CA2008059A1 - Cephalosporin derivatives and processes for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
Cephalosporin derivatives and processes for their pre-paration Cephemcarboxylic acid esters of the general formula

Description

HOECHST AKTIENGESELLSCHAFT HOE 89/F 016 Dr. KA/rh Description Cephalosporin derivatives and processes for their preparation The invention relates to novel cephalosporin derivatives uhich are particularly suitable for oral adm;nistration, a process for their preparation and phar~aceutical form-ulat;ons containing such compounds.

Although many clinically rèlevant cephalosporins ~ith abroad antibacterial spectrum have been developed, most of them are suitable only for parenteral administration, since they are absorbed only very inadequately, if at all, follo~ing oral administration. In many cases, however, it is desirable to give the patient highly active anti-biotics in oral form.

The cephalosporin antibiotics kno~n to date do not meet all the requirements ~hich have to be imposed on such a ~edicament, that is to say a high antibacterial activity against Gram-positive (specifically Staphylococci) and 6ram-negative pathogens and at the same time a good absorp-tion in the gastrointestinal trac~.

In some cases, it has been possible to increase the absorp-tion of ~ cephalosporin in the gastrointestinal tract by esterification of the 4-carboxyl group~ Since ~he cephal-osporin ~ster~ as a rule have no antibiotic activity inthemselves, the ester component ~ust be chosen so that after absorption, the ester is split back ~gain into the cephalosporin with a free carboxyl group rapidly ~nd com-pletely by endogenous enzymes, such as ester~ses.
~he degree of entsral absorption of cephalosporins depends decisively on the chemical structure of the cephalosporin and the particular ester component. Even s~all structural 2~Q~

variations on the cephalosporin basic skeleton or in the ester component can influence the absorption. ~he dis-covery of su;~able components is pureLy emp;rical. Thus~
for exa~ple, the ;ntroduction of an acid substituent into the 7 B-side chain sf aminothiazolyl-cephalosporins, such as, for example, in cefixime, leads to a compound ~hich can be absorbed enterally, whereas compounds ~ith neutral side chains, such as, for example, in cefuroxime, are ab-sorbed enterally only in the form of prodrug esters. The dose/effect relationsh;p is thereby often non-linear and the therapeut;c serum levels achieved are not satisfactory.
Carbonate esters from the aminothiazolyl-cephalosporin series are mentioned, for examplo, in European Patent 134,~20.
ey in vivo stud;es carried out systemati~ally on various 2nimal species, we have no~ found a narro~ group of ceph-3-em-4-carboxylic acid esters ~hich can be administered orally, have a sufficient che~ical stability and due to a balanced lipid- and ~ater-solubility are absorbed rap;dly and in a therapeutically substantial degree in the gastro-intestinal tract.

The invention accordingly relates to cephemcarboxylic hCid est~rs of the ~eneral for~ula I

H N ~ ~ C - CONff ~ S~ (I) 2 ~ N~OR1 N ~ H2-R
COOCH-OC OR
~.
~3 in uhich R1 denotes hydrog~n or ~ethyl and R2 denotes hydrogen or ~ethoxy, one of the t~o sub-stituents R1 or R2 al~ays representing hydrogen;
R3 denotes str3;ghe~chain or branched C1-Cs-alkyl, ~hich can be substituted by t1-C3-alko%y, C3-~g cyclolakyl or C2 C7-cysloal~oxy;
C3-Cg-cycloalkyl or C2-C7-cyclo~lkoxy, ~o~s~

in which, in the case where R1 jS hydrsgen and R2 is meth-oxy, R3 cannot be C1-C4-aLkyl, and in ~hich the group oR1 is in the syn-position, and physiologically toler-ated acid addition salts thereof.
s R3 can thus represent C1-Cs-alkyl, wh;ch can be straight-chain or branched, such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-butyl, 2-methylpropyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl or 2,2-dimethylpropyl, and preferably represents C1-C4-alkyL, and in particular represents C3-C4-alkyl, such as, for example, n-propyl, i-propyl, n-butyl, 2-butyl, 2-methylpropyl or t-butyl, wherein those alkyl radicals which are substituted in the 1-pos;tion by methyl are also preferred, and wherein the alkyl radicals can also additionally be substituted by C1-C3-alkoxy, such as, for example, methoxy, ethoxy or propoxy, by C3-Cg-cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl or cyclooctyl, preferably by Cs-C7-cycloalkyl, such as, for example, cyclopentyl, cyclohexyl or nor-bornyl, preferably cyclopentyl or cyclohexyl, in parti-cular cyclohexyl, or by C2-C7-cycloalkoxy, preferably C4-C5-cycloalkoxy, such as, for example, tetrahydro-furanyl or tetrahydropyranyl, in particular tetrahydro-pyranyl;
or represent C3-Cg-cycloalkyl~ such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl or cyclooctyl, preferably Cs-C7-cycloalkyl, such as, for example, cyclopentyl, cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, in part;cular cyclohexyl; or represents C2-C7-cycloalkoxy, preferably C4-Cs-cyclo-alkoxy, such as, for example, tetrahydrofuranyl or tetra-hydropyranyl, in particular tetrahydropyranyl.

Preferred compounds of the general for~ula 1 are those ;n - 4 - 2~ 59 ~hich R1 represents ~ethyl and R2 represents hydrogen and R3 has the following meanings:

C1-Cs-alkyl, preferably C3-C4-alkyl, ~hich can also additionally be substituted by C1-C3-alkoxy or by C5-C7-cycloalkyl or by C4-Cs-cycloalkoxy;

Cs-Cg-cycloalkyl~ preferably Cs-C7-cycloalkyl, or C4-Cs-cycloalkoxy, in which these definitions mentioned for R3 have the mean-ings given above in the discussion of the substituents of the general formula In Amongst the compounds where R1 = methyl and R2 = hydrogen, those in which R3 represents i-propyl, 2-butyl, 2-methyl-propyl, 1-~ethoxy-2-propyl, cyclopentyl or cyclohexyl, are of particular interest.

Compounds of the general formula I in which R1 repre-sents hydrogen, R2 represents methoxy and R3 represents the group t fH~ m _ R6 (~
~(CH3)~ n ~herein n = 0 or 1 m = 0 or 1 and R6 = stra;ght-chain or branched C1-C3-alkyl, ~hich is substituted by C1-C3-alkoxy~ C3-Cg-cyclo-alkyL or C2-C7-cycloalkoxy;
C3-Cg-cycloalkyl or C2-C7-cycloalkoxy, are fur~her~ore preferred.

In the case ~here n is 0, the following meanings are pos-sible for R6:

z~

C3-Cg-cycloalkyl~ preferably C5-C7-cycloalkyl, such as, for example, cyclopentyl~ cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, in part;cular cyclohexyl;
s C2-C7-cycloalkoxy, preferably C4-Cs-cycloalkoxy, such as, for example, tetrahydrofuranyl or tetrahydro-pyranyl, in part;cular tetrahydropyranyl.

