NZ198336A - 7-beta-aminothiadiazolylacetylamino-3-ammoniomethyl-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 98336 1 983 36 Priority II 4 $1 Cor^p1j';3 Specification FiJod: v. ■ ■ .4'. Ciaso-CQ7?km).

Pub'leallon Dats: ...

J-c urn r.t, f^o: I£58 ■ ■■■■■ a ^ ^ £1 ?•-^ K . \ >. / ;/f » '., . ;% & r.vv'l Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Ammoniomethyl compounds, processes for their manufacture, pharmaceutical preparations that contain these compounds, and the use of these compounds!' I-/WE CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which i/we pray that a patent may be granted to me/us , and the method by which it is to be performed, to be particularly described in and by the following statement (foJfowed by page ? A.) 1 98 3 3 - 1A - 4-13Q59/1+2/+ Ammoniomethyl compounds, processes for their manufacture, pharmaceutical preparations that contain these compounds, and the use of these compounds.

The present invention relates to novel 7p-amino-thiadiazolylacetylamino-3-ammoniomethyl-3-cephem-4-carboxylic acid compounds, processes for their manufacture, pharmaceutical preparations that contain such compounds, and their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

The invention relates especially to 7|3-aminothia-diazolylacetylamino-3-ammoniomethyl-3-cephem-4-carboxylic acid compounds of the formula Am - T - C - C II N I 0-R_ N- I H <0)n n s /\ (I) 0 .N ._CH_R_ W 2 1 too ^ 198 3 3 6 in which n represents 0 or 1, Am represents unsubstituted or substituted amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to a group of the formula -CC-H-O-Rg)-, R.j represents an unsubstituted or substituted pyrazolio group, an unsubstituted or substituted triazolio group* a tri-4ower alkylammonio group or a pyrid1.nl o group of the formula R -N \ R (A), R in which Ra represents lower alkyl substituted by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or by sulpho; unsubstituted lower alkenyl or lower alkylthio or lower alkenyl or lower alkylthio substituted by carboxyl; unsubstituted amino or amino mono-substituted by lower alkyl, lower alkanoyl or by aminobenzenesulphonyl; di-lover alkylamino; carbamoyl monosubstituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy, or by cyano; di-lower alkylcarbamoyl; thio-carbamoyl; cycloalkyl, phenyl; hydroxy; lower 1 983 3 6 alkoxy; halogen; lower alkoxycarbonyl; lower alkanoyloxy; lower alkanoyl; carboxyl; sulpho; cyano; nitro or hydroxysulpho-lower alkyl; represents carbamoyl or hydrogen or has the meanings of Ha, and Rc represents hydrogen or has the meanings of Ra, and represents hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl, or unsubstituted or substituted carbamoyl, and salts of such compounds having a salt-forming group, processes for the manufacture of these compounds, pharmaceutical agents that contain these compounds, and their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

In compounds of the formula I, the index n has especially the value 0. If n has the value 1, the corresponding 1-oxide is in the a- or ^-configuration.

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

The general definitions used hereinbefore and hereinafter preferably have the following meanings within the framework of the present description: Substituted amino Am is, for example, amino protected by the groups described hereinbelow, that is to say, substituted amino, especially acylamino, that can readily be split and can be converted into free amino.

It may, however, also be protected secondary or tertiary amino, for example amino mono- or di-substituted by lower alkyl, especially methylamino.

Lower alkyl is, for example, methyl, ethyl, n-propyl, 1 98 3 3 isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, and also n-pentyl, neopentyl, n-hexyl or n-heptyl.

A thiadiazole radical T is, for example, a 1,2,4-thiadiazole radical that is bonded in the 3- and 5-positions to Am and the group of the formula -CCall-O-Rg)-# the group Am being linked to the 1,2,4-thiadiazole radical T preferably in the 5-position. Further thiadiazole radicals T are 1,2,3-thiadiazole radicals that are bonded in the 4- and 5-positions to the group Am and the group of the formula -C(, and also the symmetric 1,3,4-and 1,2,^-thiadiazole radicals that in each case are bonded at the two ring carbon atoms to the group Am and the group of the formula -CCsJJ-O-Rg)-. The thiadiazole group T substituted by an amino group may also be in tautomeric form as a dihydrothiadiazole group substituted by an imino group or in the form of a mixture of the two forms. The equilibrium between the two tautomers depends on the type of optionally substituted amino group Am and on external factors, such as temperature, solvent or pH value. Within the framework of the present invention, the thiadiazole group is denoted in the description and the claims only by the term "thiadiazole group", although the dihydrothiadiazole form is also included.

An unsubstituted or substituted pyrazolio group is, for example, pyrazolio or pyrazolio substituted by lower alkyl, for example methyl, ethyl, propyl or tert.-butyl, lower alkenyl, for example vinyl or allyl, carboxy-lower alkyl, for example carboxymethyl or 2-carboxy-ethyl, lower alkoxycarbonyl-lower alkyl, for example methoxycarbonylmethyl or ethoxycarbonylmethyl, sulpho-lower alkyl, for example sulphomethyl or 2-sulphoethyl, amino-lower alkyl, for example aminomethyl or 2-aminoethyl, lower alkylamino-lower alkyl, for example methylaminomethyl, di-lower alkylaaino-lower alkyl, for example dimethylamino-methyl or 2-dimethylaminoethyl, carbamoyl-lower alkyl, for 1 9833 example carbamoylmethyl, di-lower alkylcarbamoyl-lower alkyl, for example dimethylcarbamoylmethyl, sulphamoyl-lower alkyl, for example aulphamoylmethyl, di-lower alkylsulphamoyl-lower alkyl, for example dimethylsulpha-moylmethyl, hydroxy-lower alkyl, for example hydroxymethyl, or by lower alkoxy-lower alkyl, for example me thoxymethyl• Preferred substituted pyrazolio groups are, for example, 2-lower alky1-1-pyrazolio, for example 2-methyl-, 2-ethyl-, 2-propyl- or 2-tert.-butyl-1-pyrazolio, 2-lower alkenyl-1 -pyrazolio, for example 2-ally1- or 2-viny1-1-pyrazolio, 2-carboxy-lower alky1-1-pyrazolio, for example 2-carboxymethy 1-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, for example 1-carboxymethyl-1-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-1-pyrazolio, for example 2-methoxycarbonylmethyl-1-pyrazolio or 2-ethoxycarbonylmethyl-1-pyrazolio, 2-sulpho-lower alkyl-1-pyrazolio, for example 2-sulphomethyl-1-pyrazolio, 2-amino-lower alkyl-1-pyrazolio, for example 2-(2-aminoethyl)-1-pyrazolio, 2-di-lower alkylamino-lower alkyl-1-pyrazolio, for example 2-(2-dimethylaminoethyl)-1 -pyrazolio, 2-carbamoyl-lower alkyl-1-pyrazolio, for example 2-carbamoyl-methy1-1-pyrazolio, 2-di-lower alkylcarbamoyl-lower alkyl- 1-pyrazolio, for example 2-dimethylcarbamoylmethyl-1-pyrazolio, 2-sulphamoyl-lower alkyl-1-pyrazolio, for example 2-eulphamoylmethyl-l-pyrazolio, 2-hydroxy-lower alkyl-1-pyrazolio, for example 2-hydroxymethyl-1-pyrazolio, and 2-lower alkoxy-lower alkyl-1-pyrazolio, for example 2-methoxymethyl-1 -pyrazolio.

An ur>substituted or substituted triazolio group R.j is, for example, triazolio or triazolio substituted by lower alkyl, for example methyl, ethyl, propyl or tert.-butyl, lower alkenyl, for example vinyl or allyl, carboxy-lower alkyl, for example carboxymethyl or 2-carboxyethyl, sulpho-lower alkyl, for example sulphomethyl or 2-aulphoethyl, 1 9833 amino-lower alkyl, for example aminomethyl or 2-amino-ethyl, di-lower alkylamino-lower alkyl, for example dimethyl-aminomethyl or 2-dimethylaminoethyl, carbamoyl-lower alkyl, for example carbamoylmethyl, sulphamoyl-lower alkyl, for example aulphamoylmethyl, hydroxy-lower alkyl, for example hydroxymethyl or by lower alkoxy-lower alkyl, for example methoxymethyl.

Preferred substituted triazolio groups are, for example, 3-lower alkyl-1 -triazolio, for example 3-methyt> 3-ethyl-, 3-propyl- or 3-tert.-butyl-1 -triazolio, 3-lower alkenyl-1-triazolio, for example 3-vinyl or 3-allyl-1-triazolio, 3-carboxy-lower alkyl-1-triazolio, for example 3*-carboxymethyl-1-triazolio, 3-sulpho-lower alkyl-1-triazolio for example 3-sulphomethyl-1 -triazolio, 3-amino-lower alkyl-1-triazolio, for example 3-(2-am1noethyl)-1-tria-zolio, 3-di-lower alkylamino-lower alkyl-1-triazolio, for example 3-(2-dimethylaminoethyl)-1-triazolio, 3-carbamoyl-lower alkyl-1-triazolio, for example 3-earbamoylmethyl-1-triazolio, 3-sulphamoyl-lower alkyl-1-triazolio, for example 3-solphamoylmethyl-l-triazolio, 3-hydroxy-lower alkyl-1-triazolio, for example 3-hydroxymethyl-1-triazolio, and 3-lower alkoxy-lower alkyl-1-triazolio, for example 3-methoxymethyl-1 -triazolio.

A tri-lower alkylammonlo group is, for example, trimethylammonlo, triethylammonio or dimethylethylammonio.

In a pyridinio group of the formula A, Ea is in the 2-, 3- or 4-position of the pyridine ring.

In a pyridinio group of the formula A, lower alkyl Ra substituted by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carbonyl or by sulpho represents, for example, cyclopropyl-, cyclopentyl- or cyclohexyl-methyl, cyclopropyl-, cyclopentyl- or cyclohexyl-1,1- or -1,2-ethyl, benzyl, 1- or 2-phenylethyl, diphenyl-methyl or trityl, hydroxymethyl, 1- or 2-hydroxyethyl, 19833 methaxymethyl, ethoxymethyl or methoxy-1,1 - or -1,2-ethyl, chlor omethyl, trifluor omethyl, 2-chloro-, 2-bromo-or 2-iodo-ethyl, 2,2,2-trifluoro- or 2,2,2-trichloro-ethyl, cyanomethyl, 1- or 2-cyanoethyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl or 2-carboxyethyl, sulpho-methyl, 1-aulpho— or 2-sulpho-ethyl.

Lower alkenyl or lower alkylthio Ra that is unsubstituted or substituted by carboxyl is, for example, vinyl, allyl, n-propenyl, 1-, 2- or 3-butenyl, 2-carboxy-vinyl or 3-carboxyallyl, methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio, 2-carboxyvinyl-thio or 3-carboxyallylthio.

Amino Ra that is unsubstituted or monosubstituted by lower alkyl, lower alkanoyl or aminobenzenesulphonyl is, for example, amino, methylamino, ethylamino or n-propylamino, f or my lam j no, acetyl.aml.no or propionyIami.no or 3- or 4~ftminobenzenesulphopylam1.no.

Di-lower alky lam in o Ra is, for example, dimethyl amino diethylamino or di-n-propylamino.

Carbamoyl Ra monosubstituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy or cyano is, for example, methylcarbamoyl or ethylcarbamoyl, hydroxy-methylcarbamoyl or 1- or 2-hydroxyethylcarbamoyl, methoxy-carbamoyl or ethoxycarbamoyl, JJ-hydroxycarbamoyl or N-cyanocarbamoyl.

Di-lower alkylcarbamoyl Ra is, for example, dime thylcarbamoyl or diethylcarbamoyl.

Cycloalkyl Ra is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Lower alkoxy Ra is, for example, methoxy, ethoxy or propoxy.

Halogen Ra is, for example, fluorine, chlorine or bromine* Lower alkoxycarbony 1 Ra is, for example, methoxy- 1 98 3 3 £> carbonyl or ethoxycarb ony 1.

Lower alkanoyloxy Ha is, for example, formyloxy or acetoxy.

Lower alkanoyl Ra is, for example, formyl, acetyl, propionyl, isobutyryl or n-butyryl.

Hydroxysulpho-lower alkyl Ra is, for example, hydroxysulphomethyl, 1-hydroxy-2-sulphoethyl, 2-hydroxy-1 -sulphoethyl or 2-hydroxy-2-sulphoethyl.

Pyridinio groups of the formula A in which Ra b o has the meanings given above, R has the meanings of R or represents carbamoyl or hydrogen, and Rc represents hydrogen are preferred.

Preferred pyridinio groups of the formula A are, for example: hydroxy-lower alkylpyridinio, for example 3- or 4-hydroxymethylpyridinio, lower alkoxy-lower alkylpyridinio, for example 4-methoxymethylpyridinio, cyano-lower alkylpyridinio, for example 3-cyanomet hy lpyridinio, carboxy-lower alkylpyridinio, for example 3-carboxymethyl-pyridinio, sulpho-lower alkylpyridinio, for example 4-(2-8ulphoethyl)-pyridinio, carboxy-lower alkenylpyridinio, for example 3-(2-carboxyvlnyl)-pyridinio, carboxy-lower alkylthiopyridinio, for example 4-carboxymethylthiopyri-dinio, thiocarbamoylpyridinio, for example 4-thiocarbamoyl-pyridinio, halopyridinio, for example 3-bromo- or 4-bromo-pyridinio, carboxypyridinio, for example 4-carboxy-pyridinio, sulphopyridinio, for example 3-sulphopyridinio, cyanopyridinio, for example 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, for example 3-carboxymethyl- 4-carbamoylpyridinio, aminocarbamoylpyridinio, for example 2-am1no-5-carbamoylpyridinio, carboxycarbamoylpyridinio, for example 3-carboxy-4-carbamoylpyridinio, cyano-halo-methylpyridinio, for example 3-cyano-4—trifluoromethylpy-ridinio, and aminocarboxypyridinio, for example 2-amino- 3-carboxypyridinio. 198336 The group of the formula ^H-O-Rg is in the syn (or 2) conformation or in the anti (or conformation, the syn (or Z) conformation being preferred.

A lower alkyl group R2 contains preferably from 1 to 4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl.

A cycloalkyl group R2 contains preferably from 3 to 8, especially from 3 to 6, ring members and is, for example, cyclobutyl, cyclopentyl or cyclohexyl and especially cyclopropyl.

Substituents of substituted lower alkyl or cycloalkyl R^ are- inter alia, optionally etherified hydroxy, for example lower alkoxy, primary, secondary or tertiary amino Am, for example amino or di-lower alkylamino, optionally functionally modified, for example esterified, amidated or protected, carboxyl or sulpho, and ureido-carbonyl optionally H-substituted by lower alkyl. The substituted lower alkyl and cycloalkyl groups are preferably substituted by a carboxyl or sulpho group, these preferably being located at the carbon atom bonded to the oxygen atom of the oxyimino group.

Substituted lower alkyl or cycloalkyl groups R2 of this type are, for example, 2-aminoethyl, 2-dimethyl-aminoethyl, carboxymethyl, 1- or 2-carboethyl, 12- or 3-carboxyprop-1-yl, 1- or 2-carboxyprop-2-yl, 1-earboxybut-1-yl, 1-carboxycycloprop-1-yl and 1-carboxycyclobutyl-1-yl, and corresponding lower alkyl and cycloalkyl groups substituted by sulpho.

