DD260070A5 - PROCESS FOR THE PREPARATION OF AMINOACYLOXYMETHYL COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of 2-amino-acyloxymethyl-2-penem compounds of the formula I, in which R1, R2, R0 have the meaning given in the descriptive documents. The compounds according to the invention exhibit a good antibiotic activity against gram-positive and gram-negative cocci and stave bacteria. They are used as orally or parenterally administrable antibacterial antibiotics in pharmaceutical preparations. Formula I

Description

Field of application of the invention

The invention relates to a process for the preparation of 2-aminoacyloxymethyl-2-penem compounds, which show a good pharmacological activity and are therefore used in pharmaceutical preparations.

Characteristic of the known state of the art

German Offenlegungsschrift 3,312,393 describes, in the 2-position, 2-penem-3-carboxylic acids substituted by hydroxymethyl or acetoxymethyl groups, and a process for their preparation. The compounds described there show a certain antibiotic activity.

Object of the invention

The aim of the invention is to find compounds which have a good antibiotic activity against gram-positive and gram-negative cocci and rod bacteria.

Explanation of the essence of the invention

The invention has for its object to develop a process for the preparation of substituted in 2-position-2-penem-3-carboxylic acids, which show a good antibiotic activity in pharmaceutical preparations.

The definitions used below in the context of the present description preferably have the following meanings:

Functionally modified carboxyl R ₂ is, in particular, cleavable esterified carboxyl or protected carboxyl R ₂ 'under physiological conditions.

A physiologically cleavable (ie metabolizable) esterified carboxyl group R ₂ is primarily an acyloxymethoxycarbonyl group or also acylaminomethoxycarbonyl group, in which acyl ζ. Β. the balance of an organic carboxylic acid, primarily an optionally, e.g. Example by amino, substituted lower alkane carboxylic acid or arenecarboxylic acid, for. Benzoic acid, or wherein acyloxymethyl forms the residue of a lactone. Such groups are eg

Lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethylcarbonyl, and lower alkanoylaminomethoxycarbonyl. Other esterified carboxyl groups R _{2 which} can be cleaved under physiological conditions are ζ. For example, 3-Phthalidyloxycarbonyl, 1-Niederalkoxycarbonyloxyniederalkoxycarbonyl, 1-Niederalkoxyniederalkoxycarbonyl or 2-oxo-i, S-dioxolen ^ -ylmethoxycarbonyl, which is optionally substituted in the 5-position of Dioxolenringes by lower alkyl or phenyl.

An acyl group R ₄ has up to 15 carbon atoms, especially up to 7 carbon atoms, and is e.g. Example, the acyl group of a carboxylic acid, a half ester of carbonic acid of a carbamic acid, a substituted carbamic acid, a sulfonic acid of sulfamic acid or a substituted sulfamic acid. Such radicals include, for example, lower alkanoyl, lower alkanoyl substituted by hydroxy, lower alkoxy, amino, halogen, carboxy and / or cyano, benzoyl, benzoyl substituted by amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, cyano, nitro, halogen and / or lower alkyl, phenyl-lower alkanoyl, in the lower alkanoyl part by hydroxy or amino substituted phenyl, lower alkanoyl, carbamoyl or sulfo. Suitable acyl radicals R ₄ are also the acyl radicals mentioned in the amino-protecting groups, for example lower alkoxycarbonyl.

An attached via a carbon atom organic radical R ₅ has up to 18, preferably up to 10 carbon atoms and is z. B. a corresponding saturated or unsaturated lower aliphatic, saturated or unsaturated cycloaliphatic, aromatic or aromatic-lower aliphatic hydrocarbon radical or a heterocyclic or heterocyclic lower aliphatic radical.

A corresponding lower aliphatic radical R ₅ is z. B. lower alkyl, and also lower alkenyl.

A corresponding cycloaliphatic radical R ₅ is, for example, cycloalkyl or unsaturated cycloalkyl, such as cycloalkenyl or cycloalkadienyl.

As the aromatic hydrocarbon radical R _{5 is} for example a corresponding monocyclic or polycyclic, such as bicyclic radical, in particular phenyl.

An aromatic-lower aliphatic hydrocarbon radical R ₅ is, for example, phenyl-lower alkyl.

A heterocyclic radical R ₅ is in particular a corresponding monocyclic or polycyclic, in particular monocyclic or bicyclic radical, such as an optionally partially saturated monocyclic 5- or 6-membered heteroaryl radical having 1-4 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group consisting of oxygen and sulfur, z. B. a corresponding aza-, diaza-, triaza-, tetraza-, oxa-, oxaza-, oxadiaza-, oxatriaza-, thia-, thiaza-, thiadiaza- or thiatriazacyclic radical of aromatic character, or a corresponding dihydro or tetrahydro radical, also optionally partially saturated benzo, pyrido or Pyrimidoderivate such 5- or 6-membered radicals. Corresponding heteroaryl radicals R ₅ are, for example, pyrrolyl, such as 2- or 3-pyrrolyl, diazolyl, such as imidazolyl, z. 2- or 4-imidazolyl, or pyrazolyl, e.g. B. 3- or 4-pyrazolyl, triazolyl, z. For example, 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl, z. B. 1 H- or 2H-tetrazol-5-yl, pyridyl, ζ. B. 2-, 3- or 4-pyridyl, diazinyl, such as pyrimidyl, ζ. B. 2-, 4- or 5-pyrimidyl, furyl, z. B. 2- or 3-furyl, thienyl, z. B. 2- or 3-thienyl, oxazolyl, z. B. 2- or 4-Oxazolyi, oxadiazolyl, z. For example, 1,2,4-oxadiazol-3-yl or 1,3,4-oxadiazol-2-yl, isoxazolyl, e.g. 3-isoxazolyl, thiazolyl, ζ. B. 2- or 4-thiazolyl, thiadiazolyl, z. B. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or isothiazolyl, ζ. B. 3- or 4-isothiazolyl. The said 5- and 6-membered heteroaryl radicals can also be present in partially saturated form. Polycyclic derivatives of said Heteroarylreste are z. Indole-3-yl or benzimidazol-2-yl.

Heterocyclic-lower aliphatic radicals R ₅ are z. B. lower alkyl radicals which is substituted by one or two, in particular one, the above-mentioned bonded via a carbon heterocyclyl or by an optionally partially saturated monocyclic 5- or 6-membered via a ring nitrogen heteroaryl radical containing as ring heteroatoms 1-4 nitrogen atoms. The last-mentioned radicals bonded via a nitrogen atom are, for example, imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl, tetrazol-2-yl or 1-pyridino.

The said organic radicals R ₅ are unsubstituted or can be replaced, for example, by optionally etherified or esterified, including protected hydroxy, ζ. As hydroxy, lower alkoxy, lower alkanoyloxy or halogen, optionally etherified mercapto, z. Mercapto or lower alkylthio, lower alkyl; by hydroxy, lower alkoxy, optionally esterified or amidated carboxy, such as carboxy, lower alkoxycarbonyl or carbamoyl, optionally N-lower alkylated amino, for example

Amino, lower alkylamino or di-lower alkylamino, lower alkylene-amino, lower alkanoyl-amino, lower alkoxycarbonylamino optionally substituted by amino and / or carboxy, lower alkylthio or sulfo substituted lower alkyl; optionally substituted amino, ζ. Amino, lower alkylamino, di-lower alkylamino, lower alkylene-amino, guanidino, ureido, acylamino such as lower alkanoyl-amino, or lower alkoxycarbonylamino optionally substituted by amino and / or carboxy; optionally functionally modified carboxyl or sulfo, e.g. Carboxyl, esterified carboxyl, such as lower alkoxycarbonyl, amidated carboxyl, such as optionally substituted carbamoyl, e.g. B. carbamoyl or mono- or N, N-di-lower alkylated carbamoyl, cyano, sulfo or sulfamoyl, optionally z. Substituted by lower alkyl, nitro, amino, hydroxy, lower alkoxy, carboxy and / or halogen substituted phenyl, nitro, oxo and / or oxido, such as

z. B. mono- or poly-, in particular mono- or di-, also be trisubstituted.

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

Lower alkanoyloxymethoxycarbonyl is e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

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

Lower alkanoylaminomethoxycarbonyl is e.g. Acetaminomethoxycarbonyl.

1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. Aethoxycarbonyloxymethoxycarbonyl or 1-Aethoxycarbonyloxyäthoxycarbonyl. 1-lower alkoxy-lower alkoxycarbonyl is e.g. Methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

In a 2-oxo-i, 3-dioxolen-4-ylmethoxy group, which is optionally substituted in the 5-position of the dioxole ring by lower alkyl or phenyl, it is mainly a 5-phenyl and primarily a 5-methyl-2-oxo-1,3-dioxolen-4-yl ethoxy-gru ppe.

Lower alkyl is z. For example, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, n-hexyl or n-heptyl, but primarily methyl or ethyl.

Azacycloalkyl R ₀ has z. B. 3 to 8, in particular 5 or 6, ring members and is bound via the ring nitrogen atom or in particular via a ring carbon atom to the carbonyl group C (= 0) -. Such radicals are, for example, azetidinyl, e.g. Azetidin-2-yl, pyrrolidinyl, e.g. Pyrrolidin-2-yl or pyrrolidin-1-yl, and piperidinyl, e.g. B. 2-, 3- or 4-piperidinyl.

Lower alkanoyl is ζ. Formyl, acetyl or propionyl, while phenyl-lower alkanoyl e.g. Phenylacetyl is.

Lower alkoxy is ζ. B. methoxy, further ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy, and n-pentyloxy, n-hexyloxy or n-heptyloxy.

Halogen is ζ. As fluorine, chlorine, bromine or iodine.

Lower alkylamino is ζ. For example, methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while di-lower alkylamino z. As dimethylamino, diethylamino, di-n-propylamino or diisopropylamino means.

Niederalkanoylamino is z. As formylamino, acetylamino or propionylamino.

Lower alkylene Y is straight-chain lower alkylene having from T to 12 carbon atoms, in particular from 1 to 7 carbon atoms, such as methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene , 1,7-heptylene, 1,8-octylene or 1,10-decylene, or branched chain lower alkylene of 2 to 10 carbon atoms, especially 2 to 7 carbon atoms, such as lower alkyl, e.g. Methyl or ethyl, mono- or disubstituted straight-chain lower alkylene, e.g. As ethylidene, 1,2-propylene, 1,2-butylene, 1,3-butylene, 2-methyl-1,2-propylene, 3-methyl-1,3-butylene or 2-methyl-1,3- butylene, wherein the carbon atom 1 of said radicals of the carbonyl group-C (= O) or the amino group-N (R ₃ , R ₄ ) may be adjacent / phenyl-substituted lower alkylene Y has 2 to 7 carbon atoms in the lower alkyl part and is for example 1 Phenyl-1,2-ethylene or 1-phenyl-1,3-propylene, wherein the carbon atom 1 of said radicals of the carbonyl group -C (= O) - or the amino group -N (R ₃ , R ₄ ) may be adjacent ,

Lower alkenyl has 2 to 7 carbon atoms and is z. As vinyl, allyl, 2-methylallyl, n-propenyl or isopropenyl.

