NO853142L - NEW AMINOAL CHILDREN PENALS. - Google Patents

Description

The present invention relates to new 2-aminolower alkyl penem compounds, methods for their preparation, pharmaceutical preparations containing such compounds and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

The invention relates in particular to 2-aminolower alkyl-2-penem compounds of the formula

where R1 is hydroxy or protected hydroxy, R2 is carboxyl or functionally converted carboxyl, R^ is amino, amino substituted by lower alkyl, lower alkanoylamino, substituted methyleneamino or protected amino, R4 is optionally substituted amino, amino substituted by lower alkyl, ... substituted methyleneamino, protected amino, hydroxy- or protected hydroxy-substituted methyl or ethyl, and n is an integer from 1 to 3, optical isomers of the compounds of formula I, mixtures of such optical isomers and salts of such compounds of formula I which exhibit a salt-forming group.

The definitions used above and in the following preferably have the following meanings within the scope of the present description: Functional converted carboxy R2 is e.g. protected carboxyl R-,<1>or esterified carboxyl that can be cleaved under physiological conditions.

An esterified carboxyl group which can be cleaved under physiological conditions protects the compounds of formula I

against salt formation in the gastrointestinal tract by oral administration, thereby preventing premature excretion, and the group

is primarily an acyloxymethoxycarbonyl group or also an acylaminomethoxycarbonyl group, where acyl e.g. is the remainder of an organic carboxylic acid, primarily a possibly e.g. by amino substituted lower alkanecarboxylic acid or arenecarboxylic acid, e.g. benzoic acid, or where acyloxymethyl forms the remainder of a lactone. Such groups are e.g. lower alkanoyloxymethoxycarbonyl, aminoloweralkanoyloxymethoxycarbonyl, especially α-aminoloweralkanoyloxymethoxycarbonyl, lower alkanoylaminomethoxycarbonyl, benzaminomethoxycarbonyl, 4-crotonlactonyl and 4-butyrolacton-4-yl. Other cleavable, esterified carboxyl groups under physiological conditions are e.g. 5-indanyloxycarbonyl, phthalidyloxycarbonyl, 1-lower oxycarbonyl-oxylaverealoxycarbonyl, 1-lower oxylaverealoxycarbonyl1 or 2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, which is optionally substituted with lower alkyl or phenyl at the 5-position in the dioxolene ring.

Amino which is substituted with lower alkyl is e.g. lower alkylamino or dilower alkylamino.

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

where X.^ stands for hydrogen, optionally substituted amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, e.g. lower methoxy or phenyl lower oxy, etherified mercapto, e.g. lower alkylthio, optionally substituted lower alkyl, e.g. loweralkyl, aminoloweralkyl1, N-loweralkylaminoloweralkyl or N,N-diloweralkylamino-loweralkyl, loweralkyl, phenyl or monocyclic heteroaryl bound over a ring carbon atom, such as corresponding 5- or 6-membered heteroaryl with 1-2 nitrogen atoms and/or a

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 X2 is optionally substituted amino, e.g.

amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, e.g. lower methoxy or phenyl lower oxy, or etherified mercapto, e.g. lower alkylthio.

In the present description, in the context of the definition of groups and compounds, the term "lower" means that the corresponding groups and compounds, unless they are expressly defined differently, contain up to 7, preferably up to 4, carbon atoms.

Lower alkanoyloxymethoxycarbonyl is e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

ct-aminolower alkanoyloxymethoxycarbonyl is e.g. glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl.

Lower alkanoylaminomethoxycarbonyl is e.g. acetaminomethoxycarbonyl.

1-lower oxycarbonyloxylavereal oxycarbonyl is e.g. ethoxycarbonyloxymethoxycarbonyl or 1-ethoxycarbonyl-oxyethoxycarbonyl.

1-lower oxyllower oxycarbonyl is e.g. methoxymetoxycarbonyl or 1-methoxyethoxycarbonyl.

At a 2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl group,

which is optionally substituted with lower alkyl or phenyl at the 5-position in the dioxolene ring, it is primarily a 5-phenyl and most of all a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl group.

Lower alkylamino is e.g. methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while diloverealkylamino e.g. means dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino.

Lower alkanoylamino is e.g. formylamino, acetylamino

or thionylamino.

Lower alkyleneamino especially has 4-6 carbon chain links

and means e.g. pyrrolidino or piperidino.

Low-area coke is e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert.-butoxy, while phenyl lower alkyl, e.g. is benzyloxy.

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 alkylaminolower alkyl is e.g. 2-methyl- or 2-ethylaminoethyl, while N,N-diloweralkylaminoloweralkyl e.g. means 2-dimethylaminoethyl or 2-diethylaminoethyl.

Lower range alkenyl is e.g. allyl, n-propenyl or isopropenyl.

Preferred, under physiological conditions cleavable, esterified carboxyl groups, R t is e.g. phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and 1-lower oxycarbonyloxylaverealoxycarbonyl, e.g. 1-Ethoxycarbonyloxyethoxycarbonyl.

In preferred methyleneamino groups of formula IA as residue R 1 or as a substituent on residue R 4 , X 2 is hydrogen, amino or lower alkyl, such as methyl, and X 2 is amino.

Preferred residues are e.g. methyl, ethyl, aminomethyl, aminoethyl, such as 1- or 2-aminoethyl, hydroxymethyl and hydroxyethyl, such as 1- or 2-hydroxyethyl.

The functional groups present in compounds of formula I, such as hydroxy, carboxyl or amino groups, in particular the hydroxy group R^, the hydroxy group as a substituent on a residue R^ and the carboxyl group R2, are optionally protected by means of protective groups, which are used within penem-, penicillin, cephalosporin and peptide chemistry. Such protecting groups protect the relevant functional groups against unwanted condensation reactions, substitution reactions, etc., during the synthesis of the compounds of formula I from the advantages.

Such protective groups are easily cleavable, i.e. that cleavage can take place without unwanted side reactions, for example solvolytic, reductive or also under physiological conditions.

Protection groups of this type, as well as their introduction

and splitting off, is e.g. described in

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

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

"ThePeptides", vol, I, Schroeder and Luebke, Academic Press, London, New York, 1965 and

Houben-Weyl, "Methoden der Organischen Chemie", Volume 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of formula (I), a hydroxy group R^,

and further a hydroxy group present in the residue R^, for example be protected by acyl residues. Suitable acyl residues

is e.g. optionally with halogen-substituted lower alkanoyl, e.g. acetyl or trifluoroacetyl, optionally with nitro substituted benzoyl, e.g. benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally with halogen-substituted lower alkoxycarbonyl, e.g. 2-bromomethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, lower alkenyloxyxalyl, e.g. allyl-oxyoxalyl, or optionally nitro-substituted phenyl-lower oxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups are e.g. trisubstituted silyl, such as trilower 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-trichloro-ethyl, and optionally with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro-substituted phenyl lower alkyl, such as corresponding benzyl. Preferred hydroxy protecting groups are tri-lower alkylsilyl, hydrogen-lower alkyl oxycarbonyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl.

a carboxyl group R_ is usually protected in esterified form, where the ester group is easily cleavable under mild conditions, e.g. under mildly reductive, such as hydrogenolytic or mildly solvolytic, such as acidolytic or especially basic and neutral hydrolytic conditions. A protected carboxyl group can further be constituted by an esterified carboxyl group which can easily be converted into a functionally derived carboxyl group, as in another esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups primarily branched in the 1-position, or in the 1- or 2-position, suitable substituted lower alkyl groups. Preferred carboxyl groups that are present in esterified form are, among other things, lower alkoxycarbonyl, such as e.g. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert.-butoxycarbonyl, and (hetero-)arylmethoxycarbonyl with 1-3 aryl residues or a monocyclic heteroaryl residue, where this may optionally be mono- or polysubstituted, e.g. with lower alkyl, such as tert.-lower alkyl, e.g. tert-butyl, halogen, e.g. chlorine, and/or nitro. Examples of such groups are possibly e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. diphenyImethoxycarbony1,

or triphenylmethoxycarbonyl, or optionally, e.g.

as mentioned above, substituted picolyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, as 2-furfuryloxycarbonyl. Other suitable groups are lower-alkanoylmethoxycarbonyl, such as acetonoyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably optionally substituted, e.g. with halogen, such as bromine, benzoyl, e.g. phenazyloxycarbonyl, halolower oxycarbonyl,

as 2-halogen lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or w-halogeno-lower oxycarbonyl, where the lower alkoxy contains 4-7 carbon atoms,

e.g. 4-chlorobutoxycarbonyl, phthalimidoethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or in the 2-position with lower alkylsulfonyl, cyano or trisubstituted silyl, such as trilower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl.

Other protected carboxyl groups present in extended form are corresponding organic silyloxycarbonyl, further corresponding organic phthanyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. methoxy, as substituents. Suitable silyl-respectively phthanyl groups are primarily lower alkylsilyl, especially trimethylsilyl or dimethyl tert.-butyl silyl, or correspondingly substituted phthanyl groups, e.g. tri-n-butylphthanyl.

Preferred protected carboxyl groups R^<1> are 4-nitrobenzyloxycarbonyl-, lower alkenyloxycarbonyl-, especially allyloxycarbonyl-, and that in the 2-position with lower alkylsulfonyl, cyano or trilower alkylsilyl, e.g. trimethylsilyl or di-n-butylmethylsilyl, substituted the ethoxycarbonyl group.

A protected amino group R^ or protected amino as a substituent in the residue R^ can e.g. present in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or phthanylamino group or as an enamino, nitro or azido group.

In such an acylamino group, acyl is, for example, the acyl residue

of an organic acid with e.g. up to 18 carbon atoms, especially one e.g. with halogen or phenyl, substituted alkanecarboxylic acid or optionally, e.g. with halogen, lower alkoxy or nitro, substituted benzoic acid, or a carboxylic acid half-ester. Such acyl groups are, for example, halogen, 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, e.g. benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl is also suitable, e.g. allyloxycarbonyl, or optionally in the 1- or 2-position substituted lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group preferably forms e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenylazyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)-

ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl residue from

an organic dicarboxylic acid with e.g. up to 12 carbon atoms, especially a corresponding aromatic dicarboxylic acid, such as phthalic acid. One such group is primarily phthalimino.

