CH605998A5 - 3-Thio-7-amino-3- and-2-cephem-4-carboxylic acids - Google Patents

Abstract

3-Thio-7-amino-3- and-2-cephem-4-carboxylic acids useful as broad-spectrum antibacterials and inters(NL-2.3.76)

Description

  

  
 



   The present invention relates to a process for the preparation of 7ss-amino-3-cephem-3-R3-thio4-carboxylic acids of the formula
EMI1. 1
 where R1a represents hydrogen or an amino protective group RIA, and Rlb represents hydrogen or an acyl group Ac, or R1a and Rlb together represent a divalent amino protective group, R2 represents hydroxy or a carboxyl group which forms a protected carboxyl group together with the carbonyl group -C (= O) - Radical R2A and R3 stands for an optionally substituted hydrocarbon radical, an optionally substituted heterocyclic radical or an acyl group, as well as S-oxides of 3-cephem compounds of the formula IA,

   and also the corresponding 2-cephem compounds of the formula
EMI1. 2
 wherein R, a, Rlb, R2 and R3 have the meanings given above, and their 5-oxides, or salts of such compounds with salt-forming groups, and also processes for their
Manufacture and pharmaceutical preparations containing such compounds with pharmacological effects and their use. 



   In 2-cephem compounds of the formula IB with the double bond in the 2,3-position, the optionally protected carboxyl group of the formula -C (= O) -R2 preferably has the a-configuration. 



      A divalent amino protective group formed together by the radicals R, a and Rlb is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl radical of a Position preferably substituted, for example-aminoacetic acid containing an aromatic or heterocyclic radical, in which the amino group is connected to the nitrogen atom via a, preferably substituted, for example two lower alkyl, such as methyl group-containing methylene radical. 

  The radicals R1a and Rsb together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms. 



   A protected carboxyl group of the formula -C (= O) -R2A is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group. 



   The group R2A can therefore be a hydroxyl group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= O) group forms an esterified carboxyl group.  Such organic radicals are, for example, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



   The group R2A can also represent an organic silylxy radical, as well as a hydroxy group etherified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a hydrocarbon radical optionally substituted by 1 to 3, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen, such as chlorine-substituted silyloxy or stannyloxy group. 



   A radical R2A with a C (= O) grouping, primarily mixed, anhydride group is, for example, halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as a aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative, such as a carbonic acid half-ester. 



   A radical R2A which forms a carbamoyl group with a -C (= O) group is an optionally substituted amino group in which substituents are optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, furthermore etherified or esterified hydroxy, in which the etherifying ones or. 

   esterifying radicals, for example, have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, primarily of organic carboxylic acids and of carbonic acid half-derivatives, preferably with up to 18 carbon atoms. 



   In a substituted hydrazinocarbonyl group of the formula -C (= O) -RA, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent aliphatic , cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups, such as acyl radicals, primarily of organic carboxylic acids or of carbonic acid half-derivatives, preferably with up to 18 carbon atoms. 



   An optionally substituted hydrocarbon radical R3 is preferably a corresponding cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, but in particular an optionally substituted aliphatic or aromatic hydrocarbon radical, and also a corresponding araliphatic hydrocarbon radical.  An optionally substituted heterocyclic radical R3 is bonded with one of its carbon atoms to the thio group, is preferably aromatic in nature, but can also be partially or fully hydrogenated and contains at least 1 heteroatom from the group nitrogen, oxygen and sulfur. 



   The general terms used in the description above and below have the following meanings, for example:
An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid and a corresponding ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, as well as lower alkenyl or lower alkynyl, furthermore lower alkylidene, for example up to 7, preferably up to 4 May contain carbon atoms. 

  Such radicals can optionally be replaced by functional groups, for example by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio, phenyl-lower alkylthio or optionally substituted lower alkylthio, heterocyclyl-alkylthio Lower alkanoyloxy, or halogen, furthermore by oxo, nitro, optionally substituted amino, for example lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-lower alkylenamino, as well as acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halo-lower alkoxycarbonylamino, optionally substituted

   optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, furthermore sulfoamino, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl such as carboxyl present in salt form, esterified carboxyl such as lower alkoxycarbonyl, optionally substituted carboxyl, such as lower alkoxycarbonyl, optionally in salt form, such as alkali metal salt form N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or O, O-disubstituted phosphono, in which Substituents represent, for example, optionally substituted lower alkyl, phenyl or phenyl-lower alkyl,

   where O-unsubstituted or O-monosubstituted phosphono can also be present in salt, such as alkali metal salt form, mono-, di- or polysubstituted. 



   A bivalent aliphatic residue, incl.  the corresponding radical of a divalent aliphatic carboxylic acid is, for example, lower alkylene or lower alkenylene, which may optionally be mono-, di- or poly-substituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur, for example like an aliphatic radical given above. 



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid, or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent, cycloaliphatic or cycloaliphatic, for example, hydro-aliphatic-mono-aliphatic radical -, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or 

  Cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, in which cycloalkyl and cycloalkylidene contains, for example, up to 12, such as 3 to 8, preferably 3 to 6 ring carbon atoms, while cycloalkenyl contains, for example, up to 12, such as 3 to Has 8, for example 5 to 8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical can contain, for example, up to 7, preferably up to 4 carbon atoms. 

  The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, for example by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, for example, like the above-mentioned aliphatic hydrocarbon radicals, by functional groups mono-, di- or be polysubstituted. 



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, for example a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, as well as biphenylyl or naphthyl, which optionally, for example like the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   A divalent aromatic radical, for example an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, which may be mono-, di- or polysubstituted, for example like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals can. 



   An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, furthermore an araliphatic ylidene radical, is, for example, an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, for example up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radical and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, also phenyl-lower alkylidene, such radicals containing, for example, 1 to 3 phenyl groups and optionally, for example, such as the aliphatic and cycloaliphatic radicals mentioned above, in the aromatic and / or aliphatic moiety can be mono-, di- or polysubstituted. 



   Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bi- or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyclic radicals of aromatic character, furthermore corresponding partially or completely saturated heterocyclic radicals of this type, where such radicals can optionally be mono-, di- or polysubstituted, for example like the above-mentioned cycloaliphatic radicals. 



  The aliphatic part in heterocyclic-aliphatic radicals has, for example, the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals. 

 

   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the organic radical of the ester group represents an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, for example in o * - Or ss-position, substituted lower alkyl half-ester of carbonic acid, and a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the organic radical. 

  Acyl radicals of a carbonic acid half-ester are also corresponding radicals of lower alkyl half-esters of carbonic acid in which the lower alkyl part contains a heterocyclic group, for example one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group being optionally substituted.  The acyl radical of a carbonic acid half-derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group. 



   An etherified hydroxyl group is primarily optionally substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, also lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocycoxyloxy or heterocyclyloxy or heterocyclyl lower alkoxy substituted phenyl lower alkoxy. 



   An optionally substituted amino group is, for example, amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino, thianiederalkylenamino, aza loweralkylenamino, hydroxyamino, lower alkoxyamino, loweralkanoyloxyamino, loweralkoxycarbonylamino or loweralkaooylamino
An optionally substituted hydrazino group is, for example, hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.    



   Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl or tert. -Butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl, for example vinyl, allyl, isopropenyl, 2 or 3-methallyl or 3-butenyl, lower alkynyl, for example
Propargylic or 2-butynyl, and lower alkylidene, for example
Can be isopropylidene or isobutylidene. 



   Lower alkylene is, for example, 1,2-ethylene, 1,2- or
1,3-propylene, 1,4 butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene is, for example, 1,2-athenylene or 2-butene-1,4-ylene.  Lower alkylene interrupted by heteroatoms is, for example, oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or azo-lower alkylene, such as 3-lower alkyl-3-aza-1, 5-penlylene.     for example 3-methyl-3-aza-1,5-pentylene.    



   Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl, for example cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1 , 4-Cyclohexadienyl, and cycloalkylidene, for example cyclopentylidene or cyclohexylidene.    Cycloalkyl-lower alkyl or-lower alkenyl is, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1 , 3-propyl, -vinyl or -allyl,

   while cycloalkenyl is lower alkyl or lower alkenyl, for example.    1-, 2- or 3-Cy clopentenyl-, 1-, 2- or 3-Cyclohexenyl- or 1-, 2- or 3-Cy cloheptenylmethyl, -1,1- or -1,2-ethyl, -1, Is 1-, -1,2- or -1,3-propyl, -vinyl or allyl.    Cycloalkyl-lower alkylidene is, for example, cyclohexylmethylene, and cycloalkenyl-lower alkylidene is, for example, 3-cyclohexenylmethylene.    



   Naphthyl is 1- or 2-naphthyl, while biphenylyl is, for example, 4-biphenylyl. 



     Phenyl-lower alkyl or phenyl-lower alkenyl is for example benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpro pyl, diphenylmethyl, trityl, styryl or cinnamyl, naphthyl-lower alkyl, for example 1- or 2-naphthylmethyl, and phenyl lower alkylidene, for example benzylidene. 



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, for example corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3 - Or 4-pyridyl, also pyridinium thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, bicyclic monoaza, monooxa or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, Quinolinyl, for example 2 or 4-quinolinyl, isoquinolinyl, for example l-isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl, monocyclic diaza-, triaza-, tetraza- , oxaza-,

   thiaza- or thiadiazacyclic radicals, such as imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidynyl, triazolyl, for example 1,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5 -Tetrazolyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3- or 4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or 4-isothiazolyl or 1,2,4- or 1, 3,4-thiadiazolyl, for example 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza or thiazacyclic radicals, such as benzimidazolyl, for Example 2-Benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl, or benzthiazolyl, for example 2-benzthiazolyl. 

  Corresponding partially or fully saturated radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, for example 2 or 4-piperidyl.       Heterocyclic-aliphatic radicals are heterocyclic groups, especially the abovementioned containing lower alkyl or lower alkkenyl.     The above-mentioned Heterocychylreste can z.  B.  be substituted by optionally substituted aliphatic or aromatic hydrocarbon radicals, in particular lower alkyl, such as methyl, or optionally, for example by halogen, such as chlorine, substituted phenyl, for example phenyl or 4-chlorophenyl, or, for example, such as the aliphatic hydrocarbon radicals, by functional groups . 



   Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy, tert. -Butyloxy, n-pentyloxy or tert. -Pentyloxy.  These groups can be substituted, for example as in halo-lower alkoxy, in particular 2-halo-lower alkoxy, for example 2,2,2-trichloro-, 2-chloro, 2-bromo- or 2-iodoethoxy. 



  Lower alkenyloxy is, for example, vinyloxy or allyloxy, lower alkylenedioxy, for example methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, for example cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, for example benzyloxy, 1- or 2-phenylethoxy or dipethoxy, -diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy, for example pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy. 



   Lower alkylthio is, for example, methylthio, ethylthio or n-butylthio, lower alkenylthio, for example allylthio, and phenyl-lower alkylthio, for example benzylthio, while mercapto groups etherified by heterocyclyl radicals or heterocyclylaliphatic radicals, in particular pyridylmidazolthio, for example, 2-imidazthio, for example 4-pyridylthio Thiazolylthio, for example 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, for example 1,2,4-thiadiazol 3-ylthio or 13ii-thiadiazol-2yl-thio, or tetrazolylthio, for example Are 1-methyl-5-tetrazolylthio. 

 

   Esterified hydroxyl groups are primarily halogen, for example fluorine, chlorine, bromine or iodine, and lower alkanoyloxy, for example acetyloxy or propionyloxy, lower alkoxycarbonyloxy, for example methoxyearbonyloxy, ethoxycarbonyloxy or tert. -Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, for example 2,2,2-trichlorethoxyearbonyloxy, 2-bromoethoxyearbonyloxy or 2-yodethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, for example phenacyloxycarbonyloxy.   



   Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert. -Butyloxycarbonyl or tert. Pentyloxycarbonyl. 



   N-lower alkyl- or N, N-di-lower alkyl-carbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, while N-lower alkylsulfamoyl is, for example, N-methylsulfamoyl or N, Represents N-dimethylsulfamoyl. 



   A carboxyl or sulfo in the form of an alkali metal salt is, for example, a carboxyl or sulfo in the sodium or potassium salt form. 



   Lower alkylamino or di-lower alkylamino is, for example, methylamino, ethylamino, dimethylamino or diethylainino, lower alkylenamino for example pyrrolidino or piperidino, oxane-lower alkylenamino for example morpholino, thi-lower alkylenamino for example thiomorpholino, and aza-lower alkylenamino for example piperazino or 4-methylpiperazino. 

  Acylamino is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, for example methoxycarbonylamino, ethoxycarbonylamino or tert. -Butyloxycarbonylamino, halo-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, furthermore for phthalimido, or, for example, sodium or alkali metal, or optionally in salt form, such as alkali metal present sulfoamino. 



   Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl. 



   O-lower alkyl-phosphono is, for example, O-methyl- or O-ethyl-phosphono, O, O'-di-lower alkyl-phosphono, for example O, O-dimethyl-phosphono or O, O'-diethylphosphono, O-phenyl-lower alkyl -phosphono, for example O-benzyl-phosphono, and O-lower alkyl-O'-phenyl-lower alkyl-phosphono, for example O-benzyl-O'-methyl-phosphono.    



   Lower alkenyloxycarbonyl is, for example, vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl are, for example, adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethoxycarbonyl. 



  Lower alkoxycarbonyl, in which lower alkyl contains, for example, a monocyclic, monoaza, monooxa or monothiacyclic group, is for example furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbonyl. 



   2-lower alkyl- and 2,2-di-lower alkylhydrazino is, for example, 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino for example 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert. -Butyloxycarbonylhydrazino, and lower alkanoylhydrazino, for example 2-acetylhydrazino. 



   An acyl group Ac stands in particular for an N-acyl derivative which is naturally occurring or which can be produced bio-, semi- or totally synthetically, preferably pharmacologically. a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound containing an acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half derivative. 



