NZ208055A - Amino-lower alkyl penem compounds and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £08055 208055 • Priority Date(s) Complete Speci.'icatior! Fi!.:>d: ^9. lass: Publication Date: P.O. J~urnr>! No: £3 JAN 1987; lift re*# N.z. pat r -4 MAY 1984 Patents Form No. 5 1 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Amino-lower alkylpenem compounds, processes for their manufacture, pharmaceutical preparations that contain these compounds, and the use of the latter" WE, CIBA-GEIGY AG of Klybeckstrasse 141, 4002 Basle, Switzerland, a Swiss Corporation, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement ffolfowei by T A.} ./ £ 055 - 1«T o 4- 144 17/1 + 2/- Amino-lower alkylpenem compounds, processes for their manufacture, pharmaceutical preparations that contain these compounds, and the use of the latter.

The present invention relates to novel 2-amino-lower alkylpenem compounds, to processes for their manufacture, to pharmaceutical preparations that contain such compounds, and to their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

The invention relates especially to 2-amino- lower alky1-2-penem compounds of the formula (I) R 2 203 0 in which R-| represents lower alkyl substituted by hydroxy or by protected hydroxy, R2 represents carboxy or protected carboxy *2'' R3 represents amino, lower alkyl-substituted amino, substituted methyleneamino or protected amino, and A represents straight-chain lower alkylene substituted by lower alkyl, with the proviso that R-) is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A is straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, and to salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I and mixtures of these optical isomers, processes for the manufacture of compounds of the formula I, pharmaceutical preparations containing such compounds, and their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

Within the scope of the present description, the definitions used hereinbefore and hereinafter have preferably the following meanings: Lower alkyl-substituted amino R3 is, for example, lower alkylamino or di-lower alkylamino.

In substituted methyleneamino, the methylene radical is preferably mono- or di-substituted. Substituted methyleneamino is, for example, a group of the formula o J U ° J 1 • i i . i \ * I i i 208 055 - N = C X, (IA) in which X-) represents hydrogen, optionally substituted amino, for example amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, for example lower alkoxy or phenyl-lower alkoxy, etherified mercapto, for example lower alkylthio, optionally substituted lower alkyl, for example lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl or N,N-di-lower alkylamino-lower ajkyl, lower alkenyl, phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl having 1 or 2 nitrogen atoms and/or an oxygen or sulphur atom, such as pyridyl, for example 2- or 4-pyridyl, thienyl, for example 2-thienyl, or thiazolyl, for example 4-thiazolyl, and X2 represents optionally substituted amino, for example amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, for example lower alkoxy or phenyl-lower alkoxy, or etherified mercapto, for example lower alkylthio.

In preferred radicals of the formula (IA) , X-j represents hydrogen, amino, lower alkylamino or lower alkyl and X2 represents amino.

Radicals of the formula (IA) that have a hydrogen atom at the a-atom of the substituent X-j or the substituent X2, for example radicals of the formula (IA) in which X-j represents amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower .alkyl and/or X2 represents amino, lower alkylamino, hydrazino or anilino, can also be in the tautomeric forms 1 -1 o J <0 O 20S C-55 ' x-, 1 / 1 -NH - C -NH-C \ X *2 2 (IB) or (IC) in which X-j' and X2 ' each represents corresponding substituted or unsubstituted methylene or imino.

In the present description, the term "lower" used in connection with definitions of groups and compounds /: denotes that, unless expressly defined otherwise, the groups and compounds so designated contain up to 7, | preferably up to 4, carbon atoms.

^ Hydroxy-substituted lower alkyl is especially j * lower alkyl substituted by hydroxy in the a-position relative to the penem ring structure and represents, | for example, 1-hydroxyprop-1-yl, 2-hydroxyprop-2-yl, 1-hydroxybut-1-yl, 2-hydroxybut-2-yl or, especially, hydroxymethyl or 1-hydroxyethyl.

Lower alkylamino is, for example, methylamino, ethylamino, n-propylamino, isopropylamino or n-butyl-amino, whilst di-lower alkylamino represents, for example, dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino.

Lower alkyleneamino has especially from 4 to 6 carbon chain members and represents, for example, pyrrolidino or piperidino.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy, whilst phenyl-lower alkoxy represents, for example, benzyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or 20s 05 O O tert.-butyl.

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

N-lower alkylamino-lower alkyl is, for example, 2-methyl- or 2-ethyl-aminoethyl, whilst N,N-di-lower alkylamino-lower alkyl represents, for example, 2-di-methylaminoethyl or 2-diethylaminoethy1.

Lower alkenyl is, for example, allyl, n-propenyl or isopropenyl.

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

Such a radical A is, for example, lower alkylidene, such as ethylidene ("methylmethylene"), 1,2-propylene, 2-lower alkyl-1,2-propylene, such as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl-1,2-butylene, such as 2-methyl- or 2-ethyl-1,2-butylene, 3-lower alkyl-1,2-butylene, such as 3-methyl-1,2-butylene, 1,3-butylene, 2-lower alkyl-1,3-butylene, such as 2-methyl-1, 3-butylene , 3-lower alkyl-1,3-butylene, such as 3-methyl-1,3-butylene, or 2,2-di-lower alkyl-1,3-butylene, such as 2,2-dimethyl-1,3-butylene, the 1-carbon atom in these radicals being bonded to the penem ring structure, or alternatively 1,2-propylene, 2-lower alkyl-1,2-propylene, such as 2- o methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl-1,2-butylene, such as 2-methyl- or 2-ethyl-1,2-butylene, 3-lower alkyl-1,2-butylene, such as 3-methyl-1,2-butylene, or 3,3-di-lower alkyl-1,2-butylene, such as 3,3-dimethyl-1,2-butylen.e, the 2-carbon atom in these radicals being bonded to the penem ring structure. Preferred radicals A are 1,2-propylene, 1,2-butylene, 1,3-butylene and 2-methyl-1,2-propylene bonded via the 1-carbon atom to the penem ring structure, and 1,2 propylene bonded via the 2-carbon atom to the penem ring structure.

The functional groups present in compounds of the formula I, such as hydroxy, carboxy or amino groups, especially the hydroxy group in the radical R-j, the carboxy group R2 and an amino group R^, are optionally protected by conventional protecting groups used in penem, penicillin, cephalosporin and peptide chemistry.

Such protecting groups can be removed readily, that is to say without undesirable secondary reactions taking place, for example by means of solvolysis or reduction, or alternatively under physiological condi tions.

Protecting groups of this type and the methods by which they are introduced and removed are described, « for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry Plenum Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1981, "The Peptides", Vol. I, Schroeder und 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 the formula (I), a hydroxy group \ 206 3 in the radical R-j may be protected, for example, by acyl radicals. Suitable acyl radicals are, for example, lower alkanoyl optionally substituted by halogen, for example acetyl or trifluoroacetyl, benzoyl optionally substituted by nitro, for example benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, lower alkoxycarbonyl optionally substituted by halogen, for example 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, or phenyl-lower alkoxycarbonyl optionally substituted by nitro,. for example 4-nitrobenzyloxycarbonyl.

Further suitable hydroxy-protecting groups are, for example, tri-substituted silyl, such as tri-lower alkylsilyl, for example trimethylsilyl or tert.-butyl-dimethylsilyl, 2-halo-lower alkyl groups, for example 2-chloro-, 2-bromo-, 2-iodo- and 2,2,2-trichloro-ethyl, and phenyl-lower alkyl optionally substituted by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or by nitro, such as corresponding benzyl. The tri-lower alkylsilyl group is preferred as hydroxy-protecting group.

A carboxy group R2 is customarily protected in esterified form, the ester group being readily cleav-able under mild conditions, for example under mildly reductive, such as hydrogenolytic, conditions, or under mildly solvolytic, such as acidolytic or especially basic or neutral hydrolytic, conditions. A protected carboxy group R2' can especially also be an esterified carboxy group that can be cleaved under physiological conditions or can readily be converted into a different functionally modified carboxy group, such as into a different esterified carboxy group.

Such esterified carboxy groups R21 contain as esterifying groups especially lower alkyl groups that are branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxy groups in 2 or o esterified form are, inter alia, lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, iso-propoxycarbonyl or tert.-butoxycarbony1, and (hetero)arylmethoxycarbonyl having from 1 to 3 aryl radicals or having a monocyclic heteroaryl radical, these optionally being mono- or poly-substituted, for example by lower alkyl, such as tert.-lower alkyl, for example tert.-butyl, halogen, for example chlorine, and/or by nitro. Examples of such groups are benzyloxycarbonyl optionally substituted, for example, as mentioned above, for example 4-nitrobenzyloxy-carbonyl, diphenylmethoxycarbonyl or triphenylmethoxy-carbonyl optionally substituted, for example, as mentioned above, for example diphenylmethoxycarbonyl, or picolyloxycarbonyl, for example 4-picolyloxy-carbonyl, or furfuryloxycarbonyl, such as 2-furfuryl-oxycarbonyl, each optionally substituted, for example, as mentioned above. Further suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group preferably represents benzoyl optionally substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, halo-lower alkoxycarbonyl, such as 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarfconyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbony1 or 2-iodoethoxycarbonyl, or w-halo-lower alkoxycarbonyl in which lower alkoxy contains from 4 to 7 carbon atoms, for example 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, for example allyloxycarbonyl, or ethoxycarbonyl substituted in the 2-position by lower alkylsulphonyl, cyano or by tri-substituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, for example 2-methylsulphonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methy1- o A -J 2Or 05 5 silyl)-ethoxycarbonyl.

Other protected carboxy groups R2' in esterified form are corresponding organic silyloxycarbonyl groups, and also corresponding organic stannyloxycarbonyl groups. In these groups the silicon or tin atom preferably has lower alkyl, especially methyl or ethyl, and also lower alkoxy, for example methoxy, as substi-tuents. Suitable silyl and stannyl groups are especially tri-lower alkylsilyl, especially trimethyl-silyl or dimethyl-tert.-butylsilyl, or correspondingly substituted stannyl groups, for example tri-n-butyl-stannyl.

An esterified carboxy group R21 that can be cleaved under physiological conditions is especially an acyloxymethoxycarbonyl group in which acyl represents, for example, the radical of an organic carboxylic acid, especially of an optionally substituted lower alkane-carboxylic acid, or in which acyloxymethyl forms the radical of a lactone, 1-lower alkoxy-lower alkoxycarbonyl or alternatively 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl in which lower alkyl represents, for example, methyl, propyl, butyl or, especially, ethyl, and lower alkoxy represents, for example, methoxy, propoxy or butoxy. Such groups are, for .*»% example, lower alkanoyloxymethoxycarbonyl, for example acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, for example glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, 4-crotonolactonyl or 4-butyrolacton-4-yl, indanyloxy-carbonyl, for example 5-indanyloxycarbonyl, 1-ethoxy-carbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Preferred protected carboxy groups R3' are the f* i 4-nitrobenzyloxycarbonyl and lower alkenyloxycarbonyl groups and the ethoxycarbonyl group substituted in the 2-position by lower alkylsulphonyl, cyano or tri-lower alkylsilyl, and especially the esterified carboxy groups that can be cleaved under physiological conditions, such as, for example, lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl.

A protected amino group can be, for example, in the form of a readily cleavable acylamino, acylimino, etherified mercaptoamino, silylamino or stannylamino group or in the form of an enamino, nitro or azido group.

In a corresponding acylamino group, acyl is, for example, the acyl radical of an organic acid having, for example, up to 18 carbon atoms, especially an alkanecarboxylic acid optionally substituted, for example, by halogen or phenyl, or of a benzoic acid optionally substituted, for example, by halogen, lower alkoxy or nitro, or of a carbonic acid semiester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, optionally substituted benzoyl, for example benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxy-benzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. Especially suitable are also lower alkenyloxycarbonyl, for example allyloxycarbonyl, or lower alkoxycarbonyl optionally substituted in the 1- or 2-position, such as lower alkoxycarbonyl, for example methoxy- or ethoxy-carbonyl, optionally substituted benzyloxycarbonyl, for example benzyloxy-carbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxy-carbonyl in which the aroyl group preferably represents 2 0 Q n benzoyl optionally substituted, for example, by halogen, such as bromine, for example phenacyloxy-carbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbony1 or 2-iodoethoxycarbonyl, or 2-(tri-substituted silyl)-ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl radical of an organic dicarboxylic acid having, for example, up to 12 carbon atoms, especially of a corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is especially phthalimino.

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

A silyl- or stannyl-amino group is especially an organic silyl- or stannyl-amino group in which the silicon or tin atom preferably contains as substituent (s) lower alkyl, for example methyl, ethyl, n-butyl or tert.-butyl, also lower alkoxy, for example methoxy. Corresponding silyl or stannyl groups are especially tri-lower alkylsilyl, especially trimethyl-silyl, also dimethyl-tert.-butylsilyl, or correspondingly substituted stannyl, for example tri-n-butyl-stannyl.

Further protected amino groups are, for example, enamino groups that contain an electron-attracting 203 0 substituent, for example a carbonyl group, at the double bond in the 2-position. Protecting groups of this type are, for example, 1-acyl-lower alk-l-en-2-yl radicals in which acyl represents, for example, the corresponding radical of a lower alkanecarboxylic acid, for example acetic acid, of a benzoic acid optionally substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid-lower alkyl semiester, for example a carbonic acid methyl semiester or ethyl semiester, and in which lower alk-l-ene represents especially 1-propene. Corresponding protecting groups are especially 1-lower alkanoylprop-1-en-2-yl, for example 1-acetylprop-1-en-2-y1, or 1-lower alkoxycarbonylprop-1 en-2-yl, for example 1-ethoxycarbonylprop-l-en-2-yl.

Preferred protected amino groups are, for example, azido, phthalimino, nitro, lower alkenyloxycarbonyl-amino, optionally nitro-substituted benzyloxycarbonyl-amino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino.

