CeftazidiMe

Description

In ceftazidime the oxime moiety is more complex, containing two methyl groups and a carboxylic acid. This assemblage conveys even more pronounced β-lactamase stability, greater anti–Pseudomonas aerugi nosa, and increased activity against Gram-positive organisms. The C-3 side chain has been replaced by a charged pyridinium moiety. The latter considerably enhances water solubility and also highly activates the β-lactam bond toward cleavage. The drug must be protected against heat and light and may darken without significant loss of potency. It is not stable under some conditions. such as the presence of aminoglycosides and vancomycin. It also is attacked readily in sodium bicarbonate solutions. Resistance is mediated by chromosomally mediated β-lactamases and by lack of penetration into target bacteria. Otherwise, it has a very broad antibacterial spectrum.

Chemical Properties

solid

Originator

Fortum,Glaxo,UK,1983

Uses

pyrimidine synthesis inhibitor disease-modifying antirheumatic drug

Uses

5-HT agonist, anti-migrane

Uses

Third generation cephalosporin antibiotic. Antibacterial

Uses

Like most of the third-generation cephalosporin antibiotics described above, ceftazidime has a broad spectrum of antimicrobial action, including the most clinically important microorganisms: Gram-positive, Gram-negative, aerobic, and anaerobic. It is resistant to most beta-lactamases of Gram-positive and Gram-negative bacteria. It is used for treating most serious bacterial infections. Synonyms of this drug are fortum, ceftim, stacef, and tazicef.

Definition

ChEBI: A cephalosporin bearing pyridinium-1-ylmethyl and {[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido groups at positions 3 and 7, respectively, of the cephem skeleton.

Manufacturing Process

(a) t-Butyl(6R,7R)-3-acetoxymethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2- oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylate: A stirred solution of (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2- tritylaminothiazol-4-yl)acetic acid (572 mg) and t-butyl(6R,7R)-3- acetoxymethyl-7-aminoceph-3-em-4-carboxylate (328 mg) in dimethylformamide (10 ml) was cooled to 0°C, and 1-hydroxybenzotriazole (150 mg) was added, followed by dicyclohexylcarbodiimide (225 mg). The mixture was warmed to room temperature, stirred for 5 hours and allowed to stand overnight. The mixture was filtered, and the white solid washed with a little ether. The filtrate and washings were diluted with water (50 ml) and extracted with ethyl acetate. The organic extracts were combined, washed successively with water, 2 N hydrochloric acid, water, sodium bicarbonate solution, and saturated brine, dried and evaporated. The residue was eluted through a silica column with ether. The product-containing eluate was collected and concentrated to give the title compound (533 mg). A portion was recrystallized from diisopropyl ether, MP 103°C to 113°C (decomp.); [α]D20 +8.5 (conc. 1.0, DMSO).
(b) (6R,7R)-3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2- carboxyprop-2-oxyimino)acetamido]ceph-3-em-4-carboxylic acid: Trifluoroacetic acid (18 ml) was added to a solution of the product of (a) (2.4 g) in anisole (18 ml) at 0°C. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the aqueous extracts was adjusted to 6, and the solution washed with ethyl acetate. The aqueous phase was acidified to pH 1.5 under ethyl acetate, saturated with sodium chloride, and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated. The residue was dissolved in warm 50% aqueous formic acid (20 ml) and allowed to stand for 2 hours. The mixture was diluted with water (50 ml) and filtered. The filtrate was concentrated. The residue was taken up in water (50 ml), refiltered, and lyophilized to give the title compound (920 mg).
(c) (6R,7R)-7-[(Z)-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2- oxyimino)acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate, monosodium salt: Pyridine (2 ml) and the product of (b) (1.8 g) were added to a stirred solution of sodium iodide (7.12 g) in water (2.2 ml) at 80°C. The solution was stirred at 80 C for 1 hour, cooled, and diluted to 100 ml with water. The pH of the solution was adjusted to 6.0 with 2N sodium hydroxide solution, and this solution was concentrated to remove pyridine. The aqueous residue was diluted to 100 ml with water, methyl isobutyl ketone (2 drops) was added, and the solution was acidified to pH 1 with 2 N hydrochloric acid. The mixture was filtered, and the solid was washed with a little water. The filtrate and washings were collected and washed with ethyl acetate, and the pH adjusted to 6.0 with 2 N sodium hydroxide solution. The solution was concentrated to 50 ml and applied to a column of 500 g Amberlite XAD-2 resin, using first water and then 20% aqueous ethanol as eluting solvent. The product-containing fractions were concentrated and lyophilized to give the title compound (0.56 g).

brand name

Fortaz (GlaxoSmithKline); Tazicef (Hospira); Tazidime (Lilly).

