CH646704A5 - Cephalosporin antibiotics, their preparation, and pharmaceutical compositions containing them - Google Patents

Description

The invention relates to cephalosporin compounds with valuable antibiotic properties.

The cephalosporin compounds in the following description are described with reference to "Cepham" according to J. Amer. Chem. Soc., 1962, 84, 3400, the term "cephem" referring to the cepham base structure with a double bond.

The cephalosporin antibiotics are used in the treatment of diseases caused by pathogenic bacteria in humans and animals and they are particularly useful in the treatment of diseases caused by bacteria which are different from other antibiotics, such as

3rd

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for example penicillin compounds, are resistant and in the treatment of penicillin sensitive patients. In many cases it is desirable to use a cephalosporin antibiotic that is effective against both gram-positive and gram-negative microorganisms, and considerable research has been directed to the development of various types of broad-spectrum cephalosporin antibiotics.

For example, GB-PS 1 399 086 describes a new class of cephalosporin antibiotics which contain a 7β- (a - etherified oximino) acylamido group, the oximino group having the syn configuration. This class of antibiotic compounds is distinguished by a high antibacterial activity against a number of gram-positive and gram-negative organisms, which is associated with a particularly high stability for / 3-lactamases, which are produced by various gram-negative organisms.

The discovery of this class of compounds has prompted further research in the field to attempt to find compounds with improved properties, for example over certain classes of organisms, particularly gram-negative organisms.

For example, GB-PS 1 496 757 describes cephalosporin antibiotics which are a 7/3 acylamido group of the formula r.c.co.nh-

No

I.

0. (ch ") c (ch0) cooh 2m, l n b

(where R is a thienyl or furyl group; RA and RB can vary within wide limits and can be, for example, Ci.4-alkyl groups or together with the carbon atom to which they are attached form a C3.7-cycloalkylidene group and m and n are each zero or 1, so that the sum of m and n is zero or 1), these compounds being syn isomers or mixtures of syn and anti isomers with at least 90% of the syn isomer. The 3-position of the cephalosporin molecule can be unsubstituted or it can have one of a variety of possible substituents. These compounds were found to have particularly good activity against gram-negative organisms.

Other compounds of similar structure have been developed from these compounds in further attempts to find antibiotics with improved broad-spectrum antibiotic activity and / or high activity against gram-negative organisms. Such developments included variations not only in the 7/3 acylamido group in the above formula, but also in the introduction of particular groups to the 3-position of the cephalosporin molecule.

For example, BE-PS 852 427 describes cephalosporin antibiotic compounds which fall within the general scope of British Patent 1,399,086 and in which the group R in the above formula can be replaced by a large number of different organic groups, including 2 -Aminothiazol-4-yl and the oxygen atom in the oxyimino group is linked to an aliphatic hydrocarbon group, which in turn can be substituted, for example by carboxy. In such compounds the 3-position substituent is an acyloxymethyl group (e.g. acetoxymethyl), hydroxymethyl, formyl or an optionally substituted heterocyclic thiomethyl group.

Furthermore, Belgian patent 836 813 describes cephalosporin compounds in which the group R in the above formula can be replaced, for example, by 2-aminothiazol-4-yl and the oxyimino group is a hydroxyimino or blocked hydroxyimino group, for example a methoxy-5 imino group. In such compounds, the 3-position of the cephalosporin molecule is substituted by a methyl group, which in turn can optionally be substituted by any of a large number of residues of the nucleophilic compounds described therein; an example of such a sub-io-substituted methyl group is an acetoxy group. No antibiotic activity is ascribed to such compounds in this patent, they are only mentioned as intermediates for the preparation of antibiotics described in this patent.

i5 BE-PS 853 545 describes cephalosporin antibiotics, the 7/3-acylamido side chain being primarily restricted to a 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetami-dog group and the substituent in the 3-position is already defined in a similar way as is the case in the mentioned Belgian patent 836 813. Compounds that are specifically mentioned in the description include compounds in which the 3-position is substituted by an acetoxymethyl group.