The carboxy and sulpho groups in the radical Rg may be esterified, for example, by lower alkyl, such as methyl or ethyl, or by a group that can be split off under physiological conditions, for example by pivaloyloxymethyl, or may be amidated by HH^, a primary or secondary amine, for example a mono- or di-lower alkylamine, for example methyl- or ethyl-aaine or dimethyl- or diethyl-amine, or may be protected by the protecting groups mentioned hereinbelow.

Optionally substituted carbamoyl as the radical R2 ia» for example, a group -C(*0)-HEE, in which B. represents hydrogen, lower alkyl, for example methyl, ethyl or 1- or 2-propyl; optionally protected carboxy-lower alkyl, for example carboxymethyl, 1- or 2-carboxyethyl or 1-, 2- or 3-carboxypropyl, wherein carboxy may be protected by one of the customary carboxy-protecting groups or may be esterified, for example by lower alkyl, for example methyl, ethyl, n-propyl or isopropyl, or n-butyl or tert«-butyl; optionally protected sulpho-lover alkyl, for example sulphomethyl, 1- or 2-sulphoethyl or 1-, 2- or 3-sulpho-propyl, wherein sulpho may be protected by one of the customary sulpho-protecting groups or may be esterified, for example by lower alkyl, for example methyl or ethyl; optionally protected hydroxy-lower alkyl, for example hydroxymethyl, 2-hydroxyethyl or 2- or 3-hydroxypropyl, wherein hydroxy may be protected by one of the customary hydroxy-protecting groups or, for example, acylated, for example acetylated; optionally protected amino-lower alkyl, for example 2-aminoethyl, 2- or 3-aminopropyl or 2-, 3- or 4-aminobutyl, wherein amino may be protected by one of the customary ami no-protecting groups or, for example, acylated, for example acetylated; aryl-lower alkyl, f or acample phenyl-lower alkyl, for scample benzyl or 1- or 2-phenylethyl; halo-lower alkyl, for example fluoro-, chloro- or bromo-lower alkyl, for example 2-chloroethyl, 3-chloropropyl or 4-chlorobutyl; aryl, for example phenyl, or phenyl mono- to tri-substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or by nitro.

As mentioned above, functional groups in compounds ofihe formula I, especially the carboxyl and amino groups and also the hydroxy and sulpho groups, may optionally be protected by protecting groups, it being customary to use the protecting groups used in penicillin, cephalosporin and peptide chemistry.

Such protecting groups can "be split off readily, that is to say without undesired side-reactions taking place, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.

Protecting groups of this type and the manner in which they are split off are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, ISTew York, 1973* in "The Peptides", vol. I, Schrttder and Lttbke, Academic Press, London, New York, 1965, and in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol. 15/lt G-eorg Thieme Terlag, Stuttgart, 1974* Thus, carboxyl groups are protected, for example in esterified form, such ester groupings being readily split under mild conditions. Carboxyl groups protected in this manner contain as esterifying groups especially lower alkyl groups branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxyl groups in esterified form are, inter alia, tert»-lower alkoxycarbonyl, for example tert.-butoxyearbonyl; aryl-methoxycarbonyl having one or two aryl radicals that are phenyl radicals optionally mono- or poly-substituted, for example by lower alkyl, such as tert.-lower alkyl, for example tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/or nitro: such as benzyloxycarbonyl optionally substituted, for example as mentioned above, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, or diphenylmethoxycarbonyl optionally substituted, for example as mentioned above, for example diphenylmethoxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl; 1-lower alkoxy-lower alkoxycarbonyl, such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl; 1-lower alkylthio-lower alkoxycarbonyl such as 1-methylthiomethoxycarbonyl or 1 -ethylthioethoxy-carbonyl; aroylmethoxycarbonyl, in which the aroyl group 198 3 36 Is benzoyl optionally substituted) for example by halogen* such as bromine, for example phenacyloxycarbonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloro-ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxy-carbonyl; or 2-(tri-substituted silyl)-ethoxycarbonyl, in which each of the substitutents represents, independently of one another, an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having, for example, up to 15 carbon atoms and being optionally substituted, for example by lower alkyl, lower alkoxy, aryl, halogen and/or nitro, for example optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl: for example 2-tri-lower alkylailylethoxycarbony 1, such as 2-trimethyl-silylethoxycarbonyl or 2-(di-n-butylmethyl-silyl)-ethoxy-carbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenyls ilylethoxycarbonyl.

Purther protected carboxyl groups in esterified form are silyloxycarbonyl groups, especially organic silyloxycarbonyl groups, and also stannyloxycarbonyl groups* In these groups, the silicon or tin atom contains as substitutent preferably lower alkyl, especially methyl, also lower alkoxy, for example methoxy, and/or halogen, for example chlorine* Suitable silyl or stannyl protecting groups are especially tri-lower alkylsilyl, especially trimethylsilyl, also dime thyl-tert.-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, for example methoxy-methyl-chloro-silyl, or di-lower alkyl-halo-silyl, for example dimethyl-chloro-silyl, or correspondingly substituted stannyl compounds, for example tri-n-butylstannyl.

Preferred protected carboxyl groups are tert.-lower alkoxycarbonyl, such as tert.-butoxycarbonyl, and especially benzyloxycarbonyl optionally substituted, for example as mentioned above, such as 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl.

A protected amino group, such as a corresponding 1 983 36 group Am* may* for example* be in the form of a readily splittable acylamino* arylmethylaroino * etherified mercap-toamino, 2-acyl-lower alk-1-en-1-ylamino, ailylamino or stannylamino group or in the form of an azido group.

In a readily splittable acylamino group, acyl is, for example * the acyl radical of an organic carboxylic acid having* for example * up to 18 carbon atoms * especially of an alkanecarboxylic acid optionally substituted* for example by halogen or aryl, 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-chloro-, 2-bromo-, 2-iodo- 2,2,2-trifluoro-or 2,2,2-trichloro-acetyl; benzoyl optionally substituted, for example by halogen, lower alkoxy or nitro, for example benzoyl, 4-chloro-, 4-methoxy- or 4-nitro-benzoyl; lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical cr suitably substituted in the 1- or 2-position, especially tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl; arylmethoxycarbonyl having one or two aryl radicals that are phenyl optionally mono- or poly-substituted, for example by lower alkyl* especially tert.-lower alkyl* such as tert.-butyl, lower alkoxy* such as methoxy, hydroxy, halogen, for example chlorine, and/or nitro: such as optionally substituted benzyloxy-carbonyl, for example 4-nitrobenzyloxycarbonyl, or optionally substituted diphenylmethoxycarbonyl, for example benzhy-dryloxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl; aroylmethoxycarbonyl, in which the aroyl group is preferably benzoyl optionally substituted, for example by halogen, such as bromine* for example phenacyloxycarbonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxy-carbonyl, 2-bromoethoxycarbonyl or 2-iodiethoxycarbonyl; or 2-(tri-substituted silyl)-ethoxycarbonyl, in which each 1 983 36 of the substituents represents* Independently of one another* an aliphatic, araliphatic* cycloaliphatic or aromatic hydrocarbon radical having, for example, up to 15 carbon atoms and being optionally substituted, for example by lower alkyl* lower alkoxy, aryl, halogen or nitro, for example optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl: far example 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethyl-silylethoxycarbonyl or 2-( di-n-butyl-methyl-silyl) -ethoxy-carbonyl, or 2-triarylailylethoxycarbonyl, such as 2-triphenyls ilylethoxycarbonyl.

Further acyl radicals coming into consideration as amino-protecting groups are corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl, for example dimethylphoephoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphos-phoryl, dicycloalkylphosphoryl, for example dlcyclohexyl-phosphoryl, optionally substituted diphenylphosphoryl* far example diphenylphosphoryl, diphenyl-lower alkylphosphoryl optionally substituted, for example by nitro, for example dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, optionally substituted phenoxyphenylphosphonyl, for example phenoxy-phenylphosphonyl, di-lower alkylphosphlnyl, for example diethylphosphinyl, or optionally substituted diphenyl-phosphinyl, for example diphenylphosphinyl.

In an arylmethylamino group that is a mono-, di- or especially tri-arylmethylamino group, the aryl radicals are especially optionally substituted phenyl radicals. Such groups are, for example, benzyl**, diphenyl-methyl- and especially trityl-amlno.

An etherified mercapto group in an amino group protected by such a radical is especially arylthio or aryl-lower alkylthio in which aryl is especially phenyl optionally substituted, for example by lower alkyl, such as methyl or tert♦-butyl, lower alkoxy, such as methoxy, halogen, such, as chlorine, and/or nitro. A corresponding amino-protecting group is, for example, 4-nitrophenylthio.

In a 2-acyl-lower alk-1-en-1-yl radical that may be used as an amino-protecting group, acyl is, for example, the corresponding radical of a lower alkanecarboxylic 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 nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester. Corresponding protecting groups are especially 1-lower alkanoylprop-1-en-2-yl, for example 1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl, for example 1-ethoxycarbonyl-prop-1-en-2-yl.

A silyl- or stannyl-amino group is especially an organic silyl- or stannyl-amino group in which the silicon or tin atom contains as substituent preferably lower alkyl, especially methyl, also lower alkoxy, for example methoxy, and/or halogen, for example chlorine. Corresponding silyl or stannyl groups are especially tri-lower alkylsilyl, especially trimethylsilyl, also dimethyl-tert.-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, for example methoxy-methyl-chlorosilyl or di-lower alkyl-halo-silyl, for example dimethylchloro-silyl, or correspondingly substituted stannyl, for example tri-n-butylstannyl.

An amino group may also be protected in protonated form; as suitable anions there come into consideration especially those of strong inorganic acids, such as hydro-halic acids, for example the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acid.

Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially tert.-butoxycarbonyl, or benzyloxycarbonyl optionally substituted, for example as indicated, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, or trityl or formyl.

Hydroxy-protecting groups are, for example, acyl radicals, such as lower alkanoyl optionally substituted, for example by halogen, such as 2,2-dichloroacetyl, or especially the acyl radicals of carbonic acid semiesters mentioned in connection with a protected amino group, especially 2,2,2-trichloroethoxycarbonyl, or organic silyl or stannyl radicals, also etherifying groups that are readily split off, such as tert .-lower alkyl, for example tert .-butyl, 2-oxa- or 2-thja-aHphatic or 2 oxa-or 2-thia-cycloaliphatic hydrocarbon radicals, especially 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for example methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1 -methylthiomethyl, 1-metbylthioethyl or 1 -ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues, and also optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenylmethyl, there coming into consideration as substituents of the phenyl radicals, for example halogen, such as chlorine, lower alkoxy, such as methoxy, and/or nitro.

A protected sulpho group is especially an esterified sulpho group, such as a sulpho group esterified by an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, for example by a lower alkanol, or by a silyl or stannyl radical, such as tri-lower alkylsilyl. In a sulpho group the hydroxy group mqr be etherified, for example in the same manner as the hydroxy group in an esterified carboxy group.

Salts of compounds according to the invention are especially pharmaceutically acceptable non-toxic salts, such as those of compounds of the formula I having acid groups, for example having a free carboxyl or sulpho group. 1 983 56 Such salts are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and also ammonium salts formed with ammonia or suitable organic amines, wherein especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines and also heterocyclic bases come into consideration for the salt formation, for example lower aJLkylamines, 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 acample 4-aminobenzoic acid 2-diethylamlnoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkyl-amines, for example dicyclohexylamine, or benzylamines, for example N,#'-dibenzylethylenediamine, also bases of the pyridine type, for example pyridine, collidine or quinoline. Compounds of the formula I having a basic group can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example trifluoroacetic acid, and also with amino acids, such as arginine and lysine. If several acid or basic groups are present, mono- or poly-salts may be formed. Compounds of the formula I having an acid group, forexample a free carboxyl group, and a basic group, for acample an amino group, may also be in the form of internal salts, i.e. in zwitterion form, or one part of ■fee molecule may be in the form of an internal salt and another may be in the form of a normal salt.

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

The compounds of the formula I in which the functional groups are in free form, i.e. not in protected form, and their pharmaceutically acceptable non-toxic salts are valuable antibiotically active substances which can be used especially as antibacterial antibiotics. They are, for example, effective vitro against gram-positive germs, for example against gram-positive cocci, for example Staphylococcus aureus, streptococci, for example Streptococcus pyogenes. Streptococcus pneumoniae and Streptococcus faecalls. against anaerobic germs, for example Clostridium perfrin&ens and Peptostreptococcua anaerobius. in concentrations of from approximately 0.05 jig/ml to approximately 64 ng/ml, against gram-negative germs, for example Bnterobacteriaceae. for example Escherichia coll. Proteus spp., Klebsiella pneumoniae. 3erratia marceacens and Bntero-bacter cloacae. and Pseudomonas aeruginosa. Haemophilus in-pi nanand Heisseria spp. , and against anaerobic gram-negative germs, for example Bacteroides fragjlis. in concentrations of from approximately 0.005 Hg/ml to approximately 32 ng/ml, and also against other gram-positive and gram-negative germs. In vivo, when administered subcutaneously to mice, they are effective against systemic infections caused by gram-positive germs, such as Staphylococcus aureus. in a dosage range of from approximately 5 mg/kg to approximately 100 mg/kg and against systemic infections caused by gram-negative germs, such as Bnterobacteriaceae. or Pseudomonas aeruginosa in a dosage range of from approximately 0.9 mg/kg to approximately 100 mg/kg. 1 983 36 Test evaluation 1. The antiobiotic activity of the following compounds was tested: 1• 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxy- iminoacetamido] -3-( 4-carboxypyridiniomethyl) -3-cephem-4-car"boxylate (Example 1); 2. 7p-[2-(5-amino-1,2,4-th.iadiazol-3-yl) -2-Z-2-carboxy-prop-2-yloxyiminoacetamido]-3-(3-carb oxymethylpyridini omethyl)-3-cephem-4-carboxylate (Example 2); 3» 7p-[2-(5-amino-1 ,2,4-thiadiazol-3-yl)-2-Z-2-carboxy- prop-2-yloxy 1 ml noacetamido j -3-( 2-methyl-1 -pyrazoliomethyl)- 3—cephem-4—carboxylate (Example 6); 4« 7p-[ 2-( 5-amino-1,2,4-th.iadiazol-3-yl) -2-Z-meth.oxy- iminoacetamido]-3-(2-methyl-1-pyrazoliomethyl)-3-cephem- 4-carboxylate (Example 8); . 7p-[2-(5-amino-1 ,2,4-thiadiazol-3-yl)-2-Z-meth.oxy-iminoacetamido]-3-(3-bromopyridiniomethyl)-3-cephem-4-carboxylate (Example 9); 6. 7p-[2-(5-amino-1 ,2,4-tliiadiazol-3-yl)-2-Z-methoxy- i mlnoacetamido] -3-( 4-hydroxymethylpyrid 1 niomethyl) -3-cephem-4-carboxylate (Example 11). 1 983 36 II. Methodology A. The antibiotic activity of the test compounds j,s vitro was established by the agar dilution method according to Bricson, H.M. and Sherris, S.C., 1221# Acta Path.

Microb. Scand. Section B, Suppl. Ho. 217, vol. 1-90, in DST agar. The minimum concentrations still inhibiting growth of the test organisms (MIC m minimum inhibiting concentrations) are given in micrograms per millilltre (|ig/ml) for the tested compounds in Table 1.

B. The chemotherapeutic activity i,n vivo against systemic infections in female SPF, mice was established according to the method of Zak, 0., et a^., 1979. Drugs Exptl. Clin. Res. 45-59. The BD^q values found in milligrams substance per kilogram mouse (mg/kg) against a number of micro-organisms are indicated in Table 2 for the test compounds administered subcutaneously (s.c.).

