, 6S) -2-f4-Allyloxycarbonylamino'athylimide

dazol-1-yl ~ [-6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester

2.85 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-] -4-allyloxycarbonylaminoethyl-imidazol-1-yl-thiocarbonylthio ^ -2-oxoazetidin-1-yl 3 -2 triphenylphosphoranylidenessigssäure allyl ester converted into the title compound. IR (CH ₂ Cl ₂ ): 3440; 1790; 1710; 1585 cm " ¹ .

The starting compound can be prepared as follows:

a) 3-Allyloxycarbonyl-2-thiazolidine-thione

16.7 g of 2-mercaptothiazoline are dissolved in 140 ml of methylene chloride and treated successively at 0 ° with 20.5 ml of triethylamine and 14.9 ml of Chlorameisensaureallylester in 35 ml of methylene chloride over 20 minutes. After further stirring at room temperature for 75 minutes, the reaction mixture is washed first with water, then brine. After drying over sodium sulfate and concentration, the crude product is purified by chromatography on silica gel (mobile phase toluene-ethyl acetate 95: 5). TLC (silica gel, toluene / ethyl acetate 1: 1); _Rf = 0.53; IR (CH ₂ Cl ₂ ): 1750; 1720 cm " ¹ .

b) 4- (2-Alyloxycarbonylamino-ethyl) imidazole

5.55 g of 4- (2-aminoethyl) -imidazole (hydrochloride) with 60 ml of abs. Added THF and dropwise with a solution of 6 g of 3-allyloxycarbonyl-2-thiazolidinthion in 60 ml abs. THF implemented. After addition of 8.4 ml of triethylamine, the mixture is stirred for 65 hours at room temperature. After dilution with 100 ml of methylene chloride and filtering off the insoluble part is on a rotary evaporator

concentrated. The residue is taken up in methylene chloride again, filtered again and purified after concentration by column chromatography. (Eluent ethyl acetate to ethyl acetate / acetone 1: 1); TLC (silica gel, ethyl acetate / acetone 2: 1), 'R _f = 0.09.

c) 2-r (3S, 4R) -3- (tert -butyldimethylsilyloxymethyl) -4-r4- (2-alyloxycarbonylaminoethyl) -imidazo1-1-yl-thiocarbonylthio ~ 2-oxoazetidin-1-yl "| -2 -triphenylphosphoranylidene-acetic acid allyl esters Analogously to Example 16, 3 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-L (imidazol-1-yl) -thiocarbonylthio] - (2-oxoazetidin-1-yl] 2-triphenylphosphoranylideneacetic acid allyl ester in 25 ml of DMF with 3.3 g of 4-allyloxycarbonylaminoethylimidazole to give the title compound, IR (GH ₂ Cl ₂ ): 3440, 1750, 1720, 1615 cm ^-1 .

Example 33: (5R, 6S) -2-f4- (2-Allyloxycarbonylaminoethyl) -imidazo-1-1-yl-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester

Analogously to Example 2, 1.13 g of (5R, 6S) -2- [4- (2-allyloxycarbonylaminoethylimidazol-1-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound IR l ₂ ): 3600; 3440; 1790; 1710; 1585 cm " ¹ .

Example 34; -6- | (5R, 6S) -2-r4- (2-aminoethyl-imidazol-l-yl "

hydroxymethyl-2-penem-3-carboxylic acid

0.51 g of (5R, 6S) -2- {4- (2-allyloxycarbonylaminoethyl-imidazol-1-ylJ-α-hyroxymethyl) -penem-S-carboxylic acid allyl ester are converted into the title compound in the same way as in Example 3. UV (phosphate buffer pH

7.4) λ = 310 nm

 Max

Example 35: (5R, 6S) -2- (4-MeEhoxy-imidazol-1-yl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester

1.85 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-L (4-methoxyimidazol-1-yl) -thiocarbonylthioJ-2-oxoazetidin-1-ylj-2 are prepared analogously to Example 1. allyl triphenylphosphoranylidene acetate is converted to the title compound. IR (CHCl): 1790; 1710; 1585 cm " ¹ .

