DE2908033A1 - NEW CEPHALOSPORIN COMPOUNDS, PROCESS FOR MANUFACTURING THE SAME AND THERAPEUTIC PREPARATIONS CONTAINING SUCH ACTIVE SUBSTANCES - Google Patents

Description

FROM KREISLER SCHÖNWALD ElSHOLD FUES FROM KREISLER KELLER SELTING WERNER

PATENT LAWYERS Dr.-Ing. by Kreisler 11973

Dr.-Ing. K. Schönwald, Cologne

Dr.-Ing. K. W. Eishold, Bad Soden

Dr. J. F. Fues, Cologne

Dipl.-Chem. Alek von Kreisler, Cologne

Dipl.-Chem. Carola Keller, Cologne

Dipl.-Ing. G. Setting, Cologne

Dr. H.-K. Werner, Cologne

DEICHMANNHAUS AT THE MAIN RAILWAY STATION

D-5000 COLOGNE 1 28.2.79 AvK / IM

Takeda Chemical Industries, Ltd., Osaka (Japan)

New Cephalospor n connections i, method for producing the same and containing such active substances therapeutic preparations

303837 / 08S3

Telephone: {0221} 131041 · Telex; 8882J07 dopa d · Telegram: Dampatent Cologne

New cephalosporin inventions, methods of manufacture the same and therapeutic preparations containing such active substances

The present invention relates to new antimicrobial compounds which can be used as therapeutic Agents for the treatment of diseases, in particular infectious diseases, which are caused by gram-negative bacteria, in humans and Animal are valuable.

In particular, the present invention relates to new α-ureido-cephaelosporin antibiotics which have a 2- (2-amihothiazol- ^i- t-yl) -acetamido group in the 7 ~ position.

Thus, the present invention relates to gephalosporin compounds of the following general ones Formula:

H ₂ N-

N-

-CH-CONH NH

CO

NHR

(D

COOH

where R is the hydrogen atom or a lower alkyl radical and Y is an acyloxy, carbamoyloxy or -S-Het group

909837/0683

interpret where Het is a substituted or unsubstituted, nitrogen-containing, heterocyclic group, namely a tetrazolyl, thiadiazolyl or triazoly group, means.

Certain semisynthetic cephalosporin compounds with a broad antimicrobial spectrum are commercially available. They are also already considered therapeutic Agents for the treatment of infectious diseases have been clinically proven. But it has been shown that a certain number of pathogenic microorganisms prove to be resistant to the known antibiotics.

For example, pathogens such as certain strains of Escherichia coli and of Citrobacterj are the Majority of the indole positive strains of the genus Proteus and some bacteria of the genera Enterobacterium, Serratia and Pseudomonas against known cephalosporin drugs resistant (see W.E. Wick: Cephalosporins and Penicillins, Chemistry and Biology, E.H. Flynn (Ed.), Academic Press, New York, N.Y. 1972, Ch. 11). This made it necessary to research further cephalosporin compounds with such a sufficiently high antimicrobial effect that they can be used against such pathogens Microorganisms can be used. "

Research in this area now has the synthesis of compounds of general formula I above result, whereby it was found that these compounds had the desired high antibiotic action against including a large number of gram negative bacteria

809837 / 0-663 *

- r-

those bacteria against which the known cephalosporin compounds are resistant to exercise. The inventive Compounds of formula I are extremely effective against a wide range of gram-negative bacteria, such as Escherichia coli, Krebsiella pneumoniae, Proteus vulgaris j Proteus mirabilis, Proteus morganii, Proteus rettgerij Citrobacter freundii, Enterobacter cloacae, Serratia mai'scecens, etc. They are therefore valuable for the treatment and prophylaxis of various diseases in humans and animals including poultry, in which such bacteria cause damage.

In the above general formula I, the lower alkyl group R is preferably a straight-chain or

15 branched alkyl groups with up to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl. The methyl radical is particularly preferred. The acyloxy group Y is preferably an alkylcarbonyloxy group with 2 to H carbon atoms, for example the acetoxy, propionyloxy group, etc., an acetoxy

group which is substituted by an alkylcarbonyl group with 2 to 4 carbon atoms, e.g. the 3-oxybutyryloxy, Propionylacetyloxy group, etc., a phenylacetyloxy group which is optionally substituted by a Hydroxyl group, through a sulfo group, through an amino group or by another substituent, such as almondoxy, a-sulfophenylacetyloxy, glycyloxy, phenylacetyloxy, etc., is α-substituted, an alkylcarbonyloxy group containing a carboxyl group as a substituent with 2 to 4 carbon atoms, e.g. the succihoyloxy group etc., or a group of the general formula:

809837/0653

-sf-

f \ -

ooo-

xiorin R ⁵ and R ⁶ hydrogen, carboxyl, carbethoxycarbamoyl,

or Carbethoxysulfamoyl or Nitro mean.72-Carboxybenzoyloxy, 2- (carbethoxycarbamoyl) -benzoyloxy, 2- (2-carbethoxysulfamoyD-benzoyloxy, 2-carboxy-3 ~ or -4- or -6-nitrobenzoyloxy, 2,4-dicarboxybenzoyloxy, etc. mean. Alkylcarbonyloxy groups with 2 up to 4 carbon atoms, e.g. the acetoxy, propionyloxy, 3-Oxobutyryloxy group, etc., preferred, whereby one under gives preference to these groups of the acetoxy and 3-oxobutyryloxy groups. The nitrogen-containing heterocyclic group Het is a tetrazolyl, thiadiazolyl or triazolyl group and in particular IH-tetrazolyl, 1,2,3-thiadiasolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl or IH-1,2,4-triazolyl. Among these nitrogen-containing, heterocyclic groups are lH-tetrazol-5-ylj 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl and 1Η-1,3,4-ΤΓΪαζο1-5-yl preferred. These nitrogen-containing, heterocyclic groups can optionally be substituted. As examples of substituents, there can be mentioned monovalent groups such as alkyl groups having 1 to 4 carbon atoms (Methyl, ethyl, trifluoromethyl, propyl, Isopropyl, butyl, isobutyl etc.), alkoxy groups with 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, Butoxy etc.), halogens (chlorine, bromine etc.),

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Hydroxyl, mercapto, amino, carboxyl, carbamoyl, etc., as well as various substituent groups obtained by the intermediary of a polyvalent group such as lower Alkylene groups with 1 to 3 carbon atoms,

_S- _s -N-, etc., adhere. If this polyvalent group represents a lower alkylene group, the substituent group adhering through their mediation can be, for example, hydroxyl, mercapto, amino, guanyl, morpholino, carboxyl, sulfo, carbamoyl, alkoxycarbonyl with 2 to 5 carbon atoms, alkylcarbamoyl with 2 to 5 carbon atoms, alkoxy with 1 up to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms, acyloxy with 1 to 4 carbon atoms, morpholinocarbonyl -etc. be. If this - polyvalent group - -S- or -N-, its substituent group can be, for example, a lower alkyl group or one of the said lower alkylene groups which have one of the said substituent groups. If the polyvalent group represents -N-, such a substituent as carboxyl, alkoxycarbonyl having 2 to 5 carbon atoms, acyl having 1 to 4 carbon atoms, carbamoyl, lower alkylcarbamoyl having 2 to 5 carbon atoms, etc., can additionally adhere directly to the nitrogen atom.