Cycloalkyl preferably contains 3 to 8, primarily 5 or 6 ring members and is for example cyclopentyl or cyclohexyl, furthermore cyclopropyl and cycloheptyl, while cycloalkenyl ζ. B. 5 or 6 ring members and cycloalkadienyl z. B. contains 6 ring members and z. 1-, 2- or 3-cyclohexenyl, 1- or 2-cyclopentenyl or 1,4-cyclohexadienyl.

Phenyl-lower alkyl is e.g. Benzyl, 1-phenylethyl or 2-phenylethyl.

Lower alkanoyloxy is e.g. B. formyloxy, acetyloxy or propionyloxy.

Lower alkylthio is z. As methylthio or ethylthio, and also n-propylthio, isopropylthio or n-butylthio.

Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl. '

Niederalkylenamino has in particular 4 to 6 carbon atoms and is z. As pyrrolidino or piperidino.

Optionally substituted by amino and / or carboxy Niederalkoxycarbonylamino z. As methoxycarbonylamino, Aethoxycarbonylamino or Isopropoxycarbonylamino, further 2-amino-2-carboxy-ethoxycarbonylamino.

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 means.

An optionally substituted by hydroxy or oxo lower alkylene group formed by the radicals R ₃ and R ₆ has 2 to 5 carbon atoms and is in particular}, 3-propylene, 2-hydroxy-1,3-propylene or 1 -Oxo- 1,3-propylene, in which

the carbon atom 1 of the propylene groups is adjacent to the ReSt NR ₄ .

Examples of lower aliphatic radicals R ₅ are z. B. lower alkyl, for. Methyl, ethyl, isopropyl, isobutyl or sec-butyl, or by hydroxy, lower alkoxy, e.g. Methoxy or ethoxy, lower alkanoyloxy, e.g. For example, acetyloxy, halogen, e.g. As chlorine or bromine, mercapto, lower alkylthio, z. Methylthio, amino, lower alkylamino, e.g. For example, methyl or ethylamino, di-lower alkylamino, z. B.

Dimethylamino, guanidino, ureido, lower alkanoylamino, e.g. Acetylamino, lower alkoxycarbonylamino substituted by amino and carboxy, such as ethoxycarbonylamino, e.g. For example, 2-amino-2-carboxyäthoxycarbonylamino, carboxyl, lower alkoxycarbonyl, z. B. methoxy or ethoxycarbonyl, carbamoyl, sulfo, sulfamoyl and / or oxo substituted lower alkyl, such as in particular methyl, ethyl, n-propyl or η-butyl. Representative representatives of such lower aliphatic radicals R ₅ are z. Methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1- or 2-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, aminomethyl, 1- or 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 3-guanidylpropyl, 3 -Ureidopropyl, carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, carboxyl or lower alkoxycarbonyl, such as methoxycarbonyl.

Examples of cycloaliphatic radicals R ₅ are z. B. cycloalkenyl, for example 1- or 2-cyclohexenyl, or in particular cyclohexadienyl,

z. B. 1,4-cyclohexadienyl.

Aromatic hydrocarbon radicals R ₅ are z. Phenyl or amino, lower alkenylamino, e.g. For example, methyl or ethylamino, di-lower alkylamino, z. Dimethylamino, lower alkyl, e.g. Methyl, amino-lower alkyl, e.g. For example, 2-aminoethyl, Niederalkylaminoniederalkyl, z. B. 2-Methylaminoäthyl, substituted by amino and carboxy Niederalkoxycarbonylaminoniederalkyl, z. B. 2- (2-amino-2-carboxy-äthoxycarbonylamino) ethyl, substituted by amino and carboxy Niederalkoxycarbonylamino, for example, 2-amino-2-carboxyäthoxycarbonylamino, nitro, hydroxy, lower alkoxy, ζ.Β.

Methoxy or ethoxy, halogen, e.g. As chlorine or bromine, or carboxy-substituted, in particular mono-, but also disubstituted phenyl.

Aromatic-lower aliphatic radicals R ₅ are, for example, optionally substituted phenyl-lower alkyl, such as in particular benzyl, wherein the substituents z. B. lower alkyl, such as methyl, nitro, hydroxy, lower alkoxy, ζ. Β. Methoxy or ethoxy, carboxy and / or halogen, e.g. As chlorine, are.

Heterocyclic radicals R ₅ are z. B. optionally z. Example by carboxy, lower alkyl, amino-lower alkyl or amino-substituted imidazolyl, for example 2- or 4-imidazolyl or 2-amino-4-imidazolyl, optionally z. Substituted by lower alkyl, amino, carboxy-lower alkyl and / or phenyl substituted triazolyl, such as 1 H-1,2,3-triazol-4-yl or 1 H-1,2,4-triazol-3-yl, z. B. the corresponding unsubstituted radicals, 5-methyl or 5-amino-1 H-1,2,4-triazol-3-yl, optionally substituted by lower alkyl, carboxy-lower alkyl, lower alkyl, di-lower alkylaminolower or optionally substituents, such as halogen, containing phenyl substituted tetrazolyl such as 1 H or 2H-tetrazol-5-yl, e.g. B. 1 H -tetrazol-5-yl, 1-carboxymethyl, 1- (2-carboxyethyl) -, 1- (2-Suifoäthyl) -, 1- (2-dimethylaminoethyl) - or 1-phenyl-1 H- tetrazol-5-yl, optionally z. B. substituted by lower alkyl or amino thiazolyl, such as 2- or 4-thiazolyl, z. For example, 2-thiazolyl, 2-amino-4-thiazolyl or 4,5-dimethyl-2-thiazolyl, optionally z. Substituted by amino, lower alkyl and / or phenyl substituted oxazolyl, such as 2- or 4-oxazolyl, for. B.

the corresponding unsubstituted groups, furthermore 4-methyl-2-oxazolyl or 2-amino-4-oxazolyl, optionally e.g. halo, lower alkyl or amino lower alkyl substituted furyl or thienyl such as 2- or 3-furyl or 2- or 3-thienyl, e.g. B. the corresponding unsubstituted radicals, 5-methyl or 5-aminomethyl-2-furyl, or 5-aminomethyl-2-thienyl or optionally z. Substituted by hydroxy, halogen, lower alkyl, amino and / or oxido substituted pyridyl, such as 2-, 3- or 4-pyridyl, e.g. the corresponding unsubstituted groups, 1-oxido-2-pyridyl or 4-chloro-1-oxido-2-pyridyl.

Heterocyclic-lower aliphatic radicals R ₅ are z. B. optionally substituted Heterocyclylmethyl radicals, such as. B.

gegebenenfallsz.B. lower alkyl-substituted imidazol-1-ylmethyl or-4-ylmethyl e.g. imidazol-4-ylmethyl, or

if necessary ζ. Tetrazolylmethyl substituted by lower alkyl, lower carboxyalkyl, lower alkyl, lower di-amino, lower or optionally halogen-substituted phenyl, such as 1-H-tetrazol-1-ylmethyl, H-tetrazol-1-ylmethyl or 1H-tetrazol-5-ylmethyl, e.g. B. the corresponding unsubstituted radicals, 5-amino, 5-carboxymethyl, 5- (2-carboxyethyl) -, 5-sulfomethyl-, 5- (2-dimethylamino-ethyl) -oder5-phenyl-1 H-tetrazole 1-ylmethyl, 5-amino, 5-carboxymethyl, 5-sulfomethyl, 5- (2-dimethylaminoethyl) - or 5-phenyl-2H-tetrazol-2-ylmethyl, or 1- (2-carboxyethyl) - or 1- (2-dimethylaminoethyl) -2H-tetrazol-5-ylmethyl, pyridylmethyl, such as pyridiniomethyl or 2-, 3- or 4-pyridylmethyl, furylmethyl,

z. 2-furylmethyl, thienylmethyl, e.g. 2-thienylmethyl, optionally, e.g. amino-substituted oxazolylmethyl, thiazolylmethyl or thiadiazolylmethyl, e.g. 2-amino-oxazol-4-yl-methyl, 2-amino-thiazol-4-ylmethyl or 5-amino-1,2,4-thiadiazol-3-ylmethyl, or indolylmethyl, e.g. B. indol-3-ylmethyl.

Preferred as the radical R- are hydroxymethyl and in the first place irhydroxyethyl.

Preferred cleavable under physiological conditions esterified carboxyl groups R ₂ are, for. B.

Lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and I-lower alkoxycarbonyl-lower alkoxycarbonyl, e.g. i-ethoxy-carbonyloxyäthoxycarbonyl.

In preferred compounds of the formula (I), the radical R _{0 is} the acyl radical of a natural, in particular a genetic encoded amino acid, such as. B. for the acyl of glycine, alanine, valine, leucine, isoleucine, proline, serine, threonine, methionine, phenylalanine, tryptophan, tyrosine, asparagine, aspartic acid, glutamine, glutamic acid, lysine, arginine or histidine, also for the acyl of a genetically unencoded amino acid, e.g. B. a substituted by amino and optionally additionally by phenyl, hydroxy and / or ureido substituted lower alkanecarboxylic acid having 3 to 12 carbon atoms or an optionally substituted by oxo by hydroxy Azacyclylcarbonsäure with 5 or 6 ring members in the azacyclyl ring, z. B.

β-alanine, homoserine, 2-, 3- or 4-aminobutyric acid, 2,3-diaminopropionic acid, 2,3-diaminobutyric acid, 5-aminopentanoic acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 11-aminoundecanoic acid, α- and β-aminoisobutyric acid, 3-amino-3-methylbutyric acid, 4-amino-4-methylpentanoic acid, 4-amino-1-methylbutyric acid, aminopivalic acid, 4-aminopentanoic acid, 3-amino-3-phenylpropionic acid, citrulline, ornithine, piperidine 3-yl carboxylic acid, piperidin-4-yl carboxylic acid, 3-hydroxyproline and pyrrolidin-5-one-2-carboxylic acid, and N-lower alkylated derivatives such as the N-methyl derivatives thereof, e.g. B. sarcosine. Such acyl residues can be found both in the natural, d. H. L configuration, as well as in the D configuration or as a mixture of both configurations (DL form).

The functional groups present in the compounds of the formula I, such as hydroxyl, carboxy, amino or sulfo groups, in particular the hydroxy group in the radical R ₁ and the carboxyl group R ₂ , are optionally protected by protecting 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, d. H. 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. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, TWGreene, "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, Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of the formula (I) it is possible for a hydroxy group in the radical R 1, furthermore a hydroxy group present in the radical R ₀ , to be protected, for example, by acyl radicals. Suitable acyl radicals are, for. B. optionally substituted by halogen lower alkanoyl, z. For example, acetyl, dichloroacetyl or trifluoroacetyl, optionally substituted by nitro benzoyl, z. B. benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally substituted by halogen lower alkoxycarbonyl, z. B.

