DD251132A5 - PROCESS FOR PREPARING AMINOENETERALKYL-PENEM COMPOUNDS - Google Patents

Abstract

2-amino-lower alkyl-2-penem compounds of formula (I) wherein R 1 is lower alkyl substituted by hydroxy or protected hydroxy, R 2 is carboxyl or protected carboxyl R 2, R 3 is amino, lower alkyl substituted amino, substituted methyleneamino or protected amino and A is lower alkyl substituted straight-chain lower alkylene, with the proviso that R1 is other than 1-hydroxyethyl or protected 1-hydroxyethyl when A is methylally substituted by two methyl straight chain lower alkylene, R2 is above and R3 is amino or protected amino, salts of such compounds of the formula I which have a salt-forming group, optical isomers of compounds of the formula I and mixtures of these optical isomers have antibiotic properties. The new connections can z. B. in the form of antibiotically effective preparations for the treatment of infectious diseases. The new compounds can be prepared in a conventional manner. Formula (I)

Description

Process for the preparation of amino-lower alkyl-penem compounds Field of application of the invention

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

Characteristic of the known technical solutions

From European Patent Application 3960 and from the

U.S. Patent 4,272,437 are in the 6-position by hydroxy lower alkyl and

2-position substituted by straight-chain amino-lower alkyl substituted 2-penem-3-carboxylic acids with antibiotic activity and process for their preparation.

Object of the invention

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

Explanation of the essence of the invention

The present invention has for its object, starting from easily accessible starting compounds new antibiotically active same 2-Amiiioniederalkyl-penem compounds and methods for their preparation to find.

t ? .8 <Τ-'ί

- la -

According to the invention, Z-amino-lower alkyl-Z-penem compounds of the formula

R 2

wherein R ₁ is lower alkyl substituted with hydroxy or protected hydroxy, R is carboxyl or protected carboxyl R ', R is amino, lower alkyl substituted amino, substituted methyleneamino or protected amino and A is lower alkyl substituted straight chain lower alkylene, provided R is other than 1-hydroxyethyl or protected 1-hydroxyethyl, when A is straight chain lower alkylene geminally substituted by two methyl groups, R- has the above meaning and R, amino or protected amino, salts of those compounds of formula I which form a salt-forming group have, optical isomers of compounds

of formula I and mixtures of these optical isomers, as well as pharmaceutical preparations containing such compounds.

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

Lower alkyl-substituted amino R_ is e.g. Lower alkylamino or di-lower alkylamino.

In substituted methyleneamino, the methylene radical is preferably mono- or disubstituted. Substituted methyleneamino is e.g. a group of the formula

N / (IA)

wherein X is hydrogen, optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, e.g. Lower alkoxy or phenyl-lower alkoxy, etherified mercapto, e.g. Lower alkylthio, optionally substituted lower alkyl, e.g. Lower alkyl, amino-lower alkyl, N'-lower alkylamino lower alkyl or Ν, Ν-di-lower alkylamino lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms and / or an oxygen or sulfur atom, such as pyridyl, e.g. 2- or 4-pyridyl, thienyl, e.g. 2-thienyl, or thiazolyl, e.g. 4-thiazolyl, and X is optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, e.g. Lower alkoxy or phenyl-lower alkoxy, or etherified mercapto, e.g. Lower alkylthio represents.

In preferred radicals of formula (IA), X _{1 is} hydrogen, amino, lower alkylamino or lower alkyl and X is amino.

Radicals of the formula (IA) which have a hydrogen atom on the α atom of the substituent X or of the substituent X ", e.g. Radicals of formula (IA) wherein X is amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower alkyl and / or X "is amino, lower alkylamino, hydrazino or anilino may also be used in the tautomeric forms

-NH-CT or -NH-C _n

(IB) (IC),

^X 2

wherein X 'and X' are corresponding substituted or unsubstituted methylene or imino.

In the present specification, the term "lower" used in connection with 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.

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

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

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

23f

Lower alkoxy is e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy, while phenyl-lower alkoxy e.g. Benzyloxy is.

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

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Amino-lower alkyl is e.g. 2-aminoethyl or 3-aminopropyl.

N-lower alkylamino lower alkyl is e.g. 2-methyl or 2-ethylaminoethyl, while Ν, Ν-di-lower alkylamino lower alkyl e.g. 2-Dimethylaminoethyl or 2-Diäthylaminoäthyl means. Lower alkenyl is e.g. Allyl, n-propenyl or isopropenyl.

Straight-chain lower alkylene in the radical A has 1 to 7, preferably 1 to 4, carbon atoms and is e.g. Methylene, ethylene, 1,3-propylene, 1,4-butylene, and also 1,5-pentylene. Such a lower alkylene radical is mono- or polysubstituted by lower alkyl having 1 to 4 carbon atoms, in particular having 1 to 2 carbon atoms, such as n-propyl, η-butyl or especially methyl or ethyl, in particular mono- or disubstituted. Two lower alkyl substituents may be located on the same carbon atom (geminal), on adjacent carbon atoms (vicinal) or on two different carbon atoms of the lower alkylene chain separated by at least one methylene group.

Such a radical A is, for example, lower alkylidene, such as ethylidene ("methylmethylene"), 1,2-propylene, 2-lower alkyl, such as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl , such as 2-methyl

or 2-ethyl-1,2-butylene, 3-lower alkyl, such as 3-methyl-1,2-butylene, 1,3-butyl, 2-lower alkyl, such as 2-methyl-1,3-butylene, 3 Lower alkyl, such as 3-methyl-l, 3-butylene, or 2,2-di-lower alkyl, such as 2,2-dimethyl-1,3-butylene, wherein in these radicals the carbon atom 1 is connected to the penem ring skeleton , or also 1,2-propylene, 2-lower alkyl, such as 2-methyl-l, 2-propylene, 1,2-butylene, 2-lower alkyl, such as 2-methyl or 2-ethyl-1, 2- butylene, 3-lower alkyl, such as 3-methyl-1,2-butylene, or 3,3-di-lower alkyl, such as 3,3-dimethyl-l, 2-butylene, wherein in these radicals the carbon atom 2 with the penem Ring skeleton is connected. Preferred radicals A are 1,2-propylene, 1,2-butylene, 1,3-butylene and 2-methyl-1,2-propylene, linked via the carbon atom 1 to the penem ring skeleton, and via the carbon atom 2 with the penem Ring scaffold connected 1,2-propylene.

The functional groups present in the compounds of the formula I, such as hydroxyl, carboxy or amino groups, in particular the hydroxy group in the radical R, the carboxyl group R and an amino group Ro, are optionally protected by conventional protecting groups which are present in the penem, penicillin , Cephalosporin and peptide chemistry.

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

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

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

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

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

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

In compounds of formula (I), a hydroxy group in the radical R may be protected, for example, by acyl radicals. Suitable acyl radicals are e.g. optionally substituted by halogen substituted lower alkanoyl, e.g. Acetyl or trifluoroacetyl, optionally nitro substituted benzoyl, e.g. Benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally lower halogenated lower alkoxycarbonyl, e.g. 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, or optionally nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups are e.g. trisubstituted silyl, such as tri-lower alkylsilyl, e.g. Trimethylsilyl or tert-butyl-dimethylsilyl, 2-halo-lower alkyl groups, e.g. 2-chloro, 2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally halogen, e.g. Chlorine, lower alkoxy, e.g. Methoxy, and / or nitro substituted phenyl-lower alkyl, such as corresponding benzyl. Preferred as hydroxy protecting group is the tri-lower alkylsilyl group.

A carboxyl group R "is usually protected in esterified form, the ester group being protected under mild conditions, e.g. a sparingly soluble, such as hydrogenolytic, or gently solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions.) A protected carboxyl group R "may in particular also be cleaved under physiological conditions or slightly modified into another functionally modified carboxyl group, such as represent an esterified carboxyl group convertible to another esterified carboxyl group.

Such esterified carboxyl groups R. ' contain as esterifying groups primarily in the 1-position branched or in the 1- or 2-position suitably substituted lower alkyl groups. Preferred in esterified

- ν

Carboxyl groups present in the form are, inter alia, lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl, and (hetero) arylmethoxycarbonyl having 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert-butyl, halogen, e.g. Chloro, and / or nitro mono- or polysubstituiert. Examples of such groups are optionally e.g. As mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as mentioned above, substituted picyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl. Other suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, halo-lower alkoxycarbonyl such as 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyi, 2-chloroethoxycarbonyi, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 10-halo-lower alkoxycarbonyl wherein lower alkoxy contains from 4 to 7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, or in the 2-position by lower alkylsulfonyl, cyano or trisubstituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl.

Other esterified protected carboxyl groups R "'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, e.g. Methoxy, as a substituent. Suitable silyl or stannyl groups are primarily trichloro

25 1 y

alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or appropriately substituted stannyl groups, e.g. Tri-nbutylstannyl.

An esterified carboxyl group R2 cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group in which acyl is e.g. the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone, 1-lower alkoxy-lower alkoxycarbonyl or also lower alkoxycarbonyloxy-lower alkoxycarbonyl, wherein lower alkyl e.g. Methyl, propyl, butyl or especially ethyl and lower alkoxy e.g. Methoxy, propoxy or butoxy. Such groups are e.g. Lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, e.g. Glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, 4-crotonolactonyl or 4-butyrolactone-4-yl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Preferred protected carboxyl groups R 'are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl and the 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl substituted ethoxycarbonyl group, and especially the cleavable under physiological conditions esterified carboxyl groups, such as. Lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl.

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

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

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

An etherified mercaptoamino group is primarily an 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.

a substituted phenylthioamino group or a pyridylthioamino group. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.

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

Further protected amino groups are e.g. Enaminogruppen containing at the double bond in the 2-position an electron-withdrawing substituent, such as a carbonyl group. Protecting groups of this kind are, for example, 1-acyl-lower-alk-1-en-2-yl radicals, in which acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, e.g. Acetic acid, an optional, e.g. lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halo, such as chloro and / or nitro substituted benzoic acid, or especially a carbonic acid half ester, such as a carbonic acid lower alkyl, e.g. methyl-half-ester or -ethyl semester, and lower alk-1-ene, in particular 1-propene. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. 1-ethoxycarbonyl-propl-en-2-yl.

Preferred protected amino groups are e.g. Azido, phthalimido, nitro, lower alkenyloxycarbonylamino, optionally nitro-substituted benzyloxycarbonylamino, 1-lower alkanoyl-lower alkene-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino.

Salts of compounds of the invention are primarily pharmaceutically acceptable non-toxic salts of compounds of formula I. Such salts are formed, for example, by compounds of formula I wherein R is carboxyl and are primarily metal or ammonium salts such as alkali metal and alkaline earth metal -, eg Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, dibenzylamine or N-benzyl-ß-phenethylamine. Compounds of formula I having a basic group, e.g. with an amino group, acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Acetic, succinic, fumaric, maleic, tartaric, oxalic, citric, benzoic, mandelic, malic, ascorbic, methanesulfonic or form 4-toluenesulfonic acid. Compounds of formula I having an acidic and a basic group may also be present in the form of internal salts, i. in zwitterionic form.

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

The penem compounds of the formula I have the R configuration at the carbon atom 5 and the S configuration at the carbon atom 6.

