IE52008B1

IE52008B1 - Novel esters

Info

Publication number: IE52008B1
Application number: IE2915/81A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1980-12-12
Filing date: 1981-12-11
Publication date: 1987-05-13
Also published as: NZ199255A; IE812915L; ES516590A0; ES8307820A1; AR231984A1; PT74119A; ES516592A0; ES516594A0; ES8401079A1; IL64506A0; AU7846681A; KR830007683A; ES8401080A1; EP0054512A3; EP0054512A2; GR76967B; HU185985B; PT74119B; GB2111043B; ES507907A0

Abstract

Die Erfindung betrifft neue, unter physiologischen Bedingungen spaltbare 1-Niederalkoxycarbonyloxyniederalkylester der 7ß-[2-(2-Amino-4-thiazolyl)-2-(syn)-methoxyimino-acetamido]-3-cephem-4-carbonsaüre, Verfahren zu ihrer Herstellung und pharmazeutische Praparate, die solche Verbindungen enthalten.

Description

The invention relates to novel esters of 7β-[2(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetamido]-3cephem-4-carboxylic acid, which esters can be split under physiological conditions, to processes for producing them, and to pharmaceutical preparations containing these compounds.

The 7β-[2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetamido ]-3-cephem-4-carboxylic acid, the sodium salt thereof (ceftizoxime), some further salts and also esters, lo including some esters which can be split physiologically, are known from the German Offenlegungsschrift No. 2,810,922 and from the European Patent Application No. 2 273. These compounds are valuable antibiotically active substances which can be used in particular as antibacterial anti15 biotics. Whereas the salts are suitable only for parenteral administeration, the esters which can be split under physiological conditions have the advantage of being effective also when administered orally.

There is a need for compounds of this type which are 20 able to be administered orally and which, compared with the known oral cephalosporins, for example of the phenylglycine type, have improved properties. It has been found that, surprisingly, the pharmacological properties can be substantially improved with certain esters.

The present invention relates to the novel compounds of the formula N-OCH.

II •-C-CONH-t Am/-γ COO-CH-O-CO-O-R. I z R, (I) wherein R^ is hydrogen or lower alkyl, R2 is lower alkyl, and Am is an optionally protected amino group, to acid addition salts of such compounds wherein Am is a free amino group, to processes for producing these compounds, and to pharmaceutical preparations containing them.

In the present specification of the invention, the term lower” in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl, and the like, denotes, except where expressly defined otherwise, that the groups concerned have up to 7 C atoms, preferably up to 4 C atoms.

A lower alkyl group R^ or R2 is in particular: C^-C^lower alkyl, such as methyl, ethyl, propyl, isopropyl or butyl. R^ is preferably methyl and R2 ethyl; Xn the protected amino group Am, the protecting group is one of those used in penicillin, cephalosporin and peptide chemistry. Protecting groups of this type can be split off readily, that is to say, without undesirable side reactions occuring, for example by solvolysis, reduction or photolysis.

Protecting groups of the kind mentioned and the manner of splitting them off are described for example in Protective Groups in Organic Chemistry, Plenum Press, London, New York, 1973, also in The Peptides, Vol. I, SchrHder and LUbke, Academic Press, London, New York, 1965, 2008 as well as in Methoden der organischen Chemie, HoubenWeyl, 4th edition, vol. 16/1, Georg Thieme Verlag, Stuttgart, 1974.

A protected amino group Am can be for example in the form of a readily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-alk-l-en-l-ylamino, silylamino or stannylamino group.

In a corresponding acylamino group, acyl is for example the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially of an alkanecarboxylic acid unsubstituted or substituted for example by halogen or aryl, or of a benzoic acid unsubstituted or substituted for example by halogen, lower alkoxy or nitro, or of a carbonic acid semiester. Such acyl groups are for example: lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, particularly 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoroor 2,2,2-trichloroacetyl, benzoyl unsubstituted or substituted for example by halogen, lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxyhenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched in the 1-position of the lower alkyl radicals, or suitably substituted in the 1- or 2-position, especially tert-loweralkoxycarbonyl, for example tert-butyloXycarbonyl, arylmethoxycarbonyl having one or two aryl groups, which are preferably phenyl unsubstituted or mono- or polysubstituted for example by lower alkyl, especially tertlower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine and/or nitro, such as unsubstituted or substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl, aroyl methoxycarbonyl, wherein the aroyl group is preferably 53008 benzoyl unsubstituted or substituted by for example halogen, such as bromine, for example phenacyloxycarbonyl, 2-halolower-alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl or 2-(trisubstituted silyl)-ethoxycarbonyl, wherein the substituents independently of one another are each an aliphatic, araliphacic, cycloaliphatic or aromatic hydrocarbon radical having for example, up to 15 C atoms and being unsubstituted or substituted for example by lower alkyl, lower alkoxy, aryl, halogen or nitro, such as corresponding, unsubstituted or substituted lower alkyl, phenyl-lower-alkyl, cycloalkyl or phenyl, for example 2-tri-lower-alkylsilylethoxycarbonyl, such as 2-trimethy1silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Further acyl radicals suitable as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as di-lower-alkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, for example dicyclohexylphosphoryl, unsubstituted or substituted diphenylphosphoryl, for example diphenylphosphoryl, diphenyl-lower-alkylphosphoryl unsubstituted or substituted by for example nitro, for example dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, unsubstituted or substituted phenyloxy-phenyl-phosphonyl, for example phenyloxyphenyl-phosphonyl, di-lower-alkylphosphinyl, for example diethylphosphinyl, or unsubstituted or substituted diphenylphosphinyl, for example diphenylphosphinyl.

