NO743484L - - Google Patents

Description

The methoxy heterocycle/containing aminomethyl.

The present invention relates to the methoxyheterocycle containing aminomethyl and in particular 6(3-acylamino-6a-methoxy-penam-3-caronic acid compounds and 7(3-acylamino-7-niethoxy-3-cephem-4-carboxylic acid compounds with the formula

where X is sulfur or oxygen, or the ethenyl of the formula -CH=CH- and where the group of the formula -S-A- is a residue of the formula where R^ is hydrogen, an etherified hydroxy group or a residue of the formula -CH^- R,,, ^2er ^ ry(^ roSerit a free» etherified or esterified hydroxy or mercapto group or a quaternary amino group and where R is hydroxy or a group which together with the carbonyl group -C(=o)- forms an etherified hydroxy group which is cleavable under physiological conditions and forms an esterified carboxy group as well as salts of these compounds and further methods for their preparation as well as pharmaceutical preparations containing such compounds and the use of such pharmaceutical preparations.

The group X is primarily sulphur, but can also be oxygen, further ethenylene with the formula -CH=CH-. The amino methyl-substituted residue is therefore aminomethyl-thienyl, e.g. k- or 5-amino-methyl-2- or 3-thienyl, further also 3-aminomethyl-2-thienyl or 2-aminomethyl-3-thienyl or corresponding aminomethyl-furyl e.g. h- or 5-aminomethyl-2-furyl, further aminomethyl-phenyl e.g. 2- or 4-aminomethylphenyl.

An etherified hydroxy group R 1 is a hydroxy group which is etherified at a lower aliphatic hydrocarbon residue. Such a group is particularly lower alkoxy, preferably with up to 7 and especially with up to k carbon atoms, primarily methoxy, as well as ethoxy, n-propyloxy or isopropyloxy, further straight or branched butyloxy, pentyloxy, hexyloxy or heptyloxy;

An etherified hydroxy or mercapto group R^ is e.g. a hydroxy or mercapto group which is etherified by a lower aliphatic hydrocarbon residue. An etherified mercapto group R^ can further be a mercapto group that is etherified by an optionally substituted heterocyclic residue with from 1 to k nitrogen atoms in the ring and optionally a further ring heteroatom from the group oxygen or sulfur

which is linked to sulfur through a ring carbon atom.

An esterified hydroxy or mercapto group R is esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid esterified hydroxy or mercapto group. A mercapto group can further be esterified by the benzoic acid or a heterocyclic carboxylic acid where the heterocyclic part is an optionally substituted heterocyclic residue with from 1 to k nitrogen atoms in the ring and optionally a further ring heteroatom of the group oxygen or sulfur which is linked to sulfur through a ring carbon atom.

Quaternary ammonium groups R, are of tertiary organic bases, preferably from the corresponding aliphatic amines or primarily quaternary ammonium groups which are derived from heterocyclic nitrogen bases which are connected to the methyl carbon atom above the nitrogen atom.

Hydroxy or mercapto groups R^ which are etherified with

an aliphatic hydrocarbon residue is particularly lower alkoxy, preferably with up to 7 and especially with up to k carbon atoms, primarily methoxy, as well as ethoxy. n-propyloxy or isopropyloxy, further straight or branched butyloxy, pentyloxy, hexyloxy or heptyloxy, or lower alkylthio, preferably with up to 7 and especially with up to k carbon atoms, primarily methylthio, as well as ethylthio, n-propylthio or isopropylthio, further straight or branched butylthio, pentylthio, hexylthio or heptylthio.

A mercapto group R 1 which is etherified at the aforementioned heterocyclic residue has aromatic properties or may be partially saturated. Substituents include lower alkyl, especially methyl, as well as ethyl, n-proyl, isopropyl or straight or branched butyl, pentyl or hexyl, hydroxy-lower alkyl e.g. hydroxymethyl, cycloalkyl, e.g. cyclopentyl or cyclohexyl, aryl as well as phenyl which may optionally be substituted with halogen, e.g. chlorine or nitro, aryl lower alkyl e.g. benzyl or heterocyclyl such as furyl e.g. 2-furyl, thienyl e.g. 2-thienyl, or oxazolyl e.g. 2-oxazolyl or functional groups such as halogen e.g. fluorine, chlorine or bromine, optionally substituted amino such as mono- or di-substituted amino which is substituted with lower alkyl, e.g. amino, methylamino or dimethylamino, nitro, hydroxy, lower alkoxy e.g. methoxy, ethoxy, n-butyloxy or 2-ethylhexyloxy or optionally functionally cleavable carboxy such as carboxy, esterified carboxy such as lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, optionally substituted such as N-mono- or N,N-dilower-alkylated carbamoyl, e.g. N-methylcarbamoyl or N,N-dimethylcarbamoyl, or cyan, as well as oxo or oxido where one or more such substituents may be present and primarily be connected to ring carbon atoms but also especially in the case of lower alkyl and oxido be connected to ring nitrogen atoms .

Such heterocyclic residues are primarily optionally substituted monocyclic, 5-membered diaza-, triaza-, tetraza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- or oxadiazacyclic residues of an aromatic character which optionally contain the above-mentioned substituents, especially lower alkyl e.g. e.g. methyl or similar residues with an ethyl-fused benzene ring which optionally contain the above-mentioned substituents such as benzodiaza- or benzooxazacyclic residues, optionally monocyclic, 6-membered monoaza- or diaza-cyclic residues of an aromatic character which may be substituted e.g. by the above-mentioned substituents and which primarily contain oxido or similar, partially saturated residues which may optionally be substituted, e.g. by the above-mentioned substituents and which primarily contain oxo or optionally substituted bicyclic triaza- or tetrazacyclic residues of an aromatic character such as e.g. may contain the above-mentioned substituents or corresponding partially saturated residues which are optionally substituted, e.g. by the above-mentioned substituents ie which primarily contain oxo.

Preferred heterocyclic etherified mercapto groups R ? where the heterocyclic residue is a suitable monocyclic, five-membered residue or a suitable benzoheterocyclic residue is, among other things, imida-zolyl-thio, e.g. 2-imidazolylthio or triazolylthio which may be substituted with lower alkyl and/or phenyl, e.g. 1-methyl-1H-1,2,3-triazol-4-ylthio, 1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-triazol-3-ylthio, 3-methyl-1-phenyl-1H-1,2,4-triazol-5-ylthio, h,5-dimethyl-4H-1,2,4-triazol-3-ylthio or k-phenyl-4H-1, 2, k-triazol-3-ylthio optionally tetrazolylthio which may optionally be substituted with lower alkyl, phenyl or halophenyl e.g. 1H-tetrazol-5-ylthio, 1-methyl-1H-tetrazol-5-ylthio, 1-phenyl-1H-tetrazol-5-ylthio or 1-(4-chlorophenyl)-1H-tetrazol-5-ylthio optionally thiazolylthio or isothiazolylthio which may be substituted with lower alkyl or thienyl e.g. 2-thiazolylthio, k-(2-thienyl)-2-thiazolylthio, 4,5-dimethyl-2-thiazolylthio, 3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, possibly thiadiazolylthio which may be substituted with lower alkyl, e.g. 1,2,3Thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3» 4-thiadiazol-2-ylthio, 2-methyl-1,3» 4-thiadiazol-5-ylthio, 1,2,k-thiadiazol-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thiatriazolylthio e.g. 1,2,3,4-thia-triazolyl-5-ylthio, optionally ofesazolylthio or isoxazolylthio which may be substituted with lower alkyl or phenyl, e.g. 5-oxazolylthio, 4-methyl-5-oxazolylthio, 2-oxazolylthio, k,5-diphenyl-2-oxazolylthio or 3-methyl-5-isoxazolylthio, optionally oxadiazolylthio which may be substituted with lower alkyl, phenyl, nitrophenyl or thienyl e.g. 1,2,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, 2-phenyl-1,3,4-oxadiazol-5-ylthio, 5-(4-nitrophenyl )-1,3,4-oxadiazol-2-ylthio or 2-(thienyl)-1,3,4-oxadiazol-5-ylthio optionally benzimidazolylthio which may be substituted with halogen, e.g. 2-benzimidazolylthio or 5-chloro-2-benzimidazolylthio or possibly benzoxazolylthio which may be substituted with halogen or nitro, e.g. 2-benzoxazolylthio, 5-nitro-2-benzoxazolylthio or 5-chloro-2-benzoxazolylthio.

Preferred heterocyclic etherified mercapto groups R2 in which the heterocyclic radical is a suitable monocyclic six-membered radical or a suitable partially saturated radical are among others 1-oxido-pyridylthio which can be substituted with halogen e.g. 1-oxido-2-pyridylthio or 4-chloro-1-oxido-2-pyridylthio, possibly pyridazinylthio which may be substituted with hydroxy, e.g. 3-hydroxy-6-pyridazinylthio, optionally N-oxido-pyridazinylthio which may be substituted with lower alkyl, lower alkyl oxy or halogen, e.g. 2-oxido-6-pyridazinylthio, 3-chloro-1-oxido-6-pyridazinyl-thio, 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio, 3- ethoxy-1-oxido-6-pyridazinylthio, 3-n-butyloxy-1-oxido-6-pyridazinylthio or 3-(2-ethylhexyloxy)-1-oxido-^-pyridazinylthio or optionally 2-oxo-1,2-dihydro -pyrimidinylthio which can be substituted with lower alkyl, amino, dilower alkylamino or carboxy, e.g. 2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-methyl-2-oxo-1,2-dihydro-4-pyrimidinyl- thio, 6-amino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-dimethylamino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-carboxy-2-oxo-1,2- dihydro-4-pyrimidinylthio or 6-carboxy-2-oxo-1,2-dihydro-4-pyrimidinylthio.

Preferred heterocyclic etherified mercapto groups Rg where the heterocyclic residue is a suitable bicyclic, optionally partially saturated residue are, among other things, triazolopyridylthio, e.g. s-triazolo[4", 3-α7pyrid-3-ylthio or 3H-v-triazolo[β,5-t>7pyrid-5-ylthio or optionally purinylthio which may be substituted with halogen and/or lower alkyl, e.g. 2 -purinylthio, 6-purinylthio or 8-chloro-2-methyl-6-purinylthio, further 2-oxo-1,2-dihydro-purinylthio, for example 2-oxo-1,2-dihydro-6-purinylthio.

Hydroxy groups R, which are esterified with aliphatic carboxylic acids are particularly lower alkanoyloxy, especially acetyloxy, further formyloxy, propionyloxy, valeryloxy, hexanoyloxy, heptanoyloxy or pivalyloxy.

An esterified hydroxy group R is furthermore a hydroxy group which is esterified by an optionally N-substituted half-amide of carboxylic acid. N-substituents are suitable halogen e.g. chlorine containing lower alkyl e.g. methyl, ethyl or 2-chloroethyl or lower alkanoyl e.g. acetyl or propionyl. In this context, esterified hydroxy groups R^ are e.g. carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-(2-chloroethyl)carbamoyloxy or N-acetylcarbamoyloxy.

A mercapto group which is esterified by a heterocyclic carboxylic acid contains as a heterocyclic residue e.g. one of the above-mentioned heterocyclic residues which are mentioned in connection with the preferred mercapto groups and which are also designated as preferred. In this context, esterified mercapto groups are particularly triazolyl-carbonylthio which are optionally substituted with lower alkyl and/or phenyl, e.g. 1-methyl-1H-1,2,3-triazol-4-ylcarbonylthio, optionally thiazolylcarbonylthio or isothiazolylcarbonylthio which may be substituted with lower alkyl or thienyl, e.g. 3-isothiazolylcarbonylthio, 4-isothiazolylcarbonylthio or 5-isothiazolylcarbonylthio, optionally thiadiazolylcarbonylthio which may be substituted with lower alkyl, e.g. 1,2,3-thiadiazol-4-ylcarbonylthio, 1,2,3-thiadiazol-5-ylcarbonylthio or 1,2,5-thiadiazol-3-ylcarbonylthio or optionally oxazolylcarbonylthio or isoxazolylcarbonylthio which may be substituted with lower alkyl or phenyl e.g. 3-methyl-3-isoxazolylcarbo-

new10.

In a quaternary ammonium group R ? which is derived from a tertiary organic base, the nitrogen atom is bound to the methyl carbon atom and accordingly exists in a quaternized, positively charged form. The quaternary ammonium groups are, among other things, trilower alkylammonium, e.g. trimethylammonium, triethylammonium, tripropylammonium or tributylammonium, but especially mono- or polysubstituted, monocyclic or bicyclic azacyclic ammonium groups of an aromatic character with 1 or 2 nitrogen atoms in the ring and optionally with 1 sulfur atom in the ring such as pyrimidine, pyridazine, thiazolium, quinoline and primarily pyridine which can be substituted e.g. with lower alkyl, such as methyl, hydroxyl lower alkyl such as hydroxymethyl, amino, substituted sulfonamido such as 4-aminophenylsulfonamido, hydroxy, halogen, such as fluorine, chlorine, bromine or iodine, halogen lower alkyl such as trifluoromethyl, sulfo, optionally functionally cleavable carboxy such as carboxy, lower alkoxycarbonyl e.g. methoxycarbonyl, cyan, optionally N-mono- or N,N-disubstituted carbamoyl which is substituted with lower alkyl, e.g. methyl or ethyl, or hydroxy lower alkyl e.g. hydroxymethyl, e.g. carbamoyl, N-methyl-carbamoyl or N,N-dimethyl-carbamoyl, N-substituted hydrazinocarbonyl which may be substituted with lower alkyl e.g. hydrazinocarbonyl, carboxy lower alkyl such as carboxymethyl, lower alkanoyl such as acetyl or 1-lower alkyl pyrrolidinyl such as 1-methyl-2-pyrrolidinyl.

Heterocyclic ammonium groups R^ are primarily pyridine which may optionally contain lower alkyl, hydroxyl lower alkyl, substituted sulfonamido, hydroxy, halogen, trifluoromethyl, sulfo, carboxy, lower alkoxycarbonyl, cyan, lower alkanoyl, 1-lower alkyl-pyrrolidinyl or optionally N-substituted carbamoyl which may be substituted with lower alkyl or hydroxy lower alkyl e.g. pyridine, 2-, 3- or 4-methyl-pyridine, 3»5-dimethyl-pyridine, 2,4,6-trimethyl-pyridine, 2-, 3- or 4-ethyl-pyridine, 2-, 3- or 4-propyl-pyridine or especially 4-hydroxymethyl-pyridine, further 2-amino- or 2-amino-6-methyl-pyridine, 2-(4-aminophenylsulfonylamido)-pyridine, 3-hydroxy-pyridine, 3-fluoro-, 3-chloro-, 3-iodo- or especially 3-bromo-pyridine, 4-trifluoromethyl-pyridine, 3-sulfo-pyridine, 2-, 3- or 4-carboxy- or 2,3-dicarboxy-pyridine, 4- methoxycarbonyl-pyridine, 3- or 4-cyano-pyridine, 3-carboxymethyl-pyridine, 3- or k-ethyl-pyridine, 3-(1-methyl-2-pyrrolidinyl)-pyridine and especially 4-carbamoyl-, as well as 3-carbamoyl-, .3- or 4-N-methylcarbamoyl-, 4-N,N-dimethylcarbamoyl-, 4-N-ethylcarbamoyl-, 3-N,N-diethylcarbamoyl-, 4-N-propylcarbamoyl- , 4-isopropylcarbamoyl- and 4-hydroxymethyl-carbamoyl-pyridine, and further optionally suitably substituted pyrimidine, pyridazine, thiazolium or quinoline.

In an esterified carboxyl group with the formula -C(=0)-R

which is cleavable under physiological conditions, R is primarily an acyloxymethoxy group where acyl e.g. is a residue of an organic carboxylic acid primarily an optionally substituted lower alkane carboxylic acid, or where acyloxymethyl forms the residue of a lactone. Such groups R,, are lower alkanoyloxymethoxy e.g. acetyloxy-methyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially (X-amino-lower alkanoyloxy-methoxy, e.g. glycyloxymethoxy, L-valyloxymethoxy or L-leucyloxymethoxy, further phthalidyloxy, e.g. 2-phthalidyloxy or indanyloxy e.g. 5 -indanyloxy.

The salts in question are written in particular from compounds of formula I with a free carboxy group -C(=0)-R primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts as well as the ammonium salt with ammonia or suitable organic amines, where primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines as well as heterocyclic bases come into play during the salt formation, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines e.g. 1-ethylpiperidine, cycloalkylamines e.g. dicyclohexylamine, or benzylamines e.g. N,N1 - dibenzyl-ethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of formula I can optionally form acid addition salts, e.g. with organic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic carbon-

or sulfuric acids, e.g. trifluoroacetic acid as well as with amino acids such as arginine or lysine. Compounds of formula I with a free

carboxyl group can also exist in the form of internal salts, i.e. in diionic form.

The compounds of formula I and their pharmaceutically usable, non-toxic salts are valuable, antibiotically active substances, which can be used in particular as antibacterial antibiotics. They are e.g. effective against microorganisms such as against gram-positive bacteria, e.g., against Staphylococcus aureus (in vitro in minimal concentrations of approx. 0.001 mg/ml and e.g. in mice in doses of from 2 to 10 mg/kg s.c.) including against penicillin-resistant Staphylococcus aureus (in vitro in minimal concentrations of approx. 0.001 mg/ml) further against Bacillus subtilis (in vitro in minimal concentrations of approx. 0.001 mg/ml) and against gram-negative bacteria e.g. against Escherichia coli (in vitro in minimal concentrations of approx. 0.005 mg/ml and e.g. in mice in doses of from 10 to 100 mg/kg s.c.) including against ampicillin-, carbenicillin- and rifamycin-resistant Escherichia coli (in vitro in minimal concentrations of approx. 0.005 mg/ml), further against Klebsiella pneumoniae and Salmonella typhimurium, including against ampicillin-, carbenicillin- and rifamycin-resistant Salmonella typhimurium (in vitro in minimal concentrations of approx. 0.005 g/ml), Proteus vulgaris, Proteus mirabilis including carbenicillin-resistant Proteus mirabilis, and Proteus rettgeri (in vitro in minimal concentrations of approx. 0.03 mg/ml). The new compounds are distinguished by a very high stability against |3-lactamases such as cephalosporinases especially from gram-negative bacteria, which can be demonstrated through the hydrolysis rate in the presence of isolated (3-lactamases from various gram-negative germs such as Escherichia coli, Aerobacter cloacae, Proteus morganii and Pseudomonas aeruginosa. The rate of hydrolysis of the new compounds against f3-lactamases is, for example, over 100 times less than that of cephalothin and cephaloridine. The new compounds may therefore find application in the treatment of infections caused by gram -positive or gram-negative bacteria in the form of antibiotic-active preparations.

The present invention primarily relates to compounds of formula I where X is oxygen and, in particular, is sulphur, further also the ethenyl with the formula -CH=CH-, where the aminomethyl-substituted residue is aminomethyl-2-thienyl such as h- or 5- »as well as 3-aminomethyl-2-thienyl, as well as aminomethyl-3-thienyl, further aminomethyl-2-furyl such as 4- or 5-> as well as 3-aminomethyl-2-furyl as well as aminomethyl-3-furyl and aminomethyl- phenyl- e.g. 2- or 4-aminomethyl-phenyl where the group with the formula -S-A- is a residue of the formula Ia, but especially a residue of the formula Ib, where is lower alkoxy, preferably with up to 4 carbon atoms, or is the group of the formula

-CH^-R2» R o is hy°^roSen» lower alkanoyloxy, especially acetyloxy, optionally substituted carbamoyloxy, etherified mercapto or quaternary ammonium and where R is hydroxy as well as salts, especially the non-toxic, pharmaceutically usable salts, especially alkali

or alkaline earth metal salts as well as inner salts of such compounds.

Primarily, the present invention relates to compounds of formula I where X is oxygen or in particular is sulphur, further also the ethenyl with the formula -CH=CH- and the aminomethyl-substituted residue is aminomethyl-2- or 3-thienyl, e.g. 4- or 5->as well as 3-aminomethyl-2-thienyl, further aminomethyl-2-furyl, e.g. 4- or 5-aminomethyl-2-furyl as well as aminomethyl-phenyl e.g.

