DE2626558A1 - Substd. phenyl-acetamido beta-lactam antibiotics - with e.g. an alkoxy(carbonyl)-alkanoyloxy substit. on the phenyl gp. - Google Patents

Abstract

beta-Lactams of formula (I) and their esters and salts are new. In the formula R is 1-6C alkyl, or when A is O also H. A is O or OCO. R is H, acetoxy or SHet. Het is 1,2,3-triazol-5-yl, 1-methyl-tetrazol-5-yl, 1,3,4-thiadiazol-2-yl or 2-methyl-1,3,4-thiadiazol-5-yl. n is 0-8). (I) are antibacterials effective against Gram negative and positive species (esp. against Staph. aureus when given orally) and also intermediates for other pharmaceuticals. In an example 6-(2-D-amino-p-ethoxycarbonyloxyphenyl-acetamido) penicillanic acid was prepd. from amoxycillin by reacting first with ethyl acetoacetate and then with ethyl chloroformate.

Description

ß-lactam antibiotics

and a process for their preparation. The invention relates to new cephem derivatives of the general formula I where R is alkyl with 1 - 6 carbon atoms, and if A = -O-, also H, A -0- or -OCO- H,, acetoxy or S-Het, Het 1,2,3-triazol-5-yl, 1-methyl-tetrazol-5-yl, 1,3,4-thiadiazol-2-yl or 2-methyl-1, 3,4-thiadiazol-5-yl, and n ai; Salts number between 0 and 8 inclusive, as well as the easily cleavable esters and the physiologically harmless salts of these compounds.

The invention was based on the object of finding new compounds that can be used to manufacture drugs. This task was solved by providing the compounds of formula I.

It has been found that these compounds are excellent especially in vivo Have antibacterial effectiveness against gram-negative and against gram-positive germs. In comparison with known semisynthetically obtained cephalosporins and penicillin they show clear differences in terms of sensitivity: the individual Germs. In numerous cases, known ß * c-tama-ntlbiotica are replaced by the new Products significantly outperformed them in fighting certain bacterial infections have decisive therapeutic advantages. It is particularly noteworthy that the compounds of the formula I have excellent antibacterial properties when administered orally Show effectiveness, for example on mice against Staphylococcus aureus (measured than nC 50).

The compounds can accordingly be used as medicaments, in particular used to fight bacterial infections. They can also be saved as Intermediate products can be used to manufacture other drugs.

The invention thus relates to the new compounds of the formula I as well as their easily cleavable esters and their physiologically harmless salts.

Preferred radicals R are hydrogen (if A = -0-), alkyl with 1 - 6 carbon atoms, in particular alkyl with 1 - 4 carbon atoms but everything unbranched alkyl with 1 - 4 carbon atoms, such as methyl, ethyl, propyl or butyl. Besides R can also be branched alkyl having 3 to 6 carbon atoms, but preferably 3 or 4 carbon atoms mean, such as isopropyl, isobutyl, sec-butyl or tert-butyl. As more leftovers R may also be mentioned pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethyl-butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethyl-1methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl and 1,2,2-trimethylpropyl.

R1 is preferably acetoxy or S-Het, in particular acetoxy. if R1 denotes S-Het, then the 1-methyl-1,2,3,4-tetrazole-5-mercapto and 1,3,4-thiadiazole-2-mercapto radicals preferred; in addition, R1 can also be 1,2,3-triazole-5-mercapto, 2-methyl-1,3,4-thiadi.azole-5-mercapto or mean hydrogen.

In addition to an oxygen atom, A is also an oxycarbnyl group, the oxygen atom of the oxy group being preferred m6t 0e is connected to the radical R, ie A can be represented by -CC (= O) -or.

The symbol n means an integer between 0 and -8, preferably 0 (especially when A is an oxygen atom) 1, 2, 3, 4 or 5, where n in particular Is 2, 3 or 4 when A represents a -OC (= O) group. So that's it with the group-CnH2n- preferably around a single bond, a methylene, dimethylene, Trimethylene, tetramethylene or pentamethylene group, or a hexamethylene, Heptamethylene group or octamethylene group. CnH2n can also be an alkylidene or a branched alkylene group, for example an ethylidene, propylidene, Butylidene, pentylidene, propylene, ethylethylene, propylethylene or a butylethylene group.

Easily cleavable esters of the compounds of the formula I are in first and foremost the tert-butyl esters, also, for example, the trimethylsilyl, Benzl-benzhydryl, trichloroethyl, benzylmethyl, p-methoxybenzyl or methoxymethyl esters, also the pivaloyloxymethyl esters.

Those compounds of the formula I are preferred in which at least one of the symbols R, R1, A and n has one of the preferred meanings given above Has.

Some of these preferred groups of compounds can be represented by the sub-formulas Ia to Iz below, which otherwise correspond to formula I, and in which the symbols which are not designated in more detail have the meaning given for formula I, but in which in means in denotes, in Ic A denotes -0-, in Id A denotes -OC (= O) - denotes, in Ie n denotes 0, in If n denotes 1, 2, 3, 4 or 5 denotes in Ig Z denotes the meaning given under Ib and R1 is acetoxy or S-Het, in Ih Z has the meaning given for Ib and is acetoxy, in Ii Z has the meaning given for Ib and R1 is 1-methyl-tetrazole-5-mercapto or 1,3,4-thiadiazole -2-mercapto means, in Ij Z has the meaning given in ia and A means -0-, in Ik Z has the meaning given in Ia and A -OC (= O) - means, in Il Z the meaning given in Ia and n is 0, in Im Z has the meaning given for Ia and n is 1, 2, 3, 4 or 5 in In Z has the meaning given for Ia, A -0-, and n is 0, in Io Z has the meaning given for Ia, A -OC (= O) -, and n is 2 or 4, in Ip Z has the meaning given for Ia, A -O-, n is 0, and R is unbranched alkyl with 1-6 C -Atoms means, in Ir Z has the meaning given for Ia, A -On 0, and R unbranched alkyl with 1-4 C atoms means, in Is Z has the meaning given for Ia, A -OC (= O) -, n 2 or 4, and R means unbranched alkyl with 1-6 C atoms, in It Z the in Ia has the meaning given, A -OC (= O) -, n 2 or 4, and R denotes unbranched alkyl having 1-4 carbon atoms, in Iu Z has the meaning given in Ib and A denotes -0-, in Iv Z has the meaning given in Ib and A -OC (= O) - means, in Iw Z has the meaning given in Ib, A -O-, n 0, and R means unbranched alkyl with 1 - 4 C atoms, in Ix Z has the meaning given for Ib, A -O-, n 0, R unbranched alkyl with 1-4 carbon atoms and R1 acetoxy or S-Het in Iy Z has the meaning given in Ib, A -OC (= O) -, n 2 or 4, and R denotes unbranched alkyl with 1-4 carbon atoms, in Iz Z has the meaning given for Ib, A -OC (= O) -, n 2 or 4, R denotes unbranched alkyl 1-4 carbon atoms, and R1 is acetoxy or S-Het.

The invention also relates to a process for the preparation of the compounds of the formula 1 and their easily cleavable esters and their physiologically acceptable salts, which is characterized in that a compound of the general formula II wherein Z has the meaning given above, or one of its functional derivatives with a compound of the general formula III RA-CnH2n -C00-p-C6H4-bH (NH2) cOOH III wherein R, A and n have the meanings given above, or one their functional derivatives or an acid addition salt of these compounds, or that one puts them in a compound which otherwise corresponds to formula I but in which an NH2 group is present in a functionally modified form, or one of its easily cleavable esters or one of its physiologically acceptable salts NH2 group is set free by treatment with hydrolyzing or hydrogenolyzing agents and / or that a radical Z in a compound of the formula I or one of its easily cleavable esters or one of its physiologically acceptable salts is obtained by reaction with reducing or hydrogenolyzing agents or by reaction with a thiol HS-Het converts into another radical Z and / or that one otherwise Compound corresponding to formula I, but in which R = H and A = -oc (= o) -, or one of its easily cleavable esters or one of its physiologically acceptable salts is reacted with alkylating agents and / or that a compound of formula I is reacted converted into one of its easily cleavable esters by reaction with an esterifying agent and / or that a compound of the formula I is liberated from one of its easily cleavable esters by reaction with a hydrolyzing agent and / or that a compound of the formula I is converted converted with an acid or a base into one of its physiologically tolerable salts and / or that a compound of the formula I is liberated from one of its salts by reaction with a base or an acid.

The "-C atom of the substituted phenylacetyl radical, which is the side chain in a compound of formula I is asymmetric. The invention covers hence pure epimers in which this C atom has the D configuration and such pure epimers in which this carbon atom has the L configuration. But also the epimer mixtures of the formula I, in which the a-carbon atom of the side chain is partly D- and partly L-configured is, are the subject of the invention.

Those epimer mixtures are preferred in which the D- and the L-configuration occur in approximately equal parts. Such compounds are particularly preferred of the formula I, in particular of the formulas Ia to Iz in which the a-carbon atom of the side chain has the D configuration.

The process for the preparation of the compounds of the formula I proceeds according to methods as they are known in cephalosporin and penicillin chemistry and in are described in more detail in the literature.

The invention also relates to mixtures used in pharmacy Contain customary auxiliaries and / or carriers, and by a content of at least a compound of the general formula I and / or one of its physiologically harmless ones Salts and / or one of their easily cleavable esters are marked.

The invention also relates to the use of a compound of the formula I or one of their physiologically acceptable salts or one of their easily cleavable ester for the production of pharmaceutical preparations.

Finally, the invention also relates to a method for production of pharmaceutical preparations, characterized in that a compound of the formula I and / or one of their physiologically acceptable salts, if appropriate together with at least one partially liquid, non-volatile auxiliary or carrier and given ILs together with at least one other active ingredient in a suitable Brings dosage form.

The starting materials for the method according to the invention are partly known, partly new. You can by methods known per se analogously to known ones Connections are made. For example, the cephem derivatives are of the formula II (R1 = -S-Het) obtainable from 7-aminocephalosporanic acid (7-ACS; II, R1 = -OCOCH3) by reaction with the known heterocyclic thiols of the formula Het-SH, or the associated metal mercaptides, e.g. through reaction of the corresponding alkali metal salts in hot, aqueous acetone.

Suitable functional derivatives of an acid of the formula II are in primarily the easily cleavable esters, e.g. the tert-butyl esters, the trimethylsilyl esters (which e.g. arise in situ from II and N-trimethylsilyl-acetamide) and the others easily cleavable esters given above. Furthermore, the salts, especially the neutral salts of these acids.

The alkali metal (e.g. sodium, potassium), Alkaline earth metal (e.g. magnesium, calcium) and ammonium salts. Among the latter are those of amines, especially vontert-amines, e.g. triethylamine, triethanolamine, Pyridine, collidine, derived salts are preferred. These salts can be used as such in be used in the reaction; you can also in situ from an acid II and a Generate base, e.g. NaHC03, Na2HPO4 or triethylamine.