It has now been found that a suitable selection 25 of a special group in the 7/3 position in combination with an acetoxymethyl group in the 3-position can give cephalosporin compounds with advantageous activity over a wide range of commonly occurring pathogenic organisms. This advantageous antibiotic activity is described in more detail below.

The invention therefore relates to (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxycyclobut-l-oxyimino) acetamido] -3-acet-

oxymethylceph-3-em-4-carboxylic acid of the formula

»"

SN J! / S

\ = l_C.CO.NH-

N

ch2ococii3

(I)

and their non-toxic salts, their non-toxic metabolically labile 45 esters and their solvates.

The compounds according to the invention are syn isomers. The syn-isomeric form is determined by the configuration of the group

O-COOH

defined with respect to the carboxamido group. In the present description, the syn configuration is structurally referred to as

NH0

Z

■ c. co. nh - N0 - ^ COOH

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It should be mentioned that since the compounds according to the invention are geometric isomers, some mixing with corresponding anti-isomers can occur. The compounds according to the invention can exist in tautomeric forms (with respect to the 2-aminothiazolyl group) and it should be mentioned that such tautomeric forms, for example the

2-IminothiazoIinyIform, fall within the scope of the invention.

As already said, the invention also includes the solvates,

especially the hydrates of the compound of formula I. It also includes the salts of the esters of the compound of formula I already mentioned.

The compounds according to the invention have good broad-spectrum antibiotic activity. The activity is unusually high towards gram-negative organisms. This high activity extends to many / 3-lactamase-producing gram-negative strains. The compounds also have high static to j8 lactamases, which are produced by a number of gram-negative organisms.

In addition to the mentioned utility as antibiotics, the above compounds are also useful as intermediates due to the ease with which the acetoxy group in

The 3-position can be replaced by a large number of nucleophiles, resulting in antibiotics which contain a 3-methyl group substituted by various nucleophilic radicals, for example pyridinium or 1-methylpyridiniumylthio radicals.

It has been found that the compounds according to the invention have an unusually high activity against strains of Pseudomonas, e.g. Strains of Pseudomonas aeroginosa as well as a high activity against different members of the Enterobacteriaceae (e.g. strains of Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Enterobacter cloacae, Serratia marcescens, Providence species, Proteus mirabilis and especially indole-positive menopause, like Proteus organote) and Proteus morganii) and strains of Haemophilus influenzae.

The non-toxic salts which can be formed by reaction of one or both of the carboxyl groups present in the compound of formula I include salts of inorganic bases, such as alkali metal salts (sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); Amino acid salts (e.g. lysine and arginine salts); Salts of organic bases (e.g. procain, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglu-cosamine salts). Other non-toxic salts include acid addition salts, e.g. formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. The salts can also be in the form of resinates formed with, for example, a polystyrene resin or cross-linked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups or sulfonic acid groups or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin. Soluble base salts (e.g. alkali metal salts such as the sodium salt) of the compound of formula I can be used in therapeutic applications because of the rapid distribution of such salts in the body after administration. However, if insoluble salts of the compound of formula I are used in a particular application, e.g. when used in depot preparations, such salts can be formed in a conventional manner, for example with suitable organic amines.

These and other salts, such as the salts with p-toluenesulfonic acid and methanesulfonic acid, can be used as intermediates in the preparation and / or purification of the compound of the formula I, for example in the process described below. Non-toxic, metabolically labile esters which can be formed by esterification of one or both carboxyl groups in the parent compound of the formula I include acyloxyalkyl esters, for example low

Alkanoyloxymethyl or ethyl esters such as acetoxymethyl, acetoxyethyl or pivaloyloxymethyl ester. In addition to the above esters, the present invention in its scope encompasses the compound of formula I in the form of other physiologically acceptable equivalents, for example physiologically acceptable compounds, which, like the metabolically labile esters, are converted into the parent antibiotic compound of formula I in vivo can. The compound of formula I for the treatment of a number of diseases which are caused by pathogenic bacteria in humans and animals, for example as infections of the respiratory tract or the urinary tract.

