CH654310A5 - 7beta-Aminoimidazolylacetylamino-3-cephem-4-carboxylic acid compounds, process for their preparation and pharmaceutical preparations which contain these compounds - Google Patents

Abstract

7 beta -Aminoimidazolylacetylamino-3-cephem-4-carboxylic acid compounds of the formula <IMAGE> in which R1 denotes hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2-R2, in which R2 represents hydroxyl, mercapto, esterified hydroxyl or mercapto, etherified hydroxyl or mercapto or a quaternary ammonio group, R3 denotes carboxyl or protected carboxyl, R4 denotes a substituted or unsubstituted hydrocarbon radical or an acyl group, and in compounds of the formula IA additionally hydrogen, and A denotes carbonyl, a methylene group or a methyl group, which is substituted by amino, protected amino, hydroxyl, protected hydroxyl, sulpho, protected sulpho or by a group of the formula =N-O-R5, in which R5 represents hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, lower alkenyl, carbamoyl or substituted carbamoyl. Hydrates and pharmaceutically acceptable salts of these compounds have antibiotic properties and are active against Gram-positive and Gram-negative microorganisms. The novel compounds can be used for the treatment of infections, e.g. in the form of antibiotically active preparations. The novel compounds are prepared in a manner known per se.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 wherein R1 and R3 have the meanings given under formula IA and IB, with optional, intermediate protection of the 7 $ -annino group and intermediate protection of functional groups present in R1 or the 7ss-amino group in a salt thereof by reaction with an acyl radical of a carboxylic acid formula
EMI2. 1
 introducing acylating agents, wherein A and R4 have the meanings given under formula IA and IB, acylated with optional intermediate protection of functional groups present in A or with a salt thereof and, if desired, converting an available salt into the free compound or into another salt and / or an available free compound is converted into a salt. 



   The present invention relates to new 7ss-aminoimide-azolylacetylamino -3-cephem-4-carboxylic acid compounds, processes for their preparation and pharmaceutical preparations which contain these compounds. 



   The present invention relates to 7ss-aminoimidazolyl-acetyl-amino-3-cephem-4-carboxylic acid compounds of the formulas:
EMI2. 2nd
 wherein R1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2-R2, wherein R2 represents hydroxy, mercapto, esterified hydroxy or mercapto, etherified hydroxy or mercapto or a quaternary ammonio group, R3 carboxyl or protected carboxyl, R4 represents a substituted or unsubstituted hydrocarbon radical or an acyl group and in compounds of the formula IA also hydrogen and A carbonyl, a methylene group or a methylene group which is substituted by amine, protected amino, hydroxyl, protected hydroxyl, sulfo, protected sulfo or by a group of the formula = N + Rs ,

   wherein Rs is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, lower alkenyl, carbamoyl or substituted carbamoyl, hydrates and salts of compounds of the formula IA and IB, pharmaceutical preparations which contain compounds of the formula IA and / or IB, and the use of compounds of formula I for the production of pharmaceutical preparations or as pharmacologically active compounds. 



   In the description of the present invention: 1 means in connection with groups, e.g. B.  Lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc. , expression used Nieder that the corresponding groups, unless expressly defined otherwise, contain up to 7 and preferably up to 4 carbon atoms. 



   The imidazolyl radical substituted by a free or a monosubstituted amino group can also be present as a dihydroimidazolyl radical substituted by an imino group, which has two tautomeric forms:
EMI2. 3rd

The position of the equilibrium between the imidazolyl and the two dihydroimidazolyl forms depends on the structure of the substituents R4 and A and on external parameters such as temperature, solvent or pH.  Only the aminoimidazolyl form is expressly mentioned in the present description.  However, the two dihydroimidazolyl forms are also included. 



   The general definitions used above and below in the context of the present description preferably have the following meanings:
Lower alkyl R1 contains 1-4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl. 



   Lower alkoxy R1 contains 1-4 carbon atoms and is, for example, ethoxy, propoxy, butoxy or especially methoxy. 



   Halogen R1 is fluorine, bromine, iodine or preferably chlorine. 



   Esterified hydroxy or mercapto R2 is a hydroxy or mercapto group which is substituted by an aliphatic carboxylic acid, by acyl, e.g. B.  Lower alkanoyl, e.g. B.  Acetyl, substituted, aliphatic carboxylic acid or the carbamic acid is esterified, for example lower alkanoyloxy, e.g. B. 



     Acetoxy, lower alkanoyl lower alkanoyloxy, e.g. B.  Acetylacetyloxy, or carbamoyloxy or    Niederalkanoylthio, e.g. B. 



  Acetylthio or formylthio, or carbamoylthio. 



   Esterified hydroxy or mercapto R2 is also a hydroxy or mercapto group which is esterified by an N-substituted carbamic acid. 



   N-substituents are, for example, lower alkyl, e.g. B. 



  Methyl or ethyl, or by halogen, e.g. B.  Chlorine, or lower alkanoyloxy, e.g. B.  Acetoxy, substituted lower alkyl, u. B.     2-chloroethyl or 2-acetoxyethyl. 



   Hydroxy or mercapto R2 esterified by an N-substituted carbamic acid is, for example, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N- (2-chloroethyl) carbamoyloxy, N- (2-acetoxyethyl) carbamoyloxy or N-methylcarbamoylthio. 



   Etherified hydroxy or mercapto R2 is a hydroxy or mercapto group which is replaced by an aliphatic



  Hydrocarbon radical is etherified, for example lower alkoxy with 14 C atoms, for. B.  Methoxy or ethoxy, or NiederaLEylthio with 14 C atoms, e.g. B.  Methylthio. 



   Etherified mercapto R2 is also etherified by a heterocycle which is connected via a ring carbon atom to the sulfur atom of the mercapto group, e.g. B. 



  by a monocyclic heterocycle which has 1 to 4 nitrogen heteroatoms and optionally an additional oxygen or sulfur atom or by a bicyclic heterocycle with 1 to 5 nitrogen heteroatoms. 



  Such an etherified mercapto group is hereinafter called heterocyclylthio group R2. 



   A heterocyclic radical in a heterocyclylthio group R2 is in particular an aromatic, monocyclic, five or six-membered, diaza, triaza, tetraaza, thiaza, thiadiaza, thia, oxaza or oxadiazacyclyl radical or is an aromatic or partially saturated or bicyclic six ring atoms per ring containing aza, diaza, triaza, tetraaza or pentazabicyclyl radical. 



   Substituents of the heterocyclic radical mentioned in a heterocyclylthio group R2 are, for example, lower alkyl, e.g. B.    Methyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -Butyl, especially methyl, lower alkenyl, e.g. B.  Allyl, or lower alkyl, e.g. B.  Methyl or ethyl, which is substituted by the following groups:
Hydroxy, esterified hydroxy, e.g. B.  Lower alkanoyloxy, e.g. B.  Acetyloxy, or halogen, e.g. B.  Fluorine or chlorine, optionally in salt form, e.g. B.  in alkali metal, e.g. B.    Sodium salt form, present lower alkylphosphonyl, e.g. B.  Methyl or ethylphosphonyl, di-lower alkylphosphonyl, e.g. B. 

  Dimethyl or diethylphosphonyl, optionally in salt form, e.g. B.  in alkali metal or ammonium salt form, e.g. B.  in sodium salt form, present carboxyl or sulfo, esterified carboxyl, e.g. B.  Lower alkoxycarbonyl, e.g. B.    Ethoxycarbonyl, sulfamoyl, amino, lower alkylamino, e.g. B.  Methyl or ethylamino, di-lower alkylamino, e.g. B.  Dimethylamino or diethylamino, acylamino, e.g. B.  Niederalkanoylamino, e.g. B. 



  Acetylamino, or by carboxyl or halogen, e.g. B.  Chlorine, substituted lower alkanoylamino, e.g. B.  Carboxyacetylamino or chloroacetylamino. 



   Such a substituted lower alkyl radical is, for example: hydroxy lower alkyl, e.g. B.  Hydroxymethyl or 2 hydroxyethyl, acetyloxy lower alkyl, e.g. B.  Acetyloxymethyl or 2-acetyloxyethyl, halogeno lower alkyl, e.g. B.  Chloromethyl, 2Chloräthyl, 2,2,2-Trichloräthyl or Trifluor- methyl, Niederalkylphosphononiederalkyl, z. B.  Ethylphosphonomethyl, Diniederalkylphosphononiederalkyl, e.g. B.  Di äthylphosphonomethyl, carboxy lower alkyl, e.g. B.  Carboxymethyl or 2-carboxyethyl, sulfone lower alkyl, e.g. B.  Sulfomethyl or 2-sulfoethyl, lower alkoxycarbonyl-lower alkyl, e.g. B.     thoxycarbonylmethyl or 2-ethoxycarbonylethyl, sulfamoyl-lower alkyl, e.g. B. 

  Sulfamoylmethyl or 2-sulfamoylethyl, amino lower alkyl, e.g. B.  Aminomethyl or 2-aminoethyl, lower alkylamino lower alkyl, e.g. B. 



  Methylaminomethyl or 2-methylaminoethyl, di-lower alkylamino-lower alkyl, e.g. B.  Dimethylaminomethyl or 2-dimethylaminoethyl, lower alkanoylamino lower alkyl, e.g. B.    2-acetylaminoethyl, carboxy lower alkanoyl amino lower alkyl, e.g. B.    3-carboxypropionylaminoethyl or 2-carboxyacetylaminoethyl, or halogenated lower alkanoyl amino lower alkyl, e.g. B.    3-chloropropionylaminoethyl or 2-chloroacetylaminoethyl.    



   Functional groups or modified, e.g. B.  protected, functional groups, e.g. B.  Halogen, e.g. B.  Fluorine,
Chlorine or bromine, unsubstituted or substituted amino, e.g. B.  unsubstituted or by lower alkyl, e.g. B.  Methyl or ethyl, mono- or disubstituted amino, e.g. B.  Amino,
Methylamino or dimethylamino, acylamino, e.g. B.  Nieder lkanoylamino, e.g. B.  Acetylamino, or lower alkylsulfonyl imino, e.g. B.    Mesylamino, or by halogen, e.g. B.  Chlorine, or carboxy substituted NiederaLkanoylamino, e.g. B. 



     3-chloropropionylamino or 3-carboxypropionylamino nitro, hydroxy, lower alkoxy, e.g. B.  Methoxy or thoxy, carboxy, esterified carboxy, e.g. B.    Lower alkoxycarbonyl, e.g. B.     Methoxycarbonyl or thoxycarbonyl, optionally substituted, e.g. B.  mono- or di-lower alkylated carbamoyl, e.g. B.  Methylcarbamoyl or dimethylcarbamoyl, or cyan, as well as oxo or oxido are also substituents of the heterocyclic radical in a heterocyclylthio group R.    



   A heterocyclylthio group R2 in which the heterocyclic radical is an aromatic, monocyclic, five-membered radical is u. a.  Imidazolylthio, e.g. B.    2-imidazolylthio, triazolylthio or by lower alkyl, e.g. B.  Methyl, and / or phenyl substituted triazolylthio, e.g. B.    1H-1,2,3-triazol-5-ylthio, 1-methyl-1H-1,2,3-triazol-4-ylthio, 1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-tnazoE3-ylthio or 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio, tetrazolylthio e.g. B. 



     1H-tetrazol-5-ylthio, or by lower alkyl, e.g. B.  Methyl or ethyl, or substituted lower alkyl, e.g. B.    Ethyl or diethylphosphonomethyl, carboxyethyl, sulfomethyl, 2-sulfoethyl, 2-dimethylaminoethyl or cyanomethyl, substituted tetrazolylthio z. B. 

  I-methyl-1H-tetrazol-5-ylthio, l-ethyl- or I-diethylphosphonomethyl-1H-tetrazol-5-yl-thio, l-carboxymethyl-lHtetrazol-5-ylthio, 1- (2-carboxy-ethyl) - IH-tetrazol-5-ylthio, l-sulfomethyl-lH-tetrazol-5-yl-thio, 1- (2-sulfoethyl) - lH-tetrazol-5-ylthio, 1- (2-dimethylaminoethyl) - lH -tetrazol-5-ylthio or l-cyanomethyl-1H-tetrazol-5-ylthio, thiazolylthio or by lower alkyl, e.g. B. 



  Methyl, substituted thiazolylthio, e.g. B.    2-thiazolylthio or 4,5-dimethyl-2-thiazolylthio, isothiazolylthio, e.g. B. 



  3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, thiadiazolylthio or by lower alkyl, e.g. B.  Methyl, substituted thiadiazolylthio e.g. B.  1,2,3-thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4-thiadiazol- 5-ylthio, 1,2,4-thiadiazol-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thiatriazolylthio, e.g. B. 



     1,2,3,4-thiatriazol-5-ylthio, oxazolylthio or by lower alkyl, e.g. B.  Methyl, substituted oxazolylthio, e.g. B.  2- or 5-oxazolylthio, or 4-methyl-5-oxazolylthio by lower alkyl, e.g. B.  Methyl, substituted isooxazolylthio, e.g. B. 



     3-methyl-5-isooxazolylthio, or oxadiazolylthio or by lower alkyl, e.g. B.  Methyl, substituted oxadiazolylthio, e.g. B.    1,2,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-oxadiazol-5-ylthio.    