The starting material 2- (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (4-methoxyimidazol-1-yl) thiocarbonylthio] -2-oxoazetidin-1-ylJ-2-triphenylphosphoranylidene acetic acid allyl ester can be made as follows:

2.15 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (imidazol-1-yl) -thiocarbonylthioJ-2-oxoazetidinl-yl3-2-triphenylphosphoranylideneacetic acid allyl ester are prepared analogously to Example 16 20 ml of DMF with 1.18 g of 4-methoxy-imidazole converted into the title compound. IR (CH ₂ Cl ₂ ): 1750, 1610 cm ^-1 .

Example 36: (5R, 6S) -2- | 4-methoxy-imidazol-1-yl | -6-hydroxy

methyl-2-penem-3-allyl-carbons'äure

Analogously to Example 2, 0.62 g of (5R, 6S) -2 - [[4-methoxy-imidazo-1-ylj-6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are converted into the title compound. IR (CH Cl): 3600; 1790; 1710; 1582 cm " ¹ .

Example 37: (5R, 6S) -2-r4-methoxy-imidazol-1-yl ~ -6-hydroxy

methyl-2-penem-3-carboxylic acid sodium salt

Analogously to Example 3, 0.31 g of (5R, 6S) -2- | 4-methoxyimidazol-1-yl-6-hydroxymethyl-2-penem-3-carboxylate are converted into the title compound. UV (water): λ = 310 nm.

Max

Example 38: (5R, 6S) -2-f "4-Al IyI oxycarbonyl aminomethyl thyinimidazole

l-yl | -6- (tert.butyldimethylsilyloxymethyl) -2-penem-3-carboxylate

As in Example 2, 0.196 g of 2-L (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) j-4-yl-4-allyloxycarbonylaminomethyl-imidazol-1-yl) -thiocarbonylthio ^ -2-oxoazetidin-1-yl] -2 Allylester -triphenylphosphoranylidenessigsäures allylester converted into the title compound. IR (CH ₉ Cl ₉ ): 3440; 1730; 1715; 1585 cm " ¹ .

The starting material 2- (3S, 4R) -3- (tert.Butyldimethylsilyloxymethyl) -4- (4-allyloxycarbonylaminomethyl-imidazol-1-yl) -thiocarbonylthio) -oxoazetidin-1-yl-yl-triphenylphosphoranylidene-1-acetic acid allyl ester can be prepared as follows getting produced:

By way of example 16, 0.286 g of allyl 2-l (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- (imidazol-1-yl) thiocarbonylthio] - 2-oxoacetate idynl-ylJ-2-triphenylphosphoranylideneacetic acid are obtained 0.29 g of 4-allyloxycarbonylaminomethyl-imidazole in 2 ml of DMF is converted into the title compound. IR (CH ₂ Cl ₂ ): 3450; 1755; 1715; 1615 cm " ¹ .

Example 39: (5R, 6S) -2-Γ4-allyloxycarbonylaminomethyl-imidazole

l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester Analogously to Example 2, 9.15 g of (5R, 6S) -2- | J4-allyloxycarbonylaminomethyl-imidazol-1-yl) -6- (tert .butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester is converted into the title compound. IR l ₂ ): 3600; 3440; 1790; 1715; 1590 cm " ¹ .

Example 40:

xymethyl-2-penem-3-carboxylic acid

2 g of (5R, 6S) -2-] j4-allyloxycarbonylaminomethyl-imidazol-1-ylj-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted into the title compound analogously to Example 3. UV (phosphate buffer, pH 7.4): = 312 nm.

Example 41 : In an analogous manner as described in the preceding examples, the following compounds can be prepared:

(5R, 6S) -2- (pyrazol-1-yl) -6 - [(1R) -l-hydroxyethyl 3-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (l, 2,4-triazol-1-yl) -6 - [(1R) -l-hydroxyethyl]] - 2-penem-3-carboxylic acid, sodium salt. UV (water) λ = 312 nm.

