CH639096A5 - Cephalosporin derivatives, process for their preparation and pharmaceutical preparations containing them - Google Patents

Description

The invention relates in particular to esters of (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3-em-4-carboxylic acid, ie the syn isomer, which has the recognized name «cefuroxime».

As described in GB-PS 1 453 049, cefuroxime is a valuable broad-spectrum antibiotic which is distinguished by a high activity against a large range of gram-positive and gram-negative microorganisms. This property is reinforced by the very high stability of the compound towards β-lactamases, which are produced by a large range of gram-negative microorganisms. In addition, the compound in the body is stable due to its resistance to the influence of mammalian esterases and gives very high serum levels after parenteral administration (e.g. in the form of the sodium salt) in humans and animals, while it has a very low serum binding.

Cefuroxime and its salts, e.g. the alkali metal salts, such as the sodium salts, are primarily of value as injectable antibiotics because they are poorly absorbed by the gastrointestinal tract and are therefore only present in sera and urine in low concentrations after oral administration. The applicant has therefore carried out extensive research and has administered various cefuroxime derivatives orally, since the development of derivatives which are absorbed by the gastrointestinal tract and which are converted in the body serum to parent antibiotics after oral administration, the valuable therapeutic potential of cefuroxime would expand even further.

It is known from the literature dealing with β-lactam antibiotics that the absorption from the gastrointestinal tract can be improved after the oral administration of certain penicillin and cephalosporin antibiotics (compared to the parent or basic antibiotic), by dividing the free 3-carboxy group in the case of the penicillin compounds or the free 4-carboxy group in the case of the cephalosporin compounds into particularly esterified carboxy-

transferred y groups. For example, penicillin G can be converted to its acetoxymethyl ester to form a compound that shows improved absorption from the gastrointestinal tract after oral administration 5 compared to penicillin G itself.

It is believed that the presence of a suitable esterification group improves the absorption of the parent antibiotic from the gastrointestinal tract, the esterification group after absorption by the io-present enzymes, e.g. is hydrolyzed in the serum and in the body tissue, with the formation of antibiotic active parent acid. It should be emphasized that the exact nature of the esterification group is critical because it requires the ester to be sufficiently stable so that the ester can quickly reach the 15 point of absorption without significant degradation, e.g. in the stomach, while, on the other hand, the ester must be sufficiently sensitive to convert the antibiotic active parent acid within a short time that the ester is absorbed. 20 Furthermore, the strength according to which the particular ester group improves the oral absorption of the β-lactam antibiotic is indefinite and unpredictable and depends on the type of the parent acid selected. For example, an esterification group found to be effective in improving the usefulness of penicillin antibiotics does not necessarily show a similar benefit with cephalosporin series antibiotics, and irregularities are observed in each of these particular series of β-lactam antibiotics.

30 It has now surprisingly been found that cefuroxime on the 4-carboxy group can be esterified with certain esterification groups (as will be explained in more detail below) with the formation of compounds which give a very high absorption value from the gastrointestinal tract and which are rapid are split after absorption to form the parent or mother antibiotic.

The new cefuroxime esters according to the invention are represented by the formula

(I)

CH2.O.CO.NH2

CO.O.CH.O.CO.OR

'2

R

shown in the

R1 represents an alkyl group with 1 to 6 carbon atoms,

R2 means hydrogen or an alkyl group with 1 to 6 carbon atoms and the asterisk means an asymmetric carbon atom if R2 has a meaning other than hydrogen.

These esters have properties that cause the compounds to have substantial potential value as orally administered antibiotics. The invention relates to both the individual diastereoisomers and their mixtures.

The esters (I) have a relative stability, which can be seen from the fact that they have a low antibacterial

Show activity in vitro compared to cefuroxime (this shows that a high ratio of ester remains unchanged during in vitro tests, thus confirming the stability of the ester). The esters, on the other hand, are extremely sensitive to esterase hydrolysis, which leads to the formation of cefuroxime, which e.g. can be shown in in vitro experiments using esterases derived from rat liver, human liver or human serum.

In vivo experiments in rats have confirmed that oral administration of the esters (I) leads to a substantially greater absorption of cefuroxime, which is shown by the higher serum contents and an increased recovery from the urine than the oral administration of cefuroxime itself.