Salts of compounds according to the invention are especially pharmaceutical^ acceptable, non-toxic salts of compounds of the formula I. Such salts are formed, for example, from compounds of the formula I in which I?2 represents carboxy and are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2- 208 0 diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example NrN1-dibenzylethylenediamine, dibenzylamine or N-benzyl-R-phenethylamine. Compounds of the formula I having a basic group, for example having an amino group, can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylie or sulphonic acids, for example acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulphonic acid or 4-toluenesulphonic acid. Compounds of the formula I having an acidic group and a basic group can also be in the form of internal salts, that is to say in zwitterionic form.

For the purposes of isolation or purification it is also possible to use pharmaceutical^ unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and these are therefore preferred.

The penem compounds of the formula I have the R-configuration at the 5-carbon atom and the S_-configur-ation at the 6-carbon atom. The compounds of the formula I can have further chirality centres in the substituents R-j and/or A, each of which can be in the R-, £- or the racemic R,S_-configuration. In compounds of the formula I in which R-j represents lower alkyl that has from 2 to 7 carbon atoms and is asymmetrically substituted in the a-position (at the 1'-carbon atom) by hydroxy, especially 1'-hydroxyethyl, the substituents at the I'-carbon atom preferably assume the Reconfiguration.

The invention relates especially to compounds of 208 0 the formula I in which represents lower alkyl substituted by hydroxy or by protected hydroxy, R2 represents carboxy or protected carboxy R2' , R3 is amino, lower alkylamino, di-lower alkylamino, a group of the formula -N=C(X-j,X2) in which X1 represents hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, lower alkenyl, phenyl, pyridyl, for example 2- or 4-pyridyl, thienyl, for example 2-thienyl, or thiazolyl, for example 4-thiazoiyi, and X2 represents amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio; or R3 is protected amino, and A represents straight-chain lower alkylene substituted by lower alkyl having from 1 to 4 carbon atoms, with the proviso that R^ is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, and to salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I that have chirality centres in the radicals R-j and/or A, and mixtures of these optical isomers.

The invention relates more especially to compounds of the formula I in which represents lower alkyl substituted by hydroxy, tri-lower alkylsilyloxy, 2-halo-lower alkoxy, 2-haio-lower aikoxycarbonyloxy or by optionally nitro-substituted phenyl-lower aikoxycarbonyloxy, R2 represents carboxy, lower alkenyloxycarbonyl, optionally nitro-substituted benzyioxy- 208 0 carbonyl, lower alkanoylmethoxycarbonyl, 2-haio-lower alkoxycarbonyl, 2-tri-lower alkylsiiyiethoxycarbonyl or an esterified carboxy group that can be cleaved under physiological conditions, for example 1-lower alkoxy-carbonyloxy-lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, a-amino-.lower alkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, Rj is amino, lower alkylamino, di-lower alkylamino, a group of the formula -N=C(X<|,X2) w^ich X-j represents hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, for example 2-pyridyl, and X2 represents amino, lower alkylamino or di-lower alkylamino; or R3 is azido, phthalimino, nitro, lower aikenyloxycarbonyl-amino, optionally nitro-substituted benzyloxycarbonyl-amino, 1-lower aikanoyl-lower alk-1-en-2-ylamino or 1-lower aikoxycarbonyl-lower alk-1-en-2-ylamino, and A represents straight-chain lower alkylene mono- or di-substituted by lower alkyl having from 1 to 4 carbon atoms, with the proviso that R<| is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, and to salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I that have, chirality centres in the radicals R.j and/or A, and mixtures of these optical isomers.

The invention relates more especially to compounds of the formula I in which R^ represents lower alkyl substituted by hydroxy and A represents straight-chain lower alkylene that has from 1 to 4 carbon atoms and is mono-substituted by methyl or ethyl, or in which R-| represents hydroxymethyl and A represents straight-chain lower alkylene that has from 1 to 4 carbon atoms and is di-substituted by methyl or ethyl, 20a c and in which R2 in each case represents carboxy, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl or lower alkanoyloxymethoxycarbonyl, and R3 in each case represents amino, lower alkylamino or formamidino, and to salts of such compounds of the formula I, optical isomers of compounds of the formula I that have chirality centres in the radicals R1 and/or A, and mixtures of these optical isomers.

The invention relates above all to compounds of the formula I in which R^ represents hydroxymethyl or 1-hydroxyethyl and A represents ethylene or 1,3-propyl ene each of which is mono-substituted by methyl or ethyl, or in which R-j represents hydroxymethyl and A represents ethylene di-substituted by methyl, and in which R2 in each case represents carboxy and R3 in each case represents amino, and to salts of such compounds of the formula I.

The invention relates also to the pure optical isomers of those compounds of the formula I that have further chirality centres in the substituents R^ and/or A, especially the (1 '!*)-isomer of compounds of the formula I in which R-j represents 1'-hydroxyethyl, and to salts of such compounds of the formula I.

The invention relates especially to the compounds of the formula I mentioned in the Examples and to the salts thereof.

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

The novel compounds are manufactured, for example as follows: a) an ylide compound of the formula 208 0 S-C-A-R, / (II) ■N -C © -X © R2* in which R^, R2' and A have the meanings given under formula I, Z represents oxygen or sulphur and represents either a tri-substituted phosphonio group, or a di-esterified phosphono group together with a cation, is cyclised, or b) a compound of the formula R. S—C—A—R_ A " \ r s I (in) N 0-^ ^-C=0 I. 2 in which R^, R2'f R3 and A have the meanings given under formula I, is treated with an organic compound of trivalent phosphorus, and, if desired or necessary, in a resulting compound of the formula I, a protected hydroxy group in a radical R^ is converted into the free hydroxy group, and/or, if desired, in a resulting compound of the formula I, a protected carboxy group R2' is converted into the free carboxy group or into a different protected carboxy group R21' a free carboxy group R2 is converted into a protected carboxy group R2', and/or, if desired, a protected amino group R^ is 208 05 converted into the free amino group, or a free amino group R3 is converted into a substituted amino group, and/or, if desired, a resulting compound having a salt-forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting mixture of isomeric compounds of the formula I is separated into the individual isomers.

In starting compounds of the formulae (II) and (III), functional groups, such as a free hydroxy group in the radical R^, and especially a free amino group R3, are preferably protected by conventional protecting groups, for example by one of those mentioned above. a) Cyclisation of the compound of the formula II The group >@in a starting material of the formula II is one of the phosphonio or phosphono groups customarily used in Wittig condensation reactions, especially a triaryl-, for example triphenyl- , or tri-lower alkyl-, for example tri-n-butyl-phosphonio group, or a phosphono group di-esterified by lower alkyl, for example ethyl, the symbol $ in the case of the phosphono group including in addition the cation of a strong base, especially a suitable metal ion, such as an alkali metal ion, for example a lithium, sodium or potassium ion. Preferred as the group X® is, on the one hand, triphenylphosphonio and, on the other hand, diethylphosphono together with an alkali metal ion, for example a sodium ion.

The ylide compounds of the formula II are, in the isomeric ylene form, also termed phosphorane compounds. In phosphonio compounds of the formula II, the negative charge is neutralised by the positively 2CS ( charged phosphonio group. In phosphono compounds of the formula II, the negative charge is neutralised by the cation of a strong base, which, depending upon the method of manufacture of the phosphono starting material, may be, for example, an alkali metal ion, for example a sodium, lithium or potassium ion. The phosphono starting materials are therefore used as salts in the reaction.

Cyclisation may take place spontaneously, that is to say in the manufacture of the starting materials, or be effected by heating, for example in a temperature range of approximately from 30° to 160°C, preferably from approximately 50° to approximately 100°C. The reaction is preferably carried out in a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, for example hexane or benzene, a halogenated hydrocarbon, for example methylene chloride, an ether, for example diethyl ether, a carboxylic acid amide, for example dimethylformamide, a di-lower alkyl sulphoxide, for example dimethyl sulphoxide, or a lower alkanol, for example methanol, or in a mixture thereof, and, if necessary, in an inert gas atmosphere, for example a nitrogen atmosphere. b) Cyclisation of the compound of the formula III An organic compound of trivalent phosphorus is derived, for example, from phosphorous acid and is especially an ester thereof with a lower alkanol, for example methanol or ethanol, and/or an optionally substituted aromatic hydroxy compound, for example phenol or pyrocatechol, or an amide ester thereof of the formula P (ORa)2-N(Rb)2 in which each of Ra and Rb, independently of the other, represents 2OSOSS lower alkyl, for example methyl, or aryl, for example phenyl. Preferred compounds of trivalent phosphorus are tri-alkyl phosphites, for example trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent, such as an aromatic hydrocarbon, for example benzene or toluene, an ether, for example dioxan or tetrahydrofuran; or a halogenated hydrocarbon, for example methylene chloride or chloroform, at a temperature of from approximately 20° to approximately 80°C, preferably at from approximately 40° to approximately 60°C, one molar equivalent of a compound of the formula III being reacted with two molar equivalents of the phosphorus compound. Preferably, the compound of the formula III is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a prolonged period, for example over a period of from 2 to 4 hours.

In a preferred embodiment of the process, the starting material of the formula III is manufactured in situ as described hereinbelow under step 1.5 and, without being isolated from the reaction mixture, is reacted with the organic compound of trivalent phosphorus, the end products of the formula I being formed.

It is preferable to use those starting materials of the formulae II and III which result in the compounds of the formula I mentioned at the beginning as being especially preferred.

In a resulting compound of the formula I in which one or more functional groups are protected, these groups, for example protected amino, carboxy or hydroxy groups, may be freed, optionally in stages or simultaneously, in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or 208055 acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction.

In a compound of the formula I obtainable according to the invention having a protected amino group R3, this group may be converted into the free amino group R3 in a manner known per se, for example, depending on the nature of the protecting group, preferably by means of solvolysis or reduction. For example, 2-halo-lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid, or by catalysis with hydrogen in the presence of a palladium catalyst. Aroylmethoxycarbonylamino may be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino may be cleaved also by treatment with an alkali metal dithionite, for example sodium dithionite. Optionally substituted benzyloxycarbonylamino may be cleaved, for example, by means of hydrogenolysis, that is to say 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, for example tetrakis(triphenylphosphine)-palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, for example 2-ethylhexanoic acid, or with a salt thereof. An amino group protected by an organic silyl or stannyl group can be freed, for example, by means of hydrolysis or alcoholysis, and an amino group protected by 2-halo- 20b 35 5 lower alkanoyl, for example 2-chloroacety1, can be freed 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 resulting ^ condensation product. An amino group protected by 2- ' I "" substituted silylethoxycarbonyl can be converted into ' the free amino group by treatment with a salt of hydrofluoric acid that yields fluoride anions, such as an alkali metal fluoride, for example sodium fluoride, ^ in the presence of a macrocyclic polyether ("Crown ' i ( ether") or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride, for example tetraethylammonium fluoride. An amino group protected in the form of an azido or nitro group is " converted into free amino, for example by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide or palladium, or by treatment with zinc in the presence of an acid, such as acetic acid. An amino group protected in the form of a phthalimido group can be converted into the free amino group by reaction with hydrazine. Furthermore, an arylthioamino group can be converted into amino by treatment with a nucleophilic reagent,- such as sulphurous acid.

Also, a free amino group can be converted in a manner known per se into a substituted amino group. Thus, for example, amino can be converted by reaction with a corresponding acyl halide, such as a chloride, »into acylamino R^, and with a fl-dicarbonyl compound, such as a 1-lower alkanoylacetone or an acetoacetic acid lower alkyl ester, into 1-lower alkanoyl- or 1-lower alkoxycarbonylprop-1-en'-2-yi-amino. The conversion of amino groups into amidino, guanidino, isourea, isothiourea, imidoether and imidothioether \ wL ) 1 208055 groups can be carried out, for example, in accordance with one of the processes mentioned in New Zealand Patent No. 182,630. Thus, for example, compounds of the formula I in which R3 represents amino can be converted into amidines by reaction with trimethylsilyl chloride and an imidohalide of the '-n formula I (X1, Y ^) C=X2 ] ® Y® in which Y^ represents halogen, for example chlorine, and Y2 represents an anion, for example chloride, and into guanidines by reaction with a substituted isourea or isothiourea of the formula (X.jY3)C=X2 in which Y3 represents lower j—s, alkoxy or lower alkylthio. Furthermore, a free amino group Rj can be converted into an amino group mono-or di-substituted by lower alkyl. The introduction of the lower alkyl group(s) is effected, for example, by reaction with corresponding reactive lower alkyl esters, such as halides, for example chlorides or bromides, or sulphonates, for example methane-sulphonates or £-toluenesulphonates, in the presence of a basic condensation agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alkanol, at room temperature or at elevated or reduced temperature, for example at approximately from -20° to +80°C.

In a compound of the formula I obtainable according to the process in which R2 represents a protected carboxy group R2'» the carboxy group can be freed in a manner known per se.

Thus, tert.-lower alkoxycarbonyl, or lower alkoxy-carbonyl substituted in the 2-position by a tri-subs-tituted silyl group or in the 1-position by lower alkoxy, or optionally substituted diphenylmethoxy-carbonyl can be converted into free carboxy, for example, by treatment with a carboxylic acid, such as'r'v ^ v I* 208 05 formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole. Optionally substituted benzyloxycarbonyl can be cleaved, for example, by means of hydrogen-olysis, that is to say by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxy-carbonyl, can also be converted into free carboxy by means of chemical reduction, for example by treatment with an alkali metal dithionite, for example sodium dithionite, or with a reducing metal, for example tin, or a reducing metal salt, such as a chromium(II) salt, for example chromium(II) chloride, customarily in the presence of a hydrogen-yielding agent that together with the metal is capable of producing nascent hydrogen, such as a suitable carboxylic acid, for example a lower alkanecarboxylic acid optionally substituted, for example, by hydroxy, for example acetic acid, formic acid or glycolic acid, or an alcohol or thiol, it being preferable to add water. The removal of an allyl protecting group can be effected, for example, by reaction with a palladium compound, for example tetra-kis(triphenylphosphine)-palladium, in the presence of triphenylphosphine .and with the addition of a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof. By treatment with a reducing metal or metal salt, as described above, it is also possible to convert 2-halo-lower alkoxycarbonyl (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxy, it being possible to cleave aroylmethoxycarbonyl likewise by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 208 05 Substituted 2-silylethoxycarbonyl can be converted into free carboxy also by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium fluoride, in the presence of a macrocyclic polyether ("Crown ether") or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride, for example tetrabutylammonium fluoride. Carboxy esterified by an organic silyl or stannyl group, such as tri-lower alkylsilyl or tri-lower alkylstannyl, can be freed in customary manner by solvolysis, for example by treatment with water or an alcohol. A lower alkoxycarbonyl group substituted in the 2-position by lower alkyl-sulphonyl or cyano can be converted into free carboxy, for example, by treatment with a basic agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or sodium or potassium carbonate.