If n = O, those compounds ;n which R6 in the group ~) represents cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl, preferably cyclohexyl or tetrahydro-pyranyl, are of particular interest.

If n = O, R6 can also represent stra;ght-cha;n or branched C1-C3-alkyl, ~hich ;s substituted by C1-C3-alkoxy, C3-Cg-cycloalkyl or C2-C7-cycloalkoxy, the alkoxy, cycloalkyl and cycloalkoxy groups, including their pre-ferred ranges ~hich are also suitable here, being as de-fined above for R3 in the general formula I.

If n = O, the following subst;tuted alkyl groups are of particular interest for R6:
2-~ethoxyethyl, cyclopentylmethyL, cyclohexyLmethyl and tetrahydropyranylmethyl.

If n in the group ~) ~ 1, suitable meanings for R6 are the same as for ~hen n = O. Only ;n the case of the sub-stituted C1-C3-alkyl group is a substituted C1-C2-alkyl group preferred ~hen n = 1.

Examples ~hich may be mentioned of R6 in the meaning of a C1-C3-alkyl group substituted as described above, especialLy if n = 1 and m = O, are:
ethoxy-methyl 2-~ethoxy-ethyL
3-~ethoxy-propyl 2-~ethoxy-~2-methyl)-ethyl 2-~ethoxy-t1-methyl)-ethyl 1-~ethoxy-t1r1-dimethyl)-methyl ethoxy-methyl 2-ethoxy-ethyl 3-ethoxy-propyl 2-ethoxy-tZ-methyl)-ethyl 2-ethoxy-(l-methyl)-ethyl 1-ethoxy-(1,1-dimethyl)-methyl t1-propyloxy)-methyl 2-t1-propyloxy)-ethyl 3-t1-propyloxy)-propyl 2-t1-propyloxy~-t2-methyl)-ethyl lS 2-~1-propyloxy)-~1-methyl)-ethyl 1-tl-propyloxy)-(1,1-dimethyl)-methyl 2-tpropylo~y)-methyl 2-t2-propyloxy)-ethyl 3-t2-propyloxy)-propyl 2-~2-propyloxy)-(2-methyl)-ethyl 2-tZ-propylo~y)-(1-methyl)-ethyl 1-(2-propyloxy)-(1,1-dimethyl)-0ethyL

(cyclopentyl)-methyl 2-~cyclopentyl)-ethyl 3-~cyclopentyl)-propyl 2-~cyclopentyl)-(2-methyl)-ethyl 2-(cyclopentyl)-(1-methyl)-ethyl 1-(cyclopentyl)-(1,1-dimethyl)-methyl ~cycLohexyl)-methyl 2-(cyclohexyl)-ethyl 3-(cyclohexyl)-propyl 2-tcyclohexyl)-(2-methyl)-ethyl 2-~cyclohexyl)-(1-~ethyl)-ethyl 3S 1-(cyclohexyl)-t1,1-dimethyl)-methyl (~-tetrahydropyranyl)-methyl 2-(4-tetrahydropyranyl)-ethyl 3-(4-tetrahydropyranyl)-propyl s~

2-(4-tetrahydropyranyl)-(2 methyl)-ethyl 2-(4-tetrahydropyranyl)-(1-methyl)-ethyl 1-(4-tetrahydropyranyl)-(1,1-dimethyl)-methyl preferably methoxymethyl, 2-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, cyclopentylmethyl, cyclohexylmethyl and tetrahydropyranylmethyl, methoxymethyl, cyclopentylmethyl, cyclohexyl~ethyl or tetrahydropyranylmethyl being parti-cularly preferred.
If R in the general formula I represents hydrogen and R represents methoxy, especially preferred meanings of R3 are accordingly Cs-C7-cycloalkyl, in particular cyclopentyl and cyclohexyl, C4-Cs-cycloalkoxy, in par-ticular tetrahydropyranyl, and C1-C3-alkyl ~hich is sub-st;tuted by C1-C3-alkoxy, such as, for example, 2-meth-oxy-(1-methyl)-ethyl.

Possible physiologically tolerated acid addit;on salts are the salts known for cephalosporin antibiotics, such as~ for example, the hydrochlor;de, sulfate, maleate, citrate, acetate or formate. They are prepared in a man-ner vh;ch is kno~n per se by bringing the corresponding acid together with I ;n an aqueous or organic solvent or a suitable solvent mixture.

~he invention furthermore relates to a process for the preparat;on of cephemcarboxyl;c acid esters of the gene-ral formula I

~2N ~ ~ N-OR~ R2 3 ~I) O~
~3 ~herein R1 denotes hydrogen or methyl and R2 denotes hydrogen or methoxy, one of the t~o substituents R1 or R2 al~ays representing hydrogen, R3 represents - 8 - 2 ~ S 9 straight-chain or branched C1-C5-alkyl, ~hich can be substituted by C1-C3-alkoxy, C3-Cg-cycloalkyl or C2-C7-cycloalkoxy, or represents C3-C8-cycloaLkyl, or represents C2-C7-cycloalkoxy, in which, in the case where R1 is hydrogen and R2 is methoxy, R3 cannot be C1-C4-alkyl, and in ~hich the group -0R1 is in the syn-pos;tion, and of phys;ologically tolerated ac;d add;tion salts thereof, which comprises a) reacting a compound of the formula II

~ C ~ CONH------~S ~
HN--~ IJ N-OR ~L ~LCH2R ( I I ) in ~hich R2 represents hydrogen or methoxy, R4 repre-sents hydrogen or an amino-protective group~ R5 repre-sents methyl or a group ~hich can easily be split off and A represents a cation, in which R4 can only represent hyd-rogen if R5 is methyl, ~ith a compound of the general formula III

CH3 2 tIII) in ~hich R3 has the above meaning and X represents a leav-ing group, to give the ester of the general formula IV

- COMH~
,4 ~ ~ OR5 L~ 3 CO2_ CH_O~C-OR
~H3 O

and removing the groups R4 and R5~ in the ~eaning of ~
protective group or a group ~hich can easily be split off, in a ~anner which is kno~n per se, or b) reacting a compound of the general formula V

_ 9 _ ~ 9 N ~ C - CO-Y
H ~ ~ N-O~

;n which R4 and R5 have the above meaning and Y repre-sents an activating group, ~ith a compound of the general formula VI
H N ~ R 2 N CH 2 ( V I ) in which R2 and R3 have the above meaning, or ~ith a salt of this compound, to give a compound of the general formula IV~ and splitting off the groups R4 and R5, in the meaning of a protective group or a group which can easily be split off, in a manner ~hich is known per se, or c) reacting a compound of the general formula VII

2 5 Z~ ~ n ~ ~
o N~Rl L ~L CH2R2 ~VI I ) O
C~)2-~HOCOR
CH3 o ;n ~hich Z represents halogen and R1, R2 and R3 have the above mean;ng, ~ith thiourea to give compounds of the general formula I and - if desired - converting the re-sultin~ conpounds into a physiologically tolerated acid addit;on salt.
In the ~eneral formulae II, IV and V, R4 stands for an amino-protective group which ;s known from pepeide and cephalosporin chemistry~ preferably formyl, chloro-acetyl, bromoacetyl, tr;chloroacetyl, trifluoroacetyl )5~

ben~yloxycarbonyl, tert.-butoxycarbonyl or trityl, and R5 stands for a group which can easily be split off and is likewise known from peptide and cephalosporin chemistry, preferably benzhydryl, trityl, tetrahydropyranyl or 1-methoxy-1-methylethyl. Trityl and chloroacetyl are par-ticularly preferred for R4, and trityl and 1-methoxy-1-methyl-ethyl are particularly preferred for R5.