It has been shown that compounds of formula (I) in which

60

639096

4th

R1 is a C, _3-alkyl group and R2 is a hydrogen atom or a methyl group, give a particularly good absorption of cefuroxime, which has been proven by animal experiments. Examples of such connections are:

Methoxycarbonyloxymethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] ceph-3-em-4-carboxylate;

1- (Ethoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate ; and l- (methoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4- carboxylate.

The esters of formula (I) can be used to treat a variety of diseases caused by pathogenic bacteria in humans and animals, such as respiratory tract and urinary tract infections.

According to the invention, the compounds (I) are reacted with cefuroxime, one of its salts (for example an alkali metal salt, such as the sodium or potassium salt, or an onium salt, for example an ammonium salt, for example a quaternary ammonium salt) or a corresponding 1-oxide with a haioester of formula

X-CH-O-CO-OR1

R2

(ii)

in which R \ R2 and the asterisk have the meanings given above and X denotes a halogen atom, such as chlorine, bromine or iodine, and, if a 1 -oxide is formed, reduction of the resulting product, e.g. by treatment with acetyl chloride and potassium iodide to form the desired compound of formula I. The reaction is conveniently carried out in solution in an inert organic solvent (for example N, N-disubst. Amide, such as N, N-dimethylformamide or N, N-dimethylacetamide, a ketone, such as acetone, a sulfoxide, such as dimethyl sulfoxide, a nitrite, such as acetonitrile or hexamethylphosphoric acid triamide) at a temperature in the range from -50 to + 150 ° C, for example —10 to + 50 ° C, conveniently between 0 ° C and room temperature. If a cefuroxime salt, e.g. the potassium salt used as the starting material and the reaction is carried out in a nitrile solvent, a "crown ether" such as an 18-crown-6 (18-crown-6) may optionally be used. If cefuroximic acid is used as the starting material, it may be advantageous to carry out the reaction in the presence of a base, e.g. a weak inorganic base such as sodium carbonate or potassium carbonate. It is convenient to add the base to the cefuroxime-containing reaction system before adding the haioester (II). It has been found that the use of potassium carbonate as a base together with the compound (II), in which X is bromine or iodine, is advantageous since under these conditions the formation of a ceph-2-em ester product is kept to a minimum . It is convenient to use essentially equivalent amounts of cefuroxime and base, e.g. use about 0.5 mole of diacid base, such as potassium carbonate, per mole of cefuroxime. The shark ester (II) is conveniently used in a slight excess, e.g. in an amount of 1 to 1.5 moles / mole of cefuroxime.

The course of the reaction can be followed by thin layer chromatography (TLC), since the process converts a polar acid or its salt, which is used as the starting material, into a neutral ester product.

The esters (I) are also by acylation of a compound of formula h

h h2n

0

N

(III)

.ch2oconh2

V?

co.o.cho.co. or u

R

in which R1 and R2 have the definitions given above, or their acid addition salt or their N-silyl derivative using an acylating agent corresponding to (Z) -2- (Fur-2-yl) -2-methoxyiminoacetic acid, e.g. an acid halide, acid anhydride or carbodiimide, for example in the manner described in GB-PS 1 453 049.

The starting materials of formula (III) described above can be prepared in a manner known per se, e.g. using the methods described in U.S. Patent 3,905,963 and UK Patents 1,041,985 and 1,350,772.

Alternatively, the esters of formula (I) are obtained by in situ carbamoylation of a compound of formula h

H

C h n

\

conh och,

ch2oh co.o.cho.co. or

è2

5

639096

in which R 'and R2 have the meanings given above, e.g. as described in GB-PS 1 453 049. The carbamoylation can e.g. using a suitable isocyanate or a cyanic acid.

The starting materials of the formula (IV) described above can be prepared in situ by esterification of the corresponding 4-carboxylic acid or one of its salts (for example an alkali metal salt, such as the sodium or potassium salt) with a haioester of the formula II, as described above except that a temperature in the range of -100 to + 150 ° C, suitably between -70 and 0 ° C, is preferred.

If the desired ester is substantially contaminated by the corresponding ceph-2-em isomer, the product can be oxidized (for example by treatment with a peracid, such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, or with t-butyl hypo- chlorite in the presence of a weak base such as pyridine) to form the corresponding ceph-3-em-1-oxide ester, which can then be reduced (eg by treatment with acetyl chloride and potassium iodide) to form essentially pure ceph-3-em- ester.

The individual diastereoisomers can be isolated from the isomeric mixture by crystallization.

