CH645905A5 - CEPHALOSPORINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL COMPOSITIONS CONTAINING SUCH COMPOUNDS. - Google Patents

Description

This invention relates to new cephalosporin derivatives of the formula (I)

ch2ococh3

co oh

(I),

645 905

in which Ri, R2 and R3 each represent hydroxyl, acyloxy and hydrogen, with the measure that two or three of the Ri, r2 and R3 are not simultaneously hydrogen and in which R4 represents hydrogen or hydroxy. The compounds according to the invention also include the nontoxic salts of r,

ch-conh nh2

Compounds of formula (I). The invention also encompasses processes for the preparation of these compounds and antibacterial compositions comprising these compounds.

The compounds of formula (II)

ch2ococh3

(ii)

cooh in which R4 stands for hydrogen is known under the name cephaloglycin and is described, inter alia, in BE Patent No. 635 137 (1964). The compound of formula (II) with R4 = OH is also known; it is disclosed in, inter alia, GB Patent No. 1,240,687 (1971).

The purpose of this invention is to provide a new antibacterial agent which can be obtained by acylation of the amino groups of phenylglycine and p-hydroxyphenylglycine molecule parts of the above compounds.

Examples of the acyloxy groups mentioned in the compounds of the formula (I) are acetoxy, propionyloxy and benzoyloxy.

Examples of the non-toxic salts of the compounds of the present invention include sodium salts, potassium salts, calcium salts, ammonium salts, triethylamine salts, dicyclo-hexylamine salts, procaine salts, etc.

The compounds of the present invention are obtained by the following methods.

Compounds of the formula (I) can be obtained by reacting compounds of the formula (II) or their salts or hydrates with compounds of the general formula (III):

R,

r,

cooh

(iii).

The reaction between the compounds of formula (II) and those of formula (III) normally takes place in 20 inert solvents at temperatures between -50 and + 50 ° C, advantageously at temperatures between -20 and 30 ° C in the presence or absence of basic or acidic reagents.

Examples of the inert solvents mentioned are acetone, tetrahydrofuran, N, N-dimethylacetamide, dioxane, dichloromethane, chloroform, benzene, toluene and ethyl acetate and mixtures thereof.

Examples of the basic reagents mentioned include alkali hydroxide such as potassium hydroxide, sodium hydroxide, etc .; Alkali hydrogen carbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc. and amines such as triethylamine, pyridine, N-methylmorpholine.

Examples of the acidic compounds mentioned (silylating reagents) include N, 0-bis (trimethyl-35 silyl) acetamide or hexamethyldisilazane.

The chromoncarboxylic acid of formula (III) as a starting compound for the above reaction can be obtained by oxidizing the aldehyde of formula (IV):

CHO

(iv)

R.

In the above formula, Ri, r2 and R3 represent the same radicals as defined above.

If the carboxylic acid is used in the form of the formula (III), it is advantageous to carry out the reaction in the presence of a condensation reagent. Examples of such reagents are: N, N'-dicyclohexylcarbodiimide, N, N'-diethylcarbodiimide, N, N'-dipropylcarbodiimide, N-cyclo-hexyl-N '-morpholinoethylcarbodiimide, trialkylphosphite, ethyl polyphosphate, phosphoryl oxychloride, examples of oxylyl chloride, etc. The carboxylic acid of formula (III) include acid halides such as acid chloride, acid bromide etc., symmetrical anhydrides, mixed anhydrides derived from chlorocarbonate, trimethyl acetic acid, thioacetic acid, diphenylacetic acid etc., reactive esters derived from 2-mercaptopyridine , Cyanomethanol, p-nitrophenol, 2,4-dinitrophenol, pen-tachlorphenol etc., reactive acid amides such as N-acylsac-charine, N-acylphthalimide etc.

50

In formula (IV), Ri, r2 and R3 represent the same radicals and substituents as in claim 1, with the exception that they never represent hydroxy. The compounds of the formula (IV) are reacted with Jones reagent (see 55, Reagents for Organic Synthesis, Vol. 1, p. 142).

The chromoncarboxylic acid with Ri, r2 or R3 hydroxy can be obtained by oxidizing the aldehyde of the formula (IV) with corresponding acyloxy groups. The acyloxy groups are then hydrolyzed. 60 The acid halides of the compounds of formula (III) can be obtained by reacting the acid of formula (III) with halogenating compounds such as phosphorus pentachloride, thionyl chloride, etc.

The aldehydes of the formula (IV) can be obtained by conventional processes, as described, for example, in Tetrahedron 30, 3553 (1974).

The compounds of the formula (I) in which Ri, r2 and r3 each represent hydroxyl or hydrogen, with the measure

that two or three of the R 1, R 2 or R 3 are not simultaneously hydrogen can also be obtained by hydrolysis of the corresponding acyloxy radicals of the compounds of the formula (I) with R 1, R 2 and R 3 each acyloxy or hydrogen. Alkali hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc. are suitable for carrying out this hydrolysis.

Illustrative and specific compounds according to the invention are listed in the following list; According to the invention, the corresponding acids also include their sodium salts:

7ß [D-2- (6,7-diacetoxychromone-3-carboxamido) -2-phenyl-acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (6,7-diacetoxychromone-3-carboxamido) -2- (4-hydro-

xyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carbo-

xylic acid;

7ß [D-2- (6,7-dihydroxychromon-3-carboxamido) -2-phenyl-

acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (6,7-dihydroxychromon-3-carboxamido) -2- (4-

hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid;

7ß [D-2- (7,8-diacetoxychromon-3-carboxamido) -2-phenyl-

acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (7,8-diacetoxychromone-3-carboxamido) -2- (4-hydro-

xyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carbo-

xylic acid;

7ß [D-2- (7,8-dihydroxychromon-3-carboxamido) -2-phenyl-

acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (7,8-dihydroxychromon-3-carboxamido) -2- (4-

hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid;

7ß [D-2- (6,8-diacetoxychromone-3-carboxamido) -2-phenyl-

acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (6,8-diacetoxychromone-3-carboxamido) -2- (4-hydro-

xyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carbo-

xylic acid;

7ß [D-2- (6,8-dihydroxychromone-3-carboxamido) -2-phenyl-

acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

7ß [D-2- (6,8-dihydroxychromon-3-carboxamido) -2- (4-

hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid;

7ß [D-2- (6,7,8-triacetoxychromon-3-carboxamido) -2-

phenyl-acetamido] -3-acetoxymethyl-3-cephem-4-carboxyl-

acid;

7ß [D-2- (6,7,8-triacetoxychromon-3-carboxamido) -2- (4-

hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid

7ß [D-2- (6,7,8-triacetoxychromon-3-carboxamido) -2-

phenyl-acetamido] -3-acetoxymethyl-3-cephem-4-carboxyl-

acid;

7ß [D-2- (6,7,8-triacetoxychromon-3-carboxamido) -2- (4-

hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid.

