DD208155A5 - NEW ESTERS WITH A P = N-Y GROUPING - Google Patents

Abstract

The invention relates to new, cleavable under physiological conditions 1-Niederalkoxycarbonyloxyniederalkylester of 7ss = (2- (2-amino-4-thiazolyl) -2- (syn) methoximinoacetamido) -3-cephem-4-carboxylic acid, process for their preparation and pharmaceutical preparations containing such compounds.

Description

235540 A

Process for the preparation of new esters Field of application of the invention

The invention relates to a process for the preparation of new ester compounds.

The esters prepared according to the invention are used as antibiotics in the form of pharmaceutical preparations.

Characteristics of known technical solutions 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, including some physiologically cleavable esters, for example pivaloyloxymethyl esters, are known from German Offenlegungsschrift 28 10 922 and European patent application 2 273, respectively. These compounds are valuable, antibiotically active substances that can be used in particular as antibacterial antibiotics. While the salts are suitable only for parenteral administration, the esters cleavable under physiological conditions have the advantage of being effective even after oral administration.

One of the disadvantages of pivaloyloxymethyl ester is that it is difficult to clean. So it has not been able to capture it in crystalline form. Because of its amorphous and impure character, it has a low stability, which adversely affects the storage and the compression of tablets. When processing into tablets and filling in ampoules also makes his

17th FE & 1982 * 990948

»La -

2355 40 4

relatively low flowability unpleasantly noticeable. The low water solubility of the ester causes a non-uniform absorption after oral administration.

There is a further need for orally administrable compounds which are resistant to the known oral cephalosporins, e.g. also of the phenylglycine type, have improved properties. Surprisingly, it has been found that with certain esters, the pharmacological properties can be substantially improved.

Object of the invention

The aim of the invention is to provide a process for the preparation of new ester compounds which develop a particularly good antibiotic activity after oral administration.

Explanation of the essence of the invention

The invention has for its object to find compounds with oral antibiotic activity and methods for their preparation.

According to the invention, novel, cleavable under physiological conditions esters of 7ß ~ [2- (2-amino-4-thiazoiyl) -2 ~ (syn) -methoxyiminoacecamido] ~ 3-cephem-4-carboxylic acid prepared.

In particular, compounds of the formula 1

235540 A

STILL_

_no . _C0NH .

- · · _y - -N

COO-CH-O-COO-R

, ^{2 R} i

wherein R is hydrogen or lower alkyl, R _{2 is} lower alkyl and Am is an optionally protected amine group, and acid addition salts of such salt-forming group compounds.

In the present description of the invention, the term "lower" in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl and the like means that the corresponding groups, unless expressly defined otherwise, contain up to 7, preferably up to 4 carbon atoms.

A lower alkyl group R or R _? in particular CC, -lower alkyl, such as methyl, ethyl, propyl, isopropyl or butyl. Preferably, R _{1 is} methyl and R "is ethyl.

In a protected amino group Am, the protecting group is one of those used in penicillin, cephalosporin and peptide chemistry.

Such a protecting group is light, that is without unwanted side reactions take place, for example, solvolytic, reductive or photolytically cleavable.

235540 4

Protecting groups of this type, as well as their cleavage, are described for example in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, also in "The Peptides", Vol. I, Schröder and Lübke, Academic Press, London, New York, 1965, and in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 16/1, Georg Thieme Verlag, Stuttgart, 1974.

A protected amino group Am may e.g. in the form of an easily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-en-1-ylamino, silyl or stannylamino group.

For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or aryl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2 , 2-trichloroacetyl, optionally, for example halo, lower alkoxy or nitro substituted benzoyl, e.g. Benzoyl, 4-chlorobenzoyl, 4-metho-cybenzoyl 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, in particular tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, preferably optionally, e.g. by lower alkyl, in particular tert-lower alkyl, such as

tert-butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, aroyl

2355/10 4

methoxycarbonyl wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, wherein the substituents each independently represent an optionally substituted, e.g. by lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical with e.g. up to 15 C-atoms, such as corresponding, optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, e.g. 2-tri-lower alkylsilylethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

Other acyl radicals which may be used as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as diloweralkylphosphoryl, e.g. Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally substituted diphenylphosphoryl, e.g. Diphenylphosphoryl, optionally, e.g. nitro-substituted diphenyl-lower alkylphosphoryl, e.g. Dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, optionally substituted phenyloxy-phenyl-phosphonyl, e.g. Phenyloxyphenyl phosphonyl, dilower alkyl phosphinyl, e.g. Diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g. Diphenylphosphinyl.