The esters of the formula I can be prepared as preparations for oral administration in a manner known per se using the customary pharmaceutical carriers or diluents. The formulations are conveniently prepared as tablets, capsules or pillows or scented pillows, advantageously in unit dosage form, and may contain conventional excipients such as binders, fillers, lubricants, disintegrants and wetting agents. Tablets can be coated in a manner known per se. Alternatively, the preparations can be made as liquid preparations, e.g. Suspensions or emulsions containing edible oils, e.g. Containing peanut oil. The active compounds can also be formulated for rectal preparations, such as suppositories or retention enemas.

The preparations can range from 0.1%, e.g. 0.1 to 99%, suitably 10 to 60%, contain active ingredient (I) depending on the route of administration. Unit dose formulations conveniently contain 50 to 500 mg of active ingredient (calculated as cefuroxime). The dose used for the treatment of adults is typically in the range of 500 to 5000 mg / day, e.g. 1500 mg / day, (calculated as cefuroxime),

although the exact dose inter alia depends on the frequency of administration.

The following examples illustrate the invention. All temperatures are given in ° C. The melting points are determined in a Mettler device and measured in the form of (MJ), where x is the heating rate (in ° C./min) and y is the immersion temperature.

The N, N-dimethylformamide used is dried by passing it through acidic aluminum oxide.

The organic solutions are dried over anhydrous magnesium sulfate.

TLC plates are developed in chloroform: methanol: formic acid (45: 8: 1) and the compounds are visualized under UV light at 254 nm and by exposure to iodine vapor or by spraying with ninhydrin and heating to 120 °.

Manufacturing process 1

J odmethyl methyl carbonate

A solution of 7.07 g (56.75 mmol) of chloromethyl methyl carbonate in 5 ml of acetone is mixed with a solution of 8.51 g

(56.75 mmol) sodium iodide treated in 30 ml acetone. The resulting suspension is stirred for 2 vi h at 22 °, after which it is evaporated in vacuo to a solid. This solid is divided between 75 ml ether and 75 ml water. The aqueous phase is extracted with further ether (2 x 75 ml) and the combined organic extracts are washed successively with 3 x75 ml of water, 50 ml of aqueous sodium metabisulfite and 100 ml of saturated saline. The solution is dried and evaporated in vacuo; 6.45 g of the title ester are obtained.

Production process 2 (R, S) -1-chloro-chloroformate 100 ml of ethyl chloroformate are treated with chlorine at room temperature for 5 h and the reaction mixture is left to stand for 5 days. Distillation of the mixture at atmospheric pressure gives 71.8 g of the title ester, bp. 120 to 130 ° C.

Production method 3 20 (R, S) -1-chloroethyl methyl carbonate

10.0 g (70 mmol) of (R, S) -1-chloroethyl chloroformate and 25 ml of methanol are stirred together for 1 h. At first the reaction is exothermic, but the reaction mixture cools down to approx. 20 °. Excess methanol is removed in a vacuum 25; 11.37 g of the title compound are obtained.

Production process 4 (R, S) -1-chloro-isopropyl carbonate 10.14 g (71 mmol) (R, S) -1-chloro-chloroformate 30 are refluxed with 35 mol of propan-2-ol for 30 min and 8 drops Triethylamine are added. The mixture is heated under reflux for a further 20 min. The solution quickly turns dark and is distilled; you get two fractions:

35

(i) Fraction 1; Kp. 80 to 90V760 mm (30 ml)

(ii) fraction 2; Kp. 60 to 70 ° / 15 mm (5.93 g), the title ester.

example 1

40 methoxycarbonyloxymethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3 -em-4-carboxy lat

0.93 g (4.3 mmol) of iodomethyl methyl carbonate in 3 ml of N, N-dimethylformamide become a solution of 1.00 g of 45 (2.2 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7- [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 10 ml of N, N-dimethylformamide. The solution is stirred at 22 ° for 45 min (TLC indicates that the reaction is essentially complete after 30 min).