   An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI4. 1
 where n is 0 and Rl is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, for example esterified or etherified, hydroxyl or mercapto or an optionally substituted amino group, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, represents an acyl group, an optionally substituted amino group or an azido group, and each of the radicals Rll and Grill is hydrogen, or in which n is 1, Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character, R11 is an optionally functionally modified, for example esterified or etherified, hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O, O'-disubstituted phosphono group, or an azido group, and Grill stands for hydrogen, or in which n stands for 1, each of the radicals RI and Rll is functional modified,

   preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or in which n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rll and Grill together represent one optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected by a double bond to the carbon atom, or in which n is 1, and Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have aromatic character, Ril an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and optionally substituted hydrogen mean aliphatic, cycloaliphatic, cy cloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 

 

   In the abovementioned acyl groups of the formula A, for example, n is 0 and Rl is hydrogen or an optionally, preferably in the 1-position by optionally protected amino, acylamino, where acyl is primarily the acyl radical of a carbonic acid half ester, such as a lower alkoxycarbonyl , 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, or a sulfoamino group optionally present in salt, for example alkali metal salt form, substituted cycloalkyl group with 5 to 7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, for example methoxy, acyloxy, in which acyl in primarily for the acyl residue of a carbonic acid half-ester,

   such as a Niederalkoxycarbonyl1 2-Halogenniederalkoxycarbonyl- or Phenylniederalkoxycarbonylrest, and / or halogen, for example chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, one optionally, for example by lower alkyl, for example methyl, and / or phenyl, which in turn Substituents such as halogen, for example chlorine, substituted heterocyclic group, such as a 4-isoxazolyl group, or an amino group preferably containing, for example, an optionally substituted lower alkyl radical, such as halogen, for example chlorine, N-substituted amino group, or n for
1, Rl for an optionally, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen,

   for example chlorine, containing phenyloxy, or by optionally protected amino and / or carboxy substituted lower alkyl group, for example for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, for example silylated, such as tri-lower alkylsylated, for Example trimethylsilylated, amino or acylamino, such as lower alkanoylamino, halo-lower alkanoylamino or phthaloylamino, and / or silylated, such as tri-lower alkylsilylated, for example trimethylsilylated, or esterified, such as by lower alkyl, 2-halo-lower alkyl, or phenyl-lower alkyl, for example for a lower alkenyl group, for an optionally substituted, such as optionally, for example as indicated above, acylated hydroxy and / or halogen,

   for example chlorine, also optionally protected, for example as indicated above, acylated, amino-lower alkyl, such as aminomethyl, or optionally substituted, as optionally, for example as indicated above, acylated hydroxy and / or halogen, for example chlorine, phenyloxy-containing phenyl group, an optionally substituted, for example by lower alkyl, such as methyl, or optionally protected, for example acylated, amino or aminomethyl, substituted as indicated above, for example pyridyl;

  ; Pyridinium, for example 4-pyridinium, thienyl, for example 2-thienyl, furyl, for example 2-furyl, imidazolyl, for example 1-imidazolyl, or tetrazolyl, for example 1-tetrazolyl, an optionally substituted lower alkoxy group , for example methoxy group, an optionally substituted, as optionally protected, for example acylated, hydroxy and / or halogen, such as chlorine, containing phenyloxy group, a lower alkylthio;

   for example n-butylthio, or lower alkenylthio, for example allylthio, an optionally substituted, for example by lower alkyl, such as methyl, phenylthio, pyridylthio, for example 4-pyridylthio, 2-imidazolylthio, 1,2,4 -Triazol-3-ylthio-, 1,3,4-triazol-2ylthio-, 1, 2,4-thiadiazol-3-ylthio-, such as 5-methyl-1, 2,4thiadiazol- 3-ylthio-, 1, 3,4-thiadiazol-2-ylthio, such as methyl-1, 3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio, a halogen, especially chlorine - Or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano or optionally,

   for example by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, for example acetyl or propionyl, or benzoyl group, or an azido group, and R "and R" 'for hydrogen, or n for 1, Rl for lower alkyl or an optionally acylated hydroxy and / or halogen, for example chlorine, substituted phenyl-, furyl-, for example 2-furyl-, thienyl-, for example 2-furyl-, for example as indicated above - or 3-thienyl, or 5-aminomethylthien-2-yl, or isothiazolyl, for example 4-isothiazolyl group, also for a 1-cyclohexenyl or 1,4-cyclohexadienyl group, Rll for optionally protected or substituted amino,

   for example amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, for
Example methoxy, or nitro-containing phenyl lower alkoxycarbonylamino, for example tert. -Butyloxycarbonylamino, 2,2,2-Trichloräthoxycarbonylamino, 4-carbonylamino or Methoxybenzyloxycar Diphenylmethyloxycarbonylamino, arylsulfonyl fonylamino, for example, 4-methylphenylsulfonylamino, Trity lamino, Arylthioamino as Nitrophenylthioamino, for a game is 2-Nitrophenylthioamino or Tritylthioamino ge or optionally substituted, such as Lower alkoxycarbonyl, for
Example ethoxycarbonyl, or lower alkanoyl, for example
Acetyl containing 2-propylideneamino, such as 1-Äthoxycarbo nyl-2-propylideneamino, or optionally substituted Car bamoylamino, such as guanidinocarbonylamino,

   or an optionally present in salt, for example alkali metal salt form, sulfoamino group, an azido group, optionally in salt, for example alkali metal salt form or in protected, such as esterified form, for example as Niederalko xycarbonyl-, for example methoxycarbonyl or Ethoxycarbonyl, or as phenyloxycarbonyl, for example diphenyl methoxycarbonyl group present carboxyl group, a
Cyano group, a sulfo group, an optionally functionally modified hydroxy group, with functionally modified hydroxy, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy, 2-halo-lower alkoxyearbonyloxy or optionally substituted, such as lower alkoxy, for example methoxy,

   or nitro-containing phenyl lower alkoxyearbonyloxy, for example tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxy carbonyloxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, for example methoxy, or phenyloxy represents a O, O'-Di-lower alkyl-phosphono group, for example O-methyl phosphono or O, O'-dimethylphosphono, or a halogen atom, for example chlorine or bromine, and RIII for hydrogen, or n for 1, Rl and Rll each for Halogen, for example
Bromine, or lower alkoxycarbonyl, for example methoxycarbonyl, and Rlll for hydrogen,

   or n for 1, Rl for an optionally, for example, acylated hydroxyl and / or halogen, for example chlorine, substituted phenyl, furyl, for example 2-furyl, or thienyl, for example 2- or 3-thienyl, or isothiazolyl, for example 4-isothiazolyl group, further for a 1,4-cyclohexadienyl group, R "for optionally, for example as indicated above, protected aminomethyl, and grill for hydrogen, or n for 1 and each of the
Group Rl, Rll and Rlll stand for lower alkyl, for example methyl. 

 

   Such acyl radicals Ac are, for example, formyl, cyclopentylcarbonyl, a-aminocyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (with optionally substituted amino group, for example optionally in salt form, the sulfoamino group, or one, preferably slightly, for example with Treat with an acidic
Agents such as trifluoroacetic acid, reductive, for example when treating with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or catalytic
Hydrogen, or hydrolytically cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid half ester, such as lower alkoxycarbonyl, for example tert. -Butyloxycarbonyl, 2-halo-lower alkylcarbonyl, for example 2,2,2-trichloroethyloxycarbonyl,

   2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, optionally substituted, such as lower alkoxy, for example methoxy, or nitro-containing phenyl-lower alkoxycarbonyl, for example 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid-substituted carbamoyl such as -Lower alkyl, for example N-methylcarbamoyl, as well as by trityl, also by arylthio, for example 2-nitrophenylthio, arylsulfonyl, for example 4-methylphenylsulfonyl or l-lower alkoxycarbonyl-2-propylidene, for example 1-ethoxycarbonyl-2-propyli- the, substituted amino group), 2,6-dimethoxybenzoyl 5,6,7,8-tetrahydro-naphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl,

   Benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl -4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, 3-chloroacetylacetyl, chloropropylacetyl, 3-chloroacetylacetyl, 3-chloroacetylacetyl, 3-chloroacetylacetyl, 3-chloroacetylacetyl, butyryl , 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxy-valeryl (with optionally, for example as indicated, such as by a monoacyl or diacyl radical, for example an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, for example in salt, such as sodium salt, or in ester,

   such as lower alkyl, for example methyl or ethyl, or aryl lower alkyl, for example diphenylmethyl ester form, carboxyl group present), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbylcyanoacetyl, N-phenylcarbyl-cyanoacetyl, 3,3-dimethyl-acrylyl, phenylacetyl, x-bromophenylacetyl, a-azido-phenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenyl-acetyl (with optionally substituted amino groups, for example as indicated), phenylacylcarbonyl, phenyloxyacetyl, 4 -Trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a-ethoxyphenylacetyl, a-methoxy-3,4-phe- chlorophenylacetyl,

   in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, α-amino-α- (1,4-cyclohexadienyl) -acetyl, α-amino-a - (1-cyclohexenyl) acetyl, α-aminomethyl-α-phenylacetyl or α-hydroxyphenylacetyl, where an amino group present in these radicals can optionally be substituted, for example as indicated above, and / or an aliphatic and / or phenolic one present bonded hydroxyl group, analogous to the amino group, for example by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half-ester), or aO-OMethyl-phosphono-phenylacetyl or aO, O-dimethyl-phosphono-phenylacetyl, furthermore benzylthioacetyl , Benzylthiopropionyl, a-carboxyphenylacetyl (with optionally,

   for example as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, for example as stated above, substituted amino group), 2-thienylacetyl, 3-thienylacetyl, 5-aminomethylthien-2-ylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, I-imidazolylacetyl, I-tetrazolylacetyl, α-carboxy-2-thienylacetyl or α-Carboxy-3-thienylacetyl (optionally with a functionally modified carboxyl group, for example as stated above), α-cyano-2-thienylacetyl, α-amino-α- (2-thienyl) -acetyl, α-amino-a (2furyl) -acetyl or a-amino-a- (4-isothiazolyl) -acetyl (optionally with, for example as stated above, substituted amino group), a-sulfophenylacetyl (optionally with,

   for example such as the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolyl-thioacetyl, 1,2,4-triazol-3-yl-thioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-met hyl-1, 2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1, 3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.    



   An easily cleavable acyl radical Ac, in particular a carbonic acid half ester, is primarily an acyl radical of a carbonic acid half ester that can be split off by reduction, for example when treating with a chemical reducing agent, or by acid treatment, for example with trifluoroacetic acid, such as one, preferably on the carbon atom in α-position to the oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or a methoxycarbonyl group substituted by arylcarbonyl, in particular benzoyl radicals, or in the β-position substituted by halogen atoms, lower alkoxycarbonyl radical, for example tert. -Butyloxycarbonyl, tert. -Pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl,

   also preferably polycyclic, cycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily α-phenyl-lower alkoxycarbonyl, in which the α-position is preferably polysubstituted, for example diphenylmethoxycarbonyl or a4-biphenylyl-α-methyl-alkoxycarbonyl, or furyl-lower alkoxycarbonyl, primarily α-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl. 



   A divalent acyl group formed by the two radicals RlA and Rlb is, for example, the acyl radical of a lower alkanoic or Ni or lower alkene dicarboxylic acid, such as succinyl, or an o-arylene dicarboxylic acid, such as phthaloyl. 



   Another divalent radical formed by the groups RXA and Rlb is, for example, a substituted, for example optionally substituted phenyl or thienyl, in particular in the 2-position, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3-aza-1,4-butylene radical, for example 4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.    



   An etherified hydroxy group R2A together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group.  Such a group R2A is, for example, lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which, together with the carbonyl group, forms an esterified carboxyl group which, especially in 2-cephem compounds, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group can. 

 

   An etherified hydroxy group R2A, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is, for example, 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the -C (= O) group, forms an esterified carboxyl group that can be easily cleaved or converted into such a group when treated with chemical reducing agents under neutral or weakly acidic conditions, for example with zinc in the presence of aqueous acetic acid esterified carboxyl group and is, for example, 2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter.    



   An etherified hydroxy group R2A, which, together with the -C (= O) grouping, is also effective when treating with chemical reducing agents under neutral or weakly acidic conditions, for example when treating with zinc in the presence of aqueous acetic acid, and also when treating with a suitable nucleophilic reagent , for example sodium thiophenolate, easily cleavable esterified carboxyl group is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy. 



   The group R2A can also stand for an arylmethoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the -C (= O) group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group is in particular lower alkoxyphenyl, for example methoxyphenyl (where methoxy is primarily in the 3-, 4- and / or 5-position), and / or especially nitrophenyl (where nitro is preferably in the 2-position) .  Such radicals are particularly lower alkoxy, for example methoxy and / or nitrobenzyloxy, primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2 -nitro-benzyloxy.    



   An etherified hydroxy group R2A can also represent a radical which, together with the —C (= O) grouping, forms an esterified carboxyl group which can be easily cleaved under acidic conditions, for example on treatment with trifluoroacetic acid or formic acid.  Such a radical is primarily a methoxy group in which methyl is polysubstituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals such as lower alkyl, for example methyl and / or phenyl, or by an electron-donating substituent, carbocyclic aryl group or a , Oxygen or sulfur as a ring member having heterocyclic group of aromatic character is monosubstituted,

   or then in a polycycloaliphatic hydrocarbon radical a ring member or in an oxa or thiacycloaliphatic radical the ring member representing the a-position to the oxygen or sulfur atom. 



   Preferred polysubstituted methoxy groups of this type are tert. -Lower alkoxy, for example tert. -Butyloxy or tert. - Pentyloxy, optionally substituted diphenylmethoxy, for example diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above-mentioned substituted aryl group or the heterocyclic group, for example a-lower alkoxyphenyl -lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or  Furfuryloxy, as is 2-furfuryloxy. 

  A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably three-fold, branched ring member is, for example, adamantyl, such as l-adamantyl, and an above-mentioned oxa or thiacycloaliphatic radical in which methyl of the methoxy group is the α-position to the oxygen or sulfur atom Representative ring member is, for example, 2-oxa- or 2-thia-lower alkylene or lower alkenylene with 5 to 7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 



   The R2A radical can also represent an etherified hydroxyl group which, together with the -C (= O) group, forms an esterified carboxyl group which can be cleaved hydrolytically, for example under weakly basic or acidic conditions.  Such a radical is preferably an etherified hydroxy group which forms an activated ester group with the -C (= O) grouping, such as nitrophenyloxy, for example 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, for example 4-nitro-benzyloxy, hydroxy-lower alkyl benzyloxy, for example 4-hydroxy-3,5-tert. -butylbenzyloxy, polyhalophenyloxy, for example 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, for example phthaliminomethoxy or succinyliminomethoxy. 



   Benzyloxy groups containing nitro groups, in particular the 4-nitrobenzyloxy group, can also initially be converted into a hydroxylamino or amino group using an agent reducing a nitro to a hydroxylamino or amino group, such as a hyposulfite, for example sodium hyposulfite (NaS204), whereupon hydrolytic cleavage occurs. 



   The group R2A can also represent an etherified hydroxyl group which, together with the carbonyl group of the formula -C (= O) - forms an esterified carboxyl group cleavable under hydrogenolytic conditions, and is, for example, optionally substituted a-phenyl-lower alkoxy, for example by lower alkoxy or nitro, such as benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



   The group R2A can also be an, together with the carbonyl group -C (= O) -, an esterified carboxyl group forming an esterified carboxyl group which can be cleaved under physiological conditions, primarily an acyloxymethoxy group, in which acyl, for example, is the residue of an organic carboxylic acid, primarily one optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the radical of a lactone.  Hydroxy groups etherified in this way are lower alkanoyloxymethoxy, for example acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, in particular a-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, L-valyloxymethoxy, L-leucyloxthaloxy, furthermore. 



   A silyloxy or stannyloxy group R2A contains, as substituents, preferably optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups, such as etherified hydroxy, for example Lower alkoxy groups, or halogen, for example chlorine atoms, and is primarily tri-lower alkylsilyloxy, for example trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyl, for example chloromethoxymethyl-silyl, or tri-lower alkylstannyloxy, for example trin-butylstannyloxy. 