In formula III, X denotes a leaving group ~hich is gen-erally known for esterification reactions, such as, for example, chlorine, bromine, iodine, phenylsulfonyloxy, p-toluene-sulfonyloxy or methylsulfonyloxy, preferably chlorine~ bromine or iodine, in particular iodine.

Examples which may be mentioned of bases on which the cation A ;n the general formula II is based are sodium bicarbonate, potass;um b;carbonate, sodium carbonate, potassium carbonate and optionally substituted~ alkylated amine bases, such as, for example, trimethylamine, tri-ethylamine, diisopropylamine, ethyldiisopropylamine, N~N-dimethylaniline, N,N-dimethylbenzylamine, 1,5-diazabicy-clo[4,3,0]non-5-ene tDBN), 1,8-diazabicyclo[5,~,0]undec-7-ene (D~U), pyridine, picoline or 2,6-dimethylpyridine.
Preferred bases are sodium b;carbonate or potassium b;car bonate, sodium carbonate or putassium carbonate, triethyl-amine, N,N-dimethylaniline, DBN or DBU.

Reaction of the free ~arboxylic acids ~ith these bases gives the salts of the general formula II ;n which A stands for a cation, such as, for example, sodium or potassium, but also ~agnesium or calcium or an optionally substituted alkylated ammonium ;on, such as, for example, ammonium, trimethylammon;um, eriethylammonium~ tetrabutylam~onium, diisopropylammonium, ethyld;isopropylammonium, diazabi-eyclotO,3,4~nonenium or diazabicyclotO,4,5~undecenium~Preferred mean;ngs of A are sodium, potassium, triethyl-ammonium, N,H-dimethylanilinium and the DBN and DBU ion.

In compounds of the formula VII, Z stands for a halogen os~
atom, preferably chlorine or bromine.

The reaction of the compounds of th~ formula II ~ith the compounds of the formula III can be carried out ;n an organic solvent at about -20 to about +50C~ preferably at about 0C to room temperature. Examples of solvents ~hich can be used are ketones, such as, for example, ace-tone or 0ethylethyl ketone, N,N-dimethylformamide (~MF), N,N-dimethylacetamide ~DMA), N-methylpyrrolidone or di-methylsulfoxide tDMSo). DMF, DMA, N-methylpyrrolidone and DMS0 are pre~erred. DMF is particularly preferred.

The groups R4 and R5 are split off from the resulting com-pounds of the formula IV in a manner ~hich is kno~n per se by ~ethods kno~n from peptide and cephalosporin chemistry, ~or example ~ith trifluoroacetic acid, dilute hydrochloric acid or preferably with formic acid, ~ith the addition of a little ~ater.

If a compound of the formula V is reacted with a compound of the formula VI, Y represents a group which activates the carboxyl group, such as is known for corresponding reactions from peptide and cephalosporin chemistry, for example a halide~ preferably chloride, an activating ester group, for example w;th 1-hydroxybenzotria~ole, or a mixed anhydride, for e~ample ~ith benzenesulfonic acid or tol-uenesulfonic acid. The activation of the carboxyl group is also possible in a manner ~hich is known from the literature via the addition of a condensing agent, such as, for example, a carbodii~ide.

The compound of the general formula VI can be used as such or in the form of a salt, for example the tosylate, hy-drochloride or hydriodide, and the use of crystalline salts may be advantageous in respect of the purity of the products.

~he reaction of compounds of the formula V with ~hose of the formula VI can be carried out in an organic solvent, Z~ 8~5~

such as, for example, methylene chloride, chlsroform, ace-tone, methylethyl ketone, dimethylformam;de, dimethy!acet-amide or ~ater~ or in mixtures of these solvents.

The acylation reaction can advantageously be carried out at temperatures from about -50C to about +50C, prefer-ably -40C to +30C, if desired in the presence of a base, such as, for example, triethylamine or pyridine.
The addition of a base serves to bond the acid component liberated during the condensation.

The cyclization of compounds of the general formula VII
~ith thiourea can be carried out by processes ~hich are known per se, such as are d~scribed, for example, in European patent 134,420. For example, it is achieved smoothly at temperatures of about û to 30C, preferably about 5C, in organic solvents, preferably aprotic polar solvents, such as, for example, dimethylformamide, dimethyl-acetamide, acetonitrile or acetone.
The compounds of the formula III can be prepared in a manner ~hich is kno~n per se, for example by reacting 1-chloroethylchloroformate Cl ~ C0 - Cl C~3 ~;th alcohols of the general formula YIII

R3 - OH (VIII) in vhich R has the abovementioned ~eaning.

The reaction is advantageously carried out in an organ;c solvent, such as a halogenated hydrocarbon, for example ~ethylene chloride or chloroform, if appropriate in the presence of a base, for example, pyridine or triethyl-aMine, at a temperature of -20C ~o ~30C.

Co~psunds of the formula III can also be prepared by 2~

halogen replacement. For example, a compound III in which X represents bromine or iodine can be prepared by react;ng the corresponding compound III in which X represents chlorine with an iodide r,r bromide salt, such as, for exampLe, sodium iodide or sodium bromide, if appropriate in the presence of a catalyst, for example ~inc chloride.

The preparation of the starting compounds of the general formula II is described in European Patent 34,536.
The starting compounds of the general formula V with the activated carboxyl group are prepared in a manner ~hich is known from the literature, and the esterification to give the compounds of the formula VI is carried out in the same manner as has been described for the preparation of the esters of the general formula IV.

