NO841788L - HETEROCYCLYL-LAVALKYL-PENEM COMPOUNDS, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS, CONTAINING THESE COMPOUNDS AND APPLICATION OF THE LATER - Google Patents

Description

The present invention relates to new 2-heterocyclyl-lower 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-heterocyclyl lower alkyl-2-penem compounds of the formula

where R 1 is hydroxy or protected hydroxy substituted lower alkyl, R 2 means carboxyl or functionally converted carboxyl, R^ means an unsaturated monocyclic azaheterocyclyl residue which is bound to residue -A- over a tertiary ring nitrogen atom and A means lower alkyl substituted straight chain lower alkylene, optical isomers of compounds of formula (I), mixtures of these optical isomers and salts of such compounds of formula (I) containing a salt-forming group.

In the definitions used above and subsequently, within the framework of the applicable description, preferably have the following meanings:

The designation functionally converted carboxyl R- means

especially under physiological conditions cleavable,

etherified carboxyl or protected carboxyl R'2.

A cleavable under physiological conditions, esterified carboxyl group R2 protects the compounds of formula I from salt formation in the digestive system upon oral administration, whereby premature excretion is prevented and is primarily an acyloxymethoxycarbonyl group,

in which acyl means e.g. the residue of an organic carboxylic acid, primarily an optionally protected lower alkane carboxylic acid, after which acyloxymethyl forms the residue of a lactone. Such groups are e.g. lower alkanoyloxymethoxycarbonyl, aminoloweralkanoyloxymethoxycarbonyl, especially α-aminoloweralkanoyloxymethoxycarbonyl, 4-croton-lactonyl and 4-butyllacton-4-yl. Further esterified carboxyl groups R2 which are cleavable under physiological conditions are e.g. 5-indanyloxycarbonyl, 3-phthalidyloxycarbonyl, 1-lower oxycarbonyloxylaverealoxycarbonyl, 1-lower oxylaverealoxy-

carbonyl or 2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, which is substituted with lower alkyl or phenyl in the 5-position of the dioxolene ring.

An unsaturated, monocyclic azaheterocyclyl residue R^ which is

bonded to the residue -A- over a tertiary ring nitrogen atom,

is particularly a corresponding possibly partially saturated

dd

5-lightened heteroaryl residue with 1 to 4 ring nitrogen atoms,

as a corresponding aza-, diaza-, triaza- or tetraza-cyclic residue of an aromatic character, or is a corresponding dihydro residue, or a corresponding partially saturated 6-

simplified heteroaryl radical with 1 to 3 ring nitrogen atoms,

e.g. a corresponding aza-, diaza- or triaza-cyclic residue, e.g. corresponding dihydro or tetrahydro residue. Corresponding residues R^ are e.g. optionally partially saturated pyrrolyl, diazolyl, triazolyl or tetrazolyl or partially saturated pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl. These residues are unsubstituted or may be substituted with optionally etherified or esterified, including optionally protected hydroxy, e.g. hydroxy,

lower alkoxy, lower alkanoyloxy or halogen, optionally etherified mercapto, e.g. mercapto, lower alkylthio or phenylthio, lower alkyl, hydroxyl lower alkyl, lower carboxy lower alkyl, carboxy lower alkyl, optionally N-lower alkylated amino lower alkyl, e.g. amino lower alkyl or di lower alkyl amino lower alkyl, sulfone lower alkyl, optionally substituted, including protected amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino or acylamino,

as lower alkanoylamino, optionally functionally converted, including protected carboxyl or sulfo, e.g. carboxyl, sulfo, esterified carboxyl as lower alkoxycarbonyl, optionally protected carbamoyl, as N-mono- or N,N-diloweralkylated carbamoyl, cyano or sulfamoyl, optionally with lower alkyl-, nitro, lower alkoxy and/or halogen substituted phenyl. cycloalkyl, nitro, oxo and/or oxido. These residues can be especially mono- or also poly-substituted, especially mono- or di-substituted.

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

With hydroxy-substituted lower alkyl R- is especially in the a-position in the penemen ring with hydroxy-substituted lower alkyl and means e.g. 1-hydroxy-prop-1-yl, 2-hydroxy-prop-2-yl, 1-hydroxybut-1-yl, 2-hydroxybut-2-yl or especially hydroxymethyl or 1-hydroxyethyl.

Lower alkanoyloxymethoxycarbonyl is e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

α-amino lower alkanoyloxymethoxycarbonyl is e.g. glycyloxymethoxycarbonyl, valyloxymethoxycarbonyl or leucyloxymethoxycarbonyl.

1-lower oxycarbonyloxylavereal oxycarbonyl is e.g. aethoxycarbonyl.oxymethoxycarbonyl or 1-aethoxycarbonyl-oxyethoxycarbonyl1.

1- lower alkoxy lower oxycarbonyl is e.g.

methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Low-area coke is e.g. methoxy, further aethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,

or tertiary butyloxy, as well as n-pentyloxy, n-hexyloxy or n-heptyloxy.

Lower alkanoyloxy is e.g. acetyloxy or propionyloxy.

Halogen is e.g. fluorine, chlorine, bromine or iodine.

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

Lower alkyl as a substituent of a residue R^ is e.g.

methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further n-pentyl, n-hexyl or n-heptyl.

Hydroxyl lower alkyl as a substituent of a residue R^er

e.g. hydroxymethyl, 2-hydroxyethyl or 2,3-dihydroxy-propyl.

Lower alkyl lower alkyl is e.g. methoxymethyl, 2-methoxyethyl, ethoxymethyl or 2-ethoxyethyl.

Carboxyl lower alkyl is e.g. carboxymethyl, 1-carboxy-, 2-carboxy- or 1,2-dicarboxyethyl.

Amino lower alkyl is e.g. aminomethyl or 2-aminoethyl,

while diloweralkylaminoloweralkyl is e.g. dimethylaminomethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl.

Sulfolaverealkyl is e.g. sulfomethyl or 2-sulfoethyl.

Lower alkylamine is e.g. methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while dilaverealkylamino means e.g. dimethylamino, diethylamino, di-n-propylamino or diisopropylamino.

Lower alkylene amino especially contains 4 to 6 carbon atom chain links and means e.g. pyrrolidino or piperidino.

Lower alkanoylamino is, for example, acetylamino or propionylamino.

Lowereal oxycarbony1 is e.g. methoxycarbonyl or ethoxycarbonyl.

N-mono-lower alkylated carbamoyl is e.g. N-methyl-,

N-ethyl- or N-propylcarbamoyl, while N,N-di-lower alkylated carbamoyl means e.g. N,N-dimethyl or N,N-diethylcarbamoyl.

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

Preferred cleavable esterified carboxyl groups R2.

which is cleavable under physiological conditions, is e.g. phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl and 1-lower oxycarbonyl oxy-lower oxycarbonyl, e.g. 1-ethoxycarbonyl-oxy-ethoxycarbonyl1.

dd

Corresponding 5-lightened, optionally partially saturated heteroaryl residues R^ are e.g. possibly, e.g. with lower alkyl or halogen substituted pyrrolyl or dihydropyrrolyl, e.g. 1-pyrrolyl, 3-methyl-1-pyrrolyl, 3,4-dichloro-1-pyrrolyl, further 2,3- or 2,5-dihydro-1-pyrrolyl, optionally with e.g. lower alkyl, amino lower alkyl, amino or nitro substituted diazolyl, such as imidazolyl or pyrazolyl, e.g. 1-imidazolyl or 1-pyrazolyl, possibly e.g. with lower alkyl, carboxy lower alkyl, amino or phenyl substituted triazolyl, such as 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazol- 1-yl or 1H-1,3,4-triazol-1-yl, e.g. the corresponding unsubstituted residues, 4- or 5-methyl-1,2,3-triazol-1-yl, 3-methyl- or 3-phenyl-1 H-1 , 2 , 4-triazol-1-yl or possibly e.g. with lower alkyl, carboxy lower alkyl, sulpho lower alkyl, di lower alkyl amino lower alkyl, amino or optionally with halogen substituted phenyl substituted tetrazolyl, such as 1H-tetrazol-1-yl or 2H-tetrazol-2-yl, e.g. the corresponding unsubstituted residues, 5-amino-, 5-methyl-, 5-carboxymethyl-, 5-(2-carboxyethyl)-, 5-sulfomethyl-, 5-(2-dimethylaminoethyl)- or 5-phenyl-1H-tetrazole -1-yl, or 5-amino-, 5-methyl-, 5-carboxymethyl-, 5-sulfomethyl-, 5-(2-dimethylaminoethyl)- or 5-phenyl-2H-tetrazol-2-yl.

Corresponding 6-lightened, partially saturated heteroaryl residues R^ are e.g. unsubstituted or special, e.g. with oxo or optionally further with halogen-substituted dihydro-1-pyridyl, such as 2H-1,2-dihydro- or 4H-1,4-dihydro-1-pyridyl, e.g. 2-oxo-2H-1,2-dihydro-1-pyridyl or 4-oxo-4H-1,4-dihydro-1-pyridyl, optionally e.g. especially with oxo and possibly further with e.g. lower-

alkyl, amino, dilower alkylamino or carboxy substituted dihydro-1-pyrimidyl, such as 2H-1,2-dihydro- or 4H-1,4-dihydro-1-pyrimidyl, e.g. 2-oxo-1,2-dihydro-1-pyrimidyl, 6-methyl-, 5-mettk-, 6-amino-, 6-dimethylamino-, 5-carboxy-or 6-carboxy-2-oxo-1,2 -dihydro-1-pyrimidyl or 4-oxo-1,4-dihydro-1-pyrimidyl, or optionally, e.g.

with lower alkyl and/or up to 2 oxo substituted dihydro- or tetrahydrotriazinyl, 2H-1,2,5,6-tetrahydro-1,2,4-triazin-1-yl, or 4H-1,4,5,6-tetrahydro -1,2,4-triazine-1-

yl or 4H-1,4,5,6-tetrahydro-1,2,4-triazin-1-yl,

e.g. 4-lower alkyl-1,4,5,6-tetrahydro-5,6-dioxo-1,2,4-triazin-1-yl, e.g. 4-methyl-1,4,5,6-tetrahydro-5,6-dioxo-1,2,4-triazin-1-yl.

The straight-chain lower alkylene in residue A contains 1 - 7

and preferably 1 - 4 carbon atoms and is e.g. methylene, ethylene, 1,3-propylene, 1,4-butylene, and also 1,5-pentylene. Such a lower alkylene residue is mono- or polysubstituted, especially mono- or disubstituted with lower alkyl with 1 to 4 carbon atoms, especially with 1 or 2 carbon atoms, such as n-propyl, n-butyl or especially methyl or ethyl.

Two lower alkyl substituents can be attached to the same carbon atom (geminal), to nearby carbon atoms (vicinal) or to different carbon atoms that are separated by at least one methylene group in the lower alkyl chain.

Such a residue A is, for example, lower alkylidene, such as ethylidene ("methyl-methylene"), 1,2-propylene, 2-lower alkyl-, such as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl- , as 2-methyl- or 2-ethyl-1,2-butylene, 3-lower alkyl-1-, as 3- methyl-1,2-butylene, 1,3-butylene, 2-lower alkyl-, as 2-methyl-1 ,3-butylene, 3-lower alkyl-, such as 3-methyl-1,3-butylene, or 2,2-dilower alkyl-, such as 2,2-dimethyl-1,3-butylene, whereby in these residues the carbon atom 1 is bound to the pene-ring rjelet, or such a residue-A- is also the lower alkylidene such as 1, 2-propylene, 2-lower alkyl-, . as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl-, as 2- methyl- or 2-ethyl-1-1,2-butylene, 3-lower alkyl-, as 3- methyl-1, 2-buty'ene, or 3,3-dilaveralalkyl-, such as 3,3-dimethyl-1,2-butylene, whereby in these residues the carbon atom 2 is bound to the pene-ring gellet.

Preferred residues A are those which are bonded above the carbon atom 1 with the penem ring gellet and are bonded ethylidene, 1,2-propylene, 1,2-butylene, 1,3-butylene and 2-methyl-1,2-propylene, as well as such residue A which is bonded over carbon atom 2 with the penemen ring gelate and is bonded 1,2-

propylene.

The functional groups present in compounds of formula I, such as the hydroxy, carboxy, amino or sulfo group, especially the hydroxy group and the carboxyl group R2, are optionally protected by protective groups used in penem, penicillin, cephalosporin and peptide chemistry.

Such protective groups are easily cleavable, for example solvolytically, reductively or also under physiological conditions, i.e. without unwanted side reactions taking place.

