CA1235689A - Cephalosporin derivatives and a process for their preparation - Google Patents

Abstract

Abstract of the disclosure:

Cephem derivatives of the formula

Description

~'~3S~9

- 2 - HOE 82/F 268 The ;nvent;on relates to new cephalosporin deriva-tives and a process for their prepara~ion, in particular polar cephem derivatives ~hich are substituted ;n the

3'-position of the cephem ring by spec;fic pyr;din;um, qu;nolinium and isoquinoLinium rad;cals and which have a very good antimicrobial action against Gram-posit;ve and Gram-negative bacter;a and are therefore suitable for use as med;caments f~r treating microbial infections. The invention therefore relates to cephem derivatives of the general formula I

N ll C - CONH ~ S ~
--~S~ ~o~ ~ C~2R2 co2~3 and physlologically acceptable acid addition salts thereof in which R1 denotes hydrogen, optionally substituted C1-C6-alkyl, optionally substituted C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7 cycloalkyl-C1-C6-alkyl, C4-C7-cycloalkenyl or the group (CH2)n(C~mR5 in Yhich m or n can each be O or 1 and R3 and R4 can be identical or different and denote hydro-gen, aryl or a C1-C4-alkyl group or, together with the .. ~

- \
~3S6~9 carbon atom to ~hich they are attached, form a methylene group or a C3-C7-cycloalkyl;dene group, ;t be;ng also pos-s;ble for alkyl and cycloalkyl to be further monosubst;tu-ted or polysubst;tuted, RS denotes a group -C02R6 ;n ~h;ch R6 denotes hydrogen, C1-C4-alkyl, -CH20-S1-C4-alkyl, -CH200C-C1-C4-alkyl or one equivalent of an alk-ali metal~ alkaline earth metal or ammonium or of an organic amine base; or a nitrile group or a carbamoyl group -CONH2 uhich can be monosubstituted or disub-1û st;tuted on the n;trogen, and R2 denotes a pyridinium radical ~N ~ ~hich is substituted by 2 alkyl ;n the ortho-position ~hich are l;nked to form an optionally sub-st;tuted d;methylene to decamethylene ring ;n which one ring carbon atom can be replaced by a hetero-atom and, further-more, one or t~o double bonds can also be presen~, ordenotes a 1-quinolinium radical or a 2-isoquinolinium radical each of ~hich can also be monosubstituted or poly-substituted in an identical or different manner by opt;onally subs~ituted C1-C6-alkyl, C1-C6 alkoxy~ halo gen, tr;fluoromethyl or hydroxyl, and in ~hich the R10 group is ;n the syn-pos;~;on.
The present ;nvention relates part;cularly to compounds ;n ~hich R1 denotes hydrogen, C1-C6-alkyl ~hich can be monosubsti~uted or polysubstituted by halogen, C1-C6-alkylthio, C1-C6-alkyloxy, aryl or hetero-arY~, C2-c6-alkenyl ~hich can be monosubstituted or polysub-stituted by halogen, C2-C3-alkynyl, C3-C7-cycloalkYl~

~2~689 C3-C7-cycloalkyl-C1-C6-alkyl or C4-C7-cycloalkenyl, and ;n wh;ch the group (CH2)n(c)mR has the above mean-ing, and R2 denotes a pyr;dinium radical ~ ~ which is substituted by 2 alkyl groups in the ortho-position which are linked to form an optionalLy substituted dimethylene to decamethylene r;ng in which one rin~ carbon atom can be replaced by a hetero-atom and, furthermore, one or t~o double bonds can also be present. Su;table optionally possible substituents of this dimethylene to decamethylene ring are, in part;cular, the follow;ng sub-stituents, which can be monosubs~i~uents or polysub-stituents, but are preferably monosubs~ituents: C1-C6-alkyl, C1-C4-alkoxy, hydroxymethyl, haLogen, hydroxyl, oxo, hydroxy;m;no, exomethylene, carboxyl, C1-C6-alkyloxycar-bonyl, cyano or carbamoyl. These subst;tuents can bepresent on the said rings which are fused to the pyri-dinium radical independently of ~hether the particular ring is saturated, unsaturated or additionally interrupted by a hetero-atom. In accordance with the invention, how-ever, they are preferably present on fused, saturatedrings ~hich do not contain a hetero-atom.
The ring fused to the pyridinium radical can con-tain 2 to-10 ring members td;methylene to decamethylene), but preferably contains 3 to 5 r;ng members and ~hus rep-resents, for example, a cyclopenteno~ cyclohexeno or ```` i~3St~89 cyclohepteno ring. If such a fused r;ng conta;ns a doublebond, examples wh;ch may be ment;oned are a dehydrocyclo-pentadieno, dehydrocyclohexadieno or dehydrocycloheptadi-eno r;ng. If a carbon atom is replaced by a hetero-atom in rings of this type, suitable hetero-atoms are, in par ticular, oxygen or sulfur. The follo~ing may be mentioned as examples of fused r;ngs containing an oxygen atom and conta;n;ng t~o double bonds or one double bond: furo, pyrano, d;hydrofuro and d;hydropyrano; examples of fused r;ngs conta;n;ng a sulfur atom and two double bonds or one double bond are thieno, th;opyrano, d;hydroth;eno and dihydrothiopyrano. Amongst ~he fused r;ngs conta;n;ng a hetero-ato~, r;ngs wh;ch are su;tabLe for subst;tution, in part;cular by the substituents ind;cated above are, in particular, rings conta;n;ng only one double bond; or R2 denotes a 1-quinolin;um rad;cal or a 2-;soqu;nol;n;um rad;-cal each of wh;ch can also be monosubstituted or polysub-st;tuted in an ident;cal or d;fferent manner by C1-C6-alkyl ~hich can be substituted by hydroxyl or C1-C6-alkoxy, or can be subst;tuted by C1-C6-alkoxy, halogen, tr;fluorome-thyl or hydroxyl, and ;n ~h;ch the R1û group is ;n the syn-pos;t;on.
The follo~;ng are examples of subst;tuents which are part;cularly preferred: R1: hydrogen, C1-C4-alkyl, such as, for example, methyl~ ethyl, propyl, ;sopropyl, butyl, isobutyl or tert.-butyl, especially methyl or e~hyL;
alkyl ~hich is substituted by halogen, for example chlor-ine, bromine, iodine or fluorine, especially trifluoroethyl , ~ .. ..