   An acyloxy radical R2A which together with a -C (= O) group forms a, preferably hydrolytically, cleavable mixed anhydride group contains, for example, the acyl radical of one of the above-mentioned organic carboxylic acids or carbonic acid half-derivatives, and is, for example, optionally, such as by halogen, for example fluorine or Chlorine, preferably in the a-position, substituted lower alkanoyloxy, for example acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, for example methoxycarbonyloxy or athoxycarbonyloxy. 

 

   A radical R2A which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is, for example, amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, for example pyrrolidino or piperidino, oxane-lower alkylene , for example morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, for example 2-methylhydrazino or 2,2-dimethylhydrazino.   



   An optionally substituted aliphatic hydrocarbon radical R3 is in particular lower alkyl with up to 7, preferably up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec. -Butyl, also lower alkenyl, for example allyl, tert. -Amino-lower alkyl, wherein the tert. -Amino group is separated from the sulfur atom by at least two carbon atoms, such as 2- or 3-di-lower alkylamino-lower alkyl, for example 2-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl, or etherified hydroxy-lower alkyl, in which the etherified
Hydroxy group, especially lower alkoxy, is separated from the sulfur atom by at least two carbon atoms, such as 2- or 3-lower alkoxy-lower alkyl, for example 2-methoxyethyl or 2-ethoxyethyl. 



   An optionally substituted aromatic hydrocarbon radical R3 is primarily phenyl, which can be substituted by 1 or more lower alkyl groups such as methyl, aryl groups such as phenyl, nederalkoxy groups such as methoxy, or halogen such as fluorine, chlorine or bromine. 



   An optionally substituted araliphatic hydrocarbon radical R3 is primarily an optionally substituted phenyl-lower alkyl, in particular 1-phenyl-lower alkyl radical with 1 to 3 optionally substituted phenyl radicals, such as benzyl, diphenylmethyl or trityl, with, for example, esterified or etherified hydroxy, such as halogen, as substituents , for example fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, are possible. 



   An optionally substituted heterocyclic radical R3, which is bonded with one of its carbon atoms to the thio group, is primarily an aromatic heterocycle with an oxygen or a sulfur atom, with lower alkyl, such as methyl, lower alkoxy, such as methoxy, or halogen, such as Fluorine or chlorine, come into question. 



   S-oxides of compounds of the formula IA and IB are primarily mono-S-oxides, in particular l-oxides, also 3-S (-0) -R3 compounds and di-S-oxides, namely I-oxide 3-S (-O) -R, compounds, and mixtures thereof. 



   Salts are in particular those of compounds of the formulas IA and IB with an acidic group, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, for example sodium, potassium, magnesium or Calcium salts, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases are possible for the salt formation, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid-2-diethylaminoethyl ester, Lower alkyleneamines,

   for example 1-ethyl-piperidine, cycloalkylamines, for example bicyclohexylamine, or benzylamines, for example N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, for example.  Pyridine, collidine or quinoline.  Compounds of the formulas IA and IB which have a basic group can also form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example trifluoroacetic acid or 4-methylphenylsulfonic acid.  Compounds of the formulas IA and IB with an acidic and a basic group can also be present in the form of internal salts, that is to say in zwitterionic form.  S-oxides of compounds of the formulas IA and IB with salt-forming groups can likewise form salts, as described above. 



   The new compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such.  Compounds of the formula IA in which, for example, R, a is an acyl radical Ac occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and R1b is hydrogen , or in which Rla and R1b together are 1-oxo-3-aza which is preferably substituted in the 2-position, for example by an aromatic or heterocyclic radical, and in the 4-position, for example by 2-lower alkyl, such as methyl Represent -1,4-butylene radical,

   R2 denotes hydroxyl or an etherified hydroxyl group R2A which, together with the carbonyl group, forms an esterified carboxyl group which can easily be cleaved under physiological conditions, and R3 has the meaning given above, with any functional groups present in an acyl radical Rla, such as amino, carboxy, hydroxyl and / or sulfo , usually in free form, or salts of such compounds with salt-forming groups, are in vitro against gram-positive and gram-negative germs, as well as against Mycobacterium tuberculosis in a dose range of about 0.02 mcg / ml to about 100 mcg / ml , as well as in vivo with parenteral and / or oral administration against microorganisms such as gram-positive bacteria, for example Staphylococcus aureus, (e.g. 

  B.  in mice at doses from about 0.0014 to about 0.023 g / kg s.  c.  or from about 0.003 to about 0.025 g / kg p.  o), and gram-negative bacteria, e.g. Escherichia coli, (e.g.  B.  in mice at doses from about 0.007 to about 0.09 g / kg s.  c.  or p.  O. ), especially effective against penicillin-resistant bacteria such as Staphylococcus aureus, with low toxicity.  These new compounds can therefore be used, for example, in the form of, in particular orally applicable, antibiotic preparations for the treatment of corresponding infections. 



   Compounds of the formula IB or S-oxides of compounds of the formulas IA and IB in which R1a, Rlb, R2 and R3 have the meanings given in connection with the formula IA, or compounds of the formula IA in which R32 has the meaning given above, the R1a and R1b radicals represent hydrogen, or R1a is an acyl radical which occurs in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds Amino protective group and R, b are hydrogen, or R1a and R1b together are one, of one in the 2-position, preferably, for example by an aromatic or heterocyclic radical, and preferably in the 4-position, for example by 2-lower alkyl, such as methyl ,

   substituted l-oxo-3-aza-1,4-butylene radical represent different divalent amino protective groups, and
R2 stands for hydroxy, or Rla and Rlb are those given above
Have meanings, R2 represents a, together with the -C (= O) grouping, a preferably easily cleavable, protected carboxyl group-forming radical R2A, a carboxyl group protected in this way being different from a physiologically cleavable carboxyl group, and R3 are those given above Has meanings are valuable intermediate products which can be converted into the above-mentioned pharmacologically active compounds in a simple manner, for example as described below. 

 

   The invention relates in particular to the 3-cephem compounds of the formula IA, in which R1a is hydrogen or preferably one, in a fermentative (i.e.  H.  naturally occurring) or bio-, semi- or totally synthetically producible, in particular pharmacologically active, such as highly active N-acyl derivative of a 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3 cephem-4-carboxylic acid compound containing acyl radical, as one of the abovementioned acyl radicals of the formula A, where in this Rl, R ", Rlll and n primarily have the preferred meanings, R1b is hydrogen, or where R1a and R1b together are preferably in the 2-position, for example through an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position,

   for example by two lower alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical, R2 for hydroxy, for optionally, preferably in a-position, for example by optionally substituted aryloxy, such as lower alkoxyphenyloxy, for example 4 -Methoxyphenyloxy, lower alkanoyloxy, for example acetyloxy or pivaloyloxy, α-amino lower alkanoyloxy, for example glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, for example benzoyl, or optionally substituted aryl, such as phenyl, lower alkoxyphenyl, for example 4-methoxyphenyl , for example 4-nitrophenyl, or biphenylyl, for example 4-biphenylyl, or in the B-position by halogen, for example chlorine, bromine or iodine, mono- or polysubstituted lower alkoxy, such as lower alkoxy,

   for example methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bisphenyloxy-methoxy optionally substituted by lower alkoxy, for example bis4-methoxyphenyloxymethoxy, lower alkanoyloxy-methoxy, for example acetyloxymethoxy or pivaloyloxymethoxy, α-amino-lower alkanoyloxy-methoxy, for example glycyloxymethoxy, such as phenyl-lower alkoxy-lower alkoxy, for example glycyloxymethoxy, such as phenyl-lower-methoxy, in particular phenoxy-lower alkoxy-lower, such as phenyl-lower-alkoxy, such as phenyl-lower-alkoxy-1-phenyl-lower-alkoxy, e.g. , wherein such radicals 1 to 3 may contain phenyl radicals substituted, for example by lower alkoxy, such as methoxy, nitro or phenyl, for example benzyloxy, 4-methoxybenzyloxy, 2-biphenylyl-2-propyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, or 2-halo-lower alkoxy,

   for example 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, furthermore for 2-phthalidyloxy, as well as for acyloxy, like lower alkoxycarbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, for example acoyetyloxy, or for tri-lower alkylsilyloxy, for example trimethylsilyloxy, or for amino or hydrazino which is optionally substituted, for example by lower alkyl, such as methyl, or hydroxy, for example amino, lower alkyl- or di-lower alkylamino, such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2 -Di-lower alkylhydrazino, for example 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R3 is lower alkyl, for example methyl, ethyl, n-propyl, isopropyl or n-butyl, lower alkenyl, for example allyl, phenyl or optionally methyl , Methoxy,

   Fluorine or chlorine-substituted phenyl, optionally substituted phenyl-lower alkyl, in particular 1-phenyl-lower alkyl with 1 to 3, optionally, for example by lower alkoxy, such as methoxy, substituted phenyl radicals, for example benzyl, diphenylmethyl, trityl and the 1-oxides thereof, furthermore the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups. 



   Primarily in a 3-cephem compound of the formula IA, and in a corresponding 2-cephem compound of the formula IB, furthermore in a 1-oxide thereof or in a salt of such a compound with salt-forming groups R1a represents hydrogen or a in fermentative (d.  H.  naturally occurring) or biosynthetically producible N-acyl derivatives of 6ss-aminopenam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds containing acyl radical, in particular of the formula A, in which Rl, Ril, Grill and n are primarily the preferred meanings have, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, for example by hydroxy, furthermore an optionally substituted, for example by lower alkylthio, or lower alkenylthio,

   and optionally substituted, such as acylated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, for example 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino-5-carboxy-valeryl, wherein the amino and / or the carboxyl groups are optionally protected and, for example, as acylamino or 

   esterified carboxyl are present, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, in particular of the formula A, in which Rl, Ril , Grill and n primarily have the preferred meanings, such as formyl, 2-haloethylcarbamoyl, for example 2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, for example 2-thienylacetyl, or 5-aminomethylthien-2ylacetyl, or tetrazolylacetyl, for example l -Tetrazolylacetyl, but especially in the a-position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, primarily monocyclic radical and by a functional group, primarily amino, carboxy,

   Sulpho or hydroxyl-substituted acetyl, in particular phenylglycyl, in which phenyl optionally, for example by optionally protected hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, for example chlorine, substituted phenyl, for example phenyl, or 3 or 4-hydroxy, 3-chloro-4-hydroxy or 3,5-dichloro-4-hydroxyphenyl (optionally also with a protected, such as acylated hydroxy group), and in which the amino group can optionally also be substituted and, for example, a optionally present in salt form represents a sulfoamino group or an amino group which, as substituents, is a hydrolytically cleavable trityl group or primarily an acyl group, such as an optionally substituted carbamoyl,

   such as an optionally substituted ureidocarbonyl group, for example ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, for example guanidinocarbonyl, or one, preferably slightly, for example when treating with an acidic agent such as trifluoroacetic acid, further reductive, as when treating with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above, for example optionally halogen or benzoyl-substituted lower alkyloxycarbonyl radicals, for Example tert. -Butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl,

   or phenacyloxycarbonyl, optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonyl, for example 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, and also one with a nucleophilic reagent, such as hydrocyanic acid, sulphurous acid, sulphurous acid or arylactic acid Aryl lower alkylthio radical, for example 2-nitrophenylthio or tritylthio, an arylsulfonyl radical that can be split off by means of electrolytic reduction, for example 4-methylphenylsulfonyl, or one with an acidic agent such as formic acid or aqueous mineral acid, for example hydrochloric or phosphoric acid,

   Cleavable l-lower alkoxycarbonyl or l-lower alkanoyl-2-propylidene radical, for example l-ethoxycarbonyl-2-propylidene, also contains aX1,4-cyclohexadienyl) glycyl, a- (1-cyclohexenyl) glycyl, a- Thienyl-glycyl, such as a-2- or a-3-thienyl-glycyl, a-furyl-glycyl, such as a-2-furyl-glycyl, a-isothiazolyl-glycyl, such as a-4-isothiazolyl-glycyl, where in such radicals the7amino group, for example as indicated for a phenylglycyl radical, can be substituted or protected, furthermore α-carboxy-phenylacetyl or a-carboxy-thienylacetyl, for example o-carboxy-2-thienylacetyl (optionally with functionally modified, for Example in salt, such as sodium salt form, or in ester, such as lower alkyl, for example methyl or ethyl,

   or phenyl lower alkyl, for example iphenylmethyl ester form, present carboxyl group), a-sulfophenylacetyl (optionally also with, for example, like the carboxyl group, functionally modified sulfo group), a-phosphono, aO-methylphosphono or aO, O'-dimethylphosphono-phenylacetyl, or a-Hydroxyphenylacetyl (optionally with a functionally modified hydroxyl group, especially with an acylo xy group, in which acyl is one, preferably slightly, for example when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid , cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above,

   for example, if appropriate by halogen or benzoyl substituted Niederalko xycarbonylrest, for example 2,2,2-Trichloräthoxycarbonyl,
2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), and 1-amino-cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethyl-phenylacetyl, or aminopyridinium acetyl, for example 4-aminopyridinium acetyl (if appropriate also with, for example as stated above, substituted amino group), or pyridylthioacetyl, for example 4-pyridylthioacetyl, and Rlb for hydrogen, or R1a and R1b together for one, preferably in the 2-position, optionally protected by hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy , and / or by halogen,

   for example chlorine, substituted phenyl, for example phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxyphenyl (optionally also with protected, for example as stated above, acylated hydroxy group) substituted 1-oxo-3-aza-1,4-butylene radical, which optionally contains two lower alkyls, such as methyl, in the 4-position, and R2 represents hydroxy, lower alkoxy, in particular a-polybranched lower alkoxy, for example tert . -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-chloroethoxy or 2-bromo ethoxy, phenacyloxy, I-phenyl-lower alkoxy which can easily be converted into this 1 to 3, optionally by lower alkoxy or nitro-substituted phenyl radicals, for example 4-methoxybenzyloxy, 4-nitrobenzyloxy,

   Diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, for example acetyloxymethoxy or pivaloyloxymethoxy, α-amino lower alkanoyloxymethoxy, for example glycyloxymethoxy, 2-phthalidyloxyloxy or, for example, trinoyloxymethoxy, for example, trinoyloxyloxy, or, for example, lower alkanoyloxymethoxy, for example, trinoyloxyloxythoxy, for example lower alkoxycarbonyloxy, for example, also lower alkoxycarbonyloxy or, for example, lower alkoxycarbonyloxy, or, for example, lower alkoxycarbonyloxy, or, for example, lower alkoxycarbonyloxy or, for example, lower alkoxycarbonyloxy Example trimethylsilyloxy, and R3 stands primarily for lower alkyl, for example methyl, ethyl or n-butyl, and for phenyl, also for lower alkenyl, for example allyl, and l-phenyl-lower alkyl, for example benzyl, diphenylmethyl or trityl . 



