CH625247A5 - Process for the preparation of alkylsulphonylamino-containing cephem derivatives - Google Patents

Abstract

7 beta -[D-2-Amino-2-(lower alkylsulphonylaminophenyl)acetylamino]-3-R-3-cephem-4-carboxylic acids of the formula I in which R is halogen, preferably chlorine, or lower alkoxy, preferably methoxy, are prepared. The process is based on sulphonation of the free amino group on the phenyl ring of corresponding 7 beta -(D-2-amino-2-aminophenylacetylamino)-3-R-3-cephem-4-carboxylic acids. The compounds are active against both Gram-positive and Gram-negative bacteria. <IMAGE>

Description

The present invention relates to a process for the preparation of new 7ß- [D-2-amino-2- (lower alkylsulfonylaminophenyl) acetylamino] -3 ~ R-3-cephem-4-carboxylic acids of the formula

V-CH-CO-NH- • -Lower alkyl-SO ^ -NHi ^ ^

wherein R is halogen with atomic number to 35 or lower alkoxy, and their salts.

Lower alkyl in lower alkylsulfonylamino contains up to 7, preferably up to 4 carbon atoms and means e.g. Ethyl, n-propyl, isopropyl, n-butyl or isobutyl and primarily methyl. Lower alkylsulfonylamino can be in any position of the phenyl radical, but primarily occupies the 3-position.

Lower alkoxy R contains up to 7, preferably up to 4 carbon atoms and means e.g. Ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy and primarily methoxy, while halogen is fluorine or bromine, but primarily chlorine.

Salts are especially pharmaceutically usable, non-toxic salts such as metal or ammonium salts, especially alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which

A - • •

■ A. J-R (I)

\ ^

I.

COOH

che are formed with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and aliphatic ss primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for salt formation, such as Lower alkylamines, e.g. Triethylamine, hydroxy-alkylamines, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphati-60 see esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylamino-ethyl ester, lower alkylene amines, e.g. 1-ethyl piperidine, cycloalkylamines, e.g. Bicyclohexylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine, furthermore bases of the pyridine type, e.g. Pyridine, collidine or quinoline. The 65 new compounds (I) can also acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbon or sulfonic acids, e.g. Trifluoroacetic acid or 4-methylphe-

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nylsulfonic acid. Preferably the new compounds are in the form of their internal salts, i.e. in zwitterionic form.

The new compounds (I) of the present invention have valuable pharmacological properties. They are in free form or in the form of their salts in vitro against cocci, such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus haemolyticus, Streptococcus faecalis, Diplococ-cus pneumoniae, Neisseria gonorrhoeae and Neisseria menin-gitidis in a dose range from 0.5 to 100 mcg / ml, against io Enterobacteria, such as Escherichia coli, Salmonella species,

Shigella flexneri, Klebsiella pneumoniae, Proteus vulgaris,

Proteus rettgeri, Proteus mirabillis in a dose range of 0.8 to 50 mcg / ml, as well as against other pathogenic germs, such as Haemophilus influenzae and Pasteurella multocida, in a dose range of 0.4 to 12.5 mcg / ml. When administered parenterally or especially orally, they are against microorganisms such as gram-positive bacteria, e.g. Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae, (e.g. in mice in doses from about 0.5 to about 10 mg / 20 kg s.c. or p.o.), and gram-negative bacteria, e.g. Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis, (e.g. in mice in doses of about 3.0 to about 200 mg / kg sc or po), especially against penicillin-resistant Bäk-2s terien effective with low toxicity.

From the German Offenlegungsschriften 2 331 133 and 2 408 698 7ß-phenylglycylamino-3-cephem-4-carboxylic acids substituted in the 3-position are known which contain no lower alkylsulfonylamino groups in the phenyl nucleus. German Offenlegungsschriften 2,422,385 and 2,432,190 list 3-substituted 7β- [2- (lower alkylsulfonylaminophenyl) glycylamino] -3-cephem-4-carboxylic acids, which are in the 3-position by methyl, heterocyclylthiomethyl or lower alkanoyl oxymethyl are substituted. 35

The invention relates primarily to a process for the preparation of new 7β- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-R'-3-cephem-4-carboxylic acids, in which R ' Represents methoxy or chlorine and their salts, in particular their pharmaceutically usable, non-toxic salts and their internal salts.

