CS199296B2 - Process for preparing 7-/n-acylamino-alpha-aryl- or thienylacetamido/-3-/condensed heterocyclic thiomethyl/-3-cephem-4-carboxylic acids - Google Patents

Description

The invention relates to a process for the preparation of novel cephalosporins which can be used as active substances, in particular against the genus Pseudomonas, otherwise they usually have a broad spectrum of activity.

It is known that cephalosporin compounds, such as cephalotin and cefazoline, are very effective against a wide range of Gram-positive and Gram-negative bacteria.

However, these substances have no effect against infections caused by Pseudomonas aeruginosa, which have been increasing recently and which are often very difficult to treat. Cephalosporins active against Pseudomonas aeruginosa are not yet available.

It has now been found that certain cephalosporin derivatives of the same broad spectrum as other substances of this type and their pharmaceutically acceptable salts also have an effect against Pseudomonas aeruginosa and can be used to prevent and treat diseases caused by the microorganism.

These derivatives have high activity against other microorganisms against which conventional cephalosporins are poorly active. Thus, it is highly effective against Pseudomonas aeruginosa, Indolpositive Proteus, Serratia, Enterobacter aerogenus and cephaloridine resistant Escherichia coli.

Accordingly, the present invention provides a process for the preparation of 7- (N-acylamino-α-aryl- or thienylacetamido) -3- (fused heterocyclic thiomethyl) -3-cep-4-carboxylic acids of the formula I μο-A-CONH-CH-CONH -, -

R

O (I)

WHAT WHERE

A represents a monocyclic or polycyclic heteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from naphthyridine, pyridopyrimidine, pyridine, pyrimidine, and pyridazine, these radicals being optionally substituted by one substituent from C1 -C4 alkyl or C1 -C4 alkylthio up to 4 carbon atoms, halogen or 2 to 4 carbon alkanoyl,

R represents a phenyl radical optionally substituted by one or two substituents from the group hydroxyl, amino or thienyl and

Het means a tetrazolopyridazine residue, a triazolopyridazine residue or a triazolopyridine residue, as well as non-toxic, pharmaceutically acceptable salts thereof, characterized in that the compound of formula II is reacted

UO-A-CONH-CH-CONHO (II) r

COOH

CH _Z OCOCH _Z where

A and R are as defined above, with a compound of formula III

HS-Het (III), where

Het has the above meaning.

The reaction may be carried out, for example, in an inert solvent such as water. Organic solvents such as acetone, acetonitrile, methanol, ethanol, dimethylformamide and the like may also be used in admixture with water or a suitable buffer. When the compounds of formula (II) are used in the form of a free carboxylic acid, the reaction is preferably carried out in the presence of a base such as sodium bicarbonate or triethylamine. The reaction is usually carried out at a temperature of 50 to 60 ° C.

The compounds of formula (I) are valuable antibacterial agents and can be used as additives to livestock feed, poultry and livestock medicaments as well as in human medicine. These agents are particularly suitable for the treatment of infectious diseases caused by Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus pyogenes, Diplococcus pneumoniae, Sarcina lutea, Bacillus subtilis, Clostridium perfringens and Coryneborrium germiae, coliaeeria, coliaeeria, Salmonella typhi, Klebsiella pneumoniae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter aerogenes, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeuruginosa and Serratia marcescens. For this purpose, the compounds according to the invention are used singly or in admixture with pharmaceutically acceptable carriers or diluents or with other active substances intramuscularly or intravenously.

The dose of the compounds of the formula I depends on the weight, age and conditions of administration, on the type of bacterium and on the pharmacological properties of the substance chosen. In general, a dose of 2 to 400 mg / kg body weight per day, preferably 8 to 120 mg / kg body weight per day, in a single dose or 1 to 5 times a day is used for intramuscular or intravenous administration of the compounds of formula (I).

For intramuscular or intravenous administration, the compounds of the invention are used in the form of sterile solutions or suspensions containing a pharmaceutical diluent or carrier such as water, saline, Ringer's solution, glycerin, polyethylene glycol and the like. These pharmaceutical preparations may contain other excipients, emulsifiers, topical anesthetics or salts for adjusting the osmotic pressure. The compounds of the invention may also be applied topically in the form of an ointment or cream to the skin or other organs for sterilization or disinfection.

The invention will be illustrated by the following examples and comparative examples, which are not intended to limit the invention. All parts, percentages and ratios are by weight unless otherwise indicated.

Example 1

Preparation of 7- [Da - (4-hydroxy-1,5-naphthyridine-D-carboxamido) - N - p -hydroxyphenylacetamido] -3- (tetrazolo [4,5-b] pyridazin-6-yl-thiomethyl) - 3-cep-4-carboxylic acid

α. » ^Ν ~ Ί! ί,

IN

1.23 g of sodium 7- [N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylate, 0.20 g sodium bicarbonate and 20 ml of phosphate buffer (pH 6.4) are heated to 60 ° C and a solution of 0.416 g of 6-mercaptotetrazolo [4,5-b] pyridazine in 10 ml of acetone is added dropwise. After completion of the addition, the mixture is left to react with the IR absorption spectrum under IR:

Example 2

Preparation of 7- [Da (4-hydroxy-1,5-winded) for 12 hours and 20 minutes at this temperature The homogeneous solution thus obtained is cooled with ice to form crystals which are filtered off, washed with 95% ethanol and dried with phosphorus pentoxide under reduced pressure to give 0.38 g of the product as the sodium salt.