   A heterocyclylthio group R2, in which the heterocyclic radical is an aromatic, monocyclic, six-membered radical, contains 1-3 nitrogen atoms and is, for example, 5,6-dioxotetrahydro-as-triazinylthio or by lower alkyl, e.g. B.  Methyl, carboxy lower alkyl, e.g. B.  Carboxymethyl, or by sulfone lower alkyl, e.g. B. 

  Sulfomethyl, substituted 5,6-dioxotetrahydro-asianzinylthio, e.g. B.  1 or 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-yl-thio, 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro -as- triazin-3-yl-thio, 1- or 2-carboxymethyl-5,6-dioxo-1,2,5,6-tetrahydro as-triazin-3-ylthio, 4-carboxymethyl-5,6-dioxo - 1,4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-sulfomethyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4 -Sulfomethyl- 5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio. 

 

   A heterocyclylthio group R2 in which the heterocyclic radical is an aromatic or partially saturated, bicyclic radical containing five or six ring atoms per ring is, for example, indolylthio, by lower alkyl, e.g. B.  Methyl, substituted indolylthio, e.g. B.    Indol-2-yl-thio or N-methylindol-2-ylthio, isoindolylthio, e.g. B.  Isoindol-2-ylthio, quinolylthio, e.g. B.    2-, 4- or 8-quinolylthio, benzimidazolylthio, by lower alkyl, e.g. B.  Methyl or carboxy lower alkyl, e.g. B.  Carboxymethyl, substituted benzimidazolylthio, e.g. B.  1-methyl-, l-carboxymethyl or 1- (2-carboxyethyl) benzimidazol-2-ylthio, benzotriazolylthio, by lower alkyl, e.g. B. 

  Methyl, or carboxy lower alkyl, e.g. B.  Carboxymethyl, substituted benzotriazolylthio, e.g. B.  1-methyl- or l-carboxymethyl-1H-benzo [d] -triazol5-ylthio, or in particular tetrazolopyridazinylthio, by lower alkyl, e.g. B.  Methyl or ethyl, carboxy, carboxy lower alkyl, e.g. B.  Carboxymethyl, carbamoyl, lower alkylcarbamoyl, e.g. B.  Methyl carbamoyl, di-lower alkyl carbamoyl, e.g. B.  Dimethylcarbamoyl, amino, lower alkylamino, e.g. B.  Methylamino, di-lower alkylamino, e.g. B.  Dimethylamino or diethylamino substituted tetrazolopyridazinylthio, e.g. B.  8-methyl, 8-ethyl, 8-carboxy, 8-carboxymethyl, 8- (2-carboxyethyl) -, 8-carbamoyl, 8- (N-methylcarbamoyl) -, 8- (N, N- Dimethylcarbamoyl) -, 8-amino-, 8-dimethylamino- or 8-diethylaminotetrazolo [1,5-b] pyridazin-6-ylthio. 



   An ammonio group R2 is derived from a tertiary organic base, for example from an aliphatic amine or preferably from a heterocyclic nitrogen base, and is bonded via the nitrogen atom to the methylene group located in the 3-position of the cephem skeleton. 



   The positive charge on the quaternary nitrogen atom is compensated for by the negatively charged carboxylate group located in the 4-position of the cephem structure. 



   An ammonio group R2 which is derived from an aliphatic amine is, for example, tri-lower alkylam monio, e.g. B.  Trimethyl or triethylammonio. 



   A quaternary ammonio group R2, which is derived from an unsubstituted or substituted heterocyclic nitrogen base, is, for example, unsubstituted or by lower alkyl, for. B.  Methyl or ethyl, lower alkenyl, e.g. B.  Vinyl or allyl, carboxy lower alkyl, e.g. B.  Carboxymethyl, lower alkoxycarbonyl-lower alkyl, e.g. B.  Methoxycar bonylmethyl, sulfoniederalkyl, e.g. B. 

  Sulfomethyl, amino lower alkyl, e.g. B.  2-aminoethyl, or di-lower alkylamino lower alkyl, e.g. B.  2-dimethylaminoethyl, l-pyrazolio substituted in the 2-position, e.g. B.  2-methyl- or 2-ethyl-l-pyrazolio, 2-A1-lyl- or 2-vinyl-l-pyrazolio, 2-carboxymethyl-l-pyrazolio, 2-methoxycarbonylmethyl-I-pyrazolio, 2-sulfometh yl-l -pyrazolio, 2- (2-aminoethyl) - l-pyrazolio or 2- (2-dimethylaminoethyl) - l-pyrazolio.    



   An ammonio group R2, which is derived from a heterocyclic nitrogen's rule, is also, for example, l-triazolio or by lower alkyl, for. B.  Methyl or ethyl, carboxy lower alkyl, e.g. B.  Carboxymethyl or di-lower alkyl amino lower alkyl, e.g. B.  2-dimethylaminoethyl, l-triazolio substituted in the 3-position, e.g. B.    3-methyl-l-triazolio, 3-carb oxymethyl-l-triazolio or 3- (2-dimethylaminoethyl) 1-triazolio.    



   An ammonio group R2, which is derived from an unsubstituted or substituted heterocyclic nitrogen base, is also, for example, pyridinio or by lower alkyl, e.g. B.  Methyl, carbamoyl, lower alkylcarbamoyl, e.g. B.  Methyl carbamoyl, hydroxy lower alkyl, e.g. B.  Hydroxymethyl, lower alkoxy lower alkyl, e.g. B.  Methoxymethyl, cyano-lower alkyl, e.g. B.  Cyanomethyl, carboxy lower alkyl, e.g. B. 



   Carboxymethyl, sulfone lower alkyl, e.g. B.  2-sulfoethyl, carboxy lower alkenyl, e.g. B.  2-carboxyvinyl, carboxy-lower alkyl thio, e.g. B.  Carboxymethylthio, thiocarbamoyl, halogen, e.g. B. 



   Bromine or chlorine, carboxy, sulfo or cyano mono- or disubstituted pyridinio, e.g. B.  Lower alkyl pyridinio, e.g. B.  2-, 3 or 4-methylpyridinio or 2-, 3- or 4-ethylpyridinio, carbamoylpyridinio, e.g. B.  3- or 4-carbamoylpyridinio, lower alkylcarbamoylpyridinio, e.g. B.  3- or 4-methylcarbamoylpyridinio, Diniederalkylcarbamoylpyridinio, e.g. B.  3 or 4-dimethylcarbamoylpyridinio, hydroxy-lower alkylpyridinio, e.g. B.  3- or 4-hydroxymethylpyridinio, lower alkoxy-lower alkylpyridinio, e.g. B.  4-methoxymethylpyridinio, cyano-lower alkylpyridinio, e.g. B.     3-cyanomethylpyridinio, carboxy-lower alkylpyridinio, e.g. B.  3-carboxymethylpyridinio, sulfoniederalkylpyridinio, e.g. B.  4- (2-sulfoethylpyridinio), carboxy-lower alkenylpyridinio, e.g. B.  3- (2-carboxyvinyl) pyridinio, carboxy-lower alkylthiopyridinio, e.g. B. 

   4-carb oxymethylthiopyridinio, thiocarbamoylpyndinio, e.g. B. 



  4-thiocarbamoylpyridinio, halopyridinio, e.g. B.  3-bromo or 4-bromopyridinio, carboxypyridinio, e.g. B.    4-carboxypyridinio, sulfopyridinio, e.g. B.  3-sulfopyridinio, cyanopyridinio, e.g. B.  3-cyanopyridinio, carboxy-lower alkyl-carbamoylpyridinio, e.g. B.    3-carboxymethyl-4-carbamoylpyridinio, aminocarbamoylpyndinio, e.g. B.    2-amino-5-carbamoylpyndinio, carboxycarbamoylpyridinio, e.g. B.  3-carboxy-4-carbamoylpyridinio, cyanohalomethylpyridinio, e.g. B.  3-cyano-4-trifluoromethylpyndinio or amino-carboxypyridinio, e.g. B. 



     2-amino-3-carboxypyridinio.    



   A quaternary ammonio group R2 is preferably 2-lower alkyl-1-pyrazolio, e.g. B.  2-methyl-l-pyrazolio, 2-carboxy-lower alkyl-l-pyrazolio, e.g. B.  2-carboxymethyl-1-pyrazolio, 3-lower alkyl-i-triazolio, e.g. B.    3-methyl-1-triazolio, pyridinio or by hydroxy lower alkyl, e.g. B.  Hydroxymethyl, carboxy, carboxy lower alkyl, e.g. B.  Carboxymethyl, halogen, e.g. B.  Chlorine or bromine, or carbamoyl substituted pyridinio, e.g. B.  3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3- or 4-carbamoylpyridinio. 



   R3 with the meaning protected carboxyl is carboxyl esterified by one of the carboxyl protective groups described below, in particular esterified carboxyl which is cleavable under physiological conditions. 



   A substituted or unsubstituted hydrocarbon radical R4 has up to 20 carbon atoms and is primarily a saturated or unsaturated, aliphatic, cycloaliphatic or cycloalaliphatic-aliphatic hydrocarbon radical, e.g. B.  Lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl, or is an aromatic or aromatic-aliphatic hydrocarbon radical, e.g. B.  Phenyl or phenyl-lower alkyl. 



   Substituents of the lower alkyl radical R4 are, for example, etherified hydroxy, for. B.  Lower alkoxy, e.g. B.  Methoxy or ethoxy, lower alkanoyloxy, e.g. B.  Acetyloxy, halogen, e.g. B. 



  Fluorine or chlorine, etherified mercapto, e.g. B.  Lower alkylthio, e.g. B.  Methylthio, lower alkylsulfonyl, e.g. B.  Methylsulfonyl or ethylsulfonyl, arylsulfonyl, e.g. B.  Phenylsulfonyl, lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or athoxycarbonyl, lower alkylcarbamoyl, e.g. B.  Methyl carbamoyl, di-lower alkyl carbamoyl, e.g. B.  Dimethylcarbamoyl, carbamoyl, lower alkylsulfamoyl, e.g. B.  Methylsulfamoyl, di-lower alkylsulfamoyl, e.g. B.  Dimethylsulfamoyl, sulfamoyl, cyano, nitro, amine, lower alkanoylamino, e.g. B.  Acetylamino, lower alkylamino, e.g. B.  Methyl or ethylamino, and di-lower alkylamino, e.g. B.  Dimethylamino. 

 

   Substituted lower alkyl R4 is, for example, lower alkoxy lower alkyl, e.g. B.    Lower alkoxymethyl or lower alkoxy ethyl, e.g. B.  Methoxymethyl or 2-methoxyethyl, lower alkanoyloxy lower alkyl, e.g. B.    Lower alkanoyloxymethyl or lower alkanoyloxyethyl, e.g. B.  Acetyloxymethyl or 2-acetyloxyethyl, halogeno lower alkyl, e.g. B.    Halogen methyf or halogen ethyl, e.g. B.  Trifluoromethyl, chloromethyl, 2-chloroethyl or 2,2,2-trichloroethyl, lower alkylthio-lower alkyl, e.g. B.    Lower alkylthlomethyl, e.g. B.  Methylthiomethyl, lower alkylsulfonyl-lower alkyl, e.g. B.  Lower alkylsulfonylmethyl or lower alkylsulfonylethyl, e.g. B.  Methylsulfonylmethyl or 2-methylsulfonylethyl, arylsulfonyl-lower alkyl, e.g. B.  Arylsulfonylmethyl, e.g. B. 

  Phenylsulfonylmethyl, lower alkoxycarbonyl-lower alkyl, e.g. B.    Niederalkoxycarbonyl-methyl, e.g. B.  Methoxycarbonylmethyl or ethoxycarbonylmethyl, lower alkylcarbamoyl-lower alkyl, e.g. B.  Niederalkylcarbamoylmethyl or Mederalkylcarbamoyläthyl, e.g. B. 



     Methylcarbamoylmethyl or 2-methylcarbamoylethyl, di lower alkylcarbamoyl lower alkyl, e.g. B.    Diniederalkylcarb- amoylmethyl or Diniederalkylcarbamoyläthyl, e.g. B.  Di methylcarbamoylmethyl or 2-dimethylcarbamoylethyl, carbamoyl-lower alkyl, e.g. B.  Carbamoylmethyl or 2-carbamoylethyl, lower alkylsulfamoyl-lower alkyl, e.g. B.  Lower alkylsulfamoy} methyl or lower alkylsulfamoylethyl, e.g. B. 



     Methylsulfamoylmethyl or 2-methylsulfamoylethyl, di lower alkylsulfamoyl-lower alkyl, e.g. B.    Di-lower alkyl-sulf amoylmethyl or di-lower alkyl sulfamoylethyl, e.g. B. 



  Dimethylsulfamoylmethyl or 2-dimethylsulfamoylethyl, sulfamoyl-lower alkyl, e.g. B.  Sulfamoylmethyl or 2-sulfamoylethyl, cyano-lower alkyl, e.g. B.    Cyanomethyl or 2-cyanoethyl, nitro-lower alkyl, e.g. B.    Nicomethyl or 2-mtroethyl, amino lower alkyl, e.g. B.  Aminomethyl or 2-aminoethyl, Mederalkanoylaminoniederalkyl, e.g. B.  Acetylamino lower alkyl, e.g. B.  Acetylaminomethyl or 2-acetylaminoethyl, mederalkylamino lower alkyl, e.g. B.    Methylamino lower alkyl, e.g. B. 

  Methylaminomethyl or 2-methylaminoethyl, or di-lower alkylamino lower alkyl, e.g. B.    Dimethylamino lower alkyl, e.g. B.  Dimethylaminomethyl or 2-dimethylaminoethyl. 