According to the invention, the new compounds are prepared in a manner known per se, in a 7β- (D-2-amino-2-aminophenyl-acetylamino) -3-R-3-cephem-4-carboxylic acid of the formula «

NH,

/ N-CH-CONH-1

A

NH,

(XVIII)

✓

-N,

l-r

Ì00H

in which R has the meaning given under formula I and in which ss the D-2-amino group is intermediately protected and the 4-carboxyl group is optionally intermediately protected and the amino group on the phenyl ring is in free form or in the form of a reactive derivative, the amino group on the phenyl ring with a Converts lower alkanesulfonic acid or a reactive functional derivative thereof into a lower alkylsulfonylamino group and, if desired, a salt obtained into the free compound (I) or into another salt and / or,

if desired, converting a free compound (I) to a salt. 65

In the above starting material of formula II, the D-2-amino group is protected as an intermediate and the 4-carboxyl group is optionally protected as an intermediate. The amino group on the phenyl ring is in the free form or in the form of a reactive derivative. The residues used in penicillin or cephalosporin chemistry and in peptide chemistry are suitable for these functional groups.

The 4-carboxyl group is optionally protected as an intermediate in esterified form, such an ester group being easily cleavable under mild conditions. Lower alkoxycarbonyl, especially tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. Adamantyloxycarbonyl, arylmethoxycarbonyl, wherein aryl is preferably one or two, optionally, e.g. by lower alkyl, especially tertiary lower alkyl, e.g. tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g. Chlorine, and / or nitro, mono- or poly-substituted phenyl radicals, such as optionally, e.g. substituted benzyloxycarbonyl as mentioned above, e.g. 4-nitro-benzyloxycarbonyl,

or e.g. substituted diphenylmethoxy-carbonyl as mentioned above, e.g. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-bromo- or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, especially aroylmethoxycarbonyl, in which the aroyl group is preferably optionally, e.g. halogen substituted by halogen such as bromine, e.g. Phenacyloxycarbonyl, in question. Esterified carboxyl groups are also corresponding silyloxycarbonyl, especially organic silyloxycarbonyl groups. In these the silicon atom preferably contains lower alkyl, especially methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Chlorine, as a substituent. Suitable silyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, also dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halosilyl, e.g. Methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, e.g. Dimethyl chlorosilyl. Here, silyl protective groups, in particular those which have a halogen atom as a substituent, can simultaneously protect the carboxyl group in two different molecules of the starting material; i.e. in such groups, such a halogen atom is replaced by the carbonyl group of another starting material molecule.

Preferred as the protected carboxyl group is in particular optionally, e.g. substituted benzyloxycarbonyl as mentioned e.g. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl.

A D-2 amino group is e.g. in the form of an easily cleavable acylamino, triarylmethylamino, etherified mercaptoamino, 1 acyl-2-lower alkylidene amino or silyl amino group or as an intermediate group protected as an azido group.

In a corresponding acylamino group, acyl is preferably the acyl residue of a carbonic acid semi-ester such as lower alkoxycarbonyl, especially tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. Adamantyloxycarbonyl, arylmethoxycarbonyl, wherein aryl is preferably one or two, optionally, e.g. by lower alkyl, especially tertiary lower alkyl, e.g. tert-butyl, lower alkoxy such as methoxy, hydroxy, halogen, e.g. Chlorine, and / or nitro, mono- or poly-substituted phenyl radicals, such as optionally, e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or e.g. substituted diphenylmethoxycarbonyl as mentioned above, e.g. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, especially aroylmethoxycarbonyl, in which the aroyl group preferably optionally, e.g. halogen substituted by halogen such as bromine, e.g. Phenacyloxycarbonyl. Acyl in an acylamino group or in an N-acyl-lower alkylsulfonyl

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amino group can also represent the corresponding residue of an organic sulfonic acid; such a radical is in particular arylsulfonyl, in which aryl optionally, e.g. phenyl radical substituted by lower alkyl such as methyl, halogen such as bromine or nitro, e.g. 4-methylphenylsulfony I.

In a triarylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals; a corresponding group is primarily trityl.

An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, in which aryl in particular optionally, e.g. 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-nitrophenyIthio.

In an 1-acyl-2-lower alkylidene residue which can be used as an amino protecting group, acyl is preferably the corresponding residue of a lower alkane carboxylic 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 a carbonic acid semi-ester, such as a carbonic acid lower alkyl half ester. Corresponding protective groups are primarily l-lower alkanoyl-2-propylidene, e.g. l-acetyl-2-propylidene, or l-lower alkoxycarbonyl-2-propylidene, e.g. l-ethoxycarbonyl-2-propylidene.

A silylamino group is primarily an organic silylamino group in which the silicon atom is preferably lower alkyl, especially methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Contains chlorine as a substituent. Corresponding silyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, also dimethyl-tert-butylsilyl, lower alkoxy-lower alkyl-halosilyl, e.g. Methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, e.g. Dimethyl chlorosilyl. Silyl protecting groups, in particular those which have a halogen atom as a substituent, can simultaneously protect the amino group in two different molecules of the starting material; i.e. in such groups, the halogen atom is replaced by the amino group of another starting material molecule.