In a specific case, substituted alkyl groups, such as carboxymethyl, carbamoylmethyl, N-lower alkylcarbamoylmethyl, can be used (e.g. Ν, Ν-dimethylcarbamoylmethyl), Hydroxy-lower alkyl (e.g. hydroxymethyl, 2-hydroxyethyl), Acyloxy-lower alkyl (e.g. acetoxymethyl, 2-acetoxyethyl), Alkoxycarbonylmethyl (e.g. methoxycarbonylmethyl, hexyloxycarbony! Methyl, Octyloxycarbony! Methyl), methylthio-

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methyl, methylsulfonylmethyl, N-lower alkylamino-lower alkyl (e.g. Ν, Ν-dimethylaminomethyl, Ν, Ν-dimethylaminoethyl, Ν, Ν, Ν-trimefchylammoniumethyl), morpholinomethyl, Guanylmethyl, guanylethyl, etc .; substituted amino groups, ie lower alkylamino (e.g. methylamino), sulfo-lower alkylamino (e.g. 2-sulfoethylamino), hydroxy-lower alkylamino (e.g. hydroxyethylamino), lower alkylamino-lower alkylamino (e.g. 2-dimethylaminoethylamino, 2-trimethylammoniumethylamino), acylamino (e.g. acetylamino), 2-dimethylaminoacetylamino, 2-trimethylammoniumacetylamino, Lower alkoxycarbonylamino (e.g. methoxycarbonylamino), etc.; and substituted thio groups such as methylthio, 2-hydroxyethylthio, 2-acyloxyethylthio (e.g. 2-ethoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxyethylthio, Carboxymethylthio, alkoxycarbonylmethylthio (e.g. methoxycarbonylmethylthio, hexyloxycarbonylmethylthio), Carbamoylmethylthio, N-lower alkylcarbamoylmethylthio (e.g. Ν, Ν-dimethylcarbamoylmethylthio), Acetylmethylthio, N-lower alkylamino-lower alkylthio (e.g. 2-N, N-dimethylaminoethylthio, 2-N, N, N-trimethylammoniumethylthio), Morpholinocarbonylmethylthio, 2-sulfoäthylthio, etc., name.

The substituted or unsubstituted, heterocyclic ones Groups can preferably be represented by one of the following formulas:

N --NNN 'N t - R ¹ NN

Jl I *?

H —Ιί Jl R '

_s o, u and it

έ ^{1 1}

In the above formulas, R denotes hydrogen, an alkyl group with 1 to 3 carbon atoms, e.g. methyl, hydroxy-substituted alkyl groups with 1 to 3 carbon atoms, e.g. 2-hydroxyethyl, carboxy-substituted alkyl groups having 1 to 3 carbon atoms, e.g., carboxymethyl, or di-lower alkyl substituted aminoalkyl groups with 1 to 3 carbon atoms, such as 2-dimethylaminoethyl. The substituent group R is an alkyl group having 1 to 3 carbon atoms, e.g., methyl, or a hydroxy-substituted one Alkyl group having 1 to 3 carbon atoms such as hydroxymethyl.

Among the compounds of the above 'general formula I, preferred compounds are the 7- [2- (2-aminothiazol-4-yl) -2- (R-aminocarbonylamino) -acetamido] -ce · phalosporin compounds of the following formula:

CH-GONH

KH

CO

NHR

(I ¹ )

wherein R is the hydrogen atom or the methyl group and Y is the Acetoxy group, the 3-oxobutyryloxy group, the carbamoyloxy group or a group of the following formulas:

JI

■ N ti

N-

S '

ι ν r.

and

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denote, where R ⁷ denotes hydrogen, methyl, 2-hydroxyethyl, carboxymethyl or 2-dimethylaminoethyl and R denotes hydrogen or methyl.

For use as therapeutic agents for combating infectious diseases, the novel compounds of the formula are used in free form or in the zwitterionic form or as a pharmacologically acceptable non-toxic salts I. These salts are also included in the present invention. Examples of such nontoxic salts of compounds of the formula I include salts with alkali metals such as sodium, potassium etc., or alkaline earth metals such as calcium, magnesium etc., salts with inorganic bases, for example ammonium salts, salts with organic bases, for example with trimethylamine , Triethylamine, pyridine, N-methylglueamine, diethanolamine and triethanolamine, salts with organic acids such as acetic acid, tartaric acid and methanesulfonic acid, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and salts with amino acids

ren, such as arginine, aspartic acid or glutamic acid, to name.

The compounds of the formula I according to the invention can be used as therapeutic medicaments for treatment of infectious diseases in the same way as the usual cephalosporin medicaments e.g. in powder form or in Administer the form of a solution or suspension in a physiologically acceptable drug carrier according to known methods. In particular, the compounds of the formula I according to the invention can easily be used as therapeutic agents for the treatment

909S37 / 06S3

treatment of various diseases in humans caused by the bacteria mentioned above such as pustular diseases, infections of the respiratory organs, infections of the bile duct, Darrainfelc infections, urinary tract infections and gynecological-obstetric Infections.

The compounds shown below, which are a selection of the compounds according to the invention

of Formula I are used, for example, either intramuscularly or intravenously in daily dosage amounts with success from about 10 to 100 mg per kg body weight in adults either as a single dose or given in two to four doses daily.

15 If the compounds of the formula I according to the invention

injected, the carrier medium can be, for example, distilled water or physiological saline solution. If the compounds of the formula I according to the invention are used in Used in the form of capsules, powders, granules or tablets, these active substances of the formula I get, for example in admixture with pharmacologically acceptable, known drug carriers, such as starch, Lactose, sucrose, calcium carbonate, calcium phosphate, with Binders, e.g. starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc., with lubricants, e.g. magnesium stearate, talc, etc., and loosening agents such as carboxymethyl calcium, talc, etc. are used.

As such, preferably to be administered Connections are the following, namely that

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Sodium salt of 7 ~ ^^ -
nyiamino ^ acetamido] ^ -acetoxymethyl ^ -cephem - ^ - carboxylic acid , the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocax-bonylamino) -acetamido] -3- (1 -methyl-1H-tetrazol-5-yl) - thiomethyl ~ 3-cephem- ⁱ J-carboxylic acidj the sodium salt of 7- [2- (2-aminothiazol- ⁱ 4-yl) -2- (aminocarbonylamino) acetamido] - 3_ [i- (2-hydroxyethyl) -lH-tetrazol-5-yl] -thiomethyl-3-cephem-4-carboxylic acid, the disodium salt of 7- [2- (2-aminothiazol ~ ^ί l-yl) -2- (aminocarbonylamino) acetamido] -3- (l-carboxymethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-i | -carboxylic acid, the 7- [2- (2-aminothiazole- ⁱ l- yl) -2- (aminocarbonylamino) acetamido] -3- (1 (2-dimethylaminoethyl) -1H-tetrazol-5-yD-thiomethyl-S-cephem-iJ-carboxylic acid, the sodium salt of 7- [2- (2- ^{aminothiazol-1} f-yl) -2- (aminocarbonylamino) -aeetamido] -3- (l _J 3, ⁱ l-thiadiazol-2-yl) _{thiomethyl-3-cephem-4-car-%} bonsäure, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3- (2-methyl-l, 3, 4-thiadiazol-5-yl) thiomethyl-3-cephem- ⁱ <-carboxylic acid _} that Sodium salt of 7- [2- ^{(2-aminothiazol-i} '-yl) -2- (aminocarbonylamino) acetamido] -3- (3-methyl-l, 2, ^ - thiadiazol-5-yl) thio methyl ^ -c ^ PHEM - ^ - carboxylic acid, the sodium salt of 7- [2- (2-AmInOtIiXaZoI- ¹ I-yl) -2- (aminocarbonylamino) acetamido] -3- ⁽ⁱ i-methyl-l, 2 _J 4-triazol-3-yl) -thioraethyl-3-cephem- ⁱ I-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol- ⁱ ! -Yl) -2- (aminocarbonylamino) acetamido] - J> - (3, ¹ I -dimethyl-1,2,4-triazol-5-yl) -thiomethyl-3-cephem- ¹ l-carboxylic acid _J the sodium salt of 7- [2- (2-aminothiazole-4- yl) -2- (aminocarbonylamino) acetamido] -3- (3-hydroxymethyl-4-methyl-l, 2 _s 4-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and the disodium salt of the 7 - [2- (2-Aminothiazol- ⁱ l-yl) -2- (aminocarbonylamino) -acetamido] -3- (2-carboxymethyl- ^{1,3, i} * -thiadiazol-5-

909837/0653

/ Ib

ylJ-thiomethyl - ^ - cephem- ¹ ! -carboxylic acid.

