CH640241A5 - CEPHALOSPORINE COMPOUNDS, METHOD FOR PRODUCING THE SAME AND THERAPEUTICAL PREPARATIONS CONTAINING SUCH ACTIVE SUBSTANCES. - Google Patents

Description

The present invention relates to new anti-

15 crobial compounds, which are valuable as therapeutic agents for the treatment of diseases, in particular infectious diseases, which are caused by gram-negative bacteria in humans and animals.

In particular, the present invention relates to 20 new a-ureido-cephalosporin antibiotics which have a 2- (2-aminothiazol-4-yl) acetamido group in the 7-position.

Thus, the present invention relates to cephalo-sporin compounds of the following general formula:

CH-CONH'NH CO NHR

(I)

0

^ N.

• CH2Y

COOH

wherein R represents the hydrogen atom or a lower alkyl radical and Y represents an acyloxy, carbamoyloxy or -S-Het group, wherein Het represents a substituted or unsubstituted tetrazolyl, thiadiazolyl or triazolyl group.

Certain semisynthetic cephalosporin compounds with a broad antimicrobial spectrum are commercially available. They have also been clinically tested as therapeutic agents for the treatment of infectious diseases. It has been shown, however, that a certain number of pathogenic microorganisms are resistant to the known antibiotics.

For example, pathogens such as certain strains of Escherichia coli and Citrobacter, the majority of the indole-positive strains of the genus Proteus and some bacteria of the genera Enterobacterium, Serratia and Pseudomonas are resistant to known cephalosporin drugs [see W.E. Wiek: Cephalosporins and Penicillins, Chemistry and Biology, E.H. Flynn (Ed.), Academic Press, New York, N.Y. 1972, Ch. 11]. This resulted in the need to research further cephalosporin compounds with a sufficiently high antimicrobial effect that they can be used against such pathogenic microorganisms.

Research in this area has now resulted in the synthesis of compounds of the general formula I above, it being found that these compounds have the desired high antibiotic activity against a large number of Gram-negative bacteria, including those bacteria to which the known cephalosporin compounds are resistant. exercise. The compounds of formula I according to the invention are extremely effective against a broad spectrum of gram-negative bacteria, such as e.g.

Escherichia coli, Krebsiella pneumoniae, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Proteus rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marscecens, etc. are therefore valuable for the treatment and prophylaxis of various diseases in humans and animals including poultry which such bacteria cause damage.

In general formula I above, the lower alkyl group R is preferably a straight or branched alkyl group having up to 3 carbon atoms, e.g.

Methyl, ethyl, n-propyl or isopropyl. The methyl radical is particularly preferred. The acyloxy group Y is preferably an alkylcarbonyloxy group having 2 to 4 carbon atoms, e.g. the acetoxy, propionyloxy group, etc., an acetoxy group substituted by an alkylcarbonyl group having 2 to 4 carbon atoms, e.g. the 3-oxybutyryloxy, propionylacetyloxy group, etc., a phenylacetyloxy group which may be substituted by a hydroxyl group, by a sulfo group, by an amino group or by another substituent such as e.g. Mande-loxy, a-sulfophenylacetyloxy, glycyloxy, phenylacetyloxy, etc., a-substituted, an alkylcarbonyloxy group having 2 to 4 carbon atoms as a substituent containing a carboxyl group, e.g. the succinoyloxy group, etc., or a group of the general formula:

R fi

R6

45

50

55

60

640 241

wherein R5 and R6 are hydrogen, carboxyl, carbäthoxycarbamoyl, carbäthoxysulfamoyl or nitro or 2-car-boxybenzoyloxy, 2- (carbäthoxycarbamoyl) -benzoyloxy, 2- (2-carbäthoxysu! famoyl) -benzoyloxy, 2-carboxy-3- or -4- or -6-nitrobenzoyloxy, 2,4-dicarboxybenzoyloxy, etc. mean. As acyloxy groups, alkylcarbonyloxy groups with 2 to 4 carbon atoms, e.g. the acetoxy, propionyloxy, 3-oxobutyryloxy group, etc., is preferred, with preference given to the acetoxy and 3-oxobutyryloxy group among these groups. The nitrogen-containing, heterocyclic group Het is a tetrazolyl, thiadiazolyl or triazolyl group and in particular IH-tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 4-thiadiazolyl, 1H-1, 2,3-triazolyl, 2H-1, 2,3-triazolyl or 1H-1,2,4-triazolyl. Among these nitrogenous heterocyclic groups are 1H-tetrazol-5-yl, 1,2,4-thia-diazol-5-yl, 1, 3,4-thiadiazol-5-yl and 1H-1, 3,4 -Triazol-5-yl preferred. These nitrogen-containing heterocyclic groups can optionally be substituted. Examples of substituents include monovalent groups such as Alkyl groups with 1 to 4 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.), trifluoromethyl, alkoxy groups with 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), halogens (chlorine, bromine, etc .), Hydroxyl, Mer-capto, Amino, Carboxyl, Carbamoyl etc. as well as various substituent groups, which by mediation of a polyvalent group such as lower alkylene groups with 1 to

I.

3 carbon atoms, -S-, -N-, etc., adhere. If this polyvalent group represents a lower alkylene group, the substituent group adhering through its mediation can be, for example, hydroxyl, mercapto, amino, guanyl, morpholino, carboxyl, sulfo, carbamoyl, alkoxycarbonyl having 2 to 5 carbon atoms, alkylcarbamoyl having 2 to 5 carbon atoms, alkoxy with 1 to 4 carbon atoms, aikylthio with I to 4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms, acyloxy with 1 to 4 carbon atoms, morpholinocarbonyl, etc. If these more

I.

is a valuable group -S- or -N-, its substituent group can be, for example, a lower alkyl group or one of said lower alkylene groups which have one of said substituent groups. If the!