The D-2-amino group in the starting material II can also be protected in an intermediate manner in protonated form; the anions are primarily those of strong inorganic acids such as hydrohalic acids, e.g. the chlorine or bromine anion, in question.

Preferred as amino protecting groups are the acyl residues of carbonic acid semiesters, especially tert-lower alkoxycarbonyl, optionally, e.g. substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halogeno-lower alkoxycarbonyl as indicated.

In the starting material XVIII the carboxyl group can preferably be in esterified form, e.g. as described above, primarily in the form of a silyl, such as trimethylsilyl ester (which is mostly produced directly from the acylation reaction by treatment with an appropriate silylating agent, e.g. trimethylchlorosilane or bis (trimethylsilyl) acetamide). However, the carboxylic acid starting material XVIII can also be in salt form, e.g. in an ammonium salt form, such as in the form of a triethylammonium salt, or in a protected form, which can be obtained by reacting the carboxylic acid starting material XVIII with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxyphosphorodihalide, such as methylphosphorodichloride, ethylphosphorodibromide or methoxyphosphoride is.

An amino group on the phenyl ring is either in the free form or in the form of a reactive derivative which allows the acylation reaction. In such a derivative the amino group is replaced by a silyl group, e.g. one of the abovementioned silyl radicals, or also by one of the abovementioned acyl radicals, e.g. tert-butyloxycarbonyl, protected.

The sulfonylation reaction of the free amino group or in the form of a reactive derivative in the starting material XVIII is carried out in a manner known per se. Lower alkyl sulfonic acids or reactive functional derivatives thereof can be used as sulfonylating agents.

If a free lower alkyl sulfonic acid is used for sulfonylation io, suitable condensing agents, such as carbodiimides, e.g. N, N'-diethyl, N, N'-dipropyl, N, N; -diisopropyl, N, N -dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, e.g. Carbonyldimidazole, or isoxazo-isium salts, e.g. N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-l-ethoxycar-bonyl-l, 2-dihydrochinoIin. The condensation reaction is carried out, for example, in an anhydrous reaction medium, for example in methylene chloride, dimethylformamide or acetonitrile.

A reactive functional derivative of a lower alkyl sulfonic acid is primarily an anhydride thereof, including, and preferably, a mixed anhydride. Mixed 25 anhydrides are e.g. those with inorganic acids, especially with hydrohalic acids, i.e. the corresponding sulfonic acid halides, e.g. the sulfonic acid chloride or bromide, furthermore the anhydride with the hydrochloric acid, i.e. the corresponding acid adid, with a phos-30 phosphoric acid, e.g. Phosphoric acid or phosphorous acid with a sulfuric acid e.g. Sulfuric acid, or with hydrocyanic acid. Other mixed anhydrides are e.g. those with organic acids such as organic carboxylic acids, such as with optionally, e.g. lower alkane carboxylic acids substituted by halogen, 35 such as fluorine or chlorine, e.g. Pivalic acid or trichloroacetic acid, or with half esters, especially lower alkyl half esters, carbonic acid, such as the ethyl or isobutyl half ester of carbonic acid, or with organic, especially aliphatic or aromatic sulfonic acids, e.g. p-toluenesulfonic acid.

Other sulfonic acid derivatives suitable for reaction with the amino group in the starting material XVIII are activated esters of lower alkyl sulfonic acids, usually with a protected amino group, such as esters with vinylogenic alcohols (i.e. 45 enols), such as vinylogenic lower alkenols, or aryl esters, such as preferably, e.g. phenyl esters substituted by nitro or halogen such as chlorine, e.g. Pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters, such as benzotriazolesters, or diacylimino esters, such as succinylimino-50 or phthalylimino esters.

Sulfonylation with a sulfonic acid derivative, such as an anhydride and especially with a sulfonic acid halide, can be carried out in the presence of an acid binding agent, e.g. an organic base such as an organic amine, 55 e.g. a tertiary amine such as tri-lower alkylamine, e.g. Triethylamine, N, N-di-lower alkyl aniline, e.g. N, N-dimethyl-aniline, or a pyridine-type base, e.g. Pyridine, an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or 1,2-propylene oxide.

The above sulfonylation can be carried out in an aqueous or preferably non-aqueous solvent or solvent mixture, for example in a carboxamide such as N, N-di-lower alkyl amide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, Tetra40

i

625 247

chlorocarbon or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrii, e.g. Acetonitrile, or mixtures thereof, and if necessary at a reduced or elevated temperature, e.g. at about 0 ° to about 100 ° C, and / or in an inert gas, e.g. Nitrogen atmosphere.