25ί

The compounds of the formula I may have, in the substituents R and / or A, further chiral centers which may each be in the R, S or racemic R, S configuration. In compounds of the formula I in which R in α-position (on the carbon atom 1 ^T ) is hydroxy-asymmetrically substituted lower alkyl having 2 to 7 carbon atoms, in particular ¹ -hydroxyethyl, the substituents on the carbon atom I ¹ preferably adopt the R-configuration ,

More particularly, the invention relates to compounds of formula I, wherein R is lower alkyl substituted by hydroxy or protected hydroxy, R "is carboxyl or protected carboxyl R ', R is amino, lower alkyl amino, di-lower alkylamino _; a group of formula -N = C (X, X ") wherein X is hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, loweralkoxy, phenylloweralkoxy, loweralkylthio, loweralkyl, amino-lower alkyl, N-loweralkylamino-lower alkyl, Ν, Ν Lower alkylamino lower alkyl, lower alkenyl, phenyl, pyridyl, eg 2- or 4-pyridyl, thienyl, eg 2-thienyl, or thiazolyl, eg 4-thiazolyl, and X is amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio, or protected amino, and A represents lower alkylene substituted by lower alkyl of 1 to 4 carbon atoms, with the proviso that R is other than 1-hydroxyethyl or protected 1-hydroxyethyl, when A is straight chain lower alkylene geminally substituted by two methyl groups R 'has the above meaning and R represents amino or protected amino; Salts of those compounds of the formula I which contain a salt-forming group, optical isomers of compounds of the formula I, which in the radicals R ₁ and / or A have chiral centers and mixtures of these optical isomers.

The invention relates, in particular, to compounds of the formula I in which R ₁ is hydroxyl, tri-lower alkylsilyloxy, 2-halo-lower alkoxy,

2 5 1 ι ν)

R _{2 is} carboxyl, lower alkenyloxycarbonyl, optionally nitro-substituted benzyloxycarbonyl, lower alkanoylmethoxycarbonyl, 2-halo-lower alkoxycarbonyl, 2-tri-lower alkylsilylethoxycarbonyl or an esterified carboxyl group cleavable under physiological conditions, eg 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, a-aminoloweralkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, R is amino, lower alkylamino, di-lower alkylamino ^ a group of formula -N = C (X, X) wherein X _{1 is} hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, eg 2-pyridyl, and X is amino, lower alkylamino or di-lower alkylamino; Azido, phthalimino, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro-substituted benzyloxycarbonylamino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino, and A by lower alkyl with 1 to 4 carbon mono- or disubstituted straight chain lower alkylene, with the proviso that R is other than 1-hydroxyethyl or protected 1-hydroxyethyl when A is methylally substituted by two methyl straight chain lower alkylene, R 'has the above meaning and R is amino or protected amino represents; Salts of compounds of the formula I which have a salt-forming group, optical isomers of compounds of the formula I which have chiral centers in the radicals R and / or A, and mixtures of these optical isomers.

The invention relates in the first place to compounds of the formula I in which R is hydroxy-substituted lower alkyl and A is methyl or ethyl monosubstituted straight-chain lower alkylene having 1 to 4 carbon atoms or R _{1 is} hydroxymethyl and A is methyl or ethyl disubstituted straight-chain lower alkylene of 1 to 4 carbon atoms, and wherein

25! 132

R each represents carboxyl, L-lower alkoxycarbonyloxy-lower alkoxycarbonyl or lower alkanoyloxymethoxycarbonyl and R- each represents amino, lower alkylamino or formamidino, salts of such compounds of formula I, optical isomers of compounds of formula I having in the radicals R. and / or A chiral centers, and Mixtures of these optical isomers.

The invention mainly relates to compounds of formula I, wherein. R is hydroxymethyl or 1-hydroxyethyl; and A is methyl or ethyl monosubstituted ethylene or 1,3-propylene, or wherein R is hydroxymethyl and A is methyl disubstituted ethylene, and R ₂ is carboxyl and R ₁ is amino, and Salts of such compounds of the formula I.

The invention furthermore relates to the pure optical isomers of those compounds of the formula I which have further chiral centers in the substituents R and / or A, in particular the (I ¹ R) isomers of compounds of the formula I in which R ^{1 is 1} -hydroxyethyl , and salts of such compounds of the formula I.

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

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

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

a) an ylide compound of the formula

R "

1 ·, ^ S -C-A-R.,

(ID,

wherein RpRi ' ^R 3 ^{and A} ^ ^e have the meanings given ^under formula I, Z is oxygen or sulfur and X 1 represents either a trisubstituted phosphonium group or a doubly esterified phosphonium group together with a cation, or

b) a compound of the formula

ττ U s

CT C = O

^R 2

wherein R, R ', R and A have the meanings given under formula I, treated with an organic compound of the trivalent phosphorus, and if desired or necessary, in an available compound of formula I a protected hydroxy group in the radical R .. in the free Hydroxy group, and / or, if desired, in an available compound of formula I a protected carboxyl group R 'in the free carboxyl group or in another protected carboxyl group R "' or a free carboxyl group R" in. A protected. Carboxyl group R 1, and / or, if desired, a protected amino group R "into the free amino group or a free amino group R converted into a substituted amino group, and / or, if desired, a compound obtainable with salt-forming

Converted group into a salt or an available salt in the free compound or in another salt, and / or, if desired, an available mixture of isomeric compounds of formula I is separated into the individual isomers, and / or an obtainable compound of formula I. or a pharmaceutically acceptable salt thereof, into a pharmaceutical preparation.

In the starting compounds of formulas II and III are functional groups such as a free hydroxy group in the radical R and in particular a free amino group R, preferably by conventional protecting groups, e.g. protected by one of the above.

a) Cyclization of the compound of formula II

The X "^ group in the starting material of formula II is one of the commonly used in Wittig condensation reactions phosphonio or phosphono, especially a triaryl, for example, triphenyl- or Triniederalkyl-, for example tri-n-butylphosphoniogruppe, or by lower alkyl, eg. 3. ethyl, diesterified phosphono group, where the symbol λ ^ in the event the phosphono addition, the cation of a strong base, particularly a suitable metal, such as alkali metal, eg lithium, sodium or potassium ion comprising. preferred as the group X ~ ^ are on the one hand and on the other hand triphenylphosphonio diethylphosphono together with an alkali metal such as sodium ion.

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

7 ^! "ί i ί - 17 -

The ring closure can be spontaneous, ie in the preparation of the starting materials, or by heating, for example in a temperature range of about 30 ° C to 16O ⁰ C, preferably from about 50 ⁰ C to about 100 ⁰ C, take place. The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, eg hexane or benzene, a halogenated hydrocarbon, eg methylene chloride

Aether, e.g. Diethyl ether, a carboxylic acid amide, e.g. Dimethylformamide, a di-lower alkyl sulfoxide, e.g. Dimethyl sulfoxide, or a lower alkanol, e.g. Methanol, or in a mixture thereof, and, if necessary, in an inert gas, e.g. Nitrogen atmosphere, performed.

b. Cyclization of the compound of formula III

An organic compound of the trivalent phosphorus is derived e.g. of phosphorous acid and is especially an ester thereof with a lower alkanol, e.g. Methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, e.g. Phenol or catechol, or an amide ester thereof of the formula P (OR) -N (R) n, where R and R independently of one another are lower alkyl, e.g. Methyl, or aryl, e.g. Phenyl, mean. Preferred compounds of the trivalent phosphorus are trialkyl phosphites, e.g. Trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, for example benzene or toluene, an ether, for example dioxane or tetrahydrofuran, or a halogenated hydrocarbon, for example methylene chloride or chloroform, at a temperature of about 20 ° to about 80 ⁰ C, preferably from about 40 ° to about 60 ⁰ C is performed to give 1 molar equivalent of a compound of formula III with 2 molar equivalents of phosphoric

L 5 i λ Λ'ί - 18 -

Implementation of connection. Preferably, the compound of formula III is pre-charged in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over an extended period, 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 in situ, as described below in step 1.5, and reacted without isolation from the reaction mixture with the organic compound of the trivalent phosphorus to give the end products of the formula I.

Preference is given to using those starting materials of the formulas II and III which lead to the compound of the formula I mentioned above as being particularly preferred.

In an available compound of formula I wherein one or more functional groups are protected, these, e.g. protected amino, carboxyl or hydroxy groups, in a conventional manner by solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or chemical reduction, optionally be released gradually or simultaneously.

In a compound of the formula I which can be obtained according to the invention and has a protected amino group R, it can be prepared in a manner known per se, e.g. depending on the nature of the protective group, preferably by solvolysis or reduction, in the free amino R. transferred

become. 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 prepared by treating with a suitable chemical reducing agent, such as

Zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid, or catalytically with hydrogen in the presence of a palladium

split catalyst. Aroylmethoxycarbonylamino may also be prepared by treatment with a nucleophilic, preferably salt-forming reagent such as xatrium thiophenolate and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. N'atriumdithionite be cleaved. Optionally substituted benzyloxycarbonylamino may be e.g. by means of hydrogenolysis, i. by treating with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino, by reacting with a compound of palladium, e.g. Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. 2-Aethylhexansäure, or a salt thereof, are cleaved. An amino group protected with an organic silyl or stannyl group may e.g. by hydrolysis or alcoholysis, one represented by 2-halo-lower alkanoyl, e.g. 2-chloroacetyl, protected amino group are released 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 alcohol or hydrolysis of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl may be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetraäthylammoniumfluorid, bedenden in the free amino group. An amino group protected in the form of an azido or nitro group is e.g. converted by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium or by treatment with zinc in the presence of an acid such as acetic acid. A protected in the form of a phthalimido group amino group

can be converted by reacting with hydrazine in the free Aniinogruppe. Furthermore, an arylthioamino group can be converted to anino by treatment with a nucleophilic reagent, such as sulfurous acid.

Furthermore, a free amino group BU can be converted in a manner known per se into a substituted amino group. Thus, for example, amino can be prepared by reacting with a corresponding acyl halide such as chloride in acylamino R and with a β-dicarbonyl compound such as a 1-lower alkanoyl-acetone or a lower acetoacetate in 1-lower alkanoyl or 1-lower alkoxycarbonylprop-1 convict -en-2-ylamino. 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. 2,652,679. Thus, for example, compounds of the formula I in which R is amino can be prepared by reaction with trimethylsilyl chloride and an imido halide of the formula [(X ₁₅ Y ₁ ) C =X ₂ ] ^Y 2 ' ^{in which Y} i is halogen, for example chlorine, and ^Y 2 is an anion, For example, chloride, means in amidines and by reacting with a substituted isourea or isothiourea of the formula (XX) C = X, wherein Y is lower alkoxy or lower alkylthio, are converted into guanidines. Furthermore, one can convert a free amino group Ro 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, eg chlorides or bromides, or sulfonates, eg methane or p-toluenesulfonates, in the presence of a basic condensing agent, such as an alkali or alkaline earth metal hydroxide or carbonate, for example potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alkanol, at room temperature or elevated or reduced temperature, eg at about -20 ° to + 8O ⁰ C.

O ς ι ι ι

In a compound of the formula I obtainable by the process in which R is a protected carboxyl group R "', the carboxyl group can be released in a manner known per se.

Thus, tert.-lower alkoxycarbonyl or lower 2-position substituted by a trisubstituted silyl group or in the 1-position by lower alkoxy-substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl, e.g. by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, into free carboxyl. Optionally substituted benzyloxycarbonyl may be e.g. by means of hydrogenolysis, i. be cleaved by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a Palladiumkatalysa'tors. Further, suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl may also be obtained by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Tin, or metal salt, such as a chromium II salt, e.g. Chrora II chloride, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen with the metal, such as a suitable carboxylic acid, e.g. an optional, e.g. by hydroxy, substituted N'-lower alkanecarboxylic acid, e.g. Acetic, formic or glycolic acid, or an alcohol or thiol, preferably adding water, into free carboxyl. The cleavage of an allyl protecting group can be e.g. by reacting with a compound of palladium, e.g.

Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. 2-Aethylhexanoic acid, or a salt thereof. By treating with a reducing metal or metal salt, as described above, it is also possible to use 2-halo-lower alkoxycarbonyl (if appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group).

25 1

nylgruppe) or aroylmethoxycarbonyl into free carboxyl, wherein aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetrabutylammonium fluoride are converted into free carboxyl. Carboxylated with an organic silyl or stannyl group, such as tri-lower alkylsilyl or -stannyl, may be solvolytically, e.g. be released by treatment with water or an alcohol. A lower alkoxycarbonyl group substituted at the 2-position by lower alkylsulfonyl or cyano can be exemplified by e.g. by treating with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium or potassium hydroxide or sodium or potassium carbonate, are converted into free carboxyl.