or 2,2,3,3-tetrafluoropropyl; alkyl which is substituted by C1-C6-alkylth;o, for example methylth;o or ethylth;o;
alkyl which ;s subst;tuted by c1-C6-alkyloxy, for example methoxy or ethoxy; alkyl which is substituted by aryL, for example phenyl, tolyl or chlorophenyl, in particular ben~yl; alkyl ~hich is substituted by hetero-aryl, for example 1,3-thiazol-4-yl, ;n particular 1,3-thiazol-4-yl-methyl, C2-C4-alkenyl, such as, for example, v;nyl, allyl, ;sopropenyl or methylallyl, especially allyl or methyl-allyl; C2-C4-alkenyl which is substituted by halogen, such as, for example, chlorine or bromine, especially 3-chloro-propen-2-yl, 2-bromoprop~n-2-yl or 2-chloropropen-2-yl;
C2-C3-alkynyl, such as, in particular, propargyl; C3-C7-cycloalkyl, such asj in particular, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl; C3-C7-cycloalkylmethyl, such as, in particular, cyclopropylmethyl;

C4-C7-cycloalkenyl, such as, ;n part;cular, cyclopen-~3 tenyl or cyclohexenyl; the group (C~ (c)~R in which R

R3 and R4 can be identical or different and can denote hydro-gen, aryl, preferably phenyl, or C1-C4-alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or sec.-butyl, preferably methyl or ethyl and especially methyl, or ;n which R3 and R4, together w;th ~he carbon atom to wh;ch they are attached, can form a methylene group or a C3-C7-cycloalkyl;dene group, such as, for example, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, 1~356~3~

preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclo-hexyl, it be;ng possible for the cycloalkylidene group to be substituted, for example by C1-C4-alkyl, preferably me-thyl, or by halogen, preferably fluor;ne and chlorine, or to be subst;tuted by alkylene having 3 - 6 carbon a~oms, m = 0 or 1 and n = 0 or 1, the total of m and n be;ng 1 or 2.
The follo~ing are preferred examples of the group - (CH2)n(f)m R

In the event that n is 0 and m is 1:

-CH (CH3), -C (CH3) 2 ~ -CH (C6H5), CH3 CH3~ CH3 <~

<Cl~

F F

in the event that m ;s 0 and n ;s 1: -CH2-and ;f n and m are 1: CH2 ll .

R5: the group -C02R~ in ~h;ch R6 denotes hydro-gen, C1-C4-aLkyl such as~ for example, methyl, ethyl, ~3S689 propyl, isopropyl, butyl, secr-bu~yl or tert.-butyl, pre-ferably methyl or ethyl and espec;ally methyl~ or one equi-valent of an alkal; metal, such as, for example, sod;um~
potassium or l;thium, preferably sod;um and potass;um, one equ;valent of an alkaline earth metal, preferably calc;um or magnes;um, or of ammon;um, and also one equ;valent of an organ;c am;ne base, such as, for example, tr;methylam-;ne, d;ethylam;ne, ~riethylamine, methylam;ne, propylam;ne, N,N-d;methylethanolamine, tr;s-~hydroxymethyl)-aminometh-ane, arginine or lysine; a nitrile group or a carbamoylgroup ~hich can be monosubs~ituted on the nitrogen by C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxycarbon yl, C1-C6-alkylcarbonyl, carboxymethyl, C1-C6-aLkoxycar-bonylmethyl, aminocarbonylmethyl, C1-C6-alkylam;nocarbonyl, t5 carbamoyl, hydroxyl or C1-C6-alkyloxy or ~hich can be di-substituted on the nitrogen by C1-C6-alkyl, R2: a pyr;d;nium rad;cal wh;ch ;s subst;tuted by t~o alkyl groups linked to form a d;methylene to decamethy-lene ring ~hich, ;n turn, can be monosubst;tuted or poly-subst;tuted, preferably monosubst;tuted and can containone or t~o double bonds, preferably the following fused ring systems: cyclopenteno, hydroxycyclopenteno,os~ocvclo-centeno, hydroxymethylcyclopenteno, exomethylenecyclopenteno, carbo~ycvclo enteno or C1~C4 alkox~carbonylcyclopenteno, especially methoxycar~onylcyclopenteno and carbamovlcyclo~enteno; cyclohexeno, hydroxycyclohexeno, oxocyclohexeno, hydro~ymethylcyclohexeno, .~

-~3S6 519 exomethylenecyclohexeno, carboxycyclohexeno or C1-C4-alk-oxycarbonylcyclohexeno, especially methoxycarbonylcyclo-hexeno and carbamoylcyclohexeno; cyclohepteno, hydroxycyc-lohepteno, chlorocyclohepteno, bromocyclohepteno, oxocyc-lohepteno, hydroxymethylcyclohepteno, exomethylenecyclo-hepteno, carboxycyclohepteno or C1-C4-alkoxycarbonylcyclo-hepteno, especially methoxycarbonylcyclohepteno and carb-amoylcyclohepteno; dehydrocyclopenteno; and dehydrocyc-lohexeno and dehydrocyclohepteno.
If a carbon atom in the fused ring systems men-tioned above is replaced by a hetero-a~om, in particular oxygen or sulfur, the follo~ing are particularly su;table:
2,3-furo, 3,4-furo, 2,3-pyrano and 3,4-pyrano, 203-d;hyd-rofuro, 3,4-dihydrofuro, 2,3-dihydropyrano and 3,4-dihyd-ropyrano, methyldihydrofuro, methoxydihydropyrano and hyd-roxydihydropyrano;
or a quinolinium radical or an isoqu;nolinium radical each of ~hich can also be monosubstituted or poly-substituted in an identical or different manner by C1-C6~
alkyl, such as, for example, methyl, e~hyl or propyl, pre-ferably methyl, by hydroxy-C1-C6-alkyl, such as, for example, hydroxyme~hyl, by C1-C6-alkoxy-Cl1~c6~alkYl~ such as, for example, methoxymethyL or ethoxymethyl, by C1~C6~
alkoxy, such as, for example methoxy or ethoxy, or by halogen, trifluoromethyl or hydroxyl.
The invent;on also relates to a process for the preparation of compounds of the formula I and their physio-logically acceptable acid addition salts, ~hich comprises , , . ~` 1~35689 a) reacting a compound of the general formula II

