137234-62-9

Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis, candidosis and other emerging fungal infections seen in immuno compromised patients. It can be synthesized in 3 steps by reaction of readily available 6-( 1 -bromoethyl)-4-chloro-5 fluoropyrimidine with I-(2,4-difluorophenyl)-2-(1,2,4-triazol-I-yl) ethanone in the presence of zinc metal. The resulting racemic mixture was submitted to a reductive dechlorination step followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurally related to fluconazole (Pfizer, diflucan^?) and acts by inhibiting the cytochrome P450- dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole. In clinical trials, voriconazole was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis and HIV patients with oropharyngeal candidiasis. Voriconazole is available as oral or intravenous formulations. Following oral administration, absorption is rapid and the bioavailability is greater than 80%. Voriconazole exhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and a relatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450 and has a drug interactions potential similar to itraconazole. Voriconazole was generally well tolerated, the most common treatment-related adverse events were transient visual disturbances.

Cyrstalline Solid

Pfizer (UK)

Voriconazole is an antifungal (systemic) that belong to an ergosterol biosynthesis inhibitor. It is used to treat serious fungal or yeast infections, such as aspergillosis (fungal infection in the lungs), candidemia (fungal infection in the blood), esophageal candidiasis (candida esophagitis), or other fungal infections (infections in the skin, stomach, kidney, bladder, or wounds).

ChEBI: A triazole-based antifungal agent used for the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. It is an inhibitor of cytochr me P450 2C9 (CYP2C9) and CYP3A4.

Voriconazole (Vfend), a derivative of fluconazole, is a second-generation triazole that has improved antifungal activity against Aspergillus and Fusarium spp., P. boydii, Penicillium marneffei, and fluconazole-resistant Candida spp. Like fluconazole, voriconazole has high oral bioavailability and good cerebrospinal fluid penetration, but unlike fluconazole, it undergoes extensive hepatic metabolism and is highly protein bound. No significant amount of bioactive drug is excreted into the urine. Dosage reduction is necessary with severe hepatic insufficiency but not with renal insufficiency.

A solution of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H- 1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (0.307 g, 0.8 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (30 mg) and sodium acetate (0.082 g, 1 mmol). After 5 hours a further 10 mg of 10% palladium-on-charcoal was added and hydrogenation was continued for an additional 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. 'Flash' chromatography of the residue on silica using 97:3 ethyl acetate/methanol as the eluent provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the 2- (2,4-difluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-I-yl)butan- 2-ol enantiomeric pair B, (0.249 g, 89%), m.p. 127°C.
2-(2,4-DifluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol enantiomeric pair A was prepared by a similar method using 3- (4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol, enantiomeric pair A as a starting material. This gave the product with m.p. 137°C.

Vfend (Pfizer).

Antifungal

The spectrum includes most fungi that cause human disease: dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Pen. marneffei and Spor. schenckii), molds (Aspergillus spp., Fusarium spp. and Scedosporium spp.), dematiaceous fungi and yeasts (Candida spp., Cryptococcus spp. and Trichosporon spp.).

Some fluconazole- and itraconazole-resistant strains of Candida and Aspergillus spp. show reduced susceptibility to voriconazole.

A synthetic triazole formulated for oral and parenteral use.

Triazole antifungal agent. Displays potent activity against Candida , Cryptococcus and Aspergillus species.

Voriconazole is an antifungal used to treat serious fungal infections. Voriconazole inhibits ergosterol synthesis by inhibiting CYP450-dependent 14-α sterol demethylase resulting in a depletion of ergosterol in fungal cell membranes.

Oral absorption: 96%
C_max 400 mg oral: c. 2 mg/L after 2 h
Plasma half-life: c. 6 h
Volume of distribution: 4.6 L/kg
Plasma protein binding: 58%
Absorption
Oral absorption is rapid and almost complete, and is unaffected by intragastric pH. In adults, there is a disproportionate increase in blood concentrations with increasing oral and parenteral dosage, due to partial saturation of first-pass metabolism. In children given low dosages of the drug, proportional changes in drug levels are seen.
Distribution
It is widely distributed into body tissues and fluids, including brain and CSF.
Metabolism and excretion
It is extensively metabolized by the liver. More than 80% of a dose appears in the urine, but less than 2% is excreted in unchanged form. It is metabolized by several different hepatic cytochrome P₄₅₀ enzymes. Some people with point mutations in the genes encoding these enzymes are poor metabolizers while others are extensive metabolizers. Drug levels are as much as four-fold lower in individuals who metabolize the drug more extensively.