In compounds of the formula I which can be obtained according to the process in which the radical R-- is substituted by protected hydroxy, the protected hydro-

xygruppe be converted in a conventional manner into the free hydroxy group. For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released as a suitably protected amino group, a tri-lower alkylsilyl group ζ .B. with tetrabutylammonium fluoride and acetic acid (Under these conditions, carboxyl groups protected by trisubstituted silylethyl groups are not cleaved). A 2-halo-lower alkyl group and an optionally substituted benzyl group are reductively removed.

On the other hand, it is also possible to convert compounds of the formula I in which R. is carboxy, into compounds of the formula I in which R "is a protected carboxyl group Ri, in particular an esterified carboxyl group

group R ', and is primarily a cleavable under physiological conditions esterified carboxyl group. Thus, the free carboxyl group can be e.g. by treating with a suitable diazo compound, such as a diazo-lower alkane, e.g. Diazomethane, or a phenyldiazole-lower alkane, e.g. Dipheny! Diazomethane, if necessary in the presence of a Lewis acid, e.g. Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. Dicyclohexylcarbodiimid, as well as carbonyldiimidazole, esterify. Esters can also be prepared by reacting an optionally in situ prepared salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid. Further, acid halides, such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed eg with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (eg with haloformic acid lower alkyl esters, such as chloroformate or Chloraineisensäureisobutylester, or with Halogenessigsäurehalogeniden, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group.

In a compound of formula I with an esterified carboxyl group R "'this can be converted into another esterified carboxyl group R ₉ ¹ , for example 2-Chloräthoxycarbonyl or 2-Bromäthoxycarbonyl by treatment with an iodine salt, for example sodium iodide, in 2-Jodäthoxycarbonyl. Further, in compounds of formula I containing an esterified carboxy group R ', 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 reaction with the reactive ester of a corresponding alcohol into a compound of formula I, wherein R _{9 represents} a cleavable esterified carboxyl group under physiological conditions.

231

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 formula I having a free carboxyl group R e.g. by treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of α-ethyl-caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Form sodium bicarbonate, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, e.g. by treatment with a suitable acid or a suitable anion exchange reagent. Internal salts of compounds of formula I can e.g. by neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.

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

Resulting mixtures of isomers can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods.

The cleavage of racemates obtained in their optical antipodes can be done in various ways.

One of these ways is to react a racemate with an optically active excipient that has been formed

O · i .j /. - 25 -

Mixture of two diastereomeric compounds by means of suitable physicochemical methods separates and then splits the individual diastereomeric compounds in the optically active compounds.

Particularly suitable racemates for separation into antipodes are those having an acidic group, e.g. Racemates of compounds of formula I, wherein R 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, (+) - dehydroabietylamine, (+) - and (-) - ephedrine, (+ ) - and (-) - l-phenylethylamine or their N-mono- or Ν, Ν-dialkylated derivatives to give mixtures consisting of two diastereomeric salts.

In carboxyl-containing racemates, this carboxyl group may also be esterified by an optically active alcohol such as (-) - menthol, (+) - borneol, (+) - or (-) - 2-0ctanol, followed by isolation of the desired Diastereomers, the carboxyl group is released.

For resolution of the racemate, the hydroxy group can also be esterified with optically active acids or their reactive, functional derivatives to form diastereomeric esters. Such acids include (-) - abietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acid, (+) - and (-) - camphanic acid, (+) - and (-) - Ketopic acid, L (+) - ascorbic acid, (+) - camphoric acid, (+) - camphorl-O-sulfonic acid (β), (+) - or (-) - α-bromo-camphor-ni-sulphonic acid, D (-) - quinic acid, D (-) - isoascorbic acid, D (-) and L (+) - mandelic acid, (+/- 1-menthoxyacetic acid, D (-) - and L (+) - tartaric acid and their di-O-benzoyl- and di -op-toluylderivate.

By reaction with optically active isocyanates, such as with (+) - or (-) - l-phenylethyl isocyanate, compounds of formula (I) wherein

R ~ protected carboxy and R, hydroxy substituted lower alkyl, are converted to a mixture of diastereomeric urethanes.

Basic racemates, for example compounds of the formula I in which the radical R _{3 is} an amino group, can form diastereomeric salts with said optically active acids.

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

Another method for separating the racemates consists in the chromatography on optically active absorption layers, for example on cane sugar.

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

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

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

25! 13

The separation of diastereomers into the individual raceirate and the racemate into the optical antipodes can be carried out at any stage of the process, i. e.g. also at the stage of the starting compounds of the formulas II or III or at any stage of the process described below for the preparation of the starting compounds of the formula II.

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

The method 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. Further, starting materials may be used in the form of derivatives or formed in situ, optionally under the reaction conditions. For example, a starting material of formula II wherein Z is oxygen can be prepared from a compound of formula II wherein Z is an optionally substituted methylidene group as described below by ozonization and subsequent reduction of the ozonide formed, analogously to the procedure given below (step 2.3) are prepared in situ, followed by the cyclization to the compound of formula I in the reaction solution.

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

Reaction scheme I

Z ¹

Il

R ₁ . · »

• -

ο ^κ

Level 1.3 ₀ / \ _c

Z ¹

UTI

(VII)

step

Z ¹

Il iS-C AR ₀

Level 1.4a

(VI)

(II ¹ )

^R 2

(VIII)

In the compounds of the formulas IV, VI, VII and II ¹ , Z 'is oxygen, sulfur or else a methylidene group optionally substituted by one or two substituents Y, which can be converted into an oxo group Z by oxidation. A substituent Y

this methylidene group is an organic radical, for example unsubstituted or substituted lower alkyl, for example methyl or ethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, phenyl or phenyl-lower alkyl, for example benzyl, or in particular a carboxyl group esterified with an optically active alcohol, such as 1-menthol, for example, one of the mentioned under R "optionally substituted Niederalkoxycarbonyl- or Arylmethoxycarbonylreste or l-menthyloxycarbonyl. The methylidene Z ¹ preferably carries one of said substituents. Of particular note are the Methoxycarbonylmethyliden- and the Aethoxycarbonylmethylidengruppe.

In the compounds of formulas IV to VIII and II ¹ R ₁ preferably contains a protected hydroxy-mentioned example, optionally substituted 1-phenyl-lower alkoxy, optionally substituted phenyl-lower alkoxycarbonyloxy, or tri-substituted silyloxy, and a free amino group R is preferably in protected form.

Step 1.1: A thio-azetidinone of formula IV is obtained by reacting a 4-W-azetidinone of formula V, wherein W represents a nucleofugic leaving group, with a mercapto compound of the formula

R -A-CC = Z ') - SH (IX)

or a salt, e.g. an alkali metal such as sodium or potassium salt thereof, and, if desired, in an available compound of formula IV wherein R is hydroxy substituted lower alkyl, converts hydroxy to protected hydroxy.

The nucleofuge leaving group W in a starting material of formula V is a through the nucleophilic radical

R ₃ -AC (= Z ') - S-

Such groups W are, for example, acyloxy radicals, sulfonyl radicals R -SO -, in which R is an organic radical

Rest is, azido or halogen. In an acyloxy radical W, acyl is z. E. The residue of an organic carboxylic acid, including an optically active carboxylic acid, and represents, for example, lower alkanoyl, e.g. Acetyl or propionyl, optionally substituted benzoyl, e.g. Benzoyl or 2,4-dinitrobenzoyl, phenyl-lower alkanoyl, e.g. Phenylacetyl, or the acyl radical of one of the above-mentioned optically active acids. In a sulfonyl radical R -SO - R is, for example, optionally hydroxy-substituted lower alkyl. such as methyl, ethyl or 2-hydroxyethyl, as well as corresponding substituted optically active lower alkyl, e.g. (2R) - or (2S) -l-hydroxyprop-2-yl, optically active group-substituted methyl, such as camphoryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen radical W is e.g. Bromine, iodine or especially chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

The nucleophilic substitution may be carried out under neutral or weakly basic conditions in the presence of water and optionally a water-miscible organic solvent. The basic conditions may be, for example, by adding an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. of sodium,. Potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents, e.g. water-miscible alcohols, e.g. Lower alkanols, such as methanol or ethanol, kerones, e.g. Lower alkanones such as acetone, amides, e.g. Niederalkancarbonsäureamide, such as dimethylformamide, acetonitrile and the like 'are used. The reaction is usually carried out at room temperature, but can also be carried out at elevated or reduced temperature. By adding a salt of hydriodic acid or thiocyanic acid, e.g. an alkali metal such as sodium salt, the reaction can be accelerated.

Both (3S, 4S) and (3S, 4R) -configured compounds of the formula V or mixtures thereof can be used in the reaction. The incoming group R ₃ -A-CC = Z ¹ ) -S-is preferably directed by the group R into the trans position, regardless of whether W is to the group R, in the cis or trans position. Although predominantly the trans (3S, 4R) isomers are formed, occasionally the cis isomers can also be isolated. The separation of the cis and trans isomers is carried out as described above by conventional methods, in particular by chromatography and / or by crystallization.

The subsequent ozonization of a methylidene group Z ¹ can be carried out as indicated further on. A obtained racemate of the formula IV can be separated into the optically active compounds.

An azetidinone of the formula V in which R _{1 is} acetoxymethyl is described in German Offenlegungsschrift No. 29 50 898. Other azetidinones of the formula V can be prepared by processes known per se, for example by reacting a vinyl ester of the formula R, -CH = CH-W with chlorosulfonyl isocyanate and reacting the resulting cycloadduct with a reducing agent, for example sodium sulfite. In this synthesis, mixtures of cis and trans isomers are usually obtained, which can be separated into the pure (3S) -isomers, for example by chromatography and / or crystallization or distillation. Obtained racemic (3S, 4RS) isomers can be separated into the pure (3S, 4R) antipodes as described above. The optically active compounds of formula V can also be prepared by the method given below in Reaction Scheme II.

Step 1.2: An α-hydroxy carboxylic acid compound of the formula VI is obtained by reacting a compound of the formula IV with a glyoxylic acid

acid compound of the formula OHC-Ro or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, e.g. a hemiacetal with a lower alkanol, e.g. Methanol or ethanol, and, if desired, in an available compound of formula VI wherein R is hydroxy substituted lower alkyl, converts hydroxy to protected hydroxy.

The compound VE is usually obtained as a mixture of the two isomers (with respect to the group CLWOH). But you can also isolate the pure isomers of it.

The addition of the Glyoxylsäureesterverbindung to the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, with heating, for example to about 10O ⁰ C, in the absence of an actual condensing agent and / or without formation of a salt instead. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, eg, azeotropically, 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 such as dioxane, toluene or dimethylformamide, or solvent mixture, if desired or necessary, in the atmosphere of an inert gas such as nitrogen.

Step 1.3 : Compounds of the formula VH in which X is a reactive esterified hydroxy group, in particular halogen or organic sulphonyloxy, prepared by reacting, in a compound of the formula VI, the secondary hydroxy group into a reactive esterified hydroxy group, in particular halogen, for example, chlorine or bromine, or into an organic sulfonyloxy group, such as lower alkanesulfonyloxy, for example methanesulfonyloxy, or arenesulfonyloxy, for example benzene or 4-methylbenzenesulfonyloxy.

In the starting compounds of formula VI, R _{1 is} preferably lower alkyl substituted by a protected hydroxy group.

The compounds of formula VII can be obtained in the form of mixtures of the isomers (with respect to the group CII ^ -X) or in the form of pure isomers.