N II C - CON~ ~ ~
R7~S~N ~ I ~L CH2R8 II
\OR1 102H

or salts thereof or a reac~;ve derivative of the compound II ;n wh;ch R1 has the mean;ng ment;oned above and R7 denotes an amino group or a protected am;no group and R8 denotes a group wh;ch can be replaced by the pyr;dine, quinoline or ;soqu;no~ine derivat;ves corresponding to the radicals R2 of the formula I, with these pyridine, quinoline or iso-quinoline deriva~;ves, and ~) spl;tting off a protect;ve group ~hich may be present and ~) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or b) reacting a 7-aminocephem compound of the general formula III

oJ N ~H2R III

or acid add;t;on salts thereof in ~hich R2 has the above-mentioned meaning and in wh;ch the amino group can also be present ;n the form of a react;ve deriva~;ve, with a 2-t5-am;no-1,2,4-thiadiazol-3-yl)-2-syn-oximinoacetic acid of .

2356~39 the general -formula IV

C - COOI~
R7 ~ N IV
` C)R

in which R1 and R7 have the meaning ment;oncd above, or w;th an act;vated der;va~;ve of this compound, and S ~) spli~ting off a pro~ec~ive group wh;ch rnay be present, and ~) i-f necessary, convert;ng the resul~ g produc~ in~o a - physiologically acceptab~e acid addition salt.
If the preparation of the cornpound of the gel1elal formula I is ~o be effected by nucleoph;lic replacement of R8 in the compoul-lds of the general formula II by the pyri~-dinet quinoline or isoquinol;ne derivat;ves rn~en~;oned, su;table radicals Ra are, ;n part;cular~ acyloxy radicals of lower aliphatic carboxylic acids, preferably having 1 lS to 4 carbon a~oms~ such a~s, for example, acetoxy or propio~
- nyloxy, espec;ally acetoxy, wh;ch can op~;onally b~ sub-stituted~ such as, for exampl~, chloroacetoxy or ace~ylace-toxy~ Other groups are also su;table for R8,~such as ~or exalnple, halogen, espe~;~ally chlor-ine~ brorn;r~e or ;od;ne, ~O or carbamoyloxy~ ;
Irl accordance w;t~h the ;nvent;on~ star~ing COM~' pounds of the genPral rormula II in which R8 represents acetoxy, or salts thereof, such as, ~or exarnple~ a sodium or po~assiurn salt, are empLoyed ln the nucleophilic replace~
ment reac~;on.~ The reac~ion ;s çarried ou~ ;n a solverl~, ..

-561~9 - 12 ~
preferab~y in wa~er or ir~ a mixture of ~ater ~nd an orclanie solvent whicl1 ;s reaci;ly m;sc;ble ~-ith water, sueh as, for example, acetone, dioxane, aceton;tr;le, d;m~thylforrnam;de, dimethyl sul~oxide or ethanol. In generalr the reaction temperature is w;.h;n the range from ahout 10 to abou~
100C, pre-ferably bet~leen ?0 and ~0~. The base component is added in quantities which are between approxilT,ately ec~u;~olar qual1tities and an cxcess of up ~o about 15-foldD
The replacel1el-t of the rad;cal r~7 is facilitated by the pre~
1~ sence ;n the react;Gn medium oF neutral sal~ ions, prefer ably ;odide or thiocyanate ions~ In par~icular, ahout 10 to abou~ 80 equivalents of potass;um ;odide, sod;um ;odide, po~ass;um ~h;ocyana~e or sod;um ~hiocyar,~ate are adcied.
rhe reac~;on is advan~a~eously carried ou~ near to the neu~
tral poin~r preferably a~ a pl~ value within the range -from about S to a~olt 8.
If the group R7 ;s ;n the form o-f a protected am;no ~funct;on, examples of suitable amirlo protective groups are optionally subst~tuted alkyl, such as~ for example, tertO-butyl, tert.-amyl~ benzyl, p-rhethoxybenzyl, trit~l or be;1zhydryl, preferably trityl; trialkylsilyl, sueh as, for example, ~rimethylsilyl; op~ionally substitu~
ted aliphat;e aeyl~ such as, fol example, forlnyl, chloro-ace~yl, bromoacetylr trichloroacetyl and trifluoroaee~yl, preferably ~forr,1yl, or optionally substituted alkoxycar-bonyl" sueh as,. for example~ trichLoroethoxycarbonyl" benz~
yloxycarbor\yl or ter~.-bu~oxycarbonyl, preferably tert.-butoxycarl)olyl and beri:~yloxycarhonyl; or ciilnethylar,lino~

~ ~35~i8~ .

~ 13 -methylene.
The pro~c~;ve group can be spl;t o-ff after ~h~
replacement reaction ;n a manner known per se, -for exarslple the tri~yl group can be split of T by Means of a carboxylic acid, such asf -for example~ acetic acidr ~rifluoroacet1c acid or formic ac;d, or the benzyloxycarbonyl group can be spli~ off by hydrogenolys;s~
The reaction products of the formula I can be iso lated -from the reaction m;x~ure ;n a ~ustomary mannerr for example by freeze~dry;r\g the wa~er phase~ chrom~ography or precip;ta~ion as a sparin~ly soluble salt, for examlple as a hydriodide or hydrothiocyanate salt.
The nucelophilic replasemen~ reaction of compounds of tne general formula II can also be effec1~ed by carrying out ~he reac~ion in the presence of the base component cor~
responding to the rad;cals R2 and of trimethyliodosilaneO
This variant of the replacernent react;on ;s advan~ageously carried out by adding trimethyliodosilane to a mixture o-f ~he compound II and the base in a suitable solvent~ How-ever~ it is also possible~ to follow a procedure in which-the compoun~ ;s first reacted with trimethyliodosilane under the reaction conditions rnentioned ~elo~l, and the base is ~hen added.
Suitable solvents are chlorina~ed hydrocarbons, such as me~hylel1e chloride~ chloroforrr,~ dichi~oroethane or carbon tetrachloride~ or lower alkyl nitrilesr such as ace-tonitrile or propionitrile.
The base is added ;n at least a stoichiome~riG

..