Protection groups of this nature, as well as the introduction

and the spin-off of these, is described, for example, in:

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

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

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

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

In compounds of formula (I), a hydroxy group in the residue R^ can, for example, be protected with acyl residues. A hydroxy group present in the residue R^ can also be protected with acyl residues, for example. Suitable acyl residues are 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-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, or optionally with nitro substituent

tuated phenyl lower oxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Further suitable hydroxy protective

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-trichloroethyl, and optionally with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro substituted phenyl lower alkyl, as corresponding benzyl. Preferred as hydroxy protecting group is trilower alkylsilyl.

A carboxyl group, and further also a carboxyl group present in the residue, is usually protected in esterified form, whereby the ester group is easily cleavable under gentle conditions, e.g. under mild reductive, such as hydrogenolytic, or mild solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions. A protected carboxyl group can further constitute a carboxyl group that is cleavable under physiological conditions or can easily be converted into another functional converted carboxyl group such as e.g. to another esterified carboxyl group.

Such esterified carboxyl groups primarily contain as esterifying groups lower alkyl groups which are branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxyl groups which are present in esterified form are i.a. lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl and (hetero-)arylmethoxycarbonyl with 1 to 3 aryl residues or a monocyclic heteroaryl residue,

whereby these are optionally mono- or poly-substituted with it. e.g. 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 above, substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl,

or triphenylmethoxycarbonyl, or optionally, e.g.

as above, substituted picolyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, as 2-furfuryloxycarbonyl. Further suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably optional, e.g. with a halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, halogenolower oxycarbonyl, such as 2-halogenolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or two-halogen lower oxycarbonyl, where lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl1,

e.g. allyloxycarbonyl, or ethoxycarbonyl which is substituted in the 2-position with lower alkylsulfonyl, cyano or trisubstituted silyl, such as trilower alkylsilyl or triphenylsilyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl.

Other protected carboxyl groups that exist in esterified form are corresponding organic silyloxycarbonyl groups, and further corresponding organic stannyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. methoxy, as well as substituents. Suitable silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stannyl groups, e.g. tri-n-butylstannyl.

Preferred protected carboxyl groups are the 4-nitrobenzyloxycarbonyl group, the lower alkenyloxycarbonyl group or the one in the 2-position with trilower alkylsilyl substituent

tuated ethoxycarbonyl group.

A protected amino group can, for example, be present in the form

of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group present as an enamino, nitro or azido group.

In a corresponding acylamino group, acyl is, for example, the acyl residue of an organic acid with e.g. up to 18 carbon atoms, especially an alkanecarboxylic acid which is optionally substituted with e.g. halogen, or phenyl, or optionally benzoic acid which is substituted by halogen, lower alkoxy or nitro, or a carboxylic acid half-ester. Such an acyl group is, for example, lower alkanoyl, such as formyl, actyl or propionyl, halolower alkanoyl1, such as 2-halo-acetyl, 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 lower alkoxycarbonyl, which is substituted in the 1- or 2-position as lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl, or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably benzoyl which is optionally substituted with e.g. halogen, such as bromine, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(tris-substituted silyl)ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilyl-

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

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 phenylthbamino group or a pyridylthioamino group, which is optionally substituted with a lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and/or nitro. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which the silicon atom or the tin atom preferably contains lower alkyl, e.g. methyl, ethyl, n-butyl or tert.-butyl, further lower alkoxy, e.g. methoxy, as substituents. Corresponding silyl or stannyl groups are primarily trilower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or similarly substituted stannyl, e.g. tri-n-butylstannyl.

Other protected amino groups are e.g. enamino group,

which at the double bond in the 2-position contains an electron-withdrawing substituent, for example a carbonyl group. Protecting groups of this kind are, for example, 1-acyl-lower alk-1-en-2-yl residues, in which acyl means e.g. a corresponding residue of a lower alkane carboxylic acid, e.g. acetic acid, a benzoic acid which is optionally substituted with e.g. lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, or especially a carboxylic acid half-ester, such as a carboxylic acid-lower alkyl half-ester, e.g. -methyl half ester or -ethyl ester, and lower alk-1-ene, especially 1-propene.

Corresponding protecting groups are primarily 1-lower alkanoyl-prop-1-en-2-yl, 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.

A protected sulfo group in the residue R is in the first row

an esterified sulfo group which is esterified with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, e.g. a lower alkanol, or with a silyl or stannyl residue, such as tri-lower alkylsilyl.

In a sulfo group, the hydroxy group can, for example, be etherified like the hydroxy group in an esterified carboxyl group.

Salts of compounds according to the invention are. in the first

a number of pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are formed, for example, from acidic groups present in the compound of formula I, e.g. the carboxyl and sulfo group, 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, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acid, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. dicyclohexylamine, or ] benzylamines, e.g. N,N<1->dibenzylethylenediamine, or N-•benzyl-B-phenethylamine. Compounds of formula I with basic groups, 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 carboxylic 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 -

with a basic group can exist in the form of internal salts, i.e. in zwitterionic form.

For isolation or purification, pharmaceutical unsuitable salts can also be used. For therapeutic use, only the pharmaceutically usable, non-toxic salts are mentioned, which are therefore preferred.

In the penem compounds of formula I, the two asymmetric carbon atoms in the 5- and 6-position can be present in R, S or racemic R,S configuration. Preferred are compounds in which the configuration of the 5-carbon atoms corresponds to that of natural penicillin (the 5R configuration). The hydrogen atoms in the 5- and 6-position can be in the cis- or preferably in the trans-position in relation to each other.

In the preferred configuration, the substituent in the 6-position assumes the S configuration. Compounds of formula I may have additional centers of chirality in residues R.j and/or A, each of which shall be in the R, S or R,S configuration. In the a-position with hydroxy-substituted lower alkyl R-], the ion preferably has the R-configuration.

The invention relates in particular to compounds of formula I, where R. is lower alkyl substituted with hydroxy or protected hydroxy, R.sub.2 means carboxyl, under physiological conditions cleavable, esterified carboxyl or protected carboxyl, R.sub.2/R.sub.2 means an eventual, partially saturated 5-reduced heteroaryl -residue with the 1-4 ring nitrogen atom, which residue is bonded to the residue -A- over a tertiary ring nitrogen atom, as a corresponding aza-, diaza-,

triaza or tetraza cyclic residue of an aromatic character, or a corresponding dihydro residue, or: a corresponding partially saturated 6-membered heteroaryl residue with 1 - 3 ring nitrogen atoms, as a corresponding aza, diaza or triaza cyclic residue, e.g. e.g. a corresponding dihydro or tetrahydro residue, whereby these residues are unsubstituted or substituted with hydroxy, lower alkoxy, lower alkanoyl

oxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxyl lower alkyl, lower hydroxy lower alkyl, carboxy lower alkyl, amino lower alkyl, di lower alkyl amino lower alkyl, sulfola lower alkyl, amino, lower alkyl amino, di lower alkyl amino, lower alkylene amino, lower alkanoylamino, carboxy, lower alkoxy carbonyl, optionally N-mono- or N,N-dil&veres. alkylated carbamoyl, cyano, sulfo, sulfamoyl, phenyl optionally substituted with a lower alkyl, nitro, lower alkoxy and/or halogen, cycloalkyl, nitro, oxo and/or oxido and A means the straight-chain lower alkylene substituted with a lower alkyl,'optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of compounds of the formula (I), which contain a salt-forming group.

The invention primarily relates to compounds of the formula (I), where R- means lower alkyl, substituted with hydroxy or tri-lower alkylsilyloxy, R2 means carboxyl, lower alkenyloxycarbonyl, benzyloxycarbonyl, and 2-trilower alkylsilylethoxycarbonyl substituted with nitro or an esterified carboxyl group that can be split off under physiological conditions, e.g. 1-loweralkoxycarbonyloxy loweralkoxycarbonyl, loweralkanoyloxymethoxycarbonyl, α-aminoloweralkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, R^ means unsubstituted pyrrolyl, or pyrrolyl substituted with loweralkyl or halogen, attached to the residue -A- over a tertiary nitrogen atom, e.g. 1-pyrrolyl, unsubstituted or with lower alkyl, substituted imidazolyl or pyrazolyl, e.g. 1-imidazolyl or 1-pyrazolyl, unsubstituted triazolyl or triazolyl substituted with lower alkyl, carboxy lower alkyl or phenyl, e.g. 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2- yl, 1H-1,2,4-triazol-1-yl, or 1H-1,3,4-triazol-1-yl, unsubstituted tetrazolyl or tetrazolyl substituted with lower alkyl, carboxy lower alkyl, sulfo lower alkyl, di lower alkyl amino lower alkyl, amino or optionally with halogen substituted phenyl, such as 1H-tetrazol-1-yl or 2H-tetrazol-2-yl, unsubstituted dihydro-1-pyridyl, or dihydro-1-pyridyl substituted with oxo and optionally further with halogen, e.g. 2H-1,2-dihydro-1-pyridyl or 4H-1,4-dihydro-1-pyridyl, unsubstituted dihydro-1-pyrimidyl, or dihydro-1-pyrimidyl substituted with oxo and optionally further with lower alkyl, amino, dilower alkylamino or carboxy, e.g. 2H-1,2-dihydro-1-pyrimidyl or 4H-1,4-dihydro-1-pyrimidyl, or unsubstituted dihydro- or tetrahydrqtriazinyl, or dihydro- or tetrahydrotriazinyl substituted with lower alkyl oxo or up to two oxo, e.g. 2H-1,2-dihydro-1,3,5-triazin-1-yl, 2H-1,2-dihydro-1,2,4-triazin-1-yl, 2H-1,2,5,6- tetrahydro-1,2,4-triazin-1-yl or 4H-1,4,5,6-tetrahydro-1,2,4-triazin-1-yl, and A means the straight chain lower alkylene substituted by lower alkyl, optical isomers have compounds of the formula (I), mixtures of these optical isomers and salts, especially pharmaceutically acceptable salts of such compounds of the formula (I), which contain a salt-forming group.

The invention primarily relates to compounds of the formula (I), where R^ is lower alkyl substituted by hydroxy, R 2 means carboxyl, 1-lower oxycarbonyloxy carbonyl or lower alkanoyloxymethoxycarbonyl, R^ means over a tertiary nitrogen atom to the residue

-A- bonded pyrrolyl, imidazolyl, e.g. 1-imidazolyl, 1H-triazolyl, e.g. 1H-1.2.4-triazolyl-1-yl, or unsubstituted 1H-tetrazolyl, or 1H-tetrazolyl substituted with amino, carboxyl lower alkyl, sulpho lower alkyl or di lower alkyl amino lower alkyl, e.g. 1H-tetrazol-1-yl or 2H-tetrazol-2-yl, and A means the lower alkylene of 1 to 4 carbon atoms, mono- or disubstituted with lower alkyl of 1 or 2 carbon atoms, optical isomers of compounds of the formula (I), e.g. e.g. (5R,6S) isomers, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds of formula (I), which contain

holds a salt-forming group.

The invention relates in particular to (5R,6S)-configured compounds of the formula (I), where means hydroxymethyl or 1-hydroxyethyl, R2 is carboxyl, R^ means 1H-tetrazol-1-yl or pyrrol-1-yl and A is 1,2 -propylene,

and pharmaceutically acceptable salts thereof.

The invention also relates to the purely optical isomers

of such compounds of the formula (I), which in the substituent with R^ and/or A have additional centers of chirality, and pharmaceutically acceptable salts thereof.

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

The compound according to the present invention can be prepared according to methods known per se

The new compounds are produced e.g. as one

a) ring-closes a ylide compound with the formula

where R.| . b) treat a compound with the formula

in which R^ , R^ and A have the meanings indicated under formula (I).

and R'2 means a protected carboxyl group, with an organic compound of the trivalent phosphorus, or

c) react a compound with formula

in which R 1 , R 2 and A have the meanings indicated under formula (I).

and Q represents a reactive esterified hydroxy group, with an agent introducing azaheterocyclyl residue R^, and, if desired or necessary, transfer in a formed compound of formula (I) a protected hydroxy group to the residue R^

in the free hydroxy group and/or, if desired, transfer in a formed compound with the formula (I), a protected carboxyl group R2' in the free, under physiological conditions cleavable esterified carboxyl group or in another protected carboxyl group R'2, and / or if

desired, transfer a free carboxyl group P^ into an esterified carboxyl group cleavable under physiological conditions, and/or, if desired, further transfer in the residue R^ containing protected functional groups in the free functional groups, and/or, if desired, transfer a formed compound with the formula (I) a residue R^ in another residue R2, and/or, if desired, transfer a formed compound with salt-forming groups in a salt or transfer a formed salt in the free compound or in another salt, and/ or, if desired, splits a formed mixture of isomeric compounds into the individual isomers.