In an arylmethylamino group, which is mono-, di- or particularly triarylmethylamino, the aryl groups are especially unsubstituted or substituted phenyl groups.

Such groups are for example benzyl, diphenylmethyl and in particular tritylamino.

An etherified mercapto group in an amino group protected by such a radical is above all arylthio or aryl-loweralkylthio, wherein aryl is particularly phenyL unsubstituted or substituted for example by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro. A corresponding amino-protecting group is for example 4-nitrophenylthio.

In a 2-acyl-lower-alk-l-en-l-yl radical applicable as an amino-protecting group, acyl is for example the corresponding radical of a lower-alkanecarboxylic acid, of a benzoic acid unsubstituted or substituted for example by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, or especially of a carbonic acid semiester, such as of a carbonic acid-lower-alkyl-semiester. Corresponding protecting groups are in particular 1-lower-alkanoylprop-l-en-2-yl, for example l-acetyl-prop-l-en-2-yl, or l-lower-alkoxycarbonylprop-l-en-2-yl, for example 1ethoxycarbonyl-prop-l-en-2-yl.

A silyl- or stannylamino group is especially an organic silyl- or stannylamino group, wherein the silicon or tin atom preferably contains as substituents lower alkyl, particularly methyl, also lower alkoxy, for example methoxy, and/or halogen, for example chlorine. Corresponding silyl or stannyl groups are in particular tri-lower-alkylsilyl, especially trimethylsilyl, also dimethyl-tert-butyl-silyl, lower-alkoxy-lower-alkyl-halo-silyl, for example methoxymethyl-chlorosilyl, or di-lower-alkyl-halosilyl, for example dimethyl-chlorosilyl, or correspondingly substituted stannyl, for example tri-n-butylstannyl.

An amino group can be protected also in protonated form; suitable as corresponding anions are in particular those of strong inorganic acids, such as of hydrohalic acids, for example the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino-protecting groups are acyl radicals 5 of carbonic acid semiesters, especially tert-butyloxycarbonyl, benzyloxycarbonyl unsubstituted or substituted for example as defined, for example 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl.

Compounds of the formula 1 having a basic amino group Am can form acid addition salts, for example with strong inorganic acids, such as hydrochloric or hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example trifluoroacetic acid or methanesulfonic acid.

The methoxyiminomethylene group is preferably in the syn form (Z form) .

The compounds of the formula I wherein Am is a free 20 amino group and their pharmaceutically acceptable non-toxic salts are valuable antibiotically effective substances which can be used in particular as antibacterial antibiotics. Por example, the compound of the formula I wherein Am is a free amino group, is methyl and Rj ethyl has in vivo, with oral administration to the mouse, in the case of systemic gram-negative infections, caused for example by Escherichia coli, Proteus spp. and others, an EDjQ-value of 0.3 to 150 mg/kg.

The novel compounds can therefore be used as anti30 bacterial oral antibiotics, for example in the form of pharmaceutical preparations to be administered orally, such as capsules, tablets, syrups or the like, for combating infections against which their use is intended. 53008 Compounds of the formula (I) wherein Am is a protected amino group are used as starting materials for producing antibiotically effective compounds of the formula I.

The esters of the present invention which can be split 5 under physiological conditions are distinguished by a surprisingly good resorption after oral administration, as is verified by the high renal output.

The present invention relates in particular to those compounds of the formula I wherein Am is a free amino group, is hydrogen or especially methyl, and Rg is ethyl, and to their pharmaceutically acceptable salts, as well as to the corresponding compounds having protected functional groups.

To be particularly emphasised is the compound of the formula (I) wherein Am is the free amino group, is methyl and Rg ethyl, and pharmaceutically acceptable salts thereof.

The invention relates in particular to the compounds of the formula I which are described in the Examples, and to their pharmaceutically acceptable salts.

The compounds of the present invention are produced by processes known perse.

Compounds of the formula I and salts thereof are thus produced by the following methods: a) the 7B-amino group in a compound of the formula H (II) COO-CH-O-CO-O-Rg R, wherein the amino group can be substituted by a group which is removed in the acylation procedure, and wherein and Rg have the meanings defined under the formula I, is acylated by treatment with an acylating agent introducing the acyl radical of a carboxylic acid of the formula AaN-OCH II 3 N-j·- C - COOH ιι II (III) wherein Am has the meanings defined under the formula I; or b) a compound of the formula N-OCH ? ii : X-CHgCO-C-CONH—· V ι COO-CH-O-CO-O-R, (IV) wherein X is halogen, and Rg have the meanings defined 10 under the formula I, is condensed with a thiourea of the formula Am-CS-NHg or with a salt thereof; or c) from a comDOund of the formula H Anr-1 N-OCH II J N-·- C - CONH ιι II (/ R / o I COO-CH-O-CO-O-R, I 2 R.

(V) wherein Am, R^ and Rg have the meanings defined under 15 the formula I, and RQ is hydroxyl, esterified hydroxyl or unsubstituted or substituted amino, a group H-Rq is split off; or d) to produce a compound of the formula I wherein Am, and Rg have the meanings defined under the formula I, the hydroxyimino group in a compound of the formula OH : A (vi) C00-CH-0-C0-0-R I 2 AaN-.·- C - CONH-* II II I wherein Am, R^ and Rg have the meanings defined under the formula I, is methylated; or e) to produce a compound of the formula I wherein Am, R^ and Rg have the meanings defined under the formula I, there is converted in a compound of the formula N-OCH II 3 •-C-COSH-* , ll Am-·.