~; ;-. ,,. ,. , :.

amount, up ~o a 20-fold excess; ;t ;s preferable to use a 5-fold to 15-fold excess.
Tr;methyl;odos;lane ;s also added ;n at least a sto;ch;ometr;c amount, up to a 20-fold excess, preferably a 5-fold to 15-fold excess.
The react;on ;s carr;ed out at temperatures between -5 and +100C, preferably between 10 and 80C.
After ~he react;on m;xture has been hydrolyzed by add;ng water of aqueous mineral acids, for example diluted 10 HCl, Br, ~J or H2S04, the ~reaction ~roducts of the fonnula I can be is~
lated from the aqueous phase ;n a customary manner, for example by freeze-dry;ng the water phase, chromatography or sim;lar methods. It is preferable to prec;p;tate the polar reaction products from the aqueous solution in the form of a spar;ngly soluble salt, for example in the form of the hydroth;ocyanate or hydr;odide salt, af~er adding KSCN or KI.
In the event that R8 represents a carbamoyloxy group, the replacement react;on ;s carried out analogously.
If R8 represents halogen, in particular bromine or ;odine, the replacement ;s carr;ed out in a manner kno~n from the literature. If the compound II ;s present here ;n the form of a react;ve derivative, examples of suitable der;vat;ves are silyl der;vat;ves which are formed when com-pounds of the general formula II are reacted with a silyl compound, such as, for example, trimethylchlorosilane or b;s-ttrimethylsilyl)-acetamide. In th;s case it ;s advan-tageous to carry out the react;on in the presence of a ~k ~ 12356~39 - 15 ~
solvent, such as methylene ehloride or aceton;trile~.
The acyla~;on of the compounds of ~he general for-mula II~ or add;t;on salts ~hereof~ for examplc- ~/;t,h hydro~
chloric acid, ~-lydrobromic acid, nitric aeid, sulfuric ac;d~
S phosphoric ac;d or an organic acid, such as, for examplc, methanesul~fon;e ac;d~ p-~oluenesulfol1;c acid or ma~eic acid, is carried out by means of carboxylie acids of the ~eneral formula IV or by means of a reacti~e derivative of such an ac;d. In ~his react;on it ;s advan~a~eous in some cases to pro~ee~ the 5-amino group in the compoul1ds of the cleneral - formula IV from ~l1e reac~cion~ Sui~able arnino pro~cective groups are the protective groups described above for R7.
After the acy~ation, the protect1ve group can be spli~ off in a manner kno~/n per se, for example the ~rityl ~roup by means of a carboxylic acid~ such 3s, for example~ formie ae;d or trifluoroacetic acid, or the chloroacetyl ~roup by meal1s of thiourea.
If the carboxylic acids of ~he general formula IV
and their derivatives which are proteeted at tl1e am1no 2~ group are themselves used as ~he acylating agent, i~ is advan~ageous to carry out the reaction in the preser,ce of a eondensation agent, for example a carbodi;mide, suc!1 as, for example, N,N' cl;cyclol1exylcarbodiirnide~
The activation of carboxyl;c ac;ds of the ~eneral ' ~formula XV ean be effected in a particularly advantageous manner by treatment with certair1 carboxamides and, for example, phosgene, phosphorus pen~achloride, tosyl chloride, thion~l chloride or oxalyl chloride, as described~ for 1~3~68g example, in German Patent 2,804,040.
Act;vated der;vatives of the carboxyl~c acids of the general formula IV wh;ch are also suitable are, in par-ticular, halides, preferably chlorides, which are obtained in a manner kno~n per se by trea~ment ~ith halogenating agents, such as, for example, phosphorus pentachloride, phosgene or thionyl chlor;de under m;ld reactlon cond;t;ons ~h;ch are known for cephalospor;n chem;stry from the literature.
Further su;table activated derivatives of the car-boxylic acids of the general formula IV are the anhydrides and ~Yed anhydrides, azides, activated esters and thioesters, ~refer-ably those formed with p-nitrophenol, 2,4-dinitrophenol, methylene cyanohydrin, N-hydroxysuccinimide and N-hydroxy-phthalimide, in particular those formed w;th 1-hydroxyben-zotriazole, 6-chloro-1-hydroRybenzotriazole and 2-mercaptQbenztriazole.
.~lxed ~ydrides which are particularly suitable are those formed w;th lower alkano;c ac;ds, such as, for example acet;c ac;d, and, part;cularly preferent;ally, those formed w;th substituted acetic ac;ds, such as, for example, trichloro-acetic acid, pival;c acid or cyanoacet;c ac;d~ Part;cularly suitable mixed anhydrldes are, however, also those formed with carbonic acid half-esters, ~hich are obta;ned, for examp~e, by reac~ting ~he carboxylic aclds of the formula IV
in wh;ch the amino group is protected, ~ith benzyl, p-nitro-benzyl, isobutyl, ethyl or allyl chloroformate. The acti-vated der;vatives can be reacted in the form of ;solated substances, but can also be reacted in situ.

