FR2530635A1 - AMINO-IMIDAZOLYL COMPOUNDS, PROCESS FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THEM, AND APPLICATION THEREOF - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS 7B-AMINO-IMIDAZOLYLACETYLAMINO-3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS OF FORMULAS: (CF DRAWING IN BOPI) AND (CF DRAWING IN BOPI) OR R REPRESENTS A HYDROGEN, AN ALCOHYL ALCOYL INFERIOR, A HALOGEN OR A GROUP - CH-R, OR R REPRESENTS A HYDROXY, A MERCAPTO, A HYDROXY OR AN ESTERIFIED MERCAPTO, A HYDROXY OR A MERCAPTO ETHERIFY OR A QUATERNARY AMMONIO GROUP, R REPRESENTS A CARBOXYL, CARBOXYL OR A CARBOXYL REPRESENTS A SUBSTITUTED OR NON-SUBSTITUTED HYDROCARBON RADICAL OR AN ACYL GROUP AND IN THE COMPOUNDS OF FORMULA IA ALSO A HYDROGEN AND A REPRESES A CARBONYL, A METHYLENE GROUP OR A METHYLENE GROUP WHICH IS SUBSTIZED BY AN AMINOX, A HYDROX, A HYDROGEN, A HYDROGEN HYDROXY PROTECTED, A SULFO, A PROTECTED SULFO OR BY A GROUP OF FORMULA NOR, OR R REPRESENTS A HYDROGEN, A LOWER ALCOYL, A LOWER ALCOYL-SUBSTITUTE, A CYCLOALCOYL, A CYCLOALCOYL SUBSTITUE ALCYLE, UNCYL N CARBAMOYL OR A SUBSTITUTE CARBAMOYL, HYDRATES AND SALTS OF COMPOUNDS OF FORMULA IA AND IB.

Description

The present invention relates to novel compounds of 7 B-

  aminoimidazolyl, a process for their

  preparation, the pharmaceutical preparations which

  these compounds, and their application to the pre-

  S paration of pharmaceutical preparations or as a com-

  pharmacologically active compounds, as well as new

  intermediate products and a process for their pre-

  repair. The invention relates to 7 eaminoimidazolylacetylamino-3-cephem-4-carboxylic acid compounds of formulas II N (IAJ

4 -

  R 3 and R 3 L -O 3 -A-C-1

H R

  R 1 represents a hydrogen, a lower alkyl, a lower alkoxy, a halogen or a group -CH-R 2, where R 2 represents a hydroxy, a mercapto, a hydroxyl or

  esterified mercapto, a hydroxy or an ethereal mercapto

  or a quaternary ammonium group, -R 3 represents a carboxyl or a protected carboxyl, R 4 represents a substituted or unsubstituted hydrocarbon radical or an acyl group and in the compounds of formula IA furthermore a hydrogen and A represents a carbonyl, a methylene group or a methylene group which is substituted by

  an amino, a protected amino, a hydroxy, a hydroxy

  teged, a sulpho, a protected sulpho or a group of

  formula = N-O-R 5, where R 5 represents a hydrogen, a

  lower alkyl, substituted lower alkyl, cy-

  cloalkyl, substituted cycloalkyl, cycloalkenyl

  a lower alkenyl, a carbamoyl or a carbamoyl

  substituted hydrates and salts of the compounds of formulas IA and IB, pharmaceutical preparations containing compounds of formula IA and / or IB,

  and applying the compounds of formula I to the preparation of

  of pharmaceutical preparations or as

l G pharmacologically active.

  In the description of the invention, the

  "lower" pressure used in connection with groups, eg lower alkanol, lower alkylene, lower alkoxy, lower alkanoyl, etc., means

  groups, unless expressly defined-

  different, contain up to 7 and preferably

up to 4 carbon atoms.

  The imidazolyl radical substituted with a free or monosubstituted amino group may also be in the form of a substituted dihydroimidazolyl radical

  by an imino group, which presents two

tomères.

NOT, -

H ___ ___

  The equilibrium position between the imidazolyl form and the two dihydroimidazolyl forms depends on the structure of the R 4 and A substituents and on external parameters such as temperature, solvent or H.sub.2.

  In the present description, only the amino form

  imidazolyl is expressly mentioned.

  two dihydroimidazolyl forms are also included.

  The general definitions used above

  above and below have in the course of this

  description preferably the following meanings:

  A lower alkyl R 1 contains from 1 to 4 carbon atoms and is for example an ethyl, a

  propyl, butyl or in particular methyl.

  A lower alkoxy R 1 contains from 1 to 4 carbon atoms and is for example an ethoxy, a

  propoxy, butoxy or in particular methoxy.

  A halogen R 1 is a fluorine, a bromine, a

iodine or preferably chlorine.

  A hydroxy or an esterified mercapto R 2 is a hydroxy or mercapto group which is esterified

  by an aliphatic carboxylic acid, a carboxylic acid

  aliphatic acid substituted by an acyl, eg an alkali

  lower kernel, eg acetyl, or carbamic acid, eg lower alkanoyloxy, eg acetyloxy, lower alkanoyl-lower alkanoyloxy, eg acetylacetyloxy, or carbamoyloxy or lower alkanoyl thio, eg acetylhtho or a formylthio, or

a carbamoylthio.

  An esterified hydroxy or mercapto R 2 is furthermore a hydroxy or mercapto group which is esterified

  by an N-substituted carbamic acid.

  The N-substituents are, for example, lower alkyl, eg methyl or ethyl, or lower alkyl substituted by halogen, eg chlorine, or lower alkanoyloxy, eg acetoxy,

  eg 2-chloroethyl or 2-acetoxyethyl.

  A hydroxy or mercapto esterified with an acid

  N-substituted carbamic acid R 2 is, for example, N-methyl-

  carbamoyloxy, N-ethylcarbamoyloxy, N- (2-chloroethyl) -

  carbamoyloxy, N- (2-acetoxyethyl) carbamoyloxy or N-methylcarbamoylthio. An etherified hydroxy or mercapto R 2 is a hydroxyl or mercapto group which is etherified with an aliphatic hydrocarbon radical, for example a C 1 -C 4 lower alkoxy, eg a methoxy or an ethoxy, or a

  C 1 -C 4 lower alkylthio, eg methylthio.

  An etherified mercapto R 2 is also ethereal

  bound by a heterocycle, which is bonded via a carbon atom of the nucleus to the sulfur atom

  of the mercapto group, eg by a monocyclic heterocycle

  that has 1 to 4 nitrogen heteroatoms and possibly

  an additional oxygen or sulfur atom

  or a bicyclic heterocycle having from 1 to 5 hetero

  Such an etherified mercapto group is hereinafter referred to as "heterocyclylthio group R 2". A heterocyclic radical in a heterocyclylthio group R 2 is in particular a diaza radical,

  triaza-, tetraaza-, thiaza-, thiadiaza-, thia-, oxoza-

  or 5-membered or 6-membered monocyclic or aromatic oxadiazacycllyl, or is an aromatic, or partially aromatic, aza, diaza-, triaza-, tetraaza or pentazabicyclo

  saturated, bicyclic, containing 5 to 6 members per nucleus.

  The substituents of the heterocyclic radical mentioned in a heterocyclylthio group R 2 are, for example, lower alkyl, eg ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular methyl, lower alkenyl, eg allyl, or lower alkyl, eg methyl or ethyl, which is substituted by the following groups: Hydroxy, esterified hydroxy, eg lower alkanoyloxy, eg acetyloxy, or halogen, eg fluorine, or chlorine, optionally in salt form, eg in the form of an alkali metal salt, eg sodium salt,

  lower alkylphosphonyl, eg methyl

  or ethyl phosphonyl, lower dialkylphosphonyl, eg dimethyl or diethylphosphonyl, carboxyl or sulfo optionally present in the form of a salt, eg in the form of an alkali metal or ammonium, e.g. as the salt of sodiim, carboxy esterified, eg alkoxy-lower carbonyl, eg ethoxycarbonyl,

  sulfamoyl, amino, lower alkylamino, p e Xo.

  methyl or ethylamino, lower dialkylamino, e.g. O dimethylamino or diethylamino, acylamino, e.g.

  lower alkanoylamino, eg acetylamino, or alkali

  carboxy-substituted lower alkyl or halogen, eg chlorine, such as carboxyacetylamino or chloroacetylamino. Such a substituted lower alkyl group is for example: a lower hydroxyalkyl, eg a

  hydroxymethyl or 2-hydroxyethyl, an acetyloxy-

  lower alkyl, eg acetyloxymethyl or 2-acetyloxyethyl, halogen-lower alkyl, e.g.

  a chloromethyl, a 2-chloroethyl, a 2,2,2-trichloro-

  ethyl or trifluoromethyl, lower alkyl-

  phosphono-lower alkyl, eg an ethylphosphono-

  methyl, lower dialkylphosphonocycloalkyl, eg diethylphosphonomethyl, carboxyalkyl

  lower, eg carboxymethyl or 2-carboxy-

  ethyl, a lower sulfoalkyl, eg a sulfo

  methyl or 2-sulfoethyl, a lower alkoxycarbonyl-

  lower alkyl, eg ethoxycarbonylmethyl or 2ethoxycarbonylethyl, sulfamoyl-lower alkyl, eg sulfamoylmethyl or mi 2-sulfamoylethyl, lower aminoalkyl, eg aminomethyl or

  2-aminoethyl, lower alkyl-amino-lower alkyl

  , eg methylaminomethyl or 2-methylamino-

  ethyl, lower dialkoyl-lower aminoalkyl,

  P eg a dmtyaih 1 or a 2-dimethylamino-

  ethyl, lower alkanil, lower aminoalkyl,

  P ex a -Thin Lhle a lower carboxyalkanoyl

  amine-aminocarboxylpropionyl-

  aminoethyl or a 2-c-irboxva-ketlamino, -noyl, or halonene alcanovie nfr'i dolcye inferior, e.g.

unc or r 2-chlorac = etyl

noéthyle

  The ones Es-n n or the groups func-

  1, eg 1, 3, 4, 4, 4, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 7, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 8, 8, 9, 9, 9, 9, 9, 8, 9, 9, 8, 8, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 5, 5, 5, 5, 5, 5, 5, 7, 8, 9, 9, 9, 9, 9, 9, 9, 9, 9

  substituted, P ex a-wino not ausiu u mono or di-

  substituted with a lower alkyl, eg methyl or ethyl, as a friend-no, methylamino or dimethylamino, acylamino, eg, Leuramino ferlanoyl, e.g. ac 4 tlaiunoou alcovie i; nfé: ieur-su lfony'La m ino, eg. mesylamino, or lower alkanoyl-a-miino substituted with

  halogen, eg chlorine, or carboxy, eg 3-

  chloropropionyl amine or 3-carbozypropionylamino, nitro, hydroxy, lower alkoxy, eg methoxy or ethoxy,

  carbo Xy, esterified carboxy, eg lower alkoxy-

  carbonyl, eg, methyl-oxycarbonyl or ethoxycarbonyl, optionally substituted carbamoyl, eg with mono- or dialkoyl, such as methylcarbamoyl or dimethylcarbamoyl. Cyano, as well as oxo or oxido, are also substituents of heterocyclic radical

  in a heterocyclylthio group R 2.

  a group he-térocyciylthio R 2 o the radical

  heterocyclic represents an aromatic radical, mono-

  cyclic, at 5 chains, is between an imidazolyl

  thio, eg 2-imidazolylthio, triazolylthio or triazolylthio substituted by lower alkyl, e.g.

  methyl, and / or phenyl, eg 1H-1,2,3-triazole;

  -ylthio, a 1-methyl-1H-11,2,3-triazol-4-ylthio,

  1H-1,2,4-triazol-3-ylthio, a 5-methyl-1H-1,2,4-tria

  zol-3-ylthio or a 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio, a tetrazolylthio, eg 1-tetrazol-5-ylthio, or a tetrazolylthio substituted with a lower alkyl, eg methyl or ethyl, or lower alkyl

  substituted, eg ethyl or diethylphosphonophosphate

  methyl, a carboxyethyl, a sulfomethyl, a 2-tallow o-

  ethyl, 1,2-dimethylaminoethyl or cyanomethyl, e.g. eg 1-methyl-1H-tetrazol-5-ylthio, 1-ethyl or 1-diethylphosphonomethyl-1H-tetrazol-5-ylthio,

  1-carboxymethyl-1H-tetrazol-5-ylthio, a 1- (2-carboxy)

  ethyl) -1H-tetrazol-5-ylthio, a 1-sulfomethyl-1H-

  tetrazol-5-ylthio, 1- (2-sulfoethyl) -1H-tetrazol 5-

  ylthio, 1- (2-dimethylaminoethyl) -H-tetrazol-5-yl-.

  thio or 1-cyanomethyl-1H-tetrazol-5-ylthio, a thiazolylthio or a thiazolylthio substituted with a

  lower alkyl, eg methyl, eg a 2-

  thiazolylthio or 4,5-dimethyl-2-thiazolylthio, an isothiazolylthio, eg 3-isothiazolylthio, a

  4-isothiazolylthio or a 5-isothiazolylthio, a thiadia-

  zolylthio or a thiadiazolylthio substituted with a

  lower alkyl, eg methyl, eg 1,2,3-

  thiadiazol-4-ylthio, a 1,2,3-thiadiazol-5-ylthio, a

  1,3,4-thiadiazol-2-ylthio, a 2-methyl-1,3,4 thiadiazole

  5-ylthio, 1,2,4,4-thiadiazol-5-ylthio or 1,2,5-thiadia-

  zol-3-ylthio, a thiatriazolylthio, eg 1,2,3,4-

  thiatriazol-5-ylthio, an oxazolylthio or an oxazolyl-

  thio substituted by lower alkyl, eg methyl, eg 2 or 5oxazolylthio, or 4-methyl-5-oxazolylthio, substituted isooxazolylthio;

  lower alkyl, eg methyl, eg 3-methyl

  isooxazolylthio, or oxadiazolylthio or oxadiazolylthio substituted with lower alkyl, eg

  methyl, eg 1,2,4-oxadiazol-5-ylthio or a 2-

methyl-1,3,4-oxadiazol-5-ylthio.