The compounds of the general formula VII can be prepared by processes which are known per se. Thus, for example ?0 (comp3re European patent 134,420), diketene can be reacted ~ith bromine and the resulting intermediate can then be reacted ~ith a compound of the general formula VI, a pre-liminary product of the formula 2, 2 ~ S~
~i-- CH2R

..

in which R2 denotes hydrogen or 0ethoxy being obtained and subsequently being converted by nitrosation (compare also European Patent 134,420) into a compound of the general formula VII~
The ceph-3-em-4-carboxylic acid esters of the general formula I have a number of physicochemical and biological properties ~hich make them useful cephalasporin antibio~ics for oral administration. They are stable, colorless ~0~ 9 compounds which are readily soluble in the customary organ;c solvents, are absorbed in the intestine, are rapidly split in the serum to give antibiot;c cephalosporin derivatives of the formula H~ ~ O ~ 2R2 in uhich R1 and R2 are as defined in formula 1, and are therefore outstandingly suitable for the treatment of bacterial infection diseases, such as, for example, in-fection of the respiratory tract or of ehe urogenital tract.

The compounds according to the invention are administered orally in the form of customary pharmaceutical formulations, for example, capsules, tablets, powders, syrups or suspen-sions. The dose depends on the age, symptoms and body weight of the patient and on the duration of treatment.
However, it is as a rule between about 0.2 9 and about 5 9 per day, preferably bet~een about 0.5 9 and about 3 9 per day. The compounds are preferably adm;nistered ;n divided doses, for example 2 to 4 times daily, and the individual dose can contain, for example, between 50 and 500 mg of ac~ive compound.

The oral formulations can contain the customary excip;en~s and/or diluents. Thus, ~or example~ binders, such as, for exam~le~ gelatin, sorbitol, polyvinylpyrrolidone sr car-boxymethyl cellulose, diluents, such as, for example,lactose, sugar, starch, calcium phosphates or polyethylene glycol~ and lubricants, such as, for example, talc or magnesium steara~e are possible for capsules or tablets, and aqueous or oily susPensions, syrups or similar kno~n formulation forms, for example, are suitable for liquid formulations.

The following examples serve to further illustrate the invention, but do not limit it to them.

20(~VS~

A. Preparation of starting substances Preparation example 1 1 Chloroethyl 1-methoxy-2-propyl carbonate 7.7 ml (70 mmol) of 1-chloroethylchloroformate and 6.6 ml (70 mmol) of 1-methoxy-2-propanol were d;ssolved in 40 ml of dry methylene chloride and the solution was cooled to 0C. A m;xture of 5.8 ml t72 mmol) of pyridine and 20 ml of dry methylene chloride was then added dropwise at 0 -5C the mixture was stirred for a further 2 hours ~hile cooling with ice and the pyrid;nium hydrochloride formed was filtered off with suction. The filtrate ~as washed twice (H20) and distilled under a water pump vacuum. 8.8 9 (64%~ of the title compound uere obtained ~boiling point30 = 100 - 105C).

1H NMR (CDCl3): ~ = (ppm) 6.46 (q, CH-Cl) 4.,93 (m, CH-OC02) 3-63 (d, CH2-0) 3-40 (8~ OCH3) 1 . 83 ( d, CH3-CHC 1 ) 2 5 1 . 46 ( a, ~H3-CHOC o2 ) -The compounds summarized in the Table 1 were prepared ~nalogously to Preparation Example 1:

z~o~s9 Table 1 Cl - CH - oCOR3 CH ~

E~ample R3 rield NMR ~CDCl3) ,5 = tppm) ~ o . _ _ 1~. 4~ Sq, I:H--Cl ) ~CH20cH3 4.~3 tm~ ~:H-DCO~. ) -CH 64 % ~ 3 (~, CH~-O
:~. 40 ~, OC~ ) CH3 1.3~ ~d~ Wy--CHCl ) , C~y~C~OCO~ ).

b. 4E~ (~, Cl~l-Cl ) t~, C~-OCa ~
2 ~ ~ 74 2.2-1.0 ~, Cyclot~Qxyl-H) l.a:5 tcl~ rH, -CHCl, ~asked ~ ~ ~q 1 C~
~ s. ~ eD, ) 3 _~ 1 45 96 2.~a.s ~Rt ~
l~O:S S~ a~Cl . ~asked . 45 5 4 -( O 47 96~11.81~ "I~la)~) a.~ .4 (~ e(~3)~
(cl, CHJ-eHE~ . masked C}l b. ~ , C~-Cl ~4-~ 6~ O~
6 -CH 57 2.1~ ~, e-c~t, )3 ~
~CH l.~O ~, ~J-C~Io, masked 3 1 . ~3 ~

, .

2~

Table 1 (continuation) Example R3 Yield NMR (CDCl3) ~= (ppm) No .
_ ~,. 43 ~q, I:~-Cl ) ~CH2CH3 4.7B tal, O-CH-) 7 -CH \ 60 ~ 1.3~ CHCI ma~ked ~R S~ 1 5~, CHI ) CH3 ~ .5 t2 K t~ O--CHtcH~, ) O. 9~ 1 ~ ~t t ~ CH~--CH~ ) .
_ _ _ _ ~.413 tq, CH--CI ) 401~ tt, CH~O) 9 -CH2CH2CH3 62 ~ (d, 1~ CHCl .masked ~ . ~7 Sa, ~ C~2 -CH,.
0.~7 tt, CH~ ) . _ .
. 41 ~q, Cl~
~. 3 6~, 1~ --OCH~ ) -CH2CH20CH3 7B % ~ , Co~cH~ ) ~3~ 45 t, IXH~ ) 2.1~ ~, CtCH2 ~. ~
i . 81 ~, C~ masked S.4E~ (q, CH--I:l ) 53 ~6 4. ~7 6--, CH2 ) ~ . !5 - 4.1 ~m, CH~ tlC~ ) CH2 P.~ -- 2.~ S~, CH~ Ha)~

A ~4~ Cl) l~ 4. 4 -- 4. 7 ~ , CH~O) 12~ ~ 40 ~ ~. g -- 5. ~ (~, CH) \V / ~.~ll ~d, e~J~ HC~, masked l . o - a . ~

Table 1 (continuation) Example R3 rield NMR (CDCl3) ~; = (ppm) ~.43 ~q, CH2CH3 4.70 ~, 0CH-13 -CH / 62 ~ ~ 5 - l.e ~m~ CHHCI~ mask~
CH3 (R) l.5 ~2 K e, O - CH~CH~ ) 0.~2 ~2 x t, C~_CH~).

