DD236097A5 - PROCESS FOR THE PREPARATION OF NEW AMINO ALKYLPENEM COMPOUNDS - Google Patents

Abstract

A process for the preparation of compounds of the formula wherein R1 is hydroxy or protected hydroxy, R2 is carboxyl or functionally modified carboxyl, R3 is amino, lower alkyl substituted amino, lower alkanoylamino, substituted methyleneamino or protected amino, R4 is optionally amino, lower alkyl substituted amino , substituted methyleneamino, protected amino, hydroxy or protected hydroxy substituted methyl or ethyl, and m is an integer from 1 to 3, optical isomers of compounds of formula I, mixtures of such optical isomers and salts of such compounds of formula I, which have a salt-forming group are described. The novel compounds producible according to the invention have antibiotic properties and can z. B. in the form of antibiotically effective preparations for the treatment of infectious diseases. Formula (I)

Description

Field of application of the invention

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

Characteristic of the known technical solutions

From European Patent Application 3960 and from US Pat. No. 4,274,437 2-penem-3-carboxylic acids having antibiotic activity and processes for their preparation have been disclosed in the 6-position by hydroxy-lower alkyl and in the 2-position by straight-chain amino-lower alkyl.

Object of the invention

The aim of the invention is to provide processes for the preparation of new, in position 6 by hydroxy and lower alkyl substituted in the 2-position by branched chain amino-2-substituted 2-penem-3-carboxylic acids with valuable pharmacological properties and of pharmaceutical preparations containing such compounds.

Explanation of the essence of the invention

The object of the present invention is to find, starting from easily accessible starting compounds, novel antibiotically active 2-amino-lower alkyl penem compounds and processes for their preparation. According to the invention 2-amino-lower alkyl-2-penem compounds of the formula

- (CH ₂ ) -CH-R ₃ (I)

wherein Ri is hydroxy or protected hydroxy, R ₂ is carboxyl or functionally modified carboxyl, R _{3 is} amino, lower alkyl substituted amino, lower alkanoylamino, substituted methyleneamino or protected amino, R _{4 is} optionally amino, lower alkyl substituted amino, substituted methyleneamino, protected amino , Hydroxy or protected hydroxy is substituted methyl or ethyl, and m is an integer of 1 to 3, optical isomers of compounds of formula I, mixtures of such optical isomers and salts of those compounds of formula I having a salt-forming group prepared ,

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

Functionally modified carboxy R ₂ is z. B. protected carboxyl R ₂ 'or cleavable under physiological conditions esterified carboxyl.

A cleavable under physiological conditions esterified carboxyl group protects the compounds of formula I from salt formation in the gastrointestinal tract when administered orally, thus preventing premature excretion, and is primarily a Acyloxymethoxycarbonylgruppe or acylaminomethoxycarbonyl, wherein 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 for. Lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a- amino-lower alkanoyloxymethoxycarbonyl, lower alkanoylaminomethoxycarbonyl, benzaminomethoxycarbonyl, 4-crotonolactonyl and 4-butyrolactone-4-yl. Further esterified carboxyl groups which can be cleaved under physiological conditions are ζ. 5-indanoyloxycarbonyl, phthalidyloxycarbonyl, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, 1

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By lower alkyl substituted amino is z. B. lower alkylamino or di-lower alkylamino.

In substituted methyleneamino, the ethylene radical is preferably mono- or disubstituted. Substituted methyleneamino is z. B. a group of the formula

wherein X _{1 is} hydrogen, optionally substituted amino, z. As amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, ζ. B. lower alkoxy or Phenylniederalkoxy, etherified mercapto, ζ. Lower alkylthio, optionally substituted lower alkyl, e.g. Lower alkyl, lower alkylamino, lower alkylamino, lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl bonded via a ring carbon, such as corresponding 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms and / or one oxygen or sulfur atom, like pyridyl, ζ. B. 2- or 4-pyridyl, thienyl, z. B. 2-thienyl, or thiazolyl, ζ. 4-thiazolyl, and X _{2 is} optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, eg lower alkoxy or phenyl-lower alkoxy, or etherified mercapto, e.g. B. lower alkylthio represents.

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

Lower alkanoyloxymethoxycarbonyl is e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

a-Aminoniederalkanoyloxymethoxycarbonyl is z. B. Glycyloxymethoxycarbonyl, L-Valyloxymethoxycarbonyl or L-Leucyloxymethoxycarbonyl.

Niederalkanoylaminomethoxycarbonyl is z. B. acetaminomethoxycarbonyl.

1-lower alkoxycarbonyloxy-lower alkoxycarbonyl is ζ. Aethoxycarbonyloxymethoxycarbonyl or 1-Aethoxycarbonyloxyäthoxycarbonyl.

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

In a 2-oxo-i, S-dioxolen ^ -ylmethoxycarbonyl group which is optionally substituted in the 5-position of the dioxene ring by lower alkyl or phenyl, it is mainly a 5-phenyl and especially a 5 -Methyl 2-oxo!, S-dioxolen ^ -ylmethoxycarbonyl group.

Lower alkylamino is e.g. Methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while di-lower alkylamino z. As dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino.

Niederalkanoylamino is z. As formylamino, acetylamino or propionylamino.

Niederalkylenamino has in particular 4 to 6 carbon chain members and means z. As pyrrolidino or piperidino.

Lower alkoxy is z. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy, while phenyl-lower alkoxy z. B.

Benzyloxy is.

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

Lower alkyl is z. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl.

Amino-lower alkyl is z. For example, 2-aminoethyl or 3-aminopropyl.

N-lower alkylamino-lower alkyl is e.g. For example, 2-methyl or 2-Aethylaminoäthyl, while Ν, Ν-Diniederalkylaminoniederalkyl z. B.

2-dimethylaminoethyl or 2-diethylaminoethyl.

Lower alkenyl is z. Allyl, n-propenyl or isopropenyl.

Preferred, cleavable under physiological conditions esterified carboxyl groups R ₂ are ζ. Phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. B. 1-Aethoxycarbonyloxyäthoxycarbonyl.

In preferred methyleneamino groups of the formula IA as the radical R ₃ or as substituent of the radical R 4, Χ 1 is hydrogen, amino or lower alkyl, such as methyl, and X _{2 is} amino.

Preferred radicals R ₄ are, for example, methyl, ethyl, aminomethyl, aminoethyl, such as 1- or 2-aminoethyl, hydroxymethyl and hydroxyethyl, such as 1- or 2-hydroxyethyl.

The functional groups present in the compounds of the formula I, such as hydroxyl, carboxy or amino groups, in particular the hydroxy group R ₁ , the hydroxy group as a substituent of a radical R ₄ 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",

Plenary 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 ", Volume 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of the formula (I) it is possible for a hydroxyl group R ₁ , furthermore a hydroxy group present in the radical R ₄ , to be protected, for example, by acyl radicals. Suitable acyl radicals are, for. B. optionally substituted by halogen lower alkanoyl, z. B.

Acetyl or trifluoroacetyl, optionally nitro substituted benzoyl, e.g. B. benzoyl, 4-nitrobenzoyl or 2,4-Dinitrobenzoyi, optionally substituted by halogen lower alkoxycarbonyl, z. B. 2-Bromäthoxycarbonyl or 2,2,2, -Trichloräthoxycarbonyl, Niederalkenyloxycarbonyl, z. Allyloxycarbonyl, lower alkenyloxyoxalyl, e.g. B. allyloxyoxalyl, or optionally substituted by nitro Phenylniederalkoxycarbonyl, z. For example, 4-nitrobenzyloxycarbonyl. Further suitable hydroxy protective groups are, for. B. trisubstituted SiIyI, such as Triniederalkylsilyl, z. B. trimethylsilyl or tert-butyl-dimethylsilyl, 2-Halogenniederalkylgruppen, z. For example, 2-chloro, 2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally by Halnnen 7 R

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Chlorine, lower alkoxy, ζ. For example, methoxy, and / or nitro substituted phenyl, such as benzyl corresponding. Preferred as hydroxy protecting group is tri-lower alkylsilyl, halo-lower alkoxycarbonyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl.

A carboxyl group R ₂ is usually protected in esterified form, the ester group under mild conditions,

z. B. under gently reductive, such as hydrogenolytic, or gently solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions, is easily split. A protected carboxyl group may further represent an esterified carboxyl group easily converted into another functionally modified carboxyl group such as another esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups primarily in the 1-position branched or in the 1- or 2-position suitably substituted lower alkyl groups. Preferred esterified carboxylic groups include lower alkoxycarbonyl, e.g. B. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl, and (hetero) arylmethoxycarbonyl having 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally

z. B. by lower alkyl, such as tert-lower alkyl, z. For example, tert-butyl, halogen, z. As chlorine, and / or nitro mono- or polysubstituiert. Examples of such groups are optionally z. As mentioned above, substituted benzyloxycarbonyl, z. B. 4-Nitrobenzyloxycarbonyl, optionally, for. As mentioned above, substituted diphenylmethoxycarbonyl, z. B.

Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. As mentioned above, substituted picolyloxycarbonyl, z. 4-picolyloxycarbonyl, or furfuryloxycarbonyl such as 2-furfuryloxycarbonyl. Further suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably present, for. B. represented by halogen, such as bromine, substituted benzoyl, z. Phenacycloxycarbonyl, halo-lower alkoxycarbonyl such as 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or omega-halo-lower alkoxycarbonyl wherein lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. B.

Allyloxycarbonyl, or substituted in the 2-position by lower alkylsulfonyl, cyano or trisubstituted SiIyI, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl.

Other protected carboxyl groups present in esterified form are corresponding organic silyloxycarbonyl, furthermore corresponding organic stannyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, in particular methyl or ethyl, furthermore lower alkoxy, z. As methoxy, as substituents. Suitable SiIyI or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stannyl groups, for. B. tri-n-butylstannyl.