So the above solution is partitioned between 80 ml of ethyl acetate and 80 ml of 2N hydrochloric acid, and the aqueous phase is extracted again with 2 x 100 ml of ethyl acetate. The combined organic extracts are successively with 100 ml of water, 2 x 75 ml of 3% aqueous sodium 55 bicarbonate solution, 75 ml of water, 50 ml of aqueous sodium metabisulfite, 50 ml of water, 4 x 50 ml of 2N hydrochloric acid, 50 ml of water and 50 ml saturated saline. The solution is dried and evaporated in vacuo to a foam (1.19 g). This foam is triturated with 50 ml of 60 anhydrous ether; the solid obtained is filtered off and washed with 2 × 20 ml of anhydrous ether and dried in vacuo; 0.93 g of the title ester, mp (MgO) 100 °; [alo + 41 ° (c 0.71, DMSO).

65 Example 2

(R and S) -l- (ethoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] -ceph -3-em-4-carboxylate

639 096

(a) (R, S) -l-iodoethyl ethyl carbonate

A solution of 13.14 g (86.4 mmol) (R, S) -l-chloroethyl-ethyl carbonate and 14.8 g (99 mmol) sodium iodide in 100 ml acetone is heated under reflux for 35 min. The acetone is removed in vacuo and the residue is partitioned between 150 ml ether and 150 ml water. The organic phase is separated and washed successively with water, aqueous sodium metabisulfite solution, water (three times) and saturated saline and dried. The ether is removed in a vacuum; you get the title nester.

(b) (R and S) -l- (ethoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] - ceph-3-em-4-carboxylate and its A Msomer

The product of (a) is immediately dissolved in 20 ml of N, N-dimethylformamide and a solution of 8.58 g (18.5 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z ) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 50 ml of N, N-dimethylformamide. The reaction mixture is stirred at 25 ° for 1 h and then partitioned between 150 ml of ethyl acetate and 200 ml of 2N hydrochloric acid. The aqueous layer is extracted with further ethyl acetate (3 x 100 ml) and the combined organic extracts are washed successively with 2 x 200 ml water, 200 ml 3% aqueous sodium bicarbonate solution, 3 x 200 ml water and 200 ml saturated saline and dried. The solvent is removed in vacuo; a glass (5.64 g.) is obtained. Trituration of this glass with ether gives 5.51 g of the title compound as a gel (this contains about 20% À msomer).

(c) (Round S) -l- (ethoxycarbonyloxy) ethyl (IS, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] -ceph-3-em-4-carboxylate, 1 -oxide

A solution of 1.985 g (3.65 mmol) of the product of (b) in 40 ml of dry dichloromethane is treated with a solution of 0.8 g (465 mmol) of m-chloroperbenzoic acid in 40 ml of dichloromethane; a gelatinous precipitate is immediately obtained. The reaction mixture is stirred at 21 ° for 45 min and the solvent is removed in vacuo; a solid is obtained. Trituration of this solid with 2 x 100 ml ether gives the title ester sulfoxide (1.47 g), which decomposes without melting at about 200 °; Âmax (EtOH) 275.5 nm (E {^ m356).

(d) (R and S) -1 - (ethoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] - ceph-3-em-4-carboxylate

A solution of 1.18 g (2.12 mmol) of the product of (c) in 20 ml of N, N-dimethylformamide is cooled to -10 ° and with 1.38 g (8.3 mmol) of potassium iodide and then with 0 , 31 ml (0.34 g, 4.35 mmol) of acetyl chloride. The reaction mixture is stirred at -10 ° for 30 min and can then warm up over the next 45 min. After this time, TLC indicates that the sulfoxide used as the starting material has disappeared.

The reaction mixture is partitioned between 80 ml of ethyl acetate and 80 ml of 2N hydrochloric acid. The aqueous solution is extracted with further ethyl acetate (80 ml). The combined organic extracts are washed successively with sodium metabisulfite solution, water and saturated saline and then dried. The solvent is removed in vacuo; 1.35 g of foam are obtained which, when triturated with 30 ml of ether, give 1.00 g of the title ester; Mp (M | 0) 103 °, [ct] D + 12.8 ° (c 1.09, DMSO).

Example 3

(R and S) -l- (methoxycarbonyloxy) ethyl (6R, 7R) -carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] -ceph-3 -em-4-carboxylate

(A) (R and S) -l- (methoxycarbonyloxy) ethyl (IS, 6R, 7R) -3-carbamoyloxymethyl-7i [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3-em-4-carboxylate, 1 -oxide method (i)

(a) (RundS) -l- (methoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacet-amido] -ceph- 3-em-4-carboxylate and its A2 isomer io A solution of 11.37 g (R, S) -l-chloroethylmethylcarbonate in 10 ml acetone is mixed with a solution of 17.0 g sodium iodide (113 mmol ) treated in 50 ml acetone. A precipitate forms immediately. After stirring for 5 minutes, the mixture is evaporated to dryness in vacuo. The residue is partitioned between 150 ml ether and 100 ml water, and the aqueous phase is extracted again with 3 x 50 ml ether.