     Lower alkenyl contains 2-4 carbon atoms and is, for example, vinyl, allyl, l-butenyl, 2-cis-butenal or isobutenyl.  Substituted mederalkenyl can be substituted by the same groups as substituted lower alkyl. 



     Cycloalkyl R4 contains 3-7 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 



   Cycloalkenyl R4 contains 3-7 carbon atoms and is, for example, cyclohecenyl, e.g. B.    1-Cydohexenyl, or Cy clohexadienyl, e.g. B.  1,4-cydohexadienyl.    



     Cycloalkyl-lower alkyl R4 contains 4-7 carbon atoms and is, for example, cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl or 2-cyclohexylethyl. 



     Cycloalkenyl-lower alkyl R4 contains 99 carbon atoms and is, for example, 1-cyclohexenylmethyl or 1,4-cyclohexadienylmethyl. 



   Substituents of the phenyl radical R4 are, for example, lower alkyl with 1-4 C atoms, e.g. B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -Butyl, hydroxy, lower alkoxy, e.g. B.  Methoxy or ethoxy, protected by conventional protecting groups or by lower alkyl, e.g. B. 



  Methyl or ethyl, esterified carboxy, amino, carbamoyl, halogen, e.g. B.  Fluorine, chlorine, bromine or iodine, sulfo, sulfamoyl, mederalkylthio, e.g. B methylthio or ethylthio, trifluoromethyl or aminosulfinyl.  Substituted phenyl-lower alkyl is also substituted on the phenyl radical by these substituents. 



   Substituted phenyl R4 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, 4-nitrophenyl or 4-aminophenyl. 



   Phenyl-lower alkyl R4 is, for example, benzyl, 2-phenyl ethyl, diphenylmethyl or trityl. 



   Substituted phenyl-lower alkyl R4 is, for example, 2-, 3- or 4-methylphenylmethyl, 2,3-, 2,4- or 3,4-dimethylphenylmethyl, 4-mtrophenylmethyl or 4-aminophenylmethyl. 



   An acyl group R4 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, a substituted thiocarbamic acid, a sulfonic acid, the amidosulfonic acid or a substituted amidosulfonic acid, e.g. B.  the acyl group of a carboxylic acid, for example lower alkanoyl, e.g. B.  Formyl or acetyl, lower alkanoyl substituted by hydroxy or amino, e.g. B.  a-hydroxypropionyl or glycyl, lower alkanoyl substituted by carboxy and amino, e.g. B.  3-amino 3-carboxypropionyl, cycloalkanoyl, e.g. B.  Cyclopentanoyl, benzoyl, phenyl-lower alkanoyl, wherein lower alkanoyl in the cs position to the phenyl radical is substituted by hydroxy or amino, e.g. B. 

  Mandeloyl or phenylglycyl, the acyl group of a half ester of carbonic acid, for example lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or isopropoxycarbonyl, lower alkanoyloxy substituted by carboxy and amino, e.g. B.    2-amino-2-carboxyethoxycarbonyl, or benzoyloxycarbonyl, the acyl group of a substituted carb amino acid, for example mederalkylcarbamoyl, e.g. B.  Methylcarbamoyl, or anilinocarbonyl, the acyl group of a substituted thiocarbamic acid, e.g. lower alkylthiocarbamoyl, e.g. B.  Methylthiocarbamoyl, or is the acyl group of a substituted amidosulfonic acid, e.g. lower alkylsulfonylamino, e.g. B.  Methylsulfonylamino, phenylsulfonylamino, aminophenylsulfonylamino, e.g. B. 



     4-aminophenylsulfonylamino. 



   In a methylene group A which is substituted by protected amino, hydroxy or sulfo, the aminomethylene, hydroxymethylene or sulfomethylene group in question is protected by the amino, hydroxy or sulfo protective groups described below. 



   The group of the formula -O-R5 is in the syn (or Z) position or anti (or E) position, the syn (or Z) position being preferred.  In the syn position, {) R5 is loosely porous to the cepha and in the anti position, it is directed opposite.    



   Lower alkyl R5 preferably has 1-4 carbon atoms and is, for example, ethyl, propyl, butyl or in particular methyl. 



   Cycloalkyl R5 preferably has 3-8, primarily 3-6, ring members and is e.g. B.  Cyclobutyl, cyclopentyl, cyclohexyl or especially cyclopropyl. 



   Substituents of a lower alkyl group or cycloalkyl group R5 are u. a.  free or etherified hydroxy, e.g. B. 



     Lower alkoxy, primary, secondary or tertiary amino, e.g. B.  Amino or di-lower alkylamino, free or functionally modified, e.g. B.  esterified, amidated or protected, carboxyl or sulfo, and optionally ureidocarbonyl which is N-substituted by lower alkyl.  A substituted lower alkyl and cycloalkyl group R5 is preferably substituted by a carboxyl or sulfo group, these preferably being on the carbon atom which is connected to the oxygen atom of the oximino group. 



   Substituted lower alkyl or cycloalkyl R5 is, for example, 2-aminoethyl, 2-dimethylaminoethyl, carboxymethyl, 1- or 2-carboxyethyl, 1-, 2- or 3-carboxyprop1-yl, 1- or 2-carboxyprop-2-yl, 2-carboxycycloprop -2-yl or 1- or 2-carboxycyclobut-1-yl, as well as a corresponding sulfo-substituted alkyl and cycloalkyl group. 

 

   The carboxy and sulfo groups in the radical Rs can be, for example, by mineral alkyl, e.g. B.  Methyl or ethyl, or by a physiologically removable group, e.g. B.  by pivaloyloxymethyl, esterified or by NH3, a primary or secondary amine, e.g. B.  a mono- or di-lower alkyl amine, e.g. B.  Methyl or ethylamine or dimethyl or diethylamine, be amidated or protected by the usual protective groups mentioned below. 



   A cycloalkenyl group R5 contains 3 to 8, preferably 3 to 6, ring members and is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.   



   Niederalkenyl R5 is in particular allyl, also vinyl, 1-propenyl or 1-, 2- or 3-butenyl. 



   Substituted carbamoyl R5 is for example a group of the formula -C (= O) -NHR, where R is lower alkyl, e.g. B.  Methyl, ethyl or 1- or 2-propyl, carboxy lower alkyl, e.g. B.  Carboxymethyl, 1- or 2-carboxyethyl or 1-, 2 or 3-carboxypropyl, in which the carboxy group is in free form or protected by one of the customary carboxy protective groups or, for example, by lower alkyl, e.g. B. 



  Methyl, ethyl, n- or isopropyl, or n- or tert. -Butyl is esterified, sulfono lower alkyl, e.g. B; Sulfomethyl, 1- or 2-sulfoethyl or 1-, 2- or 3-sulfopropyl, in which the sulfo group is in free form or protected by one of the usual sulfo protecting groups or for example by lower alkyl, e.g. B.  Methyl or ethyl is esterified, hydroxy lower alkyl, e.g. B. 

  Hydroxymethyl, 2-hydroxyethyl or 2- or 3-hydroxypropyl, in which the hydroxyl group is in free form or protected by one of the usual hydroxyl protective groups or, for example, acylated, e.g. B.  is acetylated, amino lower alkyl, e.g. B.  2-aminoethyl, 2- or 3-aminopropyl or 2-, 3- or 4-aminobutyl, in which the amino group is present in free form or protected by one of the usual amino protecting groups or, for example, acylated, e.g. B.  is acetylated, aryl-lower alkyl, for example phenyl-lower alkyl, e.g. B.  Benzyl or 1- or 2-phenylethyl, halogen-lower alkyl, for example fluorine, chloro or bromo-lower alkyl, e.g. B. 



  2-chloropropyl or 4-chlorobutyl, aryl, e.g. B.  Phenyl, or by lower alkyl, e.g. B.  Methyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine or nitro, mono- to trisubstituted phenyl. 



   The functional groups present in the compounds of the formulas IA and IB, in particular the carboxyl and amino, furthermore the hydroxyl and sulfo groups, are optionally protected by conventional protective groups (= conventional protecting groups) which are active in the penicillin, cephalo and and peptide chemistry can be used. 



   Such protective groups are easy to remove, that is to say without undesirable side reactions taking place, for example sol volytically, reductively, photolytically or even under physiological conditions. 



   Protective groups of this type and their splitting off are, for example, in Protective Groups in Organic Chemistry, Ple num Press, London, New York, 1973, and also in The Peptides des, Vol.  I, Schröder and Lubke, Academic Press, London, New York 1965, and in Methods of Organic Chemistry, Houben-Weyl, 4.  Edition, vol.  15/1, Georg Thieme
Verlag, Stuttgart, 1974. 



   A carboxyl group, e.g. B.  the carboxyl group R3, furthermore a carboxyl group present in Rl, A or R4 is usually protected in esterified form, the ester group being easily cleavable under mild conditions. 



   A carboxyl group protected in esterified form is esterified in the first place by a lower alkyl group which branches in the 1-position of the lower alkyl group or in 1- or
2-position of the lower alkyl group is substituted by suitable substituents. 



   A protected carboxyl group, which is protected by a
Lower alkyl group is esterified, which is in the 1-position of the
Lower alkyl group is branched, for example, is tert. -Lower alkoxycarbonyl, e.g. B.  tert. -Butyloxycarbonyl, Arylmeth oxycarbonyl with one or two aryl radicals, wherein aryl un substituted or z. B.  by lower alkyl, e.g. B.  tert. -Lower alkyl, e.g. B.  tert. -Butyl, lower alkoxy, e.g. B.  Methoxy, hydroxy,
Halogen, e.g. B.  Chlorine, and / or nitro, mono- or polysubstituted phenyl means, for example unsubstituted or z. B.  substituted benzyloxycarbonyl as mentioned above, e.g. B.    



     4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycar bonyl, or unsubstituted or z. B.  as mentioned above substituted diphenylmethoxycarbonyl, e.g. B.  Diphenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl. 



   A protected carboxyl group which is esterified by a lower alkyl group which is substituted in the 1- or 2-position of the lower alkyl groups by suitable substituents is, for example, l-lower alkoxy-lower alkoxycarbonyl, e.g. B.  Methoxymethoxycarbonyl, 1 -Methoxyäthoxycarbonyl or l-Athoxymethoxycarbonyl, I-Mederalkylthioniedalkoxycarbonyl, z. B.    I-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is unsubstituted or z. B.  benzoyl substituted by halogen such as bromine, e.g. B.  Phenacyloxycarbonyl, and 2-halogeno lower alkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl. 



   A carboxyl group can also be protected as an organic silyloxycarbonyl group.  A silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. B.  Trimethylsilyloxycarbonyl.  The silicon atom of the silyloxycarbonyl group can only be replaced by two lower alkyl groups, e.g. B.  Methyl groups, and the carboxyl group or amino group of a second molecule of formula I may be substituted.  Connections with such protective groups can be e.g. B.  when using dimethyldichlorosilane as a silylating agent. 



   A preferred protected carboxyl group is, for example, tert. -Lower alkoxycarbonyl, e.g. B.  tert. -Butyloxycarbonyl, unsubstituted or, as mentioned above, substituted benzyloxycarbonyl, e.g. B.    4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl. 



   An esterified carboxyl group R3 which is cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group, in which acyl, e.g. B.  is the acyl group of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the remainder of a lactone. 



   Such a group is, for example, lower alkanoyloxymethoxycarbonyl, e.g. B.  Acetyloxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, lower alkoxycarbonyloxy lower alkoxycarbonyl, e.g. B.    I-ethoxycarbonyloxy-ethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, in particular a-amino-lower alkanoyloxymethoxycarbonyl, e.g. B.  Glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, furthermore phthalidyloxycarbonyl, e.g. B.  2-phthalidyloxycarbonyl, or indanyloxycarbonyl, e.g. B.  5-indanyloxycarbonyl. 



   An amino group, e.g. B.  the amino group on the imidazolyl radical, z. B.  be protected in the form of an easily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group. 



   In an easily cleavable acylamino group, acyl is, for example, the acyl group of an organic carboxylic acid having up to 18 carbon atoms, in particular an unsubstituted or a, for. B.  by halogen or aryl, substituted alkane carboxylic acid or the unsubstituted or, for. B.  by halogen, lower alkoxy or nitro, substituted benzoic acid or a carbonic acid semi-ester.  Such an acyl group is, for example, lower alkanoyl, e.g. B.  Formyl, acetyl, or propionyl, halogen-lower alkanoyl, e.g. B.    2-haloacetyl, especially 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, unsubstituted or z. B. 

 

  benzoyl substituted by halogen, lower alkoxy or nitro, e.g. B.  Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched in the position of the lower alkyl radical or suitably substituted in the 1- or 2-position. 



   Lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical is, for example, tert. -Lower alkoxycarbonyl, e.g. B.  tert. -Butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, wherein aryl is preferably unsubstituted or z. B.  by lower alkyl, especially tert. -Lower alkyl, e.g. B.  tert. -Butyl, lower alkoxy, e.g. B.  Methoxy, hydroxy, halogen, e.g. B.  Chlorine, and / or nitro, mono- or polysubstituted phenyl means, for example unsubstituted or substituted diphenylmethoxycarbonyl, e.g. B. Benzhydroyloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl. 



   Lower alkoxycarbonyl suitably substituted in the 1- or 2-position is, for example, tri-lower alkylsilyloxycarbonyl, e.g. B.  Trimethylsilyloxycarbonyl, aroylmethoxycarbonyl, wherein aroyl is unsubstituted or z. B.  by halogen, e.g. B. 