Acute and chronic invasive aspergillosis
Serious invasive Candida infections
Serious infections caused by Scedosporium and Fusarium spp.

Unwanted effects include mild to moderate visual disturbance, rashes, and transient abnormalities of liver enzymes. Rare side effects include life-threatening hepatitis.

The synthesis of voriconazole is an excellent example of process research. As depicted in the scheme, 5-fluorouracil (229) was chlorinated in both the 2- and 4- positions using a mixture of phosphorus oxychloride and N,N-dimethylaniline at 95° C to afford 230 in 95% yield. Dichloro pyrimidine 230 was reacted with ethyl magnesium bromide to give dihydropyrimidine adduct 231. Adduct 231 was oxidized prior to quenching using a mixture of iodine and TEA in THF to give 2,4-dichloro-6-ethyl-5-fluoro pyrimidine (232) in 75% yield. Reaction of 232 with two equiv of aqueous NaOH at reflux gave selective displacement of the chloro functionality at 4-position. Acidification of the reaction and extraction with DCM gave 2-chloro-6-ethyl-5-fluoro-4(3H)- pyrimidine which was conveniently isolated as its ammonia salt 233. Dechlorination of 233 was achieved using catalytic hydrogenation at 50℃ to provide 234 in 80% yield. Alternatively, 4-fluoro-6-ethyl-5-fluoropyrimidine (234) was prepared in a two-pot process in which methyl 3- oxopentanoate (235) was fluorinated with fluorine gas to give methyl 2-fluoro-3-oxopentanoate (236) in 80-90% yield. This ester was then cyclized with formamidine acetate in the presence of NaOMe to give 234 in a moderate yield (50-70%). Reaction of 234 with phosphorus oxychloride and TEA afforded 4-chloro-6-methyl-5- fluoropyrimidine (237) in 90% yield. Reaction of 237 with NBS in the presence of AIBN initiator provided bromide 238 in 95% yield. A Reformatsky protocol was employed in the condensation of 238 with ketone 239 which was an intermediate in the commercial synthesis of Diflucan. A solution of iodine in THF was added to a slurry of zinc and lead at rt and then a mixture of bromide 238 and ketone 239 were added to the above mixture at 5°C for 30 min. This provided the best diastereomeric selectivity and the ratio of 241 and 240 enantiomeric pair reached approximately 10 to 1. Adduct 241 was de-chlorinated using standard hydrogenation condition (5% w/w Pd on carbon /15 psi hydrogen) to give the racemate of voriconazole. The racemic voriconazole was resolved using (1R)-10-camphorsulfonic acid (242) and crystallization of the required diastereomeric salt provided optically pure voriconazole (28) in 80% yield.

Voriconazole may be a useful treatment for a variety of fungal infections in veterinary patients, particularly against Blastomyces, Cryptococcus, and Aspergillus. It has high oral bioavailability in a variety of species and can cross into the CNS. Currently available human dosage forms are extremely expensive, however, and little clinical experience has occurred using voriconazole in veterinary patients. There is considerable interest in using voriconazole for treating aspergillosis in pet birds as their relative small size may allow the drug to be affordable; additional research must be performed before dosing regimens are available.