In the starting compounds of formulas (II), (III) and (IV)

are functional groups, such as a hydroxy group in the residue R^, as well as in the compounds of formulas (I) and (II) further functional groups present in the residue R^ preferably protected with conventional protecting groups, e.g. those mentioned above.

a) Cyclization of the compound of formula II

The group X in the starting material of formula II is one

of the phosphonio or phosphono groups common in Wittig condensation reactions, especially a triaryl group, e.g. triphenyl or trilower alkyl group, e.g. tri-n-butylphosphonio group, or one with lower alkyl, e.g. ethyl, di-esterified phosphono group, whereby the symbol X in the case of phosphono groups further comprises the cation of a strong base, especially a suitable metal ion,

as alkali metal ion, e.g. lithium ion, sodium ion or potassium ion. Preferred as group X are on the one hand triphenylphosphonio and on the other hand diethylphosphonio together with an alkali metal ion, e.g. sodium ion.

The ylide compounds with formula II are also referred to in the isomeric ylene form as phosphorane compounds.

In phosphonio compounds of the formula II, the nega-

tive charge neutralized by the positively charged phos-phonio group. In phosphono compounds of formula II

negative charge is neutralized by the cation of a strong base, which, depending on the production method of the phosphono starting material, can be e.g. an alkali metal ion, e.g. sodium ion, lithium ion or potassium ion. The phosphono starting materials are therefore used as salts

at the turnover.

The circular closure can occur spontaneously, i.e. during manufacture

of the starting materials, or by heating, e.g. in a temperature range 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 an aliphatic, cycloaliphatic or aromatic hydrocarbon,

e.g. hexane, or benzene, in a halogenated hydrocarbon, e.g. methylene chloride, an ether, e.g. diethyl ether, a cyclic ether, e.g. dioxane, a carboxylic acid amide, e.g. dimethylformamide, a dilave alkyl sulfoxide, e.g. dimethyl sulfoxide, or a lower alkanol, e.g. methanol, or in a mixture thereof, and, if necessary, in an inert gas atmosphere, e.g. 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 thereof with a lower alkanol, e.g. methanol or ethanol, and/or an optionally substituted aromatic hydroxy compound, e.g. phenol or benzcatechin, or an amide ester, this with the formula P(ORa)2~N(R^)2, in which and R^ independently of each other means 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 was 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 from approx. 20 to approx. 80°C, preferably from approx. 40 to approx. 60°C, whereby 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 then the phosphorus compound, preferably dissolved in the same inert solvent, is dripped in over a longer period of time, e.g. over a period of 2 to 4 hours.

In a preferred embodiment of the method, the starting material with the formula III is prepared in situ and reacted without isolation in the reaction mixture with the organic compound of trivalent phosphorus, whereby the end product with the formula I is formed.

c) Introduction of azaheterocyclyl residues R,

In connection with formula (IV) means reactive

esterified hydroxy Q, for example hydroxy which is esterified with halogen, hydrogen acid, organic sulphonic acids, such as lower alkane or optionally substituted benzene sulphonic acids, lower alkane carboxylic acids or phosphinic acids, and is primarily halogen, e.g. chlorine, bromine or iodine, sulphonyloxy, e.g. methane-, benzene-, 4-

toluene or 4-bromobenzenesulfonyloxy, lower alkanoyloxy, e.g. acetoxy, or phosphinoyloxy, e.g. dimethyl or diphenylphosphinoyloxy.

An agent that introduces azaheterocyclyl residues R 3 is in particular a compound of the formula R 3 -H, where the ring nitrogen atom which attaches to the residue -A- carries a hydrogen atom.

The turnover takes place e.g. in the presence of a basic condensing agent, for example an alkali or iodo-alkali metal hydroxide or carbonate, e.g. sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or calcium carbonate, an alkali metal lavereal alkanolate, e.g. sodium ethanolate, sodium ethanolate, or potassium tert.-butanolate, an aromatic amine, e.g. pyridine or quinoline, or a tertiary aliphatic amine, such as a trilower alkylamine, e.g. triethylamine or di-isopropyl ethylamine, in an inert solvent, such as a lower alkanol, e.g. methanol or tert.-butanol,

an amide, e.g. dimethylformamide, or by using liquid amine as basic condensation agent in excess amine at room temperature, or higher or lower temperature, e.g. at approx. 20°C to approx. 80°C.

Such starting materials of formula II, II and IV are preferably used, which lead to the compounds mentioned initially as particularly preferred, with formula I, especially compounds of formula II or III, which exhibit a 3S,4R configuration, or with formula IV, which exhibits a 5R,6S configuration.

In an achievable compound of formula I, where one or more functional groups are protected, these can, e.g. protected amino, carboxyl, hydroxy and/or sulfc groups, are released in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by reduction, especially hydrogenolysis or chemical reduction, optionally stepwise or simultaneously .

In a compound of formula I with a protected amino group which is obtained according to the invention, this can in a manner known per se, e.g. depending on the nature of the protecting group, is preferably transferred to the free amino group by means of solvolysis or reduction. For example, 2-halogen lower oxycarbonylamino (possibly after conversion of a 2-bromolower oxycarbonylamino group to a 2-iodolower oxycarbonylamino group), arolylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent, such as zinc 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 can also be cleaved by treatment with an alkali metal-,

e.g. sodium dithionite. Optionally substituted benzyl-oxycarbonylamino can e.g. is cleaved by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino, by reaction with a palladium compound, 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. An amino group that is protected with an organic silyl or stannyl group can e.g. is released by means of hydrolysis or alcoholysis, and an amino group which is protected with 2-halolower alkanoyl, e.g. 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, of thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the obtained condensation product. An amino group protected with 2-substituted silylethoxycarbonyl can be transferred to the free amino group by treatment with a salt of hydrofluoric 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. tetraethylammonium chloride. An amino group which

is protected in the form of an azido or a nitro group, is transferred for example by reduction to free amino, for example by catalytic hydrogenation with a hydrogen in the presence of a hydrogenation catalyst such as e.g. platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid, such as acetic acid. An amino group that is 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 converted to amino by treatment with a nucleophilic reagent, such as sulfuric acid.

In a compound of formula I, where R 2 means a protected carboxyl group and/or where the residue R 2 contains protected carboxyl as a substituent, which is prepared according to the invention, the carboxylic acid can be released in a manner known per se. Thus, tert.-lower alkoxycarbonyl or a lower alkoxycarbonyl which is substituted in the 2-position with a trisubstituted silyl group or in the 1-position with a lower alkoxy or optionally substituted in diphenylmethoxycarbonyl, e.g. is transferred into a free carboxyl by treatment with a monocarboxylic 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-nitrobenzyloxycarbonyl, can also be produced by chemical reduction, e.g. when treated with an alkali metal,

e.g. sodium dithionite, or with a reducing metal, e.g. tin, or metal salt, such as a chromium II salt, e.g. chromium II chloride, usually in the presence of a hydrogen-donating agent, which together with the metal can produce nascent hydrogen, such as a suitable carboxylic acid, e.g. any, e.g. with hydroxy, substituted lower alkanecarboxylic acid, e.g. acetic acid, formic acid or glycolic acid, or an alcohol or thiol, to which water is preferably added,

is transferred in free carboxyl. The removal of an allyl protecting group can e.g. take place by reaction with a compound of palladium, e.g. tetrakis(triphenyl-phosphine)palladium, in the presence of triphenylphosphine with the addition of a carboxylic acid, e.g. 2-ethylhexanoic acid, or a salt thereof. By treatment with a reducing metal or metal salt, described above, 2-halo-lower-real oxycarbonyl (possibly after conversion of a 2-bromo-lower-real oxycarbonyl group into a corresponding 2-iodo-lower-real oxycarbonyl group) or aroylmethoxycarbonyl can also be converted to free carboxyl, whereby aroylmethoxycarbonyl can likewise be cleaved off by treatment with a nucleophile , preferably a salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also, by treatment with a salt of chlorohydrogen acid which emits a fluoride anion, such as an alkali metal fluoride, e.g. sodium fluoride, in the presence of a macro-

cyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetralower alkylammonium fluoride, e.g. tetrabutylammonium fluoride, is transferred in free carboxyl. Carboxyl which is esterified with an organic silyl or stannyl group, such as trilower alkylsilyl or -stannyl,

can normally be released solvolytically, e.g. by treatment with water or an alcohol. In a lower alkoxycarbonyl group, which is substituted in the 2-position with a lower alkylsulfonyl or cyano, e.g. by treatment with a basic agent, such as an alkali metal or io-alkali metal hydroxide, or carbonate, e.g. sodium or potassium hydroxide or sodium or potassium carbonate, is transferred in free carboxyl.

In compounds which can be produced according to the invention

with formula I, where the radical R 1 is substituted with protected hydroxyl and/or where the radical R 1 holds protected hydroxyl as a substituent, the protected hydroxy group can be transferred in a manner known per se into the free

hydroxy group. For example, a hydroxy group that is protected with a suitable acyl group or an organic silyl or stannyl group is released, as a correspondingly protected amino group, a trilower 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-halo-lower alkyl group and an optionally substituted benzyl group are reductively cleaved off.

A protected, especially esterified, sulfo group is released analogously to a protected carboxyl group.

On the other hand, compounds of formula I,

in which R 2 means carboxy, is transferred to compounds of formula I, where R 2 is a protected carboxyl group, in particular an esterified carboxyl group, or an esterified carboxyl group that can be cleavable under physiological conditions. Thus, the free carboxyl group can be esterified, e.g. by treatment with a suitable diazo compound, such as a diazole veralkane, e.g. diazomethane, or a phenyldiazoleveralkane, e.g. diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as e.g. boron trifluoride, or by reaction with an alcohol suitable for esterification in the presence of an esterification agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide, as well as carbonyldiimidazole. Esters can also be produced by reacting an acid salt, possibly produced in situ, with a reactive ester of an alcohol and a strong inorganic acid, such as sulfuric acid, or a strong organic sulfonic acid, such as 4-toluenesulfonic acid. Furthermore, the acid halide, such as the chloride (prepared e.g. by treatment with oxacylyl chloride), can be activated esters (formed e.g. with N-hydroxy-nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained e.g. with haloformic acid -lower alkyl esters, such as chloroformic acid ethyl or chloroformic acid isobutyl esters, or with

haloacetic acid halide, such as trichloroacetic acid chloride)

by a reaction of alcohols, optionally in the presence of a base, such as pyridine, is transferred in an esterified carboxyl group.

In a compound of formula I with an esterified carboxyl group, this can be transferred into 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, the carboxyl protecting group can be cleaved off as described above in connection with formula I, which contains a protected carboxyl group R 2 in esterified form, and an obtained compound of formula I, with a free carboxyl group or a salt thereof, is transferred by reaction with the reactive ester of a corresponding alcohol to a compound of formula I, where is an esterified carboxyl group which is cleavable under physiological conditions.

In compounds of formula I, a residue R^ can further be transferred into another residue R^•

Thus, for example, in compounds of formula I,

where the heterocyclyl residue R^ is substituted with a carboxyl group, this carboxyl group can, by means of methods known per se, be transferred into a functional converted carboxyl group, such as in an esterified carboxyl group or in an optionally substituted carbamoyl. For example, by reacting a compound of formula I, where R^ is heterocyclyl substituted by carboxyl, with an alcohol, especially a lower alkanol, a compound of formula I is obtained,

where R 1 is heterocyclyl which is substituted with esterified carboxyl, especially lower alkoxycarbonyl, whereby work is preferably done in the presence of a suitable condensing agent, e.g. a carbodiimide, or remove the water formed by azeotropic distillation. On the other hand, it can

carboxyl groups on the residue R., are also transferred in reactive functional derivatives, such as mixed anhydrides, e.g. acid halide, or activated ester, and convert these by reaction with an alcohol, e.g. lower alkanol, ammonia or a primary or secondary amine, e.g.

a lower alkyl or dilower alkylamine, in a correspondingly esterified or amidated carboxyl group, whereby when using mixed anhydrides it is preferably worked in the presence of an acid binding agent, such as an aromatic or tertiary amine or an alkali metal or alkaline earth metal carbonate.