In compounds of the formula I obtainable according to the process in which the radical R-j is substituted by protected hydroxy, the protected hydroxy group can be converted into the free hydroxy group in a manner known per se. For example, a hydroxy group protected by a suitable acyl group or by an organic silyl or stannyl group is freed in the same manner as a correspondingly protected amino group: for example a tri-lower alkylsilyl group may be removed with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by tri-substituted silylethyl groups are not cleaved). A 2-halo-lower alkyl group and an optionally substituted benzyl group are removed by reduction.

On the other hand, also compounds of the formula I in which R2 represents carboxy can be converted into compounds of the formula I in which R2 represents a 2080 protected carboxy group especially an esterified carboxy group and more especially an esterified carboxy group that can be cleaved under physiological conditions. Thus, the free carboxy group can be esterified, for example, by treatment with a suitable diazo compound, such as a diazo-lower alkane, for example diazomethane, or a phenyldiazo-lower alkane, for example diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as, for example, boron trifluoride, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, for example dicyclohexyl carbodiimide, and carbonyldiimidazole. Esters can also be manufactured by reaction of a salt of the acid, which salt is optionally produced iji situ, with a reactive ester of an alcohol and a strong inorganic acid, such as sulphuric acid, or a strong organic sulphonic acid, such as 4-toluenesulphonic acid. Furthermore, acid halides, such as chlorides (manufactured, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with N-hydroxynitrogen compounds, such as N-hydroxy-succinimide), or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl esters, such as chloroformic acid -ethyl ester or chloroformic acid isobutyl ester, or with haloacetic acid halides, such as trichloroacetyl chloride) can be converted into esterified carboxy groups by reaction with alcohols, optionally in the presence of a base, such as pyridine.

In a compound of the formula I having an esterified carboxy group R2', this group can be converted into a different esterified carboxy group R2*: for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl may be converted by treatment with an iodine salt, for example sodium iodide, into 2-iodoethoxycarbonyl. 208 05 Furthermore, in compounds of the formula I that contain a carboxy group R2 1 protected in esterified form, the carboxy-protecting group can be removed as described above, and a resulting compound of the formula I having a free carboxy group or a salt thereof can be converted by reaction with the reactive ester of a corresponding alcohol into a compound of the formula I in which R2 represents an esterified carboxy group that can be cleaved under physiological conditions.

Salts of compounds of the formula I having (""•i, salt-forming groups may be manufactured in a manner known per se. Thus, salts of compounds of the formula I having a free carboxy group R2 can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of a-ethyl-caproic acid, or with inorganic alkali metal or alkaline earth metal salts, for example sodium bicarbonate, or with ammonia or with a suitable organic amine, it being preferable to use stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in customary manner, for example by ' treatment with a suitable acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion exchangers.

C3 Salts can be converted into the free compounds in customary manner; metal and ammonium salts, for example by treatment with suitable acids, and acid addition salts, for example by treatment with a suitable basic agent.

Resulting mixtures of isomers can be separated 20305 into the individual isomers according to methods known per se; mixtures of diastereoisomeric isomers, for example by fractional crystallisation, adsorption chromatography (column or thin-layer chromatography) or other suitable separating processes.

The cleaving of resulting racemates into their optical antipodes can be effected in various ways.

One of these ways comprises allowing a racemate to react with an optically active auxiliary, separating the resulting mixture of two diastereoisomeric compounds with the aid of suitable physico-chemical methods and then cleaving the individual diastereoisomeric compounds into the optically active compounds.

Racemates that are especially suitable for separation into the antipodes are those which contain an acidic group, such as, for example, racemates of compounds of the formula I in which R2 represents carboxy. These acidic racemates can be reacted with optically active bases, for example esters of optically active amino acids, or (-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine, (+)-dehydroabietylamine, (+)- and (-)-ephedrin, (+)- and (-)-1-phenylethylamine or their N-mono- or N,N-di-alkylated derivatives, to form mixtures consisting of two diastereoisomeric salts.

In racemates that contain carboxy groups, the carboxy group can also be esterified already or can become esterified by an optically active alcohol, such as (-)-menthol, (+)-borneol, (+)- or (-)-2-octanol, whereupon, when isolation of the desired diastereo-isomer is complete, the carboxy group is freed.

For separation of the racemates, the hydroxy group can also be esterified by optically active acids or reactive functional derivatives thereof, diastereoisomeric esters being formed. Such acids are, for o example, (-)-abietic acid, D( + )- and L(-)-malic acid, N-acylated optically active amino acid, (+)- and (-)-camphanic acid, (+)- and (-)-ketopinic acid, L(+)-ascorbic acid, (+)-camphoric acid, (+)-camphor-10-sulphonic acid (B) , ( + )- or (-) -a-bromocamphor-71'-sulphonic acid, D(-)-quinic acid, D(-)-isoascorbic acid, D_(-)- and L_( + )-mandelic acid, (+)-1-menthoxy-acetic acid, D(-)- and L(+)-tartaric acid and the di-O-benzoyl and di-O-^-toluyl derivatives thereof.

By reaction with optically active isocyanates, such as with (+)- or (-)-1-phenylethyl isocyanate, it is possible to convert compounds of the formula (I) in which R2 represents protected carboxy and R-j represents lower alkyl substituted by hydroxy into a mixture of diastereoisomeric urethanes.

Basic racemates, for example compounds of the formula I in which the radical R3 is an amino group, can form diastereoisomeric salts with the mentioned optically active acids.

The cleaving of the separated diastereoisomers into the optically active compounds of the formula I is also effected according to customary methods. The acids or the bases are freed from the salts, for example, by treatment with acids or bases that are stronger than those originally used. The desired optically active compounds are obtained from the esters and urethanes, for example, after alkaline hydrolysis or after reduction with a complex hydride, such as lithium aluminium hydride.

A further method of separating the racemates comprises chromatography on optically active absorption layers, for example on cane sugar.

According to a third method, the racemates can be dissolved in optically active solvents and the more sparingly soluble optical antipode can be crystal- 20s 0 lised out.

A fourth method utilises the different reactivities of the optical antipodes with respect to biological material, such as micro-organisms or isolated enzymes.

According to a fifth method, the racemates are dissolved and one of the optical antipodes is crystallised out by inoculation with a small quantity of an optically active product obtained according to the above methods.

The separation of diastereoisomers into the individual racemates and of the racemates into the optical antipodes can be carried out at any stage of the process, that is to say, for example, even at the stage of the starting compounds of the formula II or III or at any stage of the process for the manufacture of the starting compounds of the formula II that is described hereinafter.

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

The process also includes those embodiments according to which compounds formed as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is discontinued at any stage. Furthermore, starting materials can be used in the form of derivatives or can be formed rn situ, optionally under the reaction conditions. For example, a starting material of the formula II in which Z represents oxygen can be manufactured iji situ from a compound of the formula II in which Z represents an optionally substituted methylidene group, as described hereinafter, by ozonisa' tion and subsequent reduction of the ozonide formed, 2U3Q55 analogously to the process (Stage 2.3) described hereinafter, whereafter the cyclisation to form the compound of the formula I is effected in the reaction solution.

The starting compounds of the formulae II and III and the precursors can be manufactured as indicated in reaction schemes I and II. 32 ~ 208055 ? 4 Reaction scheme I i II i 11 • w NH R-j 11 !11 i S—C-A-R.

Stage 1.1 1 NH O /J o (V) Stage 1.5 ii i u s II S-C-A-R, -N C=0 (III) V z1 (IV) Stage 1.2 R^ 111 n .^■S-C-A-R, i i 111' Z' -.—9*S-l!-A-R.

N H^X.

Stage 1.3 .N ' CH -VW.OH (VII) R1 ill in- V Stage 1.4 Z' II IS-C—A-R.

V (VI) Stage 1.4a _N R, 11111 SM I 1 L N Xc£-;x® R2' I R_' (II1) (VIII) 208 05 In the compounds of the formulae IV, VI, VII and II', Z1 represents oxygen, sulphur or alternatively a methylidene group that is optionally substituted by one or two substituents Y and can be converted by oxidation into an oxo group Z. A substituent Y of this methylidene group is an organic radical, for example optionally substituted lower alkyl, for example methyl or ethyl, cycloalkyl, for example cyclopentyl or cyclo-hexyl, phenyl or phenyl-lower alkyl, for example benzyl, or, especially, an esterified carboxy group, including a carboxy group esterified by an optically active alcohol, such as 1-menthol, for example one of the optionally substituted lower alkoxycarbonyl or arylmethoxycarbony1 radicals mentioned under R2 or alternatively 1-menthyloxycarbonyl. The methylidene group Z' preferably carries one of the mentioned substituents. Special mention should be made of the methoxycarbonylmethylidene and ethoxycarbonylmethyl-idene groups.

In the compounds of the formulae IV to VIII and II', the radical R1 preferably contains one of the mentioned protected hydroxy groups, for example optionally substituted 1-phenyl-lower alkoxy, optionally substituted phenyl-lower alkoxycarbonyloxy, or tri-substituted silyloxy, and a free amino group R3 is preferably in protected form.

Stage 1. 1 A thioazetidinone of the formula IV is obtained by treating a 4-W-azetidinone of the formula V in which W represents a nucleofugal leaving group with a mercapto compound of the formula R3-A-C(=Z')-SH (IX) 203 or with a salt, for example an alkali metal salt, such as a sodium or potassium salt, thereof, and, if desired, in a resulting compound of the formula IV in which the radical is lower alkyl substituted by hydroxy, converting hydroxy into protected hydroxy.

The nucleofugal leaving group W in a starting material of the formula V is a radical that can be replaced by the nucleophilic radical R3-A-C(=Z')-S-.

Such groups W are, for example, acyloxy radicals, sulphonyl radicals Ro-SC>2- in which Rq is an organic radical, or azido or halogen. In an acyloxy radical W, acyl is, for example, the radical of an organic carboxylic acid, including an optically active carboxylic acid, and represents, for example, lower alkanoyl, for example acetyl or propionyl, optionally substituted benzoyl, for example benzoyl or 2,4-dinitrobenzoyl, phenyl-lower alkanoyl, for example phenylacetyl, or the acyl radical of one of the above-mentioned optically active acids. In a sulphonyl radical Rq-SC^-, Rq is, for example, lower alkyl option ally substituted by hydroxy, such as methyl, ethyl or 2-hydroxyethyl, and a'lso correspondingly substituted optically active lower alkyl, for example (2R)- or (2S_) - 1-hydroxyprop-2-yl, methyl substituted by an optically active radical, such as camphoryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylpheny1. A halogen radical W is, for example, bromine, iodine or, especially, chlorine. W is preferably methyl- or 2-hydroxyethy1-sulphonyl, acetoxy or chlorine.

The nucleophilic substitution can be carried out under neutral or weakly basic conditions in the presence of water and, optionally, a water-miscible organic solvent. The basic conditions can be produced, for example, by the addition of an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents there may be used, for example, water-miscible alcohols, for example lower alkanols, such as methanol or ethanol, ketones, for example lower alkanones, such as acetone, amides, for example lower alkanecarboxylic acid amides, such as dimethylformamide, acetonitrile and the like. The reaction is customarily carried out at room temperature but may also be carried out at elevated or reduced temperature. The reaction can be accelerated by the addition of a salt of hydriodic acid or of thiocyanic acid, for example an alkali metal salt, such as a sodium salt.

It is possible to use in the reaction (3£^,4Sj-and (3£, 4R)-configured compounds of the formula V or mixtures thereof. The group being introduced, R3"A—C( = Z1)-S—, is directed by the group R^ preferentially into the trans-position, irrespective of whether W is in the cis- or trans-position to the group R1. Although predominantly the trans-(3 S_, 4R)-isomers are formed, it is occasionally possible also to isolate the cis-isomers. The separation of the cis- and trans-isomers is effected as described above, according to conventional methods, especially by chromatography and/or by crystallisation.

The subsequent ozonisation of a methylidene group Z' can be effected.as described hereinafter. A resulting racemate of the formula IV can be separated into the optically active compounds.

An azetidinone of the formula V in which R-] 2080oo represents acetoxymethyl as described in U.S.

Patent No. 4,272,437. Other azetidinones of the formula V can be manufactured according to processes known per se, for example by reacting a vinyl ester of the formula R^-CH=CH-'W with chlorosulphonyl isocyanate and reacting the resulting cyclo adduct with a reducing agent, for example sodium sulphite. In this synthesis, mixtures of cis- and trans-isomers are customarily obtained which can be separated into the pure (3S_)-isomers, for example by chromatography and/or crystallisation or distillation. Resulting racemic (3£,4RS^-isomers can be separated into the pure (3S^, 4R)-antipodes as described above. The optically active compounds of the formula V can also be manufactured according to the process given below in reaction scheme II.

Stage 1.2 An o-hydroxycarboxylic acid compound of the formula VI is obtained by reacting a compound of the % formula IV with a glyoxylic acid compound of the formula OHC-R2' or with a suitable derivative thereof, such as a hydrate, hemihydrate or semi-acetal, for example a semiacetal with a lower alkanol, for example methanol or ethanol, and, if desired, in a resulting compound of the formula VI in which the radical R^ is lower alkyl substituted by hydroxy, converting hydroxy into protected hydroxy.