A >· · * ι A / • I COOH (VII), wherein Am has the meaning defined under the formula I, the carboxyl group, optionally in salt form, in the 4-position of the cephem ring, by treatment with an esterifying agent of the formula X-CH-O-CO-O-Rg ' (VIII), *1 wherein X is a reactive esterified hydroxyl group, and R^ and Rg have the meanings defined under the formula 1, if necessary in the presence of a base, into an esterified carboxyl group; and/or f) to produce a compound of the formula I wherein Am is 2o a free amino group, and R^ and Rg have the meanings defined 53008 under the formula I, the amino-protecting group is split off from a compound of the formula 1 wherein Am is a protected amino group, and and Rg have the meanings defined under the formula I, and is replaced by hydrogen; and, if required, a resulting compound wherein Am is a free amino group, is, converted into a salt, or a salt obtained is converted into a free compound or into another salt.

Process a): Optionally present radicals, substituting the amino group and permitting the acylation thereof, in a starting material of the formula II are for example silyl or stannyl groups, also ylidene groups, which together with the amino group form a Schiff base. The said organic silyl or stannyl groups are for example the same groups that are also able to form with the 4-carboxyl group on the cephew ring a protected carboxyl group.

The ylidene groups mentioned are in particular arylmethylene groups, wherein aryl is especially a carbocyclic, particularly monocyclic, aryl group, for example phenyl which is unsubstituted or substituted by nitro or hydroxyl; such ary Imethyl groups are for example benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, also oxaeycloalkylidenes unsubstituted or substituted for'example by carboxyl, for example 3-carboxy-2-oxacydohexylidene.

Acylating agents introducing the acyl radical of a carboxylic acid of the formula (III) are for example the carboxylic acid itself or reactive functional derivatives thereof.

When a free acid of the formula III wherein all functional groups apart from the reacting carboxyl group are protected is used as the acylating agent, there are usually employed suitable condensation agents, such as carbodiimides, for example Ν,Ν'-diethyl-, Ν,Ν'-dipropyl-, Ν,Ν'-diisopropyl-, Ν,Ν'-dicyclohexyl- or N’ethyl-N'-352008 dimetbylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazolinium-3'-sulfonate and N-tert-butyl-5-methylisoxazolinium perchlorate, or an acylamino compound, for example 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline.

The condensation reaction is preferably performed in a reaction medium free from water, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, and, if desired or necessary, with cooling or heating and/or in an inert-gas atmosphere.

A reactive (i.e. amide-forming or ester-forming) functional derivative of an acid of the formula III wherein all functional groups apart from the reacting acid group can be protected is in particular an anhydride of such an acid, including and preferably a mixed anhydride, but also an inner anhydride, that is to say, a corresponding ketene. Mixed anhydrides are for example those with inorganic acids, such as hydrohalic acids, that is, the corresponding acid halides, for example acid chlorides or acid bromides, also with hydrazoic acid, that is, the corresponding acid azides, with a phosphorus-containing acid, for example phosphoric acid or phosphorous acid, or with a sulfur-containing acid, for example sulfuric acid, or with hydrocyanic acid. Further mixed anhydrides are for example those with organic carboxylic acids, such as with lower alkanecarboxylic acids unsubstituted or substituted for example by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with semiesters, especially lower alkyl semiesters of carbonic acid, such as the ethyl- or isobutyl-semiester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, for example p-tcluenesulfonic acid.

Further reactive acid derivatives of an acid of the formula III are activated esters, such as esters with vinylogous alcohols (i.e. enols), such as vinylogous lower alkenols, or aryl esters, such as 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters, such as benztriazole esters, for example 1-benztriazole ester, or diacylimino esters, such as succinylimino or phthalylimino ester.

The acylation with an acid derivative, such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as a tri-lower alkylamine, for example trimethylamine, triethylamine or ethyl-diisopropylamine, or N,N-di-lower alkylaniline, for example Ν,Ν-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a base of the pyridine type, for example pyridine, an inorganic base, for example a hydroxide, carbonate or bicarbonate of an alkali metal or alkaline-earth metal, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2alkylene oxide, such as ethylene oxide or propylene oxide. The reactive esters, for example the 1-benztriazole ester, are also used in the presence of one of the stated carbodiimides, for example N,N-dicyclohexylcarbodiimide.

The above acylation reactions are preferably performed in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide, such as formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, at room temperature, if necessary at reduced or elevated temperature, at about -40°C to about 100°C, preferably at -10eC to +40eC, and/or in an inert gas atmosphere, for example in a nitrogen atmosphere.

In an acylating acid of the formula III or in an acid derivative thereof, a protected amino group can also be in ionic form, that is to say, the starting material of the formula III can be used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a hydrohalic acid, for example hydrochloric acid, or sulfuric acid.

Furthermore, an acid derivative can if required be formed in situ. Thus, for example, a mixed anhydride is obtained by treating an acid of the formula III having appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, for example with an organic amine, such as 4-methylmorpholine, or a metal salt, for example an alkali metal salt, with a suitable acid derivative, such as a corresponding acid halide of an unsubstituted or substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, or with a semiester of a carbonic acid semihalide, for example chloroformic acid ethyl ester or isobutyl ester, and the mixed anhydride thus obtained is used without isolation.

Process b): In a starting compound of the formula IV, X is halogen, especially chlorine, but also bromine, iodine or fluorine. The thiourea is used in the free form or as a salt, particularly as thiolate of an alkali metal, such as lithium, sodium or potassium, and also as thiolate of an ammonium compound, in an equivalent amount or up to about a six-fold excess.