The starting materials (XVIII) can be obtained by reacting in a 7β-amino-3-R-3-cephem-4-carboxylic acid (VI), in which the carboxyl group is optionally in protected form and the 7β-amino group is optionally in reactive, ie there is the protected form which permits acylation, the 7β-amino group with a D-2-amino-2- (amphenyl) acetyl radical, in which Am denotes a protected or masked amino group which can be converted into a free amino group, and in which the second -Amino group is protected, acylated and in a 7 ß- [2-amino-2- (amphenyl) acetylamino] -3-R-3-cephem-4-carboxylic acid obtained, wherein the 2-amino group in protected and the Carboxyl group may be in protected form, the Am group may be converted into a free amino group.

An Am group is, for example, a protected amino group which differs in its type of conversion into a free amino group from that of the protected 2-amino group and which is selective, i.e. can be converted into a free amino group without simultaneously liberating the 2-amino group. For example, the 2-amino group can be protected by a tert-butyloxycarbonyl group and Am can mean a 2,2,2-trifluoroacetyloxycarbonylamino group, the latter being able to be split into a free amino group with zinc and acetic acid, while under these conditions the 2- tert-Butyloxycarbonylamino group is retained. Further such pairs of amino protective groups and their selective cleavage methods can be found in the description of the additional measures given below. Masked amino groups Am are, for example, the azido and especially the nitro group.

The acylation of 7β-amino-3-R-3-cephem-4-carboxylic acid VI, in which the functional groups are protected as indicated, is carried out in a manner known per se with D-2-amino-2- (Am -phenyl) -acetic acid, in which the amino groups are in protected or masked form as indicated, or with a reactive, functional derivative thereof, for example an anhydride, such as a corresponding acid chloride, as above for the acylation of protected compounds VI with protected D-2 -Amino-2- (lower alkylsulfonylamino-phenyl) -acetic acids VII, or their reactive, functional derivatives.

As indicated above, the choice of the carboxyl group and the 2-amino protective group in the starting material VI depends on the protected or masked amino group Am to be used. These groups Am are converted into a free amino group in an acylated compound XVIII obtained in a manner known per se, as is indicated below for the conversion of protected and masked amino groups. A nitro group Am can be converted into a free amino group by reduction analogously to an azido group.

Protected carboxyl and / or amino groups and / or N-acylated lower alkylsulfonylamino groups are in the compounds obtainable according to the invention in a manner known per se, such as by means of solvolysis, including hydrolysis, alcoholysis or acidolysis, or by means of reduction, including hydrogenolysis or chemical reduction, if appropriate released at the same time.

So you can e.g. a tert-lower alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group by treating with a suitable acidic agent such as

Convert formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, to the free carboxyl group. An optionally substituted benzyloxycarbonyl group can e.g. s are released by hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst. Furthermore, certain substituted benzyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl, can also be obtained by means of chemical reduction, e.g. by io treatment with an alkali metal e.g. Sodium dithionite or with a reducing metal, e.g. Zinc, or metal salt such as a chromium II salt, e.g. Chromium (II) chloride, usually in the presence of a hydrogen-donating agent which, together with the metal nascent hydrogen, is able to produce hydrogen, such as an acid, primarily acetic and formic acid, or an alcohol, preferably water admits, convert into the free carboxyl group. By treating with a reducing metal or metal salt as described above, one can also convert a 2-20 halogeno lower alkoxycarbonyl group (if necessary after converting a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group) or an acylmethoxycarbonyl group into the free carboxyl group, wherein an aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, for 2 seconds. A e.g. Carboxyl group protected by silylation can be used in a conventional manner, e.g. by treatment with water or an alcohol. Analogously to 3o, a carboxyl group protected by reaction with an organic phosphorus halide compound can also be released by hydrolysis or alcoholysis.

A protected amino group is known in a manner known per se and in various ways depending on the type of protective group, e.g. 35 released by solvolysis or reduction. A 2-halo-lower alkoxycarbonylamino group (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group), an acylmethoxycarbonylamino group or e.g. a 4-nitrobenzyloxycarbo-40 nylamino group can e.g. by treatment with a suitable chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonylamino group also by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, 45 and a 4-nitro-benzyloxycarbonylamino group, also by treatment with an alkali metal group, e.g. Sodium Dithionite,

a diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or polycycloalkoxycarbonylamino group by treating e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonylamino group e.g. by hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst, an aryl or aryl-lower alkylthioamino group e.g. by treatment with a nucleophilic reagent such as 55 sulfuric acid, an arylsulfonylamino group e.g. by means of electrolytic reduction, an l-acyl-2-lower alkylideneamino group or a triarylmethyl group e.g. by treatment with aqueous mineral acid, and an amino group protected with an organic silyl group e.g. be released by hydrolysis 6o or alcoholysis.