The compound of the formula VI is customarily obtained in the form of a mixture of the two isomers (with respect to the ^CH^-wOH grouping). It is also possible, however, to isolate the pure isomers thereof. , The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring is 2r ^ ^ w w' effected at room temperature or, if necessary, while heating, for example up to approximately 100°C, and in the absence of a true condensation agent and/or without formation of a salt. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, for example azeotropically, or by using a suitable dehydrating agent, such as a molecular sieve. It is preferable to carry out the operation in the presence of a suitable solvent, such as, for example, dioxan, toluene or dimethylformamide, or a solvent mixture, if desired or necessary in the atmosphere of an inert gas, such as nitrogen.

Stage 1.3 Compounds of the formula VII in which XQ represents a reactive esterified hydroxy group, especially halogen or organic sulphonyloxy, are manufactured by, in a compound of the formula VI, converting the secondary hydroxy group into a reactive esterified hydroxy group, especially into halogen, for example chlorine or bromine, or into an organic sulphonyloxy group, such as lower alkanesulphonyloxy, for example methanesulphonyloxy, or arenesulphonyloxy, for example benzene- or 4-methylbenzene-sulphonyloxy.

In the starting compounds of the formula VI, R.j preferably represents lower alkyl substituted by a protected hydroxy group.

The compounds of the formula VII can be obtained in the form of mixtures of the isomers (with respect to the ^:CH ^^X0 grouping) or in the form of pure isomers.

The above reaction is carried out by treatment with a suitable esterifying agent, for example with a thionyl halide, for example the chloride, a phosphorus X I j055 A: oxyhalide, especially the oxychloride, a halophos-phonium halide, such as triphenyl phosphono-dibromide or -diiodide, or a suitable organic sulphonic acid halide, such as the chloride, preferably in the presence of a basic agent, .especially an organic basic agent, such as an aliphatic tertiary amine, for example triethylamine, diisopropylethylamine or "polystyrene Hunig base", or.a heterocyclic base of the pyridine type, for example pyridine or collidine. The operation is preferably carried out in the presence of a suitable solvent, for example dioxan or tetrahydrofuran, or a solvent mixture, if necessary while cooling and/or in the atmosphere of an inert gas, such as nitrogen.

In a compound of the formula VII obtainable in this manner, a reactive esterified hydroxy group XQ can be converted into a different reactive esterified hydroxy group in a manner known per se. Thus, for example, a chlorine atom can be replaced by a bromine or iodine atom by treatment of the corresponding chlorine compound with a suitable bromide or iodide salt, such as lithium bromide or iodide, preferably in the presence of a suitable solvent, such as ether.

Stage 1.4 The starting material o-f the formula II' is obtained by treating a compound of the formula VII in which XQ represents a reactive esterified hydroxy group with a suitable phosphine compound, such as a tri-lower alkylphosphine, for example tri-n-butylphosphine, or a triarylphosphine, for example triphenylphosphine, or with a suitable phosphite compound, such as a tri- I ! lower alkyl phosphite, for example triethyl phosphite, ■ or an alkali metal di-lower alkyl phosphite, for example diethyl phosphite. i The above reaction is preferably carried out in O U 203055 the presence of a suitable inert solvent, such as a hydrocarbon, for example hexane, cyclohexane, benzene, toluene or xylene, or an ether, for example dioxan, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. Depending upon reactivity, the operation is carried out while cooling or at elevated temperature, at approximately from -10° to +100°C, preferably at approximately from 20° to 80°C, and/or in the atmosphere of an inert gas, such as nitrogen. In order to prevent oxidative processes taking place, catalytic amounts of an antioxidant, for example hydroquinone, can be added.

When using a phosphine compound, the operation is customarily carried out in the presence of a basic agent, such as an organic base, for example an amine, such as triethylamine, diisopropylethylamine or "polystyrene Hunig base", and there is thus obtained directly the ylide starting material of the formula II (or II') which is formed from the corresponding phosphonium salt.

A starting compound of the formula II1 in which X® represents a phosphono group together with a cation is preferably manufactured rn situ by treating a resulting compound of the formula M M i « . N S-C-A-R.

-CH-X' R • 2 (Ha) in which X' represents a phosphono group with a suitable basic reagent, such as an inorganic base, for example an alkali metal carbonate, such as sodium or 8 0 potassium carbonate.

Stage 1.4a A starting compound of the formula II' in which Z1 represents oxo can furthermore be obtained by treating a mercaptide of the formula VIII, in which M represents a metal cation, with an acylating agent that introduces the radical R^-A-C^O)-.

In the starting material of the formula VIII, the metal cation M is, for example, a cation of the formula M+ or M^+/2, in which M+ represents especially a 2+ silver cation and M represents, for example, the divalent cation of a suitable transition metal, for example copper, lead or mercury.

An acylating agent that introduces the radical R3~A-C(=0)- is, for example, the acid R^-A-COOH or a reactive functional derivative thereof, such as an acid halide, for example chloride or bromide, or an azide or anhydride thereof.

If the free acid of the formula R-j-A-COOH is used, the acylation is carried out, for example, in the presence of a suitable water-removing agent, such as a carbodiimide, for example N,N'-dicyclohexyl carbodi-imide, or, if an acid derivative is used, it is carried out in the presence of a suitable acid-binding agent, such as a tertiary aliphatic or aromatic base, for example triethylamine, pyridine or quinoline, in an inert solvent, such as a chlorinated hydrocarbon, for example methylene chloride, or an ether, for example diethyl ether or dioxan, at room temperature or while heating or cooling, for example in a temperature range of from approximately -50° to approximately +60°C, especially at from approximately -30° to approximately +20°C. 208 055 The starting compounds of the formula VIII can be manufactured, for example, by converting an azetidinone of the formula by reaction with an alkali metal salt, for example the sodium salt, of a thio-lower alkanecarboxylic acid, for example thioacetic acid, or of a triphenylmethy1-mercaptan, into a compound of the formula 11111 —W' -NH (V') in which W' represents triphenyImethylthio or lower alkanoylthio, for example acetylthio, converting this, analogously to the process described in reaction stages 1.2, 1.3 and 1.4, into a compound of the formula iW' . !—N (X) 20805 and reacting this, in the presence of a base, for example pyridine or tri-n-butylamine, in a suitable solvent, for example diethyl ether or methanol, with a salt of the formula MA, in which M has the meaning given above but represents especially a silver cation, and A represents a customary anion that favours the solubility of the salt MA in the chosen solvent, for example the nitrate, acetate or fluoride anion.

The ylides of the formula II' in which Z1 represents oxygen or sulphur can be used directly in the cyclisation reaction for the manufacture of the end products of the formula I. It is also possible, however, in compounds of the formula II1 in which R-j contains as substituent a protected hydroxy group, for example a protected hydroxy group that can readily be cleaved by hydrolysis, such as tri-substituted silyloxy, first to remove the hydroxy-protecting group and then to use the resulting compound of the formula II' in which R-j represents lower alkyl substituted by hydroxy in the cyclisation reaction.

Stage 1.5 A compound of the formula (III) is obtained by treating an azetidinone of the formula (IV) in which Z' represents sulphur with a compound of the formula r2'-COOH or especially a reactive derivative, such as an acid halide, for example the acid chloride, thereof at a temperature of from 20° to 80°C, preferably from 40° to 60°C, in an inert solvent, such as one of the solvents mentioned for the reaction of compounds of the formula III to form compounds of the formula I. When using an acid halide, the operation is preferably carried out in the presence of an acid-binding agent, such as a tertiary aliphatic amine, for example / o <"> j V - 208055 triethylamine, an aromatic amine, for example pyridine, or especially an alkali metal or alkaline earth metal carbonate or bicarbonate, for example potassium carbonate or calcium carbonate.

In the compounds of the formulae II', IV, VI and VII, an optionally substituted methylidene group Z' can be converted into the oxo group Z by ozonisation and subsequent reduction of the ozonide formed, in accordance with the process described in stage 2.3 below.

Starting compounds of the formula V in which W represents a sulphonyl radical of the formula Rq-SC^- can also be manufactured according to the following reaction scheme II. u Reaction scheme II 203055 \ \ Hi a**" (XI) H 1 = o a T IX .N Stage 2.1 H H -h if (XII) I % H H St age 2.2 * f k R„ ii 11111; (XIII) SO_-R 2 o .N ^ \ \ Stage 2.3 o H H R. uii ti. 1 \ V / SCU-R 2 o NH Stage 2.4 H H R^ 11ii f -S02-Ro (XIV) -N Xxc=o (Va) V I In the compounds of the formulae (XI) to (XIV) and (Va), R i represents especially lower alkyl substituted by a protected hydroxy group.

Stage 2. 1 Compounds of the formula (XII) can be manufactured by epimerising a compound of the formula (XI).

The epimerisation is effected, for example, in the presence of a basic agent, such as an amine, for example a tri-lower alkylamine, for example triethylamine or ethyldiisopropylamine, a tertiary amine, for example N,N-dimethylaniline, an aromatic amine, for example pyridine, or a bicyclic amine, for example 1,5-diazabicyclo[5.4.0]undec-5-ene or 1,5-diazabicyclo[4.3.0]non-5-ene, or an alkali metal-lower alkoxide, for example sodium methoxide, sodium ethoxide or potassium tert.-butoxide, in an inert solvent, for example an ether, for example diethyl ether, dimethoxy-ethane, tetrahydrofuran or dioxan, acetonitrile or dimethylformamide, optionally at slightly elevated or reduced temperature, for example at from 0° to 50°C, but preferably at room temperature.

In the compounds of the formula (XII) obtainable according to the process, a protected hydroxy group contained in the radical R-j can be replaced by a different protected hydroxy group; for example a protected hydroxy group that can be cleaved by hydrogenolysis can be replaced by a protected hydroxy group that can be cleaved by solvolysis. Hydroxy-protecting groups are especially those mentioned above; protecting groups that can be removed by hydrogenolysis are, for example, 1-pheny1-lower alkyl or phenyl-lower alkoxycarbonyl, each substituted as indicated, and protecting groups that can be removed by solvolysis are, for example, silyl tri-substituted as 3 \ ■A.

J .1 i 203055 indicated.

The reaction can be carried out by first removing the hydroxy-protecting group that can be removed by hydrogenolysis and then introducing into the resulting compound of the formula XII in which R^ represents lower alkyl substituted by hydroxy, a hydroxy-protecting group that can be removed by solvolysis.

The removal of the protecting group that can be removed by hydrogenolysis is effected, for example, with hydrogen or a hydrogen-donor, for example cyclo-hexene or cyclohexadiene, in the presence of a hydrogenation catalyst, such as a palladium catalyst, for example palladium-on-carbon, in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, a lower alkanol, for example methanol or ethanol, an ether, for example dioxan or tetrahydro-furan, or alternatively in water or in mixtures thereof, at a temperature of from approximately 0° to approximately 80°C, preferably at room temperature. The removal can also be carried out with a reducing metal, such as zinc, or a reducing metal alloy, for example a copper/zinc alloy, in the presence of an agent that yields protons, such as an organic acid, for example acetic acid, or alternatively a lower alkanol, for example ethanol.' The introduction of a hydroxy-protecting group that can be removed by solvolysis is effected, for example, with a compound of the formula R'-X^ in which R1 represents the hydroxy-protecting group and X^ represents, for example, a reactive esterified hydroxy group, for example halogen, for example chlorine, bromine or iodine, or sulphonyloxy, such as methanesulphonyloxy, benzenesulphonyloxy or 4-toluene-sulphonyloxy.

Starting compounds of the formula (XI) are known, for example, from British Patent Application iJo. 20 61 930.

Stage 2.2 A compound of the formula (XIII) can be manufactured by treating a penam compound of the formula (XII) with a basic agent and with an esterifying agent that introduces the radical RQ.

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

A radical Rc is, for example, one of the organic radicals mentioned under stage 1.1, especially optionally substituted lower alkyl, for example methyl, ethyl or 2-hydroxyethyl, or benzyl.

An esterifying agent that introduces the radical Rq is, for example, a compound of the formul£ R0~X4 in which X^ represents reactive esterified hydroxy, for example halogen, such as chlorine, bromine or iodine, or sulphonyloxy, such as methanesulphonyloxy, benzenesulphonyloxy or 4-toluenesulphonyloxy. For the introduction of a 2-hydroxyethyl radical, ethylene oxide is also suitable.

The reaction is preferably carried out in two steps; in the first step the penara compound of the •formula (XII) is treated with at least equimolar amounts of the basic agent and a resulting intermediate of the formula V • .3 03 H H © © , SCU ^ B I I I I I I f f» .N (Xlla) \ V ; j O •• x -j* in which B ® represents the protonated form (cation) of the basic agent, is reacted with the esterifying agent, preferably without being isolated from the reaction mixture- The reaction is carried out in an inert solvent, for example an ether, for example diethyl ether, dimethoxyethane, tetrahydrofuran or dioxan, in acetonitrile, dimethylformamide or hexamethylphosphoric acid triamide, optionally at slightly elevated or reduced temperature, for example at approximately from 0° to 50°C, but preferably at room temperature. In a preferred embodiment of the process, the penam compound of the formula (XII) is manufactured in situ by, as described in stage 2.1, first treating a compound of the formula (XI) with catalytic amounts of the basic agent, for example 1,5-diazabicyclo [5.4.0]undec-5-ene, and then further reacting the product with at least equimolar amounts of the same basic agent and the esterifying agent to form the compounds of the formula (XIII).

Stage 2.3 An oxalylazetidinone of the.formula (XIV) can be manufactured by ozonising a compound of the formula (XIII) and cleaving the ozonide formed by reduction to form the oxo compound. w The ozonisation is customarily carried out with a mixture of ozone and oxygen in an inert solvent, such as a lower alkanol, for example methanol or ethanol, a lower alkanone, for example acetone, an optionally halogenated hydrocarbon, for example a halo-lower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably while cooling, for example at temperatures of from approximately -80° to approximately 0°C.