In an arylmethylamino group which is mono-, di- or in particular triarylmethylamino, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are for example benzyl, diphenylmethyl and especially tritylamino.

2 355AO 4

An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, wherein aryl is especially optionally, e.g. is phenyl substituted 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 e.g. 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl radical useful as an amino-protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a carbonic monoester, such as a carbonic acid lower alkyl. Corresponding protecting groups are primarily 1-lower alkanoyl-propene-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, wherein the silicon or tin atom is preferably lower alkyl, especially methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, for example. Chlorine, as a substituent. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, e.g. Methoxy-methyl-chloro-silyl, or di-lower alkyl-halosilyl, e.g. Dimethyl-chloro-silyl, or appropriately substituted stannyl, e.g. Tri-n-butylstannyl.

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

23554

Preferred amino-protecting groups are acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally, e.g. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or Fonnyl.

Compounds of formula I having a basic amino group Am may be acid addition salts, e.g. with strong inorganic acids, such as hydrochloric or hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Form trifluoroacetic acid or methanesulfonic acid.

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

The compounds of formula I wherein Am is a free amino group and their pharmaceutically acceptable non-toxic salts are valuable antibiotic active substances which can be used especially as antibacterial antibiotics. For example, the compound of the formula I in which Am is a free amino group, R is methyl and R "is ethyl, in vivo , when administered orally to the mouse, in systemic Gram-negative infections, for example by Escherichia coli, Proteus spp. and others, an ED value of 0.3 to 150 mg / kg.

oU

The new compounds can therefore be used as antibacterial oral antibiotics, e.g. in the form of orally administrable pharmaceutical preparations, such as capsules, tablets, syrups or the like, find use for controlling appropriate infections.

235 5 40

Compounds of formula (I) wherein Am is a protected amino group are used as starting materials for the preparation of antibiotic compounds of formula Ϊ.

The physiologically cleavable esters of the present invention are characterized by surprisingly good absorption after oral administration, as evidenced by high renal excretion.

The present invention relates in the first place to those compounds of the formula I in which Am is a free amino group, R is hydrogen or in particular methyl and R is ethyl, and their pharmaceutically acceptable salts, and the corresponding compounds having protected functional groups.

Of particular note is the compound of formula (I) wherein Am is the free amino group, R is methyl and R is ethyl, and their pharmaceutically acceptable salts.

The invention relates in particular to the compounds of the formula I described in the examples and their pharmaceutically acceptable salts.

The compounds of the present invention are prepared by methods known per se.

Thus, compounds of formula I are prepared by reacting a) the 7β-amino group in a compound of formula

235540 A

^H 2 ^N -j-i ^{/ N} j (II),

COO-CH-O-COO-R

^R l

wherein the amino group is optionally substituted by an acylation-permitting group and wherein R and R have the meanings given under formula I, by treatment with an acyl radical of a carboxylic acid of the formula

STILL

^0H

acylating agent, wherein Am has the meanings given under formula I acylated, or b) a compound of formula

STILL ?

II * S

     ·

c / γ

COO-CH-O-COO-R

in which X is halogen, R and R have the meanings mentioned under formula I, with a thiourea of. Formula Am-CS-NH or a salt thereof condensed, or

c) from a compound of the formula

23554

STILL.

ι! ³

N · -C - CONH - · · ·> (V),

Il

COO-CH-O-CO-O-R I

^R i

wherein Am, R and R have the meanings given under formula I and R is hydroxy, esterified hydroxy or optionally substituted amino, cleaves a group H-R, or

d) for the preparation of a compound of the formula I in which Am, R and R have the meanings given under formula I, in a compound of the formula

OH

Ii · A

N - C - CONH-- · · (VI),

COO-CH-O-CO-O-R

I ²

R

wherein Am, R and R have the meanings given under formula I, the hydroxyimino group methylated, or

e) for preparing a compound of the formula I in which Am, R and R ^ have the meanings given under formula I, in a compound of the formula

STILL

II p

COOH

235540

wherein Am has the meaning given under formula I, the optionally present in salt carboxyl group in the 4-position of the cephem ring by treatment with an esterifying agent of the formula X-CH-O-CO-O-R

I (VIII),

wherein X is a reactive, esterified hydroxy group and R and R have the meanings given under formula I, converted into an esterified carboxyl group, and / or

f) for the preparation of a compound of formula I, wherein Am is a free amino group and R and R have the meanings given under formula I, from a compound of formula I, wherein Am is a protected amino group, and R and R are the Formula I given, the amino protecting group split off and replaced by hydrogen, and, if desired, a compound obtained wherein Am a free amino group is converted into a salt or a salt obtained in a free compound or in another salt.