The acids of the formula III are derived from 2- (p-hydroxyphenyl) glycine. They are obtained from this known compound after blocking the amino group with one of the protective groups customary in peptide chemistry by Reaction with an acid of the formula IV R A CnH2n COOH IV in which R, A and n are as above have given meanings, or an activated derivative of this acid.

The activated derivatives of the acids IV are particularly suitable Halides, preferably the chlorides and bromides, also the anhydrides and mixed Anhydrides as well as azides and activated esters, e.g. those with p-nitrophenol, 2,4-dinitrophenol, p-nitrophenyl mercaptan, methylene cyanohydrin or N-hydroxysuccinimide. As mixed Anhydrides of acids IV are e.g. on the one hand those with lower alkanoic acids, especially with acetic acid or e.g. substituted acetic acids such as trichloroacetic acid, Pivalic acid or cyanoacetic acid and on the other hand anhydrides with carbonic acid half-esters, e.g. by reacting the acids IV with benzyl chloroformate, p-nitrobenzyl ester, isobutyl ester, ethyl ester and allyl ester are available. All of these functional Derivatives of IV are preferably generated in situ.

The compounds of the formula IV are known. These are preferably around CJ -alkoxycarboxylic acids with 3 - 15 a-atoms, preferably with 3 - 8 carbon atoms, the alkoxy radicals of which are especially unbranched and 1 - 4 Contain carbon atoms. Examples include: 2-methoxyacetic acid, 2-ethoxyacetic acid, 4-methoxybutyric acid, 4-butyloxybutyric acid, 8-ethoxycaprylic acid and 9-ethoxypelargonic acid. Where itere compounds of the formula IV are above all α, -dicarboxylic acid monoalkyl esters with 3-14 0 atoms, preferably 5-9 carbon atoms, in particular with unbranched Alkyl (ester) radicals with 1 - 4 carbon atoms, such as monoethyl malonate and monoethyl succinate and monobutyl ester, adipic acid mono ethyl ester and monobutyl ester; but also derivatives branched dicarboxylic acids such as methylmalonic acid monoethyl ester and 2-ethyl succinic acid monoethyl ester come into question.

A third important group of the compounds of the formula IV are those Carbonic acid half-esters with 2 to 7 0 atoms, preferably 2 to 5 carbon atoms, which are expedient be used as acid chlorides (= alkyl chloroformate).

Typical examples of these alkyl chloroformates are methyl chloroformate, Ethyl chloroformate, butyl chloroformate, hexyl chloroformate and tert-butyl chloroformate.

In general, the 2- (p-hydroxyphenyl) glycine is reacted (where the amino group is in protected form, for example as tert-butyloxycarbonylamino- or 2-ethoxycarbonyl-1-methylvinylamino group) with a compound of Formula IV (or with their activated derivatives) in the presence of an inert solvent.

Particularly suitable solvents are chlorinated hydrocarbons, e.g., methylene chloride, chloroform; Ethers, such as diethyl ether, tetrahydrofuran (THF), Dioxane; Ketones such as acetone, butanone; Amides such as dimethylformamide (DMF), dimethylacetamide, Phosphoric acid hexamethyl triamide (HMPT); Sulfoxides such as dimethyl sulfoxide (DMSO); Water; also organic or aqueous inorganic bases. Mixtures can also be used of the solvents mentioned can be used. The reaction temperatures are between about -70 and about +800, preferably between -50 and +300, in particular between -40 and 100. The reaction time depends on the type of starting materials selected and the reaction temperature dependent; it is usually between 5 minutes and 72 hours.

If a compound of the formula II or one of its functional ones is used Derivatives with an activated derivative of the formula III, this is activated Derivative always as an acid addition salt, with the proton as the amino blocking group serves and prevents self-acylation. At this point it should be noted that that "functional derivative" can mean both a compound in which a functional Group is in such a protected form that this group is in a certain Reaction not disturbing noticeable, as well as a connection in one certain functional group is present in activated form so as to be in the desired Reaction to respond particularly well. Of course, both can also be functional Modifications are present at the same time, for example in those of interest here Reactions an amino acid are used as an activated acid derivative, whereby the amino group is blocked by a protecting group.

The acid addition salts of the compounds of the formula III are especially those with strong acids, preferably with strong mineral acids like HCl, HBr, HJ, H2S04 or Hin03, but possibly also with strong organic ones Acids, for example trichloroacetic acid or trifluoroacetic acid.

It is particularly advantageous to acylate a compound of the Formula II or one of its functional derivatives is the acid chloride hydrochloride to use a compound of formula III.

The implementation of the compounds II (or their functional derivatives) with the compounds of the formula III (or

with their functional derivatives) is usually carried out in Presence of an inert solvent under reaction conditions similar to the above correspond to the acylation of 2- (m-hydroxyphenyls) -glycine mentioned. Particularly preferred reaction temperatures are between -40 and +100. Here too is that The duration of the reaction depends on the type of starting materials selected and the reaction temperature depends and is between 10 minutes and 80 hours. Suitable solvents are those above for the acylation of 2- (p-hydroxyphenyls) glycine with a compound of the formula V or their activated derivatives mentioned solvents.

The acylation of the 7-amino group of a cephalosporin, e.g. 7-aminocephalosporanic acid (= 7-ACS) or the 6-amino group of a penicillin, e.g. 6-aminopenicillanic acid (= 6-APS) is a well-known implementation, and every functional equivalent of a compound of formula III, commonly used as an acylating agent for primary amino groups is used can be used. Examples of suitable acylating derivatives (= activated derivatives) of the free acid have already been mentioned. The free acid can with a compound of formula II or one of its easily cleavable esters coupled, e.g. in the presence of enzymes or an N, N'-carbonyldiimidazole or an N, N'-carbonylditriazole or a carbodiimide reagent, e.g. N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N-cyclohexyl-N - (2-morpholinoethyl) -carbodiimide.

Another activated derivative is a corresponding azolide, i. an amide of the corresponding acid, whose amide nitrogen is a member of a quasi-aromatic 5-membered ring containing at least two nitrogen atoms, e.g. one Imidazole, pyrazole, triazole, benzimidazole or benzotriazole ring. Another suitable derivative the substituted phenylglycines of the formula III is N-carboxy anhydride (Leuchs' anhydride). Here is the group that serves activates the carboxyl group, also to protect the amino group.

In particular, it is particularly useful to have an easily split Ester, preferably a tert-butyl ester of acid II with a compound of Formula III, in which the amino group is in protected form, to implement (where it is advantageous to add a water-binding agent) and then in the obtained Reaction product to release the amino group hydrolytically or hydrogenolytically. Carbodiimides, in particular dicyclohexylcarbodiimide, can be used as water-binding agents (DCC) into consideration.

Thus, for example, 7-ACS-tert-butyl ester or 6-APS-tert-butyl ester is left with a compound of the formula V R-A- CnH2n -C00-C6H4-CH (NHR3) COOH V wherein R3 a protective group which can be split off with hydrolysing or hydrogenolysing agents means and R, A, and n have the meanings given above, and DCC in approximately equimolar proportions and with cooling in an inert solvent react, especially in chlorinated hydrocarbons such as methylene chloride, in ethers such as THF or in aprotic dipolar solvents such as DMF or DMSO or else in solvent mixtures.

The implementation of a compound of formula II or one of its functional ones Derivatives with activated derivatives (or their salts) of the acids III are preferred in the presence of a. Basic catalyst made, Suitable basic catalysts are inorganic metal hydroxides, preferably alkali metal or alkaline earth metal hydroxides, basic salts and organic amines, preferably tertiary organic amines. In particular, NaHCO3, MC03, Na2CO3, K2CO3, are used; NaOH, KOH, pyridine or a base of low nucleophilicity, e.g. a tertiary amine such as triethylamine, N-methylmorpholine, Xthyldiisopropylamine or potassium tert-butoxide.

The radical R3 means hydrolytically or hydrogenolytically easy Removable protective group as it is known in particular from peptide chemistry. In particular, the following protective groups come into question: Arylmethyloxycarbonylreste, such as benzyloxycarbonyl, Alkyloxyearbonyl, such as tert-butyloxycarbonyl 0300); Arylsulfonyl radicals, such as p-bromophenylsulfonyl or p-tolylsulfonyl; Arylmethyl radicals such as benzyl, diphenylmethyl or triphenylmethyl; Acyl groups, preferably alkanoyl groups such as formyl, acetyl or pivaloyl or substituted alkanoyl groups such as trifluoroacetyl, chloroacetyl or o-nitrophenoxyacetyl; Aryloxycarbonyl groups such as phenoxycarbonyl; Alkylthiocarbonyl or aralkylthiocarboiiyl radicals, such as benzylthiocarbonyl or activated vinyl groups such as 2-ethoxycarbonyl-1-methylvinyl.

The β-lactam compounds of the formula I are also available indene ffla £ -i a functionally contained in a compound otherwise corresponding to formula I sets modified NH2 group according to known methods in freedom.

The starting materials for the process variant are e.g.

obtainable by reacting a compound of the formula II with a compound of the formula V. It is particularly advantageous to react a compound of the formula II or one of its functional derivatives with a compound of the formula VI HO-p-C6H4-CH (NHR3) COOH VI in which R3 has the meaning given above, or one of its functional derivatives and the resulting Compounds of the formula VII in which Z and R3 have the meanings given above, or to react their functional derivatives or the salts of these compounds further with a compound of the formula IV or one of its activated derivatives.

The reaction conditions for the conversion of a compound of the formula VII or one of their functional derivatives or a salt of these compounds with a compound of the formula IV or one of its activated derivatives for the implementation of a compound of the formula II (or its functional derivatives) with a compound of the formula III (or its functional derivatives) already described conditions.

A functionally modified amino group can according to known Methods described in the literature are solvolytic, especially hydrolytic or set free by hydrogenolysis. A solvolysis, preferably one Hydrolysis, especially a tert-butyloxycarbonylamino group, is carried out, for. B. with trifluoroacetic acid or with aqueous nineral acids, e.g. hydrochloric acid, at temperatures carried out between -10 ° and 50 °. Hydrogenolysis, especially cleavage of benzyl, tert. -Butoxycarbenyl and carbobenzyloxy radicals are possible by hydrogenation in the presence of noble metal catalysts such as 5 to 50% palladium on carbon or palladium oxide. It is expedient to hydrogenolyze at temperatures between -10 and +500, especially at room temperature and at pressures between ff and 10 at, -preferably at normal pressure. Particularly mild hydrogenation conditions must be selected, unwanted reductions, for example of the C = C double bond of the cephem system to avoid.

One can also use compounds of the formula VII or their functional ones Derivatives or the salts of these compounds with acids of the formula IV in which A can be represented as -COO- or O -CO- group (in which therefore R to the C atom the carbonyl group is bonded), or react an activated derivative of this acid and after splitting off the protective group (R³), the desired compound of the formula is obtained I. The reaction conditions for this reaction have already been described.