Preferred protected carboxyl groups R ₂ 'are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, especially allyloxycarbonyl, and the 2-substituted by lower alkylsulfonyl, cyano or tri-lower alkylsilyl, e.g. B. trimethylsilyl or di-n-butyl-methyl-silyl, substituted Aethoxycarbonylgruppe.

A protected amino group R ₃ or protected amino as a substituent in the radical R ₄ may be present for example in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, SiIyI or stannylamino group or as an enamino, nitro or azido group.

In a corresponding acylamino group acyl, for example, the acyl radical of an organic acid with z. B. up to 18 carbon atoms, in particular a e.g. by halogen or phenyl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester.

Such acyl groups are, for example, lower haloalkanoyl, such as 2-haloacetyl, especially 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally substituted benzoyl, eg. Benzoyl, halobenzoyl such as 4-chlorobenzoyl, lower alkoxybenzoyl such as 4-methoxybenzoyl, or nitrobenzoyl such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl, z. B. allyloxycarbonyl, or optionally in the 1- or 2-substituted lower alkoxycarbonyl suitable, such as lower alkoxycarbonyl, for. Methoxy or ethoxycarbonyl, optionally substituted benzyloxycarbonyl,

z. Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is optionally substituted, e.g. B. represented by halogen, such as bromine, substituted benzoyl, z. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl-1-ethoxycarbonyl such as 2-tri-lower alkylsilylethoxycarbonyl, e.g., 2-trimethylsilylethoxycarbonyl or 2- (di-n -butylmethyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl radical of an organic dicarboxylic acid with z. B. up to 12 carbon atoms, in particular a corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is primarily phthalimino.

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

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which the silicon or

Tin atom, preferably lower alkyl, e.g. Methyl, ethyl, η-butyl or tert-butyl, further lower alkoxy, e.g. Methoxy, as a substituent. Corresponding SiIyI or stannyl groups are primarily tri-lower alkysilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butylsilyl, or correspondingly substituted stannyl, ζ. B. tri-n-butylstannyl.

Other protected amino groups are, for. B. enamino groups which contain an electron-withdrawing substituent on the double bond in the 2-position, for example a carbonyl group. Protecting groups of this type are, for example, i-acyl-lower-alk-i-en-2-yl radicals in which acyl ζ. B. the corresponding radical of a lower alkanecarboxylic acid, for. B.

Acetic acid, an optionally, z. Example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro-substituted benzoic acid, or in particular a carbonic monoesters, such as a Kohlensäureniederalkylhalbesters, for example methyl-ethyl ester or -ethyl, and Niederalk-1 in particular 1-propene means.

Corresponding protecting groups are primarily i-lower alkanoylprop-i-en-2-yl, e.g. i-acetyl-prop-i-en-2-yl, or 1-lower alkoxycarbonyl-prop-i-en-2-yl, e.g. i-ethoxycarbonyl-prop-i-en-2-yl.

Preferred protected amino groups are ζ. Azido, phthalimido, nitro, lower alkenyloxycarbonylamino, e.g. B. allyloxycarbonylamino, and optionally substituted by nitro 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. For example, carboxyl and sulfo groups are formed and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, z. For example, sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, z. For example, triethylamine, Hydroxyniederalkylaminen, z. For example, 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, eg. B. 4-aminobenzoic acid 2-diethylaminoethyl, lower alkylene, eg 1-Aethylpiperidin, cycloalkylamines, z. Dicyclohexylamine, or benzylamines, e.g. As Ν, Ν'-dibenzylethylenediamine, dibenzylamine or N-benzyl / 3-phenethylamine. Compounds of formula I with a basic group, for example with an amino group, acid addition salts, for example with ^rr inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acid, eg. 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 having an acidic and a basic group may also be present in the form of internal salts, ie in zwitterionic form.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred. The penem compounds of formula I have on the 6-substituent -CH (R ₂ ) (CH ₃ ), on the methine carbon -CH (R ₃ ) (R ₄ ) and optionally in the substituent R ₄ chiral centers, each in the R -, in the S or in the racemic R, S configuration may be present. In preferred compounds of formula I, the radical -CH (Ri) (CH ₃ ) has the R configuration. Radicals of the formula IA, which have a hydrogen atom on the α-atom of the substituents X ₁ or X ₂ of the substituents, such. B. radicals of formula (IA) wherein Χ _Ί amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower alkyl and / or X _{2 is} amino, lower alkylamino, hydrazino or anilino, can also in one of the tautomeric forms

-NH-cf or -NH- '

(IB) (IC)

wherein X-, 'or X ₂ ' is corresponding substituted or unsubstituted methylene or imino. 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 the formula I in which R _{1 is} hydroxyl, R _{2 is} carboxyl or a cleavable esterified carboxyl group, R _{3 is} amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or substituted methyleneamino as indicated and R _{4 is} optionally substituted by amino, lower alkylamino, di-lower alkylamino, As indicated, substituted methyleneamino or hydroxy represents substituted methyl or ethyl, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial activities. For example, they are in vitro against Gram positive and Gram negative cocci, z. Staphylococcus aureus. Streptococcus pyogenes. Streptococcus pneumoniae. Streptococcus faecalis, Neisseria meningitidis and Neisseria gonorrhoeae, against enterobacteria, e.g. Escherichia coli, Proteus mirabilis and Klebsieila pneumoniae, against Haemophilus influenzae, Pseudomonas aeruginosa and anaerobes, e.g. B. Bacteroidesfragilis and Clostridium perfringens in minimal concentrations of about 0.01 to about 64 / ig / ml. In vivo, in the systemic infection of the mouse, z. B. by Staphylococcus aureus, Escherichia coli or Streptococcus pyogenes, resulting in subcutaneous or oral application ED ₅₀ values of about 0.1 to about 100 mg / kg.

Surprisingly, the penem compounds according to the invention have a superior activity over structurally related and known penems. This can be seen in the comparison of minimum inhibitory concentrations (measured in vitro) with (5R, 6S) -2 - [(2R, S) -2-amino-but-1-yl) -6 - [(1R ) -1-hydroxyethyl] -2-penem-3-carboxylic acid (Compound A) with known homologous penems which carry a 4-aminobutyl or 1-aminobutyl substituent in position 2 of the penem ring, namely (5R, 6S ) -2- (4-aminobutyl) -6-hydroxymethyl-2-penem-3-carboxylic acid (European Patent Application No. 82113, Compound B) and (5R, 6S) -2- (1-aminobutyl) -6-hydroxymethyl- 2-Penem-3-carboxylic acid (European Patent Application No. 125208, Compound C)

 The results are summarized in the following Table 1.

- b Table 1: Antibiotic activity in vitro

in vitro MIC (/ x, g / ml) Compound B Compound C microorganism Connection A 0.5 0.05 Staphylococcus au reus 10 B 0.02 0.5 0.05 Staphylococcus aureus 2999i + p + 0.05 n.d. 0.5 Staphylococcus aureus A124 0.1 n.d. 0.05 Staphylococcus aureus Wood 46 0.02 0.5 1 Streptococcus pyogenes Aronson 1129 0.05 0.5 0.05 Streptococcus pneumoniae Ml / 84 0.05 n.d. 1 Neisseria meningitidis 1316  · 1 n.d. 2 Neisseria gonorrhoeae 1317/4 0.5 n.d. 32 Haemophilus influenzae 24 16 4 64 Escherichia coli 205 1 8th 64 Escherichia coli 205R + TEM 2 4 64 Escherichia coli 16 1 n.d. 32 Escherichia coli 2018 0.5 4 64 Escherichia coli UB1005 2 8th 64 Escherichia coli DC 2 16 n.d. 64 Escherichia coli B-1385 1 4 32 Klebsiella pneumoniae 327 1 16 > 64 Serratia marcescens344 8th 4 64 Enterobacter cloacae P99 0.5 16 > 64 Enterobacter cloacae ATCC13074 2 16 > 64 Proteus mirabilis 774 2 16 > 64 Proteus morganii 2359 8th 8th > 64 Pseudomonas aeruginosa ATCC12055 32 4 64 PseudomonasaeruginosaK799 / 61 4 n.d. > 64 Pseudomonas aeruginosa 143738R 64 4 64 Clostridium perfringens 194 AN 0.2 0.5 16 BacteroidesfragilisLOI 0.5

(nb: not determined)

The new compounds can therefore be used 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, a protected carboxyl group being different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the preparation of the abovementioned pharmacologically active compounds of the formula I.

The invention relates in particular to compounds of the formula I in which R _{1 is} hydroxy or protected hydroxy; R _{2 is} carboxyl, cleavable esterified carboxyl or protected carboxyl R ₂ 'under physiological conditions, R _{3 is} amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, a group of formula -N = C (X ₁₁ X ₂ ), where X _{1 is} hydrogen, amino, Lower alkylamino, di-lower-allylamino, lower-alkylene-amino, nitro-amino, hydrazino, anilino, lower-alkoxy, phenyl-lower-alkoxy, lower-alkylthio, lower-alkyl, amino-lower alkyl, lower N-lower alkylamino, Ⓒ, lower alkenyl, phenyl, or monocyclic 5 or 6-membered heteroaryl having 1 or 2 nitrogen atoms and bonded through a ring carbon atom or an oxygen or sulfur atom, and X _{2 is} amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio, or protected amino; R _{4 is} methyl, ethyl or by amino, lower alkylamino, di-lower alkylamino, a group of the formula -N = C (X ₁ , X ₂ ), wherein X ₁ and X _{2 have} the meanings given in the definition of R ₃ , protected amino, hydroxy or protected hydroxy-substituted methyl or ethyl, and m is an integer from 1 to 3, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group. The invention relates mainly to compounds of the formula I in which R _{1 is} hydroxyl, R _{2 is} carboxyl or cleavable esterified carboxyl, for example lower alkanoyloxymethoxycarbonyl or lower alkoxycarbonyloxy-lower alkoxycarbonyl, R _{3 is} amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or a group of the formula -N = C (X ₁ , X ₂ ), wherein X _{1 is} hydrogen, lower alkyl or amino and X _{2 is} amino, R _{4 is} methyl, ethyl or amino, lower alkylamino or hydroxy substituted methyl or ethyl, and m is 1 or 2 , Optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of those compounds of the formula I, which have a salt-forming group.