2- or 4-aminomethyl-phenyl and where the group with the formula -S-A-

is a residue of the formula Ia or Ib where R^ is lower alkoxy with up to 4 carbon atoms such as methoxy or is the group of the formula

-CHgRg» 1*2 is hydr°é>en> lower alkanoyloxy e.g. acetyloxy, possibly N-lower alkylated as well as N-halo-lower alkylated carbamoyloxy, e.g. carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy or 2-chloroethylcarbamoyloxy, lower alkylthio e.g. methyl tip, optionally substituted heterocyclylthio where heterocyclyl is a monocyclic, five-membered heterocyclic residue of an aromatic character which is connected to the thiosulfur atom via a ring carbon atom and which contains 2 or 3 ring nitrogen atoms and optionally in addition an oxygen atom, a sulfur atom or a nitrogen atom in the ring, and where such a residue may optionally be substituted with lower alkyl, especially methyl, or where heterocyclyl is an unsaturated, monocyclic, six-membered heterocyclic residue which is connected to the thiosulfur atom via a ring carbon atom and which contains 2 ring nitrogen atoms where either a ring carbon atom contains an oxido group or a ring carbon atom contains a oxo group and where such a heterocyclyl residue may optionally be substituted with lower alkyl, e.g. methyl, lower alkoxy e.g. methoxy or halogen e.g. chlorine or is a

pyridinium residue which may optionally be substituted with halogen, e.g. chlorine or bromine, lower alkyl e.g. methyl or ethyl (preferably in the 4-position), carboxy, carbamoyl or hydrazinocarbonyl and where R is hydroxy, as well as salts, especially pharmaceutically usable, non-toxic salts, especially alkali or alkaline earth metal salts, as well as internal salts of such compounds.

The invention particularly relates to 3-cephem compounds of formula I where X is primarily sulphur, further also oxygen and where the aminomethyl-substituted residue is aminomethyl-2-thienyl- or -2-furyl, e.g. k- or preferably 5-> further 3-aminomethyl-2-thienyl or k- or 5-amino-methyl-2-furyl, and where the group of formula -S-A- is a residue of formula Ib where R^ is lower alkoxy with up to h carbon atoms especially methoxy, or is the residue with the formula -CH^-R,,, where R^ is hydrogen, acetyloxy, carbamoyloxy, N-lower alkyl-carbamoyloxy e.g. methylcarbamoyloxy or ethylcarbamoyloxy, N-halolower alkylcarbamoyloxy e.g. 2-chloro-ethylcarbamyloxy, lower alkylthio e.g. methylthio, thiadiazolylthio which may optionally be substituted with lower alkyl, e.g. methyl and which is connected via the ring carbon atom with the thiosulfur atom, e.g. 1,3'4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 5-methyl-1,2,4-thiadiazol-2-ylthio or tetrazolylthio e.g. 1-methyl-5-tetrazolylthio, N-oxidopyridazinylthio which is connected to the thiosulfur atom via a ring carbon atom and which may optionally be substituted with lower alkyl, e.g. methyl, lower alkoxy e.g. methoxy, or halogen e.g. chlorine, e.g. 3-niethyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio or 3-chloro-1-oxido-6-pyridazinylthio, or pyridinium which may be substituted with carbamoyl f. e.g. pyridinium or 3-carbamoyl-pyridinium and where the group R is hydroxy, as well as salts, in particular the non-toxic, pharmaceutically usable salts and in particular alkali or alkaline earth metal salts as well as inner salts of such compounds.

Primarily, the invention relates to 3-cephem compounds of formula I where X is primarily sulfur and also oxygen and where the aminomethyl-substituted residue is aminomethyl-2-thienyl- or

-2-furyl e.g. k- or preferably 5-> further 3-aminomethyl-2-thienyl or 2-furyl and where the group of formula -S-A- is the residue of the formula aH3Hwhere R^ is methoxy or the residue of the formula -CH^R^

where R ? is hydrogen, acetyloxy, carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, 2-chloroethylcarbamoyloxy, methylthio, 5-methyl-1,3, k-thiadiazol-2-ylthio or 1-methyl-5-tetrazolylthio and where R

is hydroxy as well as salts, especially the non-toxic, pharmaceutically usable salts, especially alkali or alkaline earth metal salts, as well as inner salts of such compounds.

In particular, the invention relates to the compounds described in the examples as well as their salts and in particular the non-toxic, pharmaceutically usable salts such as alkali or alkaline earth metal salts and primarily their internal salts, which in the indicated doses exhibit outstanding antibiotic effects and which can therefore find application in the form of antibiotic active preparations.

The new compounds according to the present invention can be prepared in a manner known per se, e.g. acylates the amino group in a compound of the formula

where the amino group can optionally be substituted with a group that is present in the acylation and where the group with the formula -S-Aq-

is a remainder with the formula

where Rq corresponds to R or is, together with the carbonyl group of the formula -C(=0)- a protected carboxyl group-forming carboxyl protecting residue, or in a salt thereof by treatment with an acid of the formula where the amino group is optionally protected, or with a reactive functional acid derivative thereof or with a salt of such a compound and in the compound provided transfers the protected amino in the aminomethyl residue to free amino and/or, if this is desired or necessary, transfers a carboxyl group of the formula -C(=0)-Rq i a carboxyl group of the formula -C(=O)-R and/or, if desired, converts a group R^ into another group R^ and/or, if desired, converts a provided salt in the free compound or in another salt or a provided free compound to a salt. Existing residues which can substitute the amino group and release residues for acylation in a starting material of formula II. is e.g. organic silyl or stannyl groups, further also ylidene groups which form a Schiff base together with the amino group. They . said organic silyl or stannyl groups are e.g. the same ones that are able to form a protected carboxyl group -C(=0)-Rq together with the carboxyl group on the penam or cephem ring. When silylating or stannylating a carboxyl group in a starting material of formula II, the amino group can also be silylated or stannylated using an excess of the silylating or stannylating agent.

The mentioned ylidene groups are primarily arylmethylene groups where aryl is particularly a carbocyclic, primarily monocyclic aryl residue, e.g. phenyl which may be substituted with nitro or hydroxy; such arylmethylene groups are e.g. benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further possibly the oxa-cycloalkylidene which may be substituted, e.g. by carboxy, e.g. The 3-carboxy-2-oxacyclohexylidene.

A protected carboxyl group with the formula -C(=0)-Rq in a starting material of formula II is primarily an easily cleavable, esterified carboxyl group, where Rq is an etherified hydroxy group or a carboxyl group that exists in anhydride form where Rq is a esterified and especially a phosphorylated hydroxy group.

An etherified hydroxy group Rq like the carbonyl group with the formula -C(=0)- in the starting material with formula II forms a preferably light; cleavable esterified carboxyl group, is e.g. a preferably lower alkoxy group which can be substituted primarily in the a-position, further also in the ^-position and/or branched in the a-position. Substituents for such a group are e.g. carbocyclic aryl such as phenyl which may be substituted e.g. by lower alkyl, such as tert.-, butyl, phenyl, hydroxy, lower alkoxy such as methoxy and/or nitro, furyl such as 2-furyl, aryloxy such as phenyloxy which may be substituted e.g. by lower alkoxy such as methoxy, arylcarbonyl, such as benzoyl which may be substituted e.g. with halogen such as bromine, cyan or acylamino such as diacylamino e.g. phthalimino or succinylimino; such substituents are preferably in the a-position to the lower alkoxy group Rq, where this, depending on the type of substituent, may contain one, two or more such residues.

Further substituents which are preferably located in the (3-position to a lower carboxylic acid residue Rq are halogen, e.g. chlorine, bromine or iodine,

whereby a single chlorine or bromine atom in such residues can easily be transferred to iodine before a protected carboxyl group is released. Examples of the above-mentioned substituted lower alkoxy groups Rq are tert.-lower alkyl, e.g. tert.-butyloxy or tert.-pentyloxy, optionally α-phenyllower oxy which may be substituted in the phenyl residue, e.g. as indicated such as benzyloxy, 4-hydroxy-3>5-di-tert-butyl-benzyloxy, 2-biphenylyl-2-propyloxy, 4-methoxy-benzyloxy, n,5-dimethoxy~2-nitro-benzyloxy or 4- nitro-benzyloxy, diphenyl-methoxy which is optionally substituted in the phenyl residue, e.g. as indicated especially with lower alkoxy, e.g. methoxy, such as benzhydryloxy or h, h1-dimethoxy-diphenylmethoxy as well as trityloxy, bis-phenyloxy-methoxy which may optionally be substituted in the phenyl residue, e.g.

as indicated in particular with lower alkoxy such as bis-4-methoxyphenyloxy-methoxy, phenacyloxy which may optionally be substituted with halogen such as phenacyloxy or 4-bromo-phenacyloxy, cyanomethoxy, diacyliminomethoxy such as phthalyliminomethoxy or succinyliminomethoxy, or 2-halo-lower methoxy such as 2, 2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy.

Furthermore, an etherified hydroxy group Rq which, together with the carbonyl group with the formula -C(=0)-, forms a preferably easily cleavable esterified carboxyl group can also be a cyclo alkoxy group, which preferably has a bridgehead carbon atom in the a-position. Such a cycloalkoxy group Rq is e.g. 1-adamantyloxy.

Furthermore, preferred hy dr dHsky groups denoted by the residue Rq are organic silyloxy or stannyloxy groups, where organic residues, which may be present in a number of from 1 to 3" in particular, are optionally substituted aliphatic hydrocarbon residues such as lower alkyl e.g. methyl, ethyl, n-propyl or tert.-butyl, or halolower alkyl e.g. chloromethyl or 2-chloroethyl as well as optionally substituted cycloaliphatic, aromatic or araliphatic hydrocarbon residues such as cycloalkyl, phenyl or phenyl-lower alkyl, further organically substituted functional groups such as etherified hydroxy groups, e.g. lower alkoxy', such as methoxy or ethoxy, and which may optionally contain, as additional substituents, e.g. halogen such as chlorine. Such residues Rq are, among other things, tri-lower alkylsilyloxy, e.g. trimethylsilyloxy or tert.-butyl-dimethylsilyloxy, lower alkoxy-lower alkyl-halo-silyloxy e.g. chloro-methoxy-methyl-silyloxy or tri-lower alkylstannyl-oxy e.g. tri-n-butylstannyloxy.

The group Rq can also be a phosphoryloxy group which contains a substituted trivalent or pentavalent phosphorus atom and which together with the carboxyl group with the formula -C(=0)- forms a protected carboxyl group. The substituents of the trivalent phosphorus, which may be the same or different, are among other things optionally substituted hydrocarbon residues such as suitable aliphatic or araliphatic hydrocarbon residues, e.g. lower alkyl or halo-lower alkyl such as methyl, ethyl or chloromethyl, or phenyl lower alkyl such as benzyl, etherified hydroxy or mercapto groups such as etherified hydroxy or mercapto groups which are substituted with aliphatic, aromatic or araliphatic hydrocarbon residues e.g. lower alkoxy or lower alkylthio such as methoxy, ethoxy, methylthio or n-butylthio, possibly phenyloxy or phenylthio which may be substituted e.g. with lower alkyl, lower alkoxy or halogen or phenyl lower alkyl thio or phenyl lower alkylthio which may be substituted e.g. with lower alkyl, lower alkoxy or halogen e.g. benzyloxy or benzylthio, halogen e.g. fluorine, chlorine or bromine and/or a bivalent hydrocarbon residue which may be substituted and/or broken by heteroatoms such as oxygen or sulfur such as a suitable aliphatic or araliphatic residue e.g. the lower alkylene, such as 1,4-biethylene or 1,5-pentylene, 1-oxa-lower alkylene where also the other methylene group which is bound to the phosphorus atom may optionally be replaced by an oxygen or sulfur atom, e.g. 1-oxa-1,4-pentylene, 1-oxa-1,5-pentylene or 1,5-dioxa-1,5-pentylene or two hydroxy groups which are etherified by a bivalent, optionally substituted hydrocarbon residue as a suitable abutment , aromatic or araliphatic residue such as lower alkylene or 1,2-phenylene. Substituents for the pentavalent phosphorus are the same as for the trivalent phosphorus and preferably an oxo group,

In a starting material of formula II, any other free functional groups are present in addition to the carboxyl group of formula -C(=O)-Rq such as a free hydroxy group R^, when this is desired and necessary, for the acylation reaction usually in protected, easily cleavable form; a free hydroxy group can e.g. present in an easily cleavable etherified or esterified form, e.g. in the form of a lower alkoxy- e.g. methoxy-, or a 2-oxacycloalkoxy-e.g. 2-tetrahydropyranyloxy group or an acyloxy such as a lower alkanoyloxy, e.g. acetyloxy or a suitable etherified hydroxycarbonyloxy group.

In a starting material of formula III, the amino group is preferably protected through preferably easily cleavable amino protecting groups which are known in peptide or in penicillin and cephalosporin chemistry. Such protective groups can e.g. be acyl, arylmethyl, 2-carbonyl-1-vinyl, arylthio or aryllower alkylthio, further arylsulfonyl as well as organic silyl or stannyl groups. The amino group can also be present in the form of the azido group. The starting material with formula III can also be used in the form of an acid addition salt where the amino group is protected in ionic form.

An easily cleavable acyl group is e.g. the formyl group or the acyl residue in a half-ester of carboxylic acid such as a lower alkoxycarbonyl group which is preferably multiply aliphatically substituted or branched on the carbon atom in the α-position to the oxy group and/or aromatically or heteroaromatically substituted or a methoxycarbonyl group which may be substituted by an arylcarbonyl - in particular a benzoyl residue or a lower alkoxycarbonyl group which is substituted in the P-position with halogen such as tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl or tert-pentyloxycarbonyl, arylcarbonylmethoxycarbonyl e.g. phenacyloxycarbonyl, 2-haloethoxycarbonyl e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a group that can be transferred in the latter such as 2-chloro- or 2-bromomethoxy-carbonyl, further preferably polycyclic, cycloalkyloxycarbonyl e.g. adamantyloxycarbonyl optionally phenyl lavereal oxycarbonyl which may be substituted e.g. with lower alkyl

such as tert.-butyl, hydroxy, lower alkoxy such as methoxy and/or nitro, especially OC-tefle&yl lower oxycarbonyl e.g. 4-methoxy-benzyl-, oxycarbonyl, 4-hydroxy-3,5-bis-tert-butyl-benzyloxycarbonyl,

4-nitrobenzyloxycarbonyl or α-4-biphenylyl-α-methyl-ethyloxy-. carbonyl, further possibly diphenylmethoxycarbonyl which can be substituted with lower alkoxy such as methoxy, e.g. diphenylmethoxy-carbonyl, or furyl-vereal oxycarbonyl primarily oc-furyl-vereal oxycarbonyl e.g. furfuryloxycarbonyl. An acyl group to protect the amino group can also be a residue of a suitable carboxylic acid such as an aryldicarboxylic acid, e.g. the phthaloyl residue or a halogen-lower alkane carboxylic acid e.g. the trifluoroacetyl residue.

As easily cleavable arylmethyl groups are e.g. optionally substituted polyarylmethyl such as di- or triarylmethyl groups, e.g. optionally o- and/or p-methoxy-substituted trityl which is substituted with lower alkyl, e.g. methyl and/or lower alkoxy such as methoxy.

Easily cleavable 2-carbonyl-1-vinyl groups which together with the amino group either form an enamine or the teutomeric ketimine are e.g. 2-lower oxycarbonyl-1-lower alkylvinyl groups especially the 2-methoxycarbonyl-1-methyl-1-vinyl group.

Easily cleavable arylthio or aryl lower alkylthio groups are e.g. substituted phenylthio groups which may be substituted e.g. with nitro or halogen e.g. chlorine such as the 2-nitrophenylthio-, 2,4-dinitrophenylthio- or pentachlorophenylthio group, further the triarylmethylthio group, e.g. the triphenylmethylthio group.

An easily cleavable organic silyl or stannyl group can contain optionally substituted, particularly aliphatic hydrocarbon residues such as lower alkyl, e.g. methyl, ethyl or tert.-butyl or halo-lower alkyl e.g. 2-chloroethyl, further functional groups e.g. etherified or esterified hydroxy groups such as lower alkoxy, e.g. methoxy or ethoxy or halogen e.g. chlorine. Such silyl or stannyl residues are, among other things, trilower alkylsilyl, e.g. trimethylsilyl or tert.-butyl-dimethylsilyl, lower alkoxy-lower alkyl-halo-silyl e.g. chloro-methoxy-methyl-silyl or trilower alkyl-stannyl e.g. tri-n-butyl-stannyl.

Acylation of the free amino group or of an amino group that is substituted with a residue that is liberated during the acylation can be carried out in a known manner through treatment with an acid of formula III or a reactive functional derivative thereof.

If a free acid of formula III, preferably with a protected amino group, is used for the acylation, suitable condensing agents such as carbodiimides are usually used, e.g. N,N<1->diethyl-, N,N<1->dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, e.g. carbonyldiimidazole or isoxazolinium salts, e.g. N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate or an acylamino compound e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. methylene chloride, dimethylformamide or acetonitrile and, if desired or necessary, under Caykjølin^ or heating and/or in an inert gas atmosphere.

An amide-forming, functional derivative of an acid of formula III, preferably with a protected amino group, is primarily an anhydride of such an acid including and preferably a mixed anhydride, but also an internal anhydride, i.e. the corresponding chain. Mixed anhydrides are e.g. anhydrides with organic acids such as halogenated acids, i.e. the corresponding acid halides, e.g. -chlorides or -bromides, further with a nitric acid, i.e. the corresponding acid azides, with a phosphorus-containing acid, e.g. phosphoric acid or phosphoric acid, or with a sulphurous acid, e.g. sulfuric acid or with hydrocyanic acid. Furthermore, mixed anhydrides are e.g. those formed with organic carboxylic acids such as with a lower alkane carboxylic acid which may optionally be substituted, e.g. with halogen such as fluorine or chlorine e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of carboxylic acid, such as the ethyl or isobutyl half-ester of carboxylic acid, or with organic, especially aliphatic or aromatic sulphonic acids, e.g. p-toluenesulfonic acid.

Other acid derivatives of an acid of formula III suitable for • reaction with the amino group are activated esters, usually with a protected amino group in the aminomethyl group such as esters with vinylogenic alcohols (i.e. enols) such as vinylogenic lower alkenols, or aryl esters such as 4-nitrophenyl- or 2,4-dinitrophic-nyl esters, heteroaromatic esters such as benztriazole, e.g. 2-benz-triazole ester or diacyl imino ester such as succinyl imino or phthalyl imino ester.

Acylation with an acid derivative such as an anhydride and especially with an acid halide can be carried out in the vicinity of an acid binding agent. e.g. an organic base such as an organic amine e.g. a tertiary amine such as trilower alkylamine e.g. trimethylamine, triethylamine or ethyl-diisopropylamine, or N,N-dilaverealkyl-aniline e.g. N,N-dimethylaniline or a base of the pyridine type, e.g. pyridine,

an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, pcarbonate or bicarbonate e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate or an oxirane, e.g. a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above-mentioned acylation can be carried out in an inert, preferably anhydrous solvent or solvent mixture, e.g. in a carboxylic acid amide such as a formamide e.g. dimethylformamide, a halogenated hydrocarbon e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone e.g. acetone, an ester e.g. acetic acid ethyl ester or a nitrile e.g. acetonitrile, or mixtures thereof and, if necessary, at a reduced or elevated temperature and/or in an inert gas atmosphere, e.g. a nitrogen atmosphere.

In an acid of formula III or an acid derivative thereof, the amino group is usually present in protected form, while in a starting material of formula III the protected kmino group can also be present in ionic form, i.e. that the starting material with formula III is used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a halogenated acid, e.g. hydrochloric or sulfuric acid.

Furthermore, an acid derivative can, if desired, be formed in situ. Thus, e.g. a mixed anhydride through treatment of an acid with formula III or a suitable salt thereof, e.g. an ammonium salt e.g. with an organic amine such as 4-methylmorpholine, or a metal, e.g. alkali metal salt with a suitable acid derivative such as a suitable acid halide of an optionally substituted lower alkane carboxylic acid e.g. trichloroacetyl chloride or with a half-ester of a carboxylic acid half-halide, e.g. chloroacetic acid ethyl ester or isobutyl ester, after which the mixed anhydride provided is used without isolation.

In a provided compound, if this is desirable or necessary, functional, possibly protected groups can be transferred in a manner known per se to other functional e.g. free functional groups. First of all, a protected amino group in a compound provided according to the invention must be released as aminomethyl substituents of the acylamino grouping and/or a protected carboxyl group with the formula -C(=0)-Rq which is different from a carboxyl grouping with the formula -C(=0 )-R is transferred in a group with the formula -C(=0)-Rj furthermore, if this is desired, a free carboxyl group with the formula -C(=0)-R can be converted in a manner known per se into a physiological cleavable carboxyl group with the formula -C(=O)-R and/or converting a group R^ in a grouping with the formula Ib into another group R^. These transformations are carried out in a manner known in and of itself, whereby the order of these transformations is such that it suits best and also depends on the type of transformation and on the cleaved residues as well as on the reactions used. Furthermore, it is possible to convert more than one protected functional group simultaneously into corresponding free functional groups. Thus, one can e.g. through treatment with a suitable acid such as trifluoroacetic acid optionally in the presence of anisole, in a compound obtained simultaneously transfer a tert-butyloxycarbonylamino group or a diphenyl-methoxycarbonylamino group in the aminomethyl substituent in the acylamino residue in the 6- or 7-position and a diphenylmethoxycarbonyl group which represents as the residue with the formula -C(=0)-Rq in the 3- or 4-position in a provided penam or 3-cephem compound simultaneously in an amino and a carboxy group, respectively.