You can also use a connection which otherwise corresponds to formula I but which R = II and A = -OC (= O) - mean or one of their easily cleavable esters or one of their physiologically acceptable salts by reaction with alkylating ones Converting agents into a compound of the formula I. Come as alkylating agents especially in question alkanols with 1 - 6 carbon atoms, such as methanol, ethanol, propanol, Butanol, isopropyl alcohol, sec-butyl alcohol, isobutyl alcohol and tert-butyl alcohol, Pentanol, pentanol-2, ifexanol or hexanol-2 or acid esters, especially carboxylic acid esters, in particular alkanoic acid esters, e.g. the formates, acetates, propionates, pivalates of named alcohols. The alkyl halides derived from the alcohols mentioned, In particular, bromides with 1 to 6 carbon atoms are suitable alkylating agents.

The implementation of a compound that otherwise corresponds to Formula 1, but in which R = H and A = -OC (= O) - is carried out with an alkylating agent usually in the presence of an acidic catalyst, preferably a mineral acid such as HCl, ester or EI2S04, or an organic acid, especially a sulfonic acid such as p-toluenesulfonic acid.

It is advantageous for the alkylation in the presence of a dehydrating agent To work by means of DCO or by forming water by azeotropic distillation to.

remove if the alkylating agent is an alcohol acts with 1 - 4 carbon atoms. Usually works in inert solvents, E.g. hydrocarbons like benzene, or G (chlorohydrocarbons like dichloromethane, Chloroform, carbon tetrachloride or 1,2-dichloroethane using an excess of the alkylating agent. It is also possible to use the alkylating agent at the same time to be used as a solvent. When to use alkyl halides as alkylating agents with 16 Carbon atoms are used, the carboxyl group is H-OC (= O) - (A = -OC (= O) -, R = H) in the alkylation preferably in salt form, especially as Silver salt are present. The alkylation temperatures are between 0 and 1000. Others alkylating agents are diazoalkanes with 1-6 carbon atoms, in particular diazomethane. It is expedient to alkylate with these compounds in ethers such as diethyl ether or Dioxane, preferably at temperatures between 0 and 400, in particular at room temperature.

Among the hydrolyzing agents with which a compound of the formula I can be set free from one of their easily cleavable esters it is primarily water in the presence of a base, preferably an inorganic one Base, in particular an alkali metal hydroxide or carbonate, such as NaOH, KOH, Na2CO3 or K2003, but also an organic base such as triethylamine, triethanolamine, or Piperidine. Inert organic solvents can also be present, see above one works preferably in mixtures of dioxane, acetone or dimethylformamide and water as the reaction medium. The hydrolysis temperatures are usually between 100 and 800, preferably at room temperature.

If desired, one can in the product of formula 1 or one of its easily cleavable esters or one of its physiologically harmless ones Salts exchange one residue R1 for another residue R1.

It is particularly advantageous to use a cephalosporanic acid obtained Formula 1 (R1 = OCOCH3) by reaction with a mercaptane of the formula Het-SH in to convert the corresponding thioether (R1 = SHet). Appropriate sets man a salt of a cephalosporanic acid I with a salt of thiol in aqueous acetone at temperatures between 20 and 100 ° and pH values between 4 and 8 μm. As salts the alkali metal salts, especially the sodium salts, are particularly suitable. Particularly this synthetic route is suitable for the preparation of compounds of the formula I where the radical A is an oxygen atom and n is not equal to 0.

You can also catalytically an acetoxy radical R1 by treatment activated hydrogen, for example among those mentioned above for hydrogenolysis Convert reaction conditions into a hydrogen atom.

As already explained, the compounds of formula I have in the with the side chain linked to the ß-lactam ring a center of asymmetry.

They are therefore mostly obtained as a mixture of two epimeric forms, which due to their different physical properties from the mixture can be isolated and obtained in pure form, for example by recrystallization from suitable solvents (in particular, instead of the compounds themselves well-crystallizing derivatives can be used), but in particular also using chromatographic methods, both adsorption chromatographic or distribution chromatographic methods as well as mixed forms come into question.

It is of course also possible to use pure diasteromeric compounds of the formula I by the methods described, for example by adding compounds of the formula III (or their activated derivatives) used as starting materials, the are already optically active.

The optically active compounds of the formula III or

their activated derivatives can by a variety of known methods, as described in the literature, especially for the cleavage of racemic α-amino acids are given, can be prepared from the racemates.

The chemical separation method is preferred.

Then from the racemic mixture by reaction with a optically active auxiliary diastereomers formed; So, if necessary, you can use a react optically active base with the carboxyl group of a compound of formula III. For example, one can use diastereomeric salts of the compounds of formula III with optically active amines such as quinine, brucine, morphine or 1-phenylethylamine.

The amino group can be reacted with an optically active acid such as (+) - and (-) - tartaric acid, camphoric acid or ß-camphorsulphonic acid for the formation of more suitable diastereomeric salts are used, preferably an ester of the Amino acid used. -The difference in solubility of each resulting diastereomeric salts allows the selective crystallization of one form and the Regeneration of the respective optically active compounds from the mixture.

A free carboxylic acid I is also fed into one by esterification convert easily cleavable carboxylic acid ester.

For example, the tert-butyl esters are obtained by reacting the acids with isobutylene.

Conversely, the acid I can be obtained in freedom from an ester obtained can be set, e.g. by solvolysis, in particular by acid hydrolysis. The at the synthesis particularly advantageously obtained tert. Butyl esters are e.g. with trifluoroacetic acid cleaved at temperatures between 0 and 400.

The new cephem derivatives are solid crystalline or amorphous products They form solid, often crystalline, alkali metal, ammonium and alkaline earth metal salts as well as salts with organic bases such as diethylamine, triethylamine, diethanolamine, N-ethyl diethanolamine, pyrrolidine, piperidine, N-ethylpiperidine, i .- (2-hydroxyethyl) piperidine, Morpholine, procaine, benzylamine, dibenzylamine, 1-phenyl-2-propylamine and others Amines, such as those commonly used for the production of cephalosporin salts Find.

Of the alkali metal salts, the sodium and potassium salts are in particular significant. They can be made by taking a solution of an acid I in an organic solvent with a solution of the sodium or potassium salt a fatty acid, e.g. diethylacetic acid or 2-ethylcaproic acid, in a solvent, e.g. Acetone or n-butanol, or mixed with a solvent mixture. The one with it or salts which precipitate on the addition of ether can be filtered off.

Basic compounds of the formula I can be treated with acids in the customary manner be converted into the associated acid addition salts, e.g. into the hydrochloride or citrate.

Since the compounds I have no sharp melting points, will appropriately characterized by other physical indicators, especially advantageous due to their nuclear magnetic resonance spectra. You can also use the thin layer chromatogram be characterized. For this purpose, Merck TLC precast silica gel plates can be used F254 can be used (superplasticizer, e.g. dioxane / water 85:15).

The new compounds can be mixed with solid, liquid and / or semi-liquid auxiliaries and / or carriers commonly used in pharmacy, e.g. as pharmaceuticals used in human or veterinary medicine.

As auxiliary and / or carrier substances such organic or inorganic substances in question, which for enteral, preferably oral, e.g. but are also suitable for parenteral or topical application and those with the new compounds do not react, such as water, vegetable oils, benzyl alcohols, Polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, petroleum jelly, Cholesterol. For enteral use, e.g. tablets, capsules, coated tablets, Syrups, juices, granules (dry juices) or suppositories. For par; enteral application In particular, solutions, preferably oily or aqueous solutions, are used as well Suspensions, emulsions or implants, for topical application ointments, creams, Lotions, pastes or powders. The expert knows which of the usual pharmaceuticals Auxiliaries and / or carriers, in particular those mentioned above, he with a or more compounds of the formula I and / or their easily cleavable esters and / or can mix their physiologically harmless salts, so for the desired type of application to obtain suitable preparations. These preparations can sterilized or with auxiliaries, emulsifiers, salts to influence the osmotic pressure, buffer substances, dyes added will. They can also contain other active ingredients.

The compounds of general formula I and their easily cleavable Esters and their physiologically acceptable salts can essentially be used in the same way as the well-known compound cephalexin used to fight infections be used; they are preferably used in dosages between 1 and 5000, in particular administered between 200 and 2000 mg per dosage unit. The daily dosage is preferably between 4 and 100, in particular between 10 and 60 mg per kg Body weight.

Each of the compounds of the formula mentioned in the following examples I is particularly suitable for the production of pharmaceutical preparations.

The IR spectra were measured in KBr.

The NMR spectra are recorded in dimethyl sulfoxide.

DMF = dimethylformamide, 7-ACS = 7-aminocephalosporanic acid, 6-APS = 6-aminopenicillanic acid, DCC = dicyclohexylcarbodiimide, THP = tetrahydrofuran, BOC = tert-butyloxycarbonyl, AMV = 2-ethoxycarbonyl-1-methylvinyl, MCC = -3-methyl-3-cephem-4-carboxylic acid, CC = -3-cephem-4-carboxylic acid, CS = -cephalosporanic acid, PS = -penicillanic acid.

Unless otherwise stated, the following examples the substituted 2-phenylglycines of the formula II (or their derivatives) as racemates used; accordingly, the compounds of the formula I are then used as mixtures two primers obtained.

EXAMPLE 1 4.33 g of the triethylammonium salt of 6-8D-2- (AMV-amino) -2-p-hydroxyphenyl-acetamido) -PS are dissolved (produced by gently heating equimolar amounts of 6- (D-2-amino-p-hydroxyphenyl-acetamido) -PS (= Amox-ycillin and ethyl acetoacetate in dichloromethane in the presence of triethylamine) in 50 ml of dichloromethane and 2.1 ml of triethylamine, 1.45 ml are added dropwise while cooling with ice Ethyl chloroformate, dissolved in 5 ml of dichloromethane, is added and the mixture is stirred for 30 minutes while cooling with ice, the solvent is distilled off and the oily residue is removed in 50 ml of THF, extracted with 100 ml of dilute aqueous sodium bicarbonate solution, brings the aqueous phase after washing with diethyl ether to pH = 3 and then extracted with ethyl acetate. The organic phase is left to stand overnight and then precipitated the 6- (2-D-amino-p-ethoxycarbonyloxyphenyl-acetamido) -PS by adding petroleum ether; Rf = 0.41 (silica gel / dioxane: water = 85:15), IR: 1690, 1760 and 1770 cm 1 (Shoulder).

Analogously to Example 1, the D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -PS are obtained from the triethylammonium salt by reaction with the corresponding alkyl chloroformates, which are the acid chlorides of the carbonic acid half esters of the formula IV (A = -O-, n = 0) can be understood, and subsequent splitting off of the amino protective group (which already takes place during work-up) the penicillanic acid derivatives of the formula I mentioned in the following Examples 2 to 12 are obtainable: Bei-penicillanic acid derivative of the formula I. game 2 6- (2-D-amino-2-p-methoxycarbonyloxyphenyl-acet- amido) -PS, 3 | 6- (2-D-amino-2-p-propyloxycarbonyloxyphenyl- acetamido) -PS, 4 4 6- (2-D-amino-2-p-isopropyloxycarbonyloxy acetamido) -PS, 5 6- (2-D-amino-2-p-butyloxycarbonyloxyphenyl-acet- amido) -PS, 6 6- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl acetamido) -PS, 7 6- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetamido) -PS, t Bei-penicillanic acid derivative of the formula I. game 8 6- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenyl- acetamido) -PS, 9 6- (2-D-amino-2-p-pentyloxycarbonyloxyphenyl acetamido) -PS, 10 6- (2-D-amino-2-p-isopentyloxycarbonyloxyphenyl- acetamido) -PS, 11 | 6- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl acetamido) -PS, 12 | 6- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl- acetamido) -PS.

