CS199293B2 - Method of producing 7-/n-acylamino-alpha-aryl or thienyl-acetamido/-3-/heterocyclothiomethyl/-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 cephalaporin compounds such as cefalctin 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 derivatives of ce2 falosporins with the same broad spectrum as other substances of this type and their pharmaceutically acceptable salts also have activity against Pseudomonas aeruginosa and can be used for the prevention and treatment of diseases caused by said microorganism.

These derivatives also have high activity against other microorganisms against which conventional cephalosporins are less effective. Thus, it is highly effective against Pseudomonas aeruginosa, indolpositive Proteus, Serratia, Entercbacter 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-CON-CH-CONH

AND

R

where

A represents a polycyclic heteroaromatic ring containing at least one nitrogen atom as a heteroatom selected from the group consisting of a naphthyridine, pyridopyrimidine or pyrazolopyridine ring, each of which is optionally substituted with a substituent selected from C1-C4 alkyl or C1-C4 alkylthio carbon,

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

D represents one of the groups of the formula

I (CH 2 COOH

N — N

S (CH ^COOH N —N ^S ^CHfCOOHN --N ^with NHfCOiJCH ^C ⁰⁰¹ ^) wherein m and n are integers from 0 to 3 as well as non-toxic pharmaceutically acceptable salts of these compounds, characterized in that: reacting a compound of formula II

HO-A — COOH (II), where

A is as defined above, or a reactive derivative thereof with a compound of formula III

R and D are as defined above, or with a salt or functional derivative thereof, and the resulting compound is optionally converted to a pharmaceutically acceptable salt thereof.

The reaction may be carried out in a solvent such as polar solvents such as dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methyl isobutyl ketone, ethanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, nitromethane, hexamethylphosphoric triamide, sulfolane and the like.

Non-polar solvents include benzene, 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. Examples of such derivatives are mixed anhydrides or symmetrical anhydrides with acids such as dialkylphosphoric, phenylphosphoric halogenated phosphoric acid, dialkylphosphoric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid; alkylcarbonates; , such as cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester,

2,4-dltrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonyl ester;

phenylazophenyl ester, phenylthiophenyl ester, p-nitrophenylthioester, p-cresolthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester,

8-quinolylthioester, and esters

N, N‘-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

When the compounds of formula (II) are used in the form of the free acid or a salt thereof, it is preferable 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-ethyl-N- (3-dimethylaminopropyl) carbodiimide,

N, N‘-carbonyldi (2-methylimidazole), pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylenes,

1-alkoxy-1-chloroethylenes, 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 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 acid , tetralin sulfone, trifluoroacetic acid, hydrochloric acid 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 piogenes,

Diplococcus pneumoniae,

Sarcina lutea,

Bacillus subtilis,

Clostridium perfringens and Corynebacterium diphtheriae and 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, is administered in a single dose or 1 to 5 times daily when administered intramuscularly or intravenously.

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. 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-3-carboxamido) -ap-hydroxyphenylacetamido] -3- (5-carboxymethyl-1,3,4-thiadiazol-2-ylthiomethyl) -3 4-carboxylic acid

OH

1.23 g of sodium [4- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-acetoxymethyl-3-cephem-4-carboxylate, 0.20 g of sodium bicarbonate and 20 ml of phosphate buffer (pH 6.4) are heated to 60 DEG C. and a solution of 0.48 g of (5-mercapto-1,3,4-thiadiazole-cm @ -1 ⁾ acid is added dropwise.

Absorption spectrum in IC light: v _nu j ₀ =

Antimicrobial activity of this substance:

Staphylococcus aureus 290P 0.78 pg / mi

Escherichia coli NIHJ 1.56 / xg / ml

Klebsiella pneumoniae 602 1.53 µg / ml

Pseudomonas aeruginosa 104 3.13 µg / ml

2-yl) acetic acid in 10 mL acetone. The mixture was allowed to react for 15 hours at the same temperature, then cooled and acidified with 6 N hydrochloric acid. The precipitate was filtered off and washed with water and the product was converted to the sodium salt with sodium 2-ethylhexanoate.

1770, 1650, 1610.

Example 2

Preparation of 7- [Da- (4-hydroxy-1,4-naphthyridine-3-carboxamido) -ap-hydroxyphenylacetamido) -3- (1-carboxymethyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-Cephem-4-carboxy-

The product as the sodium salt was obtained as in Example 1 with the use of 5-mercapto-lHcm ^_1

Absorption spectrum in IC light: in nujol ⁼

Antimicrobial activity of this substance:

Staphylococcus aureus 290P 0.78 µg / ml

Escherichia coli NIHJ 1.56 µg / ml

Klebsiella pneumoniae 602 1.56 pg / ml

Pseudomonas aeruginosa 104 3.13 µg / ml

-tetrazole-1-acetic acid instead of (5-mercapto-1,3,4-thiadiazol-2-yl) acetic acid.

1765, 1655, 1610.

The compounds listed in the following table can be obtained as described above:

HO — A—

Melting point ° C

N — N

CH _AND COOH

-L * 'jy i cwcoow ji' w

CH 2 COOH

240 to 252

237 to 246

242 to 249

OH

Ν '

OH

1 = ^ s

S ^ SCH3fOOH

238 to 241

Ν '

OH

N— N

-Ji k ^ S ^ SCHCOOH &

245 to 253

OH

Ν '

OH

M / z ^with NH 2 CO 3 CH 2 COOH

247—255

N — N

Λ k ^ S ^ SCHCOOH

-I '! I ~ ^^ SCH £ OOH

239 to 248

244 to 252

N — N ii k

- ^ S ^ SCHfOOH

232 to 241

The minimum inhibitory concentrations of the compounds shown in the following tables according to the invention are compared to the known ones.

Minimum inhibitory concentration (^ g / ml)

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

* CET (Cephalotin) i—

COON &.

* CEZ (Cefazoline)

N — N | 'N-CH, CONH _n = 7 *'

J = f ^δ Ί N — N

N -? - c? S?

COON &. ³ OBJECT OF INVENTION

Claims (1)

A process for the preparation of 7- (N-acylamino-α-aryl or thienylacetamido) -3- (heterocyclothiomethyl) -3-cephem-4-carboxylic acids of the general formula I wherein: UO-A-CON-CH-CONH AND R A is a polycyclic heteroaromatic ring containing at least one nitrogen atom as a heteroatom selected from the group of naphthyridine, pyridopyrimidine or pyrazolopyridine, each of which rings is optionally substituted with a substituent selected from C 1-4 alkyl or C 1-4 alkylthio carbon, R is a phenyl radical optionally substituted by 1 or 2 substituents selected from hydroxyl, amino, hydroxymethyl, ureido, halogen or thienyl, and D is one of the groups of formula (CN = COOH Λ A S (CH 2 COOH ⁿ - N - S 2 S) (CH 2 COOH n - n ΑςΑ ^with NH (CO). "(CH ^ COOH wherein m and n are integers from O to 3 and the non-toxic pharmaceutically acceptable salts thereof, characterized by reacting a compound of formula II HO — A — COOH, (II) wherein A is as defined above, or a reactive derivative thereof with a compound of formula III R and D are as defined above, or with a salt or functional derivative thereof, and the resulting compound is optionally converted to a pharmaceutically acceptable salt thereof.