The combined organic extracts are washed successively with 100 ml of water, 75 ml of sodium metabisulphite solution, 75 ml of water and 70 ml of saturated saline and dried. Evaporation to dryness in vacuo gives 5.5 g of (R, S) -l-iodoethyl methyl carbonate as a solid.

A solution of 5.50 g (24 mmol) of (R, S) -l-iodoethylmethylcarbonate 5 ml of N, N-dimethylformamide becomes a solution of 4.0 g (8.6 mmol) of potassium (6R, 7R ) -3-carbamoyl-oxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 15 ml of N, N-dimethylformamide. The reaction mixture is stirred at 22 ° for 4 h and then left to stand overnight.

30 The mixture is then partitioned between 75 ml of ethyl acetate and 75 ml of 2N hydrochloric acid.

The aqueous phase is extracted with further ethyl acetate (3 x 50 ml). The combined organic extracts are washed successively with 50 ml of water, 2 x 50 ml of 35 3% aqueous sodium bicarbonate solution, 2 x 50 ml of water and 50 ml of saturated saline, dried and evaporated to dryness in vacuo. Trituration of the residue (3.8 g) with 100 ml of diisopropyl ether gives a solid which is filtered off and dried in vacuo 40; 2.7 g of the title ester are obtained; Mp (Mg0) <70 ° (dec.); [a] 2D2 + 183 ° (c 0.84, DMSO), X max (EtOH) 281 nm (Ej ° c ° m 278) with an inflection point at 260 nm (EI1219).

45 (b) (Round S) -l- (methoxycarbonyloxy) ethyl (IS, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido ] -ceph-3-em-4-carboxylate, 1 -oxide

A solution of 2.59 g (4.92 mmol) of the product of (a) in 20 ml of dichloromethane is treated with 1.06 g (6.14 mmol) of m-chloroperbenzoic acid. The reaction mixture is stirred at 21 ° for 1 h and then diluted with 20 ml of anhydrous ether. The resulting solid is filtered off, washed with ether and dried in vacuo; the title ester sulfoxide is obtained.

55 The filtrate is evaporated to dryness and the residue is triturated with 100 ml of anhydrous ether. The resulting solid is treated in a manner similar to that described above; a further batch of the title ester sulfoxide is obtained. The two approaches of the sulfoxide esters are thus combined; 2.26 g of product are obtained, mp (M? 40-165 °, [a] o + 44.7 ° (c 0.91, DMSO).

Procedure (ii)

65 (a) Potassium (IS, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate , 1-oxide

A solution of 0.216 g (2.2 mmol) of potassium acetate in 15 ml

639 096

Ethanol becomes a solution of 0.88 g (2 mmol) (1 S, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph -3-em-carboxylic acid, 1-oxide in 15 ml of dry N, N-dimethylformamide and further ethanol (10 ml) is added. s

The resulting suspension is cooled. The solid is filtered off and dried; the title salt is obtained as a DMF solvate (0.946 g, 86%); k max (pH 6 buffer) 263 nm (Elcm 312) with a turning point at 280 nm (E | ° c "m 278).

10th

(b) (R and S) -I- (methoxycarbonyloxy) ethyl (IS, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido ] -ceph-3-em-4-carboxylate, 1 -oxide

1.07 g (7.7 mmol) of (R, S) -l-chloroethyl-methyl carbonate in 5 ml of N, N-dimethylformamide become one at 40 ° 15

heated suspension of 2.76 g (5 mmol) of potassium (1 S, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3 -em-4-carboxylate, 1 -oxide, N, N-dimethylformamide solvate in 45 ml of dry N, N-dimethylformamide. After 2 1/2 hours, the reaction mixture is poured into 100 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The aqueous layer and the solid are extracted with 2 × 100 ml of ethyl acetate. The organic solutions are combined and successively with 3 x 100 ml of 2N hydrochloric acid, 100 ml of water, 2s

2x 100 ml of saturated aqueous sodium bicarbonate, 100 ml of water and 2x 100 ml of saturated saline. The solution is treated with activated carbon, then dried (magnesium sulfate) and evaporated to a yellow solid (0.64 g). Trituration of this material with ether gives 30 0.06 g of the title sulfoxide ester; [a] o + 40 ° C (c 0.58 in DMSO),

Xmax (CHClj) 277.5nm (E ^ m 289).