2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, lower alkenyloxyoxalyl, e.g. B. allyloxyoxalyl, or optionally substituted by nitro Phenylniederalkoxycarbonyl, z. B.

Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, Further suitable hydroxy protecting groups are e.g. + B. trisubstituted silyl, such as tri-lower alkylsilyl, for example trimethylsilyl, dimethyl (2,3-dimethylbutyl) silyl or tert-butyldimethylsilyl. Preferred hydroxy protecting groups are tri-lower alkylsilyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl.

A carboxyl group R ₂ , furthermore, a carboxyl group present in the radical R ₀ , is usually protected in esterified form, wherein the ester group under mild conditions, for. B. under gently reductive, such as hydrogenolytic, or gently solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions, is easily split.

Such esterified carboxyl groups contain ester groups which are branched in the first position in the first position or suitably substituted in the 1 or 2 position. Suitable esterified carboxylic groups are, inter alia, optionally substituted by nitro or lower alkoxy, such as methoxy, substituted benzyloxycarbonyl, e.g. B.

4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, benzoylmethoxycarbonyl, wherein the benzoyl group is preferably optionally substituted, e.g. B. is substituted by halogen, such as bromine, z. Phenacycloxycarbonyl, halo-lower alkoxycarbonyl such as 2-halo-lower alkoxycarbonyl, e.g. B.

2,2,2-trichloroethoxycarbonyl or 2-bromoethoxycarbonyl, lower alkenyloxycarbonyl, e.g. B. allyloxycarbonyl, or in the 2-position by lower alkylsulfonyl, cyano or trisubstituted SiIyI, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, z. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2- (di-n-butylmethyl-silyD-ethoxycarbonyl) Preferred protected carboxyl groups R ₂ 'are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, especially allyloxycarbonyl, and 2-position by tri-lower alkylsilyl, eg, trimethylsilyl or di-n-butyl-methylsilyl, substituted ethoxycarbonyl group.

A protected amino group, e.g. B. in the radical R ₀ , may be present for example in the form of an easily cleavable acylamino group or as an azido group. In a corresponding acylamino acyl example, the acyl radical of an organic acid with z. B. up to 18 carbon atoms, in particular an optionally z. B. by halogen or phenyl, substituted lower alkanecarboxylic acid or in particular a carbonic monoester. Such acyl groups are, for example, lower haloalkanoyl, such as 2-haloacetyl, in particular 2,2,2-trifluoro or 2,2,2-trichloroacetyl, lower alkenyloxycarbonyl,

z. Allyloxycarbonyl, lower alkoxycarbonyl optionally substituted in the 1 or 2 position, such as lower alkoxycarbonyl, e.g.

Methoxycarbonyl, ethoxycarbonyl or butoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g.

4-nitrobenzyloxycarbonyl, or 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-bromoethoxycarbonyl, or 2- (trisubstituted silyloethoxycarbonyl such as 2-tri-lower alkylsilylethoxycarbonyl, ζ, 2, 2-trimethylsilylethoxycarbonylode2- (di-n-butylmethyl-silyl) -ethoxycarbonyl. Preferred protected amino groups ζ, B. azido, lower alkenyloxycarbonylamino, ζ.b. allyloxycarbonylamino, and optionally nitro-substituted benzyloxycarbonylamino.

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. As carboxyl groups, are formed and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, z. As sodium, potassium, Mangesium- or calcium salts, and ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, z. For example, triethylamine, Hydroxyniederalkylaminen, z. B. 2-Hydroxyäth.ylamin, bis (2-hydroxyethyl) amine or Tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, such as 4-aminobenzoic acid 2-diethylaminoäthylester, Niederalkylenamineh, z. For example, 1-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. B. Ν, Ν'-Dibenzyläthylendiamin, dibenzylamine or N'-benzyl-ß-phenethylamine, compounds of formula I with a basic group, for example with an amino group, acid addition salts, eg with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acid, eg. For example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid compounds of the formula I with an acidic and a basic group can also in the form of internal salts , d. H; in zwitterionic form. For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For the purposes of zo therapy, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred. The penem compounds of the formula I can have additional chiral centers in the radicals R 1, and / or R ₀ . For example, 1-hydroxyethyl may be present as substituent R ₁ 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. Further, for example, the methine carbon atom in the residue CR ₅ R _{6 may have an} asymmetric substitution and accordingly be in the R, S or racemic R, S configuration. Accordingly, the invention relates to the pure diastereomers and mixtures of the diastereomers of compounds of the formula I which have additional chiral centers in the radical R ₁ and / or R ₀ .

More particularly, the invention relates to compounds of formula I wherein Ri is lower alkyl substituted by hydroxy or protected hydroxy; R _{2 is} carboxyl, cleavable esterified carboxyl or protected carboxyl R ₂ 'under physiological conditions; R _{0 is} azacycloalkyl or a group of the formula -YN (R ₃ , R ₄ ) wherein R _{3 is} hydrogen or lower alkyl; R _{4 is} hydrogen, lower alkyl, lower alkanoyl, lower alkanoyl substituted by hydroxy, lower alkoxy, amino, halogen, carboxy and / or cyano; Benzoyl, benzoyl substituted by amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, halo, nitro, cyano and / or lower alkyl, phenyl-lower alkanoyl, phenyl-lower alkanoyl substituted in the lower alkanoyl moiety by amino or hydroxy, carbamoyl, sulfo or an amino protecting group, and Y is straight chain lower alkylene containing 1 to Wherein R ₆ is lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl, a monocyclic-bonded via a ring carbon atom, or 6-membered optionally partially saturated heteroaryl radical having 1-4 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group oxygen and sulfur, for. B. a corresponding aza-, diaza-, triaza-, tetraza-, oxa-, oxaza-, oxadiaza-, oxatriaza-, thia-, thiaza-, thiadiaza- or thiatriaza-cyclic radical of aromatic character, or a corresponding dihydro- or Tetrahydrorest, or an optionally partially saturated benzo, pyrido or pyrimido derivative of such a 5- or 6-membered radical, or a bonded via a ring carbon monocyclic 5- or 6-membered optionally partially saturated heteroaryl having 1-4 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group of oxygen and .Schwefel, or is a substituted by a bonded via a ring nitrogen atom monocyclic, 5-or 6-membered optionally partially saturated heteroaryl having 1-4 ring nitrogen atoms, lower alkyl which R is unsubstituted ₅ or substituted by hydroxy, lower alkoxy, lower alkanoyloxy Halogen, mercapto, lower alkylthio, given when lower alkyl substituted by hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, optionally N-lower alkylated amino, lower alkyleneamino, lower alkanoylamino, optionally substituted by amino and / or carboxy substituted lower alkoxycarbonylamino, mercapto, lower alkylthio or sulfo; Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, guanidino, ureido, lower alkanoylamino, optionally substituted by amino and / or carboxy Niederalkoxycarbonylamino, carboxyl, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-lower alkylated carbamoyl, cyano, sulfo, sulfamoyl, optionally substituted by Lower alkyl, nitro, amino, hydroxy, lower alkoxy, carboxy and / or halogen substituted phenyl, nitro, oxo and / or oxido are substituted; or wherein R ₅ together with R ₃ optionally denote by hydroxy or oxo substituted lower alkylene, and R _{6 is} hydrogen or lower alkyl, the pure optical isomers of compounds of formula I, which have in the radical R ₁ and / or R ₀ chiral centers, mixtures thereof optical isomers and salts of those compounds of formula I which have a salt-forming group.

The invention relates mainly to compounds of the formula (I) in which R ₁ in α-position by hydroxy, Triniederalkylsilyloxy, Niederalkenyloxyoxalyloxy or Niederalkenyloxycarbonyloxy substituted lower alkyl, R _{2 is} carboxyl, 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, in the 2-position by tri-lower alkylsilyl-substituted ethoxycarbonyl or a under physiological conditions cleavable esterified carboxyl group and R ₀ for the acyl radical of a genetically encoded amino acid or for the acyl radical of ß-alanine, homoserine, 2-, 3- or 4-aminobutyric, 2,3-diaminopropionic, 2,3-diaminobutyric , 5-aminopentanoic acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 11-aminoundecanoic acid, α- or β-aminoisobutyric acid, 3-amino-3-methylbutyric acid, 4-amino-4-methylpentanoic acid, 4-amino-1-one methyl butyric acid, aminopivalic acid, 4-aminopentanoic acid, 3-amino-3-phenyl-propionic acid, citrulline, ornithine, piperidin-3-yl-carboxylic acid, piperidin-4-ylcarb onic acid, 3-hydroxyproline or pyrrolidone-5-one-2-carboxylic acid or an N-lower alkyl derivative of such an acyl radical, the pure diastereomers of compounds of formula (I), in the radical R ₁ and / or R ₀ chiral centers , mixtures of such diastereomers, and salts of those compounds of formula (I) having a salt-forming group.

The invention relates in particular to compounds of the formula (I) in which R _{1 is} hydroxymethyl or 1-hydroxyethyl, R _{2 is} carboxyl or, under physiological conditions, cleavable esterified carboxyl and R _{0 is} glycyl, alanyl, lysyl, β-alanyl, 2,3 Diaminopropionyl, S-amino-S-methyl-butyryl, 4-aminobutyryl or an N-methyl derivative of such an aminoacyl radical, the pure diastereomers of compounds of formula (I) wherein R 1 is hydroxyethyl and or which have a center of chirality in the radical R ₀ , mixtures of such diastereomers, and salts of those compounds of the formula (I) which have a salt-forming group.

The invention relates in the first place to compounds of the formula I in which R _{1 is} I-hydroxyethyl, R _{2 is} carboxyl or, under physiological conditions, cleavable esterified carboxyl and R _{0 is} β-alanyl, 3-amino-3-methyl-butyryl or 4- Aminobutyryl, and salts thereof.