Therapeutic Function

Antibiotic

Clinical Use

Antibacterial agent

Synthesis

Ceftazidime is 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy) imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3- yl]methyl]pyridin-2-carboxylic acid (32.1.2.82). As is the case in synthesis of ceftriazone, the synthesis of ceftazidime requires the preliminary synthesis of two starting compounds. 7-Amino-3-(1-pyridinomethyl)cef-3-en-carboxylic acid dihydrochloride is used as the cephalosporin fragment, while the acyl fragment is a modified structure of (32.1.2.77), which is not a derivative of 2-(2-amino-4-thiazolyl)-2-methoxyminoacetic acid, but a derivative of 2-(2-amino-4-thiazolyl)-2-(2-tert-butoxycarboxyl-2-propyloximino)acetic acid, which is synthesized by the following scheme. Nitration of acetoacetic ester gives isonitrosoacetoacetic ester (32.1.2.49), which undergoes chlorination by sulfuryl chloride in methylene chloride to form 4-chloro-2-hydroximinoacetoacetic ester (32.1.2.73).
Reacting this with thiourea in the classic scheme of thiazole synthesis by reacting of |á-halogencarbonyl compounds with thioamides forms the ethyl ester of (Z)-2-(2-aminothiazole-4-yl)-2-hydroxyminoacetic acid (32.1.2.74). The amino group in this molecule is protected by a reaction with triphenylchloromethane in dimethylformamide in the presence of triethylamine, which gives the ethyl ester of (Z)-2-(2-tritylaminothiazole-4-yl)- 2-hydroxyminoacetic acid (32.2.3.75). The hydroxyl group in the resulting compound is alkylated with the tert-butyl ester of |á-bromoisobutyric acid in dimethylsulfoxide in the presence of potassium carbonate, giving ethyl ester of 4-thiazoleacetic acid, |á -[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2- [(triphenylmethyl)amino], (Z) (32.1.2.76). The ethoxycarbonyl group in this molecule is hydrolyzed by sodium hydroxide, and upon working up the reaction mixture with an acid, the corresponding acid (32.1.2.77) is isolated (32.1.2.77). Upon interaction with phosphorous pentachloride the acid chloride (32.1.2.78) is obtained, which is used further as the acylating reagent.
The second necessary fragment, 7-amino-3-(1-pyridinomethyl)cef-3-en-carbonic acid (32.1.2.80), is synthesized from cefalosporidin (32.1.2.79), a cephalosporin antibiotic that is used independently in medicine and which is synthesized in the form of an internal salt by reacting cefalotin (32.1.2.1) with pyridine to replace the acetoxyl group with a pyridine group. Initially treating cephaloridin with trimethylchlorosilane in the presence of dimethylaniline and then with phosphorous pentachloride, followed by a reaction with 1, 3-butandiol results in the creation of 7-amino-3-(1-pyridinomethyl)cef-3-en-carboxylic acid (32.1.2.80). This is acylated by the acid chloride (32.1.2.78) synthesized earlier, forming the product (32.1.2.81), which is treated with a mixture of formic and hydrochloric acids to remove both protective groups (triphenylmethyl and tert-butyl), giving ceftazidime (32.1.2.82) in the form of a dihydrochloride.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: effects of coumarins may be enhanced.
Ciclosporin: may cause increased ciclosporin levels.

Metabolism

Ceftazidime is passively excreted in bile, although only a small proportion (1%) is eliminated by this route. It is mainly excreted by the kidneys, almost exclusively by glomerular filtration; probenecid has little effect on the excretion. About 80-90% of a dose appears unchanged in the urine within 24 hours.