The cephalosporin derivatives according to the invention show excellent antibacterial activities and are effective not only against Gram-positive bacteria, but also against Gram-negative bacteria. The cephalosporin derivatives mentioned are characterized in that they above all have a special effect against Pseudomonas aeruginosa, which cause infections which are difficult to cure.

In addition, it has been shown that the compounds according to the invention have deep toxicities. For example, the ld50 values (mice, administered orally) for the following compounds were more than 5 g / kg live weight:

645 905

Sodium salt of 7ß [D-2- (6,7-diacetoxychromone-3-carboxa-

mido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-

carboxylic acid;

Sodium salt of 7ß [D-2- (6,7-diacetoxychromone-3-carboxa-

mido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-

cephem-4-carboxylic acid;

Sodium salt of 7ß [D-2- (6,7-dihydroxychromone-3-carboxa-

mido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-

cephem-4-carboxylic acid.

The dosage of the compounds according to the invention in the antibacterial compositions can be in the range from 2 to 300 mg / kg live weight and day. The value is advantageously between 10 and 100 mg / kg and day. The compounds according to the invention can be administered orally or parenterally.

Pharmaceutical preparations containing the compounds according to the invention can be produced using known, conventional methods. They can contain the usual excipients.

Tablets or capsules for oral administration may be presented in unitary presentation form and may contain conventional excipients such as carriers, thinners, syrups, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone. The same tablets can contain thinners such as lactose, grain starch, calcium phosphate, sorbitol or glycine, or lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants, for example potato starch or pharmacologically acceptable humectants such as sodium lauryl sulfate.

The tablets can be coated with conventional agents according to known methods.

Liquid preparations for oral administration can be in the form of aqueous or oily emulsions, solutions, syrups, elixirs, etc.

In addition, dry products can also be made that must be dissolved in water or in any other suitable vehicle before ingestion.

The agents can also be produced as concentrates.

The liquid preparations can contain conventional additives; suspension aids such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel and hydrogenated, edible oils and fats; Emulsifying aids such as lecithin, mono-oleic acid, sorbitan and gum arabic; a non-aqueous vehicle such as almond kernel oil, fractionated coconut oil, oil ester, propylene glycol and ethanol, and antiseptics such as methyl p-hydroxybenzoate, propyl p-hydroxy xybenzoate and sorbitol acid.

The injection solutions can be provided in standard ampoules or in containers with added antiseptics. The compositions mentioned can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles. They can also contain formulation aids such as suspension aids, stabilizers and / or dispersion aids. On the other hand, the active components can be in the form of a powder which, prior to administration, is dissolved in suitable vehicles, for example in sterile, pyrogen-free water.

The injection preparations can additionally contain isotonic auxiliaries such as glucose, sodium chloride, sorbitol etc. and, if necessary, suspension auxiliaries, surface-active substances, pH control aids etc. Also for the preparation of injection solutions, the active ingredients can initially be present as powders, which can then be used in the

5

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

645905

suitable solvents before the injection.

For suppositories, the compounds according to the invention can be mixed with base agents such as cocoa butter, polyethylene glycol, Witepsol® (trademark of Dynamit-Nobel AG), etc. If necessary, the suppositories can also contain surface-active substances.

The following experiments and examples illustrate the invention; however, they should not be construed as a limitation thereof.

Experiment 1

Preparation of Chromon-3-carboxylic acid as a starting compound for the synthesis according to the invention.

A) 6,7-diacetoxychromone-3-carboxylic acid

17.8 g of 6,7-diacetoxychromone-3-carboxylaldehyde were dissolved in 1 liter of acetone. 32.8 ml of Jones reagent was added to the solution with stirring, which had previously been concentrated by dissolving 113.6 g of chromic acid in 115 ml. Sulfuric acid and

R,

by diluting with water to a volume of 500 ml.

The reaction solution was concentrated to 100 ml and poured into 900 ml of water. 6.5 g of solid precipitated out. After filtering off and recrystallization from ethyl acetate, 5.9 g of the title compound were finally obtained.

B) 6,7-dihydroxychromone-3-carboxylic acid

To 15.3 g of 6,7-diacetoxychromone-3-carboxylic acid, which had been obtained in io A), 300 ml of acetic acid and 100 ml of conc. Given hydrochloric acid. The reaction solution was stirred at about 70 ° C for 20 minutes and then cooled.

The precipitated solid was filtered off and recrystallized from 15 dimethylformamide water. 8.9 g of the title compound were obtained.

The 7,8-diacetoxy-chromon-3-carboxylic acid and the 7,8-dihydroxychromone-3-carboxylic acid were prepared in an analogous manner. The properties of the compounds thus obtained are summarized in Table 1.

r,

cooh

(iii)

No.