Example 13 6.34 g of the triethylammonium salt of 7- (2-D- (AMV-amido) -2-p-hydroxyphenyl-acetamido] -CS are dissolved (Can be prepared by heating equimolar amounts of 7- (2-D-amino-2-p-hydroxyphenylacetamido) -CS and ethyl acetoacetate in dichloromethane in the presence of triethylamine) in 60 ml of dichloromethane and 2.3 ml of triethylamine, 1.25 g of ethyl chloroformate are added dropwise while cooling with ice, dissolved in 8 ml of dichloromethane, stirred for 45 minutes with ice cooling and worked the reaction mixture as described in Example 1 on. 7- (2-D-amino-2-p-ethoxycarbonyloxyphenyl-acetamido) is obtained -CS.

Analogously to Example 13 are from the triethylammonium salt of 7-C2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido) -CS by reacting with the corresponding chloroformic acid alkyl esters of the formula IV and subsequent cleavage of the Amino protective group, the cephalosporanic acids of the formula I mentioned in Examples 14 to 24 below are available: Bei-cephalosporanic acid derivative of the formula I. game 14 | 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl- acetamido) -CS, 15 | 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl acetamido) -CS, 16 | 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl- acetamido) -CS, 17 | 7- (2-D-amino-2-p-butyloxycarbonyloxyphenyl acetamido) -CS, 18 | 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl- acetamido) -CS, 19 7- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetainido) -CS, 20 7- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenyl- acetamido) -CS, 21 | 7- (2-D-amino-2-p-pentyloxycarbonyloxyphenyl- acetamido) -CS, 22 | 7- (2-D-amino-2-p-isopentyloxycarbonyloxyphenyl- acetamido) -CS, 23 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl- acetamido) -CS, [α] D20 = + 43.60 (in ethanol), 24 | 7- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl- acetamido) -CS.

Analogously to Example 13 are from the triethylammonium salt of 7-0-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido) -MCC by reacting with the corresponding chloroformic acid alkyl esters of the formula IV and subsequent cleavage of the Amino protective group, the 3-methyl-3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following Examples 25 to 36 are available: Bei-3-methyl-3-cephem-4-carboxylic acid derivative game of formula I. 25 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl- acetamido) -MCC, 26 7- (2-D-amino-2-p-ethoxycarbonyloxyphenyl acetamido) -MCC, 27 | 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl acetamido) -MCC, 28 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl- acetamido) -MCC, 29 7- (2-D-amino-2-p-butyloxycarbonyloxyphenyl- - acetamido) -MCC, 30 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl- acetamido) -MCC, 31 7- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetamido) -MCC, 32 7- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenyl- acetamido) -MCC, 33 | 7- (2-D-amino-2-p-pentyloxycarbonyloxyphenyl- acetamido) -MCC, 34 7- (2-D-amino-2-p-isopentyloxycarbonyloxyphenyl- acetamido) -MCC, 35 | 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl- acetamido) -MCC, 36 | 7- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl- acetamido) -MCC Analogously to Example 13 are from the triethylammonium salt of 7-y2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC by reacting with the corresponding chloroformic acid alkyl esters of the formula IV and subsequent cleavage of the amino protective group (already taking place during work-up) the 3- (1,2,3-triazolyl-5-mercaptomethyl) -3-cepham-4-carboxylic acid derivatives mentioned in Examples 37 to 48 below Formula I available: Bei- 3- (1,2,3-triazolyl 5-mercaptomethyl) -3-cephem- game 4-carboxylic acid derivative of the formula I. 37 | 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl-acet- amido) -3- (1, 2,3-triazolyl-S-mercaptomethyl) -CC, 38 | 7- (2-D-amino-2-p-ethoxycarbonyloxyphenyl-acet- amido) -3- (1, 2,3-triazolyl-S-mercaptomethyl) -CC, 39 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl- acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 40 | 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl- acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 41 | 7- (2-D-amino-2-p-butyloxycarbonyloxyphenyl-acet- amido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 42 | 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl- acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 43 | 7- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 44 | 7- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenyl- . acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 45 | 7- (2-D-amino-2-p-pentyloxycarbonyloxyphenyl-acet- amido) -3- (1,2,3-tri.azolyl-5-mercaptomethyl) -CC, 46 | 7- (2-D-amino-2-p-isopentyloxycarbonyloxyphenyl- . acetamido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC, 47 | 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl-acet- amido) -3- (1, 2,3-triazolyl-5-mercaptomethyl) -CC, 48 | 7- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl-acet amido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC.

Analogously to Example 13 are from the triethylammonium salt of 7-t2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamide zolyl-5-mercaptomethyl) -CC by reacting with the corresponding chloroformic acid alkyl esters of the formula IV and subsequent (already in the Work-up taking place) splitting off of the amino protective group the 3- (1-methyltetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following examples 49 to 60 are obtainable: Bei- 3- (1-methyltetrazolyl-S-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 49 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl-acet amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 50 7- (2-D-Amino-2-p-ethoxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 51 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 52 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 53 7- (2-D-amino-2-p-butyloxycarbonyloxyphenyl-acet amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 54 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 55 7- (2-I) -amino-2-p-sec.-butyloxycarbonyloxyphenyl-acet- aniido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 56-7- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenylw acetamido) -3- (1 "methyltetrazolyl-5-mercaptomethyl)" CC 57 7- (2-D-Amino-2-p-pentyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 58 7- (2-D-Amino-2-p-isopentyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 59 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC, 60 7- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl-acet- amido) -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC.

Analogously to Example 13 are from-the triethylammonium salt of D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC by reacting with the corresponding chloroformic acid alkyl esters of Formula IV and subsequent cleavage of the amino protective group (already obtained during work-up), the 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I mentioned in Examples 61 to 72 below available: At- 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 61 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercal) tomethyl) -CC, 62 7- (2-D-Amino-2-p-ethoxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thidiazolyl-2-mercaptomethyl) -CC, 63 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 64 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl- acetamido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl-CC, 65 7 - (2-D-Amino-2-p-butyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 66 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 67 7- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetamido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 68 7- (2-D-AmJno-2-p-tert-butyloxycarbonyloxypllellyl- acetamido) -3 ~ (1,3,4-tlliadiazolyl-2-lllercaDtomethyl) -CC, 69 7- (2-D-Amino-2-p-pentyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 70 7- (2-D-amino 2-p-isopentyloxycarbonyloxypllenyl-acet- amido) -3- (1,3,4-thiadiazole) rl -2-mercaptomethylllyl) -CCZ 71 | 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC, 72 7- (2-D-Amino-2-p-isohexyloxycarbonyloxyphenyl-acet- amido) -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC.

Analogously to Example 13 are from the triethylammonium salt of 7- [2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) - CC by reaction with the corresponding alkyl chloroformate of the formula IV and subsequent cleavage of the amino protective group (which already takes place during work-up) the 3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) mentioned in Examples 73 to 84 below -3-cephem-4-carboxylic acid derivatives of the formula I available: Bei- 3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) - spiel @@@@@ em-4-carboxylic acid derivative of the formula I 73 7- (2-D-amino-2-p-methoxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 74 7- (2-D-Amino-2-p-ethoxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 75 7- (2-D-amino-2-p-propyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 76 7- (2-D-amino-2-p-isopropyloxycarbonyloxyphenyl- acetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC, 77 7- (2-D-Amino-2-p-butyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 78 7- (2-D-amino-2-p-isobutyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 79 7- (2-D-amino-2-p-sec.-butyloxycarbonyloxyphenyl- acetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC, 80 7- (2-D-amino-2-p-tert-butyloxycarbonyloxyphenyl- acetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC, 81 7- (2-D-Amino-2-p-pentyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 82 7- (2-D-amino-2-p-isopentyloxycarbonyloxyphenyl- acetamido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 83 7- (2-D-amino-2-p-hexyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC, 84 7- (2-D-amino-2-p-isohexyloxycarbonyloxyphenyl-acet- amido) -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC.

Example 85 2.89 g of the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetam are dissolved ido) -pen Lc illanoic acid (produced by heating equimolar amounts of the 6 - (2 -Rmino-2-p-hydroxyphenylacetamido) -penicillanic acid and ethyl acetoacetate in dichloromethane in the presence of triethylamine) in 250 ml of dichloromethane and 5.6 ml of triethylamine, 1.87 g of adipic acid monomethyl chloride are added dropwise with ice cooling, dissolved in 40 ml of dichloromethane, stirred for a further 30 minutes while cooling with ice, distilled the solvent, dissolves the oily residue in 50 ml of THF, filtered, gives the Filtrate with stirring in 250 ml of dilute aqueous sodium bicarbonate solution, distilled the organic solvent from, the aqueous solution extracted with ethyl acetate, then bring the aqueous phase to pH = 3 in hydrochloric acid and extract with 200 ml of ethyl acetate. After standing overnight, it is precipitated with petroleum ether and obtained 6- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamido] -penicillanic acid; Rf = 0.43 (silica gel / dioxane: water = 85:15); IR: 1G85, 1735, 1760 and 1770 cm 1 (shoulder).