The compounds of the formula I according to the invention are new compounds and can be made by one of the following methods.

Procedure 1

The compounds of the formula I aimed at according to the invention can be obtained by reacting a compound of the following general formula:

-S

(II) CH-CONH-

15 ^

2 ν

COOH

wherein Y has the above meaning, with an isocyanate of the following general formula:

R —NCO "- (III)

wherein R has the above meaning, can be obtained.

The compounds of the formula II used as starting materials can be prepared according to the German Offenlegungsschrift No. 2,556,736 'method or by an analogous method. at To carry out this reaction, the resulting compounds of the formula II can be used in free form or in the form a salt, e.g. sodium or calcium salt, hydrochloride, hydrobromide, formate, acetate, of trifluoroacetate, triethylamine salt or dibutylamine salt, or in the form of an ester, for example des

909837 / 06S3

Use benzhydryl, trichloroethyl and p-nitrobenzyl esters. If R represents a lower alkyl group, the isocyanate will be used in the free form. Provided R, on the other hand, represents the hydrogen atom, so will one preferably uses an alkali metal cyanate, e.g. Kaliuracya'-nat, insert.

The reaction is normally carried out by simply mixing a compound of the formula II with a compound of the formula III in an aqueous solution at a pH of 3 to 8. There are cases in which the reaction can be accelerated or better results can be achieved, when adding tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, acetone or the like to the reaction system. The reaction takes place at a temperature between -20 ⁰ C and +80 ⁰ C and is usually complete after about 3 hours. The compounds of the formula I thus obtained can be subjected to processes known per se, for example by solution extraction, by adjusting the pH, by phase transfer,

by recrystallization, by chromatography, etc., isolate and clean.

Procedure 2

The compounds of the formula I according to the invention

can also be obtained by using a compound of the following general formula:

909837/0653

10

R ³ NH

(IV)

CH-COOH

NH

CO

NO

3 ^l

where R has the above meaning and R and R are hydrogen or a group protecting the amino group, with a compound of the following general formula:

15th

(V)

COOH

20th

where Y has the above meaning, and then if necessary removes the group protecting the amino groups.

The compounds of the formula IV used as starting materials in this case are also new Compounds and can be obtained from the amino acid derivatives of the formula IX, which in the German Laid-Open Publication No. 2,556,736. In this procedure, the amino group will be converted into an ureido group.

30th

909837/0663

CHCOOH

(IX)

RNCO or B NCO

LcH-COOH

NH CO N-R H

V ^Sv ft

N "" CH- '

or

NH

CO

NH

COOH

wherein all symbols have the meanings mentioned above.

3 4 In the above formulas, R or R means that

Hydrogen atom or a group protecting the amino group. Any group normally used in peptide chemistry can be used as the amino group protecting group, use easily removable, amino group protecting groups, such as the formyl, chloroacetyl, Trifluoraeetyi-j trityl, diphenylphosphinothioyl, tert-butyloxycarbonyl, Trichloroethoxycarbonyl, benayloxycarbonyl, p-nitrobenzyloxycarbonyl and trimethylsilyl groups

The compounds of the formula IV are reacted in free form or in the form of a salt or a reactive derivative with regard to the carboxyl function. As examples of such reactive derivatives can be the acid halides _s anhydrides, reaktionsfähi-

909837/0663

air

gen amides, reactive esters, etc. In this context, the acid chlorides, acid azides, mixed acid anhydrides with halogenated phosphoric acids, mixed acid anhydrides with alkyl carbonic acids, mixed acid anhydrides with benzoic acid, dimethyliminomethyl ester, ie [(CH ^) ₂ N = CH -] - ester, 2,4- * dinitrophenyl ester, pentachlorophenyl ester, N -Hydroxysuccinimidoyl ester, etc., the most suitable of these derivatives being used. Examples of salts of an acid of the formula IV include salts with alkali metals, e.g. sodium and potassium, salts with organic bases, e.g. trimethylamine, triethylamine and pyridine, salts with hydrohalic acids, e.g. hydrochlorides and hydrobromides, and salts with organic acids, e.g. acetates, Trifluoraeetate and Pormiate. the

15 compounds of formula V are in the free form or

brought into reaction in the form of a salt or an ester thereof. As examples of salts of compounds of the Formula V can be, for example, salts with organic acids, such as acetates, benzenesulfonates, tartrates, trifluoro acetates and formates, salts with inorganic acids, e.g. hydrochlorides, hydrobromides, sulfates and phosphates, Salts with alkali metals, e.g. sodium and potassium, and salts with organic bases, e.g. trimethylamine, triethylamine and dibutylamine. As an ester of compounds

An ester of the formula V can be used which corresponds to the above-mentioned esters of a compound of the formula II .

This reaction is normally carried out by mixing the said compounds of formulas IV and V in a solvent at about -40 ⁰ C to +20 ⁰ C ₀ As solu-

90S837 / 08S3

solvents can be, for example, water, acetone, dioxane, Acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide or pyridia to name. Hydrophilic solvents can be used in combination with water.

If the compounds of the formula IV are used in the free form or in the form of a salt thereof, a condensing agent will be added to the reaction system. Examples of such condensing agents can be for example Ν, Ν'-dicyclohexylcarbodiimide, alkoxyacetylene, Phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, tetramethylurea-phosgene complex, Dimethylformamide phosphorus oxychloride complex, etc.

Call 15.

This reaction can be carried out in the presence of a base. Examples of bases can be, for example organic or inorganic bases, such as alkali metal hydroxides, alkali metal hydrogen carbonates. Alkali metal carbonates, Trialkylamine, N, N-Dialky! Aniline, N, N-DialkyIbenzy! Amine, Name pyridine, N-alkyl, morpholine, etc.

The compounds obtained after the above reaction are reacted further if necessary in order to remove the protective groups. For this purpose one can use the Use the usual measures in the Peptidchende. If the protective group is the formyl group, one will be in this For example, trap this group using a mixture of hydrochloric acid and methanol, a mixture of phosphorus oxychloride and methanol or a mixture of sulfur

909837/0663

remove acid and methanol,

If it is the chloroacetyl radical, then one can use thiourea. If the protecting group is the Is trifluoroacctyl group, it can be eliminated using an aqueous alkali solution. The trityl, dipheny! Phosphine »fchioyl- and tert-butyloxycarbonyl groups can be removed with hydrochloric acid or trifluoroacetic acid will. In the case of a trichloroethoxycarbonyl, benzyloxycarbonyl and p-nitrobenzyloxycarbonyl group, the Carry out removal by reduction.

• The compounds of formula I thus obtained can in a manner known per se, as has been described in connection with process 1, isolated and getting cleaned.