Ri

(ili) R2

r3

IR spectrum (cm-1, Nujol)

Molecular formula Melting point ° C

Elemental analysis: Calculated values (%) Found values (%) C H

1

HO-

HO-

H

3370,3300,1730, 1635,

CioHöOe

54.06

2.72

1620

> 300

54.05

2.60

2nd

CHbCOO-

CHsCOO-

H

1780, 1760, 1730, 1620

C14H10O8

54.91

3.29

186-188

54.95

3.08

3rd

H

HO-

HO-

3380,3275, 1725, 1620

CioHöOö

54.06

2.72

265-270 *

53.65

2.53

4th

H

CH3COO-

CH3COO-

1780, 1760, 1740, 1625

C14H10O8

54.91

3.29

178-179

54.90

3.25

s decomposition

example 1

7β- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2-phe-nylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid, such as the sodium salt thereof a) 6,7- Diacetoxychromone-3-carbonyl chloride

A mixture of 918 mg (3 mmol) of 6,7-diacetoxychro-mon-3-carboxylic acid, 20 ml of benzene, 260 ml of thionyl chloride (3.6 mmol) and 0.2 ml of N, N-dimethylformamide were refluxed for 2 hours held. Then the solvent was removed. 5 ml of benzene were added to the residue and then evaporated. This was repeated twice to remove all residues of thionyl chloride. The solid residue was used in the following synthesis.

IR spectrum (cm-1; Nujol): 1780, 1775, 1660, 1625

b) 7ß- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxyl-

so acid

1.483 ml (6 mmol) of N, 0-bis (trimethylsilyl) acetamide were added to a stirred suspension of 811 mg of cephalo-glycine (2.0 mmol) in 16 ml of dichloromethane at 0 ° C. The mixture was stirred at 0 ° C. for 20 minutes and a suspension of the acid chloride from a) (2 mmol) in 10 ml of dichloromethane was then added dropwise. Stirring was continued at 0 ° C for half an hour and then at room temperature for a further 5 hours. The solvent was then removed. The residue was taken up in 250 ml of 60 ethyl acetate, washed successively with twice 40 ml of 0.5 N hydrochloric acid solution, 2 × 40 ml of water and 2 × 40 ml of saturated salt solution and then dried over magnesium sulfate. After removing the solvent, the residue was triturated in ethyl ether to obtain the desired title compound. Finally, 920 mg of the compound mentioned were obtained, which corresponds to a yield of 66%.

Melting interval: 170-175 ° C (decomposition)

7

645905

Elemental analysis: for C32H27N3O13S

Calc .: C 55.41%; H 3.92%; N 6.06%

Found: C 54.38%; H 3.86%; N 5.05%

IR spectrum (cm-1; Nujol): 1780,1735,1690, 1665,1620

c) sodium salt of the compound of b)

2 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate were added to 694 mg of the compound from b) in 30 ml of acetone, which additionally contained 2 ml of N, N-dimethylformamide. 30 ml of ethyl acetate-ethyl ether in a ratio of 1: 1 and 50 ml of ethyl ether were then added to the solution. The precipitated solid was filtered off, washed with ethyl acetate-ethyl ether in a ratio of 1: 1 and dried. Finally 306 mg of the sodium salt sought were obtained, which corresponds to a yield of 43%.

Melting interval: 165-180 ° C (decomposition)

Elemental Analysis) for C32H2óN3NaOi3S

Calc .: C 53.77%; H 3.66%; N 5.87%

Found: C 52.35%; H 3.83%; N 5.37%

IR spectrum (cm-1; Nujol): 1785, 1770, 1742, 1670, 1605

Nuclear Magnetic Resonance Spectrum (ô, DMSO-de): 2.00 (3 H, s), 2.37 (3H, s), 2.38 (3H, s), 3.13 (1H, d, J = 17 Hz), 3.43 (1H, d, J = 17 Hz), 4.78 (1 H, d, J = 12 Hz), 4.94 (1 H, d, J = 4.5 Hz), 5 , 02 (1 H, d, J = 12 Hz), 5.61 (1H, dd, J = 8 Hz, 4.5 Hz) 5.94 (1H, d, J = 8 Hz) 7.25-7 , 7 (5H, m), 7.92 (1H, s), 8.12 (1H, 3), 9.09 (1H, s), 9.49 (1H, d, J = 8 Hz), 10 , 15 (1H, d, J = 8 Hz).

Example 2

7ß- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid and the sodium salt thereof a) 6,7- Diacetoxychromone-3-carbonyl chloride

A mixture of 18.4 g of 6,7-diacetoxychromone-3-carboxylic acid (60 mmol), 450 ml of benzene, 8.6 g of thionyl chloride (72 mmol) and 3 ml of N, N-dimethylformamide were refluxed for one hour held and then cooled to room temperature. After adding 300 ml of n-hexane, the precipitated solid was filtered off and 17.6 g of the acid chloride of a) were obtained.

IR spectrum (cm- '; Nujol): 1780, 1755, 1660, 1625

b) 7β- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyI) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

5 ml of a 1M solution of N, 0-bis (trimethylsilyl) acetamide in dichloromethane was added to a stirred suspension of 475 mg of 7β- [D-2-amino- (6,7-diacetoxychromone-3-carboxamido) -3- (4-hydroxyphenyl) acetamido] -3-acetoxy-methyl-3-cephem-4-carboxylic acid in 5 ml of ethyl acetate at 0 ° C. The mixture was stirred at 0 ° C. for 20 minutes and then 325 mg of the solution of the acid chloride from a) in 5 ml of dichloromethane were added. The reaction solution was stirred at 0 ° C for 4 hours and then diluted with ethyl acetate. The phase was then washed with water, 0.5 N hydrochloric acid, again water and then saturated saline and dried over magnesium sulfate. The solvent was evaporated and the residue was taken up in ethyl ether-n-hexane in a ratio of 2: 1. 526 mg of the desired compound were thus obtained. Melting interval: 210-220 ° C (decomposition)

Elemental analysis: for C32H27N3O14S

Calc .: C 54.16%; H 3.84%; N 5.92%

Found: C 52.54%; H 3.83%; N 5.69%

IR spectrum (cm "1; Nujol: 1760-1790, 1735, 1665, 1620

Nuclear Magnetic Resonance Spectrum: (8, DMSO-De): 2.04 (3H, s), 2.36 (3H, s), 2.37 (3H, s), 3.41 (1H, d, J = 18 Hz), 3.57 (IH, d, J = 18 Hz), 4.67 (1H, d, J = 13 Hz), 4.98 (1H, d, J = 13 Hz), 5.05 (1H , d, J = 5 Hz), 5.6-5.9 (2H, m), 6.75 (2H, d, J = 9 Hz), 7.28 (2H, d, J = 9 Hz), 7.88 (1H, s), 8.07 (1H, s), 9.05 (1H, s), 9.40 (1H, d, J = 8 Hz), 10.00 (1H, d , J = 8 Hz).

c) sodium salt of the compound from b)

According to the procedure of Example 4, step c) described below, 379 mg of the desired salt of the compound from b) were obtained.