Analogously to Example 85 are from the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetamido) -PS by reacting with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV (A = -OC -) and subsequent splitting off of the amino protective group (already taking place during work-up), the penicillanic acid derivatives of the formula I mentioned in Examples 86 to 112 below are obtainable: Bei-penicillanic acid derivative of the formula I. game 86 6- [2-D-amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido] PS 87 6- [2-D-amino-2-p- (5-propyloxycarbonylpentanoyloxy) - phenyl-acetamido] PS 88 6- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido] PS At- | Penicillanic acid derivative of the formula T. game -2 6 26558 89 6- [2-D-amino-2-p- (5-pentyloxycarbonylpentanoyloxy) - phenyl-acetamido] PS 90 6- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) - phenyl-acetamido] PS 91 6- (2-D-Ainino-2-p- (2-methoxycarbonyl acetoxy) - phenyl-acetamido,? - PS 92 6- [2-D-amino-2-p- (3-methoxycarbonylpropanoyloxy) - phenyl-acetamido] PS 93 6- [2-D-amino-2-p- (4-methoxycarbonylbutanoyloxy) - phenyl-acetamido] PS 94 6- [2-D-Ami no- 2 -p- (6-methoxycarbonylhexanoyloxy) - phenyl-acetamido] PS 95 6- [2-D-amino-2-p- (7-methoxycarbonylheptanoyloxy) - phenyl-acetafflido2-PS 96 6- [2-D-amino-2-p- (8-methoxycarbonyloctanoyloxy) - phenyl-acetamido] PS 97 6- [2-D-amino-2-p- (9-methoxycarbonylnonanoyloxy) - phenyl acetarnido PS 98 6-62-D-Amino- 2 -p - (2 -ä thoxyc arb onylac et oxy) - phenyl-acetamido] PS 99 6- [2-D-amino-2-p- (2-butoxycarbonylacetoxy) - phenyl acetamido PS 100 6- [2-D-amino-2-p- (2-hexyloxycarbonylacetoxy) - phenyl-acetamido] PS 101 6- [2-D-Amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl-acetamido] PS 102 6- [2-D-Amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamido] PS 103 6- [2-D-Amino-2-p- (7 - # thoxyc ari, onylhep t anoyl oxy) - phenyl-acetamido] PS 104 6- [2-D-Amino-2-p- (9 - a th oxy ca rb onylnonanoyl oxy) - phenyl-acetamido, 7-PS 105 6- [2-D-amino-2-p- (3-butyloxycarbonylpropanoyloxy) - phenyl-acetamido] PS Bei-penicillanic acid derivative of the formula I. game 106 6- [2-D-amino-2-p- (3-hexyloxycarbonylpropanoyloxy) - phenyl acetamido PS 107 6- [2-D-amino-2-p- (4-butyloxycarbonylbutanoyloxy) - phenyl-acetamido] PS 108 6- [2-D-amino-2-p- (4-hexyloxycarbonylbutanoyloxy) - phenyl-acetamido] PS 109 6- [2-D-amino-2-p- (7-butyloxycarbonylheptanoyloxy) - phenyl-acetamido2-PS 110 6-ZD-amino-2-p- (7-hexyloxycarbonylheptanoyloxy) - phenyl-acetamido] PS 111 6- [2-D-amino-2-p- (9-butyloxycarbonylnonanoyloxy) - phenyl-acetamido] PS 112 6- [2-D-amino-2-p- (9-hexyloxycarbonylnonanoyloxy) - phenyl-acetamido] PS Analogously to Example 85, the 7- [2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -CS are prepared from the triethylammonium salt by reaction with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV and subsequent cleavage of the amino group (already taking place during work-up), the cephalosporanic acids of the formula I mentioned in Examples 113 to 125 below are obtainable. Bei-cephalosporanic acid of the formula 1 game 113 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamido] -CS, [α] D20 = + 49.6 ° (in ethanol) 114 7- [2-D-amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido] -CS, [α] D20 = + 78.0 ° (in ethanol) 115 7-C2rD-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido] -CS 116 7-C2-D-amino-2-p- (5-hexyloxycarbollylpentanoyloxy) - phenyl-acetamido] -CS Bei-cephalosporanic acid of the formula I. game 117 7- [2-D-amino-2-p- (2-methoxycarbonylacetoxy) - phenyl-acetamido] -CS 118 7- [2-D-amino-2-p- (2-ethoxycarbonylacetoxy) - phanyl-acetamido, 7-CS 119 7- (2-D-amino-2-p- (2-butyloxycarbonylacetoxy) - phenyl-acetamido 7-CS 120 | 7- [2-D-amino-2-p- (2-hexyloxycarbonylacetoxy) - phenyl-acetamido 7-CS 121 7-f2-D-amino-2-p- (3-ethoxycarbonylpropanoyloxy) phenyl-acetamido] -CS, [α] D20 = + 37.6 ° (in ethanol) 122 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamido] -CS 123 7- [2-D-amino-2-p- (6-methoxycarbonylhexanoyloxy) - phenyl-acetamido] -CS, [α] D20 = + 67.6 ° (in ethanol) 124 7- [2-D-Amino-2-p- (7-ethoxycarbonylheptanoyloxy) - phenyl-acetamido] -CS 125 7- [2-D-amino-2-p- (9-ethoxycarbonylnonanoyloxy) - phenyl-acetamido] -CS Analogously to Example 85, the D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -MCC are obtained from the triethylammonium salt by reaction with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV and subsequent cleavage of the amino protective group (already taking place during work-up) the 3-methyl-3-cephem-4-carboxylic acid derivatives of the formula I mentioned in Examples 126 to 138 below are obtainable: Bei-3-methyl-3-cephem-4-carboxylic acid derivative game of formula I. 126 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamido] -MCC 127 7- [2-D-amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido] -MCC Bei-3-methyl-3-cephem-4-carboxylic acid derivative game of formula I. 128 7- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl acetamidol MCC 129 | 7- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) - phenyl-acetamidoj-MCC 130 | 7- [2-D-amino-2-p- (2-methoxycarbonylacetoxy) - phenyl-acetamidoj-MCC 131 7- [2-D-amino-2-p- (2-ethoxycarbonylacetoxy) - phenyl-acetamido] -MCC 132 7- [2-D-amino-2-p- (3-butyloxycarbonylacetoxy) - phenyl-acetamidoj-MCC 133 7- [2-D-amino-2-p- (2-hexyloxycarbonylacetoxy) - phenyl-acetamido] -MCC 134 7- [2-D-amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl acetamidog MCC 135 | 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl acetamido MCC 136 | 7- [2-D-amino-2-p- (6-ethoxycarbonylhexanoylxy) - phenyl acetamidog MCC 137 | 7- [2-D-amino-2-p- (7-ethoxycarbonylheptanoylxy) - phenyl-acetamido, 7-MCC 138 | 7- [2-D-amino-2-p- (8-ethoxycarbonylnonanoylxy) - phenyl acetamido MCC Analogously to Example 85, the D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC are obtained from the triethylammonium salt by reacting with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV and subsequent cleavage of the amino protective group (already taking place during work-up) the 3- (1,2,3-triazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following examples 139 to 149 are obtainable: At- 3- (1,2,3-triazolyl-5-mercaptomethyl) -3-cephem- game 4-carboxylic acid derivative of the formula I. 139 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 140 7- [2-D-amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 141 7- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 142 7- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 143 7- [2-D-amino-2-p- (2-methoxyoxycarbonylacetoxy) - phenyl-acetamidog-3 - (1, 2, 3- triazolyl- 5-mercapto- methyl) -CC 144 | 7- [2-D-amino-2-p- (2-ethoxycarbonylacetoxy) - phenyl-acetamido9-3- (1, 2, 3-triazolyl-5-mercapto methyl) -CC 145 7- [2-D-Amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 146 | 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamido9-3- (1, 2, 3-triazolyl- 5-mercapto- methyl) -CC 147 7- [2-D-Amino-2-p- (6-ethoxycarbonylhexanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 148 7- [2-D-Amino-2-p- (7-ethoxycarbonylheptanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 149 7- [2-D-amino-2-p- (9-ethoxycarbonylnonanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC Analogously to Example 85, the D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC are obtained from the triethylammonium salt by reacting with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV and subsequent cleavage of the amino protective group (already taking place during work-up) the 3- (1-methyltetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following examples 150 to 160 are obtainable: Bei- 3- (1-methyltetrazolyl-5-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 150 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamidoi-3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 151 7- [2-D-Amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 152 | 7- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido) 3 (l-methyltetrazolyl-S-mercapto- methyl) -CC 153 | 7- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) - phenyl-acetamido9-3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 154 | 7- [2-D-amino-2-p- (2-methoxycarbonylacetoxy) - pheny-acetamido-3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 155 7- [2-D-amino-2-p- (2-ethoxycarbonylacetoxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 156 | 7- [2-D-amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl-acetamido9-3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 157 | 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamidoJ-3- (1-methyltetrazolyl-5-mercapto- methyl) -CC Bei- 3- (1-methyltetrazolyl-5-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 158 7- [2-D-Amino-2-p- (6-ethoxycarbonylhexanoyloxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 159 7- [2-D-amino-2-p- (7-ethoxycarbonylheptanoyloxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5-mercapto- methyl) -CC 160 7- [2-D-Amino-2-p- (9-ethoxycarbonylnonanoyloxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5-mercapto- methyl) -CC Analogously to Example 85, the D- (AMV-amido) -2-p-hydroxyphenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC are obtained from the triethylammonium salt by reacting with the acid chlorides of the corresponding monoalkyl esters of the dicarboxylic acids of the formula IV and subsequent cleavage of the amino protective group (already taking place during work-up) the 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following examples 161 to 171 are obtainable: At- 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 161 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 162 7 2-D-Amino- 2 -p- (5-ethoxycarbonylpen tanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- me thyl jCC 163 7- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl -CC 164 7- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC At- 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3- play cephem-4-carboxylic acid derivative of the formula I. 165 7- [2-D-amino-2-p- (2-methoxycarbonylacetoxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 166 7- [2-D-amino-2-p- (2-ethoxycarbonylacetoxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 167 7- [2-D-amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 168 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 169 7- [2-D-Amino-2-p- (6-ethoxycarbonylhexanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 170 7- [2-D-amino-2-p- (7-ethoxycarbonylheptanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 171 7- [2-D-Amino-2-p- (9-ethoxycarbonylnonanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC Analogously to Example 85, the 7-t2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) -CC are obtained from the triethylammonium salt by reaction with the corresponding alkyl chloroformates of the formula IV and subsequent splitting off of the amino protective group (already taking place during work-up) the 3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula mentioned in Examples 172 to 132 below 1 available: At- | 2- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) - game 3-cephem-4-carboxylic acid derivative of the formula I. 172 | 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) - phenyl-acetamido-3- (2-methyl-1,3,4-tlliadiazolyl-5- mercaptomethyl) -CC 173 7- [2-D-amino-2-p- (5-ethoxycarbonylpentanoyloxy) - phenyl-acetamido-3- (2-methyl-i, 3,4-thia mercaptomethyl) -CC 174 | 7- [2-D-amino-2-p- (5-butyloxycarbonylpentanoyloxy) - phenyl-acetamido-3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 175 | 7- [2-D-amino-2-p- (5-hexyloxycarbonylpentanoyloxy) phenyl-acetamido) -3- (2-methyl-1,3,4-thiadia zolyl-5- mercaptomethyl) -CC 176 7- [2-D-amino-2-p- (2-methoxycarbonylacetoxy) - phenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 177 7- [2-D-Amino-2-p- (2-ethoxycarbonacetoxy) - phenyl-acetamido8-3- (2-methyl «1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 178 7- [2-D-amino-2-p- (3-ethoxycarbonylpropanoyloxy) - phenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 179 7- [2-D-amino-2-p- (4-ethoxycarbonylbutanoyloxy) - phenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 180 | 7- [2-D-amino-2-p- (6-ethoxycarbonylhexanoyloxy) - phenyl-acetamido-3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 181 | 7- [2-D-amino-2-p- (7-ethoxycarbonylheptanoyloxy) - phenyl-acetamido-3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC 182 | 7- [2-D-amino-2-p- (9-ethoxycarbonylnonanoyloxy) - phenyl-acetamido-3- (2-methyl-1,3,4-thiadiazolyl-5- mercaptomethyl) -CC EXAMPLE 183 5.78 g of the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetamido) -Ps are dissolved in 500 ml of dichloromethane and 1.3 g of triethylamine, 2.0 g are added dropwise with ice cooling 3-Ethoxycarbonyl-2-methyl-propanoyl chloride, dissolved in 60 ml of dichloromethane, is added, stirred for 50 minutes while cooling with ice, the solvent is distilled off, the residue is dissolved in IIF, filtered, the filtrate is added to 250 ml of dilute aqueous sodium bicarbonate solution, the organic is distilled The solvent is washed off, the aqueous phase is washed with ethyl acetate, the aqueous phase is then brought to pH = 4.5 with 1N hydrochloric acid, extracted with 300 ml of ethyl acetate, the solvent is distilled off and, after purification by chromatography, the residue is obtained (silica gel / dioxane: water = 85: 15) 6- [2-D-hmino-2-p- (3-ethoxycarbonyl-2-methyl-propanoyloxy) -phenyl-acetamido] -PS Analogously to Example 183, by reacting the diethylammonium salts of 7- (2-D -AMV-amino-2-p-hydroxyphenyl-acetamido) -cephemderivate of the formula VII with 3-Ät hoxycarbonyl-2-methylpropanoyl chloride and 2-ethoxycarbonyl-2-ethylethanoyl chloride and subsequent splitting off of the amino protective group (which already takes place during work-up), the compounds of formula I mentioned in Examples 184-195 below are available: Bei- compound of formula I. game 184 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -CS 185 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -MCC 186 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -3- (1,2,3- triazolyl-5-mercaptomethyl) -CC Bei- compound of formula 1 game 187 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -3- (1-methyl- tetrazolyl-5-mercaptomethyl) -CC 188 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -3- (1,3,4- thiadiazolyl-2-mercaptomethyl) -CC 189 7- [2-D-amino-2-p- (3-ethoxycarbonyl-2-methyl- propanoyloxy) -phenyl-acetamido] -3- (2-methyl- 1,3,4-thiadiazolyl-5-mercaptomethyl) -CC 190 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) -phenyl-acetamido] -CS 191 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) phenyl acetamido] -MCC 192 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) -phenyl-acetamido] -3- (1,2,3-triazolyl- 5-mercaptomethyl) -CC 193 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) -phenyl-acetamido] -3- (1-methyl- tetrazolyl-5-mercaptomethyl) -CC 194 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) -phenyl-acetamido] -3- (1,3,4-thia- diazolyl-2-mercaptomethyl) -CC 195 7- [2-D-amino-2-p- (2-ethoxycarbonyl-2-ethyl- acetoxy) -phenyl-acetamido] -3- (2-methyl-1,3,4- thiadiazolyl-5-mercaptomethyl) -CC.