III. Teat results Table 1: antibiotic activity in vitro Micro-organisms MIC (ng/ml) 1 , 2 3 4 6 Streptococcus pyogenes 0.1 1 0.5 0.1 0.05 n.t.

Aronson Clostridium perfringens 0.005 0.1 0.05 0.005 0.01 0.01 (anaerobic) Pseudomonas aeruginosa 1 0.5 2 0.5 0.5 0.1 ATCC 12055 Escherichia coli 205 0.05 1 0.5 0.1 0.1 0,05 Table 2: cheraotherapeutic activity in vivo in mice; infecting micro-organisms ED50 (mg/kg. s * c., 1 2 3 4 6 Escherichia coli 205 K 1075 0.9 2 2.4 0.9 n.t.

Pseudomonas aeruginosa &TCC 12055 6 230 -30 3-10 (n.t.= not tested) 1 9833 The novel compounds of the formula I can therefore be used# for example in the form of antibiotically active preparations, for the treatment of infections caused by gram-positive or gram-negative bacteria and cocci, especially by enterobacteria, such as Serratia marcescens or Escherichia coli. and by Pseudomonas.

Compounds of the formula I in which the functional groups are protected are used as intermediates for the manufacture of compounds of the formula I in which the functional groups are in free form.

The invention relates especially to compounds of the formula I in which n represents O, Am represents amino, lower alkylamino, di-lower alkylamine or protected amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to a group of the formula -C^N-O-I^)-, represents 2-lower alkyl-1-pyrazolio, 2-carboxy-lower alkyl-1-pyrazolio, 1-carboxy-lower alkyl-1-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-1-pyrazolio, 3-lower alkyl-l-triazolio or a pyridinio group of the formula A in which Ra represents lower alkyl substituted by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or by sulpho; unsubstituted lower alkenyl or lower alkylthio or lower alkenyl or lower alkylthio substituted by carboxyl; unsubstituted amino or amino monosubstituted by lower alkyl, lower alkanoyl or amino-benzenesulphonyl; di-lower alkylamino; carbamoyl mono-substituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy or cyano; di-lower alkylcarbamoyl; thiocarbamoyl; cycloalkyl; phenyl: hydroxy; lower alkoxy; halogen; lower alkoxycarbonyl; lower alkanoyloxy; lower alkanoyl; carboxyl; sulpho; cyano; nitro or hydroxy- sulpho-lower alkyl; R*5 represents carbamoyl or hydrogen a c or has the meanings of R , and R represents hydrogen, and R2 represents hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl, or unsubstituted or substituted carbamoyl, the group of the formula =N-0-R2 having especially the svn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of such compounds of the formula I having salt-forming groups.

The invention relates more especially to compounds of the formula I in which n represents 0, Am represents amino, lower alkylamino, for example methylamino, or i protected amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to a group of the formula -C(=N-0-R2)-, R^ represents 2-lower alkyl-l-pyrazolio, for example 2-methyl-1-pyrazolio, 2-carboxy-lower alkyl-l-pyrazolio, for example 2-carboxymethyl-l-pyrazolio, 1-carboxy-1ower alkyl-l-pyrazolio, for example 1-carboxymethyl-l-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-l-pyrazolio, for example 2-methoxycarbonylmethyl-l-pyrazolio, 3-lower alkyl-1-triazolio, for example 3-methyl-l-triazolio, or a pyridinio group of the formula A, for example hydroxy-lower alkylpyridinio, for example 3- or 4-hydroxy-methylpyridinio, lower alkoxy-lower alkylpyridinio, for example 4-methoxymethylpyridinio, cyano-lower alkylpyridinio, for example 3-cyanomethylpyridinio, carboxy-lower alkylpyridinio, for example 3-carboxymethyl-pyridinio, sulpho-lower alkylpyridinio, for example 4-(2-sulphoethyD-pyridinio, carboxy-lower alkenylpyridinio, for example 3- (2-carboxyvinyl)-pyridinio, carboxy-lower alkylthiopyridinio, for example 4-carboxymethylthio-pyridinio, thiocarbamoylpyridinio, for example 4-thio-carbamoylpyridinio, halopyridinio, for example 3-bromo-or 4-bromo-pyridinio, carboxypyridinio, for example 4-carboxypyridino, sulphopyridinio, for example 3-sulpho— pyridinio, cyanopyridinio, for example 3-cyanopyridinio, carboxy-lower alkylcarbamoylpyridinio, for example 3-carboxymethyl-4-carbamoylpyridinio, aminocarbamoyl- 1 98 3 3-6 pyridinio, for example 2-amino-5-carbamoylpyridinio, carboxycarbamoylpyridinio, for example 3-carboxy-4-carbamoylpyridinio, cyano-halomethylpyridinio, for example 3-cyano-4-trifluoromethylpyridinio, or amino-carboxypyridinio, for example 2-amino-3-carboxypyridinio, and R2 represents hydrogen, lower alkyl, for example methyl, carboxy-lower alkyl, for example 2-carboxy-2-propyl, carbamoyl, lower alkylcarbamoyl, for example methylcarbamoyl, or amino-lower alkyl, for example 2-aminoethyl, the group of the formula =N-0-R2 having the syn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of such compounds of the formula I having salt-forming groups.

Prominence should be given to compounds of the formula I in which n represents O, Am represents amino, T represents a 1,2,4--thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to a group of the formula -C(=N-0-R2)-, R1 represents 2-lower alkyl-l-pyrazolio, for example 2-methyl-l-pyrazolio, 2-carboxy-lower alkyl-l-pyrazolio, for example 2-carboxymethyl-l-pyrazolio, 2-lower alkoxy-carbonyl-lower alkyl-l-pyrazolio, for example 2-methoxy-carbonylmethyl-l-pyrazolio , 3-lower alkyl-l-triazolio, for example 3-methyl-l-triazolio, or a pyridinio group of the formula A, for example hydroxy-lower alkylpyridinio, for example 4-hydroxymethylpyridinio, carboxy-lower alkylpyridinio, for example 3-carboxymethylpyridinio, sulpho-lower alkylpyridinio, for example 4-(2-sulpho-ethyD-pyridinio, halopyridinio, for example 3-bromo-pyridinio, carboxypyridinio, for example 4-carboxy-pyridinio, sulphopyridinio, for example 3-sulphopyridinio, or aminocarbamoylpyridinio, for example 2-amino-5-carbamoylpyridinio, and R2 represents hydrogen, lower alkyl, for example methyl, carboxy-lower alkyl, for example 2-carboxy-2-propyl, carbamoyl, or lower alkyl- 1 983 3 carbamoyl, for example methylcarbamoyl, the group of the formula =N-0-R2 having the syn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I.

Special prominence should be given to compounds of the formula I in which n represents 0, Am represents amino, T represents a 1,2,4-thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to a group of the formula -C(=N-0-R2)-, R^ represents 2-lower alkyl-l-pyrazolio, for example 2-methy 1-1-pyrazolio, or a pyridinio group of the formula A, for example hydroxy-lower alkylpyridinio, for example 4-hydroxymethylpyridinio, carboxy-lower alkylpyridinio, for example 3-carboxymethylpyridinio, halopyridinio, for example 3-bromopyridinio, or carboxypyridinio, for example 4-carboxypyridinio, and R2 represents lower alkyl, for example methyl, or carboxy-lower alkyl, for example 2-carboxy-2-propyl, or aminocarbamoylpyridinio, for example 2-amino-5-carbamoylpyridinio, the group of the formula =N-0-R2- having the svn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I.

The present invention relates most especially to the conqpounds of the formula I described in the Examples and their salts, especially their pharmaceutically acceptable salts.

Very special prominence is to be given to the following compounds of the formula I: 7(3-[2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-Z-methoxyimino-acet amido ] - 3- (4-carboxypyridiniomethyl) - 3-cephem- 4-carboxylate, 70-[2_(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop- 2-yloxyiminoacetamido]-3-(3-carboxymethylpyridiniomethyl)- 3-cephem-4-carboxylate, 7|J-[2-(5-amino-l, 2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop-2-yloxyiminoacetamido]-3- (2-methyl-l-pyrazoliomethyl )-3-cephem-4-carboxylate, 70—[2-(5-amino-l,2,4-thiadiazol-3-yl) - 2-Z-methoxy imino-acetamido)-3-(2-methyl-l-pyrazoliomethyl)-3-cephem-4-carboxylate, 70—C 2-(5-amino-l,2,4-thiadiazol-3-yl)- 2-Z-methoxy imino-acetamido ]-3- (3-bromopyridiniomethyl)-3-cephem-4-carboxylate, and 7{3-[2-(5-amino-l, 2,4-thiadiazol-3-yl)-2-Z^methoxyimino-acet amido]-3-(4-hydroxymethylpyridiniomethyl)-3-cephera-4-carboxylate.

Confounds of the formula I and salts of such compounds having a salt-forming group are manufactured, for example, by a) in a compound of the formula H H2N—f 0= in which the index n represents O or 1, has the meanings given under formula I, the 7(3-amino group is optionally protected by a group allowing the acylation reaction and the 4-carboxy group is optionally protected, acylating the 7p-amino group by reaction with an acylat-ing agent that introduces the acyl radical of a carboxylic acid of the formula Am-T-C-C-OH II N I 0-R„ (III)i in which Am, T and have the meanings given under formula I and functional groups present are optionally protected, or b) for the manufacture of a compound of the formula I in which n represents 0, isomerising a 2-cephem compound of the formula Am — T - H C - C II N I 0-R- — NH H ch2R1 COO © (IV), in which Am, T, R^ and R2 have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, to form the corresponding 3-cephem compound, or c) reacting a compound of the formula Am-T-C-C- COO (V), in which n represents O or 1, Am, T and R1 have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, with a hydroxylamine derivative of the formula H2N-0-R2 (VI) in which R2 has the meanings given under formula I and functional groups are optionally protected, or d) for the manufacture of a compound of the formula I in which R^ represents hydrogen, treating a compound of the formula Am - T - CH2 (VII), in which n represents 0 or 1, Am, T and R1 have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, with a nitrosating agent, or e) for the manufacture of a compound of the formula I in which Am represents a free or secondary amino group, T represents a 1,2,4-thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to a group of the formula -C(=N-0-R2)-, treating a compound of the formula 1 OQ i Vti 29 O X1 - NaG-C-c-NK **2 ? Orrr .

N ^-CH2R1 O-R 2 (VIII) COO ® in which n represents O or 1, X^ represents hydrogen, halogen or hydroxy, and R^ has the meanings given under formula I and in which the 4-carboxy1 group and other functional groups are optionally protected, with a salt of thiocyanic acid, or an isothiocyanic acid ester, or, if represents hydrogen, with dithiocyanogen, or f) reacting a compound of the formula in which n represents 0 or 1, Am, T and R^ have the meanings given under formula I and X^ represents a radical that can be replaced by nucleophilic substitution and in which the 4-carboxy1 group and other functional groups are optionally protected, with an organic tertiary base corresponding to the radical R^, or COOH (IX) 1 98 3 3 g) for the manufacture of compounds of the formula I in which Am represents a primary, secondary or tertiary amino group, reacting a compound of the formula in which n represents 0 or 1, T, and R^ have the meanings given under formula I and Y represents halogen, with ammonia or a primary or secondary amine Am-H or a metal amide thereof and, if desired, converting a resulting compound of the formula I into a different compound of the formula I and/or, if desired, converting a resulting compound of the formula I in which n represents 0 into a compound of the formula I in which n represents 1 and/or converting a compound of the formula I in which n represents 1 into a compound of the formula I in which n represents 0 and/or in a resulting compound of the formula I converting functional groups present in protected form into the free functional groups and/or converting a resulting salt into the free compound of the formula I or into a different salt and/or converting a resulting free compound of the formula I having a salt-forming group into a salt and/or separating a resulting mixture of isomeric compounds into the individual isomers. 1 983 3 Process a) (Acylation): In a starting material of the formula II, the 7^-amino group is optionally protected by a group allowing acylation. Such groups are, for example, organic silyl or stannyl groups, also ylidene groups that form a Schiff base together with the amino group. The said organic silyl or stannyl groups are, for example, those groups which cure capable of forming a protected carboxyl group also with a carboxyl group R2. These are especially tri-lower alkylsilyl, especially tri-methylsilyl. In the silylation or stannylation for protecting a 4-carboxyl group in a starting material of the formula II, the 70-amino group may also be silylated or stannylated if an excess of the silylating or stannylating agent is used. The said ylidene groups are especially 1-aryl-lower alkylidene groups, especially 1-arylmethylene groups in which aryl represents especially a carbocyclic aryl radical and more especially a monocyclic carbocyclic aryl radical, for example phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or nitro.

Other functional groups present in a starting material of the formula II may be protected, for example by the protecting groups mentioned above; The functional groups not participating in the acylation reaction, especially optionally present amino, hydroxy and mercapto groups that are capable of being acylated, are preferably appropriately protected.

In an acyl radical of the acid of the formula III, an amino group present may be protected also in ionic form, that is to say, the starting material of the formula III having such an amino group may be used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a hydrohalic acid, for example hydrochloric acid or sulphuric acid. 1 98 3 Acylating agents introducing the acyl radical of a carboxylic acid of the formula III are, for exanple, the carboxylic acid itself or its reactive functional derivatives.

If there is used for acylation a free carboxylic acid of the formula III, in which functional groups present, apart from the 4-carboxyl group participating in the reaction, may be protected, the reaction is normally carried out in the presence of suitable condensation agents, such as carbodiimides, for example N,N'-diethyl-, N,N*-dipropyl-, N,N'-dicyclohexyl- or N-ethyl-N1-3-dimethylaminopropylcarbodi imide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-l,2 oxazolium 31-sulphonate or 2-tert.-butyl-5-methyl-l,2-oxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-l-ethoxycarbony1-1,2,-dihydro-quinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetra-hydrofuran, in a mixture of these solvents with water or in water, if desired or necessary while cooling or heating, for example in a temperature range of from approximately -40°C to approximately +100°C, preferably from approximately -20°C to approximately +50°C and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

A reactive functional derivative of a carboxylic acid of the formula III, in which functional groups present, apart from the carboxyl group participating in the reaction, may be protected, is especially an anhydride of such an acid, including and preferably a mixed anhydride. Mixed anhydrides are, for example, those with inorganic acids, such as hydrohalic acids, 1 983 3 i.e. the corresponding acid halides, for example chlorides or bromides, also with hydrazoic acid, i.e. the corresponding acid azides, with a phosphorus-containing acid, for example phosphoric acid, diethyl-phosphoric acid or phosphorous acid, or with a sulphur-containing acid, for example sulphuric acid, or with hydrocyanic acid. Other mixed anhydrides sure, for example, those with organic carboxylic acids, such as with lower alkanecarboxylic acids optionally substituted, for example, by halogen, such as fluorine or chlorine, for exanqale pivalic acid or trichloroacetic acid, or with semiesters, especially lower alkyl semiesters of carbonic acid, such as the ethyl or isobutyl semiester of carbonic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, for example g-toluenesulphonic acid.