The conversion of a protected amino group into a free amino group can be carried out in a manner known per se, usually through solvolysis or reduction.

A formyl group as an amino protecting group can e.g. is split off through treatment with an acidic agent, e.g. p-toluenesulfonic or hydrochloric acid, with a weakly basic agent, e.g. dilute ammonia or with a decarbonylation agent e.g. tris-(triphenylphosphine)rhodium chloride.

In a provided compound, an easily cleavable acyl group such as an α-polybranched lower alkoxycarbonyl group can e.g. tert.-butyloxycarbonyl, further a polycyclic cycloalkyloxycarbonyl group, e.g. 1-adamantyloxycarbonyl, an optionally substituted diphenylmethoxycarbonyl group, e.g. diphenylmethoxycarbonyl or an α-furylvareal oxycarbonyl group is cleaved from an acyl-amiho group, e.g. through acidolysis by treatment with a suitable acid such as a strong, preferably aliphatic carboxylic acid, e.g.

an optionally halogenated, especially fluorinated lower alkane carbonic acid primarily formic acid or trifluoroacetic acid, optionally in the presence of a nucleophilic reagent such as anisole, and a formyl group through treatment with a strong acid such as a mineral acid e.g. hydrochloric acid or a strong organic sulphonic acid, e.g. 4-methylphenyl-sulfonic acid, further also by treatment with a decarbonylation agent, e.g. tris-triphenylphosphine-rhodium chloride, while one can remove a suitable substituted benzyloxycarbonyl group such as k-hydroxy-3»5-bis-tert.-butyl-benzyloxycarbonyl, for example, through treatment with an optionally anhydrous weak. base such as an alkali metal salt or an organic carboxylic acid e.g. the sodium or potassium salt of 2-ethylpentanecarboxylic acid, with an alkali metal salt of a thiophenol e.g. the sodium salt of thiophenol or with a suitable organic amine, e.g. ethylamine or cyclohexylamine or a suitable substituted lower alkanoyl group e.g. trifluoroacetyl, through hydrolysis under slightly basic conditions. A 2-halo-lower oxycarbonyl group such as 2,2,2Ttrichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group can e.g. is cleaved by treatment with a chemical reducing agent such as a suitable reducing metal or a suitable metal compound, e.g. zinc, or a chromium-II compound such as -chloride or -acetate, usually in the presence of an agent which together with the metal

or the metal compound produces nascent hydrogen, preferably in the presence of aqueous acetic acid. A phenazyoxycarbonyl group can also be replaced by hydrogen by treatment with a suitable nucleophilic, preferably salt-forming reagent such as sodium thiophenolate.

Furthermore, an amino group which is protected through a suitable substituted benzyloxycarbonyl group in a provided compound, such as 4-methoxy- or 4-nitrobenzyloxycarbonylamino, can be cleaved, e.g. reductive such as hydrogenolytic e.g. through treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium and especially 4-nitrobenzyloxycarbonylamino through treatment with a chemical reducing agent, e.g. sodium dithionite.

A polyarylmethyl group such as the trityl group can be split off, e.g. through treatment with an acidic agent such as a mineral acid, e.g. hydrochloric acid.

An amino group that is protected in the form of an enamine or the tautomeric ketimine as well as an amino group that is protected with arylthio, arylloweralkylthio or arylsulfonyl can be cleaved, e.g. by treatment with an acidic agent, above all an aqueous acid such as an organic carbonic acid, e.g. formic acid, acetic acid or propionic acid, or a mineral acid e.g. hydrochloric acid or sulfuric acid, optionally in the presence of a solvent which is miscible with water such as a lower alkanol e.g. methanol, a ketone e.g. acetone, an ether e.g. tetrahydrofuran or also a nitrile, e.g. acetonitrile. The removal of the mentioned thio-protecting groups can take place particularly quickly in the presence of suitable reagents such as sodium thiosulphate, sulfuric acid, thioacetamide, thiourea and potassium iodide.

An amino group protected with an organic silyl or stannyl group in a provided compound can be released through treatment with an aqueous or alcoholic agent, e.g. with a lower alkanol such as methanol or in a mixture thereof; usually the cleavage of an amino group protected in this way already takes place during the treatment of the acylation product.

An amino group that exists in the form of an azido group

in the aminomethyl substituent in a provided compound can be transferred to the amino group in a manner known per se by means of reduction, e.g. by treatment with hydrogen in the presence of a hydration

catalyst such as a nickel or palladium catalyst e.g. of Raney nickel or palladium-on-charcoal under mild conditions e.g. under atmospheric pressure and/or at room temperature or under slight heating, further through treatment with phosphine such as a tri-arylphosphine, e.g. triphenylphosphine or with stannous chloride.

The reaction products that arise through acylation of the compounds of formula II according to the invention, where the amino group is substituted with a silyl or stannyl group and where the organic silyl or stannyl group is still located on the amide nitrogen, are usually transferred during processing, particularly during hydrolytic and/or alcoholic conditions, e.g. by those that are common during the cleavage of organic silyl or stannyl groups from amino groups to compounds of formula I..

The reaction products that arise from the acylation of compounds of formula II according to the invention where the amino group is substituted with the ylidene group are usually transferred through treatment, particularly by hydrolysis, e.g. by treatment with water to compounds of formula I.

In a compound according to the invention of formula I with a protected, particularly esterified carboxyl group of formula -C(=O)-Rq, this can be used in a manner known per se, e.g. through solvolysis, treatment with a nucleophilic reagent, irradiation or reduction depending on the nature of group Rq is transferred in the free carboxyl group. A carboxyl group which is esterified with a suitable 2-halo-lower alkyl such as 2,2,2-trichloroethyl or 2-iodoethyl, or an arylcarbonylmethyl group such as phenacyl can e.g. is split through treatment with a chemical reducing agent such as a metal e.g. zinc, or a reducing metal salt such as a chromium II salt such as chromium II acetate, usually in the presence of an agent which releases hydrogen and which together with the metal produces nascent hydrogen such as an acid, primarily acetic acid as well as formic acid , usually with the addition of water; a carboxyl group which is esterified with an arylcarbonyl group, e.g. a phenacyl group can be converted into a free carboxyl group through treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide. A carboxyl group which is esterified through a suitable substituted arylmethyl group can e.g. transferred in the free carboxyl group through irradiation, e.g. with ultraviolet light, e.g. below 290 mu when the arylmethyl group is a benzyl residue which is substituted e.g. in 3-, k- or/ and 5-position, e.g. with lower alkoxy and/or nitro groups, or with long-wave ultraviolet light, e.g. above 290 nru when the arylmethyl group is a benzyl residue which is substituted in the 2-position with a nitro group. From a carboxyl group "which is esterified with a suitable, branched lower alkyl group, e.g. tert-butyl, with a suitable cycloalkyl group such as 1-adamantyl or with a suitable diphenylmethyl group, e.g. benzhydryl, the carboxyl group can be liberated, e.g. by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid optionally with the addition of a nucleophilic reagent such as phenol or anisole A hydrolytically cleavable, esterified carboxyl group such as a carboxyl group that is esterified with a suitable, substituted phenyl residue or a diacyliminomethyl residue, further also a carboxyl group that is esterified with 4-hydroxy-3>5-di-tert-butyl-benzyl residue can, depending on the type of ester group involved, be cleaved, for example, by treatment with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium bicarbonate or an aqueous potassium phosphate buffer of pH between 7 and 9 and a hydrogenolytically cleavable esterified carboxyl group, such as an α-aryl lower alkyl group which is subst ituated in the aryl residue with e.g. benzyl, 4-methoxy-benzyl or chlorobenzyl can be split through hydrogenolysis, e.g. by treatment with hydrogen in the presence of a noble metal catalyst, e.g. a palladium catalyst.

A carboxyl group which is protected e.g. through silylation or stannylation as well as through phosphorylation can be released in the usual way, e.g. through hydrolysis or alcoholysis.

The new compounds of formula I can likewise be provided when in the 6a- or 7&-position in a penam- or 3-cephem compound of the formula

where amino in the aminomethyl group is preferably present in protected form and where the residue -S-Aq- has the above meaning pg where the carboxyl group with the formula -C(=0)-Rq is preferably present in protected form or in salts thereof, introduces a methoxy group

and, if this is desirable or necessary, carries out further reaction steps.

The introduction of the methoxy group in the 6a position in a penam starting material or in the 7<X position in a 3-cephem starting material of formula IV can be carried out in a manner known per se.

Then one can treat an acylimino compound with the formula

where amino in the aminomethyl group is present in protected form and the residue with the formula -S-Aq- has the above meaning where a carboxyl group with the formula -C(=0)-Rq is present in protected form with methanol and in a provided compound transfer protected amino in the aminomethyl group to free amino and, if this is necessary or desirable, transfers a carboxyl group of the formula -C(=0)-Rq into a carboxyl group of the formula -C(=0)-R and/or, if desired, converts a group R^ in another group R^ and/or, if this is desired, converts a provided salt into the following compound or into another salt or a provided free compound into a salt.

In the starting material with the formula IVa, there are free functional groups, especially amino in the aminomethyl substituents and a carboxyl group -C(=0)-Rq in a residue -S-Aq-, further free functional groups in a residue R ? in e.g. as indicated above protected form, an amino group jjSåreligger e.g. as preferably easily cleavable acylamino, further as an arylmethylamino, 2-carbonyl-1-vinylamino, arylthioamino or aryllower alkylthioamino group, a carboxyl group e.g. as preferably an easily cleavable, esterified carboxyl group and a free functional group in the residue R^ such as e.g. a hydroxy group as indicated above in protected form, e.g.

in the form of an acyloxy group. »

The above-mentioned reaction is carried out in a manner known per se, usually in the presence of a solvent or diluent or in mixtures of such, whereby methanol can be used as such, preferably under cooling, for example, to approx. -80° as well as at room temperature or under light heating and, if necessary, in a closed vessel and/or under an inert gas atmosphere, e.g. nitrogen atmosphere.

The starting material with formula IVa is usually reacted in untreated form, i.e. without having been isolated with the methanol after its preparation or formed in the presence of this reagent. Then you proceed from e.g. a compound of formula IV where the amino in the aminomethyl group and the carboxyl group of the formula -C(=0)-Rq as well as any other functional groups present are in protected form, and treats it with an aru ion-forming agent followed by an N-halogenating agent and reacts, if necessary with a hydrogen halogen-releasing base or a compound of the formula

where R° is an organic residue and where amino in the aminomethyl group and the carboxyl group with the formula -C(=o)-Rq as well as any other functional groups present are present in protected form, is reacted with halogen followed by a base. One can thus usually provide as a non-isolated product the corresponding 6-acylimino-penam compound or 7-acylimino-3-cephem compound of formula IVa which in the presence of methanol is transferred into the desired 6(3~acylamino-6(X- methoxy-penam compound and the desired 7(3-acylamino-7oc-methoxy-3-cephem compound) on which, if necessary or desired, the above-mentioned additional steps are carried out.

A suitable anion-forming agent with which starting material of formula IV can be reacted is primarily an organometallic base, in particular an alkali metal - primarily a lithium organobase. Such compounds are particularly suitable alcoholates such as suitable lithium lower alcoholates primarily lithium methylate or suitable metal hydrocarbon bases in particular lithium lower alkanes and preferably lithium phenyl. The reaction with the anion-forming organometallic bases is usually carried out under cooling, e.g. from approx. 0°C to approx. -80°C and in the presence of a suitable solution or thinning agent, e.g. an ether such as tetrahydrofuran, when lithium methylate is used also in the presence of methanol and, if desired, in a closed vessel and/or

in an inert gas atmosphere, e.g. a nitrogen atmosphere.

As an N-halogenating agent, a sterically hindered, organic hypohalogenite is usually used, especially -chlorite^ and primarily a suitable aliphatic hypohalogenite, e.g. -chlorite such as a tert.-lower alkyl hypohalogenite e.g. -chlorite. First of all, tert-butyl hypochlorite is used, which is reacted with the unisolated product from the anionization reaction.

The N-halogenated intermediate is converted in the presence of an excess of the anion-forming base, especially lithium methylate, under the reaction conditions and without being isolated, to the acyliminophor compound of formula IVa and this is transferred in the presence of methanol directly to the 6a-methoxypenam compound or 7α-methoxy-3-cephem- . the connection. If necessary, hydrohalic acid and particularly hydrochloric acid must be split off from the N-halogenated intermediate; this takes place by adding a halogen-hydrogen-releasing base such as a suitable alkali metal low-area anolate, e.g. lithium tert.-butylate whereby this reaction usually takes place under the conditions of the anion-forming reaction and of the reaction forming the N-halogen compound, under which one works in the presence of methanol and instead of the acylimino compound provides the 6a-methoxy-penam compound or 7a-methoxy- the 3-cephem compound directly. It means that one starts from one. compound with formula IV, where the functional groups are usually present in protected form, react these with an excess of the anion-forming agent, e.g. lithium methylate or phenyllithium in the presence of methanol, then treated with N-halogenating agent e.g. tert-butyl hypochlorite and in this way provides directly the desired compounds of formula I where protected functional groups can be released if necessary or desired. Or you can add methanol later, whereby the dehydrohalogenation and the addition of methanol can be carried out at a slightly higher temperature as the anion-forming reaction and in a reaction that forms the N-halogen compound, e.g. from approx. 0°C to approx. -20°C and, if necessary, in a closed vessel and/or in an inert gas atmosphere, e.g. a nitrogen atmosphere.

In a starting material of formula IVb, an organic residue R oi primarily means a hydrocarbon residue with an aliphatic character such as lower alkyl and especially methyl. The reaction with halogen, primarily with chlorine, and a base is usually carried out in the presence of a suitable solution' or diluent, such as a halogenated hydrocarbon e.g. methyene chloride, and during cooling e.g. to -80°C, and if necessary you work in a closed vessel and/or in an inert gas atmosphere, e.g. a nitrogen atmosphere. A suitable organic base is preferably used as a base, such as a tertiary amine, e.g. a trilower alkylamine such as triethylamine, which is usually added to the above halogenation mixture together with methanol and under the conditions applicable to the halogenation reaction. In this way, respectively, the 6-acylimino-penam starting material and the 7-acylimino-3-cephem starting material of formula IV are directly transferred into a 6(3-acylamino-6a-methoxy-penam compound and a 7(3-acylamino -7<X-methoxy-3-cephem compound of formula I which, if necessary or desired, can be transferred into the desired compounds of formula I.

The introduction of the methoxy group in the 6(X-position, respectively

in the 6(3-acylamino-penam compound and in the 7a position in the 7|3-acylamino-3-cephem compound can also take place through substitution in an exchangeable group found in this position. Thus, one can react a compound with formula IV where R° has the stated meaning, and is primarily an aliphatic hydrocarbon residue such as lower alkyl and especially methyl, and where amino in the aminomethyl group and the carboxyl group with the formula -C(=0)-R o as well as any other functional groups present are present in protected form, with methanol in the presence of a desulphurizing agent.

The desulfurization in the presence of methanol is usually carried out using a suitable silver or mercury compound such as silver oxide or mercury oxide or in particular a corresponding salt such as a silver I salt or mercury II salt with an organic carbonic acid e.g. a silver I or mercury II laveral anoate especially mercury II acetate. One then works in the presence of a solvent or diluent, e.g. an ether such as dimethoxyethane or a solvent mixture, and one can also use an excess of methanol as such, with cooling e.g. to -30°C, at room temperature or under gentle heating, e.g. to +70°C, and, if necessary in a closed vessel and/or in an inert gas atmosphere e.g. a nitrogen atmosphere.

In the compounds provided according to the above for various methylation reactions which are preferably carried out according to the methods described by Koppel and Kocher, J.Am.Chem.Soc., Vol. 95, P.2403 (1973), Spitzer and Goodson, Tetrahedron Letters, S.

273 (1973) or Slusarchyk et al., J.Org.Chem., Vol. 38, P.9^3

(1973)», the protected amino in the aminomethyl group is released after

the method specified above and, if this is necessary, a protected carboxyl group with the formula -C(=0)-Rq is transferred according to the method specified in a carboxyl group with the formula -C(=0)-Rj if this is desired, one can as indicated, a provided compound converts the carboxyl group of the formula -C(=0)-R into another carboxyl group of the formula -C(=0)-R and/or a group R1 into another group R1.

The compounds according to the present invention can likewise be provided when in a 3-cephem compound of the formula

where AmQ is a protected amino group and R^ is a residue which together with the carbonyl grouping of formula -C(=0)- forms a preferably protected carboxyl group and where amino in the aminomethyl group exists in a protected form which differs from the protected amino group AmQ by its transfer to a free amino group, transfers the group AmQ to a free amino group, whereby the 5-amino-5-carboxy-valeryl residue is cleaved under the reaction conditions and in a provided compound transfers the protected amino in the aminomethyl group to free amino and, if this is necessary and desired, transfers a carboxyl group of the formula -C(=O)«Ro in a carboxyl group of the formula -C(=O)-R and/or, if this is desired, converts a group R1 to another group R-j^ and/or, if this is desired , converts a provided salt into the free compound or into another salt or a provided free compound into a salt.

In the above-mentioned starting material, the carboxyl group in the formula -C(=0)-Rq in the residue with the formula -S-Aq- and the formula -C(=0)-R1 are usually protected carboxyl groups such as e.g. the above-mentioned protected carboxyl groups, while a group of the formula -C(=O)-R"^

o can also be a non-cleavable esterified carboxyl group such as methoxycarbonyl. Amino in the aminomethyl group is, as already noted, in protected form; usually, functional groups present in the residue R^ are also protected. Under the reaction conditions, such protected groups are usually not released.

A protected amino group AmQ is usually an amino group that can preferably be transferred to the free amino group under mild conditions. Protection groups are e.g. acyl, arylmethyl, 2-carbonyl-1-vinyl, arylthio, aryllower alkylthio or arylsulfonyl groups which can be cleaved off in various ways.

An easily cleavable acyl group is e.g. the formyl group or the acyl residue of a half-ester of carboxylic acid such as a lower alkoxycarbonyl group which in the a-position to the oxy group is multiply aliphatically substituted or branched and/or aromatically or heteroaromatically substituted or a methoxycarbonyl group which is substituted with an arylcarbonyl residue in particular a benzoyl residue or a lower alkoxycarbonyl group which is substituted in |3-position with halogen such as tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl, or tert-pentyloxycarbonyl, arylcarbonylmethoxycarbonyl e.g. fehacyloxycarbonyl, 2-haloethoxycarbonyl e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a group which can be transferred in the latter such as 2-chloro- or 2-bromo-ethoxy-carbonyl further, preferably polycyclic, cyclo- oxycarbonyl e.g. adamantyloxycarbonyl, optionally phenyl lower oxycarbonyl which is substituted e.g. by lower alkyl such as tert.-butyl, hydroxy, lower alkoxy such as methoxy and/or nitro, especially α-phenyl lower oxycarbonyl, e.g. 4-methoxy-benzyloxycarbonyl, 4-hydroxy-3'5-bis-tert-butyl-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or α-4-biphenylyl-α-methylethyloxycarbonyl as well as optionally substituted diphenylmethoxycarbonyl, e.g. with lower alkoxy such as methoxy, e.g. diphenyl methoxycarbonyl or furyl avereal oxycarbonyl primarily α-furyl avereal oxycarbonyl e.g. furfuryloxycarbonyl. An acyl group can also be a suitable residue for a suitable carboxylic acid such as an aryl dicarboxylic acid e.g. the phthaloyl residue or a halogen low-alkane carbon acid e.g. trifluoroacetyl-

the rest.

As easily cleavable arylmethyl groups can e.g. mention: optionally substituted polyarylmethyl groups such as di- or triarylmethyl groups, e.g. thiethyl which may optionally be substituted such as with lower alkoxy such as methoxy and especially o- or p-methoxy-substituted trityl.

Easily cleavable 2-carbonyl-1-vinyl groups which together with an amino group form either an enamine or the tautomeric ketimine are examples of 2-lower oxycarbonyl-1-lower alkyl vinyl groups, especially the 2-methoxycarbonyl-1-methyl-1-yinyl group.