The above reaction is carried out by treatment with a suitable esterifying agent, for example with a thionyl halide, e.g. chloride, a phosphorus oxyhalide, especially chloride, a halophosphonium halide such as triphenylphosphono dibromide or diiodide, or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary amine, e.g. Triethylamine, diisopropylethylamine or "polystyrene-Hünigbase", or a pyridone-type heterocyclic base, e.g. Pyridine or collidine. Preferably, the reaction is carried out in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.

In a compound of the formula VII which is obtainable in this way, a reactive esterified hydroxy group X can be converted in a manner known per se into another reactive esterified hydroxy group. So you can, for example a chlorine atom by treating the corresponding chlorine compound with a suitable bromide or iodide salt, such as lithium bromide or iodide, preferably in the presence of a suitable solvent, such as ether, by a bromine or iodine atom, respectively.

Stage 1.4 : The starting material of the formula II ^f is obtained by reacting a compound of the formula VII in which X is a reactive

esterified hydroxy group, with a suitable phosphine linkage

such as a tri-lower alkyl phosphine, e.g. Tri-n-butyl-phosphine, or a triarylphosphine, e.g. Triphenylphosphine, or with a

suitable phosphite compound, such as a tri-lower alkyl phosphite, e.g. Triethyl phosphite, or an alkali metal lower alkyl phosphite, e.g. diethyl phosphite, treated.

The above reaction is preferably carried out in the presence of a suitable inert solvent such as a hydrocarbon, e.g. Hexane, cyclohexane, benzene, toluene or xylene, or an ether, e.g. Dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture made. Depending on the reactivity is carried out under cooling or at elevated temperature, for example between -10 ° and + 100 °, preferably at about 20 ° to 80 °, and / or in the atmosphere of an inert gas, such as nitrogen. To prevent oxidative processes, catalytically amounts of an antioxidant, e.g. Hydroquinone, to be added.

In this case, the use of a phosphine compound is usually carried out in the presence of a basic agent, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or "polystyrene Hünigbase", and passes directly to the ylide starting material of formula II (or II '), which is formed from the corresponding phosphonium salt.

A starting compound of formula II 'wherein X 1 is a phosphono group together with a cation is preferably prepared in situ by reacting an available compound of formula

2s 1

Z '

in

<f ^X CH-X 'I

^R 2

wherein X ^{1 represents} a phosphono group, treated with a suitable basic reagent, such as an inorganic base, for example an alkali metal carbonate, such as sodium or potassium carbonate.

Level 1.4a

A starting compound of the formula II 'in which Z' is oxo can furthermore be obtained by treating a mercaptide of the formula VIII in which M is a metal cation with an acylating agent which introduces the radical R -AC (= O) - ,

In the starting material of the formula VIII, the metal cation M is, for example, a cation of the formula M or M / 2, where M is in particular

2+

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

An acylating agent introducing the radical R -A-C (= O) - is e.g. the acid R -A-COOH or a reactive functional derivative thereof, such as an acid halide, e.g. Chloride or bromide, azide or anhydride thereof.

The acylation takes place when the free acid of the formula RA-COOH is used, for example in the presence of a suitable dehydrating agent, such as a carbodiimide, eg N ₅ N'-dicyclohexylcarbodiimide, or, if an acid derivative is used, in the presence of a suitable acid-binding agent as a tertiary

aliphatic or aromatic base, for example triethylamine, pyridine or quinoline, in an inert solvent, such as a chlorinated hydrocarbon, for example methylene chloride, or an ether, for example diethyl ether or dioxane, at room temperature or under heating or cooling, for example in a temperature range of approx. 50 ° to about +60 ⁰ C, especially at about -30 ° to about +20 ⁰ C.

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

1 I ^{w νν;}

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

" ^H

where W is triphenylmethylthio or lower alkanoylthio, e.g. Acetylthio, means this analogous to that described in the reaction steps 1.2, and 1.4 in a compound of formula

R.

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

Ol \ 3 - 37 -

represents an anion which promotes the solubility of the salt MA in the chosen solvent, e.g. the nitrate, acetate or fluoride anion, is reacted.

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

Level 1.5

A compound of the formula (III) is obtained by reacting an azetidinone of the formula (IV) ', in which Z' denotes sulfur, with a compound of the formula R ¹ -COOH or, in particular,

reactive derivative, such as an acid halide, for example the acid chloride, thereof at a temperature of 20 ° to 8O ⁰ C, preferably at 40 ° to 60 ⁰ C, in an inert solvent, such as in the reaction of compounds of formula III to compounds of formula I, treated. When using an acid halide, the reaction is preferably carried out in the presence of an acid-binding agent, such as a tertiary aliphatic amine, for example triethylamine, an aromatic amine, for example pyridine, or in particular an alkali metal or alkaline earth metal carbonate or bicarbonate, for example potassium carbonate or calcium carbonate.

In the compounds II ', IV, VI and VII, an optionally substituted methylidene group Z ^! are converted into the oxo group Z by ozonization and subsequent reduction of the ozonide formed, according to the method described below in step 2.3.

Starting compounds of the formula V, wherein W is a sulfonyl radical of the formula R-SO 2 O, can also be prepared according to the following Reaction Scheme II.

Reaction scheme II

1 w \\ / 7

Hm

(XI) K '

I Level 2.1

T ftf

^Ε ι '1 χ  \ y ► ι «»

^(XII) I * (XIII) J ₁

2 R ₂

step

/ k "Level 24 - I1

Level 2.4

(Va)

^R 2

In the compounds of the formulas (XI) - (XIV) and (Va) R, in particular represents lower alkyl substituted by a protected hydroxy group.

Stage 2.1

Compounds of formula (XII) can be prepared by epimerizing a compound of formula (XI).

251 ί32

The epimerization takes place, for example, in the presence of a basic agent, such as an amine, for example a tri-lower alkylamine, for example triethylamine or ethyldiisopropylamine, of a tertiary amine. eg N, N-diethyl-aniline, an aromatic amine, eg pyridine, or a bicyclic amine, eg 1, 5-diazabicyclo [5,4,0] undec-5-ene or 1,5-diazabicyclo [4,3,0] non-5-ene, or a Alkalimetallniederalkanolats, eg sodium, sodium or potassium tert-butoxide, in an inert solvent, for example an ether, for example diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, optionally at somewhat elevated or decreased Temperature, for example at ^{0 0} C to 50 ⁰ C, preferably at room temperature.

In the compounds of the formula (XII) obtainable by the process, a protected hydroxy group contained in the radical R can be replaced by another protected hydroxy group, for example a hydrogenolytically cleavable protected hydroxy group by a solvolytically cleavable protected hydroxy group. Hydroxy protecting groups are, in particular, the abovementioned hydrogenolytically removable protective groups, for example substituted 1-phenyl-lower alkyl or phenyl-lower alkoxycarbonyl as indicated, protective groups which can be cleaved off by hydrolysis, for example trisubstituted silyl as indicated.

The reaction can be carried out by first removing the hydrogenolytically removable hydroxy protective group and introducing a solvolytically removable hydroxy protecting group into the resulting compound of the formula XII in which R is hydroxy-substituted lower alkyl.

The cleavage of the hydrogenolytically cleavable protecting group is e.g. with hydrogen or a hydrogen donor, e.g. Cyclohexene or cyclohexadiene, in the presence of a

Hydrogenation catalyst, such as a PalladiumkaCalysators, for example palladium on carbon, in an inert solvent such as a halogenated hydrocarbon, for example methylene chloride, a Nicderalkanol, for example methanol or ethanol, an ether, such as dioxane or tetrahydrofuran, or in water or in mixtures thereof, at a temperature of about 0 ° to about SO ⁰ C, preferably at room temperature. The cleavage can also be carried out with a reducing metal, such as zinc, or a reducing metal alloy, eg copper-zinc alloy, in the presence of a proton-donating agent, such as an organic acid, eg acetic acid, or else a lower alkanol, eg ethanol ,

The introduction of the solvolytically removable hydroxy protective group takes place, for example, with a compound of the formula R ¹ -X-, where R 'is the hydroxy-protecting group and X, for example a reactive esterified hydroxy group, for example halogen, for example chlorine, bromine or iodine, or sulphonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy.

Starting compounds of the formula (XI) are known, for example, from German Offenlegungsschrift 3 039 504 and from British patent application 20 61 930.

Stage 2.2

A compound of the formula (XIII) can be prepared by treating a penam compound of the formula (XII) with a basic agent and with an esterifying agent introducing the radical R.

A suitable basic agent is, for example, one of the basic agents mentioned under stage 2.1, in particular one of said bicyclic amines, and also an alkali metal amide or hydride, e.g. Sodium amide or sodium hydride.

A radical R is, for example, one of the organic radicals mentioned under step 1.1, in particular optionally substituted lower alkyl, e.g. Methyl, ethyl or 2-hydroxyethyl, or benzyl.

An esterifying agent introducing the rest R is e.g. a Vero

Compound of the formula R -X ^, wherein X, reactive esterified hydroxy, e.g. Halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy means. To introduce a 2-hydroxyethyl radical, ethylene oxide is also suitable.

The reaction is preferably carried out in two stages, wherein in the first stage the penam compound of the formula (XII) is treated with at least equimolecular amounts of the basic agent and an obtainable intermediate of the formula

_R I

¹ '' (XIIa)

wherein B ^ represents the protonated form (cation) of the basic agent, preferably without isolation from the reaction mixture with the esterifying agent. The reaction is in an inert solvent, for example an ether, ζ.BV diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, in acetonitrile, dimethylformamide or hexamethylphosphoric triamide, optionally at slightly elevated or lowered temperature, for example at about ^{0 0} C to 50 ⁰ C, preferably at room temperature. In a preferred embodiment of the process, the penam compound of the formula (XII) is prepared in situ by reacting as described under step 2.1

Compound of formula (XI) first with catalytic amounts of the basic agent, e.g. 1, 5-diazabicyclo [5,4,0] undec-5-ene, and then reacted with at least equimolar amounts of the same basic agent and esterifying agent to give the compounds of formula (XIII).

Stage 2.3

An oxalylazetidinone of formula (XIV) can be prepared by ozonating a compound of formula (XIII) and reductively cleaving the formed ozonide to the oxo compound.

The ozonization is usually carried out with an ozone-oxygen mixture in an inert solvent, such as a lower alkanol, for example methanol or ethanol, a lower alkanone, for example acetone, an optionally halogenated hydrocarbon, for example a halo-lower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably with cooling, for example at temperatures of about -80 ° to about 0 ⁰ C performed.

An intermediate ozonide, usually without being isolated, is reductively cleaved to give a compound of formula XIV, whereby catalytically activated hydrogen, e.g. Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel, further palladium catalafors, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as heavy metal reducing metals, including heavy metal alloys or amalgams, e.g. Zinc, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or an alcohol, e.g. Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g. Sodium iodide, or alkali metal hydrogen

sulfites, e.g. Sodium hydrogen sulfite, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or water, or reducing organic compounds such as formic acid. Compounds which can be easily converted into corresponding epoxide compounds or oxides can also be used as the reducing agent, the epoxide formation due to a C, C double bond and the oxide bond due to an existing oxide-forming hetero, such as sulfur, phosphorus or nitrogen atom can take place. Such compounds are e.g. suitably substituted aethene compounds (which are converted to ethylene oxide compounds in the reaction), such as tetracyanoethylene, or more particularly suitable sulfide compounds (which are converted to sulfoxide compounds in the reaction), such as dilower alkyl sulfides, primarily dimethylsulfide, suitable organic phosphorus compounds such as an optionally phenyl and or lower alkyl, eg Methyl, ethyl, n -propyl, or η-butyl, substituted phosphine (which is converted to a phosphine oxide in the reaction), such as tri-lower alkylpho-phosphines, e.g. Tri-n-butylphosphine, or triphenylphosphine, furthermore tri-lower alkyl phosphites (which are converted into phosphoric acid lower alkyl esters in the reaction), usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides which optionally contain lower alkyl as substituents, such as hexanilo-alkyl-phosphorous triamides, eg Hexamethylphosphoric triamide, the latter preferably in the form of a methanol adduct, further suitable nitrogen bases (which are converted to the corresponding N-oxides in the reaction), such as heterocyclic nitrogen bases of aromatic character, e.g. Pyridine type bases and especially pyridine itself. The cleavage of the usually unisolated ozonide normally occurs under the conditions to which it is added. its manufacture, i. in the presence of a suitable solvent or solvent mixture,

as well as cooling or gentle heating, preferably at temperatures of about -1O ⁰ C to about +25 ⁰ C and the reaction usually concludes at room temperature.