, C~
CH2CH3 4.~E~ S~, O-C~-) H 5B ~ I . B:S ~0, CH~-CHC1, maSked 1 4-C ~ 1 . ~ , Cl~
CH~ (S) 1.:5 ~2 ~ t~ CH~CH~ !
O. ~ X ~ CWa ~~ HJ ) -, _ _ ~,4~ ~q, CH l) 4.~3 ~t, CH~
-CH2CH2CH20CH2CH2CH3 32 % S S~ ~t, COaCH~) . ~7 ~
.~1 td~- c~-r~cl,m2sked a.;7 ~t, C~) .4~ t~, C~
~ CH~ ~.0 (~, CH~) 16 -CH2-CH 52 ~ S~; e~cH~ ) , CW~-~H~l,m~sked CH3 I.O S~, C~) 8) Embodiment examples 1. Compounds of the general formula IV

Example 1 1-(1-Methoxyprop-2-yloxycarbonyloxy)ethyl 7-(2-(Z-trityl-aminothiazol-4-yl)-2-~Z)-1-methyl-1-methoxy-ethoxyimino-acetamido)-3-methoxymethyl-3-cephem-4-carboxylate Step A

4.3 9 t28.3 mmol) of sodium iodide and 4.3 9 t22 mmol) of 1-chloroethyl 1-methoxy-2-propyl carbonate ~ere added in succession to a suspension of 560 mg t41 mmol) of an-hydrous ~inc chloride in 33 ml of carbon disulfide. The reaction mixture was stirred under a nitrogen atmosphere for 2 hours and then poured into a mixture of 300 ml of 9g strength NaHC03 so!ution and 300 ml of ether and the phases ~ere separated. The organic phase was uashed ~NaHC03 solution, sodium thiosulfate solution and NaCl solution) and dr;ed (MgS04). The solvent was stripped off in vacuo at 20C to give crude 1-iodoethyl-t1-meth-oxy-2-propyl carbonate as a colorless oil, which uas fur-ther used immediately ~ithout purification (Step B).

Step B

The crude product obtained from Step A ~as taken up ;n 5 ml of dry dimethylformamide and the mixture Yas addedto a solution of 3.8 9 (5 mmol~ of potassium 7-tZ-t2-t~itylaminothia2Ol-4-yl)-2-(I)-1 methyl-1-methoxy-ethoxy-i~inoacetamido)-3-methoxymethyl-3-cephem-4-carboxylate in 15 ml of dimethylformamide, while cooling with ice.
After 10 minutes, the reaction mixture u~s stirred into a 0;xture of 200 ml of 9% strength NaHC03 solution and 100 ml of ethyl acetate. The organ;c phase was ~ashed (NaHC03 soLution and NaCl solution) and dried ~MgS04) and the solvent ~as stripped o~ in v~cuo. The resulting oil was triturated with 100 ml of ether, while cooling ~ith ice, and made to crystallize. The precipitate ~as filtered off ~ith suction and rinsed ~ith ether to give 1.5 9 of crystalline 1-(1-methoxyprop-2-yloxycarbonyloxy)-ethyl 7-(2-(2-tritylaminothiazol-4-yl)-2-(Z)-1-methyl-1-methoxy-etho%yiminoacetamido)-3-methoxymethyl-3-cephem-4-carboxylate. A further 0.34 9, making 1.84 9 t41~) to-gether, of the title compound was obtained from the fil-trate by treatment ~ith pentane.
H-NMR (d6-DMS0)~ ppm) 9 . 54 ( 2 x d, CONH, J = 8 Bz ) 8.85 (8, N~-trit~l) 7.4-7.2 (m, phenyl-~) 6.85-6.8 ~2 x q, 0-C~-0) 6.7 (2 x ~, thiazole-H) 5.75 (2 x q, J = 5 ~z, C-7-~) 5.2 (2 x d, C-6~
4.~5 (m, OC02-C~) 4.15 (~, -C~2-0) 3.55 (m, C-2~B) 3.~ (q, masked) , J = 5 ~Z, C~2~0C~3) 3,25 (~, C~2-OC~3) 3.2 ~, 3-C~2-OCH3) 3.1 (e, 0-C-OC~3) 1 5 (d, J s 6 ~z, C02-CB(CH~)-OC02) 1.4 (~, C-(C~3)2) 1.2 (3 ~ t, J ~ 7 ~Z, C~-C~-OC02).

The compounds summar;zed in Table 2 ~ere obtained as amorphous solids analogously to Example 1, steps A and - 21 - 20~3~)5~
Table 2 NCH ~; OCH3 Example R3 Y;eldNMR (d6-DMS0) ~ = ppm No .

2 x c~, CDNH, J~ H~ ) t0.~3 (1~ tr~yl ) 7.4-7.2 t~, pl~ny~
S. 0 (2 x ~, O--CH--O ) .7 ~2 x ~, thiazole ~S.7g ~2 3t ~ a~ , C-7-Ha CH20CH3 ~5 2 12 ~ , C--~--H) 41 % ~. l !S t~, 5~ 0) CH :S.S3 ~, e-2-H) 3 ~ t~, mas'~ed, ~ ~OCH;~ ) CHa~~ ~J ~
:S. 2 ~ t~ ) G-DCH~
a.s s d~ 1~, Cela--~:HlC~a~-OCO~
1.4 ~8~ c-i . 2 i3: ~ t ~ ~? ~, 1~ CH~

- 2 2 - 2~ 0~i~
~able 2 ( cont inuat ion) Example R3 Yield NMR (d6-DMSO) ~5 = ppm No .
c~ n 52 t 2 ~ ~ ~ CONH ~ ~9~C Hz ) 0~ t ~- 1 t y~ ) .4-7.2 Im, pt~Rnyl-H) . 7~ 12 st ~, O--CH--D) .7 t2 t~ thiazol~
~S. 7~ t2 K 11~ ~ ;1~. H2, 1:-7~H
5.15 ~2 x cl ~ E-b-H~
2 ~ ~ 39 ~4 ~S (m, t:lCDa-CH~
GHa -o ) 2 ~ ~a, 1:-2-H~
9, ~-C~ lrHJ ) . 1 t~, O--C--OCHJ ) ~.1!15~ ycl~hnKyl-H) a~ t~ J~ l~k, C~ CH~CH" )-OCO~, masked) 1.4 ,~CH~ )a, ~m~sked) , .~!5 52 1~ t1, CONH, 5~0 H~ ) 3 t~t r~ ~yl ) 7.4--7.2 (~, p horyl--H) .7~ t2 x cl, O~ a) 7~2 J~ ~, th;azole ~11) 7~5~2 ~ ~, a~ H~ H) ~ !S. î7~2 st ~, S~
3 -< ¦ 3~ % ~.0!!5 1~, OCO~ H~
\~J 4.~, 3-C1~6~-13) 2 ~ e-2-1 .. 2 (~ Ha--l~
S- ~ t~ll; I j~6 ~0~ 1J
~, Og ~..2~s s~ Cyc1opor~ty1--H~
S2 ~t ~:1, 3~ Ha:, CDa--eH SCHs ) -000~ ~ maskeà) 4 t0 ~ tC~ sked) 2~ S~

Table 2 (continuation) Example R3 Yield NMR (d6-DMS0) ~ = ppm No. _ -s .~ S2 ~ ONH~ ~o9 H2t ~ S~, NH~ r~tyl) 7.~-7.2 (~, p~nyl-H) ~.~2-~.77 ~2 x q, O-CH-O) 6.~q ~2 a .thiazole -H
~ ~.75 ~2 ~ q, J~ 7-~
4 ~ 0 32 ~ 2 ~ ~, C-b-H) 4.77 ~, OCOa-CH~
4.l~ ~, 5-CH~-O
.7~ t~, ~C~ O) .~3 ~2 ~ A~, C-2-H) .2 ~ -C~-OCH~) , ~C-OC~ ) a.39 (~, C~tCH~)a~
~-~ i2 ~ d, J~ Hk, C9a-CH~CH~)-~C~ ) -Example 5 1-(1-Methoxyprop-2-yloxycarbonyloxy)-ethyl 7-(2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamido)-3-meth-oxymethyl-3-cephem-4-carboxylate 1.83 9 (2 mmol) of the cephalosporin obtained according to Example 1 ~ere dissolved in 18 ml of 90g s~rength ~or-mic acid at room temperature. The soLution ~as diluted ~ith 2 ml of water and stirred at room temperature for 40 minutes and the triphenylmethanoL vhich had preçipi-tated was filtered off ~ith suction. The filtrate ~as concentrated, with the addition of tol~ene, the o;ly resi-due was taken up in acetone and the solut;on ~as clari-f;ed by addition of active charcoal. n-Pent3ne ~as ~dded to the clear filtrate, wh;le cooling ~ith ice, ~hereupon the product separated out as an o;l~ The solven~ uas decanted off and the oily residue was triturated with n-pentane~ ~hereupon the amorphous product precipitated.
Yield: 0.74 9 (64%).

1H-NMR (d6-DMSo): ~= (ppm) 2~0~5~

11.4 (s, NOH) 9.5 (d, J = 8 Hz, CONH) 7.3 (s, NH2 6.85-6.8 (2 x q, J = 6 ~z, O-CH-O) 6.7 (s~t~iazolo-H) 5.85 (2 x q, J = 5 Hz, C-7-H) 5.2 (3 x d, C-6-H) 4.85 (m, CH-OCO2) 4.15 (9~ 3-CH2-O) 3.55 (A/B, C-2-H) 3-25 (9, 3-CH2-OCH3) 3-2 ( B ~ CH2-OcH3 ) 1.5 (2 ~ d, J = 6 Hz, CO2-CH(CH3)-OCO2) 1.2 (3 x t, CH3-CH-OCO2).

The compounds listed in Table 3 ~ere obtained as amor-phous solids analogously to Example 5.

20~V59 Table 3 ~OH
N

~ CONH ~ ~
H 2N S J--Ny~ CH 21~H3 Co2cHoco2R

Example R3 Y;eld NMR (d6-DMSO) ,S ~ ppm No .
. .

11.~1 1~, NOH) 9. ~ ~, J~l~ ~2, CONH~
~3 S~, NH~ t 2 x c~ ~ 306 H~: t O-Ctl-CH OCH ~ I~, thiazole-H) 2 3 ~. ~115 ~2 ~ , Jo5 H2, E-7--H~
--CH\ 64 ~ H~
CH 4.1~5 S~, El1-GCO~ ) 3 ~ ~CHa ) .35 (A~, C_2_~
:5 . 2~ S ~ CH~--Ot:H~ t 5- X (-, C#~ -OC~
1 - 3 ~2 1 d ~ C2--I:H ~CHJ ~--~eo~
a . 2 ~ CH--OrO

td~ 0 7.1 (~ ~a) ~03 g~.ll t2 il S3, ~5 H~ ~ O--I:H--Q~
t~ th;azole-H) ~ S. D~S ~2 ~ ~ ~ ;I~S Hz 9 ~:--7--Kt 6 ~ \ ~S. 3~ ~2 ~ 6-~) ~9 ~ 4 ~ cOa 4. î~!S t~ CH2-ID) 50 ~5~S (2 ~ P~13 9 C-2-H) 3 . 2 ~ IS, :~--CH~ ~OCI~
5~ c 'tC lo~;o~yl-h) ~5 t2 S~ COa~ HJ ~-CICO~ -mflsked) - 26 ~ 5~
Tab~e 3 E x amp l e R Y i e l d NMR ( d6-DMSO ) ,~ = ppm .
t~, NOH~
~,4~ ~, a~ Hs, COP~H) 70 I~S t-, NH~ ) .7~ ~2 x ~, J--~ Hz ~ O--CH-O
.bg t~- t!~iazole-H) ~ ~5.1i~3 ~2 ~ J~ Hs, C-~-H) 7 ~ ¦ 58 ~ 5. 2 ~ K d, C-b-H
\J ~. 05 t~, CH--DCO3 ) . lS tm, 3-CH~-O) . ~5g (X ~ A~ 2-H) . 2 ~ Ha -DrHJ ) . !!; tm, c yc S opl-nt yS -H) . !5 t 2 ~ ~ ~ J~ , Ce~ ~ CH ( CHJ ) ~OCO~ .
masked' NOH ) d , ~ H2, I~
7. ~2 ~ 2 ~
. 7~ t 2 ~ q ~ J~6 Hs ~ O--CH--O ) 6.~g ~, thiaZole-H) 2 ~ g H~, C-~--H ) 3 ~ t2 K 1~ H) B -~ , 4.~ -O~O~ ) \-- 4. a~ 3-CH~-O) 5. 7E~ t~ ~CHa ) 5 ~
K ~, e-2-H) 3 0 2 ( O ~ 5-CH~--OCHJ ) a.~ ~1 C~ a . !5 t2 ~ d, ~ H2, CD~ -CH ~CH~ t -DCD~, r~sk~d`

os~

E~ample 9 1-(Isopropoxycarbonyloxy)-ethyl 7-2-(2-aminothiazol-4-yl)-2-(~)-methoxyiminoacetamido-3-methyl-3-cephem-4-carbo%y-late Step A

1.5 9 (10 mmol) of sodium iodide and 1.2 9 (7.5 mmoL) of 1-chloroethylisopropyl carbonate were added in succession to a suspension of 200 mg (1.5 mmol) of anhydrous zinc chloride in 10 ml of carbon disuLfide. The reaction mi~-ture was stirred under a nitrogen atmosphere for 2 hours and poured into a mixture of 9% strength NaHC03 solution and ether and the phases ~ere separated. The organic phase was washed (NaHC03 solution, sodiuT thiosulfate solution and NaCl solution) and dried ~MgS04). The solvent was distilled off in vacuo at 2QC to give crude 1-iodo-ethyl isopropyl carbonate as a colorless oil which ~as further used immediately ~ithout purificat;on (Step 9).

Step B

The crude product obtained from Step A ~as taken up in 18 ml of dry dimethylformamide and the ~ixture ~as added to a solut;on of 1.3 9 (3 mmol) of potass;um cefetamet in 10 ml of dry dimethylformamide, ~hile cooling ~ith ice.
After 75 ~inutes~ the reaction mixture was stirred into a mixture of 9X strength NaHC03 solution and ethyl acetate.
The organic phase was ~ashed (NaHC03 solution and NaCl solut;on) and dried (MgS04) and the solvent ~as stripped off in vacuo. The crude product ~as chromatographed on 100 9 of silica gel using ethyl acetate. 300 ~9 of the title compound uere obtained.