  Bromine, substituted benzoyl, e.g. B.  Phenacyloxycarbonyl, 2-halogeno lower alkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl, wherein the substituents are each independently an unsubstituted or e.g. B.  by lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 15 carbon atoms, for. B.  unsubstituted or, as mentioned above, substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxycarbonyl, e.g. B.  2-trimethylsilyl ethoxycarbonyl or 2- (n-butyldimethylsilyl) - ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, e.g. B.  2-triphenylsilylethoxycarbonyl. 



   Other acyl groups that are suitable as amino protecting groups are also acyl groups of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl, e.g. B.  Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl e.g. B.  Dicyclohexylphosphoryl, Diphenylphosphoryl, unsubstituted or z. B.  diphenyl-lower alkylphosphoryl substituted by nitro, e.g. B.  Dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, phenyloxyphenylphosphonyl, di-lower alkylphosphinyl, e.g. B.  Diethylphosphinyl, also diphenylphosphinyl. 



   In an arylmethylamino group which is mono-, di- or in particular triarylmethylamino, the aryl radicals are in particular phenyl radicals.  Such groups are, for example, benzyl, diphenylmethyl and in particular tritylamino. 



   In an etherified mercaptoamino group, the etherified mercapto group is primarily arylthio or aryl lower alkylthio, in which aryl is in particular unsubstituted or z. B.  by lower alkyl, e.g. B.  Methyl or tert. -Butyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine, and / or nitro substituted phenyl.  Such an amino protecting group is e.g. B.  4-nitrophenylthio. 



   In a 2-acyl-lower alk-1-en-yl group which can be used as an amino protecting group, acyl is e.g. B.  the acyl group of a lower alkane carboxylic acid, the unsubstituted or z. B. 



  by lower alkyl, e.g. B.  Methyl or tert. -Butyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine, and / or nitro substituted benzoic acid, or in particular the acyl group of a carbonic acid semi-ester, e.g. B.  a carbonic acid lower alkyl half ester.  Such amino protecting groups are primarily 1-Niederalkanoylprop- 1 -en-2-yl, z. B.    1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1 -en-2-yl, e.g.  1 ethoxycarbonylprop-1-en-2-yl.    



   A silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. B.    Trimethylsilylamino.     The silicon atom of the silylamino group can also be replaced only by two lower alkyl groups, e.g. B.  Methyl groups, and the amino group or carboxyl group of a second molecule of the formula IA or IB may be substituted.  Connections with such protective groups can be e.g. B.  when using dimethyldichlorosilane as a silylating agent. 



   An amino group can also be protected in protonated form.  The anions are primarily the anions of strong inorganic acids, such as hydrogen halides, eg. B.  the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid, in question. 



   A preferred amino protecting group is, for example, the acyl residue of a carbonic acid semi-ester, especially tert.  Butyloxycarbonyl, unsubstituted or e.g. B.  substituted benzyloxycarbonyl as indicated, e.g. B.    4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl, 2-halogeno lower alkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, also trityl or formyl. 



   A hydroxy group, e.g. B.  the hydroxy group in the hydroxyimino group = N + Rs (R5 = hydrogen), for example by an acyl group, e.g. B.  lower alkanoyl substituted by halogen, e.g. B.  2,2-dichloroacetyl, or in particular be protected by an acyl radical of a carbonic acid semiester mentioned in connection with protected amino groups.  A preferred hydroxyl protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, an organic silyl radical with the substituents mentioned above, and also an easily removable etherifying group, such as tert.  Lower alkyl, e.g. B.  tert. -Butyl, 2-oxa- or a 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. B. 

  Methoxymethyl, l-methoxyethyl, 1 ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl with 97 ring atoms, e.g. B.  2-tetrahydrofuryl or 2-tetrahydropyranyl or a corresponding thia analogue, and unsubstituted or substituted 1-phenyl-lower alkyl, e.g. B.  unsubstituted or substituted benzyl or diphenylmethyl, the phenyl radicals for example by halogen, such as chlorine, lower alkoxy, e.g. B.  Methoxy, and / or nitro are substituted. 



   A sulfo group, e.g. B.  a sulfo group present in R2 is preferably replaced by an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, e.g. B.  by lower alkanol, e.g. B. 



  tert. -Butanol, or through a silyl group, e.g. B.  esterified by tri-lower alkylsilyl.  A sulfo group is e.g. B.  protected analogously to a carboxy group. 



   Salts of compounds according to the invention are primarily pharmaceutically usable, non-toxic salts of compounds of the formula IA and IB. 



   Such salts are, for example, from the acidic groups present in compounds of the formula IA and IB, e.g. B. 



  of carboxyl or sulfo groups, and are primarily metal or ammonium salts, for example alkali metal and alkaline earth metal, e.g. B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic, primary, secondary or tertiary mono-, di- or polyamines , as well as heterocyclic bases for salt formation. 

 

  Such bases are, for example, lower alkylamines, e.g. B.  Triethylamine, hydroxy-lower alkylamines, e.g. B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B. 



  4-aminobenzoic acid 2-diethyldiaminoäthylester, Niederalkylenamine, z. B.    1 -Athylpiperidine, cycloalkylamines, e.g. B. 



  Dicyclohexylamine, or Benzylamine, e.g. B.  N, N'-dibenzyl ethylenediamine, furthermore bases of the pyridine type, e.g. B.  Pyridine, collidine or quinoline.   



   The basic groups present in the compounds of the formula IA and IB, e.g. B.  Amino groups, acid addition salts, e.g. B.  with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. B.  Form trifluoroacetic acid, as well as with amino acids such as arginine and lysine. 



   Are in compounds of formula IA and IB several acidic groups, for. B.  two carboxyl groups, or more basic groups, e.g. B.  two amino groups, before, mono- or poly-salts can be formed.  If the compounds of formula Ia and IB at least one acidic group, e.g. B.  the carboxyl group R3, and at least one basic group in free form, e.g. B.  the free amino group in the 2-position of the oxazolyl radical, compounds of the formula IA or IB can be present in the form of an inner salt.  In compounds of the formula IA or IB, an acidic and a basic group in the form of an inner salt and additionally acidic and / or basic groups can be present, for example as an acid addition and / or base addition salt. 



   For isolation or purification, pharmaceutically unsuitable salts can also be used.  Only pharmaceutically usable, non-toxic salts are used for therapeutic purposes, which are therefore preferred. 



   The compounds of the formulas IA and IB, in which the functional groups are in free form and the carboxyl groups are optionally in physiologically cleavable esterified form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotically active substances which can be used in particular as antibacterial antibiotics .  For example, they are in vitro against gram-positive and gram-negative microorganisms, including ss-lactamase-producing strains, for example against gram-positive cocci, e.g. B.  against Staphylococcus aureus or streptococci, e.g. B.    Streptococcus pyrogenes, StrePtococcus pneumoniae or Streptococcus faecalis, against gram-negative cocci, e.g. B. 

  Neisseria gonorrhoeae, against gram-negative bacteria, for example Pseudomonas aeruginosa, Haemophilus influenza or against enterobacteria, e.g. B.  Escherichia coli, Proteus spp. , Klebsiella pneumoniae, Serratia marcescens or Enterobacter cloacae, effective.  In vivo, when used subcutaneously on the mouse, they are against systemic infections, which are caused by gram-positive germs such as Staphylococcus aureus and gram-negative germs such as enterobacteria, e.g. B.  Escherichia coli, caused to be effective. 



   Compounds of the formula IA and IB in which the functional groups are protected are used as intermediates for the preparation of compounds of the formula IA and IB in which the functional group is in free form or in which the 4-carboxyl group is in the form of a carboxyl group which can be cleaved under physiological conditions is present. 



   The present invention particularly relates to compounds of formula IA and IB, wherein R1 is hydrogen, lower alkyl, e.g. B.  Methyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine, or a group -CH2-R2, wherein R2 is lower alkanoyloxy, e.g. B.  Acetoxy, carbamoyloxy, N-lower alkylcarbamoyloxy, an aromatic, monocyclic, five or six-membered, diaza, triaza, tetraaza, thiaza, thiadiaza, thia, oxaza or oxadiazacyclylthio radical, e.g. B. 



  Triazolylthio, e.g. B.    1 H-1, 2,3-triazol-5-ylthio, tetrazolylthio, e.g. B.    1 H-tetrazol-5-ylthio, thiazolylthio, thiadiazolylthio, e.g. B.    1, 3,4-thiadiazol-5-yltnio, oxazolylthio, oxadiazolylthio or 5,6-dioxotetrahydro-as-triazinylthlo, e.g. B.  5,6-dioxo
1,2,5,6-tetrahydro-as-triazine-3-ylthio or 5,6-dioxo
1,4,5,6-tetrahydro-as-triazin- 3-ylthlo, which by lower alkyl, for. B.  Methyl, di-lower alkylamino lower alkyl, e.g. B.  Dimethylaminomethyl or 2-dimethylaminoethyl, sulfone lower alkyl, e.g. B.  Sulfomethyl, carboxy lower alkyl, e.g. B.  Carboxymethyl, amino, carboxy lower alkylamino, e.g. B.  2-carboxyethylamino, or may be substituted by carbamoyl, or ammonio, e.g. B.    2-lower alkyl-1-pyrazolio, e.g. B. 



     2-methyl-1-pyrazolio-, 2-carboxy-lower alkyl-1-pyrazolio, e.g. B.    2-carboxymethyl-1-pyrazolio, 3-lower alkyl-1-triazolio, e.g. B.  3-methyl-1-triazolio, pyridinio, by hydroxy lower alkyl, e.g. B.  Hydroxymethyl, carboxy, carboxy lower alkyl, e.g. B.  Carboxymethyl, halogen, e.g. B. 



  Chlorine or bromine, or carbamoyl substituted pyridinio, e.g. B.  3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3- or 4-carbamoylpyridinio, R3 carboxyl, carboxyl cleavable under physiological conditions, e.g. B.  Acyloxymethoxycarbonyl, e.g. B.  Lower alkanoyloxymethoxycarbonyl, e.g. B. 



  Lower alkanoyloxymethoxycarbonyl, e.g. B.  Pivaloyloxymethoxycarbonyl, or lower alkoxycarbonyloxy lower alkoxycarbonyl, e.g. B.    I-ethoxycarbonyloxyethoxycarbonyl, R4 lower alkyl, e.g. B.  Methyl, by hydroxy, lower alkoxy, e.g. B. 



  Methoxy, carboxy, lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or ethoxycarbonyl, amino, lower alkylamino, e.g. B. 



  Methylamino, carbamoyl, halogen, e.g. B.  Fluorine or chlorine, sulfo, lower alkylthio, e.g. B.  Methylthio, or lower alkyl substituted by aminosulfinyl, lower alkenyl, e.g. B.  Allyl, cycloalkyl, e.g. B.  Pentyl or hexyl, cycloalkenyl, e.g. B.    l-cyclohexenyl or 1,4-cyclohexadienyl, phenyl by halogen, e.g. B.  Chlorine, substituted phenyl, e.g. B.  2,3-, 2, P or 2,6-dichlorophenyl, phenyl-lower alkyl, e.g. B.  Benzyl or diphenylmethyl, or acyl, e.g. B.  Lower alkanoyl, e.g. B.  Acetyl, lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or ethoxycarbonyl, carbamoyl, lower alkylcarbamoyl, e.g. B.  Methyl carbamoyl, lower alkyl sulfonyl, e.g. B.  Methylsulfonyl or ethylsulfonyl, benzenesulfonyl or by lower alkyl, e.g. B. 



  Methyl, or halogen, e.g. B.  Chlorine, substituted benzenesulfonyl, e.g. B.  p-toluenesulfonyl or 4-methylbenzenesulfonyl and in compounds of the formula IA is hydrogen, and A is aminomethylene, hydroxymethylene, sulfomethylene or a methylene group substituted by a group = N-OR5, where R5 is hydrogen lower alkyl, e.g. B. 



  Methyl, carboxy lower alkyl, e.g. B.  2-carboxy-2-propyl, cycloalkenyl, e.g. B.  Cyclopentenyl, lower alkenyl, e.g. B.  Allyl, carbamoyl, lower alkylcarbamoyl, e.g. B.  Methyl carbamoyl or amino lower alkyl, e.g. B.  2-aminoethyl, the group -OR5 having the syn (or Z) position, and salts, in particular pharmaceutically acceptable salts, of compounds of the formula IA and IB which have salt-forming groups. 



   The present invention relates primarily to compounds of formula IA and IB, wherein R1 is hydrogen, lower alkyl, e.g. B.  Methyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine, or a group -CH2-R2, wherein R2 is lower alkanoyloxy, e.g. B.  Acetoxy, carbamoyloxy, triazolylthio, e.g. B. 



  1H-1,2,3-triazol-5-ylthio, tetrazolylthio, e.g. B.  1H-tetrazol 5-ylthlo, by lower alkyl, e.g. B.  Methyl, di-lower alkylamino lower alkyl, e.g. B.  2-dimethylaminoethyl, sulfone lower alkyl, e.g. B.  Sulfomethyl, carboxy lower alkyl, e.g. B.  Carboxymethyl, or tetrazolylthio substituted by carbamoyl, e.g. B. 