Max

(5R, 6S) -2- (pyrrol-1-yl) -6 - [(1R) -l-hydroxyethyl] - 2-penem-3-carboxylic acid sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (tetrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (tetrazol-l-yl) -6 - [(lR) -l-hydroxyäthylJ-2-penem-3-carboxylic

acid, sodium salt. UV (water) λ = 312 nm. ¹ 'max

(5R, 6S) -2- (5-aminotetrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 314 nm.

Max

(5R, 6S) -2- (5-aminotetrazol-1-yl) -6-E (1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, sodium salt, UV (water): λ = 312 nm.

Max

(5R, 6S) -2- (indol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water): λ = 311 nm.

Max

(5R, 6S) -2- (indol-1-yl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, sodium salt, UV (water): λ = 311 nm.

Max

(5R, 6S) -2- [lH-Pyrrolo (2,3-b) pyrid-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- [1H-Pyrrolo (2,3-b) pyrid-1-yl] -6 - [(1R) -l-hydroxyethyl] -2-penem-3-carboxylic acid, sodium salt. UV (water) λ = 312 nm. * Max

(5R, 6S) -2- (benzimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt. UV (water) λ = 313 nm.

Max

(5R, 6S) -2- (benzimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl] -2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 311 nm.

Max

(5R, 6S) -2- (Benzotriazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt. UV (water) λ = 312 nm.

Max

(5R, 6S) -2- (benzotriazol-l-yl) -6 - [(lR) -l-hydroxyäthyi] -2-penem

3-carboxylic acid, sodium salt, UV (water) λ = 313 nm. ¹ '. Max

(5R, 6S) -2- [lH-imidazo (4,5-b) pyrid-l-yli-6-hydroxymethy1-2-penem-3-carboxylic acid. Sodium salt, UV (water) λ = 312 nm.

Max

(5R, 6S) -2 - [(IH-imidazo (4,5-b) pyrid-l-yl] -6 - [(lR) -l-hydroxyethyl] -

2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 312 nm.

Max

(5R, 6S) -2- (Purin-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 314 nm.

Max

(5R, 6S) -2- (Purin-1-yl) -6 - [(1R) -1-hydroxyethyl) -2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 313 nm.

Max

Example 42: In an analogous manner as described in the preceding examples, the following 2- (imidazol-1-yl) -penem compounds can be prepared:

(5R ₁ 6S) -2- (2-aminoimidazol- ₁ -yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, UV (water) λ = 309 nm.

Max

(5R, 6S) -2- (2-aminoimidazol-l-yl) -6 - [(lR) -l-hydroxyethyl ^] - 2-penem

3-carboxylic acid, UV (water) λ = 311 nm. ¹ max

(5R, 6S) -2- (2-aminomethyl imidazole-l-yl) -6-hydroxymethyl-2-penem

3-carboxylic acid. UV (water) λ = 313 nm. 'Max

(5R, 6S) -2- (2-aminomethylimidazol-1-yl) -6 - [(1R) -1-hydroxyethyl-2-penpr-3-carboxylic acid, UV (water) λ = 312 nm.

^r max

(5R, 6S) -2- (2-nitroimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (2-nitroimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl 3-2-penem-3-carboxylic acid, sodium salt, UV (water) λ = 311 nm.

Max

(5R, 6S) -2- [4- (2-aminoethyl) -imidazol-1-yl] - 6 - [(1R) -l-hydroxyethyl-2-penem-3-carboxylic acid, UV (phosphate buffer, pH 7.4) λ = 312 nm.

(5R, 6S) -2- (4-aminoraethyl-imidazol-1-yl) -6 - [(1R) -l-hydroxyethyl-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4) λ = 311 nm. (5R, 6S) -2- (4,5-Dimethylimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt, UV (water) λ = 312 nm.

Max

(5R, 6S) -2- (4-ethyl-imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt. UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (4-ethyl-imidazol-1-yl) -6 - [(1R) -l-hydroxymethyl-3-penem-3-carboxylic acid sodium salt, UV (water) λ = 311 nm. ^C max

(5R, 6S) -2- (4-Propylimidazol-1-yl) -6-hydroxymetbyl-2-penem-3-carboxylic acid sodium salt, UV (water) λ = 309 nm.