Process a) : Optionally present radicals which substitute the amino group and allow their acylation in a starting material of the formula II are, for example, organic silyl or stannyl groups, and also ylidene groups which form a Schiff base together with the amino group. The said organic silyl or stannyl groups are, for example, the same as those capable of forming a protected carboxyl group with the 4-carboxyl group on the cephem ring.

The said ylidene groups are primarily arylmethylene groups in which aryl is in particular a carbocyclic, primarily monocyclic aryl radical, e.g. is optionally substituted by nitro or hydroxy-substituted phenyl; such arylmethyl groups are e.g. Benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further optionally, e.g. carboxy-substituted oxacycloalkylidene, e.g. S-carboxy-Z oxacyclohexyliden.

23554

The acylating agent which introduces the acyl radical of a carboxylic acid of the formula (III) are, for example, the carboxylic acid itself or reactive functional derivatives thereof.

If a free acid of the formula III, in which all functional groups except the reactive carboxyl group are protected, is used as the acylating agent, it is customary to use suitable condensing agents, such as carbodiimides, for example N, N'-diethyl, Ν, Ν'-dipropyl, N.N'-diisopropyl, Ν, Ν'-dicyclohexyl or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazolinium-3 'sulfonate and N-tert-butyl-S-methyl-isoxazolinium perchlorate, or an acylamino compound, eg Z-ethoxy-l-ethoxycarbonyl-L.Z-dihydroquinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, under cooling or heating and / or in an inert gas atmosphere.

A reactive, i. amide-forming, or ester-forming, functional derivative of an acid of formula III, wherein all functional groups except the reacting acid group may be protected, is primarily an anhydride of such an acid, inclusive and preferably a mixed anhydride, but also an internal anhydride, i. a corresponding ketene. Mixed anhydrides are e.g. those with inorganic acids, such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, further with hydrazoic acid, i. the corresponding acid azides, with a phosphorus acid, e.g. Phosphoric acid or phosphorous acid, or with a sulfur-containing acid, e.g. Sulfuric acid, or with hydrocyanic acid.

ι i r-rn inrtft .. t \ i% ix t \ i, Π

2 35 5 40 4

Other mixed anhydrides are e.g. those with organic carboxylic acids, such as with optionally, e.g. halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. Pivalic acid or trichloroacetic acid, or with half esters, especially lower alkyl halides of carbonic acid, such as the ethyl or Isobutylhalbester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, e.g. p-toluene sulfonic acid.

Other reactive acid derivatives of an acid of formula III are activated esters such as esters with vinylogous alcohols (i.e., snols) such as vinylogous lower alkenols, or aryl esters such as 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as benztriazole, e.g. 1-benzotriazole esters, or diacylimino esters such as succinylimino or phthalylimino esters.

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, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylarain or ethyl-diisopropylamine, or Ν, Ν-di-lower alkyl-aniline, e.g. N, N-dimethylaniline, or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g. Pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide. The reactive esters, e.g. the 1-benztriazole esters are also reacted in the presence of one of the said carbodiimides, e.g. N, N-dicyclohexylcarbodiimide.

i 7 tPl ·) HO Q Q <*. O IS A Π! Λ η

23554Q 4

The above acylations are preferably carried out in an inert, preferably anhydrous solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrile, e.g. Acetonitrile, or mixtures thereof, at room temperature, if necessary, at reduced or elevated temperature, such as at -40 ° to about 100 °, preferably at -10 ° to + 40 °, and / or in an inert gas, e.g. Nitrogen atmosphere.

In an acylating acid of formula III or in an acid derivative thereof, a protected amino group may also be in ionic form, i. the starting material of formula III may be in the form of an acid addition salt, preferably with a strong inorganic acid such as a hydrohalic acid, e.g. Hydrochloric acid, or sulfuric acid can be used.

Further, if desired, an acid derivative can be formed in situ . Thus, for example, a mixed anhydride is obtained by treating an acid of formula III with 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, eg alkali metal, salt a suitable acid derivative, such as a corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, eg trichloroacetyl chloride, or with a half ester of a carbonyl halide, eg ethyl chloroformate or isobutyl ester, and using the thus obtained mixed anhydride without isolation.

Method b) ; In a starting compound of the formula IV, X is halogen, in particular chlorine, but also bromine, iodine or fluorine. The thiourea is in free form or as a salt, in particular as

2355 ΛΟ

Thiolate of an alkali metal, such as lithium, sodium or potassium, or as a thiolate of an ammonium compound, in an equivalent amount or in up to six-fold excess used.