Easily cleavable arylthio or aryl lower alkylthio groups are preferably substituted phenylthio groups which are substituted e.g. with nitro or halogen e.g. chlorine such as the 2-nitrophenylthio group, the 2,4-dinitrophenylthio group or the pentachlorophenylthio group, further the triarylmethylthio group, e.g. the triphenylmethylthio group.

A protected amino group AmQ can be transferred to the free amino group in a manner known per se; the liberated amino group causes the intramolecular aminolysis of the 5-amino-5-carboxy-valeroyl residue which takes place under the reaction condition, which is cleaved and therefore usually in the form of the protected 2-oxo-piperidine-6-carboxylic acid.

The cleavage of a protected amino group AmQ into a free amino group can be carried out in a manner known per se, depending on the type of protecting group, in particular by solvolysis, with treatment with a nucleophilic reagent or reduction.

A formylamino group AmQ can e.g. is split through treatment with an acidic agent, e.g. p-toluenesulfonic acid or chlorine-water tof f acid with a weak basic agent, e.g. dilute ammonia, or with a decarbonylation agent, e.g. tris-(triphenylphosphine)rhodium chloride.

An α-polybranched lower alkoxycarbonylamino group

e.g. tart. -butyloxycarbonylamino, further a polycyclic cyclo- alkoxycarbonylamino group, e.g. 1-adamantyloxycarbonylamino,

an optionally substituted diphenylmethoxycarbonylamino group, e.g. diphenylmethoxycarbonylamino, or an α-furyl-lower oxycarbonylamino group AmQcan be cleaved e.g. through treatment with a suitable acid such as a strong, preferably aliphatic carboxylic acid such as

an optionally halogenated, particularly fluorinated lower alkanecarboxylic acid primarily formic acid or trifluoroacetic acid optionally in the presence of a nucleophilic reagent, e.g. anisole, while one can cleave a suitable substituted benzyloxycarbonylamino group, e.g. 4-Hydroxy-3>5-di-tert.-butyl-benzyloxycarbonylamino preferably through treatment with an optionally water-free, weak base such as an alkali metal salt of an organic carboxylic acid, e.g. the sodium salt or the potassium salt of 2-ethylpentacarboxylic acid, with an alkali metal salt of a thiophenol e.g. the sodium salt of thiophenol, or with a suitable organic amine, e.g. ethylamine or cyclohexylamine, or a suitable substituted lower-alkanoylamino group e.g. trifluoroacetylamino, hydrolytic under slightly basic conditions. One can cleave a 2-halogen-lower oxycarbonylamino group such as 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino (whereby before the cleavage a group which can be transferred to 2-iodoethoxycarbonylamino such as the corresponding 2-chloroethoxycarbonylamino or 2-bromomethoxycarbonylamino is transferred to i and in a manner known per se, for example by treatment with a suitable iodide salt such as alkali metal iodide such as sodium iodide, in the presence of a solvent such as acetone, converts this to 2-iodoethoxycarbonylamino) or a phenacyloxycarbonylamino such as phenacyloxycarbonylamino through treatment with a chemical reducing agent such as a suitable reducing agent metal or a corresponding metal compound such as zinc or a chromium-II compound such as -chloride or -acetate, usually in the presence of an agent which together with the metal or metal compound induces nascent hydrogen, preferably in the presence of aqueous acetic acid.

Furthermore, one can cleave a protected amino group AmQ which is protected preferably through a suitable substituted benzyloxycarbonyl group such as 4-methoxy- or 4-nitrobenzyloxycarbonylamino, hydrogenolytically e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium, or, particularly in the case of 4-nitrobenzyloxycarbonylamino, through treatment with a chemical reducing agent, e.g. sodium dithionite.

A polyarylmethylamino group AnQ, such as tritylamino, can be cleaved e.g. by treatment with an acidic agent such as a mineral acid, e.g. hydrochloric acid.

An amino group protected in the form of an amine or the tautomeric ketimine, as well as the said protected amino groups

Amosome is protected with arylthio, aryllaverealkylthio and arylsulfonyl can be cleaved by treatment with an acidic agent above all an aqueous acid, such as an organic carboxylic acid e.g. formic acid, acetic acid or propionic acid, or a mineral acid e.g. hydrochloric acid or sulfuric acid, possibly in the presence of a solvent which is miscible with water such as a lower alkanol, e.g. methanol, a ketone e.g. acetone, an ether e.g. tetrahydrofuran or also a nitrile, e.g. acetonitrile. The removal of the mentioned thio-protecting groups can take place particularly quickly in the presence of suitable reagents such as sodium thiosulphate, sulfuric acid, thioacetamine, thiourea and potassium iodide.

The cleavage reactions described above are carried out in a manner known per se, if necessary during cooling or heating, in a closed vessel and/or in an inert gas atmosphere, e.g.

a nitrogen atmosphere.

As pointed out above, there must not be a simultaneous release of other functional groups under the reaction conditions. Thus, e.g. the protected amino group AmQ be a cleavable amino group by treatment with a chemical reducing agent e.g.<*>, with zinc in the presence of aqueous acetic acid e.g. a cleavable 2-halogen-lower oxycarbonylamino group such as 2,2,2-trichloroethoxycarbonylamino under these conditions, while amino in the aminomethyl substituent e.g. may be protected through an α-polybranched lower alkoxycarbonyl group which can be split off by treatment with a suitable acid such as trifluoroacetic acid such as tert-butyloxycarbonyl, and a carboxyl group of the formula -G(=0)-Rq, further a free carboxyl group which is optionally found in a group in the rest with the formula -S-Aq- e.g. through an optionally substituted diphenylmethyl group which can be split off, e.g. through treatment with a suitable acid such as trifluoroacetic acid, e.g. benzhydryl, and undergo the above-mentioned reductive cleavage reaction in protected form, and are first released in the subsequent intramolecular aminolysis of a 5-amino-5-carboxy-valeryl ester if this is necessary and desirable.

The above-mentioned method can e.g. is carried out according to the method described by Sletzinger et al., J,Am.Chem.Soc., Vol. 94, P. 1410 (1972).

The compounds according to the present invention can optionally be prepared if one reacts a compound with the formula

where the residue in the formula -S-Aq- has the meaning given above, where a carboxyl group in the formula -C(=O)-Rq is preferably present in protected form with a compound of the formula R^^-NH^(Vil) where Rx is an amino protecting group and formaldehyde in the presence of a strong, very weak nucleophilic acid, and in a provided compound, the protected amino in the aminomethyl group transfers to free amino and,

if necessary or desired, transfer a carboxyl group of the formula -C(=O)-Rq to a carboxyl group of the formula -C(=O)-R o and/or, if desired, convert one group R^ to another group R-^ and/or, if this is desired, if this is a provided salt of the free compound or of another salt or a provided free compound of a salt.

An amino protecting group Rx is one of the above-mentioned amino protecting groups, e.g. in connection with amino in the aminomethyl residue and which under the reaction conditions, i.e. in the presence of a strong, very weak nichleophilic acid is not cleavable. Such a group is primarily a suitable acyl group such as formyl or a suitable, optionally substituted lower alkanoyl, especially trifluoroacetyl and primarily suitable etherified hydroxycarbonyl which, e.g. under reductive conditions, by treatment with a nucleophilic reagent or by irradiation is cleavable, primarily 2-halo-lower oxycarbonyl e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, e.g. phenacyloxycarbonyl, or α-aryllower oxycarbonyl such as optionally α-phenyl lower aryloxycarbonyl which is substituted e.g. with lower alkoxy such as methoxy and/or nitro, e.g. benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or n,5-dimethoxy-2-nitrobenzyloxycarbonyl.

Formaldehyde can be present as such or in the form of a reactive derivative primarily in the form of a polymer such as paraformaldehyde.

Strong, very weakly nucleophilic acids are primarily strong organic carboxylic acids such as preferably halogen-substituted lower alkane carboxylic acids, e.g. formic acid (optionally in the presence of a strong organic sulphonic acid such as a strong aryl sulphonic acid, e.g. k-methylbenzenesulphonic acid) and primarily trifluoroacetic acid.

The above-mentioned reactions are usually carried out by a reaction mixture of a compound of formula VII and formaldehyde or a derivative thereof (which, for example, is prepared in the presence of an inert solvent and a weakly basic agent such as an alkali metal carbonate, e.g. potassium carbonate and, if necessary, during the removal of water and during the formation of an intermediate product of the formula R^^-NH-CH^-OH (vila)) the starting material of formula VI is added and with the strong, very weak nucleophilic acid after which one works in the presence of an inert solvent or solvent mixtures, under stirring or heating and/or in an inert gas atmosphere.

In a compound of formula I which is provided according to this method, the amino group in the aminomethyl residue is present in protected form, and the amino protecting group is primarily the above-mentioned acyl residues. They are split off in a manner known per se, e.g. as described above, a formyl group e.g. by treatment with a strong acid, e.g. hydrochloric acid or 4-methylphenylsulfonic acid, a trifluoroacetyl group e.g. hydrolytically under weakly basic conditions, a suitable 2-halolower oxycarbonyl group or arylcarbonylmethoxycarbonyl group e.g. through treatment with a chemical reducing agent such as a suitable reducing metal or a suitable metal compound e.g. zinc or a chromium-II compound such as -chloride or -acetate, usually in the presence of an agent which together with the metal or metal compound produces nascent hydrogen preferably in the presence of aqueous acetic acid, an arylcarbonylmethoxycarbonyl group also by treatment with a suitable nucleophile, preferably salt-forming reagent such as sodium thiophenolate and an α-aryl lavereal oxycarbonyl group hydrogenolytically e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium or such as 4-nitrobenzyloxycarbonyl through treatment with a chemical reducing agent, e.g. sodium dithionite.

3-cephem compounds according to the present invention can optionally be provided if one isomerizes a 2-cephem compound with the formula

where amino in the aminomethyl group and/or a carboxyl group with the formula -C(=o)-Rq, if necessary or desirable, is present in protected form to the corresponding 3-cephem compound and, if this is desirable or necessary, carries out subsequent reaction steps.

The isomerization of the 2-cephem compound to the corresponding 3-cephem compound can be carried out in a manner known per se e.

Thus, a 2-cephem compound of formula VIII can be isomerized by treating it with a weak basic agent and isolating the corresponding 3-cephem compound from the equilibrium mixture provided.

Suitable isomerizing agents are e.g. organic, nitrogen-containing bases such as tertiary heterocyclic bases of an aromatic character and primarily tertiary, aliphatic, azacycloaliphatic or araliphatic bases such as N,N,N-trilower alkylamines, e.g. N,N,N-trimethylamine, N,N-dimethyl-N-ethylamine, N,N,N-triethylamine or N,N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes e.g. N-methyl-piperidine or N-phenyl-lower alkyl-N,N-dilower alkyl-amines e.g. N-benzyl-N,N-dimethylamine as well as mixtures thereof such as the mixture of a base of the pyridine type, e.g. pyridine and a N,N,N-trilower alkylamine e.g. pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal salts or ammonium salts of lower alkane carboxylic acids, e.g. sodium acetate, tri-ethylammonium acetate or N-methyl-piperidine acetate as well as other analogous bases or mixtures of such basic agents are used.

The above-mentioned isomerizations with basic agents can be carried out, e.g. in the presence of a derivative of a suitable carboxylic acid

to form a mixed anhydride such as a carbonic anhydride

or -halide e.g. with pyridine in the presence of acetic anhydride. One then preferably works in a medium free from any other medium in the presence or absence of a solvent such as a possibly halogenated one, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture where all bases which are used as a reaction agent and which are liquid under the reaction conditions can simultaneously be used as a solvent, if necessary during cooling, during heating, preferably in a temperature range from approx. -30°C to approx. +100°C in an inert gas atmosphere, e.g. a nitrogen atmosphere and/or in a closed vessel.

Provided 3-cephem compounds can be separated from possibly present 2-cephem compounds in a manner known per se, e.g. through adsorption and/or crystallization.

Isomerization of 2-cephem compounds of formula VIII

can optionally be carried out by oxidizing these in the 1-position, separating the provided isomer mixture of the 1-oxide of the 3-cephem compound if desired, and reducing the provided 1-oxide of the corresponding 3-cephem compound.

As a suitable oxidizing agent for oxidation in the 1-position

of 2-cephem compounds are inorganic peracids which have a reduction potential of at least +1.5 volts and which consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids, with a dissociation constant of at least 10 -5 on speech. Suitable inorganic peracids are periodic acid and persulphuric acid. Organic peracids are suitable percarboxylic acids and persulfonic acids which can be added as such or which can be formed in situ through the use of at least one equivalent of hydrogen peroxide and one carboxylic acid. It is then appropriate to use a large excess of carbonic acid, if e.g. acetic acid is used as a solvent. Suitable peracids are e.g. permauric acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

The oxidation can optionally be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10 - 5, whereby small concentrations can be used, e.g. 1-2$ and less but also larger quantities of the acid. The activity in the mixture therefore depends primarily on the acid strength. Suitable mixtures are e.g. mixtures of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above-mentioned oxidations can be carried out in the presence of suitable catalysts. Thus, the oxidation with percarboxylic acids can be catalyzed through the presence of an acid with a dissociation constant of at least

-5

10 , whose activity depends on the acid strength. Acids that are suitable as catalysts are e.g. acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably with a small excess of from 10$

to approx. 20$. The oxidation is carried out under mild conditions, e.g. at temperatures from approx. -50°C to approx. +100°C preferably from

-10°C to approx. +40°6.

Oxidation of 2-cephem compounds to 1-oxides of the corresponding 3-cephem compounds can also be carried out through treatment with ozone, further with organic hypohalogenite compounds such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite which is used in the presence of inert solvents such as possibly halogenated hydrocarbons, e.g. methylene chloride, and at temperatures of approx. -10°C to approx. +30°C, with periodate compounds such as alkali metal periodates e.g. potassium periodate, which is preferably used in an aqueous medium with a pH value of 6 and at temperatures of from approx. -10°C to approx. +30°C, with iodobenzene dichloride which is used in an aqueous medium, preferably in the presence of an organic base, e.g. pyridine and during cooling e.g. at temperatures of -20°C to approx. 0°C or with other oxidizing agents suitable for converting a thio or a sulfoxide group.

In the provided 1-oxides of the 3-cephem compound, necessary other reaction steps can, if desired, be carried out in connection with the isomerization reaction. Furthermore, a mixture of isomeric α- and (3-1-oxides) can be separated e.g. chromatographically.

The reduction of 1-oxides of 3-cephem compounds can be carried out in a manner known per se, e.g. by treatment with a reducing agent if necessary in the presence of an activating agent. The following reducing agents come into consideration: catalytically activated hydrogen using noble metal catalysts containing palladium, platinum or rhodium and which can optionally be used together with a suitable support material such as coal or barium sulphate; reducing tin, iron, copper or manganese cations which can be used in the form of suitable compounds or complexes of inorganic or organic type, e.g. such as tin II chloride, fluoride, acetate or formate, iron II chloride, sulphate, oxalate or succinate, copper I chloride, benzoate or oxide or manganese II chloride, - sulphate, -acetate or -oxide or as complexes e.g. with ethylenediaminetetraacetic acid or nitrolotriacetic acid; reduced dithionite, iodine or iron II cyanide ions which can be used in the form of inorganic or organic salts such as alkali metal dithionite, e.g. sodium or potassium dithionite, sodium or potassium iodide or

-iron II cyanide or in the form of suitable acids such as hydroiodic acid; reducing trivalent, organic or inorganic phosphorus compounds such as phosphine, further esters, amides and halides of phosphinic acid, phosphonic acid or phosphoric acid as well as these phosphorus-oxygen compounds' associated phosphorus-sulfur compounds where organic residues are primarily aliphatic, aromatic or araliphatic residues e.g. . optionally substituted lower alkyl, phenyl or phenyl ave alkyl groups such as e.g. triphenylphosphine, tri-n-butylphosphine, diphenylphosphinic acid methyl ester, diphenylchlorophosphine, phenyl-dichlorophosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acid methyl ester, phosphoric acid bing triphenyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, etc.; reducing halosilane compounds which have at least one hydrogen atom bound to the silicon atom and which in addition have halogen such as chlorine, bromine or iodine and also organic residues such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl groups or phenyl groups such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc.; reducing quaternary chloromethylene-iminium salts, especially chlorides or bromides where the iminium group is substituted with one bivalent or two monovalent organic residues such as optionally substituted lower alkylene or lower alkyl groups such as N-chloromethylene-N,N-diethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; and complex metal hydrides such as sodium borohydride in the presence of suitable activating agents such as

cobalt II chloride as well as borane dichloride.

As activating agents, which can be used with the above-mentioned reducing agents, and which themselves do not have Lewis acid properties, i.e. which can primarily be used with dithionite, iodine or iron II cyanide and the non-halogen-containing trivalent phosphorus reducing agents or which can be used by catalytic reduction, especially organic carbon and sulphonic acid halides, further sulfur, phosphorus or silicon halides with an equal or greater hydrolysis constant in a different arrangement than benzoyl chloride, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonic acid dichloride, dimethylchlorosilane or trichlorosilane, further suitable acid anhydrides such as trifluoroacetic anhydride or cyclic sultones such as ethanesulton, 1 ,3-propane sultone, 1,4-butane sultone or 1,3-hexane sultone.

The reduction is usually carried out in close stirring of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of reducing agents, so that e.g. lower alkane carboxylic acids or their esters such as acetic acid and acetic acid ethyl ester are used in the catalytic reaction and e.g. optionally substituted such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkane carboxylic acid esters or -nitriles, e.g. acetic acid ethyl ester or acetonitrile or amides of inorganic or organic acids, e.g. dimethylformamide or hexamethylphosphoramide, ether e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone or sulphones, especially aliphatic sulphones, e.g. dimethyl sulfone or tetramethylene sulfone etc. are used together with the chemical reducing agents, whereby these solvents preferably do not contain water. You then usually work at temperatures of from approx. -20°C to approx. 100°C, but using particularly reactive activators, the reaction can be carried out at lower temperatures.

In a compound with the formula I which is provided according to v the invention, and which contains a free carboxyl group with the formula

-C(=0)-R and where amino in the aminomethyl residue is possibly present in protected form, the free carboxyl group can be known in and of itself

way is transferred in a cleavable, esterified carboxyl group under physiological conditions. Thus, for example, the carboxyl group in connection with formula I with a free carboxyl group or in a salt thereof, for example, in an alkali metal salt such as a sodium or potassium salt, or in an alkaline earth metal salt such as a calcium or magnesium salt or in an optionally substituted ammonium salt such as triethylammonium salt, through reaction with a suitable halide, e.g. chloride or bromide is transferred in the corresponding esterified carboxyl group -C(=0)-R.

Furthermore, in a compound of formula I which is provided according to the invention and where the amino group in the aminomethyl substituent is preferably protected and where the grouping with the formula -S-A- is a residue with the formula Ib, the group R 1 can be replaced with another residue R^ or converted to another residue R-^. Thus, it is e.g. possible in a compound of formula I with a residue of formula Ib as the grouping of formula -S-A- where R^ is a group of formula -CH^-Rg and where R^ e.g. is a residue that can be replaced by nucleophilic substituents or in a salt of such a compound, and replace such a residue R,, through treatment with a mercaptan or with a thiolcarboxylic acid compound with an etherified or esterified mercapto group R^, A suitable residue which is exchangeable through an etherified mercapto group is, e.g., a hydroxy group that is esterified e.g. by a halogen hydrogen acid such as hydrochloric acid or hydrobromic acid or preferably by an organic carboxylic acid such as an aliphatic (including a formic acid), cycloaliphatic, - cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid further by a carboxylic acid half-derivative such as a carboxylic acid half-ester, Such esterified hydroxy groups are e.g. lower alkanoyloxy which is substituted e.g. with halogen, such as fluorine or chlorine, especially acetyloxy, as well as halogen-lower realkanoyloxy, such as halogenacetyloxy, e.g. trifluoroacetyloxy as well as dichloroacetyloxy, further formyloxy and also optionally substituted benzoyloxy such as 4-chlorobenzoyloxy.

The reaction between such a compound and a suitable mercaptan compound can be carried out under neutral or slightly basic conditions, in the presence of water and possibly a solvent which is not miscible with water. The basic conditions can e.g. is achieved through the addition of an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents, e.g. alcohols

which are miscible with water, e.g. lower alkanols such as methanol or ethanol, ketones e.g. lower alkanones such as acetone, amides e.g. lower alkanecarboxylic acid amides such as dimethylformamide and the like are used.

