CS199298B2 - Process for preparing 7-/n-acylamino-alpha-aryl-acetamido/-3-azidomethyl-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, for example cealotin 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 ce2 falosporins derivatives of the same broad spectrum as other agents of this type and their pharmaceutically acceptable salts also have activity against Pseudomonas aeruginosa and can be used to prevent and treat diseases caused by the microorganism.

These derivatives also 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.

The present invention therefore provides a process for the preparation of the novel cephalosporins of formula (I)

UO - A - CONU - CU - CONH

COOH (I) wherein

A represents a monocyclic or polycyclicM thieteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from the group consisting of naphthyridine, pyrimidine, pyridazine and pyridine, each of which rings is optionally substituted with a substituent of C1-C4alkyl, C1-C4alkoxy carbon or hydroxyl group; and

139298

R represents a phenyl radical optionally substituted by 1 or 2 substituents selected from hydroxyl, C1-C4alkoxy, amino, hydroxymethyl, ureido or thienyl, as well as non-toxic pharmaceutically acceptable salts thereof, characterized by: by reacting a compound of formula II

US-A-CONH-CH-CONU

AND

O

where

A and R are as defined above, or a salt of this compound with sodium azide.

The reaction may be carried out in a solvent, for example water, preferably a buffer or a mixture of a buffer with an organic solvent, for example a mixture of the above organic solvents 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 substilis,

Clostridium perfringens a

Corynebacterium diphtheriae and gram-negative bacteria such as Escherichia coli,

Neisseria gonorrhoeae,

Salmonella typhi,

Klebsiella pneumoniae,

Shigella dysenteriae,

Shigella flexneri,

Shigela sonnei,

Enterobacter aerogenes,

Próteus mirabilis,

Próteus vulgaris,

Pseudomonas aeruginosa a

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 dosage 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 selected substance. 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.

He did

Preparation of 7- [D-of- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-azidomethyl-3-cephem-4-carboxylic acid

OH

A solution of 2,0 g of sodium salt of 7- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido)] -3-acetoxymethyl-3-cephem-4-carboxylic acid, 0,328 g of sodium bicarbonate, 0.635 g of sodium azide and 40 ml of phosphate buffer pH 6.4 were reacted for 18 hours at 55 ° C with stirring. The insoluble matter is filtered off with heating and the filtrate is allowed to stand at room temperature, the resulting haze is filtered off and the resulting solution is brought to pH2 by adding 6 N hydrochloric acid and the precipitated crystals are collected by filtration and dried over phosphorus pentoxide under reduced pressure. 80 g of the title compound.

IR spectrum: v

This product was dissolved in 5 mL of dimethylsulfoxide and the mixture was reprecipitated by addition of 30 mL of methanol to give 0.55 g of purified product.

This product was redissolved in 3 mL of dimethylsulfoxide and 0.168 g of sodium 2-ethylhexanoate was added. The mixture was stirred for 10 minutes, then 30 ml of acetone was added dropwise. The precipitated sodium salt was collected by filtration, washed with acetone and dried with phosphorus pentoxide under reduced pressure to give 0.50 g of the title product as the sodium salt. Melting point: 283-290 ° C with decomposition.

= 2100, 1765, 1650, 1610.

In the above manner, the other compounds listed in the following table can be obtained.

HO-A R Melting point ° C

270

240 to 252

238 to 246

245 to 246

225 to 235> 270> 270> 270

V o

J 'N NHCONH,

The minimum inhibitory concentrations of the compounds of the invention are compared to the known ones

The microorganism of Example 1 is shown in the table below. Minimum inhibitory concentration (µg / ml)

A compound of the invention

CET * CEZ **

Staphylococcus aureus 3.13

209P

Escherichia coli NIHJ 12.5

Klebsiella pneumoniae 602 12.5

Pseudomonas aeruginosa 104 3.13

o, l 0.2 12.5 1.56 3.13 1.56 > 200 > 200

CET (Cefalothin)

CH _from CONH-i-

N

CH 2 OCOCH 2 COONa.

** CEZ (Cefazoline)

N = / b-CH, CONH

N N d ^s ~ ^ch ^ s \ h

COONa- 3

The following comparative examples illustrate processes for the preparation of the starting materials used in the preparation of the compounds of the invention. Other starting materials can be prepared in a similar manner.

Comparative Example 1

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

0.965 g of trifluoroacetic acid in the farm salt of 7- (D-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-1,4-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

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

To a solution of 6 ml of dimethylsulfoxide is added 0.566 g of triethylamine and 0.441 g of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide sulfide, 1 g of trifluoroacetic acid as the salt with 7- (Da-amino-α-p-hydroxyphenylacetamido). 3-acetoxymethyl-3-cephem-4-carboxylic acid and the mixture was 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.

Claims (1)

A process for the preparation of 7- (N-acylamino-a-arylacetamido) -3-azidomethyl-3-cephem-4-carboxylic acids of the formula I HO-A-CONH-CH-CONH J CH, N. COOH where A is a monocyclic or polycyclic heteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from the group consisting of naphthyridine, pyrimidine, pyridazine and pyridine, each of which is optionally substituted with a nitrogen atom; substituted with a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl group and R is a phenyl radical optionally substituted by 1 or 2 substituents selected from hydroxyl, C 1 -C 4 alkoxy, amino, hydroxymethyl, ureido or thienyl, as well as non-toxic pharmaceutically acceptable salts thereof; by reacting a compound of formula II HO-A-CQNH-CH-CONH R o T < (ll) CH _g pCOCH _and COOH where A and R are as hereinbefore defined, or a salt of this compound with sodium azide and optionally converting the compound to its non-toxic, pharmaceutically acceptable salt.