Where as a heteroaryl radical R^ contains a hydroxy group,

then this can be done in the usual way. The reaction to the corresponding lower alkyl1-heteroaryl ethers takes place, for example, in the presence of a base, such as alkali metal hydroxides or carbonates, e.g. sodium hydroxide or potassium carbonate, with the help of the lower alkyl sulfates or lower alkyl halides, or with diazolarealkanes, or, in the presence of a dehydrating agent, for example dicyclohexyl carbodiimide, with the help of lower alkanols. Furthermore, hydroxy can be converted to esterified hydroxy, e.g. lower alkanoyloxy, for example by reaction with the reactive derivative of a corresponding lower alkane carboxylic acid, e.g. acetic acid, as an anhydride thereof, e.g. acetic acid, as an anhydride thereof, e.g. the symmetrical anhydrides thereof or a mixed anhydride with a halohydrogen acid, if necessary in the presence of a basic condensing agent, such as an alkali metal hydroxide or carbonate, or a nitrogen base, e.g. pyridine. The conversion of lower alkanoyloxy to hydroxy takes place, for example, by alcoholysis or, preferably, hydrolysis, e.g. by base-catalyzed hydrolysis, e.g. in the presence of sodium nydrok-syd.

In connection with formula I, where R 1 means heterocyclyl

which is substituted with amino, the amino group can be transferred

in a substituted amino group, such as a lower alkylamino, dilower alkylamino, lower alkyleneamino or lower alkanoylamino group._ The transfer in a lower alkylamino or dilower alkylamino group" takes place, for example, by reaction with a reactive esterified lower alkanol, for example a lower alkyl halide or sulfonate, in the presence of a basic condensing agent, such as a hydroxide or carbonate, of an alkali or alkaline earth metal or a heteroaromatic nitrogen base, eg pyridine.In an analogous manner, amino can be converted into lower alkylene amino by treatment with a lower alkylene dihalide or disulfonate and by treatment with reactive functional derivatives of a lower alkanecarboxylic acid, eg the corresponding carboxylic acid halide, is converted into lower alkanoylamino.

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I with a free carboxyl group can be prepared, e.g. by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. sodium salt of α-ethylcaptronic acid, or with inorganic alkali or alkaline earth metal salts, e.g. sodium hydrogen carbonate, or with ammonia or with a suitable organic amine, whereby stoichiometric amounts or only a small excess of the salt-forming agent are preferably used. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with a suitable acid or a suitable anion exchange reagent, inner salts of compounds of formula I can e.g. is formed by neutralization of salts, such as acid addition salts, with the isoelectric point, e.g. with weak bases or when treated with ion exchangers.

Salts can normally be transferred in the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. during treatment

with a suitable basic agent.

Obtained mixtures of isomers can in and of themselves

known way is divided into the individual isomers, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable repair methods.

The splitting of obtained racemates into their optical antipodes can take place in different ways.

One of these methods consists in reacting a racemate with an optically active auxiliary substance, the resulting mixture of two diastereomeric compounds is produced using suitable physico-chemical methods and the individual diastereomeric compounds are then split into the optically active compounds.

Racemates which are particularly suitable for division into antipodes are those which have an acidic group, such as, for example, racemates of compounds of formula I, where R 1 is carboxy. These acidic racemic foods can be reacted with an optically active base, e.g. esters of optically active amino acids, or (-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine, (+)-dehydroabiethylamine, (+)- and (-)-ephedrine, (+ )- and (-)-1-phenylethylamine or their N-mono- or N,N-dialkylated derivatives to mixtures consisting of two diastereomeric salts.

In racemates containing a carboxyl group, this carboxyl group can also be or be esterified with an optically active alcohol, such as (-)-menthol, (+)-borneol, (+)- or (-)-2-octanol, whereupon the carboxyl group is released after isolation of the the desired diastereomers.

For racemate separation, the hydroxy group can also be esterified with optically active acids or their reactive, functional derivatives, whereby diastereomeric esters are formed. Such acids are, for example (-)-abietic acid,

D(+)- and L(-)-malic acid, N-acylated optically active amino acid, (+)- and (-)-camphoric acid, (+)- and (-)-ketopic acid, L( + )-ascorbic acid, ( +)-camphoric acid, (+)-camphor-10-sulfonic acid(3), ( + )-or (-)-a-bromocamphor-ir^-sulfonic acid, D (-)-quinic acid, D(-)-isoascorbic acid, D(-)- and L(+)-mandelic acid, (+)-menthoxyacetic acid, D(-)- and L(+)-tartaric acid and their di-O-benzoyl and di-O-p-tolyl derivatives.

When reacting with optically active isocyanates, such as with

(+)- or (-)-1-phenylethyl isocyanate, compounds of formula I, in which R 2 means protected carboxy and the residue means hydroxy substituted lower alkyl, can be transformed into a mixture of diastereomeric urethanes.

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

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

A further method of dividing the race foods consists

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

According to a third method, the racing foods can be dissolved in optically active solvents and the heaviest soluble optical

antipode is crystallized.

In a fourth method, the difference in reactivity of the optical antipodes to biological material such as microorganisms or isolated enzymes is used.

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

The division of diastereomers into the individual racemates and the racemates into the optical antipodes can be carried out in a freely chosen method step, i.e. e.g. also in the starting connection step for formula II to formula IV or in a freely chosen step in the later described method for preparing the starting materials of formula II or formula IV.

In all subsequent transformations of obtained compounds of formula I, such reactions are preferred, which take place under neutral or :alJ<c>a<l>ic conditions.

The method also includes such embodiments, according to which compounds that precipitate as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at any step. Furthermore, starting materials can be used in the form of derivatives formed in situ, possibly under the reaction conditions. For example, the starting material of formula II, where Z is oxygen, can be prepared in situ from a compound of formula II, where Z is a, as described below, optionally substituted with a methylidene group by ozonization and subsequent reduction of the formed ozonide, analogously to the method further below (step 2.3), after which the ring closure to the compound of formula I takes place in the reaction solution.

The starting compounds with formulas II, III and IV and the precursors can be prepared as indicated in reaction schemes I and II:

Reaction scheme I:

In the compounds with the formulas V, VII, VIII and II<1>, Z is oxygen, sulfur or also a methylidene group optionally substituted with one or two substituents Y, which can be transferred by oxidation into an oxo group Z. A substituent Y in this methylidene group is a organic residue, for example optionally substituted lower alkyl, e.g. methyl or ethyl, cycloalkyl, e.g. cyclopentyl or cyclohexyl, phenyl or phenyl lower alkyl, e.g. benzyl or especially one, including with an optically active alcohol, such as 1-menthol, esterified carboxyl group, e.g. one of the optionally substituted lower alkoxycarbonyl or arulmethoxycarbonyl residues mentioned under R~ or also 1-menthyloxycarbonyl. Methylidene group Z preferably carries one of the aforementioned substituents. The methoxycarbonylmethylidene, ethoxycarbonylmethylidene and 1-menthyloxycarbonylmethylidene groups Z' must be emphasized. The latter can be used for the preparation of optically active compounds with the formulas V, VII, VIII and

II'.

In connection with the formulas V, VII, VIII and II' stands either for the radical R^ or for a reactive, esterified hydroxy group Q.

In connection with formulas V to IX and II<1>, the radical R^preferably contains one of the aforementioned protected hydroxy groups, e.g. optionally substituted 1-phenyl lower aryloxy,

or trisubstituted silyloxy.

Step 1. 1;

A thio-azetidinone of the formula V is obtained by treating a 4-W-azetidinone of the formula VI where W means a nucleofuge leaving group, with a mercapto compound of the formula:

or a salt, e.g. an alkali metal-, such as sodium or potassium salt thereof, and, if desired, transfers in a formed compound of formula V, in which the residue is substituted with hydroxy, transfers hydroxy in protected hydroxy. The nucleofuge leaving group W in a starting material of the formula VI is a group that can be replaced by the nucleophilic residue

Such groups W are, for example, acyloxy acid residues, sulfonyl residues (RQ- SC>2 -, where RQ is an organic residue, azido or halogen. In an acyloxy acid residue W, acyl is, for example, the residue of an organic carboxylic acid, including an optically active carboxylic acid,

and means, for example, lower alkanoyl, e.g. acetyl or propionyl, optionally substituted benzoyl, e.g. benzoyl or 2,4-dinitrobenzoyl, phenyl laveralkanoyl, e.g. phenylacetyl, or the acyl residue of one of the optically active acids mentioned above. In a sulfonyl residue R^SG^-, RQ is, for example, optionally hydroxy-substituted lower alkyl, such as methyl, ethyl or 2-hydroxyethyl, and also correspondingly substituted, optically active lower alkyl, e.g. (2R)- or (2S)-1-hydroxyprop-2-yl, with an optically active residue substituted methyl, which

campheryl, or 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-hydroxyethyl-sulfonyl, acetoxy or chlorine.

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

In the reaction, both optically inactive cis- or trans-compounds of the formula VI, as well as mixtures thereof, or corresponding optically active compounds can be used. The constituent group R^-A-C (= Z') - S - is preferably directed in the trans position of the group R^, regardless of whether W is in the cis or trans position to the group R^. Although the trans isomers are predominantly formed, the cis isomers can also occasionally be isolated. The separation of the cis- and trans-isomers takes place as described above, using conventional methods, in particular by chromatography and/or by crystallization.

A subsequent ozonation of a methylidene group Z<1>

can be carried out as indicated further below. An up-

reached racemate with the formula V can be divided into the optically active compounds.

An azetidinone of formula VI, where means acetoxymethyl, is described in DE. Off. document no. 29 50 898.

Other azetidinones of the formula VI can be prepared on i

and in a manner known per se, for example by reacting a vinyl ester with the formula R^-CH = CH-W with chlorosulfonyl isocyanate and reacting the cycloadduct formed with a reducing agent, e.g. sodium sulfite. In this synthesis, mixtures of cis- and trans-isomers are usually obtained, which, if desired, are split off into the pure cis- or trans-isomers, e.g. by chromatography and/or crystallization or distillation. The pure cis- and trans-isomers exist as racemates and can be split into their optical antipodes, for example when acyl in an acyloxy acid residue W

in compounds of formula VI originates from an optically active acid. The compounds of formula VI, especially their optically active representatives, can also be prepared by means of the method indicated here below by reaction scheme II.

Step 1. 2:

An α-hydroxycarboxylic acid compound of the formula VIII is obtained by putting a compound of the formula V with a glyoxylic acid compound of the formula OHC-R^ or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal* e.g. a hemiacetal with a lower alkanol, e.g. methanol or ethanol, and, if desired, in a formed compound of formula VII, when the radical is substituted with a hydroxy, transfers hydroxy in protected hydroxy. The compound VII is usually obtained as a mixture of the two isomers, (with regard to the grouping; But one can also isolate the pure isomers thereof. ;The addition of the glyoxylic acid ester compound to the nitrogen atom in the lactam ring takes place at room temperature or, if necessary, under heating, e.g. up to about 100°C, and that in the absence of an actual condensing agent and/or without the formation of a salt. When using the hydrate of the glyoxylic acid compound, water is formed, which is, if necessary, removed by distillation , for example azetropic distillation or using a suitable dehydrating agent, such as a molecular sieve. Preferably, one works in the presence of a suitable solvent, such as dioxane, toluene or dimethylformamide, or solvent mixture, if desired or necessary in an inert gas atmosphere, such as nitrogen. In the reaction, both pure optically inactive cis- or trans-compounds of formula V can be used, as well as mixtures thereof, or equivalent optically active compounds. An obtained raceme of formula VII can be divided into the optically active compounds. ;Step 1. 3; Compounds with the formula VIII, where X o stands for a reactive esterified hydroxy group, especially for halogen or organic sulfonyloxy, are prepared by converting the secondary hydroxy group in a compound with the formula VII into a reactive, esterified hydroxy group, especially in halogen, f .ex. chlorine or bromine, or in an organic sulfonyloxy group, such as lower alkanesulfonyloxy, e.g. methanesulfonyloxy, or arenesulfonyloxy, e.g. benzene- or 4-methyl-;benzenesulfonyloxy. In the starting compounds of formula VII, R 1 preferably stands for lower alkyl which is substituted with a protected hydroxy group. ;The compounds of formula VIII can be obtained in the form of mixtures of the isomers (with regard to the<g>grouping ; ; or in the form of pure isomers. ;The above reaction is carried out by treatment with;a suitable esterification agent, e.g. with a thionyl halide, e.g. -chloride, a phosphorus oxyhalide, especially -chloride, a halophosphonium halide, such as triphenylphosphonium dibromide or -diiodide, or a suitable organic sulfonic acid halide, such as -chloride, preferably in the presence of a base, primarily a organic basic agent, such as an aliphatic tertiary amine, eg triethylamine, diisopropylamine or "polystyrene honey base", or a heterocyclic base of the pyridine type, eg pyridine or collidine. Preferably, one works in the presence of a suitable solvent agent, e.g. dioxane, or tetrahydrofuran, or a solvent mixture, if necessary under cooling and/or in an inert gas atmosphere, such as nitrogen. ;In such an obtainable compound of formula VIII, a reactive esterified hydroxy group X is transformed in a manner known per se into another reactive esterified hydroxy group. Thus, one can e.g. replace a chlorine atom with a bromine or iodine atom, by treating the corresponding chlorine compound with a suitable bromide or iodide salt, as well as lithium bromide or iodide, preferably in the presence of a suitable solvent, such as ether. Thus, in the reaction, pure optically inactive cis- or trans-compounds of the formula VII as well as mixtures thereof, or corresponding optically active compounds can be used. An obtained racemate of the formula VIII can be divided into optically active compounds. ;Step 1. 4:;The starting material with the formula II' is obtained by treating a compound with the formula VIII, where XQ stands for a reactive esterified hydroxy group, with a suitable phosphine compound, such as a trilower alkylphosphine, e.g. tri-n-butyl phosphine, or a triaryl phosphine, e.g. triphenylphosphine, or treat with a suitable phosphite compound, e.g. trilower alkyl phosphite, e.g. triethyl phosphite, or an alkali metal dilute alkyl phosphite, e.g. -diethyl phosphite. The above reaction is respectively carried out in the presence of a suitable inert solvent, such as a hydrocarbon, e.g. hexane, cyclohexane, benzene, toluene or xylol; or an ether, e.g. dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. ;Depending on the reactivity, one works under cooling or at an elevated temperature, approx. between -10°C and +100°C, preferably at approx. 20°C to 80°C, and/or in an inert gas atmosphere, such as nitrogen. To prevent oxidation processes, catalytic amounts of an antioxidant can be added, e.g. hydroquinone. Thereby, work is carried out using a phosphine compound, usually in the presence of a basic agent, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or "polystyrene hinig base", and then goes directly to the ylide starting material of formula II (respectively;II') which is formed from the corresponding phosphonium salt. A starting compound of formula II, where X is a phosphono group together with a cation, is preferably prepared in situ, by treating a formed compound of formula; ; where X' means a phosphono group, with a suitable basic reagent, such as an inorganic base, e.g. an alkali metal carbonate, such as sodium or potassium carbonate, or an organic base, such as a tri-lower alkylamine, e.g. triethylamine, or a cyclic base of the amidine type, such as a corresponding diazabicycloalkene compound, e.g. 1,5-diazabicyclo(5.4.0) undec-5-ene. In the reaction, both pure, optically inactive cis- or trans-compounds of the formula VIII, as well as mixtures thereof, or corresponding optically active compounds can be used. A formed racemate of the formula II<1> can be cleaved into the optically active compounds. ;Step 1. 4a:;A starting compound of the formula II', where Z<1> stands for oxo, can further be obtained when a mercaptide of the formula IX, in which M stands for a metal cation, is treated with an acylating agent introducing the residue R^- A-C (=0) -. In the starting material with the formula IX, the metal cation M is, for example, a cation with the formula M<+> or M +/2, whereby M + in particular stands for a silver cation and M 2 + in particular stands for the divalent cation of a suitable transition metal, f .ex. copper, lead or mercury. An acylating agent which introduces the residue R^-A-C(=0)- is; e.g. the acid R^-A-000H or a reactive functional derivative thereof, such as an acid halide, e.g. chloride or bromide, azide or anhydride thereof. The acylation takes place when the free acid with the formula R^-A-COOH is used, e.g. in the presence of a suitable water-extracting agent, such as a carbodiimide, e.g., N,N'-dicyclohexylcarbodiimide, or when an acid derivative is used in the presence of a suitable acid-binding agent, such as a tertiary aliphatic or aromatic base, e.g. triethylamine, pyridine or quinoline, 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°C to approx. +60°C, especially at approx. -30°C to approx. +20°C. The starting compounds with the formula IX can, for example, be prepared by transferring an azetidinone with the formula; by reaction with an alkali metal salt, e.g. sodium salt, a thiolavealkanecarboxylic acid, e.g. thioacetic acid, or triphenylmethylmercaptans in a compound with the formula where W<1> means triphenylmethylthio or lower alkanoylthio, e.g. acetylthio, transfer this compound analogously to the methods described in reaction step 1.2, 1.3 and 1.4, to a compound with the formula; and converting this in the presence of a base, e.g. pyridine or tri-n-butylamine, in a suitable solvent, e.g. diethyl ether or methanol, with a salt of the formula MA where M has the meaning stated above, but specifically stands for a silver cation, and A means a common anion, which favors the solubility of salts MA in the chosen solvent, e.g. nitrate, acetate or fluoride anion. ;Compounds of the formula (II<1>) where stands for a reactive esterified hydroxy group, can be transferred in a reaction with an agent that introduces azahetero-cyclyl radical R^, in compounds of the formula (II'), where R^ stands for the residue R ^, whereby, for example, the reaction condition specified in method variant c) is used. The ylides of the formula II', where Z' is oxygen or sulphur, can be used directly in the cyclization reaction to produce the final product of the formula I. But you can also in compounds of the formula II', where R contains a protected hydroxy group, e.g. e.g. a hydrolytically easily cleavable protected hydroxy group, such as trisubstituted silyloxy as substituents, first cleave the hydroxy protecting group and then use the formed compound of the formula II', where R^ is hydroxy substituted lower alkyl, in the ring closure reaction. In compounds II', V, VII and VIII, an optionally substituted methylidene group Z' can be transferred into the oxo group Z by ozonization and subsequent reduction of the ozonide formed, according to the method described later in step 2.3. ;Step 1. 5:;The starting compound with formula (IV) is obtained by ring-closing a ylide with the formula (II<1>), where Z' means oxygen or sulfur and R^ stands for a reactive esterified hydroxy group Q, and optionally transfers a protected carboxyl group R 1 in the free carboxyl group R 2 in an obtainable compound. The ring closure can, for example, be carried out as described in the preparation of compounds of formula (I) from ylides of formula (II) (method a.). The transfer of a protected carboxyl group R£ into a free carboxyl group R2 in an obtainable compound of formula IV can be carried out in an analogous manner to that described above regarding the compounds of formula I. Step 1. 6: A compound of formula (III) is obtained by an azetidinone of the formula (V), where Z<1> means sulphur, is treated with a compound of the formula R^-COOH or in particular a reactive derivative, such as an acid halide, e.g. the acid chloride thereof, at a temperature of from 20°C to 80°C, preferably at 40°C to 60°C, in an inert solvent such as one of the solvents 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 especially in the presence of an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, e.g. potassium carbonate or calcium carbonate. Starting compounds of formula VI, where W is a sulfonyl residue of formula R -SO2- can also be prepared according to the following reaction scheme II. ;Reaction scheme II; ; ; In the compounds of the formulas (XI) to (XIV) and (Via) R 1 stands for hydroxy substituted lower alkyl or stands in particular for the protected hydroxy group substituted lower alkyl. ;Step 2. 1; Compounds of the formula (XII) can be prepared by epimerizing a compound of the formula (XI). The epimerization is carried out, for example, in the presence of a basic agent, such as an amine, e.g. a tri-lower alkylamine, e.g. triethylamine or ethyldiisopropylamine, a tertiary amine, e.g. N,N-dimethylaniline, an aromatic amine, e.g. pyridine, or a bicyclic amine, e.g. 1,5-diazabicyclo(5,4,0)undec-5-ene, or 1,5-diazabicyclo(4,3,0)non-5-ene, or an alkali metal javeral alkanolates, e.g. sodium methanolate, sodium ethanolate, or potassium tert.-butanolate, in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, possibly with a somewhat elevated or lowered temperature, e.g. at 0°C to 50°C, preferably at room temperature. In the compounds with the formula (XII) formed by the method, a protected hydroxy group contained in the residue can be replaced with another protected hydroxy group, for example a hydrogenolytically cleavable protected hydroxy group can be replaced with a solvolytically cleavable protected hydroxy group. Hydroxy protecting groups are in particular the above-mentioned, hydrogenolytically cleavable protecting groups are, for example, as indicated substituted 1-phenyllower alkyl or phenyllower oxycarbonyl, solvolytically cleavable protecting groups are, for example, as indicated trisubstituted silyl. The reaction can be carried out so that the hydrogenolytically cleavable hydroxy protecting group is first removed and a solvolytically cleavable hydroxy protecting group is introduced into the resulting compound of formula XII, where R is with hydroxy substituted lower alkyl. The cleavage of the hydrogenolytically cleavable protecting group can be carried out e.g. with a hydrogen or a hydrogen donor, e.g. cyclohexene or cyclohexadiene, in the presence of a hydrogenation catalyst, such as a palladium catalyst, e.g. palladium on charcoal, in an inert solvent, such as a halogenated hydrocarbon, e.g. methylene chloride, a lower alkanol, e.g. methanol or ethanol, an ether, e.g. dioxane or tetrahydrofuran, or also in water or in mixtures thereof, at a temperature from approx. 0°C to approx. 80°C, preferably at room temperature. The separation can also be carried out with a reducing metal, such as zinc, or a reducing metal alloy, e.g. copper-zinc alloy, in the presence of a proton donor, such as an organic acid, e.g. acetic acid, or also a lower alkanol, e.g. ethanol. The introduction of the solvolytically cleavable hydroxy protecting group can, for example, be carried out with a compound of formula R'-X.j, where R' means hydroxy protecting group, and X^means e.g. a reactive esterified hydroxy group, for example halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy. Starting compounds with formula (XI) are known, for example, from DE Off. document 3 039 504 and British patent application 20 61 930. ;Step 2. 2:;A compound of the formula (XIII) can be prepared by treating a penam compound of the formula (XII) with a basic agent and with an esterification agent which introduces the remainder R . A suitable basic agent is, for example, one of the basic agents mentioned under step 2.1, especially of the mentioned bicyclic amines, also an alkali metal amide or hydride, e.g. sodium amide or sodium hydride. A residue RQ is, for example, one of the organic residues mentioned under step 1.1, especially optionally substituted lower alkyl, e.g. methyl, ethyl or 2-hydroxyethyl or benzyl. ;An esterification agent introduces the residue RQer e.g. a compound with the formula RQ-X^, where X^ is reactive esterified hydroxy, e.g. halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy. Ethylene oxide is also suitable for introducing a 2-hydroxyethyl residue. The reaction is preferably carried out in two steps, whereby in the first step penam compounds of the formula (XII) are treated with at least equimolar amounts of the basic agent and a formed intermediate is reacted with the formula; ; where B means the protonated form (cation) of the basic agent, preferably without isolation from the reaction mixture with the esterification agent. The reaction is carried out in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane. tetrahydrofuran or dioxane, in acetonitrile, dimethylformamide or hexamethylphosphoric acid triamide, optionally at a somewhat elevated or lowered temperature, e.g. at approx. 