Esterified hydroxy groups R 2 in a compound of formula I where the group -S-A- is the partial formula Ib and where R^ is the group -CH^-Rg where R^ is a hydroxy group that is esterified with the acyl residue of an optionally substituted half-amide of carboxylic acid, one can e.g. introduce by reacting a suitable compound of formula I where R2 is free hydroxy (which can be released, for example, by splitting off the acetyl residue from an acetyloxy group R^, e.g. by hydrolysis in a weakly basic medium such as with an aqueous sodium hydroxide solution with pH 9-10 or by treatment with a suitable esterase such as a suitable enzyme from Rhizobium tritolii, Rhizobium lu-pinii, Rhizobium japonicum or Bacillus subtilis or a suitable citrus esterase for example from orange peel $ with a suitable carbonic acid derivative in particular with an isocyanate or carbamic acid compound such as a silyl isocyanate e.g. silyltetraisocyanate, a sulfonyl isocyanate e.g. chlorosulfonyl isocyanate or carbamic acid halide e.g. chloride (leading to N-unsubstituted 3-aminocarbonyloxymethyl compounds) or also with an N-substituted isocyanate or with an N-mono- or N,N-disubstituted carbamic acid compound such as a suitable carbamic acid halide, for example -chloride, whereby one usually works in presence of a solvent or diluent and, if necessary, during cooling or heating, in a closed vessel and/or in an inert gas atmosphere e.g. a nitrogen atmosphere.

Furthermore, one can react a compound of formula I where the grouping -S-A- is a residue of formula Ib where R^, e.g. is the above-defined residue which can be replaced by nucleophilic substituents with a tertiary organic base, in particular an optionally substituted pyridine, under neutral or slightly acidic conditions, preferably at a pH value of approx. 6.5 in the presence of water and optionally in a loose -native agent which is miscible with water, and in this way arrive at compounds of formula I where the grouping of the formula -S-A- is a residue of the formula Ib where R^ is a residue of the formula -CH^-Rg and where Rp is a quaternary ammonium group. The weakly acidic conditions can be provided through the addition of a suitable organic or inorganic acid, e.g. acetic acid, hydrochloric acid, phosphoric acid or also sulfuric acid. As organic solvents, e.g. the aforementioned solvents which are miscible with water are used. To raise the yield, the reaction mixture can be added to certain salts f.e&s. alkali metal salts such as sodium salts and especially potassium salts of inorganic acids such as hydrohalic acid, e.g. hydrochloric acid and especially hydroiodic acid, as well as thiocyanic acid, or organic acids such as lower alkane carboxylic acids, e.g. acetic acid. A representative of such salts is, for example, potassium iodide and potassium thiocyanate. Also salts of suitable anion exchangers, e.g. liquid ion exchangers in salt form such as e.g. Amberlite LA-1 (liquid secondary amines with a molecular weight of from 351-393"oil-soluble and water-insolublej mAeq./g = 2.5-2.7 e.g. in acetate" form) with acids e.g. acetic acid can be used for the purpose.

Quaternary ammonium groups R^ can preferably be prepared using an intermediate with the formula I where Rp is the residue R^ in a partial formula II is a substituted and especially aromatically substituted carbonylthio group and primarily a benzoylthio group. Such an intermediate product which can be provided e.g. through reaction of a compound of formula I where -S-A- is a partial formula Ib where R,, in the remainder R^ is an esterified hydroxy group and primarily an acyloxy group, in particular a lower alkanoyloxy group, e.g. an acetyloxy group, with a suitable salt such as an alkali metal salt e.g. sodium salt, a thiocarbonic acid such as an aromatic thiocarbonic acid e.g. thiobenzoic acid is reacted with the tertiary amine, in particular a tertiary heterocyclic base such as an optionally substituted pyridine, whereby the quaternary ammonium compound is provided. The reaction is usually carried out in the presence of a suitable desulphurisation agent, in particular a mercury salt, e.g. mercury II perchlorate and a suitable solvent or diluent or a mixture, if necessary, under cooling or heating, in a closed vessel and/or under an inert gas atmosphere e.g. a nitrogen atmosphere.

Salts of the compound of formula I can be prepared in a manner known per se. Thus, one can form salts of the compounds of formula I with acidic groups, e.g. through treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. sodium salt one of (X-ethyl-caproic acid) or with ammonia or a suitable organic amine, wherein stoichiometric amounts or small excesses of the salt-forming agent are preferably used. Acid addition salts of compounds of formula I are usually provided by treatment with an acid or a suitable anion exchange reagent. Internal salts of the compounds of formula I, which contain a free carboxyl group can be formed, for example, by neutralization of salts such as the acid addition salt at the isoelectric point, for example, with weak bases or by treatment with liquid ion exchangers. Salts can in the usual way, metal eg ammonium salts are transferred in the free compounds, for example through treatment with suitable acids, and acid addition salts through treatment with suitable basic agents.

The method also includes embodiments where intermediate products of the compounds are used as starting materials and the subsequent reaction steps are carried out with these, or when the method is interrupted at one stage or another, the starting materials can also be used in the form of derivatives or formed during the reaction.

Preferably, such starting materials and such reaction conditions are used that give compounds which are particularly preferred.

Starting substances with formula II where the amino group is substituted with a group from the acylation are known, and can be prepared according to known methods.

Thus, one can provide compounds of formula II when in the corresponding compound of the formula

transfers the amino group e.g. through treatment with a suitable diazotizing agent, in particular with nitric acid or with nitrogen tetroxide to the diazo group, treating the diazo compound with a halogen azide, e.g., bromazide and treating the resulting 6-azido-6-halo-penam compound or 7-azido-7-halo-3 -cephem compound where the halogen is primarily bromine and which may optionally be in the form of 6- or 7-©Pimer mixtures with a suitable silver" salt such as silver-I-boron tetrafluoride in the presence of methanol. This gives 6|3»azido-6a-methoxy-penam- or 7|3-azido-70C-methoxy-3-cef em-f or» bonds where the azido group is transferred reductively, for example, through

catalytic hydrogenation in the presence of a noble metal catalyst such as platinum oxide or palladium-on-charcoal and, if necessary, an activator such as a cobalt salt e.g. cobalt II acetate in the amino group. This reaction pathway is described, among other things, by [- . Cama et al, J. Am. Cnem. Soc., Vol. 94, P. 1408 (1972).

In a provided starting material of formula II, the free amino group can be converted into a substituted amino group which is permitted by the acylation through e.g. silylation or stannylation such as by treatment with a suitable substituted silyl halide, e.g. trimethylsilyl chloride or by treatment with an aldehyde, in particular with an arylcarboxaldehyde, e.g. an optionally substituted benzaldehyde.

Starting substances with formula III are known or can be prepared in a manner known per se. Thus, 5-aminomethyl-2-thienyl or 5-aminomethyl-2-furfuryl-acetic acid compounds can be obtained by acylating an aminomethylthiophene or -furan where the amino group is preferably protected, e.g. through one of the aforementioned protecting groups or an acid addition salt thereof such as the hydrochloride, through treatment with a suitable acetylating agent, e.g. with an acetic anhydride including an acetyl halide such as acetyl chloride or preferably with acetic anhydride in the presence of a suitable catalyst such as a Lewis acid e.g. aluminum chloride bromide or an acid such as polyphosphoric acid or preferably trifluoroacetic acid as well as their anhydrides. This reaction can be carried out in an anhydrous solvent such as an aromatic hydrocarbon, e.g. benzene, or in an excess of the individual liquid reagents, e.g. an excess of trifluoroacetic acid or acetic acid and/or their anhydrideBr. Using trifluoroacetic acid or trifluoroacetic acid anhydride, a free amino group can be acylated through the trifluoroacetyl residue at the same time.

An acetylated aminomethylthiophene or furan compound where the amino group is preferably protected, e.g. through a trifluoroacetyl residue, can e.g. is converted into a compound with formula (ill) according to Willgerodt or is Willgerodt-Kindler<1>'s method e.g. through heating with ammonium polysulphide or a primary or secondary amine such as morpholine followed by hydrolysis of the intermediately formed thioamide.

Otherwise, an acetylated aminomethylthiophene or furan compound, in particular a compound where the amino group is protected in the indicated manner, for example, through the trifluoroacetyl residue, can be converted into a lower alkyl ester, for example, the methyl ester into an acid of the formula III by heating with thallium-(ill )-nitrate in the presence of a lower alkanol, especially methanol, and an acid, e.g. perchloric acid from which the free acid can be produced through hydrolysis.

During the hydrolysis of thioamides which have been prepared according to Willgerodt or Willgerodt-Rmndler or of an ester which has been prepared according to the thallium (II) nitrate method, depending on the hydrolysis conditions and the nature of any amino protecting groups present, these can possibly be cleaved off, or if this is desired, converted. The complete hydrolysis to a compound of formula III and the subsequent introduction of an amino protecting group can also be carried out in one step. For example, a provided methyl ester of a compound of formula III where the amino group can e.g. is acylated with the trifluoroacetyl group then hydrolysed through treatment with a base, e.g. an alkali metal hydroxide such as sodium hydroxide in water or in water together with. an organic solvent which is miscible with water such as dioxane and then in the same reaction mixture is treated with e.g. tert-butyloxycarbonyl azide after which by acidification and further treatment the desirable thiophene or furanacetic acid with a tert-butyloxycarbonylaminomethyl group can be provided.

Furthermore, one can e.g. provide 4-aminomethyl-2-thienyl or 4-aminomethyl-2-furylacetic acid compounds if one halogen-methylates, in particular chloromethylates 2-acetyl-thiophene or 2-acetyl-furan, for example, through treatment with formaldehyde or a derivative of this as paraformaldehyde in the presence of a halogenated stainless steel acid such as hydrochloric acid, and transfers halogen in the provided 2-acetyl-4-halomethyl-thiophene or 2-acetyl-4-halomethyl-furan compounds where the halogen is primarily chlorine in a manner known per se to a protected amino group, e.g., through treatment with an alkali metal compound, e.g. a potassium compound of a phthalic imide followed by hydrazinolysis or by treatment with a suitable azide such as an alkali metal azide or ammonium azide and converts the acetyl substituent e.g. as described above, to the desired carboxy Ime ty Ires t.

In a compound of formula III with an unprotected amino group, this can be transferred in a manner known per se in one of the aforementioned protected amino groups. Thus, one can introduce an acyl residue as an amino protecting group in the amino group, e.g. through the method of acylation described above, further also through treatment with a carboxylic acid halide or carboxylic acid azide compound such as tert-butyloxycarbonyl azide. Furthermore, the free amino group can be substituted with a di- or triarylmethyl group, e.g. through treatment with a reactive ester of a di- or triarylmethanol such as trityl chloride preferably in the presence of a basic agent such as pyridine.

An amino group can also be protected through the introduction of a silyl or stannyl group. Such groups are introduced in a manner known per se, e.g. through treatment with a suitable silylating agent such as a dihalolower alkyl silane or trilower alkylsilyl halide e.g. dichlorodimethylsilane or trimethylsilyl chloride or with an optional N-mono-lower alkylated, N,N-di-lower alkylated, N-trilower alkylsilylated or N-lower alkyl-N-trilower alkylsilylated

N-(tri-lower alkyl-silyl)-amine (see e.g. British Patent No. 1|073»530) or with a suitable stannylating agent such as a bis-(tri-lower alkyltin)-oxide e.g. bis-(tri-n-butyl-tin)-oxide, a tri-lower alkyl tin hydroxide e.g. triethyl tin hydroxide, a tri-lower alkyl-lower alkyl tin, tetra-lower alkyl tin or tetra-lower alkyl tin compound as well as a tri-lower alkyl tin halide e.g. tri-n-butyltin chloride (see e.g. Dutch patent review 67/HIO7).

An amino group can also be protected through the introduction of a 2-carbonyl-1-vinyl group under which amine or ketimine compounds are formed. Such groups can e.g. is provided by treating the amine with a 1,3-dicarbonyl compound, e.g. with acetoacetic acid methyl ester or acetoacetic acid-N,N-dimethylamide in an anhydrous medium, for example, a lower alkanol such as methanol.

Arylthio- or aryllaverealkylthio-, further arylsulfonyl protecting groups can be introduced into an amino group by treatment with a suitable arylthio- or aryllaverealkylthio-, further arylsulfonyl halide e.g.

The reactive, functional acid derivatives of an acid with formula III can be prepared in a manner known per se. Acid halides are produced, e.g. by reacting a compound of formula III optionally with a protected amino group or a salt thereof with a halogenating agent, e.g. with an acid halide such as -fluoride or -chloride of an inorganic phosphorus- or sulfur-containing acid, e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride. The reaction is preferably carried out in a non-aqueous solvent or solvent mixture such as in a carbonic acid amide, e.g. dimethylformamide. The acid halide provided does not need further purification, but can be brought into reaction directly with the starting material of formula II whereby e.g. the same solvent or solvent mixture is used as was used for the preparation of the acid halide.

Symmetrical anhydrides or mixed anhydrides which are different from the halides of the compounds of formula III, optionally with a protected amino group, can e.g. is prepared by reacting a suitable compound with a free carboxyl group, preferably a salt, especially an alkali metal salt, e.g. sodium salt or ammonium salt, e.g. the triethylammonium salt of this with a reactive derivative such as a halide, e.g. the chloride of a suitable acid, e.g. haldgenformic acid lower alkyl ester, e.g. chloroformate isobutyl ester or a lower alkane carboxylic acid halide e.g. trichloroacetic acid chloride.

Activated esters of the compounds of formula III with protected amino groups can e.g. is prepared by reacting a suitable compound with a free carboxyl group in the presence of a carboimide, eg N,N-dicyclohexylcarbodiimide, with a substituted phenol such as is substituted with nitro or halogen such as chlorine such as a nitrophenol e.g. 4-nitrophenol or 2,4-dinitrophenol or a polyhalophenol e.g. 2,3»4,5yé-pentachlorophenol.

The starting material with formula IV can be prepared by a group with the formula

where amino in the aminomethyl group is preferably present in protected

form, in the amino group the compounds of formula VIII where the amino group may optionally be substituted with a group from the acylation and where the group with the formula -S-Aq- has the above-mentioned meaning primarily through acylation, e.g. by the acylation process for starting substances of formula II described above.

Starting substances with formula IVb can e.g. is provided if one starts from a 6|3-amino-penam- or 7(3-amino-3-cef em compound of formula VIII where a present functional group such as, for example, a carboxyl group of the formula -C(=0 )-R preferably exists in a protected form, and converts these to the Schiff's base through reaction with an aldehyde but especially an aromatic aldehyde such as benzaldehyde and reacts this with an anion-forming agent such as a preferably sterically hindered alkali metal lower alkanoate such as potassium tert .-butylate, an alkali metal hydride eg sodium hydride, an alkali metal hydrocarbon compound eg n-butyllithium or phenyllithium, or by a suitable alkali metal compound of a secondary organic base such as eg the lithium compound of a dilower alkylamine or lower alkylene amine such as lithium diethylamide, preferably under cooling eg at temperatures from about -30°C to about 0°C and in the presence of a solvent or diluent such as glycol dimethyl ether. introduce the preferred mercapto group with the formula R°-S- directly, e.g. through treatment with a suitable thiolsulfonic acid ester such as a lower alkyl thiolsulfonic acid lower alkyl ester e.g. methanethiol sulfonic acid methyl ester, or with a sulfenyl halide such as lower alkyl sulfenyl halide e.g. methylsulfenyl chloride or indirectly via the corresponding 6α-fluro-penam- or 7oc-fluoro-3-cef em-Schiff bases; where the latter are provided e.g. through treatment with fluorine perchlorate and can be converted into the desired 6α-H°-thio-penam- or 7α-R°-thio-3-cephem-Schiff bases through reaction with a mercaptan such as a lower alkyl mercaptan, e.g. methylmercaptan in the presence of a strong acid such as an optionally halogenated lower alkanecarboxylic acid, e.g. trifluoroacetic acid. In this intermediate product, the nitrogen atom in the methyleneamino group is acylated through the introduction of a group with the formula IIa where the amino in the aminomethyl group is preferably present in a protected form, e.g. under the method described above, and this gives starting material of formula IVb. This reaction can be carried out e.g. by the methods described by Slusarchyk et al., J. Org. Chem. , Vol. 38, p. 943 (1973), and Spitzer and Goodson, Tetrahydron Letters, p. 273 (1973).

The starting material with formula V can e.g. is provided when one in a 3-cephem compound with the formula

where the carboxy group in a residue with the formula -S»Aq- usually exists in protected form, the amino group in the 5-amino-5-carboxy-valeryl residue transfers to a protected amino group AmQ and introduces the acyl residue into the nitrogen atom of the amide group in a compound that is prepared in this way with formula Illa where the amino in the aminomethyl group is present in a protected form and which, depending on how it is cleaved off, differs from the protected amino group AmQ, e.g. by acylation according to the method described above, e.g. through treatment with an acid halide, e.g. -chloride, a compound of formula III and a suitable silylating agent such as a mono- or disilylated acid amide such as an optionally halogenated N-monotrilower alkylsilyl- or N,N-bis«trilower alkylsilyl-lower alkanecarboxylic acid amide where the latter can also be present in N,0- bis-trilower alkylsilylated enol form of the amide e.g. bis-trimethylsilyl-acetic acid amide or N-trimethylsilyl-trifluoroacetic acid amide in a suitable solvent or diluent, e.g. in a halogenated hydrocarbon such as methylene chloride and, if necessary, under heating, in a closed vessel and/or in an inert gas atmosphere, e.g. a nitrogen atmosphere. Preparation of starting material with formula V according to the above-mentioned method can e.g. is carried out according to the method described by Sletzinger et al., J.Am.Chem.Soc., Vol. 94, P. 1410 (1972).

Starting substances with formula VI can be prepared in a manner known per se, e.g. through acylation of the amino group in a compound of formula II e.g. through treatment with an acid of the formula

or a suitable derivative thereof such as a mixed anhydride especially a halide e.g. chloride, e.g. according to the acylation procedure described above. 2-cephem starting materials with formula VIII can be prepared according to the above-described method for preparing the corresponding 3-cephem compound, e.g. as one in a connection with the formula

acylates the primary amino group by treatment with acid of formula III in which amino in the aminomethyl group is preferably present in protected form or by acylating a reactive functional acid derivative of the compound or a salt of such a compound. The above-mentioned acylation reaction can e.g. carried out analogously to the methods described.

In methods according to the invention as well as in addition reactions, further preparation of the starting substances, if this is necessary, free functional groups in the starting substances or in compounds according to the invention which do not participate in the reaction of

in and of itself known manner temporarily be protected e.g. free amino groups through acylation, tritylation or silylation, free hydroxy or mercapto groups e.g. through etherification or for» esteriig and free carboxyl groups, e.g. through esterification, including silylation, and after the reaction, if this is desired, is released through solvolysis or reduction, known in and of itself.

The pharmacologically usable compounds according to the present invention can, for example, be used for the production of pharmaceutical preparations containing an effective amount of the active substance together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers which is gradually used for parenteral administration. Preferably, the pharmacologically active compounds according to the invention are used in the form of injectable preparations such as e.g. can be given intravenously or in the form of infusion solutions. Such solutions are preferably isotonic, aqueous solutions or suspensions whereby these can be prepared before use from lyophilized preparations which either contain the active substance alone or together with a carrier material, e.g. mannitol. The pharmaceutical preparations may be sterilized and/or may contain auxiliary substances, for example, preservatives, stabilizers, presaturants and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations can,

if this is desirable, also contain other pharmacologically valuable substances and they are produced in a manner known per se, e.g. through normal dissolution or lyophilization and contain from approx. 0.1$

to $100, especially from approx. 1$ to approx. 50$ lyophilisate to up to 100$ active substance. Depending on the type of infection and the condition of the infected organism, daily doses of from approx. 0.5 g to approx. 5 g s.c. for the treatment of mammals weighing up to 70 kg.

Unless otherwise defined, the term "lower" means

which is used in connection with organic residues or compounds, e.g. in lower alkyl, lower alkanol and the like, those residues or compounds having up to 7 and preferably up to 4 carbon atoms.

The following examples serve to illustrate the invention and the temperatures are given in degrees Celsius.

Example 1.