The reaction is generally performed in a solvent, such as water, or in an organic non-reactive solvent, or in a S2008 mixture thereof. Suitable organic solvents are alcohols, such as methanol, ethanol or isopropanol, ketones, such as acetone, ethers, such as dioxane or tetrahydrofuran, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, esters, such as ethyl acetate, or amides, such as dimethylformamide or dimethylacetamide, and the like. When the free compounds are used, the reaction can be carried out in the presence of a base. Suitable bases are alkali metal hydroxides, such.as sodium or potassium hydroxide, alkali metal carbonates, such as sodium or potassium carbonate, or organic tertiary nitrogen bases, such as tri-lower-alkylamines, for example trimethylamine, triethylamine, ethyl-diisopropylamine, pyridine, and the like. The reaction temperature is room temperature, or it can be higher or lower, preferably between -10 and +100’C, especially between 0 and +40°C.

The reaction may also be performed stepwise, in which case the ring-open intermediate having the partial formula Am-CC^NHJ-S-CHg-CO-Ci^NOCHg)- is firstly formed, and is then dehydrated in the second stage.

Process c): The group RQ in a starting material of the formula (V) can be free hydroxyl; it is however preferably esterified hydroxyl or unsubstituted or substituted amino.

An esterified hydroxyl group RQ can be esterified by an inorganic or organic acid, such as a strong mineral acid, for example a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydriodic.acid, or an organic carboxylic or sulfonic acid, including formic acid, such as a corresponding aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acid, also by a carbonic acid semiester. Thus, for example, Ro is halogen, such as chlorine, bromine or iodine, lower alkylsulfonyloxy, for example methane52008 sulfonyloxy or ethanesulfonyloxy, arylsulfonyloxy, for example benzenesulfonyloxy, or p-toluenesulfonyloxy, lower alkanoyloxy, for example acetyloxy or propionyloxy, arylcarbonyloxy, for example benzoyloxy, or lower alkoxycarbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyloxy. An unsubstituted or substituted amino group R is a primary, secondary or tertiary amino 1 0 2 1 2 group -N(RQ) (Rq), wherein Rq and RQ independently of one another are each hydrogen, or an unsubstituted or sub10 stituted aliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, or together they are an unsubstituted or substituted polymethylene group which can be interrupted by hetero atoms, such as oxygen, sulfur or nitrogen. Such amino groups Rq are for example amino, mono- or di-lower alkylamino, such as methyl-, ethyl-, propyl-, dimethyl-, diethyl-, dipropyl-, methyl-ethyl- or methyl-propyl-amino, mono- or dicyclohexylamino, diphenylamino, benzyl-, dibenzyl- or phenylethyl- or diphenylethylamino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino or 4-lower-alkylpiperazino.

The splitting-off of a compound of the formula Rq-H, that is to say, of water, of an acid or of an amine, is preferably performed by treatment with suitable agents splitting off water, an acid or an amine. Water and amines are preferably split off in the presence of acid-, water- or amine-detaching agents, for example in the presence of an acid, preferably a strong organic carboxylic or sulfonic acid, such as halo-lower-alkanecarboxylic acid, for example trifluoroacetic acid, or an arylsulfonic acid, for example p-toluenesulfonic acid, a suitable acid derivative, such as an anhydride or, in particular, a halide, such as chloride, especially in the presence of an inorganic acid, for example a phosphorus- or sulfur17 53008 containing acid, for example phosphorus oxychloride or thionyl chloride, such a derivative, if water is to be split off, being usually employed in the presence of a base, such as a tertiary organic base, for example pyridine, or in the presence of a suitable acid ionexchanger, such as an ion exchanger based on sulfonic acid, for example a sulfonated polystyrene ion-exchanger. For splitting off water, it is also possible to use dehydrating carbodiimide compounds, for example dicyclohexylcarbodiimide, or dehydrating carbonyl compounds disubstituted by way of nitrogen atoms, for example carbodiimidazole. These agents are customarily used in the presence of a solvent, such as an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, for example benzene or toluene, or a solvent mixture; and suitable acid agents, such as trifluoroacetic acid, can also be used simultaneously as solvents. There is additionally used If necessary a water-absorbing agent or a water separator, and the reactions are performed with cooling or heating and/or in an inert gas atmosphere, for example in a nitrogen atmosphere.

In a starting material of the formula V, Rq is preferably an esterified hydroxyl group, and according to the invention an acid of the formula H-RQ is split off. There are usually employed for this purpose basic agents splitting off and/or neutralising acids, for example inorganic bases, such as diluted alkali metal hydroxides, for example sodium or potassium hydroxide; and besides water it is also possible to use organic solvents, such as suitable ketones, for example acetone, or ethers, for example dioxane, or aqueous mixtures thereof, and to perform the reactions at a pH-value of at most about 9, and if necessary with cooling or heating and/or in an inert-gas atmosphere, for example in a nitrogen atmosphere.

As agents splitting off acid, there are preferably used tert-amines, especially good proton acceptors, which do not attack the lactam ring, in particular tertaliphatic or tert-cycloaliphatic mono- and diamines, such as tri-lower-alkylamines, for example trimethylamine, triethylamine or ethyl-diisopropylamine, or bicyclic diaza compounds having an amidine-like arrangement of the ring nitrogen atoms, for example 1,5-diazabicyclo [4.3,0jnon-5-ene or l,5-diazabicyclol5.4.0]undec-5-ene.

The agents splitting off acid which are used can also be basic ion-exchangers, for example those based on ammonium hydroxide. Certain esterified hydroxyl groups RQ, in particular sulfonyloxy, for example methylsulfonyloxy groups, can be split off in the form of an acid of the formula Rq-H from compounds of the formula V also by absorption, for example on silica gel, aluminium oxide, and so forth, and by elution (chromatography).