An amino group protected in the form of an azido group is converted into the free amino group in a manner known per se by reduction, for example by catalytic hydrogenation with hydrogen and a hydrogenation catalyst, such as 65 platinum oxide, palladium or Raney nickel, or also by zinc and acid like acetic acid. Catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon e.g. Methylene

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6

chloride, or in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 to 25 °, or at a reduced or elevated temperature.

An N-acylated lower alkylsulfonylamino group is also used in a manner known per se, e.g. solvolytic or reductive, converted into a lower alkylsulfonylamino group. To remove these N-acyl groups, the same methods can be used as for the removal of acyl groups, for example from 2-halogeno-lower alkoxycarbonyl, acylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, diphenylmethoxycarbonyl, tert.-lower alkoxycarbonyl, polycycloalkoxycarbonyl or also benzyloxycarbonyl Arylsulfonyl, are specified from corresponding acylamino groups.

Salts of the new compounds I can be prepared in a manner known per se. So you can e.g. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. form the sodium salt of a-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Inner salts can e.g. by neutralizing, e.g. of salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.

Salts obtained can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.

Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed at the outset as particularly preferred are obtained.

The new compounds (I) accessible according to the invention can e.g. be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral or parenteral administration.

In connection with the present description, organic radicals labeled “lower”, unless expressly defined, contain up to 7, preferably up to 4, carbon atoms.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.

Example la) A suspension of 2.4 g (5 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-aminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in 20 ml of absolute methylene chloride, 1.4 ml of bis- (trimethylsilyl) acetamide are added under nitrogen and exclusion of moisture and the mixture is stirred at room temperature for 45 minutes. The clear pale yellow solution is cooled to 0 ° C., 1.2 ml of absolute pyridine are added with stirring and then 0.63 g (5.5 mmol) of methylsulfonyl chloride dissolved in 10 ml of absolute methylene chloride are added. After 1 hour at 0 ° C. and 4 hours at room temperature, 2 ml of methanol are added to the reaction mixture and the solvent is removed on a rotary evaporator. The oily residue is taken up in 20 ml of water, adjusted to pH 2.0 with 2 N hydrochloric acid and the aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are dried (Mg SO4) and concentrated on a rotary evaporator. The residue is purified on silica gel using a 1: 1 mixture of methylene chloride and ethyl acetate as the eluent. The 7ß- [D-2-tert-butyloxy-carbonylamino-2- (3-methylsulfonyl-aminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid obtained from thin layer chromatography is obtained Methylene chloride diethyl ether 1: 3 recrystallized at 140 ° with decomposition melts. Thin layer chromatogram (silica gel; identification with ninhydrin): Rf ~ 0.63 (system: sec-butanol / acetic acid / water 67:10:23).

The starting material can be produced as follows:

b) A suspension of 3.11 g (13.5 mmol) of finely powdered 7β-amino-3-methoxy-3-cephem-4-carboxylic acid in 60 ml of absolute methylene chloride is added under an argon atmosphere and at room temperature with 3.8 ml of bis-trimethylsilyl-acetamide were added (addition within about 10 minutes) and stirred for 45 minutes.

A solution of 4.44 g (15 mmol) of D-2-tert-butyloxycarbonylamino-2- (3-nitrophenyl) acetic acid and 1.67 ml of 4-methyl-morpholine in 90 ml of absolute acetonitrile is cooled to -15 ° 1.97 ml of isobutyl chloroformate are added under an argon atmosphere and left to react for an additional 25 minutes. The above-described silylated starting material is added dropwise to the mixed anhydride thus obtainable at −15 ° and the reaction mixture is stirred at 0 ° for 2 hours and at room temperature for 30 minutes. The solvent is then removed on a rotary evaporator, the residue is taken up in 200 ml of ethyl acetate and washed three times with a saturated aqueous sodium chloride solution. The aqueous phases are extracted again with ethyl acetate. The combined organic solutions are dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified on silica gel with a 1: 1 mixture of methylene chloride and ethyl acetate as the eluent. The 7ß- [D-2-tert-butyloxycarbonylamino-2- (3-nitrophenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid uniformly obtained by thin layer chromatography is obtained as an amorphous product; Thin layer chromatogram (Süikagel; identification with ninhydrin): Rf ~ 0.52 (system: sec-butanol / acetic acid / water 67:10:23), infrared absorption spectrum (in methylene chloride): characteristic bands at 3400.1785.1710.1535, 1355 cm "1.

c) 1.17 g (2 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-nitrophenyl) acetylamino] -3-methoxy-3-cephem-4-car-bonic acid dissolved in 30 ml Ethyl acetate is hydrogenated in the presence of 200 ml of 5% palladium-carbon until 3 equivalents of hydrogen are taken up at room temperature and normal pressure. The catalyst is filtered off and washed with a little ethyl acetate. The solvent is removed under reduced pressure. The crude product obtained, 7β- [D-2-tert-butyloxycarbonylamino-2- (3-aminophenyl) -3-methoxy-3-cephem-4-carboxylic acid, is used directly for the sulfonylation.