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

According to the invention, the 2-amino-acyloxymethyl-3-penem compounds of the formula I

Il

GH ₂ -OCR ₀

(D,

wherein R ₁ is lower alkyl substituted by hydroxy or protected hydroxy, R _{2 is} carboxyl or functionally modified carboxyl, R _{0 is} azacycloalkyl or a group of the formula -YN (R ₃ , R ₄ ) wherein R _{3 is} hydrogen or lower alkyl, R ₄ Is hydrogen, lower alkyl or acyl; and Y is lower alkylene, phenyl-substituted lower alkylene, or a radical of the formula -CR ₅ R ₅ ^ - wherein R _{5 is} an organic radical bonded through a carbon atom or together with R ₃ optionally substituted by oxo or hydroxy substituted lower alkylene and R _{6 is} hydrogen or lower alkyl, the pure optical isomers of compounds of formula (I) and mixtures of these optical isomers, salts of compounds of formula (I) having a salt-forming group, prepared by a) in a compound of the formula

.CH ₂ -Q

in which R- has the meaning given under formula (I), R ₂ 'is a protected carboxyl group and Q is a group which can be converted into R ₀ -Cf = O) -O, the group Q in R ₀ -Ct = O) -O-, or b) an ylide compound of the formula

Ri

^ SC-CH ₂ -O

-C-R

(III)

wherein R- and R _{0 have} the meanings given under formula I, R ₂ 'is a protected carboxyl group, Z is oxygen or sulfur and X® represents either a trisubstituted phosphoniogroup or a doubly esterified phosphono group together with a cation, or; c) a compound of the formula

Ri

H ^ SC-CH ₂ -O-

-C-R

(IV),

= 0

wherein R ₁ and R _{0 have} the meanings given under formula I, Z is oxygen or sulfur and R ₂ 'is a protected carboxyl group, treated with an organic compound of trivalent phosphorus, and if desired or necessary, in an available compound of formula I. a protected functional group in the free functional group

transferred, and / or, if desired, converted in an available compound of formula I, a free carboxyl group R ₂ in a cleavable under physiological conditions esterified carboxyl group, and / or, if desired, in an available compound of formula I is a radical R ₀ in converting another group Ro, and / or, if desired, separating an available mixture of isomeric compounds of formula I into the individual isomers, and / or, if desired, an available compound having a salt-forming group in a salt or an obtainable salt in the group transferred free compound or into another salt, and, if desired, processed an available compound of formula I or a pharmaceutically acceptable salt thereof to a pharmaceutical preparation.

In the starting compounds of the formulas H-IV are functional groups, such as free hydroxyl groups, for. B. in the radical R-i, and free amino groups preferably by conventional protecting groups, for. Protected by one of the above, a) substitution of the radical Q.

A group Q which can be converted into a radical R ₀ -CI = O) -O- is, in particular, hydroxyl or a group exchangeable by nucleophilic reaction. Groups which are exchangeable by nucleophilic reaction Q are in particular esterified hydroxy groups, such as by a hydrohalic acid, a di-lower alkyl or diaryl phosphoric acid, a lower alkanecarboxylic acid optionally substituted by oxo or halogen, a lower alkane optionally substituted by halogen or benzenesulfonic acid optionally substituted by halogen or lower alkyl. Such groups Q are z. As halogen, such as chlorine, bromine or iodine, di-lower alkyl or Diarylphosphoryloxy, z. For example, dimethyl, diethyl or Diphenylphosphoryloxy, optionally substituted by halogen or oxo substituted lower alkanoyloxy, z. B. formyloxy, acetyloxy or acetacetyloxy, optionally substituted by halogen Niederalkansulfonyloxy, z. Methanesulfonyloxy or trifluoromethanesulfonyloxy, or optionally substituted by halogen or lower alkyl substituted benzenesulfonyloxy, e.g. B. benzenesulfonyloxy, 4-chloro, 4-bromo or 4-methylbenzenesulfonyloxy.

The reaction of a compound of the formula (II) in which Q is a nucleophilic-reactive group is carried out, for example, with a carboxylic acid of the formula R ₀ -COOH (V) or for the preparation of a compound of the formula I in which R _{0 is} the group -YN (R ₃ , R ₄ ), with a carboxylic acid of the formula

HO-C-Y-N 1 - (V),

wherein functional groups in the radical R ₀ or in the radicals R ₃ , R ₄ and Y are in protected form, to form a salt thereof in the presence of at least equimolar amounts of a basic condensing agent, for example an alkali metal lower alkanolate, for. Sodium methoxide or potassium tert-butoxide, or an alkali metal hydride or amide, e.g. For example, sodium hydride or sodium amide, in an inert solvent, for. As an ether, such as dioxane or tetrahydrofuran, or an amide, ζ. As formamide or dimethylformamide, when using alkali metal lower alkanols in the corresponding lower alkanol, or solvent mixture at room temperature or reduced or slightly elevated temperature, for. , At about -60 ° C to about + 40 ° C, particularly at about -20 ⁰ C to about +30 ⁰ C, if necessary in an inert gas, such as nitrogen atmosphere.

It is also possible to acylate the hydroxy group Q in a compound of the formula II in which Q is hydroxy by reaction with an acylating agent introducing the acyl radical of a carboxylic acid of the formula V or V, respectively.

An acylating agent which introduces the acyl radical of a carboxylic acid of the formula V or V is either the carboxylic acid of the formula V or V itself or a reactive functional derivative thereof.

If a free acid of the formula V or V is used for acylation, the reaction is usually carried out in the presence of suitable condensing agents, such as carbodiimides, for example N, N'-dicyclohexylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as Ethyl 5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline, optionally in the presence of a base such as a pyridine derivative, e.g. 4-dimethylaminopyridine.

A reactive, ie an ester-forming, functional derivative of a carboxylic acid of formula V or V is primarily an anhydride, preferably a mixed anhydride. For example, a mixed anhydride is formed by condensation with another acid, e.g. As an inorganic acid, eg. As a hydrohalic acid, is formed and, for example, the corresponding carboxylic acid halide, z. As the carboxylic acid chloride or bromide. A mixed anhydride is further formed by condensation with hydrazoic acid and is, for example, the carboxylic acid azide. Other inorganic acids which are useful for forming mixed anhydrides are phosphorus-containing acids, e.g. As phosphoric acid, diethyl phosphoric acid or phosphorous acid, sulfur-containing acids, eg. As sulfuric acid, or hydrocyanic acid. A reactive functional derivative of a carboxylic acid of the formula V or V is also a corresponding activated ester, for example, by condensation with a vinylogous alcohol, ie with an enol, for. B. a vinylogous Niederaikenol, is formed, a Iminomethylesterhalogenid, z. B. Dimethyliminomethylesterchlorid prepared from the carboxylic acid of formula V or V and z. B. Dimethyl-Cl-chloräthylidenHminiumchlorid of the formula [(CH ₃ ) ₂ N® = C (CI) CH ₃ ] CI ⁹ , which in turn z. B. from Ν, Ν-dimethylacetamide and phosgene or oxalyl chloride, an aryl ester, ζ. Β. a by halogen, z. As chlorine, and / or nitro substituted phenyl, z. A pentachloro, 4-nitrophenyl or 2,4-dinitrophenyl ester, an N-heteroaromatic ester, e.g. B. N-Benztriazolester, or an N-Diacyliminoester, z. An N-succinimino or N-phthalimino ester.

The acylation with a reactive functional derivative of the carboxylic acid of the formula V or V, z. B. with a corresponding anhydride, in particular an acid halide, is preferably carried out in the presence of a suitable acid-binding agent, for example a suitable organic base. A suitable organic base is, for example, an amine, e.g. B. a tertiary amine, such as tri-lower alkylamine, z. B. trimethylamine, triethylamine or ethyldiisopropylamine, or a Ν, Ν-Diniederalkylanilin, z. B. Ν, Ν-dimethylaniline, or a cyclic tertiary amine, for. B. an N-lower alkylated morpholine, eg. N-methylmorpholine, or is, for example, a pyridine-type base, e.g. For example pyridine. A suitable acid-binding agent is also an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for. For example, sodium, potassium or calcium hydroxide, carbonate or bicarbonate.

The acylation with a carboxylic acid of the formula V or V or a reactive, functional derivative thereof is preferably carried out in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxamide, such as a formamide, for. For example, dimethylformamide, a halogenated hydrocarbon, eg. As methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, z. As acetone, cyclic ether, z. For example, tetrahydrofuran, an ester, for. For example, ethyl acetate, or a nitrile, for. As acetonitrile, or in mixtures thereof, if necessary or desired, at reduced or elevated temperature, for. Example, in a temperature range of about -40 ⁰ C to about + 100 ⁰ C, preferably about -2O ⁰ C to about +50 ⁰ C, and, if necessary, in an inert gas, z. B. nitrogen atmosphere. In the starting compounds of the formula V or V are functional groups present in the radicals R ₁ , R ₃ , R ₄ and Y, z. As carboxyl, amino or hydroxyl groups, by one of the above-mentioned protecting groups, for. As carboxyl, amino or hydroxyl protecting groups, b) cyclization of the compound of formula III

The group X® in the starting material of formula III is one of the commonly used in Wittig condensation reactions phosphonio or phosphono, in particular a triaryl, z. B. triphenyl, or Triniederalkyl-, z. Tri-n-butylphosphonio group, or a lower alkyl, e.g. For example, ethyl, doubly esterified phosphono group, where the symbol X® in the case of the phosphono group additionally the cation of a strong base, in particular a suitable metal such as alkali metal ion, z. As the lithium, sodium or potassium ion comprises. Preferred as group X® are on the one hand Triphenylphosphonio and on the other hand Diäthylphosphono together with an alkali metal, z. B. the sodium ion.

In phosphonio compounds of formula III, the negative charge is neutralized by the positively charged phosphonium group. In phosphono compounds of the formula III, the negative charge is neutralized by the cation of a strong base, which depends on the method of preparation of the phosphono starting material z. As an alkali metal, z. As sodium, lithium or potassium, may be. The phosphono starting materials are therefore used as salts in the reaction. The ring closure can spontaneously, ie in the preparation of the starting materials, or by heating, for. B. in a temperature range of about 3O ⁰ C to 160 ⁰ C, preferably from about 8O ⁰ C to about 110 ° 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. As cyclohexane, benzene or toluene, a halogenated hydrocarbon, eg. As methylene chloride, or an ether, z. Diethyl ether, dioxane or tetrahydrofuran, or in a mixture thereof, and, if necessary, in an inert gas, e.g. B. nitrogen atmosphere performed

c.) Cyclization of the compound of formula IV

An organic compound of trivalent phosphorus is derived z. B. of phosphorous acid and in particular an ester thereof with a lower alkanol, for. For example, methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, for example phenol or pyrocatechol, or an amide ester thereof of the formula P (OR _a ) ₂ N (R _b ) ₂ , wherein R _a and R _{b are} independently lower alkyl, z , Methyl, or aryl, e.g. As phenyl, mean. Preferred compounds of trivalent phosphorus are tri-lower alkyl phosphites, e.g. B. trimethyl phosphite or triethyl phosphite. The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. As benzene or toluene, an ether, z. As dioxane or tetrahydrofuran, or a halogenated hydrocarbon, eg. As methylene chloride or chloroform, at a temperature of about 20 ⁰ C to 140 ⁰ C, preferably at about 40 ° C to about 110 ⁰ C, carried out, wherein reacting 1 molar equivalent of a compound of formula IV with 2 molar equivalents of the phosphorus compound. The compound of the formula IV is preferably initially introduced in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a prolonged period, for. For a period of up to 4 hours.

In a preferred embodiment of the process, the starting material of the formula IV 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.

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

In an available compound of formula I, wherein one or more functional groups are protected, these, for. As protected carboxyl, hydroxyl and / or amino 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 gradually or simultaneously.