The reaction is generally carried out in a solvent such as water or an organic non-reactive solvent or a mixture thereof. Suitable organic solvents are alcohols such as methanol, ethanol, 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. If 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, e.g. Trimethylamine, triethylamine, ethyl-diisopropylamine, pyridine and the like. The reaction temperature is at room temperature, or even lower or higher, preferably between -10 to + 100 °, in particular between 0 to 40 °.

The reaction can also be carried out stepwise by first forming the ring-open intermediate with the partial formula Am-C (= NH) -S-CH ₉ -CO-C (= NOCH), which is then dehydrated in the second step.

Process c): The group R in a starting material of the formula (V) may be free hydroxy, but is preferably esterified hydroxy or optionally substituted amino. An esterified hydroxy group R can be replaced by an inorganic or organic acid, such as a strong mineral acid, for example a hydrohalic acid, such as

235540 4

Hydrogen chloride, hydrobromic or hydriodic acid, or an organic carboxylic or sulfonic acid, including formic acid, such as a corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acid, further esterified by a carbonic acid half-derivative. For example, R represents Halogen, such as chlorine, bromine or iodine, lower alkylsulfonyloxy, e.g. Methanesulfonyloxy or ethanesulfonyloxy, arylsulfonyloxy, e.g. Benzenesulfonyloxy, or p-toluenesulfonyloxy, lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, arylcarbonyloxy, e.g. Benzoyloxy, or lower alkoxycarbonyloxy, e.g. An optionally substituted amino group R is a primary, secondary or tertiary amino group

12 ° 1 2 -N (R) (R), wherein R and R are independently hydrogen, or

OO O O

an optionally substituted aliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, or together represent an optionally substituted, optionally by heteroatoms, such as oxygen, sulfur or nitrogen, interrupted polymethylene group. Such amino groups R 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 cleavage of a compound of the formula R -H, i. of water, an acid or an amine is preferably carried out by treatment with suitable water, acid or amine releasing agents. Water and amines are preferably used in the presence of an acidic amine splitting agent, e.g. an acid, preferably a strong organic carboxylic or sulphonic acid, such as a

235540 4

Halo-lower alkanecarboxylic acid, e.g. Trifluoroacetic acid, or an arylsulfonic acid, e.g. p-toluenesulfonic acid, a suitable acid derivative such as an anhydride or especially a halide such as chloride, primarily an inorganic, e.g. Phosphorus or sulfur containing acid, e.g. Phosphorus oxychloride or thionyl chloride, wherein such a derivative when water is to be split off, usually in the presence of a base such as a tertiary organic base, e.g. Pyridine, or a suitable acidic ion exchanger, such as a sulfonic acid-based ion exchanger, e.g. a sulfonated polystyrene ion exchanger, cleaved. For the removal of water, dehydrating carbodiimide compounds, e.g. Dicyclohexylcarbodiimide, or dehydrating, nitrogen atom disubstituted carbonyl compounds, e.g. Carbodiimidazole, use. These agents are usually used in the presence of a solvent such as an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Benzene or toluene, or a solvent mixture, it being possible to use suitable acidic agents such as trifluoroacetic acid simultaneously as a solvent. If necessary, one additionally uses a water-absorbing agent or a water separator and operates under cooling or heating and / or in an inert gas, e.g. Nitrogen atmosphere.

Preferably, R in a starting material of the formula V is a

esterified hydroxy group and according to the invention splits an acid

of the formula H-R. Usually one uses for this purpose ο

basic acid-cleaving and / or neutralizing agents, e.g. inorganic base such as dilute alkali metal hydroxides, e.g. 'Sodium or potassium hydroxide, which besides water also organic solvents, such as suitable ketones, e.g. Acetone, or ether, e.g. Using dioxane, or aqueous mixtures thereof, and at a pH of at most about 9, if necessary, with cooling or heating and / or in an inert gas, e.g. Nitrogen atmosphere can work.

7 IT ίI J l \ , '1 η

235540

Tertiary amines, especially good proton acceptors, which do not attack the lactam ring, are preferably used as the acid-eliminating agent, especially tertiary-aliphatic or tertiary-cycloaliphatic mono- and diamines, such as tri-lower alkylamines, e.g. Trimethylamine, triethylamine or ethyl-diisopropylamine, or bicyclic diaza compounds having an amidine-type arrangement of the ring nitrogens, e.g. l, 5-diazabicyclo-f4,3,0] non-5-ene or 1,5-diazabicyclo [5,4,0] undec-5-ene. Furthermore, basic ion exchangers, e.g. ammonium hydroxide-based, also used as acid-releasing agents. Certain esterified hydroxy groups R, in particular sulfonyl

oxy, e.g. Methylsulfonyloxy groups can also be obtained in the form of an acid of the formula R-H by absorption, e.g. on silica gel, alumina, etc., and elution (chromatography) from compounds of formula V.