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

A silyl or phthalylamino group is primarily an organic silyl or phthalylamino group, where the silicon or tin atom preferably contains lower alkyl, e.g. methyl, ethyl, n-butyl or tert.-butyl, vid-

are lower alkoxy, e.g. methoxy, as substituents.

Such silyl or phthanyl groups are primarily trilower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or similarly substituted stanyl,

e.g. tri-n-butylstannyl.

Other protected amino groups are e.g. n-amino groups

which at the double bond in the 2-position contains a substituent that attracts electrons, e.g. a carbonyl group. Protection groups of this type are e.g. 1-acyl-lower-alk-1-en-2-yl residues, where acyl e.g. is the corresponding residue of a lower alkanecarboxylic acid, e.g. acetic acid, an optionally, e.g. with lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen,

as chlorine, and/or nitro substituted benzoic acid, or in particular a carboxylic acid half-ester, such as a carboxylic acid lower alkyl half-ester, e.g. -methyl half-esters or -ethyl half-esters,

and lower alk-1-ene especially 1-propene. Such protective

groups are primarily l-lower alkanoylprop-l-en-2-

howl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower oxycarbonyl-prop-1-en-2-yl, e.g. 1-ethoxycarbonyl-prop-1-en-2-yl.

Preferred protected amino groups are e.g. azido, phthalimido, nitro, lower alkenyloxycarbonylamino, e.g. allyloxycarbonylamino, and optionally with nitro substituted benzyloxycarbonylamino.

Salts of the compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are formed, for example, by the acidic groups present in the compounds of formula I, e.g. carboxyl and sulfo groups, and are primarily metal or ammonium salts, such as alkali metal

and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkyl amines, e.g. triethylamine, hydroxyl 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 real-alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines,

e.g. dicyclohexylamine, or benzylamines, e.g. N,N'— dibenzylethylenediamine, dibenzylamine or N-benzyl-B-phenethylamine. Compounds of formula I with a basic group, e.g. with an amino group, can form acid addition salts, e.g.

with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbonic or sulphonic acids, e.g. acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid. Compounds of formula I with an acidic and a basic group,

can also exist in the form of internal salts, i.e. in double-ion form.

Pharmaceutically unsuitable salts can also be used for isolation or purification. Only the pharmaceutically tolerable, non-toxic salts are therefore preferred for therapeutic use.

The penem compounds of formula I have at the 6-substituent

-CHd^)(CH3), at the methine carbon atom -CH(R3)(R4) and optionally in the substituent R^, chirality centers, these can in each case be present in R-, in S-, or in the racemic R,S -configuration. In preferred compounds of formula

In the residue -CHCR^HCH^) the R-conf igurates the ion.

The residue of formula IA having a hydrogen atom at the -atom

in the substituent or the substituent X , e.g. the rest of formula (IA), where X^ is amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower alkyl and/or X^ is amino, lower alkylamino, hydrazino or anilino, can also exist in one of the tautomeric forms

where X^' or 1 is correspondingly substituted or unsubstituted methylene or imino.

The compounds of formula I exhibit valuable pharmacological properties or can be used as intermediates for the preparation of such compounds with valuable pharmacological properties. Compounds of formula I, where R^ is hydroxy, R^ is carboxyl or a cleavable under physiological conditions, esterified carboxyl group, R^ is amino, lower alkylamino, dilower alkylamino, lower alkanoylamino or as indicated, substituted methyleneamino and R^ is optionally with amino, lower alkylamino, dilower alkylamino, as indicated substituted methyleneamino or hydroxy substituted methyl or ethyl, and pharmacologically tolerable salts of such compounds with salt-forming groups, have anti-bacterial effects. For example, they are effective in vitro against gram-positive and gram-negative cocci, e.g. Staphylococcus eureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria meningitidis and Neisseria gonor-rhoeae, against enterobacteria, e.g. Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, against haemophilus influenzae, Pesudomonas aeruginosa and anaerobic bacteria, e.g. Bacteroides fragilis and Clostridium perfringens in minimal concentrations of approx. 0.01 to approx. 64 ug/ml. In vivo,

in case of systemic infection in mice, e.g. in the case of Staphylococcus auerus, Escherichia coli or Streptococcus pyogenes,

When administered subcutaneously or orally, they give ED,.Q values of approx. 0.1 to approx. 100 mg/kg.

Surprisingly, the penem compounds according to the invention exhibit superior activity compared to structurally related and previously known penems. This is made clear by comparing the MIC data ("minimum inhibitory concen-trations", measured in vitro) of (5R,6S)-2-/T2R,S)-2-amino-but-1-yl)-6-/ TlR)-1-hydroxyethyl/-2-penem-3-carboxylic acid (compound A) with known homologous penems, which in position 2 on the penem ring carries a 4-aminobutyl or 1-aminobutyl substituent, namely (5R,6S )-2-(4-aminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid (European patent application

nad no. 82113, compound B) and (5R,6S)-2-(1-aminobuty1)-6-hydroxymethyl-2-penem-3-carboxylic acid (European patent application

nad no. 125 208, connection C).

The results are summarized in the following table 1.

The new compounds can therefore find use as orally or parenterally applicable antibacterial antibiotics, e.g. in the form of suitable pharmaceutical preparations, for the treatment of infections.

Compounds of formula I, where at least one of the functional groups present is in protected form, where a protected carboxyl group is different from a physiologically cleavable, esterified carboxyl group, can be used as intermediates for the preparation of the above-mentioned pharmacologically active compounds of formula I .

The invention primarily relates to compounds of formula

In where is hydroxy or protected hydroxy; R2 is carboxyl, under physiological conditions cleavable esterified carboxyl R2', R^ is amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, a group of formula -N=C(X1,X2), where X-j^ is hydrogen, amino, lower alkylamino, dilower alkylamino, lower alkyleneamino . /or an oxygen or sulfur atom, and X 2 is amino, lower alkylamino, dilower alkylamino, lower alkylene amino, hydrazino, anilino, lower alkoxy, phenyl lower alkyl oxy or lower alkylthio, or protected amino;

R^ is methyl, ethyl or with amino, lower alkylamino, dilower alkylamino, a group of formula -N=C(X-^,X2), where X^ and X2 have the meanings given in the definition of R^, protected amino, hydroxy or protected hydroxy-substituted methyl or ethyl, and n is an integer from 1 to 3, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I which exhibit a salt-forming group.

The invention mainly relates to compounds of formula

In where R^ is hydroxy, R^ is carboxyl or, under physiological conditions, cleavable, esterified carboxyl, e.g. loweralkanoyloxymethoxycarbonyl or 1-loweralkoxycarbonyloxylloweralkoxycarbonyl, R^ is amino, loweralkylamino, diloweralkylamino, loweralkanoylamino or a group of formula -N=C(X-^,X2), where X^ is hydrogen, loweralkyl or amino, and X ? is amino, R^ is methyl, ethyl or with amino, lower alkylamino or hydroxy substituted methyl or ethyl, and m means 1 or 2, optical isomers of the compound of formula I, mixtures of these optical isomers and salts of such compounds of formula I as exhibits a salt-forming group.

The invention primarily relates to compounds of formula

In where R^ is hydrosky, R^ is carboxyl or under physiological conditions cleavably esterified carboxyl, e.g. lower alkanoyloxymethoxycarbonyl or 1-lower oxycar- ---bonyloxylower oxycarbonyl, R^ is amino, R^ is methyl or ethyl, and m is 1 or 2, optical isomers of the compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I which exhibits a salt-forming group.

The invention relates in particular to those compounds of formula

I mentioned in the examples, their optical isomers and their salts.

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

The new compounds are produced e.g. in that one

a) ring closes a ylid compound of formula

where R^, R^, R^ and m have the meaning given under formula I, R„' is a protected carboxyl, Z is oxygen or sulfur and X stands for either a triply substituted phosphonio group or a doubly esterified phosphono group together with a cation, or

b) processes a compound of formula

where R^, R^, R^ and m have the meaning given under formula I, R2<1> is protected carboxyl and Z is oxygen or sulphur, with an organic compound of 3-valent phosphorus, or

c) in a compound of formula

where R^ and m have the meaning given under formula I,

R2' is a protected carboxyl group, and R^<1>is a group exchangeable with the residue R_ or R^ and R^<1>is a group transferable to the residue R^ or R^, under the condition that at least one of the groups R ^' and R^<1>is different from R^respectively R^, the group R^<1> is replaced by the residue R3 and/or the group R^' is transferred to the residue R^, or

d) in a compound of formula

where R-^, R^, R^ and m have the meaning given under formula I, R 2 ' stands for a protected carboxyl group and X stands for the group -S- or for the group -SO2-, the residue X is cleaved off, and, if desired or necessary, in an accomplished connection

of formula I, a protected hydroxy group R^ or protected hydroxy in the residue R4 is transferred to the free hydroxy group, and/or, if desired, in an obtained compound of formula I, a protected carboxyl group R2<1> is transferred to the free carboxyl group, to a below physiological conditions cleavable, esterified carboxyl group or to another protected carboxyl group R2' or a free carboxyl group R2 is transferred to an esterified carboxyl group cleavable under physiological conditions, and/or if desired, a protected amino group R^ or protected amino in the residue R^ is transferred to the free amino group or a free amino group R^ or free amino in the residue R^ is transferred to a substituted amino group, and/or, if desired, a prepared mixture of isomeric compounds of formula I is separated into the individual isomers, and/or, if desired, a prepared compound with salt-forming group to a salt or a prepared salt is transferred to the free compound or to another salt.

In the starting compounds of formula II-V are functional groups, such as e.g. a free hydroxy group R, and e.g.

a free amino group R 1 , preferably protected with conventional protecting groups, e.g. one of the above mentioned groups.

a) Cyclization of compounds of formula II.

The group X in the starting material of formula II is a wood

The Wittig condensation reaction usual phosphonio or phosphono group, especially a triaryl, e.g. triphenyl-, or trilower alkyl-, e.g. tri-n-butylphosphonium group, or one at lower alkyl, e.g. ethyl, doubly esterified phosphono group, where the symbol X in the case of phosphono group additionally comprises the cation of a strong base, especially a suitable metal, such as alkali metal ion, e.g. the lithium, sodium or potassium ion. Preferred as group X

is on the one hand triphenylphosphonio and on the other hand diethylphosphono together with an alkali metal ion, e.g. the sodium ion.