Max

(5R, 6S) -2- (4-propylimidazole-l-yl) -6 - [(lR) -l-hydroxyäthyl3-2-

sodium salt of penem-3-carboxylate, UV (water) λ = 311 nm. (5R, 6S) -2- (4-methoxyimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl] -2-pen- 3-carboxylic acid sodium salt, UV (water) λ = 310 nm. (5R, 6S) -2- [4- (2-acetylaminoethyl) -imidazol-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt , UV (phosphate buffer

pH 7.4) λ = 309 nm

 Max

(5R ₁ 6S) -2- [4- (2-acetylaminoethyl) imidazol-1-yl] -6- (1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid _I sodium salt, UV (phosphate buffer pH 7.4) λ = 310 nm

^r max

(5R, 6S) -2- [j4- (2-Amino-2-thethoxycarbonyloxy-1-imidazo1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7,4)

λ = 308 nm

 Max

(5R ₁ 6S) -2- £ 4- (2-amino-2-methoxycarbonyl-1-yl) -imidazo-1-1-yl]] - 6- (1R) -1-hydroxyethyl-2-2-penem-3 carboxylic acid, UV (phosphate buffer pH 7.4) λ = 310 nm

* 'max

(5R, 6S) -2- (4-Methylimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl 3-2-penem-3-carboxylic acid sodium salt. UV (water) λ = 312 nm.

Max

(5R ₁ 6S) -2- (4-hydroxymethyl-imidazol- ₁ -yl) -o-hydroxymethyl -penem-3-carboxylic acid sodium salt, UV (water) λ - 312 nm.

Max

(5R, 6S) -2- (4-hydroxymethyl-imidazol-1-yl) -6- (1R) -l-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt, UV (water) λ = 311 nm. (5R , 6S) -2- (4-Acetoxymethyl-imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, UV (phosphate buffer pH 7.4) λ = 310 nm. (5R, 6S) - 2- (4-Acetoxymethyl-imidazol-1-yl) -6 - [(IR) -1-hydroxyethyl) -2-penem-3-carboxylic acid sodium salt, UV (water) λ = 309 nm.

Max

(5R, 6S) -2- (4-Methoxycarbonylmethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, UV (water) λ = 311 nm.

Max

(5R, 6S) -2- (4-Methoxycarbonylmethyl-imidazol-1-yl) -6-ε (IR) -l-hydroxyethyl]] - 2-penem-3-carboxylic acid sodium salt, UV (water) λ = 310 nm.

(5R, 6S) -2- (4-carbamoylmethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, UV (phosphate buffer pH 7.4)

λ = 311 nm

 Max

(5R, 6S) -2- (4-Carbamoylmethylimidazol-1-yl) -6 - [(IR) -I-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt, UV (phosphate buffer

pH 7.4) λ = 311 nm

 Max

(5R, 6S) -2- (4-chloromethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, UV (phosphate buffer pH 7.4) λ = 312 nm.

ΙΠ3Χ

(5R, 6S) -2- (4-chloro-ethyl-imidazol-1-yl) -6 - [(1R) -l-hydroxy-ethyl]] - 2-penem-3-carboxylic acid sodium salt, UV (water) λ = 310 nm.

Max

(5R, 6S) -2- (4-carboxymethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid disodium salt, UV (water) λ = 309 nm.

Max

(5R, 6S) -2- (4-Carboxymethylimidazo1-1-yl) -6- £ (lR) -l-hydroxyethyl ^] - 2-penem-3-carboxylic acid disodium salt. UV (water) λ - 309 nm.

Max

(5R, 6S) -2- (4-carbamoyloxy-ethyl-imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, UV (water) λ = 313 nm.

Max

(5R, 6S) -2- (4-carbamoyloxymethyl-imidazol-1-yl) -6 - [(IR) -I-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt, UV (water) λ = 312 mn.

(5R, 6S) -2- (4-methylthiomethyl-imidazol-l-yl) -6 - [(lR) -l-hydroxy-

ethyl ~ | -2-penem-3-carboxylic acid sodium salt, UV (water) λ = 310 nm ^J -J ^r max.