Example 2

a) A mixture of 0.557 g of 7β- [D-2-tert-butoxycarbonylamino) -2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, 2.5 ml of precooled trifluoroacetic acid and 2.5 ml of methylene chloride are stirred for 30 minutes at 0 ° under an argon atmosphere and then mixed with 25 ml of a 1: 1 mixture of petroleum ether and diethyl ether at 0 °. The beige precipitate is filtered off, washed with a little diethyl ether and dried under reduced pressure. The trifluoroacetic acid thus obtained

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Acid salt of 7ß- [D-2-amino-2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid is dissolved in 5 ml of water, twice with 3 ml each of ethyl acetate extracted, and the acidic aqueous phase (pH 1.8) by dropwise addition of an aqueous sodium hydroxide solution to pH 5.2. The solution is concentrated to about half the volume, 12 ml of acetone are added and the mixture is left at about -18 ° for 16 hours. The precipitate formed is filtered off, washed with acetone and diethyl ether and dried. This gives the 7β- [D-2-amino-2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt as a monohydrate, the decomposes from 170 °; Thin layer chromatogram (silica gel; identification with ninhydrin): Rf 0.22 (system: sec-butanol / acetic acid / water 67:10:23; ultraviolet absorption spectrum (inO, lN aqueous hydrochloric acid): Xmax = 272 nm (e = 7000).

The same connection can also be obtained as follows:

ai) A solution of 8.0 g (14.4 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylamino-phenyl) acetylamino] -3-methoxy-cooled to 0 ° 3-cephem-4-carboxylic acid in 40 ml of absolute methylene chloride is mixed with 40 ml of pre-cooled trifluoroacetic acid, stirred for 25 minutes at 0 ° under an argon atmosphere and then mixed with 500 ml of a 1: 1 mixture of petroleum ether and diethyl ether at 0 °. The beige precipitate is filtered off, washed with a little diethyl ether and dried under reduced pressure. The trifluoroacetic acid salt thus obtained of 7ß- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid is dissolved in 70 ml of ice water and three times with 30 ml each Extracted ethyl acetate. The acidic aqueous phase (pH ~ 2.0) is brought to pH 5.2 by dropwise addition of a 20% triethylamine solution in methanol and 160 ml of isopropanol are added at 0 °. The precipitate formed is recrystallized from isopropanol-water 2: 1, filtered off, washed with a little isopropanol and dried. Since the crystals still contain little organic solvent even after drying, they are digested for another V2 hours in 50% aqueous solution at 40 °, cooled to 0 °, filtered and dried again in a high vacuum at room temperature. This gives the 7β- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, which is also in the form of a monohydrate; Mp from 174 ° (with decomposition).

aii) A solution of 300 mg (0.54 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in 3 ml Formic acid is stirred for 3 hours under argon at room temperature, then cooled to 0 ° and then mixed with 30 ml of 1: 1 diethyl ether-petroleum ether. The precipitated formic acid salt of 7ß- [D-2-amino-2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid is dissolved in 3 ml of ice water, three times with 1, 5 ml of ethyl acetate extracted and freed from water and excess formic acid on a rotary evaporator. The residue is taken up twice in 3 ml of water and evaporated to dryness, from which the monohydrate of 7ß- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-4-carboxylic acid in the form pale yellow crystals of mp 173-175 ° (decomposition) can be isolated; Thin layer chromatogram (silica gel; developing with ninhydrin): Rf ~ 0.21 (system: sec. Butanol-acetic acid-water 67:10:23); UV spectrum (in 0.1 N aqueous hydrochloric acid): Xmax = 272 nm (e = 7100).

aüi) A solution of 2.2 g of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in 22 ml 99 % formic acid is left for 1½ hours at 23 ° and then evaporated in vacuo. The resin obtained is digested successively with 25 ml ether, acetonitrile and acetonitrile-H20 95: 5. The 7β- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-car-bonic acid is obtained as a light beige powder. After recrystallization from 1: 2 water-isopropanol, the monohydrate exhibits the following properties: [o] ff = + 143 ° ± 1 ° (c = 1, 0.1-n. HCl), UV absorption in 0.1- n. HCl: Xmax = 272 nm (e = 7300).