represents a polyvalent group -N-, such a substituent, such 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 the specific case, substituted alkyl groups, e.g. Carboxymethyl, carbamoylmethyl, N-lower alkyl-carbamoylmethyl (e.g. N, N-dimethylcarbamoylmethyl), hydroxy-lower alkyl (e.g. hydroxymethyl, 2-hydroxy-ethyl), acyloxy-lower alkyl (e.g. acetoxymethyl, 2-acetoxy-ethyl), alkoxycarbonylmethyl (e.g. methoxycarbonyl -methyl, hexyloxycarbonylmethyl, octyloxycarbonyl-

methyl), methylthiomethyl, methylsulfonylmethyl, N-lower alkylamino-lower alkyl (e.g. N, N-dimethylamino-methyl, N, N-dimethylaminoethyl, N, N, N-trimethylammoniumethyl), morpholinomethyl, guanylmethyl, guanyl-5 ethyl, etc. ; substituted amino groups, such as lower alkylamino (for example methylamino), sulfo-lower alkylamino (for example 2-sulfoethylamino), hydroxy-lower alkylamino (for example hydroxyethylamino), lower alkylamino-lower alkylamino (for example 2-dimethylaminoethylamino, 2-trimethylammonium-10 ethylamino), acylamino (acylamino) , 2-dimethylaminoacetylamino, 2-trimethylammoniumacetylamino, lower alkoxycarbonylamino (e.g. methoxycarbonylamino), etc .; and substituted thio such as methylthio, 2-hydroxyethylthio, 2-Acyloxyäthylthio (eg, 2-acetoxy-is ethylthio, 2-Phenylacetoxyäthylthio, 2-Caproyloxyäthylthio, carboxymethylthio, alkoxycarbonylmethylthio (eg metho-xycarbonylmethylthio, hexyloxycarbonylmethylthio), Car-bamoylmethylthio, N-Niederalkylcarbamoylmethylthio (e.g. N, N-dimethylcarbamoylmethylthio), acetylmethylthio, 20 N-lower alkylamino-lower alkylthio (e.g. 2-N, N-dimethylaminoethylthio, 2-N, N, N -trimethylammoniumethylthio), morpholiocarboylmethylthio, 2-sulfoethylthio, etc.

call.

The substituted or unsubstituted groups represented by Het can preferably be represented by one of the following formulas:

n-

30th

N

ir n

N

Number 1

-R

1

N-

-R

.N

and

40

In the above formulas, R1 represents hydrogen, an alkyl group with 1 to 3 carbon atoms, e.g. Methyl, 45 hydroxy substituted alkyl groups of 1 to 3 carbon atoms e.g. 2-hydroxyethyl, carboxy-substituted alkyl groups with 1 to 3 carbon atoms, e.g. Carboxymethyl, or di-lower alkyl substituted aminoalkyl groups having 1 to 3 carbon atoms, e.g. 2-dimethylaminoethyl. so The substituent group R2 is an alkyl group with 1 to 3 carbon atoms, e.g. Methyl, or a hydroxy substituted alkyl group of 1 to 3 carbon atoms, e.g. Hydroxymethyl.

Among the compounds of the general formula I ss above, the preferred compounds are the 7- [2- (2-aminothia-zol-4-yl) -2- (R-aminocarbonylamino) acetamido] cephalo-sporin compounds of the following formula:

H2N-

n-

-CH-CONH

r

NH I

CO 1

NHR

COOH

(I1)

640 241 6

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:

n-

s

■ n Ii n

n "

N

'7

r. '

-R '

n-

■ r7

n *

n

'n ji r8

and

N R7

mean, where R7 is hydrogen, methyl, 2-hydroxyethyl, carboxymethyl or 2-dimethylaminoethyl and R8 is hydrogen or methyl.

For use as a therapeutic agent for controlling infectious diseases, the compounds of the formula I according to the invention are used in free form or in the zwitterion form or as pharmacologically permissible, non-toxic salts. These salts also come under the present invention. As examples of such non-toxic salts of compounds of formula I there can be given salts with alkali metals such as sodium, potassium etc. or alkaline earth metals such as calcium, magnesium etc., salts with inorganic bases e.g. Ammonium salts, salts with organic bases, e.g. with trimethylamine, triethylamine, pyridine, 25 N-methylglucamine, diethanolamine and triethanolamine,

Salts with organic acids, e.g. Acetic acid, tartaric acid and methanesulfonic acid, salts with inorganic acids, e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and salts with amino acids such as e.g. 30th

Arginine, aspartic acid or glutamic acid.

The compounds of formula I according to the invention can be used as therapeutic medicaments for the treatment of infectious diseases in the same way as the usual cephalosporin medicaments, e.g. in powder form or 35 in the form of a solution or suspension in a physiologically acceptable pharmaceutical 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 of various diseases 4n in humans which are caused by the bacteria mentioned above, such as e.g. pustular diseases, infections of the respiratory system, infections of the bile duct, intestinal infections, infections of the urinary tract and gynecological-obstetric infections. * »S

The compounds reproduced below, which represent a selection of the compounds of the formula I according to the invention, are, for example, successfully either intramuscularly or intravenously in daily dosage amounts of approximately 10 to 100 mg per kg of body weight in adults, either as a single dose or divided into two to four Doses administered daily. If the compounds of the formula I according to the invention are injected, the carrier can be, for example, distilled water or physiological saline. If the compounds of the formula I according to the invention are used in the form of capsules, powders, granules or tablets, these active substances of the formula I are mixed, for example, with pharmacologically acceptable, known pharmaceutical carriers, such as e.g. 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, e.g. Carboxymethyl calcium, talc, etc., for use.

The following compounds are to be preferably administered, namely the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3-acetoxymethyl-3-cephem-4- carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3- (1-methyl-1-H-tetrazol-5-yl) thio -methyl-3-cephem-4-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -

3- [l - (2-hydroxyethyl) -1 H-tetrazol-5-yl] thiomethyl-3-cephem-

4-carboxylic acid, the disodium salt of 7- [2- (2-ami-nothiazole-

4-yl) -2- (aminocarbonylamino) acetamido] -3- (l-carboxymethyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, the 7- [2- (2-aminothiazole -4-yl) -2- (aminocarbonylamino) acetamido] -3- (1,2-dimethylaminoethyl) -1 H-tetrazole-

5-yl) -thiomethyl-3-cephem-4-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3 - (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, 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-4-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbo-nylamino) - acetamido] -3- (3-methyl-l, 2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) -acet-amido] -3 - (4-methy 1-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid, the sodium salt of 7- [2 - (2-aminothiazol-4-yI) -2- (aminocarbonylamino) acetamido] -3 - (3,4-dimethyl-

1,2,4-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido ] -3- (3-hydroxymethyl-4-methyl-l, 2,4-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and the disodium salt of 7- [2- (2-aminothiazol-4 -yl) -2- (aminocar-bonylamino) acetamido] -3- (2-carboxymethyl-l, 3,4-thia-diazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid.