   The invention relates primarily to 3-cephem compounds of the formula IA, in which Rla is hydrogen or an acyl group of the formula
EMI10. 1
 wherein Ra is phenyl or hydroxyphenyl, for example 3- or 4-hydroxyphenyl, furthermore hydroxylchlorophenyl, for example 3-chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, with hydroxyl substituents in such radicals by acyl radicals , such as optionally halogenated lower alkoxycarbonyl radicals, for example tert. -Butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, and thienyl, for example 2- or 3-thienyl, also pyridyl, for example 4-pyridyl, aminopyridinium, for example 4-aminopyridinium, furyl, for example 2- Furyl, isothiazolyl, for example 4-isothiazolyl, or tetrazolyl, for example l-tetrazolyl, I-cyclohexenyl or 1,4-cyclohexadienyl,

   X is oxygen or sulfur, m is 0 or 1, and Rb is hydrogen or, if m is 0, amino, and protected amino, such as acylamino, for example a-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, for example 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, or 3-methoxycarbonylamino, e.g. Sulfoamino or tritylamino, and arylthioamino, for example 2-nitrophenylthioamino, arylsulfonylamino, for example 4-methylphenylsulfonylamino,

   or 1-lower alkoxycarbonyl-2-propylideneamino, for example 1-ethoxycarbonyl-2-propylideneamino, carboxy or in salt, for example alkali metal, such as sodium salt form, as well as protected carboxy, for example esterified carboxy, such as phenyl-lower alkoxycarbonyl, for For example diphenylmethoxycarbonyl, sulfo or sulfo present in salt, for example alkali metal, such as sodium salt form, and protected sulfo, hydroxy, and protected hydroxy, such as acyloxy, for example a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also formyloxy, or O-lower alkylphosphono or O, O'-di-lower alkylphosphono or O ', for example O-methylphosphono or O-methylphosphono -Dimethylphosphono,

   or a 5-amino-5carboxy-valeryl radical, in which the amino and / or carboxy groups can also be protected and, for example, as acylamino, for example lower alkanoylamino, such as acetylamino, halogen-lower alkanoylamino, such as dichloroacetylamino, benzoylamino or phthaloylamino, or  as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, where preferably m is 1 when Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and Rb is different from hydrogen when Ra is phenyl, hydroxyphenyl, hydroxy- represents chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or l-cyclohexenyl, R3b denotes hydrogen, R2 primarily denotes hydroxy, furthermore denotes lower alkoxy, in particular α-polybranched lower alkoxy, for example tert. -Butyloxy,

   2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or where appropriate, for example by lower alkoxy, for example methoxy, substituted diphenylmethoxy, for example diphenylmethoxy or 4,4'-dimethoxy -diphenylmethoxy also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and R3 is lower alkyl, for example methyl, ethyl or n-butyl, and lower alkenyl, for example allyl, phenyl or phenyl-lower alkyl, for example benzyl, diphenylmethyl or trityl, and the 1-oxides of such 3-cephem compounds of the formula IA, also the corresponding 2-cephem compounds of the formula IB, or salts, in particular pharmaceutically usable, non-toxic salts of such compounds with salt-forming groups, such as alkali metal, for example sodium, or alkaline earth metal,

   for example calcium salts, or ammonium salts, incl.  those with amines, of compounds in which R2 is hydroxy, or internal salts of compounds in which R2 is hydroxy, and which contain a free amino group in the acyl radical of the formula B. 



   Primarily in 3-cephem compounds of the formula IA, furthermore in corresponding 2-cephem compounds of the formula IB, as well as in salts, in particular in pharmaceutically acceptable, non-toxic salts of such compounds with salt-forming groups, as in the section above mentioned salts R1a for hydrogen, for the acyl radical of the formula B, in which Ra is phenyl and hydroxyphenyl, for example 4-hydroxyphenyl, thienyl, for example 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl, or 1-Cyclohexenyl, X is oxygen, m is 0 or 1, and Rb is hydrogen or, when m is 0, amino, and protected amino, such as acylamino, for example a-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, for example 2,2,2-trichloroethoxycarbonylamino,

   2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, for example 4-methoxybenzyloxycarbonylamino, or hydroxy, as well as protected hydroxy, such as acyloxy, for example a-polybranched lower alkoxycarbonyloxy or 2-branched lower alkoxycarbonyloxy, for example a-poly-branched alkarbonyloxy or 2-branched alkoxycarbonyloxy or 2-branched alkoxycarbonyloxy-lower alkoxycarbonyloxy, such as such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jod äthoxycarbonyloxy or 2-Bromoäthoxycarbonyloxy, also mean formyloxy, or for a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups can also be protected and, for example, as Acylamino, for
Example lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or 

   as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, where preferably m is 1, when Ra is phenyl or hydroxyphenyl, R1b is hydrogen, R2 is primarily hydroxy, also optionally halogen in the 2-position, for example Chlorine-, bromine- or iodine-substituted lower alkoxy, in particular a-polybranched lower alkoxy, for example tert. -Butyloxy, or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally
Lower alkoxy, such as methoxy-substituted Diphenylmethy loxy, for example diphenylmethoxy or 4,4'-dimethoxy-di phenylmethoxy, also tri-lower alkylsilyloxy, for example
Trimethylsilyloxy, and R3 means lower alkyl, for example
Methyl, ethyl or n-butyl, as well as lower alkenyl,

   for example allyl, phenyl or phenyl lower alkyl, for example benzyl, diphenylmethyl or trityl. 



   The invention relates primarily to 7 (Da-amino-a-Ra-acetylamino) - 3-R3-thio-3-cephem4-carboxylic acids, where Ra is phenyl, 4-hydroxyphenyl, 2-thienyl, 1,4-cyclohexadienyl or 1-Cyclohexenyl, and R3 is methyl, phenyl or Tri tyl, and the inner salts thereof, and especially those
3-M ethylthio- and 3-phenylthio-7ss- (D-a-phenyl-glycyl-amino) -3-cephem4-carboxylic acid and the inner salts thereof; In the above-mentioned concentrations, in particular when administered orally, these compounds have excellent antibiotic properties, both against gram-positive and especially against gram-negative bacteria with low toxicity. 



   The process for the preparation of compounds of the
Formulas IA and IB, their S-oxides and salts are characterized in that a compound of the formula
EMI11. 1
 or an S-oxide thereof, in which the dashed lines denote the a-configuration, and in which R is an optionally substituted hydrocarbon radical and Rta, R1b, R2 and R3 have the meaning given under formula IA or IB, in the presence of an acid, the compound HO -R5 splits off, and, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained into the free compound or into another salt. 

  If desired, in a compound of the formula IA or IB obtained or a 1-oxide thereof, the protected carboxyl group of the formula -C (= O) -R2A can be converted into the free or into another protected carboxyl group, and / or, if desired, within the definition of the end products, a compound obtained is converted into another compound, and / or, if desired, a mixture of isomeric compounds obtained is separated into the individual isomers. 



   In a starting material of the formula IV, R3 is preferably an optionally substituted hydrocarbon radical or an optionally substituted heterocyclic radical, the carbon atom bonded to the thio group being saturated, that is to say does not form a double bond. 



   In a starting material of the formula IV, R5 stands for an optionally substituted hydrocarbon radical and can thus have the same meaning as the optionally substituted hydrocarbon radical R3 in the end product of the formula IA or IB.  Preferred hydrocarbon radicals R5 are lower alkyl radicals, in particular the methyl radical. 



  The substituent -O-R5 to be split off can only have the ss configuration.  The group -C (= O) -R2A usually has the a-configuration.  Either the pure 3ss- (O-Rs) isomer or the epimeric mixture of 3P- (O-R5) -3a- (S-R3) -Cepham4-carboxylic acid derivatives and 3a- (O-Rs) - can be used in the reaction. 3ss- (S-R3) -Cepham-4-carboxylic acid derivatives are used, although only the former HO-R5 are able to split off. 



   In a starting material of the formula IV, R2 is preferably an etherified hydroxy group R2A which, with the -C (= O) grouping, forms an esterified carboxyl group that can be cleaved, especially under mild conditions, with any functional groups present in a carboxyl protective group R2A known manner, for example as indicated above, can be protected. 

 

  A group R2A is, for example, in particular an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, for example tert. -Butyloxy, or 2-halo-lower alkoxy, in which halogen is, for example, chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted one, such as lower alkoxy, for Example methoxy, or nitro-containing 1-phenyl-lower alkoxy group, as optionally, for example as stated, substituted benzyloxy or diphenylmethoxy, for example benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsily loxy,

   for example trimethylsilyloxy.  In a starting material of the formula IV, the radical Rta is preferably an amino protective group R1A, such as an acyl group Ac, in which any free functional groups present, for example amino, hydroxyl, carboxyl or phosphono groups, in a manner known per se, for example through the above acyl, trityl, silyl or stannyl, as well as substituted thio or sulfonyl radicals, and hydroxy, carboxy or phosphono groups, for example through the above ether or ester groups, incl.  Silyl or stannyl groups, and R, b hydrogen. 



   Particularly preferred starting materials of the formula IV are those which have no basic group, in particular no amino group, or no protected basic group which can be converted into a free basic group during the cleavage reaction with acids. 



   A mixture of a compound of the formula IV and the corresponding l-oxide can also be used as starting material and the product obtained is the mixture of compounds of the formulas IA and IB and the l-oxide of a compound of the formula IA.  A starting material can be used in pure form or in the form of the crude reaction mixture obtainable during its preparation. 



   The process according to which the alcohol HO-R5 is split off takes place in the presence of an acid, in the presence or absence of a suitable, inert solvent and with cooling at room temperature or with heating, i.e. at temperatures between -70 "and +100" C, preferably about 5 C to about 40 "C instead. 

  Acids suitable for splitting HO-Rs are strong organic or inorganic protic acids, in particular mineral acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, and also sulfonic acids such as lower alkanesulfonic acids, for example methanesulfonic acid, or aromatic sulfonic acids, for example benzene or toluenesulfonic acid, halogenated lower alkanecarboxylic acids such as trifluoroacetic or trichloroacetic acid or also formic acid. 

  Suitable solvents are, for example, aliphatic, cycloaliphatic or aromatic, optionally substituted, such as halogenated, for example fluorinated or chlorinated hydrocarbons, such as hexane, cyclohexane, benzene, toluene, xylene, methylene chloride, chloroform or carbon tetrachloride, ethereal solvents such as di-lower alkyl ethers, for example diethyl ether, Diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, di-lower alkyl amides such as N, N-dimethylformamide, N, N-dimethylacetamide, lower alkyl nitriles such as acetonitrile, di-lower alkyl sulfides such as dimethyl sulfide, di-lower alkyl sulfoxides such as dimethyl sulfoxide or mixtures thereof. 



   Depending on the starting material and reaction conditions, single compounds of the formulas IA or IB or mixtures thereof can be obtained in the reactions according to the invention. 



   Mixtures obtained can be processed in a manner known per se, for example with the help of suitable separation methods, for example by adsorption and fractional elution, incl. 



  Chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further by fractional crystallization, solvent distribution, etc.  be separated. 



   In the process according to the invention, as well as in additional measures to be carried out, if necessary, free functional groups not participating in the reaction in the starting materials or in the compounds obtainable according to the process, for example free amino groups, for example by acylation, tritylation or silylation, free hydroxyl - or mercapto groups, for example by etherification or esterification, and free carboxyl groups, for example by esterification, incl.  Silylation, temporarily protected in a manner known per se and, depending on the reaction, released in a manner known per se, if desired, individually or together, whoever the. 

  For example, amino, hydroxy, carboxyl or phosphono groups in an acyl radical R, A or    Rtb, for example, in the form of acylamino, such as those mentioned above, for example 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonylamino or tert. -Butylo xycarbonylamino, of aryl or aryl-lower alkylthioamino, for example 2-nitrophenylthioamino, or arylsulfonylamino, for example 4-methylphenylsulfonylamino, or of l-lower alkoxycarbonyl-2-propylidene amino groups, or 



   of acyloxy, such as the above, for example tert. -Butyloxycarbonyloxy-, 2,2,2-Trichloräthoxycarbonyloxy- or 2-Bro mäthoxycarbonyloxygruppen, or  of esterified Carbo xy, such as the above, for example Diphenylmethoxycar bonylgruppen, or  O, O'-disubstituted phosphono groups, such as those mentioned above, for example O, O'-Diniederalkylphospho no-, for example O, O-dimethylphosphono groups, protect and subsequently, optionally after conversion of the
Protective group, for example a 2-bromoethoxycarbonyl in a 2-iodoethoxycarbonyl group, in a manner known per se and depending on the type of protective group, for example a 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treating with suitable reducing agents such as zinc in the presence of aqueous acetic acid,

   a diphenylmethoxycarbonylamino.     or tert. -Butyloxycar bonylamino group by treatment with formic or trifluoroacetic acid, an aryl or aryl-lower alkylthioamino group by treatment with a nucleophilic reagent, such as sulphurous acid, an arylsulfonylamino group by means of electrolytic reduction, an L-lower alkoxycarbonyl-2-propylidene amino group or by treatment with aqueous minerals .  a tert. -Butyloxycarbonyloxy group by treatment with formic or trifluoroacetic acid, or a 2,2,2-Trichloräthoxycarbonyloxygruppe by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or  a diphenylmethoxycarbonyl group by treatment with formic or trifluoroacetic acid or by hydrogenolysis, or 

   cleaving an O, O'-disubstituted phosphono group by treatment with an alkali metal halide, for example partially, if desired. 



   In a compound of formula IA or IB obtainable according to the invention with a protected, in particular esterified, carboxyl group of formula -C (= O) -R2A, this can be converted into the free carboxyl group in a manner known per se, for example depending on the type of group R2A .  An esterified, for example by a lower alkyl radical, in particular methyl or ethyl, esterified carboxyl group, in particular in a 2-cephem compound of the formula IB, can be obtained by hydrolysis in a weakly basic medium, for example by treatment with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, can be converted into a free carboxyl group.  

  A carboxyl group esterified by a suitable 2-halo-lower alkyl or an arylcarbonylmethyl group can, for example, by treatment with a chemical reducing agent, such as a metal, for example zinc, or a reducing metal salt, such as a chromium-II-salt, for example chromium-II chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably adding water, a carboxyl group esterified by an aryl carbonylmethyl group likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl group, for example by irradiation,

   preferably with ultraviolet light, for example below 290 mu, if the arylmethyl group is, for example, a benzyl radical optionally substituted in the 3-, 4- and / or 5-position, for example by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, for example over 290 m, u, if the arylmethyl group is, for example, a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert. -Butyl or diphenylmethyl, esterified carboxyl group, for example by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group, furthermore a carboxyl group present in anhydride form by hydrolysis,

   for example by treating with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, for example by treating with hydrogen in the presence of a
Noble metal, for example palladium catalyst, are split. 



   A carboxyl group protected, for example, by silylation or stannylation can be liberated in a customary manner, for example by treatment with water or an alcohol. 



   Compounds of the formula IA or IB obtained can be converted into other compounds of the formula IA or IB in a manner known per se. 



   In a compound obtained, for example, an amino protective group R1A or    Rlb, in particular an easily cleavable acyl group, in a manner known per se, for example an α-polybranched lower alkoxycarbonyl group, such as tert-butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2- Iodethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, for example zinc, or a chromium II compound, such as chloride or acetate, advantageously in the presence of a hydrogen-generating agent which noses together with the metal or the metal compound ,

   preferably in the presence of hydrous acetic acid, are split off. 