The acid eliminations described above are in the absence, but usually 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, e.g. Acetone, or ethers, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, including an aqueous mixture, if necessary with cooling or heating, at -30 ° to 150 °, preferably at about -10 ° to 60 °, and / or in an inert gas, e.g. Nitrogen atmosphere made.

Method d) : The methylation of the Hydroxyiminomethylengruppe in a compound of formula VI is carried out in a conventional manner by treatment with a methylating agent. In the starting material, apart from the hydroxyimino group, all optionally present further functional groups are preferably protected.

Suitable methylating agents are, for example, diazomethane, reactive esters of methanol, such as methyl halides, e.g. Methyl iodol, sulfonic acid ester, e.g. MeChansulfonic acid, trifluoro-

355 40 A

methyl sulfonate or p-toluene sulfonic acid methyl ester, or sulfuric acid ester, e.g. Dimethyl sulfate, dimethyl acetals, e.g. 2,2-dimethoxypropane, orthoester, e.g. Trimethyl orthoformate, trimethyloxonium salts, e.g. Trimethyloxonium fluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbonium salts, e.g. Dimethoxycarbonium hexafluorophosphate, or dimethylhalonium salts, e.g. Dimethylbromonium hexafluoroantimonate, or 3-aryl-1-methyl triazene compounds, e.g. 3-p-tolyl-l-methyltriazeno. The methylation is carried out in a manner known per se, usually in an inert solvent such as an ether, e.g. Dioxane or tetrahydrofuran, or an optionally halogenated hydrocarbon such as benzene, chlorobenzoyl, methylene chloride, or the like, optionally in the presence of suitable condensing agents such as bases or acids, with cooling or heating at temperatures between about -20 ° to about 100 °, performed.

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

The esterification of the optionally present in salt form 4-carboxyl group is, in a known per se, in the presence of an acid-binding agent, such as an organic base, such as a

organic amine, e.g., a tertiary amine such as tri-lower alkylamine,

'E.g. Trimethylamine, triethylamine or ethyl-diisopropylamine, an N, N-di-lower alkyl-aniline, e.g. N, N-dimethylaniline, a cyclic tertiary amine such as an N-lower alkylated morpholine, e.g. N-methylmorpholine, a pyridine-type base, e.g. Pyridine, one

2355 AO 4

inorganic base, for example, an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or a quaternary ammonium base such as a tetraalkylammonium hydroxide, carbonate or hydrogen carbonate, e.g. wherein is alkyl, 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 performed.

Preferably, the carboxylic acid of the formula VII is first converted into a salt of one of said organic or inorganic bases, in particular into the sodium salt, and this is reacted with a compound of the formula VIII.

A compound of formula VIII can also be prepared in s itu . For example, a compound of the formula VIII in which X is chlorine by treatment with sodium iodide in a solvent, for example in acetone or acetonitrile, to convert a compound of formula VIII wherein X is iodine, or the esterification with a chlorine compound of formula VIII in Perform the presence of sodium iodide.

The esterification reaction is carried out in a suitable solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Acetic, acid ethyl ester, or. e, inera nitrile, e.g. Acetonitrile, or mixtures thereof, at room temperature, if necessary, at reduced or elevated temperature, such as at -40 ° to about 100 °, preferably at -10 ° to + 40 °, and / or in an inert gas, e.g. Nitrogen atmosphere.

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Method f); A protected amino group Am is set free in a manner known per se and, depending on the nature of the protective groups, in various ways, preferably by means of solvolysis or reduction. For example, 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid become. Aroylmethoxycarbonylamino may also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, eg, sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.-lower alkoxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino can be obtained by treatment with a suitable acid, eg. Formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino eg by hydrogenolysis, ie by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted Triarylmethylamino, formylamino or 2-acyl-lower alk-l-en-l-yl-amino, for example by treatment with an acid such as mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, optionally in Presence of water, and protected with an organic silyl or stannyl group amino group are released, for example by hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, eg 2-chloroacetyl, may be prepared by treatment with thiourea in the presence of a base, or with a thiolate salt,

such as an alkali metal thiolate, the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product are liberated. An amino group protected by 2-substituted silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid salt yielding fluoride anions,

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be converted into the free amino group. A phosphorus, phosphine or phosphine amido group may e.g. by treatment with a phosphorus acid such as a phosphoric, phosphonic or phosphinic acid, e.g. Orthophosphoric acid or polyphosphoric acid, an acidic ester, e.g. Monomethyl, monoethyl, dimethyl or diethyl phosphate 'or monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide, are converted into the free amino group.