The acid removals described above can be performed in the absence of a solvent, but usually they are performed in the presence of a solvent, such as an optionally halogenated hydrocarbon of aliphatic, cycloaliphatic or aromatic character, such as methylene chloride, a lower alkanone, for example acetone, or in the presence of an ether, for example tetrahydrofuran or dioxane, or of a solvent mixture, including an aqueous mixture, if necessary with cooling or heating, at -30° to 150°C, preferably at about -10° to 60°C, and/or in an inert-gas atmosphere, for example in a nitrogen atmosphere.

Process d): The methylation of the hydroxyiminomethylene group in a compound of the formula VI is performed, in a manner known per se, by treatment with a methylating agent.

Besides the hydroxyimino group in the starting material, all optionally present further functional groups are preferably protected.

Suitable methylating agents are for example: diazomethane, reactive esters of methanol, such as methyl halides, for example methyl iodide, sulfonic acid esters, for example methanesulfonic acid, trifluoromethanesulfonic or p-toluenesulfonic acid methyl esters, or sulfuric acid esters, for example dimethyl sulfate, dimethylacetals, for example 2,2-dimethoxypropane, ortho esters, for example orthoformic acid trimethyl esters, trimethyloxonium salts, for example trimethyloxoniumfluoroantimonate, -hexachloroantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbonium salts, for example dimethoxycarboniumhexafluorophosphate, or dimethylhalonium salts, for example dimethylbromonium-hexafluoroantimonate, or 3-aryl-lmethyl-triazene compounds, for example 3-p-tolyl-l-methyltriazene. The methylation reaction is performed in a manner known per se, usually in an inert solvent, such as an ether, for example dioxane or tetrahydrofuran, or in an optionally halogenated hydrocarbon, such as benzene, chlorobenzene, methylene chloride, and the like, optionally in the presence of suitable condensation agents, such as bases or acids, with cooling or heating, for example at temperatures between about -20° and about 10Q°C.

Process e): A reactive esterified hydroxyl group X in a compound of the formula VIII is a hydroxyl group esterified by a strong inorganic or organic acid. Corresponding X groups are in particular halogen, for example chlorine, bromine or preferably iodine, also sulfonyloxy groups, such as lower alkane- or arenesulfonyloxy groups, for example methane-, ethane, benzene- or toluenesulfonyloxy groups, or halosulfone groups, for example the chlorosulfone group, and the like.

The esterification of the 4-carboxyl group, optionally in salt form, is performed in a manner known per se, if necessary in 2008 the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower-alkylamine, for example trimethylamine, triethylamine or ethyl-diisopropylamine, an Ν,Ν-di-lower-alkyl-aniline, for example Ν,Ν-dimethylaniline, a cyclic tertiary amine, such as an N-loweralkylated morpholine, for example N-methylmorpholine, a base of the pyridine type, for example pyridine, an inorganic base, for example hydroxides, carbonates or hydrogen carbonates of alkali metals or alkaline-earth metals, for example sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or a quaternary ammonium base, such as a tetraalkylammonium hydroxide, carbonate or hydrogen carbonate, for example in which there is alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, or the like, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The carboxylic acid of the formula VII is preferably firstly converted into a salt of one of the stated organic or inorganic bases, especially into the sodium salt, and this is then reacted with a compound of the formula VIII.

A compound of the formula VIII can also be produced in situ. For example, a compound of the formula VIII wherein X is chlorine can be converted by treatment with sodium iodide in a solvent, for example in acetone or acetonitrile, into a compound of the formula VIII wherein X is iodine; or esterification can be carried out with a chlorine compound of the formula VIII in the presence of sodium iodide.

The esterification reaction is performed in a suitable solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, at room temperature, if necessary at a reduced or elevated temperature, about at -40° to about 100°C, preferably at -10’ to +40’C, and/or in an inert-gas atmosphere, for example in a nitrogen atmosphere.

Process f): A protected amino group Am is liberated, in a manner known per se, and depending on the protecting groups in various ways, preferably by means of solvolysis or reduction. 2-Halo-lower-alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower-alkoxycarbonylamino group into a 2-iodo-lower-alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be split for example by treatment with a suitable chemical reducing agent, such as zinc, in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can be split also by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitro-benzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite. Unsuhstituted or substituted diphenylmethoxycarhonylamino, tert-loweralkoxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino can be liberated by treatment with a suitable acid, for example formic or trifluoroacetic acid; unsubstituted or substituted benzyloxycarbonylamino for example by means of hydrogenolysis, that is., by treatment with hydrogen in the presence of a suitable hydrogenating catalyst, such as a palladium catalyst; unsubstituted or substituted triarylwethylamino, formylamino or 2-acyl-lower-alk-l-en-lyl-amino for example by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, 2008 optionally in the presence of water; and an amino group protected with an organic silyl or stannyl group can be liberated for example by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the formed condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can also be converted, by treatment with a hydrofluoric acid salt supplying fluoride anions, into the free amino group. A phosphorus-, phosphone- or phosphine-amido group can be converted into the free amino group for example by treatment with a phosphorus-containing acid, such as phosphoric, phosphonic or phosphinic acid, for example orthophosphoric acid or polyphosphoric acid, an acidic es.ter, for example monomethyl-, monoethyl-, dimethyl- or diethylphosphate or monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide.

The cleavage reactions described are performed in other respects under conditions known per se, if necessary with cooling or heating, in a closed'vessel and/or in an inertgas atmosphere, for example in a nitrogen atmosphere.

Selective cleavage reactions are preferably performed, that is to say, those in which the ester grouping and the methoxyimino group are not attacked at all or are only slightly attacked. A preferred method of this type is the acidolytic splitting-off of a tert-lower-alkoxycarbonyl group, especially the tert-butoxycarbonyl group, by means of a suitable acid, particularly trifluoroacetic acid, optionally in an inert solvent, such as an optionally halogenated hydrocarbon, for example methylene chloride, at temperatures of about -20° to about 50°C, preferably at 0° to room temperature.