Melting interval: around 230 ° C (decomposition)

Elemental analysis: for C32H26N3NaOi4S

Calc .: C 52.53%; H 3.58%; N 5.74%

Found: C 49.85%; H 4.11%; N 5.54%

IR spectrum (cm-1; Nujol): 1720-1780, 1665, 1610

Example 3

7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2-phe-nylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid and the sodium salt thereof a) 6,7-dihydroxychromone-3 -carbonyl chloride A mixture of 9.0 g of 6,7-dihydroxychromone-3-carboxylic acid (4 mmol) and 150 ml of thionyl chloride was kept at reflux temperature for 45 minutes. The unreacted thionyl chloride was then evaporated off. After the addition of benzene, the mixture was evaporated to dryness again and the residue was taken up in n-hexane. This gave 9.1 g of the compound sought, which corresponds to a yield of 93.4%.

IR spectrum (cm-1; Nujol): 1780, 1765, 1645, 1625

b) 7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-4-carboxylic acid

44.8 g of N, 0-bis (trimethylsilyl) acetamide (54.4 ml, corresponding to 220 mmol) were added to a stirred suspension of 16.2 g of cephaloglycine (40 mmol) in 400 ml of dichloromethane at 2 ° C. The mixture was stirred at 2 ° C. for 2 hours and 8.7 g of the acid chloride (36 mmol) obtained in a) above were then added. Stirring was continued for another 1.5 hours at 2 ° C. The reaction solution was then diluted with 1 liter of ethyl acetate, washed successively with an ice-cooled, saturated salt solution, an ice-cooled mixture of 0.5 N hydrochloric acid and saturated salt solution (4 times) and then dried over magnesium sulfate. The solvent was evaporated and the residue taken up in n-hexane. 8.25 g of the crude product were obtained in this way. A suspension of a portion (1.8 g) of the product in 60 ml of acetone was stirred at room temperature for 2 days after which the acetone was evaporated. The residue was taken up in ethyl ether and washed out with n-hexane. 1.5 g of the pure title product were obtained, which corresponds to a yield of 28.2%. Melting interval: 240-255 ° C (decomposition)

s

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55

60

65

645 9 »p

Elemental analysis: for C28H23N3O11S

Calc .: C 55.17%; H 3.80%; N 6.89%

Found: C 50.37%; H 3.68%; N 5.41%

IR spectrum (cm "', Nujol): 1780.1735.1710, 1660.1630

Nuclear Magnetic Resonance Spectrum (5, DMSO-dó): 2.04 (3H, s), 3.40 (1H, d, J = 18 Hz), 3.52 (1 H, d, J = 18 Hz), 4 , 70 (1 H, d, J = 12 Hz), 4.98 (1H, d, J-12 Hz), 5.03 (1H, d, J = 5 Hz), 5.74 (1H, dd, J = 8 Hz, 5 Hz), 5.87 (1H, d, J = 8 Hz), 7.02 (1H, s), 7.20-7.52 (5H, m), 7.44 (1 H, s), 8.88 (1H, s), 9.50 (1H, d, J = 8 Hz), 10.42 (1H, d, J = 8 Hz).

c) sodium salt of the compound from b)

6.0 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate were added to a solution of 1.83 g of the compound from b) (3 mmol) in a mixture of 850 ml of acetone and 13 ml of N, N- Given dimethylformamide. The addition was made drop by drop. The mixture was then stirred at room temperature for 20 minutes. Now the mixture was successively mixed with 800 ml of a mixture of ethyl acetate-ethyl ether in a ratio of 1: 1 and then with 200 ml of ether. After stirring for a further 30 minutes at room temperature, the precipitated solid was filtered off and washed with ethyl acetate. After drying the solid, 1.24 g of the salt were obtained, which corresponds to a yield of 65.4%.

Melting interval: 185-195 ° C (decomposition)

Elemental analysis: for C2sH22N3NaOi 1S

Calc .: C 53.25%; H 3.67%; N 6.65%

Found: C 48.73%; H 3.74%; N 5.53%

IR spectrum (cm "1; Nujol): 1765.2740.1660.1630.1610

NMR spectrum (Ô, DMSO-dö): 2.01 (3H, s), 3.20 (IH, d, J = 18 Hz), 3.42 (IH, d, J = 18 Hz), 4, 80 (IH, d, J = 12 Hz), 4.94 (IH, d, J = 5 Hz), 5.01 (IH, d, J = 12 Hz), 5.59 (IH, br.s) , 5.90 (IH, d, J = 8 Hz), 6.80 (IH, s), 7.20-7.60 (5H, m), 7.29 (IH, s), 8.76 ( IH, s), 9.43 (IH, br.s), 10.64 (IH, d, J = 8 Hz).

Example 4

7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid and the sodium salt thereof a) 6,7- Dihydroxychromone-3-carbonyl chloride

A mixture of 888 mg of 6,7-dihydroxychromon-3-car-boxylic acid (4 mmol) and 25 ml of thionyl chloride were kept at reflux temperature for one hour. The excess thionyl chloride was then evaporated. After the addition of benzene, the mixture was again evaporated to dryness. The residue was taken up in dichloromethane. This gave 719 mg of the title compound.

IR spectrum (cm "1; Nujol): 1780.1765.1645.1625

b) 7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

742 ml of N, 0-bis (trimethylsilyl) acetamide were added to a stirred suspension of 238 mg of 7β- [D-2-amino-2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid placed in 10 ml of ethyl acetate at 0 ° C. The mixture was stirred at 0 ° C for 20 minutes. Then 120 mg of the acid chloride obtained under a) were added. The solution was stirred at room temperature for 4 hours. Then it was diluted by adding ethyl acetate and then washed out with water and saturated saline. After drying with magnesium sulfate, the solvent was evaporated.