0°C to 50°C, preferably at room temperature. In a preferred embodiment of the method, the penam compound with the formula (XII) is produced in situ, as described in step 2.1, a compound with the formula (XI) is first treated with catalytic agents of the basic agent, e.g. 1,5-diazabicyclo(5,4,0)undec-5-ene), and then reacts with at least equimolar amounts of the same basic agent and the esterifying agent in the compounds of the formula; (XIII). ;Step 2. 3; An oxalyl-azetidinone of the formula (XIV) can be prepared by ozonizing a compound of the formula (XIII) and cleaving the formed ozonide reductively to the oxo compound. The ozonation is usually carried out with an ozone-oxygen mixture in an inert solvent, such as a lower alkanol, e.g. methanol or ethanol, a lower alkanol, e.g. acetone, an optionally halogenated hydrocarbon, e.g. a halolower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably under cooling, e.g. at temperatures from approx. -80°C to approx. 0°C. An ozonide obtained as an intermediate is usually cleaved without isolation, reductively to a compound of the formula XIV, whereby catalytically activated hydrogen is used, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel and further palladium catalyst, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or amalgam, e.g. ;zinc, in the presence of a hydrogen donor, such as an acid, e.g. acetic acid, or an alcohol, e.g. lower alkanol, reducing inorganic salts, such as alkali metal iodide, e.g. sodium iodide, or alkali metal hydrogen sulphite, e.g. sodium hydrogen sulphite in the presence of a hydrogen donor, such as an acid, e.g. acetic acid, or water, or reducing organic compounds, such as formic acid. As a reducing agent, compounds can also be used which can easily be transformed into corresponding epoxy compounds or oxides, whereby the epoxide formation can take place due to a C,C double bond and the oxide formation can take place due to a present oxide-forming hetero-, such as sulphur, phosphorus - or nitrogen atoms. Such compounds are e.g. suitably substituted ethylene compounds (which in the reaction are transformed into ethylene oxide compounds), such as tetracyanethylene, or particularly suitable sulphide compounds (which in the reaction are transformed into sulphoxide compounds), such as dilave alkyl sulphides, primarily dimethyl sulphide, suitable organic phosphorus compounds, such as a phosphine which is optionally substituted with phenyl and/or lower alkyl, e.g. methyl, ethyl, n-propyl or n-butyl, (which in reaction is transformed into a phosphine oxide), such as trilower alkyl phosphines, e.g. tri-n-butylphosphine, or triphenylphosphine, further trilower alkyl phosphite (which in the reaction is transformed into phosphoric acid trilower alkyl esters), usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphoric acid triamides, which likewise contain lower alkyl as a substituent, such as hexalower alkyl phosphoric acid triamide, f .ex. hexamethylphosforsyl triamide, the latter preferably being in the form of a methanol adduct, further suitable nitrogen gases (which in reaction are transformed into the corresponding N-oxides), such as heterocyclic nitrogen bases of an aromatic character, e.g. bases of the pyridine type, and especially pyridine itself. The cleavage of the usually unisolated ozonide normally takes place under conditions used for its preparation, e.g. in the presence of a suitable solvent or solvent mixture, as well as during cooling or slight heating, whereby temperatures from approx. -10°C to approx. ;+25°C and the reaction is usually terminated at room temperature. ;Step 2. 4:;Etazetidinone with the formula (Via) can be prepared by solvolyzing an oxalyl-azetidinone with the formula (XIV). The solvolysis can be carried out as hydrolysis, as alcoholysis or also as hydrazinolysis. The hydrolysis is carried out with water, possibly in a solvent which is miscible with water. The alcoholysis is usually carried out with a lower alkanol, e.g. methanol or ethanol, preferably in the presence of water and an organic solvent, such as a lower alkane carboxylic acid lower alkyl ester, e.g. acetic acid ethyl ester, preferably at room temperature, if necessary during cooling or heating, e.g. at a temperature from about. 0°C to approx. 80°C. The hydrazinolysis is carried out in a conventional manner, with a substituted hydrazine, e.g. with phenyl or a nitrophenylhydrazine, such as 2-nitrophenylhydrazine, 4-nitrogenylhydrazine, or 2,4-dinitrophenylhydrazine, which is preferably used in approx. equimolar amounts, in an organic solvent, such as an ether, e.g. diethyl ether, an aromatic hydrocarbon, such as benzene, a halogenated hydrocarbon, such as methylene chloride, an ester, such as ethyl acetate, and the like, at temperatures between about room temperature and approx. 65°C. In a preferred embodiment of the method, one starts from a compound with the formula (XIII) which, as indicated, is ozonized and then cleaved reductively to oxaly1-azetidinone with the formula (XIV) which, without isolation from the reaction mixture, is further converted to azetidinone with the formula (Via) . During the ozonolysis, possibly small amounts of acids are produced, which can cause the cleavage of a solvolytically easily cleavable hydroxy protecting group R<1> in the residue R^ , e.g.; a trisubstituted silyl residue. The thereby obtained connection with the formula; ; where RJj is hydroxy-substituted lower alkyl, can for example be chromatographically separated from protected azetidinone (Via) and by renewed reaction with the agent of the formula R'-X^ which introduces hydroxy protecting groups R<1>, transferred to azetidinone with the formula (Via). In the compounds with the formulas (II), (II'), (III), (IV), (VII) to (IX) and (XII) to (XIV), a protected carboxyl group R 2 can by means of methods known per se is transformed into another protected carboxyl group R^, whereby, taking into account further functional groups that may possibly be contained in these compounds, the same methods are used as indicated for the transformation of these substituents in the compounds of formula (I). The invention also relates to new starting products as well as new intermediate products obtainable according to the method, such as those with the formulas (II) to (IX) (including II<1>, Ila and Via), as well as the specified methods for producing these. Such starting materials are preferably used and the reaction conditions are chosen so that the compounds listed above as particularly preferred are obtained. The compounds of formula I exhibit valuable pharmacological properties or can be used as intermediates for the production of such compounds with valuable pharmacological properties. The compounds of formula I, where R is hydroxy-substituted lower alkyl, R 2 means carboxyl or a cleavable esterified carboxyl group under physiological conditions and R 3 and A have the meanings given under formula I, and pharmacologically acceptable salts of such compounds with salt-forming groups have antibacterial effects. For example, they are effective in vitro against gram-positive and gram-negative cocci, e.g. Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria meningitidis and Neisseria gonorrhoeae against enterobacteria, e.g. ;Escherichia coli and Proteus sp., against Haemophilus influenzae, Pseudomonas aeruginosa and anaerobes, e.g. B acteroides sp. ;in minimal concentrations from approx. 0.02 to approx. 64 etc. ;In vivo, in case of systemic infection.house mice, e.g. in the case of Staphylococcus aureus, Escherichia coli or Streptococcus pyogenes, ED^Q values of approx. 10 to approx. 70 mg/kg. The new compounds may find application for the treatment of infections as orally or parenterally applicable antibacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations. Compounds of formula I, where at least one of the functional groups present is in a protected form, whereby a protected carboxyl group is different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the production of the above-mentioned pharmacologically active compounds of formula I. ; The pharmacological compounds produced according to the present invention can, e.g. is used for the preparation of pharmaceutical preparations containing a therapeutically effective amount of the active substance, together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for administration orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally . For oral administration, tablets or gelatin capsules are used, which contain the active substance together with a diluent, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, the explosive, e.g. starches, agar, alginic acids or a salt thereof, such as sodium alginate, and/or fizzy mixes or adsorbents, colourings, flavorings or sweeteners. ;Parenteral administration is primarily suitable for infusion solutions, preferably isotonic aqueous solutions or suspensions, whereby these can be prepared before use, e.g. from lyophilized preparations, which contain the active substance alone, or together with a carrier material, e.g. mannite. Such preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers. ;In the present pharmaceutical preparations which, if desired, may contain additional pharmacologically valuable substances, are prepared in a manner known per se, e.g. using conventional mixing, dissolving or lyophilization procedures, and then contains approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisate to 100% of the active substance. ;Depending on the nature of the infection and the condition of the infected organism, daily doses of approx. ;125 mg to approx. 1.5 g for oral or parenteral treatment of warm-blooded animals (humans and animals) with approx. 70 kg weight. ;The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius. ;In the examples the following abbreviations are used:;DC: Thin layer chromatogram;IR: Infrared spectrum;UV: Ultraviolet spectrum;NMR: Nuclear resonance spectrum;Experimental part:;Example 1: ( 3R, S)- 3-( tetrazol-1- yl)- butyric acid; a) (3R, S)-(tetrazol-1-yl)-butyric acid methyl ester; 10 g of tetrazole are dissolved in 50 ml of crotonic acid methyl ester and 10 drops of pyridine are added. The reaction mixture is then stirred for 18 hours at 90°C. After cooling, take 3 times in toluene and evaporate on the rotary evaporator. The crude product is purified by column chromatography (toluene/ethyl acetate 1:1), (DC silica gel, toluene/ethyl acetate 1:1): Rf = 0.26. ;b) (3R,S)-3-(tetrazol-1-yl)-butyric acid; 9.05 g (3R,S)-3-(tetrazol-1-yl)-butyric acid methyl ester; is added with 53, 2 ml of acetic acid, 10.6 ml of concentrated hydrochloric acid, and 21.3 ml of water and heated for 3 hours at <1>reflux temperature. After cooling, evaporate to dryness. The residue is evaporated 3 times with toluene under a water jet vacuum and then finely divided twice with ether. After filtration, the solid is dried with high vacuum. ;Example 2: (3R,S)-3-(tetrazol-1-yl)-butyric acid chloride; 2.34 g of (3R,S)-3-(tetrazol-1-yl)-butyric acid are added with 1.5 ml of thionyl chloride and 6 drops of abs. DMF and stirred for 1 h at 80°C. After cooling, the reaction mixture is evaporated on a rotary evaporator, evaporated three more times in the presence of methylene chloride and dried under high vacuum. IR(CH 2 Cl 2 ): 1780 cm"<1. >; Example 3: ( 3R, S )- 3-( pyrrole)- 1- yl)- butyric acid chloride; 2.47 g of (3R, S)-3-(pyrrole- 1-yl)-butyric acid (Chem. Pharm. Bull.; 30, 2586 (1982)) is dissolved in 30 ml of absolute methylene chloride and added with 2.6 4 ml of 1-dimethylamino-1-chloro-2-methylpropene. The reaction mixture is stirred 2 hours and 15 minutes at room temperature and is reacted further without isolation, as described in example 11. ;Example 4: 2- ( ( 3S , 4R) - 3- ( tert . butyl-dimethylsilyloxymethyl) - ; 4- triphenylmethylthio- 2- oxo - azetidin-1-yl)'-2-hydroxyacetic acid allyl ester; 8.4 g (3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-triphenyl-methylthio-azetidin-2-one and 8.23 g glyoxylic acid - Allyl ester ethyl hemiacetal in 170 ml of absolute toluene is added with 27 g of molecular sieve (4 A) and stirred for 10 hours at 55° C. After filtering and evaporation on a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel. (Lubricant toluene/ethyl acetate 95:5) DC (silica gel, toluene/ethyl acetate 10:1): Rf= 0.37 and 0.27: IR (CH 2 Cl 2 ): 3520, 1760, 1745 cm"<1. >;The starting material (3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-triphenylmethylthio-azetidin-2-one can be prepared as follows: a) ( 3S, 5R, 6R)- 2, 2- dimethyl- 6 -( tert.-buty1- dimethylsilyloxymethyl)- penam- 3- carboxylic acid methyl ester- 1, 1- dioxide; A solution of 23.6 g (85 mmol) (3S,5R,6R)-2,2-dimethyl-6-hydroxymethyl -penam-3-carboxylic acid methyl ester-1,1-dioxide in 50 ml of dimethylformamide is stirred with 25.5 g (170 mmol) of tert-butyl dimethylchlorosilane and 11.5 g (170 mmol) of imidazole at room temperature for 45 minutes. The solvent is then distilled off under high vacuum and the residue is taken up in ethyl acetate. The solution is washed with 1N sulfuric acid and then with water, and the aqueous solution is extracted twice with ethyl acetate. The organic phase is dried with sodium sulphate and evaporated on a rotary evaporator. The product is obtained as a crystalline mass. ;DC silica gel, toluene/acetyl acetate (4:1): Rf = 0.56; IR (CH 2 Cl 2 ) 3.4; 5.57; 5.65 mm. ;b) 2-(( 3S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4-methylsulfonyl- 2- oxo- azetidin-1- yl)-3- methyl- 2- butenoic acid methyl ester ; A solution of 202 g (0.51 Mol) (3R,5R,6R)-2,2-dimethyl-6-;(tert-butyl-dimethylsilyloxymethyl)-penam-3-carboxylic acid methyl ester-1,1-dioxide-1 ,1-dioxide in 800 ml of tetrahydrofuran, is added with 9 ml of DBU and stirred for 5 minutes at room temperature. A further 95 ml of DBU is then added and stirred for 30 minutes at room temperature. Then you add wood. cooling 42.3 ml (0.68 Mol) methyl iodide. After a reaction time of 3 hours, the crystallized DBU hydroiodide is filtered off and the filtrate is evaporated. The residue is taken up in ethyl acetate and the solution is washed with 11N sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solution is evaporated to a thick oil. ;DC (silica gel, toluene/ethyl acetate (4:1)); Rf = 0.42; IR (CH 2 Cl 2 ) 5.63; 5.81; 6.17 etc. ;c) ( 3S, 4R)- 3- hydroxymethyl- 4- methylsulfonyl- azetidin- 2- one and ( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4- methylsulfonyl- azetidin- 2 - one ; A solution of 25 g (61.7 mmol) 2-((3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-2-oxo-azetidin-1-yl) -3-methyl-2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10°C with an ozone/oxygen mixture. The disappearance of the starting material is controlled by thick-layer chromatography. After the end of the reaction, 30 ml of dimethyl sulphide is added and stirred for a further 3 hours at room temperature. The solution is evaporated and the residue taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated for 40 minutes at 70°C. The solvent is then drawn off and the residue is extracted twice with toluene. The crystallizing oil is taken up in methylene chloride and the crystals, consisting of (3S,4R)-3-hydroxymethyl-4-methylsulphonyl-azetidin-2-one, are isolated by filtration. The filtrate is evaporated and (3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one is obtained by chromatography on silica gel with toluene/ethyl acetate (3:1) in pure form: ;( 3S, 4R)- 3- hydroxymethyl- 4- methylsulfonyl- azetidin- 2- one:; DC, silica gel, toluene/ethyl acetate (1:1; Rf = 0.36, IR: (CH2C12) 2.96; 3 .54; 5.61 ym.; (3S, 4R)-3-(tert.