Acid addition salts of compounds of the formula I wherein Am is a free amino group are obtained in a customary manner, for example by treatment with an acid or a suitable anion-exchange reagent.

The processes embrace also those embodiments wherein compounds occurring as intermediates are used as starting materials, and the remaining steps of the process are then carried out with them; or wherein the process is interrupted at some stage; or wherein starting materials are used in the form of derivatives, or are formed in situ, optionally under the reaction conditions .

The starting compounds of the formulae II to VIII are known, or can be produced by methods analogous to known methods .

The pharmacologically acceptable compounds of the present invention can be used, for example, for producing pharmaceutical preparations which contain an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral administration.

For enteral administration are used tablets or gelatine capsules which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, for example diatomaceous earth, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; tablets likewise contain binders, for example magnesium aluminium silicate, starches, such as maize, wheat, rice or arrowroot starch, gelatine, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if required, disintegrating agents, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or 2008 effervescent mixtures, or adsorption agents, colouring agents, flavouring agents and sweetening agents. Suppositories are in particular fatty emulsions or suspensions.

The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, dissolving or lyophilising processes, and they contain from about 0.1% to 100%, particularly from about 1% to about 50%, of lyophilisates to up to 100% of active substance. Depending on the nature of the infection and condition of the infected organism, there are used daily dosages of about 0.25 g to about 2 g orally for the treatment of warm-blooded animals of about 70 kg in weight.

The following Examples serve to further illustrate the invention. Temperatures are in degrees Centigrade. The methoxyimino group has the syn configuration.

Example 1 g of α-iododiethyl carbonate are added to an icecooled solution of 10 g of 70-[2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4carboxylic acid sodium salt In 40 ml of dimethylformamide, and the mixture is firstly stirred for 15 minutes with icecooling and then for 45 minutes at room temperature. The · reaction mixture is poured into ice-water, and subsequently extracted with ethyl acetate. The organic phase is washed successively with aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution; it is then concentrated in vacuo and dried under high vacuum.

The crude product is chromatographed on 200 g of silica gel with toluene and toluene containing increasing amounts of ethyl acetate (10 to 30%). The fractions containing the product of the Rf value/v0.26 (silica gel; ethyl acetate) are combined and concentrated in vacuo. The residue is dispersed in a mixture of diethyl ether and hexane , and the dispersion is dried under high vacuum to thus obtain 70-(2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2methoxyiminoacetamidol-3-cephem-4-carboxylic acid-1ethoxycarbonyloxyethyl ester.

IR spectrum (CHgClg): characteristic absorption bands at 3400, 1796, 1765, 1728, 1690; 1548 cm’1·; UV spectrum (ethanol): λ max - 228 (£- 18,800), 260 (£ « 17,000) mg. Example 2 .5 ml of trifluoroacetic acid are added to a solution of 6 g of 70-[2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2methoxyiminoacetamidoJ-3-cephem-4-carboxylic acid-1ethoxycarbonyloxyethyl ester in 30.5 ml of methylene chloride, and the mixture is stirred for one hour at room temperature. To the reaction mixture is added twice a mixture of toluene and chloroform (1:1) and once diethyl ether, and each time the mixture is evaporated in vacuo.

The residue is taken up in ethyl acetate, and the solution is washed three times with concentrated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution, and is subsequently concentrated in vacuo. The residue is chromatographed on silica gel with toluene and toluene containing increasing amounts of ethyl acetate (10 to 50%). The fractions containing the pure product of Rf value az 0.22 (silica gel; ethyl acetate) are combined, and then concentrated in vacuo. The residue is digested with diethyl ether, and dried under high vacuum to give the 70-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester; decomposition point: 122-128’C; IR spectrum (CHgClg): characteristic absorption bands at 3400, 1785 (wide), 1765, 1608, 1530 cm”1·; UV spectrum (ethanol): λ fflax 235 (16500) and shoulder at 258 mp. Example 3 In a manner analogous to that of the preceding Examples, there is produced, starting with the sodium salt of 70-(2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido ]-3-cephem-4-carboxylic acid, by reaction with iodomethylethylcarbonate, the 70-(2-(2-tert-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3cephem-4-carboxylic acid-ethoxycarbonyloxymethyl ester, which, after treatment with trifluoroacetic acid, yields the 70-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3cephem-4-carboxylic acid-ethoxycarbonylaminomethyl ester; IR spectrum (CH^C^): characteristic absorption bands at, inter alia, 3400; 1782; 1760; 1610; 1535 cm .

Example 4 ml of an 0.18 M HCl solution in C^Clj (1.1 molar equivalents, produced by introducing anhydrous gaseous hydrogen chloride into anhydrous CHgClg) are added to a solution, cooled to 0°C, of 5 g of 70-(2-(2-amino-4thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxyLie acid-l-ethoxycarbonyloxyethyl ester (free base) in 50 ml of CHjC^· After the solution has been stirred for 10 minutes, diethyl ether is added and a precipitate is formed. The mixture is subsequently stirred at 0°C for 1/2 hour; the precipitate is then filtered off, washed with diethyl ether, and dried at 30°C under high vacuum. The crude hydrochloride obtained is dissolved in about 50 ml of c^e solution is to some extent concentrated by evaporation, and is left to stand overnight at about +5°C.

The 70-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester hydrochloride which has precipitated is filtered off, washed with a small amount of CHjClj and diethyl ether and dried as before.