  A heterocyclylthio group R 2, where the radical

  heterocyclic represents an aromatic radical, mono-

  cyclic, 6-membered, contains 1 to 3 nitrogen atoms

  and is for example a 5,6-dioxo-tetrahydro-as-triazinyl-

  thio or a substituted 5,6-dioxotetrahydro-as-triazinylthio

  by lower alkyl, eg methyl, carboxy-

  lower alkyl, eg carboxymethyl, or lower sulfoalkyl, eg sulfomethyl, e.g.

  a 1 or 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazine;

  3-ylthio, a 4-methyl-5,6-dioxo-1, 4,5,6-tetrahydro-as-

  triazine-3-ylthio, a 1 or 2-carboxymethyl-5,6-dioxo

  1,2,5,6-tetrahydro-as-triazin-3-ylthio, a 4-carboxy-

  methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio, a 1 or 2-sulfomethyl-5,6-dioxo-1,2,5,6-tetrahydro-as

  triazin-3-ylthio or a 4-sulfomethyl-5,6-dioxo-1,4,5,6-

  tetrahydro-as-triazine-3-ylthio. A heterocyclylthio group R 2, where the 2 'heterocyclic radical represents an aromatic or partially saturated, bicyclic radical containing 5 or 6 atoms per nucleus, is for example an indolylthio, a lower alkyl substituted indolylthio, e.g.

  methyl, eg indol-2-ylthio or N-methylindol-

  2-ylthio, an isoindolylthio, eg isoindol-2-ylthio, quinolylthio, eg 2-, 4 or 8-quinolylthio, benzimidazolylthio, benzimidazolylthio substituted by lower alkyl, eg methyl or lower carboxyalkyl , eg carboxymethyl, e.g.

  eg a 1-methyl-, 1-carboxymethyl or 1- (2-carboxyethyl) -

  benzimidazol-2-ylthio, benzotriazolylthio, benzotriazolylthio substituted by lower alkyl, eg methyl, or lower carboxyalkyl, e.g.

  carboxymethyl, eg 1-methyl or 1-carboxymethyl

  methyl-1H-benzoldl-triazol-5-ylthio, or in particular tetrazolopyridazinylthio, lower alkyl substituted tetrazolopyridazinylthio, eg methyl or ethyl, carboxy, lower carboxyalkyl, e.g.

  carboxymethyl, carbamoyl, lower alkyl,

  carbamoyl, eg methylcarbamoyl, di-lower alkylcarbamoyl, eg dimethylcarbamoyl, amino, lower alkylamino, eg methylamino, lower dialkylamino, eg dimethylamino or diethylamino, ex. 8-methyl-, 8-ethyl-, 8-carboxy-, 8-carboxymethyl-, 8- (2-carboxyethyl),

  8-carbamoyl-, 8- (N-methylcarbamoyl) -, 8- (N, N-dimethyl)

  carbamoyl) -, 8-amino-, 8-dimethylamino or 8-diethylamino-

  tétrazololl, 5-blpyridazin-6-ylthio. An ammonio group R 2 is derived from a tertiary organic base, for example an aliphatic amine or preferably a heterocyclic nitrogen base, and is bonded via the nitrogen atom to the methylene group. finding in position 3 of the skeleton

  cephem The positive charge on the nitrogen atom quater-

  is compensated for example by the carboxylate group

  negative charge in position 4 of the skeleton

cephem.

  An ammonio group R 2, which is derived from an amine

  aliphatic, is for example a lower trialkyl-

  ammonio, eg trimethyl or triethylammonio.

  An ammonio quaternary group R 2 derived from an unsubstituted or substituted heterocyclic nitrogen base is, for example, an unsubstituted or lower alkyl substituted pyrazole, eg methyl or ethyl, lower alkenyl, eg vinyl, or

  an allyl, a lower carboxyalkyl, eg a carboxy

  methyl, a lower alkoxy-lower carbonylalkyl,

  eg methoxycarbonylmethyl, a lower sulfoalkyl

  , eg sulphomethyl, lower aminoalkyl,

  eg 2-aminoethyl, or di-lower alkyl-

  lower aminoalkyl, eg 2-dimethylaminoethyl,

  in position 2, eg 2-methyl or 2-ethyl-1-pyra-

  zolio, a 2-allyl or a 2-vinyl-1-pyrazole, a 2-carboxyl

  methyl-i-pyrazolio, a 2-methoxycarbonylmethyl-1-pyrazol

  LiO, a 2-sulfomethyl-1-pyrazole, a 2- (2-aminoethyl) -

  1-pyrazolio or 2- (2-dimethylaminoethyl) -1-pyrazole.

  A grouse amrionio R_ C Ui derives from a base

  heterocyclic nitrogen is also for example a

  triazolio or a -trizolio substituted by an alkyl

  lower, eg, methyl or ethyl, carboxy-

  lower alkyl, eg carboxymethyl or di-

  lower alkyl-amino-lower alkyl, eg

  2-dimethylaminoethyl, in position 3, eg a 3-

  methyl-1-triazolate, a 3-carboxymethyl-1-triazolate or

  3- (2-dimethylaminoethyl) -1-triazolate.

  An ammonio group R 2, which is derived from an unsubstituted or substituted heterocyclic nitrogen base, is also for example pyridinio or pyridinio mono- or disubstituted by lower alkyl, e.g.

  a methyl, a carbamoyl, a lower alkyl-carbamoyl

  a methylcarbamoyl, a hydroxyalkyl

  lower, eg hydroxymethyl, lower alkoxy-

  lower alkyl, eg methoxymethyl, cyano-

  lower alkyl, eg cyanomethyl, carboxy-

  lower alkyl, eg carboxymethyl, sulfo

  lower alkyl, eg 2-sulfoethyl, a carboxy

  lower alkenyl, eg 2-carboxyvinyl, a

  carboxy-lower alkylthio, eg carboxymethyl-

  thio, thiocarbamoyl, halogen, eg bromine or chlorine, carboxy, sulfo or cyano, eg

  lower alkylpyridinio, eg a 2-, 3- or 4-methyl-

  pyridinio or a 2-, 3 or 4-ethylpyridinio, a carbamoyl-

  pyridinio, eg 3 or 4-carbamoylpyridinio, lower alkylcarbamoyl-pyridinio, eg 3 or

  4-methyl-carbamoylpyridinio, a lower dialkoyl

  carbamoylpyridinio, eg a 3 or 4-dimethylcarbarnoyl

  pyridinio, a lower hydroxyalkyl-pyridinio, e.g.

  a 3 or 4-hydroxymethylpyridinio, a lower alkoxy-

  lower alkylpyridinio, eg 4-methoxymethylpyridinio, lower cyanoalkyl-pyridinio, eg

  3-cyanomethylpyridinio, a lower carboxyalkyl-

  pyridinio, eg 3-carboxymethyl-pyriedinio, sulfo-lower alkylpyridinio, eg 4-2

  sulfoethylpyridinio), a lower carboxyalkenyl

  pyridinio, eg, a 3- (2-carboxyvinyl) -pyridinio, a lower carboxyalkyl-thio-pyridinio, eg 4-carboxymethylthiopyridinio, thiocarbamoylpyridinio, eg 4-thiocarbamoylpyridinio, halogenpyridinio,

  eg 3-bromo or 4-bromopyridinio, a carboxyl

  pyridinio, eg 4-carboxypyridinio, sulfopyridinio, eg 3sulfopyridinio, cyanopyridinio, eg

  3-cyanopyridinio, a carboxy-lower alkyl carbamoyl

  pyridinio, eg 3-carboxymethyl-4-carbamoylpyridi

  nio, an amino-carbamoylpyridinio, eg a 2-affino-5-

  carbamoylpyridinio, a carboxycarbamoylpyridinio,

  For example, a 3-carboxy-4-carbamoylpyridinio, a cyano-

  halogenmethylpyridinio, eg 3-cyano 4-trifluoro-

  methylpyridinio or an amino carboxypyridinio, eg a

2-amino-3-carboxypyridinio.

  An ammonio quaternary group R 2 is preferably a 2-lower alkyl-1-pyrazolio, e.g.

  a 2-methyl-1-pyrazole, a 2-carboxy-lower alkyl-

  1-pyrazolio, eg 2-carboxymethyl-1-pyrazole, a

  3-lower alkyl-1-triazolio, eg 3-methyl-1-

  triazolio, pyridinio or pyridinio substituted with a lower hydroxyalkyl, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl, halogen, eg chlorine or bromine,

  or a carbamoyl, eg a 3 or 4-hydroxymethyl

  pyridinio, a 4-carboxypyridinio, a 3 or a 4-carboxy-

  methylpyridinio, a 3 or 4-chloropyridinio,

  a 3 or 4-bromopyridinio or a 3 or 4-carbamoyl-

  pyridinio. R 3 with the meaning "protected carboxy" is a carboxyl esterified by one of the protecting groups

  described below, in particular a separate carboxyl

  -ble in physiological conditions.

  A substituted or unsubstituted hydrocarbon radical R has up to 20 carbon atoms and is in the first place a saturated or unsaturated hydrocarbon radical,

  aliphatic, cycloaliphatic or cycloaliphatic-aliphatic

  tick, eg lower alkyl, lower alkenyl,

  a cycloalkyl, a cycloalkenyl, a cycloalkyl

  lower alkyl, or cycloalkenyl-lower alkyl,

  or is an aromatic or aromatic hydrocarbon radical

  aliphatic, eg phenyl or lower phenylalkyl.

  Substituents of the lower alkyl radical

  R 4 are, for example, etherified hydroxy, eg lower alkoxy, eg methoxy or ethoxy,

  a lower alkanoyloxy, eg acetyloxy, a halogen

* e.g. fluorine or chlorine, an etherified mercapto, eg lower alkylthio, eg methylthio, lower alkylsulfonyl, eg methylsulfonyl or ethylsulfonyl, arylsulfonyl, eg phenylsulfonyl, lower alkoxycarbonyl, e.g. a methoxycarbonyl or an ethoxycarbonyl, a lower alkylcarbamoyl, eg a methylcarbamoyl, a

  lower dialkylcarbamoyl, eg dimethyl

  carbamoyl, carbamoyl, lower alkyl-

  sulfamoyl, eg methylsulfamoyl, di-lower alkylsulfamoyl, eg dimethylsulfamoyl, sulfamoyl, cyano, nitro, amino, alkanoyl

  lower-amino, eg acetylamino, lower alkyl

  amino-acid, eg methyl or ethylamino, and a

  di-lower alkylamino, eg dimethylamino.

  Lower-substituted alkyl R 4 is, for example, lower alkoxy-lower alkyl, e.g.

  lower alkoxy or lower alkoxy-

  ethyl, eg methoxymethyl or 2-methoxyethyl, lower alkanoyloxy-lower alkyl, e.g. lower alkanoyloxy-methyl or lower alkanoyloxy-ethyl, eg acetyloxymethyl or 2-acetyloxyethyl, halogen-lower alkyl, e.g. halogenethyl or halogenethyl, eg trifluoromethyl, chloromethyl, 2chloroethyl or 2,2,2-trichloroethyl, lower alkylthio;

  lower alkyl, eg lower alkyl-thio-

  methyl, eg methylthiomethyl, lower alkyl,

  sulfonyl-lower alkyl, eg alkyl

  lower-sulfonyl-methyl or lower alkyl-

  sulfonylethyl, eg methylsulphonylmethyl or 2-methylsulphonylethyl, arylsulphonyl-lower alkyl,

  eg arylsulfonylmethyl, eg phenylsulfonyl-

  methyl, lower alkoxycarbonyl-lower alkyl, eg lower alkoxycarbonylmethyl, e.g. methoxycarbonylmethyl or ethoxycarbonylmethyl, lower alkylcarbamoyl-lower alkyl, eg lower alkylcarbamoylmethyl or

  lower alkylcarbamoylethyl, eg methyl

  carbamoylmethyl or 2-methylcarbamoylethyl, a di-

  lower alkyl-carbamoyl-lower alkyl, e.g. a lower dialkyl carbamoylmethyl or a dialkyl

  lower carbamoylethyl, eg dimethylcarbamoyl

  methyl or 2-dimethylcarbamoylethyl, a carbamoyl

  lower alkyl, eg carbamoylmethyl or

  2-carbamoylethyl, a lower alkyl sulfamoyl

  lower alkyl, eg lower alkyl-sulfamoyl

  methyl or lower alkyl sulfamoylethyl, e.g. methylsulfamoylmethyl or 2-methylsulfamoylethyl, lower dialkylsulfamoyl-lower alkyl, e.g. a di-lower alkylsulfamoylmethyl or a di-alkyl

  less than sulfoyl 1? 3 N dimethylsulfamoyl

  metbvyl or 9-dimethylsulfide, a sulfamoyl

  a 3-lower alkyl, eg sulfanoylmethyl or 2-

  sulfamoylethyl, a lower cyanoalkyl, eg a

  cyanomethyl or 2-cyanoeth Yie, a lower nitroalkyl

  for example nitromethyl or 2-nitroethyl, a

  lower aminoalkyl, eg aminomethyl or 2-

  aminoethyl, lower alkanoyl-lower aminoalkyl

  lighter, eg, lower acetylaminoalkyl, e.g. acetylaminomethyl or 2-acetylaminoethyl, lower alkyl-lower aminoalkyl, eg

  lower methylaminoalkyl, eg an ethylamino

  methyl or 2-methylaminorthyl, or a dialkyl

  lower-amino-lower alkyl, eg dimethylamino-

  lower alkyl, eg dimethylaminomethyl or 2-dimethylaminoethyl. Lower alkenyl contains from 2 to 4 carbon atoms and is for example a vinyl, a

  allyl, 1-butenyl, 2-cis-butenyl or iso-

  Butenyl A lower-substituted alkenyl may be substituted by the same groups as substituted lower alkyl. A cycloalkyl R 4 contains from 3 to 7 carbon atoms and is for example a cyclopropyl, a

  cyclobutyl, cyclopentyl or cyclohexyl.

  A cycloalkenyl R 4 contains from 3 to 7 carbon atoms and is, for example, cyclohexenyl, eg 1-cyclohexenyl, or cyclohexadienyl, eg 1,4-cyclohexadienyl.

  A cycloalkyl-lower alkyl R 4

  holds from 4 to 7 carbon atoms and is for example

  cyclopropylmethyl, cyclopentylmethyl, 2-cyclopropylmethyl,

  pentylethyl, cyclohexylmethyl or 2-cyclohexyl-

ethyl.

  A cycloalkenyl-lower alkyl R 4 con-

  holds from 5 to 9 carbon atoms and is for example

  1-cyclohexenylmethyl or 1,4-cyclohexadienyl-

  methyl. The substituents of the phenyl radical R 4 are, for example, a C 1 to C 4 lower alkyl, for example a methyl, an ethyl, a n-propyl, an isopropyl, n-butyl, isobutyl or tert-butyl, a hydroxy, lower alkoxy, eg methoxy or ethoxy, carboxy protected by the usual protecting groups or esterified with lower alkyl, eg methyl or ethyl, amino, carbamoyl, halogen, eg fluorine , a chlorine, a bromine or a

  iodine, a sulfo, a sulfamoyl, a lower alkyl-

  thio, eg methylthio or ethylthio, triethyl

  fluoromethyl or aminosulfynyl A lower-substituted phenylalkyl is also substituted on the

  phenyl radical by these substituents.