The invention relates in the first place to compounds of the formula I in which R _{1 is} hydroxyl, R _{2 is} carboxyl or cleavable esterified carboxyl, for example lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, R _{3 is} amino, R _{4 is} methyl or ethyl and m 1 or 2 is optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group.

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

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

The novel compounds and pharmaceutical preparations containing such compounds are e.g. B. prepared by

a) an ylide compound of the formula

₃ -CH ^ ^ SC-

CH ₃ -CH ^

(ID

wherein R ₁ , R ₃ , R ₄ and m have the meanings given under formula I, R ₂ 'is protected carboxyl, Z is oxygen or sulfur and X® represents either a trisubstituted phosphoniogroup or a di-esterified phosphono group together with a cation , or b) a compound of the formula

^CHs * iZ4

wherein Ri, R ₃ , R ₄ and m have the meanings given under formula I, R ₂ 'is protected carboxyl and Z is oxygen or sulfur, treated with an organic compound of trivalent phosphorus, or c) in a compound of formula

CH ₃ -OH S

• · N

1> - (CH ₂ ) -CH-R ₃ '(IV),

\ / ^M RV

R ₂ '

wherein R, and m have the meanings given under formula I, R ₂ 'is a protected carboxyl group, and R ₃ ' is a group displaceable by the radical R ₃ or R ₃ and R ₄ 'is a group displaceable by the radical R ₃ or R ₃ is and R ₄ 'is a radical R ₄ convertible group or R ₄ , with the proviso that at least one of the groups R ₃ ' and R ₄ 'of R ₃ and R _{4 is} different, the group R ₃ 'replaced by the radical R ₃ and / or the group R ₄ ' converted into the radical R ₄ , or d) in a compound of formula

I i

(/ γ ^N (CH ₂ ) -CH-R ₃

L ' ^m L

12

wherein R ₁ , R ₃ , R ₄ and m have the meanings given under formula I, R ₂ 'represents a protected carboxyl group and X represents the group-S or the group -SO ₂ -, the radical X is split off, and if desired or necessary, in a compound of the formula I obtainable, a protected hydroxy group Ri or protected hydroxy in the radical R _{4 is converted} into the free hydroxy group, and / or, if desired, in a compound of the formula I obtainable a protected carboxyl group R ₂ ' into the free carboxyl group, into a cleavable under physiological conditions esterified carboxyl group or into another protected carboxyl group R ₂ 'or a free carboxyl group R ₂ in a cleavable under physiological conditions esterified carboxyl group, and / or, if desired, a protected amino group R ₃ or protected amino in the radical R ₄ in the free amino group or a free amino group R ₃ or free amino in the radical R ₄ in a s substituted, and / or, if desired, an available mixture of isomeric compounds of formula I is separated into the individual isomers, and / or, if desired, a compound having salt-forming group in a salt or an available salt in the free compound or converted into another salt, and / or processed an available compound of formula I or a pharmaceutically acceptable salt thereof to a pharmaceutical preparation.

In the starting compounds of the formulas HV are functional groups, such as. B. a free hydroxy group R ₁ and z. B. a free amino group R ₃ , preferably by conventional protecting groups, for. Example by one of the above, protected, a) cyclization of the compound of formula II

The group X® in the starting material of formula II 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. B. ethyl, doubly esterified phosphono, where the symbol X® in the case of

-8- 794 61

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, ζ. B. the sodium ion.

In phosphonio compounds of the formula II, the negative charge is neutralized by the positively charged phosphonium group. In phosphono compounds of the formula II, 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, ζ. For example, sodium, lithium or potassium can be. The phosphono starting materials are therefore used as salts in the reaction. The ring closure may occur spontaneously, ie, take place in the preparation of the starting materials, or by heating, for example in a temperature range of about 3O ⁰ C to 160 ° C, preferably from about 50 ⁰ C to about 100 ⁰ C. 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, for example methylene chloride, an ether, ζ. As diethyl ether, a cyclic ether, ζ. As dioxane or tetrahydrofuran, a carboxylic acid amide, for. B. dimethylformamide, a Diniederalkylsulfoxid, z. For example, dimethyl sulfoxide, or a lower alkanol, z. As ethanol, or in a mixture thereof, and, if necessary, in an inert gas, ζ. Β. Nitrogen atmosphere, performed.

b) cyclization of the compound of formula III

An organic compound of trivalent phosphorus is derived z. B. of phosphorous acid and in particular an ester thereof with a lower alkanol, for. Methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, e.g. For example, phenol or catechol, or an amide ester thereof of the formula P (OR _a) -N (R _{b) 2,} wherein R _a and R _{b are} independently lower alkyl, eg. Methyl, or aryl, e.g. As phenyl, mean. Preferred compounds of the trivalent phosphorus are trialkyl 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, such as dioxane or tetrahydrofuran, or a halogenated hydrocarbon ^. For example, methylene chloride or chloroform, at a temperature of about 20 ° to 140 ° C, preferably from about 40 ° to about 110 ⁰ C, wherein reacting 1 molar equivalent of a compound of formula 111 with 2 molar equivalent of the phosphorus compound.

Preferably, the compound of formula III is presented in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a prolonged period of time, e.g. During a period of 2 to 4 hours.

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

c) replacement of the radical R ₃ and / or R ₄

A group R ₃ 'which can be replaced by the radical R ₃ is, for example, a corresponding group which can be replaced by nucleophilic reaction. Such groups R ₃ 'are in particular esterified hydroxy groups, such as by a hydrohalic acid, a di-lower alkyl or Diarylphosphorsäure, optionally substituted by oxo or halogeno lower alkanecarboxylic acid, optionally substituted by halogeno lower alkane or an optionally substituted by halogen or lower alkyl benzenesulphonic esterified hydroxy groups. Corresponding groups R ₄ 'which can be converted into the radical R ₄ are, for example, methyl or ethyl which is substituted by one of the abovementioned esterified hydroxyl groups. Such esterified hydroxy groups are, for. 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.

Here, for example, an esterified hydroxy group R ₃ 'by an amino group or by a, as defined in the definition of R ₃ , substituted amino group R ₃ and / or an esterified hydroxy group in the radical R ₄ ' by an amino group, by a, as in the Definition of R ₄ indicated, substituted amino group or replaced by a hydroxy group. The reaction takes place with a compound of the formula Z'-H, where Z 'in the case of dpr substitution of the radical R ₃ ' is amino, lower alkanoylamino, lower alkyl-substituted amino, substituted amino or protected amino and in the case of substitution at the radical R ₄ ' is amino, lower alkyl substituted amino, substituted methyleneamino, protected amino, hydroxy or protected hydroxy, or a salt such as an alkali metal salt, e.g. B. the sodium or potassium salt thereof, ie for the preparation of corresponding amino compounds with hydrazoic acid or with phthalimide or in particular with alkali metal salts, for. Example, the sodium or potassium salt thereof, further with ammonia, lower alkyl and Diniederalkylaminen, amidines, guanidines and the like, which may be present in protected form, wherein at the reacting amino group but at least one hydrogen atom must be present, and for the preparation of corresponding hydroxy compounds ζ , B. with the hydroxide or carbonate of an alkali metal, for. As sodium hydroxide, sodium carbonate or potassium carbonate, further with alkali metal, such as sodium salts, corresponding carbonic monoesters, such as. Carbonic allyl ester or carbonyl haloalkyl ester, and the like. The reaction is carried out in a known manner in an inert solvent, such as. As a lower alkanol, dimethylformamide, a cyclic ether, ζ. As dioxane, in dimethyl sulfoxide, in water or in mixtures thereof, at room temperature or slightly elevated or reduced temperature, for example at about O ^{0 to} 40 ⁰ C, in particular at room temperature, carried out.

The starting compounds of the formula IV can be prepared in an analogous manner as described under process a) by ring closure of the phosphorane of the formula

ϊ ¹

3-CR.

CH ₃ -CR, .SC- (CH ₂ ) -QH-R ₃

Υ-χ ^Θ

d) Elimination of the radical X from compounds of the forms! V

The compounds of the formula V are appropriately substituted 2-thia-3-cephem-4-carboxylic acids or, in particular, 2-thia-3-cephem-4-carboxylic acid 1,1-dioxides.

The elimination of sulfur from a 2-thia-3-cephem-4-carboxylic acid of the formula V (X = S) is carried out for example with an organic compound of trivalent phosphorus, such as. B. one of the compounds mentioned under process b). Suitable compounds of trivalent phosphorus are, for. B. Triniederalkylphosphite, z. For example, triethyl phosphite, and in particular triphenylphosphine. The elimination is carried out at room temperature or slightly elevated temperature, e.g. B. at about 20 ° to about 60 ⁰ C, in an inert solvent or solvent mixture, ζ. B. in a hydrocarbon, for. As benzene, a chlorinated hydrocarbon, eg. For example, chloroform, or a lower alkanone, z. For example, acetone, if necessary in an inert gas, such as nitrogen atmosphere performed.

The elimination of sulfur dioxide from a compound of formula V, wherein X is SO ₂ , is carried out, for example, in a solution containing this compound by mild to moderate heating, e.g. B. to about 30 ° to about 80 ° C, being used as the solvent, in particular inert solvent such. B. optionally chlorinated hydrocarbons, eg. As chloroform, aliphatic ethers or aromatic hydrocarbons, eg. As benzene, in question.

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

Available compounds of the formula I can be converted in a manner known per se within the scope of the definitions into other compounds of the formula I.

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, otherwise be released stepwise or simultaneously.