The compounds of formula I are new. They are made by using a compound of the formula:

h2N-

n-

• ch-conh f

nh "

(II)

—Ch2y cooh

7

640 241

in which Y has the above meaning, with an isocyanate of the formula R-NCO, in which R has the above meaning, (process 1).

The compounds of the formula II used as starting materials can be obtained by the process described in German Offenlegungsschrift No. 2,556,736 or by an analogous process. When carrying out this reaction, the resulting compounds of formula II can be obtained in free form or in the form of a salt, e.g. the sodium or calcium salt, the hydrochloride, the hydrobromide, the formate, the acetate, the trifluoroacetate, the triethylamine salt or dibutylamine salt, or in the form of an ester, for example the benzhydryl, trichloroethyl and p-nitrobenzyl ester. If R represents a lower alkyl group, the isocyanate will be used in the free form. On the other hand, if R represents the hydrogen atom, an alkali metal cyanate, e.g. Potassium cyanate.

The reaction is usually carried out by merely mixing a compound of formula II with a compound of 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 obtained if tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, acetone or the like are added to the reaction system. The reaction takes place at a temperature between -20 ° C and + 80 ° C and is usually complete after about 3 hours. The compounds of formula I thus obtained can be prepared by processes known per se, e.g. isolate and purify by solution extraction, by adjusting the pH, by phase transfer, by recrystallization, by chromatography, etc.

The compounds of the formula I according to the invention are also obtained by

r3nh

(iv)

10th

s3mi

Ysi

In l-

-CHCOOH

l

NH2

-ch-cooh!

nh 1

CO i n-r u

R

in which R has the meaning given above and R3 or R4 denote hydrogen or a group protecting the amino group, with a compound of the formula:

20th

h2n-

0

-N

■ ch2y

(V)

COOH

in which Y has the meaning given above, and removes existing groups protecting the amino group (s) thereon (method 2).

The compounds of the formula IV used in this case as starting materials are likewise new compounds and can be obtained from the amino acid derivatives of the formula IX, which has been described in West German Offenlegungsschrift No. 2,556,736. In this way of working, the amino group will be converted into an ureido group,

(IX)

RNCO or rSco

R ^ HN \ ^ S-

, 3rd

n-

-CH-COOH i

NH I

CO i n-R i

H

N ll

or

-CH-COOH 1

NH i

CO l

NH; «

where all symbols have the meanings mentioned above.

In the above formulas, R3 and R4 represent the hydrogen atom or a group protecting the amino group. Any amino group protecting group that is commonly used in peptide chemistry, such as e.g. the formyl, chloroacetyl, triés fluoroacetyl, trityl, diphenylphosphinothioyl, tert-butyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trimethylsilyl groups.

The compounds of the formula IV can be reacted in free form or in the form of a salt or a reactive derivative with respect to the carboxyl function. As examples of such reactive derivatives

640241

8th

can be called the acid halides, acid anhydrides, reactive amides, reactive esters, etc. In this context, especially 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, i.e. Name [(CH -): N '= CH -] - ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimidoyl ester, etc., the most suitable of these derivatives being used. As examples of salts of an acid of formula IV there can be given 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, trifluoroacetates and formates. The compounds of the formula V are reacted in the free form or in the form of a salt or an ester thereof. As examples of salts of compounds of formula V there can be given, for example, salts with organic acids, e.g. Acetates, benzenesulfonates, tartrates, trifluoroacetates 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. An ester of compounds of the formula V which corresponds to the above-mentioned esters of a compound of the formula II can be used.

This reaction is usually carried out by mixing said compounds of the formulas IV and V in a solvent at about -40 ° C to + 20 ° C. Examples of solvents which can be mentioned are water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide or pyridine. Hydrophilic solvents can be used in combination with water.

If the compounds of 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 are, for example, N, N'-dicyclohexylcarbodiimide, alkoxyacetylene, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, tetramethylurea-phosgene complex, dimethylformamide-phosphorus oxychloride complex, etc.

This reaction can be carried out in the presence of a base. Examples of bases include, for example, organic or inorganic bases, e.g. Alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, trialkylamine, N, N-dialkylanilines, N, N-dialkylbenzylamines, pyridine, N-alkylmorpholines, etc.

If necessary, the compounds obtained after the above reaction are further reacted to remove the protecting groups. For this purpose, the measures customary in peptide chemistry can be used. If the protecting group is the formyl group, this group will be removed in this case, for example, using a mixture of hydrochloric acid and methanol, a mixture of phosphorus oxychloride and methanol or a mixture of sulfuric acid and methanol.

If it is the chloroacetyl residue, you can use thio-urea. If the protective group is the trifluoroacetyl group, it can be removed using an aqueous alkali solution. The trityl, diphenylphosphi-nothioyl and tert-butyloxycarbonyl groups can be removed with hydrochloric acid or trifluoroacetic acid. In the case of a trichloroethoxycarbonyl, benzyloxycarbonyl and p-nitrobenzyloxycarbonyl group, the removal can be carried out by reduction.

The compounds of the formula I thus obtained can be isolated and purified in a manner known per se, as has been described in connection with process 5.

The compounds of the formula:

10th

• 9

H — C CM-

is

NH!

CO NHR

Ö

N JLCH0Y2

2nd

COOH

(VIII)

where Y2 represents the -S-Het group are also prepared by using a compound of the formula:

P-HiK ^ S

"il

N

25th

30th

CH-CCNH-NH

0

CO

Î

NO ;"

COOH

-N

CHpY

(VI}

wherein R, R3 and R4 have the above meanings and Y1 represents the acetoxy or 3-oxobutyryloxy group, with a thiol of the formula:

HS-Het

(VII)

in which Het has the meaning given above, and then removes existing groups protecting the amino group (process 3).