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

The ring closure can take place spontaneously, i.e. during the production of the starting materials, or during heating, e.g. within a temperature range of from approx. 30°C to 160°C, preferably from approx. 50°C to approx. 100°C. The reaction is preferably carried out in a suitable, inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. cyclohexane, benzene or toluene, in a halogenated hydrocarbon, e.g. raethylene chloride, an ether, e.g. diethyl ether, a cyclic ether, e.g. dioxane or tetrahydrofuran, a carboxylic acid amide, e.g. dimethylformamide, a dilave alkyl sulfoxide, e.g. dimethyl sulfoxide, or a lower alkanol, e.g. ethanol, or in a mixture thereof, and if necessary, in an atmosphere of inert gas, e.g. in a nitrogen atmosphere.

b) Cyclization of the compound of formula III.

An organic compound of trivalent phosphorus is derived, e.g.

from phosphoric acid and is especially an ester of this with a lower alkanol, e.g. methanol or ethanol, and/or an optionally substituted, aromatic hydroxy compound, e.g. phenol or pyrocatechin, or an amide ester thereof of the formula P(OR cl )-N(R, D )Z „, where R cl and R, D, independently of each other, mean lower alkyl, e.g. methyl, or aryl, e.g. phenyl. Preferred compounds of trivalent phosphorus are trialkyl phosphite, e.g. trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene, an ether, e.g. dioxane or tetrahydrofuran,

or a halogenated hydrocarbon, e.g. methylene chloride or chloroform, at a temperature of approx. 20°C to 140°C, preferably from approx. 40°C to approx. 110°C, 1 mol equivalent of a compound of formula III is reacted with 2 mol equivalents of the phosphorus compound. Preferably, the compound of formula III is dissolved in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a longer period of time, e.g. during a period of 2-4 hours.

In a preferred embodiment of the method, the starting material of formula III is prepared as described below, and it is reacted without isolation from the reaction mixture with the organic compound of trivalent phosphorus, whereby the end product of formula I is produced.

c) Replacement of the residue R^ and/or .

A group R^1 exchangeable with the residue R^1 is e.g. a group

which can be exchanged by a nucleophilic reaction. Such groups R^' are particularly esterified hydroxy groups, as in the case of a halohydrogen acid, a dilavealkyl or diarylphosphoric acid, an optionally oxo- or halogen-substituted lower alkanecarboxylic acid, an optionally halogen-substituted lower alkane or an optionally halogen- or lower alkyl-substituted benzenesulfonic acid esterified hydroxy groups. Corresponding to the residue R4transferable groups R^'

is e.g. with one of the aforementioned esterified hydroxy groups substituted with methyl or ethyl. Such esterified hydroxy groups are e.g. halogen, such as chlorine, bromine or iodine, diloweralkyl- or diarylphosphoryloxy, e.g. dimethyl, diethyl or diphenylphosphoryloxy, optionally with halogen or oxo substituted lower alkanoyloxy, e.g. formyloxy, acetyloxy or acetacetyloxy, optionally with halogen substituted lower alkanesulfonyloxy, e.g. methanesulfonyloxy or trifluoromethanesulfonyloxy, or optionally with halogen or lower alkyl substituted benzenesulfonyloxy, e.g. benzenesulfonyloxy, 4-chloro-, 4-bromo- or 4-methyl-benzenesulfonyloxy.

For example, an esterified hydroxy group R^<1> is replaced with

an amino group or with a, as indicated by the definition of R^, substituted amino group R^ and/or an esterified hydroxy group in the residue R^<1>, is replaced by an amino group,

of a, as indicated by the definition of R4, substituted amino group or of a hydroxy group.

The reaction takes place with a compound of the formula Z'-H, where Z' in the case of substitution of the residue R^<1> stands for amino, lower alkanoylamino, with lower alkyl substituted amino, substituted amino or protected amino and in the case of the substitution of the residue R4<1> for amino, with lower alkyl substituted amino, substituted methyleneamino, protected amino, hydroxy or protected hydroxy, or a salt,

as an alkali metal salt, e.g. the sodium or potassium salt thereof, i.e. for the preparation of corresponding amino compounds with nitric acid or with phthalimide or especially with alkali metal salts, e.g. the sodium or potassium salts thereof, further with ammonia, lower alkyl and dilower alkyl amines, amidines, guanidines etc., which may be available in a protected form, where at least one hydrogen atom must be present on the reacting amino group, and for the production of corresponding hydroxy compounds, e.g. . with the hydroxide or carbonate of an alkali metal, e.g. sodium hydroxide, sodium carbonate or potassium carbonate, further with alkali metal salts, such as the sodium salts, corresponding carbonic acid half-esters, such as e.g. carboxylic acid allyl esters or carboxylic acid haloalkyl esters, etc. The reaction takes place in a known manner in an inert solvent, such as e.g. a lower alkanol, dimethylformamide, a cyclic ether, e.g. dioxane, in dimethylsulfoxide, in water or in mixtures thereof, at room temperature or slightly elevated or reduced temperature, e.g. from approx. 0° to 40°C, especially at room temperature.

The starting compounds of formula IV can be prepared by a method analogous to that described under method a) by cyclization of the phosphorane of formula

where Z and X have the meaning given under formula II.

d) Elimination of the residue X from compounds of formula V.

In the case of compounds of formula V, the same applies

substituted 2-thia-3-cephem-4-carboxylic acids or especially about 2-thia-3-cephem-4-carboxylic acid 1,1-dioxide.

The elimination of sulfur from a 2-thia-3-cephem-4-carboxylic acid

of formula V (X=S) takes place, for example, with an organic compound of trivalent phosphorus, which e.g. one of the compounds mentioned under method b). Suitable compounds of trivalent phosphorus are e.g. trilower alkyl phosphite, e.g. triethylphosphite, and especially triphenylphosphine. The elimination is carried out at room temperature or slightly elevated temperature, e.g. from approx. 20° to approx. 60°C, in an inert solvent, solvent or a solvent mixture, e.g.

in a hydrocarbon, e.g. benzene, a chlorinated hydrocarbon, e.g. chloroform, or a lower alkane, e.g. acetone,

when necessary under an atmosphere of inert gas, such as a nitrogen atmosphere.

The elimination of sulfur dioxide from a compound of formula

V, where X stands for SG^, takes place, for example, in a solution

which contains this compound by weak or medium heating, e.g. from approx. 30° to approx. 80°C, where inert solvents, such as e.g. optionally chlorinated hydrocarbons, e.g. chloroform, aliphatic ethers or aromatic hydrocarbons, such as e.g. benzene.

Such starting materials of the formulas II-VI which are mentioned at the outset as particularly preferred compounds of the formula I are preferably used.

Obtained compounds of formula I can be transferred to other compounds of formula I in a manner known per se within the scope of the definitions.

In an obtained compound of formula I where one or more functional groups are protected, these can, e.g. the protected carboxyl, hydroxy and/or amino groups are released in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction. The release can take place in stages or simultaneously.

In an obtained compound of formula I according to the invention,

where R_ means a protected carboxyl group, the protected carboxyl group can be set free in a manner known per se. In this way, one can transfer tert.-lower alkoxycarbonyl or in the 2-position with a trisubstituted silyl group or in the 1-position with lower alkoxy substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl, to free carboxyl, 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. Optionally substituted benzyloxycarbonyl can be cleaved e.g. by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitable substituted benzyloxycarbonyl, such as 4-nitrobenzoyloxycarbonyl, can also be transferred to free carboxyl by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. sodium dithionite, or with a reducing metal, e.g. tin,

or metal salt, such as a chromium II salt, e.g. chromium II chloride, usually in the presence of a hydrogen emitting agent, which together with the metal forms masking hydrogen, such as a suitable carboxylic acid, e.g. one possibly, e.g. with hydroxy substituted lower alkane carboxylic acid, e.g. acetic acid, formic acid or glycolic acid, or an alcohol or thiol to which water is preferably added. The removal of an allyl protecting group can e.g. take place by reaction with a compound of palladium, e.g. tetrakis-(triphenylphosphine)-palladium in the presence of triphenylphosphine and under addn

of a carboxylic acid, e.g. 2-ethylhexanoic acid or a salt thereof. By treatment with a reducing metal or metal salt, as described above, one can also convert 2-halo lower alkoxycarbonyl (possibly after conversion of a 2-bromo lower alkoxycarbonyl group to a corresponding 2-iodo lower alkoxycarbonyl group), or aroylmethoxycarbonyl to free carboxyl, while aroylmethoxycarbonyl also

can be cleaved for treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also be transferred to free carboxyl by treatment with a salt of fluors-

acid which releases the fluoride anion, 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 tetralower alkylammonium fluoride, e.g. tetrabutylammonium fluoride. Carboxyl which is esterified with an organic silyl or stannyl group, such as trilower alkylsilyl or -stannyl, can be set free solvolytically in the usual way, e.g. by treatment with water or an alcohol.

A lower alkoxycarbonyl group which is substituted in the 2-position with lower alkylsulfonyl or cyano can be transferred to free carboxyl, e.g. by treatment with a basic agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium or potassium hydroxide or sodium or potassium carbonate.

On the other hand, compounds of formula I, where

R2 means carboxy, transferred to compounds of formula

In where R 2 is a protected carboxyl group, especially an esterified carboxyl group, or an esterified carboxyl group that is cleavable under physiological conditions. Consequently, the free carboxyl group can be esterified, e.g. by treatment with a suitable diazo compound, such as a diazolavere alkane, e.g. diazomethane, or a phenyldiazoleveralkane, e.g. diphenyldiazolmethane, if necessary, in the presence of a Lewis acid, such as boron trifluoride, or by turnover

with an alcohol suitable for esterification in the presence of an ester-

ringing agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide, as well as carbonyldiimidazole. Esters can also be prepared by reacting an optionally in situ produced salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, such as sulfuric acid, or a strong organic sulphonic acid, such as 4-toluenesulphonic acid. Furthermore, acid halides, such as chlorides (prepared e.g. by treatment with oxalyl chloride), activated esters (formed e.g. with N-hydroxy-nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (prepared e.g. with halogen formic acid lower alkyl esters such as chloroformate ethyl or chloroformate isobutyl ester, or with halogen acetic acid halides, such as trichloroacetic acid chloride) is transferred to an esterified carboxyl group by reaction with suitable alcohols, possibly in the presence of a base such as pyridine.