1~35689 In general, the reaction of the cephem derivatives of the general formula III with a carboxyl;c acid of the general formula IV or an act;vated derivative thereof ;s carried out in the presence of an inert solven~. Particu-larly suitable solvents are chlorinated hydrocarbons, suchas, preferably, methylene chloride and chloroform; ethers, such as, for example, diethyl ether, preferably tetrahydro-furan and dioxane; ketones, such as, preferably, acetone and butanone; amides, such as, preferably, dlmethylforma-mide and dimethylacetamide, or pyridine. It can also beadvantageous to use mixtures of ~he solvents mentioned.
This is often the case if the cephem compound of the general formula III is reacted with an activated derivative, pro-duced in situ, of a carboxylic acid of the formula IV.
The reaction of cephem compounds of the formula III
with carboxylic acids of the formula IV or activated deriva-tives thereof can be carried out within a temperature range from about -80 to about ~80C, preferably between -30 and ~50C, but particularly between about -20C and room temperature.
The duration of the reaction depends on the react-ants, the temperature and the solvent or solvent mixture and is normally between about 1/4 and about 7~ hours.
The reaction with acid halides can, if appropriate, be carried out in the presence of an acid-binding agent to bind the hydrogen halide liberated~ Suitable acid-binding agents are, in particular, tertiary amines, such as, for ~le, triethyl~N~, dimethylaniline or pyridine, inor~c bases, ~356l~9 such as, for example, potassium carbonate or sodium carbon-ate, or alkylene ox;des, such as, for example, propylene oxide. The presence of a catalyst, such as, for example, dimethylam;nopyr;d;ne, can also be advantageous in some cases.
If ~he amino ~roup in the compounds of the general formula III is in the form of a reactive der;vative, this can be a derivative such as is known from the literature for amida~ions. Thus, examples of suitable derivatives are silyl derivatives which are formed ~hen compounds of the general formula III are reacted with a silyl compound, such as, for example, trimethylchlorosilane or bis-ttrime-thylsilyl)-acetamide. If the reaction is carried out wi~h a compound of this type which is activated at the am;no group, ;t is advantageous to carry out the react;on in an inert solvent, such as, for example, methylene chloride, tetrahydrofuran or dimethylformamide.
Examples of physiologically acceptable acid addi-tion salts of the compounds of the general formula I which may be mentioned are those formed w;th hydrochloric acid, hydrobromic acid, nitric acid, phosphor;c acid, sulfur;c ac;d or organ;c ac;ds, such as, ~or example, methanesul-fonic acid, p-toluenesulfonic ac;d or maleic acid.
The compounds of the general formula III can be obtained ;n a manner kno~n per se, for example from 7-ami-nocephalosporanic acid or 7-aminocephalosporanic acid which is protected on the am;no group, ;n the same way as has been described above for the nucleophilic replacement `' lZ3S68 of R8.
The compounds of the general formula IV and the pyridine, quinoline and isoqu;nol;ne bases corresponding to the rad;cals R2 are known from the l;terat~re or can be prepared by processes kno~n from the literature.
The compounds of the general formula I and their physiolo~ically acceptable acid addition salts ~hich are obta;ned in accordance ~ith the invention exhibit a remark-ably good anti-bacter;al activity against both Gram-positive and Gram-negat;ve bacter;al organ;sms.
The compounds of the formula ~ also have an unexpec-tedly good activity aga;nst pen;c;ll;nase-form;ng and cephalosporinase-form;ng bacter;a. Since they exh;b;t, ;n add;t;on, advantageous tox;colog;cal and pharmacolog;cal propert;es, they const;tute valuable chemotherapeut;c agents.
The ;nvent;on also relates, therefore, to med;c;nal fDrmulations for the treatment of microbial infect;ons, ~h;ch conta;n one or more of the compounds accord;ng to the ;nvent;on.
The products accord;ng to the invent;on can also be used ;n comb;nation ~;th other act;ve compounds, for example those belong;ng to the ser;es compr;s;ng the pen;c;llins, cephalospor;ns or aminoglycosides.
The compounds of the general formula I and their phys;ologically acceptable acid add;tion salts can be adm;n-istered orally, ;ntramuscularly or intravenously~ Med;c;nal formulations conta;n;ng one or more compounds of the general ~3~689 formula I as the act;ve compound, can be prepared by m;x-ing the compounds of the formula I w;th var;ous pharmaco-logically acceptable excipients or d;Luents, such as, for example, ~;llers, emulsif;ers, lubr;cants, taste correct-;ves, colorants or buffer substances and br;ng;ng the m;x-ture ;nto a sui~able pharmaceutical formulat;on, such as, for example, tablets, dragees, capsules or a suspens;on or solution wh;ch is suitable for parenteral admin;stration.
Example of excip;ents or diluents which may be mentioned are tragacanth, lactose, talc, agar-agar, poly-glycols, ethanol and ~ater. Examples of buffer substances are organ;c compounds, such as, for example, N,N'-d;benzyl-ethylened;am;ne, die~hanolam;ne~ ethylened;am;ne, N-methyl-glucam;ne, N-benzylphenethylam;ne, d;ethylam;ne or tris-thydroxymethyL)-am;nomethane, or ;norganic sompounds, such as, for example, phosphate buffers, sod;um b;carbonate or sod;um carbonate. Suspensions or solut;ons in water with or ~;thout buffer substances are preferent;ally su;table for parenteral adm;nistrat;on. It is also poss;ble to adm;nister the act;ve compounds as such, without an excipi-ent or ~`;luent, ;n a suitable form, for example in capsules.
Suitable doses of compounds of the general formula I or thelr physiologically acceptable acid addition salts are about 0.4 to 20 g/day, preferably 0~5 to 4 g/day for an adult of about 60 kg body weight.
It is poss;ble to admin;ster s;ngle doses or, ;n general, multipLe doses, and the s;ngLe dose can conta;n the active compound ;n an amount of abou~ 50 to 1,000 mg, ~ ~3S689 preferably about 100 to 500 mg.
The follo~;ng ;llustrative embod;ments of syn-compounds wh;ch can be prepared ;n accordance ~;th the ;nvention serve to illwstrate the invent;on further, but do not l;m;t ;~ therero.
Example 1 3-~t2,3-Cyclopenteno-1-p~r;d;n;um)methyl~-7~2-syn-meth-oxyim;no-2-t5 ~ 9~3~ ~h~g~3~J~3-yl)-acetam;d ceph-3-em-4-carboxylate a) c~) A m;xture of 0.57 9 t1 mmole) of 7-E2-t5-am;no-1,2,4-thiadiazol-3-yl)-2-syn-methoxy;m;no-ac~tam;do~-ceph-alosporan;c ac;d tr;fluoroacetate, 30 mg of ascorb;c ac;d, 6.65 9 (40 mmoles) of potass;um iodide, 1.8 mL t15 mmoles) of 2,3-cyclopentenopyr;d;ne, 7 ml of water and 3 ml of acetone ;s heated at 65-67C for 4 hours, wh;le stirr;ng.
After cool;ng, the dark-colored solut;on is chromatographed over sil;ca gel tMerck "Lobar-C"*column) us;ng 2:1 acetone:
water. The product fractions are concentrated and freeze-dried. Th;s gives 0.14 9 (27X of theory) of a colorless, amorphous sol;d.
IR ~K3r): 1770 cm 1 (lacta~-CO) H-NMR (CF3C02D): ~ = 2.20-2.80 ~m, 2H~ cyclopentene-H);
3.10-4.05 ~m, 6H, 4 cyclopen-tene-H and SCH2); 4.30 ~s, 3H, OCH3); 5.20-6.25 (m, 4H, 3-CH2 and 2 lactam-H); 7.66-8.70 ppm (m~ 3H, Py) ~ ) 1.4 9 (7 mmoles) of tr;methyl;odos;lane are *denotes trade mark ;~