Incidentally, the decomposition reactions described are carried out under conditions known per se, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.

Preferably, selective cleavage reactions are performed, i. those in which the ester grouping and the methoxyimino group are either not or only slightly attacked. Such a preferred method is the acidolytic cleavage of a tert-lower alkoxycarbonyl group, in particular the tert-butoxycarbonyl group, by means of a suitable acid, in particular trifluoroacetic acid, optionally in an inert solvent, such as an optionally

halogenated hydrocarbon, e.g. Methylene chloride, at temperatures from about -20 ° to about 50 °, preferably at 0 ° to room temperature.

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

The processes also include those embodiments in which intermediate compounds are used as starting materials and the remaining process steps are carried out with them, or the process is stopped at any stage; In addition, starting materials may be used in the form of derivatives or formed in situ, optionally under the reaction conditions.

235 5 40 4

The starting compounds of the formulas II to VIII are known or can be prepared analogously to known processes.

The pharmacologically useful compounds of the present invention may e.g. be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral administration. For enteral administration, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Suppositories are primarily fat emulsions or suspensions.

The present pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by means of conventional mixing, solution, or lyophilization processes, and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active ingredient. Depending on the type of infection, condition of the infected organism is used daily doses of about 0.25 g to about 2g p.o. for the treatment of warm-blooded animals weighing about 70 kg.

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The following examples serve to illustrate the invention; Above and below temperatures in degrees Celsius are given.

The methoxyimino group has the syn - configuration.

EXAMPLE 1 An ice-cooled solution of 10 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 40 ml of dimethylformamide is treated with 14 g of Joddiäthylcarbonat added and stirred for 15 minutes under ice cooling and then for 45 minutes at room temperature. The reaction mixture is poured into ice-water and extracted by shaking with ethyl acetate. The organic phase is washed successively with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, 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 Rf a-0.26 (silica gel, ethyl acetate) are combined and evaporated in vacuo. After dispersing the residue with a mixture of diethyl ether and hexane and drying under high vacuum to give the 7ß- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephera-4-carboxylic acid-1 -äthoxycarbonyloxyäthy! ester.

IR spectrum (CH Cl): characteristic absorption bands at 3400,, 1765, 1728, 1690; 1548 cm "¹; = 18,800), 260 (£ = 17,000) mu.

1796, 1765, 1728, 1690; 1548 cm '¹; UV spectrum (ethanol): X =

Max

Example 2; To a solution of 6 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -znmethoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-oxycarbonyloxyethyl ester in 30.5 ml of methylene chloride is added 30.5 ml of trifluoroacetic acid and stirred for one hour at room temperature. The reaction mixture is treated twice with a mixture of toluene and chloroform 1: 1 and once with diethyl ether and each time evaporated in vacuo. The residue is taken up in ethyl acetate. The solution is washed three times with concentrated aqueous sodium bicarbonate.

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carbonate solution and washed once with saturated aqueous sodium chloride solution and evaporated 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 <v 0.22 (silica gel, ethyl acetate) are combined and evaporated in vacuo. The residue is digested with diethyl ether, dried under high vacuum to give the 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester. Decomposition point: 122-128 °; IR spectrum (CH Cl): characteristic absorption bands at 3400, 1785 (broad), 1765, 1685, 1608, 1530 cm ^-1 , UV spectrum (ethanol):

λ = 235 ( £ = 16500) and shoulder at 258 mu. max γ

EXAMPLE 3 Analogously to the above examples, starting from 7ß-12- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt by reaction with iodomethyl ethyl carbonate of the 7β- [2 - (2-tert-Butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid athoxycarbonyloxymethyl ester which, after treatment with trifluoroacetic acid, yields the 7β- [2- (2-amino-4-thiazolyl) - 2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid ethoxycarbonylaminomethyl ester. IR spectrum (CH Cl "): characteristic absorption bands at, inter alia, 3400; 1782; 1760; 1610; 1535 cm " ¹ .