If in this implementation the 3-position of the cephem ring, i.e. the substituted position, considered,

it can in principle be compared to a nucleophilic substitution reaction of the 3-acyloxy group, as is known from the prior art and from the patent literature [e.g. C.F. Murphy & J. A. Webber: Cephalosporins and Penicillins: Chemistry and Biology, E.H. Flynn (Ed.), Academic Press, New York, N.Y., 1972, Ch. 4; British patents so No. 982 252, 1,012,943.1,028,563 and 1,030,630]. This reaction can thus be carried out by one of these known methods or by an analogous method.

For example, the reaction can be carried out by vermi-55 a compound of formula VI or a salt thereof with a compound of formula VII or with a reactive derivative thereof with respect to the thiol function with a solvent either at room temperature or at elevated temperature.

60 As salts of compounds of the formula VI, the alkali metal or alkaline earth metal salts are generally used among the various salts of compounds of the formula I mentioned above. As examples of reactive derivatives with respect to the thiol function of Verbin-6s fertilizer of formula VI, for example the alkali metal salts, e.g. the sodium and potassium salts. Examples of solvents which can be used are water, acetone, chloroform, nitrobenzene, dichloromethane, dimethylform

9

640 241

Use amide, methanol, ethanol, tetrahydrofuran or dimethyl sulfoxide or a suitable mixture thereof. If the compounds of the formulas VI and VII are used in the free form, better results are achieved in some cases if the reaction is carried out in a 5th

weakly 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 bicarbonate, e.g. Sodium hy- drogen carbonate or potassium hydrogen carbonate. The reaction is carried out 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 100.degree. The compounds thus obtained are then treated, if necessary, in such a way that the protective groups can be removed. The methods used to achieve this purpose are similar to those described above in connection with method 2. The compounds of formula VIII thus obtained 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 the formula IV can be present both in the D form and in the L form or in the form of a mixture of the D and L forms. If it is a mixture of the D and L forms, such a mixture can be optically split in a manner known per se at a suitable time in the process.

The compounds of formula I according to the invention can be attributed to two tautomeric structures, namely the thiazole form and the thiazoline form, as can be seen from the two formulas below.

Ii2ivs "n

N 11

-CH-CG — Z i

NH l

CO!

NHR

where Z is the group

-NH-

0 '

S

CN

_ / Sx

• »yw

COOH

■ CH-CO-Z!

NH

I.

CO NHR

means and the other symbols have the corresponding meanings defined above.

Although the present invention encompasses all such tautomeric forms, the compounds are each designated in thiazole form 4 (1) below for convenience.

The invention will be explained in more detail below with the aid of working examples. The nuclear magnetic resonance spectra given in these examples are determined with a Varian XL-100 (100 MHz), EM-390 (90 MHz) or 45 T-60 (60 MHz) photo spectrometer with tetramethylsilane as the internal standard, the chemical shifts in S ( ppm) are expressed.

The following tables show the minimum inhibitory concentration values (MIC) and the therapeutic activity data (ED 50) of the various particularly noteworthy cephalosporin derivatives obtained according to the examples with respect to different bacteria, and similar data of commercially available cephalosporins which can be found in daily clinical use , ie Cephalothin, i.e. the sodium salt of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid, cephaloridine, i.e. the sodium salt of 7- (2-thienylacetamido) -3- (l-pyridyl) methyI-3-cephem-4-carboxyl-betaine, cefazolin, i.e. the sodium salt of 7- (1 H-tetrazol-1-yl) acetamido-3- (2-methyl-l, 3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and cefoxitin, ie the sodium salt of 7a-methoxy-7ß- (2-thie-nylacetamido) -3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid. [Compare New England Journal of Medicine, 294.24 (1976) and Journal of Pharmaceutical Science, 64.1899 (1975)].

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

Method: Agar serial dilution Medium: TSA

Table I

Test connection

E. coli

E. coli

E. coli

K. pneumoniae

K. pneumoniae

S. marceseens

S. marcescens

P. vulgaris;

P. vulgaris

P. mirabilis

NIHJJC-2

O-Ill

T-7

DT

GN 3835

IFO 12 648

TN-24

IFO 3988

GN 4413

GN 435lJ

Cephalotin

12.5

3.13

100

1.56

12.5

> 100

> 100

1.56

> 100

3.13

Cephaloridine

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

6.25

6.25

12.5

3.13

Example 3

0.1

0.024

0.78

0.05

0.2

1.56

3.13

0.2

6.25

0.1

Example 4

0.1

-10.012

1.56

0.05

0.2

0.78

0.39

0.1

1.56

0.1

Example 5

0.05

-'0.012

0.39

0.05

0.1

0.39

0.39

0.1

6.25

0.1

Example 6-1

0.024

- £ 0.012

0.39

0.024

0.05

0.78

0.39

0.05

3.13

0.1

Example 6-2

0.024

é = 0.012

0.2

- £ 0.012

0.024

0.2

0.2

0.024

1.56

0.024

Example 6-3

0.05

^ 0.012

3.13

0.05

0.2

1.56

0.78

0.024

25th

0.024

Example 6-4

0.024

- £ 0.012

1.56

0.024

0.1

1.56

0.2

0.05

3.13

0.5

Example 6-6

- £ 0.05

- £ 0.05

0.39

^ £ 0.05

- £ 0.05

0.2

0.78

0.1

0.78

£ 0.05

Example 6-7

0.024

- £ 0.012

0.39

0.024

0.05

0.39

0.2

0.05

1.56

0.05

Table II

Test compound P, morganii P, rettgeri P. rettgeri E. cloacae C. freundii C. freundii

