AU613164B2 - Cephalosporin derivatives and processes for their preparation - Google Patents

Description

v ,r 'II I I c I I II I II r ,r \i

I

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

6 las16 Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: ,r Priority: Related Art: Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany FRIEDHEL: ADAM, WALTER DURCKHEIMER, GERD FISCHER, BURGHARD MENCKE, HUBERT SELIGER, DIETER ISERT, NORBERT KLESEL and GERHARD SEIBERT EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: CEPHALOSPORIN DERIVATIVES AND PROCESSES FOR THEIR

PREPARATION

The following statement is a ft lescription of this invention, including the best method of performing it known to: 1.

us i; i ^1 n 14 acetone/water to which 5.6 g (66 mmol) of sodium bicarbonate and 18 ml (132 mmoL) of triethylamine had first been added. After the mixture had been stirred at I L^ j 4h k 1M h V r4 pn- HOECHST AKTIENGESELLSCHAFT Description Cephalosporin derivatives preparation The invention relates to n which are particularly sui a process for their prepar Lations containing such co tc, HOE 88/F 068 Dr.KA/rh and processes for their ovel cephalosporin derivatives table for oral administration, ation and pharmaceutical formumpounds.

EC

C C C Cr C C C

C

C C C S C. C: Although many clinically relevant cephalosporins with a broad antibacterial spectrum have been developed, most of them are suitable only for parenteral administration, since after oral administration they are absorbed only very inadequately, if at all. 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 20 all the requirements which must be imposed on such a medicament, in particular a high antibacterial activity against Gram-positive (specifically Staphylococci) and Gram-negative pathogens and at the same time good absorption in the gastrointestinal tract.

In some cases, the absorption of a cephalosporin in the gastrointestinal tract has successfully been increased by esterification of the 4-carboxyl group. Since the cephalosporin esters as a rule have no antibiotic activity per se, the ester components must be chosen so that after absorption the ester is split back again rapidly and completely to the cephalosporin with the free carboxyl group by endogenous enzymes, such as esterases.

The degree of enteral absorption of cephalosporins depends decisively on the chemical structure of the CC C C C C Ct 2 cephalosporin and the particular ester components. Even small structural 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 the 7B-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 dose/effect proportionality is thereby often non-linear and the therapeutic serum levels t t 15 achieved are not satisfactory. Further esters from the V r, series of aminothiazolyl-cephalosporins are mentioned, t for example, in European Patents 29,557, 34,536, 49,119 L and 134,420.

c c We have now found, by in vivo studies carried out systematically on various animal species, a narrow group of c: c ceph-3-em-4-carboxylic acid esters which can be adminis- C C V e c tered orally, have an adequate chemical stability and cs cc a result of a balanced lipid- and water-solubility a 'e S' 25 absorbed rapidly and to a therapeutically remarkable degree in the gastrointestinal tract.

CCCCi SThe invention accordingly relates to cephemcarboxylic C C S ct acid esters of the general formula I CON N H2N N-H

H

2 0CH 3 CO2-CH-COR2

OR

in which R and R denote C 1

-C

6 -alkyl and the HO group is in the syn-position, and physiologically tolerated -3acid addition salts thereof.

1 2 Preferred meanings for R and R are

R

1

C-C

4 -alkyL, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or sec.-butyl, preferably methyl or ethyl, in particular ethyl,

R

2

C-C

4 -alkyl, such as, for example, methyl, ethyl, propyL, isopropyl, butyl or sec.-butyl, preferably methyl or ethyl, in particular ethyl.

Possible physiologically tolerated acid addition salts are the salts known for cephalosporin antibiotics, such S' 15 as, for example, the hydrochloride, sulfate, maleate, citrate, acetate or formate. They are prepared in a Smanner which is known per se by bringing together the t components in an aqueous or organic solvent or a suitable solvent mixture.

The compounds of the general formula I have a chiral t center in the ester component. If racemic compounds of the general formula III are used, the cephemcarboxylic ,acid esters of the general formula I are in the form of a mixture of two diastereomers, which can be separated into the two individual components by known methods.