  A substituted phenyl R 4 is for example

  2-, 3 or 4-methylphenyl, 2,3, 2,4 or 3,4-

  dimethylphenyl, 2-, 3 or 4-methoxyphenyl, 2-, 3 or 4-chlorophenyl, 2,3-, 2,4-, 2,6 or

  3,4-dichlorophenyl, a 4-nitrophenyl or a 4-amino-

  phenyl. Phenyl-lower alkyl R 4 is, for example, benzyl, 2-phenylethyl, diphenylmethyl or

a trityle.

  A substituted lower phenyl-lower alkyl R 4 is for example a 2-, 3 or 4-methylphenylmethyl,

  2,3-, 2,4- or 3,4-dimethylphenylmethyl, a 4-

  nitro-phenylmethyl or 4-aminophenylmethyl.

  An acyl group R 4 has up to 19 carbon atoms and is derived from a carboxylic acid, a half ester of carbonic acid, carbamic acid, a substituted carbamic acid, thiocarbamic acid, of a substituted thiocarbamic acid, a sulpho

  nique, amidosulphonic acid or a starchy acid

  substituted sulfonic acid, eg the acyl group of a carboxylic acid, eg lower alkanoyl, e.g.

  formyl or acetyl, lower alkanoyl

  by a hydroxy or an amino, eg an a-hydroxy-

  propionyl or a glycyl, lower alkanoyl

  substituted with a carboxy or an amino, eg a 3-amino

  3-carboxypropionyl, a cycloalkanoyl, eg a

  cyclopentanoyl, benzoyl, lower phenylalkanoyl,

  lower alkanoyl is substituted in

  the acyl group of a carbonic acid half-ester, for example a lower alkoxycarbonyl, eg, a hydroxy or an amino, eg a mandeloyl or phenylglycyl, is substituted for the phenyl radical; a methoxycarbonyl or an isopropoxycarbonyl, a lower alkanoyloxy substituted with a carboxy and an amino, eg a 2-amino-2-carboxyethoxycarbonyl, or a benzoyloxycarbonyl, the acyl group of an acid

  substituted carbamic acid, for example lower alkyl-

  carbamoyl, eg methylcarbamoyl, or

  an anilinocarbonyl, the acyl group of a thiocarbonic acid

  substituted beryl, for example lower alkyl-

  thiocarbamoyl, eg methylthiocarbamoyl, or is the acyl group of a substituted amidosulphonic acid, for example lower alkylsulphonylamino, e.g.

  methylsulfonylamino, phenylsulfonylamino, amino

  phenylsulfonylamino, eg 4-aminophenylsulfonyl-

  amino. In a methylene group A, which is substituted by amino, hydroxy or sulfo present in protected form, the aminomethylene, hydroxymethylene or sulfomethylene group in question is protected by the amino, hydroxy or sulfo protecting groups described herein. - below. The group of formula -O-R 5 is in the syn (or Z) or anti (or E) position, and the syn (or Z) position is preferred. In the syn position, -OR 5 is oriented towards the cephalosporin skeleton, and

  Antipositioning in the opposite direction.

  A lower alkyl R 5 preferably has 1 to 4 carbon atoms and is, for example, an ethyl, a propyl, a butyl or in particular a methyl. A cycloalkyl R 5 preferably has from 3 to 8 ring members, in the first place from 3 to 6, and is, for example, cyclobutyl, cyclopentyl, cyclohexyl or especially cyclopropyl. Substituents of a lower alkyl group

  or a cycloalkyl group R 5 are, inter alia, a hydro-

  free or etherified, for example lower alkoxy, primary, secondary or tertiary amino, eg amino or dialkylamino, carboxyl or free or functionally modified sulfo, eg esterified,

  amide or protected, as well as a possible ureidocarbonyl-

  N-Substituted by lower alkyl Preferably

  a lower alkyl and cycloalkyl group R 5

  titué is substituted by a carboxyl or sulfo group, these being preferably on the carbon atom

  which is bound with the oxygen atom of the oximino group.

  Lower alkyl or substituted cycloalkyl

  R 5 is for example 2-aminoethyl, 2-dimethyl-

  aminoethyl, carboxymethyl, 1 or 2-carboxyethyl,

  1-, 2 or 3-carboxy-prop-1-yl, a 1 or 2-carboxy-

  prop-2-yl, a 2-carboxycycloprop-2-yl or a 1 or 2-

  carboxycyclonut-1-yl and a lower alkyl group

  corresponding cycloalkyl substituted with a sulfo. The carboxy and sulpho groups in the radical R 5 may be esterified for example with lower alkyl, eg methyl or ethyl, or with a physiologically separable group, eg with pivaloyloxymethyl, or be amide with NH 3, an amine. 3, primary or secondary, eg a mono- or lower-dialkylamine, eg a minhyl or ethylamine, or a dimethyl or di-tnyiarire, or be protected by

  protective groups listed below.

  The cycloalkenyl group R contains from 3 to 8, preferably from 3 to 6, members, and is for example a cyclopropenyl, a cyclobutenyl, a cycipentenyl

or cyclohexenyl.

  A lower alkenyl R 5 is in particular an allyl, or a vinyl, a 1-propenyl or a

1-, 2 or 3-butenyl.

  A substituted carbamoyl R 5 is for example a group of formula -C (= O) NHR, where R represents an alkyl

  lower, eg methyl, ethyl or 1 or 2

  propyl, a lower carboxyalkyl, eg a carboxyl

  methyl, a 1 or 2-carboxyethyl or a 1, 2 or 3

  carboxypropyl, the carboxy group is in free form or is protected by one of the usual carboxy protecting groups or esterified for example by a

  lower alkyl, eg methyl, ethyl, n-

  or an isopropyl, or an n or tert-butyl, a sulpho

  lower alkyl, eg sulfomethyl, a 1 or 2

  sulfoethyl, or 1-, 2- or 3-sulfopropyl, where the sulfo group is in free form or is protected by one of the usual sulfo protecting groups or is esterified with lower alkyl such as methyl or ethyl, a lower hydroxyalkyl, eg a

  hydroxymethyl, a 2-hydroxyethyl or a 2 or 3-hydroxy-

  propyl, the hydroxy group is in free form or is protected by one of the usual hydroxyl protecting groups or, for example, acylated, eg acetylated, a lower aminoalkyl, for example a 2-aminoethyl, a 2 or a aminopropyl or 2-, 3- or 4-aminobutyl, where the amino group is in free form or is protected by one of the usual amino protecting groups or, for example, acylated, eg acetylated, lower arylalkyl, for example phenylalkyl lower, eg

  benzyl or 1 or 2-phenylethyl, a halogenated

  lower alkyl, for example fluoro, chloro or lower bromoalkyl; eg 2-chloropropyl or 4-chlorobutyl, aryl, p-phenyl, or mono-to-trisubstituted lower alkyl, eg methyl, lower alkoxy, eg

  methoxy, a halogen, eg chlorine or nitro.

  The functional groups present in the compounds of formula IA and IB, in particular the carboxyl and amino groups, or the hydroxy groups or

  sulpho, are eventually protected by

  the usual protecting groups that are used in penicillin chemistry,

cephalosporins and peptides.

  These protective groups separate easily

  that is, without the appearance of secondary reactions

  res, for example by solvolysis, by reduction

  by photolysis or under physiological conditions.

  logical. Protecting groups of this type and their separation are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, and in "The Peptides", Vol. I, Schrader and Lubke, Academic Press. , London, New York,

  as well as in "Methoden der organischen Chemie" Houben-

  Weyl, 4th ed., Vol. 15/1, Gerg Thieme Verlag, Stuttgart, 1974. A carboxyl group, eg the carboxyl group R 3, or a carboxyl group present in R 1, A or R 4 is usually protected in the form of esterified group, the ester group being easily separable in

  mild conditions A carboxyl group protected under

  Esterified is first esterified with a lower alkyl group, which is branched at the 1-position of the lower alkyl group or substituted at the 1-or 2-position

  lower alkyl group by an appropriate substituent

prayed.

  A protected carboxyl group which is esterified

  by a lower alkyl group which is branched in the 1-position of the lower alkyl group is, for example

  a tert-lower alkoxycarbonyl, eg a tert-

  butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, aryl represents unsubstituted or mono or poly-substituted phenyl by lower alkyl, eg tert-lower alkyl, eg tertbutyl, lower alkoxy P; methoxy, hydroxy, halogen, eg chlorine, and / or nitro, for example benzyloxycarbonyl not

  substituted or substituted p ex as described above

  sus, eg 4-nitrobenzyloxycarbonyl or 4-methoxy-

  benzyloxycarbonyl, or unsubstituted or substituted p-substituted diphenylmethoxycarbonyl as described above,

  eg diphenylmethoxycarbonyl or di- (4-methoxy)

  phenyl) -méthoxycarbonyle. A protected carboxyl group which is esterified with a lower alkyl group which is substituted in the 1 or 2 position of the lower alkyl groups by

  suitable substituents is, for example, 1-alkoxy

  lower alkoxycarbonyl, eg methoxy

  methoxycarbonyl, 1-methoxyethoxycarbonyl or a

  ethoxymethoxycarbonyl, a 1-lower alkyl-thio-

  lower alkoxycarbonyl, eg 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl D an aroylmethoxycarbonyl, where the aroyl represents benzoyl unsubstituted or substituted by halogen, such as bromine, eg phenacyloxycarbonyl, and a 2-halogeno-lower alkoxycarbonyl, for ex. 2,2,2-trichloroethoxycarbonyl, 2-bromethoxycarbonyl

or 2-iodethoxycarbonyl.

  A carboxyl group can also be

  in the form of an organic silyloxycarbonyl group

  A silyloxycarbonyl group is, for example, a lower alkylsilyloxycarbonyl group, eg a trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be substituted only by two lower alkyl groups, for example methyl groups, and the carboxyl group or the amino group of a second molecule of formula I Compounds having such protective groups may be prepared eg.

  using dimethyldichlorosilane as the silylating agent

  lant. A preferred protected carboxyl group is, for example, tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, an unsubstituted or substituted benzyloxycarbonyl as described above,

  eg 4-nitro-benzyloxycarbonyl, or diphenyl-

methoxycarbonyl.

  An esterified carboxyl group R 3 separable under physiological conditions is in the first place acyloxymethoxycarbonyl, acyl, e.g.

  the acyl group of an organic carboxylic acid,

  firstly presents a lower alkane

  optionally substituted carboxylic acid, or

  acyloxymethyl forms the radical of a lactone.

  Such a group is, for example, a lower alkanoyloxy-methoxycarbonyl group. acetyloxymethyloxycarbonyl ether; acetyloxymethylcarbonyl; acetyloxymethylcarbonyl, a carboxylic acid, a carboxylic acid;

  p ae 1 yy> c L Loyc f yarbonyle, an amino-

  aic-noylo Zy ii: ieu tl c b le, especially

  an aminocarboxylamine, e.g.

  u Cn yi Als y'-mt hoxyca -? -5-oa: yloxymethoxy-

  as onyl or -alkyl Lt, carbonyl, or

  a phthalidyloxycarbonyl, eg a 2-phthalidyloxycarbonyl

  bonyl, or an inanyloxycarbonyl, eg 5-indanylo-

xycarbonyle.

  An amino group, eg the amino group on the imidazo-3-yl radical can be protected, eg under the

  form of an acyl ino arylmethylamino, mercapto

  amino etherified, 2-acylalc-1-enyl lower-amino or

silylamino easily separable.

  In an easily separated acylamino group

  ble, an acyl is for example the acyl group of an acid

  organic carboxylic acid having up to 18 carbon atoms

  including an alkanecarboxylic acid, in particular

  unsubstituted or substituted, eg by a halogen or

  aryl, or unsubstituted or substituted benzoic acid

  The acyl group is, for example, lower alkanoyl, eg, halogen, lower alkoxy or nitro, or a half ester of carbonic acid.

  formyl, acetyl or propionyl, halogen-

  lower alkanoyl, eg 2-haloacetyl, in particular

  particular a 2-chloro, 2-bromo-, 2-iodo-, 2,2,2-trifluoro-

  or 2,2,2-trichloroacetyl, a benzoyl unsubstituted or substituted for example by halogen, lower alkoxy or nitro, eg benzoyl, 4chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxy -carbonyl branched in position 1 of

  lower alkyl radical or substan-

requested in position 1 or 2.

  A lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical is, for example

  a tert-lower alkoxycarbonyl, eg a tert-

  butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, aryl represents unsubstituted phenyl or mono or polysubstituted by lower alkyl, especially tertiary lower alkyl, eg tert-butyl, lower alkoxy, eg methoxy, hydroxy, halogen, eg

  chlorine, and / or a nitro, for example a diphenylraethoxy-

  unsubstituted or substituted carbonyl, eg benzhydryl

  oxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl.

  A lower alkoxycarbonyl suitably substituted in the 1 or 2 position is, for example, a

  lower trialkyl-silyloxycarbonyl, eg tri

  methylsilyloxycarbonyl, an aroylmethoxycarbonyl, o aroyl represents a benzoyl unsubstituted or substituted by a halogen, such as a bromine, eg a

  phenacyloxycarbonyl, a 2-halogeno lower alkoxy-

  carbonyl, eg 2,2,2-trichloroethoxycarbonyl, 2-bromethoxycarbonyl or 2-iodethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, where the substituents are each independently

  on the other an aliphatic hydrocarbon radical, arali-

  unsubstituted or substituted phatic, cycloaliphatic or aromatic, eg by lower alkyl, lower alkoxy, aryl, halogen or nitro, and having up to 15 carbon atoms, eg unsubstituted or substituted lower alkyl it is said above, a lower phenyl-lower alkyl, a cycloalkyl or a phenyl, for example a 2-lower-alkyl-silylethoxycarbonyl, eg a 2-trimethylsilylethoxycarbonyl or a 2- (n-butyldimethylsilyl) ethoxycarbonyl, or a

  2-triarylsilylethoxycarbonyl, eg 2-triphenyl-

  silylethoxycarbonyl. Other acyl groups contemplated as amino protecting groups are also the groups

  Acyls of phosphoric, phosphonic or phosphoric acids

  organic compounds, such as lower dialkyl-

  phosphorylate, eg dimethylphosphoryl, diethyl ether,

  phosphoryl, di-n-propylphosphoryl or diisopropyl-

  phosphoryl, a dicycloalkylphosphoryl, eg a

  dicyclohexylphosphoryl, a diphenylphosphoryl, a di-

  unsubstituted or substituted phenyl-lower alkylphosphoryl p eg nitro, eg dibenzylphosphoryl

  or a di-4-nitro-benzylphosphoryl, a phenyloxyphenyl-

  phosphonyl, a lower dialkylphosphinyl, e.g.

  diethylphosphinyl, or diphenylphosphinyl.