In a compound of the formula I obtainable by the process according to the invention in which R _{2 represents} a protected carboxyl group, the protected carboxyl group can be released in a manner known per se. Thus, tert.-lower alkoxycarbonyl or in the 2-position by a trisubstituted silyl group or in the 1-position by lower alkoxy-substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl z. Example, by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, into free carboxyl. Optionally substituted benzyloxycarbonyl may 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. As tin, or metal salt, such as a chromium-Il salt, z. For example, chromium-ll-chloride, usually in the presence of a hydrogen donating agent, which is capable of producing together with the metal nascent hydrogen, such as a suitable carboxylic acid, for example an optionally, for. B. substituted by hydroxy, lower alkanecarboxylic, z. As acetic acid, formic acid or glycolic 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. As tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, for. For example, 2-Aethylhexansäure, or a salt thereof. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxyl, while aroylmethoxycarbonyl can also be converted by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, can be cleaved. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride, eg tetrabutylammonium fluoride, are converted to free carboxyl with an organic SiIyI or stannyl group, such as tri-lower alkylsilyl or Stannyl, esterified carboxyl can be liberated in a conventional manner solvolytically, for example by treatment with water or an alcohol A lower alkoxycarbonyl group substituted in the 2-position by lower alkylsulfonyl or cyano can be prepared, for example, by treatment with a basic agent such as Alkali metal or alkaline earth metal hydroxide or carbonate, e.g., sodium or potassium hydroxide or sodium or potassium carbonate, are converted to free carboxyl.

On the other hand, compounds of the formula I in which R ₂ denotes carboxy can also be converted into compounds of the formula I in which R _{2 represents} a protected carboxyl group, in particular an esterified carboxyl group, or an esterified carboxyl group which can be cleaved under physiological conditions. So you can the free carboxyl group z. By treating with a suitable diazo compound such as a diazo-lower alkane, e.g. Diazomethane, or a phenyl-diazo-lower alkane, e.g. B. diphenyldiazomethane, if necessary, in the presence of a Lewis acid, such as. As boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, z. As dicyclohexylcarbodiimide, as well as carbonyldiimidazole, esterify. Esters can also be prepared by reacting an optionally in situ prepared salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid. Further, acid halides such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with N-hydroxy nitrogen compounds such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl ester , such as ethyl chloroformate or isobutyl chloroformate, or with Halogenessigsäurehalogenide ^ such as trichloroacetic acid chloride) by reaction with suitable alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group.

In a compound of the formula I with an esterified carboxyl group R ₂ , this can be converted into another esterified carboxyl group z. For example, 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, e.g. For example, sodium iodide, in 2-iodo-ethoxycarbonyl. Further, in compounds of formula I containing an esterified carboxyl group, the carboxyl protecting group can be cleaved as described above and a resulting compound of formula I having a free carboxyl group or a salt thereof by reacting with the reactive ester of a starting alcohol in < = ine> VerhinHimn Listen Pnrmol I i "l- <orfiihran.» / ^ r -; .-, D. n \ na κπιλ. "k, _m i" i "~: -u ^. γ> ~ -ι:

-ί-- 794 61

In compounds of the formula I obtainable in accordance with the process in which R-i is protected hydroxyl and / or optionally the radical R4 contains protected hydroxyl as substituent, the protected hydroxy group can be converted into the free hydroxy group in a manner known per se. For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released as an appropriately protected amino group (see below); a tri-lower alkylsilyl group e.g. Also with tetrabutylammonium fluoride and acetic acid (under these conditions carboxy groups protected by trisubstituted silylethoxy are not cleaved). A 2-halo-lower alkyl group and an optionally substituted benzyl group are reductively removed.

In a compound of the formula I 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), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino may be treated by treatment with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid or catalytically with hydrogen Cleaved presence of a palladium catalyst. Aroylmethoxycarbonylamino may also be prepared by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. As sodium dithionite be cleaved. Optionally substituted benzyloxycarbonylamino may be 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. As tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treating with a carboxylic acid, eg. For example, 2-ethylhexanoic acid, or a salt thereof, are cleaved. A protected with an organic SiIyI or stannyl amino group may, for. Example by hydrolysis or alcoholysis, a by 2-Halogenniederalkanoyl, z. B. 2-chloroacetyl, protected amino group by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the resulting condensation product are released. An amino group protected by 2-substituted silylethoxycarbonyl may be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, e.g. For example, sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as Tetraniederalkylammoniumfluorid, eg., Tetraäthylammoniumfluorid be converted into the free amino group is protected in the form of an azido or nitro group amino group For example, by reduction to free amino, for example, by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid such as acetic acid, an amino group protected in the form of a phthalimido group In addition, an arylthioamino group may be converted by treatment with a nucleophilic reagent, such as sulfurous acid, into the free amino group

Amino be converted. _ -

Further, one can convert a free amino group R ₃ or amino as a substituent of the radical R ₄ in a conventional manner in a substituted amino group. Thus, for example, amino R3 can be converted to lower alkanoylamino R3 by reaction with a corresponding lower alkanoyl halide, such as chloride. The conversion of amino groups into amidino, guanidino, isourea, isothiourea, imidoether and imidothioether groups can be carried out, for example, according to one of the processes mentioned in German Offenlegungsschrift No. 2652679. Thus, for example, compounds of formula I in which R _{3 is} amino or R ₄ is methyl or ethyl substituted by amino may be prepared by reaction with an imido halide or ester of formula [(X ₁ , Y ₁ ) C = X ₂ H] Y ₂ ®, wherein X _{1 is} hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, X ₂ 'is optionally substituted imino, Y i is halogen, e.g. As chlorine, or lower alkoxy, z. Ethoxy, and Y _{2 is} an anion, ζ. As chloride, means in amidines or by reacting with a thiourea of the formula X ₁ -Cf = S) -X ₂ , wherein X ₁ and X _{2 are the} same or different, optionally substituted amino groups, or with an isourea or isothiourea Formula (XiY ₃ ) C = X ₂ ', wherein Y _{3 is} lower alkoxy or lower alkylthio, X _{1 is} optionally substituted amino and X ₂ ' is optionally substituted imino, are converted into guanidines. Furthermore, it is possible to convert a free amino group R ₃ or amino as a substituent of the radical R ₄ into a mono- or disubstituted by lower alkyl amino group. The introduction of the lower alkyl group (s) is carried out, for example, by reaction with corresponding reactive lower alkyl esters, such as halides, e.g. B. chlorides or bromides, or sulfonates, eg. For example, methane or p-toluenesulfonates, in the presence of a basic condensing agent such as an alkali or alkaline earth metal hydroxide or carbonate, e.g. As potassium hydroxide or sodium carbonate, in an inert solvent such as a lower alkanol, at room temperature or elevated or lowered temperature, for. B. at about -20 ° to + 8O ⁰ C.

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, for example by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acid, for. As the sodium salt of a- Aethylcapronsäure, 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 into the free compounds, metal and ammonium salts z. B. by treatment with suitable acids and acid addition salts z. 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 adjuvant, the resulting mixture of two diastereomeric compounds can be separated by means of suitable physicochemical methods (eg fractional crystallization, adsorption chromatography) and the individual diastereomeric compounds can then be dissolved in α-formic acid -iwon VerhinriiιηπΑΠ snaltfin.

-11- / »4 0 1

Particularly suitable racemates for separation into antipodes are those having an acidic group, such as racemates of compounds of formula I, wherein R _{2 is} carboxy. These acidic racemates can be reacted with optically active bases, e.g. Esters of optically active amino acids, or (-! - brucine, (+! - quinidine, (-) - quinine, (+! - cinchonine, (-t -) - dehydroabietylamine, (+) - and (-) - Ephedrine, (+) - and (-) - i-phenylethylamine or their N-mono- or N, N-dialkylated derivatives to mixtures consisting of two diastereomeric salts, are reacted.

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

For resolution of the racemate, it is also possible to esterify an existing hydroxy group with optically active acids or their reactive, functional derivatives to form diastereomeric esters. Such acids are, for example, (-) - abietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acids, (+) - and (- (- camphanic acid, (+) - and (-) - Ketopic acid,! (+! - ascorbic acid, (+) - camphoric acid, (+) - camphor-10-sulfonic acid (/ 3), (+) - or (-) a-bromocampher-J7-sulfonic acid, D (-! Cinic acid, D (-) - isoascorbic acid, D (-) - and (- + - mandelic acid, (+) - 1-menthoxyacetic acid, D (-) - and (-) - tartaric acid and their di-O Benzoyl and di-op-tolyl derivatives.

By reaction with optically active isocyanates, such as with (+! - or (-! - 1-Phenyläthylisocyanat, compounds of formula (I), wherein R, is hydroxy or R ₄ is hydroxy-substituted methyl or ethyl and the remaining functional groups are protected, are converted into a mixture of diastereomeric urethanes.

Basic racemates, e.g. B. Compounds of formula I, wherein R _{3 is} amino or the ReStR ₄ is substituted by amino, can form diastereomeric salts with said optically active acids.

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

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

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

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

the separation of the racemates into the optical antipodes can be carried out at any stage of the process, i. H. z. B. also be carried out at the stage of the starting compounds of the formulas M-VI or at any stage of the processes described below for preparing the starting compounds of formula H-Vl.

In all subsequent conversions obtained compounds of formula I are those reactions which take place under slightly 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 III can be prepared as indicated in the following Reaction Scheme I:

Reaction scheme I

^-1 -CH,

.W

CH ₃ -CH

I hope

</ (VII)

step 1

.SC- (CH ₂ ) -CH-R ₃

* ml

-L ·

(VIII)

level 3

Level 2

CH ₃ -CH, ^ -C- (CH ₂ ) -CH-R ₃ CH ₃ -CH, .SC- (CH ₂ ) -CH-R ₃ .-. R. | -r I R,

(/ CH ^ X Qf C = O

R ₂ '° (IX) R ₂ ¹ (III)

I Level 4

i i}

CH ₃

fi -CH ,,

-QH-R ₃

CH ₃

, SM

Level 5

(ID

(X) R ₂ '

V-x®

- \ Z- - / 34 OI

step 1

A thioazetidinone of formula VIII is obtained by reacting a compound of formula VII with a compound introducing the residue SC (= Z) - (CH ₂ ) _m -CH (R ₃₁ R ₄ ).