The invention furthermore relates to a process for the preparation of cephemcarboxylic acid esters of the general formula I

CON

H

2 N ES N-OH O NnH 2

OCH

3

(I)

CO2 -CH-CO2

R

2 R1

OR

in which R and R denote C 1

-C

6 -alkyl and the HO group is in the syn-position, and of physiologically tolerated ~C--~llllli ,r 4 acid addition salts thereof, which comprises reacting a compound of the general formula II CON--r' N-OR H OC (I '3 R3 COOA in which R stands for an amino-protective group, R 4 stands for a group which can easily be split off and A stands for a cation, with a compound of the general formula III t t 2 X CH C 2 R (III) 15 X 1

OR

*1 2 in which R and R have the above meaning and X stands for a leaving group, to give the ester of the general formula IV -H-N SH 2OCH 3

(IV)

3 0 2 3 R3 CO2CHCO2R2 1

OR

3 4 i9 tJCand removing the groups R and R in a manner which is known per se, or reacting a compound of the general formula V C CO-Y H" 4 (V) Hn_,t

N-OR

3

R

in which R and R have the above meaning and Y stands for an activating group, with a compound of the general formula VI C 5 HCH OCH (VI) 2 CO 2 -CH-CO R

OR

in which R and R 2 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 R and R in a manner which is known per se, or reacting a compound of the general formula VII I Z-CF -C-C-CONH 0 ;-OH iCH OCH (VII)

C

2 3 CO -CH-CO R r 2 2 1

OR

C 1 2 in which Z stands for halogen and R and R have the above meaning, with thiourea to give compounds of the general formula I and if desired converting the tt resulting compounds into a physiologically tolerated acid addition salt.

t c S t In the general formulae II, IV and V, R 3 stands for an amino-protective group which is known from peptide and coe& ,cephalosporin chemistry, preferably formyl, chloroacetyl, tt bromoacetyl, trichloroacetyl, benzyloxycarbonyl, tert.butoxycarbonyl, trityl or methoxytrityl, and R 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. R is particularly preferably trityl or 1-methoxy-l-methylethyl.

In formula III, X denotes a Leaving group which is generally known for esterification reactions, such as, for example, chlorine, bromine, iodine, phenylsulfonyl- 6 oxy, 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 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, triethylamine, diisopropyLamine, ethyldiisopropylamine, N,Ndimethylaniline, N,N-dimethylbenzylamine, bicyclo[4,3,0]non-5-ene (DBN), 1,8-diazabicyclo[5,4,03undec-7-ene (DBU), pyridine, picoline or 2,6-dimethylpyridine. Preferred bases are sodium bicarbonate or a O* potassium bicarbonate, sodium carbonate or potassium Q00 o 15 carbonate, triethylamine, N,N-dimethylaniline, DBN or 0 00 oo aDBU. D00 U 900000 0 6 00 oo Reaction of the free carboxylic acids with these bases 0 0 0 gives the salts of the general formula II, in which A stands for a cation, such as, for example, sodium or 00°o potassium, but also magnesium or calcium, or an optiono0 o oo 0 00 ally substituted alkylated ammonium ion, such as, for a 00 example, ammonium, trimethylammonium, triethylammonium, o0 a" tetrabutylammonium, diisopropyLammonium, ethyldiisopropylammonium, diazabicycloC0,3,4]nonenium or diazabicyclo- [0,4,5]undecenium. Preferred meanings of A are sodium, oao0o8 potassium, triethylammonium, N,N-dimethylanilinium and 0 0 o o the DBN and DBU ion.

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

The reaction of the compounds of the formula II with the compounds of the formula III can be carried out in an organic solvent at about -20 to about +500C, preferably at about 0 C to room temperature. Examples of solvents which can be used are ketones, such as, for example, acetone or methyl ethyl ketone, N,N-dimethylformamide 7 (DMF), N,N-dimethylacetamide (DMA), N-methyLpyrrolidone or dimethyl sulfoxide (DMSO). DMF, DMA, N-methylpyrrolidone and DMSO are preferred. DMF is particularly preferred.