   Furthermore, in a compound of the formula IA or IB obtained, in which a carboxyl group of the formula -C (= O) -R2 is preferably one, for example by esterification, including by silylation, for example by reaction with a suitable organic halosilicon or halogen tin-IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, is a protected carboxyl group, an acyl group Rta or Rlb, in which any free functional groups that may be present are optionally protected, by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, a protected one, for example one protected by an organic silyl radical,

   Carboxyl group can be released in the course of the reaction. 



   Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides.  These are primarily acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, for example phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, especially chlorides , sulfur-containing acids or carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride. 



   The reaction with one of the imide halide-forming agents mentioned is usually in the presence of a suitable, in particular organic base, primarily a tertiary amine, for example a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, for example trimethyl, triethyl or N, N-diisopropyl-N-ethyl-amine, also an N, N, N ', N'-tetraniederalkyl-lower alkylenediamine, for example N, N, N', N'-tetramethyl-1,5-pentylenediamine or N, N, N ', N'-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine, such as an N-substituted, for example N-lower alkylated, alkylene-, azaalkylene- or oxaalkyleneamine, for example N- Methylpiperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo- [1,2-al-pyrimidine (diazabicyclonones:

  DBN), or a tertiary aromatic amine such as a di-lower alkyl aniline, for example N, N-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, in particular pyridine, preferably in the presence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic or aromatic hydrocarbon, for example methylene chloride.  Approximately equimolar amounts of the imide halide-forming agent and the base can be used; However, the latter can also be present in excess or deficiency, for example in about 0.2 to about 1 times the amount or then in about up to 10 times, in particular about 3 to 5 times, excess. 



   The reaction with the imide halide-forming agent is preferably carried out with cooling, for example at temperatures from about -50 "C to about +10" C, but also at higher temperatures, that is, for example up to about 75 "C, can work if the stability of the starting materials and products allow an increased temperature. 



   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to form the imino ether.  Suitable alcohols are, for example, aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, for example chlorinated, or lower alkanols containing additional hydroxyl groups, for example ethanol, propanol or butanol, in particular methanol, also 2-halo-lower alkanols, for Example 2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl lower alkanols, such as benzyl alcohol.  

   Usually one uses, for example up to about 100 times, an excess of the alcohol and works preferably with cooling, for example at temperatures of about -50 "C to about 10" C.    



   The imino ether product can advantageously be subjected to cleavage without isolation.  The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, the latter being able to take place directly after the imino ether formation when using an excess of the alcohol.  It is preferred to use water or an alcohol, especially a lower alkanol, for example methanol, or an aqueous mixture of an organic solvent, such as an alcohol. 

  One usually works in an acidic medium, for example at a pH of about 1 to about 5, which, if necessary, can be obtained by adding a basic agent, such as an aqueous alkali metal hydroxide, for example sodium or potassium hydroxide, or an acid, for example a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, borofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid. 



   The three-step process described above for splitting off an acyl group is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent that is inert towards the reactants, such as an optionally halogenated hydrocarbon, for example methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere. 



   If the imide halide intermediate product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula IA or IB is obtained in which both radicals Rla and Rlb Represent acyl groups. 



   In a compound of the formula IA or IB in which both radicals R1a and Rlb are acyl groups, one of these groups, preferably the less sterically hindered one, can be selectively removed, for example by hydrolysis or aminolysis. 



   In a compound of the formulas IA or IB in which RIA and R, b together with the nitrogen atom represent a phthalimido group, this can be converted into the free amino group, for example by hydrazinolysis, that is, when treating such a compound with hydrazine. 



   Certain acyl radicals R> A of an acylamino group in compounds obtainable according to the invention, such as the 5-amino-5-carboxy-valeryl radical, in which carboxyl, for example by esterification, in particular by diphenylmethyl, and / or the amino group, for example by acylation, ins Particularly protected by an acyl radical of an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl, or phthaloyl, can also be obtained by treating with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen , such as an N-halo-amide or -imide, for example N-bromosuccinimide, preferably in a suitable solvent or solvent mixture such as formic acid,

   together with a nitro or cyano-lower alkane and adding a hydroxyl-containing agent to the reaction product, such as water or a lower alkanol, for example methanol, or, if the amino group is unsubstituted and the carboxy group in the 5-amino-5-carboxy-valeryl radical R, A is protected for example by esterification, and R, b is preferably an acyl radical, but can also mean hydrogen, by leaving it to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, for example methylene chloride, and, if necessary, working up the free or monoacylated amino compound are split off by methods known per se. 



   A formyl group R, A can also be split off by treatment with an acidic agent, for example p-toluenesulphonic or hydrochloric acid, a weakly basic agent, for example dilute ammonia, or a decarbonylating agent, for example tris (triphenylphosphine) rhodium chloride . 



   A triarylmethyl, such as the trityl group RtA, can be cleaved, for example, by treatment with an acidic agent such as a mineral acid, for example hydrochloric acid. 



   In a compound of the formula IA or IB in which R1a and R1b are hydrogen, the free amino group can be substituted by methods known per se, primarily acylating by treatment with acids, such as carboxylic acids, or reactive derivatives thereof. 



   If a free acid, preferably with protected, optionally present functional groups, such as an optionally present amino group, is used for the acylation, suitable condensation agents such as carbodiimides, for example N, N'-diethyl-, N, N'-dipropyl, are usually used -, N, N'-diisopropyl, N, N'-dicyclohexyl or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazolinium-3'- sulfonate and N-tert. -Butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.    



   The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned below, for example in methylene chloride, dimethylformamide or acetonitrile. 



   An amide-forming functional derivative of an acid, preferably with protected optional groups such as an optional amino group, is primarily an anhydride of such an acid, including, and preferably, a mixed anhydride.  Mixed anhydrides are, for example, those with inorganic acids, in particular with hydrohalic acids, i.e. the corresponding acid halides, for example chlorides or bromides, furthermore with hydrazoic acid, i.e. the corresponding acid azides, with a phosphoric acid, for example phosphoric acid or phosphorous acid, with a sulfur-containing acid, for example sulfuric acid, or with hydrocyanic acid. 

  Further mixed anhydrides are, for example, those with organic acids, such as organic carboxylic acids, such as with optionally substituted lower alkanecarboxylic acids, for example pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters, of carbonic acid, such as Ethyl or isobutyl half esters of carbonic acid, or with organic, in particular aliphatic or aromatic, sulfonic acids, for example p-toluenesulfonic acid. 



   Furthermore, internal anhydrides such as ketenes, for example diketene, isocyanates (i.e.  H.  internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxyl or amino groups, such as mandelic acid-O-carboxy anhydride or the anhydride of l-N-carboxyamino-cyclohexanecarboxylic acid. 

 

   Further acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected functional groups that may be present, such as esters with vinylogous alcohols (i.e.  H.  Enols), such as vinylogous lower alkanols, or aryl esters, such as, preferably, phenyl esters substituted by nitro or halogen such as chlorine, for example pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as benzotriazol esters, or diacylimino esters such as succinylimino or phthalylimino esters. 



   Further acylation derivatives are, for example, substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives of acids, or N-substituted N, N-diacylamines, such as an N, N-diacylated aniline. 



   The acylation with an acid derivative such as an anhydride and in particular with an acid halide, in the presence of an acid-binding agent, for example an organic base such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example triethylamine, N, N-di-lower alkyl aniline, for example N, N-dimethylaniline, or a base of the pyridine type, for example pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide. 



   The above acylation can be carried out in an aqueous or preferably non-aqueous solvent or solvent mixture, for example in a carboxylic acid amide, such as N, N-di-lower alkylamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example Acetone, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, and, if necessary, at a reduced or elevated temperature and / or in an inert gas, for example nitrogen atmosphere. 



   In the above N-acylation reactions one can start from compounds of the formulas IA or IB, where R2 has the above meaning, compounds with free carboxyl groups of the formula -C (= O) -R2, where R2 is hydroxy, also in the form of Salts, for example ammonium salts such as with triethylamine, or in the form of a compound with a carboxyl group protected by reaction with a suitable organic phosphorus halide compound such as with a lower alkyl or lower alkoxy phosphorus dihalide such as methyl phosphorus dichloride, ethyl phosphorus dibromide or methoxyphosphorus dichloride can be used; In the acylation product obtained, the protected carboxyl group can be added in a manner known per se, for example as described above, incl.  by hydrolysis or alcoholysis. 



   An acyl group can also be introduced by adding a compound of the formula IA or IB, where R1a and R1b together represent a ylidene radical (which can also be added subsequently, e.g.  B.  by treating a compound in which R1a and R1b is hydrogen with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde), for example acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium , hydrolyzed. 



   An acyl group can also be introduced in stages.  For example, in a compound of the formula IA or IB with a free amino group, a halo-lower alkanoyl, for example bromoacetyl group, or, for example, by treatment with a carbonic acid dihalide such as phosgene, a halocarbonyl, for example chlorocarbonyl group, and a thus obtainable N- (halo-lower alkanoyl) or  N- (halocarbonyl) -amino compound with suitable exchange reagents, such as basic compounds, for example tetrazole, thio compounds, for example 2-mercapto-1-methyl-imidazole, or metal salts, for example sodium azide, or  Alcohols such as lower alkanols, for example tert. -Butanol, convert and so to substituted N-lower alkanoyl or  N-hydroxycarbonylamino compounds arrive. 



   In both reaction participants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and released after the acylation by methods known per se, for example as described above. 



   The acylation can also be carried out by replacing an already existing acyl group with another, preferably sterically hindered acyl group, for example by the method described above, by preparing the imide halide compound, treating it with a salt of an acid and one of those obtainable in this way Acyl groups present in the product, usually the less sterically hindered acyl group, are hydrolytically split off. 



   Furthermore, for example, a compound of the formula IA or IB in which R1a is a glycyl group, preferably substituted in a-position, such as phenylglycyl, and R, b is hydrogen, with an aldehyde, for example formaldehyde, or a ketone, such as lower alkanone, for example acetone, convert and so to compounds of formula IA or
IB arrive in which RIA and R1b together with the nitrogen atom represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position. 



   In a compound of the formula IA or IB, in which R1a and R1b are hydrogen, the free amino group can also be removed by introducing a triarylmethyl group, for example by treating with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine , to be protected. 



   An amino group can also be protected by introducing a silyl and stannyl group.  Such groups are introduced in a manner known per se, for example by treatment with a suitable silylating agent, such as with a dihalo-di-lower alkyl-silane, lower alkoxy-lower alkyl-dihalo-silane or tri-lower alkyl-silyl halide, for example dichloro-dimethylsilane, methoxy-methyl- dichlorosilane, trimethylsilyl chloride or dimethyl tert. -butyl-silyl chloride, where such silyl halide compounds are preferably used in the presence of a base, for example pyridine, with an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N - (Tri-lower alkylsilyl) amine (see e.g. 

  B.  British patent no.  1 073 530), or with a silylated carboxamide, such as a bis-tri-lower alkylsilyl-acetamide, for example bis-trimethylsilyl-acetamide, or trifluorosilylacetamide, furthermore with a suitable stannylating agent, such as a bis (tri-lower alkyl-tin) oxide, for Example bis (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, for example triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, for example tri-n-butyltin chloride (see e.g.  B.  Dutch interpretation 67111107).    

 

   In a compound of the formula IA or IB obtainable according to the process which contains a free carboxyl group of the formula -C (= O) -R2, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se.  For example, esters are obtained by treating with a suitable diazo compound, such as a diazo lower alkane, for example diazomethane or diazobutane, or a phenyldiazo lower alkane, for example diphenyldiazomethane, if necessary, in the presence of a Lewis acid such as boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, for example dicyclohexylcarbodiimide, and carbonyldiimidazole, furthermore with an N, N'-disubstituted O- or 

  S-substituted isourea or isothiourea, in which a 0- and S-substituent, for example lower alkyl, especially tert. -Butyl, phenyl-lower alkyl or cycloalkyl, and N- or  N'-substituents are, for example, lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.  Furthermore, acid halides, such as chlorides (produced e.g.  B.  by treatment with oxalyl chloride), activated esters (formed e.g.  B.  with N-hydroxy nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g. 

  B.  with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride), by reaction with alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group. 



   In a compound obtained with an esterified group of the formula -C (= O) -R2, this can be converted into another esterified carboxy group of this formula, for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence a suitable solvent such as acetone in 2-iodoethoxycarbonyl. 



   Mixed anhydrides can be prepared by adding a compound of formula IA or IB with a free carboxyl group of formula -C (= O) -R2, preferably a salt, especially an alkali metal, for example sodium, or ammonium, for example Triethylammonium salt thereof with a reactive derivative such as a halide, for example the chloride, an acid, for example a lower alkyl haloformate or a lower alkanecarboxylic acid chloride. 



   In a compound obtainable according to the process with a free carboxyl group of the formula -C (= O) -R2, this can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters, as well as the above-mentioned activated esters or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines. 



   A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, for example by adding compounds of the formulas IA or IB, in which R2 is hydroxy, or salts such as alkali metal, for example sodium salts thereof, with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see for example British Patent No.  1 073 530 or  Dutch exposition no.  67/17107. 



   Furthermore, modified functional substituents in groups RIA, Rsb and / or R2, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or O, O'-disubstituted phosphono groups, according to methods known per se, for. For example, the above-described, release, or free functional substituents in groups R1A, Rlb and / or R2, such as free amino, hydroxy, carboxy or phosphono groups, according to processes known per se, for example acylation or  Esterify or 



   Substitute, modify functionally.  For example, an amino group can be converted into a sulfoamino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, for example triethylamine.  Furthermore, the reaction mixture, obtained by reacting an acid addition salt of a 4-guanyl semicarbazide with sodium nitrite, can be reacted with a compound of the formula IA or IB in which, for example, the amino protective group RIA is an optionally substituted glycyl group, and so the amino group can be converted into a 3-guanylureido group convict. 

  Furthermore, compounds with aliphatically bound halogen, for example with an optionally substituted α-bromoacetyl group, can be reacted with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and corresponding phosphono compounds can be obtained. 



   A mixture of a compound of the formula IA and a corresponding l-oxide obtainable according to the process can be oxidized directly either partially to the 1-oxide or, if an excess of oxidizing agent is used, to the di-S-oxide of a compound of the formula IA or to a 3- Reduce cephem compound of formula IA or IB. 



  These oxidation and reduction steps are described below in connection with the isomerization of a 2-cephem compound of the formula IB to the corresponding 3-cephem compound of the formula IA using an 1-oxide as an intermediate. 



   Cephem compounds of the formulas IA and IB obtained can be converted into 1-oxides or di-S-oxides of the corresponding cephem compounds of the formula IA or IB by oxidation with suitable oxidizing agents, such as those described below.  S-oxides obtained from 3-cephem compounds of the formula IA can be reduced to the corresponding 3-cephem compounds of the formula IA by reduction with suitable reducing agents, for example those described below.  In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, are subsequently released again. 



   Obtained cephem compounds can be isomerized.  Thus obtained 2-cephem compounds of the formula IB can be converted into the corresponding 3-cephem compounds of the formula IA by isomerizing a 2-cephem compound of the formula IB, in which free functional groups may optionally be temporarily protected, for example as indicated.  For example, 2-cephem compounds of the formula IB can be used, in which the group of the formula -C (= O) -R2 represents a free or protected carboxyl group, it being possible for a protected carboxyl group to also be formed during the reaction. 