An ozonide obtained as intermediate is cleaved by reduction, customarily without being isolated, to form a compound of the formula XIV, there being used catalytically activated hydrogen, for example hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel catalyst, also a palladium catalyst, preferably on a suitable carrier, such as calcium carbonate or carbon, or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or amalgams, for example zinc, in the presence of a hydrogen-donor, such as an acid, for example acetic acid, or an alcohol, for example lower alkanol, reducing inorganic salts, such as alkali metal iodides, for example sodium iodide, or alkali metal bisulphites, for example sodium bisulphite, in the presence of a hydrogen-donor, such as an acid, for example acetic acid, or water, or reducing organic compounds, such as formic acid. As reducing agents there may also be used compounds that can readily be converted into corresponding epoxide compounds or oxides, it being possible for the epoxide formation to be effected as a result of a C-C double bond and the oxide formation in view of the presence of an oxide-forming hetero atom, such as a sulphur, phosphorus or nitrogen atom. Such compounds are, for 2or example, suitably substituted ethene compounds (which are converted into ethylene oxide compounds in the reaction), such as tetracyanoethylene; or, especially, suitable sulphide compounds (which are converted into sulphoxide compounds in the reaction), such as di-lower alkyl sulphides, especially dimethyl sulphide; suitable organic phosphorus compounds, such as a phosphine optionally substituted by phenyl and/or by lower alkyl, for example methyl, ethyl, n-propyl or n-butyl (which phosphine is converted into a phosphine oxide in the reaction), such as tri-lower alkylphosphines, for example tri-n-butylphosphine, or triphenylphosphine; and also tri-lower alkyl phosphites (which are converted into phosphoric acid tri-lower alkyl esters in the reaction), customarily in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides, which optionally contain lower alkyl as substituent, such as hexa-lower alkyl phosphorous acid triamides, for example hexamethyl-phosphorous acid triamide, the latter preferably being in the form of a methanol adduct; and also suitable nitrogen bases (which are converted into the corresponding N-oxides in the reaction), such as heterocyclic nitrogen bases of aromatic character, for example bases of the pyridine type and, especially, pyridine itself. The cleaving of the ozonide, which customarily is not isolated, is normally effected under the same conditions as those used for its manufacture, that is to say, in the presence of a suitable solvent or solvent mixture, and while cooling or gently heating, the operation preferably being carried out at temperatures of from approximately -10° to approximately +25°C, and the reaction customarily being concluded at room temperature. 208 05 Stage 2.4 An azetidinone of the formula (Va) can be manufactured by solvolysing an oxalylazetidinone of the formula (XIV).

The solvolysis can be carried out in the form of hydrolysis, alcoholysis or alternatively in the form of hydrazinolysis. Hydrolysis is carried out with water, optionally in a water-miscible solvent. Alcoholysis is customarily carried out with a lower alkanol, for example methanol or ethanol, preferably in the presence of water and an organic solvent, such as a lower alkanecarboxylic acid lower alkyl ester, for example ethyl acetate, preferably at room temperature, if necessary while cooling or heating, for example at a temperature of from approximately 0° to approximately 80°C. Hydrazinolysis is carried out in conventional manner with a substituted hydrazine, for example with phenyl- or a nitrophenyl-hydrazine, such as 2-nitro-phenylhydrazine, 4-nitrophenylhydrazine or 2,4-dinitro-phenylhydrazine, which is preferably used in an approximately equimolar amount, in an organic solvent, such as an ether, for example diethyl ether, an aromatic hydrocarbon, such as benzene, a halogenated hydrocarbon, such as methylene chloride or chloro-benzene, an ester, such as ethyl acetate, and the like, at temperatures of from approximately room temperature to approximately 65°C.

In a preferred embodiment of the process, a compound of the formula (XIII) is used as starting material and is ozonised as indicated and then cleaved by reduction to form an oxalylazetidinone of the formula (XIV) whi.ch is reacted further, without being isolated from the reaction mixture, to form an azetidinone of the formula (Va).

In the ozonolysis there may be produced small 203 0 52 amounts of acid which can effect the removal of a hydroxy-protecting group in the radical R1 that can readily be removed by solvolysis, for example a tri-substituted silyl radical. The resulting compound of the formula in which R-j' represents lower alkyl substituted by hydroxy can be separated from the protected azetidinone (Va), for example by chromatography, and converted into the azetidinone of' the formula (Va) by fresh reaction with the agent of the formula R'-X-j that introduces the hydroxy-protecting group R'.

In the compounds of the formulae (II), (II'), (III), (VI), (VII) and (XII) to (XIV), a protected carboxy group R2' can be converted into a different protected carboxy group R2' according to methods known per se, and when so doing it is possible, taking into consideration the other functional groups which may be contained in these compounds, to use the same methods as those indicated for the conversion of this substituent in the compounds of the formula (I).

The invention relates also to novel starting materials and to novel intermediates obtainable according to the process, such as those of the formulae (II) to (VIII) (including II', Ila, Va and Vb) and to the processes given for their manufacture.

The starting materials used and the reaction (Vb) 203 0 conditions chosen are preferably those which result in the compounds described hereinbefore as being especially preferred.

The compounds of the formula I have valuable pharmacological properties or can be used as intermediates for the manufacture of such compounds having valuable pharmacological properties. Compounds of the formula I in which R-| represents hydroxy-lower alkyl, R2 represents carboxy or an esterified carboxy group that'can be cleaved under physiological conditions, and R3 represents amino, lower alkylamino, di-lower alkylamino or substituted methyleneamino, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial activity. For example, they are effective in vitro against gram-positive and gram-negative cocci, for example Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria meningitidis and Neisseria gonorrhoeae, and against enterobacteria, for example Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, against Haemophilus influenzae and Pseudomonas aeruginosa, and anaerobes, for example Bacteroides sp. and Clostridium sp., in minimum concentrations of from approximately 0.02 to approximately 64 yg/ml. Ill vivo, in the case of systemic infection of mice, for example by Staphylococcus aureus, Escherichia coli or Streptococcus pyogenes, on subcutaneous or oral administration ED50 values of from approximately 0.3 to approximately 100 mg/kg are obtained.

The novel compounds can therefore be used as orally or parenterally administrable antibacterial antibiotics, for example in the form of corresponding pharmaceutical preparations, for the treatment of j infections.

Compounds of the formula I in which at least one of the functional groups present is in protected form, a protected carboxy group being other than an esterified carboxy group that can be cleaved under physiological conditions, can be used as intermediates for the manufacture of the above-mentioned pharmacologically active compounds of the formula I.

The pharmacologically acceptable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutical^ acceptable carriers that are suitable for oral or for parenteral, that is to say intramuscular, subcutaneous or intraperitoneal, administration.

For oral administration there are used tablets or gelatine capsules that contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; tablets also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures or adsorbents, colourings, flavourings or sweeteners.

For parenteral administration there are suitable especially infusion solutions, preferably isotonic aqueous solutions or suspensions, it being possible to ? o q A K ^ ^ O w J 55 prepare these before use, for example from lyophilised preparations that contain the active ingredient alone or together with a carrier, for example mannitol. Such preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are manufactured in a manner known per se, for example by means of conventional mixing, dissolving or lyophilising processes, and contain from approximately 0.1 % to 100 %, especially from approximately 1 % to approximately 50 % or, in the case of lyophili-sates, up to 100 %, of the active ingredient.

Depending upon the type of infection and the condition of the infected organism, the daily dose used for the treatment of a warm-blooded animal (human or animal) weighing approximately 70 kg is from 125 mg to approximately 5 g.

The following Examples serve to illustrate the invention. Temperatures are given in degrees Centigrade.

The following abbreviations are used in the Examples: O the osmotic pressure and/or buffers.

Q G NMR TLC UV THF DMF DBU IR thin-layer chromatograph infra-red spectrum ultraviolet spectrum nuclear resonance spectrum 1,5-diazabicyclo[5.4.0]undec-5-ene tetrahydrofuran dimethyIformamide 208035 Experimental part I ? ? >, » . t .

Example 1: (5R,6S)-2-[(2RfS)-2-(4-nitrobenzyloxycarbonylamino )-prop-1-yl]-6-(tert.-butyl dimethyIsilyloxymethyl)-2-penem-3-carboxylic acid p-nitrobenzyl ester Al A solution of 6.27 g of 2-[(3S^4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(3R,S)-3-(4-nitro-benzyloxycarbonylamino)-butyroylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid £-nitro-benzyl ester in 1 litre of toluene is stirred under an argon atmosphere for 12 hours at reflux temperature. The solvent is then evaporated off and the crude product is purified by chromatography over silica gel (eiuant: toluene/ethyl acetate 9:1). TLC (silica gel, toluene/ethyl acetate 1:1): R^ = 0.56; IR (CH2C12): 3430, 1780, 1715, 1510, 1340, 1310 cm -1 The starting material can be manufactured as follows: O o a) (3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyric acid At 0°, solid chloroformic acid 4-nitrobenzyl ester (47.4 g) is added to a solution of (3R,SJ-3-aminobutyric acid (20.6 g) in 41 mi of water and 90 mi of 5N NaOH solution and the beige-coloured suspension is then stirred for 16 hours at room temperature. After removal of the insoluble material by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH2C12. The aqueous phase is adjusted to pH 2 with 4N HCi and extracted 2 0J 05 O - 57 twice with CH2C12. The combined organic extracts are washed once with brine, dried over MgS04 and concentrated by evaporation to form white crystals of the title compound. IR in CH2C12: 3425, 1710, 1500, 1335 cm"1. o b) (3R,S)-3-(4-nitrobenzyloxycarbonylamino)-thio- butyric acid (3R,!5) -3-(4-nitrobenzyloxycarbonylamino) -butyric acid (14.1 g) is suspended in methylene O chloride (250 ml) and, after cooling to -10°, dissolved by the addition of 15.33 ml of triethylamine. At the same temperature, a solution of chloroformic acid isobutyl ester (7.19 ml) in 50 ml of methylene chloride is added and the whole is then stirred at -10° for one hour. is then introduced over a period of 2 hours. After removal of the excess H2S with nitrogen, 2N H2SO4 solution is added to the reaction mixture and the whole is shaken well. The organic phase is separated off and extracted once with 400 mi of 1.5% NaHCO^ solution. The aqueous phase is rendered acidic with 2N f^SO^, extracted twice with CH2CI2 and these extracts are then dried over MgS04. Concentration of the filtered organic solution by evaporation yields the title compound in the form of a yellowish oil. IR (CH2Cl2): 3430, 2580, 1715, 1500, 1345 cm"1. c) (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-azetidin-2-one 8.22 g of (3Sy4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-methylsulphonylazetidin-2-one and 11.7 g 2w. j of ( 31*,S_) -3- (4-nitrobenzyloxycarbonylamino) -thio-butyric acid are dissolved in 180 ml of CH2C12. To the yellowish solution there is added first 180 ml of water and then 42 ml of 1N NaOH. The vigorously stirred emulsion is stirred at room temperature for 1.5 hours. The organic phase is then separated off in a separating funnel and the aqueous phase is extracted twice more with CH2C12. The combined organic extracts are washed with a saturated aqueous NaHCO^ solution and then with brine, dried over MgSO^ and concentrated by evaporation. The resulting crude product is purified by chromatography over silica gel with toluene/ethyl acetate 9:1. TLC (silica gel, ethyl acetate): Rf = 0.65; IR (CH2C12): 3420, 1765, 1710, 1680, 1500, 1340 cm"1.

The starting material (3£,4R)-3-(tert.-butyl-dimethyl silyloxymethyl)-4-methylsulphonylazetidin-2-one can be manufactured as follows: ca) (3S,5R,6R)-2,2-dimethyl-6-(tert.-butyIdimethy1-silyloxymethyl)-penam-3-carboxylic acid methyl ester 1,1-dioxide A solution of 23.6 g (85 mmol) of (3Sy5R,6R)-2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid methyl ester 1, 1-dioxide in 50 ml of dimethylformamide is stirred at room temperature for 45 minutes with 25.5 g (170 mmol) of tert.-butyldimethylchlorosilane and 11.5 g (170 mmol) of imidazole. The solvent is then distilled off under a high vacuum and the residue is taken up in. ethyl acetate. The solution is washed with IN sulphuric acid and then with water, and the aqueous solutions are extracted twice with ethyl acetate. The organic phase is dried with sodium 20s 0 sulphate and concentrated in a rotary evaporator. The product is obtained in the form of a crystalline mass. TLC, silica gel, toluene/ethyl acetate (4:1): Rf = 0.56; IR (CH2C12): 3.4, 5.57, 5. 65 jim. cb) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphony1-2-oxoazetidin-1-yl]-3-methy1-2-butenoic acid methyl ester 9 ml of DBCJ are added to a solution of 202 g (0.51 mol) Of (3R,5R,6R)-2,2-dimethyl-6-(tert.-butyldimethylsilyloxymethyl)-penam-3-carboxylic acid methyl ester 1, 1-dioxide in 800 ml of tetrahydrofuran and the whole is stirred for 5 minutes at room temperature. A further 95 ml of DBU are then added and the whole is stirred for 30 minutes at room temperature. 42.3 ml (0.68 mol) of methyl iodide are then added while cooling. After a reaction period of 3 hours, the DBD hydriodide that has crystallised out is filtered off and the filtrate is concentrated. The residue is taken up in ethyl acetate and the solution is washed with 1N sulphuric 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 concentrated to a thick oil. TLC [silica gel, toluene/ethyl acetate (4:1)]; Rf = 0.42; IR (CH2C12): 5.63, 5.81, 6.17 ym. cc) (3S,4R)-3-hydroxymethy1-4-methylsulphonylaze-tidin-2-one and (3S,4R)-3-(tert.-butyldimethy1-silyloxymethyl)-4-methylsulphonylazetidin-2-one A solution of 25 g (6 1.7 mmol) of 2-[(3S_, 4R) -3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphonyl 2-oxoazetidin-1-yl]-3-methyl-2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10° with an ozone/oxygen mixture. The disappearance of the starting material is monitored by thin-layer chromatography. When the reaction is complete, 30 ml of dimethyl sulphide are added and the whole is stirred for 3 hours at room temperature. The solution is concentrated and the residue is taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water arid heated at 70° for 40 minutes. The solvent is then removed and the residue is extracted twice with toluene. The crystallising oil is taken up in methylene chloride and the crystals, comprising (3S_, 4R) -3-hydroxyme thy 1-4-methyl sulphony laze t id in-2-one, are isolated by filtration. The filtrate is concentrated and (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl )-4-methylsulphonylazetidin-2-one is obtained in pure form by chromatography over silica gel with toluene/ethyl acetate (3:1): (3S,4R)-3-hydroxymethyl-4-methylsulphonylazetidin-2-one: TLC, silica gel, toluene/ethyl acetate (1:1): Rf = 0.36, IR: (CH2C12): 2.96, 3.54, 5.65 um. (3S,4R)-3-(tert.-butyIdimethyIsilyloxymethyl)-4-methy1-sulphonylazetidin-2-one: TLC, silica gel, toluene/ethyl acetate (1:1): R^ = 0.06.