In a compound of formula I with an esterified carboxyl group R_, this can be transferred to another esterified carboxyl group, e.g. 2-chloroethoxycarbonyl or 2-bromomethoxycarbonyl by treatment with an iodine salt, e.g. sodium iodide to 2-iodoethoxycarbonyl. Furthermore, in compounds of formula I which contain a protected carboxyl group in esterified form, the carboxyl protecting group can be cleaved off as described above, and a prepared compound of formula I can be transferred with a free carboxyl group or a salt thereof, by reaction with a reactive ester of a corresponding alcohol

hol to a compound of formula I where 1*2 is an esterified carboxyl group that can easily be split off under physiological conditions.

In compounds of formula I which can be prepared by the method according to the invention, where hydroxyl is protected and/or optionally the residue R contains protected hydroxy 1 as a substituent, the protected hydroxy group can be transferred in a manner known per se to the free hydroxy group . For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is set free in the same way as a corresponding protected amino group (see below); a tri-lower alkylsilyl group e.g. also with tetrabutylammonium fluoride and acetic acid (under these conditions carboxy groups protected with trisubstituted silylethoxy are not cleaved). A 2-halogen lower alkyl group and an optionally substituted benzyl group are cleaved off reductively.

In a compound of formula prepared according to the invention

With a protected amino group, this can be transferred in a manner known per se to the free amino group, depending on the type of protecting group, preferably by means of solvolysis or reduction. For example, 2-halogen-lower-alkoxycarbonylamino (possibly after conversion of a 2-bromo-lower-alkoxycarbonylamino group to a 2-iodo-lower-alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid, or catalytically with hydrogen in the presence of a palladium catalyst. Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also

by treatment with an alkali metal, e.g. sodium dithionite. Optionally substituted benzyloxycarbonylamino can e.g. is split by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst,

as a palladium catalyst, and allyloxycarbonylamino can be cleaved by reaction with a compound of palladium, e.g. tetrakis(triphenylphosphine)palladium in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. 2-ethylhexanoic acid or a salt thereof. One with organic silyl-

or stannyl group protected amino group can e.g. is set free by means of hydrolysis or alcoholysis, one with 2-halo-gen laveralkanoyl, e.g. 2-chloroacetyl, protected amino group, can be set free by treatment with thiourea in the presence of a base or with a thiolate salt, as an alkali-

metal thiolate of the thiourea and then solvolysis, such as alcoholysis or hydrolysis of the produced condensation product. A 2-substituted silylethoxycarbonyl protected amino group can be transferred to the free amino group by treatment with a salt of hydrofluoric acid which emits fluoride anions, 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 tetralower alkylammonium fluoride, e.g. tetraethylammonium fluoride. An amino group protected in the form of an azido or nitro group is transferred, e.g. by reduction to the free amino group, e.g. by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid such as acetic acid. An amino group protected in the form of a phthalimido group can be transferred to the free amino group by reaction with hydrazine. Furthermore, an arylthioamino group can be transferred to amino by treatment with a nucleophilic reagent, such as sulfuric acid.

Furthermore, one can transfer a free amino group or amino as a substituent in the residue R^ to a substituted amino group in a manner known per se. This is how you can e.g. transfer amino R^ by reaction with a suitable lower alkanoyl halide, such as -chloride, to lower alkanoylamino R^. The conversions of amino groups into amidino, guanidino, isourea, isothiourea, imidoether and imidothioether groups can e.g. carried out by the method indicated in the German explanatory document no. 26 52 679. In this way, for example, compounds of formula I where R^ is amino or R^ is methyl or ethyl substituted with amino, can be transferred to amidine by reaction with an imido halide or ester of the formula 1~{X1, Y1)C=X2 'H/®Y2e, where X^ is hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, X^<1>is optionally substituted imino, Y^. is halogen, e.g. chlorine, or lower alkoxy, e.g. ethoxy, and is an anion, e.g. chloride, or they can

is transferred to guanidine by reaction with a thiourea

of the formula X^-C(=X)-X2, where X^ and X2 can be the same or different and mean optionally substituted amino residues,

or with an isourea or isothiourea of the formula (X-^Y.^) C=X2' , where is lower alkoxy or lower alkylthio, X-^ is optionally substituted amino and X2' is optionally substituted imino. Furthermore, one can transfer a free amino group R-, or amino as a substituent in the residue R^

to one with a lower alkyl mono- or disubstituted amino group. The introduction of the lower alkyl group(s) takes place, for example, by reaction with correspondingly reactive lower alkyl esters,

as -halides, e.g. -chlorides or -bromides, or

-sulfonates, e.g. -methane- or -p-toluenesulfonates,

in the presence of a basic condensing agent, such as an alkali or alkaline earth metal hydroxide or carbonate, e.g. potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alcohol, at room temperature or elevated or reduced temperature, e.g. at -20° to +80°C.

Salts r of the compounds of formula I with salt-forming groups can be prepared in a manner known per se. This is how you can e.g. form salts of compounds of formula I with a free carboxyl or sulfo group, e.g. by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of α-ethylcaproic acid, or with organic alkali or alkaline earth metal salts, e.g. sodium bicarbonate, or with ammonia

ack or with a suitable organic amine, whereby a stoichiometric amount or a small excess of the salt-forming agent is preferably used. Acid addition salts of compounds of formula I are obtained in a similar way, e.g. by treatment with a suitable acid or with a suitable anion-exchange reagent. Internal salts of compounds of formula I can e.g. formed by neutralization of salts,

as acid addition salts, to the isoelectric point, e.g. with weak bases or when treated with ion exchangers.

Salts can normally be transferred to the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. by treatment with a suitable basic agent.

Prepared mixtures of isomeric compounds can by i

and known methods are separated into the individual isomers. For example, a prepared racemate can be allowed to react with an optically active auxiliary substance, the resulting mixture of two diastereomeric compounds can be separated by suitable physicochemical methods (e.g. fractional crystallization, adsorption chromatography) and the individual diastereomeric compounds can be split in the optically active compounds. Racemates that are particularly suitable for separation in antipodes are those that have an acidic group, e.g. racemates of compounds of formula I wherein R 2 is carboxy. These acidic racemates can be reacted with optically active bases, e.g. esters of optically active amino acids, or (-)-brucine, (+)-quinidine,

(-)-Quinine, (+)-Cinchonine, (+)-Dehydroabiethylamine, (+)-

and (-)-ephedrine, (-)- and (-)-phenylethylamine or their N-mono- or N,N-dialkylated derivatives, to mixtures consisting of two diastereomeric salts.

In racemates containing carboxyl groups, these carboxyl groups can be esterified using an optically active alcohol, such as (-)-menthol, (+)-borneol, (+)- or (-)-2-octanol, after which the carboxyl group can be set free after isolation of the desired diastereomer.

For the racemate separation, a hydroxy group present can also be esterified with optically active acids or reactive, functional derivatives thereof, so that diastereomeric esters are formed. Such acids are, for example (-)-abietic acid, D(+)- and L(-)-malic acid, N-acylated optically active amino acids, (+)- and (-)-camphanic acid, ( + )- and (-)- ketopic acid, L(+)-ascorbic acid, (+)-camphoric acid, ( + )-camphor-10-sulfonic acid(B),

( + )- or (-)-α-bromocamphor-ir-sulfonic acid, D (-)-quinic acid, D(-)-isoascorbic acid, D(-)- and L(+)-mandelic acid, (+)- l-Methoxyacetic acid, D(-)- and L(+)-tartaric acid and their di-O-benzoyl and di-O-p-tolyl derivatives.

Basic racemates, e.g. compounds of formula I, where R 1 is amino or the residue is substituted with amino, can form diastereomeric salts with the aforementioned optically active acids.

The cleavage of the separated diastereomers in optically active compounds of formula I also takes place by known methods. From the salts the acids or bases are set free,

e.g. with acids or bases that are stronger than those originally used. The desired optically active compounds are obtained from the esters and urethanes, e.g.

by alkaline hydrolysis or by reduction with a complex hydride, such as lithium aluminum hydride.

A second method for splitting the racemate consists

in chromatography on optically active adsorption layers, for example on cane sugar.

In a third method, the racemates can be dissolved in optically active solvents and the poorly soluble optical antipodes crystallized out.

In a fourth method, the racemates are dissolved and the optical antipode is crystallized by grafting with a small amount of an optically active product produced by the above method.

The division of the racemate into optical antipodes can find

place at any stage of the process, i.e. e.g. at the step involving the starting compounds of formulas II-VI, or at any subsequent step in the below-mentioned method of preparation

of the starting compounds of formula II-VT.

Of all the transformations of prepared compounds of formula I which follow, reactions which take place under weakly alkaline or especially neutral conditions are preferred.

The method also includes those embodiments where the compounds that occur as intermediates are used as starting compounds and the remaining method steps are carried out with these, or the method can be interrupted at any step. Furthermore, the starting materials can be used in the form of derivatives or produced in situ, possibly under the reaction conditions.

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

Step 1

A thioacetidinone of formula VII is obtained by reacting

a compound of formula VII with a compound introducing the residue -S-C(=Z)-(CH2)m-CH(R3,R4).

In a starting material of formula VII, W is a nucleophilic residue which can be replaced by the group -S-S(=Z)-(CH2)m_CH(R^,R^).

Such residues W are e.g. acyloxy esters, sulfonyl residues Ro-SO2~, where RQ is an organic residue, acido or halogen.

In an acyloxy acid residue W, acyl is e.g. the remainder of an organic carbonic acid and means e.g. lower alkanoyl, e.g. acetyl or propionyl, optionally substituted benzoyl, e.g. benzoyl or 2,4-dinitrobenzoyl, or phenyl laveralkanoyl, e.g. phenylacetyl. In a sulfonyl residue Rq-SO2-, Rq is optionally hydroxy-substituted lower alkyl, such as methyl,

ethyl, 2-hydroxyethyl, 1-hydroxyprop-2-yl or 1-hydroxy-2-methyl-prop-2-yl, benzyl or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen residue W is e.g. bromine, iodine or especially chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

A compound which introduces the residue -S-S(=Z)-(CH2)m-CH(R , R 4 ) is e.g. an acid of formula (R3,R4)CH-(CH2)m-C( = Z)-SH or especially a salt thereof, e.g. an alkali metal salt such as the sodium or potassium salt. The substitution can be carried out in an organic solvent, such as a lower alkanol, e.g. methanol or ethanol, a lower alkane, e.g. acetone, a lower alkanecarboxylic acid amide, e.g. dimethylformamide, a cyclic ether, e.g. tetrahydrofuran or dioxane, or in a similar inert solvent. The reaction is usually carried out at room temperature, but can also be carried out at an elevated or reduced temperature, e.g. at approx. 0° to approx. 40°C. By adding a salt of hydroiodic acid or thiocyanic acid, e.g. an alkali metal salt such as sodium salt, the reaction rate can be increased.