In a starting material of the formula VII, W is a nucleofugic radical which can be replaced by the group -SC (= Z) - (CH ₂ ) _m -CH (R ₃ , R ₄ ). Such radicals W are, for example, aryloxy radicals, sulfonyl radicals R ₀ -SO ₂ -, wherein R _{0 is} an organic radical, azido or halogen. In an acyloxy radical W, acyl is ζ. B. the radical of an organic carboxylic acid and is, for example, lower alkanoyl, z. Acetyl or propionyl, optionally substituted benzoyl, e.g. Benzoyl or 2,4-dinitrobenzoyl, or phenyl-lower alkanoyl, e.g. B. phenylacetyl. In a sulfonyl radical R ₀ -SO ₂ - R _{0 is,} for example, optionally substituted by hydroxy lower alkyl, such as methyl, ethyl, 2-hydroxyethyl, 1-hydroxyprop-2-yl or 1-hydroxy ^ -methyl-prop ^ -yl, benzyl or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen radical W is z. As bromine, iodine or especially chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

A compound introducing the radical SC (ZZ) - (CH ₂ ) _m -CH (R ₃ , R ₄ ) is, for example, an acid of the formula (R ₃ , R ₄ ) CH- (CH ₂ ) _m -C (= Z) -SH or in particular a salt, for. An alkali metal salt, such as the sodium or potassium salt thereof. The substitution can be carried out in an organic solvent, such as in a lower alkanol, e.g. As methanol or ethanol, a lower alkane, z. For example, acetone, a Niederalkancarbonsäureamid, z. B. dimethylformamide, a cyclic ether, ζ. Β. Tetrahydrofuran or dioxane, or in a similar inert solvent. The reaction is usually carried out at room temperature, but can also be carried out at elevated or reduced temperature, for example at about 0 ° to about 40 ° C. By adding a salt of hydriodic acid or thiocyanic acid, z. As an alkali metal such as sodium salt, the reaction can be accelerated.

The incoming group-SC (= Z) - (CH ₂ ) m -CH (R ₃ , R ₄ ) is directed by the CH ₃ -CH (R ₁ ) - preferably in the trans position. Therefore, both (3S, 4R) and (3S, 4R) -configured starting compounds of formula VII can be used, although the trans-isomers are predominantly formed, occasionally small amounts of the cis-isomer may arise. The separation of the cis isomers, as described above, by conventional methods, in particular by chromatography and / or by crystallization.

Suitable starting compounds of formula VII are known, for example, from European Patent Application No. 82113, German Offenlegungsschrift No. 3224055 and German Offenlegungsschrift No. 3013997 or can be prepared in an analogous manner. They can also be prepared by the methods described in the examples.

Level 2

A starting compound of formula (III) is obtained by reacting an azetidinone of formula (VIII) with an acid of formula R ₂ '--COOH or, in particular, a reactive derivative such as an ester or acid halide, e.g. B. the acid chloride, thereof at a temperature of 20 ° to 8O ⁰ C, preferably at 40 ° to 6O ⁰ C, in an inert solvent, such as one of the in the implementation of compounds of formula IiI to compounds of formula I, treated , When using an acid halide is preferably carried out in the presence of an acid-binding agent, such as a tertiary aliphatic amine, for. For example, triethylamine, an aromatic amine, eg. As pyridine, or in particular an alkali metal or alkaline earth metal carbonate or bicarbonate, z. For example, potassium carbonate or calcium carbonate.

level 3

Compounds of the formula IX, wherein X _{0 is} a reactive esterified hydroxy group, in particular halogen, z. As chlorine or bromine, or organic sulfonyloxy, z. B. lower alkanesulfonyloxy, such as methanesulfonyloxy, or arenesulfonyloxy, z. Benzene or 4-methylbenzenesulfonyloxy, are prepared by reacting a compound of formula VIII with a glyoxylic acid compound of formula OHC-R ₂ 'or a suitable derivative thereof such as a hydrate, hemihydrate and hemiacetal, e.g. B. a hemiacetal with a lower alkanol, z. B, methanol or ethanol, and in an obtained compound of formula IX, wherein X _{0 is} hydroxy, the hydroxy group converts to a reactive esterified hydroxy group.

The compounds of formula IX are usually obtained as a mixture of the two isomers [with respect to the grouping -CH (R ₂ ') X ₀ ].

But you can also isolate the pure isomers thereof, z. By chromatography.

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

The conversion of a hydroxy group X ₀ into a reactive esterified hydroxy group X ₀ in a compound of formula IX is carried out by treatment with a suitable esterifying agent, e.g. With a thionyl halide, e.g. Chloride, a phosphorous oxyhalide, especially chloride, a halophosphonium halide such as triphenylphosphonium dibromide or dichloride or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily organic basic agent such as an aliphatic tertiary amine, e.g. , Triethylamine or diisopropylamine, or a pyridone-type heterocyclic base, e.g. As pyridine or collidine. 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. B. at about -30 ° to about 30 ⁰ C, and optionally in the atmosphere of an inert gas, such as nitrogen.

Level 4

The starting material of formula (II) is obtained by reacting a compound of formula (IX) 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 Triniederalkylphosphit, z. Triethyl phosphite, or an alkali metal lower alkyl phosphite, e.g. B. diethyl phosphite treated.

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

In this case, it is usually carried out in the presence of a basic agent, such as an organic base, for. Example, an amine such as triethylamine, diisopropylethylamine, pyridine, lutidine, or "polystyrene Hünigbase", or an inorganic base, eg., An alkali metal carbonate, eg., Sodium or potassium carbonate, wherein the primary resulting phosphonium salt of the formula

Ri _/ S-δ- (CH ₂ ) _- CH-R ₃

j-CH " ¹ » » ¹ ? ·

^{CH 3 CH} 1 i ^R * (Ha),

wherein X 'is a phosphono group or a phosphoniogroup together with an anion, depending on the meaning of the radical R ₀ z. B. chloride, is converted into the ylide starting material of the formula II. But you can also work in the absence of a base and a compound of formula (Na), in particular a corresponding phosphono-isolate, and convert them in the preparation of the end products of formula (I) in situ in the starting material of the formula II.

Level 5

A compound of the formula (II) can furthermore be obtained by reacting a mercaptide of the formula (X) in which M is a metal cation with a radical (R ₃ , R ₄ ) CH- (CH ₂ ) m C (= Z) -introduced acylating agent.

In the starting material of formula (X) is the metal cation M, for example, a cation of the formula M ⁺ or M ²⁺ / 2, where M ⁺ in particular for a silver cation, and M ²⁺ in particular for the divalent cation of a suitable transition metal, eg. B.

Copper, lead or mercury, stands.

An acylating agent which introduces the radical (R ₃ , R ₄ ) CH- (CH ₂ ) m C (= Z) is e.g. For example, the acid (R ₃ , R ₄ ) CH- (CH ₂ ) _m -C (= Z) -OH, or in particular a reactive functional derivative thereof, such as an acid halide, e.g. As chloride or bromide, azide or anhydride thereof.

The acylation occurs when a reactive functional derivative of the acid of formula (R ₃ , R ₄ ) is CH- (CH ₂ ) _m -C (= Z) -OH, e.g. B.

the acid chloride is used in an inert solvent such as a chlorinated hydrocarbon, e.g.

Methylene chloride, or an ether, ζ. As diethyl ether or dioxane, at room temperature or under heating or cooling, for. B. in a temperature range of about -50 ° to about + 60 ° C, especially at about -30 ° to about + 20 ° C.

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

CH ₃ -CH _x /

) -K

by reaction with an alkali metal salt, ζ. B. the sodium salt, a Thioniederalkancarbonsäure, z. As thioacetic acid, or the Triphenylmethylmercaptans in a compound of formula

CH ₃ -CR ^ .W

'I-century

where W is triphenylmethylthio or lower alkanoylthio, e.g. Acetylthio, means this analogous to the method described in the reaction steps 3 and 4 in a compound of formula

(XII)

transferred and these in the presence of a base, for. Pyridine or tri-n-butylamine, in a suitable solvent, e.g. Diethyl ether or methanol, with a salt of the formula MA, in which M has the above meaning, but especially for a silver

- --4 - / S> t O I

Cation and A is a common anion which determines the solubility of the salt MA in the chosen solvent,

z. As the nitrate, acetate or fluoride anion reacted.

The ylides of the formula II can be used directly in the cyclization reaction for the preparation of the end products of the formula I. But you can also in compounds of formula II, wherein Ri is a protected hydroxy group, for. B. a hydrolytically * easily cleavable protected hydroxy group, such as trisubstituted silyloxy is, first cleave the hydroxy protecting group and then use the resulting compound of formula II, wherein R _{1 is} hydroxy, in the cyclization reaction.

The starting compounds of the formula V in which X represents the group -S- are known (for example from Belgian Patent 898382 and from Tetrahedron Letters 1983, 1631-1634) or can be prepared in an analogous manner. Compounds of formula V wherein X is a sulfonyl group -SO ₂ - are prepared by reacting a compound of formula

ί-Γ?