Procedure 5

The compounds of the following general formula;

CH NH CO NHR

COKH

COOH

(VIII)

wherein Y ^{2 is} the -S-Het group, can be prepared by a compound of the following general formula:

909837/0853

V
N

-X

CH WH CO N-R

-CONI

1908033

COOH

wherein R _3, R and R have the above meanings and Y is acetoxy or 3-Oxobutyryloxygruppe means init _s stickstoffhaltigenj a heterocyclic thiol of the following formula:

HY

(VII)

where Y has the above meaning., and then if necessary removes the groups protecting the amino group.

If one considers specifically the 3-position of the cephem ring _3, ie the substituted position, in this reaction, it can in principle be compared with a nucleophilic substitution reaction of the 3-acyloxy group, this is known from the prior art and from the patent literature is [2.B. CP. Murphy & JA Webber: Cephalosporins and Penicillins: Chemistry and Biology, "EoH ₅ , Wljnn (Ed.), Academic Press, New York _s NoY., 1972, Ch. Hζ British Patents Νσ. 982252 ₃ 1Ο129ίί3 ₅ 1028563 and 1030630]. This implementation can thus be carried out by one of these known methods or by an analogous method.

So you can, for example, the reaction by '/ he-heisehen a compound of the formula VI or a Sal-

zes thereof with a compound of the formula VII, wherein Het is a nitrogen-containing heterocyclic, or with a reactive derivative thereof with respect to the thiol function with a solvent either at room temperature or Perform at elevated temperature.

The salts of compounds of the formula VI are generally chosen from among the various compounds mentioned above Salts of compounds of the formula I which use alkali metal or alkaline earth metal salts. As examples of Reactive derivatives with respect to the thiol function of compounds of the formula vil can be used, for example name the alkali metal salts, e.g. the sodium and potassium salts. The solvent can be, for example, water, Acetone, chloroform, nitrobenzene, dichloromethane, dimethylformamide, methanol, ethanol, tetrahydrofuran or dimethyl sulfoxide or use a suitable mixture thereof. V / ground the compounds of the formulas VI and VII in the If you use the free form, you will get better results in some cases if you implement it in a weak form basic to neutral range using an appropriate amount of an alkali metal hydroxide, e.g., sodium hydroxide or potassium hydroxide, an alkali metal carbonate, e.g. sodium carbonate or potassium carbonate, or an alkali metal hydrogen carbonate, e.g. sodium hydrogen carbonate or potassium hydrogen carbonate. The reaction takes place by mixing in each case 1 molar equivalent of a compound of the formula VI or a salt thereof with 1 to 2 molar equivalents of a compound of the formula VII or a salt thereof in one of the solvents mentioned above at a temperature between room temperature and

909837/0653

100 ^° C. The compounds obtained in this way are then treated, if necessary, in such a way that the protective groups can be removed. The application to achieve this purpose
The methods obtained are similar to the one above
has been described in connection with process 2, -The compounds of the formula VIII obtained in this way can be isolated and purified by methods known per se in the manner described above.

The compounds of the formula I according to the invention and the starting compounds of formula IV can both the D-shape as well as in the L-shape or in the form of a mixture of the D- and L-shapes are available. If it is a mixture of the D- and L-shape, such a mixture can be used split optically in a manner known per se at a suitable point in time of the process.

Two tautomeric structures can be ascribed to the compounds of the formula I according to the invention,
namely the thiazole form and the T-hiazoline form like this
can be seen from the following two formulas.

N-

CH-GO-Z

NH ι

CO

HN-

IR

H-CO-Z

NH ι

CO

fflffi

wherein Z is the group

-NH-

means

COOH

and the other symbols the corresponding ones above

909837/0653

- 26 -

have defined meanings.

While the present invention encompasses all such tauterous forms, the following are presented for convenience the compounds in each case in the thiazole form designated.

The invention will be explained in more detail below with reference to working examples. The ones in these

Nuclear magnetic resonance spectra given in the examples are determined with a Varian XL-100 (100 MHz), EM-390 (90 MHz) or T-60 (60 MHz) photospectrometer with tetramethylsilane as the internal standard, the chemical shifts being expressed in S (ppm) are.

15 -

The following tables show the minimum inhibitory concentration values (MIC) and the therapeutic effect _{data (ED, - 0} ) of the various particularly noteworthy cephalosporin derivatives obtained according to the examples with regard to various bacteria, as well as similar data from commercially available cephalosporins which can be found in daily clinical use, ie cephalothin, ie the sodium salt of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem- ^! l-carboxylic acid, cephaloridine, ie

of the sodium salt of 7- (2-thienylacetamido) -3- (l-pyridyl) -methyl-3-cephem- ⁱ t-carboxyl-betaine, cefazolin, ie the sodium salt of 7- (1H-tetrazol-l-yl) -acetamido-3- (2-methyl-1,3, ⁱ l-thiadiazol-5-yl) -thiomethyl-3-cephem- ¹ i-carboxylic acid and cefoxitin, ie the sodium salt of the 7'-methoxy

30 7β- (2-thienylacetamido) -3-carbamoyloxy-methyl-3-cephem- ^z lcarboxylic acid. [See New England Journal of Medicine,

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2U (1976) and Journal of Pharmaceutical Science, 6J_, 1899 (1975) 1

(a) Measurement of the minimum inhibitory concentration values (Table 1 and Table II)

Method: Agar serial dilution

Medium: TSA

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Table I.

CD ο to

Test connection
manure E.
coli
NIHJ
JC-2 E.
coli
0-111 E.
coli
T-7 K.
pneumatic
moniae
DT K.
pneumatic
moniae
GIT
3835 s.
mar-
cescens
IFO
.12 648 s.
mar-
cescens
TN-24 P.
vul-
garis
IFO
3988 P.
vul
even is
GN
4413 P.
mirabilis
GN
4359 Cephalotin 12.5 3.13 100 1.56 12.5 > 100 > 100 1.56 > 100 3.13 Cephaloridin 3.13 1.56 > 100 1.56 12.5 > 100 > 100 6.25 > 100 6.25 Cefazolin 1.56 1.56 100 1.56 6.25 > 100 > 100 3.13 > 100 6.25 Cefoxitin 6.25 1.56 50 3.13 6.25 25th 6 _? 25th .6.25 12.5 3.13 Example, 3 o, ¹ 0.024 0.78 0.05 0.2 1.56 3.13 .0.2 6.25 "4 £ 0.012 1.56 0.05 0.2 0.78 0.39 °, i 1.56 °, 1 5 0.05 S), 012 0.39 0.05 0.39 0.39 .0.1 6.25 ¹¹ 6-1 0.024 SO, 012 0.39 0.024 0.05 0.78 0.39 0.05 3.13 "6-2 0.024 φ, 012 0.2 £ 0.012 0.024 0.2 0.024 1.56 0.024 "6-3 0.05 £ 0.012 3.13 0.05 0.2 1.56 0.78 .0.024 25th 0.024 "6-4 0.024 £ 0, 012 1.56 0.024 1.56 0.2 0.05 3.13 0.05 ■ '"' 6-6 . £ 0.05 S), 05 0.39 £ 0.05 ^ 0.05 0.2 0.78 °, i 0.78 <0.05 "6-7 O ₇ 024 £ 0.012 0.39 0.024 0.05 ' 0.39 , 0.2 0.05 1.56 0.05