The residue was poured into acetone and the mixture was left to stand overnight. After the acetone had been evaporated off, the residue was taken up in ethyl ether. 101 mg of the title compound were thus obtained. Melting interval: about 250 ° C (decomposition)

Elemental analysis: for C32H23N3O12S

Calc .: C 57.06%; H 3.44%; N 6.24%

Found: C 51.84%; H 3.96%; N 5.76%

IR spectrum (cm-1; Nujol): 1785, 1730, 1715, 1660, 1630, 1610

Nuclear Magnetic Resonance Spectrum (5, DMSO-de): 2.04 (3H, s), 3.40 (IH, d, J = 18 Hz), 3.58 (IH, d, J = 18 Hz), 4, 67 (IH, d, J = 13 Hz), 4.99 (IH, d, J = 13 Hz), 5.05 (IH, d, J = 5 Hz), 5.64-5.88 (2H, m), 6.74 (2H, d, J = 5 Hz), 7.00 (IH, s), 7.27 (2H, d, J = 8.5 Hz), 7.44 (IH, s) , 8.88 (IH, s), 9.36 (IH, d, J = 8 Hz), 10.28 (IH, d, J = 8 Hz).

c) sodium salt of the compound from b)

0.24 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate was added to a solution of 80 mg of the compound from b) in 3 ml of the mixture acetone / N, N-dimethylformamide in a ratio of 2: 1 . 10 ml of a 1: 1 mixture of ethyl acetate / ethyl ether were then added. The solid which precipitated was filtered off, washed with ethyl acetate / ethyl ether in a ratio of 1: 1 and dried. 67 mg of the desired sodium salt were thus obtained.

Melting interval: about 235 ° C (decomposition)

Elemental analysis: for C32H22N3NaOi2S

Calc .: C 55.25%; H 3.19%; N 6.04%

Found: C 50.03%; H 4.06%; N 7.04%

IR spectrum (cm "1; Nujol): 1730-1780,1660,1600-1630

Nuclear Magnetic Resonance Spectrum (S, DMS0-d6-D20): 2.04 (3H, s), 3.16 (IH, d, J = 18 Hz), 3.48 (IH, d, J = 18 Hz), 4.74 (IH, d, J = 13 Hz), 4.90 (IH, d, J-13 Hz), 4.91 (IH, d, J = 5 Hz), 5.60 (IH, d, J = 5 Hz), 5.64 (IH, s), 6.80 (2H, d, J = 8.5 Hz), 7.03 (IH, s), 7.31 (2H, d, J = 8.5 Hz), 7.44 (1H, s), 8.83 (IH, s).

Example 5

7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2-phe-nylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

0.698 1 of a 1 M sodium hydrogen carbonate solution in water was added to a solution of 200 mg of the compound of Example 1, step c) (0.279 mmol) in 160 ml of water. The reaction solution was left to stand at room temperature for 7 days. Then it was acidified to pH 2.0 and extracted with ethyl acetate (4x 50 ml). The organic phases were washed successively with water and with saturated saline and then dried over magnesium sulfate. After evaporation of the solvent, the residue was taken up in ethyl ether; This gave 51 mg of the acid sought, which corresponds to a yield of 30%. The compound was identical to that obtained in Example 3, step b). Agreement

8th

s

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15

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35

40

45

50

55

60

65

affects all measurement results of NMR spectra, IR spectra and thin layer chromatography on silica gel, Merck 5715, and eluent benzene / dioxane / acetic acid in a ratio of 4: 1: 1.

Example 6

7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

546 yes.1 of a 1N solution of sodium hydrogen carbonate in water was added to 200 mg of the compound obtained in Example 2, step b). The compound was in 15.45 ml of water. The mixture was left to stand at room temperature overnight, then brought to a pH of 2.0 by adding 1N hydrochloric acid. Then it was extracted with ethyl acetate. The organic phases were washed successively with water and saturated saline and dried over magnesium sulfate. After the solvent had been evaporated off, the residue was purified by thin layer chromatography and 108 mg of the acid sought were obtained. The product was identical to the compound obtained in Example 4, step b). All measurement results from NMR, IR and thin layer chromatography on silica gel, Merck 5715 and eluent benzene / dioxane / acetic acid in the ratio 4: 1: 1 were identical.

Example 7

7ß- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2-phe-nylacetamido] -3-acetoxymethyI-3-cephem-4-carboxylic acid a) 7,8-diacetoxychromone-3-carbonyl chloride

A mixture of 9.5 g of 7,8-diacetoxy-3-carboxylic acid (31 mmol), 2.6 ml of thionyl chloride, 0.1 ml of N, N-dimethylformamide and 300 ml of benzene was refluxed for 1.5 hours held. After the addition of a further 2.6 ml of thionyl chloride and 0.1 ml of N, N-dimethylformamide, the mixture was again held at the reflux temperature for one hour and then evaporated to dryness. The residue was taken up in n-hexane; 9.3 g of the title substance sought were thus obtained. This corresponds to a yield of 92.6%.

IR spectrum (cm-1; Nujol): 1780.1770.1670.1620

b) 7β- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

5.0 ml of an 1M solution of N, 0-bis (trimethylsilyl) acetamide in dichloromethane was added dropwise to the stirred suspension of 405 mg of cephaloglycine (10 mmol) in 10 ml of ethyl acetate at 0 ° C. The mixture was then stirred at 0 ° C for one hour. Then 325 mg of the acid chloride (1.0 mmol) from a) were added. The reaction solution was then stirred for a further 4 hours at 0 ° C. and then diluted with 300 ml of ethyl acetate. The solution was then washed with 40 ml of water, 2 × 40 ml of 0.5N hydrochloric acid, 2 × 40 ml of water and 2 × 40 ml of saturated saline and then dried over magnesium sulfate.