-CH-R ₃

wherein R ₁ , R ₃ , R ₄ and m have the meanings given under formula I and R ₂ 'is protected carboxyl, with an aliphatic or aromatic percarboxylic acid, for. As peracetic acid, m-chloroperbenzoic acid or monoperphthalic acid, in an inert solvent or solvent mixture, ζ. In a halohydrocarbon, e.g. As chloroform, an ether or an aromatic hydrocarbon, for example benzene, at a temperature of about 0 ° to about 6O ⁰ C reacted. The starting compounds of the formula VI can z. Example, be prepared by reacting the compound of formula

i-fa ^(VII>

with a compound of the formula (R ₃ ', R ₄ ') CH- (CH ₂ ) _m -C (= Z) -SH or a salt thereof and an obtainable compound of the formula

CH ₃ -CH ^ ^ -C- (CHa) _1n-R -CH ₃ ¹

J-- L ·

converted into the starting compounds of formula VI according to the procedure given in Reaction Scheme I.

The processes described for the preparation of the compounds of the formula M-VI and VIII-X, and the specified processes for the preparation of the end products of the formula I can also be carried out with optically inactive compounds and at any stage of the process from a diastereomeric mixture or racemate obtained, as above described isolating the optically active compounds according to the present invention.

The invention also relates to the novel starting compounds as well as novel intermediate products obtainable by the process, such as those of the formula H-VI, VIII and IX and the specified processes for their preparation.

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

The pharmacologically useful compounds of the present invention may e.g. Example, 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 are for oral or parenteral, d. H. intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. B.

Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol have.

Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylceulose, 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 are primarily infusion solutions, preferably isotonic aqueous solutions or suspensions, these z. B. from lyophilized preparations containing the active substance alone or together with a carrier material, for. 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 conventional mixing, 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.

-15- 794 61

Depending on the type of infection and condition of the infected organism, daily doses (oral or parenteral) of about 100mg to about 500mg are used to treat warm-blooded animals (humans and animals) weighing about 70kg.

The said pharmaceutical preparations and the use of the compounds of the formula I according to the invention for the therapeutic treatment of the human and animal body also form an object of the present invention.

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

The following abbreviations are used in the examples:

DC: thin-layer chromatogram

IR: Infrared spectrum

UV: ultraviolet spectrum

THF: tetrahydrofuran

Example 1: (5R, 6S) -2 - [(2R, S) -2-Allyloxycarbonylamino-prop-1-yl] - 6 - [(1R) -1-allyloxycarbonyloxy-oxy-ethyl] -2-penem-3-carboxylic acid allyl

A solution of 2g 2 - [(3S, 4R) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4 - [(3R, S) -3-allyloxycarbonylaminobutyroylthio] -2-oxoazetidin-1-yl] -2- Triphenylphosphoranylidenessigsäure allylester in 400 ml of toluene is stirred under argon atmosphere for 6.5 hours at reflux temperature. Then the solvent is evaporated and the crude product is purified by chromatography on silica gel (eluent toluene / ethyl acetate 4: 1), R _f = 0.54; IR (CH ₂ Cl ₂ ) 3430; 1790; 1740; 1730; 1580cm " ¹ The starting material can be prepared as follows:

a) (3R, S) -3-allyloxycarbonylaminobutyric acid

7.83 g of (3R, S) -3-aminobutyric acid are dissolved in 17 ml of water and 35 ml of 5N sodium hydroxide, and after cooling through an ice bath, 8.88 ml allyl chloroformate are added. After removal of the cooling bath, the reaction mixture is stirred for 16 hours at room temperature, then diluted with 150 ml of water and washed twice with ethyl acetate. The aqueous phase is adjusted to pH 2 with 4N hydrochloric acid solution and extracted twice with ethyl acetate. The organic extracts are washed once with brine, dried over MgSO 4 and evaporated. IR (CH ₂ Cl ₂ ) 3440; 1715cm " ¹ .

b) (SR.SJ-S-allyloxycarbonylaminobutyric acid chloride

1.87 g of (3R, S) -3-allyloxycarbonylaminobutyric acid is added at 0 ° with 2.85 ml of thionyl chloride. After stirring for 1.25 hours at 0 °, the reaction mixture is evaporated three times with toluene. The crude title compound [IR (CH ₂ Cl ₂ ): 3440; 1795; 1 720cm " ¹ ] will be implemented immediately.

c) Z-IOS ^ RI-S-KIRJ-i-allyloxycarbonyloxyethyl-A-IOR.SJ-S-allyloxycarbonylaminobutyroylthiol-Z-oxo-azetidin-i-yl-atriphenylphosphoranylidenessigsäureallylester

2.79 g of silver salt of 2 - {(3S, 4R) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1-yl} -2-triphenylphosphoranylidenessigsäureallylesters are dissolved in 25 ml of methylene chloride, 0.97 ml of pyridine at 0 ° and then a solution of 1.23 g (SR.Sl-S-allyloxycarbonylaminobutyric acid chloride in 10 ml of methylene chloride, after stirring for 30 minutes at 0 °, the solid is filtered through Hyflo and the filtrate is After drying over MgSO ₄ , the solvent is evaporated and the residue is purified by chromatography on silica gel (eluent toluene-ethyl acetate 3: 2) TLC (silica gel, toluene / ethyl acetate 2: 3) , R _f = 0.38, IR (CH ₂ Cl ₂ ) 3440, 1755, 1725, 1 625 cm ^-1 .

The silver salt of the 2 - {(3S, 4R) -3 - [(1R, 1-allyloxycarbonyloxyethyl) -mercapto ^ -oxoazetidin-i-yl} ^ -triphenylphosphoranylideneacetic acid allyl ester is prepared as follows:

ca) (2S, 3R) -2-bromo-3-hydroxybutyric acid p-methoxybenzylamide

To a stirred at room temperature under an argon atmosphere solution of 5g (2S, 3R) -2-bromo-3-hydroxybutyric acid and 3.52g p-methoxybenzylamine in 60ml abs. THF are added dropwise within 20 minutes 4.16 g of 1-hydroxybenzotriazole and 5.63 g of dicyclohexylcarbodiimide in 60 ml of THF. The reaction mixture is stirred for 48 hours, the precipitated dicyclohexylurea is filtered off, washed several times with THF and the filtrate is evaporated. The obtained crude product contains dicyclohexylurea and hydroxybenzotriazole as an impurity. After chromatography of the mixture on silica gel (system: toluene / toluene / ethyl acetate 1: 4) and crystallization of the pure fractions from methylene chloride / diethyl ether the title compound is obtained, mp 122-124 °, [α] = -7 ± 1 ° (1,112 % in chloroform).

cb) (2R, 3R) -2,3-epoxybutyric acid p-methoxybenzylamide

A solution of 6.04 g (2OmM) (2S, 3R) -2-bromo-3-hydroxybutyric acid p-methoxybenzylamide in 150 ml of methylene chloride is mixed with 50 ml of 50% NaOH solution in 456 mg (2mM) of benzyltriethylammonium chloride. The two-phase mixture is stirred vigorously for 20 hours at room temperature. The organic layer is separated and the aqueous phase is back-extracted with methylene chloride. The combined methylene chloride solutions are dried and evaporated. The resulting crude product is chromatographed on 40 times the amount by weight of silica gel in the system methylene chloride / methanol (99: 1). After crystallization of the pure fractions from methylene chloride-diethyl ether-petroleum ether, the title compound, F.: 75-76 °, is obtained.

cc) (2R, 3R) -2,3-epoxybutyric acid N-tert-butoxycarbonylmethyl-N-p-methoxybenzylamide

To a stirred at 0 ° under argon atmosphere mixture of 550mg sodium hydride dispersion (55-60% in oil) and 1.52ml bromoacetic acid tert-butyl ester in 25 ml of THF, a solution of 2.21 g (2R, 3R) -2 , 3-epoxybutyric acid p-methoxybenzylamide in 100 ml of THF was added dropwise. The mixture is warmed to room temperature and the reaction mixture is stirred for a further 1 hour (control of the course of the reaction by thin-layer chromatography). Total reaction time: 90 minutes. The insoluble fractions are filtered off and washed with THF and the combined filtrates are evaporated. The resulting crude product is purified by chromatography on 150 g of silica gel (system: toluene, toluene / ethyl acetate 80:20). Evaporation of the pure fractions gives the amorphous title compound. IR spectrum: bands at, inter alia, 1740.1 670.1 650.1 615.1 517.1465, 1360 and 1035 cm ^-1 .

-ΊΟ- / 94 O I

cd) (3S, 4S) -1 - (p-Methoxybenzyl) -3 - [(1R) -1-hydroxyethyl] -4-tert-butoxycarbonyl-2-azetidinone

9.23 g of tetrabutylammonium fluoride trihydrate are allowed to stand with 40 g of molecular sieve (Type 4171/16 pre-dried at 300 °) in 80 ml of THF for 16 hours at 5 °. The mixture is cooled to 0 °, treated with a solution of 2.8 g of (2R, 3R) -2,3-epoxybutyric acid N-tert-butoxycarbonylmethyl-N-p-methoxybenzylamide in 2OMITHF and stirred for 2 hours at 0-5 °. The molecular sieve is filtered off with THF after washing and the filtrate is applied directly to a column prepared in toluene with 250 g of silica gel. The evaporated, with toluene / ethyl acetate (70:30 mixture) eluted fractions are taken up in methylene chloride, washed successively twice with 1N sulfuric acid, with saturated aqueous NaHCO3 solution and with water, dried and evaporated. After short chromatography on silica gel (toluene, toluene / ethyl acetate 60:40) and crystallization from methylene chloride / diethyl ether / petroleum ether, the pure title compound, mp 85-87 ° is obtained.

ce) (3S, 4S) -1- (p-Methoxybenzyl) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4-tert-butoxycarbonyl-2-azetidinone

A solution of 2 g of PS ^ SJ-i-ip-methoxybenzyl-S-HIRM-hydroxyethyl-tert-butoxycarbonyl-azetidinone in 24 ml of methylene chloride is added at 0 ° with 24 ml of 1N NaOH, 820 mg of tetrabutylammonium hydrogen sulfate and 1 ml of allyl chloroformate and stirred vigorously. After 20 and 40 minutes of reaction time, additional portions (1 ml each) of allyl chloroformate are added. The reaction mixture is diluted with methylene chloride, the aqueous phase separated and the organic layer washed successively with 5% aqueous citric acid and 8% aqueous NaHCO3 solution, dried and evaporated. After chromatographic purification, the pure, amorphous title compound. IR spectrum: bands at, inter alia, 1765.1745 (sh), 1615.1 593.1, 515.1160 and 1035 cm ^-1 .