The groups R and R are split off from the resulting compounds of the formula IV in a manner which is known per se 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 t a 6 Sof the formula VI, Y represents a group which activates g 15 the carboxyl group, such as is known for corresponding L reactions from peptide and cephalosporin chemistry, for example a halide, preferably chloride, or an activating gt ester group, for example with 1-hydroxybenzotriazole, Nhydroxy-succinimide or a mixed anhydride, for example with benzenesulfonic acid or toluenesulfonic acid. The te carboxyl group can also be activated in a manner which tC Ce,. is known from the literature via addition of a condensing agent, such as, for example, a carbodiimide.

CC Vt 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 hydroiodide, and the use of crystalline c 4 salts may be advantageous as regards 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, such as, for example, methylene chloride, chloroform, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide or water, or in mixtures of these solvents.

The acylation reaction can advantageously be carried out 8 at temperatures from about -50 0 C to about +50 0 C, preferably -40 0 C to +300C, 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 with thiourea can be carried out by processes which are known per se, such as are described, for example, in European Patent 134,420. It is effected, for example, smoothly at temperatures of about 0 to 300C, preferably about 5 0 C, in organic solvents, preferably aprotic polar solvents, such as, for example, dimethylformamide, dimethylacetamide, acetonitrile or acetone.

The preparation of the starting compounds of the general formula III is carried out in a manner which is known from the literature or an analogous manner and is described in Chemische Ber. 44, p.3211, and the preparation of the starting compounds of the general formula II is described in European Patent 34,536.

The preparation of starting compounds of the general formula V with the activated carboxyl group is carried out in a manner which is known from the Literature, and the esterification Leading to 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 (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, to give a precursor of the formula i t t c r t Ct C C 7- r 9 0 CH20CH 3

CO

2 CHCO

R

OR

which is then converted into a compound of the general formula VII by nitrosation (cf. likewise European Patent 134,420).

The ceph-3-em-4-carboxylic acid esters of the general formula I have a number of physicochemical and biological properties which render them useful cephalosporin antibiotics for oral administration. They are stable colorless compounds which are readily soluble in the customary organic solvents, are absorbed in the intestine and after absorption from the intestine are split rapidly into the antibiotically active cephalosporin derivative of the formuLa C CONH

N-OH

H

2 N N CH 2

OCH

3 CO2H and are therefore outstandingly suitable for the treatment of bacterial infection diseases, such as, for example, infection of the respiratory tract or of the 0' urogenital tract.

The compounds according to the invention are administered orally in the form of customary pharmaceutical formulations, such as, 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 the treatment. However, it is as a rule between about 0.2 g and about 5 g daily, preferably between about g and about 3 g daily. The compounds are preferably administered in divided doses, for example 2 to 4 times i S- daily, in which case the individual dose can contain, for example, between 50 and 1,000 mg of active compound.

The oral formulations can contain the customary excipi- I 5 ents and/or diluents. Thus, for example, binders, such as, for example, gelatin, sorbitol, polyvinylpyrrolidone or carboxymethylcellulose, diluents, such as, for example, lactose, sugar, starch, calcium phosphates or polyethylene glycol, lubricants, such as, for example, talc or magnesium stearate, and for liquid formulations, for example aqueous or oily suspensions, syrups or similar known formulation forms are suitable for capsules or tablets.

S' The following examples serve to further illustrate the 15 invention, but do not limit it to them. In the examples, S in agreement with the literature, the notation is t identical to the "syn" position.

A. Preparation of starting substances i Preparation Example 1 Methyl chloro-methoxy-acetate 25 13.4 g (100 mmol) of methyl dimethoxy-acetate were poured over 21 g of phosphorus pentachloride (100 mmol) and the mixture was stirred. After 4 hours, the phosphorus *pentachloride had dissolved completely, with gentle warming. The solution was then heated slowly to 1400C and was kept at this temperature for a further hour. The residue was then subjected to fractional distillation in vacuo.