PO CO O OO O CO

Table II

O C0 OO

ο σ> cn

Test connection P.
morganii
IFO 3168 P.
rettgeri
OT 338 P.
rettgeri
GN 4733 E.
cloacae
TM 1282 c.
Freundii
GN 99 c.
Freundii
GN 1706 Cephalotin > 100 1.56 > 100 > 100 25th > 100 Cephaloridin > 100 1.56 > 100 > 100 50 > 100 Cefazolin 100 0.39 100 > 100 ^Ί 2 5 > 100 Cefoxitin 12.5 0.78 25th > 100 100 > 100 Example "3 0.39 <0.012 0.05 ' 0.25 0.39 0.39 <0.012 .0.2 V 0.2 5 0.05 <0 ^ 012 0.05 0.39 o, ¹ 0.2 "6-1 0.1. <0.012 0.2 0.78 0.2 0 _r 2 "6-2 0.024 <0.015 0.05 0.78 ° Λ 0.2 6-3 O ₃ 024 <0.012 0.024 0.78 0.39 0.78 "6-4 V <0.012 V 0.78 0.2 "■ 6-6 <0.05 <0.05 <°, ° 5 1.56 £ 0.05 ^ 0.05 "6-7 0 _? 05 ^ 0.012 0.05 0.39 0.2

(b) Therapeutic effects in infected mice (Table III) Test animals: male mice, ICR / SLC

A group of 5 animals was given for each drug

used.

Carrying out the infection: Intraperitoneally Infectious bacteria: 10 CPU from Serratia

Marcescens TN 66 per animal

Duration of observation: 7 days

Administration method: 1 mg, 10 mg, 100 mg and 200 mg of the respective test compound were used in 100 ml of sterile saline solution and then 0.2 ml of this solution subcutaneously as a single dose immediately administered after infection. Twofold dilutions of each solution were made on 5th Administered to groups of 5 mice each.

CPU = colony forming unit (referred to in English as "colony forming unit").

Table III

Test connection way
of administration ED ₅₀ , mg / kg Example 6-6
Cefoxitin S .C.
SC 4th
13.1

909837/0653

B _f

Reference example 1

Preparation of J- [DL- {2- (2-aminothiazol-i | -yl) -2- (aminocarbonylamino) acetamido]] -3-diethyl-3-cephem- ⁱ l-carboxylic acid.
5

1) 2. Ί g of the sodium salt of 7- [2- (2-aminothiazol- ⁱ l-yl) -2-hydroxyiminoacetamido] -3-methyl-3-cephem- ⁱ l- are dissolved in 50 ml of 90% formic acid carboxylic acid (syn isomer) (German OS 2.727-753) , whereupon 3.9 g of zinc dust are added while cooling the solution to ⁰ ° C. and with stirring and the whole is stirred for 1 hour. The reaction mixture is then filtered off, the filtrate is concentrated under reduced pressure, 20 ml of water are added to the residue and the mixture is concentrated. This procedure is carried out a second time. The residue is then dissolved in 50 ml of water and lyophilized. In this way, 2.8 g of 7- [DL ~ £ 2- (2-aminothiazol-4-yl) -glycylamido]] -3-methyl-3-cephem-4-carboxylic acid formate are obtained.

2) 0.1 g of the resultant is dissolved in 1 ml of water 7- [DL- {2- (2-aminothiazol-4-yl) -glycylamido}] -3-methyl-3-cephem-4-carboxylic acid formate and 0.3 g of potassium cyanate, whereupon this solution for 2 hours at room temperature stirs. The reaction mixture is then adjusted to a pH of 2.5 using 1N hydrochloric acid, which insoluble constituents are filtered off and the piltrate is poured over a polystyrene resin column (Amberlite ^ XAD-2, Rohm and Haas Co.). The pillar is with Washed water thoroughly, and then eluted with 30% ethanol. The fractions rich in the desired product are collected and lyophilized, leaving 0.08 g

909637/0651

of the above-mentioned connection.

IR (KBr, cm ^"1): ₃ 3IiOO 1755 I66O, I6OO, 1510, I36O

NMR (90 MHz, dg-DMSO, δ):

2.10 (s, CH), 3.16 & 3, lt6; 3.23 & 3.50 (each ABq, J = 18Hz, 2-H ₂ ), ll, 93; ¹ 1.97 (each d, J = 5Hz, 6-H), 5.22 (d, J = 8 Hz,> C H NH), 5, ¹ ^; 5.55 (each dd,

J = 5 & 8Hz, 7 "H), 5.68 (br.s, CONH), 6.31;

6.35 (each s, thiazole 5-H), 6, * »5; 6.49 (each d,

J = 8Hz, Jb CHNHCO 3), 6.8iJ (br. S, thiazole NH ₃ ), 8.65; 8.75 (each d, J = 8Hz, 7-CONH).

Elemental Analysis for C ₁ → H, → NgO ₅ S ₃ -I, 75 H ₃ O: Calculated: C = 37.87; H = 4, ^ 3; N = 18.93

Found: C = 37.92 '; H = '1.22; N = 19.07

example 1

Preparation of the sodium salt of J- [DL- {2- (2-aminothiazol-20 4-yl) -2- (aminocarbonylamino) acetamido]] - 3-acetoxymethyl-3-cephem- ⁱ l-carboxylic acid.

1) 0.95.6 g of J- [2- (2-amino-25 thiazol-l {-yl) -2-hydroxyiminoacetamido] - ^ are dissolved in a mixture of H ml of formic acid, 0.5 ml of water and 4 ml of methanol -acetoxymethyl ^ - cephem-i) -carboxylic acid · HCl (syn isomer) DE-OS 2,727.753), followed by stirring under ice-cooling g 3 zinc dust gradually within about 1 hour at an internal temperature of from 0 to 10 ⁰ C. adds. 30th

When the dropwise addition is complete

909837/0653

the mixture was stirred in the same temperature range for a further hour. Then the insoluble components filtered off and with a little methanol and formic acid washed. The filtrate and the wash waters are combined and concentrated. The residue is by adding 10 ml Dissolved in hydrochloric acid and the solution over a column (3 x 30 cm) of polystyrene resin (Amberlite ^ XAD-2, Rohm and Haas Co.), using

uses water and 20% ethanol as eluent.

The fractions rich in the desired product are collected, concentrated and lyophilized. To this In this way, 0.538 g of 7- [DL- (2- (2-aminothiazol-4-yl) -glyoylamidoj3-3-acetoxymethyl-3-cephem - ^ - carboxylic acid are obtained

15 (yield = $ 59.2).

IR (KBr ₅ cm ^"1): 3 ¹ IOO, I76O, l68O, I610, 1520, 1390, 1350,

1240.

20 NMR (100 MHz, DO, 6):

2.13 (s, OAc), 3.31 &3.64; 3.38 & 3.70 (each ABq,

J = ISHz, 2-H ₂ ),

4.71 & 4.92 (ABq, J = 13Hz, 3-CH ₃ ), 5.12; 5.18 (each d,

J = 5Hz, 6-H), 5.2O (s, CHNH ₉ ), 5.63; 5.78 (each d, - ^

J = 5Hz, 7-H), 6.95; 6.98 (each s, thiazole 5-H).