  In an arylmethylamino group, which represents

  is a mono-, a di or especially a triaryl-

  methylamino, aryl radicals are in particular phenyl radicals. These groups are for example a

  benzyl-, a diphenylmethyl and in particular a trityl-

  amino. In an etherified mercaptoamino group, the

  mercapto etherified group is primarily an aryl-

  thio or lower aryl-thio, aryl is in particular phenyl unsubstituted or substituted pex by lower alkyl, eg methyl or tert-butyl, lower alkoxy, eg methoxy, halogen, ex. chlorine, and / or nitro Such

  amino protecting group is eg a 4-nitrophenylthio.

  In a lower 2-acylalc-1-en-yl group usable as an amino protecting group, acyl is

  eg the acyl group of a lower alkane acid

  carboxylic acid, benzoic acid unsubstituted or substituted by lower alkyl, eg methyl or tert-butyl, lower alkoxy, e.g. a methoxy, a halogen, eg a chlorine, and / or a nitro, or in particular the acyl group of a hermiester

  carbonic acid, eg lower alkyl,

  carbonic acid hemiester These protecting groups

  are primarily 1-lower alkanoyl-

  prop-1-en-2-yl, eg 1-acetyl-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl, eg 1-ethoxycarbonylprop-1-en -2-yl. A silylamino group is, for example, a lower alkylsilylamino trialkyl group, eg a trimethylsilylamino. The silicon atom of the silylamino group may also be substituted by only two lower alkyl groups, eg two methyl groups, and the amino group or the carboxyl group. a second molecule of formula IA or I Bo can be prepared compounds having such protective groups p ex. using dimethyldichlorosilane as the silylating agent. An amino group may also be protected in protonated form As anions, it is firstly necessary to mention the anions of strong inorganic acids, such as hydrohalic acids, for example the anion of chlorine or bromine, or of organic sulphonic acids,

as p-toluenesulfonic acid.

  A preferred amino protecting group is, for example, the acyl radical of a half-ester of carbonic acid, in particular tert-butyloxycarbonyl, an unsubstituted or substituted benzyloxycarbonyl, e.g.

  as stated above, eg a 4-nitrobenzyloxy-

  carbonyl or diphenylmethoxycarbonyl, a 2-halogen

  lower alkoxycarbonyl, eg 2,2,2-trichloroethane

  tnoxycarbonyl, or trityl or formyl.

  A hydroxy group, eg the hydroxy group in the hydroxyimino group = NO-R 5 (R 5 = hydrogen), D may be protected by, for example, an acyl group, e.g. lower alkanoyl substituted with halogen, e.g. a 2, 2-dichloroacetyl, or in particular an acyl radical of a half ester of carbonic acid mentioned in connection with the protected amino groups A group

  Cr-ydroxy protector is, for example, a 2,2,2-

  trichloroethoxycarbonyl, an organic silyl radical having the abovementioned substituents, or a readily separable ether-forming group such as tert-lower alkyl, eg tertbutyl, a 2-oxa or a 2-thia-aliphatic hydrocarbon radical, or

  -cycloaliphatic, for example 1-lower alkoxy-

  lower alkyl or an II-lower alkyl-thio-

  lower alkyl, for example methethoxymethyl, l-methoxy

  ethyl, a 1-ethoxyethyl, a 1-methylthiomethyl, a

  1-methylthioethyl, a 1-ethylthioethyl, or a 2-oxa

  or 5- to 7-membered 2-thiacycloalkyl, eg a 2-

  tetrahydrofuryl or a 2-tetrahydropyranyl or a corresponding thia analog, as well as unsubstituted or substituted 1-phenyl-lower alkyl, eg benzoyl or unsubstituted or substituted benzoylmethyl, the phenyl radicals being substituted, for example, with halogen, such as chlorine, lower alkoxy, eg methoxy,

and / or a nitro.

  A sulfo group, eg a sulfo group present in R 2, is preferably esterified with a

  aliphatic, cycloaliphatic, cycloaliphatic alcohol

aliphatic, aromatic or araliphatic, eg by a lower alkanol, eg tert-butanol, or by

  a silyl group, eg by a tri-lower alkyl-

  silyl A sulfo group is protected p ex so

analogous to a carboxy group.

  The salts of the compounds of the invention

  in the first place are non-toxic pharmaceutic

  acceptable for compounds of formula IA and IB.

  These salts are, for example, formed by the acidic groups present in the compounds of formula IA and IB, eg by the carboxyl or sulfo groups, and are in the first place metal or ammonium salts, eg alkali metal salts and alkaline earth metals, eg salts of sodium, potassium,

  magnesium or calcium, as well as ammonium salts

  which are formed with ammonia or appropriate organic amines, among which should be mentioned in the first place mono, di or polyamines

  aliphatic, cycloaliphatic, cycloaliphatic-

  aliphatic or araliphatic, primary, secondary or tertiary, as well as heterocyclic bases for salification These bases are for example alkyls

  lower-amines, eg triethylamine, hydroxyl

  lower alkyl-amines, eg 2-hydroxyethylamine,

  bis- (2-hydroxyethyl) -amine, or tris- (2-hydroxy-

  ethyl) amine, basic aliphatic esters of carboxylic acids, eg 4-aminobenzoic acid 2-diethyldiaminoethyl ester, lower alkylene amines, eg 1-ethylpiperidine, cycloalkylamines, e.g. eg dicyclohexylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine, or bases of the pyridine type, eg pyridine, collidine

or quinoline.

  The basic groups present in the compounds of formula IA and IB, eg, amino groups, can form acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with

  organic carboxylic or sulphonic acids

  p 4> s P eg trifluoroacetic acid, as well as with

  amino acids, such as arginine C lysine.

  If there are several acidic groups in the compounds of formula IA or IB, e.g. two carboxyl groups, or several basic groups,

  For example, two amino groups may form mono-

  or polysels When the compounds of formula IA and IB have at least one acid group, eg the carboxyl group R 3, and at least one basic group

  in free form, eg the free amino group in posi-

  2 of the oxazolyl radical, the compounds of formula IA

  or IB may be in the form of an internal salt.

  In the compounds of formula I A or IB, an acidic group and a basic group may be in the form of an internal salt, and the additional acidic and / or basic groups may be present for example under

  form of acid addition salts and / or

basic edition.

  For purposes of isolation or purification, it is also possible to use pharmacologically unacceptable salts. For the therapeutic application, only the non-toxic pharmaceutically acceptable salts are used.

  acceptable, which are therefore preferred.

  The compounds of formula IA and IB, the functional groups are in free form and

  carboxyl groups, possibly in esterified form

  physiologically separable protein and their non-toxic pharmaceutically acceptable salts are useful antibiotic-active bodies which can be

  particularly as antibacterial antibiotics.

  For example, they are active in vitro against microorganisms.

  gram-positive and gram-negative organisms, including O-lactamase-producing strains, for example against gram-positive shells, eg against Staphylococcus aureus or streptococci, eg Streptococcus pyogenes, Streptococcus pneumoniae or Streptococcus faecalis, against gram-negative shells, eg Neisseria gonorrhoeae, against gram-negative bacteria, eg. Pseudomonas aeruginosa, Haemophilus influenza or enterobacteria, eg Escherichia parcel Proteus spp., Klebsiella pneumoniae, Serratia marcescens or Enterobacter cloacae In vivo, when applied subcutaneously in mice, they are active against general infections that are caused gram-positive organisms such as Staphylococcus aureus and gran-negative organisms such as enterobacteria,

eg Escherichia coli.

  The compounds of formula IA and IB where the functional groups are protected are used as intermediates to prepare compounds of formula

  formula IA and IB where the functional groups are presented

  in free form or where the 4-carboxyl group is in the form of a separable carboxyl group in

physiological conditions.

  The invention relates in particular to

  compounds of formula IA and IB o R 1 represents a hydro-

  gene, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen, e.g. a chlorine, or a group -CH 2 -R 2, where R 2 represents a lower alkanoyloxy, eg an acetoxy, a carbamoyloxy, an N-lower alkylcarbamoyloxy, a diaza- radical,

  triaza-, tetraaza-, thiaza-, thiadiaza-, thia-, oxaza-

  or aromatic oxadiazacyclyl, monocyclic, 5 or 6

  chain members, eg triazolylthio, eg H-1,2,3-

  triazol-5-ylthio, a tetrazolylthio, eg, an IH-1

  tetrazol-5-yltilio, a thiazolylthio, a thiadiazolyl-

  thio, eg, 1,31,4-thiadiazol-5-ylthio, an oxazolyl-

  thio, an ozadiazolylthio or a 5,6-dioxotetrahydro-as-

  S 5 ainiho eg 5,6-dioxo-1,2,5,6-tetrahydro-as-

  triain-3-vinyl or a 5,6-dlio -o 1,4,5,6-tetrahydro-as -

  triary y 1 t 1 where the alkyl is substituted by an alkyl

  in 1 iron; a lower alkyl lower alkyl

  For example, a dimethylaminomethyl or a dimethylaminoethyl, a lower alkyl, eg a lower alkanoyl, may be used.

  carboxy-1-eeyl, unicyclo-carboxyalkyl,

  amino-acid, eg 2-carboethylamine, or by a

  cai-bamoyl, or an aoemon-io, eg a 2-lower alkyl-

  1-pyrazoijo, eg 2-methyl-1-pyrazole, a 2-

  lower carboxyalkyl-1-pyrazole, eg a 2-

  carboxymethyl-1-py-razolio, a 3-lower alkyl-1 -

  triazole, e.g. 3-triethyltriazolyl, pyridinio, pyridinol substituted for lower hydroxyalkyl, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl, halogen, e.g.

  chlorine or bromine, or carbamoyl, eg 3-

  or 4-hydroxymethylpyridinio, a 4-carboxypyridinio,

  a 3 or 4-carboxymethylpyridinio, a 3 or 4-chloro

  pyridinio, a 3 or 4-bromopyridinio or a 3 or 4

  carbamoylpyridinio, R 3 represents a carboxyl, a car-

  boxyl separable under physiological conditions, p. eg an acyloxymethoxycarbonyl, eg alkanoyloxy

  lower-methoxycarbonyl, p -ex a pivaloyloxyrnethoxy-

  carbonyl-, or a lower alkoxy-lower carbonyloxyalkoxy

  carbonyl, eg 1-ethoxycarbonyloxyethoxycar-

  R 4 is a lower alkyl, eg methyl, lower alkyl substituted by hydroxy, lower alkoxy, eg methoxy, carboxy, lower alkoxycarbonyl, eg methoxycarbonyl

  or an ethoxycarbonyl, an amino, a lower alkyl-

  amino, eg methylamino, carbamoyl, halogen, eg fluorine or chlorine, sulfo, lower alkylthio, eg methylthio, or amino sulfinyl, lower alkenyl, eg allyl ,

  cycloalkyl, eg pentyl or hexyl, cycloalkenyl, eg 1-cyclohexenyl or 1,4-cyclohexane;

  dienyl, phenyl, phenyl substituted by halogen,

  eg chlorine, eg 2,3-, 2,4- or 2,6-dichlorobenzene

  phenyl, phenyl-lower alkyl, eg benzyl or diphenylmethyl, or acyl, eg alkanoyl

  lower, eg acetyl, lower alkoxy-

  carbonyl, eg methoxycarbonyl, or ethoxylated

  carbonyl, carbamoyl, lower alkyl-

  carbamoyl, eg methylcarbamoyl, a lower alkyl

  lower sulfonyl, eg methylsulfonyl or a

  ethylsulfonyl, benzenesulphonyl or benzenesulphonyl

  nyl substituted by lower alkyl, eg methyl, or halogen, eg chlorine, eg p-toluenesulfonyl or 4-methylbenzenesulfonyl and in the compounds of formula IA represents hydrogen, and A represents aminomethylene, a hydroxymethylene, a sulfomethylene or a methylene group substituted by a group = NOR 5, where R 5 represents a hydrogen, a lower alkyl, eg a methyl, a lower carboxyalkyl, eg a 2-carboxy-2-propyl, a cycloalkenyl, eg cyclopentenyl, lower alkenyl, e.g. an allyl, a carbamoyl, a lower alkylcarbamoyl, eg a methylcarbamoyl or a lower aminoalkyl, eg a 2-aminoethyl, the -O-R 5 group has the syn (or Z) position, and the salts, particular pharmaceutically acceptable salts,

  Formula IA and IB which have salt groups.