2.40 g of 3-acetyloxymethyl-7P-(2-(5-tert-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid diphenyl methyl ester are dissolved in 180 ml of tetrahydrofuran and the solution is cooled under a nitrogen atmosphere to -70 to -75°C, and during 1 minute a solution of 0.46 g of lithium methoxide in 10 ml of methanol is added with stirring. After 3 minutes, add 0.42 ml tert.-

butyl hypochlorite, stirring is continued for 20 minutes at -70 to -75°C, the mixture is neutralized with 0.80 ml of acetic acid and the volume is reduced to 70 ml under water jet vacuum. 200 ml of water is added and extracted twice with 300 ml of ethyl acetate. The organic extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The unpurified products are chromatographed on 250 g of silica gel, eluting with a 6:4 mixture of toluene and acetic acid ethyl ester 13~acetyloxymethyl-7a-methoxy-7(3-/2*-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino7-3-cef>ene"-4-carboxylic acid diphenylmethyl ester; thin layer chromatogram (silica gel): Rf = 0.20 (system: toluene/ethyl acetate 6:4); ultraviolet absorption spectrum (in 95% aqueous ethanol ) : ^ max =m/i^ = 13900) andAfflin = 236 mja (£ = 13600); infrared absorption spectrum (in methylene chloride) : characteristic bands at 2.92 ^ u, 5»6l u, 5, lh ^ a, 5, 79 p9 6.23 jx and 6.67 f.

The starting material can be produced in the following way:

A solution of 20 g of 2-tynylamine hydrochloride in a mixture of 100 ml of trifluoroacetic acid and 100 ml of acetic anhydride is stirred for 2 hours at 55°C without the addition of moisture. The "reaction" mixture is completely dried under reduced pressure, in which the residue is taken up in 50 ml of toluene and evaporated once more. The impure product is dissolved in acetic acid ethyl ester, treated with activated charcoal, filtered through silica gel and dried under reduced pressure. After recrystallization from diethyl ether, 2'acetyl-5-trifluoroacetylaminomethyl-thiophene is obtained, m.p. 83-84°C.

A solution of 34.2 g of thallium-(II)-nitrate trihydrate in 100 ml of methanol is added under ice-cooling with 40 ml of 70% aqueous perchloric acid and added dropwise at +5°C under a nitrogen atmosphere a solution of 20 g of 2- acetyl-5-trifluoroacetylamino-thiophene in 500 ml of methanol during 15 minutes. The solution is heated to 50°C and stirred at this temperature for 2 hours. The reaction mixture is cooled to +5°C and an ice-cold solution of 120 g of dipotassium hydrogen phosphate in 300 ml of water is added. The filter residue is filtered and washed with methanol. The filtrate is evaporated under reduced pressure to approx. 300 ml and extracted three times with 150 ml of chloroform. The extracts are washed first with water and then with saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under water

beam vacuum. This gives 2-(5-trifluoroacetylaminomethyl~2-thienyl)-acetic acid methyl ester; thin layer chromatogram (silica gel: system: toluene/ethyl acetate 6@:4o): Rf = 0.65; infrared absorption spectrum (in methylene chloride) : characteristic bands at 2.93^»3»39^u, 5.75yu, and 5.80^u. To a solution of 9.7 g of 2-(5-trifluoroacetylamino-methyl-2-thienyl)-acetic acid methyl ester in 50 ml of dioxane is added at 20°C under a nitrogen atmosphere 40 ml of 2-n aqueous sodium hydroxide solution. It is stirred for 2 hours at 20-25°C, after which it is diluted with 50 ml of dioxane and 8.5 ml of tert-butyloxycarbonyl-azide is added to the solution, after which it is stirred at 2©-25°C for 1 16 hours. The reaction mixture is cooled to approx. 5° and adjusted to pH 2.5 with approx. 40 ml 20$-ig aqueous phosphoric acid. The mixture is evaporated to approx. 50 ml under reduced pressure, after which it is extracted three times with §00 ml acetic acid ethyl ester. The extracts are washed with a saturated, aqueous sodium chloride solution, dried over magnesium sulfate, decolorized by treatment with an activated carbon preparation and dried under reduced pressure. It is crystallized from diethyl ether and 2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid is obtained in this way. Sm.p. ll4-115°C.

0.90 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid is dissolved in 20 ml of methylene chloride (distilled over phosphorus-pentoxy) containing 0.334 g of N-methylmorpholine, after which the solution is cooled to -20°C without access to moisture and 0.45 ml of chloroformate isobutyl ester is added dropwise, during which the temperature is kept between -15 and -20°C. After 30 minutes, a solution of 1.04 g of 3-acetyloxymethyl-7|3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride is added and the mixture is stirred for 2 hours at -10° and for 8 hours at room temperature. The resolution

ice-cold water is added, the pH is adjusted to 8.0 with dipotassium hydrogen phosphate and extracted several times with methylene chloride^ The organic extracts are washed with aqueous sodium chloride solution, and dried over magnesium sulfate after which the solvent is removed under reduced pressure. This provides 3-acetyloxymethyl-7|3-/ £-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid diphenyl methyl ester as a colorless foam which is directly further processed. Thin layer x chromatogram (silica gel): Rf = 0.71 (system: hexane/ethyl acetate/methanol 20:40:4o). The product

recrystallized from diethyl ether, m.p. 134-136°Cj infrared absorption spectrum (in mineral oil): characteristic bands 3.03 jx% 5.68 ^ l, 5.77JX) 6.02 ^a, 6.26 u and 6.57 jx\ultraviolet absorption spectrum (in 95$-ig aqueous ethanol):= 245mu = 15100).

The starting material can optionally be provided in the following way: A solution of 1.34 g of N-hydroxymethylacetamide (Einhorn, Ann.Chem., Vol. 343, P. 264 (1905)) in 10 ml of trifluoroacetic acid which is kept at between 0 -5°C, 1.42 g of 2-thienylacetic acid is added in portions while stirring. The solution is stirred for 2 hours at 0-5°C and trifluoroacetic acid is distilled off under reduced pressure. The residue is taken up in 30 ml of water and extracted twice with 50 ml of ethyl acetate. The organic extracts are washed with an aqueous sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and filtered through silica gel. The residue is recrystallized from acetic acid ethyl ester and this gives 2-(5-acetylaminomethyl-2-thienyl)-acetic acid. Thin layer chromatogram (silica gel): Rf = 0.61 (system: butanol/acetic acid/water 45:45:10)j infrared absorption spectrum (mineral oil): characteristic bands at 2.95^1»5.82 ^,u, 6.23 ^,6,38^.

To a solution of 0.6 g of 2-(5-acetylamino-methyl-3-thienyl)-acetic acid in 5 ml of dioxane is added 0.3 ml of 2-n aqueous sodium hydroxide solution. The solution is stirred for 12 hours at 55-60°C, cooled to 25°C, 0.2 ml of tert-butyloxycarbonylazide is added, stirred for 16 hours at room temperature, after which 2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl )-acetic acid is isolated according to the method described above.

Example 2.

A solution of 0.247 g of 3-acetyloxymethyl-7|3-azido-7a-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester (Cama et al., J. Am.Chem. Soc. Bd. 94, P. 1408 ( l972)j Deutsche Offenlegungsschrift 2 129 675) in 7.6 ml of tetrahydrofuran is hydrogenated in the presence of 0.167 g of platinum oxide and 0.076 g of cobalt II acetate at room temperature for 1-1/4 hours with hydrogen under a pressure of 2 atmospheres. The reaction mixture is filtered, and the filtrate containing 3-acetyloxy-methyl-7β-amino-70C-methoxy-3-cef em-4-carboxylic acid edifenyl methyl ester is used without further purification in the subsequent acylation steps,

A solution of 0.237 g of 2-(5-tert-butyloxycarbonyl-aminomethyl-2-thienyl)-acetic acid in 20 ml of methylene chloride is treated at -15°C with 0.095 ml of 4-methylmorpholine, followed by 0.119 ml of chloroformate isobutyl ester. The mixture is stirred for 15 minutes at -15°C and at this temperature the above-mentioned solution of 3-acetyloxy-methyl-7p-amino-7oc-methoxy-3-cephem-3-carbonic acid diphenyl methyl ester is added dropwise. The reaction mixture is stirred at 0°C for 3 hours, diluted with methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The aqueous washing solutions are extracted with methylene chloride and the combined organic extracts are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is subjected to a thick-layer chromatogram (silica gel), which is developed with a 5 s 3-t>landing of toluene and acetic acid ethyl ester. This gives 3-acetyloxymethyl-7|3-/2-(5-tert.-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy«3-cephem-4-carboxylic acid diphenylmethyl ester with Rf = 0.2 which are identical to the product from example 1.

Example 3.

A solution of 0.271 g of 2-(5-tert-butyloxycarbonyl-aminomethyl-2-thienyl)-acetic acid in 5 ml of methylene chloride is added at 0°C to 0.168 g of chloromethylene-dimethyl-ammonium chloride (obtained as a solid through the reaction of equimolar amounts of dimethylformamide and phosgene in methylene chloride) and the reaction mixture is stirred for 10 minutes. The reaction mixture is added at 0°C 0.081 ml of pyridine, stirred for 5 minutes at this temperature, after which the solution provided in example 2 and which contains 3-acetyloxy-methyl-7(3-amino-7a-methoxy-3-cef em- 4-carboxylic acid diphenylmethyl ester is added. It is stirred for 30 minutes at 0°C, diluted with methylene chloride and the solution is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The aqueous washing solutions are extracted with methylene chloride and the combined , organic extracts are dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is subjected to thick-layer chromatography (silica gel) which is developed with a 5:3 mixture of toluene and ethyl acetate. De-fcte gives 3-acetyloxymethyl-7P-/5-(5- tert-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf = 0.2, which is identical to the product described in example 1.

Example 4.

A solution of 0.90 g of 3-acetyloxymethyl-7α-methoxy-7[3-(2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of trifluoroacetic acid and 1.5 ml of anisole are left at 0°C for 30 minutes and evaporated while adding 20 ml of toluene in a water jet vacuum. The residue is taken up in 10 ml of diethyl ether and 40 ml of petroleum ether and filtered. The filter residue containing the trifluoroacetic acid salt of 3-acetyloxymethyl-7|3-/2-(5-aminomethyl-2-thienyl)-acetylamino7-7^-methoxy-3-cephem-4-carboxylic acid is dried, during 5 hours under high vacuum at room temperature and dissolve in 30 ml of methanol, after which the solution is decolorized with the addition of activated charcoal and filtered. The filtrate is adjusted to pH 6.0 with triethylamine and allowed to stand for 2 hours at from 0-5°C. The precipitated inner salt of 3-ac ethyloxymethyl-7(3-(2-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-cephem-4-carboxylic acid) is filtered off and dried for 20 hours under high vacuum at room temperature . M.p. above 180°C (with decomposition), - /a7^° = + 177° + 1° (c = 0.972 in a 0.15 molar aqueous potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, pH 7.3 - 7» 4); thin-layer chromatogram (silica gel): Rf = 0.12 (system: n-butanol/acetic acid/water 45:45:10)j ultraviolet absorption spectrum (in a 0.15-molar aqueous potassium dihydrogen phosphate-dicalcium -puf f er solution, pH 7.3 - 7.4):^.=241m/ji

m ci x

(£=15700 and A-= 214 mu (£ = 8700); infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 yu, 5.515^u, 6.00 jx, 6, 34yu and 6.55 yx.

Example 5.

A solution of 0.15 g of the inner salt of 3-acetyl-oxymethyl-7|3-/2*-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-cephem-4-carboxylic acid and 0.053 g of the sodium salt of 5-mercapto-1-methyl-tetrazole in 7 ml of acetone and 10 ml of water is added to 0.028 g of sodium bicarbonate and heated for 5 hours at 60°C. The mixture is filtered, the filtrate is reduced under reduced pressure to a volume of approx. 10 ml, adjusted with acetic acid to pH 5.5 and allowed to stand for a few hours at 0-5°C. The precipitate is filtered off and washed with acetone. This gives the inner salt of 7f3-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-(1-methyl-5-tetrazolyl-thiomethyl)-3-cephem-4- carbonic acid dried for 12 hours relieves high vacuum. Thin layer chromatogram (silica gel): Rf = 0.25 (system: chloroform/methanol 1:1).

In another variant, the reaction is carried out in the presence of 0.028 g of sodium bicarbonate and 0.055 g of potassium iodide.

Example 6.

9.1 g of 3-acetyloxymethyl-7β-[2*-(5-tert-butyloxycarbonyl-aminomethyl-2-furyl)-acetylamino7-3-cef-em-4-carboxylic acid e-diphenylmethyl ester in 400 ml of tetrahydrofuran, the solution is cooled under a nitrogen atmosphere to -70 to -75°0, after which a solution of 1.80 g of lithium methoxide in 50 ml of methanol is added with stirring over the course of 1 minute. After 2 minutes, 1.62 ml of tert-butyl hypochlorite is added, stirring is continued for 20 minutes at "70 to -75°C, the mixture is neutralized with 2.5 ml of acetic acid and concentrated under water jet vacuum to approx. 100 ml. The mixture is added to 500 ml of water and extracted twice with 500 ml of ethyl acetate. The organic extract is washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium and evaporated under reduced pressure.

The crude product is chromatographed on 600 g of silica gel, eluting with a 6:4 mixture of toluene and acetic acid ethyl ester and providing 3-acetyloxymethyl-7ct-methoxy-713-/2- (5-tert. -butyl-oxycarbonylaminomethyl-2- furyl)-acetylamino7-3-cephem«4-carboxylic acid diphenyl methyl ester. Thin layer chromatogram (silica gel): Rf = 0.30 (system: toluene/ethyl acetate 6:4); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92 yu, 5»6lyu, 5.76u (broad) 6.24^u and 6.67 ji.

The starting material can be produced in the following way:

A mixture of 50 g of furfurylamine and 150 ml of fluoroacetic acid anhydride is stirred at room temperature for 2 hours without moisture occurring. The mixture is added with 150 ml of acetic acid and stirred for 2 hours at 55°C. The reaction mixture is completely evaporated under reduced pressure, 50 ml of toluene is added and reduced once more. The impure product is dissolved in acetic acid ethyl ester, treated with activated carbon, filtered through silica gel and evaporated under reduced pressure. After recrystallization from diethyl ether, 2'acetyl-5-trifluoroacetaminomethylfuran is obtained, m.p. 99-100°C, Ultraviolet absorption spectrum (in ethanol): max= ^75. mu (^=15500).

A solution of 39.8 g of thallium (III) nitrate trihydrate

in 100 ml of methanol is added under ice-cooling with 50 ml of 70% perchloric acid and a solution of 20 g of 2-acetyl«.5« trifluoroacetaminomethylfuran in 500 ml of methanol is added dropwise under a nitrogen atmosphere over the course of 15 minutes. The solution is heated to 50°C and stirred at this temperature for 2 hours. The reactive ion mixture is cooled to approx. +5°C and an ice-cold solution of 120 g of dipotassium hydrogen phosphate in 300 ml of water is added. The mixture is filtered and the filter residue is washed with methanol. The filtrate is evaporated under reduced pressure to approx. 300 ml and extracted three times with 150 ml of chloroform. The extracts are washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under water jet vacuum.

This leaves 2-(5-trifluoroacetaminomethyl-2-furyl)-acetic acid methyl ester. Thin layer chromatogram (silica gel): Rf = 0.35 (system: toluene/

acetic acid ethyl ester 60:4o)j infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ^u, 3»39/u and 5.80jx.

To a solution of 18.4 g of 2".(5""trifluoroacetaminomethyl"2-furyl)-acetic acid methyl ester in 100 ml of dioxane is added at 20°C under a nitrogen atmosphere 75 ml of 2-n aqueous sodium hydroxide solution. The solution is stirred for 4 hours at 20-25°C, diluted with 100 ml of dioxane and 34 ml of tert-butyloxycarbonylazide is added to dissolve, after which stirring is continued for 16 hours at 20-25°C. The reaction mixture is cooled to 5°C and adjusted to pH 2.5 with approx. 40 ml 20$=ig aqueous phosphoric acid. The mixture is evaporated under reduced pressure to a volume of approx. 100 ml and extracted three times with 200 ml of ethyl acetate. The extracts are washed with a saturated, aqueous sodium chloride solution, dried over magnesium sulphate, de-coloured by treatment with an activated charcoal preparation and evaporated. After recrystallization from diethyl ether, 2'(5-tert,-butyl-oxycarbonylaminomethyl-2-furyl)-acetic acid is obtained, m.p. 72-73°C.

1.87 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-furyl)-acetic acid in 200 ml of methylene chloride are dissolved (distilled over phosphorus pentoxide) and 0.80 ml of 4-methylmorpholine, and the resulting solution is cooled without access to moisture to -20°C, after which 1.0 ml of chloroformic acid isobutyl ester is added dropwise, during which the temperature is kept between -15 and -20°C. After 30 minutes, a solution of 2.31 g of 3-acetyloxymethyl-7|3-amino«3-cef em- is added 4-carbon acid diphenyl methyl ester and stirring is continued for 2 hours at -10°C

and for 8 hours at room temperature. Ice-cold water is added, the pH is adjusted with dipotassium hydrogen phosphate to 8.0 and extracted several times with methylene chloride. The organic extracts are washed.

with a saturated, aqueous sodium chloride solution and dried over magnesium sulphide, after which the solvent is removed under reduced pressure. This provides 3-acetyloxymethyl-7|3-/2-(5-tert.-butyloxy-carbonylaminomethyl-2-fury1)»acetylamino7-3-oephem-4-carboxylic acid diphenylmethyl ester as a colorless foam which is directly further processed. Thin layer chromatogram (silica gel): Rf = 0.84 (system: hexane/ethyl acetate/methanol 20:40:40).

Example 7.

A solution of 2.95 g of 3-acetyloxymethyl-7cte.methoxy-7|3«,^2*- (5»tert.-butyloxycarbonylaminomethyl=2«furyl )-acetylamino7-3-cephem-4-carboxylic acid diphenylmethyl ester in 3 ml of anisole and 12 ml of trifluoroacetic acid are allowed to stand for 30 minutes at 0°C and evaporated using a water trawl under vacuum while adding 100 ml of toluene. The residue is recorded -

in 50 ml of diethyl ether and filtered. The filter residue is dried, affording as the trifluoroacetic acid salt of 3-acetyloxymethyl-7β-/"-(5-aminomethylar2-furyl)-acetylamino7-7<X-methoxy-3-cephem-4-carboxylic acid in the course of 5 hours under high vacuum at room temperature after which it is dissolved in 30 ml of methanol, and the solution is decolorized by the addition of activated charcoal and filtered. The filtrate is adjusted with triethylamine to pH 6.0 and allowed to stand for 2 hours at 0-5° C. The precipitated inner salt of 3-acetyloxymethyl-7 (3-/2'-(5-aminomethyl-2-furyl)-acetyl-amino7-7a-nietoxy-3-cephem-4-carboxylic acid is filtered off and dried for 20 hours under high vacuum and at room temperature. M.p. above l65 °C (with decomposition) Thin-layer chromatography (silica gel): Rf = 0.22 (system: chloroform/methanol 1:1); ultraviolet absorption spectrum

(in .95$-ig aqueous ethanol):X max = 222 mu (£ =12500) and \ =

max / ^ ' to max2

266 np 6200)j infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 y. t 5.77 ya, 5.91 yi, 6.22 jny and 6.52 jx.

Example 8.

4.0 g of 3-acetyloxymethyl-7P-/"<*>2-(5-tert.-butyloxycarbonyl-.aminomethyl-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid tert.-butyl ester is dissolved in 250 ml of tetrahydrofuran, the solution is cooled under a nitrogen atmosphere to -70-75°C, after which in the course of

For 1 minute add, with stirring, a lithium methylate solution prepared by dissolving 0.170 g of lithium wires in 30 ml of methanol. After 5 minutes, 0.80 ml of tert-butyl hypochlorite is added, stirring is continued for 20 minutes at -70 to -75°C, the mixture is neutralized with 4.0 ml of acetic acid and evaporated under water jet vacuum to a volume of approx. 70 ml. 200 ml of water is added and extracted twice with 300 ml of ethyl acetate. The organic extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium and evaporated under reduced pressure. The crude product is precipitated from a mixture of acetic acid ethyl ester and petroleum ether and the obtained 3-acetyloxymethyl-7ct-methoxy-7 p«/2-(5-1 tert.-butyloxycarbonylaminomethyl-2-thienyl)-ac ethylamino7-3-cephem-4 -carbonic acid tert-butyl ester is filtered off and dried. Thin-layer chromatogram (silica gel): Rf = 0.48 (system: acetic acid ethyl ester/chloroform/acetic acid 80:19:1), ultraviolet absorption spectrum (in 95% aqueous ethanol):"^ ^^ = 243 mm 15800)j infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.88 -u, 2.93 f, 5.6l 5.75 ft 5.83 /u and 6.66 ya.