Example 3

a) Analogously to Example 1, the 7β- [D-2-tert-butyloxycarbonylamino-2- (3-aminophenyl) acetylamino] -3-chloro-3-cephem-4-carboxylic acid can be mesylated to give the 7β- [D-2-tert-Butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-chloro-3-cephem-4-carboxylic acid, thin layer 20 chromatogram (silica gel, identification with ninhydrin): Rf ~ 0.68 (System: sec. Butanol-acetic acid-water 67:10:23), IR spectrum (in methylene chloride): characteristic bands at 3390, 2930, 1775, 1685, 1485 and 1160 cm "1 can be obtained.

25th

ai) In a manner analogous to Example 2 ai), reaction with trifluoroacetic acid in the 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylamino-phenyl) acetylamino] -3- chloro-3-cephem-4-carboxylic acid release the amino group 30 and the obtained trifluoroacetic acid salt of 7ß- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] - 3-chloro-3-cephem-4-carboxylic acid Treat with a 20% triethylamine solution in methanol to the isoelectric point in the inner salt of the 7ß- [D-2-amino-2- (3-me-35 thylsulfonylamino-phenyl) -acetyl-amino] -3-chloro-3 convert cephem-4-carboxylic acid, which is in the form of the hydrate; Mp from 165 ° (decomposition); Thin layer chromatogram (silica gel, developing with ninhydrin: RF ~ 0.17 (system: sec.butanol-acetic acid-water 67:10:23); UV spectrum (0.1 N 40 hydrochloric acid): Xmax = 267 nm (s = 7600 ).

aii) In a manner analogous to Example 2 aii), reaction with formic acid in the 7β- [D-2-tert-butyloxycar-bonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-45 chloro-3 -cephem-4-carboxylic acid release the amino group. The hydrate of 7β- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-chloro-cephem-4-carboxylic acid is obtained as a fine crystallizate with the same physical properties as given under ai) .

50

Example 4

Analogously to Example 1, by treating 7β- [D-2-tert-butyloxycarbonylamino-2- (3-aminophenyl) -3-chloro-3-ce-phem-4-carboxylic acid diphenylmethyl ester with methylsulfonyl-55 chloride and pyridine in methylene chloride the 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) ac-ethylamino] -3-chloro-3-cephem-4-carboxylic acid diphenylmethyl ester of mp. 184-187 ° (from acetone-ether-petroleum ether 1: 2: 2), thin layer chromatogram (silica gel; identification 60 with ninhydrin): Rf ~ 0.52 (system: toluene-ethyl acetate 1: 1), IR spectrum (in methylene chloride): characteristic bands at 3420.1790.1725.1700.1620.1158 cm "1.

A solution of 2.18 g (3 mmol) of 7β- [D-2-tert-butyloxy-carbonylamino-2- (3-methylsulfonylaminophenyl) -3-chloro-3 - "s cephem-4-carboxylic acid diphenylmethyl ester, 1.8 ml of anisole and 9.6 ml of trifluoroacetic acid in 20 ml of methylene chloride are stirred for 30 minutes at 0 ° and then mixed with 200 ml of ether-petroleum ether 1: 1. The trifluoroacetic acid salt

625 247

8th

is dissolved in 10 ml of ice water and extracted twice with 4 ml of ethyl acetate. The aqueous phase is adjusted to pH 5.0 with a 20% triethylamine solution in methanol, a colorless precipitate being formed after the addition of 24 ml of isopropanol. After filtration, washing with a little isopropanol and drying under reduced pressure, colorless crystals of the hydrate of 7β- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-chloro-3-cephem are obtained -4-carboxylic acid; Mp from 165 ° (decomposition); Thin layer chromatogram (silica gel, developing with ninhydride): Rf ~ 0.17 (system: sec. Butanol-acetic acid-water 67:10:23); IR spectrum (in Njol): characteristic bands at 3500, 3220, 1780, 1685, 1340 and 1155 cm "1.