  The present invention relates especially to

  compounds of formula IA and IB, where R 1 represents a hydrogen

  gene, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen, eg chlorine, or -CH 2 -R 2, where R 2 is lower alkanoyloxy, eg acetoxy carbamoyloxy, triazolylthio, eg JH-1,2,3-triazol-5-ylthio, tetrazolylthio, eg 1H-tetrazol-5-ylthio, tetrazolylthio substituted by lower alkyl, e.g. a methyl, a lower dialkoyl-amino-lower alkyl,

  eg 2-dimethylaminoethyl, a lower sulfoalkyl

  , eg sulphomethyl, lower carboxyalkyl,

  , eg carboxymethyl, or carbamoyl,

  eg 1-methyl-1H-tetrazol-5-ylthio, a 1-sulfo

  methyl-1H-tetrazol-5-ylthio, a 1-carboxymethyl-1H-

  tetrazol-5-ylthio or 1- (2-dimethylaminoethyl) -1 H-

  tetrazol-5-ylthio, thiadiazolylthio, eg 1,3,4-thiadiazol-5-ylthio, thiadiazolylthio substituted by lower alkyl, eg methyl, eg

  2-methyl-1,3,4-thiadiazol-5-ylthio, a 5,6-dioxotetra-

  hydro-as-triazin-3-ylthio substituted by lower alkyl

  , eg methyl, eg 2-methyl-5,6-dioxo

  1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-

  , 6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio, a

  pyridinio or a pyridinio substituted with a hydroxyl

  lower alkyl, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl,

  a halogen, eg chlorine or bromine, or a carbamide

  mole, eg 3 or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3 or 4-carboxymethylpyridinio, 3 or 4-chloropyridinio, 3 or 4bromopyridinio or 3 or 4-carbamoylpyridinio, R 3 represents a carboxyl, a lower alkanoyloxy-methoxycarbonyl, p.

  pivaloyloxymethoxycarbonyl, or lower alkoxy-

  carbonyloxy-lower alkoxycarbonyl, eg 1-ethoxycarbonyloxyethoxycarbonyl, R 4 represents lower alkyl, eg methyl, carboxyalkyl

  lower, eg carboxymethyl or 2-carboxy-

  ethyl, lower dialkoyl-lower aminoalkyl,

  eg 2-dimethylaminoethyl, lower alkoxy-

  carbonyl, eg methoxy or ethoxycarbonyl, carbamoyl, lower alkenyl, eg allyl, phenyl, halogen substituted phenyl, e.g. chlorine, eg 2,3-, 2,4- or 2,6-dichlorophenyl, phenyl-lower alkyl, eg benzyl, or lower alkylsulfonyl, eg methylsulfonyl, and in compounds of formula IA represents

  hydrogen, and A represents a methylene substitute group

  killed by the group = N-O-R 5, where R 5 represents a hydro-

  gene, lower alkyl, eg methyl, lower carboxyalkyl, eg 2-carboxy-2-propyl, lower alkenyl, eg allyl, carbamoyl

  or lower alkylcarbamoyl, eg methyl

  carbamoyl, the group -O-R 5 has the position syn (or Z) and o -Aest connected to the 4-position of the imidazolyl radical, and the salts, in particular the pharmaceutically acceptable salts, of the compounds of

  formulas IA and IB which have salt groups

tors.

  The present invention relates primarily to the compounds of formula IA and IB where R 1 represents hydrogen, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen,

  p eg a chlorine, or a group -CH 2 -R 2, where R 2 represents

  a lower alkanoyloxy, eg acetoxy, a

  carbamoyloxy, a tetrazolylthio, eg 1H-tetrazol-

  -ylthio, an alkyl substituted tetrazolylthio

  lower, eg methyl, lower dialkoyl

  lower aminoalkyl, eg 2-dimethylaminoethyl, lower sulfoalkyl, eg sulfomethyl, or lower carboxyalkyl, eg carboxymethyl,

  substituted tetrazolylthio, eg 1-methyl-1H-

  tetrazol-5-ylthio, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio,

  1-sulfomethyl-1H-tetrazol-5-ylthio, or 1-carboxy-

  1-Methyl-1H-tetrazol-5-ylthio, a thiadiazolylthio, e.g. 1,3,4thiadiazol-5-ylthio, or thiadiazolylthio substituted by lower alkyl, eg methyl,

  For example, a 2-methyl-13,4-thiadiazol-5-ylthio, a 5,6-

  dioxo-tetrahydro-as-trizinylthio substituted with

  lower alkyl, eg methyl, eg 2-methyl-

  6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio, or 4-methyl-5,6-dioxol, 4,5,6-tetrahydro-as-triazin-3-ylthio ,

  pyridinio or pyridinio substituted with hydroxy

  lower alkyl, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl,

  a halogen, eg chlorine or bromine, or a car-

  Bamyl, eg a 3 or 4-hydroxymethylpyridinio, a 4-carboxypyridinio, a 3 or 4-carboxymethylpyridinio, a 3 or 4-chloropyridinio, a 3 or 4bromopyridinio or a 3 or 4-carbamoylpyridinio, R 3 represents a carboxy, an alkanoyloxy lower-methoxycarbonyl, p.

  ex pivaloyloxymethoxycarbonyl or lower alkoxy

  lower carbonyloxyalkoxycarbonyl, eg 1-ethoxycarbonyloxyethoxycarbonyl, R 4 represents lower alkyl, eg methyl, carboxyalkyl

  lower, eg carboxymethyl or 2-carboxy-

  ethyl, lower dialkylamino-lower alkyl, eg 2-dimethylaminoethyl, phenyl, phenyl substituted by halogen, eg chlorine, eg 2,3, 2,4 or 2,6-dichlorophenyl, or lower phenylalkyl , eg benzyl, and in the compounds of formula IA represents hydrogen, and A represents a methylene group substituted by the group = NOR 5, where R 5 represents a lower alkyl, for example a methyl,

  a lower carboxyalkyl, eg 2-carboxy-2-

  propyl, carbamoyl or lower alkyl-carbamoyl, eg methylcarbamoyl, where the group -OR 5 has the syn (or Z) position and A is attached to the 4-position of the imidazolyl radical, and the salts, in particular the salts, pharmaceutically acceptable compounds

  of formula IA and IB, which have salt groups

  ers. The invention relates especially to the compounds of formula IA and IB described in the examples and their salts, in particular the pharmaceutically acceptable salts

acceptable.

  The compounds of formula IA and IB and the salts of such compounds which have a salt group are prepared for example a) in a compound of formula

H 2 N / S

I (1 I)

  R 1, R 3, R 1 and R 3 have the meanings given for formula I and the 75-amino group is in the form of

  free or is protected by a group allowing the reaction

  Acylatim and the functional groups present in R 1 are protected, or in its salts, by acylating the 7-amino group by reaction with an acylating agent introducing the acyl radical of a carboxylic acid of formula I * N-4 A-COOE (IIIA) ## STR2 ##

  o A and R 4 have the meanings given for the formulas

  mules IA and IB and Am represents a substituted amino and

  o the functional groups present in A are protected

  or a salt thereof and, if desired, by converting a compound of formula IA or IB obtained into another compound of formula IA or IB and / or into a compound obtained by converting the functional groups present in protected form in free functional groups and / or by transforming a salt obtained into the free compound or into another salt and / or by transforming a compound obtained into a salt and / or by splitting an isomeric mixture obtained to give the separated isomers. Process a) (acylation): In a starting material of formula II, a functional group present in R 1, eg carboxyl, sulfo, amino or hydroxyl is protected by

  one of the protective groups mentioned above.

  The 7-amino group in a starting material of formula II is optionally protected by a group allowing the acylation reaction. One such group is, for example, an organic silyl group, or a ylidene group, which forms with the amino group a Schiff base An organic silyl group is p ex a silyl group that can also form

  with a carboxyl group R 3 a carboxyl protecting group

  This is primarily a trialcoyle group

  lower-silyl, primarily trimethylsilyl.

  In the silylation to protect a 4-carboxyl group in a starting material of formula II the amino group can also be silylated when an excess of silylating agent is used. A ylidene group is firstly a lower 1-arylalkylidene group, in particular a 1-arylcycloalkyl radical, in particular a monocyclic aryl radical, eg a phenyl optionally substituted with a lower alkyl, a hydroxy, a lower alkoxy and / or a nitroo; an acylating agent introducing the acyl radical; a carboxylic acid of formula IIIA or IIIB and the carboxylic acid of formula IIIA or IIIB itself or one of its reactive functional derivatives or their

salts.

  In a starting material of formula IIIA or IIIB, a functional group present in R 5 D p exo a carboxyl, amino, or hydroxyl group, which must not participate in the acylation reaction, is protected by a

  protective groups mentioned above.

  In a starting material of formula IIIA or IIIB, an amino group present may also be protected in ionic form, eg in the form of an acid addition salt, which is formed for example with a strong inorganic acid, eg hydrohalic acid, eg hydrochloric acid or sulfuric acid, or with an organic acid, eg p-toluenesulfonic acid. If a free acid of formula IIIA or IIIB is used for the acylation, the reaction is usually carried out in the presence of condensation agents

  such as carbodiimides, eg N, N'-

  diethyl-, N, N'-dipropyl-, N, N'-dicyclohexyl or N-ethyl-N'-3dimethylaminopropylcarbodiimide,

  suitable carbonyl compounds, for example car-

  bonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium sulphonate or 2-tertbutyl-5-methyl-l-2-sulphonate; oxazolium or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate,

  or a suitable acylamino compound, eg 2-

  ethoxy-1-ethoxycarbonyl-112-dihydroquinoline.

  The condensation reaction is conducted

  preferably in an anhydrous reaction medium, preferably

  in the presence of a suitable solvent or diluent, eg methyl chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or if necessary by cooling or heating, e.g. in a temperature range from about -40 ° C to about + 100 ° C, preferably from about -20 ° C to about + 50, and / or in an inert gas atmosphere, e.g.

a nitrogen atmosphere.

  A reactive functional derivative, that is to say a carboxamide-forming derivative, of a carboxylic acid of formula IIIA or IIIB is in the first place a carboxylic acid allyl of formula IIIA or IIIB, preferably a mixed anhydride. An anhydride For example, the reaction mixture is formed by condensation with another acid, eg an inorganic acid, eg a hydrohalic acid, and is, for example, the corresponding carboxylic acid halide, eg carboxylic acid chloride or bromide. It is furthermore formed by condensation with hydrazoic acid and is, for example, the carboxylic acid azide.

  inorganic compounds suitable for the formation of anhy-

  mixed dride are acids containing phosphorus, p. eg phosphoric acid, diethylphosphoric acid or phosphorous acid, sulfur-containing acids,

  eg sulfuric acid or hydrocyanic acid.

  A reactive functional derivative of a carboxylic acid

  Formula IIIA or IIIB is furthermore formed by condensation.

  with an organic carboxylic acid, eg with an unsubstituted or halogen-substituted alkane-lower alkyl carboxylic acid, eg fluorine or chlorine, eg pivalic acid or trifluoroacetic acid,

  with a lower alkyl-hemiester of the carbon

  that, eg ethyl or isobutyl-hemester of carbonic acid, or with an organic sulfonic acid, p; ex.

  aliphatic or aromatic, eg methane

  sulfonic acid or p-toluenesulfonic acid.

  A reactive functional derivative of a carboxylic acid of formula IIIA or IIIB is also an activated ester of the carboxylic acid of formula IIIA or IIIB, which is formed, for example, by condensation with a vinylogenic alcohol, that is to say with an enol, eg a

  vinylogenic lower alkenol, an imino halide

  methyl ester, eg dimethyliminomethyl chloride

  ester, prepared from the carboxylic acid of

  formula IIIA or IIIB and eg dimethyl chloride

  (1-Chlorethylidene) -iminium of formula I (CH 3) 2 NC (Cl) CH 3 1C 11 O which can be obtained on its side, for example, from N, N-dimethylacetamide and phosgene or sodium chloride; oxalyl, an arylester, eg a halogen substituted phenyl ester, e.g. a chlorine and / or a nitro, eg a pentachloro-,

  4-nitrophenyl or 2,3-dinitrophenyl ester, an N-ester

  heteroaromatic, eg N-benztriazolester, or N-diacyliminoester, eg N-succinylimino or

N-phtaliminoester.

  Lacylation with a reactive functional derivative of the carboxylic acid of formula IIIA or IIIB, e.g. with a corresponding anhydride, in particular a

  acid halide is preferably carried out in

  A suitable organic base is, for example, an amine, eg a tertiary amine, eg a lower trialkyl amine, eg trimethylamine, triethylamine or triethylamine. ethyl diisopropylamine, or N, N-lower dialkylaniline, e.g. N, N-dimethylaniline, or a cyclic tertiary amine, eg a lower N-alkylated morpholine, e.g. N-methylmorpholine, or is, for example, a pyridinyl base, eg pyridine. A suitable acidic binder is also an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or acidic carbonate, eg . the hydroxide, carbonate or acidic carbonate of sodium, potassium or calcium, or is an oxirane, for example a lower 1,2-alkylene oxide, such as

  ethylenoxide or propylenoxide.

  The acylation with a reactive functional derivative of the carboxylic acid of formula IIIA or IIIB is effected for example in a solvent or mixture of inert solvents, preferably anhydrous, for example in a carboxylic acid amide, such as a formamide, eg dimethylformamide, a halogenated hydrocarbon, eg methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, eg acetone, a cyclic ether, eg tetrahydrofuran, an ester, eg acetate of ethyl, or a nitrile, eg acetonitrile, or mixtures thereof if desired or necessary at lowered or increased temperatures, eg in a temperature range of about -40 ° C to about 100 ° C. C, preferably from about -10 ° C to about + 50 ° C, and / or in an atmosphere

inert gas, eg nitrogen.

  A reactive functional derivative of an acid

  formula IIIA or IIIB used in the acylation reaction.

  lation can, if desired, be formed in situ.

  It is thus possible to prepare a mixed anhydride in situ by reacting an acid of formula IIIA or IIIB,

  o the functional groups are possibly

  or one of its appropriate salts, eg salt of am-

  monium, which is formed p with an organic base, such as pyridine or 4-methylmorpholine, or a metal salt, eg an alkali metal salt, eg the sodium salt, with a suitable derivative of another acid , eg, an acid halide, an unsubstituted or unhalogen substituted alkane-lower alkane carboxylic acid, eg chlorine, eg trichloroacetyl chloride, a hemiester such as carbonic acid hemihalogenide, eg the ethyl ester or isobutyl ester of chloroformic acid or with a halide of a lower dialkylphosphoric acid, eg diethylphosphorobromide, which can be

  form by reaction of triethylphosphite with bromine.

  The mixed anhydride thus obtained can be used without

  be isolated in the acylation reaction.

  Subsequent operations Transformations of R 1 In a compound of formula IA or IB obtained, where the functional groups are optionally protected, it is possible to replace, in a conventional manner, a group R 1 with another radical R 1 or to transform it into another radical R 1 On can for example in a compound where R 1 represents a group of formula -CH 2 -R 2 and R 2, eg a radical which can be replaced by nucleophilic substituents, or in one of its salts, replace by treatment with a mercaptan compound, p ex a

  heterocyclylmercaptan compound, or with a compound of a-

  thiocarboxylic acid, such a radical R 2 by an etherified mercapto group, eg a heterocyclylmercapto group, or an esterified mercapto group R 2. An ester-substituted radical, replaceable with Fucleopenic substituents such as an etherified mercapto group, is example Ui esterified hydroxy group

  by aliphatic lower carboxylic acid.

  One such esterified hydroxy group is especially acetyloxy and acetoacetoxy. The reaction of such a compound of formula IA or IB with a suitable mercaptan compound, e.g. a compound of heterocyclylmercaptan can be carried out

  under acidic, neutral or weakly

  In acidic conditions, the presence of concentrated sulfuric acid is

  diluted with an inorganic solvent, eg poly

  phosphoric In neutral or weakly basic conditions, the reaction is carried out in the presence of water and

  optionally an organic solvent miscible with water.