The incoming group -S-C(=Z)-(CH_) -CH(R.,,R.) is directed by the residue CH^-CHCR^)- preferably to the trans position. Accordingly, both (3S,4SR)- and also (3S,4S)-configured starting compounds of formula VII can be used. Although the trans-isomer is predominantly formed, small amounts of the cis-isomer can still occur. The separation of the cis-isomer takes place, as described above, by conventional methods, in particular by chromatography and/or by crystallization.

Starting compounds of formula VII are known, for example

from European Patent Application No. 82113, German Patent Application No. 3,224,055 and German Patent Application No. 3,013,997, or can be produced in an analogous manner. They can also be produced by the methods described in the examples.

Step 2.

A starting compound of formula III is obtained by treating an acetidinone of formula VII with an acid of formula f^'-COOH or in particular a reactive derivative thereof, such as an ester or an acid halide, e.g. the acid chloride, at a temperature of 20° to 80°C, preferably at 40° to 60°C, in an inert solvent, e.g. one of those mentioned in the reaction of compounds of formula III to compounds of formula I. When using an acid halide, one preferably works in the presence of an acid binding agent, such as a tertiary aliphatic amine, e.g. triethylamine, an aromatic amine, e.g. pyridine, or in particular an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, e.g. potassium carbonate or calcium carbonate.

Step 3.

Compounds of formula IX where X stands for a reactive, esterified hydroxy group, especially for halogen, e.g. chlorine or bromine, or organic sulfonyloxy,

e.g. lower alkanesulfonyloxy, such as methanesulfonyloxy,

or arylsulfonyloxy, e.g. benzene-, or 4-methylbenzene-sulfonyloxy, is prepared by reacting a compound of formula VIII with a glyoxylic acid compound of formula OHC-R2<1> or a suitable derivative thereof, as a hydrate, hemi-hydrate or hemiacetal, f .ex. a hemiacetal with a lower alkanol, e.g. methanol or ethanol, and a prepared compound of formula IX where Xq stands for hydroxy, the hydroxy group is converted into a reactive, esterified hydroxy group.

The compounds of formula IX are usually obtained as mixtures

of both isomers /with regard to the grouping -CH ( R^ 1 )v-'X__/. However, the pure isomers can also be isolated, e.g.

by chromatography.

The placement of the glyoxylic acid ester compound on the nitrogen atom of the lactam ring in the compound of formula VIII takes place at room temperature, or if necessary under heating, e.g. at approx. 100°C, and in the absence of an actual condensing agent. When using a hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, e.g. azeotropic distillation, or by using a suitable dehydrating agent, such as e.g. a molecular sieve. Preferably, one works in the presence of a suitable solvent, such as e.g. dioxane, toluene or dimethylformamide, or a mixture of solvents, and, if desired or necessary, in an atmosphere of an inert gas, e.g. nitrogen.

The transfer of a hydroxy group Xq to a reactive esterified hydroxy group Xq in a compound of formula IX is carried out by treatment with a suitable esterifying agent, e.g. with a thionyl halide, e.g. -chloride,

a phosphorus oxyhalide, especially -chloride, a halophosphonium halide, such as triphenylphosphonium dibromide or -dichloride or a suitable organic sulfonic acid halide, such as -chloride,

preferably in the presence of a basic, primarily organic basic agent, such as an aliphatic tertiary amine, such as triethylamine or diisopropylamine, or a heterocyclic base of the pyridine type, e.g. pyridine or collidine. Preferably, one works in the presence of a suitable solvent, e.g. dioxane or tetrahydrofuran, or a solvent mixture, if necessary under cooling, e.g. at approx. -30°C to approx. +30°C, and possibly in an atmosphere of inert gas, such as nitrogen.

Step 4.

The starting material of formula II is obtained by processing

a compound of formula IX with a suitable phosphine compound, such as a tri-lower alkylphosphine, e.g. tri-n-butyl-phosphine,

or a triarylphosphine, e.g. triphenylphosphine, or with a suitable phosphite compound, such as a trilower alkyl phosphite, e.g. triethyl phosphite, or an alkali metal diaverealkyl phosphite, e.g. -diethyl phosphite.

The conversion of the compound of formula IX to the compound

of formula II is preferably carried out in the presence of a suitable inert solvent, such as a hydrocarbon, e.g. cyclohexane or benzene, or an ether, e.g. dioxane or a solvent mixture. Depending on the reactivity, one works under cooling or at an elevated temperature, e.g. between -10° and +100°C, preferably at approx. 20°

to 80°C, and/or in an inert gas atmosphere, such as a nitrogen atmosphere. To prevent oxidation processes, catalytic amounts of an anti-oxidant can be added,

e.g. hydroquinone.

One usually works in the presence of a basic agent, such as

an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine, pyridine, lutidine or "polystyrene-Hunig base", or an inorganic base, e.g. an alkali metal carbonate, e.g. sodium or potassium carbonate, where it primarily

the resulting phosphonium salt of formula

where X<1> means a phosphono group hires a phosphino group together with an anion which, depending on the meaning of the residue Rq, e.g. is chloride, is converted to the ylide starting material of formula II. However, one can also work in the absence of a base

and isolating a compound of formula (Ila), especially such a phosphono compound, and transferring this in the preparation of the final product of formula I in situ to the starting material of formula II.

Step 5.

A compound of formula II can further be obtained by treating a mercaptide of formula X, where M stands for a metal cation, with an acylating agent which introduces the residue (R3,R4)CH-(CH2)m-C(=Z)-.

In the starting material of formula (X), the metal cation M is, for example, a cation of formula M or M /2, where M preferably stands for a silver cation and M 2 + especially stands for a 2-valent cation of a suitable transition metal, e.g. copper, lead or mercury.

An acylating agent that introduces the residue (R_,R.)CH-(CH_) —

j 42. m C(=Z)-- is e.g. the acid :(R3 ,R4 )CH- (CH2 )m~C ( = Z ) -OH or especially a reactive functional derivative thereof, such as an acid halide, e.g. chloride or bromide, azide or anhydride thereof.

The acylation takes place when a reactive functional derivative of the acid of formula (R^,R4)CH-(CH2)m~C(=Z)-OH is used,

e.g. the acid chloride, in an inert solvent, such as a chlorinated hydrocarbon, e.g. methylene chloride, or an ether, e.g. diethyl ether or dioxane, at room temperature or during heating or cooling, e.g. in a temperature range from approx. -50° to approx. +60°C, especially at approx.

-30° to approx. +20°C.

The starting compounds of formula X can, for example, be prepared by transferring an acetidinone of formula

by reaction with an alkali metal salt, e.g. the sodium salt of a thiolower alkanecarboxylic acid, e.g. thioacetic acid, or the thiphenyl mercaptan of a compound of formula where W means triphenylmethylthio or lower alkanoylthio, e.g. acetylthio, this is transferred analogously to the method described in reaction steps 3 and 4, to a compound of formula

and this is employed 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 formula MA, where M has the meaning given above, but in particular stands

for a silver cation, and A is a common anion, which affects the solubility of the salt MA in the chosen solvent in a favorable direction, e.g. the nitrate, acetate or fluoran ion.

Ylides of formula II can be used directly in the ring closure reaction to produce the end product of formula I. However, one can also in compounds of formula II, where a protected hydroxy group, e.g. a hydrolytically easily cleavable protected hydroxy group, such as trisubstituted silyl, first cleave off the hydroxy protecting group and then use the prepared compound of formula II, where R 1 is hydroxy, in the ring closure reaction.

Starting compounds of formula V, where X represents the group

-S-, are known (e.g. from Belgian patent no. 898382 or from Tetrahydroen Letters 1983, 1631-1634) or can be prepared in an analogous manner. Compounds of formula V, where X stands for a sulfonyl group -SG^-/ are prepared by reacting a compound of formula

where R^, R^, R^ and m have the meaning given under formula I, and R2' is protected acarboxyl, with an aliphatic or aromatic percarboxylic acid, e.g. peracetic acid, m-chloroperbenzoic acid or monoperphthalic acid, in an inert solvent or a solvent mixture, e.g. in a halogen

hydrocarbon, e.g. chloroform, an ether or an aromatic hydrocarbon, such as benzene, at a temperature from approx. 0° to approx. 60°C.

The starting compounds of formula VI can, for example, be prepared by reacting the compound of formula

with a compound of formula (R3', R4' )CH-(CH2)m~C( = Z)- SH or a salt thereof, and converts a prepared compound of the formula

to starting compounds of formula VI by the method indicated in reaction scheme I.

One can also carry out the described methods for preparing compounds of the formulas II-VI and VIII-

X, as well as the specified methods for preparing the final product of formula I, with optically inactive compounds, and at any method step isolate the optically active compounds according to the present invention from the obtained diastereomer mixture or racemate as described above.

The invention also includes the new output connections

as well as the new intermediate products that can be obtained by the method according to the invention, such as those of the formulas II-VI, VIII

and IX as well as the specified methods for the preparation of these intermediates.

Preferably such starting materials are used, and the reaction conditions are chosen in such a way that the compounds listed above as particularly preferred are obtained.

The pharmacologically applicable compounds according to the present invention can e.g. used for the production of pharmaceutical preparations containing a therapeutically effective amount of the active substance together with, or in admixture with, inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for oral or parenteral administration, i.e. intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or potassium 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, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, and, if desired, explosives, e.g. starches, agar, alginic acid or salts thereof, such as sodium alginate, and/or fizzy mixes or absorbents, dyes, flavorings or sweeteners.

For parenteral administration, infusion solutions are primarily suitable, preferably isotonic aqueous solutions or suspensions, where these, before use, e.g. can be produced from lyophilized preparations, which contain the active substance alone or together with a carrier material such as e.g. mannite. Such preparations may be sterilized and/or contain excipients, e.g. preservative, stabilizing, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers.