Ninhydrin: positive (yellow)

Elemental analysis for ^ 5H ₁₇ N ₅ OgS "1.5 HUO: Calculated: C = 39.64; H = 4.44; N = 15.41 Found: C, 39.86; H = 4.47; N = 15 , 74

909837/0653

2) A mixture of 2 g of 7- [DL- [2- (2-aminothiazol-4-y 1) -glyeylamido}] -3 -ac et oxymethyl-3-c ephem-4 -carboxylic acid and 1.5 g Potassium cyanate is rapidly mixed with 30 ml of water heated ^{to 75 ° C. while stirring vigorously.} The mixture is then stirred for 2 minutes and the solution is then rapidly cooled to room temperature. After adding 3 g of sodium chloride and 2 g of lithium hydrogen carbonate, the mixture is stirred and rapidly chromatographed over a column (3 × 30 cm) of polystyrene resin (Amberlite® XAD-2, Rohm and Haas Co.) using water as the eluent. The fractions which are rich in the desired product are collected, concentrated and chromatographed on a dextran column (Sephadex® LH-20, Pharmacia Fine Chemicals) using water as the eluent. The desired fractions are collected, concentrated and lyophilized to give the above-identified compound. This product, obtained in an amount of 0.937 g, is a mixture of equal parts of the two diastereoxsomeric compounds (yield = 39.6 %).

IR (KBr, cm " ¹ ): 3400, 1760, 1660, 1610, 1520, 1385, 1240.

NMR (100 MHz, D ₃ O, 6):

2, 16 (s, OAc), 3.32 &3.65; 3.39 & 3.69 (each ABq, J = 18Hz, 2-H ₂ ), 4.73 & 4.94 (ABq, J = 13Hz, 3-CH ₂ ), 5.12; 5.16 (each d, J = 5Hz, 6-H), 5.29; 5.32 (each s,> CH-NH-), 5.64; 5.74 (each d, J = 5Hz, 7-H), 6.71; 6.74 (each s, thiazole 5-H);

909837/0653

NMR (100 MHz, Dg-DMSO, 6 '):

2302 (S ₁ OAc) ₅ 3.15 &3.44; 3.20 & 3.50 (each ABq, J = 18Hz ₃ 2-H ₂ ), 4.82 & 5.04 (ABq, J = 13Hz, 3 "CH ₂ ), 4.92j 4.96 (each d , J = 5Hz ₃ 6-R), 5.24; 5.28 (each d ₃ J = 8Hz, ^ CHNH-), 5.46; 5.56 (each dd, J = 5 & 8Hz, 7-H ) ₃ 5.80 (br.s, -CONH ₂ ), 6.37; 6.40 (each s, thiazole 5-H), 6.64; 6.72 (each d, J = 8Hz, ^ CHNHCQ- ), 6.92; 6.94 (each br.s, thiazole NH ₂ ), 8.68; 8.76 (each d, J = 8Hz, 7-CONH-)
10

Ninhydr in: negative iv

Elemental analysis for C ₁ ^ H _{17 NgO 7} S ₂ Na «2.5 H _? 0: Calculated: C - 35.75; H = 4.13j N = 15.64 Found: C = 35.82; H = 4.06; N = 15.48.

Example 2

Preparation of the sodium salt of 7- [DL- [* 2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) -acetamido ^] - 3-carbamoyloxy-

methyl-3-cephem- ^! 4-carboxylic acid.

It operates in the same manner as in Example l _s used but the sodium salt of 7- [2- (2-amino

thiazol-4-yl) -2-hydroxyiminoacetamido] -3-carbamoyloxy-25

methyl-3-cephem-4-carboxylic acid.

In this way the compound mentioned in the above title is obtained.

IR (KBr ₃ cm " ¹ ): 3350, 176O ₃ 1660 _a 160 5, 1520, 1400 ₃ 1330.

909837 / 06S3

NMR (90 MHz, D ₂ 0.6):

3.29 &3.61; 3.25 & 3.65 (each ABq, J = 18Hz, 2-H ₃ ) 4.66 & 4.90 (ABq, J = 13Hz, 3-CH ₂ ), 5.07; 5.12 (each d, J = 5Hz, 6-H), 5.24; 5.26 (each s, ^ CHNH · ^, 6.66 & 6.70 (each s, thiazole 5-H).

Example 3

Preparation of the sodium salt of 7- [DL-12- (2-aminothiazol-4-yi) -2- (methylaminoearbonylamino) acetamido ^] -3-acetoxymethyl-3-cephem-14-carboxylic acid.

0.454 g of 7- [DL-fe- (2-aminothiazol-4-yl) -glycylamido ^] ^ - acetoxymethyl-S-cephem-4-carboxylic acid are suspended in 10 ml of acetonitrile and then this suspension with 0.1 ml of methyl isocyanate and 0.14 ml of triethylamine are added at room temperature. The mixture is stirred at this temperature for 1 hour, after which it is concentrated. After adding 10 ml of water and 2 g of sodium hydrogen carbonate, the mixture is degassed and rapidly passed through a chromatographic column (3 x JO cm) made of polystyrene resin (Amberlite ^ XAD-2, Rohm and Haas Co.) using V / water as Eluent allowed to flow. The desired fractions are concentrated and lyophilized to give 0.166 g of the above-mentioned compound in a yield of 29.6% .

IR (KBr, cm " ¹ ): 3300, 176O, 1660, 16IO, 1520, 1-400, 1350,

1240.

30 NMR (90 MHz, D ₂ Q, δ):

, OAc), 2.71 (3.5NCH,), 5.30 &3.64; 3.35 & 3.67

909S37 / 06B3

(each ABq, J = 18llz, 2-H ₃ ), '1.70 & 1.91 (ABq, J = 13Hz, 3-CH ₂ ), 5.10, 5.12 (each d, J = 5Hz, 6-H), 5.25; 5.27 (each s, ^ CHNH-), 5.62; 5.70 (each d, J = 5Hz, 7-II), 6.67; 6.70 (3 each, thiazole 5-H). 5

NMR (90 MHz, dg-DMSO, 6 ):

1.98 (s, OAc), 2.53 (d, J = 5Hz, -NCH ₃ ), 3.10 &3.40; 3.16 & 3, ^ 6 (each ABq, J = 18Hz, 2-H ₃ ), 4.76 & 5.00 (ABq, J = 13Hz, 3-CH ₂ ), 4.85; 4.90 (each d, J = 5Hz,

6-H), 5.22 (d, J = 8Hz,> CHNH ·}, 5, -41; 5.50 (each dd, J = 5 & 8Hz, 7-H), 6.29 (q, J = 5Hz, -CONHMe), 6.31, 6.34 (each s, Thiazole 5 ~ H), 6.44, 6.55 (each d, J-8Hz, -CHNHCON), 6.87, 6.90 (each br.s, thiazole NH ₂ ), 8.62; 0.72 (each d, J = 8Hz, 7-CONH-).

Elemental analysis for C ₁₁₇ H- _o N ^ 0 "S" Na · 3H_0

L ( 19 Ό (dd

Calculated: C = 36.43; H = 4.50; N = 14.99 Found: C = 36.77; H = 4.32; N = 14.76

20 Example 4

Preparation of the matrix salt of 7- [DL- £ 2- (2-aminothiazol-4-yl) -2- (methylaminocarbonylamino) acetamido ^] - 3- (1-methy1-lH-tetrazol-5-yl) -thiomethyl- 3-cephem-4-carboxylic acid.
25th

1) 1.07 g of the sodium salt is dissolved in a mixture of 5 ml of formic acid, 0.5 ml of water and 5 ml of methanol of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid, whereupon, with ice-cooling and stirring, 6.0 g of zinc dust in a period of approximately

909837 / 06S3

Gradually add for 30 minutes at an internal temperature of 0 to ICPC. After the end of the dropwise addition, the mixture is stirred for a further 30 minutes at the temperature just mentioned, whereupon the insoluble constituents are filtered off and washed with a little methanol and formic acid. The filtrate and wash waters are collected and concentrated to give a glassy residue which contains the J- [DL- (2- (2-aminothiazol-Jt-yli-glycylamido]] -3- (1-methyl-1H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid.