According to the invention, a process for the preparation of the compound of the formula I as defined above or its non-toxic salts or non-toxic, metabolically labile ester is also created, which consists in that a compound of the formulas IIA, IIB or HC:

h h r

h2n.

cf

.n h2ococh3

(IIA)

coor h2n.

H "

i h

r

S \

<t

.n

(IIB)

h20c0ch3

coor '

(HC)

h2ococh3

coor so in which R1 is hydrogen or a carboxyl blocking group, e.g. the remainder of an ester-forming aliphatic or aliphatic alcohol or an ester-forming phenol, silanol or stannanol (this alcohol, phenol, silanol or stannanol preferably containing 1 to 20 carbon atoms), or a salt, e.g. an acid addition salt (formed with, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid or an organic acid such as methane-sulfonic or toluene-p-sulfonic acid) or a base salt formed 60 with a cation such as Na + or K + or an N-silyl derivative thereof with an acid of the formula:

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c. cooh (ni)

II

n 2

\) .. coor wherein R2 is a carboxyl-blocking group, for example as described above for R1, and R3 is an amino or protected amino group, or acylated with one of these corresponding acylating agents, whereupon any carboxyl-blocking and / or N present Protective groups removed and optionally a carboxyl group converted into a non-toxic salt. If a ceph-2-em-4-carboxylic acid of the formula IIB or a sulfoxide of the formula HC has been used as the starting product, the A2 isomer obtained is converted into the desired A3 isomer after the acylation, or the sulfoxide obtained is converted to the corresponding one Thio connection reduced; the isomerization to the A3 isomer and the reduction to the thio compound can be carried out before or after the removal of the carboxyl-blocking and / or the N-protecting group. A compound of the formula IIA is preferably used as the starting product.

The acylating agents which can be used in the preparation of the compounds of formula I include acid halides, especially acid chlorides or bromides. Such acylating agents can be prepared by reacting an acid III or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride.

The acylation using acid halides can advantageously be carried out in aqueous or non-aqueous reaction media at temperatures of from -50 ° C. to + 50 ° C., preferably from -20 ° C. to + 30 ° C., if desired in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents.

Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as low 1,2-alkylene oxide (e.g. ethylene oxide or propylene oxide) which bind the hydrogen halide liberated in the acylation reaction.

Acids of the formula III can also themselves be used as acylating agents in the preparation of the compounds of the formula I. The acylation using the acids III is expediently carried out in the presence of a condensing agent, for example a carbodiimide, such as N, N'-di-cyclohexylcarbodiimide or N-ethyl-N'-Y-dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimide-azole or an isoxazolium salt such as N-ethyl-5-phenylisoxazolium perchlorate.

The acylation can also be carried out with other amide-forming derivatives of acids of formula III, such as an activated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with a haloformate such as lower alkyl haloformate). Mixed anhydrides can also be formed with phosphoric acids (e.g. phosphoric or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. para-toluenesulfonic acid). An activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensed agent as mentioned above. Alternatively, the activated ester can be preformed.

The acylation reactions, which include the free acids or their amide-forming derivatives mentioned above, 10 are conveniently carried out in an anhydrous reaction medium, e.g. Methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.

If desired, the above acylation reactions can be carried out in the presence of a catalyst such as 4-dimethylaminopyridine i5.

The acids of formula III and the acylating agents corresponding to them can, if desired, be prepared and used in the form of their acid addition salts. For example, the acid chlorides can suitably be used as hydro-20 chlorides and the acid bromides as hydrobromides.

The A2-cephalosporin compound obtained by the process according to the invention can be converted into the corresponding A3 derivative by, for example, treating the A2 ester with a base such as pyridine or triethylamine.

A ceph-2-em reaction product can also be oxidized to give the corresponding ceph-3-em-l-oxide, for example by reaction with a peracid, e.g. Peracetic acid or m-chloroperbenzoic acid; the resulting sulfoxide 3o can then be reduced as described below to give the corresponding ceph-3-em sulfide.