Other derivatives, suitable for reaction with the amino group, of an acid of the formula III, in which functional groups present, apart from the carboxyl group participating in the reaction, may be protected, cure activated esters, such as esters with vinylogous alcohols, i.e. with enols, such as vinylogous lower alkenols, or iminomethyl ester halides, such as dimethyliminomethy1 ester chloride, manufactured from the carboxylic acid of the formula III and, for example, dimethyl-(1-chloro-ethylidene)-iminium chloride of the formula ^^(CDCH^Cl ® which, in turn, can be obtained, for example, from N,N-dimethylacetamide and phosgene, aryl esters, for example phenyl esters substituted, for example by halogen, such as chlorine, and/or nitro, for example 4-nitrophenyl, 2,3-dinitrophenyl or penta-chlorophenyl ester, N-heteroaromatic esters, such as N-benztriazole esters, for exanqale 1-benztriazole ester, or N-diacylimino esters, such as N-succinylimino or N-phthalylimino ester.

The acylation with a reactive functional derivative of a carboxylic acid of the formula III, such as a 1 983 36 corresponding anhydride, especially an acid halide, is preferably carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or N,N-di-lower alkylaniline, for example N,N-dimethy1aniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a base of the pyridine type, for example pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a 1,2-lower aJLkylene oxide, such as ethylene oxide or propylene oxide.

The above acylations are preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or a mixture thereof, if necessary or desired at reduced or elevated temperature, for example in a temperature range of from approximately -40°C to approximately +100°C, preferably from approximately -10°C to approximately +50°C, and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

The acylation can also be carried out by using a suitable derivative of the acid of the formula III in the presence of a suitable acylase. Such acylases are known and can be formed by a number of micro-organisms, for example by acetobacter, such as Acetobacter aurantinm. achromobacter, such as Achromobacter aeris, aeromonas, 1 983 3 such as Aeromonas hvdrophila. or bacillus, for example Bacillus meqaterium 4-00. In an enzymatic acylation of this type there are used as corresponding derivatives especially amides, esters or thioesters, such as lower alkyl esters, for example methyl or ethyl ester, of the carboxylic acid of the formula III. Acylation of this type is customarily carried out in a nutrient medium containing the corresponding micro-organism, in a filtrate of the culture broth or, optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous medium optionally containing a buffer, for example in a temperature range of from approximately +20°C to approximately +4-0°C, preferably at approximately 37°C.

A reactive functional derivative of an acid of the formula III used in the acylation reaction may, if desired, be formed in situ. Thus, for example, a mixed anhydride can be manufactured by reacting an acid of the formula III, optionally having appropriately protected functional groups, or a suitable salt thereof, for example an ammonium salt, which is formed, for example, with an organic base, such as pyridine or 4—methyl-mo rpholine , or a metal salt, for example an alkali metal salt, with a suitable acid derivative, for example a corresponding acid halide, of an optionally substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, with a semiester of a carbonic acid semihalide, for example chloroformic acid ethyl ester or isobutyl ester, or with a halide of a di-lower alkylphosphoric acid, for example diethyl phosphorobromidate, which can be formed by reacting triethyl phosphite with bromine. The mixed anhydride so obtained may be used in the acylation reaction without isolation.

Process b) (Isomeriaation): In a 2-cephem starting material of the formula IV, the optionally protected 4-carboxyl group is preferably in the a-configuration. 2-cephem compounds of the formula IV can be iso-merised by treatment with a weakly basic agent and isolating the corresponding 3-cephem compound. Suitable isomerising agents are, for example, organic nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, especially bases of the pyridine type, such as pyridine itself, and picolines, collidines or lutidines, also quinoline, tertiary aromatic bases, for example those of the aniline type, such as N,N-di-lower alkylanilines, for example N,N-dimethylaniline or N,N-diethylaniline, or tertiary aliphatic, azacyclo-aliphatic or araliphatic bases, such as tri-lower alkylamines, for example trimethylamine or N,N-diiso-propylethylamine, N-lower alkylazacycloalkanes, for example N-methylpiperidine, or N,N-di-lower alkylphenyl-lower alkylamines, for example N,N-dimethylbenzylamine, and mixtures of such basic agents, such as the mixture of a base of the pyridine type and a tri-lower alkylamine, for exanqple pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, especially of medium-strength to strong bases with weak acids, such as alkali metal salts or ammonium salts of lower alkane-carboxylic acids, for example sodium acetate, tri-ethylammonium acetate or N-methylpiperidine acetate, and other analogous bases or mixtures of such basic agents can also be used.

The isomerisation of 2-cephem compounds of the formula IV with basic agents is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, it being possible for the bases used as reagents that are liquid under the reaction conditions to serve simultaneously as solvents, optionally while cooling or while heating, preferably in a temperature range of from approximately -30°G to approximately +100°C, in an inert gas atmosphere, for example a nitrogen atmosphere, and/or in a closed vessel.

The 3-cephem compounds of the formula I obtainable in this manner can be separated from the 2-cephem starting materials which may still be present in a manner known per se, for example by adsorption and/or crystallisation.

The isomerisation of 2-cephem compounds of the formula IV to form the corresponding 3-cephem compound is preferably carried out by oxidising these in the 1-position, is desired, separating optionally isomeric mixtures of the 1—oxides formed, and reducing the \ 1-oxides of the corresponding 3-cephem compounds obtained in this manner.

There come into consideration as suitable oxidising agents for the oxidation in the 1-position of 2-cephem compounds of the formula IV, inorganic peracids that have a reduction potential of at least +1.5 volts and comprise non-metallic elements, organic peracids or mixtures consisting of hydrogen peroxide and acids, especially organic carboxylic acids, having a disso- -5 ciation constant of at least 10 . Suitable inorganic peracids are periodic acid and persulphuric acid.

Organic peracids are corresponding percarboxylic and persulphonic acids which are added as such or may be formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid. In this case, it is expedient to use a large excess of the carboxylic acid if, for example, acetic acid is used as solvent. Suitable peracids are, for example, performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid. 1 983 36 perbenzoic acid, 3-chloroperbenzoic acid, monoper-phthalic acid or p-toluenepersulphonic acid.

The oxidation can likewise be effected using hydrogen peroxide with catalytic quantities of an acid having a dissociation constant of at least 10~^, it being possible to use low concentrations, for example 1 - 2 % and below, or alternatively relatively large amounts of the acid. In this case, the effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above-mentioned oxidation may be carried out in the presence of suitable catalysts. Thus, for example, the oxidation with percarboxylic acids can be catalysed by the presence of an acid having a dissociation con- -5 stant of at least 10 , the effectiveness of this acid being dependent on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually, at least equi-molar amounts of the oxidising agent, and preferably a slight excess of from approximately 10 % to approximately 20 %, are used, it also being possible to use relatively large excesses, i.e. up to 10 times the amount or more of the oxidising agent. The oxidation is carried out under mild conditions, for example at temperatures of from approximately -50°C to approximately +100°C, preferably from approximately -10°C to approximately +40°C.

The reduction of the 1-oxides of 3-cephem compounds can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. There come into consideration as reducing agents, for example: catalytically activated hydrogen, there being used noble metal catalysts that 1 983 contain palladium, platinum or rhodium and which are optionally employed together with a suitable carrier material, such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations, which are used in the form of corresponding compounds or complexes of an inorganic or organic kind, for example, in the form of tin(Il) chloride, fluoride, acetate or formate, iron(II) chloride, sulphate, oxalate or succinate, copper(I) chloride, benzoate or oxide, or manganese(H) chloride, sulphate, acetate or oxide, or in the form of complexes, for example with ethylene-diaminetetraacetic acid or nitrolotriacetic acid; reducing dithionite, iodide or iron(II) cyanide anions, which are used in the form of corresponding inorganic or organic salts, such as alkali metal dithionite, iodide or iron(II) cyanide, for example sodium or potassium dithionite, sodium or potassium iodide or sodium or potassium iron(Il) cyanide, or in the form of the corresponding acids, such as hydriodic acid; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphonous, phosphinous or phosphorous acid, and also phosphorus-sulphur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are especially aliphatic, aromatic or araliphatic radicals for example optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, such as, for example, triphenyl-phosphine, tri-n-butylphosphine, diphenylphosphonous acid methyl ester, diphenylchlorophosphine, phenyldichloro phosphine, benzenephosphonous acid dimethyl ester, butanephosphonous acid methyl ester, phosphoric acid triphenyl ester, phosphorous acid trimethyl ester, phosphorous trichloride, phosphorus tribromide, etc.; reducing halosilane compounds that have at least one hydrogen atom bonded to the silicon atom and which may 1 98 3 contain, apart from halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups, for example optionally substituted lower alkyl or phenyl, such as chlorosilane, bromosilane, di- or tri-chlorosilane, di- or tri-bromosilane, diphenylchlorosilane, or dimethylchlorosilane, or alternatively halosilane compounds in which all the hydrogen atoms are replaced by organic radicals, such as a tri-lower alkylhalosilane, for example trimethyl-chlorosilane or trimethyliodosilane, or cyclic sulphur-containing silanes, such as 1,3-dithia-2,4-disilacyclo-butanes or l,3,5-trithia-2,4,6-trisilacyclohexanes, of which the silicon atoms are substituted by hydrocarbon radicals, such as especially lower alkyl, for example 2,2,4,4-tetramethyl-l,3-dithia-2,4-disilacyclobutane or 2,2,4,4,6,6-hexamethyl-l,3,5-trithia-2,4,6-tri-silacyclohexane, etc.; reducing quaternary chloro-methyleneiminium salts, especially chlorides or bromides, in which the iminium group is substituted by one divalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl, such as N-chloromethylene-N,N-diethyliminium chloride or N-chloromethylenepyrrolidinium chloride; or complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt(II) chloride, and also borane dichloride.

As activating agents which are used together with those of the above-mentioned reducing agents that do not themselves have the properties of Lewis acids, i.e. especially together with the dithionite, iodide or iron(II) cyanide reducing agents and the trivalent phosporus reducing agents that do not contain halogen, or are used in the catalytic reduction, there may be mentioned especially organic carboxylic and sulphonic acid halides, but also sulphur, phosphorus or silicon halides having a second order hydrolysis constant which is the same as or greater than that of benzoyl chloride, for example phosgene, oxalyl chloride, acetyl chloride or bromide, chloroacetic acid chloride, pivaloyl chloride, 4-methoxybenzoyl chloride, 4-cyanobenzoyl chloride, g-toluenesulphonyl chloride, methanesulphonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichloro-phosphine, benzenephosphonous acid dichloride, dimethyl-chlorosilane or trichlorosilane, also suitable acid anhydrides, such as trifluoroacetic acid anhydride, or cyclic sultones, such as ethanesultone, propanesultone, 1,3-butanesultone or 1,3-hexanesultone.

The reduction is carried out preferably in the presence of solvents or mixtures thereof, the choice of which is determined primarily by the solubility of the starting materials and by the chosen reducing agent; thus, for example, lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the case of catalytic reduction, and, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride, chloroform or nitrobethane, suitable acid derivatives, such as lower alkanecarboxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides of inorganic or organic acids, for exanple dimethylformamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydrofuran or dioxan, ketones, for example acetone, or sulphones, especially aliphatic sulphones, for example dimethylsulphone or tetramethylenesulphone, etc., together with the chemical reducing agents, these solvents preferably containing no water. The reaction is usually carried out at temperatures of from approximately -20°C to approximately 100°C, it being possible, when using very reactive activating agents, to carry out the reaction at lower temperatures. 1 98 3 3 Process c) (Formation of the optionally substituted hydroxyimino group): In a starting material of the formula V in which the 4-carboxyl group and other functional groups are optionally protected, the oxo group in the 70-acylamido group that does not belong to the amide group may be converted into an optionally O-substituted hydroxy-imino group by treatment with a hydroxylamine derivative of the formula VI. The reaction of a starting material of the formula V with a hydroxylamine derivative of the formula VI is carried out in customary manner, for exainple by iTertCtiiig the two reaction partners in a solvent, such as water or an organic solvent, such as an alcohol, for example methanol, at slightly elevated or reduced tenperature, for exanple in a temperature range of from approximately -20°C to approximately +100°C, preferably from approximately 0°C to approximately 30°C, optionally in an inert gas atmosphere, such as a nitrogen atmosphere. The hydroxylamine compound of the formula VI may also be freed in situ, for exanple from one of its salts, such as a hydrohalide, such as a hydrochloride, by treatment with an inorganic base, such as an alkali metal hydroxide, for exanple sodium hydroxide, or an organic base, such as a tertiary amine, for exanple a tri-lower alkylamine, such as triethylamine or ethyldiisopropylamine, or a heterocyclic tertiary base, such as pyridine.

Process d) (Formation of the unsubstituted hydroxyimino group): In a starting material of the formula VII, the functional groups are preferably protected. Suitable nitrosating agents are nitrous acid and derivatives thereof, such as nitrosyl halides, for exanple nitrosyl 1 98 3 chloride or nitrosyl bromide, salts of nitrous acid, such as alkali metal salts, for exanple sodium or potassium nitrite, or especially esters of nitrous acid, such as corresponding lower alkyl esters, for example butyl, pentyl or especially iso-amyl nitrite. If a salt of nitrous acid is used as nitrosating agent, the reaction is preferably carried out in the presence of a strong inorganic or organic acid, for example hydrochloric acid, sulphuric acid, formic acid or acetic acid. When using an ester of nitrous acid, the reaction is preferably carried out in the presence of a strong base, such as an alkali metal alkanolate.

The nitrosation is carried out in a suitable solvent, such as water, a carboxylic acid, for example acetic acid, a lower alkanol, for exanple methanol or ethanol, an ether, for exanple dioxan or tetrahydrofuran, or a hydrocarbon, for exanple hexane or benzene, or in mixtures thereof, if necessary while cooling or heating, especially in a tenperature range of from approximately -15°C to approximately room temperature, and/or in an inert gas atmosphere.

/ Process e) (Formation of the aminothiadiazolyl group): In a starting material of the formula VIII, X^ as halogen is, for example, chlorine or iodine, but preferably bromine. Suitable salts of thiocyanic acid are, for example, corresponding alkali, alkaline earth or alternatively heavy metal salts, for exanple sodium, potassium, magnesium or lead thiocyanate, or alternatively ammonium thiocyanates, in which the ammonium group is derived from ammonia or from organic nitrogen bases, for exanple ammonium thiocyanate or a mono-, di-, trior tetra-lower alkyl ancoonium thiocyanate in which lower alkyl represents, for example, methyl, ethyl or isopropyl. 198 3 Suitable isothiocyanic acid esters are, for example, isothiocyanic acid lower alkyl esters, which are also called lower alkyl isothiocyanates, such as methyl, ethyl, propyl or butyl isothiocyanate.

The condensation of compounds of the formula VIII with a salt of thiocyanic acid or with dithiocyanogen yields compounds of the formula I in which Am is a primary amino group, whilst condensation with an isothiocyanic acid ester yields a compound of the formula I in which Am is a free secondary amino group, for exanple a lower alkylamino group.

The reaction is preferably carried out in an inert solvent, such as a lower alkanol, for exanple methanol, ethanol, propanol or isopropanol, an ether, such as diethyl ether, dioxan or tetrahydrofuran, an amide, such as dimethylformamide, an aliphatic or aromatic hydrocarbon, such as hexane, benzene or toluene, or alternatively in a mixture thereof, and, if desired, while cooling or heating, that is to say, at temperatures of between approximately -80°C and approximately +100°C, preferably between approximately -20°C and approximately +20°C, and/or in an inert gas atmosphere.

A starting material of the formula VIII in which X^ is halogen may also be formed in situ, optionally in the presence of the thiocyanic acid salt, for exanple by treating a compound of the formula VIII in which X^ is hydrogen in one of the above-mentioned solvents with a hypohalite, for exanple sodium or potassium hypo-bromite, or with a: halogen and an alkali metal base, such as a hydroxide, carbonate or lower alkanolate, for exanple with bromine and sodium methoxide or potassium carbonate. The halogenation preferably takes place while cooling, for exanple at a tenperature of from approximately -15°C to approximately 0°C.