At room temperature, 24 g (183 mmol) of tert.-butyldimethylchlorosilane and 11 g (163 mmol) of imidazole are added over a period of 45 minutes to a solution of 14.6 g (81.5 mmol) of (3S^,4R)-3-hydroxymethyl-4-methylsulphonylazetidin-2-one in 40 ml of dimethylformamide. The solvent is then removed under a high vacuum and the residue is taken up in 208 0 ethyl acetate. The organic phase is washed in succession with IN sulphuric 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 concentrated in a rotary evaporator. The crystalline residue is pure (3£,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphonylazetidin-2-one. d) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester 80 g of molecular sieve (4&) are added to a mixture of 10.23 g of (3S_,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4- [ (3R,£)-3-(4-nitrobenzyloxycarbonylamino) -butyroylthio)-azetidin-2-one and 10.21 g of glyoxylic acid £-nitrobenzyl ester ethyl hemiacetal in 170 ml of toluene and 10 ml of absolute DMF and the whole is stirred for 16 hours at room temperature and then for 2 hours at 50°. The mixture is filtered and the filtration residue is then washed with toluene. Concentration of the filtrate by evaporation and drying under a high vacuum at 50° yield the product in the form of a yellow oil. TLC (silica gel, ethyl acetate): Rf = 0.67; IR (CH2C12): 3430, 1765, 1730, 1690, 1505, 1340 cm""'. 208 05 O ..far 0 e) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxoazetidin-1-yl]-2-triphenyl-phosphoranylideneacetic acid p-nitrobenzyl ester While stirring at 0°, there are added, in succession, to a solution of 13.7 g of 2-[(3£, 4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(3R,Sj-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxo-azetidin-1-yl]-2-hydroxyacetic acid £-nitrobenzyl ester in 250 ml of absolute tetrahydrofuran, 2.03 ml of thionyl chloride and 2.3 ml of pyridine. The white suspension is stirred for a further 30 minutes at 0° and filtered. After concentration by evaporation, the resulting yellow foam is dissolved in 100 ml of dioxan, and 3.1 ml of 2,6-dimethylpyridine and 6.98 g of triphenylphosphine are added. After stirring for 17 hours at 40°, the solid substances are separated off and the filtrate is concentrated by evaporation. The crude product is purified by chromatography over silica gel (eluant: toluene/ethyl acetate 9:1). TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.36; IR (CH2C12): 3430, 1745, 1715, 1615, 1510, 1430 cm-"'.

Example 2 (5R,6S)-2-[(2RrS)-2-(4-nitrobenzyloxycarbonylamino) -prop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester 1.83 ml of acetic acid and 80 ml of a 0.1N tetra-butylammonium fluoride solution in THF are added in succession to a solution of 3.14 g of (5R,6Sj-2-[(2R,£) -2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl]-6-(tert.-butyldimethylsilyloxymethyl)-2-penem-3- carboxylic acid jD-nitrobenzyl ester in 50 ml of absolute THF. After stirring for 4.5 hours, the mixture is diluted with 1.4 litres of CH2C12 and the whole is washed with 200 ml of a saturated solution of NaHCO^ in H20. The organic phase is then washed with brine, dried over MgSO^ and, after filtration, concentrated by evaporation. The crude product is purified by chromatography on silica gel (eluant: from toluene/ethyl acetate 1:1 to ethyl acetate absolute). TLC (silica gel, ethyl acetate): Rf = 0.46; IR (CH2C12): 3600, 3430, 1780, 1715, 1515, 1340 cm"1.

Example 3 (5R,6S)-2-[(2R,S)-2-aminoprop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid 0.15 g of Pd/C (10%) is added to 229 mg of (5R,6SJ-2-[(2R,S_)-2-(4-nitrobenzyloxycarbonylamino) -prop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid jD-nitrobenzyl ester in 30 ml of ethyl acetate, 12 ml of THF and 24 ml of water, and hydrogenation is carried out for 2 hours at room temperature and normal pressure. The catalyst is filtered off and a further 0.1 g of Pd/C (10%) and then 4 ml of 0.1N HC1 are added to the reaction mixt.ure and hydrogenation is continued for 1 hour. The catalyst is filtered off, the aqueous phase is separated off and the organic phase is again extracted with water. 1 equivalent of NaHCOg is added to the combined aqueous extracts and the whole is washed with ethyl acetate. The aqueous phase is then lyophilised. TLC (reversed phase Opti-OPC^2) in water: Rf = 0.13; UV (phosphate buffer pH 7.4): X_,v = 304 nm. max 20s 05 % Example 4 (5R,6S)-2-[2-methyl-2-(4-nitrobenzyloxycarbonylamino) -prop-1-yl]-6-(tert.-butyl-dime thyIsilyloxymethyl)-2-penem-3-carboxylie acid p-nitrobenzyl ester i C A' o In a manner analogous to that described in Example 1, 1.51 g of 2-[ (3S_, 4R)-3-(tert .-butyldimethylsilyloxymethyl) -4- [3-methyl-3- (4-nitrobenzyloxycarbonylamino) -butyroylthio] -2-oxoazetidin-1-yl]-2-triphenyl-phosphoranylideneacetic acid jD-nitrobenzyl ester in 250 ml of toluene, after stirring for 46 hours at reflux temperature, are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf - 0.6; IR (CH2C12) : 3430, 1775, 1710, 1510, 1340, 1300 cm'1.

The starting material can be manufactured as follows: a) 3-methy1-3-(4-nitrobenzyloxycarbonylamino)-butyric acid In a manner analogous to that described in Example 1a, 7.79 g of 3-methyl-3-aminobutyric acid are reacted to form the title compound. IR in CH2C12: 3430, 1710, 1500, 1340 cm -1 O b) 3-methy1-3-(4-nitrobenzyloxycarbonylamino)-thio-butyric acid In a manner analogous to that described in Example lb, 9.5 g of 3-methyl-3-(4-nitrobenzyloxycarbonylamino) -butyric acid are converted into the title compound.

IR (CH2C12): 3420, 2570, 1710, 1490, 1340 cm -1 203 c) (3S,4R)-3-(tert.-butyIdimethylsilyloxymethyl)-4-[3-methy1-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-azetidin-2-one In a manner analogous, to that described in Exampl 1c, 5.98 g of 3-methyl-3-(4-nitrobenzyloxycarbonylamino)-thiobutyric acid and 3.75 g of (3S_,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphony1-azetidin-2-one are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): R^ = 0.44; IR (CH2C12): 3400, 1765, 1715, 1675, 1490, 1335 cm-1. d) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1d, 3.75 g of (3£, 4R)-3-(tert.-butyldimethylsilyloxymethyl) -2-[3-methyl-3- (4-nitrobenzyloxycarbonylamino)-butyroylthio]-azetidin-2-one and 3.57 g of glyoxylic acid £-nitrobenzyl ester ethyl hemiacetal are converted into the title compound. TLC (silica gel, toluene/ethyl apetate): R^ = 0.43 and 0.36; IR (CH2C12): 3420, 1760, 1735, 1710, 1680, 1505, 1335 cm-1. e) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxoazetidin-1-yl]-2-triphenyl-phosphoranylideneacetic acid p-nitrobenzyl ester In a manner analogous to that described ir» Example 1e, 2.32 g of 2- [ (3S,4R)-3-(tert.-butyl- /' o 203 05 5 dimethyIsilyloxymethyl)-4-[3-methy1-3-(4-nitrobenzyloxycarbonylamino) -butyroylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid D-nitrobenzyl ester are reacted to form the title compound. TLC (silica gel, toluene/-ethyl acetate 1:1): Rf = 0.47; IR (CH2C12): 3420, 1740, 1730, 1675, 1610, 1600, 1500, 1335 cm'1.

Example 5 (5R,6S)-2-[2-methy1-2-(4-nitrobenzyloxycarbonylamino) -prop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester In a manner analogous to that described in Example 2, 2.29 g of (5R, 6S_) -2-[2-methyl-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl]-6-(tert.-butyldimethylsilyloxymethyl)-2-penem-3-carboxylie acid £-nitrobenzyl ester are reacted to form the title compound. TLC (silica gel, toluene/ethyl acetate): Rf = 0.23; IR (CH2C12): 3600, 3430, 1780, 1710, 1510, 1345 cm"1.

Example 6 (5R,6S)-2-(2-amino-2-methylprop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylie acid In a manner analogous to that described in Example 3, 0.7 g of (5R,6Sj-2-[2-methyl-2-(4-nitrobenzyloxycarbonylamino) -prop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester is reacted to form the title compound. TLC (reversed phase Opti UPC -j 2) in water: Rf » 0.15. UV (phosphate buffer pH 7.4): Xmax = 307 nm. aits' w \J 55 "t Example 7 (5R,6S)-2-[(3R,S)-3-(4-nitrobenzyloxycarbonylamino) -but- 1-yl] -6-(tert.-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid p-nitrobenzyl ester Jj O O In a manner analogous to that described in Example 1, 2.3 g of 2-[ (3£f4R)-3-(tert.-butyldimethylsilyloxymethyl) -4- [ (4R,S_) -4- (4-nitrobenzyloxycarbonyl-amino)-valeroylthio]-2-oxoazetidin-1-yl]-2-triphenyl-phosphoranylideneacetic acid ja-nitrobenzyl ester are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.49.

The starting material can be manufactured as follows: a) (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeric acid In a manner analogous to that described in Example la, 9.5 g of (411,S)-4-aminovaleric acid are reacted to form the title compound. NMR (DMSO-dg): & = 12.0 (br;1H), 8.3 (m; 2H), 7.7 (m; 2H), 7.25 (br; 1H), 5.2 (s; 2H), 3.6 (m; 1H), 2.25 (t; 2H), 1.7 (m? 2H), 1.1 ppm (d; 3H). b) (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-thio-valeric acid o In a manner analogous to that described in Example lb, 15 g of (4R, S_)-4-(4-nitrobenzyloxycarbonyl-amino)-valeric acid are converted into the title compound. 1345 cm-1.

IR (CH2C12): 3430, 2570, 1715, 1505, 208 0 c) (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroylthio]-azetidin-2-one In a manner analogous to that described in Example 1c, 11.4 g of (4R,£)-4-(4-nitrobenzyloxycarbonylamino) -thiovaleric acid and 8.31 g of (3S_,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphonyl-azetidin-2-one are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0. 14. d) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1d, 11.18 g of (3S_,4R)-3-tert.-butyldimethylsilyloxymethyl) -4- [ (4R,S_) -4- (4-nitrobenzyloxycarbonylamino)-valeroylthio]-azetidin-2-one and 8.14 g of glyoxylic acid p-nitrobenzyl ester ethyl hemiacetal are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.25 and 0.28. e) 2-[(3S,4R)-3-(tert.-butyIdimethylsilyloxymethyl)-4-[(4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroylthio]-2-oxoazetidin-1-yl]-2-triphenyl-phosphoranylideneacetic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1e, 5.2 g of 2-[(3£, 4R)-3-(tert.-butyldimethylsilyloxymethyl) -4- [ (4R,S_) -4- (4-nit robenzy loxycarbonylamino) -valeroylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester are reacted to form the title compound. TLC (silica gel, toluene/-ethyl acetate 1:1): Rf = 0.32.

Example 8 (5R,6S)-2-[(3R,S)-3-(4-nitrobenzyloxycarbonylamino) -but- 1-yl] -6-hydroxymethyl]-2-penem-3-carboxylic acid p-nitrobenzyl ester In a manner analogous to that described in Example 2, 1.34 g of (5R,6£)-2-[(3R,SJ-3-(4-nitrobenzyloxycarbonylamino) -but-1-yl]-6-(tert.-butyldimethylsilyl oxymethyl)-2-penem-3-carboxylic acid £-nitrobenzyl ester are reacted to form the title compound.

IR (CH2C12): 3600, 3420, 1780, 1715, 1510, 1340 cm"1.

Example 9 (5R,6S)-2-[(3R,S)-3-aminobut-1-y1]-6- hydroxymethyl-2-penem-3-carboxylic acid In a manner analogous to that described in Example 3, 0.82 g of (5R, 6S_)-2-[ (3R,Sj -3-(4-nitrobenzyloxycarbonylamino) -but-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid jo-nitrobenzyl ester is reacted to form the title compound. UV (phosphate buffer pH 7.4): X „ = 305 nm. max Example 10 (5R,6S)-2-[(2R,S)-1- (4-nitrobenzyloxycarbonylamino) -prop-2-yl]-5-(tert.-butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1, 1.13 g of 2-[(3£,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4- [ (2R,S_) -2-methyl-3- (4-nitrobenzyloxy-carbonylamino)-propionylthio]-2-oxoazetidin-1-yl]-2-phosphoranylideneacetic acid £-nitrobenzyl ester are c 0 converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.4.

The starting material can be manufactured as follows: a) (2R,S) -2-methy1-3-(4-nitrobenzyloxycarbonylamino)-propionic acid In a manner analogous to that described in Example 1a, 5.69 g of (2R,£)-3-amino-2-methylpropionic acid are reacted to form the title compound.