- - ~23S~

added at SC to a mixture of 0~57 g t1 mmole~ of 7~C2-(S-am;no-1,2,4-thiad;azol-3-yl)~ syn~ ethoxy~miroaceta-rnido]~cephalosporanic ~Icic~ trifluoroacetate and 1~07 g (9 mmoles~ of 2,3~cycLopentenopyridine in ~0 ~nl of rneth~lene chloride, and the m;xture is ~hen heated for ~ hours under reflux. After coolin~, 7 ml of 2N HCl are added~ the mix-ture is stirred for 10 minu~es at approx. 15C and ~he p~l is adjus~ed to 6~5 by addir~ solid potass;um bicarbonate~
The aqueous phase ;s separated 07f and chromato~r2phed over a "Lobar-C" columll usinc~ 2:1 acetone:~JaterD Freeze-drying the product fractions ~ives 0.2~ y tS6~ of ~cheory?
oF a colorless sol;d ~hich ;s identical in ail ;~is proper-~ies with that described above. ~ ' t ) ``
. ~G4 mg (2 mmoles) of 2-t5-amino-1,2,tt thiac';a~ol~
3-y~)-2~syn~methoY~yirl;noacet;c ac;d are dissolved in 6 ml o~f N~N-dime~hylfcrmamlde. AFter adding 280 m~ (2~1 mmoles) o~f 1-hydroxybenz~riazole hydrate and 410 mg t2 mmc)les) of N,N'-dicyclohexylcarbodiimirle, ~he mixture is s~irred a~
~n room temperature for 2 hours. The precipitated dicyclo~
hexyluFea is filtered orf and a solution of 80~ mg (2 rnmoles) o-f 7-amino 3-Ct2,3 cyclopen~eno-1-pyridinium)lne-~hyl~ceph-3-~m-4-carboxylate d;hydrochloride 1n 10 ml oF
N,N-dimethylforrnam;de and 1 ml oF water is added ~o the filtrate. The mix~ure is stirred at room ~ernperature ror 3 hours and is concentrated in vacuo and the residue is dissolved ;n 10 ml of water. A little undissol~eci mat~er is -f~l~ered orF ar~d the solu~ion is c7lromato~raplled over . . . ~ . . .

~ ~3S689 a "Lobar-C" columr. using 2:1 acetone:wa'cer~ The product fractions are ~reez~-dried and 5~0 m~ ~56% of theory) of the t;tle compound are obtained in ~h~ form o~ an arnor~
phous solid~
This is identical il7 all its properties with the compoul1d described above.
The compounds listed bclo~J, which correspond to the general formula I in ~hich ~1 = methyl and which carry~ as the radical R2, the substituent indicated in the second column of Table 1, are obtained as amorphous solids analo~ousLy to Example 1.
Ta~le 1 E~ample R2 H-N'~1R in CF~CO~D cS (P~
__ ___ 2.15-4~0 (m, 6H, 4 cyclpentene--H, SCH2); 4.30 ts, 3H, OC'13);
2~ ~ ~ 5.15-6.35 (m, 5H, 3-CI-l2, cyclo-I I
OH pentene H, 2 lactam H); 7~7-$.8 ppm (m, 3H, Py~
.. . .~
~ 2.2-3.9 (m, 8H, 6 cyc!open~ene-~ ~ H,~SCH2);, 4.27 (s, 3H, OCH3);
3 ~ ~ 5.10-6.30 (m, 4H, 3--CH2 and 2 lac-I tam-H); 7.7-8.8 ppm (m" 3H, Py) 1.7-2.4 (m, 4 cyclohexene~H);

4 ~ ~ 2.8-4.0 (m, hH, 4 cyclohexene--11 and SCH2); 4.30 (s~ 3H, OCH3);

5.15-6.20 (m, 4H, 3-CH2 and 2 lactam-H); 7.55-8.68 ppm (m, 3H, Py) ~ .

Example R 1H~NI'lR in C~:~C02D: ~ (pprn) 1.8~2.35 tm, 4-cyclohexetle-H; 2.7-3.9 (m, 611, 4 cyclohexene-H and SC~12); 4.28 (s, 3~1, OC~I3); SA1O
¦ ~ 6.25 (m, 4H, 3-CH2 and Z lactam-H); 7.6-8.7 ~m. 3H, Py)

6 1.S-2.4 (rn 4 cyclohexcne-ll); 2.58 ts, 3H, CH3); 2~8~3.9 (m, 6H, 4 cyclohexene-l-l and SCHz); 4.28 (s~
3H, OCH3) j 5~15~6.3() (n, 4H, 3--CH2 and 2 lactam-H); 8.15 and 8.42 ppm (each 1 broad s, 2 Py-~l)

7 1.6-~2.4 (m, 6 cyclopenterle-H); 3.0~
4.0 tm, ~6H, 4 cyclopentene-l-' and / SCH2); 4.30 ts, 311, OCH3); 5.20-~ ~6.35 (m, 4H, 3-CH2 and~2 lactdrn ~ H); 7.6-8.7 pprn tm, 3H, Py) S 3.43 and 3.90 (AB, J=1911z, 2H, ~ ~ SCH2) j 4.30 (s, 3H, OCH3); 5.25--6.40 (m~ 4H, 3-Ci-12 and Z la~:tam-H) j 7.90~-~.60 (rn, SH, quinol1rle-'1);

- 8.9[)~9.40 pPm~ (m~ 2H, quinolir,e~H) ~ ~ , :~
:

q ' :

i ;~35689 1H-NMR in C~C02~: S (ppr,l) 3.41 and 3.92 (AB, J=19Hz, 2H, SCH2); 4~2a (s~ 3H, OCH3); 5~Z6-6.30 (rr,, 4H, 3-CH2 and 2 lactam-H
/ each having 1 d a~ s.42 and 6.11, ~N~ J=5Hz, C-6 and C--7~H); 8.0-8.8 (m, 6H, isoquinoline-ll); 9.78 ppm (broad s, iH, ;soquinollne-H) .
3~36 and 3.~8 (AB, J=18Hz, 2H, `C~l -3 SCH2); '.. 30 (s, 3H, OCH3); 5.25~
j 6.40 (m, 4H, 3-CH2 and 2 lactam-~J H); 7~8-8.8 tm, 5~, quinoline-H);

9.1~ppm (d, I=6Hz (1-quinoline-H) 3.17 ppm (s, 3H, CH3) The compounds l;sted below, which correspond to the general formula 1 (R2 = 2,3-cyclopenteno-1-pyridiniurn) and which carry, as the ra~dical R1r the substituent indi-cated in the second~col~umn of Table 2, are obtained as amorphous solids analogously tR Example 1.