Example 5 In a manner analogous to that of Example 4, there is obtained, by reaction of 5 g of 70-(2-(2-amino-4-thiazolyl)2-methoxyiminoacetamidol-3-cephem-4-carboxylic acid-1ethoxycarbonyloxyethyl ester (free base) in methylene chloride with 27.2 ml of a 0.46 M hydrogen bromide solution in methylene chloride, 70-{2-(2-amino~4-thiazolyl)-2methoxyiminoacetamido] -3~cephem-4-carboxylic acid-1ethoxycarbonyloxyethyl ester hydrobromide.

Example 6 0.6 g of “-iodafifithyl carbonate is added to a suspension of 0.405 g of the sodium salt of 70-(2-(2-amino-4thiazolyl) -2-methoxyiminoacetamidol -3-cephem-4-carboxylic acid in 4 ml of dimethylformamide, and the mixture is stirred at about -5°C for 40 minutes. The reaction mixture obtained is poured into ice-cooled phosphate buffer solution pH 8; the mixture is then stirred for 15 minutes and extracted with ethyl acetate. The organic phase is extracted successively with phosphate buffer solution and saturated aqueous sodium chloride solution, and concentrated in vacuo to a volume of about 15 ml. To the solution obtained are added 8 ml of a 1.46 N hydrochloric acid solution in methylene chloride and subsequently diethyl ether. The resulting precipitate is reprecipitated twice from methylene chloride/diethyl ether to yield, after drying, 70-(2-(2-amino-4-thiazoly1)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester hydrochloride; melting point from 145°C (decomposition). Rf^'0.20 (silicagel; ethyl acetate); IR spectrum (paraffin oil): characteristic absorption bands at 3400, 1783 (b), 1766, 1740 (sh), 1680, 1605 cm*1 .

Example 7 A mixture of 0.18 ml of dimethylformamide, 0.2 ml of oxalyl chloride and 8 ml of methylene chloride is allowed to react at about -5°C for 30 minutes; there are subsequently added 0.57 g of 2-(2-tert-butOxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetic acid and 0.3 ml of N-methylmorpholine, and the mixture is stirred at -5°C for a further 30 minutes. After the addition of a solution of 0.71 g of 7p-amino-3-cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester hydrochloride and 0.6 ml of N-methylmorpholine in 7 ml of methylene chloride, the reaction mixture is further stirred for 30 minutes at -5°C and for 30 minutes at 0°C; it is then diluted with ethyl acetate, and washed successively with 1 N hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with toluene containing 10-20% of ethyl acetate to thus obtain 7β-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester having the same properties as in Example 2.

The starting material is produced as follows: A suspension of 2 g of 70-amino-3-cephem-4-carboxylic acid in 20 ml of dimethylacetamide is stirred v?ith 1.5 ml of l,5-diazabicyclo[5.4.0]undec-5-ene for 15 minutes at room temperature; the mixture is cooled to -10°C, 2.6 g of α-iododiethyl carbonate are added, and the mixture is allowed to react at -10°0 for 30 minutes. The mixture is subsequently poured into ice-water, the pH value is adjusted to 6, and extraction is performed with ethyl acetate. The organic phase is extracted with saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated in vacuo to about 30 ml. To the solution obtained are added 1.3 mol equivalents of an ethanolic hydrochloric acid solution, and after being stirred for 30 minutes with ice-cooling the mixture is treated with diethyl ether. The formed precipitate of 70-amino-3cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester hydrochloride is filtered off, washed several times with diethyl ether and dried; melting point about 200°C (decomposition); Rf/v 0.23 (silicagel, toluene/ethyl acetate 1:1).

Example 8 Capsules containing 0.250 g of 70-2-(2-amino-4thiazolyl)-2-methoxyiminoacetamidol-3-cephem-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester are produced as follows: Composition (for 100,000 capsules) 70-[2-(2-amino-4-thiazolyl)-2-methoxy-iminoacetamido]-3-cephem-4-carboxylic acid-115 ethoxycarbonyloxyethyl ester 25,000 g wheat starch 2,500 g magnesium stearate 1,000 g .

The 7β-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidoI-3-cephem-4-carboxylic acid-l-ethoxycarbonyl2o oxyethyl ester, the wheat starch and the magnesium stearate are well mixed together and filled into capsules No. 1.

Example 9 Capsules containing 0.5 g of 7)3-[2-(2-amino-425 thiazolyl) -2-methoxyiminoacetaraidol-3-cephern-4-carboxylic acid-l-ethoxycarbonyloxyethyl ester are produced as follows: Composition (for 2000 capsules) 7β-[2-(2-amino-4-thiazolyl)-2-methoxyimino30 acetamidoI-3-cephem-4-carboxylic acid-lethoxycarbonyloxyethyl ester 1000.00 g polyvinylpyrrolidone 15.00 g maize starch 115.00 g magnesium stearate 20.00 g .

The 7β-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-l-ethoxycarboriyloxyethyl ester is moistened with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol; the mixture is then put through a sieve of 3 mm mesh size, and the granulate is dried at 40-50eC under reduced pressure. It is subsequently- put through a sieve having a mesh size of 0.8 mm, the maize starch and magnesium stearate are added, and the mixture is filled into hard gelatine capsules (size 0).

Example 10 Tablets containing 250 mg of 7£-[2-(2-amino-4thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-lrethoxycarbonyloxyethyl ester are produced as follows: Composition (for 1 tablet) 7/5-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid-l-ethoxy- carbonyloxyathyl ester 250 mg microcrystalline cellulose 80 mg sodium carboxymethyl starch 10 mg magnesium stearate 3 mg talcum 7 mg 350 mg The active substance is homogeneously mixed with the additives, and the mixture is pressed to form tablets.

To produce coated dragees,the tablets are each coated with 1 mg of aqueous lacquer.

It is also possible to use sodium carboxymethyl 30 cellulose in place of sodium carboxymethyl starch.

