Itraconazole
Beschreibung
Itraconazole is a triazole antifungal agent used to treat a variety of fungal infections, including aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis . It was first synthesized in the early 1980s and approved for medical use in the United States in 1992 . This compound is known for its broad-spectrum activity against fungal pathogens and is available in oral and intravenous formulations .
Eigenschaften
Key on ui mechanism of action |
Itraconazole mediates its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, a vital component of fungal cell membranes. The azole nitrogen atoms in the chemical structure of itraconazole form a complex with the active site, or the haem iron, of the fungal enzyme to impede its function. The accumulation of lanosterol and 14-methylated sterols results in increased permeability of the fungal cell membrane, and modified membrane-bound enzyme activity, and dysregulated chitin synthesis. Other proposed mechanisms of action of itraconazole include the inhibition of fungal cytochrome c oxidative and peroxidative enzymes that also lead to the disruption of fungal cell membranes. In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. |
|---|---|
CAS-Nummer |
84625-61-6 |
Molekularformel |
C35H38Cl2N8O4 |
Molekulargewicht |
705.6 g/mol |
IUPAC-Name |
2-butan-2-yl-4-[4-[4-[4-[[(2R)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one |
InChI |
InChI=1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3/t25?,31?,35-/m0/s1 |
InChI-Schlüssel |
VHVPQPYKVGDNFY-WSTHBRJPSA-N |
Verunreinigungen |
Impurities: 4-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(4H-1,2,4-triazol-4-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-propyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-(1-methylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[trans-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-butyl-4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one. |
SMILES |
CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl |
Isomerische SMILES |
CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5CO[C@](O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl |
Kanonische SMILES |
CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl |
Aussehen |
Solid powder |
Color/Form |
Solid Crystals from toluene |
melting_point |
168-170 166.2 °C |
Andere CAS-Nummern |
84625-61-6 84604-65-9 |
Physikalische Beschreibung |
Solid |
Piktogramme |
Irritant |
Reinheit |
>98% (or refer to the Certificate of Analysis) |
Haltbarkeit |
>2 years if stored properly |
Löslichkeit |
Practically insoluble in water and dilute acidic solutions |
Lagerung |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
Synonyme |
Itraconazole, R51211, Orungal, Oriconazole, