NZ232135A - Cephemcarboxylic acid ester derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £32135 232 135 WO DRAWINGS Priority Date(s): Complete Specification Filed: ..

Class: Publication Date: ... mlll P.O. Journal, No: ... I N.Z.

NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION CEPHALOSPORIN DERIVATIVES AND PROCESSES FOR THEIR PREPARATION We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) 232 135 * HOECHST AKTIENGESELLSCHAFT HOE 89/F 016 Dr. KA/rh Description 1A Cephalosporin derivatives and processes for their 5 preparation The invention relates to novel cephalosporin derivatives which are particularly suitable for oral administrate on, a process for their preparation and pharmaceutical form-10 ulations containing such compounds.

Although many clinically relevant cephalosporins with a broad antibacterial spectrum have been developed, most of them are suitable only for parenteral administration, 15 since they are absorbed only very inadequately, if at all, following oral admin i strati on. In many cases, however, it is desirable to give the patient highly active antibiotics in oral form.

The cephalosporin antibiotics known to date do not meet all the requirements which have to be imposed on such a medicament, that is to say a high antibacterial activity against Gram-positive (specifically Staphylococci) and Gram-negative pathogens and at the same time a good absorp-25 tion in the gastrointestinal tract.

In some cases, it has been possible to increase the absorption of a cephalosporin in the gastrointestinal tract by esterif icat ion of the 4-carboxyl group. Since the cephal- osporin esters as a rule have no antibiotic activity in themselves, the ester component must be chosen so that after absorption, the ester is split back again into the cephalosporin with a free carboxyl group rapidly and completely by endogenous enzymes, such as esterases.

The degree of enteral absorption of cephalosporins depends decisively on the chemical structure of the cephalosporin \ and the particular ester component. Even small structural 232135 r - 2 - variations on the cephalosporin basic skeleton or in the ester component can influence the absorption. The discovery of suitable components is purely empirical. Thus, for example, the introduction of an acid substituent into 5 the 7 B-side chain of aminothiazolyl-cephalosporins, such as, for example, in cefixime, leads to a compound which can be absorbed enterally, whereas compounds with neutral side chains, such as, for example, in cefuroxime, are absorbed enterally only in the form of prodrug esters. The 10 dose/effect relationship is thereby often non-linear and ,. the therapeutic serum levels achieved are not satisfactory.

Carbonate esters from the aminothiazolyl-cephalosporin series are mentioned, for example, in European Patent 134,420.

By in vivo studies carried out systematically on various animal species, we have now found a narrow group of ceph-3-em-4-carboxyIic acid esters which can be administered orally, have a sufficient chemical stability and due to 20 a balanced lipid- and water-solubility are absorbed rapidly and in a therapeutically substantial degree in the gastrointestinal tract.

The invention accordingly relates to cephemcarboxylic acid esters of the general formula I (I) COOCH-OC-OF3 30 CH3 O in which denotes hydrogen or methyl and R^ denotes hydrogen or methoxy, one of the two sub-stituents or always representing hydrogen; 35 R^ denotes straight-chain or branched C^-05-*IkyI, which can be substituted by C-j-Cj-alkoxy, Cj-Cg-cyclolakyl or C2~C7-cycloalkoxy; C3-C8-cycloalkyl or Cg-Cy-cycloalkoxy, 232 135 in which, in the case where R ^ is hydrogen and R^ is me t h-oxy, R^ cannot be C-|-C4-alkyl, and in which the group OR1 is in the syn-position, and physiologically tolerated acid addition salts thereof.

R^ can thus represent Ci~C5-alkyl, which 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, 2-10 pentyl, 2-methyIbutyI, 3-methyIbutyI, 1,1-dimethyIpropyI, O 1,2-dimethylpropyl or 2,2-dimethylpropyl, and preferably represents Ci-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 15 those alkyl radicals which are substituted in the 1-position by methyl are also preferred, and wherein the alkyl radicals can also additionally be substituted by Ci-Cj-alkoxy, such as, for example, methoxy, ethoxy or propoxy, by Cj-Cg-cycloalkyl, such as, for example, 20 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl or cyclooctyl, preferably by C5"C7~cycIoaIky I , such as, for example, cyclopentyl, cyclohexyl or nor-bornyl, preferably cyclopentyl or cyclohexyl, in particular cyclohexyl, or by C2-C7-cycloalkoxy, preferably 25 C4-C5~cycloalkoxy, such as, for example, tetrahydro- furanyl or tetrahydropyranyl, in particular tetrahydro-pyranyl; or represent C3-C8~cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,. cycloid 30 heptyl or cyclooctyl, preferably C5-C7~cycloalkyl, such as, for example, cyclopentyl, cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, in particular cyclohexyl; or represents C2-C7-cycloalkoxy, preferably C4-C5~cyclo- alkoxy, such as, for example, tetrahydrofuranyI or tetra-hydropyranyI, in particular tetrahydropyranyI.

Preferred compounds of the general formula I are those in 232 135 1 2 which R represents methyl and R represents hydrogen and has the following meanings: C-j-Cs-alkyl, preferably C3-C4~alkyl, which can also 5 additionally be substituted by C-j-Cj-alkoxy or by C5-C7-cycloalkyl or by C4-C5-cycIoaIkoxy ; C5-C8-cycloalkyl, preferably C5~C7-cycloalkyl, or C4-C5~cycloalkoxy, in which these definitions mentioned for R^ have the mean-/"""S ings given above in the discussion of the substituents of the general formula I.

Amongst the compounds where = methyl and = hydrogen, 15 those in which R^ represents i-propyl, 2-butyl, 2-methyl-propyl, 1-nethoxy-2-propyI, cyclopentyl or cyclohexyl, are of particular interest.

Compounds of the general formula I in which R repre- 2 3 sents hydrogen, R represents methoxy and R represents the group B (B) O 25 where i n n = 0 or 1 ■ = 0 or 1 and R = straight-chain or branched C1-C3-alkyl, which is substituted by Ci-C3~alkoxy, C3-Cg-cyclo-alkyl or C2-C7-cycloalkoxy; C3-C8-cycloalkyl or 35 C2-C7-cycloalkoxy, are furthermore preferred.

In the case where n is 0, the following meanings are possible for R^: 232135 C3~Cg-cycloalkyl, preferably C5-C7-CycIoaIkyI, such as, for example, cyclopentyl, cyclohexyl or norbornyl, preferably cyclopentyl or cyclohexyl, in particular cyclohexyl; C2-C7~cycloalkoxy, preferably C4~C5-cycIoaIkoxy, such as, for example, tetrahydrofuranyI or tetrahydro-pyranyl, in particular tetrahydropyranyl.

If n = 0, those compounds in which R^ in the group (B) represents cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl, preferably cyclohexyl or tetrahydropyranyl, are of particular interest.

If n = 0, can also represent straight-chain or branched Ci-C3~alkyl, which is substituted by C-j-C3-alkoxy, C3~Cg-cycloalky I or C2~C7-cycloaIkoxy, the alkoxy, cycloalkyl and cycloalkoxy groups, including their preferred ranges which are also suitable here, being as de-20 fined above for in the general formula I.

If n = 0, the following substituted alkyl groups are of particular interest for : 2-methoxyethyl, eyelopentyImethyI, cyclohexylmethyl and 25 tetrahydropyranylmethyl.

If n in the group (B) = 1, suitable meanings for are the same as for when n = 0. Only in the case of the substituted C<j-C3~alkyl group is a substituted C1-C2-30 alkyl group preferred when n = 1.

Examples which may be mentioned of R^ in the meaning of a C-j-Cj-alkyl group substituted as described above, especially if n = 1 and m = 0, are: ■ethoxy-methyl 2-«ethoxy-ethyl 3-»ethoxy-propyI 2-methoxy-(2-methyI)-ethyl ~*§$-'~' "';"• ' 232 135 r 2-»et hoxy-(1-methyl)-ethyl 1-«ethoxy-(1,1-dimethyl)-methyl ethox y-met hyI 5 2-ethoxy-ethy I 3-ethoxy-propyl 2-ethoxy-(2-methyl)-ethyl 2-ethoxy-(1-methyl)-ethyl 1-ethoxy-(1,1-dimethyl)-methyl (l-propyloxy)-methyl 2-(1-propyloxy)-ethyl 3-(1-propyloxy)-propyl 2-(1-propyloxy)-(2-methyl)-ethyl 2-(1-propyloxy)-(1-methyl)-ethyl 1-(1-propyloxy)-(1,1-dimethyl)-methyI 2-(propyloxy)-met hyI 2-(2-propyloxy)-ethyl 3-(2-propyloxy)-propyl 2-C2-propyloxy)-(2-methyl)-ethyl 2-(2-propyloxy)-(1-methyl)-ethyl 1-(2-propyloxy)-(1,1-dimethyl)-methyl (cyclopentyl)-methyl CT) 25 2-(cyclopentyl)-ethyl 3-(cyclopentyl)-propyl 2-(eyelopentyI)-(2-methyI)-ethyl 2-(cyelopentyl)-(1-methyl)-ethyl 1-(cycIopentyl)-(1,1-dimethyl)-methyl 30 (cyclohexyl )-methyI 2-(cyclohexyl)-ethyl 3-(cyclohexyl)-propyl 2-(cyclohexyl)-(2-methyl)-ethyl 2-(cyclohexyl)-(1-methyl)-ethyl 1-(cyclohexyl)-(1,1-dimethyl)-methy I (4-tetrahydropyranyI)-methyl 2-(4-tetrahydropyranyI)-ethyI 3-(4-tetrahydropyranyI)-propyl 232135 * sj 25 O 30 2-(4-tetrahydropyranyl)-(2-methyl)-ethyl 2-(4-tetrahydropyranyl)-(1-methyl)-ethyl 1-(4-tetrahydropyranyl)-(1,1-dimethyl)-methyl preferably methoxymethyI, 2-methoxyethyI, ethoxymethyI, 2-ethoxyethyI, cycI opentyI methyI, eyelohexyImethyI and tetrahydropyrany Imethy I , methoxymethy I , cy c I open ty line t hy I , eyelohexyI methyI or tetrahydropyrany1 methyI being particularly preferred.

If R ^ in the general formula I represents hydrogen and R^ represents methoxy, especially preferred meanings of R^ are accordingly Cs-Cy-cycloalkyl, in particular cyclopentyl and cyclohexyl, C4~C5-cycloaIkoxy, in particular tetrahydropyranyl, and C-j-Cj-alkyl which is substituted by Ci-C3~alkoxy, such as, for example, 2-meth-oxy-(1-methyl)-ethyl.

Possible physiologically tolerated acid addition salts are the salts known for cephalosporin antibiotics, such as, for example, the hydrochloride, sulfate, maleate, citrate, acetate or formate. They are prepared in a manner which is known per se by bringing the corresponding acid together with I in an aqueous or organic solvent or a suitable solvent nixture.

The invention furthermore relates to a process for the preparation of cephemcarboxylic acid esters of the general formula I COOCH-OC-OR (I) • m cb3 O wherein R^ denotes hydrogen or nethyl and R^ denotes hydrogen or methoxy, one of the two substituents R1 ? 3 or R always representing hydrogen, R represents 232135 straight-chain or branched C-|-C5-alkyl, which can be substituted by Ci-C3~aIkoxy, Cj-Cg-cycloalkyl or C2~ C7~cycloalkoxy, or represents C3-Cg-cycIoaIkyI, or represents C2-C7-cycloalkoxy, in which, in the case 1 2 3 where R is hydrogen and R is methoxy, R cannot be C-]-C4-alkyl, and in which the group -OR^ is in the syn-position, and of physiologically tolerated acid addition salts thereof, which comprises a) reacting a compound of the formula II N C — CONH —: 'xS > .2 " .1 v_wi*n 1 „N—!i N-OR5 J ' i- • 4 s 0 ' CH2R (II) ~ COOA 2 4 in which R represents hydrogen or methoxy, R represents hydrogen or an amino-protective group, R^ represents methyl or a group which can easily be split off and 4 A represents a cation, in which R can only represent hydrogen if R^ is methyl, with a compound of the general formula III >3 X - CH - OCO, - R- £h3 2 <»" in which R^ has the above meaning and X represents a leaving group, to give the ester of the general formula IV ? (IV) CO,- CH-O-C-OR3 *■ % - CH3 O 4 5 and removing the groups R and R , 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 * 23 2' N 7T— c co-y (v) Hr '■ :;-°s5 N 1— C - -< 14 R A 5 in which R and R have the above meaning and Y represents an activating group, with a compound of the general formula VI H2N -n ] CH,R2 (VI) 0 I 3 CO.-CH-OC-OR ^ • « CH3 0 in which R^ and R^ have the above meaning, or with a salt of this compound, to give a compound of the general / 5 formula IV, and splitting off the groups R and R , in the meaning of a protective group or a group which can 20 easily be split off, in a manner which is known per se, or c) reacting a compound of the general formula VII Z-CBJ-C-C-CCNH " —j— ON-OR1 j (VII) CO--CHOCOR3 * I M O^O in which Z represents halogen and R^, R^ and R^ have the above aeaning, with thiourea to give compounds of the general formula I and - if desired - converting the resulting compounds into a physiologically tolerated acid addition salt.

/ In the general formulae II, IV and V, R stands for an amino-protective group which is known from peptide and cephalosporin chemistry, preferably formyl, chloro-acetyI, bromoacetyI, trichloroacetyl, trifluoroacetyl 232 135 benzyloxycarbonyl, tert.-butoxycarbonyl or trityl, and 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-methyIethyI. Trityl and chloroacetyl are par- ,5 L ticularly preferred for R , and trityl and 1-methoxy-1- methyl-ethyl are particularly preferred for R" In formula III, X denotes a leaving group which is gen-10 erally known for esterificat ion reactions, such as, for example, chlorine, bromine, iodine, phenylsulfonyloxy, p-toluene-sulfonyIoxy or methyIsuIfonyIoxy, preferably chlorine, bromine or iodine, in particular iodine.

Examples which may be mentioned of bases on which the cation A in the general formula II is based are sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and optionally substituted, alkylated amine bases, such as, for example, trimethylamine, tri-20 ethylamine, diisopropyI amine, ethyldiisopropylamine, N,N-dimethylaniIine, N,N-dimethyIbenzylamine, 1,5-diazabicy-cloC4,3,0Dnon-5-ene (DBN), 1,8-diazabicycIoE5,4,0Dundee-7-ene (DBU), pyridine, picoline or 2,6-dimethylpyridine. Preferred bases are sodium bicarbonate or potassium bicar-25 bonate, sodium carbonate or potassium carbonate, triethyl-amine, N,N-dimethylaniline, DBN or DBU.

Reaction of the free carboxylic acids with these bases gives the salts of the general formula II in which A stands 30 for a cation, such as, for example, sodium or potassium, but also Magnesium or calcium or an optionally substituted alkylated ammonium ion, such as, for example, ammoniurn, tr imethy I amnion ium, t r ie thy I ammon ium, tet rabuty I ammon ium, diisopropylammoniurn, ethyldiisopropylammonium, diazabi-35 cycloC0,3,43nonenium or diazabieyeloC0,4,51undecenium. Preferred meanings of A are sodium, potassium, triethyl-ammonium, N,N-dimethylaniIinium and the DBN and DBU ion.

In compounds of the formula VII, Z stands for a halogen 232 1 3 atom, preferably chlorine or bromine, The reaction of the compounds of the formula II with the compounds of the formula III can be carried out in an 5 organic solvent at about -20 to about +50°C, preferably at about 0°C to room temperature. Examples of solvents which can be used are ketones, such as, for example, acetone or methylethyl ketone, N,N-dimethyIformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone or di-10 wethyIsuIfoxide (DMSO). DMF, DMA, N-methyIpyrrolidone and DMSO are preferred. DMF is particularly preferred.

The groups and are split off from the resulting compounds of the formula IV in a manner which is known per se 15 by methods known from peptide and cephalosporin chemistry, for example with trifluoroacetic acid, dilute hydrochloric acid or preferably with formic acid, with the addition of a little water.

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 25 group, for example with 1-hydroxybenzotriazole, or a mixed anhydride, for example with benzenesulfonic acid or tol-uenesulfonic acid. The activation of the carboxyl group is also possible in a manner which is known from the literature via the addition of a condensing agent, such as, 30 for example, a carbodiimide.

The compound of the general formula VI can be used as such or in the form of a salt, for example the tosylate, hydrochloride or hydriodide, and the use of crystalline 35 salts may be advantageous in respect of the purity of the products.

The reaction of compounds of the formula V with those of the formula VI can be carried out in an organic solvent. 232135 such as, for example, methylene chloride, chloroform, acetone, methylethyl ketone, dimethylformamide, dimethylacet-amide or water, or in mixtures of these solvents.

The acylation reaction can advantageously be carried out at temperatures from about -50°C to about +50°C, preferably -40°C to +30°C, 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 10 liberated during the condensation.

The cyclization of compounds of the general formula VII with thiourea can be carried out by processes which are known per se, such as are described, for example, in 15 European patent 134,420. For example, it is achieved smoothly at temperatures of about 0 to 30°C, preferably about 5°C, 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 which is known per se, for example by reacting 1-chloroethylchlorofornate CI - CH - 0C0 - CI i CH3 with alcohols of the general formula VIII R3 - OH (VIII) in which R3 has the abovenentioned neaning.

The reaction is advantageously carried out in an organic solvent, such as a halogenated hydrocarbon, for example 35 nethylene chloride or chloroform, if appropriate in the presence of a base, for example, pyridine or triethyl-anine, at a temperature of -20°C to +30°C.

Conpounds of the formula III can also be prepared by 23 ii 1 5 b halogen replacement. For example, a compound III in which X represents bromine or iodine can be prepared by reacting the corresponding compound III in which X represents chlorine with an iodide or bromide salt, such as, for example, sodium iodide or sodium bromide, if appropriate in the presence of a catalyst, for example zinc 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 which is known from the literature, and the esterification to give the compounds of the formula VI is carried out in 15 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 20 (compare European patent 134,420), diketene can be reacted with bromine and the resulting intermediate can then be reacted with a compound of the general formula VI, a preliminary product of the formula Br-CH,C-CH,-CONH AM • in which R^ denotes hydrogen or nethoxy being obtained and subsequently being converted by nitrosation (compare also European Patent 134,420) into a compound of the general fornula VII.

The ceph-3-em-4-carboxy I ic acid esters of the general formula I have a number of physicochemical and biological properties which nake them useful cephalosporin antibiotics for oral administration. They are stable, colorless 232135 u compounds which are readily soluble in the customary organic solvents, are absorbed in the intestine, are rapidly split in the serum to give antibiotic cephalosporin derivatives of the formula therefore outstandingly suitable for the treatment of bacterial infection diseases, such as, for example, infection of the respiratory tract or of the 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 suspensions. The dose depends on the age, symptoms and body weight of the patient and on the duration of treatment. 20 However, it is as a rule between about 0.2 g and about g per day, preferably between about 0.5 g and about 3 g per day. The compounds a re preferably admin istered in divided doses, for example 2 to 4 times daily, and the individual dose can contain, for example, between 50 and 25 500 ng of active compound.

The oral formulations can contain the customary excipients and/or diluents. Thus, for example, binders, such as, for example, gelatin, sorbitol, polyvinylpyrrolidone or cai— 30 boxymethyl cellulose, diluents, such as, for example, lactose, sugar, starch, calcium phosphates or polyethylene glycol, and lubricants, such as, for example, talc or nagnesium stearate are possible for capsules or tablets, and aqueous or oily suspensions, syrups or similar known 35 fomutation forms, for example, are suitable for liquid fornulat ions.

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

CCLH 12 in which R and R are as defined in formula I, and are jc ■. 232 135 A. Preparation of starting substances Preparation example 1 1-ChIoroethyI 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 dissolved in 40 ml of dry methylene chloride and the solution was cooled to 10 0°C. A mixture of 5.8 ml (72 mmol) of pyridine and 20 ml of dry methylene chloride was then added dropwise at 0 -5°C, the mixture was stirred for a further 2 hours, while cooling with ice, and the pyridinium hydrochloride formed was filtered off with suction. The filtrate was 15 washed twice (H£0) and distilled under a water pump vacuum. 8.8 g (64%) of the title compound were obtained (boiling pointjg = 100 - 105°C). 1H-NMR (COCI3): 6 = (ppm) 6.46 (q, CH-Cl) 4-93 (a, CH-C>C02) 3-63 (d, CH2-0) 3.40 (s, OCHj) 1.83 (d, CHj-CHCl) 1.46 (d, CH3-CH0C02).

The compounds summarized in the Table 1 were prepared analogously to Preparation Example 1: Table 1 232 135 CI - CH - OCOR^ » CHj Example R" No.

Yield NMR C CD C 13) 6 = (ppm) -CH ^CHgOCHj \ 64 % CH, 4.46 4.93 3.63 3.40 1.83 1.46 (n, <«a, <»» <d, <d.

CH-C1) CH-OCO; ) CH,-0) OCHj) CH,-CHCl) CH,-CH0C02) o 6.4B (q, CH—CI) 7A < 4,7 tm• CH-OCO,) 2.2—1.0 (a, Cyclohexyl—H) 1.B3 (d, CH,—CHCl, masked A.®3 (q, CH-C2) S.16 (a, CH-OCO 2.0-1.S <a, CH,) 1.B3 (0, CH,-CHCl f masked 0._ S. 16 (a, CH-OCO,) 45 * 2.0-1.S <a, CH,) o *.43 Cq, CH—CI) S.OB-4.6 (a, CH-OCO-) 47 % 4.16-3.3 (a, <CH,),0) 2.16-1.4 (a, C(CH,),) l.»3 <d, CH,—CHCl t oasked .CH, *-49 (q, CH-Cl) , P c7 < S.OB-4.6 (a, CH-OCO,) 6 -CH 57 % 2.16-1.4 <a( C(CH,),) CH, *••<> . Cd, CH,-CHCl, masked ? 1.33 <d, CHtCH,),) 232 135 Table 1 (continuation) Example R3 Yield NMR (CDC13) 6= (ppm) No. '6. 43 <q, CH—CI) 4.78 <«, 0-CH-) 1.63 (d, CHj—CHCl, masked 1.5 - 1.8 Ca, CH, ) 1.3 12 k t, O—CH(CHj) 0.92 (2 x t, CHj-CH, ).

-CH /CH2CH3 (R, S) 60 * 6.48 (q, CH—CI) 4.16 Ct, CH,0) -CH2CH2CH3 62 * 1.83 Cd, CH,-CHC1 ,masked 1.67 Ca, CH,-CH2-CH, 0.97 Ct, CH,> *.48 <q, CH—CI) 4.3 CHj"OCH*) -CH2CH20CH3 78 * 3.6 Ca, COjCH, > 3.43 <«, OCH,) 2.16-1.4 <a, CCCH, >,) 1.81 Cd, CHa-CHCl.^ed O 4.48 Cq, CH—CI) 11 II 53 * CH«) / 3.5 - 4.1 («, CH,OCH, > CH 0 1.5-2.1 Ca, CH,CH,). 12 *.48 (q, CH-Cl) 4.4 - 4.7 Ca, CH—0) 40 % 3.5-3.9 Ca, CH) ua 2.4 (a, CH) 1.81 Cd, CH,-CHC1 , masked 1.0 - 1.9 Ca, CH,) Table 1 (continuation) 232135 Example R3 Yield NMR (CD C13) ^ = (ppm) Wo. *•43 (q, CH-Cl) CH2CHj 4.78 (a, 0-CH-) 13 -CH^ 62 % 1,83 CH,-CHC1. mssked l.S - 1.8 C«t CH;) CH3 1•3 (2 x t, 0-CH(CH,) 0.92 (2 x t, CHa-CH, ). *•43 Cq, CH-Cl) 4.78 (a, 0—CH—) 1.83 Cd, CHj —CH 1.5 — 2.8 (n, CHS .

CH, (S) 1.3 C2 x t, O—CH^CHj) 0.92 (2 x t, CH;—CHj) . CH2CH? 4.78 Ca, O—CH—) 14 -CH^ 58 % }*®3 CH,—CHCl, masked \ 1.3-2.8 (n, CH; ) *.48 Cq, CH-Cl) 4.33 Ct, CH; ) -CHpCH^CH^OCHpCHpCH, 32 % 5-53 Ct, COjCHa) * * * £ * * 3.47 Cq, CHa) 2.87 Ca, CH;) 1.81 Cd,* CHj-CHCl ,masked 1.17 Ct, CH, ) CH, *.48 Cq, CH-Cl) 3 4.03 Cd, CHa) 16 -CH2-CH^ 52 % 3.* Ca, COaCHa> 1.81 Cd, CH,-CHC1, maskea 3 1.0 Cq, CH,) B) Embodiment examples 232 135 1. Compounds of the general formula IV 5 Example 1 1-(1-Methoxyprop-2-yloxycarbonyloxy)ethyl 7-(2-(2-trityl-aminoth i azol-4-yI)-2-(Z)-1-methyl-1-methoxy-ethoxyimino-acetamido)-3-methoxymethyl-3-cephem-4-carboxylate Step A 4.3 g (28.3 mmol) of sodium iodide and 4.3 g (22 mmol) of 1-chloroethyl 1-methoxy-2-propyI carbonate were added 15 in succession to a suspension of 560 mg (41 mmol) of anhydrous zinc 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 92 strength NaHCOj solution and 300 ml of ether and 20 the phases were separated. The organic phase was washed (NaHC03 solution, sodium thiosulfate solution and NaCl solution) and dried (MgS(>4). The solvent was stripped off in vacuo at 20°C to give crude 1-iodoethyl-(1-meth-oxy-2-propyl carbonate as a colorless oil, which was fur-25 ther used immediately without purification (Step B).

Step B The crude product obtained from Step A was taken up in 30 5 ml of dry dimethylformamide and the mixture was added to a solution of 3.8 g (5 mmol) of potassium 7-(2-(2-tritylaminoth iazol-4-yI>-2-(Z)-1-»ethyl-1-methoxy-ethoxy-iminoacetamido)-3-methoxymethyl-3-cephem-4-carboxyI ate in 15 ml of dimethylformamide, while cooling with ice. 35 After 10 minutes, the react i on mixture was stirred into a mixture of 200 ml of 9Z strength NaHC03 solution and 100 ml of ethyl acetate. The organic phase was washed (NaHC03 solution and NaCl solution) and dried (MgS04) and the solvent was stripped off in vacuo. The resulting 232135 ^ - 20 - oil was triturated with 100 ml of ether, while cooling with ice, and made to crystallize. The precipitate was filtered off with suction and rinsed with ether to give 1.5 g of crystalline 1-(1-methoxyprop-2-yIoxycarbonyloxy)-5 ethyl 7-(2-(2-trityI aminothiazol-4-yI)-2-(Z)-1-methyl-1-methoxy-ethoxyiminoacetamido)-3-methoxymethyl-3-cephem-4-carboxylate. A further 0.34 g, making 1.84 g (412) together, of the title compound was obtained from the filtrate by treatment with pentane. 1H-NMR (d6-DMSO>: 6 = (ppm) 9.54 (2 x d, C0NH, J = 8 Hz) 8.85 (s, KH-trityl) 7.4-7.2 (b, phenyl-H) 6.85-6.8 (2 x q, O-CH-O) 6.7 (2 x 8, thiazole-H) .75 (2 x q, J = 5 Hz, C-7-H) 5.2 (2 x d, C-6-H) 4.85 (m, 0C02-CH) 4.15 (o, -CH2-0) 3.55 On, C-2-H) 3.4 (q, masked) , J = 5 HZ, CH^OCH^) 3,25 (s, CH2-0CH3) 3.2 (e, 3-CH2-0CH5) 3.1 (B, 0-C-0CH5) 1.5 (d, J » 6 Hz, C02-CH(CH5)-0C02) 1 .4 (8, C-(CH3)2) 1.2 (3 x t, J «= 7 Hz, CH5-CH-0C02).

The compounds summarized in Table 2 were obtained as amorphous solids analogously to Example 1, steps A and B.

Table 2 232 135 TrNH N r aJ CHj ,O-C-OCH, / • 5 N CHj II CONH OCH.

CO,CHOCOR" * t N CH30 Example No.

Yield NMR (dfi-DMSO) 6 = ppm ch2och3 ch, 9.54 (2 x d, CONH, J"0 Hz) IB.85 C«, HH-trityl) 7.4-7.2 C«, phenyl-H) 6.85—6.8 C2 x q, O—CH—0) 6.7 (2 x t, thiazole .73 (2 k Q, J«5 Hz, C—7—H) .2 <2 k d, C—6—H) 4.83 (•, OCOj-CH) 41 % 4.13 <«, 3—CHj—0) 3.55 <«, C-2-H) 3.4 <q, masked, J-5 Hz, CHa-OCH, > 3.25 (s, CHj—OCH, ) 3.2 <•, 3-CHj-OCH,) 3.1 <•, O-C-OCH,) 1.5 Cd, J»6 Hz, COj-CH(CH,)-OCOa) 1.4 <«, C-CCH, )3> 1.2 C3 k t, J-7 Hz, CH,-CH-OCOa).

Table 2 (continuation) 232 135 Example R3 Yield NMR (d^-DMSO) j = ppm No. <3 *.52 ' «2 x d, CONH, J-8 Hz) ®*®5 («, NH—trityl) 7*4-7.2 (in, ptienyl-H) *.*3-6.75 12 x q, 0—CH—0) *2 x • , thiazolff'H) .75 (2 x q, J«5 Hz, C-7-H) „ . 5'13 (2x0, C-6-H) ■»y * 4.55 <«, OCOa -CH) 4.15 <m, 3—CHa-0) 3.55 (2 x A6, C-2-H) 3.2 <s, 3-CHj -OCH, ) 3.1 (s, O-C-OCH,) 1.15-1.25 (at, cyclohexyl-H) 1.5 Cd, J-6 Hz , COa-CH(CH, )-OCOa , masked) !•* <•» C-(CH, )a, masked; O 9.55 (2 x d, CONH, J-B Hz) •.•5 (S, NH-trityl) 7.4-7.2 <•, phenyl —H) 6.8-6.75 12 x Q, O—CH—0) 6.7 (2 x »»thiazole —H) 5.75 <2 x q, J-5 Hz, C-7-H) 5.17 (2 x d, C-6-H) 38 % S.05 (•, OCOa-CH) 4.15 C«, 3—CHa —0) 3.55 C2 x AB, C-2-H) 3.2 <«, 3—CHj-OCH,) 3.1 <«, O-C-OCH,) l.as-1.25 («, CyCiopentyl-H) 1.45 (2 x d, J-6 Hz, COa-CH(CH,)< 0C03 , masked) 1.4 <•, C—(CH, )# , masked) Table 2 (continuation) 232135 Example R 3 Yield NMR (d6-DMSO) & = ppm No. 9.5 (2 x d, CONH, J-8 Hz) • .•5 Ca, NH-trityl) 7.4-7.2 Ca, phanyl-H) 4.92-6.77 (2 x q, O-CH-O) 6.49 (2 x a,thiazole —1M) 5.75 (2 x q, J»5 Hz, C-7-H) 4 32 % 5.IB (2 x d, C-6-H) 4.77 Ca, OCOa-CH) 4.15 (a, 3—CHa —0) 3.75 (a, (CHa)a0) 3.55 (2 x AB, C-2-H) 3.2 Ca, 3—CHa —OCH,) 3.1 Ca, O-C-OCH,) 1.59 Ca, CH(CH,)j) 1.5 (2 x d, J-6 Hz, COa-CH(CH,) OCOs ) 1,4 <«. C-(CH,)j, Example 5 1-(1-Methoxyprop-2-yloxycarbonyloxy)-ethyl 7-(2-(2-aminoth iazol-4-y I )-2-(Z)-hydroxy iminoacetamido)-3-meth-oxymethyl-3-cephem-4-carboxylate 1.83 g (2 mmol) of the cephalosporin obtained according to Example 1 were dissolved in 18 ml of 902 strength formic acid at room temperature. The solution was diluted with 2 ml of water and stirred at room temperature for 30 40 minutes and the triphenyImethanol which had precipitated was filtered off with suction. The filtrate was concentrated, with the addition of toluene, the oily residue was taken up in acetone and the solution was clarified by addition of active charcoal. n-Pentane was added 35 to the clear filtrate, while cooling with ice, whereupon the product separated out as an oil. The solvent was decanted off and the oily residue was triturated with n-pentane, whereupon the amorphous product precipitated. Yield: 0.74 g (642). 1H-NMR (d6-DMS0): 6= (ppm) 232 135 11.4 (s. NOH) 9-5 (d, J = 8 Hz, CONH) 7-3 (s, NH2 6.85-6.8 (2 x q, J = 6 Hz, O-CH-O) 6.7 (s, thiszoLe -H) -85 (2 x q, J = 5 Hz, C-7-H) -2 (3 x d, C-6-H) 4.85 (m, CH-0C02) 4.15 (s, 3-CH2-0) 3-55 (A/B, C-2-H) 3-25 (e, 3-CH2-0CH3) 3.2 (s, CH2-OCH3) 1.5 (2 x a, J = 6 Hz, C02-CH(CH3)-0C02) 1.2 (3 x t, CH3-CH-0C02).

The compounds listed in Table 3 were obtained as amorphous solids analogously to Example 5. 232135 Table 3 OH N o JL CONH H2N' S' o I 3 C0,CH0C02R" CH.

Example R3 Yield NMR (da-DMSO) s = PPm No. 11.4 («, NOH) 9.3 Cd, JmB Hz, CONH) [>3 <•, NHa) - 6.85 - 6.8 (2 x q, J-6 Hz, O-CH-O) rw nr« 6.7 (s, "thiazole—H) / 20CH3 5.es <2 x q, J-5 Hz, C-7-H) -CH. 64 ^ 3.2 <3 x d, C-6-H) ^CH 4.83 (ai, CH-OCO;) 3 4.15 <s, 3-CHj-O) 3.55 (A/B, C-2-H) 3. 25 (s, 3-CHa —OCH, > 3.2 (s, CHa -OCH, ) 1.5 (2 x d, J»6 Hz, COa-CHCCH,)-OCOa 1.2 (3 x t, CH, —CH—OCOa ) . o II.3 (f, NOH) 9.45 (d, J-B Hz, CONH) 7.1 (I, NHj > *.85-6.8 (2 x q, J-6 Hz, O-CH-O) 4.65 Cs, thiazole—H) 9.83 C2 x q, J«5 Hz, C-7-H) ,Q - 5.15 (2 x d, C-6-H) 09 * 4.5* <», CH-OCO,) 4.15 <•, 3-CHs-O) 3.55 (2 x AB, C—2—H) 3.2 (•, 3—CHj—OCH, > . 1«85-1.25 (a, c yeloh»xyl-H) r.5 (2 x d, J-6 Hz, CO,-CH(CH,)-0C0a , masked) 232135 Table 3 Example R3 Yield NMR (d6-DMS0) c = ppm O 11.3 Cs, NOH) 9.45 <d, J"B Hz, CONH) 7.15 <S, NHa) 6.95—6.75 (2 x q, J"6 Hz, O-CH-O) 4.65 («, thiazole"*'"') .83 (2 x q, J-5 Hi, C-7-H) 58 % 5.2 (2 x d, C-6-H) .05 Cm, CH—OCOj) 4.15 Cs, 3-CHj-O) 3.55 (2 x AB, C-2-H) 3.2 (S, 3-CHj-OCH, ) 1.85-1.5 <m, cyclop»ntyl-H) 1.3 (2 x d, J-6 Hz, COa-CH(CH,)-OCOa masked) 11.3 (s, NOH) 9.45 Cd, J«B Hz, CONH) 7.12 Cs, NH3) 4.91-6.75 (2 x q, J»6 Hz, O-CH-O) 4.45 (t, thiazole _H) S.8S (2 x q, J«3 Hz, C-7-H) p / ^(-> ce j 5.19 C2 x d, C—6—H) 8 V_/ **7- ("f 4.15 Cs, 3—CHj-0) 3.78 (R, (CHa ),0) 3.55 (2 x AB, C-2-H) 3.2 Cs, 3—CHj-OCHj> 1.6 C«, C(CH3)j> 1.5 C2 x d, J-6 Hz, C0S—CH(CHj)-OCDa masked) 232135 Example 9 1-(Isopropoxycarbonyloxy)-ethyl 7-2-(2-aminothiazol-4-yI)-2~(Z)-methoxyiminoacetamido-3-inethyt-3-cephem-4-carboxy-5 late Step A 1.5 g (10 mmol) of sodium iodide and 1.2 g (7.5 mmol) of 10 1-chloroethyIisopropyI 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 mixture was stirred under a nitrogen atmosphere for 2 hours and poured into a mixture of 9% strength NaHC(>3 solution 15 and ether and the phases were separated. The organic phase was washed (NaHC03 solution, sodium thiosulfate solution and NaCl solution) and dried (HgSO^.). The solvent was distilled off in vacuo at 20°C to give crude 1-iodo-ethyl isopropyI carbonate as a colorless oil which was 20 further used immediately without purification (Step B).

Step B The crude product obtained from Step A was taken up in 25 18 ml of dry dimethylformamide and the mixture was added to a solution of 1.3 g (3 mmol) of potassium cefetamet in 10 ml of dry dimethylformamide, while cooling with ice.

After 75 minutes, the reaction mixture was stirred into a mixture of 9% strength NaHC03 solution and ethyl acetate. 30 The organic phase was washed (NaHC(>3 solution and NaCl solution) and dried (MgSO^ and the solvent was stripped off in vacuo. The crude product was chromatographed on 100 g of silica gel using ethyl acetate. 300 mg of the title compound we re obtained. 232135 1H-NMR (d6-DMS0): 6 = ppm 9.6 (2 x d, CONH, J = 8Hz) 7.23 (br, e, NH2) 6.78 and 6.83 (2 x q, O-CH-O) 6.73 (2 x 8, thiazole-H) .77 (2 x q, J = 5 Hz, C-7-H) .13 (2 x d, C-6-H) 3.85 (e, 0CH3) 3.4-3.68 (m, C-2-H) 2.03 (b, CH3) 1.5 Cd, J = 6 Hz, Co2-CH(CH3)-0C02) 1.25 (d, (CH3)2-CH).

The compounds listed in Table 4 were obtained as amorphous solids analogously to Example 9.

Table 4 OCH.

N rj*—- ws H2N o>— CO-CHOCOR" * • - CH,0 Example R3 Yield NMR Cd^-DMSO) 6= ppm No. 9.6 (2 x d, CONH, J-8 Hr) 7.23 (br |, NHa ) rn 4.78 sncj 4.83 (2 K q, O-CH-O) s 3 **73 (2 k s, thiszole-H) -CH^ 47 % 3.77 (2 x q, J«5 Hs, C-7-H) »rw S. 13 C2 x d, C—6-H) CH3 3.83 (•, OCH,) 3.4 - 3.68 C», C-2-H) 2.03 <«, CH, ) -1*3 (d, J-4 Hz, 60s -CH (CH, > -0C0, > .1.23 (d, (CH,)t-CH). 232135 Table 4 (continuation) Example R3 Yield NMR (d6-DMSO> 5 = (ppm) No. 9.6 (2 k d, CONH, Hr) 7.23 (br s, NHj ) 6.78 6.83 <2 x q, O-CH-O) 4.73 (2 k «, thiazole _H) 5.77 (2 x q, J«5 Hz, C-7-H) 5.13 (2 x d, C-6-H) 4.58 and 4.4 (m, 1H, O-CH) 3.85 (s, OCH,) 3.38 - 3.68 (m, C-2-H) 2.03 (s, CH,) 1.5 (d, J"6 Hz, CO, —CH (CH, > —OCOj ) 1.05 ~ 1.9 (0, 10H, cyclohexyl-H). o 9.57 (2 x d, CONH, JmB Hz) 7.20 (br s, NHa) 6.78 and 6.83 (2 x q, O-CH-O) qjj 6.73 (2 x s, thiazole —H) / '3 5.73 (2 x q, J-5 Hz, C-7-H) 11 -CH 46 % 5.13 .(2 x d, C-6-H) CH^CH-* 4.62 <«, IH, O-CH) 2 3 3.82 <•, OCH,) 3.38 - 3.68 (m, C-2-H) 2.03 <•, CH,) 1.5 <d, J«6 Hz, COj-CH(CH,)-OCOj) 1.58, 1.2, 0.85 (•, 8H, —CHa- and -CH,) Table 4 (continuation) 232 1 3d Example R3 Yield NMR (d^-DMSO) 6 = (ppm) No. 9.6 (2 x d, CONH, J—8 Hz) 7.23 (br t, NH, > 4.76 and 4.S3 (2 x q, O-CH-O) 4.73 (2 x s, thiazole -H) .77 (2 x q, J-5 Hr, C-7-H) 5.15 (2 x d, C-6-H) 12 -CHCH?0CH, 43 % J'JJ ("' 1 £ j 3.85 (s, N-OCH,) 4H3 3.4 - 3.68 (m, C-2-H) 3.4 (d, CHa ) 3.25 (s, 3H, OCH,) 2.03 («, CHj ) 1.5 (d, J-6 Hz, CO,-CH(CH, )-OCOj ) 1.2 (0, 3H, CH,) 7.23 (br s, NHj ) 4.78 and 4.83 (2 x q, O-CH-O) 4.73 (2 x s, thiazole-H) .7 - 5.8 (2 x q, J-5 Hr, C-7-H) 47 pn nu pu a"i a 5.13 (^ x d, C—4—H) -Cil2CH2CH5 4.09 (2 x t, 2H, O-CHO 3.85 (s, OCH,) 3.38 - 3.48 (m, C-2-H) 2.03 (•, CH, ) 1.42 (a, 2H, —CHj-) 1.5 (d, J-6 Hz, C0»-CH(CH,)-OCOj) 0.89 (t, -CH, ) . 9.59 (2 x d, CONH, J-8 Hz) 7.23 (br s, NHj ) 4.78 and 6.83 (2 x q, O-CH-O) 4.73 (2 x s, thiazole-H) 5.77 (2 x q, J—5 Hz, C-7-H) 14 -CH2CH20CH3 39 % 3.13 (2 x d, C-6-H) 4.25 (0, 2H, O-CH, ) 3.85 (s, N—OCH,) 3.4 - 3.66 (0, C-2-H) 3.52 (0, 2H, O-CH,) 3.25 (s, 3H, OCH,) 2.03 (•, CH,) 1.5 (d, J-6 Hz, CO,-CH(CHj )-0C05 ) Table 4 (continuation) 232 135 Example R3 Yield NMR (d6-DMS0) 6 = (ppm) No. 9.6 (2 x d, CONH, J-8 Hz) 7.23 (br i, NH2 > 0 6.7B and 6.83 <2 x q, O-CH-O) 6.73 (2 x s, thiazole-H) 42 * 3.77 (2 x q, J«5 Hz, C-7-H) 5.13 <2 x d, C-6-H) 3.85 (s, OCH,) 3.4 - 3.68 <m, C-2-H) 2.03 (s, CH,) 1.5 (d, J-6 Hz, CO j -CH (CH, ) —DCOj ) JQ 16 31 % 9.6 <2 x d, CONH, J-8 Hz) 7.23 Cbr • , NHa) 6.78 and 6.83 (2 x q, O-CH-O) 6.73 (2 x s, thiazole-H) 5.77 (2 x q, J-5 Hz, C-7-H) 5.13 (2 x d, C-6-H) c 2 4.09 (oi, 3H, O-CHj and 2 -H) 3.85 <», OCH,) 3.4 — 3.68 («, C-2-H) 2.03 (s, CH,) 1.8 <•) 1.5 (d, J-6 Hz, COg —CH(CH, ) —OCOj 9.6 .(2 k d, CONH, J-8 Hz) 7.22 (br •, NHS) 6.78 and 6.82 (2 x q, O-CH-O) ,o . 6.73 (2 x f, thiazole-H) 17 ^ ^ ",0 * 3.73 (2 x q, J-5 Hz, C-7-H) 3.13 C2 x d, C-6-H) 4.3 («, 1H, 2'—H) 3.85 (•, OCH,) 3.4 - 3.68 (a, C-2-H) 2.03 (s, CH,) 1.3 <d, J-6 Hz, CO»-CH(CH,)-OCOa) Table 4 (continuation) 232 135 Example R3 Yield NMR (d^-DMSO) s = (ppm) No.

O 18 A 0 35 % 9.6 (2 x d, CONH, J-B Hr) 7.21 (br •, NHj) 6.79 6.88 (2k q, O-CH-O) 6.73 (2 x «, thiazole-H) .76 (2 x q, J-5 Hr, C-7-H) .13 (2 x d, C-6-H) 4.8 (m. 1H, 4 *—H) 3.85 («, OCHj> 3.4 - 3.68 (in, C-2-H) 2.03 C«, CHa) 1.5 Cd, J-6 Hz, COa-CH(CH,)-OCOj> 9.55 (2 x d, CONH, J-8 Hr) 7.20 Cbr «, NHj) *•78 and 6.83 <2 x q, O-CH-O) 6.73 (2 x s, thiazole-H) 19 -CH-CH,CH, 45 % 5*74 <2 x q, J-5 Hr, C-7-H) ' d * 5.13 (2 x d, C-6-H) Cd3 4*63 2H, CHj-CH,) 3.85 (s, OCH,) 3.4 — 3.68 (m, C—2—H) 2.03 Cs, CH, ) 1.51 (d, J-6 Hr, COs-CH(CH,)-OCOj ) 1.2 (2 x t, 3H, O-CH (CH,)-CH,-) 0.83 Ct, 3H, CH,) 9.55 (2 x d, CONH, J-8 Hr) 7.20 Cbr s, NHj) 6.78 and 6.13 (2 x q, O-CH-O) 6.73 (2 x s, thiazole-H) .74 (2 x q, J-5 Hr, C-7-H) 20 -ch2ch2ch3 45 * 5.13 C2 * d, C-6-H) CH (S) J-JJ 12 * CHS-CH,) 3 3. 85 Cs , OCH,) 3.4 - 3.68 <•, C-2-H) 2.03 C«, CH,> 1.51 Cd« J*6 He, COj-CH(CHj )-OCOj 1.2 C2 x t, 3H, O-CHCCH,)-CHj-) 0.83 C2 * t, 3H, CH,)

Claims (8)

- 33 - Table 4 (continuation) 232 135 Example R3 Yield NMR (d6-DMS0) 6 = (ppm) No. 9.57 (2xd, CONH, J * 8 Hz) 7.20 (br •, NHa ) 4.78 and 6.83 (2k q, O-CH-O) 4.73 (2 k i, thiazole-H) 21 -ch2ch2ch2och2ch3 38 % c"7"h> 4.19 (m, 2H, C03CHJ) 3.85 (s, OCH, ) 3.4 - 3.68 («f C-2-H) 3.4 (a, 2H, O-CHaCH,) 2.03 (•, CH,) 1.84 (m( 2H, CH, CHa CHj ) 1.5 <d, J»4 Hz, CO,—CH(CH,)—OCOa 1.1 (t, 3H, CH,) 9.37 (2 K d, CONH, J-8 Hz) 7.21 (br f, NHa > 4.78 and 4.83 (2 k q. O-CH-O) 4.73 (2 x s, thiazole-H) 3.74 (2 x q, J»5 Hr, C-7-H) / 2 3.13 (2 x d, C-4-H) 22 -CHpCHT 40 % 3.92 (2 x d, 2H, OCH-CH) \nw 3.83 (»f OCH,) UH3 3.4 - 3.48 (a, C-2-H) 2.03 («, CH,) 1.9 (a, 1H, -CHtCH, >,> l.S (d, J"4 Hz, COa-CH(CH, ) —OCOa 0.89 (2 x 0, CH(CH, >,) •38^ •' ' ^ - 34 - HoQffyfoi 3 5 what we claim is:

1. A cephemcarboxylic acid ester of the general formula ch3 o in which R^ denotes hydrogen or methyl, and denotes hydrogen or methoxy, one of the two substituents or R^ always representing hydrogen; R3 denotes straight-chain or branched C-j-Cs-alkyl, which can be substituted by C1-C3~aIkoxy, C3-C8-cycloalkyl or Cj-Cy-cycloalkoxy; C3-C8-cycloalkyI or C2-C7~cycloalkoxy, 1 2 in which, in the case where R is hydrogen and R is methoxy, R3 cannot be Ci-C^-alkyl, and in which the group OR^ is in the syn-position, and physiologically tolerated acid addition salts thereof.

2. A process for the preparation of a cephemcarboxyIic acid ester of the general formula I COOCH-OC-OR3 • ■ CH3 0 in which R^ denotes hydrogen or methyl and R^ denotes hydrogen or methoxy, one of the two substituents or 2 3 R always representing hydrogen, R represents straight- chain or branched C^ — C5-alkyl, which can be substituted by C-|-c3-alkoxy, C3~C8_cyc loa I ky 1 or c2-c7-cycloalkoxy, or represents C3~C8_cycloaIkyl, or represents C2-C7- 232 135 - 35 - i cycloalkoxy, in which, in the case where R is hydrogen and is methoxy, R3 cannot be C-]-C4~alkyl, and in which the group -OR ^ is in the syn-position, and of physiologically tolerated acid addition salts thereof, which comprises a) reacting a compound of the formula II «r-jj—S-CONH-j—cm CH_R COOA 2 4 in which R represents hydrogen or methoxy, R represents hydrogen or an amino-protective group, R^ represents methyl or a group which can easily be split off and 4 A represents a cation, in which R can only represent hydrogen if R^ is methyl, with a compound of the general formula III X - CH - 0C02 - R' (III) ch5 in which R3 has the above meaning and X represents a leaving group, to give the ester of the general formula IV M j—C CONH —j ®®~or5 J—Ns^J-CH2R 2 I 3 (IV) CO.. CH-O-C-OR * » m CH3 O and removing the groups R and R , 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 - 36 - 232135 (V) 4 5 in which R and R have the above meaning and Y represents an activating group, with a compound of the general formula VI ch3 o 2 3 in which R and R have the above meaning, or with a salt of this compound, to give a compound of the general 4 5 formula IV, and splitting off the groups R and R , in the meaning of a protective group or a group which can easily be split off, in a manner which is known per se, c) reacting a compound of the general formula VII 0 N-OR } 2 x-c^-c-c-ccnh CH_R 3 (VII) CO--CHOCOR * I • CH^O in which Z represents halogen and r\ and R3 have the above meaning, with thiourea to give compounds of the general formula I and - if desired - converting the compounds obtained into a physiologically tolerated acid addition salt.

3. A pharmaceutical formulat ion wh ich is ac t ive aga inst bacterial infections, which contains a cephemcarboxylic acid ester of the formula I. - 37 - 232135

A process for the preparation of a pharmaceutical formulation which is active against bacterial infections, which compr ises bringing a cephemcarboxylic acid ester of the formula I into a pharmaceutical^ suitable administration form with pharmaceutical^ customary excipients or diluents.

5 . A compound according to claim 1 substantially as herein as described or exemplified.

6 . A process according to* claim 2 substantially as herein described or exemplified.

7. A pharmaceutical formulation according to claim 3 substantially as herein described or exemplified.

8. A process according to claim 4 substantially as herein described or exemplified. J HOECHST AKTIEN^gSELLSCHAFT By Their Attorneys HENRY HUGHES LTD f\ I ~ 7 JUNfOOf(