In a compound of the formula I obtainable by the process in which R _{2 represents} a protected carboxyl group and / or in which the radical R 0 contains protected carboxyl as a substituent, the protected carboxyl group can be released in a manner known per se. For example, ethoxycarbonyl substituted in the 2-position by a trisubstituted silyl group may be converted to free carboxyl by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid, optionally with addition of a nucleophilic compound such as phenol or anisole. Optionally substituted benzyloxycarbonyl may e.g. B. by hydrogenolysis, ie by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst are cleaved. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by means of chemical reduction, for. By treatment with an alkali metal, e.g. As sodium dithionite, or with a reducing metal, for. Tin, usually in the presence of a hydrogen donating agent which is capable of producing nascent hydrogen together with the metal, such as a suitable carboxylic acid, e.g. B. an eventual, z. B. substituted by hydroxy, lower alkanecarboxylic, z. As acetic acid, or an alcohol or thiol, preferably adding water, convert into free carboxyl. The cleavage of an allyl protecting group may, for. B. by reaction with a compound of palladium, z. B. tetrakis (triphenylphosphine) palladium, optionally in the presence of triphenylphosphine and with the addition of an allyl group acceptor, such as a carboxylic acid, eg. 2-ethylhexanoic acid, or a salt thereof, or dimedone or tributyltin hydride. 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 benzoylmethoxycarbonyl into free carboxyl, while benzoylmethoxycarbonyl also by treating 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. B.

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 to free carboxyl, a lower alkoxycarbonyl group substituted at the 2-position by lower alkylsulfonyl or cyano. By treatment 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, into free carboxyl.

On the other hand, compounds of the formula I in which R _{2 is} carboxyl can also be converted into compounds of the formula I in which R _{2 represents} an esterified carboxyl group which can be cleaved under physiological conditions. So you can the free carboxyl group z. Example, by reacting with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, z. As dicyclohexylcarbodiimide, or 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.

In compounds of the formula I obtainable in accordance with the process in which the radical R 1 and optionally the radical R ₀ contain 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 group is released as an appropriately protected amino group (see below); a tri-lower alkylsilyl group may e.g. B. are split off with tetrabutylammonium fluoride and acetic acid (under these conditions protected by trisubstituted silylethoxy carboxy groups are not cleaved).

In a compound of the formula I according to the invention with a protected amino group, this can be prepared in a manner known per se, for. B. depending on the nature of the protecting group, preferably by means of solvolysis or reduction, are converted into 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) or 4-nitrobenzyloxycarbonylamino may be cleaved 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 in the presence of a palladium catalyst become. 4-Nitrobenzyloxycarbonylamino can also be obtained by treatment with an alkali metal, ζ. As 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. B. tetrakis (triphenylphosphine) palladium, optionally in the presence of triphenylphosphine and in the presence of an allyl group acceptor, such as a carboxylic acid, ζ. For example, 2-ethylhexanoic acid, or a salt thereof or dimedone or tributyltin hydride, are cleaved. One represented by 2-halo-lower alkanoyl, e.g. 2-Chloroacetyl, protected amino group can be released by treatment with thiourea in the presence of a base or with a salt such as an alkali metal salt, the thioureas and subsequent solvolysis such as alcoholysis or hydrolysis of the resulting condensation product. 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, eg tetraethylammonium fluoride, are converted to the free amino group converted free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium, or by treatment with zinc in the presence of an acid such as acetic acid.

In compounds of the formula I in which R _{0 is} the group -YN (R ₃ , R ₄ ), it is also possible to convert one radical R ₃ and / or Y into another radical R ₃ and / or R ₄ and / or Y. ,

Thus, for example, in compounds of formula I in which the radical Y is substituted by a carboxyl group, this carboxyl group according to known methods in a functionally modified carboxyl group, such as. In an esterified carboxyl group or in optionally substituted carbamoyl. For example, by reacting a compound of the formula I in which Y is a group of the formula -CR ₅ R ₆ - and R _{5 is} an organic radical substituted by carboxy, with a lower alkanol there is obtained a compound of the formula I wherein Y is a group of the formula -CR ₅ R ₆ - is and R _{5 is} a substituted by lower alkoxycarbonyl organic radical, wherein preferably in the presence of a suitable condensing agent, for. As a carbodiimide, works or the resulting water z. B. removed by azeotropic distillation. On the other hand, one can carboxyl groups in the radical Y in reactive functional derivatives such as mixed anhydrides, eg. As acid halides, or activated esters, and convert them by reacting with a lower alkanol, ammonia or a primary or secondary amine, for. As a lower alkyl or di-lower alkylamine, in accordance with 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 (hetero) aryl group in the radical R _{0 has} a hydroxyl group, it can be etherified in the usual way. The reaction to the corresponding lower alkyl (hetero) aryl ethers takes place, for example, in the presence of bases, such as alkali metal hydroxides or carbonates, ζ. As sodium hydroxide or potassium carbonate, with the aid of Diniederalkylsulfaten or Niederalkylhalogeniden. Furthermore, hydroxy can be converted into esterified hydroxy, eg lower alkanoyloxy, for example by reaction with the reactive derivative of a corresponding lower alkanecarboxylic acid, eg. 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. For example pyridine. The conversion of lower alkanoyloxy to hydroxy is carried out, for example, by alcoholysis or, preferably, hydrolysis, e.g. B. by base-catalyzed hydrolysis, eg. In the presence of sodium hydroxide.

In compounds of formula I having a free amino group, the amino group may be substituted into a substituted amino group, e.g. For example, a Niederalkylamino-, Diniederalkylamino-, Niederalkylenamino- or Niederalkanoylaminogruppe be transferred. The conversion into a Niederalkylamino- or Diniederalkylaminogruppe takes place 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 an alkali or alkaline earth metal or a heteroaromatic nitrogen base, ζ. For example pyridine. In an analogous manner, amino may be prepared by treatment with a lower alkylene dihalide or disulfonate in lower alkylene amino and by treatment with the reactive functional derivative of a lower alkanecarboxylic acid, e.g. As the corresponding carboxylic acid halide, be converted into Niederalkanoylamino. Compounds of the formula I having a substitutable ring nitrogen atom in the radical R ₀ can be converted in the same manner into compounds of the formula I which contain, in the radical R _0, a ring nitrogen atom substituted by an optionally substituted lower alkyl radical. Furthermore, compounds of formula I wherein R _{4 is} hydrogen may be prepared by reacting with an acyl radical of a carboxylic acid, a haloester of carbonic acid, an optionally substituted carbamic acid, sulfonic acid or amidosulfonic acid, e.g. B. an acid halide of such an acid, for. The chloride or bromide thereof, preferably in the presence of an acid-binding agent, such as one of those mentioned above, are converted into compounds of formula I wherein R _{4 is} acyl.

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 with 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. As the sodium salt of a-Äthylcapronsäure, or with inorganic alkali or alkaline earth metal salts, eg. As sodium bicarbonate, or form 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 customary, for. Example by treatment with a suitable acid or a suitable Anionenaustauscherreagenz. Internal salts of compounds of formula I may, for. By neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. B. with weak bases, or by treatment with ion exchangers are formed. Salts can usually be converted to the free compounds. Metal and ammonium salts z. B. by treatment with suitable acids and acid addition salts, for. 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 resulting racemate 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, absorption chromatography) and the individual diastereomeric compounds then converted into the optically active Split connections.

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

The process also includes those embodiments in which intermediate compounds 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 IV can be prepared as indicated in Reaction Scheme I below:

Reaction scheme I

Γ V (VI) step 1 T V (VII) ι -hü ) Level 2 step 3 / / j *

Rr-: τ Rr

σc = o

R ₂ ¹ ° (VIII) R ₂ '(IV)

Level 4

ti ··· "T T

</ \ ^θ -χ ^Θ

(III ¹ )

In the compounds of the formulas III ", VII and VIII, W stands for R ₀ or for triphenylmethylthio or lower alkanoylthio

Geeigente starting compounds of formula IV, wherein W is an easily exchangeable by nucleophilic reaction radical, z. B, lower alkanoyloxy, such as acetyloxy, or sulfonyloxy R-SO ₂ -, wherein R, for example, optionally substituted by hydroxy-substituted lower alkyl, such as methyl, tert. Butyl or 2-hydroxyethyl, are known, for example, from published European Patent Application No. 82113, German Offenlegungsschrift No. 3224055 and German Offenlegungsschrift No. 3013997 or can be prepared analogously thereto.

A compound which introduces the residue SC (= 2) -CH ₂ -PC (= O) -R ₀ is, for example, an acid of the formula R ₀ -Cf = O) -O-CH ₂ Cf = Z) -SH or, in particular Salt, z. 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, a lower alkanecarboxamide, a cyclic ether, or in a similar inert solvent at room temperature or at a slightly elevated or reduced temperature, e.g. B. at about 0 ° C to about 4O ⁰ C, are performed. The introduction of a triphenylmethylthio or lower alkanoylthio radical W is carried out in an analogous manner by reacting with an alkali metal salt, for. B. the sodium salt, a Niederalkanthiocarbonsäure, z. As thioacetic acid, or the Triphenylmethylmercaptans. Level 2

A starting compound of the formula (IV) is obtained by reacting an azetidinone of the formula (VII) in which W 'is the radical -S-Cl = Z) -CH ₂ -O-Cf = O) -R ₀ an acid of the formula R ₂ -COOH or, in particular, a reactive derivative, such as an ester or acid halide, e.g. Example, the acid chloride, thereof at a temperature of -5O ⁰ C to 80 ⁰ C, preferably at -20 ⁰ C to 0 ° C, in an inert solvent, such as one of in the reaction of compounds of formula (IV) to compounds of formula I, treated. When using an acid halide, it is preferable to work in the presence of an acid-binding agent, such as a tertiary aliphatic amine, an aromatic amine, or especially an alkali metal or alkaline earth metal carbonate or bicarbonate.

Compounds of the formula (VII) in which W 'is triphenylmethylthio or lower alkanoylthio can be converted into the starting compounds of the formula VII in which W' for the ReSt-S-Cf = Z) -CH ₂ -O-Cf = O) -R ₀ in the presence of a base, for example pyridine or tri-n-butylamine, in a suitable solvent, for example diethyl ether or methanol, with a salt of the formula MA in which M is a transition metal cation, in particular the silver cation, and A represents a common anion / which promotes the solubility of the salt MA in the chosen solvent, e.g. As the nitrate, acetate or fluoride anion, and the resulting salt of the formula

? .SM

with an acylating agent which introduces the radical R ₀ -C f = O) -O-CH ₂ C f = Z), for example with an acid R ₀ -Cf = O) -O-CH ₂ -Cf = Z) -OH or a reactive one functional derivative such as an acid halide, eg the chloride or bromide, azide or anhydride thereof. The acylation takes place when a reactive functional derivative of the acid of the formula R ₀ -Cf = O) -O-CH ₂ -Cf = Z) -OH, for example the acid chloride, is used in an inert solvent, such as a chlorinated hydrocarbon, or an ether, at room temperature or under heating or cooling, e.g. B. in a temperature range of about -50 ⁰ C to about +60 ⁰ C, in particular at about -30 ⁰ C to about +20 ⁰ C.

level 3

Compounds of formula VIII, wherein X _{0 is} a reactive esterified hydroxy group, in particular halogen, z. Chloro or bromo, are prepared by reacting a compound of formula VII with a glyoxylic acid compound of the formula R ₂ '--CHO or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, e.g. B. a hemiacetal with a lower alkanol, z. As methanol or ethanol, and in an obtained compound of formula VIII, wherein X _{0 is} hydroxy, the hydroxy group converts to a reactive esterified hydroxy group. The compounds of formula VIII are usually obtained as a mixture of the two isomers [with respect to the group -CH (R ' ₂ ) ~ X ₀ ]. The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound of formula VII takes place at room temperature or, if necessary, with heating. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is purified by distillation, e.g. B. azeotrope, or by using a suitable dehydrating agent is removed. The reaction is preferably carried out in the presence of a suitable inert solvent or solvent mixture.