Potentially hazardous interactions with other drugs
Analgesics: concentration of diclofenac, ibuprofen, alfentanil, methadone and oxycodone increased, consider reducing alfentanil and methadone dose; concentration of fentanyl possibly increased.
Anti-arrhythmics: avoid with dronedarone.
Antibacterials: concentration reduced by rifabutin; increase dose of voriconazole from 200 to 350 mg and from 100 to 200 mg (depends on patient’s weight), and increase IV dose to 5 mg/kg if used in combination - avoid concomitant use if possible; increased rifabutin levels - monitor for toxicity; concentration reduced by rifampicin - avoid.
Anticoagulants: avoid with apixiban and rivaroxaban; enhanced effect of coumarins.
Antidepressants: avoid concomitant use with reboxetine; concentration reduced by St John’s wort - avoid.
Antidiabetics: possibly increased concentration of sulphonylureas.
Antiepileptics: concentration possibly reduced by carbamazepine, phenobarbital and primidone - avoid; fosphenytoin and phenytoin reduces voriconazole concentration and voriconazole increases fosphenytoin and phenytoin concentration - double oral voriconazole dose and increase IV to 5 mg/kg dose if using with phenytoin; avoid if possible.
Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: concentration of lurasidone increased - avoid concomitant use; increased risk of ventricular arrhythmias with pimozide - avoid concomitant use; possibly increased quetiapine levels - avoid concomitant use.
Antivirals: concentration increased or decreased by atazanavir and concentration of atazanavir reduced; concentration of daclatasvir possibly increased - reduce daclatasvir dose; concentration possibly affected by darunavir; concentration reduced by efavirenz and ritonavir; also concentration of efavirenz increased - avoid with ritonavir; with efavirenz reduce dose by 50
% and increase dose of voriconazole to 400 mg twice daily; concentration possibly increased by simeprevir - avoid; concentration possibly affected by telaprevir - increased risk of ventricular arrhythmias; possibly increased saquinavir levels; concentration of simeprevir possibly increased - avoid.
Avanafil: possibly increased avanafil concentration - avoid.
Benzodiazepines: may inhibit metabolism of diazepam and midazolam.
Ciclosporin: AUC increased - reduce ciclosporin dose by 50
% and monitor closely.
Clopidogrel: possibly reduced antiplatelet effect.
Cytotoxics: possibly increases bosutinib concentration - avoid or reduce dose of bosutinib; possibly increases crizotinib and everolimus concentration - avoid; possibly increases ibrutinib, pazopanib and ponatinib concentration - reduce dose of ibrutinib, pazopanib and ponatinib; avoid with ceritinib, lapatinib, nilotinib, cabazitaxel and docetaxel (or reduce dose of cabazitaxel, ceritinib and docetaxel); reduce dose of panobinostat and ruxolitinib.
Domperidone: possible increased risk of arrhythmias - avoid.
Ergot alkaloids: risk of ergotism - avoid.
Ivacaftor and lumacaftor: possibly increase ivacaftor concentration - reduce dose of ivacaftor and ivacaftor with lumacaftor.
Lipid-lowering drugs: possibly increased risk of myopathy with atorvastatin or simvastatin; avoid with lomitapide.
Ranolazine: possibly increased ranolazine concentration - avoid.
Retinoids: possibly increased risk of tretinoin toxicity.
Sirolimus: increased sirolimus concentration - avoid.
Tacrolimus: AUC increased - reduce tacrolimus dose to a third and monitor closely.
Ulcer-healing drugs: esomeprazole and omeprazole concentration increased - reduce omeprazole dose by 50
%.

Voriconazole is metabolised by hepatic cytochrome P450 isoenzyme CYP2C19; the major metabolite is the inactive N-oxide. Metabolism via isoenzymes CYP2C9 and CYP3A4 has also been shown in vitro.
Voriconazole is eliminated via hepatic metabolism with less than 2
% of the dose excreted unchanged in the urine. After administration of a radiolabelled dose of voriconazole, approximately 80
% of the radioactivity is recovered in the urine as metabolites. The majority (>94
%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing

Store at -20°C

Voriconazole is structurally related to fluconazole (Pfizer, diflucan) and acts by inhibiting the cytochrome P450- dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole.

Significant drug interactions include cyclosporins(increased cyclosporine levels), phenytoin, rifampin,and rifabutin (decreased voriconazole levels). Becauseof its low toxicity profile, this drug may gain importancein the chronic treatment of infections with invasive dimorphicfungi and resistant Candida spp.

[1] sabo ja, abdel-rahman sm. voriconazole: a new triazole antifungal. ann pharmacother. 2000 sep;34(9):1032-43.
[2] johnson lb, kauffman ca. voriconazole: a new triazole antifungal agent. clin infect dis. 2003 mar 1;36(5):630-7.