IR (CH2C12): 3450, 1720, 1510, 1345 cm-1. b) (2R,S)-2-methy1-3-(4-nitrobenzyloxycarbonylamino)-thiopropionic acid In a manner analogous to that described in Example 1b, 10.4 g of (2R, S_) - 2—me thy 1-3- (4-ni trobenzy loxycarbonylamino) -propionic acid are reacted to form the title compound. IR (CH2Ci2): 4440, 2570, 1715, 1690, 1510, 1345 cm-1. c) (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(2R,S)-2-methy1-3-(4-nitrobenzyloxycarbonylamino) -propionylthio]-azetidin-2-one In a manner analogous to that described in Example 1c, 9.27 g of (2R,£)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-thiopropionic acid and 6.07 g of (3S^ 4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsuiphonyiazetidin-2-one are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.34; IR (CH2C12): 3440, 3400, 1765, v/ U J 1710, 1675, 1500, 1335 cm"1. d) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(2R,S)-2-methy1-3-(4-nitrobenzyloxycarbonylamino ) -propionylthio]-2-oxoazetidin-1-yl] -2-hydroxyacetic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1d, 0.98 g of (3S_,4R) -3-(tert .-butyldimethylsilyloxymethyl) -4- [ (2J*,£) -2-methyl-3- (4-nitrobenzyloxycarbonylamino) -propionylthio]-azetidin-2-one is converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.5; IR (CH2C12): 3510, 3420, 1765, 1740, 1715, 1690 cm"1. e) 2- [ (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(2R,S)-2-methy1-3-(4-nitrobenzyloxycarbonylamino) -propionylthio]-2-oxoazetidin-1-yl]-2-phosphoranylideneacetic acid p-nitrobenzyl ester In a manner analogous to that described in Example 1e, 2.6 g of 2-[ (3S_,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4- [ (2R,£)-2-methyl-3-(4-nitrobenzyloxycarbonylamino) -propionylthio]-2-oxoazetidin-1-yl]-2-hydroxyacetic acid D-nitrobenzyl ester are converted into the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.36; IR (CH2C12): 3440, 1745, 1715, 1675, 1615, 1600 cm"1. 20C 05 Example 11 (5R,6S)-2-[(2R,S)-1-(4-nitrobenzyloxycarbonylamino) -prop-2-yl] -6-hydroxymethy1-2-penem-3-carboxylie acid p-nitrobenzyl ester In a manner analogous to that described in Example ^ 2, 0.28 g of (5R,6S)-2-[(2R,S)-1-(4-nitrobenzyl oxycarbonylamino) -prop-2-yl]-6-(tert.-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid £-nitrobenzyl ester is converted into the title compound, s TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.17; IR (CH2C12): 3440, 1775, 1715, 1510, 1340 cm-1.

Example 12 (5R,6S)-2-[(2R,S)-1-aminoprop-2-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid In a manner analogous to that described in Example 3 , 750 mg of (5R,6S_)-2-[ (2R,S_)-1-(4-nitro-benzyloxycarbonylamino)-prop-2-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid £-nitrobenzyl ester are converted into the title compound. UV (phosphate buffer pH 7.4) Xmax = 301 nm.

Example 13 the sodium salt of (5R,6S)-2-[(2R,S)-2-(1-ethoxycarbonylprop-1-en-2-ylamino)-prop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylie acid 0.139 ml (1.1 mmol) of acetoacetic acid ethyl ester is added to a suspension of 0.257 mg (1 mmol) of (5R,6Sj-2-[(2R,S)r2-aminoprop-1-yl]-6-hydroxy-methyl-2-penem-3-carboxylic acid and 0.5 ml of 2N sodium hydroxide solution in 3 ml of isopropanol and the whole is stirred for 3 hours at room temperature. 206 '' The product is precipitated by the addition of diethyl ether. IR spectrum (Nujol): absorption bands at 3330, 1791, 1739 cm"1.

Example 14 (5R,6S)-2-[(2R,S)- 1-allyloxycarbonylamino-prop-2-yl]-6-(tert.-butyldimethylsilyloxymethyl )-2-penem-3-carboxylic acid allyl ester A solution of 0.9 g of 2-[ (3:3 , 4R)-3-(tert. -butyldimethylsilyloxymethyl) -4- f (2R,S_)-2-methyl-3-allyloxycarbonylaminopropionylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester in 150 ml of absolute toluene is stirred under an argon atmosphere for 24 hours at reflux temperature. The solvent is then evaporated off and the crude product is purified by chromatography over silica gel (eluant: toluene/ethyl acetate 9:1). IR (CH2CI2): 3440, 1780, 1710 cm-1.

The starting material can be manufactured as follows: a) (3S,4R) -3-(tert.-butyldimethylsilyloxymethyl)- 4-triphenylmethylthioazetidin-2-one At 0°, 12.5 g of triphenylmethylmercaptan are suspended in 70 ml of methanol, and a total of 2.2 g of a 50% sodium hydride suspension in oil are added, in portions, over a period of 10 minutes. An emulsion of 11.1 g of (3S_,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-methylsulphonylazetidin-2-one in 70 ml of acetone and 70 ml of water is then added dropwise over a period of 30 minutes. After stirring for 30 minutes at 0° and for 1 hour at room tempe rature, the reaction mixture is concentrated in a rotary evaporator, methylene chloride is added and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulphate.

After concentration, the crude title compound is purified by chromatography on silica gel (eluant: toluene/ethyl acetate 19:1). TLC (toluene/ethyl acetate 19:1): Rf = 0.64; IR (methylene chloride): 3390, 1760, 1117, 835 cm-1. b) 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-trjphenylmethylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acid allyl ester 27 g of molecular sieve (4&) are added to 8.4 g of (3£,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-triphenylmethylthioazetidin-2-one and 8.23 g of glyoxylic acid allyl ester ethyl hemiacetal in 170 ml of absolute toluene and the whole is stirred for 10 hours at 55°. After filtration and concentration in a rotary evaporator under reduced, pressure, the crude product is purified by chromatography over silica gel (eluant: toluene/ethyl acetate 95:5). TLC (silica gel, toluene/ethyl acetate 10:1): Rf = 0.37 and 0.27; IR (CH2C12): 3520, 1760, 1745 cm-1. c) 2-I(3S,4R)-3-(tert♦-butyldimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester While stirring at -15°, 80 ul of thionyl chloride and 88 yl of pyridine are added in succession over a period of 5 minutes to a solution of 604 mg of 2-[ (3S_, 4R) -3- (tert. -butyldimethylsilyloxymethyl) -4- 0^ 208 Oj5 triphenylmethylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acid aiiyi ester in 5 ml of tetrahydrofuran. The white suspension is then stirred for 1 hour at -10° and filtered over Hyflo. After washing the residue with toluene, concentration is .effected in a rotary evaporator. The residue is dissolved in 3ml of dioxan; 293 mg of triphenylphosphine and 0.13 ml of 2,6-lutidine are added and the whole is stirred for 2 hours at a bath temperature of 115°. The mixture is filtered over Hyflo and the residue is then washed with toluene. The combined filtrates are concentrated by evaporation.

',J Chromatography of the residue over silica gel yields the pure product (eluant: toluene/ethyl acetate 95:5). TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.18; IR (CH2C12): 1745, 1605 cm-1. d) the silver salt of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-mercapto-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester 7.5 g of 2- [ (3S_, 4R) -3-(tert. -butyldimethylsilyloxymethyl )-4-triphenyImethylthio-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are placed in 87 mi <?£ ether and, at room temperature, 70 ml of a 0.5M aqueous silver nitrate solution are added. A mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is then added dropwise thereto and the reaction mixture is stirred for 20 minutes. The solid is then filtered off with suction and washed with ether, water and again with ether. For purification, the solid is finally made into a slurry with 40 ml of ether and 40 ml of water, filtered with suction and dried.

IR (CH2C12): 1760, 1620 cm-1. 203 0 e) 2- [ (3S,4R)-3-(tert.-butyIdimethylsilyloxymethyl)-4- [ (2R,S) -2-methyl-3-allyloxycarbonylamino-propionylthio]-2-oxoazetidin-l-yl]-2-triphenyl-phosphoranylideneacetic acid allyl ester 1.7 ml of pyridine are added to 5 g of the silver salt of 2-[(3£f4R)-3-(tert.-butyldimethylsilyloxymethyl )-4-mercapto-2-oxoazetidin-1-yl]-2-tripheny1-phosphoranylideneacetic acid allyl ester in 20 ml of absolute methylene chloride and then, at 0°, a mixture of 2.47 g of (2I*,£) -2-methyl-3-allyloxycarbonylaminopropionic acid chloride and 10 ml of absolute methylene chloride is added dropwise thereto. After stirring for 30 minutes, the solid is filtered off over Hyflo and the filtrate is washed with aqueous NaHCO-j solution and then with brine. After drying over Na2S04, concentration is effected in vacuo. The residue is purified by chromatography over silica gel (eluant: toluene/ethyl acetate 4:1). TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.3; IR (CH2C12): 3440, 1750, 1715, 1680, 1610 cm-1.

The starting material (2R,S_)-2-methyl-3-allyl-oxycarbonylaminopropionic acid chloride can be manufactured as follows: ea) (2R,S)-2-methyl-3-allyloxycarbonylaminopropionic acid At 0°, 11.2 ml of chloroformic acid allyl ester are added dropwise to a solution of 10 g of (2R,Sj-3-amino-2-methylpropionic acid in 20 ml of water and 44 ml of 5N NaOH solution. After stirring for 15 hours at room temperature, working up is carried out as in 20s 0.

Example la. IR (CH2C12): 3450, 1710, 1505, 1220 cm"1. eb) (2R,S)-2-methy1-3-allyloxycarbonylaminopropionic acid chloride At 0°, 0.6 ml of thionyl chloride is added to 0.347 g of (2jR,.SJ -2-methyl-3-allyloxycarbonylamino-propionic acid. The mixture is then stirred at the same temperature under a protective gas for 2 hours. The mixture is then diluted with absolute toluene and concentrated in a rotary evaporator. IR (CH2C12): 3440, 1780, 1710, 1500, 1215 cm"1.

Example 15 (5R,6S)-2-[(2R,5)- 1-allyloxycarbonylamino-prop-2-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester In a manner analogous to that described in Example 2, 138 mg of (5R, 6£)-2-[ (2R,S_)-1-allyloxycarbonyl-aminoprop-2-yl]-6-(tert.-butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester are converted into the title compound, TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.08; IR (CH2C12): 3610, 3440, 1780, 1710 cm"1..

Example 16 (5R,6S)-2-[(2R,S)-1-aminoprop-2-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid At -10°, 9 mg of tetrakis(triphenylphosphine)-palladium and then 0.17 ml of tributyltin hydride are added to a solution of 82 mg of (5R, 6Sj-2-[ (21*,^) -1-allyloxycarbony1aminoprop-2-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid allyl ester in 3.5 ml of r - #-■*> *- vJ- u vJ '07*? o absolute THF. After stirring for 20 minutes at -10°, 0.037 ml of acetic acid is added and, after removal of the cooling bath, the reaction mixture is stirred for a further 30 minutes. After concentration in a rotary evaporator, the residue is taken up in water/ethyl acetate, the aqueous phase is separated off and the organic phase is extracted a further 3 times with water. After brief concentration in a rotary evaporator, the combined aqueous phases are lyophilised. UV (phosphate buffer pH 7.4): Xmax = 301 nm* The reaction product is identical with that produced in Example 12.

Example 17 (5R,6S)-2-[(2R,S)-2-aminoprop- 1-yl]-6-hydroxyrnethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester 1.2 g of sodium iodide are dissolved in 3.7 ml of acetone, and 0.275 ml of ethyl-1-chloroethyl carbonate is added. The mixture is stirred for 3 hours at room temperature. The solution is then added dropwise to 15.0 ml of methylene chloride and the inorganic salts that are formed are filtered off. The methylene chloride solution is concentrated to 2 ml and, at 0°, added to a solution of 0. 257 g (1 mmol) of (5R,6S_)- 2- [ (2JR,£) - 2-aminoprop- 1-yl] - 6-hydroxymethy 1-2-penem- 3-carboxylic acid in 4 ml of dimethylacetamide. The mixture is then stirred for 3 hours at 0°, diluted with ethyl acetate and washed three times with water. The organic phases are dried over sodium sulphate and concentrated in a.rotary evaporator. The crude product is purified over 10 g of silica gel using ethyl acetate as eluant. The title compound is obtained in the form of a white foam. IR spectrum (methylene chloride): \ J V -V- / 2 0 " A ■■■: V w .j absorption bands at 1790 and 1740 cm-"'.

Example 18 (5R,6S)-2-[(2R,S)-2-aminoprop-1-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid pivaloyloxymethyl ester 0.6 g of sodium iodide is dissolved in 2 ml of acetone, and 0.15 ml of pivalic acid chloromethyl ester is added. The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride. The inorganic salts that are formed are filtered off. The methylene chloride solution is concentrated to 1 ml and, at 0°, added to a solution of 0.1 g (0.4 mmol) of (5R,6£)-2-[(2R,£)-2-aminoprop-1-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of N,N-dimethy1acetamide. The mixture is stirred for 3 hours at 0°, then diluted with ethyl acetate and washed 3 times with water. The organic phase is dried over sodium sulphate and concentrated in a rotary evaporator. The crude product is purified over 10 g of silica gel using ethyl acetate as eluant. The title compound is obtained in the form of a white foam. IR spectrum (methylene chloride): absorption bands at 1790 and 1730 cm"1. .