H-NMR (d6-DMSO): ~ = ppm 9.6 ~2 x d~ CONH, J = ~Hz) 7.23 (br, ~, NH2) 6.78 and 6.83 (2 x q, O-C~-O) 6.7~ (2 x 3, thiazole~H) 5.77 (2 x q, J = 5 ~z, C-7-~) 5.13 (2 x d, C-6-H) .85 (8, OCH3) 304-3.6B (m, C-2-~) 2.03 (8, C~3) 1.5 (d, J = 6 Hz, Co2-CH(CH~)-OC02) 1~25 (a, (c~,)2-c~).
The compounds listed in Table 4 ~ere obtained 3s amor-phous solids analogously to Exanple 9.

Table 4 ~OCH3 ~ CONH ~ S~
H2N S O ~ CH3 3 CH3~

Ex~mple R3 Yield NMR ~d6-DMSO) ~ = ppm No.
~ 7 C~W~ J-~ ~s~
7.2~ ~r ~ a3 and ~-~5 i2 ~ ~, O-~H-D~
~ C~3 ~.75 ~2 ~ ~, thiazol~1 9 -~H 47 ~ S.77 ~2 K ~, J~S ~a, E-7-H) CH ~ 2 ~ d, C~
8~, DC~3~
t~ 2-W) 2.0~ ~, CH~
. a . ~ o~ P~3 ~b-CH~H~

2~

-- _ z9 _ TabLe 4 (continuation) Example R3 Yield NMR (d6-DMS0) ~ = (ppm) llo .

. b t2 K el ~ CONIAI, J~EI H:
7.2'~ Sbr ~, NH~ ) 0 cand ~,.E35 l2 s~ cl, 0-CH-D
~-7:5 t2 1~ s, thiazole -~ ~. 77 ~2 It q, J~S h~, C-7-H~
1 0 ~ ~ 5 l 2 ~ ~, C--~--H
42 ~ 4.~S3 and ~ n, IH, 0-I:H~
.B5 (3, DC~J ~
:5. 5El -- 3. ~l3 S ~ 2--H) 2.0~ J ~
. ~ td, ~o~ Hz, 1~ EH ~CH~ )--OC0~ ) .0~ -- 1.9 1~, IOH9 Cyclo~--xyl--H).

.g7 ~2 It ~ GON~t~ JD8 HZ) 7. 20 (2~r ~ a ) b.7B and b.~:S l2 ~ Q, 0-CH-0) ~H ~.7~ (2 x ~, thiazoLe -H) 3 ~S.7~ l2 1~ q, J~S H~ --7--H) 1 1 -CH~ 46 ~ !g. 13, lZ ~ ~, C--~H) CH CH 4. ~2 ~, lH, O-CH~
2 3 ~.~2 ~ OCHJ~
.511 - 3.~ m, C-2-H) :2. 0:5 ~, CH~ ) . ~S te~, 9~ Hs ~CH lCH~ OC0~ ) I . S13, 1 . 2 9 0 . ~S 6 ~ ~ IIH, ~CI~l ~ - and -CHJ ) Z~ Q~

Table 4 (continuation) Example R3 Yield NMR (d6-DMSO) ~ = (ppm) No .
_ Y. ~ t2 K 1~, CONH~ 3-~8 H2 ) 7. 2~ tbr 61~, NH~ ) 7a and ~ t2 K q ~ O-CH-O) ~.7~ 12 X ~, th;aZOle -~) S . 77 t 2 X q, J~5 H~, C-7-H ) ( 2 ~S d, C--~--H ) 43 ~ 4.e2 ~m, ~H, 0~ CH) -CHCH20CH3 3. 0~S t~, N-OCH~ ) CH ~ B (m, e-2~-3 3.~ ~d, Cll~) S. 2!5 ~CHJ ) E, ~ 12, f~ H tGH~ ) -OCO~ ) a . 2 ~ CH

7.2_. t~r ~, ~H~) .78 and ~ t2 K tl~ O-C~ O) ~S.75 ~2 K ~ thiazoLe-H) ~i. 7 -- ~. G (2 K 1~ ~ J~S H~, C-7-H~
g. ~ t2 x d, 1: ~-H) 1~ -CH2CH2CH3 47 ~ ~. 0~ ~2 K t, 2H, O-OH2 ) OCI'13 ~ .
:~ . SEI 3 . ~8 t ~, 1::--2--H ) 2. 0~ HJ ) . ~2 ~al, 2H, --CH~
~ . ~ t~, ~S ~, ~ H ~C~J ) ~ 2 ) 0. ~9 ~e ~ J ) .

2 9~ o3 ~4Z) 7.25 ~l~r ~. ~23 . 7a and ~ , O-CH-O
~.7:5 ~2 s~ ~, thiazole-H) S. ~7 (2 ~ 7-H) 14 -CH2cH20cH3 39 % ~. a5 ~2 ~ d, E-~-H) 4. 25 ~, 9 3~ æ~
. 4 ~ W ) t~, 2H, O~:H~ 3 3H~ H~ ) 2. 03 J~ ~læ 9 CO7~--C~ H~ DC0~ ) - 31 - X0(~05~3 Table 4 (continuation) " .
Example R3 Yield IIMR (d6-DMSO) ,5 = (ppm) No .

~.b ~2 K cl~ eoNH, JoO Hz) 7. 2~ tbr . 7d and b . l~ 2 K q, O-CH-O
42 ~ ~2 K ~ thiazoLe-H) -~ !5~77t:~ x t~ J~5 H:, C-7--H) ~5. 13I~ C-~--H) ~ . Ila5 l 1~, OCHJ ) 3.4 ~m, C-2-H) 2.03(~, C~
l,~S td, a~b H~, IZ:02--Ctl~CH~ )--OC0 9.~ ~2 ~ d~ CONW~ J~0 1 7. 2S S~r ~
~ k. 79 and ~ S (2 ~ t~, 0-CH-0) r 1 ~. 7~ t2 ~ thiazole-H~
J ~- 77 ~2 ~ , a-~ H- ~ C--7--H) 16 ~ ~0~ 31 ~ 5. ~5 (2 ~ C ~ H) CH2 ~O.OV (x, :5H~ 0-CH~ and 2'-H) 3. 131~ ClCI l~ ) S . ~ -2--H ) 2. 0 Z ~ ONH, ~3 H;c ) A 7.~2 (br 51~ ~a ~
7~ and ~ 2 ~ D -C~l-0) ~1 38 P6 ~- ~3 (2 K gl, thiazoLe -~) 7 ~l ~ ~S. 75 ~2 ~ lz ~ C-7 3(2 K t9~ H) ~/ 4.~S~, aH, 2' H) 5~ H~ 3 3.~ - 3.
2. 0~ , I.g (~ .a~ ~, ~lt~HJ ) ~t~C~

. . _ .

