CS199292B2 - Method of producing novel 7-/n-arylcarbonylamino-alpha-arylacetamido/-3-carbamoyl-3-cephem-4-carboxylic acids - Google Patents

Abstract

PURPOSE:Title compounds of formula I (A is mono-or polycyclic, N-containing, 6-membered aromatic hetero-ring; R is (substd.) phenyl, thienyl; R1, R2 are H, lower alkyl); for example, 7-[D-alpha-(4-hydroxypyridine-3-carbonamide)-d-phydroxyphenylacetamido ]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid of formula II.

Description

The invention relates to a process for the production 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. 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 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 of the microorganism.

These derivatives also have high activity against other microorganisms against which conventional cephalosporins are poorly active. It is therefore 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 the novel 7- (N-arylcarbonylamino-alpha-arylacetamido-4-carbamoyl-4-cephem-a-carboxylic acids of formula (I)

HO-A-CONH-CH-C ON i

R

CH.OCON ^ _{COOH ()} ^R A.

substituted with 1 or 2 substituents selected from hydroxy, halogen or

Ahienyl group a

R 1 and R 2 are hydrogen atoms or C 1 -C 4 alkyl radicals wherein

A is a naphthyl, pyridopyrimine or pyridine residue,

R represents a phenyl radical, optionally as well as a non-toxic, pharmaceutically acceptable salt thereof, characterized in that a compound of formula II is reacted

-HO — A — COOH where

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

where

R, R 1 and R e are as defined above, or with a salt thereof or a functional derivative 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. 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 carboxylic acid derivatives, for example halide, anhydride, azolid, active ester, azide and the like. Examples of such derivatives include mixed anhydrides or symmetrical anhydrides with acids such as dialkylphosphoric, phenylphosphoric, diphenylphosphoric, halogenated phosphoric acid, dialkylphosphoric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, alkyl carbonates, aliphatic carboxylic acids, e.g. dimethylpyrazole, triazole, tetrazole, and the like, and the active esters such as cyanomethyl, methoxymethyl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, methanesulfonylphenyl, phenyl phenyl. thiophenyl ester, p-nitrophenylthioester, p-cresolthioester, carboxymethylthioester, pyranyl ester, pyridylester, piperidylester, 8-quinolylthioester and esters of N, N'-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysucinimide or N-hydroxyysphthalimide .

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-N-ethylcarbodiimide, - (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyl-di (2-methylimidazole), pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylenes, 1-alkoxy-1-chlorethylenes, trialkylphosphites, polyphosphoric acids in ethyl ester form , isopropyl ester of polyphosphoric acid, phosphorus oxychloride, oxalyl chloride, triphenylphosphine, diethylphosphonylazide, diphenylphosphonylazide, 2-ethyl-7-hydroxybenzisoxallic acid salts, 2-ethyl-5- (m-sulfonyljisoxazolium) - internal salts with hydroxide, - (chloromethylene chloride) dimethyl ammonium ammonium

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, naphthalene, lion, tetralin sulfone, trifluoroacetic acid, hydrochloric acid and the like.

The reactive derivatives of the compounds of formula (III) may be carboxy-protected derivatives, which are protected in a conventional manner, or may be an ester, amide or anhydride of a compound of formula (III).

Examples of such carboxy-protected derivatives are silyl esters, tin-containing organic esters, toluenesulfonyl ester, p-nitrobenzyl ester, benzyl esters, phenacyl ester, 2-furylmethyl ester, diphenylmethyl ester, substituted diphenylmethyl ethyl ester, p-methoxybenzyl ester, p-methoxybenzyl ester, , p-nitrophenyl ester, methylsulfonylphenyl ester, methylthiophenyl ester, tert-butyl ester, 4-picolylester, iodoethyl ester, trichloroethyl ester, phthalimidomethyl ester, 3,4-dimethoxy or 3,5-dimethylbenzyl ester, 2-nitrobenzyl ester acetylacetyl ester, 2,2-nitrobenzyl ester acetylene ester, 2,2-nitrobenzyl ester . Compounds of formula (III) in which the carboxyl group is protected by a group of formula (I) may also be used

a group of the formula wherein —N = CH — R‘,

R‘ represents an alkyl or aryl group, or a group of the formula

Ό

II

In the case of the silyl ester, other optional substituents of the compound of formula III, for example hydroxy or amino, may also be silylated.

Salts of hydrochloric acid, p-toluenesulfonic acid, naphthalenesulfonic acid or tetralinsulfonic acid can also be used for the compounds of the formula III.

After completion of the reaction, the carboxyl protecting group may be removed. This removal can be carried out, for example, in a solvent such as hydrolysis, alcoholysis, or catalytic hydrogenation, reduction, oxidation, nuclear substitution, photochemical reactions or enzymatic reactions.

Reaction between an acid of formula II or a reactive derivative thereof and a. the compound of formula III or a derivative thereof is usually carried out at a temperature of -50 to (50 ° C).

The starting materials of the formula II and their reactive derivatives are known compounds which can be prepared in a manner known per se, as described, for example, in J. Am. Chem. Soc. 68, 1317 (1946), J. Chem. Soc., (C), 19S6, 1816, J. Chem. Soc., 1953, 4175, Helvetica Chimica Acta, 37, 134 (1954), Chem. Pharm. Bull., 19 (7), 1482-1486 (1971), J. Am. Chem. Soc., 78, 1938 (1956); J. Het. Chem., 9, 235 (1972), Roczuiki Chemii, 48, (2) 321-324 (1974).