The present pharmaceutical preparations which, if desired,

may contain other valuable pharmacological substances, prepared in a known manner, e.g. by means of conventional mixing, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisate up to 100% of the active substance.

Depending on the type of infection and the condition of the infected organism, daily doses (oral or parenteral) of approx. 100 mg of approx. 500 mg for the treatment of warm-blooded organisms (humans and animals) with a weight of approx. 70 kg.

The mentioned pharmaceutical preparations and the use of compounds of formula I for the therapeutic treatment of humans and animals are also the subject of the present invention.

The following examples illustrate the invention. The temperatures are given in °C.

In the examples, the following abbreviations are used:

DC: Thin layer chromatogram

IR: Infrared spectrum.

UV: Ultraviolet spectrum.

THF: Tetrahydrofuran.

Example 1.

(5R,S)-2-(T2-R,S)-2-allyloxycarbonylamino-prop-1-yl/-6-(T1R)-1-allyloxycarbonyloxyethyl/-2-penem-3-carboxylic acid allyl ester.

A solution of 2 g of 2-(T3S,4R)-2-(T1R)-1-allyloxycarbonyloxyethyl/-4-/"('3R,S)-2-allyloxycarbonylaminobutyroyl-thio/-2-oxo-azetidine-1- yl/-2-triphenylphosphoranylideneacetic acid allyl ester in 400 ml toluene is stirred under an argon atmosphere for 1 6.5 hours at the reflux temperature. The solvent is then evaporated and the crude product is purified by chromatography on silica gel (eluent toluene/ethyl acetate 4:1), Rf = 0.54; IR (CH2C12) 3430; 1790; 1740; 1730; 1580

The starting materials can be produced in the following way:

a) (3R, S1.)-3-allyloxycarbonylaminobutyric acid.

7.83 g of (3R,S)-3-aminobutyric acid is dissolved in 17 ml of water and

35 ml of 5N sodium hydroxide and mixed after cooling on

ice bath with 8.88 ml chloroformate allyl ester. After removing the cooling bath, the reaction mixture is stirred for 16 hours at room temperature, then diluted with 150 ml of water and washed twice with ethyl acetate. The aqueous phase is adjusted to pH 2 with 4N hydrochloric acid solution and extracted twice with ethyl acetate. The organic extracts are washed once with saline solution, dried over MgSO4 and evaporated.

IR (CH 2 Cl 2 ) 3440; 1775 cm"<1>.

b) (3R,S)-3-allyloxycarbonylaminobutyric acid chloride.

1.87 g of (3R,S)-3-allyloxycarbonylaminobutyric acid are mixed

at 0° with 2.85 ml of thionyl chloride. After stirring for 1.25

hours at 0°C, the reaction mixture is evaporated 3 times with toluene. The crude compound in the title (IR (CH2C12): 3440, 1795, 1720 cm~^7 is reacted immediately further. c) 2- (( 3S, 4R) - 3-/ T1R) - l- allyloxycarbonyloxyethyl7- 4-/(~ 3R,S)-3-allyloxycarbonylaminobutyroylthio7-2-oxo-azetidin-1-yl-2-triphenylphosphoranylidene acetic acid allyl ester.

2.79 g of the silver salt of 2-C(3S,4R)-2-(QR)-1-allyloxycarbonyloxyethyl7-4-mercapto-2-oxo-azetidin-1-yl}-2-triphenyl-phosphoranylideneacetic acid allyl ester are dissolved in 25 ml of methylene -

chloride, is mixed at 0°C with 0.97 ml of pyridine and then dropwise with a solution of .123 g of (3R,S)-3-allyloxycarbonylaminobutyric acid chloride in 10 ml of methylene chloride. After stirring for 30 minutes at 0°C, the solid substance is filtered off over Hyflo and the filtrate is washed with aqueous sodium bicarbonate solution and then with salt water. After drying over MgSO4, the solvent is evaporated. The residue is purified by chromatography on silica cell (eluent) toluene-ethyl acetate 3:2). CD (Silica gel, toluene/ethyl acetate 2:3), Rf =

0.38; IR (CH 2 Cl 2 ) 3440; 1755; 1725; 1625 cm"<1>.

The silver salt of 2-{'(3S,4R)-3-((T1R)-1-allyloxycarbonyloxyethyl]_/-4-mercapto-2-oxozeitin-1-yl3-2-triphenylphosphoranylideneacetic acid allyl ester is prepared by the following way: ca) (2S, 3R)- 2- bromo- 3- hydroxybutyric acid- p- methoxybenzylamide. To a stirred solution of 5 g of (2S,3R)-2-bromo-3-hydroxybutyric acid and 3.52 g of p-methoxybenzylamine in 60 ml of absolute THF, which is stirred at room temperature under an argon atmosphere, is added dropwise over the course of 20 minutes 4, 16 g of 1-hydroxybenztriazole and 5.63 g of dicyclohexylcarbodiimide in 60 ml of THF. The manufactured raw product contains cyclohexylurea and hydroxybenztriazole as impurities. After chromatography of the mixture on silica gel (system: toluene; toluene/ethyl acetate 1:4) and crystallization of the pure fraction from methylene chloride/diethyl ether, the title compound is obtained with m.p. 122-124°C. /a/=-7+ 1° (1.112% in chloroform).

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

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

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

To a at 0° under an argon atmosphere, a stirred mixture of

550 mg sodium hydride dispersion (56-60% in oil) and 1.52

ml of bromoacetic acid tert-butyl ester in 25 ml of THF, a solution of 2.21 g of (2R,3R)-2,3-epoxy-butyric acid-p-methoxybenzylamide in 100 ml of THF is added dropwise. It is heated to room temperature and the reaction mixture is stirred for at least 1 hour (the course of the reaction is checked using thin-layer chromatography). Total reaction time: 90 min. The insoluble parts are filtered off and washed with THF and the combined filtrate is evaporated. The raw product that arises clean-

is seen by chromatography on 150 g of silica gel (system: toluene, toluene/ethyl acetate 80:20). Evaporation of the pure fraction gives the amorphous compound in the title.

IR spectrum: band i.a. at 1740, 1670, 1650, 1615, 1517, 1465, 1360 and 1035 cm"<1>.

cd) ( 3S, 4S)- 1-( p- methoxybenzyl)- 3-/ TlR)- 1- hydroxyethyl"/-

4- tert.- butoxycarbonyl- 2- azetidinone.

9.23 g tetrabutylammonium fluoride trihydrate is allowed to stand with 40 g molecular sieve (type 4171/16 - pre-dried at 300°C)

in 80 ml THF for 16 h at 5°. The mixture is cooled to 0°C, mixed with a solution of 2.8 g of (2R,3R)-2,3-epoxy-butyric acid-N-tert.-butoxycarbonylmethyl-N-p-methoxybenzylamide in 20 ml of THF and stirred for 2 hours at 0-5°. The molecular sieve is filtered off while washing with THF and the filtrate is passed directly onto a column prepared in toluene with 250 g of silica gel.

The evaporated fractions eluted with toluene/ethyl acetate (70:30 mixture) are taken up in methylene chloride, washed twice successively with 1N sulfuric acid, with saturated aqueous NaHCO 3 solution with water, dried and evaporated. After short chroma-

tography on silica gel (toluene, toluene/ethyl acetate 60:40)

and crystallization from methylene chloride/diethyl ether/petroleum ether, the pure title compound is obtained at m.p. 85-87°C.

ce) (3S,4S)-1-(p-methoxybenzyl)-3-/TlR)-1-allyloxycarbonyloxyethyl/-4-tert.-butoxycarbonyl-2-azetidinone.

A solution of 2 g of (3S,4S9-1-(p-methoxybenzyl)-3-/TlR)-1-hydroxyethyl/-4-tert.-butoxycarbonyl1-2-azetidinone in 24 ml of methylene chloride in 24 ml of methylene chloride is mixed at 0 °C

with 24 ml of 1N NaOH, 820 mg of tetrabutylammonium hydrogen sulfate and 1 ml of chloroformate allyl ester and stir vigorously. After a reaction time of 20 and 40 minutes, further portions (each time 1 ml) of chloroformic acid allyl ester are added. The reaction mixture is diluted with methylene chloride, the aqueous phase is separated and the organic layer is washed successively with 5% aqueous citric acid and 8% aqueous NaHCO 3 solution, dried and evaporated. After chromatographic purification, the pure, amorphous compound in the title is obtained. IR spectrum: band i.a. at 1765, 1745(sh), 1616, 1593, 1515, 1160

and 103 5 cm<1>.

cf) (3S,4S)-1-(p-Methoxybenzyl)-3-(TlR)-1-allyloxycarbonylethyl/-4-carboxylic acid-2-azetidinone.

1.6 g of (3S,4S)-1-(p-methoxybenzyl-2-(T1R)-1-allyloxycarbonyloxyethyl)-4-tert.-butoxycarbonyl-2-azetidinone is dissolved at 0° in 10 ml of trifluoroacetic acid. After a reaction time of 1 hour at room temperature, the reaction mixture is evaporated under high vacuum, and the compound produced in the title is processed further without purification. /_/= +85 +1% (1.0% in chloroform) .

cg) (3R,4R)-1-(p-Methoxybenzyl)-3-/TlR)-1-allyloxycarbonyl-oxyethyl/-4-acetoxy-2-azetidinone.

A stirred solution of 1.4 g of (3S,4S)-1-(p-methoxybenzyl)-3-((TlR)-allyloxycarbonyloxyethyl)-4-carboxylic acid-2-azetidinone under an argon atmosphere at room temperature in a mixture of

4 5 ml of THF and 6.6 ml of dimethylformamide are mixed with 1.6 g of lead (IV) acetate (approx. 10% acetic acid content), and stirred for approx. 1 hour until the substrate has completely reacted. Excess oxidizing agent is destroyed by the addition of

0.5 ml ethylene glycol (10 min. at room temperature). Precipitated lead(II) acetate is filtered from the reaction mixture, the filtration residue is washed out with THF and the filtrate is evaporated. The oily residue produced is taken up in methylene chloride, washed successively 2 times with saturated, aqueous NaHCO^ solution,

water and saturated NaCl solution, dried and evaporated. Chromatography of the residue on silica gel (toluene; toluene/ethyl acetate 90:10) gives the pure compound in the title /a/ =+90° + 1° (1.0% in chloroform.

ch) (3R,4R)-3-/TlR)-1-allyloxycarbonyloxyethyl/-4-acetoxy-2-azetidinone.