Level 2.4

An azetidinone of formula (Va) can be prepared by solvolysing an oxalyl-azetidinone of formula (XIV).

The solvolysis can be used as hydrolysis, as alcoholysis or as hydrazine. be carried out. The hydrolysis is carried out with water, optionally in a water-miscible solvent. The alcoholysis is usually carried out with a lower alkanol, for example methanol or ethanol, preferably in the presence of water and an organic solvent, such as a lower alkanecarboxylic acid lower alkyl ester, for example ethyl acetate, preferably at room temperature, if necessary with cooling or heating, for example at a temperature of about 0 ° to about SO ⁰ C performed. Hydrazinolysis is preferred in a conventional manner with a substituted hydrazine, for example with phenyl or a nitrophenylhydrazine, such as 2-nitrophenylhydrazine, 4-nitrophenylhydrazine or 2,4-dinitrophenylhydrazine

in an approximately equimolar amount, in an organic solvent such as an ether, eg, diethyl ether, an aromatic hydrocarbon such as benzene, a halogenated hydrocarbon such as methylene chloride or chlorobenzene, an ester such as ethyl acetate, and the like, at temperatures between about room temperature and about 65 ⁰ C performed.

In a preferred embodiment of the process, a compound of the formula (XIII) is used which is ozonized as indicated and then reductively cleaved to form the oxalylazetidinone of the formula (XIV) which, without isolation from the reaction mixture, passes on to the azetidinone of the formula (Va ) is implemented.

251

During ozonolysis, small quantities of acid may be formed which may cause the removal of a solvolytically readily cleavable hydroxy-protecting group in the radical R, e.g. of a trisubstituted silyl radical. The resulting compound of the formula

HH, .SO-R W r & 2 ο

f ~ ^m

wherein R 'is lower alkyl substituted by hydroxy, can be separated, for example chromatographically, from the protected azetidinone (Va) and converted by reacting with the hydroxy protecting group R' introducing means of the formula R'-X in the azetidinone of the formula (Va).

In the compounds of the formulas (II), (II '), (III), (VI), (VII) and (XII) to (XIV) a protected carboxyl group R' can be converted into another protected carboxyl group R by methods known per se Taking into account the optionally present in these compounds contained further functional groups, the same methods may be used as indicated for the conversion of this substituent in the compounds of formula (I).

The invention also relates to novel starting materials as well as novel intermediates obtainable according to the process, such as those of the formula (II) to (VIII), (incl. II ', Ha, Va and Vb) and the processes for their preparation.

Preferably, such starting materials are used and the reaction conditions are selected so that one arrives at the compounds listed above as being particularly preferred.

25!

The compounds of the formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds having valuable pharmacological properties. Compounds of formula I wherein R is hydroxy lower alkyl, R _{2 is} carboxyl or a physiologically cleavable esterified carboxyl group and R is amino, lower alkylamino, di-lower alkylamino or substituted methyleneamino, and pharmacologically acceptable salts of such salt-forming group compounds have antibacterial activities. For example, they are in vitro against Gram positive and Gram negative cocci, eg Staphylococcus aureus , Streptococcus pyogenes , Streptococcus pneumoniae , Streptococcus faecalis , Neisseria meningitidis and Neisseria gonorrhoeae against enterobacteria, eg Escherichia coli , Proteus mirabilis and Klebsiella pneumoniae , against Haemophilus influenzae , Pseudomonas aeruginosa and Anaerobes, eg Bacteroides sp., And Clostridium sp. in minimum concentrations of about 0.02 to about 64 μg / ml. In vivo, in the case of systemic infection of the mouse, for example by Staphylococcus aureus , Escherichia coli or Streptococcus pyogenes , subcutaneous or oral administration results in ED values of about 0.3 to about 100 mg / kg.

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

Compounds of the formula I in which at least one of the functional groups present is in protected form, 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 pharmacologically useful compounds of the present invention may e.g. for the manufacture 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 oral or parenteral, i. intramuscular, subcutaneous or intraperitoneal administration.

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

thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, dyes, flavorings or sweeteners.

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

The present pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances

2 5 1 I 3

in a manner known per se, e.g. by means of conventional mixing, solution or lyophilization processes, and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active ingredient.

Depending on the nature of the infection and the condition of the infected organism, daily doses of from 125 mg to about 5 g are used to treat warm-blooded animals (humans and animals) weighing about 70 kg.

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

The following abbreviations are used in the examples:

DC: thin-layer chromatogram,

IR: infrared spectrum,

UV: ultraviolet spectrum,

NMR: nuclear magnetic resonance spectrum,

DBU: 1,5-diazabicyclo [5.4.0] undec-5-ene,

THF: tetrahydrofuran,

DMF: dimethylformamide.

"- J i

Experimental part

Example 1; (5R, 6S) -2 - [(2R, S) -2- (4-nitrobenzyloxycarbonylamino) -propl-yl] -6- (tert.butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid p-nitrobenzy ester!

A solution of 6.27 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxo-azetidine-1 -yl] -2-triphenylphosphoranylideneacetic acid p-nitrobenzyl ester in 1 liter of toluene is stirred under argon atmosphere for 12 hours at reflux temperature. The solvent is then evaporated off and the crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 9: 1). TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.56; IR (CH ₂ Cl ₂ ): 3430; 1780; 1715; 1510; 1340; 1310 cm " ¹ .

The starting material can be prepared as follows:

a. Butyric acid (3R, S) -3- (4-nitrobenzyloxycarbonylamino)

To a solution of (3R, S) -3-aminobutyric acid (20.6 g) in 41 ml of water and 90 ml of 5N NaOH solution at 0 ° is added solid 4-nitrobenzyl chloroformate (47.4 g) and the beige-colored suspension stirred for 16 hours at room temperature. After removing the insoluble by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH "Cl". The aqueous phase is adjusted to pH 2 with HCl 4 N and extracted twice with CH "Cl". The combined organic extracts are washed once with brine, dried over MgSO 4, and evaporated to the white crystals of the title compound. IR in CH ₂ Cl ₂ : 3425; 1710; 1500; 1335 cm ~.

b. -Thiobuttersäure (3R, S) -3- (4-nitrobenzyloxycarbonylamino)

(3R, S) -3- (4-Nitrobenzyloxycarbonylamino) -butyric acid (14.1 g) is suspended in methylene chloride (250 ml) and, after cooling to -10 °, dissolved by adding 15.33 ml of triethylamine. At the same temperature, a solution of isobutyl chloroformate (7.19 ml) in 50 ml of methylene chloride is added and stirred at -10 ° for one hour. Then

H ₂ S is introduced during 2 hours. After removal of the excess H "S with nitrogen, the reaction mixture is treated with 2NH ₂ SO ₄ , solution and shaken well. The organic phase is separated off and extracted once with 400 ml of 1.5% strength NaHCO 3 solution. The aqueous phase is acidified with 2NH ₂ SO _4, extracted twice with CH ₂ Cl ₂ , and these extracts are then dried over MgSO 4. After evaporation of the filtered organic solution, the title compound is obtained as a yellowish OeI. IR (CH ₂ Cl ₂ ): 3430; 2580; 1715; 1500; 1345 cm " ¹ .

c. (3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] azetidin-2-one

8.22 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonylazetidin-2-one and 11.7 g of (3R, S) -3- (4-nitrobenzyloxycarbonylamino) -thiobutyric acid are dissolved in 180 ml of CH "C1" solved. The yellowish solution is first mixed with 180 ml of water, then with 42 ml of 1 N NaOH. The vigorously stirred emulsion is stirred for 1.5 h at room temperature. The organic phase is then separated in a separating funnel and the aqueous extracted twice more with CH "C1". The combined organic extracts are washed with a saturated aqueous NaHCO 3 solution and then with brine, dried over MgSO 4, and evaporated. The crude product obtained is purified by chromatography on silica gel with toluene / ethyl acetate 9: 1. TLC (silica gel, ethyl acetate): Rf = 0.65; IR (CH ₂ Cl ₂ ): 3420; 1765; 1710; 1680; 1500; 1340 cm " ¹ .

The starting material (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one can be prepared as follows:

about (3S, 5R, 6R) -2 _> 2-dimethyl-6- (tert-butyl-dimethylsilyloxymethyl) - pen'am-3-carboxylic acid methyl ester 1,1-dioxide

A solution of 23.6 g (85 mmol) of (3S, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid methyl ester 1,1-dioxide in 50 ml of dimethylformamide is mixed with 25.5 g (170 mmol) tert-butyl-dimethylchlorosilane and 11.5 g (170 mmol) imidazole at room temperature for 45 minutes.

  251 Ui;

stir. The solvent is then distilled off in a high vacuum and the residue is taken up in ethyl acetate. The solution is washed with 1N sulfuric acid and then with water, and the aqueous solutions are extracted twice with ethyl acetate. The organic phase is dried with sodium sulfate and concentrated on a rotary evaporator. The product accumulates as a crystalline mass

TLC silica gel, toluene / ethyl acetate (4: 1): R f = 0.56 IR (CH ₂ Cl ₂ ) 3.4; 5.57; 5.65 fm.

cb. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxoazetidin-l-yl] -3-methyl-2-butensäuremethy ester

A solution of 202 g (0.51 mol) of (3R, 5R, 6R) -2,2-dimethyl-6- (tert -butyldimethylsilyloxymethyl) -penam-3-carboxylic acid methyl ester 1,1-dioxide in 800 ml of tetrahydrofuran are mixed with 9 ml of DBU and stirred for 5 minutes at room temperature. Then another 95 ml of DBU are added and stirred for 30 minutes at room temperature. Then added with cooling 42.3 ml (0.68 mol) of methyl iodide. After a reaction time of 3 hours, the crystallized DBU-hydroiodide is filtered off and the filtrate is concentrated. The residue is taken up in ethyl acetate and the solution is washed with 1 N sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solution is concentrated to a thick oil.

TLC [silica gel, toluene / ethyl acetate (4: 1)]; R f = 0.42 IR (CH ₂ Cl ₂ ) 5.63; 5.81; 6.17 fm.

cc. (3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one and (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one

A solution of 25 g (61.7 mmol) of 2- [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxo-azetide in-1-yl] -3-methyl Methyl -2-butenate in 400 ml of methylene chloride at -10 ° with an ozone /

25

Treated oxygen mixture. The disappearance of the starting material is monitored by thin-layer chromatography. After completion of the reaction, 30 ml of dimethyl sulfide are added and stirred for 3 hours at room temperature. The solution is concentrated and the residue taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated to 70 ° for 40 minutes. The solvent is then stripped off and the residue is stripped off twice with toluene. The crystallizing OeI is taken up in methylene chloride and the crystals, consisting of (3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one, isolated by filtration. The filtrate is concentrated and (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one obtained by chromatography on silica gel with toluene / ethyl acetate (3: 1) in pure form:

(3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one: TLC, silica gel, toluene / ethyl acetate (1: 1); Rf = 0.36, IR: (CH ₂ Cl ₂ ) 2.96; 3.54, 5.65 pm.

(3S, 4R) -3- (tert-butyldimethylsilyl-oxy-ethyl) -4-methylsulfonyl-azetidin-2-one : TLC; Silica gel, toluene / ethyl acetate (1: 1) Rf = 0.06.