If a 1-sulfoxide is obtained, it can be converted into the corresponding sulfide by, for example, reducing the corresponding acyloxysulfonium or alkoxysulfonium salt 35, which can be reacted in situ by reaction with e.g. Acetyl chloride in the case of an acetoxysulfonium salt, the reduction being effected for example with sodium dithio-nit or iodide ion, such as in a solution of potassium iodide in a water-miscible solvent, e.g. 40 acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be effected at a temperature of from -20 ° C to + 50 ° C.

Metabolically labile esters of the compound of the formula I can be prepared by reacting a compound of the formula I or a salt thereof with a suitable esterifying agent, such as acyloxyalkyl halide (for example iodide), expediently in an inert organic solvent, such as dimethylformamide or acetone and subsequently - if necessary - by removing any protective groups, so The salts of the compound of formula I with bases can be formed by reaction of an acid of formula I with a suitable base. For example, the sodium or potassium salts can be prepared using the corresponding 2-ethylhexanoate or hydrogen carbonate. 55 The acid addition salts can be prepared by reacting the compound of formula I or a metabolically labile ester thereof with a suitable acid.

If the compound of formula I is obtained as a mixture of the isomers, the syn isomer can be obtained by, for example, customary methods, such as crystallization or chromatography.

For use as starting materials for the preparation of the compound of the formula I according to the invention, preference is given to compounds of the general formulas III and 65 corresponding acid halides and anhydrides in the syn-isomeric form or in the form of mixtures of the syn isomers and the corresponding anti Isomers containing at least 90% of the syn isomer used.

s n

W-

646 704

6

The acids of general formula III can by reaction of a compound of formula IV

IV

t- F 4

x 1-co. coor

(wherein R3 is as defined above and R4 represents a carboxyl blocking group) with a compound of formula V.

(wherein R2 is as defined above) and then by removing the carboxyl blocking group R4 and - if necessary - by separating the syn and anti isomers.

The acids of the formula III can be converted into the corresponding acid halides and anhydrides and acid addition salts by customary methods, for example as described above.

It should be noted that in some of the above conversions it may be necessary to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions. For example, during any of the above-mentioned sequences of reactions, it may be necessary to protect the NH2 group of the aminothiazolyl moiety, for example by tritylation, acylation (e.g. chloroacetylation), protonation, or some other convenient method. The protecting group can then be removed in any suitable manner which does not cause degradation of the desired compound, e.g. in the case of a trityl group, by using an optionally halogenated carboxylic acid, e.g. Acetic acid formic acid, chloroacetic acid or trifluoroacetic acid or by using a mineral acid e.g. Hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent such as water or, in the case of a chloroacetyl group, by treatment with thiourea.

The carboxyl-blocking groups which are used in the preparation of the compound of the formula I or in the preparation of the necessary starting materials are expediently groups which can easily be split off in a suitable stage of the reaction sequence, expediently in the last stage. However, in some cases it may be appropriate to use non-toxic, metabolically labile carboxy-blocking groups, such as acyloxymethyl groups (e.g. acetoxymethyl and pivaloyloxymethyl), and to maintain these groups in the final product to give a suitable ester of the compound of formula I. .

Suitable carboxyl blocking groups are known and a list of representative blocked carboxyl groups is contained in GB-PS 1 399 086. Preferred blocked carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups, such as tert-butoxycarbonyl, and lower haloalkoxycarbonyl groups, such as 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking group or groups can then be removed by any suitable method known from the literature; for example, an acid or base

Talysed hydrolysis can be used in many cases, such as enzymatically catalyzed hydrolysis.

The antibiotic compounds according to the invention can be formulated for administration in any suitable manner in analogy to other antibiotics and the invention also includes pharmaceutical compositions which contain an antibiotic compound according to the invention, adapted for use in human or veterinary medicine. Such compositions can be presented for use in a conventional manner by means of any necessary pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention can be formulated for injection and can be presented in unit dose form, in ampoules or in multiple dose containers, if necessary with the addition of a preservative. The compositions may also have forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents. Alternatively, the active ingredient can be in powder form for dissolution in a suitable medium, e.g. sterile pyrogen-free water, available before use.