Example 196 Analogous to Example 183 by reacting the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetamide) -PS with 2-ethoxycarbonyl-2-ethyl-ethanoyl chloride and subsequent splitting off of the amino protective group (already taking place during work-up) the 6- [2-D-amino-2-p- (4-ethoxycarbonyl- 2-ethyl-acetoxy) -phenyl-acetamido] -PS available Example 197 is added dropwise to 5.78 g of the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetamido) -PS, dissolved in 300 ml of dichloromethane and 1.3 g of triethylamine while cooling with ice, 2.3 g of 2-ethoxycarbonyl-2-butylethyl chloride dissolved in 40 ml of dichloromethane, stirred for 70 minutes at 0-50, the solvent is distilled and works up the residue as described in Example 183. 6- [2wD-Amino-2-p- (2-ethoxy-carbonyl-2-butyl-acetoxy) -phenyl-acetamido] -PS is obtained.

Analogously to Example 197, from the corresponding penicillan and cephem derivatives of the formula VII by reaction with monochlorides which are derived from the compounds of the formula IV O (A = -oc-) and subsequent cleavage of the amino protective group (already taking place during work-up) Compounds of formula 1 mentioned in the following examples 198-218 available: Bei- compound of formula I. game 198 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) -phenyl-acetamido] -CS 199 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) phenyl acetamido] -MCC 200 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) -phenyl-acetamido] -3- (1,2,3-triazolyl- 5-mercaptomethyl) -CC Bei- compound of formula I. game 201 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) -phenyl-acetamido] -3- (1-methyltetra- zolyl-5-mercaptomethyl) -ca 202 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) -phenyl-acetamido] -3- (1,3,4-thia- diazolyl-2-mercaptomethyl) -CC 203 7- [2-D-amino-2-p- (2-methoxycarbonyl-2-methyl- acetoxy) -phenyl-acetamido] -3- (2-methyl-1,3,4- thiadiazolyl-5-mercaptomethyl) -CC 204 6- [2-D-amino-2-p- (5-ethoxycarbonyl-2-methyl- pentanoyloxy) -phenyl-acetamido] -PS 205 | 7- [2-D-amino-2-p- (5-ethoxycarbonyl-3-methyl- pentanoyloxy) -phenyl-acetamido] -CS 206 7- [2-D-amino-2-p- (5-ethoxycarbonyl-4-methyl- pentanoyloxy) -phenyl-acetamido] -MCC 207 7- [2-D-amino-2-p- (5-ethoxycarbonyl-5-methyl- pentanoyloxy) -phenyl-acetamido] -3- (1,2,3- triazolyl-5-mercaptomethyl) -CC 208 7- [2-D-amino-2-p- (5-methoxycarbonyl-2-ethyl- pentanoyloxy) -phenyl-acetamido] -3- (1-methyl- tetrazolyl-5-mercaptomethyl) -CC 209 7- [2-D-amino-2-p- (5-butyloxycarbonyl-2- propyl-pentanoyloxy) -phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl-CC 210 7- [2-D-amino-2-p- (5-hexyloxycarbonyl-3- propyl-pentanoyloxy) -phenyl-acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC Bei- compound of formula I. game 211 G- [2-D-amino-2-p- (6-methoxycarbonyl-2- methyl-hexanoyloxy) -phenyl-acetamido] -PS 212 7- [2-D-amino-2-p- (6-methoxycarbonyl-2- ethyl-hexanoyloxy) -phenyl-acetamido] -CS 213 6- [2-D-amino-2-p- (7-propyloxycarbonyl-2- methyl-heptanoyloxy) -phenyl-acetamido] -PS 214 7- [2-D-amino-2-p- (7-propyloxycarbonyl-2- methyl-heptanoyloxy) -phenyl-acetamido] -CS 215 6- [2-D-amino-2-p- (8-ethoxycarbonyl-2-methyl octanoyloxy) phenyl acetamido 3-PS 216 7- [2-D-amino-2-p- (8-ethoxycarbonyl-2-methyl- octanoyloxy) -phenyl-acetamido] -CS 217 6- [2-D-amino-2-p- (9-tert-butyloxycarbonyl- nonanoyloxy) -phenyl-acetamido] -PS 218 7- [2-D-amino-2-p- (9-tert-butyloxycarbonyl- nonanoyloxy) -phenyl-acetamido] -as Example 219 Dissolve 2.89 g of the triethylammonium salt of 6- (2-D-AMV-amino-2-p-hydroxyphenyl-acetamido) -penicillanic acid in 250 ml of dichloromethane and 5.6 ml of triethylamine, 0.6 g is added dropwise with ice-cooling 2-Methoxyacetic acid chloride, dissolved in 40 ml of dichloromethane, is stirred for 30 minutes while cooling with ice, the solvent is distilled off, the oily residue is dissolved in 50 ml of THF, filtered, the filtrate is added to 250 ml of dilute aqueous sodium bicarbonate solution with stirring, the organic solvent is distilled off, the aqueous solution is extracted with ethyl acetate, then the aqueous phase is brought to pH = 3 with 1N hydrochloric acid and extracted with 200 ml of ethyl acetate, the solvent is distilled off and the residue is obtained after chromatographic purification (silica gel / dioxane: water = 85:15) 6- [2-D-amino-2-p- (2-methoxyacetoxy) phenyl-ace tamido9-PS.

Analogously to Example 219 are from the triethylammonium salt of 6- / 2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -PS by reacting with the corresponding acid chlorides of the # -hydroxy- or C-alkyloxycarboxylic acids of the formula IV ( A = -0-) and subsequent splitting off of the amino protective group (already taking place during work-up) the penicillanic acid derivatives of the formula I mentioned in the following examples 220 to 228 are obtainable: Bei-penicillanic acid derivative of the formula I. game 220 | 6- [2-D-amino-2-p- (2-hydroxyacetoxy) -phenyl- acetamido PS 221 6- [2-D-Amino-2-p- (2-ethoxyacetoxy) -phenyl- acetamido] PS 222 6- [2-D-amino-2-p- (2-butyloxyacetoxy) -phenyl- acetamido9-PS 223 | 6- [2-D-amino-2-p- (2-hexyloxyacetoxy) -phenyl- acetamido, 7-PS Bei-penicillanic acid derivative of the formula I. game 224 6- [2-D-Amino-2-p- (3-ethoxypropanoyloxy) -phenyl- acetamido] PS 225 6- [2-D-amino-2-p- (4-hydroxybutanoyloxy) -phenyl- acetamido] PS 226 6- [2-D-amino-2-p- (4-ethoxybutanoyloxy) -phenyl- acetamido] PS 227 6- [2-D-Amino-2-p- (6-ethoxyhexanoyloxy) -phenyl- acetamido] PS 228 6- [2-D-Amino-2-p- (8-ethoxyoctanoyloxy) -phenyl- acetamido] PS.