A solution of 14.6 g (81.5 mmol) of (3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one in 40 ml of dimethylformamide is treated with 24 g (183 mmol) of tert-butyldimethylchlorosilane and 11 g (163 mmol) of imidazole for 45 minutes at room temperature. Then the solvent is removed under high vacuum and the residue taken up in ethyl acetate. The organic phase is washed successively with 1N sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crystalline residue is pure (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one.

251

d. 2 - [(3S, 4R) -3- (tert -butyl-dimethylsilyloxymethyl) -4 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxo-azetidin-1-yl] -2 hydroxyacetic acid p-nitrobenzy! ester

A mixture of 10.23 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) butyroylthio] azetidin-2-one and 10.21 g Glyoxylic acid p-nitrobenzyl ester ethylhemiacetal in 170 ml

Toluene and 10 ml abs. DMF is mixed with 80 g of molecular sieve (4 A) and stirred for 16 h at room temperature and then for 2 h at 50 °. The mixture is filtered and the filter residue washed with toluene. Evaporation of the filtrate and drying in a high vacuum at 50 ° gives the product as a yellow OeI. TLC (silica gel, ethyl acetate): Rf = 0.67; IR (CH ₂ Cl ₂ ): 3430; 1765; 1730; 1690; 1505; 1340 cm " ¹ .

e. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4 - [(3R, S) -

3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid p-nitrobenzene ester To a solution of 13.7 g of 2 - [(3S, 4R) -3- (tert Butyldimethylsilyloxymethyl) -4 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxo-azetidin-1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester in 250 ml abs. Tetrahydrofuran are added with stirring at 0 ° successively 2.03 ml of thionyl chloride and 2.3 ml of pyridine. The white suspension is stirred at 0 ° for 30 minutes and filtered. After evaporation, the resulting yellow foam is dissolved in 100 ml of dioxane and treated with 3.1 ml of 2,6-dimethylpyridine and 6.98 g of triphenylphosphine. After stirring at 40 ° for 17 hours, the solids are separated and the filtrate is evaporated. The crude product is purified by chromatography on silica gel (eluent toluene-ethyl acetate 9: 1). TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.36; IR (CH ₂ Cl): 3430; 1745; 1715; 1615; 1510; 1430 cm " ¹ .

25

Example 2: (5R, 6S) -2 - [(2R, S) -2- (4-nitrobenzyloxycarbonylamino) -prop-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid pnitrobenzene ester

A solution of 3.14 g of (5R, 6S) -2 - [(2R, S) -2- (4-nitrobenzyloxycarbonylamino) -prop-1-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penera- 3-carboxylic acid p-nitrobenzyl ester in 50 ml abs. THF is treated successively with 1.83 ml of acetic acid and 80 ml of a 0.1 N tetrabutylammonium fluoride solution in THF. After stirring for 4.5 h, it is diluted with 1.4 l of CH ₂ Cl ₂ and concentrated with 200 ml of a saturated NaHCO 3 in H "0 solution washed. The organic phase is then washed with brine, dried over MgSO 4, and filtered off with suction. The crude product is purified by chromatography on silica gel (mobile phase: from toluene / ethyl acetate 1: 1 to ethyl acetate absolute). TLC (silica gel, ethyl acetate): Rf = 0.46; IR (CH ₂ Cl ₂ ): 3600; 3430, 1780; 1715; 1515; 1340 cm " ¹ .

Example 3: (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid

229 mg of (5R, 6S) -2 - [(2R, S) -2- (4-nitrobenzyloxycarbonylamino) -prop-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester are obtained in 30 ml of ethyl acetate, 12 ml of THF and 24 ml of water with 0.15 g Pd / C (10%) and hydrogenated at room temperature and atmospheric pressure for 2 h. The catalyst is filtered off and the reaction mixture is treated again with 0.1 g Pd / C (10%) and then 4 ml of 0.1 N HCl and hydrogenated for 1 h further. The catalyst is filtered off, the aqueous phase is separated off and the organic phase is extracted again with water. The combined aqueous extracts are mixed with 1 equivalent of NaHCO 3 and washed with ethyl acetate. Subsequently, the aqueous phase is lyophilized.DC (reversed phase Opti-UPC) in water: Rf = 0.13; UV (phosphate buffer pH 7.4) : \ = 304 nm.

Hl 3.x

Example 4: (5R, 6S) -2- [2-Methyl-2- (4-nitrobenzyloxycarbonylamino) -propl-yl-o-Ctert.-butyldimethylsilyloxymethyl-Z-penem-S-carboxylic acid p-nitrobenzene ester

Analogously to Example 1, 1.51 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [3-methyl-3- (4-nitrobenzyloxycarbonylamino) butyroylthio] -2-oxo-azetidin l-yl] -2-triphenylphosphoranylidenessigsäure p-nitrobenzyl ester in 250 ml of toluene after 46 h stirring at reflux temperature in the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.6; IR (CH ₂ Cl ₂ ): 3430; 1775; 1710; 1510; 1340; 1300 cm ".

The starting material can be prepared as follows:

a. 3-Methyl-3- (4-nitrobenzyloxycarbonylamino) -butyric acid. Analogously to Example 1a , 7.79 g of 3-methyl-3-aminobutyric acid are converted to the title compound. IR in CH ₂ Cl ₂ : 3430, 1710, 1500, 1340 cm.

b. 3- Methyl-3- (4-nitrobenzyloxycarbonylamino) thiobutyric acid. Analogously to Example Ib, 9.5 g of 3-methyl-3- (4-nitrobenzyloxycarbonylamino) butyric acid are converted into the title compound. IR (CH ₂ Cl-): 3420; 2570; 1710; 1490; 1340 cm " ¹ .

c. (3S, 4R) -3- (tert> -Butyldimethylsilyloxymethyl) -4- [3-methy1-3- (4-nitrobenzyloxycarbonylamino) -butyroylthio ^ azetidin-2-one

5.98 g of 3-methyl-3- (4-nitrobenzyloxycarbonylamino) -thiobutyric acid and 3.75 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one in Example Ic transferred the title compound. TLC (silica gel, toluene-ethyl acetate 1: 1): Rf = 0.44; IR (CH ₂ Cl): 3400; 1765; 1715; 1675; 1490; 1335 cm " ¹ .

d. 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [3-methyl-3- (4-nitrobenzyloxycarbonylamino) -butyroylthio3-2-oxo-azetidin-l-yl ·] -2-hydroxyacetic acid -p-nitrobenzy! ester

3.75 g of (3S, 4R) -3- (tert-butyldimethylsilyloxy)

methyl) -2- [3-methyl-3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -azetidin-2-one and 3.57 g of glyoxylic acid p-nitrobenzyl ester ethylhemiacetal are converted to the title compound. TLC (silica gel, toluene-ethyl acetate): Rf = 0.43 and 0.36; IR: (CH ₉ Cl ₉ ): 3420; 1760; 1735; 1710;

-1 1680; 1505; 1335 cm.

e. 2 - [(3S, 4R) -3- (tert-butyldimethylsilylxymethyl) -4- [3-methyl-3-nitrobenzyloxycarbonylamino) -butyroylthiol-1-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid p-Nitrobenzyl ester Analogously to Example Ie, 2.32 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [3-methyl-3 - (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxo -azetidin-1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester to the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1) Rf = 0.47; IR (CH ₂ Cl ₂ ): 3420; 1740; 1730; 1675; 1610; 1600; 1500; 1335 cm " ¹ .

Example 5: (5R, 6S) -2- [2-methyl-2- (nitrobenzyloxycarbonylamino) -

prop-l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

2.29 g of (5R, 6S) -2- [2-methyl-2- (4-nitrobenzyloxycarbonylamino) -prop-1-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3 are prepared analogously to Example 2. carboxylic acid p-nitrobenzyl ester to give the title compound. TLC (silica gel, toluene / ethyl acetate): Rf = 0.23. IR (CH ₉ Cl ₉ ): 3600; 3430; 1780; 1710; 1510; 1345 cm " ¹ .

Example 6: (5R, 6S) -2- (2-amino-2-methyl.-prop-1-yl) -6-hydroxymethyl

2-penem-3-carboxylic acid

Analogously to Example 3, 0.7 g of (5R, 6S) -2- [2-methyl-2- (4-nitrobenzyloxycarbonylamino) -prop-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid pnitrobenzylester to Title compound implemented. DC (Reversed Phase Opti UPC) in water: Rf - 0.15. UV (phosphate buffer pH 7.4):

\ = 307 nm

ⁿ max

251 \ 22

Example 7: (5R, 6S) -2 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -

but-l-yl] -6- (tert.-butyldimethylsilyloxymethyl) -2-peneni-3 ~ carboxylic acid p ~ nitrobenzy! ester

2.3 g of 2 - [(3S, .4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4-nitrobenzyloxycarbonylamino) valerolylthio] -2-oxo are prepared analogously to Example 1 -azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid p-nitrobenzyl ester to the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.49.

The starting material can be prepared as follows:

a. Valeric acid (4R, S) -4- (4-nitrobenzyloxycarbonylamino)

9.5 g of 4-aminovaleric acid are converted to the title compound analogously to Example la. NMR (DMSO-d ^: <£ = 12.0 (br, IH), 8.3 (m, 2H), 7.7 (m, 2H), 7.25 (br, IH), 5.2 ( 2H), 3.6 (m, IH), 2.25 (t, 2H), 1.7 (m, 2H), 1.1 ppm (d, 3H).

b. -Thiovaleriansäure (4R, S) -4- (4-nitrobenzyloxycarbonylamino)

15 g of (4R, S) -4- (4-nitrobenzyloxycarbonylamino) -valeric acid are converted into the title compound analogously to Example Ib. IR (CH ₂ Cl): 3430; 2570; 1715; 1505; 1345 cm " ¹ .

c. (3S, 4R) -3- (tert -butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4- nitrobenzyloxycarbonylamino) -valeroylthio] -azetidin-2-one

11.4 g of (4R, S) -4- (4-nitrobenzyloxycarbonylamino) -thiovaleric acid and 8.31 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidine-2 are obtained analogously to Example Ic -on into the title compound. TLC (silica gel, toluene / ethyl acetate i: l); Rf = 0.14.

251 'ί3

d. 2 - [(3S, 4R) -3- (tert.-Butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4-nitrobenzyloxycarbonylamino) -valeroylthio] -2-oxo-azetidin-l-yl] -2 hydroxyacetic acid p-nitrobenzyl

Analogously to Example Id, 11.18 g of (3S, 4R) -3-tert-butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4-nitrobenzyloxycarbonylamino) valerolylthio] azetidin-2-one and 8, 14 g of glyoxylic acid p-nitrobenzyl ester-Äthylenhemiacetal converted into the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1); Rf = 0.25 and 0.28.

e. 2 - [(3Sy4RV3- (tert-butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4-nitrobenzyloxycarbonylamino) -valeroyl · thio] -2-oxo-azetidin-I ~ ~ 2-YL3 triphenylphosphoranylidenessigsäure-p -nitrobenzylester

5.2 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(4R, S) -4- (4-nitrobenzyloxycarbonylamino) valerolylthio] -2-oxo are analogously to Example Ie -azetidin-1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester to the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.32.

Example 8: (5R, 6S) -2 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -

but-l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester

Analogously to Example 2, 1.34 g of (5R, 6S) -2 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -but-1-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penems -3-carboxylic acid p-nitrobenzyl ester converted into the title compound. IR (CH ₂ Cl ₂ ): 3600; 3420; 1780; 1715; 1510; 1340 cm " ¹ .

Example 9: (5R, 6S) -2 - [(3R, S) -3-Amino-but-1-yl] -6-hydroxymethyl-2-

penem-3-carboxylic acid

As in Example 3, 0.82 g of (5R, 6S) -2 - [(3R, S) -3- (4-nitrobenzyloxycarbonylamino) -but-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester converted to the title compound. UV (phosphate buffer pH 7.4): λ = 305 mn

rj / _max

Example 10: (5R, 6S) -2 - [(ZR 1 -1 -O-nitrobenzyloxycarbonylamino] prop-2-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid p-nitrobenzyl ester

As in Example 1, 1.13 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4 - [(2R, S) -2-methyl-3- (4-nitrobenzyloxycarbonylamino) -propionylthio ] -2-oxo-azetidin-1-yl] -2-phosphoranylidenessigsäure pnitrobenzylester converted into the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.4.