(5R, 6S) -2- (4-ethylthiomethyl-imidazol-1-yl) -6 - [(1R) -l-hydroxyethyl-l-2-penem-3-carboxylic acid sodium salt, UV (water) λ = 309 nm ,

- ¹ max

Example 43: (5R, 6S) -2- (imidazol-1-yl) -6-f ~ (IR) -l-hydroxyethyl] -

2-penem-3-carboxylic acid acetoxymethyl ester

60.7 g of (5R, 6S) -2- (imidazol-1-yl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt are dissolved in 2 ml of abs. DMF and 0.2 ml abs. DMSO dissolved and at 0 ° with stirring, dropwise with a solution of 39.8 mg of acetoxy-bromide in 0.3 ml abs. DMF offset. After stirring for a minute at 0 ° and then for 30 minutes at room temperature, the reaction mixture is diluted with ethyl acetate and washed twice with brine. The organic phase is dried over magnesium sulfate and evaporated. Purification by column chromatography (eluent ethyl acetate) gives the title compound. , TLC (silica gel, acetone) R = 0.7; IR (methylene chloride): 3590; 1790;

1765; 1725; 1580 cm '¹; UV (ethanol) λ = 328.5 nm.

Max

Example 44: (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penemethylene

3-carboxylic acid-l-äthoxycarbonyloxyäthylester

1.2 g of sodium iodide are dissolved in 3.7 ml of acetone and treated with 0.275 ml of ethyl-1-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. Subsequently, the solution is added dropwise to 15 ml of methylene chloride and filtered from the precipitated inorganic salts. The methylene chloride solution is concentrated to 2 ml and at 0 ° to a solution of 0.267 g (1 mmol) (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid in Added 4 ml of dimethylacetamide. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the mobile phase ethyl acetate. The title compound is obtained as a white foam. IR spectrum (methylene chloride): 3600; 1790; 1750; 1720; 1670 cm " ¹ .

Example 45: (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penemethylene

3-carboxylic acid pivaloyloxymethyl ester

0.6 g of sodium iodide are dissolved in 2 ml of acetone and treated with 0.15 ml Pivalinsaurechlormethylester. The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to 1 ml and added to a solution of 0.11 g (0.4 mmol) of (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid and 0.17 ml of diisopropylethylamine in 4 ml of Ν, Ν-dimethylacetamide at 0 °. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the mobile phase ethyl acetate. The title compound is obtained as a white foam. IR spectrum (methylene chloride): 3600; 1795; 1745; 1725; 1670 cm " ¹ .

Example 46: In an analogous manner as described in Examples 43-45, the following esters can be prepared:

(5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 3620; 1795; 1765; 1725; 1670 cm " ¹ .

(5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 3605; 1795; 1760; 1720 cm " ¹ .

(5R, 6S) -2-j_4-Methoxyimidazol-1-yl ^ -6-hydroxymethyl-2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 3625; 1790; 1755; 1730; 1680 cm " ¹ .

(5R, 6S) -2 -] - 4-aminomethyl-imidazol-1-ylJ-6-hydroxymethyl-2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 1785 j 1760; 1725; 1685 cm " ¹ .

(5R, 6S) -2- ^ 4-Aminomethyl-imidazol-1-yl [] - 6-hydroxymethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR (methylene chloride): 1790; 1755; 1720; 1675 cm " ¹ .

(5R, 6S) -2- (4,5-Dimethylimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl] -2-penem-3-carboxylic acid acetoxymethyl ester, IR (powdered flour): 3615; 1795; 1760; 1720; 1675 cm " ¹ .

(5R, 6S) -2- (4,5-Dimethylimidazol-1-yl) -6 - [(1R) -l-hydroxyethyl-3-methylpene-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR (methylene chloride): 3610; 1785; 1755; 1715; 1665 cm " ¹ .

(5R, 6S) -2- (4,5-dimethy1-imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 3605; 1790; 1755; 1725; 1685 cm " ¹ .