(B) (R and S) -l- (methoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyl-oxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino- 35 acetamido] -ceph-3-em-4-carboxylate

A cooled solution of 2.12 g (3.9 mmol) (R and S) -l - (methoxycarbonyloxy) ethyl (IS, 6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide in 10 ml of N, N-dimethylformamide 40 is sequentially treated with 2.59 g (15.6 mmol) of potassium iodide and Treated 0.55 ml acetyl chloride. The mixture is stirred at about 4 ° for 1 h and then partitioned between 60 ml of ethyl acetate and 60 ml of 2N hydrochloric acid. The aqueous phase is extracted with 3 x 40 ml of ethyl acetate. The combined organic extracts are washed successively with 40 ml of water, 40 ml of aqueous 3% sodium bicarbonate solution, 40 ml of water, 50 ml of aqueous sodium metabisulphite, 40 ml of water and 50 ml of saturated saline. The organic solution is dried and evaporated to dryness in a vacuum.

Trituration of the residue (2.1 g) with 50 ml of diisopropyl ether gives a solid which is filtered off, washed with further di-isopropyl ether and dried in vacuo.

This solid (1.99 g) is stirred with 20 ml of anhydrous ether for 2 h and filtered in succession, washed with further ether, filtered off and dried in vacuo; 1.6 g of the title ester are obtained; Mp (Mg0) 121 ° C (dec.), [Ci] d + 11.8 ° (c 0.91, DMSO).

oxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3-em-4-carboxylate and its À 2 isomer

A solution of 1.0 g (6 mmol) (R, S) -l-chloroethylisopropyl carbonate in 5 ml acetone is stirred with a solution of 1.50 g (10 mmol) sodium iodide in 20 ml acetone for 4 h.

The mixture is then evaporated to dryness in vacuo. The residue becomes a solution of 2.50 g (5.4 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -

2- (fur-2-yl) -2-methyloxyiminoacetamido] -ceph-3-em-4-car-boxylate in 20 ml of N, N-dimethylformamide. Then the mixture is stirred for 2 hours. Further portions of (R, S) -l-chloroethylisopropyl carbonate (1.0 g, 1.0 g and 1.5 g; 6.6 and 9 mmol) are added after 0.16 and 22 h, and the reaction mixture is stirred for a further 16 h. After this time, the implementation is essentially completed (by TLC). The reaction mixture is between 70 ml of ethyl acetate and

Distributed 80 ml of 2N hydrochloric acid. The aqueous phase is extracted with 3 × 40 ml of ethyl acetate. The combined organic extracts are washed successively with 2x50 ml of water, 50 ml of aqueous sodium bicarbonate solution, 50 ml of water and 50 ml of saturated saline, dried and evaporated to dryness in vacuo. Trituration of the residue with 50 ml of diisopropyl ether gives a mixture of the two title esters. This mixture has the following physical properties: Ä.max (EtOH) 277.5 nm (Ej ° cm303).

(b) (R and S) -l- (isopropoxycarbonyloxy) ethyl

(1 S, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide

A solution of 1.90 g (3.43 mmol) of the product of (a) in 20 ml dichloromethane is treated with 0.74 g (4.3 mmol) of m-chloroperbenzoic acid.

The mixture is stirred at 22 ° for 1 h and then evaporated to dryness in vacuo. Trituration of the residue with 80 ml of anhydrous ether gives a solid which is filtered off, washed with anhydrous ether and dried in vacuo; 1.50 g of title ester sulfoxide are obtained; Mp (M? 40) 176 ° (dec.), [A] 2D2 + 55.4 ° (c 1.0, DMSO).

(c) (R and S) -l- (isopropoxycarbonyloxy) ethyl (6R, 7R) -

3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3-em-4-carboxylate

60

Example 4

(R and S) -1 - (isopropoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph -3-em-4-carboxylate 6s

(a) (R and

S) -1 - (isopropoxycarbonyloxy) ethyl (6R, 7R) -3-carboamoyl-

A cooled (about 4 °) solution from 1.37 g (2.4 mmol) of the product of (b) in 20 ml of N, N-dimethylformamide is mixed with 1.60 g (9.64 mmol) of potassium iodide and Treated 34 ml acetyl chloride. The reaction mixture is stirred at 4 ° for 1 h.