Example 5

a) Analogously to Example 4, by treating 1.08 g (1.5 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -3- Diphenyl methyl methoxy-3-cephem-4-carboxylate with 4.5 ml trifluoroacetic acid and 0.8 ml anisole in 10 ml methylene chloride release the amino group and the protected 4-carboxyl group and the trifluoroacetic acid salt obtained by treatment with 20% strength Triethylamine solution in methanol on the iso-electric point in the inner salt of 7 ß- [D-2-amino-2- (3-methyl-sulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid convert; Mp from 172 ° (decomposition).

ai) A mixture of 10.12 g (14 mmol) of 7β- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid- Diphenyl methyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid are stirred at 0 ° C. for 15 minutes, then 400 ml of pre-cooled toluene are added and the mixture is evaporated under reduced pressure. The residue is dried under high vacuum, digested with diethyl ether and filtered off. The trifluoroacetate of 7β- [D-2-amino-2- (3-methylsulfonyl-aminophenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, which is dissolved in 70 ml of water, is thus obtained in powder form becomes. The mixture is washed three times with 25 ml of ethyl acetate and the pH is adjusted to about 5.6 with a 20% triethylamine solution in methanol, a colorless precipitate being formed after the addition of 160 ml of isopropanol. Stir in an ice bath for one hour. The colorless precipitate is filtered off, washed with isopropanol and diethyl ether and dried under reduced pressure. Since the crystals still little isopropanol or even after drying. Contains diethyl ether, this is digested for another V2 hours in 50% aqueous solution at 40 ° C, cooled to 0 °, filtered and dried again. This gives 7ß- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carbon acid as the inner salt in the form of a micro-15 crystalline powder , which is also in the form of a monohydrate, mp. from 175 ° C (with decomposition); [a] J ° = + 144 ° (c = 1.035 in 0.1N hydrochloric acid); Thin layer chromatogram 20 (silica gel; developing with ninhydrin): Rf ~ 0.19 (system: sec. Butanol-acetic acid-water 67:10:23); Ultraviolet absorption spectrum (in 0.1N aqueous hydrochloric acid): Xmax = 272 nm (b = 7300); Infrared absorption spectrum (in mineral oil): characteristic bands etc. at 3500, 3180, 1760, 1692, 25 1608, 1150 and 978 cm \

Example 6

A suspension of 4.75 g of 7β- [D-2-amino-2- (3-methyl-sulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-30 carboxylic acid in 50 ml water and 2 ml Alcohol becomes slow with a total of about 5 ml of 2-n with stirring and pH control at a pH value less than 7.6. Bring sodium hydroxide solution. The solution, freed from few residues by filtration, gives, after lyophilization, 4.9 g of 7β- [D-2-amino-2-35 (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid sodium salt.

b

Claims (10)

625 247 1. Process for the preparation of new 7β- [D-2-amino-2- 4-carboxylic acids of the formula A> - • -CH-CO-NH- * i. y-A / - * Lower alkyl-SO ^ NH Q: COOH wherein R is halogen with atomic number up to 35 or lower alkoxy and their salts, characterized in that in a 7 ß- [D-2-amino-2- (aminophenyl) acetylamino] -3-R-3-cephem-4- carboxylic acid of the formula is • - • p A \ / \ • C> -CH-CONH-. • • A «'I J N., * _ R (XVIII) NH \ v 20 2. The method according to claim 1, characterized in that 35 is used as the lower alkanesulfonic acid methanesulfonic acid. 2 NH2 CT • COOH in which R has the meaning given under formula I and in which the D-2-amino group is intermediately protected and the 4-carboxyl group 2s is optionally protected intermediately and the amino group on the phenyl ring is in free form or in the form of a reactive derivative, the amino group on the phenyl ring with a Converted lower alkanesulfonic acid or a reactive functional derivative thereof into a lower alkylsulfonylamino group and, if desired, a salt obtained into the free compound (I) or into another salt and / or, if desired, converting a free compound (I) to a salt. 2nd PATENT CLAIMS (NiederaIkylsulfonylaminophenyl) -acetylamino] -3-R-3-cephem- 3. The method according to claim 1 or 2, characterized in that mesyl chloride is used as the reactive functional derivative of a lower alkanesulfonic acid. 40 4. The method according to any one of claims 1-3, characterized in that one converts the amino group on the phenyl ring with a reactive functional derivative of a lower alkanesulfonic acid in the presence of a base in a lower alkyl sulfonylamino group. 5. The method according to claim 4, characterized in that pyridine is used as the base. 6. The method according to any one of claims 1-5, characterized in that compounds (I) and salts thereof are prepared in which lower alkylsulfonylamino means methylsulfonylamino. 7. The method according to any one of claims 1-5, characterized in that compounds (I) and salts thereof are prepared in which lower alkylsulfonylamino is in the 3-position of the phenyl radical. 8. The method according to any one of claims 1-7, characterized in that the 7 ß- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-chloro-3-cephem-4- produces carboxylic acid or pharmaceutically acceptable salts thereof. 9. The method according to any one of claims 1-7, characterized in that the 7 ß- [D-2-amino-2- (3-methylsul-fonylaminophenyI) -acetyIamino] -3-methoxy-3-cephem-4- car-bonic acid or pharmaceutically acceptable salts thereof. 10. The compounds obtained by the process of claim 1.