The conversion of a hydroxy group X ₀ into a reactive esterified hydroxy group X ₀ in a compound of formula VIII is carried out by treatment with a suitable esterifying agent, e.g. With a thionyl halide, e.g. Chloride, preferably in the presence of a basic, primarily organic, basic agent such as an aliphatic tertiary amine, or a pyridine-type heterocyclic base. Preference is given to working in the presence of a suitable solvent, for. As dioxane or tetrahydrofuran, or a solvent mixture, if necessary with cooling, for. At about -30 ° C to about 30 ° C

Level 4

The starting material of formula III is obtained by reacting a compound of formula VIII with a suitable phosphine compound, such as a tri-lower alkyl phosphine, e.g. Tri-n-butyl-phosphine, or a triaryl-phosphine, e.g. Triphenylphosphine, or with a suitable phosphite compound, such as a tri-lower alkyl phosphite, eg, triethyl phosphite, or an alkali metal lower alkyl phosphite, e.g. B. diethyl phosphite, and an optionally available compound of formula III "wherein W 'is Triphenylmethylthio or Niederalkanoylthio converted into a compound of formula IN" (= III), wherein W' for the ReSt-S-Cf = Z ) -CH ₂ -O-Cf = O) -R ₀ .

The reaction with a phosphine or phosphite compound is preferably carried out in a suitable inert solvent, such as a hydrocarbon, or an ether or in a solvent mixture. Depending on the reactivity is carried out under cooling or at elevated temperature, for example between -10 ⁰ C and +100 ' ⁰ C, preferably at about 20 ⁰ C to 80 ⁰ C. Usually, one works in the presence of a basic agent, such as an organic base, for example, an amine, or "polystyol-Hünigbase", or an inorganic base, for example an alkali metal carbonates, wherein the primary resulting phosphonium compound of the formula

-14- 260 Ü7Ü

(purple),

wherein X 'is a phosphono group or a phosphonium group together with an anion, depending on the meaning of the radical X ₀ (see formula VIII) ζ. As chloride, is converted into the ylide starting material of the formula IM.

The introduction of the radical -S-Cf = Z) -CH ₂ -O-Cl = O) -R ₀ in compounds of the formula ΙΙΓ in which W 'is lower alkanoylthio or triphenylmethylthio can be carried out in an analogous manner as described under step 2 ,

The starting compounds of the formula II can z. Example, be prepared by reacting a phosphorane of the formula

^S SC-CH ₂ -Q

Kl. F

- ·

which can be synthesized in an analogous manner as shown in Reaction Scheme I, e.g. as described under method b).

The process described in Reaction Scheme I for the preparation of the compounds of the formulas (III), (IV), (VII) and (VIII), as well as the stated process for the preparation of the compounds of the formula II and the end products of the formula (I) can also be used perform with optically inactive compounds and isolate the optically active compounds of the present invention in a known manner from any obtained diastereomeric mixture or racemate at any stage of the process.

The invention likewise relates to the novel starting compounds and to novel intermediates obtainable by the process, such as those of the formulas H-IV, furthermore VII and VIII (W 'is the radical-SC (= Z) -CH ₂ -O-C (= 0) - Ro and the specified methods for their preparation.

Preferably, such starting compounds are used and the reaction compounds are selected so that one arrives at the compounds of the formula I 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 Ri is lower alkyl substituted by hydroxy, R _{0 has} the meanings given under formula I, wherein functional groups are in unprotected form, and R _{2 represents} carboxyl or a cleavable esterified carboxyl group, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial effects. For example, they are in vitro against gram positive and gram negative cocci, including methicillin resistant staphylococci, e.g. Staphylococcus aureus. Streptococcus pyogenes. Streptococcus pneumoniae and Streptococcus faecalis, in minimal concentrations of about 0.05 to about δμς / ηηΙ and against Gram-negative rod bacteria, such as Enterobacteriaceae, Haemophilus influenzae and Pseudomonas aeruginosa, and anaerobic beer, e.g. B.

Bacteroides sp., In minimum concentrations of about 0.05 to about 16 ^ g / ml. In vivo, in the systemic infection of the mouse, z. B. by Staphylococcus aureus, resulting in subcutaneous or oral administration of compounds of the invention ED ₆₀ values of about 2.5 to about 10 mg / kg.

The new compounds can be administered as orally or parenterally administrable antibacterial antibiotics, eg. B. in the form of corresponding pharmaceutical preparations for the treatment of infections 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. B. be used for the preparation of pharmaceutical preparations containing a therapeutically effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients, which can be used for oral and parenteral, d. H. z. Intramuscular, intravenous, 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 Polyäthylenglykoi have.

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 or adsorbents, dyes, flavors or sweeteners.

For parenteral administration, infusion solutions are preferred, preferably isotonic aqueous solutions or suspensions, e.g. from lyophilized preparations containing the active substance alone or together with a carrier material, eg. As mannitol, can be prepared before use. Such preparations may be sterilized and / or adjuvants, eg. As 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 conventional manner, for. Example by means of conventional Mischuhgs-, solution or lyophilization process, prepared and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active ingredient.

Depending on the nature of the infection and condition of the infected organism, one uses daily doses (oral or parenteral) of about 100 mg to about 1 g for the treatment of warm-blooded animals (humans and animals) of about 70 kg in weight.

embodiments

The following examples serve to illustrate the invention. Temperatures are given in degrees centigrade.

Example 1:

(5R, 6S) -2- (2,2,2-trichloroethoxycarbonyloxy-methyl) -6 - ((1R) 1-allyloxycarbonyloxyethyl) -2-penem-3-carboxylic acid allyl ester A solution of 0.46 g 2 - ((3S, 4R) -3 - ((1R) -I-Allyloxycarbonyloxyethyl) -4- (2,2,2-trichloroethoxycarbonyloxyacetylthio) -2-oxoazetidin-1-yl) -2-triphenylphosphoranylidenessigsäureallyll ester in 46 ml of toluene under argon atmosphere for 3 hours stirred at reflux temperature. Then the solvent is evaporated off and the crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 9: 1). R _f (toluene / ethyl acetate 1: 1) = 0.8. IR (CH ₂ Cl ₂ ): 1795; 1765; 1745;

The starting material can be prepared as follows:

2 - [(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyäthyl] -4- (2,2,2-trichloräthoxycarbonyloxyacetylthio) -2-oxo-azetidin-1-yl} 2-triphenylphosphoranylideneacetate

8 g of silver salt of 2- [3S, 4R) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1-yl] -2-triphenylphosphoranylidenessigsäureallylesters be dissolved in 100 ml of methylene chloride, at 0 ⁰ C with 1.85 ml of pyridine, 80 mg of 4-dimethylaminopyridine and then treated dropwise with a solution of 5.4 g of 2,2,2-Trichloräthoxycarbonyloxyacethylchlorid in 50 ml of methylene chloride. After stirring for 45 minutes at 0 °, the solid is filtered off over Hyflo and the filtrate is washed with aqueous sodium bicarbonate solution and then with brine. After drying over MgSO ₄ , the solvent is evaporated. The residue is purified by chromatography on silica gel (eluent toluene / ethyl acetate 15:85 to 1: 1).

TLC (toluene / ethyl acetate 1: 1) R _f = 0.5;

IR (CH ₂ Cl ₂ ): 1765; 1750; 1705; 1620cm " ¹ .

Example 2:

(5R, 6S) -2-hydroxymethyl-6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester.

A solution of allyl 0,23g (5R, 6S) -2- (2,2,2-trichloroethoxycarbonyloxymethyl) -6 - [(1R) -1-allyloxycarbonyoxethyl] -2-penem-3-carboxylate in 5 ml abs. Tetrahydrofuran and 0.46 ml of an aqueous 1 M potassium dihydrogen phosphate solution is mixed with 0.41 g of zinc dust and stirred for 5 hours at room temperature. The suspension is filtered through Hyflo and the filtrate is then concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The title substance is purified by chromatography on silica gel. (Eluent: toluene / ethyl acetate 95: 5 to 90:10). TLC (toluene / ethyl acetate 1: 1) R _f = 0.38; IR (CH ₂ Cl ₂ ): 3600; 1795; 1750; 1705; 1580cm " ¹ .

Example 3: (5R, 6S) -2- (N-Allyloxycarbonylglycyloxymethyl) -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic Acid Allyl Ester A solution of 179 mg (5R, 6S) -2-hydroxymethyl- 3 ml of absolute methylene chloride are admixed with 80 mg of N-allyloxycarbonylglycine and 2 mg of 4-dimethylaminopyridine at room temperature, and 113 mg of dicyclohexylcarbodiimide are added after cooling the solution to ⁰ ° C. The suspension is stirred for 5 minutes at 0 ° C. and then for 3 hours at room temperature The solid is filtered off, washed and the filtrate is washed with aqueous sodium bicarbonate and brine After drying over sodium sulfate, the organic phase is completely evaporated Title substance is purified by chromatography on silica gel (eluent toluene / ethyl acetate 95: 5) TLC (toluene / ethyl acetate 1: 1) R _f = 0.4

IR (CH ₂ Cl ₂ ): 3440; 1792; 1745; 1725; 1585 cm " ¹ .

Example 4: (SR.eSl ^ -glycyloxymethyl-e-tfiRM-hydroxyethyl) -penic-S-carboxylic acid A solution of 0.66g (5R, 6S) -2- (N-allyloxycarbonylglycyloxymethyl) -6 - [(1R) 81 ml of tetrakis-triphenylphosphine palladium and 1.4 ml of tributyltin hydride are added to 1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester in 26 ml of absolute THF After stirring for 2 hours at room temperature, 0.33 ml of acetic acid is added dropwise and more are added After concentrating on a rotary evaporator, the residue is taken up in water-ethyl acetate and neutralized with NaHCO _3. The aqueous phase is taken up twice more with ethyl acetate and neutralized with NaHCO _3. The aqueous phase is washed twice with ethyl acetate and washed on Purification by chromatography on Opti UPC, ₂ (eluent water) gives the title substance, TLC (Opti UPd ₂ , water) R, = 0.43

IR (DMSO-d ₆ ): 3428; 2969; 1776; 1755; 1619cm " ¹

UV (water): \ _max : = 308nm.