IF03168 TN 338 GN4733 TM 1282 GN99 GN 1706

Cephalotin

> 100

1.56

> 100

> 100

25th

> 100

Cephaloridine

> 100

1.56

> 100

> 100

50

> 100

Cefazolin

100

0.39

100

> 100

12.5

> 100

Cefoxitin

12.5

0.78

25th

> 100

100

> 100

Example 3

0.39

- £ 0.012

0.05

0.25

0.39

0.39

Example 4

0.1

- £ 0.012

0.2

0.2

0.1

0.2

Example 5

0.05

- £ 0.012

0.05

0.39

0.1

0.2

Example 6-1

0.1

- £ 0.012

0.2

0.78

0.2

0.2

Example 6-2

0.024

- £ 0.015

0.05

0.78

0.1

0.2

Example 6-3

0.024

- £ 0.012

0.024

0.78

0.39

0.78

Example 6-4

0.1

- £ 0.012

0.1

0.78

0.1

0.2

Example 6-6

^ 0.05

- £ 0.05

- £ 0.05

1.56

- £ 0.05

- £ 0.05

Example 6-7

0.05

- £ 0.012

0.05

0.39

0.1

0.2

Il

640 241

(b) Therapeutic effects in infected mice (Table HI)

Test Animals: Male Mice, ICR / SLC A group of 5 animals was used for each drug.

Carrying out the infection: Intraperitoneal Infectious Bacteria: 103CFU 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 dissolved in 100 ml of sterile saline and then 0.2 ml of this solution was administered subcutaneously as a single dose immediately after infection. Twice dilutions of each solution were administered to 5 groups of 5 mice each. CFU = colony forming unit (referred to as "colony forming unit").

Table III

Test connection

Way of

EDso, mg / kg

administration

Example 6-6

S.C.

4th

Cefoxitin

S.C.

13.1

Reference Example 1

Preparation of 7- [DL- {2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido}] - 3-methyl-3-cephem-4-carboxylic acid.

1) 2.4 g of the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-methyl-3-cephem-4- are dissolved in 50 ml of 90% formic acid. carboxylic acid (syn isomer) (West German OS 2 727 753), whereupon 3.9 g of zinc dust are added while the solution is cooled 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) gly-cylamido}] - 3-methyl-3-cephem-4-carboxylic acid formate are obtained.

2) In 1 ml of water, 0.4 g of the 7- [DL- {2- (2-aminothiazol-4-yl) glycylamido}] - 3-methyl-3-cephem-4-carboxylic acid formate obtained is dissolved and 0.3 g of potassium cyanate, whereupon this solution is stirred for 2 hours at room temperature. Then the reaction mixture is adjusted to a pH of 2.5 using in hydrochloric acid, the insoluble constituents are filtered off and the filtrate is chromatographed over a polystyrene resin column (Amberlite® XAD-2, Rohm and Haas Co.). The column is washed thoroughly with water and then eluted with 30% ethanol. The fractions rich in the desired product are collected and lyophilized to obtain 0.08 g of the above-mentioned compound.

IR (KBr, cm-1): 3400, 1755, 1660, 1600, 1510, 1360 NMR (90 MHz, de-DMSO, 5):

2.10 (s, CHs), 3.16 &3.46; 3.23 & 3.50 (each ABq, J = 18Hz, 2-H2), 4.93; 4.97 (each d, J = 5Hz, 6-H), 5.22 (d, J = 8Hz,> CHNH), 5.44; 5.55 (each dd, J = 5 & 8Hz, 7-H), 5.68 (br.s, CONH2), 6.31; 6.35 (each s, thiazole 5-H), 6.45; 6.49 (each d, J = 8Hz,> CHNHCO), 6.84 (br. S, thiazole NH2), 8.65; 8.75 (each d, J = 8Hz, 7-CONH).

Elemental analysis for Ci4HióN605S2- 1.75 H2O:

Calculated: C 37.87; H 4.43; N, 18.93. Found: C, 37.92; H 4.22; N 19.07

example 1

Preparation of the sodium salt of 7- [DL- {2- (2-aminothia-zol-4-yl) -2- (aminocarbonylamino) -acetamido}] - 3-acet-oxymethyl-3-cephem-4-carboxylic acid.

1) 0.96 g of 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem is dissolved in a mixture of 4 ml of formic acid, 0.5 ml of water and 4 ml of methanol -4-carboxylic acid • HCl (syn isomer) (West German OS

2 727 753), followed by stirring and cooling with ice

Gradually add 3 g of zinc dust over an hour at an internal temperature of 0 to 10 ° C.

After the dropwise addition is complete, the mixture is stirred in the same temperature range for a further hour. Then the insoluble constituents are filtered off and washed with a little methanol and formic acid. The filtrate and the wash water are combined and concentrated. The residue is dissolved by adding 10 ml of 1N hydrochloric acid and the solution is chromatographed over a column (3 × 30 cm) of polystyrene resin (Amberlite® XAD-2, Rohm and Haas Co.) (3 × 30 cm), using water and Use 20% ethanol.

The fractions rich in the desired product are collected, concentrated and lyophilized. In this way, 0.538 g of 7- [DL- {2- (2-aminothiazol-4-yI) -glycyl-amido}] - 3-acetoxymethyl-3-cephem-4-carboxylic acid are obtained (yield = 59.2%) .

IR (KBr, cm-1): 3400.1760, 1680, 1610, 1520, 1390, 1350,

1240.

NMR (100 MHz, D2.5):

2.13 (s, OAc), 3.31 &3.64; 3.38 & 3.70 (ABq, J = 18Hz, 2-H :), 4.71 & 4.92 (ABq, J = 13Hz, 3-CH2), 5.12; 5.18 (each d, J = 5Hz, 6-H), 5.20 (s, CHNH2), 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 CisHnNsOóS • 1.5 H2O:

Calc .: C 39.64; H 4.44; N, 15.41. Found: C, 39.86; H 4.47; N 15.74

2) A mixture of 2 g of 7- [DL- {2- (2-aminothiazol-4-yl) glycylamido) -] - 3-acetoxymethyl-3-cephem-4-carboxylic acid and 1.5 g of potassium cyanate is vigorously Stir quickly with 30 ml of water heated to 75 ° C. 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 sodium 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 gel column (Sephadex® LH-20, Pharmacia Fine Chemicals) using water as the eluent. The desired fractions are collected, concentrated and lyophilized to give the compound identified above. This product obtained in an amount of 0.937 g represents a mixture of equal parts of the two diastereoisomeric compounds. (Yield = 39.6%).