Analogously to Example 219, the 7-g2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -CS are obtained from the triethylammonium salt by reacting with the corresponding acid chlorides of the -hydroxy- or # -alkoxycarboxylic acids of the formula IV and subsequent ( Cleavage of the amino protective group already taking place during work-up, the cephalosporanic acids of the formula I mentioned in Examples 229 to 238 below are obtainable: Bei-cephalosporanic acid of the formula I. game 229 7- [2-D-amino-2-p- (2-hydroxyacetoxy) -phenyl-acet- amido-CS 230 7- [2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido] -CS 231 7- [2-D-Amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amido] -CS 232 7- [2-D-Amino-2-p- (2-butyloxyacetoxy) -phenyl-acet- amidoJ-cs 233 | 7- [2-D-amino-2-p- (2-hexyloxyacetoxy) -phenyl-acet amido7-CS Bei-cephalosporanic acid of the formula I. game 234 | 7- [2-D-amino-2-p- (3-ethoxypropanoyloxy) -phenyl- acetamido) -CS, [α] D20 = + 36.50 (in ethanol) 235 7- [2-D-amino-2-p- (4-hydroxybutanoyloxy) -phenyl- acetamido] -CS 236 7- [2-D-amino-2-p- (4-ethoxybutanoyloxy) -phenyl- acetamido] -CS 237 7- [2-D-Amino-2-p- (6-ethoxyhexanoyloxy) -phenyl- acetamido] -CS 238 7- [2-D-Amino-2-p- (8-ethoxyoctanoyloxy) -phenyl- acetamido] -CS Analogously to Example 219, the 7-W2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -MCC are obtained from the triethylammonium salt by reaction with the corresponding acid chlorides of the # -hydroxy- or # -alkoxycarboxylic acids of the formula IV and then Cleavage of the amino protective group (already taking place during work-up) the 3-methyl-3-cephem-4-carboxylic acid derivatives of the formula I mentioned in the following Examples 239 to 243 are available: Bei- 3-methyl-3-cephem-4-carboxylic acid derivative of game formula I. 239 | 7- [2-D-amino-2-p- (2-hydroxyacetoxy) -phenyl-acet- amido9-MCC 240 | 7- [2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido2-MCO 241 | 7- [2-D-amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amidoi-MCC 242 | 7- [2-D-amino-2-p- (4-hydroxybutanoyloxy) -phenyl- acetamido-MCC 243 | 7- [2-D-amino-2-p- (4-ethoxybutanoyloxy) -phenyl- acetamidog-MCC Analogous to the example. 219 are from the triethylamine ionic salt of 7-02-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC by reacting with the corresponding acid chlorides of the s-hydroxy- or co-alkoxycarboxylic acids of the formula IV and subsequent splitting off of the amino protective group (which already takes place during work-up) the 3- (1,2,3-triazolyl-5-mercaptomethyl) mentioned in Examples 244 to 253 below -3-cephem-4-carboxylic acid derivatives of the formula I available: Bei- compound of formula I. game 244 | 7- [2-D-amino-2-p- (2-hydroxyacetoxy) -phenyl-acet amido9-3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 245 | 7- [2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 246 7- [2-D-Amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 247 7- [2-D-Amino-2-p- (2-butyloxyacetoxy) -phenyl-acet- amido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 248 7- [2-D-amino-2-p- (2-hexyloxyacetoxy) -phenyl-acet- amj; do) -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 249 7- [2-D-Amino-2-p- (3-ethoxypropanoyloxy) -phenyl-acet- amido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 250 7-t2-D-Amino-2-p- (4-hydroxybutanoyloxy) -phenyl-acet- amido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 251 7- [2-D-Amino-2-p- (4-ethoxybutanoyloxy) -phenyl-acet- amido) -3 (1,2,3-triazolyl-5-mercaptomethyl) -CC 252 | 7- [2-D-amino-2-p- (6-ethoxyhexanoyloxy) -phenyl-acet- amido9-3- (1,2,3-triazolyl-5-mercaptomethyl) -CC 253 7- [2-D-Amino-2-p- (8-ethoxyoctanoyloxy) -phenyl-acet- amido] -3- (1,2,3-triazolyl-5-mercaptomethyl) -CC Analogously to Example 219, the 7-W2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC are obtained from the triethylammonium salt by reacting with the corresponding acid chlorides of # -Hydroxy- or w-alkoxycarboxylic acids of the formula IV and subsequent splitting off of the amino protective group (already taking place during work-up) the 3- (1-methyltetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid derivatives mentioned in Examples 254 to 263 below of formula I available: Bei- compound of formula I. game 254 7- [2-D-Amino-2-p- (2-hydroxyacetoxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 255 7- [2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido-3- (1-methyltetrazolyl-5-mercap lomethyl) -CC 256 7- [2-D-Amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 257 7- [2-D-Amino-2-p- (2-butyloxyacetoxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 258 7- [2-D-Amino-2-p- (2-hexyloxyacetoxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 259 7 - C2-D-Amino-2-p- (3-ethoxypropanoylo.xy) -p} lellyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 260 7-C2-D-Amino-2-p- (4-llyd.roxybutanoyloxy) -phenylFacet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 261 7- [2-D-Amino-2-p- (4-ethoxybutanoyloxy) -phenyl-acet- amidojl-3- (1-ethyltctrazolyl-5-ercaptonletyl) -CC 262 7- [2-D-amino-2-p- (6-ethoxyhexanoyloxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC 263 7- [2-D-Amino-2-p- (8-ethoxyoctanoyloxy) -phenyl-acet- amido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -CC Analogously to Example 219, the 7-W2-D- (AMV-amino) -2-p-hydroxyphenyl-acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC are obtained by reacting with the triethylammonium salt corresponding acid chlorides of the # -hydroxy- or # -alkoxycarboxylic acids of the formula IV and subsequent splitting off of the amino protective group (which already takes place during work-up) the 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) mentioned in Examples 264 to 273 below -3-cephem-4-carboxylic acid derivatives of the formula I available: Bei- compound of formula I. game 264 7- [2-D-amino-2-p- (2-hydroxyacetoxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 265 7- [2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 266 7- [2-D-Amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 267 7-C2-D-Amino-2-p- (2-butyloxyacetoxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 268 7- [2-D-amino-2-p- (2-hexyloxyacetoxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 269 7- [2-D-amino-2-p- (3-ethoxypropanoyloxy) -phenyl- acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 270 7- [2-D-amino-2-p- (4-hydroxybutanoyloxy) -phenyl- acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 271 7- [2-D-Amino-2-p- (4-ethoxybutanoyloxy) -phenylacet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 272 7- [2-D-Amino-2-p- (6-ethoxyhexanoyloxy) -phenyl-acet- amido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -CC 273 7- [2-D-Amino-2-p- (8-ethoxyoctanoyloxy) -phenyl- acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC Analogously to Example 219, the D- (AMV-amino) -2-p-hydroxyphenyl-acetamide] -3- (2-methyl-1,3,4-thiadiazolyl-5-mercaptomethyl) -CC are obtained from the triethylamnionium salt by reacting with the corresponding acid chlorides of the # -hydroxy- or o -alkoxycarboxylic acids of the formula IV and subsequent cleavage of the amino protective group (which takes place during work-up) the 3- (2-methyl-1,3,4-thiadiazolyl-5 -mercaptomethyl) -3-cephem-4-carboxylic acid derivatives of the formula I available: Bei- compound of formula I. game 274 7- [2-D-Amino-2-p- (2-hydroxyacetoxy) -phenyl-acet- amido] -3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC 275 7-C2-D-amino-2-p- (2-methoxyacetoxy) -phenyl-acet- amido9-3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC 276 | 7- [2-D-amino-2-p- (2-ethoxyacetoxy) -phenyl-acet- amido-3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC 277 7-62-D-Amino-2-p- (2-butyloxyacetoxy) -phenyl-acet- amidoi-3- (2-methyl-1,3,4-thiadiazolyl-5-mercapto- methyl) -CC 278 7-62-D-Amino-2-p- (2-hexyloxyacetoxy) -phenyl-acet- amido) -3- (2 -methyl-1,3,4-thi adlazolyl-5-mercapto- methyl) -CC 279 | 7- [2-D-amino-2-p- (3-ethoxypropanoyloxy) -phenyl- acetamido9-3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC 280 7- [2-D-amino-2-p- (4-hydroxybutanoyloxy) -phenyl- acetamido] -3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC Bei- compound of formula I. game 281 7-r2-D-Amino-2-p- (4-ethoxybutanoyloxy) -phenyl- acetamidop-3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC 282 | 7- [2-D-amino-2-p- (6-ethoxyhexanoyloxy) -phenyl- acetamidop-3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC 283 | 7- [2-D-amino-2-p- (8-ethoxyoctanoyloxy) -phenyl- acetamido9-3- (2-methyl-1,3,4-thiadiazolyl-5-mer- captomethyl) -CC ~ Example 284 a) A mixture of 3.28 g of 3-deacetoxy-7-aminocephalosporanic acid-tert is stirred. butyl ester (= 7-amino-MCC-tert-butyl ester), 3.51 g of 2-formylamino-2-p- (4-hydroxybutanoyloxy) phenylacetic acid (obtainable from 2-formylamino-2-p-hydroxyphenylacetic acid and g -Butyrolactone in the presence of triethylamine) 2.5 g of DCC, 20 ml of dry DMF and 10 ml of dry dichloromethane for 2 hours at room temperature, filtered, about half of the solvent is distilled off, the residue is allowed to seep into a silica gel column, eluted with ethyl acetate and obtained from the eluate after distilling off the solvent 7- [2-formylamino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido) -MCC-tert-butyl ester as residue.

b) 1.8 g of 7- (2-formylamino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido) -MCC-tert-butyl ester are dissolved in 15 ml of dry trifluoroacetic acid, stirred for 15 minutes at room temperature, distilled the trifluoroacetic acid is removed and the residue is 7- [2-formylamino-2-p- (4-hydroxybutanoyloxy) phenylacetamido) -MCC.

c) A mixture of 0.6 g of 7-formylamino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido] -MCC-tert-butyl ester is allowed, Stand 30 ml of THF and 4 ml of concentrated aqueous HCl at 5 ° overnight, pour in water, extracted with ethyl acetate and obtained after the solvent has been distilled off 7- [2-Amino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamidop-MCC-tert-butyl ester as Residue.

d) 0.4 g of 7- [2-amino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido] -MCC-tert-butyl ester is stirred, dissolved in 10 ml of trifluoroacetic acid, 30 minutes at 50, the solvent is distilled and the residue obtained is the trifluoroacetate of 7-W2-amino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido-MCC. This salt, dissolved in 25 ml of water, is stirred for 1 hour at 250 with 15 g of a polystyrene-amine ion exchange resin (Amberlite IR-45), separates the ion exchanger and lyophilises the aqueous Solution. 7- [2-Amino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamide] -MCC (betaine form) is obtained.

Example 285 2.8 g of 7-62-BOC-amino-2-p- (2-hydroxyacetoxy) -phenyl-acetamido / -CS are stirred 30 minutes at 200 in a mixture of 10 ml of trifluoroacetic acid and 5 ml of anisole, the solvent is distilled off and 7-g2-amino-2-p- (2-hydroxyacetoxy) -phenyl-acetamido9-CS is obtained as trifluoroacetate. The free acid can therefrom (as described in Example 284d) can be obtained as betaine.

The starting material is obtained by reacting 2-BOC-amino-2-p- (2-hydroxyacetoxy) phenylacetic acid (available from 2-amino-2-p- (2-hydroxyacetoxy) phenylacetic acid and tert-butoxycarbonylazide in the presence of MgO) with 7-ACS in the presence of ethyl chloroformate.

Example 286 3.17 g of 6-APS-triethylamine salt, dissolved, are added dropwise at -10 ° in 40 ml of dichloromethane to a solution of ethyl-2-D- (2-ethoxycarbonyl-1-methylvinylamino) -2-p-ethoxycarbonyloxyphenyl-ethanoyl carbonate (prepared in situ from 2.79 g of 2-D- (2-ethoxycarbonyl-1-methylvinylamino) -2-p-hydroxyphenylacetic acid and 2.17 g of ethyl chloroformate in the presence of 7 ml of triethylamine) in 100 ml of dichloromethane, the reaction mixture leaves slowly come to room temperature, extracted with 80 ml of water, bring the aqueous phase with in aqueous HCl to pH = 3, extracted with ethyl acetate, left to stand overnight and the 6- (2-D-aminop-ethoxycarbonyloxyphenyl-acetamido) -PS falls with petroleum ether the end; Rf = 0.41 (silica gel / dioxane: water = 85:15).