A solution of 900 mg (1.19 mmol) of (3R,4R)-1-(p-methoxybenzyl)-3-(TlR)-1-allyloxycarbonyloxyethyl/-4-acetoxy-2-azitidinone in 30 ml of acetonitrile is mixed at 10° with a solution of 5.37 g of cerium-(IV)-ammonium nitrate in 15 ml of water and stirred for 2 hours at room temperature. After extraction with ethyl acetate, washing with saturated NaHCO3 solution, drying of the organic phase over sodium sulfate and evaporation under reduced pressure, the crude compound in the title is obtained, which is purified chromatographically on silica gel with toluene-ethyl acetate (4:1 and 1:1 ). / a/ = +84 +1° (1.0% in chloroform) .

ci) (3S,4R)-3-/TlR)-1-allyloxycarbonyloxyethyl1/-4-triphenylmethylthio-azetidin-2-one.

892 mg of triphenylmethyl mercaptan are suspended in 5 ml of methanol at 0° and mixed over the course of 10 minutes in portions with a total of 0.16 g of a 50% sodium hydride suspension in oil. A solution of 0.62 g of (3S,4R)-2-(TlR)-1-allyloxycarbonyloxyethyl/-4-acetoxy-azetidin-2-one in 7 ml of acetone and 5 ml of water is then added dropwise over the course of 15 minutes. . After stirring for 1 hour at 0° and a further 3 hours at room temperature, the reaction mixture is evaporated on a rotary evaporator and extracted with 20 ml of methylene chloride. The organic phase is washed with brine solution and dried over MgSO 4 . After evaporation, the crude title compound is purified by chromatography on silica gel (eluent toluene-ethyl acetate 19:1).

TLC (toluene-ethyl acetate 4:1) Rf = 0.3, IR (CH 2 Cl 2 ) 3400;

1770, 1745 cm"<1>.

cf) 2- C( 3S, 4R)- 3-/ TlR)- 1- allyloxycarbonyloxyethyl 1/- 4-triphenylmethylthio- 2- oxo-azetidin- 1- y 1}- 2- hydroxy-acetic acid allyl ester.

0.82 g of (3S,4R)-3-/T1R)-1-allyloxycarbonyloxyethyl/-4-triphenylmethylthio-azetidin-2-one and 0.416 g of glyoxylic acid allyl ester ethyl hemiacetal in 10 ml of absolute toluene are mixed with 4 g of molecular sieve (4Å ) and stirred for 61 hours at 60°. After filtration and evaporation on a rotary evaporator under reduced pressure, the title compound is obtained. DCi.(silica gel/toluene/ethyl acetate 4:1), Rf= 0.1. IR (CH 2 Cl 2 ): 3510, 1770, 1745, cm"<1>.

ck) 2- £( 3S, 4R)- 3-/ TlR)- 1- allyloxycarbonyloxyethyl/- 4-triphenylmethylthio- 2- oxo- azetidin- 1- yl}- 2- triphenylphosphoranylidene- acetic acid allyl ester.

To a solution of 1 g of 2-(3S,4R)-2-(TlR)-allyloxycarbonyloxyethyl/-4-triphenylmethylthio-2-oxo-azetidin-1-yl-2-hydroxyacetic acid allyl ester in 10 ml of tetrahydrofuran is added while stirring at 0° successively 0.182 ml of thionyl chloride and 0.206 ml of pyridine during 5 minutes. The white suspension is stirred for 30 minutes at 0° and filtered over "Hyflo". After washing the residue with toluene, it is evaporated on a rotary evaporator. The residue is dissolved in 10 ml of dioxane, mixed with 0.624 g of triphenylphosphine and 0.257 ml of lutidine,

and stirred for 46 hours at a bath temperature of 80°. The mixture is filtered over "Hyflo" and the residue is washed with toluene.

The combined filtrates are evaporated and the residue chromatographed

on silica gel gives the pure product (eluent toluene/

ethyl acetate 19:1 to 4:1), TLC (silica gel; toluene/ethyl acetate 4:1), R = 0.24, IR (CH 2 Cl 2 ) 1745; 1620 cm"<1>.

cl) Silver salt of 2-{(3S, 4R)-1-/TlR)-1-allyloxycarbonyloxyethyl/-4-triphenylmethylthio-2-oxo-azetidin-1-yl3-2-triphenyl1-phosphoroanylidene-acetic acid allyl ester.

0.46 g of 2--f(3S,4R)-3-((TlR)-1-allyloxycarbonyloxyethyl/- 4-triphenylmethylthio-2-oxo-azetidin-1-yl)-2-triphenylphosphoro-anylideneacetic acid allyl ester is dissolved in 6 ml of diethyl ether and mixed at room temperature with 4.4 ml of a 0.5M aqueous silver nitrate solution. 0.077 ml of triethylamine is then added and the reaction mixture is stirred for 30 minutes. The solid is filtered off and washed thoroughly with water and diethyl ether. The residue is once again slurried in 300 ml of water and 300 ml of diethyl ether, stirred and filtered off. After renewed washing with diethyl ether, the solid is dried under high vacuum. IR (CH 2 Cl 2 ) 1760; 1745; 1630 cm<-1>.

Example 2.

(5R,6S)-2-(T2R,S)-2-amino-prop-1-yl/-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid.

1.05 g of (5R,6S)-2-(T2R,S)-2-allyloxycarbonylamino-prop-1-yl/-6-(T1R)-1-allyloxycarbonyloxyethyl/-2-penem-3-carboxylic acid allyl ester is dissolved in 25 ml of absolute tetrahydrofuran and is then mixed successively with 105 mg of tetrakis-(triphenyl-phosphine)-palladium and in portions with 2.03 ml of tri-n-butyltin hydride. After stirring for 2 hours at room temperature, the reaction mixture is mixed with 0.813 ml of acetic acid. After a further 30 minutes of stirring at room temperature, 40 ml of hexane are added. The solid is filtered off and then dissolved in water. The solution is clarified with a little activated charcoal and filtered over a "Minipor" filter. The compound in the title is obtained by lyophilization. UV (phosphate buffer pH 7.4) \ max = 304.5 nm, (IR (DMSO.d6,.):1772 cm"<1>,

The prepared diastereomer mixture, consisting of bonds with a (2R)-2-aminoprop-l-yl or a (2S)-2-aminoprop-l-yl group in the 2-position can be divided into the individual components by Column chromatography ("Antecgel OPTI UP C12"; eluent: water):

Isomer A: Rf ("Antecgel OPTI-UPC12", water) = 0.2.

NMR (360 MHz; D 2 O; reference TSP): = 1.3 (3H,d), 1.37

(3H,d), 2.95 and 3.18 (2H,m), 3.6 (lH,m), 3.9(lH,dd), 4.25 (lH,m) and 5.7 ppm (lH, d).

Isomer B: Rf ("Antecgel" OPTI-UPC12", water = 0.17.

NMR (360 MHz; D 2 O; reference TSP): = 1.3 (3H,d), .139

(3H,d), 2.97 and 3.27 (2H,m), 3.65 (lH,m), 3.92 (lH,dd),

4.26 (lH,m), and 5.67 ppm (lH,d).

Example 3.

(5R,6S)-2-((T2R,S)-2-allyloxycarbonylamino-but-1-y1/-6-[\IR)-1-allyloxycarbonyloxyethyl/-2-penem-3-carboxylic acid allyl ester.

Analogous to example 1, 1.98 g of 2-{(3S,4R)-2-[T1R)-1-allyloxycarbonyloxyethyl]-4-[13R,S)-3-allyloxycarbonyl-aminovaleroylthio]-2-oxoazetidin-1-yl are transferred }-2-triphenylphosphorus anylideneacetic acid allyl ester of the title compound. IR (CH 2 Cl 2 ): 3400; 1790, 1740; 1720; 1710; 1580 cm"<1>.

The starting material can be produced in the following way:

a) (3R,S)-3-allyloxycarbonylamnovaleric acid.

Analogously to example la), 5.86 g of (3R,S)-3-aminovaleric acid is transferred to the title compound. IR (CH 2 Cl 2 ): 3430; 1710 cm<-1>.

b) (3R,S)-3-allyloxycarbonylaminovaleric acid chloride. Analogously to example 1b), 0.4 g of (3R,S)-3-allyloxy-carbonylaminovaleric acid is transferred to the title compound. IR

(CH2C12: 3430; 1785; 1710 cm"<1>. c) 2- {( 3S, 4R)- 3-/( IR)- 1- allyloxycarbonyloxyethyl/- 4-/( 3R, S)- 3- allyloxycarbonylaminovaleroylthio/ - 2-oxo-azetidin-1-yl3-2-triphenylphosphoranylidene-acetic acid allyl ester.

Analogously to example lc), 2.79 g of the silver salt of 2-(3S,4R)-3-(TlR)-1-allyloxycarbonyloxyethyl/-4-mercapto-2-oxo-azetidin-1-yl-2-triphenylphosphoranylideneacetic acid allyl ester are transferred with 1, 32 g of (3R,S)-3-allyloxycarbonylaminovaleric acid chloride to the title compound. IR (CH 2 Cl 2 ) 3440; 1760; 1725; 1625 cm"<1>.

Example 4.

(5R,6S)-2-((T2R,S)-2-amino-but-1-yl)-6-((T1R)-1-hydroxyethyl)-2-penem-3-carboxylic acid.

Analogous to example 2, 0.8 g of (5R,6S)-2-(T2R,S)-2-allyloxycarbonylamino-but-1-yl/-6-(TlR)-1-allyloxycarbonyloxyethyl/-2-penem-3- carboxylic acid allyl ester to the title compound. UV (phosphate buffer pH 7.4); x max= 306 nm.

f''' max

Example 5.

(5R,6S)-2-(T2R,S)-2-N-formamidinoprop-1-yl/-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid.