Boiling point 75 770C; yield 9.5 g

II

I 11 Preparation Example 2 i Ethyl chloro-ethoxy-acetate 5 18 g (100 mmoL) of ethyl diethoxy-acetate were poured over 21 g of phosphorus pentachloride (100 mmol) and the mixture was stirred. After 4 hours, the phosphorus pentachloride had dissolved completely, with gentle warming. The solution was then heated gradually to 140 0 C and kept at this temperature until thr 'volution Sof gas (ethyl chloride) had ended. The residue was then i subjected to fractional distillation in vacuo.

i Boiling point 80 81 0 C; yield 11.5 g I SI Preparation Example 3 n-Propyl chloro-n-propoxy-acetate Stage 1 n-PropyL di-n-propoxy-acetate A solution of 52.5 g (0.57 mole) of glyoxylic acid hydrate and 338 g (1.78 moles) of tri-n-propyL orthoformate, to which 1.7 g of p-toluenesulfonic acid had been added, was heated under reflux for 30 minutes and I 'Ci 197 g of a mixture of n-propanol and n-propyL formate were then distilled off. The residue was distilled over a column.

i Yield: 76 g (Boiling point 2 1 126 1280C).

Stage 2 n-PropyL chloro-n-propoxy-acetate 76 g (0.35 mole) of n-propyL di-n-propoxy-acetate were added dropwise to 72.5 g (0.35 mole) of phosphorus penta- I -12 chloride and the mixture was heated slowly to 600C. A solution was obtained. After heating under reflux for minutes, the solution was subjected to fractional distillation in vacuo.

Yield: 59.4 g (Boiling point23 115 1170C)

C

8

H

15 CL0 3 (194.7) i Calculated C 49.35 H 7.8 CL 18.25 Found C 49.6 H 7.9 CL 17.8 Preparation Example 4 n-ButyL chloro-n-butoxy-acetate 1 Stage 1 n-Butyl di-n-butoxy-acetate 61 g (0.66 mole) of glyoxylic acid hydrate were dissolved in 480 g (1.07 mole) of tri-n-butyl orthoformate, 2 g of p-toluenesuLfonic acid were added and the mixture was heated under reflux for 30 minutes. Subsequent frac- S tional distillation gave the desired title compound.

Yield: 70.3 g (Boiling point .0 9 90 92 0

C)

e, Stage 2 n-Butyl chloro-n-butoxy-acetate 70.3 g (0.27 mole) of n-butyl di-n-butoxy-acetate were added dropwise to 56.1 g (0.27 mole) of phosphorus pentachloride and the mixture was heated slowly, with stirring.

After being heated under reflux for 30 minutes, the mixture was subjected to fractional distillation in vacuo.

The desired title compound is thus obtained.

I_ 11 I I I i WN x tli 13 Yield: 46.2 g (BoiLing point 2 4 145 1470C)

C

10

H

19 CL0 3 (222.7) Calculated C 53.9 H 8.6 CL 15.95 Found C 54.2 H 8.7 CL 15.3 i Preparation Example 7-C2-(2-TrityLaminothiazo-4-y)-2-Z)-trityL-oximinoacetamidol-3-(methoxymethyl)-3-cephem-4-carboxyLic acid Stage 1 2-(2-Trityaminothiazol-4-yl)-2-(Z)-trityLoximino-acetyL chloride 46.5 g (60 mmol) of triethyammonium 2-(2-tritylaminothiazol-4-yL)-2-(Z)-trityoximino-acetate are dissolved in 400 mL of anhydrous methylene chloride and the solution is cooLed to -70 0 C. A solution of 12.3 g mmol) of phosphorus pentachloride in 200 mt of anhydrous methylene chloride was added dropwise so that the temperature did not rise above -60 0 C. Thereafter, the mixture was subsequently stirred at this temperature for a further hour and the solution was then concentrated immediately in vacuo. 100 mL portions of methylene chLoride were added and the mixture was evaporated on a rotary evaporator twice more. The title compound was K used for the 2nd stage without further purification.