If desired, such powder formulations may contain a suitable non-toxic base to improve the water solubility of the active ingredient and / or to ensure that when the powder is dissolved in water the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base can be present in the water that is used to prepare the powder for a solution for injection. The base can be, for example, an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base, such as lysine or lysine acetate.

The antibiotic compounds can also be formulated as suppositories, e.g. containing common supplement bases, such as cocoa butter or other glycerides.

The veterinary compositions can be formulated, for example, as intramammary preparations, either on a long-term basis or on a fast-acting basis.

The compositions can range from 0.1%, e.g. Contain 0.1 to 99% of active material depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 50 to 1500 mg of the active ingredient. The dosage as used for an adult in human medicine will preferably be from 500 to 6000 mg per day depending on the route of administration and the frequency of administration. For example, in human medicine, 1000 to 3000 mg per day, administered intravenously or intramuscularly, will normally suffice. Higher daily doses may be required to treat Pseudomonas infections.

The antibiotic compounds according to the invention can be administered in combination with other therapeutic agents, such as antibiotics, for example penicillins or other cephalosporins.

The following examples illustrate the invention. All temperatures are in ° C. “Petrol” is supposed to mean petroleum ether with a boiling range of 40 to 60 ° C.

Manufacturing 1

Ethyl (Z) -2- (2-aminothiazpl-4-yl) -2- (hydroxyimino) acetate

A solution of 180 g of sodium nitrite in 400 ml of water was added to a stirred and ice-cold solution of 292 g of ethyl acetoacetate in 296 ml of glacial acetic acid in such a way that the reaction temperature was kept below 10 ° C. Stirring and

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65

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Cooling was continued for about 30 minutes when a solution of 160 g of potassium chloride in 800 ml of water was added. The resulting mixture was stirred for 1 hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated hydrochloric acid, dried and evaporated. The remaining oil, which solidified on standing, was washed with petroleum ether and dried in vacuo over potassium hydroxide and gave 309 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate.

A stirred and ice-cold solution of 150 g of ethyl (Z) -2 - (hydroxyimino) -3-oxobutyrate in 400 ml of dichloromethane was treated dropwise with 140 g of sulfuryl chloride. The resulting solution was kept at room temperature for 3 days and then evaporated. The residue was dissolved in diethyl ether, washed with water until the washings were almost neutral, dried and evaporated. The remaining oil (177 g) was dissolved in 500 ml of ethanol and 77 ml of dimethylaniline and 42 g of thiourea were added with stirring. After 2 hours the product was collected by filtration, washed with ethanol and dried to give 73 g of the title compound; F. = 188 ° C (dec.).

Manufacturing 2

Ethyl- (Z) -2-hydroxyimino-2- (2-tritylaminothiazol-4-yl) acetate, hydrochloride

16.75 g of trityl chloride was added portionwise over 2 hours to a stirred and cooled to -30 ° C solution of 12.91 g of the product of Preparation 1 in 28 ml of dimethylformamide containing 8.4 ml of triethylamine. The mixture was allowed to warm to 15 ° C over 1 hour, stirred for an additional 2 hours and then partitioned between 500 ml water and 500 ml ethyl acetate. The organic phase was separated, washed twice with 500 ml of water and then shaken with 500 ml of 1N HCl. The precipitate was collected, washed successively with 100 ml of water, 200 ml of ethyl acetate and 200 ml of ether and dried in vacuo to give 16.4 g of the title compound as a white solid; F. = 184 to 186 ° C (dec.).