~O~V~.3 Table 4 (continuation) Example R Y;eld NMR (d6-DMSO) ,5 = (ppm) No .
. .
9. ~, ~2 x ~, CONH, 3--E!I H:
7.21 ~br ~s, NH~ ) ~, . 7q and ~ 2 x q, O-cH-O ) ~,~ 7~ , thiazole -H) S. 7~ ~2 K q ~ J~S ~lz, C-~-H) 1 8 ~ ~0 35 4 ~ t2 ~ 61, C-~-H) 4 . 0 ~ 0, 4 ' -~ ) S ~, OCIl~ ) 8 ~m, C-:~-H) 2 . 0~ ( ~, CH~ ) .~ t~, a--~ ~3, CO~--CH~CHJ?--~l:O,) !5 t2 ~ d, EO~H, J~a H2 ) 7. 20 ll~r ~ ~Ha ) 6. 7~ and ~ 2 ~ CH-~ ) ~- 73 ~2 ~ ~, thiazole _~) 19 -CH-CH2CH 45 ~ ~5.7~1 ~2 x ~, J~S W:, C-7-H) 3 ~. lS ~ K ~J~ rO~
CH3 (R ~ , 2H, CH~ H~ ) 3 ~ B~i ~ 3, OCHJ ~
4 ~ a ~ m, C--2--t l ) 2,. 0-~ (~
.51 S~ H2, C0~--I H~CI/y ~~OC0~ ) 133 I t ~ ~ 3~H O--CH ~ g:HJ ~ 2 -. !5S ~ t el ~ , Jol3 H~
7020 tbr ~a, IY~13 ) and ~. ~13 t2 3t ~, 0--I:H~
~.7;S t2 ~ ~, thiazo~-H3 95.7~ ~2 ~ 5 H:~ $ C 7-11) 20 -CH2CH2CH3 45 ~g- ~3 ~2 s~
CH3 (S) ~~H2~ e~
~- 4 ~ 3. ~0 ~Sl ( 3a~ gH~C1~ C0 2 ~ CH~
0.~5 i2 - Z~ i9 Table 4 (continuation) Example R3 Yield NMR (d6-DMSO) ~; = tppm) No .
_ _ _ _ _ _ 9.57 (2xd, CONH, J ~ 8 ~z) 7 20 ~br i~
~d. 70 and ~ 2 ~t ~1 O-CH-O ) ~ 73 ~2 ~s 1~, thiazo~e -H) 21 -CH2CH2CH20CH2CH3 38 ~ 2 ~ q, J ~ Hz; C-7-H) .19 ~m, ~H, CC~CH~) .85 aO, OCH~) - 5.~ ~, C-2-H) ~ 4 t~, 2H, O-CH2CH~1 2.0~ ~-, CH~) 0~ (m, 2H, CH~CH~EPb) a ~ a, CO~ ~:H ( CH~ ) -OC
1.1 ~e, ~H, eH~) _ . .

. ~57 12 x d, CO~, J~B H: ) 7.21 tbr ~, NH~ ) . 78 and ~5 . 61:5 t 2 ~ ~ O-CI 1-0 ) . 7 t2 ~ , thiazo~e _H) ~1.74 t2 ~ q, J~ H~, C-7-H) ~ CH3 ~ S2 x d, C-~-H) 22 --CH2CH 4n ~ 2 ~2 ~ d, 2H, OCH~CH) 3.131~ t~, OCH~ ) CH3 3.~ t~, C-2 - H) 2.0~ (~, CHJ) ..
.~ a~ CHa )~ ' EOa -t:H ~I:H~ )--OrO3 .
0.11~ t;2 ~ tl, C~

Claims (6)

1. A cephemcarboxylic acid ester of the general formula in which R1 denotes hydrogen or methyl, and R2 denotes hydrogen or methoxy, one of the two substi-tuents R1 or R2 always representing hydrogen;
R3 denotes-straight-chain or branched C1-C5-alkyl, which can be substituted by C1-C3-alkoxy, C3-C8-cycloalkyl or C2-C7-cycloalkoxy;
C3-C8-cycloalkyl or C2-C7-cycloalkoxy, in which, in the case where R1 is hydrogen and R2 is meth-oxy, R3 cannot be C1-C4-alkyl, and in which the group OR1 is in the syn-position, and physiologically toler-ated acid addition salts thereof.

2. A process for the preparation of a cephemcarboxylic acid ester of the general formula I

(1) in which R1 denotes hydrogen or methyl and R2 denotes hydrogen or methoxy, one of the two substituents R1 or R2 always representing hydrogen, R3 represents straight-chain or branched C1-C5-alkyl, which can be substituted by C1-C3-alkoxy, C3-C8-cycloalkyl or C2-C7-cycloalkoxy, or represents C3-C8-cycloalkyl, or represents C2-C7-cycloalkoxy, in which, in the case where R1 is hudrogen R2 is methoxy, R3 cannot be C1-C4-alkyl, and in which the group -OR1 is in the syn-position, and of physiologically tolerated acid addition salts thereof, which comprises a) reacting a compound of the formula II

(II) in which R2 represents hydrogen or methoxy, R4 repre-sents hydrogen or an amino-protective group, R5 repre-sents methyl or a group which can easily be split off and A represents a cation, in which R4 can only represent hyd-rogen if R5 is methyl, with a compound of the general formula III

(III) in which R3 has the above meaning and X represents a leav-ing group, to give the ester of the general formula IV

(IV) and removing the groups R4 and R5, in the meaning of a protective group or a group which can easily be split off, in a manner which is known per se, or b) reacting a compound of the general formula V

( V ) in which R4 and R5 have the above meaning and Y repre-sents an activating group, with a compound of the general formula VI

(VI) in which R2 and R3 have the above meaning, or with a salt of this compound, to give a compound of the general formula IV, and splitting off the groups R4 and R5, in the meaning of a protective group or a group which can easily be split off, in a manner which is known per se, or c) reacting a compound of the general formula VII

(VII) in which Z represents halogen and R1, R2 and R3 have the above meaning, with thiourea to give compounds of the general formula I and - if desired - converting the com-pounds obtained into a physiologically tolerated acid addition salt.

3. A pharmaceutical formulation which is active against bacterial infections, which contains a cephemcarboxylic acid ester of the formula I.

4. A process for the preparation of a pharmaceutical form-ulation which is active against bacterial infections, which comprises bringing a cephemcarboxylic acid ester of the formula I into a pharmaceutically suitable admini-stration form with pharmaceutically customary excipients or diluenes.

5. The use of a cephemcarboxylic acid ester of the formula I
for combating bacterial infections.

6. The cephemcarboxylic acid ester as claimed in claim 1, and substantially as described herein,