(5R ₁ 6S) -2- (4-Aminomethyl-1-imidazo-II-yl) -6 - [(IR) -1-hydroxyethyl] -2-penem-3-carboxylic acid acetoxymethyl ester, IR (methylene chloride): 1785; 1760; 1720; 1630 cm " ¹

(5R, 6S) -2- (4-Aminomethylimidazol-1-yl) -6-ε (IR) -1-hydroxyethyl] -2-penem-3-carboxylic acid 1-ethoxycarbonyl ethyl ester, IR (methylene chloride): 1785; 1755; 1720; 1670 cm " ¹

 (5R, 6S) -2- (imidazol-l-yl) -6 - [(lR) -l-hydroxyethyl] -2-penem-3 '

carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR (methylene chloride): 3600; 1790; 1760; 1720; 1675 cm " ¹ .

Example 47: Dried ampoules or vials containing 0.5 g of (5R, 6S) -2- (imidazol-1-yl) -6- (1-R) -l-hydroxyethyl-2-penem-3-carboxylic acid Sodium salt as active substance, are prepared as follows:

Composition (for 1 ampoule or vial): active substance 0.5 g

Mannitol 0.05 g

A sterile aqueous solution of the active substance and the mannitol is subjected to aseptic conditions in 5 ml vials or 5 ml vials of the freeze-drying and the ampoules or vials are closed and tested.

Instead of the abovementioned active ingredient, the same amount of another active ingredient of the preceding examples, such as (5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt, (5R, 6S) -2- (4-aminomethylthiimidazo) yl) -6 - {[(IR) -I-hydroxyethyl} -2-penem-3-carboxylic acid, (5R, 6S) -2- (4,5-dimethy1-imidazol-1-yl) -6- £ (lR) -1-hydroxyethyl] -2-penem-3-carboxylic acid sodium salt or (5R _I 6S) -2-j_4-methoxyimidazol-1-ylJ-6-hydroxymethyl-2-penem-3-carboxylic acid sodium salt become.

Claims (17)