-butyl-dimethylsilyloxymethyl)-4- methyl-sulfonyl-azetidin-2-one: DC, silica gel, toluene/ethyl acetate (1:1 ) Rf = 0.06. ;A solution of 14.6 g (81.5 mmol) (3S,4R)-3-hydroxy-'methyl-4-methylsulfonyl-azetidin-2-one in 40 ml of dimethylformamide is added with 24 g (183 mmol) tert-butyldimethylchlorosilane and 11 g (T63 mmol) imidazole for 45 minutes at room temperature. The solvent is then extracted under high vacuum and the residue is taken up in ethyl acetate. The organic phase is washed in order with 1N-sulfuric acid, water and sodium bicarbonate solution. The aqueous the phases are extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulph that and evaporated on a rotary evaporator. The crystalline residue is pure (3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one). ;d) (3S, 4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-triphenylmethylthio-azetidin-2-one; 12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol at 0°C and added over 10 minutes in portions; show with a total of 2.2 g of a 50% sodium hydride suspension in oil. An emulsion of 11.1 g of (3-(tert.butyl-dimethylsilyloxymethyl)-4-methylsulphonyl-azetidin-2-one in 70 ml of acetone and 70 ml of water is then added dropwise over 30 minutes. After 30 minutes of stirring at 0°C and 1 hour at room temperature, the reaction mixture is evaporated on a rotary evaporator, methylene chloride is added and the aqueous phase is separated. The organic solution is washed with saline solution and dried over sodium sulfate. ;After evaporation, the crude title compound is purified by chromatography on silica gel (eluent toluene/ethyl acetate 19:1 ). ;DC (toluene acetate 19:1): Rf = 0.64; ;IR (methylene chloride): 3390, 1760, 1117, 835 cm<-1>. ;Example 5: 2-(( 3S, 4R)- 3-(tert.butyl-dimethylsilyloxymethyl-4-triphenylmethylthio-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylidene-acetic acid allyl ester; To a solution of 604 mg 2-((3S,4R)-3-( tert.butyl-dimethyl-silyloxymethyl=-4-triphenylmethylthio-2-oxo-azetidin-1-yl)-2-hydroxyacetic acid allyl ester in 5 ml tetrahydrofuran is added after stirring ve d -15°C in sequence 80 µl of thionyl chloride and 88 µl of pyridine in the course of 5 minutes. The white suspension is stirred for 1 hour at -10°C and filtered over "Hyflo". After washing the residue with toluene, it is evaporated on a rotary evaporator. The residue is dissolved in 3 ml of dioxane, 293 mg of triphenylphosphine and 0.13 ml of 2,6-lutidine are added and stirred for 2 hours at a basic temperature of 115°C. The mixture is filtered over "Hyflo" and the residue is washed with toluene. The combined filtrates are evaporated. Chromatography of the residue on silica gel gave pure product (eluent toluene/ethyl acetate 95:5). ;DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.18; ;IR (CH 2 C 12 ): 1745, 1605 cm"<1>. ;Example 6: Silver salt of 2-(( 3S, 4R)- 3-( tert. butyl- dimethyl-silyloxymethyl)- 4- mercapto- 2- oxo - azetidin-1-yl)-2-triphenylphosphoranylidene-acetic acid allyl ester; 7.5 g (2-(3S,4R)-3-tert.butyl-dimethylsilyloxymethyl)-4-triphenylmethylthio-2-oxo-azetidine-1- yl)-2-triphenylphosphorus-anylideneacetic acid allyl ester is dissolved in 87 ml of ether and added at room temperature with 70 ml of a 0.5 M aqueous silver nitrate solution.Then a mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether to this and stir the reaction mixture for 20 minutes. The solid is then filtered off with suction and washed with ether, water and once more with ether. Finally, for purification, the solid is further slurried in 40 ml of ether and 40 ml of water, filtered off with suction and dried IR (CH 2 Cl 2 ): 1760, 1620 cm"<1>. ;Example 7: 2 - ( ( 3R, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl) - 4-( ( 3R, S)- 3-( tetrazol- 1- yl)- butyroyl-thio)- 2- oxo - azetidin-1-yl) 2-triphenylphosphoro-anylideneacetic acid- allyl ester 5 g silver salt of 2.((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yl )-2-triphenyl-phosphoranylideneacetic acid-2-allyl esters are dissolved in 100 ml of absolute methylene chloride, cooled to 0°C, 85 mg of 4-dimethylaminopyridine and 1.23 ml of pyridine are added. After the addition of 1.9 g of 3-(tetrazol-1-yl)-butyric acid chloride, the reaction mixture is stirred for 30 minutes at 0°C. The precipitate is filtered off, the filtrate is diluted with methylene chloride, washed with aqueous Na^CO-^ solution and then with saline solution. After drying over Na2<S0>4<i>nn, the solution is evaporated and the residue is chromatographed on silica gel (eluent toluene/ethyl acetate). ;DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.18; ;IR (CH 2 Cl 2 ): 1750, 1680, 1610 cm"<1>. ;Example 8: ( 5R, 6S)-2-(( 2R, S)- 2-( tetrazol-1- yl)- prop- 1- yl)- 6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3- carboxylic acid allyl ester; A solution of 3.4 g of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4 -((3R,S)-3-tetrazol-1-yl)-butyloylthio=-2-bxo-azetidin-1-yl)-2-triphenhlphosphoranylideneacetic acid allyl ester in 500 ml of absolute toluene, stirred under an argon atmosphere for 2 hours at reflux temperature. The solvent is then evaporated and the crude product is purified by chromatography on silica gel (eluent toluene/ethyl acetate) 9:1). ;DC (silica gel, ethyl acetate) ; Rf = 0.55; ;IR (CH2C12): 1780, 1695, 1575 cm "<1. >;Example 9: ( 5R, 6S )- 2-(( 2R, S )- 2- tetrazol- 1- yl)- prop- 1-yl)- 6- hydroxy, ethyl ^- penem- S- carboxylic acid allyl ester ; solution of 1.5 g of (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester dissolve in 32 mL of abs. THF, cool to -70°C and add sequentially with 1.31 mL of acetic acid and dropwise over 15 min with 70 mL of a 0.2 M tetrabutylammonium fluoride solution in THF. The cooling bath is then removed and the reaction mixture is slowly brought to room temperature. After 5 hours of stirring at room temperature, the reaction mixture is concentrated on a rotary evaporator and taken up in ethyl acetate and aqueous NaHCO^. ;The organic phase is separated, washed with a saline solution and dried over Na2SO^ and evaporated. The crude product is purified by chromatography on silica gel ( eluent toluene/acetyl acetate 4:1 to 1:1). ;DC (silica gel, ethyl acetate): Rf = 0.22; ;IR (CH 2 Cl 2 ): 3600, 1780, 1695, 1575 cm"<1. >;Example 10: ( 5R, 6S)- 1-(( 2R, S)- 2-( tetrazol)- 1- yl)-prop- 1- yl)- 6- hydroxymethyl- 2- penem- 3-carboxylic acid, sodium salt ; o ; 0.85 g (5R,6S)-2- ((2R,S)-(tetrazol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester is dissolved in 32 ml of abs. THF, cooled to -10°C and added with 53 mg of tetrakis-triphenylphosphine palladium and 9.75 ml of tributyltin hydride. After 65 minutes of stirring at -10°C, 0.16 ml of acetic acid is added and the reaction mixture is further stirred for 10 minutes at -5°C. After concentration on a rotary evaporator, the residue is taken up in water/ethyl acetate, cooled and adjusted to pH 7.5 with NaHCO^. The aqueous phase is separated, washed twice with ethyl acetate, concentrated on a rotary evaporator and purified on an XAD-2 column. (Lubricant: water). The combined fractions are lyophilized under high vacuum. ;DC (reversed-phase opti UPC 12, water): Rf = 0.3; ;UV (phosphate buffer pH 7.4): X max. = 304 nm. Example 11: 2-(( 3S, 4R)- 3-( tert. butyl methylsilyloxymethyl)-4-(( 3R, S)- 3-( pyrrol- 1- yl))- butyloylthio)- 2-oxo- azetidin-1-yl)-2-triphenylphosphoranylidene-acetic acid-allyl ester; Analogous to example 7, 5 g of the silver salt of 2-((3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidine- 1-yl)-2-triphenylphosphoranylidene-acetic acid.2.allyl ester and 1.5 molar equivalent of 3-(pyrrol-1-yl)-butyric acid chloride to the title compound. ;DC (silica gel, ethyl acetate): Rf = 0.62; ;IR (CH 2 Cl 2 ): 1750, 1680, 1625 cm"<1. >;Example 12: ( 5R, 6S)- 2-(( 2R, S)- 2-( pyrrol-1- yl)- 6-( tert .-butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester; Analogous to example 8, 3.86 g of (2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-((3R, S)-3-(pyrrol-1-yl)-butyroylthio)-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylide-acetic acid allyl ester of the title compound.;DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.7; ;IR (CH 2 Cl 2 ): 1780, 1700, 1575 cm"<1>. ;Example 13: (5R,6S)-2-((2R,S)-2-(pyrrol-1-yl )-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester; Analogous to example 9, 1.5 g of (5R,6S)-2-((2R,S)-2-( pyrrol-1-yl)-prop-1-yl)6-[tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester of the title compound. ;DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.35; ;IR (CH 2 Cl 2 ): 3600, 1780, 1695, 1575 c-"1 . ;Example 14; (5R,6S)-2-((2R,S)-2-(pyrrol-1-yl) - prop- 1- yl)-6- hydroxymethyl- 2- penem- 3- carboxylic acid, sodium salt; Analogous to example 10, 1 g of (5R,6S)-2-((2R,S)-2-pyrrol-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid is transferred to the title compound. ;DC (refersed phase; opti UTC 12, water-acetonitrile 4:1) Rf = 0.38; ;UV (water): X max. = 30 8 nm. Example 15: (3R,S)-3-(tetrazol-1-yl)-thiobutyric acid; 2 g of (3R,S)-3-(tetrazol-1-yl)-butyric acid chloride in 4 ml abs. methylene chloride is added at 0°C to an excess of a pyridine/hydrogen sulphide solution in methylene chloride. The reaction mixture is stirred for 1 hour at 0°C, diluted with chloroform and acidified with 2N sulfuric acid. The aqueous solution is re-extracted twice with chloroform. The combined organic phases are extracted with aqueous NaHCO 2 solution. After acidifying the extracts with H 2 SO 4 (2N) and washing several times with chloroform, the organic solution is dried over Na 2 SO 4 and evaporated to dryness. One gets the title connection. ;IR (CH 2 Cl 2 ): 2560, 1695 cm"<1>. ;Example 16: ( 3S, 4R)- 3-( tert. butyldimethylsilyloxymethyl)- 4-(( 3R, S)- 3- tetrazol- 1- yl) - butyroylthio)-azetidin-2-one; 8.2 g (3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-methylsulfonylazetidin-2-one and ;,6.7 g (3R,S)-3- (tetrazol-1.yl)-thiobutyric acid is dissolved in 180 ml of methylene chloride and added with 180 ml of water and 42 ml of 1N NaOH. The emulsion is stirred vigorously for 1 hour at room temperature. The organic phase is separated and the aqueous phase is extracted a further 2 times with CH2C12 . The combined organic extracts are washed with a saturated aqueous NaHCO 3 solution, then with a saline solution, dried over Na 2 SO 4 and evaporated. The crude product formed is purified by chromatography on silica gel. ;IR (CH 2 Cl 2 ): 3425, 1765, 1685 cm"<1> . The preparation of the starting material (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one is described in example 4. Example. 1 7 : 2- ( ( 3S, 4R) - 3- ( tert . butyl- dimethylsilyloxymethyl)--4-( ( 3R, S)- 3-( tetrazol- 1- yl)- butyroylthio)- 2- oxo-azetidine - 1-yl)-2-hydroxyacetic acid allyl ester; Analogous to example 4, 8.1 g of ((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-((3R,S)-3-(tetrazole) is reacted -1-yl)-butyroyl-thio)-azetidin-2-one to the title compound. ;IR (CH 2 Cl 2 ): 3515, 1760, 1745, 1685 cm"<1. >;Example 18: 2-(( 3S, 4R) - 3-(tert.butyl-dimethylsilyloxymethyl)-4-((3R,S)-3-(tetrazol-1-yl)-butyroylthio)-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester; Analogously to example 5, 7.43 g of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-((3R,S)-3-(tetrazol-1-yl)-butyroyl-thio) -2-oxo-azetidin-1-yl)-2-hydroxyacetic acid allyl ester of the title compound.;DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.18;;IR (CH2Cl2): 1750, 1680, 1610 cm"<1>. ;The product is identical to that from example 7. ;Example 19: In an analogous way as described in the above;specified examples, the the following compounds: (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-but-1-yl)-6-hydroxymethyl-2-penem. 3- carboxylic acid, sodium salt, UV water: X max.= 306 nm; (5R,6S)-2-((2R,S)-2-(1,2,4-triazol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt, UV (phosphate buffer pH 7.4). ^ max_ = 303 nm; ( 5R, 6S)- 2-(( 2R, S)- 2-( 5- amino- tetrazol- 1- yl)- pro p-1- yl)-6- hydroxymethyl- 2- penem- 3- carboxylic acids, UV :(water) : X max. = 30b nm; ;( 5R, 6S) . 2. ( ( 2R, S)- 2-( imidazol-1- yl)- prop- 1- yl)- 6-hydroxymethyl- 2- penem- 3- carboxylic acid, sodium salt, ; UV (water): X max. = 308 nm; ;( 5R, 6S)- 2-(( 2R, S)- 2-( pyrazol- 1- yl)- prop- 1- yl)- 6- hydroxymethyl-2- penem- 3- carboxylic acid, sodium salt, UV {water ): Xmax = ;309 nm; ;( 5R, 6S)- 2-(( 1R, S)- 1-( tetrazol- 1- yl)- ethyl)- 6- hydroxymethyl- 2-penem- 3- carboxylic acid and sodium salt, UV (phosphate buffer pH 7.4 ): X max.=305 nm; ;( 5R, 6S)- 2-( 2R, S)- 2-( tetrazol- 1- yl)- prop- 1- yl)- 6-(( 1R)-hydroxyethyl)- 2- penem- 3- carboxylic acid, sodium salt, UV (water): X max.= 306 nm; ;and ;(5R,6S)-2-((2R,S)-2-(tetrazol-1-y1)-prop-1-yl)-6-(2-hydroxy-prop-2-yl)-2 - penem- 3- carboxylic acid, sodium salt, ;UV (water): X max. = 30 7 nm. ;Example 20. : ( 5R, 6S) - 2- ( ( 2R, S) - 2- ( tetrazol-1- yl) - prop-1- yl) 6- hydroxymethyl- 2- penem- 3- carboxylic acid-1- ethoxycarbonyloxyethyl ester; 1.2 g of sodium iodide is dissolved in 3.7 ml of acetone and 0.275 ml of ethyl-1-chloroethyl carbonate is added. The mixture is then stirred at room temperature for 3 hours. The solution is then added dropwise to 15.0 ml of methylene chloride and filtered from the precipitated inorganic salts. The methylene chloride solution is evaporated to 2 ml and added at 0°C to a solution of 0.332 g (1 mmol) (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-prop-1 -yl)-6-hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. It is then stirred for 3 hours at 0°C, after which it is diluted with acetyl acetate and washed three times with water. The organic phases are dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluant ethyl acetate. The title compound is obtained as a white foam. IR spectrum (methylene chloride): -1 ; absorption bpnd at 1788 and 17 40 cm; Example 21: In an analogous manner as described in example 20, starting from (5R,6S)-2-((2R,S)-2 -(pyrrol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid ( 5R , 6S )- 2-(( 2R , 6S )- 2-( pyrrol-1- yl )- prop- 1- yl)- 6-hydroxymethyl- 2- penem- 3- carboxylic acid- 1- ethoxycarboxylic ethyl ester. ;_i ;IR spectrum (methylene chloride): 1786 and 1743 cm; Example 22: ( 5R, 6S)- 2-(( 2R, S)- 2-( tetrazol-1- yl)- prop- 1-yl)- 6 - hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester; dissolve 0.6 g of sodium iodide in 2 ml of acetone and add 0.15 ml of pivalic acid chloromethyl ester. The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 1 ml and added to a solution of 0.133 g (0.4 mmol) (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-prop-1-yl) -6-hydroxymethyl-2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of N,N-dimethylacetamide at 0°C. It is then stirred for 3 hours at 0°C, after which it is diluted with ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluent ethyl acetate

