TROVAFLOXACIN

Absorption

Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.

Toxicity

Symptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.

Originator

Trovan,Pfizer,USA

The Uses of TROVAFLOXACIN

Trovafloxacin is a fluroquinolone antibiotic, recently identified as an inhibitor of pannexin-1 (Panx1) channels. Trovafloxacin attenuates neuroinflammation and improves outcome after traumatic brain injury in mice.

The Uses of TROVAFLOXACIN

Antibacterial.

Indications

For treatment of infections caused by susceptible strains of the designated microorganisms in uncomplicated urethral gonorrhea in males and endocervical and rectal gonorrhea in females caused by Neisseria gonorrhoeae as well as non gonoccocal urethritis and cervicitis due to Chlamydia trachomatis.

Background

Trovafloxacin is a broad spectrum antibiotic that has been commonly marketed under the brand name Trovan by Pfizer. It exerts its antibacterial activity by inhibiting the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was shown to be more effective against Gram-positive bacteria than Gram-negative bacteria when compared to previous fluoroquinolones. Due to its hepatotoxic potential, trovafloxacin was withdrawn from the market.

Definition

ChEBI: A 1,8-naphthyridine derivative that is 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid bearing additional 2,4-difluorophenyl, fluoro and 6-amino-3-azabicyclo[3.1.0]hex-3-yl substituents at positions 1, 6 and 7 respectively. A broad-spectrum antibiot c that was withdrawn from the market due to risk of liver failure.

Manufacturing Process

N-Benzylmaleimide (500 g, 2.67 mole), 90% bromonitromethane (831 g, 5.34 mole), powdered molecular sieves 200 mesh (2020 g) and toluene (12 dm3) were stirred under nitrogen at -10°C. 1,2-Dimethyl-1,4,5,6- tetrahydropyrimidine (616 g, 5.49 mole) was added slowly over about 3 h maintaining the reaction temperature at <-8°C throughout the addition. After completion of the addition, the reaction mixture was stirred for 1.5 h at 25°C, filtered under a nitrogen atmosphere in a sealed pressure filter to remove sieves and resulting tar, and the sieves were washed with toluene (2 L). The combined filtrates were washed with 2 N dilute hydrochloric acid (3 times 750 cm3), treated with carbon (50 g) at 70°C, 1 h filtered, concentrated, and triturated with 2-propanol (about 4 dm3) to obtain crystals of the (1α,5α,6α)- 3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane (223 g, 34%) melting point 116°-118°C.
Tetrahydrofuran (350 cm3), sodium borohydride (14.1 g) and (1α,5α,6α)-3-N_x0002_benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane (35.0 g, mmol) obtained above were stirred under nitrogen for 0.25 h and then treated dropwise with boron trifluoride-THF complex containing 21.5% BF3 (44.9 cm3) so that the exotherm was controlled to <40°C. After addition was completed, the reaction mixture was stirred for 3 h at 40°C, quenched slowly with water/THF 1:1 (70 cm3) to avoid excessive foaming, and stirred for 0.5 h at 50°C to ensure that the quench of unreacted diborane generated in situ was completed. The quench formed a salt slurry which was filtered and washed with THF (140 cm3); the combined filtrate was partially concentrated, diluted with water (350 cm3) and further concentrated to remove most of the THF, and extracted with ethyl acetate (140 cm3). The resulting ethyl acetate solution was concentrated to afford the (1α,5α,6α)-3-N-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane as a clear oil (30.6 g, 97%).
(1α,5α,6α)-3-N-Benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (30.9 g, 142 mmol) obtained above, 2-propanol (310 cm3), water (30 cm3), and 10% Pd on carbon, 50% water content (12.3 g) were hydrogenated at 50 psi and 50°C for 18-24 h in a Parr shaker. The Pd catalyst was filtered off, and the resulting pale yellow filtrate was azeotropically distilled at constant volume to remove water. The resulting solution was treated with triethylamine (46 g, 456 mmol) and heated to reflux. Benzaldehyde (15.0 g, 141 mmol) was added dropwise over 15 min. The reaction mixture was heated at reflux for 4 h to form (1α,5α,6α)-6-benzylidenylamino-3-azabicyclo[3.1.0]hexane in situ. The resulting orange solution was cooled to 40°-50°C, and ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (42.45 g, 111 mmol; see United Kingdom Patent Publication No. GB 2,191,776) and triethylamine (13.1 g, 130 mmol) were added. The resulting slurry was heated at reflux for 16-18 h, cooled to 20°C and stirred for 5 h. The slurry was filtered, and the compound was isolated as a white solid (75.5% yield based on (1α,5α,6α)-3-N-benzyl-6-nitro-2,4-dioxo-3- azabicyclo[3.1.0]hexane; 96.6% based on ethyl 7-chloro-1-(2,4- difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid). The ethyl (1α,5α,6α)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex- 3yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylate was recrystallized from acetonitrile, melting point 148°-155°C decomp.
Tetrahydrofuran (250 cm3), ethyl (1α,5α,6α)-7-(6-benzylidenylamino-3- azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylate (25.05 g, 47 mmol) obtained above, and water (250 cm3) were treated with 97% methanesulfonic acid (13.3 g, 138 mmol) and heated to reflux for 24 h. The resulting solution was cooled to 45°C, treated with activated carbon (2.5 g) for 1 h and filtered. The resulting filtrate was concentrated under vacuum to approximately 25% of its original volume to provide a white crystal slurry, cooled to 15°-25°C, granulated for 4 h and filtered to yield the trovafloxacin methanesulfonate salt (mesylate) (16.86 g, 70.0%). Melting point 253°-256°C decomp.

brand name

Trovan (Pfizer).

Therapeutic Function

Antibacterial

Pharmacokinetics

Trovafloxacin is a broad spectrum antibiotic that inhibits DNA supercoiling in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It is not used widely due to the risk of hepatotoxicity. It tends to have better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.

Metabolism

Metabolism Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). The major metabolites include the ester glucuronide, which appears in the urine (13% of the administered dose); and the N -acetyl metabolite, which appears in the feces and serum (9% and 2.5% of the administered dose, respectively). Other minor metabolites include diacid, hydroxycarboxylic acid, and sulfamate, which have been identified in both the feces and the urine in small amounts (< 4% of the administered dose).