Melting point: 267-274 ° C with decomposition.

phthyridine-3-carboxamido) -E-p-hydroxyphenylacetamido) -3- (pyrido [2,1-c] -s-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid

CONH - CH - CONH

N ·

COOH ^N ,

OF'

OH

1.23 g of sodium [4- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylate, 0.45 g of sodium bicarbonate, ml of phosphate buffer (pH 6.4), 0.906 g of 3-mercaptopyrido [2,1-c] -s-triazole and 20 ml of acetone are charged to the reactor and the mixture is allowed to react at 60 ° C for 23 hours IR absorption light spectrum: v

Example 3

In a similar manner as in Examples 1 and 2, appropriate initial mixing may be used. The reaction mixture was cooled and adjusted to pH 3.2-3.6 with 6 N hydrochloric acid. After stirring under ice-cooling, the crystalline precipitate was filtered off, washed with water and dried over phosphorus pentoxide under reduced pressure to give 0.88 g of the title compound.

Mp 221-224 ° C with decomposition. cm ^-1 nujol = ^176θ ' ¹⁶⁵⁵ ' ¹⁶¹ ° to obtain 7- [Da- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3- (tetrazolo [4,5-b] pyridazine- 6-ylthiomethyl) -3-cephem-4-carboxylic acid

OH with / ^ CONH-CH-CONH 7Γ

N \ ^ CHGS - <^ - _N COOH ^N; mp 253-257 ° C.

Other compounds listed in the following table can be obtained as described above.

261 to 270

263 to 272

253 to 261

251 to 261

248 to 255

245 to 253

252 to 259

242 to 250

250 to 257> 270 decomposes

Comparative Example 1

Method for the preparation of 7- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

0.965 g of trifluoroacetic acid salt form of 7- (D-α-amino-α-p-hydroxyphenylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid is dissolved in 8 ml of dimethylsulfoxide and 0.545 g of triethylamine is added. Subsequently, 0.516 g of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid N-hydroxysuccinimide ester are then added and the mixture is stirred for one hour and 15 minutes at room temperature. 0.598 g of sodium 2-ethylhexanoate was added to the resulting solution, and the mixture was stirred for 10 minutes, after which the insoluble matter was filtered off. Acetone (100 ml) was added to the filtrate and the resulting crystalline precipitate was collected by filtration and dried under reduced pressure of phosphorus pentoxide to give 0.93 g of the title compound as the sodium salt, m.p. 261-265 ° C with decomposition.

Comparative Example 2

Process for the preparation of 7- [D-N- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid

To a solution of 6 ml of dimethylsulfoxide, 0.566 g of triethylamine and 0.411 g of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide ester, 1 g of trifluoroacetic acid, in the form of the salt with 7- (Da-amino-? - p-hydroxyphenylacetamido) -3 acetoxymethyl-3-cephem-4-carboxylic acid and the mixture is allowed to react at room temperature with stirring for 14 minutes. The reaction mixture was then added dropwise to 250 ml of acetone and 100 ml of diethyl ether was added after the acetone addition was complete. The resulting crystalline precipitate was collected by filtration and dried under phosphorus pentoxide under reduced pressure to give 0.99 g (82.5%) of the title compound as a triethylamine salt, mp 135 ° C decomp. At 142-147 ° C.

The salt was added to a solution of 0.31 g of sodium 2-ethylhexanoate in 8 ml of dimethylsulfoxide and the mixture was stirred at room temperature for 10 minutes. Then 180 ml of acetone and 50 ml of diethyl ether were added to the resulting mixture. The resulting crystalline precipitate was collected by filtration and dried under phosphorus pentoxide under reduced pressure to give the title compound as the sodium salt, m.p. 150-165 ° C with decomposition.

The minimum inhibitory concentration of the compounds of the invention has the results shown in the following table.

Minimum inhibitory concentration (µg / ml)

Microorganism 1 Example compound CEZ * 2 3 CET * Staphylococcus aureus 209P 0.2 1.56 0.05 0.1 0.2 Escherichia coli NIHJ Klebsiella 0.78 0.78 3.13 12.5 1.56 pneumoniae 602 Pseudomonas 0.78 3.13 6.25 3.13 1.56 aeruginosa 104 0.78 3.13 3.13 > 200 > 200

199299 * CET (cephalotin)

CHtCONH-i ⁰ Coon.

** CEZ (cefazoline)

N-H

I N - CH, CONH N = S - i (Ί n - ty> I

COO / Va.

SUBJECT

Claims (1)

SUBJECT VYNALEZU A process for the preparation of 7- (N-acylainino-α-aryl- or thienylacetamido) -3- (fused heterocyclic thiomethyl) -3-cefern-4-carboxylic acids of formula I HO - A - CONH - CH - CONH where A represents a monocyclic or polycyclic heteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from naphthyridine, pyridopyrimidine, pyridine, pyrimidine, and pyridazine, these radicals being optionally substituted by one substituent from C1 -C4 alkyl or C1 -C4 alkylthio up to 4 carbon atoms, R represents a phenyl radical optionally substituted by one or two substituents selected from hydroxyl, amino or thienyl, and Het means a tetrazolopyridazine residue, a triazolopyridazine residue or a triazole pyridine residue, as well as non-toxic, pharmaceutically acceptable salts of these compounds, characterized in that the reaction comprises a compound of formula II HO-A-CONH-CH-CONH R COOH (in CH 2 OCOCH 3 where A and R are as defined above, with a compound of formula III HS-Het (HI) where Het is as defined above, and optionally the compound is converted to a non-toxic, pharmaceutically acceptable salt. Severography, n. P., Plant 7, Most