The starting material can be prepared as follows.

a. (2R, S) ^ - Methyl-S - ^ - nitrobenzyloxycarbonylamino) -propionic acid 5.69 g (2R, S) -3-amino-2-methyl-propionic acid are converted into the title compound analogously to Example la. IR (CH ₂ Cl): 3450; 1720; 1510; 1345 cm

b. (2R, S) -2-Methyl-3- (4-nitrobenzyloxycarbonyl-amino) -thiopropionic acid. Analogously to Example Ib, 10.4 g of (2R, S) -2-methyl-3- (4-nitrobenzyloxycarbonylamino) -propionic acid are converted to the title compound. IR (CH ₂ Cl ₂ ): 4440; 2570; 1715; 1690; 1510; 1345 cm " ¹ .

c. (3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4 - [(2R, S) -2-methyl-3- (4-nitrobenzyl · oxycarbonylamino) -propionyl · thio] azetidin-2-one

9.27 g (2R, S) -2-methyl-3- (4-nitrobenzyloxycarbonylamino) thiopropionic acid and 6.07 g (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl azetidin-2-one converted into the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.34; IR (CH ₂ Cl ₂ ): 3440; 3400; 1765; 1710; 1675; 1500; 1335 cm " ¹ .

25!

d. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4 - [(2R, S) -2-methy1-3- (4-nitrobenzyloxycarbony amino!) -Propionylthio] -2-oxoazetidin- 1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester Analogously to Example 1d, 0.98 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4 - [(2R, S) -2-methyl-3- (4-nitrobenzyloxycarbonylamino) -propionylthio] azetidin-2-one converted into the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.5; IR (CH ₂ Cl ₂ ): 3510; 3420; 1765; 1740; 1715; 1690 cm " ¹ .

e. 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxyniethyl) -4 - [(2R, S) -2-methy1-3- (4-nitrobenzyloxycarbony amino!) -Propionylthio] -2-oxoazetidin- l-ylj 1 -phosphoranylidene-acetic acid p-nitrobenzene ester Analogously to Example 1, 2.6 g of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxyethyl) -4 - [(2R, S) - 2-Methy1-3- (4-nitrobenzyloxycarbonylamino) -propionylthio] -2-oxo-azetidin-1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester is converted to the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.36; IR (CH ₂ Cl ₂ ): 3440, 1745; 1715; 1675; 1615; 1600 cm " ¹ .

Example 11; (5R, 6S) -2 - [(2R, S) -I- (4-nitrobenzyloxycarbonylamino) -prop-2-yl] -o-hydroxymethyl -penem-S-carboxylic acid p-nitrobenzyl ester

0.28 g of (5R, 6S) -2 - [(2R, S) -1- (4-nitrobenzyloxycarbonylamino) -prop-2-yl] -6- (tert-butyldimethylsilyloxymethyl) -2-penemethylene are used as in Example 2. 3-carboxylic acid p-nitrobenzyl ester converted into the title compound. TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.17; IR 3440; 1775; 1715; 1510; 1340 cm " ¹ .

25 1 η ::

Example 12: (5R, 6S) -2 - [(2R, S) -1-aminoprop-2-yl] -o-hydroxymethyl.

penem-3-carboxylic acid

Analg. Example 3, 750 mg of (5R, 6S) -2 - [(2R, S) -l- (4-nitrobenzyloxycarbonylamino) -proρ-2-yl] -6-hydroxymethyl. 2-penem-3-carboxylic acid p-nitrobenzyl ester converted into the Tite ^ compound. UV (phosphate buffer pH 7.4): X = 301 mn.

ΙΠ 3.x

Example 13: sodium salt of (5R, 6S) -2 - [(2R, S) -2- (l-Aethoxycarbonylprop-l-en-2-ylamino) -prop-1-yl ·] -o-hydroxymethyl ^ - penem -3-carboxylic acid

0.139 ml (1.1 mmol) of ethyl acetoacetate are added to a suspension of 0.257 mg (1 mmol) of (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl-2 -penem-3-carboxylic acid and 0.5 ml of 2N sodium hydroxide solution in 3 ml of isopropanol and stirred for 3 hours at room temperature. By adding diethyl ether, the product is squeezed out. IR Spectrum (Nujol): absorption bands at 3330; 1791; 1739 cm " ¹ .

Example 14: ( 5R, 6S) -2 - [(2R, S) -1-yl-oxycarbonyl-amino-prop-2-yl] -6- (tert-butyldimethylsilyl) -xy-methyl-2-penem-3 Carboxylic acid ethyl ester .

A solution of 0.9 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethyl-silyloxymethyl) -benz (2R, S) -2-methyl-3-al-yl-oxycarbonyl · Amino-propionyl · thio] -2-oxo-azetidin-1-yl] -2-triphenyl · phosphoranyl · idenessigsäure allyl · ester in i50 ml · abs. To ^ Dl · is stirred under argon atmosphere for 24 hours at reflux temperature. The solvent is then evaporated and the crude product is purified by chromatography on Siiicagei. (Mobile phase toluene-ethyl acetate 9: 1). IR 3440, l · 78O, l · cm.

Ol ί .j

The starting material can be prepared as follows:

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

12.5 g of triphenylmethylmercaptan are suspended in 70 ml of methanol at 0 ° and treated in portions with a total of 2.2 g of a 50 g sodium hydride suspension in 10 ml. Subsequently, an emulsion of 11.1 g of 3- (tert-butyldimethylsilyloxymethyl) -4-methyl-sulfonyl-azetidin-2-one in 70 ml of acetone and 70 ml of water is added dropwise over 30 minutes. After 30 minutes of stirring at 0 ° and 1 hour at room temperature, the reaction mixture is concentrated on a rotary evaporator, treated with methylene chloride, and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulfate. After concentration, the crude title compound is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 19: 1). TLC (toluene-ethyl acetate 19: 1): R _f = 0.64; IR (methylene chloride): 3390, 1760, 1117, 835Cm " ¹ .

b. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-l-yl] -2-hydroxyacetic acid allyl ester

8.4 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-azetidin-2-one and 8.23 g of (glyoxylic acid allyl ester ethyl)

hemiacetal in 170 ml abs. Toluene are mixed with 27 g of molecular sieve (4 A) and stirred for 10 hours at 55 °. After filtering off and concentrating on a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel. (Eluent toluene / ethyl acetate 95: 5). TLC (silica gel, toluene / ethyl acetate 10: 1): R = 0.37 and 0.27; IR (CH ₂ CH ₂ ): 3520, 1760, 1745 cm ^-1 .

c. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4-triphenyl-

methylthio ^ oxo-azetidin-l-yli ^ -triphenylphosphoranylidenessigsäure allyl ester

To a solution of 604 mg of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl] -2-hydroxyacetic acid

^ O ». ι ό - 63 -

Acid allyl ester in 5 ml of tetrahydrofuran are added with stirring at -15 ° successively 80 ul thionyl chloride and 88 ul pyridine within 5 minutes. The white suspension is stirred for 1 hour at -10 ° and filtered through Hyflo. After washing the residue with toluene is concentrated on a rotary evaporator. The residue is dissolved in 3 ml dioxane, mixed with 293 mg triphenylphosphine and 0.13 ml 2,6-lutidine and stirred for 2 hrs. At 115 ° bath temperature. The mixture is filtered through Hyflo and the residue is washed with toluene. The combined filtrates are evaporated. Chromatography of the residue on silica gel gives the pure product (eluent toluene / ethyl acetate 95: 5). TLC (silica gel, toluene / ethyl acetate 1: 1): R = 0.18; IR (CH-Cl,): 1745, 1605 cm ^-1 .

d. Silver salt of 2 - [(3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl-yl] -2-tri-phenylphosphoranylideneacetic acid allyl ester

7.5 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl] -2-triphenylphosphoranylidenessigsäureallylester be presented in 87 ml of ether and at room temperature added with 70 ml of a 0.5 M aqueous silver nitrate solution. Thereafter, a mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is added dropwise, and the reaction mixture is stirred for 20 minutes. The solid is then filtered off with suction and washed with ether, water and again ether. Finally, the solid is again suspended in 40 ml of ether and 40 ml of water for cleaning, filtered off with suction and dried. IR (CHCl): 1760, 1620 cm ^-1 .

e. 2 - [(3S, 4R) -3- (tert.-Butyl-dimethylsilyloxymethyl) -4 - [(2R, S) -2-methyl-3-allyloxycarbonylamino-propionylthio] -2-oxo-azetidin-ll-yl] -2-triphenylphosphoranylideneacetate. 5 g of silver salt of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -

4-mercapto-2-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 20 ml of abs. Methylene chloride with 1.7.ml of pyridine and then at 0 ° dropwise with a mixture of 2.47 g (2R, S) -2-methyl-3-allyloxycarbonylamino-propionic acid chloride and 10 ml of abs. Methylene chloride added. After stirring for 30 minutes, the dye is filtered off through Hyflo and the filtrate is washed with aqueous NaHCO 3 solution and then with brine. After drying over Na ₂ SO, it is concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent toluene / ethyl acetate 4: 1). TLC (silica gel, toluene / ethyl acetate 1: 1): R = 0.3; IR (CHCl): 3440, 1750, 1715, 1680,

-1 1610 cm.

The starting material (2R, S) -2-methyl-3-allyloxycarbonylaminopropionic acid chloride can be prepared as follows:

ea. (2R, S) -2-methyl-3-allyloxycarbonylamino-propionic acid

To a solution of 10 g of (2R, S) -3-amino-2-methyl-propionic acid in 20 ml of water and 44 ml of 5N NaOH solution is added dropwise at 0 ° 11.2 ml of allyl chloroformate. After stirring at room temperature for 15 hours, the mixture is worked up as in Example 1a. IR (CH ₇ Cl ₇ ): 3450; 1710; 1505; 1220 cm " ¹ .

eb. (2R, S) -2-Methyl-3-allyloxycarbonyl-amino-propionic acid chloride 0.374 g of (2R, S) -2-methyl-3-allyloxycarbonylamino-propionic acid is used at 0 ° with 0.6 ml of thionyl chloride. The mixture is then stirred at the same temperature for 2 hours under inert gas. It is then diluted with absolute toluene and concentrated on a rotary evaporator. IR (CH ₂ Cl ₂ ): 3440, 1780, 1710, 1500, 1215 cm ^-1 .

Example 15: (5R, 6S) -2 - [(2R, S) -1-Allyloxycarbonylamino-prop-2-yl] -6-

hydroxymethyl-2-penem-3-carboxylic acid allyl ester Analogously to Example 2, 138 mg of (5R, 6S) -2 - [(2R, S) -1-allyloxy-

carbonylamino-prop-2-yl] -6- (tert -butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester to the title compound: TLC (silica gel, toluene / ethyl acetate 1: 1): R = 0.08; IR (CH ₂ Cl ₂ ): 3610, 3440, 1780, 1710 cm ^-1 .

Example 16: (5R, 6S) -2 - [(2R, S) -1-aminoprop-2-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid

A solution of 82 mg (5R, 6S) -2 - [(2R, S) -1-allyloxycarbonylaminoprop-2-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester in 3.5 ml abs. THF is treated at -10 ° with 9 mg of tetrakis (triphenylphosphine) palladium and then with 0.17 ml of tributyltin hydride. After stirring for 20 minutes at -10 °, 0.037 ml of acetic acid are added and the reaction mixture is stirred for a further 30 minutes after removal of the cooling bath. After concentrating on a rotary evaporator, the residue is taken up in water-ethyl acetate, the aqueous phase is separated off and the organic phase is extracted 3 more times with water. The combined aqueous phases are lyophilized after brief concentration on a rotary evaporator. UV (phosphate buffer pH 7.4): λ max = 301 nm.