After removing the solvent, the product was in light yellow crystals. It was weighed to 402 mg. Part of the scale, i.e. 108 mg were purified by preparative thin layer chromatography. Chromatography was carried out on silica gel with the developing solutions chloroform / methanol / formic acid in a ratio of 90: 10: 4. This gave 24 mg of the product sought, which corresponds to an overall yield of 14.0%. Melting interval: 150-160 ° C (decomposition)

645 905

Elemental analysis: for C32H27N3O13S

Calc .: C 55.40%; H 3.92%; N 6.06%

Found: C 54.64%; H 4.10%; N 4.85%

IR spectrum (cm-1; Nujol): 1780.1740.1720.1685.1670,

1516

Nuclear Magnetic Resonance Spectrum (S, DMSO-de): 2.03 (3H, s), 2.38 (3H, s), 2.44 (3H, s), 3.42 (1 H, d, J = 18 Hz), 3.52 (IH, d, J = 18 Hz), 4.66 (1H, d, J = 14 Hz), 4.98 (1H, d, J = 14 Hz), 5.04 (IH , d, J = 5 Hz), 5.76 (IH, dd, J = 8 Hz, 5 Hz), 5.84 (IH, d, J = 8Hz), 7.38-7.50 (5H, m ), 7.57 (1H, d, J = 8.5 Hz), 8.16 (1H, d, J = 8.5 Hz), 9.00 (IH, s), 9.52 (IH, d , J = 8 Hz), 10.09 (IH, d, J = 8 Hz).

Example 8

7ß- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid a) 7,8-diacetoxychromone-3- carbonyl chloride

A mixture of 9.5 g of 7,8-diacetoxychromone-3-carboxylic acid (31 mmol), 2.6 ml of thionyl chloride, 0.1 ml of N, N-dimethylformamide and 300 ml of benzene were refluxed for 1.5 hours held. After the addition of a further 2.6 ml of thionyl chloride and 0.1 ml of N, N-dimethylformamide, the mixture was again kept at the reflux temperature for one hour and then evaporated to dryness. The residue was taken up in n-hexane; 9.3 g of the title product were thus obtained. The yield was therefore 92.6%.

IR spectrum (cm "1; Nujol): 1780, 1770, 1670, 1620

b) 7ß- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

1.23 ml of N, 0-bis (trimethylsilyl) acetamide was added dropwise to a suspension of 7β- [D-2-amino-2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4- carboxylic acid (211 mg) in 5 ml of ethyl acetate at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. Then 162 mg of the acid chloride obtained under a) were added. The reaction solution was then stirred at 0 ° C. for 4 hours and then diluted by adding 150 ml of ethyl acetate. The solution was finally washed out with water, 0.5 N hydrochloric acid, water and saturated hydrochloric acid; it was dried over magnesium sulfate. The solvent was then evaporated off and the residue was taken up in 10 ml of acetone. The mixture was stirred at room temperature for 4 hours and then concentrated to a volume of approximately 5 ml. The mixture was then separated on silica gel using thin layer chromatography; finally 24 mg of the title product were obtained.

Melting interval: 200-210 ° C (decomposition)

Elemental analysis: for C32H27N3O14S

Calc .: C 54.16%; H 3.84%; N 5.92%

Found: C 50.34%; H 3.75%; N 6.34%

IR spectrum (cm "1; Nujol): 1785, 1775, 1770, 1740, 1710, 1675, 1655, 1630, 1610, 1600

Nuclear Magnetic Resonance Spectrum (8, DMSO-de): 2.04 (3H, s), 2.39 (3H, s), 2.45 (3H, s), 3.48 (2H, m), 4.68 (IH, d, J = 13 Hz), 4.96 (IH, d, J = 13 Hz), 5.04 (IH, d, J = 5 Hz), 5.72 (IH, d, J = 8 Hz), 7.26

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

645905

10th

(2H, d, J = 8.5 Hz), 7.58 (1H, d, J = 9 Hz), 8.14 (1 H, d, ductin salt form, which gives a total yield of 85.8%

J = 9 Hz), 9.00 (1H, s), 9.40 (1H, d, J = 8 Hz), 9.46 (1H, s), 9.97.

(1 H, d, J = 8 Hz). Melting invert: 230-240 ° C (decomposition)

Example 9

7ß- [D-2- (7,8-dihydroxychromone-3-carboxamido) -2-phe-nylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid and the sodium salt thereof a) 7,8-dihydroxychromone-3 -carbonyl chloride

A mixture of 6.6 g of 7,8-dihydroxychromone-3-4-car-boxylic acid (30 mmol) and 25 ml of thionyl chloride was kept at reflux temperature for one hour. The excess thionyl chloride was then removed. After adding benzene to the residue, the mixture was evaporated to dryness and the residue was taken up in n-hexane. This gave 7.2 g of the product sought.

IR spectrum (cm-1; Nujol): 1775, 1660, 1620

b) 7ß- [D-2- (7,8-dihydroxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

13.6 ml of N, 0-bis (trimethylsilyl) acetamide (55 mmol) was added dropwise to a stirred suspension of 4.05 g of cephaloglycine (10 mmol) in 100 ml of dichloromethane at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and then 2.3 g of the acid chloride (9.5 mmol) obtained under a) were added. The reaction solution was then stirred again at 0 ° C. for 1.5 hours and then diluted with 500 ml of ethyl acetate. The solution was then washed successively with saturated saline / 1N hydrochloric acid (1: 1.4 x 200 ml) and 6x200 ml saturated saline and then dried over magnesium sulfate.

After removing the solvent, the solid was mixed with 100 ml of acetone. The solution was stirred at 25 ° C overnight and then concentrated to a volume of 10 ml. Ethyl acetate and n-hexane were added to the solution. The solid which precipitated out was filtered off and dried. In this way, 1.1 g of the compound sought were obtained, which corresponds to a total yield of 18.8%.