 

     I-methyl-1H-tetrazol-5-ylthlo, 1-sulfomethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio or 1- (2-dimethylaminoethyl) - 1H-tetrazol-5- ylthio, thiadiazolylthio, e.g. B.  1,3,4-thiadiazol-5-ylthio, by lower alkyl, e.g. B. 



  Methyl, substituted thiadiazolylthio, e.g. B.    2-methyl-1,3,4-thladiazol-5-yltliio, by lower alkyl, e.g. B.  Methyl, substituted 5,6-dioxotetrahydro-astriazin-3-ylthio, e.g. B. 



  2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazine-3-ylthlo or 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as- triazin-3-yl- thio, pyridinio or by hydroxy lower alkyl, e.g. B.  Hydr oxymethyl, carboxy, carboxy lower alkyl, e.g. B; Carboxymethyl, halogen, e.g. B.  Chlorine or bromine, or carbamoyl substituted pyiidinio, e.g. B.  3- or 4-hydroxymethylpyndino, 4-carboxypyridinio, 3- or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3- or 4-bromopyridinio or 3 or 4-carbamoylpyridinio means, R3 carboxyl, lower alkanoyloxymethoxycarbonyl, z. B.  Pivaloyloxymethoxycarbonyl, or lower alkoxycarbonyloxy lower alkoxycarbonyl, e.g. B.    1-ethoxycarbonyloxyethoxycarbonyl, R4 lower alkyl, e.g. B.  Methyl, carboxy lower alkyl, e.g. B. 

  Carboxymethyl or 2-carboxyethyl, di-lower alkylamino lower alkyl, e.g. B.  2-dimethylaminoethyl, lower alkoxycarbonyl, e.g. B.  Methoxy or ethoxycarbonyl, carbamoyl, lower alkenyl, e.g. B.  Allyl, phenyl, by halogen, e.g. B.  Chlorine, substituted phenyl, e.g. B. 



  2,3-, 2,4- or 2,6-dichloropbenyl, phenyl-lower alkyl, e.g. B. 



  Benzyl, or lower alkylsulfonyl, e.g. B.  Methylsulfonyl, and in compounds of the formula IA is hydrogen, and A is a methylene group substituted by the group = N-OR5, where R5 is hydrogen, lower alkyl, e.g. B.  Methyl, carboxy lower alkyl, e.g. B.  2-carboxy-2-propyl, lower alkenyl, e.g. B.  Allyl, carbamoyl or lower alkylcarbamoyl, e.g. B. 



  Methylcarbamoyl, where the group OR5 has the syn (or Z) position and where -A- is linked to the 4-position of the imidazolyl radical, and salts, in particular pharmaceutically acceptable salts, of compounds of the formula IA and IB, which have salt-forming groups. 



   The present invention relates primarily to compounds of formula IA and IB, wherein R1 is hydrogen, lower alkyl, e.g. B.  Methyl, lower alkoxy, e.g. B.  Methoxy, halogen, e.g. B.  Chlorine, or a group -CH2-R2, wherein R2 is lower alkanoyloxy, e.g. B.  Acetoxy, carbamoyloxy, tetrazolylthio, e.g. B. 



  1H-tetrazol-5-ylthio, by lower alkyl, e.g. B.  Methyl, di-lower alkylamino lower alkyl, e.g. B.  2-dimethylaminoethyl, sulfone lower alkyl, e.g. B.  Sulfomethyl, or carboxy lower alkyl, e.g. B.     Carboxymethyl, substituted tetrazolylthio, e.g. B. 



     1-methyl-lH-tetrazol-5-ylthio, 1- (2-dimethylaminoethyl) - 1H-tetrazol-5-ylthio, 1-carboxymethyl-lH-tetrazol-5-ylthio, l-sulfomethyl-lH-tetrazol- 5- ylthlo, or 1-carboxymethyl-1H-tetrazol-5-ylthio, thiadiazolylthio, e.g. B.  1,3,4-thiadiazol 5-ylthlo, or by lower alkyl, e.g. B.     Methyl, substituted thiadiazolylthio, e.g. B. 

   2-methyl-1,3,4-thiadiazol-5-ylthio, by lower alkyl, e.g. B.     Methyl, substituted 5,6-dioxotetrahydro-as- triazinylthio, e.g. B.    2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-astriazin-3-ylthio or 4-methyl-5,6-dioxo1,4,5,6-tetrahydro-astriazine 3-ylthlo, pyridinio or by hydroxy lower alkyl, e.g. B.  Hydroxymethyl, carboxy, carboxy lower alkyl, e.g. B.     Carboxymethyl, halogen, e.g. B. 

  Chlorine or bromine, or carbamoyl substituted pyridinio, e.g. B.  3 or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3 or 4-carboxymethylpyridinio, 3- or 4-chloropyridinio, 3 or 4-bromopyridinio or 3- or 4-carbamoylpyridinio means, R3 carboxy, lower alkanoyloxymethoxycarbonyl, e.g. B.     Pivaloyloxymethoxycarbonyl or Niederalkoxycarbonyloxyniederalkoxycarbonyl, e.g. B.    1-ethoxycarbonyloxy-ethoxycarbonyl, R4 lower alkyl, e.g. B.  Methyl, carboxy lower alkyl, e.g. B.     Carboxymethyl or 2-carboxyethyl, di-lower alkylamino lower alkyl, e.g. B.  2-dimethylaminoethyl, phenyl, by halogen, e.g. B.  Chlorine, substituted phenyl, e.g. B. 



  2,3-, 2,4- or 2,6-dichlorophenyl, or phenyl-lower alkyl, e.g. B.  Benzyl, and in compounds of the formula IA is hydrogen, and A is a methylene group substituted by the group = N-OR5, in which R5 is lower alkyl, e.g. B.    



  Methyl, carboxy lower alkyl, e.g. B.  2-carboxy-2-propyl, carbamoyl or lower alkylcarbamoyl, e.g. B.  Methylcarbamoyl, where the group 4-R5 has the syn (or Z) position and -A- is linked to the 4-position of the imidazolyl radical, and salts, in particular pharmaceutically acceptable salts, of compounds of the formulas 1A and IB, which have salt-forming groups. 



   Above all, the present invention relates to the compounds of the formula IA and IB and their salts described in the examples, in particular pharmaceutically usable salts. 



   Compounds of the formula IA and IB and salts of such compounds which have a salt-forming group are prepared, for example, by using a compound of the formula
EMI9. 1
 wherein R1 and R3 have the meanings given under formula I, with optional, intermediate protection of the 7ss-amino group and intermediate protection of functional groups present in R1 or in a salt thereof the 7ss-amino group by reaction with an acyl radical of a carboxylic acid of the formula
EMI9. 2nd
 introductory acylating agents, in which A and R4 have the meanings given under formulas LA and IB, with optional intermediate protection, functional groups present in A or with a salt thereof and, if desired, acylated

   an available salt is converted into the free compound or into another salt and / or an available free compound is converted into a salt. 



   In a starting material of formula II is a functional group present in R1, e.g. B.  a carboxyl, sulfo, amino or hydroxyl group, intermediately protected by one of the protective groups mentioned above. 



   The 7ss-amino group in a starting material of the formula II is optionally protected intermediately by a group which allows the acylation reaction.  Such a group is, for example, an organic silyl group and also a ylidene.    

 

  group which forms a Schiff base together with the amino group.  An organic silyl group is e.g. B.  such a group, which can also form a protected carboxyl group with a carboxyl group R3.  This is primarily a tri-lower alkylsilyl group, especially trimethylsilyl. 



  In the silylation to protect a 4-carboxyl group in a starting material of the formula II, the amino group can also be silylated if an excess of the silylating agent is used.  A ylidene group is primarily an l-aryl-lower alkylidene, in particular a 1-arylmethylene group, in which aryl is particularly a carbocyclic, primarily monocyclic, aryl radical, e.g. B.  for phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and / or nitro. 



   An acylating agent introducing the acyl radical of a carboxylic acid of the formula IIIA or IIIB is the carboxylic acid of the formula IIIA or IIIB itself or a reactive functional derivative or a salt thereof. 



   In a starting material of formula IIIA or IIIB a functional group present in R5, e.g. B.  a carboxyl, amino or hydroxyl group, which should not participate in the acylation reaction, is temporarily protected by one of the protective groups mentioned above. 



   In a starting material of the formula IIIA or IIIB, an existing amino group can also be temporarily protected in ionic form, e.g. B.  in the form of an acid addition salt, for example with a strong inorganic acid, e.g. B.  a hydrohalic acid, e.g. B.  Hydrochloric acid or sulfuric acid, or with an organic acid, e.g. B.  p-toluenesulfonic acid is formed. 



   If a free acid of the formula IIIA or IIIB is used for the acylation, the reaction is usually carried out in the presence of suitable condensing agents, such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl N, N'-dicyclohexyl or N -Ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3 'sulfonate or 2-tert. -Butyl-5-methyl-1,2-oxazolium-3 'sulfonate or 2-tert.  Butyl 5-methyl-1,2-oxazolium perchlorate, or a suitable acylamino compound, e.g. B.    2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline. 



   The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. B.  Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, with cooling or adult. poor, e.g. B.  in a temperature range from about - 40 C to about + 100 C, preferably from about - 20 C to about + 50 C, and / or in an inert gas, e.g. B.  Nitrogen atmosphere. 



   A responsive, i.e. H.  a carboxamide-forming, functional derivative of a carboxylic acid of the formula IIIA or IIIB is primarily an anhydride of the carboxylic acid of the formula IIIA or IIIB, preferably a mixed anhydride.  A mixed anhydride is, for example, by condensation with another acid, e.g. B.  an inorganic acid, e.g. B.  a hydrohalic acid, and is, for example, the corresponding carboxylic acid halide, for. B.  the carboxylic acid chloride or bromide.  A mixed anhydride is also formed by condensation with hydrochloric acid and is, for example, the carboxylic acid azide.  Other inorganic acids which are suitable for forming the mixed anhydride are phosphorus-containing acids, e.g. B.  Phosphoric acid, diethylphosphoric acid or phosphorous acid, sulfur-containing acids, e.g. B.  Sulfuric or hydrocyanic acid. 

  A reactive, functional derivative of a carboxylic acid of formula IIIA or IIIB is also ge by condensation with an organic carboxylic acid, z. B.  with an unsubstituted or halogen, e.g. B.  Fluorine or chlorine, substituted lower alkanecarboxylic acid, e.g. B.  Pivalic acid or trifluoroacetic acid, with a
Lower alkyl half ester of carbonic acid, e.g. B.  the ethyl or isobutyl half-ester of carbonic acid, or with an organic, z. B.  aliphatic or aromatic sulfonic acid, e.g. B. 



   Methanesulfonic acid or p-toluenesulfonic acid. 



   A reactive functional derivative of a carboxylic acid of formula IIIA or IIIB is also an activated one
Ester of the carboxylic acid of the formula IIIA or IIIB, which, for example, by condensation with a vinylogenic alcohol, d. H.  with an enol, e.g. B.  a vinylogenic lower alkenol, an iminomethyl ester halide, e.g. B.  Dimethyliminomethyl ester chloride, made from the carboxylic acid of formula IIIA or IIIB and z. B.  Dimethyl- (l-chloroethylidene) - iminium chloride of the formula [(CH3) 2Ns = C (Cl) CH3jCle, which in turn is used for. B.  can be obtained from N, N-dimethylacetamide and phosgene or oxalyl chloride, an aryl ester, e.g. B.  one by halogen, e.g. B.  Chlorine, and / or nitro substituted phenyl ester, e.g. B.  a pentachloro, 4-nitrophenyl or 2,3-dinitrophenyl ester, an N-heteroaromatic ester, e.g. B. 

  N-benzotriazole ester, or an N-diacylimino ester, e.g. B.  an N-succinylimino or N-phthalimino ester. 



   The acylation with a reactive functional derivative of the carboxylic acid of formula IIIA or IIIB, e.g. B.  with an appropriate anhydride, in particular an acid halide, is preferably carried out in the presence of a suitable acid-binding agent, for example a suitable organic base.  A suitable organic base is, for example, an amine, e.g. B.  a tertiary amine, e.g. B.  Tri-lower alkylamine, e.g. B.  Trimethylamine, triethylamine, or ethyl-diisopropylamine, or an N, N-di-lower alkylaniline, e.g. B.  N, N-dimethylaniline, or a cyclic tertiary amine, e.g. B.  an N-lower alkylated morpholine, e.g. B.  N-methylmorpholine, or is, for example, a base of the pyridine type, e.g. B.  Pyridine. 

  A suitable acid-binding agent is also an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. B.  Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or is an oxirane, for example a 1,2-lower alkylene oxide, such as ethylene oxide or propylene oxide. 



   The acylation with a reactive, functional derivative of the carboxylic acid of the formula IIIA or IIIB is preferably carried out in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxamide, such as a formamide, for. B.  Dimethylformamide, a halogenated hydrocarbon, e.g. B.  Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. B.  Acetone, cyclic ether, e.g. B.  Tetrahydrofuran, an ester, e.g. B.  Ethyl acetate, or a nitrile, e.g. B. 

  Acetonitrile, or in mixtures thereof, if necessary or desired, at reduced or elevated temperature, e.g. B.  in a temperature range from about -40 C to about + 100 C, preferably from about -10 C to about + 50 C, and / or in an inert gas, e.g. B.  Nitrogen atmosphere. 