Claim 1. Process for the preparation of. 2- (N-Azaheterocyclyl) -pene compounds of the formula Rs • - · \ ^R 3 wherein R. is lower alkyl substituted by hydroxy or protected hydroxy, R represents an unsaturated azaheterocyclyl radical attached to the penem via a ring nitrogen atom, and R_ is carboxyl or functionally modified carboxyl, optical isomers of compounds of formula I ₁ mixtures of these optical isomers, salts thereof Compounds of the formula I which have a salt-forming group and of pharmaceutical preparations which contain such compounds, characterized in that a. an ylide compound of the formula ^R l / \ θ θ 0 C-X ^R 3 wherein R and R have the meanings given under formula I and R 'represents a protected carboxyl group, Z is oxygen or sulfur and X represents either a triply substituted phosphoniogroup or a doubly esterified phosphono group together with a cation, ringschliesst, or b. a compound of the formula (III) wherein R and R "have the meanings given under formula I, Z has the meaning given under formula II and R 'represents a protected carboxyl group, treated with an organic compound of trivalent phosphorus, or c. a compound of the formula
RS I i. ^R 3 wherein R has the meaning given under formula I, R 'represents a protected carboxyl group and Y represents a nucleophilic reaction-exchangeable group, reacting with a radical R introducing compound and, if desired or necessary, in a compound of formula I obtainable, converts a protected hydroxy group in the radical R. into the free hydroxy group, and / or, if desired, in a compound of formula I obtainable a protected carboxyl group R 'into the free, in a cleavable under physiological conditions esterified carboxyl group or in another protected carboxyl group R 'or a free carboxyl group R. in a cleavable under physiological conditions esterified carboxyl group or in a 2 8.DEZ. 19 S4 * 222ü38 protected carboxyl group R ', and / or, if desired, other protected functional groups contained in the radical R "converted into the free functional groups, and / or, if desired, in an obtainable compound of the formula I a radical R" in another radical R _? and / or, if desired, converting an available compound having a salt-forming group into a salt or an available salt into the free compound or into another salt, and / or, if desired, a mixture of isomeric compounds obtainable into the individual isomers separates, and / or, if desired, processed an available compound to a pharmaceutical preparation. 2. A process according to item 1, characterized in that compounds of the formula I in which R ₁ is lower alkyl substituted by hydroxy or protected hydroxy, R is a monocyclic 5-membered heteroaryl radical which is optionally partially saturated and is attached to the penem radical via a ring nitrogen atom. Radical having 1-4 ring nitrogen atoms, for example a corresponding aza-, diaza-, triaza- or tetrazacyclic radical of aromatic character or a corresponding dihydroro radical, a corresponding partially saturated monocyclic 6-membered heteroaryl radical having 1-3 ring nitrogen atoms, such as a corresponding azido radical , diaza or triaza-cyclic radical, or a corresponding optionally partially saturated benzo, dibenzo, pyrido or pyrimido derivative of such a 5- or 6-membered radical, where these radicals are unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, Halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxyloweralkyl, loweralkanoyloxy lower alkyl, lower alkoxy, lower alkyl, lower alkoxycarbonyl, lower alkylthione, optionally lower alkylated lower alkyl, lower alkanoylamino, lower alkyl, lower alkyl, lower alkyl, lower alkylamino, lower alkylamino, lower alkyleneamino, lower alkanoylamino, carboxyl, Lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-lower alkylated carbamoyl, cyano, sulfo, sulfamoyl, optionally substituted by lower alkyl, micro, lower alkoxy and / or halogen substituted phenyl, cycloalkyl, nitro, imino, oxo and / or oxido, R_ Carboxyl, esterifiable under physiological conditions Carboxyl or protected carboxyl R 'denotes optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of compounds of the formula I ₁ which have a salt-forming group. 3. Process according to item 1, characterized in that compounds of the formula I in which R 1 is lower alkyl substituted by hydroxy or tri-lower alkylsilyloxy, R 1-pyrrolyl or dihydro-1-pyrrolyl optionally substituted by lower alkyl or halogen, optionally by lower alkyl, Lower alkoxy, lower amino alkyl, lower N-lower alkanoylamino, lower carboxy-lower, lower alkoxycarbonyl, lower alkyl, lower alkoxycarbonyl, lower alkyl, lower alkanoyloxy, lower alkyl, lower alkylthio, amino, lower alkylamino, di-lower alkylaraino, lower alkanoylamino or nitro substituted imidazol-1-yl, optionally substituted by lower alkyl, amino-lower alkyl, amino-carboxy-lower alkyl, amino or nitro-substituted pyrazol-1-yl, optionally substituted by lower alkyl, carboxy-lower alkyl or phenyl 1,2,3-, 1,2,4- or 1,3,4-triazol-1-yl, optionally substituted by lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl, di-lower alkylamino-lower alkyl, amino or optionally substituted by halogen-substituted phenyl 1- or 2- Tetrazolyl, dihydro-1-pyridyl, unsubstituted or substituted by oxo and