Melting interval: 235-250 ° C (decomposition)

Elemental analysis: for C28H23N3O11S

Calc .: C 55.17%; Found: C 53.21%;

H 3.80%; H 3.47%;

N 6.89% N 5.45%

IR spectrum (cm-1; Nujol): 1780.1740.1720.1660.1615

Nuclear Magnetic Resonance Spectrum (5, DMSO-d «): 2.03 (3H, s), 3.44 (1H, d, J = 18 Hz), 3.48 (1H, d, J = 18 Hz), 4 , 68 (1H, d, J = 13 Hz), 4.96 (1H, d, J = 13 Hz), 5.04 (1H, d, J = 5 Hz), 5.76 (1H, m), 5.86 (1H, d, J = 8 Hz), 7.08 (1H, d, J = 8 Hz), 7.28-7.52 (5H, m), 7.56 (1H, d, J = 8 Hz), 8.92 (1H, s), 9.59 (1H, d, J = 8 Hz), 10.34 (1H, d, J = 8 Hz).

c) sodium salt of the acid from b)

A suspension of 0.98 g of the compound from b) (1.6 mmol) in 200 ml of acetone was filtered off and 3.04 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate were added to the filtrate. The solution was then mixed with 200 ml of ethyl acetate / ethyl ether in a ratio of 1: 1. The precipitated solid was filtered off, washed with ethyl acetate / ethyl ether in a ratio of 1: 1 and dried. This gave 0.871 g of title pro's elementary analysis: for C28H22N3NaO »S

Calc .: C 53.25%; H 3.67%; N 6.65%

Found: C 49.67%; H 3.29%; N 5.00%

10 IR spectrum (cm-1, nujol): 1760, 1660, 1610

Nuclear Magnetic Resonance Spectrum (5, DMSO-de): 2.00 (3H, s), 3.18 (IH, d, J = 18 Hz), 3.40 (IH, d, J = 18 Hz), 4, 64 (IH, d, J = 12 Hz), 4.98 (2H, m), 5.60 (IH, m), 5.78 (IH, d, J = 8 Hz), 7.04 (IH, d, 15 J = 8 Hz), 7.12-7.56 (6H, m), 8.90 (IH, s), 9.40 (IH, br.s.), 10.42 (IH, d , J = 8 Hz).

The compounds obtained in this example are used below for the antibacterial activities in 20 vitro.

Example 10

7ß- [D-2- (7,8-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-25 carboxylic acid and its sodium salts a) 7,8- Dihydroxychromone-3-carbonyl chloride

A mixture of 6.6 g of 7,8-dihydroxychromone-3-carboxylic acid (30 mmol) and 25 ml of thionyl chloride was refluxed for 30 hours, after which the excess thionyl chloride was removed. After adding benzene to the residue, the mixture was evaporated to dryness and the residue was taken up in n-hexane. This gave 7.2 g of the title substance sought.

35

IR spectrum (cm-1; Nujol): 1775, 1660, 1620

b) 7β- [D-2- (7,8-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

40 carboxylic acid

17.3 ml of N, 0-bis (trimethylsilyl) acetamide was added dropwise to a stirred suspension of 4.8 g of 7β- [D-2-amino-2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem -4-carboxylic acid in 200 ml of ethyl acetate at 2 ° C 45. The mixture was stirred at room temperature for 2 hours and then cooled to 2 ° C. 2.4 g of the acid chloride obtained under a) were then added to the cooled solution. The reaction solution was then stirred at 2 ° C. for 4 hours and then poured into 800 ml of ice-cooled 50 0.5 N hydrochloric acid solution. The diluted solution was then stirred in an ice bath for 30 minutes. The solid which precipitated out was filtered off and washed with water. After drying, 6.5 g of the crude product could be weighed out. A portion of the weight, 55 namely 5.6 g, was stirred in 200 ml of methanol at room temperature for 2 hours and then filtered off again. The filtrate was concentrated to a volume of 30 ml, and the crystals thereby precipitated were filtered off. After washing with methanol and ethyl ether, 60 1.2 g of the acid sought were weighed out.

Melting interval: 220-250 ° C (decomposition)

Elemental analysis: for C28H23N3O12S

es calc .: C 53.76%; Found: C 50.34%;

H 3.71%; H 3.78%;

N 6.72% N 6.34%

IR spectrum (cm-1; Nujol): 3250.1770.1720.1665, 1615

11

645905

Nuclear Magnetic Resonance Spectrum (S, DMSO-de): 2.04 (3H, s), 3.48 (2H, m), 4.68 (IH, d, J = 14 Hz), 5.00 (1H, d , J = 14 Hz), 5.04 (1H, d, J = 5 Hz), 5.76 (2H, m), 6.75 (2H, d, J = 8 Hz), 7.06 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8 Hz), 7.56 (1H, d, J = 8.5 Hz), 8.94 (1 H, s), 9.38 (1H, d, J = 8 Hz), 10.24 (1H, d, J = 8 Hz).

c) sodium salt of the compound from b)

According to the method described in Example 4, step c), 623 mg of the salt sought were weighed out of 626 mg of the acid obtained under b) above. Melting interval: 210-230 ° C (decomposition)

Elemental analysis: for C2sH22N3NaOi2S

Calc .: C 51.93%; H 3.42%; N 6.49%

Found: C 49.46%; H 3.88%; N 6.67%

IR spectrum (cm-1; Nujol): 3250.1770.1670.1620

NMR spectrum (8, DMSO-de): 2.02 (3H, s), 3.24 (IH, d, J = 18 Hz), 3.44 (IH, d, J = 18 Hz), 4, 80 (IH, d, J = 12 Hz), 4.94 (IH, d, J = 4.5 Hz), 5.04 (IH, d, J = 12 Hz), 5.68 (2H, m) , 6.76 (2H, d, J = 8 Hz), 7.00 (IH, d, J = 8.5 Hz), 7.28 (2H, d, J = 8 Hz), 7.46 (IH , d, J = 8.5 Hz), 8.88 (IH, s), 9.02 (4H, bs), 10.36 (ÎH, d, J = 8 Hz).

The compounds of this example were also tested in further studies regarding their antibacterial activities in vitro.

The antibacterial effect was examined according to the following method:

The minimum inhibitory concentration (MIC) was determined according to the standard agar dilution method of the Japan Society of Chemotherapy.

The compounds from Examples 1, 2, 3, 4, 9 and 10 were dissolved in sterilized water. The compounds s from Examples 7 and 8 were dissolved in a mixture of acetone-water in a ratio of 1: 1. The comparison compounds, i.e. Cephaloglycin and cephalexin monohydrate were dissolved in a 3% sodium hydrogen carbonate solution.