The reaction product is identical to that shown in Example 12.

Example 17: (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl-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-l-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. Subsequently, the solution is added dropwise to 15.0 ml of methylene chloride and filtered from the precipitated inorganic salts. The methylene chloride solution is concentrated to 2 ml and added at 0 ° to a solution of 0.257 g (1 mmol) (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl- 2-Penem-3-carboxylic acid in 4 ml of dimethylacetamide. It is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water.

to wash. 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 1740 cm

Example 18; (5R, 6S) -2- [(2R, S) -2-aminoprop-1-yl 1-o-hydroxymethyl] -penem-3-carboxylic acid pivaloyloxymethyl ester

0.6 g of sodium iodide are dissolved in 2 ml of acetone and treated with 0.15 ml 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 0.1 g (0.4 mmol) (5R, 6S) -2 - [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl 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

Example 19: In an analogous manner, as described in the preceding examples, the following compounds are obtained:

(5R, 6S) -2 - [(2R, S) -2-aminobut-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4): λ = 302 nm,

(5R, 6S) -2 - [(2R, S) -1-aminoprop-2-yl] -6 - [(IR) -1-hydroxyethyl] -2-penem-3-carboxylic acid , UV (phosphate buffer pH 7, 4): A = 303 nm,

(5R, 6S) -2 - [(IS) -1-amino-but-1-yl3-6 - [(1R) -1-hydroxyethyl] -2-penem-3-carboxylic acid , UV (phosphate buffer pH 7.4 ) 7-308 nm;

Max

(5R, 6S) -2 - [(1S) -1-AlII-linobut-1-yl] -6-hydroxymethyl * -2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4): 307.5 nm;

(5R, 6S) -2 - [(L * R) -1-aminoethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid UV (phosphate buffer pH 7.4) λ: 308 nm,

(5R, 6S) -2- [(1S-1-aminoethyl-o-hydroxymethyl) -penic-S-carboxylic acid , UV (phosphate buffer pH 7.4) λ: 307

nm,

(5R, 6S) -2- (2-Amino-2-methylprop-β-yl) -6-hydroxymethyl-2-penem-3 - carboxylic acid 1-ethoxycarbonyloxyethyl ester , IR spectrum (CH Cl ") : 1788 and 1738 cm;

(5R, 6S) -2- [(3R, S) -3-amino-but-1-yl] -o-hydroxymethyl-Z-penem-S-carbon

acid 1-ethoxycarbonyloxyethyl ester , IR spectrum (CH ₂ Cl ₂ ): 1790 and 1736 cm ^-1 ;

(5R, 6S) -2 - [(2R, S) -1-aminoprop-2-vl] -6-hydroxymethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester , IR spectrum (CH ₂ Cl ,,) : 1787 and 1735 cm "¹;

(5R, 6S) -2- (2-amino-2-methyl-prop-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester , IR spectrum (CH ₂ Cl ₂ ): 1791 and 1733 cm ";

(5R, 6S) -2 - [(3R, S) -3-Amino-but-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester , IR spectrum (CH "C1") : 1789 and 1732 cm;

(5R, 6S) -2 - [(2R, S) -1-aminoprop-2-yl] -e-hydroxymethyl -penem-S-carboxylic acid pivaloyloxymethyl ester , IR spectrum (CHCl "): 1788 and 1729 cm

Ol : J

Example 20: (5R, 6S) -2 - [(1R) -l-formamido-ethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid

A solution of 110 mg of ethyl formimidate hydrochloride and 84 mg of sodium bicarbonate in 4 ml of water at room temperature with a solution of 24 mg (5_R, 6i5) -2- [(lR) -l-aminoethyl] -6-hydroxymethyl-2 -penem-3-carboxylic acid and 8.4 mg of sodium bicarbonate in 1 ml of water. After 50 min. Stirring at room temperature is combined with 1 ml of 1N HCl and concentrated under high vacuum. The crude substance is purified by chromatography on OPTI UP C. UV (phosphate buffer pH 7.4): \ : 305 nm.

t IU3.X

Example 21: Dry Ampoules or Vials Containing 0.5 g (5R, 6S) -2-

[(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid as an active substance are prepared as follows:

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

Mannitol 0.05 g

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

In place of the above-mentioned active ingredient, the same amount of another active ingredient of the preceding examples, e.g. (5R, 6S) -2- (2-amino-2-methyl-prop-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid containing (5R, 6S) -2 - [(3R, S) -3-Amino-but-1-yl] -o-hydroxymethyl-penpene-S-carboxylic acid or the (5R, 6S) -2 - [(2R, S) -1-aminoprop-2-yl] 6-hydroxymethyl-2-penem-3-carboxylic acid.

Claims (14)

25 invention claim 1. A process for the preparation of compounds of the formula R
2 wherein R is lower alkyl substituted by hydroxy or protected hydroxy, R represents carboxyl or protected carboxyl R ₂ ', R _{3 is} amino, lower alkyl substituted amino, substituted methyleneamino, or protected amino, and A is lower alkyl substituted straight chain lower alkylene, with the proviso R is other than 1-hydroxyethyl or protected 1-hydroxyethyl, when A is straight chain lower alkyl which is geminally substituted by two methyl groups, R 'has the above meaning and R _{3 is} amino or protected amino, pharmaceutically acceptable salts of such compounds of formula I which a salt-forming group, optical isomers of compounds of the formula I, mixtures of these optical isomers and of pharmaceutical preparations containing these compounds, characterized in that a) an ylide compound of the formula R " 1 ·. ^ S-C-A-R. S ^ ³ (ID, in which R 1, R 1, R ₃ and A have the meanings given under formula I, Z is oxygen or sulfur and X 1 is either a trisubstituted phosphonium group or a double represents esterified phosphonium group together with a cation, ring closure, or b) a compound of the formula (HD, wherein R, R ¹ , R and A have the meanings given under formula I, treated with an organic compound of the trivalent phosphorus, and if desired or necessary, in a compound of the formula I obtainable a protected hydroxy group in the radical R ₁ in the free Converted hydroxy group, and / or, if desired, in a obtainable compound of formula I, a protected carboxyl group R 'in the free carboxyl group or in another protected carboxyl group R-' or a free carboxyl group R ₂ into a protected carboxyl group Rl transferred, and / or, if desired, a protected amino group R, into the free amino group or a free amino group R converted into a substituted amino group, and / or, if desired, an available compound having salt-forming group in a salt or an available salt in the free compound or converted into another salt, and / or, if desired, an available mixture of isomeric Ver compounds of the formula I is separated into the individual isomers, and / or processed an available compound of formula I or a pharmaceutically acceptable salt thereof to a pharmaceutical preparation. 2. The method according to item 1, characterized in that compounds of formula I, wherein R ₁ is lower alkyl substituted by hydroxy or protected hydroxy, R _{2 is} carboxyl or protected carboxyl R ', R is amino, lower alkylamino, di-lower alkylamino, a group of formula -N = C (X, X), where X _{1 is} hydrogen, amino, Lower alkylamino, di-lower alkylamino, lower deralkylenami.no, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower-alkyl-amino-lower alkyl, Ⓒ, lower alkenyl, phenyl, pyridyl, eg 2- or 4-pyridyl, thienyl, eg 2-thienyl or is thiazolyl, for example 4-thiazolyl, and X is amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower-alkoxy or lower-alkylthio, or is protected amino, and A is lower alkyl substituted by lower alkyl of 1 to 4 carbon atoms, with the proviso that R ₁ is other than 1-hydroxyethyl or protected 1-hydroxyethyl when A is straight chain lower alkylene geminally substituted by two methyl groups, R ₁ is as above, and R is amino or protected amino; pharmaceutically acceptable salts of those compounds of the formula I which contain a salt-forming group, optical isomers of compounds of the formula I which have chiral centers in the radicals R ₁ and / or A and mixtures of these optical isomers. 3. Process according to item 1, characterized in that compounds of the formula I in which R is carboxy, lower alkenyloxycarbonyl, optionally nitro-substituted benzyloxycarbonyl, lower alkanoylmethoxycarbonyl, 2-halo-lower alkoxycarbonyl, 2-tri-lower alkylsilylethoxycarbonyl, or a cleavable under physiological conditions esterified carboxyl group, eg 1-lower alkoxycarbonyloxy lower alkanoyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, alpha-amino lower alkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, R represents amino, lower alkylamino, di-lower alkylamino; a group of formula -N = C (X, X) wherein X. is hydrogen, amino, lower alkylamino, lower alkyl, phenyl or Pyridyl, eg 2-pyridyl, and X amino, lower alkyl 25! amino or di-lower alkylamino; Azido, phthalimino, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro-substituted benzyloxycarbonylamino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino, and A by lower alkyl with 1 to 4 carbon mono- or di-substituted straight-chain lower alkylene, with the proviso that R ₁ is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is geminally substituted by two methyl groups straight-chain lower alkylene, R_ has the above meaning and R. Amino or protected Amino represents; pharmaceutically acceptable salts, of those compounds of the formula I which have a salt-forming group, optical isomers of compounds of the formula I which have in the radicals R .. and / or A chiral centers, and mixtures of these optical isomers. 4. The method according to item 1, characterized by reacting compounds of formula I, wherein R- substituted by hydroxy lower alkyl and A by Methyl or ethyl monosubstituted straight-chain lower alkylene having 1 to 4 carbon atoms or in which R is hydroxymethyl and A is straight-chain disubstituted by methyl or ethyl Lower alkylene having 1 to 4 carbon atoms, and wherein each R represents carboxyl, L-lower alkoxycarbonyloxy-lower alkoxycarbonyl or lower alkanoyloxymethoxycarbonyl and R each represents amino, lower alkylamino or formamidino, pharmaceutically acceptable salts of such compounds of formula I, optical isomers of compounds of formula I which are described in U.S. Pat have the radicals R- and / or A chiral centers, and produces mixtures of these optical isomers. 5. Process according to item 1, characterized in that compounds of the formula I in which R is hydroxymethyl or 1-hydroxyethyl and A is methyl or ethyl monosubstituted ethylene or 1,3-propylene or wherein R is hydroxymethyl and A is methyl disubstituted ethylene, and wherein R- are each carboxyl and R 1 are each amino, and pharmaceutically acceptable salts of such compounds of formula I. 6. The method according to item 1, characterized in that the pure optical isomers of compounds of the formula I, which have in the substituents R ₁ and / or A further chiral centers, in particular the (l'R) isomers of compounds of formula I. in which R 1 is hydroxyethyl, and produces pharmaceutically acceptable salts of such compounds of formula I. 7. The method according to item 1, characterized in that cleavable esters of compounds of formula I are prepared under physiological conditions. 8. Process according to item 1, characterized in that (5R, 6S) -2- [2R, S) -2-aminoprop-1-yl3-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof manufactures. 9. The method according to item 1, characterized in that (5R, 6S) -2- (2-amino-2-methyl-prop-1-yl) -6-hydroxymethyl-2-penem-3-. carboxylic acid and pharmaceutically acceptable salts thereof. 10. The method according to item 1, characterized in that (5R, 6S) -2 - [(3R, S) -3-amino-but-l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid and preparing pharmaceutically acceptable salts thereof. 11. The method according to item 1, characterized in that one produces (5R, 6S) -2- (1-formamidinoethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. 231 i32 12. The method according to item 1, characterized in that one produces (5R, 6S) -2 - [(lR) -l-aminoethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. Process according to item 1, characterized in that (5R, 6S) -2 - [(1S) -l-aminoethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 14. The method according to item 1, characterized in that (5R, 6S) -2 - [(2R, S) -2-amino-but-l-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid and preparing pharmaceutically acceptable salts thereof.