A compound of the formula VIII in which X is hydroxy may likewise be produced in situ, for exanple 1 983 3 by treating a compound of the formula VIII in which X is hydrogen with an oxidising agent, such as hydrogen peroxide.

The reaction of a starting material of the formula VIII in which X is hydrogen with dithiocyanogen is preferably likewise carried out in one of the above-mentioned inert solvents and under similar reaction conditions. If desired, it is also possible to use an acid addition salt of a compound of the formula VIII, which is converted into the free compound in situ, or the dithiocyanogen may be formed in situ, for exanple from a thiocyanate, for exanple lead thiocyanate, and a halogen, for exanple bromine.

Process f) (Introduction of an ammonio group): In a starting material of the formula IX in which the 4-carboxyl group and other functional groups are optionally protected, the group X^ preferably represents an esterified hydroxy group, especially a hydroxy group esterified by an organic acid, such as a lower alkanecarboxylic acid, for exanple formic or acetic acid, or by an inorganic acid, such as a hydrohalic acid, for example hydrobromic acid or hydriodic acid.

The reaction with a tertiary organic base corresponding to the radical R^, especially with an optionally substituted pyridine, is carried out under neutral or weakly basic conditions in a pH range of 3 - 8, preferably at approximately pH 6.5, in the presence of water and optionally in a water-miscible organic solvent. The weakly acidic conditions may be obtained by the addition of a suitable organic or inorganic acid, for exanple acetic acid, hydrochloric acid, phosphoric acid or alternatively sulphuric acid. As organic solvents there may be used, for exanple, water-miscible solvents. 1 983 36 such as lower alkanols, for example methanol or ethanol, lower alkanones, for exanple acetone, lower alkanecarboxylic acid amides, for exanple dimethylformamide, or lower alkanecarboxylic acid nitriles, for exanple acertonitrile. It is also possible, for exanple in order to increase yields, to add to the reaction mixture suitable salts, such as alkali metal salts, for exanple sodium salts and especially potassium salts, of inorganic acids, such as hydrohalic acids, for exanple hydrochloric and especially hydriodic acids, or of thiocyanic acid, or of organic acids, such as lower alkanecarboxylic acids, for exanple acetic acid, especially potassium iodide and potassium thiocyanate. For this purpose it is also possible to use salts of suitable anion exchangers with acids, such as acetic acid, for exanple liquid anion exchangers in salt form, for exanple Amberlite LA-1 (liquid secondary amines having a molecular weight of 351-393: oil-soluble and water-insoluble; m.eq./g = 2.5 - 2.7, for exanple in acetate form).

Ammonio groups may be introduced advantageously using an intermediate of the formula IX in which X2 represents a substituted, especially aromatically substituted, carbonylthio group and especially the benzoylthio group. Such an intermediate may be obtained, for exanple, by reacting a starting material of the formula IX in which X2 represents an esterified hydroxy group, especially lower alkanoyloxy, for example acetoxy, with a suitable salt, such as an alkali metal salt, for example the sodium salt, of a thiocarboxylic acid,' such as an aromatic thiocarboxylic acid, for exanple thiobenzoic acid. The intermediate is then reacted with the tertiary amine base, especially a corresponding heterocyclic base, such as an optionally substituted pyridine, to give the desired ammonium compound. The reaction is customarily carried out in the presence of a suitable 1 983 3 desulphurising agent, especially a mercury salt, for example mercury(II) perchlorate, and a suitable solvent or diluent, or a mixture thereof, if necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for exanple a nitrogen atmosphere.

Process g) (Exchange of Y for amines Ara-H): In a compound of the formula X, Y is bromine, iodine or preferably chlorine.

The amines Am-H are used in free form, that is to say, in the form of ammonia, lower alkylamines, such as methyl-, ethyl-, propyl- or butyl-amine, or di-lower alkylamines, such as dimethyl-, diethyl-, dipropyl-, dibutyl-, methylethyl-, ethylpropyl-, methylbutyl- or propylbutyl-amine, or the like, or in the form of metal amides thereof, for exanple in the form of alkali metal amides, such as lithium, sodium or potassium amides.

The exchange reaction preferably takes place in an inert organic solvent, such as benzene, toluene, dimethylformamide, tetrahydrofuran, or the like, or, when exchanging Y for NH2, also in liquid ammonia, it being possible to add bases that capture the acid H-Y, such as tertiary amines, for exanple ethyldiisopropylamine, pyridine, or the like.

Depending on the reactivity, the reaction takes place at room tenperature or while cooling or heating, between approximately -70°C and approximately +100°C, preferably between approximately -70°C and approximately +50°C.

The conpounds of the formula I obtainable according to the invention can be converted into different conpounds of the formula I in a manner known per se. 1 983 Substitution of a hydroxyimino group: In a compound of the formula I in which the 4-carboxyl group and other functional groups, especially those functional groups which can be substituted in an analogous maimer to the hydroxyimino group, are preferably protected, the hydroxy group of the unsubstituted hydroxyimino radical can be etherified in a manner known per se.

Suitable etherifying agents are, for exanple, diazo-lower alkanes, for exanple diazomethane, esters of alcohols of the formula R2-OH in which R2 represents optionally substituted lower alkyl or cycloalkyl, with strong inorganic or organic acids, such as lower alkyl halides or cycloalkyl halides, for exanple lower alkyl or cycloalkyl chlorides, bromides or iodides, or di-lower alkyl sulphates, also fluorosulphonic acid lower alkyl esters, or optionally halo-substituted methane-sulphonic acid lower alkyl esters, and suitable acetals, for exanple gem-di-lower alkoxy-lower alkanes, tri-R2~ oxonium salts (so-called Meerwein salts), di-R2~0-carbenium salts or di-R2~halonium salts, in which R2 represents optionally substituted lower alkyl or cycloalkyl, such as tri-lower alkyloxonium salts, and di-lower alkoxycarbenium or di-lower alkylhalonium salts, especially the corresponding salts with conplex fluorine-containing acids, or'l-R2-3-aryltriazene conpounds in which R2 represents optionally substituted lower alkyl or cycloalkyl, and aryl preferably represents an optionally substituted phenyl radical. These etheri-fying reagents are used in a manner known per se. for exanple as described above, customarily in a suitable solvent or solvent mixture, if necessary in the presence of a condensation agent, such as a base, while cooling or heating, in a closed vessel under pressure and/or in an inert gas atmosphere, for exanple a nitrogen atmosphere. 1 98 3 The introduction of a carbamoyl group -C(=0)-NHR-in place of the hydrogen atom takes place by carbamoyl-ation in a manner known per se. For this purpose, a compound of the formula I in which R2 represents hydrogen and all reactive groups that are not to be carbamoylated or could consume or destroy the reagents are in protected form, is treated, optionally stepwise, with a carbamoylat-ing agent. Suitable carbamoylating agents are reactive derivatives of carbamic acids R-NH-(=0)0H, especially isocyanates R-N=C=0 or mixed anhydrides, for exanple carbamic acid chlorides R-NH-C(=0)C1, which may also be produced in situ from phosgene and an amine R-NH^.

The reaction with isocyanates is effected in one of the customary inert solvents, for exanple an optionally halogenated hydrocarbon, for exanple benzene, xylene or methylene chloride, an ether, for exanple diethyl ether, dioxan or tetrahydrofuran, or an ester, for exanple ethyl acetate, optionally in the presence of a basic catalyst, for exanple a tertiary amine, for example triethylamine or pyridine, at room tenperature or at slightly reduced or elevated tenperature, approximately between -20°C and +50°C.

For the reaction with a mixed anhydride of carbamic acid, the alcohol group is preferably first metallated, for exanple with an alkali metal hydride, for exanple sodium? or lithium hydride. The compound of the formula I metallated at the hydroxy group can also be treated first with phosgene and then with the amine R-NHj and in this manner carbamoylated stepwise. These reactions likewise take place in an inert solvent and at the temperatures given above.

Substitution of an amino group : An optionally monosubstituted amino group Am in a conpound of the formula I obtainable according to the 1 983 3 invention in which the other functional groups present, especially those which can be substituted analogously to an amino group, are preferably protected, can be substituted in a manner known per se, for exanple by treatment with a reactive ester of a lower alkanol, such as a lower alkyl halide, for exanple a lower alkyl chloride, bromide or iodide, preferably in the presence of a solvent, or, with the introduction of methyl, with formaldehyde in the presence of formic acid. It is also possible to acylate an optionally monosubstituted amino group Am with a suitable derivative of a lower alkanecarboxylic acid, such as a corresponding halide, for exanple a chloride, and in a lower alkanoyl am ino compound obtainable in this manner, to reduce the carbonyl group to a methylene group, for exanple by treatment with a suitable hydride reducing agent, such as diborane. The substitution reaction is carried out in a manner known per se, preferably in the presence of a solvent, and, if necessary, while cooling or heating, and/or in an inert gas atmosphere.

Formation of the 1-oxide: A conpound of the formula I in which n represents 0 can be converted into a compound of the formula I in which n represents 1 by oxidation, for exanple according to one of the oxidation methods described under process b).

Reduction of the 1-oxide: A conpound of the formula I in which n represents 1 can be converted into a conpound of the formula I in which n represents 0 by reduction, for exanple according to one of the reduction methods described under process b). 1 983 36 Splitting off of protecting groups: In a resulting conpound of the formula I in which one or more functional groups are protected, these, for exanple protected carboxyl, amino, hydroxy and/or sulpho groups, can be freed, in a manner known per se, by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction, optionally stepwise or simultaneously.

Thus, tert.-lower alkoxycarbonyl, or lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio, or optionally substituted diphenylmethoxycarbonyl can be converted into free carboxyl, for exanple, by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic conpound, such as phenol or anisole. Optionally substituted benzyloxycarbonyl can be freed, for exanple, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can be converted into free carboxyl also by chemical reduction, for example by treatment with an alkali metal dithionite, for exanple sodium dithionite, or with a reducing metal, for exanple zinc, or metal salt, such as a chromium(II) salt, for exanple chromium(II) chloride, usually in the presence of a hydrogen-yielding agent which, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as a lower alkanecarboxylic acid optionally substituted, for exanple by hydroxy, for exanple acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, 1 983 or an alcohol or thiol, water preferably being added. By treatment with a reducing metal or metal salt it is also possible, as described above, 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 carboxyl, it being possible to split aroylmethoxycarbonyl likewise by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also be converted into free carboxyl by treatment with a salt of hydrofluoric acid which yields the fluoride anion, such as an alkali metal fluoride, for exanple sodium or potassium 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 or tri-lower alkyl-arylammonium fluoride, for exanple tetraethylammonium fluoride or tetra-butylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethyl sulphoxide or N,N-dimethylacetamide. A carboxyl group esterified by an organic silyl or stannyl group, such as tri-lower alkyl-silyl or tri-lower alkylstannyl, for exanple trimethyl-silyl, can be freed in the usual manner by solvolysis, for exanple by treatment with water, an alcohol or an acid.

A protected amino group, for exanple Am, is freed in a manner known per se and, depending on the type of protecting group, in various ways, preferably by means of solvolysis or reduction. 2-halo-lower alkoxycarbonyl-amino, optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonyl amino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be split, for exanple 1 98 3 by treatment with a suitable chemical reducing agent, such as zinc, in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxy-carbonylamino can also be split by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonyl-amino also by treatment with an alkali metal dithionite, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.-lower alkoxycarbonyl-amino or 2-trisubstituted silylethoxycarbony1amino can be freedby treatment with a suitable acid, for exanple formic or trifluoroacetic acid, optionally substituted benzyloxycarbonyl amino, for example by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino, formylamino or 2-acyl-lower alk-l-enylamino, for exanple by treatment with an acid, such as a mineral acid, for exanple hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected by an organic silyl or stannyl group, for exanple by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for exanple 2-chloroacetyl, 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 by subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treatment with a salt of hydrofluoric acid which yields fluoride anions, as stated above in connectinn with the freeing of a correspondingly protected carboxyl group. A phosphor-amido, phosphonamido or phosphinamido group can be converted into the free amino group, for exanple by treatment with a phosphorus-containing acid, such as 1 983 3 6 a phosphoric, phosphonic or phosphinic acid, for exanple orthophosphoric acid or polyphosphoric acid, an acid ester thereof, for example monomethyl, monoethyl, dimethyl or diethyl phosphate, or monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide.

Amino protected in the form of an azido group is converted into free amino, for exanple by reduction, for exanple by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, or alternatively by treatment with zinc in the presence of an acid, such as acetic acid. Catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for exanple methylene chloride, or alternatively in water or a mixture of water and an organic solvent, such as an alcohol or dioxan, at approximately from 20°C to 25°C, or alternatively while cooling or heating.

A hydroxy group protected by a suitable acyl group, an organic silyl or stannyl group or by optionally substituted 1-phenyl-lower alkyl is freed in the same manner as a correspondingly protected amino group. A hydroxy group protected by 2,2-dichloroacetyl is freed, for exanple, by basic hydrolysis, whilst a hydroxy group etherified by tert.-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or a 2-oxa- or 2-thia-cycloaliphatic hydrocarbon radical is freed by acidolysis, for exanple by treatment with a mineral acid or a strong carboxylic acid, for exanple trifluoroacetic acid.

A protected, especially esterified, sulpho group is freed analogously to a protected carboxyl group.

The described splitting reactions are carried out under conditions known per se. if necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for exanple a nitrogen atmosphere.

I 98 3 3 When several protected functional groups are present, the protecting groups are preferably so chosen that more than one such group can be split off simultaneously, for exanple by acidolysis, such as by treatment with trifluoroacetic acid or formic acid, or by reduction, such as by treatment with zinc and acetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium-carbon catalyst.

Salt formation: Salts of conpounds of the formula I having salt-forming groups can be manufactured in a manner known per se. Thus, salts of conpounds of the formula I having acid groups can be formed, for exanple, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for exanple the sodium salt of a-ethylcaproic acid, or with inorganic alkali metal or alkaline earth metal salts, for exanple sodium bicarbonate, or with ammonia or a suitable organic amine, preferably stoichiometric quantities or only a small excess of the salt-forming agent being used. Acid addition salts of conpounds of the formula I are obtained in customary manner, for exanple by treatment with an acid or a suitable anion exchange reagent. Internal salts of conpounds of the formula I that contain, for exanple, a free carboxyl group can be formed, for exanple, by neutralising salts, such as acid addition salts, to the isoelectric point, for exanple with weak bases, or by treatment with liquid ion exchangers.

Salts can be converted into the free conpounds in customary manner; metal and ammonium salts can be converted, for exanple, by treatment with suitable acids, and acid addition salts, for exanple, by treatment with a suitable basic agent. 1 98 3 3 Mixtures of isomers can be separated into the individual iosmers in a manner known per se. for example by fractional crystallisation, chromatography etc..

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 these, or the process is discontinued at any stage; in addition, starting materials may be used in the form of derivatives or may be formed during the reaction.

Preferably, the starting materials and the reaction conditions are so chosen that the compounds mentioned above as being especially preferred are obtained.

Starting materials: The starting materials used in the process for the manufacture of the conpounds of the present invention are known or, if novel, can be manufactured according to processes known per se.

The starting conpounds of the type of the formulae II and III and also corresponding compounds having protected functional groups are known or can be manufactured in a manner known per se.