   A reactive functional derivative of an acid of formula IIIA or IIIB used in the acylation reaction can, if desired, be formed in situ.  So you can z. B.  prepare a mixed anhydride in situ by using an acid of formula IIIA or IIIB, in which functional groups are optionally protected, or a suitable salt thereof, e.g. B.  an ammonium salt, e.g. B.  is formed with an organic base such as pyridine or 4-methylmorpholine, or a metal salt, e.g. B.  an alkali metal salt, e.g. B. 

 

  Sodium salt, with a suitable derivative of another acid, for example an acid halide, an unsubstituted or by halogen, e.g. B.  Chlorine, substituted lower alkane carboxylic acid, e.g. B.    Trichloroacetyl chloride, a half ester as carbonic acid halide, e.g. B.  Ethyl chloroformate, or isobutyl ester, or with a halide of a di-lower alkyl phosphoric acid, e.g. B.  Diethylphosphorobromidate, which can be formed by reacting triethylphos with bromine.  The mixed anhydride thus obtainable can be used in the acylation reaction without isolation.   



  After operations: RS conversions:
In a compound of the formula IA or IB obtained, in which functional groups are optionally protected, a group R1 can be replaced by another R1 group or converted into another R1 group in a manner known per se.  For example, in a compound in which R1 is a group of the formula -CH2-R2 and R2 is, for. B.  represents a residue which can be replaced by nuceophilic substituents, or in a salt thereof by treatment with a mercaptan compound, e.g. B.  a heterocyclyl mercaptan compound, or with a thiocarboxylic acid compound, such a radical R2 through an etherified mercapto group, e.g. B.  Heterocyclyl mercapto group, or  replace an esterified R2 mercapto group. 



   A suitable, by nucleophilic substituents, e.g. B.  an etherified mercapto group, replaceable radical is, for example, a hydroxy group esterified by a lower aliphatic carboxylic acid.  Such an 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. B.  Heterocyclyl mercaptan compound, can be carried out under acidic, neutral or weakly basic conditions.  In acidic conditions, one works in the presence of concentrated sulfuric acid, which may be replaced by an inorganic solvent, e.g. B.  Polyphosphoric acid, is diluted.  Under neutral or weakly basic conditions, the reaction is carried out in the presence of water and, if appropriate, a water-miscible organic solvent. 



   The basic conditions can, for example, by adding an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. B.  can be adjusted by adding sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate.  As organic solvents such. B.  water-miscible alcohols, e.g. B.  Lower alkanols, such as methanol or ethanol, ketones, e.g. B.  Lower alkanons, such as acetone, amides, e.g. B.  Lower alkanecarboxamides, e.g. B. 



  Dimethylformamide, or nitriles, e.g. B.  Lower alkanitriles, e.g. B.  Acetonitrile. 



   In a compound of the formula IA or IB, in which R1 denotes a group of the formula-CH2-R2, in which R denotes free hydroxyl, the free hydroxyl group can be esterified by the acyl radical of an optionally N-substituted carbamic acid.  The esterification of the free hydroxy group with an isocyanate compound, e.g. B.  Halogen sulfonyl isocyanate, e.g. B.  Chlorosulfonyl isocyanate, or with a carbamic acid halide, e.g. B.    Carbamic acid chloride, leads to N-unsubstituted 3-carbamoyloxymethyl-cephalosporins. 

  The 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. B.  an appropriately substituted carbamic acid halide, e.g. B.  an N-mono- or N, N-disubstituted carbamic acid chloride leads to N-mono- or N, N-disubstituted 3-carbamoyloxymethyl-cephalosporins of the formula IA or IB. 



  It is usually carried out in the presence of a solvent or diluent and, if necessary, with cooling or heating, in a closed vessel and, if appropriate, under an inert gas, for. B.  Nitrogen atmosphere.  The compounds in which R1 is a group of the formula-CH2-R2, in which R2 is free hydroxy, can be prepared from a compound of the formula IA or IB by splitting off the acetyl radical from an acetyloxy group R2, e.g. B. 



  by hydrolysis in a weakly basic medium, e.g. B.  in an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinü, Rhizobium japonicum or Bacillus subtilis, or a suitable citrus esterase, e.g. B.  from orange peel. 



   Furthermore, you can a compound of formula IA or IB, wherein R1 is a group WH2-R2, where R2 z. B. 



  represents the radical defined above which can be replaced by nucleophilic substitution, with a tertiary organic base, in particular an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH of about 6.5, in the presence of water and, if appropriate, in one react with water-miscible organic solvents and thus arrive at compounds in which R1 represents the remainder of the formula -CH2-R2 and R2 a quaternary ammonio group. 



   The weakly acidic conditions can be adjusted by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or sulfuric acid.  For example, the above-mentioned water-miscible solvents can be used as organic solvents.  To increase the yield, certain salts can be added to the reaction mixture, for example alkali metal salts, such as sodium and in particular potassium salts, of inorganic acids, such as hydrohalic acid, e.g. B. 



  Hydrochloric and in particular hydroiodic acid, and thiocyanic acid, or of organic acids such as lower alkane carboxylic acids, e.g. B.  Acetic acid.  Suitable salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate.  Salts of suitable anion exchangers, e.g. B.  liquid ion exchanger in salt form, such as. B.  Amberlite LA-1 (liquid secondary amines with a molecular weight of 351-393; oil-soluble and water-insoluble; mAeq. / g = 2.5-2.7, e.g. B.  in acetate form), with acids, e.g. B.  Acetic acid can be used for this purpose. 



   Ammonio groups R2 can advantageously be prepared using an intermediate of the formula IA or IB, in which R2 represents a substituted, in particular an aromatic, substituted carbonylthio group and primarily the benzoylthio group.  Such an intermediate, which one z. B.  by reacting a compound in which R2 in the radical R1 is an esterified hydroxyl group, in particular a lower alkanoyloxy, e.g. B.  Acetyloxy group means with a suitable salt, e.g. B.  the alkali metal, e.g. B.  Sodium salt, a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, e.g. B.    Thiobenzoic acid can be obtained, is reacted with the tertiary amine, in particular a tertiary heterocyclic base, such as an optionally substituted pyridine, to give the corresponding compound having an ammonio group. 

  The reaction is usually carried out in the presence of a suitable desulfurization agent, in particular a mercury salt, e.g. B.  Mercury II perchlorate, and a suitable solvent or diluent or mixture, if necessary, with cooling or heating, in a closed vessel and / or in an inert gas, e.g. B.  Nitrogen atmosphere. 

 

  Oxidation of hydroxymethylene group A:
In a compound of formula IA or IB obtained, a hydroxymethylene group A can be oxidized to an oxomethylene group.  The oxidation can, optionally under the protection of a free amino and carboxyl group, on d. H.  known for the oxidation of hydroxy to oxo groups.  As oxidizing agents come oxidizing oxides, e.g. B.  of manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium trioxide, e.g. B. 

  Jones reagent or chromium trioxide in the presence of acetic acid, sulfuric acid or pyridine, nitrous oxide, dimethyl sulfoxide, optionally in the presence of dicyclohexylcarbodiimide or oxygen, and peroxides, such as hydrogen peroxide, oxygen-containing acids, such as permanganic acid, chromic acid or hypochloric acid or salts thereof, such as potassium, or potassium dichromate or potassium hypochlorite, in question.  The hydroxymethylene group can also be converted to the oxomethylene group by Oppenauer oxidation, i. H.  by treating with the salt of a sterically hindered alcohol such as aluminum or potassium tere. -butoxide, -isopropoxide or -phenoxide in the presence of a ketone, such as acetone, cyclohexanone or fluorenone. 

  Another way to convert the hydroxymethylene group to the oxomethylene group is by dehydration, e.g. B.  with Raney nickel. 



   Depending on the oxidizing agent, the oxidation is carried out in water or an optionally water-containing organic solvent at temperatures from about 0 to about 100. 



   Reaction of carbonyl group A with a hydroxylamine derivative:
In a compound of the formula IA or IB obtained, in which A denotes a carbonyl group, this can, optionally with protection of functional groups, be treated by treatment with hydroxylamine or O-methylhydroxylamine in a hydroxyiminomethylene or  Methoxyiminomethylene group are transferred. 



   The reaction of the carbonyl group with the hydroxylamine compound is carried out in a conventional manner, e.g. B.  by the two reactants in a solvent such as water or an organic solvent such as an alcohol, e.g. B.  Methanol, can react at a slightly elevated or reduced temperature, optionally in an inert gas, such as nitrogen atmosphere.  The hydroxylamine compound can, also in situ from one of its salts, for example a hydrohalide such as hydrochloride, by treatment with an inorganic base such as an alkali metal hydroxide, e.g. B.  Sodium hydroxide, or an organic
Base, such as a tertiary amine, e.g. B.  a tri-lower alkyl amine, such as tri-lower alkyl amine, such as triethylamine or ethyl diisopropylamine, or a heterocyclic tertiary base, such as pyridine, are liberated. 



   Removal of protective groups: In a compound of the formula IA or IB obtained, in which one or more functional groups are protected, these, e.g. B.  protected carboxyl, amino, hydroxyl and / or sulfo groups, in a manner known per se, by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis, if appropriate in stages or simultaneously, are released. 



   A protected carboxyl group is released in a manner known per se and in various ways depending on the nature of the protective groups, preferably by means of solvolysis or reduction.  So you can tert. -Lower alkoxycarbonyl or in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl z. B.  by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylene thioglycol, converted into free carboxyl.  Optionally substituted benzyloxycarbonyl can e.g. B.  by means of hydrogenolysis, d. H.  by treatment with hydrogen in the presence of a metallic hydrogenation catalyst such as a palladium catalyst. 

  You can also suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by chemical reduction, e.g. B.  by treatment with an alkali metal, e.g. B.  Sodium dithionite, or with a reducing metal, e.g. B.  Zinc, or metal salt, such as a chromium II salt, e.g. B.  Chromium (II) chloride, usually in the presence of a hydrogen-donating agent capable of generating nascent hydrogen together with the metal, such as an acid, primarily a suitable carboxylic acid, such as an optionally, e.g. B.  by hydroxy, substituted lower alkane carboxylic acid, e.g. B.  Convert acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably with water, into free carboxyl. 

  By treatment with a reducing metal or metal salt, 2-halo-lower alkoxycarbonyl can also be converted, as described above, optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group, or aroylmethoxycarbonyl into free carboxyl, with aroylmethoxycarbonyl also by treatment with a nucleophilic, preferably salt-forming Reagent, such as sodium thiophenolate or sodium iodide, can be cleaved.  Substituted 2-silylethoxycarbonyl can also be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. B. 

  Sodium or potassium fluoride, in the presence of a macrocyclic polyether (crown ether), or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride or tri-lower alkyl arylammonium fluoride, e.g. B.  Tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethyl sulfoxide or N, N-dimethylacetamide, are converted into free carboxyl.  With an organic silyl group such as tri-lower alkylsilyl, e.g. B.  Trimethylsilyl, esterified carboxyl can usually be solvolytically, e.g. B.  can be released by treatment with water, an alcohol or an acid. 



   A protected amino group is released in a manner known per se and in various ways depending on the type of protective group, preferably by means of solvolysis or reduction.  2-halo-lower alkoxycarbonylamino, optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can, for. B.  by treatment with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid.  Aroylmethoxycarbonylamino can also be treated by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino, also by treatment with an alkali metal, e.g. B.  Sodium dithionite. 

  Optionally substituted diphenylmethoxycarbonylamino, tert.  - Lower alkoxycarbonylamino or 2-trisubstituted silyl ethoxycarbonylamino can be obtained by treatment with a suitable acid, e.g. B.  Formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino, e.g. B.  by means of hydrogenolysis, d. H.  by treatment with water in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino, formylamino or 2-acyl-lower alk-1-en-1-amylamino, e.g. B.  by treatment with an acid such as mineral acid, e.g. B. 

 

  Hydrochloric acid, or an organic acid, e.g. B. 



  Formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected with an organic silyl group, e.g. B.  are released by hydrolysis or alcoholysis.  One by 2-haloacetyl, e.g. B.  2-Chloroacetyl, protected amino group can be released by acting with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the condensation product formed.  An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treatment with a salt of hydrofluoric acid which provides fluoride anions, as indicated above in connection with the release of a correspondingly protected carboxyl group. 

  A phosphorus, phosphon or phosphine amido group can e.g. B.  by treatment with a phosphoric acid, such as a phosphoric, phosphonic or phosphinic acid, e.g. B.  Orthophosphoric acid or polyphosphoric acid, an acidic ester, e.g. B.  Monomethyl, monoethyl, dimethyl or diethyl phosphate or monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide, can be converted into the free amino group. 



   A hydroxyl group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl-lower alkyl is released like an appropriately protected amino group.  A hydroxy group protected by 2,2-dichloroacetyl is e.g. B.  by basic hydrolysis, one by tert. -Lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical etherified hydroxy group by acidolysis, e.g. B.  by treatment with a mineral acid or a strong carboxylic acid, e.g. B.  Trifluoroacetic acid, released. 



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



   The cleavage reactions described are carried out under conditions known per se, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, for. B.  Nitrogen atmosphere. 



   If there are several protected functional groups, the protective groups are preferably selected such that more than one such group can be split off simultaneously, for example acidolytically, such as by treatment with trifluoroacetic acid or formic acid, or reductively, such as by treatment with zinc and acetic acid, or with Hydrogen and a hydrogenation catalyst such as a palladium / carbon / catalyst. 