A silica gel from Merck is used for thin-layer chromatography with the use of a mixture of ethyl acetate, acetic acid and water in a mixing ratio of 4: 1: 1 as developer solvent.

f
R 0.15; positive ninhydrin reaction (yellow).

2) The total amount of the glass-like product thus obtained, ie the J- [DL- [2- (2-aminothiazol-4-yl) -glyeylamido ^] - 3- (l-methyl-lH-tetrazol-5-yl) -thio-methyl-3-cephem-4-carboxylic acid, as obtained in accordance with paragraph 1) above, is admixed with 10 ml of acetonitrile and 5 ml of water while stirring. Then triethylamine is added gradually at room temperature to the pH of the mixture to J to adjust. 5

After adding 0.4 ml of methyl isocyanate, the mixture becomes the same for 30 minutes Stirred temperature and then concentrated. The residue is dissolved in 20 ml of water with 3 g of sodium hydrogen carbonate moved and after removing the existing

909837/0653

Gas, the solution is rapidly over a polystyrene resin column ,. ^^ "^ XAD-2, Rohm and Haas Co.) using

chromatographed of water and aqueous ethanol as eluent. The desired fractions were collected _s concentrated and chromatographierfc over a Dextrangelsäule (Sephadex LH-^ 2Q., Pharmacia Fine Chemicals), using water as the eluent. The appropriate fractions are collected, concentrated and lyophilized. 0.25 ¹ l g of the above-mentioned compound is obtained »

IR (KBp, em " ¹ ): 3300, 1760, 1660, 1610, 1550 ₅ 1390, 1350.

NMR (90 MHz, D ₂ O δ) ■:

2.70 (s,> NCH ₃ ), 3.39 & 3 ₅ 74; 3, ¹ H 3 ₃ 78 (each ABq, J = ISHs _{3, 2-H2),} 4.02 (s, tetrazole-CH), 4.05 & 4.30 (ABq ₅ Jrl3Hz, 3-CH ₂ ), 5 ₃ 04; 5 _s O8 (each d, J = 5Hz ₅ 6-H), 5 _a 3O (s, ^ rCHNH), 5 _S 56; 5.63 (each d, J = 5Hz, 7-H) ₉ 6.67; 6.70 (each s, thiazole 5-H).

Example 5

Preparation of the 7- [DL- {2- (2-aminothiazol-4-yl) -2- (aminocarbonyl) acetamido}] - 3- (1- (2-dimethylaminoethyl) -IH-

t6trazo.l-5-yl) thiomethyl-3-cephem-4-carboxylic acid. 25th

0.985 of the sodium salt of 7- [DL- £ 2- (2-aminothia2ol-4-yl) -2- (aiiiinocarbonylamino) -acetamido]] -S-aeetoxymethyl-cephein is dissolved in 20 ml of phosphate buffer (pH 6.4) -4-carboxylic acid and 0.433 g of [1- (2-dimethylaminoethyl) -IH-tetrazol-5-ylI-thiol. The mixture xiird then stirred for 4 hours at 70 ⁰ C, is preceded by the addition of

Acetic acid adjusts the pH to 3.3. The insoluble components are filtered off and the filtrate over a Polystyrene resin column (Amberlite ^ XAD-2, Rohm and Haas Co.) Ehromatographiert, using water and 5 aqueous ethanol as the eluent. The appropriate factions are concentrated and chromatographed on a dextran column (Sephadex ^ LH-20, Pharmacia Fine Chemicals), using water as the eluent. The appropriate fractions are collected and concentrated 10 and lyophilized. In this way, 0.205 g of the above-mentioned compound is obtained in a yield of $ 17.8.

IR (KBr, cm " ¹ ): 3300, 1760, 1660, 1610, 1510, 1380, 1340.

15 NMR (90 MHz, D ₂ O, 6):

3.04 (s, -N (CH ₃ ) ₂ ), 3.43 &3.76; 3.49 & 3.81 (respectively

ABq, J = 18Hz, 2-H ₂ ), 3.83 (t, J = 5Hz, CH ₂ CH ₂ NC). 4.09 &

4.30 (ABq, J = 13Hz, 3-CH ₂ ), 4.92 (t, J = 5Hz, -CH ₃ CH 1K),

5.04; 5.10 (each d, J = 5Hz, 6-H), 5.34 (sTScHNH),

5.57; 5.64 (each d, J = 5Hz, 7-H), 5.77; 6.80 (each- ', Weil s, thiazole 5-H).

Example 6-1

Preparation of the sodium salt of 7- [DL- £ 2- (2-amino-25 thiazol-4-yl) -2- (aminocarbonylamino) acetamido]] - 3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid.

0.958 g of des is dissolved in a mixture of 20 ml of phosphate buffer 30 (pH 6.4) and 3 ml of tetrahydrofuran

Sodium salt of 7- [DL - {. 2- (2-Aminothiazol-4-yl) -2- (aminocarbonylamino) -acetamido]] - 3-acetoxymethyl-3-cephem-4-

S09837 / 0653

-Mf-

carboxylic acid and 0.33 g (2-Methy1-1,3,4-thiadiazol-5-yl) -thiol. After the solution has been adjusted to a pH value of 6.4 by adding 1N sodium hydrogen carbonate, the mixture is heated ^{to 70 ° C. on the water bath for 4 hours.} The mixture is then concentrated to a volume of approximately 15 nil and then 2 g of sodium hydrogen carbonate are added. The mixture is stirred and, after any gases present have been removed, chromatographed over a polystyrene resin column (Amberlite ^ XAD-2, Rohm and Haas Go.) Using water and aqueous ethanol as the eluent. The desired fractions are collected, concentrated and lyophilized. In this way, 0.21 g of the above-mentioned compound is obtained in a yield of 18.6 %.

15 IR (KBr, cm " ¹ ): 3300, 176O, 1660, 1610, 1535, 1385 NMR (90 MHz, D ₂ O, S ):

2 _f 71 (s ₅ CH ₅ ), 3.30 & 3 _f 7O; 3.36 & 3 _f 76 (each ABq ₁ J = 18Hz, 2-H ₂ ), 3 _f 96 &. 4 44; 3 96 & 4 _f 48 (each ABq, .J = IJHz, 3-CH _o ), 5.01; 5 06 (each d, J = 5Hz, 6-H), 5.23; "5.26

(each s, ^ CHNH), 5.56; -5 _f 64 (each d, J = 5Hz, 7-H), 6.63; O ₁ SG (JeWeUs s, Thiazol 5-H).

Example 6-2 through Example 6-7

In the same manner as in Example 6-1 above, the following compounds are obtained from the respective ones Thiols and from the sodium salt of 7- [DL- £ 2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido}] - 3-acetoxymethyl-3-cephem-4-carboxylic acid.