A solution of 109.5 ml of ethyl formimidate hydrochloride and

84 mg of sodium bicarbonate in 4 ml of water, mixed at room temperature with a solution of 25 mg of (5R,6S)-2-/T2R,S)-2-amino-prop-1-yl/-6-/TlR)-1- hydroxyethyl/-2-penem-3-carboxylic acid and 8.4 mg of sodium bicarbonate in 1 ml of water. After stirring for 50 minutes at room temperature, 1 ml IN HC1 is added and evaporated under high vacuum. The produced substance is purified by chromatography on "OPTI-UPC12".

UV (phosphate buffer pH 7.4) :XITlclX= 304.5 nm.

Example 6.

(5R,6S)-2-(T2R,S)-2-aminoprop-1-yl/-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester.

1.2 g of sodium iodide is dissolved in 3.7 ml of acetone and mixed with 0.275 ml of ethyl-1-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. The solution is then added dropwise to 10.5 ml of methylene chloride and the precipitated inorganic salt is filtered off. The methylene chloride solution is evaporated to 2 ml and added at 0° to a solution of 0.272 g (lmmol), (5R,6S)-2-(2R,S)-2-aminoprop-1-yl/-6-(TlR)-1 -hydroxyethyl/-2-penem-3-carboxylic acid in 4 ml of dimethyl f-acetamide. It is then stirred for 3 hours at 0°, then diluted with ethyl acetate and washed 3 times with water.

The organic phase is dried over sodium sulfate and evaporated

on rotary evaporator. The crude product is purified on 10 g of silica

gel with ethyl acetate as eluent. You get connect-

late in the headline like a white foam. IR spectrum (methylene chloride): absorption bands at 1790 and 1740 cm

Example 7.

(5R, 6S) -2-(T2R,S),-2-aminoprop-1-yl/-6-(T1R9-1-hydroxyethyl 7-2-penem-3-carboxylic acid pivaloyloxyn rethyl ester).

0.6 g of sodium iodide is dissolved in 2 ml of acetone and mixed with 0.15 ml of pivalic acid chloromethyl ester. The mixture is stirred at room temperature for 3 hours and is then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 1 ml and added to a solution of 0.11 g (0.4 mmol)

(5R,6S)-2-(T2R,S)-2-aminoprop-1-yl/-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4

ml of N,N-dimethylacetamide at 0°. It is then stirred at 0° for 3 hours, diluted with ethyl acetate and washed 3

times with water. The inorganic phase is dried over sodium sulphate and evaporated on a rotary evaporator. The crude product is purified on silica gel with ethyl acetate as eluent.

You get the compound in the header as a white foam. IR spectrum (methylene chloride): absorption band at 1790 and

1730 cm

Example 8:

In a similar way as described in the preceding examples, the following compounds can be prepared: (5R,6S)-2- (T3R,S)-2-aminobut-1-yl/-6-/T1R9-1-hydroxyethyl7-2-penem -2-carbonic acid.

UV (phosphate buffer pH 7.4) X = 305 nm,

c' ' max

(5R,6S)-2-((T2R,S)-2-amino-3-hydroxy-prop-1-yl7-6-((T1R)-1-hydroxyethyl)-2-penem-3-carboxylic acid.

UV (phosphate buffer ^ pH 7.4) x max= 304 nm,

(5R,6S9-2-/T2R,S)-2,3-diamino-prop-1-yl/-6-/T1R9-1-hydroxyethyl/-2-penem-3-carboxylic acid.

UV (phosphate buffer pH 7.4) Xmsx= 305.5 nm.

r'1max

(5R,6S)-2-/T2R,S)-2-N-methylaminoprop-1-yl/-6-/(1R9-1-hydroxyethyl/-2-penem-3-carboxylic acid. UV (phosphate buffer pH 7, 4) X = 306 nm,

f ' ' max

(5R,6S)-2-(T2R,S)-2-N-formylamino-prop-1-yl/-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid.

UV (phosphate buffer ^ pH 7.4) x max= 305 nm,

(SR,6S)-2-(T2R,S)-2-N-acetylamino-prop-1-yl7-6-(T1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid.

UV (phosphate buffer pH 7.4) x max<=>304 , 5 nm,

Example 9.

Dry ampoules or bottles containing (5R,6S)-/T2R,S)-2-amino-prop-1-yl7_6-/IIR)-1-hydroxyethyl/-2-penem-3-carboxylic acid as active substance are produced in the following manner:

Composition (for 1 ampoule or bottle):

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

Instead of the active substance mentioned above, the same amount of another active substance from the previous examples, such as e.g. (5R,6S)-2-(12R,S)-2-amino-but-1-yl/-6-(1R)-1-hydroxyethyl/-2-penem-3-carboxylic acid is used.

Claims (10)

1. v.. ■ j.ii.. Procedure for the preparation of compounds of the formula where is hydroxy or protected hydroxy, R2 is carboxyl or functionally converted carboxyl, R^ is amino, with lower alkyl substituted amino, lower alkanoylamino, substituted methyleneamino or protected amino, R^ is optionally with amino, with lower alkyl substituted amino, substituted methyleneamino, protected amino, hydroxy or protected hydroxy substituted methyl or ethyl, and n is an integer from 1 to 3, optical isomers of compounds of formula I, mixtures of such optical isomers and salts of such compounds of formula I which exhibit a salt-forming group, characterized in that mana) ring-closes a ylide compound of formula where R-^, R^, R4 and m have the meaning given under formula I, R9<1> is protected carboxyl, Z is oxygen or sulfur and X is either a triply substituted phosphonio group or a doubly esterified phosphono group together with a cation, orb ) treats a compound of formula where R-^ , R^ , R^ and m have the meaning given under formula I, R,,' is protected carboxyl and Z is oxygen or sulphur, with an organic compound of trivalent phosphorus, orc) in a compound of formula where R^ and m have the meaning given under formula I, R2 ' is a protected carboxyl group, and R^ ' is a group exchangeable with the residue R^ or R^ , and R4 ' is a group transferable to the residue R4 or R^ , on the condition that at least one of the groups R^ ' and R ^ ' is different from R^ respectively R^ , replaces the group R^<1> with the residue R^ and/or transfers the group R4 1 to the residue R4 , or d) in a compound of formula where R-^, R^ , R^ and m have the meaning given under formula I, R,,' is a protected carboxyl group and S stands for the group -S-,or for the group -SO.-,-, the residue X , and, if desired or necessary, in a prepared compound of formula I transfers a protected hydroxy group R-^ or protected hydroxy residue R^ to the free hydroxy group, and/or, if desired, in a prepared compound of formula I transfers a protected carboxyl group R,,' to the free carboxyl group, to a cleavable under physiological conditions, esterified carboxyl group or to another protected carboxyl group R2' or transfers a free carboxyl group R2 to a cleavable under physiological conditions, esterified carboxyl group, and/or, if desired, transfer - converts a protected amino group R^ or the protected amino residue R^ to the free amino group, or transfers a free amino group R^ or free amino in the residue R^ to a substituted amino group, and/or, if desired, divides a prepared mixture of isomeric compounds of formula I in the individual isomers, and/or, if desired, transfer a prepared compound with a salt-forming group to a salt or a prepared salt to the free compound or to another salt. 2. Process according to claim 1 for the production of compounds of formula I, characterized in that R 1 is hydroxy or protected hydroxy; R2 is carboxyl, under physiological conditions cleavable esterified carboxyl or protected carboxyl R2 ', R^ is amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, a group of the formula N=C(X^ ,X2 ), where X^ is hydrogen, amino, lower alkylamino . with one or two nitrogen atoms and/or an oxygen atom or sulfur atom, and X2 is amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl lower alkyl or lower alkylthio, or protected amino; is methyl, ethyl or with amino, lower alkylamino, dilower alkylamino, a group of formula N=C (X^ ,X2 ), where X^ and X2 have the meaning given in the definition of R^, protected amino, hydroxy or protected hydroxy substituted methyl or ethyl, and m is an integer from 1 to 3, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I which exhibit a salt-forming group 3. Process according to claim 1 for the preparation of compounds of formula I, characterized in that R 1 is hydroxy, R 2 is carboxyl or, under physiological conditions, cleavable, esterified carboxyl, e.g. loweralkanoyloxymethoxycarbonyl or 1-loweralkoxycarbonyloxylloweralkoxycarbonyl, R^ is amino, loweralkylamino, diloweralkylamino, loweralkanoylamino or a group of the formula -N=C (X^ ,X2 ), where X^ is hydrogen, loweralkyl or amino and X2 is amino, R^ is methyl , ethyl or with amino, lower alkylamino or hydroxy substituted methyl or ethyl, and n is 1 or 2, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I exhibiting a salt-forming group. 4. Process according to claim 1 for the preparation of compounds of formula I, characterized in that R-1 is hydrosky, R2 is carboxyl or under physiological conditions; cleavable esterified carboxyl, e.g. loweralkanoyloxymethoxycarbonyl or 1-loweralkoxycarbonyloxylloweralkoxycarbonyl, is amino, R^ is methyl or ethyl, and n is 1 or 2, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I exhibiting a salt-forming group. 5. Method according to claim 1, characterized in that pharmaceutically acceptable salts of compounds of formula I according to claim 1 are prepared. 6. Process according to claim 1, characterized in that esters of compounds of formula I are produced which can be cleaved under physiological conditions. 7. Process according to claim 1 for the preparation of compounds of formula I, characterized in that the residue -CH(R^ )(CH^ ) has the R configuration. 8. Method according to claim 1, characterized in that (5R,6S)-2-/T2R,S)-2-amino-prop-1-yl/-6-/T1R)-1-hydroxyethyl/-2- penem-3-carboxylic acid, (5R, 6S) -2- (12R)-2-aminoprop-1-yl/-6-(/T1R)-1-hydroxyethyl/- 2-penem-3-carboxylic acid, and (5R ,6S)-2-/T2S)-2-amino-prop-1-yl/-6-/T1R)-1-hydroxyethyl/- 2-penem-3-carboxylic acid, pharmaceutically acceptable salts thereof and under physiological conditions cleavable esters hence. 9. Process according to claim 1, characterized in that (5R,6S)-2- (T2R,S)-2-amino-but-1-yl)-6- ((T1R)-1-hydroxy-ethyl)-1 is produced 2-penem-3-carboxylic acid, optical isomers thereof, pharmaceutically acceptable salts thereof, and under physiological conditions cleavable esters thereof. 10. Process for the production of pharmaceutical preparations, characterized in that a compound of formula I prepared according to claim 1 is mixed with a pharmaceutically acceptable carrier.