The starting material can be produced in the following way:

8.15 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 500 ml of methylene chloride containing 2.06 ml of N-methylphorfoline, the solution is cooled without access to moisture

to -20°C after which 4.13 ml of chloroformate isobutyl ester is added dropwise while the temperature is kept between -15°C and -20°C. After 30 minutes, a solution of 9.85 g of 3-acetyloxymethyl-7|3-amino-3-cephem-4-carboxylic acid tert-butyl ester in 50 ml of methylene chloride is added, while the solution is stirred for a further 15 hours and the temperature in this time slowly rise to 20-25°C. Ice-cold water is added, neutralized with dipotassium hydrogen phosphate and extracted several times with methylene chloride. The organic extracts are washed with an aqueous, saturated sodium chloride solution and dried over magnesium sulfate, after which the solvent is removed under reduced pressure. The residue is recrystallized from diethyl ether and provides 3-acetyloxymethyl 1-7 (3-/2*-(5-tert.-butyloxycarbonylaminomethyl 1-2-thienyl)-acetyl-amino7-3-cephem-4-carboxylic acid- tert-butyl ester with m.p. 76-78° C. Thin-layer chromatogram (silica gel): Rf = 0.44 (system: chloroform/ethyl acetate/acetic acid 80:19:1).

Example 9.

A solution of 3.80 g of 3-acetyloxymethyl-7oc-methoxy-7β- /2-(5-tert-butyloxycarbonylaminomethyl 1-2-thienyl)-acetylamino/-3-cephem-4-carboxylic acid tert-butyl ester in 15 ml of trifluoroacetic acid is allowed to stand for 30 minutes and evaporated while adding 50 ml of water using a water jet vacuum. The residue is taken up in 30 ml of diethyl ether and filtered. The filter residue, which contains the trifluoroacetic acid salt of 3-[2-(5-aminomethyl-2-thienyl)-ethyl-amino-7-7<X-methoxy~3-cephem-4-carboxylic acid, is transferred as described in Example 4, to the inner salt of 3-acetyloxymethyl-7β-[2-(5-aminomethyl-2-tyl)-acetylamino7-7α-methoxy-3-cephem-4-carboxylic acid.

Example 10.

1.55 g of 3-acetyloxymethyl-7β-[2-(3-tert-butyloxycarbonyl-aminomethyl 1-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid-1-tert-butyl ester is reacted with 0.065 g lithium in 20 ml methanol and 0.31 ml tert-butyl hypochlorite as described in Example 8 and provides 3-acetyloxymethyl-70C-methoxy-7P-/2-(3-tert-butyloxycarbonylamino-methyl- 2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid tert-butyl ester. Thin layer chromatogram (silica gel): Rf = 0.52 (system: toluene/ethyl acetate 3:2); ultraviolet absorption spectrum (in 95$-ig aqueous ethanol) i^1^ = 24l myi (£= 14200); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88 yx, 2.93 yx, 5.59 yx, 5.74 yx, 5.83 yx and 6.64 yi.

The starting material can be produced in the following way:

A mixture of 75.0 g of 3-bromomethylthiophene and 78.5 g of potassium phthalimide in 1000 ml of dimethylformamide is stirred for 90 minutes at 100°C. The reaction mixture is cooled, a mixture of ice and water is added and extracted four times with a total of 1500 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure, during which 3-phthaloylaminomethylthiophene crystallizes out. Thin-layer chromatogram (silica gel): Rf = 0.7.8 (system: toluene-acetic acid ethyl ester. 4:1);

ultraviolet absorption spectrum (in 95$-ig aqueous ethanol):^ =

IHcLX

220 mp. = 44000); infrared absorption spectrum (in methylene chloride):

characteristic bands at 5.59 yx 5.86 yx and 6.20 yx,

90.8 g of 3-phthaloylaminomethylthiophene is taken up in 250 ml of acetic anhydride, 250 ml of trifluoroacetic acid is added dropwise without access to moisture and the mixture is stirred for 3 hours at 50°C. The reaction mixture is evaporated under reduced pressure, 500 ml of water are added, neutralized with a 2-n aqueous sodium hydroxide solution while cooling

with ice and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated. This gives mixed crystals of 2-acetyl-3-phthaloxyaminomethyl-thiophene and 2-acetyl-4-phthaloylaminomethyl-thiophene. Thin layer chromatogram (silica gel): Rf = 0.53 and 0.45 (system: toluene/ethyl acetate 4:1).

38.0 g of the mixture of 2-acetyl-3-phthaloylaminomethylthiophene and 2-acetyl-4-phthaloylaminomethylthiophene are dissolved in 1500 ml of methanol, 65 g of thallium (III) nitrate-BxydlligcArate are added under a nitrogen atmosphere and stirred for 6 hours at 50°C. The reaction mixture is cooled to 5-10°C, neutralized with a 2N aqueous sodium hydroxide solution, evaporated under reduced pressure and extracted with 1000 ml of chloroform. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and . is evaporated. This gives a mixture of 2-(3-phthaloylaminomethyl-2-thienyl)-acetic acid methyl ester and 2-(4-phthaloylaminomethyl-2-thienyl)-acetic acid methyl ester. Thin layer chromatogram (silica gel): Rf = 0.59 and 0.54 (system: toluene/ethyl acetate 4:1).

21 g of the mixture of 2-(3-phthaloylaminomethyl-2-thienyl^-acetic acid methyl ester and 2-(4-phthaloylaminomethyl-2-thienyl)-acetic acid methyl ester are dissolved in 400 ml of dioxane, 50 ml of a 2-Ji van-

sodium hydroxide solution and stir for 2 hours at between 20

and 25°C. The volume is reduced to approx. 200 ml, diluted with 200 ml of water, acidified with 20% aqueous phosphoric acid and extracted three times with a total of 400 ml of acetic acid ethyl ester. The extracts are dried over magnesium sulfate and evaporated under reduced pressure.

To 250 ml of the residue from the evaporation, 3.0 g of hydrazine hydrate is added, the mixture is heated for 3 hours to 60°C and then evaporated. The residue is taken up in 200 ml of dioxane, and reacted with 75 ml of a 2-n aqueous sodium hydroxide solution and 5.0 ml of tert-butyloxycarbonyl azide. The mixture is stirred for 20 hours at 20 to 25°C, the volume is reduced to 100 ml, diluted with 100 ml

water and extracted with 200 ml ethyl acetate. The aqueous solution is adjusted to pH 2 with approx. 50 ml 20$-ig aqueous phosphoric acid. The precipitate is filtered off, the filter residue is washed with acetic acid ethyl ester and the filtrate is extracted three times with 200 ml of acetic acid ethyl ester. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated

under reduced pressure. The residue is dried under reduced pressure at 30°C and this gives a mixture of 2-(3-tert.-butyloxycarbonylamino-methyl-2-thienyl)-acetic acid and 2-(4-tert.-butyloxycarbonylamino-methyl-2-thienyl) -acetic acid which can be separated by chromatography on 200 g of silica gel with a mixture of chloroform/acetic acid ethyl ester/acetic acid (80:19:1) as eluent. Thin layer chromatogram: Rf = 0.44 and 0.34 (system: chloroform/ethyl acetate/acetic acid 80:19:1). In the next steps, however, the mixture of the two compounds is used.

4.0 g of the mixture of 2-(3-tert-butyloxycarbonylamino-methyl-2-thienyl)-acetic acid and 2-(4-tert-butyloxycarbonylamino-methyl-2-thienyl)-acetic acid are dissolved in 125 ml of methylene chloride, cooled to -20°C and 1.80 ml of N-methyl-morpholine and 0.864 formic acid isobutyl ester are added without access to moisture. After 30 minutes, a solution of 1.97 g of 3-acetyloxymethyl-.7|3-amino-3-cephem-4-carboxylic acid tert-butyl ester in 10 ml of methylene chloride is added, which is allowed to react for 2 hours at -10 °C and for 14 hours at 20°C. The mixture is diluted with water, the organic layer is separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The impure product is chromatographed on 200 g of silica gel. One elutes with a 4:1 mixture of methylene chloride/acetic acid ethyl ester, first 3-acetyloxymethyl-7[3-/2*-(3-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid-tert .-butyl ester. Thin layer chromatogram (silica gel): Rf = 0.55 (system: toluene/ethyl acetate 6:4); ultraviolet absorption spectrum (in 95$-ig aqueous ethanol): max~241 mu (£=14000); infrared absorption spectrum (in mineral oil): characteristic bands at 2.97^u, 3.02 ya, 5.62 ya, 5.72 yx, 5.83 yi, 5, 96 yi, 6.05/i, 6.49 /i and 6.69 yi proton resonance spectrum (chloroform-d): characteristic signals for both protons in the thiophenation: & = 6.94 and 7.17 (AB/J = 5.5). The 3-acetyloxymethyl-7(3-/2"-(4-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino-7-3-cephem-4-carboxylic acid tert.-butyl ester is then eluted with the same solvent. Thin layer chromatogram (silica gel): Rf = 0.4l (system: toluene/ethyl acetate 6:4); ultraviolet absorption spectrum

(in 95$-ig aqueous ethanol) :Nmax<=><2>42 mja 14200); infrared absorb ion spectrum (in mineral oil): characteristic bands at 2.99/i,

5.62 yi, 5.73^*» 5.83^i and 6.59 y-$ proton resonance spectrum (chloroform-d): characteristic signals for both protons on the thiophene ring: S = 6.86(s) and £ = 6.99(3).

Example 11.

A solution of 1.5 g of 3-acetyloxymethyl-7tt-methoxy-7(3-/2- ( 3-» tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino/-3" cephem-4-carboxylic acid-tert.- butyl ester in 6.0 ml of trifluoroacetic acid is transferred according to example 4 to the inner salt of 3"*acetyloxy-methyl-7|3-/2*"(3-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3- "Cef em-4-carboxylic acid. Thin-layer chromatogram (silica gel): Rf = 0.27 (system: n-butanol/acetic acid/water 45:45:10); ultraviolet absorption spectrum (in water): ^ max = 237 rnjj (£= 12700); infrared absorption spectrum (in mineral oil): characteristic bands at 5.64 yx, 5.57 yx, 5.97 yx and

6, 55 y-t proton resonance spectrum (formic acid d^): characteristic AB system at = 7.17 and 7.38 (j = 5.5) of the two hydrogen substituents on the disubstituted thiophene ring.

Example 12.

3-acetyloxymethyl-7a-methoxy-7|3-/2"-(4-tert-butyloxy-carbonylaminomethyl 1-2-thienyl)-acetylamino7-3-cephem-4-carboxylic acid tert-butyl ester is prepared by a method which is described in example 10. Thin-layer chromatogram (silica gel): Rf = 0.37 (system: toluene/acetic acid ethyl 3:2); ultraviolet absorption spectrum (in 95$-ig aqueous ethanol):^- max = 2kjyx(£= 14300); infrared absorption spectrum (in methylene chloride); characteristic bands at 2.Q9 yx, 2.93 yx, 5.60 yx, 5.15 y-, 5.84 y and 6.65 y..

Example 13.

A solution of 1.5 g of 3-acetyloxymethyl-7α-methoxy-7|3-/2-(4-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetylaminoj-3-cephem-4-carboxylic acid tert-butyl ester in 6.0 ml of trifluoroacetic acid is transferred according to the method described in example 4 to the inner salt of 3-"acetyloxymethyl-7|3-/2"-(4-aminomethyl-2-tyl eny 1 )-acetylamino7 -70C-methoxy-3-cef em-4-carboxylic acid e. Thin gel chromatogram (silica gel): Rf = 0.27 (system: n-butanol/acetic acid/water

"45:45:10); ultraviolet absorption spectrum (in water)^- = 238 mu

x 7 max /

(£ =13100); infrared absorption spectrum (in mineral oil): characteristic bands at 5.64 yx, 5.75 yx, 5.98 yx and 6.55 yx*

Example 14.

A lithium methoxide solution prepared by dissolving 0.14 g of lithium wire in 20 ml of methanol is added at -70°C and under a nitrogen atmosphere to a solution of 4.48 g of 7(3-/2*-(5-tert. - butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester in 100 ml of tetrahydrofuran and 100 ml of methanol. Immediately thereafter, 0.860 ml of tert-butyl hypochlorite is added, the mixture stirred for 35 minutes at -70 to -75°C, 3.0 ml of acetic acid is added and evaporated under reduced pressure. The residue is added to 50 ml of ice-cold water, the water mixture is extracted twice with 100 ml of ethyl acetate. The organic extracts are washed with a saturated , aqueous sodium chloride solution, is dried over magnesium sulfate, filtered through 10 g of silica gel and evaporated. The residue is taken up in petroleum ether and 7P-/2-(5-tert-butyl-oxycarbonylaminomethy1-2-thienyl)-acetylamino7-7tt-methoxy- 3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester is filtered off . Thin layer chromatogram (silica gel): Rf = 0.26 (system: toluene/ethyl acetate 3s2); ultraviolet absorption spectrum (in 95$-ig aqueous ethanol): inflections at 239 mu (£ = 13100) and 276 myx (£=5800); infrared absorption spectrum (in mineral oil): characteristic bands at 2.90 yx, 5, 60 yx, 5.78 and 6.59 /u.

The starting material can e.g. is prepared as follows: To a suspension of 5.0 g of 7|3-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid (US Patent No. 3,516,997) in 200 ml of methanol is added with stirring 2.09 S P-toluenesulfonic acid monohydrate, from which a clear solution slowly forms which evaporates under reduced pressure. Diethyl ether is added to the residue and the p-toluenesulfonic acid salt of the 7|3-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid is filtered off. This is dissolved in 100 ml of dioxane and 2.5 g of diphenyldiazomethane are added in portions to the solution. The solution is stirred for 18 hours at room temperature and evaporated under reduced pressure; the residue is added to 100 ml of a 0.1 aqueous sodium bicarbonate solution and extracted twice with 100 ml of ethyl acetate. The organic extracts are washed successively with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. Crystallization from diethyl ether gives 7(3-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cef em-4-carboxylic acid diphenyl methyl ester. Thin-layer chromatogram (silica gel): Rf = 0.21 (system: chloroform/ethyl acetate/ acetic acid 80:19:l); ultra-

violet absorption spectrum (ethanol):^ max = 269 mu (£ = 6400)j infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93/1, 5.60ya, 6.15 /u.

5.43 g of 2"(5-tert."butyloxycarbonylaminomethyl-2-thienyl)-acetic acid is dissolved in 200 ml of methylene chloride containing 2.20 ml of 4-methyl-morpholine, the solution is cooled without access to moisture to

-20°C and 2.86 ml of chloroformic acid isobutyl ester are added dropwise. After 30 minutes, a solution of 9.35 g of 7P-amino-3-(l»methyl-5-tetrazolylthiomethyl)-3-cef em-4- carboxylic acid diphenylmethyl ester in 100 ml of methylene chloride which is stirred for 1 hour at -20°C and for 16 hours under slow heating to room temperature. Ice-cold water is added, the organic solution is separated and the water phase is extracted several times with 100 ml of methylene chloride. The organic extracts are washed with a saturated, stable sodium chloride solution, dried over magnesium sulfate and evaporated. Crystallization of the residue from a mixture of acetic acid methyl ester and diethyl ether provides 7P«* /2-(5-tert«butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-(1-methyl-5-tetrazolylthiomethyl)«3-cephem-4- carboxylic acid diphenyl methyl ester. Thin layer chromatogram (silica gel): Rf = 0.38 (system: chloroform/ethyl acetate/acetic acid 80:19 sl)} ultraviolet absorption spectrum (in 95 µg aqueous ethanol): shoulders at 242 mm (£= 16400) and 274 mu (£ = 9200); infrared absorption spectrum (in mineral oil): characteristic bands at 3.03 yi» 5.58 ^1, 5.79 yu, 5.96u, 6.12 yu and 6.51 yu

The starting material can optionally be produced in the following way

manner:

To a suspension of 2.0 g of 7(3=amino-3-(1-methyl-5-tetrazolyl-thiomethyl)-3-cephem-4-carboxylic acid in 60 ml of methylene chloride is added 1.5 ml of triethylamine, 1.6 ml N,N-dimethylaniline and 2.3 ml of trimethylchlorosilane. The solution is heated with stirring for 20 minutes to 40° C. and then cooled to -10° C. To the reaction mixture is added a solution of 2'(5-tert-butyloxycarbonylaminomethyl-2 -thienyl)"acetic acid chloride in methylene chloride which is prepared as follows: a solution of 1.95 g of 2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid in 20 ml of methylene chloride is treated with 0.05 ml of dimethylformamide and 5 ml of oxalyl chloride.The mixture is stirred under a nitrogen flow for 30 minutes at reflux temperature, the volatile components are distilled off and the oily residue is taken up in 20 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 to 25°C, water is added, the mixture is adjusted to a pH value of approx. 7 with sodium bicarbonate, extracted with methylene chloride, carefully acidified with concentrated hydrochloric acid and the precipitate formed filtered off. It is washed with water and dried under reduced pressure at room temperature.

The product containing 7(3-/2"-(5-tert.-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino7-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid is dissolved in 30 ml of dioxane, 1.5 g of diphenyldiazomethane is added to the solution, which is stirred for 12 hours at room temperature and then evaporated. The residue gives after recrystallization from a mixture of acetic acid methyl ester and diethyl ether 7(3-/2-(5-tert-butyloxycarbonylaminomethyl-2- thienyl)-acetylamino7-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester.

Example 15»

A solution of 3.91 g of 7(3-/2-(5-tert.-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino7-7oc-methoxy-3-(1-methyl 1-5-1etra-zolylthiomethyl) -3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of trifluoroacetic acid and 5 ml of anisole is heated without access to moisture for 1 1 hour at 20° C. and then evaporated under reduced pressure. The residue is dried for 16 hours under high vacuum and then dissolved in 30 ml of methanol . The solution is treated with an activated charcoal preparation and filtered. The filtrate is added dropwise with approximately 0.95 ml of triethylamine to obtain

a pH value of 6.0 and the precipitated inner salt of 7(3-/2-(5-amino-methyl-2-thienyl)-acetylamino7-7oc-methoxy- 3-(1-methy 1-5 - 1 etrazolyl-thiomethyl )-3-cephem-4-carboxylic acid is filtered off. Thin-layer chromatogram (silica gel): Rf = 0.10 (system: n-butanol/acetic acid/water 45:45:10); ultraviolet absorption spectrum (in 0.01- n. aqueous sodium hydrogencarbonate):^ max = 240 mu (^ =15900); infrared absorption spectrum (in mineral oil): characteristic bands at 5>67/i, 5»96yU and 6.48 ya.

In an analogous manner, the following compounds are prepared through selection of the corresponding starting materials: 7|3_/2-(5-aminomethyl-2-thienyl)-acetylamino7-3,7ct-dimethoxy-3-cephem-4-carboxylic acid;

3-aminocarbonyloxymethyl-7(3-(2-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-cephem-4-carboxylic acid);

7-(3-(2-(5-aminomethyl 1-2-thienyl)-acetylamino7-3-methylaminocarbonyl-oxymethyl-7a-methoxy-3-cephem-4-carboxylic acid);

7 (3-/2-(5-aminomethyl-2-thienyl)-acetylamino7-3-N-(2-chloroethyl)-aminocarbonyloxymethyl-7oc-methoxy-3-cef em-4-carboxylic acid; and 7P-/2 - (5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-methylthio-methyl-3-cephem-4-carboxylic acid

which are usually provided in the form of their internal salts.

Example 16.

Dry ampoules or vials containing 0.5 g of the inner salt of 3-acetyloxymethyl-7(3-/2-(5-aminomethyl-2-thienyl)-acetylamino7-7oc-nietoxy-3-cephem-4-carboxylic acid are prepared on following way: Composition (for 1 ampoule or vial) 3-acetyloxymethyl-7|3-/2 - (5-aminomethyl-2-thienyl) -acetylamino7-7a-methoxy-3-cef em-

A sterile aqueous solution of the inner salt of 3-acetyl-oxymethyl-7(3-/2-( 5-aminomethyl-2-thienyl)-acetylamino7-70C-methoxy-3-cephem-4-carboxylic acid and mannitol contained under aseptic conditions in 5 ml ampoules or 5 ml vials and tested.

Example 17.

Dry vials or vials containing 0.5 g of the inner salt of 7(3-(2-(5-aminomethyl-2-thienyl)-acetylamino-70C-methoxy-3-(1-methyl-5- tetrazolyl-thiomethyl)-3-cephem-4-carboxylic acid is prepared as follows: Composition (for 1 ampoule or vial) 7(3-/2-(5-aminomethyl 1-2-thienyl)-acetylamino7-7oc-methoxy-3 - (1-methyl-5-tetrazolyl-thiomethyl)-

A sterile aqueous solution of the inner salt of 7(3-(2-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-(1-methyl-5-tetra-zolyl-thiomethyl)-3 -cephem-4-carboxylic acid and the mannitol are submitted under aseptic conditions in 5 ml ampoules or 5 ml vials to freeze-drying and the ampoules and vials are closed and tested.