Stage 2 7-E2-(2-Trityaminothiazo-4-y)-2-(Z)-trityL-oximinoacetamidol-3-(methoxymethyL)-3-cephem-4 carboxyLic acid A solution of the product from stage 1 in 50 mL of methylene chloride and 400 ml of acetone was added dropwise to a solution, cooLed to 0 0 C, of 18 g of 7-amino- 3-methoxymethyl-ceph-3-em-4-carboxyLic acid in 400 ml of I 14 acetone/water to which 5.6 g (66 mmol) of sodium bicarbonate and 18 mL (132 mmol) of triethylamine had first been added. After the mixture had been stirred at 0 C for 2 hours, it was brought to pH 4 with 1N hydrochloric acid and extracted with twice the amount of ethyl acetate. The phases were then separated and the organic solution was extracted with 5% strength potassium bisulfate solution. After drying over magnesium sulfate, the extract was concentrated, the residue was dissolved in 150 ml of methylene chloride, and 1.8 L of diisopropyL ether were added dropwise, with vigorous stirring. After filtration with suction, 45.7 g of the title compound were obtained.

15 B. Embodiment Examples Example 1 Methoxy-methoxycarbonyl-methyl 7-E2-(2-aminothiazol-4yl)-2-(Z)-hydroximinoacetamido]-3-(methoxy-methyL)-3cephem-4-carboxylate 460 mg (3.3 mmol) of potassium carbonate were added to a solution of 6 g (6.7 mmol) of 7-[2-(2-tritylaminothiazol- 4-yl)-2-(Z)-trityl-oximacetamido3-3-(methoxymethyL)-3cephem-4-carboxylic acid in 150 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for one hour. The mixture was then cooled to 00C, 1 g mmol) of methyl chloro-methoxy-acetate was added and the mixture was subsequently stirred for 3 hours. The solvent was then stripped off in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnerium sulfate. 7 g of crude product were obtained and were purified by flash chromatography (Si02; toluene/ethyl acetate: 4 3.1 g of a mixture of the two diastereomers were obtained.

C.

3 g of the diastereomer mixture were dissolved in 50 ml liarr~ i~ ul l- lll-- 15 of formic acid, and 10 ml of water were added. After 1 hour, the triphenylcarbinol which had precipitated was filtered off with suction, the filtrate was concentrated, the residue was taken up in toluene and the solvent was stripped off again. The product was then extracted by stirring with diisopropyl ether.

Yield: 1.15 g of the title compound as a mixture of the two diastereomers.

1 H-NMR (270 MHz, DMSO-d 6 6 3.23 (3H, s, OCH 3 3.57 (2H, m, SCH 2 3.52 and 3.55 (3H, 2 x s, CHOCH 3 4.18 and 4.22 (2H, 2 x s, CH 2 0CH 3 5.23 (1H, dd, 5.85 S (1H, m, 6.05 and 6.13 (1H, 2 x s, CH-OCH 3 6.65 (1H, s, thiazole-H), 7.1 (2H, broad s, NH 2 9.45 (1H, d, NH), 11.3 (1H, s, oxime-H).

S 2 Example 2 j 20 Ethcxy-ethoxycarbonyl-methyl 7 -E2-(2-aminothiazol-4-yl)- 2 -(Z)-hydroxyiminoacetamidol-3-(methoxy-methyl)-3-cephem- 4-carboxylate 536 mg (3.9 mmol) of potassium carbonate were added to a solution of 6 g (6.7 mmol) of 7-[2-(2-tritylaminothiazol- 4-yl)- 2 -(Z)-trityl-oximinoacetamidol-3-(methoxymethyL)-3cephem-4-carboxylic acid in 150 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 hour. Thereafter, it was cooled to 0°C, 1.3 g (8 mmol) of ethyl chloro-ethoxy-acetate were added and the mixture was subsequently stirred for 4 hours. After the solvent had been stripped off in vacuo, the residue was partitioned between ethyl acetate and water and the organic phase was dried over magnesium sulfate. 8.2 g of crude product were obtained and were purified by flash chromatography (Si02; toluene/ethyl acetate: 4 1).