The mixture is then partitioned between 70 ml of ethyl acetate and 80 ml of 2N hydrochloric acid.

The aqueous phase is extracted with 3 x 50 ml of ethyl acetate. The combined organic extracts are washed successively with 2x50 ml of water, 50 ml of aqueous sodium metabisulphite solution, 50 ml of water and 50 ml of saturated saline and evaporated to dryness in vacuo. The resulting residue is triturated with 100 ml of anhydrous ether, filtered off and dried in vacuo; 0.86 g of the title ester is obtained; Mp (Mg0) 109 ° C (dec.), [Ci] d + 18.2 ° (c 1.0, DMSO).

Pharmaceutical examples

(A) Powder for oral suspension (in pillows or sachets) composition per pillow

8th

639096

equivalent to 250 mg of cefuroxime

(R and S) -l- (methoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino-acetamido] -ceph-3 -em-4-carboxylate (ground product from Example 3) sodium carboxymethyl cellulose (low viscosity)

Sunset Yellow FCF spray dried orange flavor powdered sugar

The product of Example 3 is milled using a fluid energy mill and intimately mixed with the sodium carboxycellulose and flavor and color. This mixture is then further mixed with powdered sugar, the latter being added in two stages. The required weight is transferred to a paper / aluminum / polythene cushion and then sealed in the heat. The content of each pillow is determined for constitution in approximately 15 ml of water shortly before administration.

90 mg

5 mg 150 mg 2.2 g s (B) product of Example 3, micronized (250 mg acid)

Sodium starch glycolate magnesium stearate microcrystalline cellulose io total weight

338.4 mg 8.0 mg 2.0 mg 51.6 mg 400.0 mg

method

The ingredients are mixed in increasing order of weights and the mixture is compressed on an F3 single-tray stamping device using a 1.03 cm (13/32 ") normal concave stamp to form the required tablet.

B

Claims (3)

639096 1. Compounds of the formula k n j— c.co. M PATENT CLAIMS h h (I) ch2.o.co.nh2 co.0.ch.o.co.or * in the R 'is an alkyl group with 1 to 6 carbon atoms, R2 represents hydrogen or an alkyl group with 1 to 6 carbon atoms and the asterisk indicates an asymmetric carbon atom if R2 has a meaning other than hydrogen. 2. Compounds according to claim 1, characterized in that R 'is an alkyl group having 1 to 3 carbon atoms and R2 is hydrogen or a methyl group. 3. methoxycarbonyloxymethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate as a compound according to claim 1. 4. 1 - (Ethoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4 carboxylate as a compound according to claim 1. 5. 1 - (Methoxycarbonyloxy) ethyl (6R, 7R) -3-carbamoyl-oxymethyl-7 - [(Z) -2- (fur-2-yI) -2-methoxyiminoacetamido] -ceph-3-em-4 carboxylate as a compound according to claim 1. 6. A process for the preparation of a compound of formula I according to claim 1, characterized in that (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (ie cefuroxime), one of its salts or the corresponding 1 -oxide with a shark ester of the formula: have and X represents halogen, and, when the 1-oxide is formed, the resulting product is reduced to form the desired compound of the formula I. 7. A process for the preparation of a compound of the formula I according to claim 1, characterized in that a compound of the formula: 25th 3 "h2n 35 40 h h ch2.o.co.nh2 co.0.ch.o.co.or1 r2 (iii) X-CH-O-CO-OR " I. R2 (II) in which R1 and R2 have the meanings given in Claim 1, in R1 and R2 have the definitions given in Claim 1, or an acid addition salt or an N-silyl derivative thereof with an acylating agent corresponding to the (Z) -2-4s (Fur-2- yl) acylated -2-methoxyiminoacetic acid. 8. A process for the preparation of a compound of the formula I according to claim 1, characterized in that the 3-hydroxymethyl group of a compound of the formula: 0 c- It n h c0nh h = / s \ \ 0 oh r \ y (iv) ch20h co.o.cho.co.or in which R1 and R2 have the meanings given above, it shows that they carbamoylate a compound of the formula I together. with at least one pharmaceutical carrier or agent 9. Pharmaceutical preparation, thereby containing thinners. 3rd 639096