the title compound as a white foam.

IF spectrum (methylene chloride): absorption band at 1790 and

1730 cm"<1>.

Example 23: In an analogous way as described in example 22

starting from (5R,6S)-2-((2R,S)-2-(pyrrol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid ( 5R, 6S)-2-((2R,S)-2-(pyrrol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester.

-1

IR spectrum (methylene chloride): 1789 and 1726 cm .

Example 24: Dry ampoules or vials containing 0.5 g sodium salt (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-prop-1-yl)-6- Hydroxymethyl-2-penem-3-carboxylate as active substance is prepared as follows:

Composition (for 1 ampoule or vial):

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

Instead of the above-mentioned active substance, the same amount of another active substance can also be used according to the above-mentioned examples, such as e.g. the sodium salt of (5R,6S)-2-((2R,S)-2-(pyrrol-1-yl)-prcp-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid.

Claims (8)

1. Process for the preparation of 2-heterocyclyl-lower alkyl-2-penem compound of the formula where R.j is lower alkyl substituted with a hydroxy or protected hydroxy, R2 means carboxyl or functional, converted carboxyl, Rg means an unsaturated, monocyclic azaheterocyclyl-rect. which is attached to the residue -A- over a tertiary ring nitrogen atom and A means straight chain lower alkyl, which is substituted by lower alkyl, optical isomers of compounds of the formula (I), mixtures of these optical isomers and salts of such compounds of the formula (1^ as contains a salt-forming group, characterized by ring-closing a ylide compound with the formula where R^ , R^ and A have the meanings indicated under formula (I), R' means a protected carboxyl group, Z means oxygen or sulfur and X means either a triply substituted phosphonio group or a doubly esterified phosphono group together with a cation, or one treats a for- bond with the formula where R^ , R^ and A have the meanings indicated under formula (I), and R^ means a protected carboxyl group, with an organic compound of trivalent phosphorus, or one reacts a compound with the formula where R.j , R^ and A have the meanings indicated under formula (I), and Q means a reactive esterified hydroxy group, with an agent which introduces an azaheterocyclyl residue R^, and, if desired or necessary, transfers in a mixed compound with the formula (I) a protected hydroxy group in the residue R^ in the free hydroxy group and/or, if desired, transfers in a formed compound with the formula (I) a protected carboxyl group R^ in the free, in a cleavable esterified carboxyl group under physiological conditions or in another protected carboxyl group, and/or, if desired, transfer a free carboxyl group R£ in a cleavable under physiological conditions for esterified carboxyl group, and/or if desired, transfer further protected, functional groups contained in the residue R^ into the free functional groups, and/or, if desired, transfer in a formed compound with the formula (I) a residue R^ in another residue R^ , and/or if desired, transfers a formed compound with salt-forming groups in a salt or a formed salt in the free compound or in another salt, and/or, if desired, splits a formed mixture of isomeric compounds to the individual isomers. 2. Process for preparing compounds of formula I according to claim 1, where R 1 is lower alkyl substituted with hydroxy or protected hydroxy, R 2 means carboxyl, under physiological conditions cleavable esterified carboxyl or protected carboxyl. R R^ means an optionally partially saturated 5-membered neteroaryl residue with 1-4 ring nitrogen atoms which is bound to the residue -A- via a tertiary ring nitrogen atom, as a corresponding aza-, diaza-, triaza- or tetraza-cyclic residue of an aromatic character or a corresponding dihydro residue, or a corresponding partial, saturated, 6-membered heteroaryl residue with 1-3 ring nitrogen atoms, such as a corresponding aza-, diaza- or triaza-cyclic residue, e.g. a corresponding dihydro or tetrahydro residue, whereby these residues are unsubstituted or substituted with hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxyl lower alkyl, lower carboxy lower alkyl, carboxy lower alkyl, amino lower alkyl, di lower alkyl amino lower alkyl, sulfola lower alkyl, amino, lower alkyl amino, dilower alkylamino, lower alkyleneamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, optionally N-mono- or N,N-dilower alkylated carbamoyl, cyano. sulfo, sulfamoyl, optionally with a lower alkyl, nitro, lower alkoxy and/or halogen substituted phenyl, cycloalkyl, nitro, oxo and/or oxido and A means the straight chain lower alkyl substituted with lower alkyl, of optical isomers of compounds of formula I, of mixtures of these optical isomers and salts of compounds of formula I containing a salt-forming group. 3. Process for the preparation of compounds of formula I, according to patent claim 1, where R^ is lower alkyl substituted with hydroxy or trilower alkylsiloxy, R^ means carboxyl, lower alkenyloxycarbonyl, possibly benzyloxycarbonyl, 2-trilaverealKylsilylethoxycarbonyl which is substituted with nitro, or a cleavable esterified carboxyl group under physiological conditions, e.g. 1-lower oxycarbonyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, α-aminoloweralkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, R^ means unsubstituted or with a lower alkyl or halogen substituted pyrrolyl, which is attached to the residue -A- via a tertiary ring nitrogen atom, e.g. 1-pyrrolyl, unsubstituted with a lower alkyl, substituted imidazolyl or pyrazolyl, e.g. 1-imidazolyl or 1-pyrazolyl, unsubstituted triazolyl or triazolyl substituted with a lower alkyl, carboxy lower alkyl or phenyl, e.g. 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2 -yl, 1H-1,2,4-triazol-1-yl or 1H-1,3,4-triazol-1-yl, unsubstituted tetrazolyl or tetrazolyl substituted with a lower alkyl, carboxy lower alkyl, sulfola lower alkyl, di lower alkyl amino lower alkyl, amino or optionally phenyl , substituted with a haloene such as 1H-tetrazol-1-yl or 2H-tetrazol-2-yl, unsubstituted dihydro-1-pyridyl, or dihydro-1-pyridyl substituted with oxo and optionally further with a halogen, e.g. 2H-1,2-dihydro-1-pyridyl or 4H-1,4-dehydro-1-pyridyl, unsubstituted dihydro-1-pyrimidyl or dihydro-1-pyrimidyl substituted with oxo and optionally further with lower alkyl, amino, dilower alkylamino or carboxy , e.g. 2H-1,2-dihydro-1-pyrimidyl or 4H-1,4-dihydro1-pyrimidyl, or unsubstituted dihydro- or tetrahydrotriazinyl, or dihydro- or tetrahydrotriazinyl substituted with a lower alkyl and/or up to 2.oxo, e.g. 2H-1,2-dihydro-1,3,5-triazin-1-yl, 2H-1,2-dihydro-1,2,4-triazin-1-yl, 2H-1,2,5,6- tetrahydro-1,2,4-triazin-1-yl or 4H-1,4,5,6-tetrahydro-1,2,4,triazin-1-yl, and A means straight chain lower alkyl substituted with lower alkyl, of optical isomers of compounds of formula I, of mixtures of these optical isomers and salt, especially pharmaceutically acceptable salts of such compounds of formula II, which contain a salt-forming group. 4. Process for the preparation of compounds of formula I according to patent claim 1, where R^ is a lower alkyl substituted with a hydroxy, R2 means carboxyl 1-lower oxycarbonyloxycarbonyl or lower alkanoyloxymethoxycarbonyl, R^ means pyrrolyl, imidazolyl bound to the residue -A- over a tertiary nitrogen atom, e.g. 1-imidazolyl, 1H-triazolyl, e.g. 1H-1,2,4-triazol-1-yl, or unsubstituted 1H-tetrazolyl or 1H-tetrazolyl substituted with amino, carboxyl lower alkyl, sulfolaverealkyl or diloweralkylaminoloweralkyl, e.g. 1H.tetrazol-1-yl or 2H-tetrazol-2-yl, and A means the lower alkylene of 1-4 carbon atoms which is mono- or di-substituted with lower alkyl of 1-2 carbon atoms, of optical isomers of compounds of formula I, e.g. (5R ,6S)) isomers, of mixtures of these optical isomers, and of pharmaceutically acceptable salts of such compounds of formula I, which contain a salt-forming group. 5. Process for the preparation of (5R,6S)-configured compounds of formula I according to patent claim 1, where means hydroxymethyl or 1-hydroxyethyl, R2 is carboxyl, R3 means pyrrol-1-yl, or 1H-tetrazol- 1-yl and A is 1,2-propylene, and of pharmaceutically acceptable salts thereof. 6. Process for the production of (5R,6S)-2-((2R,S)-2-(pyrrol-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid and of pharmaceutically acceptable salts thereof, according to patent claim 1. 7. Process for the preparation of (5R,6S)-2-((2R,S)-2-(tetrazol)-1-yl)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid and of pharmaceutically acceptable salts thereof, according to patent claim 1. 8. Process for the production of pharmaceutical preparations, characterized by mixing a compound with the formula I or by a pharmaceutically acceptable salt of such a compound formed according to the method according to patent claim 1, with a pharmaceutically acceptable carrier material.