, 3~689 Table 2 ~12~,S~r ~ L c~2~

~ Examp~e R1 1H-NMR ;n CF3C02D: ~ (ppm) ___ _ ~
11 C2ll5 1~42 (t, J=7Hz, 3H, CH2CH3); 2-15--2i80 M, 2H, cyclopentene-ll); 3~1-4.0 (mf 6H, 4 cyclopen.ene-H and SCH2~; 4~48 (q, J=7Hz, 2H, CH2CH3);
5.15 6.35 (m, 4H, 3-CH~ and 2 lac-tarrl~H); 7.65-8.70 ppm (m, 3H, Py) . . ~
12 CH2CH2CH3 1.10 (t, J=6Hz, 3H, CH3); 1~5-2.1 S (M, 2H, CH2); 2.15-2.~ (m, 2H, cyclopentelle-H); 3.1-4.0 (rr!, 6H, 4 cyclopentene-H and SCH2); ~.45 (t, J=6Hz, NOCH2); 5.15-6.30 (m~
4H, 3-CH2 and 2 !actdm-H); 7.6-~.7 pp ~m, 3~l, ry) 13 CH(CH3)2 1.40 and 1.50 (cl,~J-6Hz, hH, 2 CH3);
2.2-2~8 (m, 2 cyclopentene-H); 3 10-4.00 (m, 61i, 4 cyclopentene-H and SCH2)r 4.73 (rn, 1H, CHj; 5.20-.
~6~30 (rn, 4H, 3-CH2 and 2 lactam-H);
7.65-8.72 ppm (m~ 3H, Py) ' :~

~ ~235689 Example R1 ~H-NMR ;n CF3CO?D: ~ (ppm) . . ~
14 CH CH--CH 2.2-2.8 (m, 2H, cyclopentene-H);
- . . - 3.1-4.0 (m, 6H, 4 cyclopent~ne-ll an~ SCH2); ¢.80~6~42 tm, 9H, 5 allyl-H, 3-CH2 and 2 ~actam-ll); 7.65-8.70 ppm (m, 3H _Py) CH2SCH3 2.2-2.8 (m, 5H, 2 cyclopenterle-H
and SCH3); 3.1-4.0 (rn, 6H, 4 cyclo-pentene-l~ and SCH3); 5.15-6~30 (m, , 2S, 3 CH2 and 2 lactam-H);
7 67~8 72 ppm (In~ 3H, Py) 16 1.1-1.7 (m, 5H, cyclopropyl-H)r 2.2-2~8 (m, 2H, cyclopentene H);
2 ~ 3.1-4=0 (m~ 6H~ 4 cyciopentPne~~i and SCH2~; 4.25 (d, J-7Hz, 2H, NOCH2); 5.20-6.30 (m~. 411, 3--CH2 and 2 lactam-H); 7.66-~.70 ppm (m, .

17 1.3-2.8 (m, 10H, 2 c~clopentene-H, ~ ~ 8~cyclopentyl--H); 3~1-L~o~(m~6 4 cyclopentene-ll and:SCI'2); 5.,15-I 6.25 (m~, 4ll, 3-CH2 and 2 lactam-H);
_ _ 7~6-8v7 ppm (m, 3H, Py) _ :

: ~ :

, : ' ' :`: : ::
,.

~ . __ .,. . _ _.. ~ _ ... ._.. . . _ ........ . ..

3S6~g A

- 2~ -Example R1 1H-~MR in CF3C02D: ~ (ppm) 18 -CH2C02CH3 2.2-2.~ (m, cyclopentene-H); 3.1-4.0 (m, 6H, 4 cyclopentene~H ar,~
SCH2); 3.95 (s, 3H, CH3); 5.05 (s, 2H, NOCH2); 5.2-6.~ (m, 4H, 3-C~I2 and 2 lactam-H); 7.65-~.7 ppm (m, 3H, Py) 2 H2 2.2--2.8 (m, 2H, cyclopenten H); 3.1-4.0 (m, 611, 4 cyclopenTene-H and ~CH2); 4.90-6~35 (m, 6H, NOC1l2, 3-CH2- and 2 lactam-ll); 7.65-8~70 ppm (m, 3H, Py) Cl12COOH~ 2.15-2~ (m,''2H, cyclopentene-H);
3.1-3.9 (m, 4 cyclopentene-H and SCH2); 5~08 (s, 2H, OCH2); 5-15-.
6.25 (m, 4H, 3-CH2 and 2 lac'cam-Hj;
7.65-8.70 ppm (m, 3H, Py) 21 -C(CI~3)2COOH~ 1.80 (s, 6H, 2 x CH3); 2.10-2.8 (m, 2H, cyclopentene-H); 3.1~-3.9 (m, 6H, 5CH2, 4 cyclopente~ne-H~
5.20-6.30 (n,, 411, 3-CH2 and 2~lac~ ~ -tarn-H); 7.68~8.7~ ppm (m, 3Hr PY) ___._ ____ :: ~
22 -CH~CCOOH 2.1-2.8~(m, 2H, cyclopente~rle~H);
C~
2 ~ 3.1-3~? (m,~ 6H~ cyclopentene-!l and SCH2); 5~1-6.40 (m, 6H, NOCH2, 3-CHz and 2 lactam H)~; 6.50-6.8 ~m, 2H, C~=~CH2); 7.66-8'.70 ppm (m, ~ ~?$689 Example ~ N~1R ;n CF3C02D: S (ppm~
23 1.5-2.8 (m, 6~, 2 cycloperltene-H, -C-C~OI~ 4 cyclopropyl-~l); 3.1-3.9 ~rb, 6H, /~ 4 cyclopentene-H and SCH2); 5.15-6.30 (m, 4H, 3-CH2 and 2 lactam-H);
_ __ _ __ 7~66-8.70 ppm_(m, 3H_ Py) 24 2.0-4.0 (m, 14~, 6 cyclobutyl-H, -C~ COO~l 6 cyclopentene-H and SCH2); 5.15--6~40 (m, 4H, 3-CH2 and 2 lactam-H);
7.60 ~.70 pprn (m 3H Py) , :
.