optionally additionally by halogen, unsubstituted or by oxo and optionally additionally by lower alkyl, amino, di-lower alkylamino and / or carboxy-substituted dihydro- or tetrahydro-1-pyrimidyl, optionally lower alkyl, lower alkoxy , Amino and / or dihydro- or tetrahydro-1,2,4- or 1,3,3-triazin-1-yl, indol-1-yl, benzimidazol-1-yl, benzotriazole-1 substituted by up to 2 oxo groups -yl, pyrido-pyrrol-1-yl, pyrido-imidazol-1-yl, optionally substituted by amino, imino and / or oxo pyrimido-, dihydropyrimido- or tetrahydropyrimido-imidazol-1-yl, or optionally by amino, imino and or oxo substituted pyrimido-, dihydropyr imido or tetrahydropyrimido-1,2,3-triazol-1-yl, and R, carboxyl, 4-nitrobenzyloxycarbonyl, lower alkenyl oxycarbonyl, in the 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl substituted ethoxycarbonyl or a cleavable under physiological conditions esterified carboxy represents optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I having a salt-forming group , is prepared. 4. The method according to item 1, characterized by reacting compounds of formula I, wherein IL. R 'is lower alkyl substituted by hydroxy, R' is unsubstituted or lower alkyl or halogen substituted pyrrol-1-yl, unsubstituted or lower alkyl or amino lower alkyl substituted pyrazol-1-yl, unsubstituted or lower alkyl, lower alkoxy, amino lower alkyl, lower alkanoylamino lower alkyl, amino -carboxy-lower alkyl, amino-lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, halo-lower alkyl, lower alkylthione-lower alkyl, amino or nitro-substituted imidazol-1-yl, unsubstituted or lower alkyl-substituted 1,2,4- or 1,3,4-triazol-1-yl, 1- or 2-tetrazolyl unsubstituted or substituted by lower alkyl, amino or phenyl; Indol-1-yl, benzimidazol-1-yl, benzotriazol-1-yl, 1H-pyrrolo (2,3-b) pyrid-1-yl, 1H-imidazo (4,5-b) pyrid-1-yl or R 'is carboxyl or physiologically cleavable esterified carboxyl, such as lower alkanoyloxy-ethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I containing a salt-forming group. 5. The method according to item 1, characterized by reacting compounds of formula I, wherein R is hydroxymethyl or 1-hydroxyethyl, R Pyr pyrrol-1-yl, unsubstituted or substituted by lower alkyl, lower alkoxy, amino or amino lower alkyl imidazole-1 yl, unsubstituted or substituted by lower alkyl or amino lower alkyl pyrazol-1-yl, 1,2,4-triazol-l-yl or unsubstituted or substituted by amino tetrazol-1-yl, and R is carboxyl or esterified carboxyl cleavable under physiological conditions, such as lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, means optical isomers, in particular the (IR) isomers of compounds of formula I wherein R 1 is 1-hydroxyethyl, mixtures of these optical isomers and salts of compounds the formula I, produces. 6. The method according to item 1, characterized in that compounds of formula I, wherein R .. hydroxymethyl or (IR) -1-hydroxyethyl, R "is unsubstituted or substituted by lower alkyl or amino lower alkyl imidazol-1-yl, and R is , Carboxyl or physiologically cleavable esterified carboxyl, such as Niederalkanoyloxymethoxycarbonyl or L-Niederalkoxycarbonyloxyniederalkoxycarbonyl, and salts of compounds of formula I, produces. 7. Process according to item 1, characterized in that pharmaceutically acceptable salts of compounds of formula I are prepared. 8. The method according to item 1, characterized in that cleavable esters of compounds of formula I are prepared under physiological conditions. Method according to item 1, characterized in that (5R, 6S) -2- (imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 10. The method according to item 1, characterized in that (5R, 6S) -2- (imidazol-1-yl) -6 - [(l'R) -l-hydroxyethyl] -2-penem-3-carboxylic acid and preparing pharmaceutically acceptable salts thereof. Process according to item 1, characterized in that (5R, 6S) -2- (4-methyl-imidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 12. A process according to item 1, characterized in that (5R, 6S) -2- (4,5-dimethylimidazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 13. The method according to item 1, characterized in that (5R, 6S) -2- [4- (2-aminoethyl) -imidazol-1-yl] -o-hydroxymethyl ^ -penem-S-carboxylic acid and pharmaceutically acceptable salts of it manufactures. 14. The method according to item 1, characterized in that one produces (5R, 6S) -2- [4-methoxyimidazol-1-yl] -ö-hydroxymethyl-Z-penem-S-carboxylic acid and pharmaceutically acceptable salts thereof. 15. The method according to item 1, characterized in that (5R, 6S) -2- [4-aminomethyl-imidazol-l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid and preparing pharmaceutically acceptable salts thereof. 16. The method according to item 1, characterized in that (5R, 6S) -2- (l, 2,4-triazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid, (5R, 6S) -2- (pyrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboic acid, (5R, 6S) -2- (pyrrol-1-yl) -6-hydroxymethyl-2- penem-3-carboxylic acid and (5R, 6S) -2- (4-methyl-pyrazol-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid. 17. The method according to item 1, characterized in that one produces (5R, 6S) -2- (imidazol-l-yl) -6 - [(lR) -l-hydroxyethyl] -2-penem-3-carboxylic acid acetoxymethylester , FO 7.4 UL / Gs * / bg * / jt * / gb *