Example 5:

(SR ^ S ^ -P-in-Allyloxycarbonylaminol-propionyloxy-methyne e-KIRJ-i ^ allyloxycarbonyloxyäthyll penem-a-carboxylate

213 mg of S-fN-allyloxycarbonylaminotr-propionic acid are converted into the title compound analogously to Example 3 by reaction with (5R, 6S) -2-hydroxymethyl-6 - [(1R) -1-allyioxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester.

IR (CH ₂ Cl ₂ ): 3450; 1795; 1745; 1725; 1240cm " ¹ .

The starting material can be prepared as follows:

3- (N-allyloxycarbonylamino) propionic acid

A solution of 17.8 g of β-alanine in 100 ml of 5N-sodium hydroxide solution and 50 ml of water is added at 0 ° and admixed with 23.3 ml allyl chloroformate for 10 minutes. The reaction mixture is then stirred for 12 hours at room temperature, washed twice with ethyl acetate and adjusted to pH 2 with 2N HCl. After extracting twice with ethyl acetate, the combined extracts are washed with brine, dried over sodium sulfate and evaporated. IR (CH ₂ Cl ₂ ): 3445; 2950; 1720; 1230cm " ¹ .

Example 6: (SR.e.sub.1) S-aminopropionyloxymethyl-e-IlI-R-i-hydroxyethylpiperpene-S-carboxylic acid In analogy to Example 4, 0.43 g of (5R, 6S) -2- [3- (N-allyloxycarbonylamino) -propionyloxymethyl] -6 - [(1 R) -1-allyloxycarbonyloxyethylphenyl -penem-S-carboxylic acid allyl ester is converted to the title compound, IR (DMSO-d _e ): 3300; 2969; 1774; 1736; 1617; 1585; 1356 cm ^-1

UV (water): \ _max : = 308nm.

Example 7:

(5R, 6S) -2 - [(2S) -N _a , N _E -Bis (allyloxycarbonyl) -lysyloxymethyl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester

Analogously to Example 3, 387 mg (2S) -N _a , N _! -Bis (allyloxycarbonyl) -lysine by reaction with (5R, 6S) -2-hydroxymethyl-6 - [(1 Rl-i-allyloxycarbonyloxyäthyll ^ -penem-S-carboxylic acid allylester converted into the title compound.

IR (CH ₂ Cl ₂ ): 3440; 1795; 1750; 1725; 1240cm " ¹ .

The starting material can be prepared as follows:

(2S) -N _a , N _e -bis (allyloxycarbonyl) -lysine

Apart from the fact that 2 mol of allyl chloroformate and 1 mol of amino acid are used, the title compound is prepared in the same way as 3- (N-allyloxycarbonylamino) -propionic acid (see Example 5).

IR (CH ₂ Cl ₂ ): 3445; 2960; 1725; 1515cm " ¹ .

Example 8: (5R, 6S) -2 - [(2S) -Lysyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid.

Analogously to Example 4, 0.55 g of (5R, 6S) -2 - [(2S) -N _a , N _s -bis (allyloxycarbonyl) -lysyloxymethyl] -6 - [(1R) -1-allyloxycarbonyloxyäthyU ^ -penem-S -carbonsäureallylester converted into the title compound. IR (DMSO-D ₆ ): 3434; 2934; 1773; 1732 and 1617; 1360cm " ¹

UV (water): A _max : = 307nm.

Example 9:

(ΒΒ, βΒί-Ζ- ^ Β, εΐ ^^ - Βίβ-ΐΒΐΙγΙοχγοβΛοηνίΒΓηϊηοΙ-ρΓορΐοηνΙοχγΓηβΐΗνΠ-β- ^ ΙΡί-Ι-βΙΙνΙοχγοΒΛοηνΙοχγθΐΗνΙΙ-Ζ-ρβηΘηι ^ -carbonsäureallylester

Analogously to Example 3, 335 mg of (2R, S) -2,3-bis (allyloxycarbonylamino) propionic acid are converted into the title compound.

IR (CH ₂ Cl ₂ ): 3430; 1795; 1720; 1585cm " ¹ .

Apart from the fact that 2MoI allyl chloroformate and 1 mol of amino acid are used, the starting material, (2R, S) -2,3-bis (allyloxycarbonylamino) propionic acid, in an analogous manner as 3- (N-allyloxycarbonylamino) propionic acid (see Example 5).

IR (CH ₂ Cl ₂ ): 3440; 1710; 1505; 1220cm " ¹ .

Example 10: (5R, 6S) -2 - [(2R, S) -2,3-diaminopropionyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid Analogously to Example 4, 0.2 g (5R, 6S) -2 - [(2R, S) -2,3-Bis- (allyloxycarbonylamino) -propionyloxymethyl] -6 - [(1R) -1-allyloxycarbonyloxyethyl} -piperime-S-carboxylic acid allyl ester is converted to the title compound , IR (DMSOd ₆ ): 3430; 2972; 1775; 1750; 1620cm " ¹

UV (water): \ _max : = 307nm.

Example 11: (5R, 6S) -2 - [(2S) -1-Allyloxycarbonyl-prolyloxymethyl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic Acid Allyl Ester Analogously to Example 3, 1.5 g (2S) - 1-allyloxycarbonylproline converted into the title compound.

IR (CH ₂ Cl ₂ ): 1792; 1715; 1585cm " ¹ .

The starting material, (2S) -1-allyloxycarbonylproline, is prepared analogously to 3- (N-allyloxycarbonylamino) -propionic acid (see Example 5).

IR (CH ₂ Cl ₂ ): 2960; 1705; 1410cm " ¹ .

Example 12:

{5R, 6S) -2 - [(2S) -Prolyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid

Analogously to Example 4, 0.7 g of (5R, 6S) -2 - [(2S) -1-allyloxycarbonylprolyloxymethyl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-

allyl penem-3-carboxylate is converted into the title compound.

UV (water): K _max : = 305nm.

Example 13:

(SR.eSJ-e-i-TDRi Allyloxycarbonyloxyäthylj ^ -f ^ iN-allyloxycarbonylaminol-butyryloxymethyl ^ penem-S-carboxylate)

Analogously to Example 3, 0.98 g of 4- (N-allyloxycarbony-amino) -butyric acid are obtained by reaction with (5R, 6S) -2-hydroxymethyl-6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3. carboxylic allyl ester in the title compound. IR (CH ₂ Cl ₂ ): 3450, 1795, 1750, 1720, 1590 cm " ¹ .

Example 14: (SR.eSI) -t ^ aminobutyryloxymethyO-e-CCIRJ-i-hydroxyethylppenem-S-carboxylic acid Analogously to Example 4, 3,15g (5R, 6S) -6 - [(1 RJ-i-allyloxycarbonyloxyethyl] Allyl (W-N-allyloxycarbonylamino) -butyryloxymethyl] -2-penem-3-carboxylate is converted to the title compound, IR (DMSO-d ₆ ): 3349; 1787; 1742; 1619 cm ^-1 , UV (water): A _max : = 306nm.

Example 15:

(5R, 6S) -6- [(1R) -1-Allyloxycarbonyloxyethyl I] -2- [5- (N-allyloxycarbonylamino) pentanoyloxymethyl I] -2-penem-3-carboxylic acid allyl ester)

By analogy with Example 3, 0.31 g of (S-i-N-allyloxycarbonylaminol-pentanoic acid) is converted into the title compound by reaction with (5R, 6S) -2-hydroxymethyl-6 - [(IRl-i-allyloxycarbonyloxyethyl) -penem-S-carboxylic acid allyl ester IR (CH ₂ Cl ₂ ): 3430; 1792; 1750; 1718; 1590 cm ^-1 .

Example 16:

(5R, 6S) -2- (5-Aminopentanoyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic Acid Analogously to Example 4, 0.5 g (5R, 6S) -6 - [( 1 Rl-i-allyloxycarbonyloxyethyl J ^ -IB-fN-allyloxycarbonylamino) -pentanoyloxymethyl] -2-penem-3-carboxylic acid allyl ester) was converted to the title compound. IR (DMSO-de): 3439; 1774; 1733; 1618cm " ¹ UV (water): \ _max : 307nm.

Example 17:

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

(SR ^ SJ-e-hydroxymethyl ^ -sarcosyloxymethyl ^ -penic-S-carboxylic acid, UV (water) K _max : = 307 nm.

(BRjeSt-e-hydroxymethyl ^ -glycyloxymethyl ^ -penem-S-carboxylic acid, UV (water) A _max : = 307nm.

(5R, 6S) -6-hydroxymethyl-2 - [(2S) -alanyloxymethyl] -2-penem-3-carboxylic acid, UV (water) A _max : = 308nm.

(5R, 6S) -6-hydroxymethyl-2 - [(2S) -prolyloxymethyl] -2-penem-3-carboxylic acid, UV (water) A _max : = 308nm, IR (DMSO-d ₆ ): 3305, 1778, 1620cm " ¹ .

(5R, 6S) -2- (6-aminohexanoyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, IR (DMSO-d _e ): 3435; 1780; 1735; 1618cm " ¹ , UV (water) A _max : = 306nm.

(5R, 6S) -2- (8-aminooctanoyloxamethyl) -6 - [(1R) -hydroxyethyl] -2-penem-3-carboxylic acid, IR (DMSO-d ₆ ): 3437; 1776; 1740; 1620cm " ¹ , UV (water) A _max : = 307nm.

(5R, 6S) -2- (11-aminoundecanoyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, IR (DMSO-d ₆ ): 3435; 1780; 1738; 1619cm " ¹ , UV (water) A _max : = 307nm.

(5R, 6S) -2 - [(3R, S) -3-aminobutyryloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307 nm, IR (DMSO-de): 3440, 1775, 1735, 1617 cm " ¹ .

(5R, 6S) -2- (3-Amino-3-methyl-butyryloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307 nm,

IR (DMSO-d ₆ ): 3438, 1775, 1734, 1618cm " ¹ '."

(5R, 6S) -2-r (2R, S) -3-amino-2-methylpropionyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max :

307 nm, IR (DMSO-d ₆ ): 3440, 1777, 1734, 1618 cm " ¹ .

(5R, 6S) -2 - [(3R, S) -3-amino-3-phenylpropionyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 308 nm, IR (DMSO-d ₆ ): 3439, 1774, 1734, 1617 cm ^-1 .

(5R, 6S) -2 [(2S) -valyloxymethyl] -6- [1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 308nm, (DMSO-d ₆ ): 3299, 1778, 1745, 1620cm " ¹ .

(5R, 6S) -2 - [(2R) -valyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 308nm, IR ( DMSO-d _e ): 3427, 1778, 1745, 1621cm " ¹ .

(5R, 6S) -2 - [(2S) -Alanyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 308 nm, IR ( DMSO-de): 3435, 1776, 1750, 1620cm " ¹ .

(5R, 6S) -2 - [(2 R, alanyloxymethyl-e-tdRJ-i-hydroxyethyl) -penic-S-carboxylic acid, UV (H ₂ O) A _max : 308 nm, IR (KBr): 3184.1776 , 1760,1602cm " ¹ .