   For example, a 2-cephem compound of the formula IB can be isomerized by treating it with a weakly basic agent and isolating the corresponding 3-cephem compound of the formula IA from an optionally obtained equilibrium mixture of the 2- and 3-cephem compounds. 



   Suitable isomerizing agents are, for example, organic nitrogen-containing bases, such as tertiary heterocyclic bases of aromatic character, and primarily tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkylamines, for example N, N, N-trimethylamine, N, N -Dimethyl-N-ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, for example N-methyl-piperidine, or N-phenyl-lower alkyl N, N-di-lower alkyl amines, for example N-benzyl-N, N-dimethylamine, and mixtures thereof, such as the mixture of a base of the pyridine type, for example pyridine, and an N, N, N-tri-lower alkylamine, for example pyridine and triethylamine.  

  Furthermore, inorganic or organic salts of bases, especially of medium to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, for example sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, and other analogous bases or mixtures of such basic agents be used.   



   The above isomerization with basic agents can be carried out, for example, in the presence of a derivative of a carboxylic acid capable of forming a mixed anhydride, such as a carboxylic anhydride or halide, for example with pyridine in the presence of acetic anhydride. 

  It is preferred to work in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, with bases used as reactants that are liquid under the reaction conditions also as solvents can serve, if necessary, with cooling or heating, preferably in a temperature range from about -30 "C to about +100" C, in an inert gas, for
Example nitrogen atmosphere and / or in a closed vessel. 



   The thus obtainable 3-cephem compounds of the formula
IA can be obtained in a manner known per se, for example by adsorption and / or crystallization, of any 2-cephem compounds of the formula that are still present
Disconnect IB. 



   The isomerization of 2-cephem compounds of the formula IB can also be carried out by oxidizing them in the 1-position and optionally on the -S-R3 group, if desired, an obtainable mixture of
S-oxides of 2- and / or 3-cephem compounds of the formula
IA and IB separates, or to the corresponding S-oxides of
3-cephem compounds isomerized, and the thus obtainable
S-oxides of the corresponding 3-cephem compounds of the formula IA reduced. 



   Inorganic peracids which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids, are suitable oxidizing agents for the oxidation in the 1 position and on the -S-R3 group of 2-cephem compounds or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids, with a dissociation constant of at least 10-5 in question.  Suitable inorganic per acids are periodic and persulfuric acid.  Organic per acids are corresponding percarboxylic and persulfonic acids, which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid. 

  It is advisable to use a large excess of the carboxylic acid if, for example, acetic acid is used as the solvent.  Suitable peracids are, for example, performic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid. 



   The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10-5, it being possible to use low concentrations, for example 1-2% and less, but also larger amounts of the acid.  The effectiveness of the mixture depends primarily on the strength of the acid.  Suitable mixtures are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid. 



   The above oxidation can be carried out in the presence of suitable catalysts.  For example, the oxidation with percarboxylic acids can be catalyzed by the presence of an acid with a dissociation constant of at least 10-5, the effectiveness of which depends on its strength.  Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid.  Approximately equimolar amounts of the oxidizing agent are used to prepare the l-oxides.  If an excess is used, more Di-S-oxides are formed.  The oxidation is carried out under mild conditions, for example at temperatures from about -50 "C to about +100" C, preferably from about -10 C to about +40 "C. 



   The oxidation of cephem compounds to their S-oxides can also be achieved by treatment with ozone, furthermore with organic hypohalite compounds such as lower alkyl hypochlorites, for example tert. -Butyl hypochlorite, which is used in the presence of inert solvents, such as optionally halogenated hydrocarbons, for example methylene chloride, and at temperatures from about -10 C to about +30 C, with periodate compounds, such as alkali metal periodates, for example potassium periodate, which are preferably in one aqueous medium at a pH of about 6 and at temperatures of about -10 "C to about +30" C, with iodobenzene dichloride, which is in an aqueous medium, preferably in the presence of an organic base, for example pyridine, and below Cool,

   for example at temperatures from about -20 "C to about 0, or carried out with any other oxidizing agent suitable for converting a thio to a sulfoxide group. 



   In the oxidation of 2-cephem compounds of the formula IB to the 1-oxides or di-S-oxides, if the
Reaction is carried out in a non-polar solvent, for example tetrahydrofuran or chloroform, initially preferably the S-oxides of 2-cephem compounds formed by treatment with acids, such as formic acid, or with polar solvents such as dimethyl sulfoxide or dimethylformamide, or by the usual means Working up in aqueous solvents can easily be isomerized to the S-oxides of the corresponding 3-cephem compounds. 



   In the S-oxides of 3-cephem compounds of the formula IA obtainable in this way, in particular in those compounds in which R1a, R1b and R2 have the preferred meanings given above, the groups R1a, Rjb and / or R2 can be converted into one another within the defined framework , split off or introduced.  A mixture of isomers a- and ss-1-oxides can be separated, for example by chromatography. 



   The reduction of the S-oxides of 3-cephem compounds of the formula IA can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. 



  Possible reducing agents are: catalytically activated hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium and which are optionally used together with a suitable carrier material such as carbon or barium sulfate; Reducing tin, iron, copper or manganese cations, which are in the form of corresponding compounds or complexes of an inorganic or organic nature, for example as tin (II) chloride, fluoride, acetate or formate, iron (II) chloride, sulphate , oxalate or succinate, copper l-chloride, -benzoate or oxide, or manganese II-chloride, sulfate, acetate or oxide, or as complexes, for example with ethylenediaminetetraacetic acid or nitrolotriacetic acid, can be used ;

   reducing dithionite, iodine or iron-l-cyanide anions, which in the form of corresponding inorganic or organic salts, such as alkali metal, for example sodium or potassium dithionite, sodium or potassium iodide or iron II-cyanide, or in the form of corresponding acids such as hydriodic acid can be used;

   reducing trivalent inorganic or organic phosphorus compounds, such as
Phosphines, also esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as these
Phosphorus-oxygen compounds correspond to phosphorus-sulfur compounds, in which organic residues are primarily aliphatic, aromatic or araliphatic residues, for example optionally substituted lower alkyl, phenyl or phenyl-lower alkyl groups, such as triphenylphosphine, tri-n-butylphosphine, diphenylphosphinous acid methyl ester, methyl chlorophosphonate, diphenylchlorophosphine, phenyl chlorophosphine, diphenylchlorophosphine. Butane phosphonous acid methyl ester, phosphorous acid triphenyl ester,
Phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, etc. ;

   reducing halosilvanic compounds which have at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen, such as chlorine, bromine or iodine, also contain organic radicals such as aliphatic or aromatic groups, for example optionally substituted
May have lower alkyl or phenyl groups, such as
Chlorosilane, bromosilane, di- or trichlorosilane, di- or tri-bromosilane, diphenylchlorosilane, dimethylchlorosilane, etc. ; reducing quaternary chloromethylene iminium salts, in particular chlorides or bromides, in which the iminium group is replaced by one divalent or two monovalent organic
Radicals such as optionally substituted lower alkylene or
Lower alkyl groups, such as N-chloromethylene-N, N diethyliminium chloride or N-chloromethylene pyrrolidinium chloride;

   and complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt-II chloride, and borane dichloride. 



   As activating agents, which are used together with those of the above-mentioned reducing agents which do not themselves have Lewis acid properties, i.e. the trivial ones primarily together with the dithionite, iodine or iron-II-cyanide and the non-halogen-containing trivial ones Phosphorus reducing agents or catalytic
Reduction are used, in particular, are organic
Carboxylic and sulphonic acid halides, also sulfur, phosphorus or silicon halides with the same or greater
Second order hydrolysis constant as benzoyl chloride, for example phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride, pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulphonic acid chloride, methanesulphonic acid chloride, thionyl chloride,
Phosphorus oxychloride,

   Phosphorus trichloride, phosphorus tribromide,
Phenyldichlorophosphine, Benzolphosphonigsäuredichlorid, dimethylchlorosilane or trichlorosilane, also suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sulfones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1,3-hexanesultone, to mention. 



   The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of reducing agent, for example lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the case of catalytic reduction, and for example optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanoic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides of inorganic or organic acids , for example dimethylformamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydrofuran or dioxane, ketones,

   for example acetone, or sulfones, especially aliphatic sulfones, for example dimethyl sulfone or tetramethylene sulfone, etc. , together with the chemical reducing agents, these solvents preferably containing no water.  Usually, temperatures of about -20 ° C. to about 100 ° C. are used, and the reaction can be carried out at lower temperatures when using very reactive activating agents. 



   In the 3-cephem compounds of the formula IA obtainable in this way, Rla, R1b and / or R22 can, as described above, be converted into other groups R1a, Rçb or  R2 must be transferred, whereby it must be ensured that the 3-cephem compounds are significantly more sensitive to basic agents than the corresponding 2-cephem compounds of the formula IB. 



   Furthermore, 3-cephem compounds can be isomerized in a manner known per se to 2-cephem compounds, this reaction being carried out by treatment with a base, preferably an organic base such as a heterocyclic base, for example pyridine, and / or a tertiary amine such as a tri-lower alkylamine , for example triethylamine, and, if a free 3-cephem-4-carboxylic acid compound is used, additionally in the presence of a suitable acid derivative capable of forming a mixed anhydride group, such as a carboxylic acid anhydride, such as lower alkanecarboxylic anhydride, for example acetic anhydride.  The desired 2-cephem compound can be isolated in a manner known per se from an equilibrium mixture of the 2- and 3-cephem compounds obtained, if any. 



   Salts of compounds of the formulas IA and IB can be prepared in a manner known per se.  So you can form salts of such compounds with acidic groups, for example, by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of a-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably stoichiometric amounts or only used a small excess of the salt-forming agent.  Acid addition salts of compounds of the formulas IA and IB with basic groups are obtained in a customary manner, for example by treatment with an acid or a suitable anion exchange reagent. 

  Internal salts of compounds of the formulas IA and IB which contain a salt-forming amino group and a free carboxyl group can be formed, for example, by neutralizing salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with liquid ion exchangers .  Salts of l-oxides of compounds of the formula IA with salt-forming groups can be prepared in an analogous manner. 



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



   Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, for example by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes.  Racemates obtained can in the customary manner, if appropriate after introducing suitable salt-forming groups, for example by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated. 

 

   The method also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is terminated at any stage; furthermore, 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 such that the compounds listed at the beginning as being particularly preferred are obtained. 



   Starting materials of the formula IV and their l-oxides are new and likewise a subject of the present invention.  They can be obtained by adding sulfide to a compound of the formula, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, or mixtures thereof.  The reaction is carried out with cooling, that is to say at temperatures between about -80 "C and about -58" C, preferably at about -78 C, optionally in an inert gas, for example nitrogen atmosphere.  Surprisingly, only the sterically uniform compounds of the formula IV are formed at low temperatures and not the 3ss- (O-Rs) -3a - (- S-R3) -cepham4a-carboxylic acid derivatives which are epimeric thereto and which only form at higher temperatures educate more. 



   The 2-cephem compounds analogous to the compounds of the formula VII or mixtures of the corresponding 2- and 3-cephem compounds can also be used in the addition reaction, the 2,3 double bond initially being rearranged into a 3,4 double bond under the basic addition conditions, whereupon the addition of thiol HS-R3 (III) takes place in the desired manner. 



   A compound of the formula IV obtained, or an l-oxide obtained thereof, can be converted into another compound of the formula IV or an l-oxide thereof, whereby, while avoiding reactions in which HO-R5 is split off, analogously the the same reactions can be carried out as above for the conversion of the end products of the formula IA and IB, or  whose l-oxides are given.  Isomer mixtures obtained can be prepared by analogous methods, as above for isomer mixtures of compounds of the formulas IA and IB, or    I-oxides thereof, is indicated, are separated into the individual isomers. 

  In the case of compounds of the formula IV and 1-oxides thereof, the separation of 3ss- (O-Rs) -3a- (S-R3) -Cepham4ss-carboxylic acid derivatives and in 3ss- (O-R5) -3a- (S-R3) -Cepham-4a-carboxylic acid derivatives should be observed, which can be carried out, for example, by chromatographic methods and / or fractional crystallization. 



   The pharmacologically usable compounds of the present invention can be used, for example, for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers which are suitable for enteral or parenteral use Suitable for administration. 

  So you use tablets or gelatin capsules, which the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or Calcium stearate and / or polyethylene glycol; Tablets also contain binders, for example magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixes, or adsorbents, colorants, flavorings and sweeteners. 

  The new pharmacologically active compounds can also be used in the form of injectable, for example intravenously administrable, preparations or infusion solutions.  Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible for them to be prepared, for example, from lyophilized preparations which contain the active substance alone or together with a carrier material, for example mannitol, before use. 

  The pharmaceutical preparations can be sterilized and / or auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmosis
EMI19. 1
 wherein R> a, Rlb, R2A and R5 have the meaning given under formula IV, or a thiol of the formula HS-R3 (III) is added to an 1-oxide thereof, and, if desired, one obtained within the definition of the end products Compound converted into another compound, and / or, if desired, a mixture of isomeric compounds obtained is separated into the individual isomers. 



   In a starting material of the formula VII, the radicals R1a, Rlb and R2A preferably have the same meaning as indicated for the preferred starting materials of the formula IV. 



   Thiols of the formula III suitable for the addition reaction are in particular those in which R3 represents an optionally substituted hydrocarbon radical or an optionally substituted heterocyclic radical, the carbon atom bonded to the mercapto group being saturated, i.e. not forming a double bond. 



   The addition of the thiol of the formula HS-R3 (III) to the 3,4 double bond of a compound of the formula VII surprisingly takes place stereospecifically under the conditions of the Michael addition.  The reaction takes place in a suitable solvent in the presence of a base which forms the nucleophilic anion S-R3 from the thiol HS-R3 with elimination of the proton. 

  Such bases are, for example, bicyclic amidines, such as diazabicycloalkenes, for example 1,5-diazabicyclo- [4,3,0] -non-5-en or 1,5-diazabicyclo- [5,4,0 undec-5-en, substituted guanidines, for example polysubstituted by lower alkyl, such as tetramethylguanidine, and in particular alkali metal hydrides, amides and alcoholates, such as sodium hydride, sodium or lithium amide, or sodium, lithium or potassium alcoholates of lower alkanols such as methanol, ethanol, propanol, isopropanol, Butanol or tert. -Butanol, for example sodium methylate or -äthy lat, or preferably potassium tert. butylate, as well as alkali metal hydrocarbons, especially of lithium, such as lower alkyl or aryl lithium, for example ethyl, n-butyl, sec-butyl, tert. -Butyl- or phenyllithium.  

  Suitable solvents are, for example, aliphatic, cycloaliphatic or aromatic, optionally substituted, ethereal solvents, such as di-lower alkyl ethers, for example diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, di-lower alkylamides such as N, N-dimethylformamide, N, N-dimethylacetamide or N , N-diethylacetamide, lower alkyl nitriles such as acetonitrile, di-lower alkyl sulfides such as dimethyl's pressure and / or buffers. 

  The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain about 0.1 % to 100%, in particular from about 1% to about 500/0, lyophilisates up to 1000 / o of the active substance. 