Manufacturing 3

Ethyl- (Z) -2- (2-tritylaminothiazol-4-yl) -2- (l-t-butoxycarbonyl-cyclobut-l-oxyimino) acetate

55.8 g of the product of preparation 2 were stirred under nitrogen in 400 ml of dimethyl sulphoxide with 31.2 g of finely ground potassium carbonate at room temperature. After 30 minutes, 29.2 g of tert-butyl-1-bromo-cyclobutane carboxylate were added. After 8 hours, a further 31.2 g of potassium carbonate were added. Additional potassium carbonate was added over the next 3 days (6 x 16 g portions) and after 3 days a further 3.45 g of tert-butyl-1-bromo-cyclobutane-carboxylate were added. After a total of 4 days, the mixture was poured into about 3 liters of ice water and the solid was collected by filtration and washed well with water and petroleum ether. The solid was dissolved in ethyl acetate and the solution washed twice with brine, dried over magnesium sulfate and evaporated to a foam. This foam was dissolved in ethyl acetate-petroleum ether (1: 2) and filtered through 500 g of silica gel. Evaporation gave 60 g of the title compound as a foam, pmax (CHBr3) 3400 (NH) and 1730 cm-1 (ester).

Manufacturing 4

(Z) -2- (l-t-Butoxycarbonylcyclobut-l-oxyimino) -2- (2-trityl-aminothiazol-4-yl) acetic acid

A mixture of 3.2 g of the product of Preparation 3 and 1.65 g of calcium carbonate was refluxed in 180 ml of methanol and 20 ml of water for 9 hours and the mixture was cooled to room temperature. The mixture was concentrated and the residue was partitioned between ethyl acetate and water to which 12.2 ml of 2N HCl was added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated to give 2.3 g of the title compound, Xmax 1%

(Ethanol) 265 nm (E ^ 243).

example 1

a) t-Butyl- (6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (lt-butoxycarbonylcyclobut-l-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acet -amido] -ceph-3-em-4-carboxylate

A stirred solution of 24.2 g of the product of preparation 4 and 13.6 g of t-butyl- (6R, 7R) -3-acetoxymethyl-7-amino-ceph-3-em-4-carboxylate in 300 ml of dimethylformamide was added cooled to 0 ° C and 4.5 g of 1-hydroxybenzotriazole monohydrate and then 6.4 g of dicyclohexylcarbodiimide were added. The mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the white solid washed with a little ether. The filtrate and the washings were diluted with 1.5 l of water and extracted with ethyl acetate. The organic extracts were combined, washed successively with water and saturated saline, dried and evaporated. The residue was taken up in ether, filtered and evaporated again. The desired product was isolated after elution through two silica columns with ether and concentration of the appropriate fractions. The residues were recrystallized from diisopropyl ether and gave 12.8 g of the title compound, mp = 113.5 to 116.5 ° C; [a] D20 + 15.0 ° (C1.0, DMSO).

b) (6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2 - (l-carboxycyclobut-l-oxyimino) -acetamido] -ceph-3 -em-4 - carboxylic acid

100 ml of trifluoroacetic acid were added to a mixture of 12.5 g of the product of step a) and 5 ml of anisole at 0 ° C. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate and concentrated again. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The aqueous extracts were washed at pH 7 to 7.5 with ethyl acetate, acidified to pH 1.5 and extracted several times with ethyl acetate. These extracts were washed with saturated saline, dried and evaporated. The residue was dissolved in 70 ml of formic acid, 18 ml of water was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 300 ml of water and filtered. The filtrate was concentrated. The residue was taken up in 400 ml of water, filtered again and lyophilized and gave 4 g of the title compound, Amax (pH 6 buffer) 246 nm

(Elcm264) 'Xi' f 295 nm (ElJm 118) 'Wd2 ° + 21'3 ° (c 1'0' DMSO).

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646 704

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Example 2

(6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l - carboxycyclobut-l-oxyimino) -acetamido] -ceph-3-em -4-carbon acid hydrate