909837/0653

NILE

Table IV

CHCONH

NH

C = O

-N

0 ^<

CH ₂ Y

COONa

co ο co

example Y IE (KBr, cm " ¹ ) NME (90 MHz, D ₂ O, δ) example
6-2 N-N 33OO, 1760, 1660
I6O5, I5IO, 3-360 3.33 &3.72; 3.40 & 3.77 (each ABq,
J = 18Hz, _ 2-H _? ), 4.04 &4.50; 4.03 &
4.53 (Jew. ABq, J = IJHz, 3-CH ^),
5.03; 5.06 (each d, J = 5Hz, 6-H),
5.24; 5.26 (each s, ^ CHNH), 5.55;
5.64 (each d, J = 5Hz, 7-H), 6.66; 6.70
(in each case s, thiazole -5H, 9, '4O (s,
Thiadiazole 5-H) example
6-3 NN
~ ^ S ^ ~ CH ^ COONa
d 33OO, 1760, 1660
1600, I5IO, I36O 3.35 &3.74; 3.40 & 3.77 (each ABq,
J = 18Hz 2-H, _2), 4.01 (s, CH ₂ COO), 4.03
&4.40; 4.03 & 4 _? 49 (each ABq, J = 13Hz,
3-CH ₂ ), 5.06; 5, H (Jew. D, J = 5Hz, 6-H),
5.25; 5 _y 27 (each s, ^ CH NH), 5.56; 5.68
(each d, J = 5Hz, 7-H), 6.67; 6 _? 70 (each
because s, thiazole 5-H)

example Y N-N IR (KBr, cm " ¹ ) NMR (90 MHz, DgO, δ) Xv JLM 3.33 &3.70; 3.3β & 3.73 (each ABq, N-N I. J = ISHz, 2-Hg), 4 _; 02 &4.42; 4.02 & example S Ag } - CHgCONH ₂ CH ^ 3300, 1760, 1665, 4.46 (each ABq, J = 13Hz, 3-CHg), 4.15 6-4 1610, I5IO, I38O (s, CHgCO), 5.02, 5.06 (each d, J = 5Hz, 6-H), 5.24; 5.26 (each s, ^ CH NH), 5.56; 5.66 (each d, J = 5Hz, 7-H, 6.64; · 6.67 (each s, thiazole 5-H) - 3.30 &3.69; 3.35 & 3.78 (each ABq, J = ISHz, 2-Hg), 3.64 &4.26; 3.64 & example 3300, 1760, 1660, 4 _? 28 (each ABq, J = 13Hz, 3-CHg), 3 _? 7O 6-5 1605, I5IO, I39O (s, CH ₃ ), 4 _? 79 (s, triazole 5-CHg), 5.02 & 5.06 (each d, J = 5Hz, 6-H), 5.24 & 5.26 (each s, > CHLTO), 5.53; 5.56 (each d, J = 5Hz, 7 ~ H), 6.67; 6 _? 70 (each s, thiazole 5-H)

example Ύ IR (KBr, cm " ¹ ) ME (90 MHz, DgO, δ) 5.36 &3.74; 3 Λ2 & 3.78 (each ABq, J = 18Hz, 2-Hg), 5.95 (s, CH ₃ ), 4.05 & example -SA _n Y 3300, 1760 , 1660, 4.29; 4.Ο3 & 4.31 (each ABq, J = 15Hz, 6-6 ι 1605, I5IO , 1590, 5-CHg), 5.05; 5.08 (each d, J = 5Hz, CH-, I36O 6-H), 5.24; 5.26 (each s ^ CfflH), 5.55; 5.66 (each d, J = 5Hz, 7-H), 6.67; 6.70 (each s, thiazole 5 ~ H) 5.56 &5.75; 5.41 & 3.77 (each ABq, N-N J = 18Hz, 2-Hg), 4.01 (t, J = 5Hz, CHg0H), example -S-kj ^ N 550C, I76O , 1665, 4.09 &4.54; 4.09 & 4.56 (each ABq, 6-7 I.
CH ^ CH ^ OH 1605, I5IO , 1390 J = 15Hz, 5-CH ₂ ), 4.53 (t, J = 5Hz, 156Ο CHgCHgOH), 5.04; 5.08 (each d, J = 5Hz, 6 ^ H), 5.25; 5.26 (each s,> CHNH), 5.57; 5.67 (each. D, J = 5Hz, 7-H), 6.67; 6.70Ö ^ew s, thiazole? -H)

Claims (2)

10 15 formula Claims Connections of the following general COOH wherein R is the hydrogen atom or a lower alkyl radical and Y is an acyloxy, carbamoyloxy or -S-Het group, in which Het is a substituted or unsubstituted, nitrogen-containing heterocyclic group, namely a Tetrazolyl, thiadiazolyl or triazolyl group, means or pharmaceutically acceptable salts of these compounds. 2. Compounds according to claim 1, wherein R is the hydrogen atom. 3. Compounds according to claim 1, wherein the lower alkyl radical R is the methyl radical. 4. Compounds according to claim 1, wherein the acyloxy group Y is the acetoxy group. 5. Compounds according to claim 1, wherein the symbol Het corresponds to one of the following formulas, namely 909897/0653 • Ν Il N N JJ JLj N- -R N " and R ¹ wherein R ^{1 is} the hydrogen atom, an alkyl radical with 1 to 3 carbon atoms, a hydroxyalkyl radical with 1 to 3 carbon atoms, a carbalkoxy radical, the alkyl radical of which has 1 to 3 carbon atoms, a die-lower-alkylaminoalkyl radical, the latter of which has 1 to 3 carbon atoms, or a carbamoylalkyl group, the alkyl radical of which has 1 to 3 carbon atoms, and R ² denotes the hydrogen atom, an alkyl radical having 1 to 3 carbon atoms or a hydroxyalkyl radical having 1 to 3 carbon atoms. 6. Compounds according to claim 5, characterized in that the substituent R is methyl, 2-hydroxyethyl, carboxymethyl or 2-dimethylaminoethyl and the substituent R ^{2 is} hydrogen, methyl or hydroxymethyl. 7. 7- [2- (2-Aniinothiazol-4-yl) -2- (methylaminocarbonylamino) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4- carboxylic acid. 8. 7- [2- (2-Aminothiazol-4-yl) -2- (aminocarbonylamino) -acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-cephem - ^ - carboxylic acid. 9. 7- [2- (2-aminothiazol- ⁱ t-yl) -2- (aminocarbonyl- 909837 / 0SS3 amino) acetamido] -3- (Ij 3,4-thiadiazol-5-yl) thiomethyl-J-cephem-Jj-carboxylic acid. 10. 7- [2- (2-aminothiazol- ⁱ f-yl) -2- (aminoearbonylamino) -acetamido] -3- (l-methyl-1H-tetrazol-5-yl) -thio- methyl-3 * "cephem- ¹ i-carboxylic acid. 11. 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) -acetamido] -3- [1- (2-hydroxyethyl) -lH-tetrazol-5-yl] - 10 thiomethyl - ^ - cephem-ii-carboxylic acid. 12. Pharmaceutical preparations which contain a compound according to claim 1 together with at least one pharmaceutical acceptable excipient or diluent 15 remedies included. 13. Process for the preparation of compounds of the following general formula: 20 ^H 2 ^N - N ^J - CH-CONH CO NHR ^C00H in which R denotes the hydrogen atom or a lower alkyl radical and Υ denotes an acyloxy, carbamoyloxy or -S-Het group ₃ in which Het denotes a substituted or unsubstituted, nitrogen-containing, heterocyclic group, namely a tetrazolyl, thiadiazolyl or triazolyl group, thereby marked that one either 90I837 / 06IS (1) a compound of the following general formula: H ₂ N- - ⁿ - CH - CONH - i - f NH ₀ 2 ν COOH wherein Y has the above meaning with an isocyanate of the following formula R-NCO, in which R has the above meaning, or (2) a compound of the following general formula: COOH wherein R has the above meaning, Y ^x the acetoxy or 3-oxobutyryloxy group and both R and Ii R are hydrogen atoms and / or the amino group protective groups mean having a nitrogenous 2-containing _} heterocyclic thiol of the formula HY, ρ where Y is a substituted or unsubstituted, nitrogen-containing, heterocyclic thio group, namely tetrazolylthio, thiadiazolylthio or triasolylthio, means, brings to implementation and then, if necessary, the amino group protecting Groups removed. 909S37 / 06S3