Example 4: To a cooled to 0 ° solution of 5 g of 7ß- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem ^ -carboxylic acid-l-ethoxycarbonyloxyäthylester (free base) in 50 ml CH Cl is added to 61 ml of a 0.18M HCl solution in CH Gl ^ (1.1 mol equivalent, prepared by bubbling dry gaseous hydrogen chloride into dry CH Cl.). After stirring for 10 minutes, the solution is treated with diethyl ether, wherein a precipitate precipitates. The mixture is followed for 1/2 hour at 0 °, the precipitate filtered off, washed with diethyl ether and dried under high vacuum at 30 °. The obtained raw

Λ 1. Γ. ,

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Hydrochloric !, is dissolved in about 50 ml of CH Cl, slightly concentrated and allowed to stand overnight at about + 5 °. The precipitated 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester hydrochloride is filtered off, washed with a little CH 2 Cl- and diethyl ether and dried as before ,

EXAMPLE 5 Analogously to Example 4, 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid thethoxycarbonyloxyethyl ester (free base) in methylene chloride with 27.2 ml of an O.46M hydrogen bromide solution in methylene chloride, the 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem-1-carboxylic acid 1-ethoxycarbonyloxyethyl hydrobromide was obtained.

EXAMPLE 6 A suspension of 0.405 g of 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 4 ml of dimethylformamide is mixed with 0.6 g of iodoethyl carbonate and Stirred for 40 minutes at about -5 °. The resulting reaction mixture is poured into ice-cooled phosphate buffer pH 8, stirred for 15 minutes and extracted with ethyl acetate. The organic phase is extracted successively with phosphate buffer and saturated aqueous sodium chloride solution and concentrated in vacuo to a volume of about 15 ml. The resulting solution is mixed with 8 ml of a 1.46N hydrochloric acid solution in methylene chloride and then with diethyl ether. The resulting precipitate is reprecipitated twice from methylene chloride / diethyl ether and gives, after drying, the 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyl oxyäthylester hydrochloride ; Melting point from 145 ° (decomposition). Rf 0.20 0.20 XSilikagerrÄStTTylacetat); IR spectrum (nujol): characteristic absorption bands at 3400, 1783 (b), 1766, 1740 (sh), 1680, 1605 cm " ¹ .

235 5 ΛΟ 4

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 for 30 minutes at about -5 °, then treated with 0.57 g of 2- (2-tert. Butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetic acid and 0.3 ml of N-methylmorpholine and allowed to stir for a further 30 minutes at -5 °. After addition of a solution of 0.71 g of 7ß-amino-3-cephem-4-carboxylic acid Läthoxycarbonyloxyäthylester hydrochloride and 0.6 ml of N-methylmorpholine in 7 ml of methylene chloride, the reaction mixture is stirred for 30 minutes at -5 ° and 30 minutes at 0 °, with Ethyl acetate diluted and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene containing 10-20% ethyl acetate to give the 7β- [2- (2-amino-4-thiazolyl) -2-Z-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester with the same properties as given in Example 2.

The starting material is prepared as follows: A suspension of 2 g of 7β-amino-3-cephem-4-carboxylic acid in 20 ml of dimethylacetamide is treated with 1.5 ml of l, 5-diazabicyclo [5.4.0] undec-5-ene for 15 minutes at room temperature stirred, cooled to -10 °, treated with 2.6 g of a-Joddiäthylcarbonat and allowed to react at -10 ° for 30 minutes. The reaction mixture is poured into ice-water, the pH adjusted to 6, and extracted with ethyl acetate. The organic phase is extracted by shaking with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to about 30 ml. The resulting solution is treated with 1.3 molar equivalents of an ethanolic hydrochloric acid solution and treated after stirring for 30 minutes with ice cooling with diethyl ether. The precipitate of 7β-amino-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester hydrochloride is filtered off, washed several times with diethyl ether and dried. Melting point about 200 ° (decomposition); Rf ν 0.23 (silica gel, toluene: ethyl acetate 1: 1).

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In the case of 8j capsules containing 0.250 g of 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester are prepared as follows:

Composition (for 100 ¹ OOO capsules): 7ß- [2- (2-amino-4-thiazolyl) -2-methoxy-iminoacetamido] -3-cephem-4-carboxylic acid-l-äthoxycarbonyloxyäthylester 25 ¹ OOO g

Wheat starch 2'5OO g

Magnesium stearate 1'000 g

The 7ß- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] - ^ - cephem · ^ - carboxylic acid 1-ethoxycarbonyloxyäthylester, the wheat starch and the magnesium stearate are well mixed together and filled into capsules no.