Serial, two-fold dilutions were made from the above solutions.

One ml aliquot of each dilution was placed in Petri dishes with 9 ml Heart Influsion Agar or Müller Hinton Agar. The agar plates thus contained the compounds according to the invention in serially diluted concentrations. After the agar had hardened, the corresponding plates were placed in incubators at 37 ° C. The plates were left therein for 1.5 to 2 hours, an opening in the incubator allowing the acetone to be completely evaporated from the agar plates.

Test organisms were grown in trip-ticase soy culture at 37 ° C for 18 hours. Then the culture was diluted by adding saline to a concentration of approximately 106 organism units per ml. Each agar plate 25 was now loaded with a certain amount of cell suspension. The plates were then incubated at 37 ° C for 18 hours. The MIC value was then determined.

The MIC values of the compounds from Examples 1, 2, 3, 4, and 10 were determined in the form of their sodium salts and the 30 compounds of Examples 7 and 8 in the form of their free carboxylic acid.

The results are summarized in Table 2.

MIC (ixg / ml) Table 2

Test compounds test bacteria

Staphylococcus Escherichia coli Klebsiella Proteus morganii Pseudomonas Serratia marcescens "

aureus pneumoniae aeruginosa

209 P NIHJ EK-6 EP-14 EP-172 ES-75

1*

3.13

1.56

^ 0.1

50

0.8

0.4

2 **

6.25

12.5

0.2

100

3.13

6.25

3 *

1.56

0.8

^ 0.1

12.5

0.8

0.2

4 **

3.13

3.13

0.2

50

3.13

3.13

7 *

1.56

0.8

^ 0.1

3.13

1.56

0.8

8th**

6.25

3.13

0.4

25th

3.13

25th

9 *

1.56

3.13

0.2

12.5

1.56

1.56

10 **

0.8

12.5

0.2

100

1.56

100

Cephaloglycine *, **

0.8

3.13

1.56

25th

> 100

> 100

Cephalexin monohydrate

1.56

6.25

3.13

> 100

> 100

> 100

* Heart infusion agar ** Muiler-Hinton agar

Application 1

A vial containing 125 mg of the sodium salt of 7β- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid was sealed aseptically. A finished solution for injection was obtained by adding 5 ml of distilled water to the above salt.

Application 2

tablet

Sodium salt of 7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2-phenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid 250 mg

Crystalline cellulose calcium salt of carboxymethyl cellulose calcium stearate fio unit tablet

80 mg

38 mg 2 mg 370 mg

The tablet was made by conventional methods based on the above formulation.

65 Use 3 tablets

7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cephem-4-

645905

carboxylic acid 250 mg

Crystalline cellulose 80 mg calcium salt of

Carboxymethyl cellulose 38 mg

Calcium stearate 2 mg

Unit tablet 370 mg

The tablet was made by conventional methods based on the above formulation.

B

Claims (3)

645 905 1. Cephalosporin derivatives of the formula (I) PATENT CLAIMS ch2ococh3 (I), cooh in which Ri, Ri and R3 stand for hydroxy, acyloxy and H, with the measure that two or three of the Ri, r2 or R3 are not simultaneously H and R4 stands for H or hydroxy, and the non-toxic salts from that. 2. 7ß- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2-phenyl-acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid as a compound of formula (I) according to claim 1 and their non-toxic salts. 3. 7ß- [D-2- (6,7-diacetoxychromone-3-carboxamido) -2- (4-hydroxy-phenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid as a compound of the formula (I ) according to claim 1 and their non-toxic salts. 4. 7ß- [D ~ 2- (6,7-dihydroxychromone-3-carboxamido) -2-phenyl-acetamido] -3-acetoxymethyl-3-cephem ~ 4-carboxylic acid as a compound according to claim 1 and its non-toxic salts . 5. 7ß- [D-2- (6,7-dihydroxychromone-3-carboxamido) -2- (4-hydroxy-phenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid according to claim 1 and its not -toxic salts. 20 6. 7ß- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2-phenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid according to claim 1 and its non-toxic Salts. 7. 7ß- [D-2- (7,8-diacetoxychromone-3-carboxamido) -2- (4-hydroxy-phenyl) acetamido] -3-acetoxymethyl-3-cephem-4- 2s carboxylic acid according to claim 1 and its non-toxic salts. 8. 7ß- [D-2- (7,8-dihydroxychromone-3-carboxamido) -2-phenyl-acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid according to claim 1 and its non-toxic salts . 30 9. 7ß- [D-2-dihydroxychromone-3-carboxamido) -2- (4-hydroxy-phenyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid according to claim 1 and its non-toxic Salts. 10. Process for the preparation of cephalosporin 35 vaten of formula (1) according to claim 1, characterized by the reaction of a compound of formula (II) R. / T \ ch-conh nh2 V s s X 0 ch2ococh3 (ii) cooh in which R4 is H or hydroxy or a salt or hydrate thereof with a compound of the formula (III) in Ri, r2 and R3 the same meaning as in the patent 65 toxic salt. have 1 or a reactive derivative with respect to the 11 • Process for the preparation of compounds of Carboxyl group thereof and, if appropriate, subsequent reaction by the formula (I) -1 to a corresponding, non- 2nd 3rd 645905 ch-conh (I) -1 ch2ococh cooh in which R |, Ri, and Ri each represent hydroxy or H, with which the hydrolysis of compounds means that two or three of the R {, R £ and R3 are not 15 formula (I) ~ 2 at the same time Are H and R4 is H or hydroxy, CH2OCOCH3 (I) -2 cooh in which R ", R" and R "each represent acyloxy or H, with a corresponding, non-toxic salt. Measure that two or three of the R "1, R" 2 and R "3 are not 12. Antibacterial composition, are simultaneously H, and in which R4 represents H or hydroxy,. tend at least one cephalosporin derivative of the formula (I) and, if necessary, by the subsequent implementation according to claim 1, ch2ococh3 cooh (I), with Ri, r2 and R4 as defined in claim 1, or non-toxic salts thereof.