3.75 g of the diastereomer mixture thus obtained were dissolved in 56 ml of formic acid, and 14 ml of water 16 were added. The triphenyLcarbinol which precipitated shortly thereafter was filtered off with suction after minutes, the filtrate was concentrated, the residue i was taken up in toluene and the solvent was stripped off a g a i n Yield: 1.4 g of the title compound as a mixture of the two diastereomers.

V 10 1 H-NMR (270 MHz, DMSO-d 6 6 1.12 1.28 (6H, m, 2 x CH3), 3.23 (3H, s, OCH 3 3.47 (2H, m, SCH 2 3.65 3.92 (2H, m, I C0 2

CH

2

CH

3 4.2 (4H, m, CH 2 0CH 3 and OCH 2

CH

3 5.23 (1 H, dd, 5.85 (1H, m, 6.03 and 6.17 (1H, s, CH-OEt), 6.65 (1H, s, thiazole-H), 7.1 (2H, broad s, NH 2 9.47 S 15 (1H, d, NH), 11.3 (1H, s, oxime-H).

t Example 3 6I c Propoxy-propoxycarbonyl-methyl 7-E2-(2-aminothiazol-4-yl)- Ii 20 2-(Z)-hydroiminoacetamido]-3-(methoxymethyL)-3-cephem-4carboxylic acid 920 mg (6.6 mmol) of potassium carbonate were added to a I solution of 12 g (13.4 mmol) of 7-E2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityl-oximinoacetamido]-3-(methoxymethyl)-3-cephem-4-carboxylic acid in 300 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 hour. Thereafter, it was cooled to 00C, 3.1 g (16 mmol) of n-propyl chloro-n-propoxy- 30 acetate were added and the mixture was subsequently stirred for 3 hours, After the solvent had been stripped off in vacuo, the residue was partitioned between ethyl acetate and water and the organic phase was dried over magnesium sulfate. 14.8 g of crude product were obtained and gave, after flash chromatography (Si0 2 toluene/ ethyL acetate: 4 5.6 g of ester as a mixture of diastereomers. Renewed chromatography (toluene/ethyl acetate: 3 1) gave 3.8 g of a mixture of the two di- 17 astereomers. The product was dissolved in 50 ml of formic acid, 12.5 ml of water were added and the mixture was stirred at room temperature for 1 hour. Thereafter, the triphenyLcarbinol formed was filtered off with suction, the residue was taken up in toluene, the soli vent was distilled off again and the residue was stirred with diisopropyl ether. 1.5 g of the desired title com- I pound were obtained as a mixture of the two diastereomers.

i 1 i IH-NMR (270 MHz, DMSO-d 6 6 0.87 (6H, t, 2 x CH3), J 1.6 (4H, m, OCH 2

CH

3 3.22 (3H, s, OCH 3 3.48 3.82 i(4H, m, CO 2

CH

2 and SCH 2 4.15 (4H, m, CH 2 0CH 3 and I CHOCH 2 5.25 (1H, d, 5.85 (1H, dd, 6.05 (1H, s, CH-Oprop.), 6.65 (1H, broad s, thiazole-H), 7.1 i (2H, broad s, NH 2 9.45 (1H, d, NH), 11.25 (1H, broad s, oxime-H).

Example 4 Butoxy-butoxycarbonyl-methyl 7-C2-(2-aminothiazoL-4-yl)- 2 -(Z)-hydroziminacetamidol-3-(methoxymethyl)-3-cephem-4- Scarboxylate 460 mg (3.3 mmol) of potassium carbonate were added to a solution of 6 g (6.7 mmol) of 7-[2-(2-tritylaminothiazol- 4 -yl)- 2 -(Z)-trityl-oximacetamido-3-(methoxymethyl)-3- Scephem-4-carboxylic acid in 150 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was cooled in an ice-bath and 1.8 g (8 mmol) of n-butyl chloro-n-butoxyacetate were added. After 3.5 hours at 90 0 C, the solvent was stripped off in vacuo, the residue was taken up in ethyl acetate and the mixture was washed with water.