The method of manufacture of starting materials of the formula III is illustrated with the aid of the following reaction scheme for the manufacture of a 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid conpound: 1 98 3 3 6 N CH_ N CH II || stage 1 II H stage 2 N > Am . N > \s/ \./ (A) (B) (AmQ = protected amino group: RQ = lower alkyl; X^ = hydrogen or halogen) t 983 3 Starting materials of the formula IV may be obtained, inter alia* as a by-product in the manufacture of compounds of the type of the formula I, for exanple if these are formed under basic conditions. They need not be in pure form but may be used, for example, also in admixture with corresponding conpounds of the formula I.

Compounds of the formula V can be obtained, for exanple by acylating conpounds of the formula II with conpounds of the formula D or a reactive functional derivative thereof, for exanple according to one of the methods described under process a).

Conpounds of the formula VII can be obtained, for example by acylating compounds of the formula II with an acylating agent that introduces the acyl radical of an acid of the formula C, for exanple according to one of the methods described under process a).

Conpounds of the formula VIII can be obtained, for exanple by acylating compounds of the formula II with an acylating agent that introduces the acyl radical of an acid of the formula E, for exanple according to one of the methods described under process a). It is also possible, analogously to steps 6 and 7 in the reaction scheme for the manufacture of starting materials of the formula III, to obtain the desired starting materials of the formula VIII starting from compounds of the formula c N = C - C - C II N I o-r2 (H) 1 98 3 3 via compounds of the formula 0 II HN = C - C — C — 0R_ N ° I O-R.

COOH (J), The conpounds of the formulaeH and J can, in their turn, be obtained by acylating conpounds of the formula II with an acylating agent that introduces the acyl radical of an acid of the formula FandG, respectively, for exanple according to one of the methods described under process a).

Starting materials of the formula IX can be obtained, for example by starting from the corresponding 7p-amino-3-(X2-CH2)-3-cephem-4-carboxylic acid conpounds and acylating the amino group, for exanple by treatment with an acylating agent that introduces the acyl radical of an acid of the formula III, for exanple according to one of the methods described under process a).

Conpounds of the formula X can be obtained in various ways, for example analogously to process a) or b) or step 7, especially, analogously to process a), by in a conpound of the formula II in which n, R^ and R2 have the meanings given and in which the 7@-amino group is optionally substituted by a group that allows acylation, acylating the 70-amino group by treatment with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula L, or, analogously to step 7, by reacting a conpound of the formula VIII in which X^ represents hydrogen and n, R^ and R2 have the meanings given, or a salt thereof, 1 983 36 with a perhalomethyl mercaptan of the formula Y^C-S-Y and, if desired, carrying out the subsequent operations mentioned in the manufacture of conpound of the formula I.

The present invention relates also to novel starting conpounds, and intermediates and processes for the manufacture thereof.

The pharmacologically acceptable conpounds of the present invention may be used, for exanple, for the preparation of pharmaceutical preparations that contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable preferably for parenteral administration.

The pharmacologically active conpounds of the present invention are preferably used in the form of parenterally, for exanple intramuscularly or intravenously, administrable preparations or infusion solutions.

Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible to prepare these before use, for exanple from lyophilised preparations which contain the active substance alone or together with a carrier, for exanple mannitol. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which may, if desired, contain further pharmacologically valuable substances, are produced in a manner known per se, for exanple by means of conventional dissolving or lyophilising processes, and contain from approximately 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, and in the case of lyophilisates up to 100 %, of the active substance. 1 98 3 36 - 61 _ Conpounds of the formula I may also be administered orally, for exanple in the form of capsules. These contain the active substance, optionally together with suitable carriers, in the form of a granulate and in doses of from approximately 0.2 g to approximately 0.5 g per dosage unit.

Depending on the kind of infection and the condition of the infected organism, daily doses of from approximately 0.5 g to approximately 5 g s.c. are used for treating warm-blooded animals of approximately 70 kg body weight.

The following Exanples serve to illustrate the invention: tenperatures are given in degrees Centigrade.

The following abbreviations are used in the Exanples: BOC: tert.-butoxycarbonyl M.p. : melting point.

Thin-layer chromatography: Opti-UPC12 plates manufactured by Antec are glass plates coated with silica gel which has been treated with dodecyltrichlorosilane (for reverse-phase chromatography). 1 98 3 3 Exanple 1 a) 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxy-iminoacetamido]-3-(4-carboxypyridiniomethyl)-3-c ephem-4-carboxylate A solution of 0.478 g (1.0 mmol) of sodium 7(3-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate in 1 ml of water is added to a warm (80°) solution of 0.17 g (1.39 mmol) of isonicotinic acid and 1.71 g of sodium iodide in 0.4 ml of water and the mixture is stirred at 70° for 2 hours. After cooling to room temperature, the reaction mixture is poured onto 100 ml of cold acetone and the precipitate that forms is filtered and dried. After purifying the crude product by chromatography, (silica gel "Opti UPC^2", water) the homogeneous title conpound is obtained having an value of 0.25 (UPC^2 plates, water/acetonitrile 6:1): IR spectrum (Nujol): characteristic absorption bands at 3.05; 5.70; 6.25; 9.60 fi.

The starting material may be prepared as follows: b) sodium 7{3-[2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate 7(3-C2-(5-amino-l, 2, 4-thiadiazol-3-yl )-2-Z-metho3y-iminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid is dissolved in methanol-containing water (10 ml methanol/ 500 ml of water) and the aqueous phase is adjusted to pH 6.8 with aqueous sodium bicarbonate solution. The solution is lyophilised and the resulting sodium salts are purified by chromatography on silica gel "Opti UPC12" 1 90 3 (Antec) with water/acetonitrile 6:1. The homogeneous title conpound is obtained having an R^ value of O.30 (UPC^2 plates, water/acetonitrile 6:1); M.p. from 150° (decomposition); UV spectrum (methanol): X (e): 234 (12240) nm; max IR spectrum (Nujol): characteristic absorption bands at 3.00; 5.65; 5.95; 6.20; 6.52; 8.10; 9.60 p,.

Exanple 2 a) 7(3-[2-(.5-amino-l,2,4-thiadiazol-3-yl)-2-Z-2- carboxyprop-2-yloxyiminoacetamido]-3-(3-carboxy-methylpyridiniomethyl)-3-cephem-4-carboxylate To a solution preheated to 80°C of 6.6 g (44 mmol) of sodium iodide and 0.58 g (4.22 mmol) of pyridyl-3-acetic acid in 1.6 ml of distilled water there is added a solution, prepared separately, of 2.28 g (3.84 mmol) of disodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z- 2-carboxyprop-2-yloxyiminoacetamido]-2-acetoxymethyl- 3-cephem-4-carboxylate in 4 ml of distilled water.

After the addition of 0.23 ml of acetic acid (100 %), the mixture is stirred at 70°C for 3 hours. While cooling to -20°, the reaction solution is introduced into 150 ml of acetone. The precipitate that forms is filtered off, dissolved in 40 ml of distilled water and lyophilised. After purifying the crude product by chromatography (silica gel, "Opti UPC^2", water), the homogeneous title conpound is obtained having an R^ value of 0.19 (UPC12 plates, water).

IR spectrum: 2.95; 5.64; 6.27 and 6.52 p.

The starting material may be prepared as follows: 1 983 36 b) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetic acid methyl ester 26.16 g of N.N'-dicyclohexylcarbodiimide, 5.13 ml of absolute methanol and 1.71 g of 4-pyrrolidinopyridine are added in succession to a mixture of 30.0 g (115.0 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetic acid in 350 ml of methylene chloride and the mixture is stirred at room tenperature for 3 hours. After the addition of a further 0.5 ml of absolute methanol and 2.6 g of N,N'-dicyclohexylcarbodiimide, the mixture is stirred for a further 60 minutes. The precipitate is filtered with suction, the filtrate is washed in succession with aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is triturated with diethyl ether. The homogeneous title conpound is obtained having an value of 0.50 (silica gel, toluene/ethyl acetate 1:1): IR spectrum (C^C^): characteristic absorption bands at 2.90; 5.75; 5.85; 6.50; 8.70 p,. c) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid methyl ester A suspension of 20.0 g (73.18 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-acetic acid methyl ester and 22.0 g of selenium dioxide in 330 ml of absolute dioxan is stirred at 95° for 3 hours. After filtration of the reaction mixture, the filtrate is concentrated in vacuo. The residue is diluted with ethyl acetate, washed in succession with water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The title conpound is obtained in the form of a foam having 1 983 an value of 0.35 (silica gel, toluene/ethyl acetate 1:1); IR spectrum (CH^l^): characteristic absorption bands at 2.95; 5.75; 5.85; 6.50 (X. d) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetic acid methyl ester A suspension of 21.8 g (75.88 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid methyl ester, 7.48 g of hydroxylamine hydrochloride and 9.8 ml of pyridine in 300 ml of 95 % ethanol is stirred at room tenperature for 3 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is extracted in succession with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is crystallised from diethyl ether. The title conpound is obtained having an R^ value of 0.30 (silica gel, chloroform/methanol 95:5); M.p. 131-132°; IR spectrum (CH^Clj): characteristic absorption bands at 2.85; 5.75; 5.85; 6.50; 8.70; 8.90 [i. e) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxydmino)-acetic acid methyl ester A solution of 1.70 g (5.62 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxy-iminoacetic acid methyl ester in 7.5 ml of dimethyl sulphoxide is added at room tenperature under nitrogen 1 98 3 to a solution of 1.4 g (6.27 mmol) of 2-bromoisobutyric acid tert.-butyl ester and 1.84 g (14.03 mmol) of finely pulverised potassium carbonate in 12.50 ml of dimethyl sulphoxide and the mixture is stirred at this temperature for 14 hours. The reaction mixture is concentrated to dryness by evaporation at 30° in a high vacuum. The residue is taken up in 200 ml of ethyl acetate and washed in succession with water, dilute hydrochloric acid (IN), water and saturated,sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation in vacuo. The residue is crystallised from approximately 5 ml of ether and yields the title conpound having a melting point of 142 - 144°. f) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxyimino)-acetic acid A solution of 11 g (22.55 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxyimino)-acetic acid methyl ester in 290 ml of methanol and 96 ml of 2N sodium hydroxide solution is stirred at a tenperature of 50° for 6% hours. The reaction mixture is concentrated to dryness by evaporation at 35° in a high vacuum. The residue is taken up in 200 ml of water (distilled) and extracted once with 200 ml of ethyl acetate. The aqueous phase is covered with a layer of 200 ml of ethyl acetate and rendered acidic with concentrated hydrochloric acid. The ethyl acetate phase is washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo, yielding the title compound in crystalline form. 1 98 3 TLC value: 0.2 (silica gel, chloroforra/methanol 4:1): IR spectrum (dioxan): characteristic bands at 5.81: .74; 3.3 (i.

M.p. 180 - 183°. 9) 7 p-[ 2-(5-tert ..-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxyimino)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid A suspension of 15 ml of absolute methylene chloride 0.3 ml of dimethylformamide and 0.33 ml (7.84 mmol) of oxalic acid dichloride is stirred at -10° under nitrogen for 30 minutes. 1.3 g (3.01 mmol) of 2-(5-tert.-butoxycarbonylamino-1 ,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxy-carbonylprop-2-yloxyimino)-acetic acid are then added to the suspension. The resulting clear solution is stirred at 0 - 5° under nitrogen for 30 minutes. A freshly prepared solution of 0.87 g (3.19 mmol) of 7p-aminocephalosporanic acid in 18 ml of absolute methylene chloride and 3 ml of N,0-bis-(trimethylsilyl)-acetamide is added dropwise to this solution and the mixture is stirred at a temperature of 0 - 5° under nitrogen for 16 hours. The reaction solution is washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation in vacuo to a dry slurry. The title conpound is obtained having an R^ value of 0.43 (silica gel, ethyl acetate/ acetic acid 9:1); IR spectrum (Nujol): characteristic absorption bands at .6; 5.82; 6.04 |i. h) disodium 7|3-[2-(5-amino-l, 2,4-thiadiazol-3-yl)-2-Z- (2-carboxyprop-2-yloxyimino)-acetamido]-acetoxymethy1- 3-cephem-4-carboxylate 1 983 3 A solution of 2.3 g (3.35 mmol) of 70-[2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-(2-tert.-butoxycarbonylprop-2-yloxyimino)-acetamido]-3-acetoxy-methyl-3-cephem-4-carboxylic acid in 12.54 ml (16.38 mmol) of trifluoroacetic acid and 2.10 ml (19.28 mmol) of anisole is stirred at room temperature for 1 hour. The reaction mixture is concentrated to dryness by evaporation in vacuo at a bath temperature of 30°, the residue is stirred with ether and the product filtered off. The product is then dissolved in 28 ml of methanol and sodium ethylhexanoate is added. The solution is stirred into 50 ml of ethyl acetate. The precipitated product is filtered off and dried in a high vacuum. The title conpound is obtained having an value of 0.78 (UPC^2 plates, water/acetonitrile 4:1): IR spectrum (Nujol): characteristic absorption bands at 3.04: 5.68: 6.24: 6.57 |i.

Example 3 7(3-[2- (5-amino-l, 2,4-thiadiazol-3-yl )-2-methylcarbamoyloxy-iminoacetamido]-3-(4-carboxypyridiniomethyl)-3-cephem-4-carboxylate (A) and 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-hydroxyimino-acetamido]-3-(4-carboxypyridiniomethyl)-3-cephem-4-carboxylate (B) Analogously to Exanple 1, from 1.50 g (2.88 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methyl-carbamoyloxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.49 g (3.98 mmol) of isonicotinic acid and 4.90 g (32.7 mmol) of sodium iodide in 4.2 ml of 1 983 water there are obtained title conpound A having an value of O.30 (UPC^ plates, water/acetonitrile 6:1) and title conpound B having an R^ value of 0.55 (UPC^ plates, water/acetonitrile 6:1).

The starting material may be prepared as follows: b) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetic acid 8.6 g of potassium hydroxide and 70 ml of water are added to a solution of 8.0 g (26.46 mmol) of 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetic acid methyl ester in 175 ml of ethanol and the mixture is stirred at 40° for 5 hours. The reaction mixture is concentrated in vacuo, the residue is dissolved in water and the solution is adjusted to pH 8.5 with dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase is separated off, adjusted to pH 2.0 with 2N HCl and extracted with ethyl acetate. The organic phase is separated off, washed with aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is crystallised from diethyl ether. The homogeneous title conpound is obtained having an R^. value of 0.60 (silica gel, s-butanol/glacial acetic acid/water 67:10:23): M.p. 158 - 160° (decomposition): IR spectrum: (Nujol): characteristic absorption bands at 3.10: 5.85: 8.65 ^i. c) 2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoylimino acetic acid. ml of methyl isocyanate are added at 0 - 5° to a solution of 2.85 g (8.95 mmol) of 2-(5-tert.-butoxy-carbony1amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetic acid in 20 ml of tetrahydrofuran and the mixture is stirred at this tenperature for 2 hours. n-Hexane is 1 98 3 3 6 added to the reaction mixture and the resulting precipitate is filtered with suction. After recrystallisation of the precipitate from methylene chloride, the homogeneous title conpound is obtained having an value of 0.25 (UPC^2 plates, water/acetonitrile 6:1); M.p. 124 - 127°; IR spectrum (Nujol): characteristic absorption bands at .75T 5.85: 6.40 p.. d) 7(3-[2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl )-2-Z-methylcarbamoyloxyiminoacetamido]-3- acetoxymethyl-3-cephem-4-carboxylie acid diphenylmethyl ester 1.05 g (3.70 mmol) of 2-(5-tert.-butoxycarbonylamino' 1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetic acid and 0.4 ml of N-raethylmorpholine are added at -5° to a stirred suspension of a Vilsmeier reagent (prepared from 0.031 ml of oxalyl chloride and 0.29 ml of N,N-dimethylformamide in 10 ml of ethyl acetate). The mixture is stirred at 0° for 30 minutes and then cooled to -10°. After the addition of 1.357 g (3.1 mmol) of 7p-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester, the mixture is stirred at 0° for 2*3 hours, then diluted with ethyl acetate and washed in succession with water, phosphate buffer pH 8.0 and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. A portion of the crude product is purified by preparative layer chromatography with ethyl acetate. The homogeneous title compound is obtained having an R^ value of 0.60 (silica gel, ethyl acetate); IR spectrum (CH2C12): characteristic absorption bands at 2.95; 3.10; 5.65; 5.80; 5.95; 8.20 fx. 1 98 3 3 6 e) sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z- methy lcarbamoyloxy iminoacet amido ] -3-acetoxymethyl-3-cephem-4-carboxylate Analogously to Exanple 2h, from 0.519 g (0.68 mmol) of 70-[2-(5-tert.-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-Z-methylcarbamoyloxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester in 1.1 ml of methylene chloride, 0.37 ml of anisole and 5 ml of trifluoroacetic acid the title conpound is obtained having an value of 0.40 (upc^2 Plates, water/acetonitrile 6:1) IR spectrum (Nujol): characteristic absorption bands at 3.0; 5.67: 6.22; 8.10 fi.