  The basic conditions can be established for example by the addition of an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or acidic carbonate, eg by the addition of hydroxide, carbonate or

  sodium, potassium or calcium as organic solvents

  For example, water-miscible alcohols, eg lower alkanols such as methanol, may be used.

  or ethanol, ketones, eg lower alkanones

  res, such as acetone, amides, eg amides

  of lower alkane carboxylic acid, eg dimethyl

  formamide, or nitriles, eg acid nitriles

  lower alkanoic acid, eg acetonitrile.

  In a compound of formula IA or IB, where R 1 represents a group of formula -CH 2 -R 2, where R 2 represents a free carboxy, it is possible to esterify the hydroxyl group.

  free from the acyl radical of a carbamic acid, possibly

  N-substituted esterification of the free hydroxy group with an isocyanate compound, eg a

  halogenulphonyl isocyanate, eg chlorosulphonyl

  isocyanate, or with a carbamic acid halide, eg carbamic acid chloride, leads to

  N-insubstituted 3-carbamoyloxymethyl cephalosporins

  Esterification of the free hydroxy group with an N-substituted isocyanate compound or with an N-mono- or N, N-disubstituted carbamic acid compound, e.g.

  a substituted carbamic acid halide corresponding to

  such as N-monocarboxylic acid chloride

  or N, N-disubstituted, driven to 3-carbamoyloxy

  N-mono- or N, N-disubstituted methyl-cephalosporins of formula IA or IB It is usually employed in the presence of a solvent or diluent, if necessary, by cooling or by heating, in a closed container and optionally in an atmosphere Inert gas, eg, nitrogen, can be prepared. R 1 represents a group of formula -CH 2 -R 2, or R 2 represents a free hydroxy, from a compound of formula IA or IB by separation. of the acetyl radical of an R 2 acetyloxy group, for example by hydrolysis in a weakly basic medium, eg in a solution

  aqueous sodium hydroxide solution at pH 9-10, or by treatment with

  with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, e.g.

* from orange peels

  A compound of formula IA or IB may also be reacted, where R 1 represents a group -CH 2 -R 2 o R 2 represents p ex the nucleophilic substitution-replaceable radical defined above (with a tertiary organic base), especially an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH of about

  6.5, in the presence of water and possibly in soil

  organic compound which can be miscible with water and thus lead to compounds where R 1 represents a radical of formula

  -CH 2 2 and R 2 an ammonio quaternary group.

  Low acid conditions can be established by addition of an organic or inorganic acid

  suitable, for example, acetic acid, hydrochloric acid,

  drique, phosphoric acid or sulfuric acid.

  As organic solvents it is possible to use for example

  the water-miscible solvents mentioned above.

  To increase the yield may be added to the reaction mixture certain salts, for example alkali metal salts, such as sodium and in particular potassium, inorganic acids, such as a hydrohalic acid, eg hydrochloric acid or particularly hydroiodic acid, as well as thiocyanic acid, or organic acids, such as

  lower alkane carboxylic acids, eg acetic acid

  Suitable salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate.

  salts of suitable anion exchangers, eg

  liquid ion generators in the form of salt, eg p. Amberlite LA-1 (secondary liquid amine of a weight

  molecular 351-393; soluble in oil and

  luble in water; m Eq / g = 2.5-2.7, for example in the form

  acetate), with acids, eg acetic acid.

  The ammonio R 2 groups can be prepared in an interesting manner using an intermediate product

  of formula IA or IB, where R 2 represents a carbonyl group

  substituted thio, in the first place a carbonyl group

  Substituted aromatic thio and is primarily the benzoylthio group. Such an intermediate product, which can be obtained eg by reaction of a compound o R 2 in the radical R 1 represents an esterified hydroxy group, is reacted, in particular a lower alkanoyloxy group, eg acetyloxy group, with a suitable salt, eg the alkali metal salt, e.g. sodium salt, a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, e.g.

  thiobenzoic acid, with the tertiary amine, in particular

  of a tertiary heterocyclic base, such as an optionally substituted pyridine, and

  corresponding compound with a group ammonio The reaction

  It is usually carried out in the presence of a suitable desulfurizing agent, in particular a mercury salt, eg mercury (II) eprchlorate, and a suitable solvent or diluent or a mixture, if necessary while cooling. or by heating, in a closed container and / or in a gas atmosphere

inert, eg nitrogen.

  Oxidation of hydroxymethylene group A In a compound obtained of formula IA or IB a hydroxymethylene group A can be oxidized in a group

  The oxidation can take place, possibly

  with protection of an amino group and

  of a free carboxyl group, in known manner, that is to say

  in the known manner for the oxidation of hydroxyl groups to oxo groups Oxidizing agents include oxidizing oxides, eg manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium trioxide , eg Jones' reagent or chromium trioxide in the presence of acetic acid, sulfuric acid or pyridine, diazotized tetroxide, dimethylsulfoxide, optionally in the presence of dicyclohexylbenzalbodiimide or oxygen and peroxides, such as Hydrogen oxide includes oxygen-containing acids, such as oermaglene acid, cir- icic acid or hypochloric acid or their salts, such as potassium permanganate, sodium dichromate or potassium or

  potassium hypochlorite is also trans-

  form the group vdro hvl e because oxidation of op-

  to the oxomethyl group, ie by treatment with the salts of a sterically hindered alcohol, such as tert-rutyo; soprcopoxide or aluminum or onssium phenoxide in the presence of a ketone,

  such as acetone, cyclohexanone or fluorenone.

  Another possibility to reformulate the hydroxyl group

  methylene to the oxomethylene group consists of a

  dehydrogenation, eg with Raney nickel.

  Oxidation is conducted according to the oxidant in water or an appropriate aqueous organic solvent

  at temperatures ranging from about 0 to about 100.

  Reaction of the carbonyl group A with a hydroxyl derivative

  In a compound of formula IA or IB obtained, where A represents a carbonyl group, it may be, optionally with protection of the functional groups, converted by treatment with hydroxylamine or

  from O-methylhydroxylamine to a hydroxyimino group

  methylene or methoxyiminomethylene.

  The reaction of the carbonyl group with the

  hydroxylamine compound is routinely

  that is to say, by reacting the two

  reagents in a solvent, such as water or a solvent

  as an alcohol, eg a methanol, to a

  temperature slightly raised or lowered,

  The hydroxylamine compound can also be liberated in situ from one of its salts, for example a hydrohalide, such as the hydrochloride, by treatment with an inorganic base. as an alkali metal hydroxide, eg sodium hydroxide, or an organic base, such as a tertiary amine, e.g. a lower trialkylamine, such as triethylamine or ethyl-diisopropylamine, or a tertiary base

  heterocyclic, such as pyridine.

  Separation of protecting groups In a compound of formula IA or IB obtained, one or more functional groups are protected, these, eg carboxyl, amino, hydroxy and / or protected sulpho groups, can be liberated conventionally by means of solvolysis, in particular

  hydrolysis, alcoholysis or acidolysis, -

  or by means of a reduction, in particular of a

  hydrogenolysis, optionally in stages or simultaneously.

  A carboxyl group protected from

  classic way and varies according to the type of groups

  It is thus possible to convert a tert-alkoxy-lower-carbonyl or lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by an alkoxy to a free carboxyl.

  lower or lower alkyl-thio, or diphenyl-

  optionally substituted methoxycarbonyl, eg by

  treatment with an appropriate acid, such as formal

  or a trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylenethioglycol. An optionally substituted benzyloxycarbonyl may be liberated by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. Alternatively, an optionally substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can be converted to free carboxyl by chemical reduction. eg by treatment with alkali metal dithionite, eg sodium dithionite, or with a reducing metal, eg zinc, or a metal salt, such as a chromium-II salt, e.g. chromium-II chloride, generally in the presence of a hydrogen-donating agent, which allows with the metal to produce nascent hydrogen, such as an acid, primarily a carboxylic acid, such as a lower alkane carboxylic acid; optionally substituted, eg with hydroxy, eg acetic acid, acid

  formic acid, glycolic acid, diphenylglycol

  lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or alcohol

  or a thiol, and water is preferably added.

  By treatment with a metal or reduced metal salt

  it is also possible, as mentioned above, to transform a 2-halogeno-lower alkoxycarbonyl,

  possibly after transformation of a 2-bromo group

  lower alkoxycarbonyl to a 2-iodoalkoxy group

  corresponding lower-crabonyl, or an aroylmethoxy

  carbonyl, to a free carboxyl, aroylmethoxycarbonyl may also be separated by treatment with a nucleophilic reagent, preferably salifier, such as sodium thiophenolate or sodium iodide

  also transform a 2-silylethoxycarbonyl

  by treatment with a salt of hydrofluoric acid

  that delivers the fluoride anion, such as an alkali metal fluoride, eg sodium fluoride or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of a quaternary base organic, such as tetraalkyl fluoride

  lower ammonium or lower trialkyl fluoride

  arylammonium, eg tetraethyl fluoride

  ammonium or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethylsulfoxide, or N, N-dimethylacetamide, in free carboxyl With an organic silyl group, such as a lower-silyl trialkyl, po exo trimethylsilyl, an esterified carboxyl may be

  usually released by solvolysis, eg by treatment

  with water, alcohol or acid.

  A protected amino group is liberated

  classical and varying according to the type of group

  preferably by means of solvolysis or

  reduction A 2-halogeno lower alkoxy can be separated

  carbonylamino, optionally after conversion of a 2-bromoalkoxy-lower carbonylamino group to a

  2-iodoalkoxy lower carbonylamino group, an aroyl

  methoxycarbonylamino or a 4-nitrobenzyloxycarbonyl-

  amino p ex by treatment with a chemical reducer

  appropriate, such as zinc, in the presence of a car-

  appropriate boxylic, such as aqueous acetic acid.

  We can also separate an aroylmethoxycarbonylamino

  by treatment with a nucleophilic reagent, preferably

  salt-forming agent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino, also by treatment with an alkali metal dithionite, e.g.

  sodium dithionite A diphenyl-

  optionally substituted methoxycarbonylamino, a

  tert-lower alkoxycarbonylamino or a silylethoxy

  2-trisubstituted carbonylamino by treatment with an acid

  appropriate, eg Formic acid or trifluoroacid

  cation, a benzyloxycarbonylamino

  tituated, eg by means of hydrogenolysis, i.e.

  by treatment with hydrogen in the presence of a catalytic

  a suitable hydrogenation catalyst, such as a palladium catalyst, optionally triarylmethylamino

  substituted formylamino or 2-acylalc-1-en-1-yl

  lower-amino, eg by treatment with an acid, such as a mineral acid, eg hydrochloric acid, or an organic acid, eg formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water and an amino group protected with an organic silyl group, eg by means of hydrolysis or alcoholysis. An amino group protected by a 2-halogeneacetyl, eg 2-chloroacetyl, can be released by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, thiourea and then by solvolysis, such as an alcoholysis or a hydrolysis, the condensation product appeared can also be transformed into the group amino-free amino group protected by a silylethoxycarbonyl-2 substituted by treatment with

  a fluoride anion donor salt of the hydrofluoric acid

  as stated above in connection with the release of a correspondingly protected carboxyl group. It is possible to convert to the free amino group a phosphorphosphon or phosphin-amido group.

  eg by treatment with an acid containing phosphorus

  phosphorus, phosphonic or phosphinic acid, eg orthophosphoric acid or polyphosphoric acid, an acidic ester, eg monomethyl-, monoethyl-, dimethyl- or diethylphosphate or monomethylphosphoric acid, or its anhydride,

like phosphorus pentoxide.

  A hydroxy group protected with a suitable acyl group, an organic silyl group or an optionally substituted 1-phenyl-lower alkyl is released as an optionally

  A hydroxy group protected by a 2,2-dichloro-

  tyl is liberated eg by basic hydrolysis, a hydroxy group etherified with a tert-lower alkyl

  or by a hydrocarbon radical 2-oxa or 2-thia-alipha-

  or cycloaliphatic by acidolysis, eg by treatment with a mineral acid or a carboxylic acid

  strong, eg trifluoroacetic acid.

  A protected sulfo group, in particular esterified, is released in a group-like manner.

protected carboxyl.

  The cleavage reactions described are carried out under standard conditions, if necessary by cooling or heating, in a closed vessel and / or in an inert gas atmosphere, e.g.

nitrogen.

  When several protected functional groups are present, the preferred

  protective groups so as to be able to separate simul-

  more than one such group, for example by acidolysis, as by treatment with trifluoroacetic acid,

  formic acid, or by reduction, as

  with zinc and acetic acid, or with hydrogen and a hydrogenation catalyst, as a

palladium / coal catalyst.

  Esterification of a free carboxy group The conversion of a free carboxy group, eg from the free carboxy group R 3, to an esterified carboxy group, in particular to a carboxy group which can be separated under physiological conditions, is carried out according to For example, a compound of formula IA or IB is reacted, wherein the carboxyl group to be esterified is in free form and or other functional groups, eg amino or hydroxyl groups, are in protected form, or a compound of formula IA or IB, where the carboxy group to be esterified is in the form of a reactive functional derivative, or a salt of a compound of formula IA or IB with the corresponding alcohol or a derivative

reactive functional of this alcohol.

  During the esterification, the carboxyl group to be esterified is in free form, with the desired alcohol, the same condensing agents are used, eg carbodiimides, the same

  solvents and the same reaction conditions are maintained

  only in acylation according to process a).

  A compound of formula IA or IB, where the carboxy group to be esterified is in the form of a reactive functional derivative, is for example a mixed anhydride or an activated ester, which can be obtained in the manner described in US Pat. process a) (acylation), by condensation of the carboxylic acid of formula IA or IB with an inorganic acid, a carboxylic acid, with a half-ester of carbonic acid, a sulfonic acid

  or by condensation with a vinyl alcoholic alcohol.

  A reactive functional derivative of the alcohol to be esterified is in the first place the ester, which is formed by condensation with a strong inorganic or organic acid, for example the corresponding halide, eg chloride, bromide or iodide, or the corresponding lower alkyl or aryl compound, eg the

  composed of methylsulfonyloxy or 4-methylsulfonyloxy.

  In the esterification o the carboxyl group to be esterified is in the form of a reactive functional derivative, with the corresponding alcohol or in the esterification o the carboxyl group to be esterified is in free form, with a functional derivative reagent of the corresponding alcohol, the same solvent is used and the same reaction conditions are maintained as in the acylation with a reactive functional derivative of a carboxylic acid of formula IIIA or IIIB according to

the process a).

  It is also possible to prepare a compound of formula IA or IB where the carboxyl group to be esterified is in the form of a reactive functional derivative in a manner analogous to the procedure described in process a) (acylation) in situ and to do so.

  react without isolating it with the corresponding alcohol.

