CS199297B2 - Process for preparing 7-/n-acylamino-alpha-aryl-acetamido/-3-azidomethyl-3-cephem-4-carboxylic acids - Google Patents

Description

(54) A method for producing 7- (N-acylamino-α-arylacetamido) -3-azidomethyl-3-cephem-4-carboxylic acid

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 compounds 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.

Accordingly, the present invention provides a process for the preparation of 7- (N-acylamino-N-arylacetamido) -3-azidomethyl-3-cephem-4-carboxylic acids of the general formula I

HO-A-CONH-CH-CONH

COOH where

A represents a monocyclic or polycyclic heteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from naphthyridine, pyrimidine, pyridazine and pyridine; substituted with one substituent selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or hydroxyl of 99297 na, and

R represents a phenyl radical optionally substituted by one or two substituents selected from the group consisting of hydroxyl, C 1 -C 4 alkoxy, amino, hydroxymethyl, ureido or thienyl, as well as non-toxic pharmaceutically acceptable salts thereof, The method of claim 1, wherein the compound of formula II is reacted with t-LN-CU-CONU x I

O (in

COOH where

R is as defined above, or a salt thereof or a functional derivative thereof with a compound of formula III HO-A-COOH (III), wherein A is as defined above - or a reactive derivative thereof.

The reaction may be carried out in a solvent such as polar solvents such as dichloromethane, chloroform, acetone, tetrahydrofuran, dloxane, acetonitrile, methyl isobutyl ketone, ethanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, nitromethane, hexamethylphosphoric triamide, sulfolane and the like. toluene, petroleum ether, n-hexane and the like. Mixtures of these solvents with one another or mixtures thereof with water may also be used.

Reactive derivatives of a compound of formula (II) are carboxyl group derivatives, for example halogens, anhydride, azolide, active ester, azide and the like. Thus, such derivatives may be mixed anhydrides or symmetrical anhydrides with acids such as dialkylphosphoric, phenylphosphoric, diphenylphosphoric, dibenzylphosphoric phosphoric acid, dialkylphosphoric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid; alkylcarbonates; aliphatic carboxylic acids such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid; active esters such as cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthiophenyl ester, p-nitrophenylthio ester, p-cresolthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester and esters of N, N‘-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide or N-hydroxynaphthalimide

When the compounds of formula (II) are used in the form of the free acid or a salt thereof, it is preferred to carry out the reaction in the presence of agents which facilitate it. Such agents are, for example

N, N‘-dicyclohexylcarbodiimide,

N-cyclohexyl-N-morpholinethylcarbodiimide,

N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide,

N, N‘-diethylcarbodiimide,

N, N‘-diisopropylcarbodiimide,

N, N‘-carbonyldi (2-methylimidazole), N-ethyl-N- (3-dimethylaminopropyl] carbodiimide, pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylenes,

1-alkoxy-1-chlorethylenes, trialkylphosphites, polyphosphoric acids in the form of ethyl ester, isopropyl ester of polyphosphoric acid, phosphorus oxychloride, oxalyl chloride, triphenylphosphine, diethylphosphonylazide, diphenylphosphonylazide,

2-ethyl-7-hydroxybenzisoxazolium salts,

2-ethyl-5- (m-sulfonyl) isoxazolium inner salt with hydroxide, (chloromethylene) dimethylammonium chloride and the like.

Examples of salts of the compounds of formula III are alkali metal or alkaline earth metal salts, for example, sodium, potassium, calcium and the like, salts with organic amines such as trimethylamine, triethylamine, quinoline, collidine and the like and with organic sulfonic acids such as toluenesulfonic acid, naphthalenesulfonic, tetralinsulfonic, trifluoroacetic, hydrochloric and the like.

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,

Diprococcus pneumoniae,

Sarcina lutea,

Bacillus subtilis,

WITH

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

Neisseria gonorrhoeae,

Salmonella typhi,

Klebsiella pneumoniae,

Shiegella dysenteriae,

Shiegella flexneri,

Shiegella sonnei,

Enterobacter aerogenes,

Próteus mirabilis,

Próteus vulgaris,

Pseudomonas aeruginosa 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 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. Generally, the intramuscular or intravenous administration of the compounds of formula I will employ 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 daily.

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 additional excipients, emulsifiers, local 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- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-azidomethyl-3-cephem-4-carboxylic acid

To a suspension of 1.43 g of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid N-hydroxysuccinimide ester, 0.01 g of triethylamine and 30 ml of dimethyl sulfoxide and 2.11 g of 7- (Da-amino-p-) are added. hydroxyphenylacetamido] -3-aminocarbonyloxymethyl-3-cephem-4-carboxylic acid was allowed to react for 40 minutes at room temperature with stirring, a small amount of insoluble material was collected by filtration, and the filtrate was added dropwise to 600 ml of acetone. The solid was collected by filtration and dried over phosphorus pentoxide under reduced pressure to give the title compound as a triethylamine salt (2.7 g), and the sodium salt was prepared by treatment with sodium 2-ethylhexanoate, m.p. 283-290 ° C.

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

HO - A R

Melting point ° C

nhconh _a

235 to 246

225 to 235> 270> 270> 270

238 to 250> 270

239 to 246

270

The minimum inhibitory concentration of the compounds of the invention has the results indicated in the following table. Minimum inhibitory concentration Microorganism (jig / mlj The product name of Example 1 CET * CEZ ** Staphylococcus aureus 209P 3.13 0.1 0.2 Escherichia coli NIHJ 12.5 12.5 1.56 Klebsiella pneumoniae 602 12.5 3.13 1.56 Pseudomonas 3.13 > 200 > 200

aeruginosa 104

Claims (1)

OBJECT OF INVENTION A process for the preparation of 7- (N-acylamino-α-arylacetamido) -3-azidomethyl-3-cephem-4-carboxylic acids of the formula I HO - A - CONH - CH - CO NH - QT CH 2 (I) ^{C ° H H} where A represents a monocyclic or polycyclic heteroaromatic radical containing at least one nitrogen atom as a heteroatom selected from naphthyridine, pyrimidine, pyridazine and pyridine; substituted with one substituent selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxyl, and R is a phenyl radical optionally substituted by one or two substituents selected from hydroxyl, C1-C4alkoxy, amino, hydroxymethyl, ureido or thienyl, as well as non-toxic pharmaceutically acceptable salts thereof, by reacting a compound of formula II U.N-CU-CONH * I R O </ n COOH where R is as defined above, or a salt of a compound or functional derivative thereof with a compound of formula III HO-A-COOH (III), wherein A is as defined above, or a reactive derivative thereof, and optionally converted to its a non-toxic, pharmaceutically acceptable salt.