~; ~
.

:

~ . . - . . .. .

3568~

- 29 a -The compounds listed below, which correspond to the general formula I wherein R1 = methyl and which carry, as the radical R2, the substituent indicated in the second column of Table 3, are obtained as amorphous solids analo-S gously to Example 1.

Example R2 1H-NMR in CF 002D: (ppm) ~ 1.9-2.45 (m, 2H, pyran-H); 2.65-3.25 (m, 2H, pyran-H);
N~ ~ 3.42 and 3.75 (AB, J = 19 Hz, 2 H, SCH2);
4.26 (s, 3H, OCH3); 4.4-4.8 (m, 2H, pyran-H);
4.85-6.20 (m, 4Hj CH2Py and 2 lactanrH); 7.25 (d, J = 7 Hz, Py-H); 8.2-8.6 (m, 2H, Py) 26 3.45 and 3.85 (AB, J = 19 Hz, 2H, SCH2); 4.22 ~ (s, 3H, OCH3); 5.2-6.45 ~m, 4H, CH2py and 2 lactamrH);
7.3 (m, 1H), 8.0-8.3 (m, 2H), 8.88 (d, J = 7 Hz, 1 H) and 9.43 (s, 1H) furopyridine-H) 27 3.47 and 3.85 (AB, J = 19 Hz, 2H, SCH2); 4.22 ~ (s, 3H, OCH3); 5.25 - 6.5 (m, 4H, CH2Py and 2 lactam-H); 7.90 and 8.18 (each time one d, J = 5Hz, 2 thiopene-H); 8.35 - 8.8 (m, 2H, Py), 9.50 (s,1H,Py) _ 28 3.50 and 3.86 (AB, J = 19 Hz, 2H, SCH2); 4.21 (s, ~ 3H, OCH3); 5.3 - 6.5 (m, 4H, CH2Py and 2 lactam,H);
SJ 7.85 (d, J = S Hz, 1 thiophene-H, 8.2 - 8.8 (m, 3H); 9.63 (s, 1H, Py) 29 3.26 (s, 3H, CH3); 3.40 and 3.72 (ABj J = 19 Hz, 2H, SCH2); 4.23 (s, 3H, OCH3); 5.25 - 6.45 (m, 4H, ~ ~ CH2Py and 2 lactam=H); 7.75 (d, J = 5 Hz, thiophene-CH3 H); 8.0 - 8.7 (m, 3H, thienopyridine) 3.46 and 3.75 (AB, J = 19 Hz, 2H, SCH2); 4.21 (s, 3H, OCH3) 5.2 - 6.5 (m, 4H, CH2Py and 2 S~ lactam-H); 7.6 - 8.2 (m, 3H) and 8.5 - 9.3 I (m, 2H), thienopyridine __ _

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a cephem derivative of the formula I

I

and the physiologically acceptable acid addition salts thereof wherein R1 denotes hydrogen, C1-C6-alkyl which may be substituted by halogen, C1-C6-alkylthio or C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkyl, C4-C7-cycloalkenyl or the group in which m or n can each be 0 or 1 and R3 and R4 can be identical or different and denote hydrogen, phenyl or a C1-C4-alkyl group or, together with the carbon atom to which they are attached, form a methylene group or a C3-C7-cycloalkylidene group, R5 denotes a group -CO2R6 in which R6 denotes hydrogen, C1-C4-alkyl, -CH2O-C1-C4-alkyl, -CH2-OOC-C1-C4-alkyl or one equivalent of an alkali metal, alkaline earth metal or ammonium or of an organic amine base; or a nitrile group or a carbamoyl group -CONH2 which can be monosubstituted or disubstituted on the nitrogen by C1-C6-alkyl, and R2 denotes a pyridium radical which is substituted by 2 alkyl in the ortho-position which are linked to from dimethylene to decamethylene ring, in which one carbon atom can be replaced by an oxygen or sulfur atom and, furthermore, one or two double bonds can also be present, or denotes a 1-quinolinium radical or a 2-isoquinolinium radical each of which can also be monosubstituted or disubstituted in an identical or different manner by C1-C6-alkyl, C1-C6-alkoxy, halogen, trifluoromethyl or hydroxyl, and in which the R1O group is in the syn-position, in which (a) a compound of the general formula II

II

or salts thereof or a reactive derivative of the compound II in which R1 has the meaning mentioned above and R7 denotes an amino group or a protected amino group and R8 denotes a group which can be replaced by the pyridine, quinoline or isoquinoline derivatives corresponding to the radicals R2 of the formula I is reacted with pyridine, quinoline or isoquinoline derivatives, and (.alpha.) splitting off a protective group which may be present and (.beta.) if necessary, converting the resulting product into a physiologically acceptable acid addition salt, or (b) a 7-aminocephem compound of the general formula III

III

or acid addition salts thereof in which R2 have the above-mentioned meaning and in which the amino group can also be present in the form of a reactive derivative is reacted with a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-syn-oximinoacetic acid of the general formula IV

IV

in which R1 and R7 have the meaning mentioned above, or with an activated derivative of this compound, and (.alpha.) splitting off a protective group which may be present, and (.beta.) if necessary, converting the resulting product into a physiologically acceptable acid addition salt.

2. A process as claimed in claim 1 in which the nucleophilic replacement of the substituent R8 is effected in the presence of neutral salt ions.

3. A process as claimed in claim 1 wherein the nucleophilic replacement of the substituent R8 is effected in the presence of the base from which the radical R2 is derived, and of trimethyliodosilane.

4. A cephem derivative of the formula I as defined in claim 1 and the physiologically acceptable acid addition salts thereof, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a).

6. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b).

7. A cephem derivative of the formula I as defined in claim 1 and the physiologically acceptable acid addition salts thereof, whenever obtained according to a process as claimed in claim 5 or claim 6 or by an obvious chemical equivalent thereof.

8. A cephem derivative of the formula I as defined in claim 1 and the physiologically acceptable acid addi-tion salts thereof.

9. A pharmaceutical composition containing a cephem derivative of the formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable auxiliaries, carriers, diluents, or excipients, for use in the treatment of bacterial infections.