5

10th

15

'20

25th

30th

35

40

45

50

55

60

65

640241

12

IR (KBr, cm '}: 3400, 1760, 1660, 1610, 1520, 1385, 1240. NMR (100 MHz, D: 0.8):

2.16 (s, OAc), 3.32 &3.65; 3.39 & 3.69 (each ABq, J = 18Hz, 2-H :). 4.73 & 4.94 (ABq, J = 13Hz, 3-CH2), 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);

NMR (100 MHz. D.-DMSO, 5):

2.02 (s, OAc), 3.15 &3.44; 3.20 & 3.50 (each ABq, J = 18Hz, 2-H :). 4.82 & 5.04 (ABq, J-13Hz, 3-CH :), 4.92; 4.96 (each d, J = 5Hz, 6-H), 5.24; 5.28 (each d, J = 8Hz,> CHNH-), 5.46; 5.56 {each dd, J = 5 & 8Hz, 7-H), 5.80 (br.s, -CONH :), 6.37; 6.40 (each s, thiazole 5-H), 6.64; 6.72 (each d, J = 8Hz,> CHNHCO-), 6.92; 6.94 (each br.s, thiazole NH :), 8.68; 8.76 (each d, J = 8Hz, 7-CONH-).

Ninhydrin: negative

Elemental analysis for CiaHnNóO ^ Na • 2.5 H2O:

Calc .: C 35.75; H 4.13; 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-aminothia-zol-4-yl) -2- (aminocarbonylamino) -acetamido}] - 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.

The procedure is as in Example 1, but using the sodium salt of 7- [2- (2-aminothiazol-4-yl) -

2-hydroxyiminoacetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.

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

IR (KBr, cm- '): 3350.1760, 1660, 1605, 1520, 1400, 1330. NMR (90 MHz, D: 0.8):

3.29 &3.61; 3.25 & 3.65 (each ABq, J = 18Hz, 2-H :) 4.66 & 4.90 (ABq, J = 13 Hz, 3-CH :), 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- (2- (2-aminothia-zol-4-yl) -2- (methylaminocarbonylamino) -acetamido} -] - 3-acetoxymethyl-3-cephem-4-carboxylic acid.

0.454 g of 7- [DL- {2- (2-aminothiazol-4-yl) glycylamido}] - 3-acetoxymethyl-3-cephem-4-carboxylic acid are suspended in 10 ml of acetonitrile and then this suspension is mixed 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 freed of gas and rapidly through a chromatographic column (3 x 30 cm) made of polystyrene resin (Amberlite® XAD-2, Rohm and Haas Co.) using water as Eluent flowed. The desired fractions are concentrated and lyophilized, whereby 0.166 g of the above-mentioned compound is obtained in a yield of 29.6%.

IR (KBr, cm-1): 3300, 1760, 1660, 1610, 1520, 1400, 1350,

1240.

NMR (90 MHz, D: 0.8):

2.11 (s, OAc), 2.7 Ks,> NCHj), 3.30 &3.64; 3.35 & 3.67 (ABq, J = 18Hz, 2-H :), 4.70 & 4.91 (ABq, J = 13Hz,

3-CH :), 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-H), 6.67; 6.70 (each s, thiazole 5-H).

NMR (90 MHz, do-DMSO, 8):

1.98 (s, OAc), 2.53 (d, J = 5Hz,> NCHa), 3.10 &3.40; 3.16 & 3.46 (ABq, J = 18Hz, 2-H :), 4.76 & 5.00 (ABq, J = 13 Hz, 3-CHz), 4.85; 4.90 (each d, J = 5Hz, 6-H), 5.22 (d, J = 8Hz,> CHNH-), 5.41; 5.50 (each dd, J = 5 ° C 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 :), 8.62; 8.72 (each d, J = 8Hz, 7-CONH-).

Elemental analysis for Ci? H «NaO ^ Na • 3H: 0

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

Example 4

Preparation of the sodium salt der7- [DL- {2- (2-aminothiazol-4-yl) -2- (methylaminocarbonylamino) acetamido) -] - 3- (1-methyl-1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid.

1) 1.07 g of the sodium salt of 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] - is dissolved in a mixture of 5 ml of formic acid, 0.5 ml of water and 5 ml of methanol.

3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-car-bonic acid, followed by 6.0 g of zinc dust over a period of about 30 minutes at an internal temperature with ice cooling and stirring gradually add from 0 to 10 ° C. When the dropwise addition has ended, the mixture is further stirred at the temperature just mentioned for 30 minutes, after which the insoluble constituents are filtered off and washed with a little methanol and formic acid. The filtrate and the wash water are collected and concentrated to give a glassy residue which contains the 7- [DL- {2- (2-aminothiazol-4-yl) glycylamido) -] - 3- (l-methyl -lH-tetrazol-5-yl) -thiomethyl-3-cephem-

Contains 4-carboxylic acid.

For thin-layer chromatography, a silica gel from Merck is used using a mixture of ethyl acetate, acetic acid and water in a mixing ratio of 4: 1: 1 as the developer solvent. Rf 0.15; positive ninhydrin reaction (yellow).

2) The total amount of the vitreous product thus obtained, i.e. the 7- [DL- {2- (2-aminothiazol-4-yl) glycylamido) -] - 3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid, as it is obtained according to paragraph 1) above, is mixed with 10 ml of acetonitrile and 5 ml of water with stirring. Then triethylamine is gradually added at room temperature to adjust the pH of the mixture to 7.5.

After the addition of 0.4 ml of methyl isocyanate, the mixture is stirred at the same temperature for 30 minutes and then concentrated. The residue is dissolved in 20 ml of water, 3 g of sodium hydrogen carbonate are added and, after removing the gas present, the solution is rapidly passed over a polystyrene resin column (Amberlite® XAD-2, Rohm and Haas Co.) using water and aqueous ethanol as eluent chromatographed. The desired fractions are collected, concentrated and chromatographed on a dextrangels column (Sephadex® LH-20, Pharmacia Fine Chemicals) using water as the eluent. The appropriate fractions are collected, concentrated and lyophilized to give 0.254 g of the compound mentioned above.