cf) (3S, 4S) -1- (p-Methoxybenzyl) -3 - [(1R) -1 -allyloxycarbonyloxyethyl] -carboxylic acid ^ -azetidinone

1.6 g of OS ^ SI-i-ip-methoxybenzyD-S-KIRI-i-allyoxycarbonyloxyäthyll ^ -tert-butoxycarbonyl ^ -azetidinone are dissolved at 0 ° in 10 ml of trifluoroacetic acid. After one hour reaction time at room temperature, the reaction mixture is evaporated under high vacuum and the available title compound is further processed without purification, [α] = + 85 ± Γ (1.0% in chloroform).

cg) OR ^ R1-i-ip-methoxybenzyl J-S-KIRJ-i-allyloxycarbonyloxyäthyn ^ -acetoxy-Z-azetidinone

A stirred under argon atmosphere at room temperature solution of 1,4g (3S, 4S) -1- (p-methoxybenzyl) -3 - [(1R) -1-allyloxycarbonyloxyäthyl] -4-carboxylic acid 2-azetidinone in a mixture of 45ml THF and 6.6 ml of dimethylformamide is mixed with 1.6 g of lead (IV) acetate (about 10% acetic acid content) and stirred for about 1 hour until complete reaction of the substrate. Excess oxidant is decomposed by adding 0.5 ml of ethylene glycol (10 minutes room temperature).

The reaction mixture is filtered off from precipitated lead (II) acetate, the filtrate residue is washed with THF and the filtrate is evaporated. The resulting oily residue is taken up in methylene chloride, successively twice each with saturated, aqueous NaHCO ₃ solution, water and sat. NaCl solution, dried and evaporated. Chromatography of the residue on silica gel (toluene: toluene / ethyl acetate 90:10) gives the pure title compound [α] = + 90 ° ± 1 ° (1.0% in chloroform).

ch) (3R, 4R) -3 - [(1R) -I -allyloxycarbonyloxyethyl] -acetoxy-azetidinone

A solution of 900 mg (1.18 mmol) of (SR 1) RM-fp-methoxybenzyl J-S-II-R1-allyloxycarbonyloxyethyl] -acetoxy-azetidinone in 30 ml of acetonitrile is treated at 10 ° with a solution of 5.37 g of cerium ( IV) -ammonium nitrate in 15 ml of water and stirred for two hours at room temperature.After extraction with ethyl acetate, washing with saturated NaHCOs solution, drying the organic phase over sodium sulfate and evaporation under reduced pressure to give the crude title compound, which is purified by chromatography on silica gel with toluene-ethyl acetate (4: 1 and 1: 1), [α] = +84 ± 1 ° (1.0% in chloroform).

ei) (SSR1-S-CdR11-allyloxycarbonyloxyethyl) -triphenyl-methylthio-azetidin-a-one 892 mg of triphenylmethylmercaptan are suspended in 5 ml of methanol at 0 ° and treated portionwise over 10 minutes with a total of 0.16 g of a 50% sodium hydride A solution of 0.62 g of (3S, 4R) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4-acetoxy-azetidin-2-one in 7 ml of acetone and 5 ml of water over 15 minutes is then added After 1 hour of stirring at 0 ° and three more hours at room temperature, the reaction mixture is concentrated on a rotary evaporator and extracted with 20 ml of methylene chloride.The organic phase is washed with brine and dried over MgSO ₄ .

After concentration, the crude title compound is purified by chromatography on silica gel (eluent toluene-ethyl acetate 19: 1). TLC (toluene-ethyl acetate 4: 1) R _f = 0.3, IR (CH ₂ Cl ₂ ) 3400; 1770 1 745cm ~ ¹ .

cj) 2 - {(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyethyl] -4-triphenyl-methylthio-2-oxo-azetidin-1-yl} -2-hydroxyacetic acid allyl ester 0.82g (SS ^ RJ-S-tliRl-i-allyloxycarbonyloxyethyl M-triphenylmethylthio-azetidin ^ -one and 0.416 g allylester ethylalcohol acetal in 10 ml of absolute toluene are mixed with 4 g of molecular sieve (4A) and stirred for 61 hours at 60 ° C. After filtering off and concentrating on The title compound is obtained under reduced pressure, rotary evaporator, TLC (silica gel / toluene / ethyl acetate 4: 1), R, = 0.1 × IR (CH ₂ Cl ₂ ): 3510, 1770, 1745 cm ^-1 .

ck) 2 - {(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyethyl] -triphenylmethylthio-a-oxo-azetidin-i-yl-a-triphenylphosphoranylidenessigsäureallylester

To a solution of 1 g of 2 - {(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyethyl] -4-triphenylmethylthio-2-oxo-azetidin-1-yl} -2-hydroxyacetic acid allyl ester in 10 ml of tetrahydrofuran 0.182 ml of thionyl chloride and 0.206 ml of pyridine are added in succession with stirring at 0 ° in succession within 5 minutes. The white suspension is stirred for 30 minutes at 0 ° and filtered through Hyflo. After washing the residue with toluene is concentrated on a rotary evaporator. The residue is dissolved in 10 ml of dioxane, treated with 0.624 g of triphenylphosphine and 0.257 ml of lutidine and stirred for 46 hours at 80 ° bath temperature. The mixture is filtered through Hyflo and the residue is washed with toluene. The combined filtrates are evaporated and chromatography of the residue on silica gel gives the pure product (eluent toluene / ethyl acetate 19: 1 to 4: 1), TLC (silica gel, toluene / ethyl acetate 4: 1), R _f = 0.24, IR (CH ₂ Cl ₂ ) 1745; 1620cm " ¹

 el) Silver salt of the α-iOS ^ Ry-S-tdRl-i-allyloxycarbonyloxyethyl) -triphenylmethylthio-a-oxo-azetidin-i-yl} ^ -triphenylphosphoranylidene-acetic acid allyl ester

0.46 g of 2 - {(3S, 4R) -3 - [(1R) -1 _: allyloxycarbonyloxyethyl] -4-triphenyl-methylthio-2-oxo-azetidin-1-yl} -2-triphenylphosphoranylidenessigsäureallylesterwerden be presented in 6ml of diethyl ether and at Room temperature with 4.4 ml of a 0.5 M aqueous silver nitrate solution. Thereafter, 0.077 ml of triethylamine are added and the reaction mixture is stirred for 30 minutes. The solid is filtered off with suction and washed well with water and diethyl ether. The residue is slurried again in 300 ml of water and 300 ml of diethyl ether, stirred and then filtered off. After renewed washing with diethyl ether, the solid is dried under high vacuum. IR (CH ₂ Cl ₂ ) 1760; 1745; 1630cm " ¹ .

Example 2: (5R, 6S) -2 - [(2R, S) -2-Amino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid

1.05 g of (5R, 6S) -2 - [(2R, S) -2-allyloxycarbonylamino-prop-1-yl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester are disclosed in US Pat 28ml abs. Submitted tetrahydrofuran and treated sequentially with 105 mg of tetrakis (triphenylphosphine) palladium and portionwise with 2.03ml tri-n-butyltin hydride. After stirring for 2 hours at room temperature, the reaction mixture is treated with 0.813 ml of acetic acid. After further stirring for 30 minutes at room temperature, 40 ml of hexane are added. The solid is filtered off and then dissolved in water. The solution is clarified with a little charcoal and filtered through Minipor filter. The title compound is obtained by lyophilization. UV (PhosphatpufferpH7,4) \ _mm = 304,5nm, IR (DMSO · d _6): 1772cnrT. ¹

The resulting diastereomeric mixture, consisting of compounds having a (2R) -2-aminoprop-1-yl or a (2S) -2-aminoprop-1-yl group in the 2-position, can be purified by column chromatography (Antecgel OPTI UP C ₁₂ ; run medium: water) into its components:.-.- ··

Isomer A: R _f (Antec gel OPTI-UPCi ₂ , water) = 0.2.

NMR (360 MHz; D ₂ O; reference TSP): δ = 1.3 (3H, d), 1.37 (3H, d) 2.95 and 3.18 (2H, m), 3.6 (iH, m), 3.9 (1H, dd), 4.25 (1H, m) and 5.7ppm (1H, d).

Isomer B: R _f (Antec gel OPTI-UPC ₁₂ , water) = 0.17

NMR (360 MHz; D ₂ O; reference TSP): δ = 1.3 (3H, d), 1.39 (3H, d), 2.97 and 3.27 (2H, m), 3.65 (1H , m), 3.92 (1H, dd), 4.26 (1H, m) and 5.67ppm (1H, d).

Example 3: (5R, 6S) -2 - [(2R, S) -2-Allyloxycarbonylamino-but-1-yl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester

1,98g2 - {(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyethyl] -4 - [(3R, S) -3-allyloxycarbonylaminovaleroylthio] -2-oxo-azetidin-1-yl are used as in Example 1 } -2-triphenylphosphoranylidenessigsäure allylester converted into the title compound. IR (CH ₂ Cl ₂ ): 3440; 1790; 1740; 1720; 1710; 1 580cm "" ¹

 The starting material can be prepared as follows:

a) (3R, S) -3-allyloxycarbonylaminovaleric acid

Analogously to Example 1 a), 5.86 g (3R, S) -3-aminovaleric acid are converted into the title compound. IR (CH ₂ Cl ₂ ): 3430; 1710cm " ¹ .

b) (SR.Sl-S-allyloxycarbonylaminovaleric acid chloride

Analogously to Example 1 b), 0.4 g of (3R, S) -3-allyloxycarbonylaminovaleric acid are converted into the title compound. IR (CH ₂ Cl ₂ ): 3430; 1785; 1710cm " ¹ .

c) 2 - {(3S, 4R) -3 - [(1R) -1-Allyloxycarbonyloxyethyl] -4 - [{3R, S) -3-allyloxycarbonylaminovaleroylthio] -2-oxo-azetidin-1-yl} - 2-triphenyl-phosphoranylideneamino essigsäureallylester

Analogously to Example 1c), 2.79 g of silver salt of 2 - {(3S, 4R) -3 - [(1R) -1-allyloxycarbonyloxyethyl] -4-mercapto-2-oxoazetidin-1-yl} -2-triphenylphosphoranylidenessigsäureallylesters with 1, 32 g of SR.SJ-S-allyloxycarbonylaminovaleric acid chloride are converted to the title compound, IR (CH ₂ Cl ₂ ) 3440, 1760, 1725, 1625 cm ^-1 .