A solution of 89.41 g of t-butyl- (6R, 7R) -3-acetoxymethyl - 7 - [(Z) -2- (lt-butoxycarbonylcyclobut-l-oxyimino) -2- (2-trityl-aminothiazole- 4-yl) -acetamido] -ceph-3-em-4-carboxylate in 240 ml of 98% formic acid was stirred for 15 minutes and 25 ml of concentrated hydrochloric acid were added. The suspension was stirred at 23 ° C for 2.25 hours, cooled to 8 ° C and filtered. The filtrate was concentrated to 60 ml and diluted with 11 water. The solution was adjusted to pH 4.75 with ammonia and filtered. The filtrate was adjusted to pH 3 with phosphoric acid and the suspension was cooled to 0 ° C. overnight. The precipitate was collected by filtration to give 49.4 g of the title compound. A sample (10 g) was again precipitated from water, dissolved in 60 ml of IMS at 58 ° C and diluted with 300 ml of water at 55 ° C. The solution was cooled slowly when the title compound was obtained as a microcrystalline solid (5.64 g). Xmax 253 nm

1% 1%

(Elcm 332) 'XinfI 293 nm (lcm 151) (pH 6 phosphate buffer),

H2O 7.8% (Karl Fischer).

X-ray data were obtained from Debye-Scher-rer powder diffraction photographs taken under Co Ka (= 1.79024 Â).

there)

I / I100

16.5

54

11.2

62

5

8.43

85

5.96

31

5.78

77

5.51

46

5.06

15

10th

4.91

4th

4.73

31

4.53

100

4.39

85

4.26

38

15

4.02

23

3.94

31

3.86

31

3.74

77

3.67

62

20th

3.50

92

3.35

31

3.04

46

2.99

31

2.93

23

25th

2.83

15

2.73

23

2.64

23

2.54

23

2.44

8th

30th

2.39

8th

2.31

15

2.14

8th

2.09

8th

2.01

8th

35

1.95

8th

v

Claims (7)

646 704 2nd PATENT CLAIMS 1. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (l-carboxycy-clobut-I-oxyimino) acetamido] -3-acetoxymethylceph-3 -em-4 - carboxylic acid of the formula: m2 fS \ - / -. C. CO. zero N 1 (I) ^ O ^ r ^ COOH 'N \ j ^ J ^ CH2OCOCH3 cocm and its non-toxic salts and its solvates. 2. Non-toxic metabolically labile esters of the compound of claim 1. 3. A process for the preparation of the compound of formula I as defined in claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: fln h2ococh3 s "ivi \ = JL c00r wherein R2 represents a carboxyl-blocking group and R3 is an amino or protected amino group, or acylated with one of these corresponding acylating agents, whereupon any carboxyl-blocking and / or N-protecting groups present are removed and, if appropriate, a carboxyl group into a non - transferred toxic salt. 4. A process for the preparation of the compound of formula I as defined in claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: (IIB) h2ococh3 c00r 1U wherein R1 is hydrogen or a carboxyl-blocking group, or a salt or N-silyl derivative thereof acylated with an acid of the formula III reproduced in claim 3 or with an acylating agent corresponding thereto, which contains A2 isomers in the desired A3 Converts isomers, any carboxyl-blocking and / or N-protecting groups present are removed, the latter two stages also being able to be carried out in the reverse order, and, if appropriate, a carboxyl group is converted into a non-toxic salt 20. 5. A process for the preparation of the compound of formula I as defined in claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: (IIA) 30th coor " wherein R1 represents hydrogen or a carboxy-blocking group, or a salt or N-silyl derivative thereof with an acid of the formula: r * (HC) (III) h2ococh3 coor wherein R1 is hydrogen or a carboxyl-blocking group, or a salt or N-silyl derivative thereof acylated with an acid of the formula III reproduced in claim 3 or with an acylating agent corresponding thereto, the sulfoxide which it contains by reduction into the corresponding thio -converted compound, possibly removing carboxyl-blocking and / or N-protecting groups, the latter two stages also being able to be carried out in reverse order, and optionally converting a carboxyl group into a non-toxic salt. 6. A process for the preparation of non-toxic, metabolically labile esters of the compound of the formula I according to claim 1, characterized in that said compound or a salt thereof is reacted with an esterifying agent corresponding to the ester ester mentioned. 7. A pharmaceutical composition for use in human or veterinary medicine, containing an antibiotic compound according to claim 1 or 2 together with a pharmaceutical carrier or excipient.