   In connection with the present description, organic radicals designated lower contain, unless expressly defined, up to 7, preferably up to 4, carbon atoms; Acyl radicals contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms. 



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



  example 1
A solution of 53 mg of 3-methylthio-7ss-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 5 ml of a warm mixture of tetrahydrofuran and methanol 2: 1 becomes a mixture which has been pre-hydrogenated in a hydrogenation apparatus for 30 minutes of 51 mg of 5/0 palladium / carbon catalyst in 1 ml of tetrahydrofuran / methanol 1: 1 and hydrogenated for 4 hours with stirring.  The solution is filtered, the catalyst is washed with 4 × 6 ml of ethyl acetate and the filtrate and washing liquid are evaporated in vacuo.  The residue is dissolved in methylene chloride and extracted with dilute aqueous sodium bicarbonate solution.  The aqueous phase is extracted three times with methylene chloride and the yellow oil of the intermediate layer is discarded. 

  The aqueous bicarbonate solution is cooled in an ice bath, covered with a layer of ethyl acetate and acidified to about pH 2 with 2N hydrochloric acid.  The organic phase is separated off, the yellow oil of the intermediate layer is again discarded and the aqueous phase is extracted with methylene chloride.  The combined ethyl acetate and methylene chloride phases are washed with water, dried over sodium sulfate and evaporated in vacuo.  The residue is recrystallized from methylene chloride / diethyl ether and gives 3-methylthio-7ss-phenoxyacetylamino-3-cephem-4-carboxylic acid with a melting point of 160 "C (decomposition); IR spectrum (KBr): characteristic bands at 5.64; 5.95; 6.25; 6.55; 6.70; 8.20; 8.58; 8.94; 13.25 p.    



   The starting material can be obtained as follows: a) A solution of 50 mg (0.1 mmol) of 3-methoxy-78-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 4 ml of dimethylformamide is dissolved in a dimethoxyethane Dry ice bath is cooled to about -58 "C and under a nitrogen atmosphere, dropwise with a solution of
13 mg potassium tert. butoxide and 4 drops of methyl mercaptan in 4 ml of dimethylformamide are added.  The reaction mixture is stirred for a further 5 minutes at -58 C and then shaken with 50 ml of ethyl acetate and 50 ml of dilute, aqueous sodium bicarbonate solution.  The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 

  The residue, consisting of the two epimeric addition products 3ss-methoxy-3a-methylthio-7ss-phe noxyacetylamino-cepham-4ss-carboxylic acid p-nitrobenzyl ester and the 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4a- carboxylic acid p-nitrobenzyl ester is dissolved in 1 ml of benzene / trifluoroacetic acid 3: 1 and left to stand at 5 ° C. for about 90 hours.  The solution is diluted with ethyl acetate, washed successively with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 

  The residue is recrystallized from chloroform / diethyl ether and gives the analytically pure 3-methylthio-7ss-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester with a melting point of 188 to 189 ".    



   IR spectrum (in methylene chloride): characteristic bands at 2.91; 5.57; 5.87; 6.22; 6.55; 7.40; 8.21; 8.58; 8.94; 11.71 u
The two epimeric addition products formed as intermediates can also be obtained as follows: ai) A solution of 50 mg (0.1 mmol) of 3-methoxy-7ss-phenoxyacetylamino-2-cephem-4a-carboxylic acid p-nitrobenzyl ester in 2 ml of dimethylformamide is cooled to about -58 ° C. in a dimethoxyethane / dry ice bath and quickly treated with a solution of about 0.5 ml of methyl mercaptan and 4 mg of potassium under a nitrogen atmosphere and stirring. butoxide in 2 ml of dimethylformamide are added. 

  The reaction mixture is stirred for a further 30 minutes at -58 ° C., then poured while cold into a mixture of 50% aqueous sodium bicarbonate solution and ethyl acetate and shaken.  The organic phase is separated off, washed successively with water, dilute aqueous citric acid, water and aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo.  According to thin-layer chromatography (silica gel, toluene / ethyl acetate 1: 1), NMR and IR spectra, the residue contains the two isomeric addition products 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4ss-carboxylic acid p-nitrobenzyl ester and 3ss -Methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4a-carboxylic acid p-nitrobenzyl ester. 



   The addition of methyl mercaptan to the C3-C4 double bond can also be carried out in tetrahydrofuran instead of in dimethylformamide under otherwise identical conditions. 



   The elimination of methanol described under a) can also be carried out in chloroform instead of benzene under otherwise identical conditions. 



   A crystalline intermediate can be obtained as follows. 



   aii) A solution of 5 g (10 mmol) of a mixture consisting of the 3-methoxy-7ss-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester and the 3-methoxy-7ss-phenoxyacetylamino-2-cephem -4a-carboxylic acid p-nitrobenzyl ester in a ratio of about 1: 1 in 75 ml of tetrahydrofuran (peroxide-free) is cooled in an isopropanol dry ice bath to about -78 "C and, under a nitrogen atmosphere and with stirring, dropwise with 20 ml of a Tetrahydrofuran solution containing 5 ml of methyl mercaptan and 1 ml of n-butyllithium are added. 

  The reaction mixture is stirred for a further 1 hour at an internal temperature of -72 "C and then, again at -78" C, a solution of 5 ml of glacial acetic acid in 15 ml of tetrahydrofuran is added dropwise so that the internal temperature does not rise above -72 "C.  The reaction mixture is poured into water and extracted with ethyl acetate.  The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 

  The residue, consisting of the two epimeric addition products 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-ce pham-4ss-carboxylic acid p-nitrobenzyl ester and the 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4a -carboxylic acid p-nitrobenzyl ester, is recrystallized from toluene / hexane and gives the pure 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4ss-carboxylic acid p-nitrobenzyl ester of melting point 132 to 134 "C; [a ] i7) = + 185 + 10 (c = 1; chloroform); thin-layer chromatogram silica gel (toluene / ethyl acetate 1: 1): Rf = 0.64;

  UV spectrum (ethanol): Xmax 268 mju (± 11,600) and 265 mR (± = 11,500); IR spectrum (methylene chloride): characteristic bands at 2.94; 3.41; 5.61; 5.70; 5.90; 6.24; 6.55; 6.69; 7.42; 8.55; 9.28 lt
The pure 3ss-methoxy-3a-methylthio-7ss-phenoxyacetylamino-cepham-4Q-carboxylic acid p-nitrobenzyl ester can also be further processed as follows: b) A solution of 4.5 g (8.2 mmol) of 3ss-methoxy -3a-methylthio-7ss-phenoxyacetylamino-cepham4ss-carboxylic acid p-nitrobenzyl ester in 100 ml of a mixture of dry benzene and trifluoroacetic acid 9: 1 is stirred at 40 ° C. under nitrogen for 15 to 18 hours. 

  The reaction mixture is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated.  The residue is recrystallized from methylene chloride / diethyl ether and gives the 3-methylthio-7ss-phenoxyacetylamino-3-cephem4-carboxylic acid p-nitrobenzyl ester with a melting point of 190 to 191; [a] DU = +44 + 1 "(c = I; chloroform); UV spectrum (acetonitrile): Xmax = 268 nm (E = 13 400), 275 nm (± = 12 500) and 314 nm ( g = 10,200);

  IR spectrum (methylene chloride): characteristic bands at 2.92; 5.57; 5.86; 6.23; 6.55; 7.40; 8.20; 8.60; 8.95; 9.25; 9.40; 9.95;
11.70 lt; Thin layer chromatogram silica gel: (toluene / ethyl acetate 1: 1): Rf = 0.70. 



   The analytically pure 3-methylthio-7ss-phenoxyacetyl-amino-3-cephem4-carboxylic acid p-nitrobenzyl ester can also be further processed as follows: c) A solution of 2.6 g (5 mmol) of 3-methylthio-7ss- phenoxyacetylamino-3-cephem4-carboxylic acid p-nitrobenzyl ester in 75 ml of a warm mixture of tetrahydrofuran and ethanol 5: 1 is converted into a mixture of 2.5 g of SOlo palladium / carbon catalyst in 10, which has been pre-hydrogenated for 30 minutes in a hydrogenation apparatus ml of tetrahydrofuran / ethanol 1: 1 and hydrogenated with stirring for 4 hours. 

  The solution is filtered, the catalyst is washed with ethyl acetate, the filtrate and washing liquid are combined, washed successively with an aqueous citric acid solution and water and then extracted several times with 50% aqueous sodium bicarbonate solution.  The bicarbonate extracts are combined, washed with methylene chloride, cooled to 0 C, slowly acidified with 2N hydrochloric acid and extracted with ethyl acetate. 



   The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated.  The residue is recrystallized from methylene chloride / diethyl ether and gives 3-methylthio-7ss-phenoxyacetylamino-3-cephem4-carboxylic acid with a melting point of 164 to 166 "C (decomposition); [a] 20 = +109 + 10 (c = 1; Dioxane); thin-layer chromatogram:

  Silica gel (toluene / ethyl acetate / water 5: 5: 1) Rf =
0.16; UV spectrum (ethanol); Ämax = 269 nm (± = 4800),
276 nm (r = 5200) and 308 nm (± = 7700); IR spectrum (KBr): characteristic bands at 3.00; 3.40; 5.63; 5.91;
6.25; 6.53; 6.68; 8.20; 8.55; 8.90; 9.25; 9.43; 13.20; 14.45 u.    



   Example 2
A solution of 855 mg (1.37 mmol) of a mixture of the 3ss-methoxy-3a-benzylthio-7ss-phenoxyacetylamino-4ss-carboxylic acid p-nitrobenzyl ester and the epimeric 3ss-methoxy-3a-benzylthio-7ss-phenoxyacetylamino4a- carbonic acid p-nitrobenzyl ester in a ratio of about 8: 2 in 17 ml
Benzene is mixed with 17 ml of trifluoroacetic acid and 16
Left to stand for hours at room temperature.  The solvent is evaporated in vacuo and the residue to
Removal of trifluoroacetic acid evaporated three times together with toluene. 

  The residue is recrystallized from ethyl acetate and hexane and gives the 3-benzylthio-7ss-phenoxyacetylamino-3-cephem4-carboxylic acid p-nitrobenzyl ester with a melting point of 174 to 175 ° C; [a] 2rj0 = 16 + 1 (c =
0.725, chloroform); Ultraviolet spectrum (ethanol); man
268 nm (g = 9600) and 318 nm (e = 6500);

  IR spectrum (methylene chloride): characteristic bands at 2.95; 5.61; 5.91 lot
The product obtained can be further processed as follows: a) A solution of 425 mg (0.72 mmol) of 3-benzylthio-78-phenoxyacetylamino-3-cephem4-carboxylic acid p-nitrobenzyl ester in 40 ml of glacial acetic acid is mixed with 425 mg of activated zinc powder and stirred vigorously for 2 hours at room temperature and under nitrogen.  The solvent is removed in vacuo, the residue is stirred with ethyl acetate and filtered. 



  The solution is extracted with aqueous sodium bicarbonate solution and water.  The combined aqueous phases are washed with ethyl acetate, acidified with hydrochloric acid and extracted with ethyl acetate.  The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo.  The residue is chromatographed on silica gel with toluene containing 10% acetone and gives 3-benzylthio-7ss-phenyloxyacetylamino-3-cephem-4-carboxylic acid; [a] D = = +19 + 1 "(c = 0.8; chloroform); IR spectrum (methylene chloride): characteristic bands at 5.61 and 5.90, u.    



   The starting material can be obtained as follows: b) A solution of 1 g (2 mmol) of 3-methoxy-7ss-phenoxy-acetylamino-4-carboxylic acid p-nitrobenzyl ester in 100 ml of tetrahydrofuran is cooled to -78 "under nitrogen, successively with 0 , 3 ml (2.56 mmol) of benzyl mercaptan and 0.5 ml of a 200 / above n-butyllithium solution in hexane are added and the mixture is stirred at the same temperature for 90 minutes.  After 2 ml of the above 500% acetic acid solution in tetrahydrofuran have been added dropwise, the solution is warmed to room temperature and most of the tetrahydrofuran is distilled off in vacuo and replaced by ethyl acetate. 

  The organic phase is washed successively with water, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on silica gel, with toluene initially excess benzyl mercaptan and toluene / ethyl acetate 7: 3 a mixture consisting of 3ss-methoxy-3a-benzylthio-7ss-phenoxyacetylamino-ss-carboxylic acid p-nitrobenzyl ester and the epimeric 3ss -Methoxy-3a-benzylthio-7ss-phenoxyacetylamino-4a-carboxylic acid p-nitrobenzyl ester in a ratio of about 8: 2.  This mixture of epimers is sufficiently pure for further processing. 

  The pure 3ss-methoxy-3a-benzylthio-7ss-phenoxyacetylamino4ss-carboxylic acid p-nitrobenzyl ester with a melting point of 113 to 115 ° C can be obtained therefrom by recrystallization from benzene; [am20 = +217 + 10 (c = 0.778; chloroform ); UV spectrum (ethanol): Xmax = 264 m, u (± = 1 1 11 300) and 267 (± = 11 400);

  IR spectrum (methylene chloride): characteristic bands at 2.95; 5.65; 5.74; 595 according to example 3
A suspension of 3.80 g (10 mmol) of 7ss-phenoxyacetamido-3-methylthio-ceph-3-em4-carboxylic acid in 38 ml of absolute methylene chloride is mixed with 4.45 ml of dimethylaniline and 1.50 ml of dimethyldichlorosilane for 30 minutes at room temperature touched.  The reaction mixture is cooled to -20 ", treated with 2.60 g of phosphorus pentachloride, stirred for 30 minutes at -20" and then added dropwise to a mixture of 15.5 ml of n-butanol and 1.47 ml of dimethylaniline which has been cooled to -20 ".  The temperature is allowed to rise to -10 "and 15.5 ml of dioxane and 0.53 ml of water are added.  

  When crystallization begins, the pH is adjusted to 4.1 with tributylamine and the crystallization is completed by stirring at 0-5 "for 2 hours.  The precipitate is filtered off, washed with 10 ml of dioxane and 5 ml of methylene chloride and dried in a high vacuum. 

  The 7ss-amino-3-methylthio-ceph-3-em-4-carboxylic acid is obtained with a melting point of 205 (dec. ); UV spectrum (O, In-NaHCO3): Xm0x = 293 (r = 7600); IR spectrum (Nujol): characteristic bands at 3.15; 5.55; 6.17; 6.53 according to example 4
A mixture, cooled to 0, of 1.23 g (5.0 mmol) 7ss-amino-3-methylthio-ceph-3-em-4-carboxylic acid and 630 mg (7.5 mmol) sodium bicarbonate in 50 ml acetone / water 1 : 1. 1.68 g (15 mmol) of (D) -mandelic acid carboxyanhydride are added within 15 minutes and the mixture is then stirred for a further 30 minutes at pH 7.5.  The reaction mixture is concentrated in vacuo and extracted with ethyl acetate. 

  The aqueous phase is acidified to pH 2, extracted with ethyl acetate, the organic extract is extracted by shaking with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.  The crude product is chromatographed on 50 g of silica gel which had been deactivated by adding 5/0 water. 