Example 19 The following compounds are obtained in a manner analogous to that described in the preceding Examples: (5R,6S)-2-[(2R,S)-2-aminobut- 1-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4): Xmax = 302 nm' \ 4 o 208 055 (5R,6S)-2-[(2R,S)-l-aminoprop-2-yl]-6-[(IR)-1-hydroxyethyl] -2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4): Xmax = 303 nm, (5R,6S)-2-[(IS)-1-aminobut-1-yi]-6-[(IR)-1-hydroxy-ethyi]-2-penem-3-carboxylic acid, UV (phosphate buffer PH 7.4) : Xmax = 308 nm, (5R,6S)-2-[(IS)-1-aminobut-1-yl]-6-hydroxymethy1-2-penem-3-carboxyiic acid, UV (phosphate buffer pH 7.4): Xmax = 307•5 nm' (5R, 6S) -2- [ (IR) -1-aminoethyl] -6-hydroxymethyi-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4): Xmax = 308 nm' (5R,6S)-2-[(IS)-1-aminoethyl]-6-hydroxymethyi-2-penem-3-carboxyiic acid, UV (phosphate buffer pH 7.4): Xmax = 307 nm' (5R,6S)-2-(2-amino-2-methylprop-1-yI)-6-hydroxymethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR spectrum (CH^Clo): 1788 and 1738 cm-"', (5R, 6S) -2- [ (3R,S) -3-aminobut- 1-yl] -6-hydroxymethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR spectrum (CH2CI2) : 1790 and 1736 cm-"', (5R,6S)-2-[(2R,S)-l-aminoprop-2-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid 1-ethoxycarbonyloxyethyl ester, IR spectrum (CH2C12): 1787 and 1735 cm-1, 208055 (5R,6S)-2-(2-amino-2-methylprop-1-yl)-6-hydroxymethyi-2-penem-3-carboxylie acid pivaioyioxymethyl ester, IR spectrum (CH2CI2) : 1791 and 1733 cm-'', (5R,6S)-2-[(3R,S)-3-aminobut-1-yl]-6-hydroxymethy1-2-penem-3-carboxylic acid pivaioyioxymethyl ester, IR spectrum (0^012) : 1789 and 1732 cm-1, and (5R,6S)-2-[(2R,S)-l-aminoprop-2-yl]-6-hydroxymethyl-2-penem-3-carboxylic acid pivaioyioxymethyl ester, IR spectrum (CH2CI2) : 1788 and 1729 cm-"'.

Example 20 (5R,6S)-2-[(IR)-1-formamidinoethyl]-6-hydroxymethyl-2-penem-3-carboxylic acid A solution of 24 mg of (5R,6£)-2-[(1R)-1-aminoethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid and 8.4 mg of sodium bicarbonate in 1 mi of water is added at room temperature to a solution of 110 mg of ethyl-formimidate hydrochloride and 84 mg of sodium bicarbonate in 4 ml of water. After stirring for 50 minutes at room temperature, 1 mi of 1N HCi is added and the whole is concentrated under a high vacuum. The crude substance is purified by chromatography on OPTI UPC-J2* ^ (phosphate buffer pH 7.4): Xmax = 3 05 nm.

Example 21 Dry ampoules or phials, each containing 0.5 g of (5R,6S)-2-[(2R,£) -2-aminoprop-1-yl]-6-hydroxy-methyl-2-penem-3-carboxylic acid as active ingredient, are manufactured as follows:-

Claims (36)

I ■ V - 82 - 2OR 05 Composition: (for 1 ampoule or phial): active ingredient 0.5 g mannitol 0.05 g A sterile aqueous solution of the active ■xW ingredient and the mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 mi phiais and the ampoules or phiais are sealed and tested. Instead of the active ingredient mentioned above, it is also possible to use the same amount of a different active ingredient from the preceding Examples, such as, for example: (5R, 6S_) - 2- (2-amino-2-methy lprop- 1-yl) -6-hydro xy-methyl-2-penem-3-carboxylic acid, (5R,6£) -2- [ (3R,£) -3-aminobut-1-yl]-6-hydroxy-methyl-2-penem-3-carboxylic acid, or (5R, 6S) -2- [ (2R,S_) - 1-aminoprop-2-yi] -6-hydroxymethy l-2-penem-3-carboxy lie acid. WHAT -+/WE CLAIM IS:- Glaimo

1. Compounds of the formula R 1 O __A-R 3 (I) R. 2 in which R-j represents lower alkyl substituted by hydroxy or by protected hydroxy, R2 represents carboxy or protected carboxy V' R^ represents amino, lower alkyl-substituted amino, substituted methyleneamino or protected amino, and A represents straight-chain lower alkylene substituted by lower alkyl, with the proviso that R-j is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A is straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, and salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I and mixtures of these optical isomers.

2. Compounds of the formula I according to claim 1 in which R-j, R2 and A have the meanings given in claim 1 and R3 represents amino, substituted methyleneamino - 84 - 208065* [y si i • i » > or protected amino, with the proviso that R-j is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, optical isomers, mixtures of these optical isomers and salts thereof.

3. Compounds of the formula I according to claim 1 in which R-j represents lower alkyl substituted by hydroxy or by protected hydroxy, R2 represents carboxy or protected carboxy R2', R3 is amino, lower alkylamino, di-lower alkylamino, a group of the formula -N=C(X^,X2) in which X^ represents hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-iower alkylamino-lower alkyl, lower alkenyl, phenyl, pyridyl, thienyl, or thiazolyl, and represents amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio; or R3 is protected amino, and A represents straight-chain lower alkylene substituted by lower alkyl having from 1 to 4 carbon atoms, with the proviso that R^ is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino, and salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I that have chirality centres in the radicals R« and/or A, and mixtures of these optical isomers. o I - 85 - 208055

4. Compounds of the formula I according to claim 2 in which R^, R2 and A have the meanings given in claim 3 and R3 is amino, a group of the formula -N=C(X^,X2) *n which X^ represents hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, lower alkenyl, phenyl, pyridyl, thienyl, or thiazolyl, and X^ represents amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio; or R3 is protected amino, with the proviso that R^ is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino.

5. Compounds of the formula I according to claim 1 in which R^ represents lower alkyl substituted by hydroxy, tri-lower alkylsiiyioxy, 2-halo-lower alkoxy, 2-halo-lower alkoxycarbonyloxy or by optionally nitro-substituted phenyl-lower alkoxycarbonyloxy, R2 represents carboxy, lower alkenyloxycarbonyl, optionally nitro-substituted benzyloxycarbonyl, lower alkanoyl-methoxycarbonyl, 2-halo-lower alkoxycarbonyl, 2-tri-lower alkylsilylethoxycarbonyl or an esterified carboxy group that can be cleaved under physiological condi-tions, ^ 208055 /-s - 86 - is amino, lower alkylamino, di-lower alkylamino, a group of the formula —N=C (X-j,X2) in which represents hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, and X^ represents amino, lower alkylamino or di-lower alkylamino; or R3 is azido, phthalimino, nitro, lower alkenyloxycarbonyl-amino, optionally nitro-substituted benzyloxycarbonyl-amino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino, and A represents straight-chain lower alkylene mono- or di-substituted by lower alkyl having from 1 to 4 carbon atoms, with the proviso that R^j is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R-j represents amino or protected amino, and salts of such compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I that have chirality centres in the radicals t R.j and/or A, and mixtures of these optical isomers.

6. Compounds of the formula I according to claim 2 irv^ which R-j, R2 and A have the meanings given in claim £ % ©^ 5 and R3 is amino, a group of the formula -N=C(X^,X2) in which X-j represents hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, and X^ represents amino, lower alkylamino or di-lower alkylamino; or R3 is azido, phthalimido, nitro, lower aikenyloxycarbonyl-amino, optionally nitro-substituted benzyloxycarbonyl-amino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino, with the proviso that R^ is other than 1-hydroxyethyl or protected 1-hydroxyethyl if A represents straight-chain - 87 - 2 0 3 0 lower alkylene geminally substituted by two methyl groups, R2 has the meaning given above and R3 represents amino or protected amino.

7. Compounds of the formula I according to claim 1 in which R-j represents lower alkyl substituted by hydroxy and A represents straight-chain lower alkylene that has from 1 to 4 carbon atoms and is mono-substituted by methyl or ethyl, or in which R-| represents hydroxymethyl and A represents straight-chain lower alkylene that has from 1 to 4 carbon atoms and is di-substituted by methyl or ethyl, and in which R2 in each case represents carboxy, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl or lower alkanoyloxymethoxycarbonyl, and R3 in each case represents amino, lower alkylamino or formamidino, and salts of such compounds of the formula I, optical isomers of compounds of the formula I that have chirality centres in the radicals R-j and/or A, and mixtures of these optical isomers.

8. Compounds of the formula I according to claim 2 in which R-j, R2 and A have the meanings given in claim 7 and R3 represents amino or formamidino.

9. Compounds of the formula I according to claim 1 or 2 in which R^ represents hydroxymethyl or 1-hydroxyethyl and A represents ethylene or 1,3-propylene each of which is mono-substituted by methyl or ethyl, or in which R.j represents hydroxymethyl and A represents ethylene di-substituted by methyl, and in which R2 in each case represents carboxy and R3 in each case represents amino, and salts of such compounds of the formula I.

10. The pure optical isomers of compounds of the 208055 88 formula I according to claim 1 that have farther chirality centres in the substituents and/or A, and salts of such compounds of the formula I.

11. The pure optical isomers of compounds of the formula I according to claim 2 that have further chirality centres in the substituents R^ and/or A, and salts of such compounds of the formula I.

12. Pharmaceutically acceptable salts of compounds of the formula I according to claim 1.

13. Pharmaceutically acceptable salts of compounds of the formula I according to claim 2.

14. Esters of compounds of the formula I according to claim 1 that can be cleaved under physiological conditions.

15. Esters of compounds of the formula I according to claim 2 that can be cleaved under physiological conditions.

16 . (51*, 6SJ -2- [ (2R, Sj -2-aminoprop- 1-yl ] -6-hydroxy-•methyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 2.

17. (5R,6£) -2-(2-amino-2-methylprop-1-yl)-6-hydroxy-methyi-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 2. - 89 - 208 C

18. (51?, 6S_) - 2- [ (3Rr S_) - 3-aminobut - 1-yl] -6-hydroxy— methyI-2-penem-3-carboxyiic acid and pharmaceutically acceptable salts thereof according to claim 2.

19. (5R,6SJ-2-(1-formamidinoethyl)-6-hydroxy-methyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.

20. (5R, 6S_) -2- [ (1R)-1-aminoethyl]-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.

21. (5R,615) - 2- [ (iSj - 1-aminoethyl] -6-hydroxymethyl-2-penem-3-carboxyiic acid and pharmaceutically acceptable salts thereof according to claim 1.

22. (5R,6S_)-2-[ (2R^,S^) -2-aminobut-1—yl] — 6-hydroxymethyl—2—penem—3-car boxy lie acid and pharmaceutically acceptable salts thereof according to claim 2.

23. Pharmaceutical preparations containing compounds of the formula I according to claim 1 or pharmaceutically acceptable salts of such compounds.

24. Pharmaceutical preparations containing compounds of the formula I according to claim 2 or pharmaceutically acceptable salts of such compounds.

25. Use of compounds of the formula I according to claim 1 and pharmaceutically acceptable salts of such compounds for the manufacture of pharmaceutical preparations .

26. Use of compounds of the formula I according to claim 2 and pharmaceutically acceptable salts of such 208055 - 90 - compounds for the manufacture of pharmaceutical preparations.

27. Compounds of the formula I according to claim 1 and pharmaceutically acceptable salts of such compounds for use in a method for the therapeutic treatment of the human or animal body.

28. Compounds of the formula I according to claim 2 and pharmaceutically acceptable salts of such compounds for use in a method for the therapeutic treatment of the human or animal body.

29. Process for the manufacture of compounds of the formula I according to claim 1, their salts, their optical isomers and mixtures of their optical isomers, characterised in that a) an ylide compound of the formula o. - 91 -z II S-C-A-R„ / 208 05 (ID in which R^, R2'f R3 an<3 A have the meanings given in claim 1, the hydroxy group in a radical R^ and a free amino group R3 optionally being in protected form, Z represents oxygen or sulphur and X® represents either a tri-substituted phosphonio group, or a di-esterified phosphono group together with a cation, is cyciised, or b) a compound of the formula / -C-A-R, _N -c=o L. (in) in which R^r R2 1 r R3 an<3 A have the meanings given in claim 1, the hydroxy group in a radical R^ and a free amino group R3 optionally being in protected form, is treated with an organic compound of trivalent phosphorus, and, if desired or necessary, in a resulting compound of the formula I, a protected hydroxy group in a radical R-j is converted into the free hydroxy group, and/or, if desired, in a resulting compound of the formula I, a protected carboxy group R2' is converted \ 208055 o 92 into the free carboxy group or into a different protected carboxy group R2 1, or a free carboxy group R2 is converted into a protected carboxy group R2'» and/or, if desired, a protected amino group R-j is converted into the free amino group, or a free amino group R3 is converted into a substituted amino group, and/or, if desired, a resulting compound having a salt-forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting mixture of isomeric compounds of the formula I is separated into the individual isomers.

30. Process for the manufacture of compounds of the formula I according to claim 2, their salts, their optical isomers and mixtures of their optical isomers, characterised in that a) an ylide compound of the formula (II) in which R^, R2', R.j and A have the meanings given in claim 2, the hydroxy group in a radical Rq and a free amino group R3 optionally being in protected form, Z represents oxygen or sulphur and X® represents either a tri-substituted phosphonio group, or a di-esterified phosphono group together with a cation, is cyciised, or b) a compound of the formula (III) in which R,j, R2 •, R^ and A have the meanings given in claim 2, the hydroxy group in a radical R-j and a free amino group R3 optionally being in protected form, is treated with an organic compound of trivalent phosphorus, and, if desired or necessary, in a resulting compoun of the formula I, a protected hydroxy group in a / I ... - - ' 208055 - 93 - radical is converted into the free hydroxy group, and/or, if desired, in a resulting compound of the formula I, a protected carboxy group R2' is converted into the free carboxy group or into a different protected carboxy group R2', or a free carboxy group R2 is converted into a protected carboxy group R2', j and/or, if desired, a protected amino group R3 is converted into the free amino group, or a free amino group R3 is converted into a substituted amino group, and/or, if desired, a resulting compound having a salt- forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting mixture of isomeric compounds of the formula I is separated / s :(-v -» into the individual isomers. if-; \ I 17 NOV1986!

31. The compounds of formula I, as defined in claim 1, obtained by the process according to claim 29.

32. The compounds of formula I, as defined in claim 2, obtained by the process according to claim 30.

33. A compound of the formula I, as defined in claim 1, if manufactured according to the method of claim 29.

34. A compound of the formula I, as defined in claim 2, if manufactured according to the method of claim 30.

35. A compound of the formula I, as defined in claim 1, substantially as herein described.

36. A method for the manufacture of a compound of the formula I, as defined in claim 1, substantially as herein described. CIBA-GEIGY AG BY THEIR ATTORNEYS BALDWIN, SON & C^"v' &■ $1.