  Esterification of a free carboxy group: The conversion of a free carboxy group, e.g. B.  the free carboxy group R3, into an esterified carboxy group, in particular into a carboxy group which can be cleaved under physiological conditions, is carried out according to known esterification methods. 



  For example, a compound of formula IA or IB is used in which the carboxyl group to be esterified is in free form and other functional groups, e.g. B.  Amino or hydroxyl groups, are in protected form, or a compound of formula IA or IB, in which 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 reactive functional derivative of this alcohol. 



   In the esterification, in which the carboxyl group to be esterified is in free form, with the desired alcohol, the same condensing agents, e.g. B.  Carbodiimides, the same solvents are used and the same reaction conditions are observed as for the acylation according to process a). 



   A compound of the formula IA or IB, in which 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, in the manner described under process a) (acylation), by condensation of the carboxylic acid of the formula IA or IB can be obtained with an inorganic acid of a carboxylic acid, with a half ester of carbonic acid, a sulfonic acid or by condensation with a vinylogenic alcohol. 



   A reactive, functional derivative of the alcohol to be esterified is primarily the ester, which is formed by condensation with a strong inorganic or organic acid, for example the corresponding halide, e.g. B.  Chloride, bromide or iodide, or the corresponding lower alkyl, or aryl, e.g. B.  the methylsulfonyloxy or methylsuffonyloxy compound.    



   In the esterification in which the carboxyl group to be esterified is in the form of a reactive functional derivative with the corresponding alcohol or in the esterification in which the carboxyl group to be esterified is in free form with a reactive, functional derivative of the corresponding alcohol, the same solvents are used used and the same reaction conditions observed as for the acylation with a reactive, functional derivative of a carboxylic acid of the formula IIIA or IIIB according to process a). 



   A compound of the formula IA or IB in which the carboxyl group to be esterified is in the form of a reactive, functional derivative can also be prepared in situ analogously to the method described in process (a) (acylation) and reacted with the corresponding alcohol without isolation. 



  Salt formation: Salts of compounds of the formula IA or IB can be prepared in a manner known per se.  So you can salts of compounds of formula IA or IB, for. B.  by reaction of the acidic groups with metal compounds, such as alkali metal salts of suitable carboxylic acids, e.g. B.  the sodium salt or a-ethyl caproic acid or sodium carbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts are obtained in a conventional manner, e.g. B.  by treatment with an acid or a suitable anion exchange reagent.  Inner salts can e.g. B.  by neutralizing salts such as acid addition salts to the isoelectric point, e.g. B.  with weak bases, or by treatment with liquid ion exchangers. 



   Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g.  B.  by treatment with suitable acids, and acid addition salts e.g. B.  by treating with a suitable basic agent. 



   In all the reactions mentioned above, which are carried out under basic conditions, 3-cephem compounds, if appropriate partially, can isomerize to 2-cephem compounds.  A 2-cephem compound obtained or a mixture of a 2- and a 3-cephem compound can be isomerized in a manner known per se to the desired 3-cephem compound. 

 

   Mixtures of isomers can in a conventional manner, for. B.  by fractional crystallization, chromatography, etc.  be separated into the individual isomers. 



   The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; In addition, starting materials in the form of derivatives can be used or formed during the reaction. 



   Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as particularly preferred above are obtained. 



  Pharmaceutical preparations:
The pharmacologically usable compounds of the formula IA or IB, their hydrates or salts can be used for the production of pharmaceutical preparations. 



   Pharmaceutical preparations contain an effective amount of the pure active ingredient itself or an effective amount of the active ingredient of the formula IA or IB in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients, which are preferably suitable for parenteral administration. 



   The active compounds of the present invention are preferably used in the form of injectable, e.g. B.  intravenously, administrable preparations or infusion solutions.  Such solutions are preferably isotonic aqueous solutions or suspensions, which, for. B.  from lyophilized preparations which contain the pure active ingredient or the active ingredient together with a carrier material, e.g. B.  Mannitol can be prepared before use.  The pharmaceutical preparations are preferably sterilized and can contain adjuvants, e.g. B.  Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. 

  The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



   The pharmaceutical preparations are made in a manner known per se, e.g. B.  by means of conventional solution or lyophilization processes. 



  Use:
Compounds of formula IA or IB, their hydrates or pharmaceutically acceptable salts can be used as antibiotic agents in the form of pharmaceutical preparations in a process for the therapeutic treatment of the human or animal body, e.g. B.  for the treatment of infections caused by gram-positive or gram-negative bacteria and cocci, e.g. B.  by enteric bacteria, e.g. B.  Escherichia coli, Klebsiella pneumo niae or Proteus spp. , caused. 



   Depending on the type of infection and the condition of the infected organism, daily doses of approximately 0.5 g to approximately 5 g s are used. c. , i. v.  or I. m.  for the treatment of warm-blooded animals (humans and animals) weighing about 70 kg. 



   Starting materials:
The starting materials used in the process for the preparation of the compounds of the present invention are mannitol or, if new, can be prepared in a manner known per se. 



   Starting materials of formula II, as well as corresponding
Compounds with protected functional groups are known or can be prepared in a manner known per se. 



   Starting materials of the formula IIIA or IIIB are known or can be prepared in a manner known per se.  Starting materials of formula IIIA or IIIB are. B.     in European patent application no.  8150 described.     In addition, esters of acids of the formula IIIA or IB are in European patent application no.  59 156.     These esters can be known in a conventional manner
Way, e.g. B.  by saponification to produce the acids of formulas IIIA and IIIB. 



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius; BOC: tert. Butoxycarbonyl. 



   Example 1 a) Sodium 3-acetoxymethyl-7ss f2- (2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl) - acetylamino] - 3-cephem-4-carboxylate
A solution of 1.10 g (1.56 mmol) of 3-acetoxymethyl-7ss- [2- (2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl) - acetylamino] - 3 -cephem-4-carboxylic acid diphenylmethyl ester in 3 ml methylene chloride and 0.87 ml anisole is mixed with 11 ml trifluoroacetic acid at room temperature and 30 min. 



  long stirred.  Then 300 ml of diethyl ether / hexane (1: 2) are added with stirring.  The precipitate is separated off and dissolved in methanol.  The solution is approx. 



  3 molar sodium 2-ethylhexanoate solution in methanol brought to pH 7.0.  After adding diethyl ether, the precipitate formed is filtered off and dried.  The title compound of Rf values is obtained: 0.35 (UPC12 plates, water / acetonitrile 9: 1); IR spectrum (Nujol): characteristic absorption bands at 3400, 3045, 1765, 1615 com¯ '.    



  b) 3-Acetoxymethyl-7ss [2- (2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl) - acetylaminoj-3-cephem-4-carboxylic acid di phenylmethyl ester
2.86 g (10.0 mmol) of 2- [2-amino-1- (2,6-dichlorophenyl) 1H-imidazol-4-yl] acetic acid and 40 ml of methylene chloride are converted into a stirred suspension at - 5 ' Vilsmeier reagent (prepared from 1.0 ml oxalyl chloride and 0.9 ml N, N-dimethylformamide in 10 ml methylene chloride). 



  The mixture is kept for 20 min.  stirred at 0 "and then cooled to - 10".  After adding 4.40 ml (10.0 mmol) of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester, it is stirred for 2.5 hours at 0 "and diluted with 50 ml of methylene chloride. 



  The organic phase is washed successively with water, phosphate buffer solution (pH 8.0) and aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.  The residue contains the title compound with an Rf value of 0.55 (silica gel, chloroform / methanol / glacial acetic acid 85: 12: 3); IR spectrum (Nujol): characteristic absorption bands at 3450 and 1765 cm- '.    



   Example 2a) Sodium 3-acetoxymethyl 7 [2- (2- (2,6-dichlorophenylamino) - IH-imidazol-4-yl) acetylaminoj-3-cephem-4-carboxylate
By reacting 0.8 g (1.13 mmol) of 3-acetoxy methyl-7ss- [2- (2- (2,6-dichlorophenylamino) - 1H-imidazol-4-yl) - 2-acetylamino] - 3- cephem-4-carboxylic acid diphenylmethyl ester in 2 ml of methylene chloride and 0.55 ml of anisole with 8.2 ml of trifluoroacetic acid and subsequent treatment with methanolic sodium 2-ethylhexanoate solution gives the title compound of Rf 0.20 (UPC12 Plates, water / acetonitrile 95: 5), IR spectrum (Nujol): characteristic absorption bands at 3350; 1765; 1605 cm-1.    

 

  b) 3-Acetoxymethyl-7ss [2- (2- (2,6-dichlorophenylamino) - iH-imidazol-4yl) -acetylamino] - 3-cephem-4-carboxylic acid diphenylmethyl ester
A mixture of 0.858 g (3.0 mmol) of 2- [2- (2,6-dichlorophenylamino) - 1H-imidazol-4-yl] acetic acid and 1.95 g (4.45 mmol) of 3-acetoxymethyl-7ss -amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of dry tetrahydrofuran is added at 0 "with 0.5 g of 1-hydroxybenzotriazole and 1.42 g of N, N'-dicyclohexylcarbodiimide in 4 ml of dry tetrahydrofuran, for 2 hours 0 "and stirred for a further 5 hours at room temperature. 

  After filtering the reaction mixture, the filtrate is diluted with ethyl acetate and washed successively with phosphate buffer solution (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 / glacial acetic acid 85: 12: 3); IR spectrum (Nujol): characteristic absorption bands at 3350; 1765; 1735cm- '. 



   Example 3 a) Sodium 3-acetoxymethyl 7 [2- (2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol4-yi) - 2-Z-methoxyiminoacetylamino] - 3-cephem-4-carboxylate
By reacting 1.5 g (2.0 mmol) of 3-acetoxymethyl yl-7ss- [2- (2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl) - 2-Z -methoxyiminoacetylamino] - 3-cephem-4-carboxylic acid diphenylmethyl ester in 2.5 ml methylene chloride and 1.05 ml anisole with 8 ml trifluoroacetic acid and subsequent treatment with methanolic sodium 2-ethylhexanoate solution, the title compound is obtained from Rf- Value approx. 

   0.50 (UPCir plates, water / acetonitrile 2: 1); IR spectrum (Nujol): characteristic absorption bands at 3350; 1765; 1620; 1050 cm¯lb) 3-acetoxymethyl-7-P [2- (2-amino-1- (2,6-dichlorophenyl) - lH-imidazol-t-yl) 2-Z-methoxyiminoacetylamino] - 3-ceph em- 4-carboxylic acid diphenylmethyl ester
By reacting 1.74 g (5.30 mmol) of 2- [2-amino-1 [2,6-dichlorophenyl) -1H-imidazol-4-yl] -2-methoxyiminoacetic acid and 2.30 g (5th , 30 mmol) 3-acetoxymethyl-7p-amino-
3-cephem-4-carboxylic acid diphenylmethyl ester in 40 ml of methylene chloride is obtained analogously to Example lb), the title compound having an Rf value of 0.60 (silica gel, chloroform / methanol /
Glacial acetic acid 85: 12: 3);

  IR spectrum (CH2C12): characteristic absorption bands at 1765; 1735; 1045 cm- '.    



  c) 2- [2-Amino-1- (2,6-dichlorophenyl) - IH-imidazol-4-yl] 2-methoxyiminoacetic acid
A solution of 8.00 g (23.30 mmol) of 2- [2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl] - 2-methoxyimino-methyl acetate in 100 ml of methanol with 69 ml 1N
Sodium hydroxide solution was added and the mixture was stirred at room temperature for 2 hours.  The reaction mixture is in
Concentrated vacuum, the residue dissolved in water, the solution adjusted to pH 8.5 with dilute hydrochloric acid and extracted with ethyl acetate.  The aqueous phase is separated off, brought to pH 2.5 with dilute hydrochloric acid and the precipitated product is filtered off with suction. 

  The title compound of Rf 0.35 (silica gel, s-butanol / glacial acetic acid / water 67:10:23) is obtained.     IR spectrum (Nujol): characteristic absorption bands at 3550; 3245; 1620; 1045 com¯ '.    



   d) Methyl 2- [2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl] 2-methoxyiminoacetate
In a mixture of 36.0 g (0.148 mol) of 2,6-dichlorophenyl isocyanide dichloride with 150 ml of acetonitrile is stirred for 60 minutes.  Ammonia gas introduced.  This mixture is then cooled to 20 and with a solution of
52.8 g (0.222 mol) of 2-methoxyimino-4-bromo-acetoacetic acid remethyl ester in 150 ml of acetonitrile.  While introducing ammonia gas, the mixture is heated to 75 and stirred at this temperature for 6 hours and then cooled to room temperature.  The insoluble components are filtered off and the filtrate is concentrated in vacuo.  The residue is triturated with diethyl ether. 

  The title compound with an Rf value of approx.  0.60 (silica gel, chloroform / methanol 9: 1).  IR spectrum (CH2C12): characteristic absorption bands at 3460; 3380; 1743; 1630; 1040 com¯ '.    



   Example 4 Sodium 7 [2- (2-amino-1- (2,6-dichlorophenyl) -1H-imide azol-4-yl) -2-Z-methoxyiminoacetylamino] -3-cephem-4 carboxylate
A mixture of 1.15 g (3.50 mmol) of 2- [2-amino-1 (2,6-dichlorophenyl) -1H-imidazol-4-yl] - 2-methoxyiminoacetic acid and 0.82 g of phosphorus pentachloride in 15 ml Methyl enchloride is 30 min.    stirred at - 10 "(solution 1).  A mixture of 0.70 g of 7ss-amino-3-cephem-4-carboxylic acid, 5.80 g of trimethylsilylacetamide and 15 ml of methylene chloride is stirred for 20 minutes.  stirred at room temperature and then cooled to -10 '(solution 2).  Solution 1 and solution 2 are combined. 