(5R, 6S) -2 - [(4R, S) -4-aminopentanoyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307nm,.

IR (DMSO-d ₆ ): 3435, 1775, 1735, 1618 cm " ¹ .

(5R, 6S) -2- (4-amino-4-methylpentanoyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307nm, IR (DMSO-de): 3481,1776,1738,1618cm " ¹ .

(5R, 6S) -2 - [(2R, S) -4-Amino-2-methyl-butyryloxymethyl] -6 - [(1R) -hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O ) A _max : 307nm, IR (DMSO-de): 3439, 1775, 1730, 1618cm " ¹ .

(5R, 6S) -2 - [(2R, S) -4-Amino-2-methyl-butyryloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _{ma! T} : 307nm, IR (DMSO-d ₆ ): 3439, 1775, 1730, 1618cm " ¹ .

(SR ^ SJ ^ -O-amino ^^ - dimethylpropionyloxymethylie-tdRi-i-hydroxyethyl) -penic-S-carboxylic acid, UV (H ₂ O) A _max : 307nm, IR (DMSO-de): 3435, 1775, 1733 , 1618cm " ¹ .

(5R, 6S) -2- (2-amino-2-methylpropionyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307nm , IR (DMSO-d _e ): 3431, 1777, 1745, 1619 cm " ¹ .

(5R, 6S) -2-sarcosyloxymethyl-6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 307 nm, IR (DMSO-d ₆ ): 3307, 1778,1752,1618cm " ¹ .

5R, 6S) -2- (N-methyl-N-methoxycarbonyl-glycyloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max :

307 nm, IR (DMSO-d ₆ ): 3427, 1772, 1748, 173, 1618 cm " ¹ .

(5R, 6S) -2 - [(4R, S) -piperidin-4-ylcarbonyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 306nm, IR (DMOS-d ₆ ): 3435,1774,1731,1618cm " ¹ .

(5R, 6S) -2 - [(3R, S) -piperidin-3-ylcarbonyloxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (H ₂ O) A _max : 306 nm, IR (DMSO-d ₆ ): 3439, 1775, 1730, 1618 cm " ¹ .

Example 18: Dry ampoules or vials containing 0.5 g of (5R, 6S) -2- (4-aminobutyryloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid as an active substance are treated as follows:

Composition (for 1 ampoule or vial):

Active substance 0.5g

Mannitol 0.5g

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

Instead of the above-mentioned active ingredient, the same amount of another active ingredient of the preceding examples may also be used.

Claims (10)

claims: 1. A process for the preparation of compounds of the formula I 1, - CH ₂ -OCR ₀ (D. wherein Ri is lower alkyl substituted by hydroxy or protected hydroxy, R _{2 is} carboxyl or functionally modified carboxyl, R _{0 is} azacycloalkyl or a group of the formula -YN (R ₃ , R ₄ ) wherein R _{3 is} hydrogen or lower alkyl, R _{4 is} hydrogen , Lower alkyl or acyl and Y is lower alkylene, phenyl-substituted lower alkylene or a radical of the formula -CR ₅ R ₆ -is, in which R _{5 is} an organic radical bonded via a carbon atom or together with R ₃ optionally substituted by oxo or hydroxy-substituted lower alkylene and R _{6 is} hydrogen or lower alkyl, the pure optical isomers of compounds of the formula I, mixtures of these optical isomers and salts thereof, characterized in that
a) in a compound of the formula - K / in which Ri has the meaning given under formula (I), R ₂ 'is a protected carboxyl group and Q is a group which can be converted into R ₀ -C (= O) -O, the group Q in R ₀ -C (= O) -O-converted, or b) an ylide compound of the formula H g SC-CH ₂ -OCR Vx ^@ wherein R ₁ and R _{0 have} the meanings given under formula I, R ₂ 'is a protected carboxyl group, Z is oxygen or sulfur and X® represents either a trisubstituted phosphoniogroup or a doubly esterified phosphono group together with a cation, ring closure, or
c) a compound of the formula HH .SC-CH ₂ -OCR ι · / ü O (IV), wherein R ₁ and R _{0 have} the meanings given under formula I, Z is oxygen or sulfur and R ₂ 'is a protected carboxyl group, treated with an organic compound of trivalent phosphorus, and if desired or necessary, in an available compound of formula I. converting a protected functional group into the free functional group, and / or, if desired, converting, in an available compound of formula I, a free carboxyl group R ₂ into a physiologically-cleavable esterified carboxyl group, and / or, if desired, in one obtainable Compound of formula I converts one radical R ₀ into another radical R ₀ , and / or, if desired, a obtainable mixture of isomeric compounds the forms! Separating I into the individual isomers, 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, if desired, an available compound of the formula I or a pharmaceutically acceptable salt thereof is processed into a pharmaceutical product. Process according to claim 1, characterized in that compounds of formula I wherein R ₁ is lower alkyl substituted by hydroxy or protected hydroxy; R _{2 is} carboxyl, cleavable esterified carboxyl or protected carboxyl R ₂ 'under physiological conditions; R _{3 is} azacycloalkyl or a group of the formula -YN (R ₃ , R ₄ ) wherein R _{3 is} hydrogen or lower alkyl; R _{4 is} hydrogen, lower alkyl, lower alkanoyl, lower alkanoyl substituted by hydroxy, lower alkoxy, amino, halogen, carboxy and / or cyano; Benzoyl, benzoyl substituted by amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, halo, nitro, cyano and / or lower alkyl, phenyl-lower alkanoyl, phenyl-lower alkanoyl substituted in the lower alkanoyl moiety by amino or hydroxy, carbamoyl, sulfo or an amino protecting group, and Y is straight chain lower alkylene 1 to 12 carbon atoms, branched chain lower alkylene of 2 to 10 carbon atoms, phenyl-substituted lower alkylene or a group of the formula -CR ₅ R ₆ - wherein R ₅ is lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl, one via a Ring carbon atom bonded monocyclic 5- or 6-membered optionally partially saturated heteroaryl radical having 1-4 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group oxygen and sulfur, or an optionally partially saturated benzo, pyrido or pyrimido derivative of such 5 or 6-membered radical, or a bonded through a ring carbon monocyclic 5- or 6-membered optionally partially saturated heteroaryl having 1-4 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group oxygen and sulfur, or a bonded through a ring nitrogen atom monocyclic, 5- or 6-membered optionally partially saturated heteroaryl having 1-4 ring nitrogen atoms substituted lower alkyl group which R ₅ is unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, optionally substituted by hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, optionally N-lower alkylated amino, lower alkyleneamino, lower alkanoylamino, lower alkoxycarbonylamino optionally substituted by amino and / or carboxy, lower alkylthio or sulfo substituted lower alkyl; Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, guanidino, ureido, lower alkanoylamino, lower alkoxycarbonylamino optionally substituted by amino and / or carboxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N-mono or N, N-di-lower alkylated carbamoyl, cyano, sulfo, sulfamoyl, optionally substituted by Lower alkyl, nitro, amino, hydroxy, lower alkoxy, carboxy and / or halogen substituted phenyl, nitro, oxo and / or oxido are substituted; or wherein R _{5 3} is optionally substituted by hydroxy or oxo is substituted lower alkylene together with R, and R ₆ is hydrogen or lower alkyl, the pure optical isomers of compounds of formula I, which have ₀ chiral centers in the remainder of Ri and / or R, mixtures of these optical Isomers and salts of those compounds of formula I, which have a salt-forming group produces. Process according to claim 1, characterized in that compounds of the formula I in which R 1 is α-substituted by hydroxy, tri-lower alkylsilyloxy, lower alkenyloxyoxalyloxy or lower alkenyloxycarbonyloxy, R _{2 is} carboxyl, 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, substituted in the 2-position by tri-lower alkylsilyl Aethoxycarbonyl or an esterified carboxyl group cleavable under physiological conditions and R _{0 is} the acyl radical of a genetically encoded amino acid, or the acyl radical of O-alanine, homoserine, 2-, 3- or 4-aminobutyric acid, 2,3-diaminopropionic acid, 2, 3-diaminobutyric acid, 5-aminopentanoic acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 11-aminoundecanoic acid, α- or β-aminoisobutyric acid, 3-amino-3-methylbutyric acid, 4-amino-4-methylpentanoic acid, 4-amino-1 -methyl-butyric acid, aminopivalic acid, 4-aminopentanoic acid, 3-amino-3-phenylpropionic acid, citrulline, ornithine, piperidin-3-ylcarboxylic acid, Piperidin-4-yl-carboxylic acid, 3-hydroxyproline or pyrrolidin-5-one-2-carboxylic acid or an N-lower alkyl derivative of such an acyl radical, the pure optical isomers of compounds of formula I which in the radical R ₁ and or have chiral centers. Mixtures of these optical isomers and salts of those compounds of formula I, which have a salt-forming group produces. 4. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} hydroxymethyl or 1-hydroxyethyl, R _{2 is} carboxyl or cleavable under physiological conditions esterified carboxyl and R _{0 is} glycyl, alanyl, lysyl, ß- Alanyl, 2,3-diaminopropionyl, 3-amino-3-methyl-butyryl, 4-aminobutyryl or an N-methyl derivative of such an aminoacyl radical, the pure diastereomers of compounds of formula I, wherein Ri is 1-Hydroxyäthyi and / or having a chiral center in the radical R ₀ , mixtures of such diastereomers, and salts of those compounds of the formula I which have a salt-forming group. 5. The method according to claim 1, characterized in that compounds of formula I, wherein R _{1 is} 1-hydroxyethyl, R _{2 is} carboxyl or cleavable under physiological conditions esterified carboxyl and R ₀ isßß-alanyl, 3-amino-3-methyl butyryl or 4-aminobutyryl, and produces salts thereof. Process according to claim 1, characterized in that it produces (5R, 6S) -2-glycyloxymethyl-6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid. 7. Process according to claim 1, characterized in that the (5R, 6S) -2 - [(1S) -lysyloxymethyl] -6 - [(1R) -1-hydroxyethyl)] - 2-penem-3 produces carboxylic acid. 8. The method according to claim 1, characterized in that one prepares the (5 R, 6S) -2- (3-aminopropionyloxymethyl) -6 - [(1 R) -1-hydroxyethyl] -2-penem-3-carboxylic acid. 9. The method according to claim 1, characterized in that one prepares the (5 R, 6S) -2 - [(2R, S) -2,3-Diaminopropionyloxymethyll-e-fdRj-i-hydroxyäthyll ^ -penem-S-carboxylic acid , A process according to claim 1, characterized in that the (5R, 6S) -2 - [(2S) -polyoxymethyl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid is prepared. 11. The method according to claim 1, characterized in that one prepares the (5R, 6S) -2- (4-aminobutyryloxymethyl) -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid. 12. The method according to claim 1, characterized in that the (5 R, 6S) -2- (3-amino-3-methyl-butyryloxymethyl) -6 - [(1 R) -1-hydroxyethyl] -2-penems 3-carboxylic acid produces.