Instead of the free base in Examples 8 to 10, there can also be used a salt, for example the hydrochloride or hydrobromide, as the active ingredient.

Claims

1. CLAIMS:1. A compound of the formula I I I -\ / (I) • I COO-CH-O-CO-O-R, I 2 wherein R^ is hydrogen or lower alkyl, R 2 is lower alkyl, 5 and Am is an optionally protected amino group, and acid addition salts of such a compound, wherein Am is a free amino group.

2. A compound acoording to claim 1, wherein Am is a free amino group. 10

3. A compound according to Claim 1 or 2, wherein Am is a free amino group, R^ is hydrogen or methyl, and R 2 is ethyl.

4. A compound according to Claim 1, wherein Am is a free amino group, R^ is methyl, and R 2 is ethyl. 15 5. The acid addition salts of a compound according to any one of Claims 1-4. 6. The hydrochloride of a compound according to any one of Claims 1-4. 7. The hydrobromide of a compound according to any 20 one of Claims 1-4. 8. Pharmaceutical preparations containing any one of the compounds of the formula I, wherein Am is a free amino group or a pharmaceutically acceptable acid addition salt thereof described in Claims 1-7 and a pharmaceutically acceptable carrier.

5. 9. Compounds of the formula I wherein Am is a free amino group and pharmaceutically acceptable salts thereof according to any one of Claims 1-7 for use in a method of combatting bacterial infections.

6. 10. Compounds according to any one of Claims 1-7 for 10 use as oral antibiotics.

7. 11. A process for producing a compound of the formula I and acid addition salts of such a compound, according to Claim 1, characterised in that a, the 7S-amino group in a compound of the formula H C00-CH-0-C0-0-R 2 wherein the amino group can be substituted by a group which is removed in the acylation procedure, and wherein γ and have the meanings defined under the formula I, is acylated by treatment with an acylating agent intro20 ducing the acyl radical of a carboxylic acid of the formula N-OCH, II 3 κ-—C-C00H II II • · (IU) Απτ* wherein Am has the meanings defined under the formula I; or b) a compound of the formula N-OCH, II 3 5 X-ClljCO-C-CONK:h-o-co-o-r 2 (XV) wherein X is halogen, R^ and Rg have the meanings defined under the formula I, is condensed with a thiourea of the formula Am-CS-NHg or with a salt thereof; or ¢) from a compound of the formula H . 11 Am··, II N-OCH, . 11 3 : A -C-CONH-*(V) I COO-CH-O-CO-O-R, I 2 R ! wherein Am, R^ and Rg have the meanings defined under the formula I, and R Q is hydroxyl, esterified hydroxyl or unsubstituted or substituted amino, a group H-R Q is split off; or IQ d) to produce a compound of the formula I wherein Am, R^ and Rg have the meanings defined under the formula I, the hydroxyimino group in a compound of the formula OH \ N II -C-CONHAmII (VI) COO-CH-O-CO-O-Rg wherein Am, R^ and Rg have the meanings defined under the formula I, is methylated; or e) to produce a compound of the formula I wherein Am, R^ and Rg have the meanings defined under the formula I, there is converted in a compound of the formula N-OCH, II i —C-CONH— AmCOOH A V (VII), wherein Am has the meaning defined under the formula I, the carboxyl group, optionally in salt fora, in the 4-position of the cephem ring, by. treatment with an esterifying agent of the formula X-CH-O-CO-O-R. I *1 wherein X is a reactive esterified hydroxyl group, and R^ and Rj have the meanings defined under the formula I, if necessary in the presence of a base, into an esterified carboxyl group; and/or f) to produce a compound of the formula I wherein Am is a free amino group, and Rj and R 2 have the meanings defined under the formula I, the amino-protecting group is split off from a compound of the formula I wherein Am is a protected amino group, and R^ and R 2 have the meanings defined under the formula I, and is replaced by hydrogen; and, if required, a resulting compound wherein Am is a free amino group, is converted into a salt, or a salt obtained is converted into a free compound or into another salt.

8. 12. A process for producing a compound of tha formula I according to Claim 11, wherein Am is a free amino group.

9. 13. A process for producing a compound of the formula I according to Claim 11 or 12, wherein Am is a free amino group, R^ is hydrogen or methyl, and R 2 is ethyl.

10. 14. A process for producing a compound of the formula I according to Claim 11, wherein Am is a free amino group, R^ is methyl, and R 2 is ethyl.

11. 15. A process according to Claim 11 for producing acid addition salts of a compound of the formula X wherein Am is a free amino group obtained according to any one of Claims 11-14.

12. 16. A process according to Claim 11 for producing the hydrochloride of a compound of the formula I wherein Am is a free amino group obtained according to any one of Claims 11-14. 5

13. 17. A process according to Claim 11 for producing the hydrobromide of a compound of the formula I wherein Am is a free amino group obtained according to any one of Claims 11-14.

14. 18. Compounds of the formula (I) and salts thereof 10 according to Claim 1 substantially as herein described, particularly with reference to the accompanying examples.

15. 19. A process for the manufacture of compounds of the formula (I) and salts thereof according to Claim 1 substantially as herein described, particularly with X5 reference to the accompanying examples.

16. 20. Pharmaceutical preparations according to Claim 8 substantially as herein described, particularly with reference to the accompanying examples.

17. 21. Compounds of the formula (X) wherein Am is a free 20 amino group and pharmaceutically acceptable acid addition salts thereof according to any of claims 1 to 7 substantially as herein described, particularly with reference to the accompanying examples, for use in a method of combatting bacterial infections.

18. 25 22. Compounds of the formula (I) and salts thereof whenever prepared by the process of any one of Claims 11-17 or Claim 19.