CS199294B2 - Process for preparing new 7-n-acylamino-alpha-aryl-or thienylacetamido-3-/heterocyclothiomethyl/-3-cephem-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 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 in recent times 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 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 novel 7- [N-acylamino-α-aryl- or thienylation of tamido-3- (heterocyclothiomethyl) -3-cephem-carboxylic acids of formula I (I) COOH wherein:

A is a polyocyclic lietheroaromatic ring containing at least one nitrogen atom as a heteroatom selected from naphthyridine, pyridopyrimidine or pyrazolopyridine, each of which is optionally substituted with 1 substituent selected from C1-C4 alkyl or C1-C4 alkylthio ,

R is a phenyl radical optionally substituted by 1 or 2 substituents from the group hydroxyl, amino, ihydroxymethyl, ureido, halogen or thienyl and

D represents one of the groups 'N' ^N

I (CH 2 COOH

N — N _D if

With ICH ^ COOU

Ν'— Ν “^ S ^ SfCH ^ COOH

N — N

AoA

Wherein m and n are integers from 0 to 3 as well as non-toxic pharmaceutically acceptable salts of these compounds, characterized in that a compound of formula II is reacted

HO-A-CONH-CH-CONH i?

CHOCOCH.

COOH (in

R is as defined above, with a compound of formula III

HS-D (III), where

D is as defined above.

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, for example 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 auerus,

Staphylococcus epidermidis,

Staphilococcus piogenes,

Diplococcus pneumoniae,

Sarcina lutea,

Bacillus subtilis,

Clostridium pergringens a

Corynebacterium diphtheriae with gram - negative bacteria such as

Escherichia coli,

Neisseria gonorrhoeae,

Salmonella typhi,

Klebsiella pneumoniae,

Shigella dysenteriae,

Shigella flexneri,

Shigella 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 compounds of the following table can be obtained by the process of the invention.

Example

HO — A-

OH

OH

-D

N — N

S CHfOOH

N ~ f ^ í Ά. 'w i

CHCOOH \ ' ^N

AND

CHCOOH

N — N i o

S SCH 3 CH 2 COOH

Melting point ° C (dec.)

240 to 252

237 to 246

242 to 249

230 to 241

OH

OH

Cl

N — N and I

S ^ SCH £OQH

242 to 252

N — N

S ^ SCH COOH

N-N 'S ^ SCH-pOOH

N - N - (S) - NHCO (CH ₃ ) _f COOH

N - N '^ S ^ SCKCOOH

NH,

OH

SCHfOOH

N — N

Ji il ^ S ^ SCH.COOH

238 to 241

245 to 253

247 to 255

239 to 248

244 to 252

232 to 241

The minimum inhibitory concentration is shown in the following table. Minimum inhibitory concentration (.mu.g / ml)

Microorganism Compound Compound CET * CEZ * of Example 1 of Example 2

Staphylococcus 0.78 0.78 0.1 0.2 aureus 209P Escherichia 1.56 1.56 12.5 1.56 coli NIHJ Klebsiella 1.56 1.56 3.13 1.56 pneumoniae 602 Pseudomonas 3.13 3.13 > 200 > 200

* CET (ceilotin)

CHfCONl ·! ·

BYE

COONz ** CEZ (cefazoline)

N-N | -CH, COWW ·

NTíA o

COONa.

Claims (1)

A process for the preparation of the novel 7- [N-acylamino-α-aryl- or thienylacetamido] -3- (heterocyclothioromethyl) -3-cephem-carboxylic acids of the formula I HO - A - CONH - CH - CONH where A is a polycyclic heteroaromatic ring containing at least one nitrogen atom selected as the heteroatom selected from naphthyridine, pyridopyrimidine or pyrazolopyridine, each of which is optionally substituted with 1 substituent from C1-C4 alkyl or C1-C4 alkylthio . R represents a phenyl radical optionally substituted with 1 or 2 substituents selected pyridine, wherein each of these rings is a pose of the group hydroxy, amino, hydroxymethyl, ureldoskupina, halogen or thienyl, and ¹ D is one of the groups Λ Λ S _h ÍCWJ -COOW W — ΛΖ -AIL A With SfCH3COOH N-N ^AA NHfCOiJCH COOH where disc acceptable salts thereof, ye characterized in that reacting a compound m and n represent integers from 0 to 3, the compounds of general formula II as well as non-toxic pharmaceutically-A- hleHO CONH- CH-CONH R COOH CHgCOCH3 where R is as defined above, with a compound of formula IIi HS-D (III), where D is as defined above, and optionally the compound is converted to its non-toxic, pharmaceutically acceptable salt.