IR (KBr, cm-1): 3300, 1760, 1660, 1610, 1520, 1390, 1350. NMR (90 MHz, D: 0 8):

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

13

640 241

2.70 (s,> NCHb), 3.39 &3.74; 3.41 & 3.78 (each ABq, J = 18 Hz, 2-H :), 4.02 (s, tetrazole-CHa), 4.05 & 4.30 (ABq, J = 13 Hz, 3-CH2 ), 5.04; 5.08 (each d, J = 5Hz, 6-H), 5.30 (s,> CHNH), 5.56; 5.63 (each d, J = 5Hz, 7-H), 6.67; 6.70 (each s, thiazole 5-H).

Example 5

Preparation of 7- [DL- {2- (2-aminothiazol-4-yl) -2- (amino-carbonyl) -acetamido}] - 3- [l- (2-dimethylaminoethyl) -lH-tetrazol-5-yl ] thiomethyl-3-cephem-4-carboxylic acid.

0.985 g of the sodium salt of 7- [DL- {2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido}] - 3-acetoxymethyl is dissolved in 20 ml of phosphate buffer (pH 6.4) -3-cephem-4-carboxylic acid and 0.433 g of [1 - (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiol. The mixture is then stirred at 70 ° C. for 4 hours, whereupon the pH is adjusted to 3.3 by adding acetic acid. The insoluble constituents are filtered off and the filtrate is chromatographed on a polystyrene resin column (Amberlite® XAD-2, Rohm and Haas Co.), water and aqueous ethanol being used as the eluent. The corresponding fractions are concentrated and chromatographed on a dextran gel column (Sephadex® LH-20, Pharmacia Fine Chemicals), water being used as the eluent. The appropriate fractions are collected, concentrated 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. NMR (90 MHz, D20.5):

3.04 [s, -N (CH3) 2], 3.43 &3.76; 3.49 & 3.81 (each ABq, J = 18Hz, 2-H2), 3.83 (t, J = 5Hz, CH2CH2N <). 4.09 & 4.30 (ABq, J = 13Hz, 3-CHa), 4.92 (t, J = 5Hz, -CH2CH2N <), 5.04; 5.10 (each d, J = 5Hz, 6-H), 5.34 (s,> CHNH), 5.57; 5.64 (each d, J = 5Hz, 7-H), 5.77; 6.80 (each s, thiazole 5-H).

Example 6-1

Preparation of the sodium salt of 7- [DL- {2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido}] - 3- (2-methyl-1,3,4-thiadiazol-5 -yl) -thiomethyl-3-cephem-4-car-5 bonic acid.

In a mixture of 20 ml of phosphate buffer (pH 6.4) and 3 ml of tetrahydrofuran, 0.958 g of the sodium salt of 7- [DL- {2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido} is dissolved. ] -3-acetoxymethyl-3-cephem-4-carboxylic acid and 10 0.33 g (2-methyl-l, 3,4-thiadiazol-5-yl) thiol. After the solution has been adjusted to a pH of 6.4 by adding in sodium hydrogen carbonate, the mixture is heated on the water bath at 70 ° C. for 4 hours. The mixture is then concentrated to a volume of approximately 15 ml and then 2 g of sodium hydrogen carbonate are added. The mixture is stirred and, after removal of any gases, is chromatographed on a polystyrene resin column (Amberlite® XAD-2, Rohm and Haas Co.) using water and aqueous ethanol as the eluent-20. 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%.

25 IR (KBr, cm-1): 3300.1760, 1660, 1610, 1515, 1385 NMR (90 MHz, D20.8);

2.71 (s, CHs), 3.30 &3.70; 3.36 & 3.76 (each ABq, J = 18Hz, 2-H2), 3.96 &4.44; 3.96 & 4.48 (each ABq, J = 13Hz, 3-CH2), 5.01; 5.06 (each d, J = 5Hz, 6-H), 5.23; 5.26 (each, s,> CH NH), 30 5.56; 5.64 (each d, J = 5Hz, 7-H), 6.63; 6.66 (each s, thiazole 5-H).

Example 6-2 to Example 6- 7

In the same manner as in Example 6-1 above, the following compounds are obtained from the corresponding 35 thiols and from the sodium salt of

7- [DL - (2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido}] - 3-acetoxymethyl-3-cephem-4-carboxylic acid.

Table IV

hpn

YSÌ]

N Li_

chconh nh

C = 0

0

- * lj ~ ch2y COONa

example

IR (KBr, cm "')

NMR (90 MHz, D: 0.8)

Example 6-2

Example 6-3

n - n

.4J

n - n

CHoCOONa

3300.1760.1660.1605.1510.1360

3300.1760.1660.1600.1510.1360

3.33 &3.72; 3.40 & 3.77 (each ABq, J = 18Hz, 2-Hh), 4.04 &4.50; 4.03 & 4.53 (each ABq, J = 13Hz, 3-CH2), 5.03; 5.06 (each d, J = 5Hz, 6-H), 5.24; 5.26 (each s,> CH NH), 5.55; 5.64 (each d, J = 5Hz, 7-H), 6.66; 6.70 (each s, thiazole -5H, 9.40 (s, thiadiazole 5-H)

3.35 &3.74; 3.40 & 3.77 (each ABq, J = 18Hz, 2-Ha), 4.01 (s, CH2COO), 4.03 &4.40; 4.03 & 4.49 (each ABq, J = 13Hz, 3-CH2), 5.06; 5.11 (each d, J = 5Hz, 6-H), 5.25; 5.27 (each s,> CH NH), 5.56; 5.68 (each d, J = 5Hz, 7-H), 6.67; 6.70 (each s, thiazole 5-H)