Compounds of formula (III) can be obtained as described in DE-OS 2 203 653.

Compounds of formula III wherein T is -CH 2 N 3 can be obtained as described in British Patent Specification No. 1,297,069.

Alternatively, a compound of formula (I) may be obtained by reacting an acylaminocarboxylic acid of formula (VI).

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. They 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 Corynebacterium colieriae Salmonella typhi, Kltebsiella pneumoniae, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter aerogenes, Proteus mirabilis, Proteus 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, 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, etc. 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- [D- [alpha] - (4-hydroxypyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid

ОН

4.22 g of 7- (Da-amino-α-hydroxyphenylacetamido) -3- (carbamoyloxymethyl) -3-cephem-4-carboxylic acid, 2.02 g of triethylamine and 30 ml of dimethyl sulfoxide are stirred at room temperature, 2.36 g of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide ester and the mixture was allowed to react for 20 minutes at the same temperature with stirring. Sodium 2-ethylhexanoate (1.66 g) was added and the solution was added dropwise to the solution over 10 minutes

500 ml acetone. The product precipitated as the sodium salt, filtered off and dried under phosphorus pentoxide under reduced pressure. 3.82 g of product are obtained.

Examples 2 to 9

The following compounds can be prepared by the method of Example 4.

HO-A-CONH-CH-CONH

AND

R

Example #

HO — A—

COOH —R

OH

OH

OH

OH

OH

OH

The anti-microbial properties of these compounds in vitro are shown in the following table. Table

Minimum inhibitory concentration (µg / ml)

Example Staphylo- Staphylo- Escherichia Klebsiella Proteus Pseudo- C. coccus coccus coli pneumoniae vulgaris monas aureus aureus NIHJ 602 HX 19 aeruginosa 209P FS 289 104

4 0.39 3.13 12.5 12.5 0.2 6.25 5 0.39 3.13 6.25 12.5 0.2 6.25 6 0.39 3.13 12.5 12.5 0.2 12.5 7 0.78 6.25 3.13 1.56 0.78 6.25 8 0.78 6.25 3.13 1.56 0.78 6.25 9 0.78 3.13 1.56 1.56 0.78 6.25 10 0.78 3.13 6.25 6.25 1.56 6.25 11 1.56 6.25 6.25 6.25 1.56 12.5 12 1.56 6.25 3.13 1.56 0.78 6.25 HO-A -CONH-CH- 1 CONH— | - AND 1 R 0 ^ XCHOCONH. COOH

HO — A— —R

Example #

OH

OH

Example #

Minimum inhibitory concentration (MIC) [g g / ml]

Example Staphylo- Staphylo- Escheri- Klebsiella Proteus Pseudomo- C. coccus coccus chia pneumoniae vulgaris nas aerugi- aureus aureus coli 602 HX 19 nosa 104 209 P FS 289 NIHJ 1 0.39 3.13 1.56 0.78 0.39 3.13 2 0.78 6.25 1.56 0.78 0.78 6.25 3 0.78 6.25 3.13 0.78 0.39 3.13 4 0.78 6.25 3.13 0.78 0.78 6.25 5 0.78 6.25 3.13 1.56 0.78 6.25 6 0.78 6.25 6.25 1.56 0.78 6.25 7 0.78 6.25 3.13 0.78 0.78 6.25 8 0.78 6.25 3.13 0.78 0.78 6.25 9 0.78 6.25 3.13 0.78 0.78 6.25 10 1.56 6.25 6.25 1.56 0.78 6.25 11 0.39 3.13 6.25 6.25 0.2 6.25 12 0.39 3.13 12.5 6.25 0.78 12.5 13 0.39 3.13 6.25 12.5 0.2 6.25 14 1.56 12.5 6.25 12.5 1.56 6.25 15 Dec 0.78 6.25 6.25 1.56 0.78 6.25

In the manner described in the above examples, the appropriate starting materials are possible. to obtain other compounds which are listed in the following table.

Compounds of formula I *

HO - A - CONH - CH - CONH

R ·. r

COOH λ * R configuration = D-diastereomer

HO — A— —R

OH

- NH2

OH

- NH2

- NH2

HO — A— —R

Ri

Z —N \

Rž

OH

OH

OH

—NH2 —NH2 —NH2

-nh ₂ —NHa

Claims (1)

OBJECT OF INVENTION Process for the preparation of new 7- (N-arylcarbonyl-amino-alpha-arylacetamido) -3-carbamoyl-3- HO-A-CONH-C 1 H-CONH ....... R where A is a naphthyridine, pyridopyrimidine or pyridine residue, R is a phenyl radical optionally substituted by 1 or 2 substituents from. a hydroxy group, a halogen atom, or a thienyl group; and R 1 and R 2 are hydrogen atoms or C 1 -C 4 alkyl radicals, as well as non-toxic, pharmaceutically acceptable salts of the compounds of formula (I), characterized in that: in the reaction, a compound of formula II HO — A — COOH (Π) where A is as hereinbefore defined or a reactive derivative thereof with a compound of formula III a functional derivative and optionally converting the compound obtained to its non-toxic pharmaceutically acceptable salt. where R, R 1 and R 2 are as defined above, or with a salt of the compound or its compound