After the organic phase had been dried over magnesium sulfate and concentrated, 10.1 g of an oily residue were obtained and were separated by flash chromatography (Si02; toluene/ethyl acetate: 8 3.2 g of an 18 amorphous product were obtained and were dissolved in ml of formic acid, and 12.5 mL of water were then added. After 2 hours, the mixture was filtered with suction, the filtrate was concentrated and the residue was twice taken up in toluene and distilled again. The residue was triturated with diisopropyl ether and filtered off with suction. 1.3 g of the title compound were obtained as an amorphous powder and mixture of the two diastereomers.

H-NMR (270 MHz, DMSO-d 6 6= 0.9 (6H, m, 2 x CH 3 1.32 (4H, m, CH 2

CH

3 1.55 (4H, m, CH 2

-CH

2

-CH

3 3.2 (3H, s, OCH 3 3.45 3.85 (4H, m, SCH 2 and CO 2

CH

2 4.17 (4H, m, CH20CH 3 and CH-O-CH 2 5.25 (1H, dd, 6-H), 5.75 (1H, m, 6.03 and 6.15 (1H, 2 x s, CH-OCH 2 6.15 (1H, s, thiazole-H), 7.1 (2H, broad s, NH 2 9.55 (1H, d, NH), 11.25 (1H, broad s, oxime-H).

c Example Methoxy-methoxycarbonyL-methyl 7-[2-(2-aminothiazol-4yl)-2-(Z)-hydroxyimino-acetamido]-3-(methoxymethyl)-3cephem-4-carboxyLate Precursor 2-(2-Tritylaminothiazol-4-yl)-2-(Z)-(1-methyl-1-methoxy)ethoxy-imino-acetic acid-p-toluenesulfonic acid anhydride 2.1 g (11 mmol) of p-toluenesulfonyl chloride were added to a suspension of 6 g (10 mmol) of triethylammonium 2- (2-tritylaminothiazol-4-yl)-2-( )--(1-methy -1-methoxy)ethoxyimino-acetate in 30 ml of acetone and the m-xture was stirred at room temperature for 1.5 hours. 40 ml of diethyl ether were then added and the mixture was cooled to -10 0 C and subsequently filtered with suction. The product was rinsed three times more with 20 ml of ether each time and dried. 10 g of product consisting of a T- ~l iii i 19 mixture of the title compound and triethylamine hydrochLoride were obtained.

Stage 1 Methoxy-methoxycarbonyl-methyl 7-[2-(2-trityLaminothiazoL- 4-yl)-2-(Z)-(1-methyl-1-methoxy)-ethoxyiminoacetamido]- 3-(methoxymethyL)-3-cephem-4-carboxylate 0.73 g (3 mmol) of 7-amino-3-methoxymethyl-ceph-3-em- 4 carboxylic acid were suspended in 30 ml of methylene chloride, and 0.37 ml (2.4 mmol) of 1,8-diazabicyclo- (5,4,0)-undec-7-ene (DBU) were added at 0 0 C. The solution formed was subsequently stirred for a further minutes, 0.4 g (3 mmol) of methyl chloromethoxy-acetate (Preparation Example 1) were then added dropwise and the mixture was subsequently stirred at this temperature for minutes. Thereafter, 2.8 g (3 mmol) of the mixed anhydride obtained in the precursor were added and the solution was kept at OOC for 30 minutes.

When the reaction had ended, the solvent was stripped off Sin vacuo and the residue was chromatographed (Si02; toluene/ethyl acetate 1 1.6 g of the 25 desired compound were obtained as a mixture of the two diastereomers.