  The mixture is stirred at 0 "for 3 hours and then poured onto saturated sodium bicarbonate solution.  The aqueous phase is separated off, adjusted to pH 4.5 with aqueous hydrochloric acid and chromatographed (XAD-2 adsorber resin, water).  The product-containing fractions are concentrated, dissolved in methanol and treated with an approx.  3N sodium 2-ethylhexanoate solution adjusted to pH 7.  After adding diethyl ether, the precipitate formed is filtered off with suction and chromatographed. 



  The title compound of Rf 0.35 (UPC12 plates, water / acetonitrile 2: 1) is obtained; IR spectrum (Nujol): characteristic absorption bands at 3350; 1765; 1610; 1045 com¯ '.    



   Example 5 7/3 [2- (2-Amino-1- (2,6-dichlorophenyl) - IH-imidazol-4-yl] - 2-ZmethoxyiminoacetylaminoJ- 3-cephem-4-carboxylic acid pivoyloxymethyl ester
A mixture of 1.33 g (2.49 mmol) of sodium 7ss- [2 (2-amino-1- (2,6-dichlorophenyl) - 1H-imidazol-4-yl) - 2-zmethoxyiminoacetylamino] - 3- cephem-4-carboxylate in 15 ml of N, N'-dimethylformamide is mixed at 0 "with 0.56 ml of iodomethyl pivalate and 60 min.  stirred, poured into 70 ml of pH 7.0 phosphate buffer and extracted with ethyl acetate / acetone (4: 1).  The organic extracts are washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.  

  After triturating the residue with diethyl ether / hexane, the title compound is obtained with an Rf value of 0.85 (silica gel, sec. -Butanol / glacial acetic acid / water 67:10:23); IR spectrum (Nujol): characteristic absorption bands at 3030; 1765; 1735; 780 cm
Example 6
Dry ampoules or vials containing 0.5 g of active ingredient, e.g. B. 3-acetoxymethyl-7p- [2- (2-amino-1 H-imidazol-4-yl) - 2-Z-methoxyiminoacetylamino] - 3-cephem-4-carboxylic acid can be prepared as follows: composition (for 1 ampoule or Viale): active ingredient 0.5 g mannitol 0.05 g
A sterile aqueous solution consisting of active ingredient and
Mannitol is filled into 5 ml ampoules or 5 ml vials under aseptic conditions, after which these are sealed and checked.  


    

Claims (9)

 PATENT CLAIMS 1. 7ss-aminoimidazolylacetylamino-3-cephem-4-carboxylic acid compounds of the formula EMI1.1    wherein R1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2-R2, wherein R2 represents hydroxy, mercapto, esterified hydroxy or mercapto, etherified hyoroxy or mercapto or a quaternary ammonio group, R3 carboxyl or protected carboxyl, R4 represents a substituted or unsubstituted hydrocarbon radical or an acyl group and in compounds of the formula IA also hydrogen and A carbonyl, a methylene group or a methylene group which are protected by amino, protected amino, hydroxy, protected hydroxy, sulfo,  protected sulfo or substituted by a group of the formula = N (} Rs, where R5 is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, lower alkenyl, carbamoyl or substituted carbamoyl, hydrates and salts of compounds of the formula IA and IB.  2. Compounds of formula IA and IB according to claim 1, wherein R1 is hydrogen, lower alkyl, lower alkoxy, halogen, or a group -CH2-R2, wherein R2 NiederaLkanoyl-oxy, carbamoyloxy, N-lower alkylcarbamoyloxy, an aromatic, monocyclic, five or six-membered diaza, triaza, tetraza, thiaza, thiadiaza, thia, oxaza or oxadiazacyclylthio radical, which may be substituted by lower alkyl, di-lower alkylamino-lower alkyl, sulfon-lower alkyl, carboxy-lower alkyl, amino, carboxy-lower alkylamino or by carbamoyl or ammonio  R3 carboxyl or esterified carboxyl which is cleavable under physiological conditions, R4 lower alkyl, by hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, carbamoyl, halogen, sulfo, lower alkylthio or lower alkyl substituted by aminosulfinyl, mederalkenyl, cycloalkyl, cycloalkenyl, phenyl , phenyl-lower alkyl substituted by halogen and, in compounds of the formula IA, also hydrogen and A aminomethylene, hydroxymethylene, sulfomethylene or a methylene group substituted by a group = NO-R5, where R5 is hydrogen, lower alkyl, carboxy-lower alkyl, cycloalkenyl, lower alkenyl,  Carbamoyl, Mederalkylcarb- amoyl, or amino lower alkyl, where the group -O-R5 has the syn (or Z) position and pharmaceutically acceptable salts of compounds of formula IA and IB, which have salt-forming groups.  3. Compounds of formula IA and IB according to claim 2, wherein R, hydrogen, lower alkyl, lower alkoxy, halogen or a group-CH2-R2, wherein R2 NiederaLkanoyloxy, carbamoyloxy, triazolylthio, tetrazolylthio, byMederalkyl, Diniederalkylaminoniederalkyl, sulfoniederalkyl, or carboxy-lower alkyl or tetrazolylthio substituted by carbamoyl, 5,6-dioxo-tetrahydro-as-triazine -3-ylthio substituted by lower alkyl or 4-methyl-5,6-dioxo1,4,5,6-tetrahydro-as-triazine -3-ylthio, pyridinio or by hydroxymederalkyl, carboxy, carboxy-lower alkyl,  Halogen or carbamoyl substituted pyridinio, R3 carboxyl, Mederalkanoyloxymethoxycarbonyl or Niederalkoxy carbonyloxyniederalkoxycarbonyl, R4 Niederalkyl, Carboxyniederalkyl Diniederalkylaminoniederalkyl, Niederalkoxycarbonyl, Carbamoyl, Mederalkenyl, Phenyl, Halogen substituted phenyl, Phenylniederalkyl and Niederalkylsulfonyl a the by I and A Alkyldenulfonyl in the compounds A and I alkylalkonylsulfonyl with the alkyl or lower alkylsulfonyl in the formula A by I and lower alkyl A compounds in the = N + R5 are substituted methylene groups, where R5 is hydrogen, lower alkyl, carboxy-lower alkyl, lower alkenyl, carbamoyl or mederalkylcarbamoyl,  wherein the group -O-R5 has the syn- (or Z-) position and wherein -A- is linked to the 4-position of the imidazolyl radical, and pharmaceutically acceptable salts of compounds of the formula IA and IB which have salt-forming groups.  4. Compounds of formula IA and IB according to claim 3, wherein Rl is hydrogen, methyl, methoxy, chlorine or a group -CH2-R2, wherein R2 is acetoxy, carbamoyloxy, IH-tetrazol-5-ylthio, l-methyl-lH-tetrazole -5-ylthio, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-ylthio, l-carboxymeth-yl-lH-tetrazol-5-ylthio, l-sulfomethyl -1H-tetrazol-5-ylthio, l-carboxymethyl -1H-tetrazol-5-ylthio, 1,3,4-thiadiazol-5ylthio, 2-methyl-1,3,4-thiadiazol -5-ylthio,  2-methyl-5,6-dioxo -1,2,5,6- tetra-hydro-as-triazin-3-ylthio, 4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as- triazin- 3-ylthio, pyridinio, 3- or 4-hydroxymethylpyridinio, 4-carboxypyridinio, 3 or 4-carboxymethylpyridino, 3- or 4-chloropyridinio, 3 or 4-bromopyridinio or 3- or 4-carbamoylpyridinio means R3 carboxy, pivaloyloxymethoxycarbonyl or l-ethoxycarbonyloxyethoxycarbonyl, R4 methyl, carboxymethyl, 2-carboxyethyl, 2-dimethylaminoethyl, phenyl,  2,3-, 2,4- or 2,6-dichlorophenyl or benzyl and in compounds of the formula IA also hydrogen and A is a methylene group substituted by the group = N + R5, where R5 is methyl, 2-carboxy-2-propyl , Carbamoyl or methylcarbamoyl, where the group -OR5 has the syn- (or Z-) position and -A- is linked to the 4-position of the imidazolyl radical, and pharmaceutically acceptable salts of compounds of the formula IA and IB, which are salt-forming groups have.  5. Sodium-3-acetoxymethyl-7ss- [2- (2-amino-1- (2,6-di-chlorophenyl) -1H-imidazole -4- yl) -2-Z-methoxyiminoacetylamino] -3- cephem-4-carboxylate according to claim 4.  6. 7ss- [2- (2-amino-1- (2,6-dichlorophenyl) -1H-imidazol-4-yl] -2-Z-methoxyiminoacetylamino] -3- cephem-4-carboxylic acid according to claim 4 .    7. 70- [2- (2-amino-1- (2,6-dichlorophenyl) -lH-itnidazol-4-yl] -2-Z-methoxyiminoacetylaminol -3- cephem-4-carboxylic acid repivaloyloxymethyl ester according to claim 4.  8. Pharmaceutical preparations containing compounds of the formula IA and / or IB, hydrates or pharmaceutically usable salts of compounds of the formula IA and / or IB with salt-forming groups.  9. A process for the preparation of compounds of the formula IA and IB, in which Rl, R2, R3, R4 and A have the meanings given in claim 1, characterized in that in a compound of the formula EMI1.2    wherein R1 and R3 have the meanings given under formula IA and IB, with optional, intermediate protection of the 7 $ -annino group and intermediate protection of functional groups present in R1 or the 7ss-amino group in a salt thereof by reaction with an acyl radical of a carboxylic acid formula EMI2.1  introductory acylating agents, in which A and R4 have the meanings given under formula IA and IB,  acylated with optional intermediate protection of functional groups present in A or with a salt thereof and, if desired, converting an available salt into the free compound or into another salt and / or converting an available free compound into a salt.  The present invention relates to new 7ss-aminoimide-azolylacetylamino -3-cephem-4-carboxylic acid compounds, processes for their preparation and pharmaceutical preparations which contain these compounds.  The present invention relates to 7ss-aminoimidazolyl-acetyl-amino-3-cephem-4-carboxylic acid compounds of the formulas: EMI2.2  wherein R1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group -CH2-R2, wherein R2 represents hydroxy, mercapto, esterified hydroxy or mercapto, etherified hydroxy or mercapto or a quaternary ammonio group, R3 carboxyl or protected carboxyl, R4 represents a substituted or unsubstituted hydrocarbon radical or an acyl group and in compounds of the formula IA also hydrogen and A carbonyl, a methylene group or a methylene group which is substituted by amine, protected amino, hydroxyl, protected hydroxyl, sulfo, protected sulfo or by a group of the formula = N + Rs ,  wherein Rs is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, lower alkenyl, carbamoyl or substituted carbamoyl, hydrates and salts of compounds of the formula IA and IB, pharmaceutical preparations which contain compounds of the formula IA and / or IB, and the use of compounds of formula I for the production of pharmaceutical preparations or as pharmacologically active compounds.  In the description of the present invention: 1 means in the context of groups, e.g. Lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc., expression Nieder used that the corresponding groups, unless expressly defined otherwise, contain up to 7 and preferably up to 4 carbon atoms.  The imidazolyl radical substituted by a free or a monosubstituted amino group can also be present as a dihydroimidazolyl radical substituted by an imino group, which has two tautomeric forms: EMI2.3 The position of the equilibrium between the imidazolyl and the two dihydroimidazolyl forms depends on the structure of the substituents R4 and A and on external parameters such as temperature, solvent or pH. Only the aminoimidazolyl form is expressly mentioned in the present description. However, the two dihydroimidazolyl forms are also included.  The general definitions used above and below in the context of the present description preferably have the following meanings: Lower alkyl R1 contains 1-4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl.  Lower alkoxy R1 contains 1-4 carbon atoms and is, for example, ethoxy, propoxy, butoxy or especially methoxy.  Halogen R1 is fluorine, bromine, iodine or preferably chlorine.  Esterified hydroxy or mercapto R2 is a hydroxy or mercapto group which is replaced by an aliphatic carboxylic acid, one by acyl, e.g. Lower alkanoyl, e.g. Acetyl, substituted aliphatic carboxylic acid or the carbamic acid is esterified, e.g. lower alkanoyloxy, e.g.    Acetoxy, lower alkanoyl lower alkanoyloxy, e.g. Acetylacetyloxy, or carbamoyloxy or lower alkanoylthio, e.g.   Acetylthio or formylthio, or carbamoylthio.  Esterified hydroxy or mercapto R2 is also a hydroxy or mercapto group which is esterified by an N-substituted carbamic acid.  N-substituents are, for example, lower alkyl, e.g. Methyl or ethyl, or by halogen, e.g. Chlorine, or lower alkanoyloxy, e.g. Acetoxy, substituted lower alkyl, e.g. 2-chloroethyl or 2-acetoxyethyl.  Hydroxy or mercapto R2 esterified by an N-substituted carbamic acid is, for example, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N- (2-chloroethyl) carbamoyloxy, N- (2-acetoxyethyl) carbamoyloxy or N-methylcarbamoylthio.  Etherified hydroxy or mercapto R2 is a hydroxy or mercapto group which is replaced by an aliphatic ** WARNING ** End of CLMS field could overlap beginning of DESC **.