Example 4: (5R, 6S) -2 - [(2R, S) -2-Amino-but-1-yl) -6 - [{1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid

Analogously to Example 2, 0.8 g (5R, 6S) -2 - [(2R, S) -2-allyloxycarbonylamino-but-1-yl] -6 - [(1R) -1-allyloxycarbonyloxyethyl] -2-penem-3 carboxylic acid allyl ester in the title compound. UV (phosphate buffer pH7.4): \ _max = 306nm.

Example 5: (5R, 6S) -2 - [(2R, S) -2-N-formamidiniprop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid

A solution of 109.5 mg of ethyl formimidate hydrochloride and 84 mg of sodium bicarbonate in 4 ml of water at room temperature with a solution of 25 mg (5R, 6S) -2 - [(2R, S) -2-amino-prop-1-yl ] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid and 8.4 mg sodium bicarbonate in 1 ml of water. After stirring for 50 min at room temperature, 1 ml of 1N HCl is added and the mixture is evaporated under high vacuum. The crude substance is purified by chromatography on OPTI-UPC ₁₂ . UV (phosphate buffer pH 7.4): K _msx 304.5nm.

Examples: (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester

1.2 g of sodium iodide are dissolved in 3.7 ml of acetone and treated with 0.275 ml of ethyl-i-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. The solution is then added dropwise to 10.5 ml of methylene chloride and filtered off from the precipitated inorganic salts. The methylene chloride solution is concentrated to 2 ml and added at 0 ° to a solution of 0.272 g (ImMoI) (5R, 6S) -2- [2R, S) -2-aminoprop-1-yl] -6 - [(1R) - 1-hydroxyethyl] -2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the mobile phase ethyl acetate. The title compound is obtained as a white foam. IR spectrum (methylene chloride): absorption bands at 1790 and 1740cm " ¹ .

Example 7: (5R, 6S) -2 - [(2R, S) -2-Aminoprop-1-yl] -6 - [{1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid pivaloyl oxymethyl ester 0.6 g of sodium iodide are dissolved in 2 ml of acetone and treated with 0.15 ml of Pivalinsäurechlormethylester. The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to 1 ml and added to a solution of 0.11 g (0.4 mmol) (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6 - [( 1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of Ν, Ν-dimethylacetamide at 0 °. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the mobile phase ethyl acetate. The title compound is obtained as a white foam. IR spectrum (methylene chloride): absorption bands at 1790 and 1730 cm ^-1 .

Example 8: In an analogous manner as described in the preceding examples, the following compounds can be prepared:

(5R, 6S) -2 - [(3R, S) -3-aminobut-1-yl] -64 (1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4) _max = 305 nm,

(5R, 6S) -2 - [(2R, S) -2-amino-3-hydroxy-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (Phosphate buffer pH 7.4) A _max = 304 nm,

(5R, 6S) -2 - [(2R, S) -2,3-diamino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4) \ _m3X = 305.5 nm,

(5R, 6S) -2 - [(2R, S) -2-N-methylaminoprop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (phosphate buffer pH 7 , 4) A _max = 306 nm,

(5R, 6S) -2 - [(2R, S) -2-N-Formylamino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4) X _max = 305 nm,

(5R, 6S) -2 - [(2R, S) -2-N-acetylamino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4) X _max = 304.5 nm,

Example 9: Dry ampoules or vials containing (5R, 6S) -2 - [(2R, S) -2-amino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3 -carboxylic acid as active substance, are prepared as follows:

Composition (for 1 ampoule or vial):

Active substance 0.5 g

Mannitol 0.05 g

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

Instead of the above-mentioned active substance, the same amount of another active substance of the preceding examples, for. B.

(5R, 6S) -2 - [(2R, S) -2-amino-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid.

Claims (9)

-ι- / a * foι Invention claim: 1. A process for the preparation of compounds of the formula wherein R _{1 is} hydroxy or protected hydroxy, R _{2 is} carboxyl or functionally modified carboxyl, R _{3 is} amino, lower alkyl substituted amino, lower alkanoylamino, substituted methyleneamino or protected amino, R _{4 is} optionally amino, lower alkyl substituted amino, substituted methyleneamino, is protected amino, hydroxy or protected hydroxy-substituted methyl or ethyl, and m is an integer from 1 to 3, optical isomers of compounds of formula I, mixtures of such optical isomers, salts of those compounds of formula I having a salt-forming group , and pharmaceutical preparations containing these compounds, characterized in that
a) an ylide compound of the formula CH ₃ -CH. _> SC- (CH 2) _a -CH-R ₃ * j-J * · (H), wherein Ri, R ₃ , R ₄ and m have the meanings given under formula I, R ₂ 'is protected carboxyl, Z is oxygen or sulfur and X® represents either a trisubstituted phosphoniogroup or a di-esterified phosphono group together with a cation or in which R 1, R ₃ , R ₄ and m have the meanings given under formula I, R ₂ 'represents a protected carboxyl group and X is the group -S- or the group -SO ₂ -, the radical X is split off, and, if desired or necessary, into an obtainable compound of formula I a protected hydroxy group Ri or protected hydroxy in the radical R ₄ in the free hydroxy group, and / or, if desired, in an obtainable compound of formula I a protected carboxy group R ₂ 'in the free carboxyl group, in a cleavable under physiological conditions esterified carboxyl group or in another protected carboxyl group R ₂ ' or a free e carboxyl group R _{2 converted} into a cleavable under physiological conditions esterified carboxyl group, and / or, if desired, a protected amino group R ₃ or protected amino in the radical R ₄ in the free amino group or a free amino group R ₃ or free amino in the radical R ₄ converted into a substituted amino group; 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 available salt in the free compound or in another Salt, and / or processed an available compound of formula I or a pharmaceutically acceptable salt thereof to a pharmaceutical preparation. 2. Method according to item 1, characterized in that compounds of formula I, wherein Ri is hydroxy or protected hydroxy; R _{2 is} carboxyl, cleavable esterified carboxyl or protected carboxyl R ₂ 'under physiological conditions, R _{3 is} amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, a group of formula -N = C (Xi, X ₂ ) where X i is hydrogen, amino, lower alkylamino, Di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower-alkylamino-lower alkyl, N, N-di-lower-alkylamino-lower alkyl, lower alkenyl, phenyl or monocyclic 5- or 6-membered heteroaryl having 1 or 2 nitrogen atoms bonded through a ring carbon atom or an oxygen or sulfur atom, and X _{2 is} amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio, or protected amino; R _{4 is} methyl, ethyl or by amino, lower alkylamino, di-lower alkylamino, a group of the formula N =C (X 1, X ₂ ) in which Xi and X _{2 have} the meanings given in the definition of R ₃ , protected amino, hydroxy or protected hydroxy is substituted methyl or ethyl, and my integer is from 1 to 3, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of those compounds of formula I, which have a salt-forming group produces. 3. The method according to item 1, characterized by reacting compounds of formula I, wherein R _{1 is} hydroxy, R _{2 is} carboxyl or esterified carboxyl cleavable under physiological conditions, ζ. Lower alkanoyloxymethoxycarbonyl or I-lower alkoxycarbonyloxy-lower alkoxycarbonyl, R _{3 represents} amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or a group of formula -N = C (X ₁₁ X ₂ ) wherein X _{1 is} hydrogen, lower alkyl or amino and X _{2 is} amino , R _{4 is} methyl, ethyl or by amino, lower alkylamino or hydroxy-substituted methyl or ethyl, and m is 1 or 2, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I, which is a salt-forming Group having manufactures. 4. The method according to item!, Characterized by reacting compounds of formula!, Wherein R, is hydroxy, R _{2 is} carboxyl or esterified carboxyl cleavable under physiological conditions, ζ. B. Lower alkanoyloxymethoxycarbonyl or I-Niederalkoxycarbonyloxyniederalkoxycarbonyl, R _{3 is} amino, R _{4 is} methyl or ethyl and m is 1 or 2, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I, which have a salt-forming group manufactures. -2- 794 61 5. The method according to item 1, characterized in that pharmaceutically acceptable salts of compounds of formula I are prepared. 6. The method according to item!, Characterized in that cleavable esters of compounds of formula I, prepared under physiological conditions. 7. The method according to item 1, characterized in that one produces compounds of the formula!, Wherein the radical CH (Ri) (CH ₃ ) has the R-configuration. 8. The method according to item 1, characterized in that (5R, 6S) -2 - [(2R, S) -2-amino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] - 2-penem-3-carboxylic acid, (5R, 6S) -2 - [(2R) -2-aminoprop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, and (5R, 6S) -2 - [(2S) -2-amino-prop-1-yl] -6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid, pharmaceutically acceptable salts thereof, and physiologically cleavable esters thereof. 9. The method according to item!, Characterized in that (5R, 6S) -2 - [(2R, S) -2-amino-but-1-yl) -6 - [(1R) -1-hydroxy-ethyl ] -2-penem-3-carboxylic acid, optical isomers thereof, pharmaceutically acceptable salts thereof and, under physiological conditions, cleavable esters thereof.