  Salification: The salts of compounds of formula IA or IB can be prepared in a conventional manner.

  form salts of compounds IA or IB, eg by reaction

  acid groups with metal compounds, such as alkali metal salts of carboxylic acids

  appropriate, eg the sodium salt of "-ethyl-

  caproic acid or sodium carbonate, or with ammonia

  niac or an appropriate organic amine, and

  preferably stoichiometric amounts or only

  A slight excess of the salifying agent is obtained. The acid addition salts are obtained in the usual manner, e.g. eg by treatment with an appropriate acid or anion exchange reagent Internal salts can be formed

  eg by neutralization of salts, such as salts of

  acid addition, at the isoelectric point, eg with weak bases, or by treatment with exchangers

of liquid ions.

  The salts can be converted in the usual way into free compounds, metal and ammonium salts, for example, treatment with suitable acids, and acid addition salts, for example

  treated with a suitable basic agent.

  In the entirety of the reactions mentioned above, which can be carried out under basic conditions, the 3-cephem compounds, possibly part thereof, can be isomerized to 2-cephem compounds. A compound 2 can be isomerized in a conventional manner. -celephem obtained or a mixture of a compound 2 and a compound

  3-cephem to give the desired 3-cephem compound.

  We can split in a classic way the

  mixtures of isomers, eg by fractional crystallisation

  by chromatography, etc., to give the

isolated isomers.

  The process also includes the variants in which the starting materials are used

  compounds which appear as intermediates

  areas and where one carries out with them the rest of the steps of the process, or else the process is interrupted at any stage; it is also possible to use starting materials in the form of derivatives or to form them

during the reaction.

  Starting materials are preferably used, and the reaction conditions are chosen so as to result in the compounds mentioned above.

as particularly appreciated.

Pharmaceutical preparations

  The compounds of formula IA or IB pharma-

  their acceptable hydrates or salts may be

  can be used to prepare pharma-

  ceutical. The pharmaceutical preparations contain an effective amount of the pure active material itself or an effective amount of the active ingredient of formula IA or IB, mixed with inorganic or organic carriers, solid or liquid, pharmaceutically

  acceptable, which are preferably suitable for

parenteral administration.

  The active substances are preferably used.

  of the invention in the form of injection preparations

  intravenous solutions, or solutions for transfusion. These solutions are preferably isotonic aqueous solutions or suspensions, which are

  can prepare before use, eg from preparation

  lyophilised preparations which contain the pure active substance or the active substance with a carrier, eg. mannitol Pharmaceutical preparations are preferably sterilized and may contain additives, preservatives, stabilizers, wetting agents and / or emulsifiers,

  solvents, salts to regulate the osmotic pressure

  and / or buffers.

  which may, if desired, contain other pharmacologically useful bodies, contain from about 0.1% to 100%, in particular from about 1 to about 50%, the lyophilizates up to 100%, of substance. active. The pharmaceutical preparations are prepared in a known manner, for example by means of conventional methods of

dissolution or lyophilization.

  Application The compounds of formula IA or IB, their hydrates or pharmaceutically acceptable salts, can be applied as antibiotic agents in the form of pharmaceutical preparations, in a process for the therapeutic treatment of the human or animal body, for example for the treatment of infections which are caused by bacteria or hulls that are gran-positive or gram-negative, eg by enterobacteria, e.g.

  Escherichia coli, Klebsiella pneumoniae or Proteus spp.

  Depending on the type of infection and the state of the infected organism, daily doses ranging from about 0.5 g to about 5 g are used s c, i. v or i m, for the treatment of homeotherms

  (men and animals) weighing about 70 kg.

  Starting materials The starting materials used in the process for preparing the compounds of the invention are known or can, if they are new, be prepared

in a classic way.

  The starting materials of formula II,

  that the corresponding compounds having functional groups

  protected, are known or can be prepared

in a classic way.

  The starting materials of formula IIIA or IIIB are known or can be prepared in a conventional manner. The starting products of formula IIIA or IIIB are described, for example, in European Patent Application No. 8150. In addition, the esters of acids of formula IIIA or IIIB are described in European Patent Application No. 59,156. From these esters it is possible to prepare conventionally, for example by saponification,

  the acids of formulas IIIA and IIIB.

  The following examples serve to clarify the invention, the temperatures are given in degrees

  Celsius; BOC = tert butoxycarbonyl.

Example 1

  a) 3-acetoxymethyl-7 el 2- (2-amino-1- (2,6-dichlorophenyl) -1 Himidazol-4-yl) -acetylaminol-3-cephem-4-carboxylate sodium Mixture at room temperature a solution of 1.10 g (1.56 moles) of diphenylmethyl ester

  3-acetoxymethyl-7 g-1 2- (2-amino-1- (206-dichloroacetic acid)

  rophenyl) -1H-imidazol-4-yl) -acetylaminol-3-cephem-4-

  3 ml of methylene chloride and 0.87 ml of anisole with 11 ml of trifluoroacetic acid and the mixture is stirred for 30 minutes. 300 ml of diethyl ether / hexane (1: 2) are then added with stirring.

  separates the precipitate and dissolves it in methanol.

  The solution is brought to pH 7.0 with about a solution

  3 M sodium 2-ethylhexanoate in methanol.

  After addition of diethyl ether, the precipitate formed is filtered with a filter funnel and the title compound of Rf 0.35 is obtained (UPC 12 plates, water / acetonitrile 9: 1); IR spectrum (Nujol): Characteristic absorption bands -1 at 3400, 3045, 1765, 1615 cm

  b) Diphenylmethyl ester of 3-acetoxymethyl-7-1 acid

  (2-Amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl) acetyl-

  aminol-3-cephem-4-carboxylic acid 2.86 g (1070 moles) of acid are added

  2- [2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl]

  acetic acid and 40 ml of methylene chloride at -5

  to a stirred suspension of a Vilsmeier reagent (prepa-

  1.0 ml of oxalyl chloride and 0.9 ml of N, N-dimethylformamide in 10 ml of methylene chloride). The mixture is stirred for 20 minutes at 0 and then cooled to -10. 4.40 ml

  (10.0 moles) of diphenylmethyl ester of 3-acetoxy-

  methyl-7-amino-3-cephem-4-carboxylic acid is stirred

  2 ml at 0 ° C. and diluted with 50 ml of methylene chloride. The organic phase is washed successively with water, a phosphate buffer solution (pH 8.0) and an aqueous solution of sodium chloride, dried

  on magnesium sulfate and concentrated in vacuo.

  The residue contains the title compound of Rf 0.55 (silica gel, chloroform / methanol / glacial acetic acid)

  : 12: 3); IR and Nujol spectra): Absorption bands

at 3450 and 1765 cm-o

Example 2

  a) 3-acetoxymethyl-7-l-2- (2,6-dichlorophenylamino) -1 H-

  Sodium Vlaminol-3-cephem-4-carboxylate (Imidazol-4-v))

  By reacting 0.8 g (1.13 m mol) of

  phenylmethyl ester of 3-acetoxymethyl-7-en-2- acid (2-

  (2,6-dichlorophenylamino) -1H-imidazol-4-yl) -2-acetylaminol

  3-Cephem-4-carboxylic acid in 2 ml of methylene chloride and 0.55 ml of anisole with 8.2 ml of trifluoroacetic acid and then treating with a methanolic solution of sodium 2-ethylhexanoate is obtained analogously to Example 1a) the title compound of Rf 0.20 (UPC plates 12, water / acetonitrile 95: 5), IR spectrum (Nujol): characteristic absorption bands at 3350; 1765; 1605 cm-1

  b) Diphenylmethyl ester of 3-acetoxymethyl-70-

  2- (2- (2,6-dichlorophenylamino) -1H-imidazol-4-yl) acetyl-

  aminol-3-cephem-4-carboxylic acid A mixture of 0.858 g (3.0 m Moles) of 2- [2- (2,6-dichlorophenylamino) -1H-imidazol-4-ylacetic acid and 1, 95 g (4.45 moles) of diphenylmethyl ester

  3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid

  in 20 ml dry tetrahydrofuran at 0 with 0.5 g

  1-hydroxybenztriazole and 1.42 g of N, N'-dicyclohexyl-

  carbodiimide in 4 ml of dry tetrahydrofuran, stirred for 2 h at 0 and then for another 5 h at room temperature. After filtering the reaction mixture, the filtrate is diluted with ethyl acetate and washed successively with a solution of phosphate buffer (pH 8.0) and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo The residue contains the title compound of Rf 0.60 (silica gel, chloroform / methanol / acid acetic

  freezing 85: 12: 3); IR spectrum (Nujol): absorption bands

  characterization at 3350; 1765; 1735 cm 1.

Example 3

  a) 3-acetoxymethyl-75-1- (2-amino-1- (2,6-dichlorophenyl) -

  1H-Imidazol-4-yl) -2-Z-methoxyiminoacetylaminol-3-

  sodium cephem-4-carboxylate by reacting 1.5 g (2.0 m Moles) of

  diphenylmethyl ester of 3-acetoxymethyl-7B-1 2- acid

  (2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl) -2-Z-

  methoxyiminoacetylaminol-3-cephem-4-carboxylic acid in 2.5 ml of methylene chloride and 1.05 ml of anisole with 8 ml of trifluoroacetic acid and then treating with a methanolic solution of sodium 2-ethylhexanoate, analogously to Example I a) the title compound of Rf env 0.50 (UPC 12 plates, water / acetonitrile

  2: 1); IR spectrum (Nujol): characteristic absorption bands

  ticks at 3350; 1765; 1620; 1050 cm-1

  b) Diphenylmethyl ester of 3-acetoxymethyl-7B-1 2- acid

  (2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl) -2-methoxyiminoacetylaminol-3-cephem-4-carboxylic acid by reaction of 1.74 g (5.30 moles) acid

  2-1 2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl-2-

methoxyiminoacetic acid and 2.30 g (5.30 moles) of diphenyl

  3-acetoxymethyl-7-amino-3-nylmethyl ester

  Cephem-4-carboxylic acid in 40 ml of methylene chloride is obtained analogously to Example 1b) the title compound of Rf 0.60 (silica gel, chloroform / methanol /

  85: 12: 3 glacial acetic acid); IR spectrum (CH 2 C 12): -

  characteristic absorption bands at 1765; 1735; 1045 cm 1.

  c) 2- (2-amino-1- (2,6-dichlorophenyl) -1H-imidazole

  4-yll-2-methoxyiminoacetic A solution of 8.00 g (23.30 moles) is mixed

  2- (2-Amino-1- (2,6-dichloroacetic acid) methyl ester

  phenyl) -1H-imidazol-4-yl-2-methoxyiminoacetic acid in ml of methanol with 69 ml of 1N sodium hydroxide solution and stirred for 2 hours at room temperature. The reaction mixture is concentrated under vacuum. The residue is dissolved in water, the solution is brought to pH 8.5 with dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase is separated off, brought to room temperature. 2.5 g with dilute hydrochloric acid and filtered with a filter funnel the precipitated product The title compound of Rf 0.35 (silica gel, sbutanol / glacial acetic acid / water

  67:10:23) IR spectrum (Nujol): absorption bands characteristic of

  characteristics at 3550; 3245; 1620; 1045 cm-1.

  d) Methyl ester of 2-l-2-aminc-1- (2,6-dichloroacetic acid)

  phenyl) -1H-imidazol-4-yl-2-methoxyiminoacetic acid In a mixture of 36.0 g (0.148 mol) of 2,6-dichlorophenylisocyanide dichloride with 150 ml of acetonitrile was introduced for 60 minutes. gaseous monium This mixture is then cooled to 20 and mixed with a solution of 52.8 g (0.222 mol)

  of methyl ester of 2-methoxyimino-4-bromo-

  acetoacetic acid in 150 ml of acetonitrile.

  Ammonia gas is heated to 75 and

  stir at this temperature for 5 hours and then cool

  at room temperature The insoluble fractions are filtered off and the filtrate

  The residue is triturated with diethyl ether.

  holds the title compound of Rf approx 0.60 (silica gel, chloroform / methanol 9: 1) IR spectrum (CH 2 C 12): characteristic absorption bands at 3460; 3380; 1743 1630; 1040 cm

Example 4

  7 e-1- (2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl) -2-

  Sodium Z-methoxyiminoacetylaminol-3-cephem-4-carboxylate is stirred for 30 minutes at -10 a mixture

  1.15 g (3.50 moles) of 2-l-2-amino-1- (2,6-l

  dichlorophenyl) -1H-imidazol-4-yl-2-methoxyiminoacetic acid and 0.82 g of phosphorus pentachloride in 15 ml of methylene chloride (solution 1) A mixture of 0.70 g is stirred at room temperature for a period of minutes. of 70-amino-3-cephem-4-carboxylic acid, 5.80 g of trimethylsilylacetamide and 15 ml of methylene chloride and then cooled to -10 (solution 2). The solution 1 and the solution 2 are stirred. mixture at 0 ° for 3 h and then poured on a saturated solution of sodium bicarbonate The aqueous phase is separated, it is placed at pH 4.5 with acid

  hydrochloric acid and chromatography (ad-

  XAD-2 sorbent, water).

  the product, they are dissolved in methanol and

  bring e p H 7 with a solution of about 3 N of 2-ethyl-

  According to the present invention, the precipitate formed is filtered and the title compound of Rf 5 is obtained. 2: 1), ts? {', H,): b'-de? O tion characteristics

  at 9335 fE E 7 E; 316 M; 1 '5 i 11 -

El-example

  Pivaloyloxyimetylsylate, and the 2- (2-amino-1- (2,6-diol)

  dichlorophnyl) -NH-di (iidazol-4-yl) -2-yl-methoxy-iminoacetyl

  amino-3-ceperpher-4-carbo-yl lalng a mixture of 1.33 g (2.49 moles)

  75-1- 2- (2-Amino-1- (2,6-dichlorophenyl) -1H-imidazole-4-

  (1) -2-Z-methoxyiminoacetylamino-3-cephem-4-carboxidate of sodium in 15 ml of N, 11'-dimethylformamide

  with 0.56 ml of iodomethyl pivalate and shake

  After 60 minutes, it is poured into 70 ml of phosphate buffer of pH 7.0 and extracted with ethyl acetate / acetone (4: 1). The organic extracts are washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo After trituration of the residue with diethyl ether / hexane the title compound of Rf 0.85 (silica gel, sec-butanol / glacial acetic acid / water 67:10:23) is obtained) ; IR spectrum (Nujol): characteristic absorption bands at 3030; 1765 1735; 780 m 1 to 3030; 1765; 1735; 780 cm

Example 6

  Dry ampoules or flasks containing 0.5 g of active ingredient, eg acid, can be prepared

  3-Acetoxymethyl-7 e-1 2- (2-amino-1H-imidazol-4-yl) -2-Z-

  methoxyiminoacetylaminol-3-cephem-4-carboxylic acid, as follows: Composition (for 1 ampoule or 1 vial): Active substance 0.5 g Mannitol 0.05 g A sterile aqueous solution composed of active substance and mannitol, under aseptic conditions, in ampoules or vials

  5 ml, then sealed and tested.

