ChemicalBook > Product Catalog > API > Synthetic Anti-infective Drugs > Antifungal Drugs > Voriconazole
Voriconazole Chemical Properties
- Melting point:127-130°C
- alpha D25 -62° (c = 1 in methanol)
- Boiling point:508.6±60.0 °C(Predicted)
- Density 1.42±0.1 g/cm3(Predicted)
- Flash point:9℃
- storage temp. Store at +4°C
- solubility DMSO: >20mg/mL
- form white powder
- Merck 14,10033
- CAS DataBase Reference137234-62-9(CAS DataBase Reference)
- Hazard Codes Xn,T,F
- Risk Statements 22-36/38-52/53-48/22-40-25-61-39/23/24/25-23/24/25-11
- Safety Statements 26-36-45-36/37-22-53-16
- RIDADR UN1230 - class 3 - PG 2 - Methanol, solution
- WGK Germany 3
- RTECS UV9145000
- HazardClass 6.1
- PackingGroup III
- HS Code 29335990
Voriconazole Usage And Synthesis
- Product description Voriconazole is a broad-spectrum triazole antifungal ,it is primarily used for the treatment of progressive, possibly life-threatening infections in immune deficiency patients. Indications include: immunosuppressed patients with severe fungal infections, acute invasive aspergillosis (the most common pathogen is Aspergillus fumigatus, followed by A. flavus, Aspergillus niger and Aspergillus soil), severe invasive infections caused by fluconazole-resistant Candida (including C. krusei) severe infection caused by Foot actinomycetes bacteria genus and Fusarium bacteria genus . Moderate to severe renal insufficiency is administered intravenously paying caution.
- Pharmacological interactionsCombination With the CYP3A4 substrates, terfenadine, sirolimus, astemizole, cisapride, pimozide or quinidine , can increase blood concentrations of this drug, leading to QT prolongation, and occasionally torsades de pointes ventricular tachycardia.
Combination With Rifampicin, rifabutin, efavirenz, ritonavir (each 400mg, once every 12 hours), carbamazepine and phenobarbital, can significantly lower blood concentrations of voriconazole.
Combination with ergot alkaloids (ergotamine, dihydroergotamine) plasma concentrations of ergot drugs can cause increased ergot poisoning.
The above information is edited by the chemicalbook of Tian Ye.
- Usesbroad-spectrum antifungal
- DescriptionVoriconazole 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.
- Chemical PropertiesCyrstalline Solid
- OriginatorPfizer (UK)
- UsesAn antifungal. An Ergosterol Biosynthesis inhibitor
- UsesAn antifungal (systemic). An ergosterol biosynthesis inhibitor.
- UsesVoriconazole is a triazole, antifungal agent that inhibits a broad range of pathogenic yeasts, including Candida (MIC = 0.03-8 μg/ml), and filamentous fungi such as Aspergillus, Scedosporium, and Fusarium. Its inhibitory action results from its ability to inhibit the synthesis of ergosterol, the major sterol of the fungal cell membrane.
- DefinitionChEBI: 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.
- IndicationsVoriconazole (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.
- Manufacturing ProcessA 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-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.
- brand nameVfend (Pfizer).
- Therapeutic FunctionAntifungal
- Antimicrobial activityThe 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.).
- Acquired resistanceSome fluconazole- and itraconazole-resistant strains of Candida and Aspergillus spp. show reduced susceptibility to voriconazole.
- Pharmaceutical ApplicationsA synthetic triazole formulated for oral and parenteral use.
- Biological ActivityTriazole antifungal agent. Displays potent activity against Candida , Cryptococcus and Aspergillus species.
- PharmacokineticsOral absorption: 96%
Cmax 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%
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.
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.
- Clinical UseAcute and chronic invasive aspergillosis
Serious invasive Candida infections
Serious infections caused by Scedosporium and Fusarium spp.
- Side effectsUnwanted effects include mild to moderate visual disturbance, rashes, and transient abnormalities of liver enzymes. Rare side effects include life-threatening hepatitis.
- Veterinary Drugs and TreatmentsVoriconazole 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.
- PrecautionsSignificant 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.
- Itraconazole Ambroxol Ravuconazole Candesartan Human serum albumin Fluconazole DEXMEDETOMIDINE Linezolid Meropenem Tigecycline (+)-Griseofulvin Ceftriaxone sodium Nystatin Clindamycin (2RS, 3RS)-2-(2,4-Difluorophenyl)-3-(5-fluoropyriMidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) 5-Fluoropyrimidine Pyrimidine 6-ethyl-5-fluoropyrimidine-4(3H) one (intermediate of voriconazole)
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