Example 287 a) 1.5 g g of 7-foimylamino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido-cs are suspended (obtainable analogously to Example 284a and b from 7-ACS-tert-butyl ester and 2-formylamino-2-p- (4-hydroxybtanoyloxy) phenylacetic acid and subsequent treatment of the reaction product with trifluoroacetic acid) and 230 mg of 1-methyltetrazolyl-5-thiol in 8 ml of water at room temperature, bring the reactants by adding NaHCO3 in solution, the pH value being between 4 and 7, heated 30 minutes to 700, bring the reaction mixture after cooling with concentrated Hydrochloric acid to pH 2, filtered and obtained after chromatographic purification of the Precipitation (silica gel / dioxane: water = 85:15) 7-T2-formylamino-2-p- (4-hydroxybutanoyloxy) -phenyl-acetamido) -3 (1-methyltetrazolyl-5-mercaptomethyl) -CC.

b) Analogously to Example 284c, 7- (2-formylamino-2-p- (4-hydroxybtltanoyloxy) -pheIlyl-acetanlidop-3- (1-meth tetrazolyl-5-mcrcaptomethyl) -CC by reacting with HCl the 7- [2-amino-2-p- (4-hydroxybutanolyloxy) -phenyl-acetamidoJ-3- (1-methyltetrazolyl-5-mercaptomethyl) -CC.

Example 288 6.22 g of the triethylammonium salt of 7- (2-D-BOC-amino-2-p-hydroxyphenyl-acetamido) -CS are dissolved in 250 ml of dichloromethane and 10 ml of triethylamine, 1.7 g of succinic acid monomethyl ester monochloride are added dropwise with ice cooling, dissolved in 40 ml of dichloromethane, stirred for 40 minutes at 0-5 °, the distilled Solvent off, the residue is stirred for 30 minutes with trifluoroacetic acid, distilled the trifluoroacetic acid from, dissolve the residue in 80 ml of THF, filtered, gives the Filtrate in 350 ml of dilute aqueous sodium bicarbonate solution, the organic is distilled Remove the solvent, extract the aqueous solution with ethyl acetate, adjust the pH the aqueous phase with HCl to 3 and extracted with ethyl acetate. After distilling off the solvent gives 7-62-D-amino-2-p- (3-methoxycarbonylpropanoyloxy) -phenyl-acetamidov-CS; Rf = 0.58 (silica gel / dioxane: water = 9: 1); [α] D20 = + 61.20 (in ethanol).

Example 289 Example 288 is obtained from the triethylammonium salt of 7- (2-D-BOC-amino-2-p-hydroxyphenyl-acetamido) -CS by reaction with 3-methoxypropionyl chloride and subsequent cleavage of the BOC group with trifluoroacetic acid, the 7-C2-D-amino-2-p- (3-methoxypropionyloxy) -phenyl-acetamidoR-CS; Rf 0.28 (silica gel / dioxane: water = 9: 1); [α] D20 = + 59.80 (in ethanol).

Example 290 2.7 g of 7-ACS are suspended in 50 ml of dry acetonitrile, gives 1 g of triethylamine and 2 ml of N, N-dimethylaniline, cools to 5 ° and drops 12.7 g of trimethylchlorosilane. After 10 minutes, 3.3 g of 2-D-amino-2-p- (3-ethoxypropionyl oxy) phenylacetyl chloride hydrochloride (obtainable from a suspension of 2-D-amino-2-p- (3-ethoxypropionyloxy) phenylacetic acid in dry dioxane by successive introduction of dry phosgene and dry HCl gas) dissolved in 80 ml of dry dioxane, stirred for 1 hour at 100 drops Add 40 ml of water, adjust the pH to 2.5 with solid Na2C03, separate the organic Phase off, adjust the pH of the aqueous phase with HCl. 2, wash with Diethyl ether, bring the aqueous phase to pH 4 with dilute aqueous NaOH, concentrated until clouding formed, left to stand overnight at 50, filtered and dried the precipitation. 7- [2-D-amino-2-p- (3-ethoxypropionyloxy) -phenyl-acetamido) -CS is obtained; Rf = 0.29 (silica gel / dioxane water = 9: 1); CH2 D20 = + 36.50 (in ethanol).

Those mentioned in Examples 1 to 289 above are analogous Compounds of formula I by reacting the trimethylsilyl esters prepared in situ of the compounds of the formula II with the corresponding acid chloride hydrochlorides of the compounds of the formula III available.

Example 291 563 mg of 7- [2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamido9-CS are dissolved and 84 mg of NaHCO3 in 13 ml of water, stirred for 30 minutes at room temperature and obtained after freeze-drying the solution, the sodium salt of 7-t2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamidoR-CS.

Analogously to Example 288, the compounds of the formula I mentioned in the following Examples 292-298 can be obtained from 2-acetoxyacetyl chloride by reacting with the corresponding BOC derivatives of the formula VII and subsequent cleavage of the amino protective group (already taking place during work-up): Bei- compound of formula I. game 292 | 6- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] PS 293 7- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] -CS 294 7- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] -MCC 295 7- [2-D-amino-2-p- (2-acetoxyacetoxy) phenyl acetamido] -3- (1,2,3-triazolyl-5-mercapto- methyl) -CC 296 7- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] -3- (1-methyltetraxolyl-5-mercapto- methyl) -CC 297 7- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] -3- (1,3,4-thiadiazolyl-2-mercapto- methyl) -CC 298 7- [2-D-amino-2-p- (2-acetoxyacetoxy) -phenyl- acetamido] -3- (2-methyl-1,3,4-thiadiazolyl- 5-mercaptomethyl) -CC Analogously to Example 288, the compounds of the formula I mentioned in the following examples 299-305 can be obtained from 2 acetoxypropanoyl chloride by reacting with the corresponding BOU derivatives of the formula VII and subsequent cleavage of the amino protective group (which already takes place during work-up): Bei- compound of formula 1 game 299 | 6- [2-D-amino-2-p- (2-acetoxypropanoyloxy) phenyl-acetamido] -ps 300 7- [2-D-amino-2-p- (2-acetoxypropanoyloxy) phenyl-acetamido] -CS 301 | 7- [2-D-amino-2-p- (2-acetoxypropynoyloxy) - phenyl-acetamido] -MOC 302 7- [2-D-amino-2-p- (2-acetoxypropanoyloxy) - phenyl-acetamido] -3- (1,2,3-triazolyl-5- mercaptomethyl) -CC 303 7- [2-D-amino-2-p- (2-acetoxypropanoyloxy) - phenyl-acetamido] -3- (1-methyltetrazolyl-5- mercaptomethyl) -CC 304 7- [2-D-amino-2-p- (2-acetoxypropanoyloxy) - phenyl-acetamido] -3- (1,3,4-thiadiazolyl-2- mercaptomethyl) -CC 305 | 7- [2-D-amino-2-p- (2-acetoxypropanoyloxy) - phenyl-acetamido] -3- (2-methyl-1,3,4- thiadiazolyl-5-mercaptomethyl) -GC.

The carboxylic acids mentioned in the above examples are analogous of the formula I can be obtained by reacting with NaHCO 3 their sodium salts.

The active ingredients of the formula I, in particular those in the preceding Examples mentioned, their easily cleavable esters and the physiologically harmless Salts of these compounds can be prepared using methods known from the literature are, together with auxiliaries and / or carriers customary in pharmacy process, which are mainly used as pharmaceutical preparations. This is illustrated by the following examples: Example A: Ampoules One Solution of 100 g of 7-g2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamido-9-cephalosporanic acid, sodium salt is dissolved in 0.3 l of double-distilled water, sterile filtered, in ampoules filled, lyophilized under sterile conditions and sealed under sterile conditions. Every Ampoule contains 1 g of active ingredient.

The solution ampoules are behaved by adding 50 g of lidocaine hydrochloride Dissolves in 3 l of double-distilled water and, after sterile filtration, in ampoules which are sterilized at 1200 for 20 minutes. Each ampoule of solution contains 50 mg lidocaine hydrochloride in 3 ml water.

Example B: Tablets A mixture consisting of 100 g of 7-g2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamido-penicillanic acid, sodium salt, 500 g milk sugar, 180 g wheat starch, 10 g cellulose powder and 10 g magnesium stearate is compressed into tablets in the usual way, so that each tablet 50 mg des Contains active ingredient.

Claims (8)

Claims 19 Compounds of the general formula I RA-Cn2n -COO-p-C6114-CH (NH2) -CONH Mm wherein R alkyl with 1 - 6 carbon atoms, and if A = -0--, also H, A -0- or -OCO-, R1 H, acetoxy or S-Het, Het 1,2,3-triazol-5-yl, 1-methyl-tetrazol-5-yl, 1, 3,4-thiadiazol-2-yl or 2-methyl-1, 3,4-thiadiazol-5-yl, and n is an integer between 0 and: 8 inclusive, as well as the easily cleavable esters and the physiologically acceptable salts of these compounds. 2. 6- [2-D-Amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyl-acetamide] penicillanic acid. 3. 6- (2-D-amino-2-p-ethoxycarbonyloxyphenyl-acetamido) -penicillanic acid. 4. 7- [2-D-Amino-2-p- (3-ethoxypropionyloxy) -phenyl-acetamido] -cephalosporanic acid. 5. 7 - / - 2-D-amino-2-p- (5-methoxycarbonylpentanoyloxy) -phenyi-acetamido) -cephalosporanic acid. 6. Process for the preparation of a compound of the general formula I. where RH or alkyl with 1 - 6 carbon atoms, A -0- or -OCO-, R1 H, acetoxy or S-Het, Het 1,2,3-triazol-5-yl, 1-methyl-tetrazol-5-yl, 1,3,4-thiadiazol-2-yl or 2-methyl-1, 3,4-thiadiazol-5-yl, and n is a whole number between 0 and 8 inclusive, as well as their easily cleavable esters and their physiologically acceptable salts, characterized in that a compound of the general formula II in which Z has the meaning given above, or one of its functional derivatives with a compound of the general formula III RA-CnH2n -COO-p-C6H4-CH (NH2) COOH III in which X, A and n have the meanings given above, or a their functional derivatives or an acid addition salt of these compounds, or in a compound which otherwise corresponds to formula I, but in which an NH2 group is present in a functionally modified form, or one of its easily cleavable esters or one of its physiologically tolerable salts NH2-G group is set free by treatment with hydrolyzing or hydrogenolyzing agents and / or that in a compound of formula I obtained or one of its easily cleavable esters or one of its physiologically acceptable salts, a radical Z by reaction with reducing or hydrogenolyzing agents or by reaction converts with a triol HS-Het into another radical Z and / or that one son st of the formula I compound, but in which R = H and A = or one of its easily cleavable esters or one of its physiologically acceptable salts is reacted with alkylating agents and / or that a compound of the formula I is reacted with an esterifying agent in one of its easily cleavable esters and / or that a compound of the formula I is set free from one of its easily cleavable esters by reaction with a hydrolyzing agent and / or that a compound of the formula I is converted into one of their physiologically tolerable salts is converted and / or that a compound of the formula I is set free from one of its salts by reaction with a base or an acid. 7. Mixture, containing the auxiliaries and / or carriers customary in pharmacy (barley, characterized by a content of at least one compound of the general Formula I and / or one of its easily cleavable esters and / or one of its physiologically harmless salts. 8. Process for the production of pharmaceutical preparations, thereby characterized in that a compound of the formula I and / or one of its physiologically harmless salts, optionally together with at least one solid, liquid or semi-liquid auxiliary or carrier and optionally together with at least another active ingredient in a suitable dosage form.