IR (KBr): 3060 and 3020 aromatic), 1790 B-lactam), a t 1745 ester-carbonyl), 1590 aromatic), 700 aromatic) cm Stage 2 Methoxy-methoxycarbonyl-methyl 7-E2-(2-aminothiazol-4yl)-2-(Z)-hydroxyimino-acetamido3-3-(methoxymethyL)-3cephem-4-carboxylat( g (1.8 mmol) of the compound obtained in stage 1 were 7 Cr-~ i 20 dissolved in 25 ul of formic acid, and 5 mL of water were then added. After 1 hour at 0 0 C, the triphenylcarbinol formed was filtered off with suction and the filtrate was concentrated in vacuo. The residue was taken up in i 5 100 ml of toluene and the solvent was stripped off again i in vacuo. The residue was triturated with diisopropyl f ether and 700 mg of the desired title compound were 1 thus obtained as a mixture of the two diastereomers, the compound being identical to the product prepared according to Example 1 in all its properties.

'i

Claims (8)

1. A cephemcarboxyLic acid ester of the formula I C CONH N H HOCH (I -OH2 3 H 2N 23 2O C0-H-C0 2 R OR in which Rland R2denote Cl-C 6 -aLkyL and the HO group is in the syn-position, or a physiologically toLerated acid addition salt thereof.

2. A cephemcarboxyLic acid ester of the generaL formuLa as claimed in claim 1, in which Rand R stand for Cl-C 4 -aLkyL.

3. Methoxy-methoxycarbonyL--methyL 7-[2-(2-aminoth iazoL-4- yL )-2-(Z)-hydroximino-acetamidoj-3-(methoxymethyL cephem-4--carboxyL ate.

4. Ethoxy-ethoxycarbonyL-methyL 7-[2-(2-aminoth iazoL-4- yL)-2-CZ)-hydroximino--acetamidoJ-3-CmethoxymethyL)-3- cephem-4-carboxyL ate. A process for the preparation of a cephemcarboxyLic acid ester of the formuLa I or of a physiologicaLLy toLerated acid addition salt thereof J -CON H 2 N

5 'N-OH TI N H(I)H C0 2 -CH-CO 2 R 2 in hih R1 nd 2denote Cl-C 6 -aLkyL and the HO group is in the syn-position, which comprises reacting a compound of the formula II I, 22 N-OR 4 'H OCH HN 0 2 3 R 3 COOA in which R 3 stands for an amino-protective group, R stands for a group which can easily be split off and A stands for a cation, with a compound of the formula III X CH CO 2 R (III) OR 1 2 in which R and R have the above meaning and X stands for a leaving group, to give the ester of the formula IV C- CONH--- N-OR N H-2S o H2 0 CH3 (IV) 2R 2 l R CO2CHCO2R OR and removing the groups R and R in a manner which is known per se, or reacting a compound of the formula V C CO-Y SN-OR4 (V) H N-OR R 3 in which R 3 and R 4 have the above meaning and Y stands for an activating group, with a compound of the formula VI r S SH 2 N (VI) N CH 2 OCH 3 CO -CH-CO R 2 2 OR 1 i in which R 1 and R 2 have the above meaning, or with a salt of this compound, to give a 1 compound of the formula IV and splitting off the groups R 3 and R 4 in a manner which is known per se, or reacting a compound of the formula VII S Z-CH -C-CONH 2 1 )1 SZC2 I (Vll) O N-OH CH2 OCH3 CO -CH-CO R 2 2 OR in which Z stands for halogen and R 1 and R 2 have the above meaning, with thiourea to give a compound of the formula I and if desired converting the resulting compound into a physiologically tolerated acid addition salt.

6. A pharmaceutical formulation which is active against bacterial infections, containing a cephemcarboxylic acid ester of the formula I in adjunct with pharmaceutically acceptable carriers or excipients. c i I

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

8. A method of combating bacterial infections comprising administering to a patient suffering therefrom a pharmaceutically effective amount of a cephemcarboxylic acid ester of the formula I as claimed in claim 1. DATED this 2nd day of May, 1991. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA DBM/KJS/ML SC£