Claims (4)

  1. 7-Amino-3-aminophenylacetylamino-3-cephem-4-carboxylic acid compounds of formulas H 2 N '^': XY * 1 (IA) 4 3 and O Il / S R H - '-4 A-C * * N * -R (l B) H R 3   R 1 represents a hydrogen, a lower alkyl, a lower alkoxy, a halogen or a group -CH-R 2, where R 2 represents a hydroxy, a mercapto, a hydroxyl or   esterified mercapto, a hydroxy or an ethereal mercapto   embedded image or a quaternary ammonium group, R 3 represents a carboxyl or a protected carboxyl, R 4 represents a substituted or unsubstituted hydrocarbon radical or an acyl group and in the compounds of formula IA furthermore a hydrogen and A represents a carbonyl, a group methylene or a methylene group which is substituted by   an amino, a protected amino, a hydroxy, a hydroxy   or a group of the formula = N-O-R 5, where R 5 represents hydrogen, lower alkyl, lower substituted   cycloalkyl, substituted cycloalkyl, cycloalkyl   nyl, lower alkenyl, carbamoyl or substituted carbamoyl, hydrates and salts of formula IA and IB.   2 Compounds of formula IA and IB according to claim 1, where R 1 represents a hydro-   gene, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen, e.g. a chlorine, or a group -CH 2 -R 2, where R 2 represents a lower alkanoyloxy, eg an acetoxy, a carbamoyloxy, an N-lower alkylcarbamoyloxy, a diaza- radical,   triaza-, tetraaza-, thiaza-, thiadiaza-, thia-, oxaza-   or aromatic oxadiazacyclyl, monocyclic, 5 or 6   chain members, eg triazolylthio, eg H-1,2,3-   triazol-5-ylthio, a tetrazolylthio, eg a 1 H-   tetrazol-5-ylthio, a thiazolylthio, a thiadiazolyl-   thio, eg 1,3,4-thiadiazol-5-ylthio, an oxazolyl-   thio, an oxadiazolylthio or a 5,6-dioxotetrahydro-as-   triazinylthio, eg a 5,6-dioxo-1, 2,5,6-tetrahydro-as-   triazin-3-ylthio or a 5,6-dioxo-1,4; 5,6-tetrahydro-as-   triazin-3-ylthio, which may be substituted by alkyl   lower, eg methyl, lower dialkoyl;   lower aminoalkyl, eg dimethylaminomethyl or dimethylaminoethyl, lower sulfoalkyl, eg sulfomethyl, lower carboxyalkyl, e.g.   carboxymethyl, amino, lower carboxyalkyl   amino-acid, eg 2-carboxyethylamino, or by a   carbamoyl, or an ammonio, eg 2-lower alkyl-   1-pyrazolio, eg 2-methyl-1-pyrazole, a 2-   carboxy-lower alkyl-1-pyrazole, eg a 2-   carboxymethyl-1-pyrazole, a 3-lower alkyl-1   triazolio, eg 3-methyl-1-triazolio, pyridinio, lower hydroxyalkyl substituted pyridinio, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl, halogen, e.g.   chlorine or bromine, or carbamoyl, eg 3-   or 4-hydroxymethylpyridinio, a 4-carboxypyridinio,   a 3 or 4-carboxymethylpyridinio, a 3 or 4-chloro   pyridinio, a 3 or 4-bromopyridinio or a 3 or 4   carbamoylpyridinio, R 3 represents a carboxyl, a car-   boxyl separable under physiological conditions, p. eg an acyloxymethoxycarbonyl, eg alkanoyloxy   lower-methoxycarbonyl, eg pivaloyloxymethoxy-   carbonyl, or a lower alkoxy-lower carbonyloxyalkoxy   carbonyl, eg, 1-ethoxycarbonyloxyethoxycarbonyl, R 4 represents lower alkyl, eg methyl, hydroxy-lower alkoxy, lower alkoxy, eg methoxy, carboxy, lower alkoxy; carbonyl, for ex methoxycarbonyl   or an ethoxycarbonyl, an amino, a lower alkyl-   amino, eg methylamino, carbamoyl, halogen, eg fluorine or chlorine, sulfo, alkyl   lower-thio, eg methylthio, or amino   sulfinyl, a lower alkenyl, eg allyl,   cycloalkyl, eg pentyl or hexyl, cycloalkyl,   alkenyl, eg 1-cyclohexenyl or 1,4-cyclohexane   dienyl, phenyl, phenyl substituted by halogen,   eg chlorine, eg 2,3-, 2,4- or 2,6-dichlorobenzene   phenyl, phenyl-lower alkyl, eg benzyl or diphenylmethyl, or acyl, eg alkanoyl   lower, eg acetyl, lower alkoxy-   carbonyl, eg methoxycarbonyl, or ethoxylated   carbonyl, carbamoyl, lower alkyl-   carbamoyl, eg methylcarbamoyl, a lower alkyl   lower sulfonyl, eg methylsulfonyl or a   ethylsulfonyl, benzenesulphonyl or benzenesulphonyl   nyl substituted by lower alkyl, eg methyl, or halogen, eg chlorine, eg p-toluenesulfonyl or 4-methylbenzenesulfonyl and in the compounds of formula IA represents hydrogen, and A represents aminomethylene, a hydroxymethylene, a sulfomethylene or a methylene group substituted by a group = NOR 5, where R 5 represents a hydrogen, a lower alkyl, eg a methyl, a lower carboxyalkyl, eg a 2-carboxy-2-propyl, a cycloalkenyl, eg cyclopentenyl, lower alkenyl, e.g. an allyl, a carbamoyl, a lower alkylcarbamoyl, eg a methylcarbamoyl or a lower aminoalkyl, eg a 2-aminoethyl, the -OR 5 group has the syn (or Z) position, and the salts, particularly the pharmaceutically acceptable salts,   Formula IA and IB which have salt groups.   Compounds of formulas IA and IB according to claim 2, where R 1 represents a hydro-   gene, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen, eg chlorine, or -CH 2 -R 2, where R 2 is lower alkanoyloxy, eg acetoxy carbamoyloxy, triazolylthio, eg 1H-1,2,3-triazol-5-ylthio, tetrazolylthio, eg 1H-tetrazol-5-ylthio, tetrazolylthio substituted by lower alkyl, eg . a methyl, a lower dialkoyl-amino-lower alkyl,   eg 2-dimethylaminoethyl, a lower sulfoalkyl   , eg sulphomethyl, lower carboxyalkyl,   , eg carboxymethyl, or carbamoyl,   eg, 1-methyl-1H-tetrazol-5-ylthio, a 1-sulfo   methyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-   tetrazol-5-ylthio or 1- (2-dimethylaminoethyl) -1 H-   tetrazol-5-ylthio, thiadiazolylthio, eg 1,3,4-thiadiazol-5-ylthio, thiadiazolylthio substituted by lower alkyl, eg methyl, eg   2-methyl-1,3,4-thiadiazol-5-ylthio, a 5,6-dioxotetra-   hydro-as-triazin-3-ylthio substituted by lower alkyl   , eg methyl, eg 2-methyl-5,6-dioxo   1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-   , 6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio, a   pyridinio or a pyridinio substituted with a hydroxyl   lower alkyl, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl,   a halogen, eg chlorine or bromine, or a carbamide   mole, eg 3 or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3 or 4-carboxymethylpyridinio, 3 or 4-chloropyridinio, 3 or 4bromopyridinio or 3 or 4-carbamoylpyridinio, R 3 represents a carboxyl, a lower alkanoyloxy-methoxycarbonyl, p.   pivaloyloxymethoxycarbonyl, or lower alkoxy-   carbonyloxyalkoxy lower carbonyl, eg 1-ethoxycarbonyloxyethoxycarbonyl, R 4 represents lower alkyl, eg methyl, carboxyalkyl   lower, eg carboxymethyl or 2-carboxy-   ethyl, lower dialkoyl-lower aminoalkyl,   eg 2-dimethylaminoethyl, lower alkoxy-   carbonyl, eg methoxy or ethoxycarbonyl, carbamoyl, lower alkenyl, eg allyl, phenyl, halogen substituted phenyl, e.g. chlorine, eg 2,3-, 2,4- or 2,6-dichlorophenyl, phenyl-lower alkyl, eg, benzyl, or lower alkylsulfonyl, eg methylsulfonyl, and in compounds of formula IA represents   hydrogen, and A represents a methylene substitute group   killed by the group = N-O-R 5 and R 5 represents a hydro-   gene, lower alkyl, eg, lower carboxyalkyl, eg 2-carboxy-2-propyl, lower alkenyl, eg allyl O, carbamoyl   or lower alkylcarbamoyl, eg methyl   carbamoyl, the group -O-R 5 has the position syn (or Z) and o -Aest connected to the 4-position of the imidazolyl radical, and the salts, in particular the pharmaceutically acceptable salts, of the compounds of   formulas IA and IB which have salt groups tors.   Compounds of formulas IA and IB according to claim 3, wherein R 1 represents hydrogen, lower alkyl, eg methyl, lower alkoxy, eg methoxy, halogen,   p eg chlorine, or a group -CH 2 I-R 2, where R 2 represents   a lower alkanoyloxy, eg acetoxy, a   carbamoyloxy, a tetrazolylthio, eg 1H-tetrazol-   -ylthio, an alkyl substituted tetrazolylthio   lower, eg methyl, lower dialkoyl   lower aminoalkyl, eg 2-dimethylaminoethyl, lower sulfoalkyl, eg sulfomethyl, or lower carboxyalkyl, eg carboxymethyl,   substituted tetrazolylthio, eg 1-methyl-H-   tetrazol-5-ylthio, 1- (2-d-imethylaminoethyl) -1H-tetrazol-5-ylthio, a 1-carboxy; m -ethyl-1H-tetrazol-5-ylthio,   1-sulfomethyl-1-yl-9-tetrazol-5-ylthio, or a 1-carboxy-   1-methyl-1H-tetrazol-5-ylthio a thiadiazolylthio, e.g. 1,3,4-thiadiazol-5-n-ylthio, or thiadiazolylthio substituted with a lower alkanol, eg methyl,   p ex 2-methyl-1,3,4-thiadiazol-5-ylthio, a 5,6-   dioxo-té-trahyd-ro-es-trizinylthio substituted by a   lower alkyl, eg methyl, eg 2-methyl-   6-dioxo-11,2,5,6-tetrahydro-as-triazin-3-ylthio, or 4-methyl-5,6d-3-oxo-1,4,5,5-ethanedro-as triazin-3-ylthio,   pyridinio or pyridinico substituted with hydroxy   lower alkanol, eg hydroxymethyl, carboxy, lower carboxyalkyl, eg carboxymethyl,   a halogen, eg chlorine or bromine, or a car-   Bamyl, eg 3-or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3 or 4-carboxymethylpyridinio, 3 or 4-chloropyridin-10, 3 or 4-bromopyridinio or 3 or 4-carbamoylpyridinio, R represents a carboxy, a lower alkanoyloxy-methoxycarbonyl, p.   ex pivaloyloxymethoxycarbornyl or lower alkoxy   lower carbonyloxyalkoxycarbonyl, eg 1-ethoxycarbonyloxyethoxycarbonyl, R 4 represents lower alkyl, eg methyl, aralkylalkyl,   lower, eg carboxymethyl or 2-carboxy-   ethyl, lower dialkoyl-lower aminoalkyl, eg dimethylaminoethyl, phenyl, phenyl substituted by halogen, eg chlorine, eg 2,3, 2,4 or 2,6-dichlorophenyl, or phenylalkyl lower, eg benzyl, and in the compounds of formula IA represents hydrogen, and A represents a methylene group substituted by the group = NOR 5, where R 5 represents lower alkyl, eg methyl,   a lower carboxyalkyl, eg 2-carboxy-2-   propyl, a carbamoyl or a lower alkyl-caramoyl, eg methylcarbamoyl, where the group -OR 5 has the syn (or Z) position and A is attached to the 4-position of the imidazolyl radical, and the salts, in particular the pharmaceutically acceptable salts, compounds   of formula IA and IB, which have salt groups   ers. 3-acetoxymethyl-7 e-1 2- (2-amino-1- (2,6-dichlorophenyl) -   1H-imidazol-4-yl) -2-Z-methoxyiminoacetylaminol-3-cephem-   Sodium 4-carboxylate according to Claim 4.   Acid 7 e-1 2- (2-amino-1- (2,6-dichlorophenyl) -1H-   imidazol-4-yll-2-methoxy-iminoacetylaminol-3-cephem   4-carboxylic acid according to claim 4.   7 Pivaloyloxymethyl ester of 70-l 2- (2-amino-1-   (2,6-dichlorophenyl) -1H-imidazol-4-yl-2-Z-methoxy   iminoacetylaminol-3-cephem-4-carboxylic acid according to claim 4.   8 Pharmaceutical preparations containing compounds   of formula IA and / or IB, hydrides or pharmaceutical salts-   acceptable amounts of compounds of formula IA and / or IB with salifiers.   Process for the preparation of compounds of formulas IA and IB, wherein R 1, R 2, R 3, R 4 and A have the meanings given in claim 1, characterized in that a) is carried out in a compound of formula O FN   o R 1 and -R 3 have the meanings given for the   mules IA and IB and 7-amino group is in free form or is protected by a group allowing the acylation reaction and the functional groups present in R 1 are protected, or in its salts, by acylating group 7 α-amino by reaction with an acylating agent introducing the acyl radical of a carboxylic acid of formula HC III A) or 4 (IIIB) I o   o A and R 4 have the meanings given for the formulas   mules IA and IB and Am represents a substituted amino and   o the functional groups present in A are protected   or a salt thereof and, if desired, by converting a compound of formula IA or IB obtained into another compound of formula IA or IB and / or into a compound obtained by converting the functional groups present in the form of protected in free functional groups and / or by transforming a salt obtained into the free compound or into another salt and / or by transforming a compound obtained into a salt and / or by splitting an isomeric mixture obtained to give the separated isomers.