  With toluene / ethyl acetate 1: 1, the 7ss- (D-mandeloyl amino) is uniform by thin-layer chromatography. 3-methylthio-3-cephem4-carboxylic acid eluted, which is reprecipitated from methylene chloride / ethyl acetate with diethyl ether-hexane; Thin layer chromatogram (silica gel: ethyl acetate / pyridine / acetic acid / water 61: 21: 6: 11) Rf = 0.37; UV spectrum (ethanol) Xmax = 309 mlt (s = 8000); IR spectrum (Nujol): characteristic bands at 2.98; 5.63; 5.93; 6.55, 1; M.p.  117 to 119 C (decomposition). 



  Example 5
A suspension of 6.62 g (10 mmol) 7ss- (D [-] - a-tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methylthio-4-carboxylic acid-diphenylmethyl ester-1-oxide in 200 ml of methylene chloride is mixed with 2.04 g (10 mmol) of 85% m-chloroperbenzoic acid and stirred for 1 hour at room temperature .  The reaction mixture is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The crude product is chromatographed on 150 g of silica gel.  Ethyl acetate elutes the 7 (D [-a-tert. -Butyloxycarbonylamino-a-phenylacetyl amino-3-methylsulfinyl-3-cephem-4-carboxylic acid-diphenylmet hylester-1-oxide, which is crystallized from methylene chloride / petroleum ether. 

  Melting point 160 to 161 "C; [a] D = -156 + 1 (c = 0.885; CHCl3), UV spectrum (ethanol): Xmax = 282 mlt (± = 6900); IR spectrum (Nujol): characteristic bands at 2.96; 3.04; 5.55; 5.82; 5.91; 6.02; 6.22; 6.58; 6.67 lot
The compound obtained can analogously to Example 4a) with twice the amount of phosphorus trichloride in the 7p- (D-a-tert. - Butyloxycarbonylamino-n-phenyl-acetylamino) - 3-methylthio-3cephem-4-carboxylic acid diphenylmethyl ester are transferred. 



  Example 6
A solution of 16 mg of 7ss-phenoxyacetylamino-3-mercapto-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 1 ml of tetrahydrofuran is mixed with an excess of methyl iodide and N-ethyl-N, N-diisopropylamine, stirred for 10 minutes and im Evaporated in vacuo.  The residue is chromatographed on silica gel with toluene and increasing amounts of ethyl acetate and gives a mixture consisting of the 7ss-phenoxyacetylamino-3-methylthio-3-cephem-4-carboxylic acid p-nitrobenzyl ester and the corresponding 2-cephem derivative. 



  Thin-layer chromatogram: double spot at Rf = 0.6 (silica gel; toluene / ethyl acetate 1: 1); IR spectrum (methylene chloride): characteristic bands at 2.95; 5.60; 5.70; 5.90; 6.25; 6.58; 6.70; 6.97; 7.43; 8.20; 8.60; 9.00; 9.75; 9.95 lt
The starting material can be made as follows:

   a) A solution of 52 mg of a mixture consisting of the 7ss-phenoxyacetylamino-3-methoxy-3-cephem-4-carboxylic acid-p-nitrobenzyl ester and the 7ss-phenoxyacetylamino-3-methoxy-2-cephem-4-carboxylic acid-p nitrobenzyl ester in 5 ml of dimethylformamide is mixed with 300 mg of sodium hydrogen sulfide, 50 mg of benzyltrimethylammonium chloride and 40 mg of 1,5-diazabicyclo- [5.4.0] -undec-5-ene at -5 ° C. and stirred for 5 minutes .    The reaction mixture is diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 



   The residue is purified by preparative silica gel layer chromatography using toluene / ethyl acetate as the mobile phase and gives the 7ss-phenoxyacetylamino-3-mercapto-3-cephem-4-carboxylic acid p-nitrobenzyl ester; Thin-layer chromatogram: Rf = 0.08 (silica gel; toluene / ethyl acetate 1: 1). 



   Example 7
Analogously to the above examples, starting from the corresponding and suitable 3-p-toluenesulfonyl thio or 3-methoxy-cephem-4-carboxylic acid esters, the following end products can be prepared: 7ss- [2- (5-aminomethylthiene-2- yl) acetylamino] -3-methylthio-3-cephem-4-carboxylic acid; M.p.  2100 (decomposition); UV spectrum (in In-CHI):
237 nm (± = 12,800); 315 nm (± = 8800);

  IR spectrum (in
Nujol): 3.05; 5.68; 6.06; 6.47; 7.42 lt; 3-allylthio-7ss-phenoxyacetamido-ceph-3-em-4-carboxylic acid; amorphous substance; IR spectrum (in methylene chloride): 5.60; 5.90 lt; Nuclear Magnetic Resonance Spectrum (in deuterized DMSO; 3 in ppm): 3.46 (2 H); 3.64 (2H); 4.58 (2H); 5.0 to 5.9 (5H); 7ss-phenylacetylamino-3-phenylthio-3 cephem-4-carboxylic acid; microcrystalline, colorless powder, which can be recrystallized from acetone / methylene chloride / diethyl ether; M.p.  190 "(decomposition). 

  Thin-layer chromatogram (silica gel): Rf¯0.60 (n-butanol / pyridine / acetic acid / H2O 40: 24: 6:30) UV spectrum (ethanol): Xm0x = 263 nm (± = = 7000); 305 nm (c = 9000); IR spectrum (Nujol): characteristic bands at 3.02; 5.59; 5.81; 6.01; 6.22; 6.48 lt: 7ss- (D-a-phenylglycylamino) -3-phenylthio-3-cephem-4-carboxylic acid; colorless powder; UV spectrum (0.01n hydrochloric acid):

  Xmax =
260 m, u (± = 5800); 313 m, uh (± = 9000); 7ss- (D-a-phenylglycylamino) -3-methylthio-3-cephem-4-carboxylic acid; Melting point
185 "C; Rf value = 0.40 (silica gel; n-butanol / pyridine / acetic acid / water 40:24: 6:30); UV spectrum (0.01N hydrochloric acid): λmax = 315 mlt (± = 9000), (in water): Ämax = 292 mlt (± =
7790); IR spectrum (Nujol): characteristic bands at 3.01; 5.63; 5.87; 6.27; 6.66; [am20 = + 70 + 10 (c = 1; water). 



   Trifluoroacetate of 7ss- (D-α-phenylglycylamino) -3-allylthio-3-cephem-4-carboxylic acid; Decomposition above 145 "C; IR spectrum (Nujol): characteristic bands at 5.64; 5.93 lt
Example 8
Analogous to the above examples, starting from the corresponding and suitable 3-p-toluenesulfonyl thio- or 3-methoxy-cephem4-carboxylic acid esters, the following end products can be prepared:

  : 7ss-cyanoacetylamino-3-methylthio-3-cephem-4-carboxylic acid; 7ss- [D-a- (p-hydroxyphenyl) -glycylamino] -3-methylthio-3-cephem-4-carboxylic acid, 7ss- (2-thienylacetylamino) -3-methylthio-3-cephem-4-carboxylic acid; 7ss- (tetrazol-1-ylacetylamino) -3-methylthio-3-cephem4 carboxylic acid; 7 P- [Da- (1,4-cyclohexadienyl) -glycyl amino] -3-methylthio-3-cephem-4-carboxylic acid and 7ss-CD-a- (1-cyclohexenyl) -glycylamino) -3-methylthio - 3-cephem-4-carboxylic acid.  

 

Claims (1)

PATENT CLAIM Process for the preparation of new 7ss-amino-3-cephem-3-R3-thio-4-carboxylic acid compounds of the formula EMI22.1 Formula IA or IB reduced by means of nascent hydrogen or by means of another reducing agent to the corresponding compound of the formula IA or IB. 7. The method according to claim, characterized in that a compound of the formula IA or IB, in which R, b is hydrogen, is converted into a corresponding compound of the formula IA or IB in which Rlb is acyl. 8. The method according to claim, characterized in that one obtained compound of formula IA or IB, wherein Rtb is an acyl radical, cleaves the acyl radical. 9. The method according to claim, characterized in that a free amino group in a compound obtained is protected, for example acylated. 10. The method according to claim, characterized in that one obtained compound of the formula IB, or an S-oxide thereof, isomerized to a compound of the formula IA, or an S-oxide thereof. 11. The method according to dependent claim I, characterized in that an acyl radical Rtb is split off in a compound of the formula IA or IB by means of an imide halide-forming agent with subsequent solvolysis or hydrolysis. 12. The method according to claim or one of the subclaims 1-11, characterized in that one compounds of the formula IA, wherein a) Rla for a pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss -Amino-3-cephem4-carboxylic acid compounds occurring acyl radical are different amino protective groups and Rlb is hydrogen, or R1a and Rlb together are one, preferably in the 2-position, for example by an aromatic or heterocyclic radical, and preferably in the 4-position, For example, by 2 lower alkyl, such as 2-methyl, substituted l-oxo-3-aza-1,4-butylene radical represent different divalent amino protective groups, and R2 stands for hydroxy, or b) R1a and Rlb have the meanings given under a), R2 for one together with the -C (= O) grouping represents a preferably easily cleavable, protected carboxyl group-forming radical R2A, a carboxyl group thus protected being different from a physiologically cleavable carboxyl group. 13. The method according to claim or one of the dependent claims 1-11, characterized in that 3-cephem compounds of the formula IA, wherein R, a is hydrogen or an acyl radical of the formula EMI23.1 denotes where n is 0 and Rl denotes hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, for example esterified or etherified, hydroxy or mercapto or an optionally substituted amino group, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, in which R1a is hydrogen or an amino protecting group RIA, and Rlb is hydrogen or a Acyl group Ac, or R1a and R1b together represent a divalent amino protective group, R2 represents hydroxy or a radical R2A which together with the carbonyl group -C (= O) - forms a protected carboxyl group, and R3 represents an optionally substituted hydrocarbon radical or an optionally substituted one heterocyclic radical, and their S-oxides, and / or of corresponding 2-cephem compounds of the formula EMI23.2 wherein Rla, R1b, R2 and R3 have the meanings given above, and their S-oxides, or salts of such compounds with salt-forming groups, characterized in that a compound of the formula EMI23.3 or an S-oxide thereof, in which the dashed lines denote the a-configuration and in which R9 represents an optionally substituted hydrocarbon radical and R1a, Rlb, R2 and R3 have the meaning given under formula IA or IB, in the presence of an acid, the compound HO -R9 splits off, and, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula IV are used in which R5 and / or R3 is optionally substituted lower alkyl. 2. The method according to claim, characterized in that the cleavage of HO-R5 is carried out at temperatures between -70 "C and +100" C in an inert solvent and in the presence of an acid. 3. The method according to dependent claim 2, characterized in that trifluoroacetic acid is used as the acid. 4. The method according to claim, characterized in that in a compound of formula IA or IB or an l-oxide thereof obtained, a protected functional group is converted into a free functional group. 5. The method according to claim, characterized in that a compound of the formula IA or IB obtained is oxidized to a corresponding S-oxide. 6. The method according to claim, characterized in that a obtained S-oxide of a compound of the preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R1 and Grill denotes hydrogen, or where n denotes 1, R1 denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic radical is preferably aromatic Has character, R11 is an optionally functionally modified, for example esterified or etherified hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O, O '-disubstituted phosphono group, or an azido group, and R111 is hydrogen, or where n is 1, each of the radicals Rl and Ril is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R Represents hydrogen, or where n is 1, R1 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R11 and Rlll together denote an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic connected by a double bond with the carbon atom -aliphatic or araliphatic hydrocarbon radical represent, or in which n is 1, and R1 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein heterocyclic radicals preferably have aromatic character, Ril an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and grill hydrogen or an optionally substituted aliphatic, cyclossliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical Rtb represents hydrogen, or in which R1a and R1b together represent an 1-oxo-3-aza-1 abutylene radical substituted in the 2-position by an aromatic or heterocyclic radical and in the 4-position by two lower alkyl, R2 represents hydroxy , for optionally substituted aryloxy, lower alkanoyl oxy, a-amino-lower alkanoyloxy, arylcarbonyl, or optionally substituted aryl in the a-position, or in the B-position by halogen, mono- or poly-substituted lower alkoxy, optionally substituted by lower alkoxy bis-phenyloxy met hoxy, lower alkanoyloxymethoxy, a-amino lower alkanoyloxy methoxy, phenacyloxy, optionally substituted phenyl lower alkoxy, such radicals 1-3 optionally, for For example, phenyl radical substituted by lower alkoxy, such as methoxy, nitro or phenyl, and also for acyl oxy, for tri-lower alkylsilyloxy, or for amino or hydrazino optionally substituted by lower alkyl, or for hydroxyamino, and R3 is lower alkyl, lower alkene nyl, phenyl or possibly by methyl, Methoxy, fluorine or chlorine substituted phenyl, optionally substituted 1-phenyl-lower alkyl with 1 to 3, optionally, for example by lower alkoxy, such as methoxy, substituted phenyl radicals, or aromatic heterocyclyl, optionally substituted by lower alkyl, lower alkoxy or halogen, with one oxygen or sulfur atom , as well as the l-oxides thereof, and also the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups. 14. The method according to claim or one of the dependent claims 1-11, characterized in that 3-cephem compounds of the formula IA, wherein R1a is hydrogen or an acyl group of the formula EMI24.1 where Ra is phenyl, hydroxyphenyl, hydroxyphenyl, thienyl, pyridiyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl, 1-cyclohexenyl or 1,4-cyclohexadienyl, X is oxygen or sulfur, m is 0 or 1, and Rb is hydrogen or, when m represents 0, Rb represents amino, a-polybranched lower alkoxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, optionally lower alkoxy or nitro-substituted phenyl-lower alkoxycarbonylamino, diphenylmethoxycarbonylamino, 3-guanylureido, sulfoamino, tritylamino, arylthioamino, Arylsulfonylamino, 1-lower alkoxycarbonyl-2-propylideneamino, carboxy or carboxy present in salt form, esterified carboxy, sulfo, sulfo present in salt form, protected sulfo, hydroxy, acyloxy, O-lower alkylphosphono or O, O'-di-lower alkylphosphono, or a 5- Amino-5-carboxyvaleryl radical, in which the amino and / or carboxy groups can also be protected, where preferably m is 1 when Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and Rb is different from hydrogen when Ra is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or l-cyclohexenyl, Rjb is hydrogen, R2 is hydroxy, lower alkoxy, optionally by lower alkoxy, substituted diphenylmethoxy, or is tri-lower alkylsilyloxy, and R3 is lower alkyl, lower alkenyl, phenyl or phenyl-lower alkyl, and the oxides of such 3-cephem compounds of the formula IA, furthermore the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups. 15. The method according to claim or one of the dependent claims 1-11, characterized in that amino-a-Ra-acetylamino) -3-R3-thio-3-cephem-4-carboxylic acids, wherein Ra is phenyl, 4-hydroxyphenyl, 2-thienyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, and R3 is methyl, phenyl or trityl, or prepares the pharmaceutically acceptable salts thereof. 16. The method according to claim or one of the dependent claims 1-11, characterized in that the 3-methylthio-7P-phenoxyacetylamino-3-cephem.4-carboxylic acid or salts thereof are prepared.