Example 9: Capsules containing 0.5 g of 7β- [2 ~ (2-amino-4-thiazolyl) -2-methoxyiminoacetamidol-β-cephem] -carboxylic acid 1-ethoxycarbonyloxy-1-ethyl ester are prepared as follows:

Composition (for 2000 capsules): 7β- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephenr ^ -carboxylic acid 1-ethoxycarbonyloxyethyl ester 1000'00 g

Polyvinylpyrrolidone 15'00 g

Corn starch 115 ¹ OO g

Magnesium stearate 20'00 g

The 7ß - ['2' - "C2'-Am'ino-4-thiazolyl) -2-methoxyiminoacetamido} -3-cephem-4-carboxylic acid l-ethoxycarbonyloxyäthy! Ester is moistened with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol, drive the mixture through a 3 mm mesh sieve and dry the granules under reduced pressure at 40-50 °, sieve through a sieve of 0.8 mm mesh, add the corn starch and magnesium stearate, mix and fill the mixture in capsules (size O).

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Example 10 Tablets containing 250 mg of 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester are prepared as follows:

Composition (for 1 tablet):

7ß- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid l-ethoxycarbonyl

oxyäthylester

Microcrystalline cellulose Sodium carboxymethyl starch Magnesium stearate talc

250 mg 80 mg 10 mg 3 mg 7 mg

350 mg

The active ingredient is homogeneously mixed with the additives and pressed into tablets.

For the production of film dragees, the tablets are each coated with 1 mg aqueous varnish.

Instead of sodium carboxymethyl starch also sodium carboxymethylcellulose can be used.

Instead of the free base, in Examples 6 to 8, a salt, e.g. the hydrochloride or hydrobromide, are used as active substance.

Claims (5)

claims 1. A process for the preparation of compounds of the formula N-OCH ₃ o Il Il III COO-CH-O-CO-O-R-I 2 wherein R is hydrogen or lower alkyl, R is lower alkyl and Am is an optionally protected amino group, and acid addition salts of those compounds wherein Am means a free amino group, characterized in that a) the 7β-amino group in a compound of the formula H. U VT__ 1 - - I (ID, I
COO-CH-O-CO-OR wherein the amino group is optionally substituted by an acylation-permitting group and wherein R and R "are as defined for formula I, by treatment with an acyl radical of a carboxylic acid of the formula N-OCH ₃ · C -C COOH (III) acylating agent in which Am has the meanings given under formula I, acylated, or 235540 k b) a compound of the formula H
N-OCH · ς ti ³ : / \ X-CH CO-C-CONH · · (IV), COO-CH O-CO-O-R " wherein X is halogen, R and R have the meanings mentioned under formula I, with a thiourea of the formula Am-CS-NH or a salt thereof condensed, or
c) from a compound of the formula STILL. At the-·, • -C-CONH-i II (V) COO-CH-O-CO-O-R-I 2 ^R i wherein Am, R "and R" have the meanings given under formula I. and R is hydroxy, esterified hydroxy or optionally substituted o Amino is split off, a group H-R, or d) for the preparation of a compound of the formula I in which Am, R and R "have the meanings given under formula I, in a compound of the formula OH --C-CONH- - - Il. Il I i (VI), COO-CH-O-CO-OR- ² R. wherein Am, R and R have the meanings given under formula I, the hydroxyimino group methylated, or l - * u 235540 e) for the preparation of a compound of the formula I in which Am, R ₁ and R "have the meanings given under formula I, in a compound of the formula STILL COOH wherein Am has the meaning given under formula I, the optionally present in salt carboxyl group in the Α-position of the cephem ring by treatment with an esterifying agent of the formula X-CH-O-CO-OR ₂ (VIII), wherein X is a reactive esterified hydroxy group and R and R ₂ have the meanings given under formula I, converted into an esterified carboxyl group, and / or f) for the preparation of a compound of formula I, wherein Am is a free amino group and R. and R_ have the meanings given under formula I, from a compound of formula I, wherein Am is a protected amino group, and R ₁ and R ₂ have the meanings given under formula I, the amino protecting group removed and replaced by hydrogen, and, if desired, a resulting compound wherein Am is a free amino group converted into a SMureadrücktssalz or a resulting acid addition salt in a free compound or in another acid addition salt. 60 137 11 -32- 235 5 ΛΟ 2. A process for the preparation of compounds of formula I and acid addition salts thereof according to item 1, characterized in that Am means a free amino group. 3 · A process for the preparation of compounds of formula I and acid addition salts thereof, according to item 1 or 2, characterized in that Am is a free amino group, R is hydrogen or methyl and Rp is ethyl. 4. A process for the preparation of compounds of formula I and acid addition salts thereof according to item 1, characterized in that Am is a free amino group, R _{1 is} methyl and R _{p is} ethyl. 5. The method of item 1 to 4 », characterized in that the hydrochloride of a compound of formula I is prepared. 6. Method according to items 1 to 4 »characterized in that that the hydrobromide of a compound of formula I is prepared. 1 & DEC19 Β 9. * OiK) -l · '3