Example 18.

A solution of 1.96 g of 7(3-[2-(5-tert.-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino-7-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester in 150 ml tetrahydrofuran is added at -70° C. a solution of 0.073 S lithium in 20 ml methanol and immediately afterwards 0.391 ml tert-butyl hypochlorite. After a reaction time of 15 minutes at -70°C, 3 ml of acetic acid are added and the reaction mixture is evaporated under a water jet vacuum. The residue is taken up in 150 ml of ethyl acetate, the organic solution is washed with aqueous sodium thiosulphate solution over saturated, aqueous sodium chloride solution, dried over magnesium sulphate and reduced under a water jet vacuum to a volume of approx. 10 ml . The concentrated solution is slowly diluted with 100 ml of petroleum ether; the precipitate is filtered off and dried under high vacuum at room temperature. This affords 7(3-/2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-7ct-methoxy-3- (5-methyl-1,3'4-thiadiazol-2-yl thiomethyl) - 3-cephem-4-carboxylic acid tert-butyl ester. Thin-layer chromatogram (silica gel): Rf = 0.12 (system: toluene/ethyl acetate 3:2), The starting material can be prepared as follows: 4.08 g of 2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid is dissolved in 200 ml of methylene chloride, which contains 1.65 ml of N-methyl-morpholine, the solution is cooled without access to moisture to -20°C and 1.95 ml of chloroformate isobutyl ester is added dropwise. After 30 minutes, a solution of 5>16 g of 7(3-amino-3-(5-methyl-1,3»4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7»20 ml of N ,0-bis-(trimethylsilyl)-acetamide in 150 ml of methylene chloride after which the reaction mixture is stirred for 1 hour at -20°C and for 4 hours under slow heating to room temperature after which it is evaporated under reduced pressure. The residue is dissolved in water under the addition of sodium bicarbonate to a pH value of 8. The solution is washed with ethyl acetate, the separated aqueous solution is acidified with 20% aqueous phosphoric acid to pH 2 and extracted with ethyl acetate.

The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. This gives 7(3-/~2-(5-tert-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino7-3-(5-methyl-1,3»4-thiadiazol-2-ylthiomethyl)-3-cephem-4 -carbonic acid. Thin-layer chromatogram (silica gel): Rf = 0.40 (system: n-butanol/acetic acid/"water 45:45:10); ultraviolet absorption spectrum (ethanol):^* max=

244 mu I69OO); infrared absorption spectrum (in mineral oil): characteristic bands at 2.93 y- t 5»60ya, 5.90 yx and 6.55 y-

A mixture of 6.1 g of dicyclohexylcarbodiimide, 2.1 g of tert-butyl alcohol and 0.06 g of copper (I) chloride is stirred for 5 days at room temperature. The obtained suspension of 0-tert.-butyl-N,N'-dicyclohexyl-isourea is diluted with 30 ml of methylene chloride and added to a solution of 2.0 g of 7(3-/2-(5-tert.-butyloxy-carbonylaminomethyl -2-thienyl)-acetylamino7-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of methylene chloride which is kept at room temperature. After 5 hours, filter the mixture and the filtrate are evaporated under reduced pressure. The residue is chromatographed on 40 g of silica gel and 7(3-/2-(5-1-ter.-butyloxycarbonylamino-methyl-2-thienyl)-acetylamino7-3-(5-methyl-1,3" 4-thiadiazol-2-ylthio-methyl)-3-cephem-4-carboxylic acid tert-butyl ester is eluted with acetic acid ethyl ester Thin-layer chromatogram (silica gel): Rf = 0.70 (n-butanol/acetic acid/water 45:45:10 ).

Example 19.

A solution of 1.52 g of 713-[2-(5-tert.-butyloxycarbonyl-aminomethyl-2-thienyl)-acetylamino7-7oc-methoxy-(5-methyl-1,3,4-thia-diazole-2- ylthiomethyl)-3-cephem-4-carboxylic acid tert-butyl ester in 20 ml of trifluoroacetic acid is allowed to stand without access to moisture for 15 minutes at room temperature and evaporated under a water jet vacuum while adding toluene. The residue is taken up in diethyl ether and the provided trifluoroacetic acid salt of 7(3-(2-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3-(5-methyl-1,3»4-thiadiazole-2- ylthiomethyl)-3-cephem-4-carboxylic acid is dried under high vacuum at room temperature and then dissolved in 20 ml of water. The aqueous solution is washed with ethyl acetate, adjusted to a pH of 6 with triethylamine and reduced to 5 ml under water jet vacuum. The solution is diluted through the dropwise addition of 30 ml of acetone, leave for 2 hours at 4°C, after which the precipitate is filtered off. This is washed with diethyl ether and dried under high vacuum. This provides the inner salt of 7(3-/2- ( 5-aminomethy 1-2 -thienyl)-acetylamino7-70C-methoxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-eephen-4-carboxylic acid. Thin layer chromatogram (silica gel): Rf = 0.11 ( system: n-butanol/acetic acid/water 45:45:110); ultraviolet absorbance spectrum (0.1-n aqueous sodium

bicarbonate solution):^> = 242 mu (£ = l6400); infrared

month xf

absorption spectrum (in mineral oil): characteristic bands at 5.66 yx, 5.97 yx, 6.25 yx and 6.50 yx.

Claims (38)

1. Method for the preparation of 6(3-acylamino-6a- methoxy-penam-3-carboxylic acid compounds and 7|3-acylamino-7ct-methoxy- 3-cephem-4-carboxylic acid compounds of the formula where X is sulfur or oxygen or ethenylene with the formula -CH=CH- and where the group with the formula -S-A- is a residue with the formula where R, is oxygen, an etherified hydroxy group or a residue with the formula -CH~2-R2 where Rp is hydrogen, a free, etherified or for ester hydroxy or marcapto group or a quaternary amino group and where R is hydroxy or an etherified hydroxy group which together with the carbonyl group -C(=0)- forms an esterified carboxy group, cleavable under physiological conditions, as well as salts thereof, characterized by manyacylating the amino group in a compound with the formula where the amino group may optionally be substituted through a group (which is released in the acylation and where the group with the formula -S-Aq- is a residue with the formula where RQ has the same meaning as R or is a carboxyl protecting residue which together with the carbonyl group of the formula -C(=0)-forms a protected carboxyl group^or in salts thereof through treatment with an acid of the formula where the amino group is possibly protected, or with a reaction-wild <i> g, functional acid derivative thereof or with a salt of such a compound in the 6a or 7a position in a penam or 3-cephem compound with the formula in which amino in the aminomethyl group is preferably present in protected form and the residue with the formula rS-AQ- has the meaning given above whereby a carboxyl group with the formula -C(=0)-Rq is preferably present in protected form. or in a salt thereof introduces a methoxy group , or/in a connection with the formula where AmQ is a protected amino group and R is a residue which together with the carbonyl group with the formula -C(=0)- forms a preferably protected carboxyl group and where amino in the aminomethyl group is present in protected form and which differs from the protected amino group AmQ through how it is transferred to the free amino group, the group Am transfers to the free amino group whereby 5-amino-5-carboxy- ° cU the valeryl residue is cleaved off under the reaction conditions, or/or sets a connection with the formula where the residue with the formula -S-Aq- has the above meaning where a carboxyl group with the formula -C(=O)-Rq is preferably present in protected form with a compound of the formula R^^ -NH^ (Vil) where R is an amino protecting group and formaldehyde in the presence of a / strong, mostly some nucleophilic acid or isomerizes a 2- cefem compound with the formula where amino in the aminomethyl group and/or a carboxyl group with the formula -C(=0)-Rq if this is necessary or desirable, exists in protected form, to the corresponding 3-cephem compound ej~ and transfers protected amino in the aminomethyl group to free amino in a provided connection and, if this is necessary or desirable, transfers a carboxyl group with the formula -C(=0)-Rq to a carboxy- /-| , syl group with the formula -C(=0)-R and/or, if this is desiredj _ojv^ r-^ , I leads a group of the formula -C(=o)-R and/or, if this is desired, one group R~^ViT transforms another group R^ and/or, if this is desirable, converts a provided salt into the free compound or into another salt or a provided free compound into a salt. 2. Method according to claim 1, characterized in that in a starting material with formula II any residues from the acylation of amino groups are organic silyl or stannyl groups or ylidene groups which together with the amino group form a Schiff base. 3. Method according to claim 1 or 2, characterized in that a protected carboxyl group with the formula -C(=0)-Rq in a starting material is a preferably easily cleavable, esterified carboxyl group where Rq is an etherified hydroxy group. k.. Method according to claims 1-3" characterized in that any free functional groups initially present, in addition to a carboxyl group with the formula -C(=0)-Rq, are in a protected, preferably easily cleavable form. 5. Method according to claims 1- <*> $, characterized in that amino in the aminomethyl group in the starting material is protected through preferably easily cleavable amino protecting groups or is present in the form of azido groups. 6. Method according to claims 1-5" characterized in that the acylation of a starting material of formula II is carried out through treatment with an acid of formula III in the presence of a condensing agent. 7. Process according to any one of claims 1-5" characterized in that the acylation of a starting material of formula II is carried out through treatment with an anhydride including a mixed or internal anhydride of an acid of formula III, in particular the anhydride of such an acid with a hydrohalic acid, hydronic acid, a phosphoric or sulphurous acid, hydrocyanic acid, a lower alkanecarboxylic acid which is optionally substituted, e.g. with halogen or with a half-ester of carboxylic acid. 8. Process according to any one of claims 1-5, characterized in that the acylation of a starting material of formula II is carried out through treatment with an activated ester of an acid of formula III. 9. Method according to any one of claims 3-5"characterized by introducing a methoxy group in the 6a- or 7oc-position of a penam- or 3-cephem compound of formula IV while treating an acylimino compound with the formula where amino in the aminomethyl group is present in protected form and the remainder with the formula -S-Aq- has the meaning mentioned above and where a carboxyl group with the formula -C(=0)-Rq is present in protected form with methanol. 10. Process according to claim 9" characterized in that a starting material of formula IVa according to claim 9 is prepared in the presence of methanol, while treating a compound of formula IV where amino in the aminomethyl group and the carboxyl group with the formula -C(=0)-Rq as well as any other functional groups present are in protected form^ with an anion-forming agent followed by an N-halogenating agent and, if necessary, reacting with a halohydrogen-releasing base, or treating a compound of the formula where R° is an organic residue and where amino in the aminomethyl group and the carboxyl group with the formula -C(=0)-R as well as any other functional groups present are in protected form with halogen followed by a base and where this reaction is carried out in the presence of methanol so that one provides a 6a-methoxy-penam or 7oc-methoxy-3-cef em compound with which, if necessary, the reaction steps described in claim 1 are carried out. 11. Method according to claim 10, characterized in that an anion-forming agent is used as an organometallic base such as an alkali metal, particularly lithium alcoholate, particularly an alkali metal, e.g. lithium lower alkanolate, where such a base can simultaneously serve as a halogen hydrogen-releasing agent and where a sterically hindered organic hypohalogenite such as a tert.-lower alkyl hypohalogenite is used as an N-halogenating agent. 12. Method according to claim 10, characterized in that R° in a starting material with formula IVb according to claim 10 is a hydrocarbon residue of an aliphatic character such as lower alkyl, especially methyl. 13. Method according to claim 10 or 11, characterized in that a starting material with the formula IVb according to claim 10 is reacted with chlorine followed by an organic base such as a tertiary aliphatic amine, e.g. a tri-lower alkylamine, 14. Method according to any one of claims 1 and 3-5"characterized by introducing a methoxy group in the 6a or 7a position in a penam or 3-cephem compound of formula IV while reacting a compound of formula IVb according to claim 10 where R° has the meaning given in claim 10 or claim 12 and where amino in the aminomethyl group and the carboxyl group by formula -C(=0)-RQ , as well as any other functional groups present, are present in protected form with methanol in the presence of a desulphurisation agent. 15. Method according to claim 14, characterized in that a silver or mercury compound such as a silver oxide or mercury oxide or a silver I or mercury II salt is used as a desulfurization agent. 16. Method according to any one of claims 1 and 3-5" characterized in that a protected amino group AmQ in the starting material with the formula V is protected through an acyl-, arylmethyl-, 2-carbonyl-1-vinyl-, arylthio-, aryl -lower alkylthio or arylsulfonyl group. 17. Method according to claim 16, characterized in that the protected amino group AmQ is transferred to the free amino group in different ways depending on the type of protective group, particularly through solvolysis or reduction. 18. Method according to claims 1, 3 and 4, characterized in that an amino protecting group Rx in the starting material with formula VII is an acyl group which cannot be split off in the presence of a strong, largely weak nucleophilic acid. 19. Method according to any one of claims 1, 3, 4 and 18, characterized in that formaldehyde is used in the form of a reactive derivative thereof, in particular a polymer. 20. Method according to any one of claims 1, 3, 4, 18 and 19, characterized in that strong organic carboxylic acids such as preferably halogen-substituted lower alkane carboxylic acids, in particular trifluoroacetic acid, are used as strong, mostly weakly nucleophilic acids. 21. Process according to any one of claims 1 and 3-5, characterized in that one isomerizes a 2-cephem derivative with formula VIII by treating it with a weak basic agent and before the equilibrium mixture obtained isolates the corresponding 3- cefem compound. 22. Method according to any one of claims 1 and 3-5, characterized in that one isomerizes a 2-cephem compound of formula VIII while oxidizing this in the 1-position separates the 1-oxide of the corresponding 3-cephem compound desired from a provided isomer mixture, and reduces the provided 1-oxide of the corresponding 3-cephem compound. 23. Method according to any one of claims 1-22, characterized in that in a provided compound of formula I where the amino group in the aminomethyl substituent is preferably protected and where the group of the formula -S-A- is a residue of the formula Ib, the group R is replaced , with another residue R^ or converts it to another residue R^ in a known manner. 24. Method according to claim 23, characterized in that in a compound of formula I where a residue of formula Ib is included as the group of the formula -S-A- where R^ is a group of the formula -CH2 -R2 and where R^ is a residue which is exchangeable with nucleophilic substituents or a salt of such a compound replaces such a residue R^ with an etherified mercapto group R^ through treatment with a mercaptan compound. 25. Method according to claim 23, characterized in that one reacts a compound of formula I where the group -S-A- is the partial formula Ib and where R.^ is the group -CH^ -R^ and R^ is free hydroxy with an isocyanate or carbamic acid compound and thereby arrives at a compound of formula I where the group -S-A- is the partial formula Ib and where R is the group -CH^ R^ where R^ is a hydroxy group which is esterified with an optionally substituted half-amide of carbonic acid. 26. Method according to claim 23, characterized in that in a compound of formula I with a residue of the formula Ib as the group of the formula -S-A- where R^ is a group of the formula -CH^-R,, and where R^ is a residue which is exchangeable with nucleophilic substituents or a salt of such a compound replaces such residue R^ with a quaternary ammonium group through treatment with a tertiary organic base preferably forming a intermediate product. 27. Process according to any one of claims 1-26, characterized in that intermediate products can be used as starting materials so that the subsequent reaction steps are carried out with them or the reaction can be interrupted at any step. 28. Method according to any one of claims 1-27, characterized in that the starting substances can be used in the form of derivatives or formed during the reaction. 29. Process according to any one of claims 1-28, characterized in that compounds of formula I according to claim 1 or salts thereof are prepared, where X has the meaning given in claim 1, the remainder with the formula -S-A- is the partial formula Ia or Ib according to claim 1 where R has the meaning given in claim 1 and R^ is hydrogen, an etherified hydroxy group or a group with the formula - CK^- R^ where R^ is hydrogen, hydroxy, a hydroxy or mercapto group which is preferred through a lower aliphatic hydrocarbon residue, a mercapto group which is esterified through an optionally substituted heterocyclic residue with from 1 to h ring nitrogen atoms which are linked to sulfur through a ring carbon atom and where optionally a further ring heteroatom belongs to the group of oxygen and sulphur, a hydroxy or mercapto group which is esterified by a lower aliphatic carboxylic acid or an optionally N-substituted carbamic acid, a carboxyl group that is esterified with benzoic acid or with a heterocyclic carboxylic acid where the heterocyclic part is an optionally substituted heterocyclic ether with from 1 to h ring nitrogen atoms which are linked above a ring carbon atom to sulfur and where possibly a further ring heteroatom belongs to the group oxygen or sulphur, or a quaternary ammonium group which is derived from a tertiary organic base and which is linked above the nitrogen atom to the methylene carbon atom. 30. Method according to any one of claims 1-28, characterized in that compounds of formula I according to claim 1 or salts thereof are prepared, in which X is oxygen or sulfur or is et^nylene with the formula -CH=CH- and where the aminomethyl-substituted residue is aminomethyl-2- or -3-thienyl, aminomethyl-2-furyl or aminomethylphenyl, the group of the formula -S-A- is a residue of formula Ia or Ib according to claim 1, in which R1 is lower alkoxy or the group of formula -011 ^2 where R~ is hydrogen, lower alkanoyloxy, optionally N-lower alkylated or N-halo-lower alkylated carbamoyloxy, optionally substituted heterocyclylthio where heterocyclyl is a monocyclic, five-membered heterocyclic residue of an aromatic character which is connected to the thiosulfur atom via a ring carbon atom and which contains 2 or 3 ring hydrogen atoms and optionally in addition a ring oxygen atom, ring sulfur atom or ring nitrogen atom, and where such a residue may optionally be substituted through lower alkyl, or where heterocyclyl is an unsaturated, monocyclic, six-membered heterocyclic residue which is attached to the thiosulfur atom over a ring carbon atom and which contains 2 ring nitrogen atoms where either a ring nitrogen atom contains an oxido group or a ring carbon atom contains an oxo group and where such a heterocyclyl residue may optionally be substituted through lower alkyl, lower alcohol xy or halogen or is a pyridinium residue which may optionally be substituted with carboxy, carbamoyl or hydrazinocarbonyl and where R is hydroxy. 31. Process according to any one of claims 1-28, characterized in that 3-cephem compounds of formula I according to claim 1 or salts thereof are prepared, wherein X is sulfur or oxygen and where the aminomethyl-substituted residue is aminomethyl-2- thienyl- or -2-furyl, the group with the formula -S-A-is a residue of formula Ib according to claim 1 where R^ is lower alkoxy with up to h carbon atoms or is a residue of the formula -CR\,-R2 where R2 is hydrogen, acetyloxy . and which is connected via a ring carbon atom with the thiosulfur atom or pyridinium which is substituted with carbamoyl and where R is hydroxy. 32. Method according to claims 1-25, 27 and 28, characterized in that one prepares 3-cephem compounds of formula I according to claim 1 or salts thereof, where X is sulfur or oxygen and where the aminomethyl-substituted residue is aminomethyl-2- thienyl or -2-furyl, the group with the formula -S-A- with the formula Ib according to claim 1 where R^ is methoxy or the residue with the formula -CH^-Rg where R^ is hydrogen, acetyloxy, carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, 2-chloroethylcarbamoyloxy , methylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-methyl-5-tetrazolylthio and where R is hydroxy. 33» Method according to any one of claims 1-23, 27 and 28, characterized in that 3-acetyloxymethyl-7β-[2-(5-aminomethyl-2-thienyl)-acetylamino7-7ct-methoxy-3-cephem is produced -4-carbonic acid or salts thereof. 34. Method according to any one of claims 1-24, 27-,° g 28, characterized in that 7|3-/2-(5-aminomethyl-2-thienyl)-acetylamino7-7a-methoxy-3- (1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid or salts thereof. 35" Process according to any one of claims 1-23, 27 and 28, characterized in that 3-ethyl-oxymethyl-7(3-/2-(5-aminomethyl-2-furyl)-acetylamino7-7a-methoxy -3-cephem-4-carboxylic acid or salts thereof. 36. Process according to any one of claims 1-23, 27 and 28, characterized in that 3-acetyloxymethyl-7|3-/2-(3-aminomethyl-2-thienyl)-acetylamino7-70C-methoxy-3 -cephem-4-carboxylic acid or salts thereof. 37 • Process according to any of claims 1-23, 27 and 28, characterized in that 3-acetyl-oxymethyl-7|3-/2-(4-aminomethyl 1-2-thienyl)-acetylamino7-7a is produced -methoxy-3-cephem-4-carboxylic acid or salts thereof. 38. Procedure, characterized in that it is described in the attached examples.