Example 6-4

Example 6-5

n - n

■ sAsJ-

n - n

• sJUJL

CH,

ch2c0nh2

ch2oh

3300.1760.1665.1610.1510.1380

3300.1760.1660.1605.1510.1390

3.33 &3.70; 3.36 & 3.73 (each ABq, J = 18Hz, 2-H2), 4.02 &4.42; 4.02 & 4.46 (each ABq, J = 13 Hz, 3-CHz), 4.15 (s, CH2CO), 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 = 18Hz, 2-Hi), 3.64 &4.26; 3.64 & 4.28 (each ABq, J = 13Hz, 3-CH2), 3.70 (s, CHj), 4.79 (s, triazole 5-CH2), 5.02 & 5.06 (each d, J = 5Hz, 6-H), 5.24 & 5.26 (each s,> CHNH), 5.53; 5.56 (each d, J = 5Hz, 7-H), 6.67; 6.70 (each s, thiazole 5-H)

Example 6-6

Example 6-7

s-

n - n 1

CIL

n - n

CHpCHgOH

3300.1760.1660.1605.1510.1390, 3.36 &3.74; 3.42 & 3.78 (each ABq, J = 18Hz, 2-H2), 3.93 (s, CHa), 4.03 &4.29; 1360 4.03 & 4.31 (each ABq, J = 13Hz, 3-CHz), 5.05; 5.08 (each d, J = 5Hz, 6-H), 5.24;

5.26 (each s,> CHNH), 5.55; 5.66 (each d, J = 5Hz, 7-H), 6.67; 6.70 (each s, thiazole 5-H)

3300.1760.1665.1605.1510.1390, 3.36 &3.73; 3.41 & 3.77 (each ABq, J = 18Hz, 2-H2), 4.01 (t, J = 5Hz, CH2OH), 4.09 1360 &4.34; 4.09 & 4.36 (each ABq, J = 13Hz, 3-CHj), 4.53 (t, J = 5Hz, CH2CH2OH),

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; 6.70 (each s, thiazole 5-H)

Claims (4)

640 241 PATENT CLAIMS 1. Compounds of the following general formula: c00h (I) wherein R represents the hydrogen atom or a lower alkyl radical and Y represents an acyloxy, carbamoyloxy or -S-Het group, wherein Het represents a substituted or unsubstituted tetrazolyl, thiadiazolyl or triazolyl group, or pharmaceutically acceptable salts of these compounds. 2. Compounds according to claim 1, wherein R is the water n n " Matter atom means. 3rd 640241 h2n- _ / - s n- • ch-conh [ NH " / S CH2Y (H) cooh wherein Y has the above meaning, with an isocyanate of the 14th process for the preparation of compounds of the Formula R-NCO, in which R has the meaning given above, is implemented. Formula: h2N- n- - ch-conh nh> ^ n '0 co nhr ■ ch2y (I) cooh in which 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 tetrazolyl, thiadiazolyl or triazolyl group, characterized in that a compound of the formula : R3NH- N- (IV) - ch-cooh I nh I co I NO J « in which R has the meaning given above and R3 or R4 denote hydrogen or a group protecting the amino group, with a compound of the formula: 40 (v) cooh 45 where Y has the meaning given above, and removes existing groups protecting the amino group (s). 15. Process for the preparation of compounds of the formula: h2n- n- ■ ch-conh nh ^ -n <0 co t nhr • ch2y cooh (VIII) wherein R represents the hydrogen atom or a lower alkyl radical triazolyl group, characterized in that and Y2 represents the -S-Het group, in which Het is a compound of the formula: tuated or unsubstituted tetrazolyl, thiadiazolyl or 640241 3. Compounds according spoke 1, wherein the lower alkyl radical R is the methyl radical. 4. Compounds according to claim 1, wherein the acyloxy-20 group Y is the acetoxy group. 5. Compounds according to claim 1, wherein the symbol Het corresponds to one of the following formulas, namely in which R1 is the hydrogen atom, an alkyl radical having 1 to 3 carbon atoms, a hydroxyalkyl radical having 1 to 3 carbon atoms, a carboxy-substituted alkyl radical having 1 to 3 carbon atoms, an alkoxycarbonyl radical , whose alkyl radical has 1 to 3 carbon atoms, a di-lower alkylaminoalkyl radical, the latter alkyl radical having 1 to 3 carbon atoms, or a carbamoylalkyl group, whose alkyl radical has 1 to 3 carbon atoms, and R2 the hydrogen atom, an alkyl radical with 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 R1 is methyl, 2-hydroxyethyl, carboxymethyl or 2-dimethylaminoethyl and the substituent R2 is hydrogen, methyl or hydroxymethyl. 7. 7- [2- (2-aminothiazol-4-yl) -2- (methylaminocarbonylamino) acetamido] -3- (1-methyl-1 H-tetrazol-5-yl) thio-methyl-3 -cephem-4-carboxylic acid as a compound according to claim 5. 8. 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3- (2-methyl-l, 3,4-thiadiazol-5-yl) thiomethyl-3- 35 cephem-4-carboxylic acid as a compound according to claim 5. 9. 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3- (l, 3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid as a compound according to claim 5. 10. 7- [2- (2-aminothiazol-4-yl) -2- (aminocarbonylamino) - 40 acetamido] -3- (l-methyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid as a compound according to claim 5. 11. 7- [2- (2-Aminothiazol-4-yl) -2- (aminocarbonylamino) acetamido] -3- [l - (2-hydroxyethyl) -1 H-tetrazol-5-yl] thio-methyl -3-cephem-4-carboxylic acid as a compound 45 Claim 5. 12. Pharmaceutical preparations which contain a compound according to claim 1 together with at least one pharmaceutically acceptable pharmaceutical carrier or diluent. so 13. Process for the preparation of compounds of the formula: h2n- N- CH-CONH-t— ^ NH CO NHR 0 ^ N. COOH (I) wherein R represents the hydrogen atom or a lower alkyl radical tetrazolyl, thiadiazolyl or triazolyl group, and Y represents an acyloxy, carbamoyloxy or -S-Het group, characterized in that a compound of those in which Het represents a substituted or unsubstituted formula: 4th R ^ HN l1 N- - û ■ CH-CONH-rr NH CO î NO J-l 0 \ • CH ^ 1 (VI) COOH R wherein R has the above meaning, Y1 the acetoxy or 3-oxobutyryloxy group and both R3 and R4 are hydrogen atoms and / or the amino group protecting groups, with a thiol of the formula HS-Het, in which Het has the above meaning, to react and removes existing groups protecting the amino group (s).