Exanple 4 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(3-carboxymethyl-pyridiniomethyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.77 g (1.48 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-y1)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 2.63 g (1.93 mmol) of 3-pyridylacetic acid and 2.52 g of sodium iodide in 2.15 ml of water, the title conpound is obtained having an R^ value of 0.20 (UPC^2 plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 3.0; 5.67; 6.22 and 9.62 p.

Exanple 5 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop-2-yloxyiminoacetamido]-3-(3-methyl-l-triazoliomethyl)-3-cephem-4-carboxylate The title conpound is obtained analogously to Exanple 1 983 36 2 starting from 0.573 g (1 mmol) of disodium 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxy imino )-acet amido ]- 3-acetoxymethyl-3-cephem- 4-carboxylate, 0.3 g (3.57 mmol) of 1-methyl-l,2,3-triazole and 1.9 g of sodium iodide in 0.3 ml of water.

Exanple 6 70-[2-(5—amino-1,2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop-2-yloxyiminoacetamido]-3-(2-methyl-l-pyrazoliomethyl)-3-cephem-4-carboxylate Analogously to Exanple 2, starting from 0.286 g (O.5 mmol) of disodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop—2-yloxyiminoacetamido]-3-acetoxy-methyl-3-cephem-4-carboxylate, 0.4 g (4.8 mmol) of N-methylpyrazole and 1.0 g of sodium iodide in 0.3 ml of water, the title conpound is obtained having an value of 0.39 (UPC^ plates, water/acetonitrile 9:1).

Exanple 7 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(3-methyl-l-triazoliomethyl)-3-cephem-4-carboxylate The title conpound is obtained analogously to Exanple 1 starting from 0.24 g (0.5 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.3 g of 1-methyl-l,2,3-triazole and 1.9 g of sodium iodide in 0.3 ml of water.

Exanple 8 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(2-methyl-l-pyrazoliomethyl )-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g 1 983 (1.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl) - 2-Z-methoxy iminoacet amido ]-3-acetoxymethyl- 3-cephem-4-carboxylate, 0.115 g (1.4 mmol) of N-methylpyrazole and 7 g of sodium iodide in 1 ml of water the title conpound is obtained having an R^ value of 0.22 (UPC^2 plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 3.0; 5.75; 5.95; 6.20 and 9.62 |i.

Exanple 9 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(3-bromopyridinio-methyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 1.9 g (3.97 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.54 ml (5.6 mmol) of 3-bromopyridine and 6.84 g of sodium iodide in 4 ml of water, the title conpound is obtained having an Rf value of 0.20 (UPC12 plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.75; 6.20; 6.70; 9.60 Exanple 10 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(4-bromopyridinio-methyl)—3-cephem-4-carboxylate Analogously to Exanple 1, starting from 1.44 g (3.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.5319 g (3.3 mmol) of 4-bromopyridine, 5.2 g of sodium iodide and 3.15 ml of water, the title conpound is obtained having an Rf value of 0.22 (UPC12 plates, water/acetonitrile 6:1); 19S3 36 IR spectrum (Nujol): characteristic absorption bands at 2.95: 5.70; 6.17; 9.65 \i.

Exanple 11 7|3-[ 2-(5-amino-l, 2,4-thiadiazol-3-yl)- 2-Z-methoxyiminoacetamido]-3-(4-hydroxy-methylpyr idiniomethyl) - 3-cephem- 4-carboxylate 2.87 g (6.0 mmol) of sodium 7p-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate are added to a solution preheated to 70° of 9.9 g of sodium iodide in 5.0 ml of water.

After the addition of 0.72 g (6.6 mmol) of 4-hydroxy-methylpyridine and 0.36 ml of acetic acid, the mixture is stirred at 70° for 5 hours. The reaction solution is cooled to room tenperature and introduced into 120 ml of cold (0°) methanol. The precipitate that forms is filtered off, washed with ethanol and dried. After purifying the crude product by chromatography on XAD-2 resin (water/isopropyl alcohol 95:5) and subsequent thick-layer chromatography on silica gel "Opti UPC^2" with water/acetonitrile 4:1, the homogeneous title conpound is obtained having an R^ value of 0.45 (UPC^2 plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.70; 6.20; 9.80 |i.

Exanple 12 7p-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2- Z-methoxyiminoacetamido]-3-[4-(2-sulphoethyl)-pyridiniomethyl]-3-cephem-4-carboxylate sodium salt Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 7|3-[2-(5-amino— 1,2, 4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.294 g (1.4 mmol) of sodium 4-pyridine- ethanesulphonate and 1.71 g of sodium iodide in 1 ml of water, the title compound is obtained having an value of 0.40 (UPC12 plates, water/acetonitrile 95:5); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.65; 6.20; 9.80 fi.

Exanple 13 sodium 7|3-[2-(5-amino-l, 2, 4-thiadiazol-3- yl)-2-Z-methoxyiminoacetamido]-3-(2-amino-3-carboxypyridiniomethyl)-3-cephem-4-carboxylate Starting from 1.90 g (4.0 mmol) of sodium 7(3-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacet amido ]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.83 g (6.0 mmol) of 2-aminonicotinic acid and 6.8 g of sodium iodide in 4 ml of water, the title conpound is obtained having an R^ value of 0.35 (UPC^2 plates, water/acetonitrile 95:5).

Exanple 14 7p-[2-(5-amino-l,2,4-thiadiazol-3-yl)- 2-Z-methoxyiminoacetamido]—3-(2-amino-5-carbamoylpyridiniomethyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g (l.O mmol) of sodium 7(3-[2-(5-amino-l, 2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, O.192 g (1.4 mmol) of 2-amino-5-carbamoyl-pyridine and 1.71 g of sodium iodide in 1 ml of water, the title conpound is obtained having an R^ value of 0.28 (UPC12 plates, water/acetonitrile 6:1); 1 983 36 IR spectrum (Nujol): characteristic absorption bands at 3.10; 5.65; 7.40; 9.60 ji.

Exanple 15 sodium 78-[2-(5-amino-l,2,4-thiadiazol- 3-yl)-2-Z-methoxyiminoacetamido]-3-[3- (2-carboxyvinyl)-pyridiniomethyl]-3-cephem- 4-carboxylate Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 7(3-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.241 g (1.4 mmol) of sodium 3-(3-pyridyl)-acrylate and 1.71 g of sodium iodide in 1 ml of water, the title conpound is obtained having an R^ value of 0.85 (UPC^ plates, water/acetonitrile 1:1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.67; 6.15; 9.65; .20 \i.

Exanple 16 sodium 7p-[2-(5-amino-1,2,4-thiadiazol- 3-yl)-2-Z-methoxyiminoacetamido]-3-(3-sulphopyridiniomethyl )-3-cephem-4— carboxylate Analogously to Example 1, starting from 1.9 g (4.0 mmol) of sodium 70-[2-(5-amino-1,2,4—thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 1.02 g (5.6 mmol) of sodium pyridine-3-sulphonate and 6.84 g of sodium iodide in 3 ml of water, the title compound is obtained having an R^ value of 0.35 (UPC.j£ plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 3.10: 5.82; 8.15; 9.10 ji.

Exanple 17 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2- Z-methoxyiminoacetamido ] - 3- (4-me thoxy-me thy lpyr idiniomethyl )-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 7$-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.16 g (1.3 mmol) of 4—methoxymethy1-pyridine and 1.70 g of sodium iodide in 1.0 ml of water, the title conpound is obtained having an R^ value of 0.30 (UPCJ2 plates, water/acetonitrile 6:1). 1 98 3 36 Exanple 18 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2- 2-methoxy iminoacetamido ] -3- (4-thiocarbamoyl pyridiniomethyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxy iminoacet amido ] - 3-acetoxymethyl- 3-cephem- 4-carboxylate, 0.166 g (1.20 mmol) of thioisonicotinic acid amide and 1.65 g of sodium iodide in 0.8 ml of water, the title conpound is obtained having an value of 0.37 (UPC^2 plates, water/acetonitrile 4:1).

Exanple 19 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2- Z-methoxyiminoacetamido]-3- (3-cyanopyridinio-methyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.956 g (2.0 mmol) of sodium 7(3-[2-(5-amino-l, 2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.25 g (2.40 mmol) of 3-cyanopyridine and 3.4 g of sodium iodide in 3 ml of water, the title conpound is obtained having an R^ value of 0.30 (UPC^ plates, water/acetonitrile 6:1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 4.65; 5.70; 6.20 p,. 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxy iminoacet amido}-3-( 3-cyanomethyl-pyridiniomethyl)-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxy iminoacetamido ]-3-acetoxymethyl-3-cephem-4- Exanple 20 .X carboxylate, 0.156 g (1.5 mmol) of 3-cyanomethylpyridine and 1.70 g of sodium iodide in 1.2 ml of water, the title conpound is obtained having sua value of 0.15 (UPC plates, water/acetonitrile 9:i)r 12 IR spectrum (Nujol): characteristic absorption bands at 3.0; 4.65; 5.67 |i.

Example 21 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2- methoxyiminoacetamido]-3-(3-hydroxymethyl-pyridiniomethyl)-3-cephem-4-carboxylate Analogously to Example 11, starting from 0.478 g (1.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxy1ate, O.164 g (1.5 mmol) of 3-hydroxymethyl-pyridine and 1.70 g of sodium iodide in 1 ml of water and 0.05 ml of acetic acid, the title compound is obtained having an Rf value of 0.40 2 plates, water/acetonitrile 9:1); IR spectrum (Nujol): characteristic absorption bands at 2.95; 5.67; 6.20 |i.

Exanple 22 7(5-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2- methylcarbamoyloxyiminoacetamido]-3-(4-hydroxymethylpyridiniomethyl)-3-cephem-4-carboxylate (A) and 7p-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-hydroxyiminoacetamido]-3-(4-hydroxymethyl-pyridiniomethyl)-3-cephem-4-carboxylate (B) Analogously to Exanple 1, starting from 1.042 g (2.0 mmol) of sodium 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)- 1 ^ A T "% y (Q> <sJ 2-methylcarbamoyloxyiminoacetamido ]-3-acetoxymethyl-3-cephem-4-carboxylate, 0.24 g (2.2 mmol) of 4-hydroxy-methylpyridine and 3.5 g of sodium iodide in 2.1 ml of water, there are obtained title compound (A) having an value of 0.40 (UPC^ plates, water/acetonitrile 6:1) and title conpound (B) having an R^ value of 0.60 (UPC^ plates, water/acetonitrile 6:1).

Exanple 23 sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(3-carboxypyridiniomethyl)-3-cephem-4-carboxylate Analogously to Exanple 1, starting from 0.478 g (1.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)- 2-Z-methoxy iminoacet amido ]- 3-acetoxymethyl-3-cephem-4-carboxylate, 0.20 g (1.64 mmol) of nicotinic acid and 1.70 g of sodium iodide in 1 ml of water, the title compound is obtained having an R^ value of 0.20 (UPC^ plates, water/acetonitrile 9:1): IR spectrum: (Nujol): characteristic absorption bands at 3.0: 5.70; 6.20 (i.

Exanple 24 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(2-carboxy-methyl-1-pyrazoliomethyl)-3-cephem-4-carboxylic acid A) and 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(1-carboxymethyl-l-pyrazoliomethyl)-3-cephem-4-carboxylic acid B) Analogously to Exanple 1, from 1.44 g (3.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-methoxyimino- - 80. - acetamido]-3-acetoxymethyl-3-cephem-4-carboxy late* 0.53 g (4.2 mmol) of pyrazolylacetic acid and 5.15 g of sodium iodide in 3 ml of water there is obtained a mixture of title conpound A having an R^ value of 0.75 (UPC12 plates, water/acetonitrile 6:1) and title conpound B having an R^ value of 0.70 (UPC^2 plates, water/acetonitrile 6:1).

Exanple 25 disodium 70-[2-(5-amino-l,2,4-thiadiazol-3-y 1) - 2-Z- 2-carboxyprop- 2-yloxy iminoacet amido ] 3-(2-carboxymethyl-l-pyrazoliomethyl)-3-cephem-4-carboxy1ate A solution of 2.8 g (6.0 mmol) of sodium 70-[2-(5-amino-l,2,4-thiadiazol-3-yl )-2-methoxy iminoacet amido ]-3-acetoxymethyl-3-cephem-4-carboxylate in 4 ml of water is added at 70° to a solution of 0.9 g (7.14 mmol) of pyrazolylacetic acid and 0.9 g of sodium iodide in 2.0 ml of water. The reaction is carried out analogously to Exanple 1 and the title conpound is obtained.

IR spectrum (Nujol): 2.90; 5.65; 6.22 and 7.05 p.

Exanple 26 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Zr methoxyiminoacetamido]-3-(2-ethoxycarbonyl-methyl-l-pyrazoliomethyl)-3-cephem-4-carboxylate Analogously to Exanple 1, the title conpound is obtained from 1.0 g (2.1 mmol) of sodium 70-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacet amido]-3-acetoxymethyl-3-cephem-4-carboxylate, 3.08 g (20 mmol) of pyrazolylacetic acid ethyl ester and 3.73 g (25 mmol) of sodium iodide.

IR spectrum (Nujol): 5.66; 5.77; 6.23 (i. 1 98336 Exanple 27 Using suitable starting materials it is possible to obtain the following conpounds in analogous manner: 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacet amido] -3- ( 2-methyl-l-pyrazoliomethyl)-3-cephem— 4-carboxylate: R^: 0.40 (water/acetonitrile 6:1); IR: 3.0; 5.67; 6.20; 8.30 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyimino-acetamido]-3-(3-methyl-l-triazoliomethyl)-3-cephem-4-carboxylate; Rf: 0.25 (water/acetonitrile 6:1); IR: 5.65; 6.20 |i; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamido]-3-(4-hydroxymethylpyridinio-methyl)-3-cephem-4-carboxylate; R^: 0.50 (water/acetonitrile 6:1); IR: 5.67; 5.95; 9.2o \x; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido ]-3-(4-hydroxymethylpyridiniomethyl)-3-cephem-4-carboxylate; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydr oxy iminoacetamido ]-3-( 3-sulphopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.45 (water/acetonitrile 6:1); IR: 3.0; 5.75; 9.15 \x; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop- 2-yloxyimino)-acetamido]-3-(3-sulphopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.50 (water/acetonitrile 6:1); IR: 3.05; 5.67; 5.95 p. 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacet amido] -3- (3-carboxymethyl-4-carbamoylpyridiniomethyl)- 3-cephem-4-carboxylate; R^: 0.35 (water/acetonitrile 4:1); IR: 3.0; 5.67; 6.20 p; 7p_[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacet amido] -3- ( 3-carboxymethyl-4-carbamoy lpyr idiniomethyl )-3-cephem-4-carboxylate; R^: 0.30 (water/acetonitrile 4:1)7 IR: 3.0; 5.65; 6.20 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-(2-carboxy-prop-2-yloxyimino)-acet amido]-3-(3-carboxymethy1-4-carbamoylpyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.37 (water/acetonitrile 4:1); IR: 3.0; 5.67; 6.20 p; 7|3-[2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido ]-3- (3-carboxy-4-carbamoylpyridiniomethyl)-3-cephem-4-carboxylate; Rf: 0.45 (water/acetonitrile 6:1); IR: 3.0; 5.65; 6.17 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido ]-3- (3-carboxy-4-carbamoylpyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.35 (water/acetonitrile 6:1); IR: 5.67; 6.20 p; 70-[2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamido]-3-(3-carboxy-4-carbamoylpyridiniomethyl )-3-cephem-4-carboxylate; R^: 0.35 (water/ acetonitrile 6:1); IR: 5.67; 5.95 p.; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyimino-acetamido]-3-(3-bromopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.35 (water/acetonitrile 6:1); R^: 0.35 (water/acetonitrile 6:1); IR: 3.0; 5.65; 6.20 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamido]-3-(3-bromopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.20 (water/acetonitrile 9:1); IR: 3.0; 5.67 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-hydroxyiminoacetamido ]-3-(4-bromopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.30 (water/acetonitrile 9:1): IR: 2.95; 5.65; 6.17 p; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-(2-carboxyprop-2-yloxyimino)-acetamido]-3-(4-bromopyridiniomethyl)-3-cephem-4-carboxylate; R^: 0.20 (water/acetonitrile 9:1); IR: 3.0; 5.70 |i; 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyimino-acetamido]-3-(4-carboxymethylthiopyridiniomethyl)-3-cephem-4-carboxylate; IR: 2.95; 5.65; and

Claims (5)

- 84 - 7(3- [2- (5-amino-l, 2,4-thiadiazol-3-yl)-2-Z-methoxy-iminoacet amido ]-3-(3-cyano-4-tr if luoromethylpyr idinio methyl)-3-cephem-4-carboxylate; R^: 0.40 (water/ acetonitrile 4:1): IR: 5.67; 6.20 p (R^ values on plates, and IR spectra in Nujol). Exanple 28 Dry ampoules or phials containing 0.5 g of active substance, for exanple the sodium salt of 70-[2-(5-amino-1,2, 4-thiadiazol-3-yl )-2-Z-methoxyiminoacetylamido]-3-(4-carboxypyridiniomethyl)-3-cephem-4-carboxylate, may be prepared, for exanple as follows: Composition (for 1 ampoule or phial): active substance 0.5 g mannitol 0.05 g A sterile aqueous solution of the active substance and the mannitol is introduced into 5 ml ampoules or 5 ml phials under aseptic conditions and these are sealed and tested. - 85 - o o / u J U what we claim is:

1. Compounds of the formula Am - T - 0 II C - C II N I 0-R_ N. I H // ^ n s /\ N (I) \S cocP CH2R1 xn which n represents O or 1, Am represents unsubstituted or substituted amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to the group of the formula -C(=N-0—R2)-, represents an unsubstituted or substituted pyrazolio group, an unsubstituted or substituted triazolio group, a tri-lower alkyl-ammonio group or a pyridinio group of the formula -N'/ X=: (a), N.Z. PATENT OFFICE 2 4 NOV 1983 RECEIVED r i n 7 t' r i ✓ .. o - 36 - in which Ra represents lower alkyl substituted by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or by sulpho: unsubstituted lower alkenyl or lower alkylthio or lower alkenyl or lower alkylthio substituted by carboxyl; unsubstituted amino or amino mono-substituted by lower alkyl, lower alkanoyl or by aminobenzenesulphonyl; di-lower alkylamino; carbamoyl mono-substituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy or by cyano; di-lower alkylcarbamoyl; thiocarbamoyl; cycloalkyl; phenyl; hydroxy; lower alkoxy; halogen; lower alkoxycarbonyl; lower alkanoyloxy; lower alkanoyl; carboxyl; sulpho; cyano; nitro or hydroxysulpho-lower alkyl; Rb represents carbamoyl or hydrogen or has the meanings of Ra, and R° represents hydrogen, or has the meanings of Ra, and R2 represents hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl, or unsubstituted or substituted carbamoyl, and salts of such compounds having a salt-forming group. 2. Compounds of the formula I according to claim 1 in which n represents O, Am represents amino, lower alkylamino, di-lower alkylamino or protected amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to the group of the formula n.2. patent offfcf| 1 98336 87 -C(=N-0-R2)-, R^ represents 2-lower alkyl-l-pyrazolio,

2-carboxy-lower alkyl-l-pyrazolio, 1-carboxy-lower alkyl-l-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-l-pyrazolio, 3-lower alkyl-l-triazolio or a pyridinio group of the by cycloalkyl, phenyl, hydroxy, lower alkoxy, halogen, cyano, carbamoyl, carboxyl or by sulpho; unsubstituted lower alkenyl or lower alkylthio or lower alkenyl or lower alkylthio substituted by carboxyl; unsubstituted amino or amino monosubstituted by lower alkyl, lower alkanoyl or aminobenzenesulphonyl; di-lower alkylamino; carbamoyl monosubstituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy or cyano; di-lower alkylcarbamoyl; thiocarbamoyl; cycloalkyl; phenyl; hydroxy; lower alkoxy; halogen; lower alkoxycarbonyl; lower alkanoyloxy; lower alkanoyl; carboxyl; sulpho; cyano; nitro or hydroxy sulpho- lower alkyl; and represents carbamoyl or hydrogen or SI c has the meanings of R , and R represents hydrogen, and 2 R represents hydrogen, unsubstituted or substituted lower alkyl or cycloalkyl, or unsubstituted or substituted carbamoyl, the group of the formula =N-0-R2 having especially the syn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of such conpounds of the formula I having salt-forming groups.

3. Compounds of the formula I according to claim 2 in which n represents 0, Am represents amino, lower alkylamino, or protected amino, T represents a thiadiazole radical that is bonded at one carbon atom to Am and at the other carbon atom to the group of the formula —C(=N—0—R2)—, represents 2-lower alkyl-l-pyrazolio, 2-carboxy-lower alkyl-l-pyrazolio, 1-carboxy-lower alkyl-l-pyrazolio', 2-lower alkoxycarbonyl-lower alkyl-l-pyrazolio, 3-lower alkyl-l-triazolio/ hydroxy-lower alkylpyridinio,-3— or 4-hydroKymothylpyridinioT lower alkoxy-lower alkylpyridinio, cyano-lower alkylpyridinio, carboxy-lower alkyl- formula A in which Ra represents lower alkyl substituted 13 DEC 1983 - 88 - pyridinio, sulpho-lower alkylpyridinio, carboxy-lower alkenylpyridinio, carboxy-lower alkylthiopyridinio, thiocarbamoylpyridinio, halopyridinio, carboxypyridinio, sulphopyridinio, cyanopyridinio, carboxy-lower alkylcarba-moylpyridinio, aminocarbamoylpyridinio, carboxy-carbamoyl-pyridinio, cyano-halomethylpyridinio or aminocarboxy-pyridinio and R2 represents hydrogen, lower alkyl, carboxy- lower alkyl,carbamoyl,lower alkylcarbamoyl or amino-lower alkyl, the group of the formula =N-0-R2 having the syn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of such compounds of the formula I.

4. Compounds of the formula I according to claim 3 in which n represents 0, Am represents amino, T represents a 1,2,4-thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to the group of the formula -C(=N-0-R2)-, R^ represents 2-lower alkyl-l-pyrazolio, 2-carboxy-lower alkyl-l-pyrazolio, 2-lower alkoxycarbonyl-lower alkyl-l-pyrazolio, 3-lower alkyl-l-triazolio, hydroxy-lower alkylpyridinio, carboxy-lower alkylpyridinio, sulpho-lower alkylpyridinio, halopyridinio, carboxypyridinio, sulphopyridinio or aminocarbamoylpyridinio, and R2 represents hydrogen, lower alkyl, carboxy-lower alkyl, carbamoyl or lower alkylcarbamoyl, the group of the formula -N-0-R2 having the syn (or Z) conformation, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I *;m.z. patent off ice;19 JAN 1984;ftSCSIVED;198336;89;5.;Compounds of the formula I according to claim 4;in which n represents 0, Am represents amino, T represents a 1,2,4-thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to the group of the formula -C(=N-0-R2)-, R-^ represents 2-methyl-l-pyrazolio, 4-hydroxymethylpyridinio, 3-carboxy-methylpyridinio, 4-(2-sulfoethyl) -pyridinio-, 3-bromo-pyridinio, 4-carboxypyridinio or 2-amino-5-carbamoylpyridinio and R2 represents methyl or 2-carboxy-2-propyl, the group of the formula =N-0-R2 having the syn (or conformation, and salts, especially pharmaceutically acceptable salts, of compounds of the formula I.;ELZ. PATENT OFFICE;13 DEC 1983;198336;- 90 -;6. 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(4-carboxypyridiniomethyl)-3-cephem-4-carboxylate, according to claim 5.;7. 7B-[2- (5-amino-l,2,4-thiadiazol-3-yl)-2-Z-2-carboxyprop-2-yloxyiminoacetamido]-3-(3-carboxymethyl-pyridiniomethyl)-3-cephem-4-carboxylate, according to claim 5.;8. 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(2-methyl-l-pyrazoliomethyl)-3-cephem-4-carboxylate, according to claim 5.;9. 70-[ 2- (5-amino-l, 2,4-thiadiazol-3-yl)-2-Z-methoxy iminoacet amido]-3-[ 4-(2-sulphoethyl)-pyridinio-methyl]-3-cephem-4-carboxylate, according to claim 5.;10. 70-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxy iminoacet amido] -3- (2-amino-5-carbamoylpyridiniomethyl )-3-cephem-4~carboxylate, according to claim 5.;11. 78-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(3-bromopyridiniomethyl)-3-cephem-4-carboxylate, according to claim 5.;12. 78-[2-(5-amino-l,2,4-thiadiazol-3-yl)-2-Z-methoxyiminoacetamido]-3-(4-hydroxymethylpyridiniomethyl)-3-cephem-4-carboxylate, according to claim 5.;13. Pharmaceutical preparations containing conpounds of the formula I according to claim 1, ox pharmaceutically acceptable salts of such conpounds.;14 . Compounds of the formula I according to claim 1 in a form suitable for use in the treatment of bacterial infections of the human or animal body.;1

5. Process for the manufacture of compounds of the formula I as defined in claim 1 and salts of compounds of the formula I having a salt-forming group, characterised in that a) in a compound of the formula;0fF|CE;r -;- 91 -;h2N-;<°>n;+ 11;H S :/\;o-:;.N : CH2RI;(ii),;\//;i e coo ^;in which the index n represents 0 or 1, R1 has the meanings given under formula I, the 70-amino group is optionally protected by a group allowing the acylation reaction and the 4-carboxy group is optionally protected, the 70-amino group is acylated by reaction with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula;Am - T -;0;H;c - c;II;N;- OH;(III);O-R,;in which Am, T and R2 have the meanings given under formula I and functional groups present are optionally protected,;or b) for the manufacture of a conpound of the formula I in which n represents 0, a 2-cephem conpound of the formula;- 92 -;Am - T -;c - c;II;N;I;O—R_;h nh -;0=1.;? s :/\;.N 2 CH«R1;\/ 2 1;(IV),;:oo;<=>;in which Am, T, R1 and R2 have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, is isomerised to form the corresponding 3-cephem compound, or c) a compound of the formula;Am - T -;0;c J;II o;H;hh—: oJ;H;(O);T;n;_ s;:/\ • •;i • i;(V),;N;Y;coo^;-CH2R1;in which n represents 0 or 1, Am, T and R^ have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, is reacted with a hydroxylamine derivative of the formula H2N-0-R2 (VI) in which R2 has the meanings given under formula I and functional groups are optionally protected, or d) for the manufacture of a conpound of the formula;I in which R2 represents hydrogen, a conpound of the formula;- 93 -;Am - T - CHn -;O;I!;c h;nh—;(O);n s;:/ \;h;(VII),;cl=r. n : ch-r.;\/ 21;coo;0;in which n represents O or 1, Am, T and R^ have the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected is treated with a nitrosating agent, or e) for the manufacture of a conpound of the formula;I in which Am represents a free or secondary amino group, T represents a 1,2,4-thiadiazole radical that is bonded in the 5-position to Am and in the 3-position to the group of the formula -C(=N-0-R2)a compound of the formula o ^;u h h ';H " "A , ,;x, -n=c-c-c- nh—i V \ (viii),;1;" I;n 1;I;0-R;nh- n a=:—n :—ch0r.,;2 , V;2 1 ©;coo ^;in which n represents 0 or 1, X1 represents hydrogen, halogen or hydroxy, and R1 has the meanings given under formula I and in which the 4-carboxyl group and other functional groups are optionally protected, is treated with a salt of thiocyanic acid, or an isothiocyanic acid ester, or, if X1 represents hydrogen, with dithiocyanogen, or;24&C7$33 :;1 98 3;- 94 -;£) a compound of the formula;/f* ^ 0 H H ' II : :/ \ Am-T-C-C- HN— : :7 \ (IX), N O—I N I CH - X I \// 2 2 °-R2 i COOH in which n represents O or 1, Am, T and have the meanings given under formula I and X2 represents a radical that can be replaced by nucleophilic substitution and in which the 4-carboxyl group and other functional groups are optionally protected, is reacted with an organic tertiary base corresponding to the radical R^, or g) for the manufacture of compounds of the formula I in which Am represents a primary, secondary or tertiary amino group, a compound of the formula <0)n yK n 0 H H ' II • •/ \ Y-T-C-C - HN : V \ I ! (x), N Oz=l N 1 -CH-R.. i \/ 2 1 °~R2 i © COO ^ in which n represents 0 or 1, T, R1 and R2 have the meanings given under formula I and Y represents halogen, is reacted with ammonia or a primary or secondary amine Am-H or a metal amide thereof and, if desired, a resulting conpound of the formula I is converted into a different compound of the formula I and/or, if desired, a 1 V; • " 1983 36 % - 95 - resulting conpound of the formula I in which n represents 0 is converted into a conpound of the formula I in which n represents 1 and/or a compound of the formula I in which n represents 1 is converted into a conpound of the formula 1 in which n represents 0 and/or in a resulting conpound of the formula I functional groups present in protected form are converted into the free functional groups and/or a resulting salt is converted into the free conpound or into a different salt and/or a resulting free conpound having a salt-forming group is converted into a salt and/or a resulting mixture of isomeric conpounds of the formula I is separated into the individual isomers. BALE ~attorneys" FOR THE APPLICANTS"- m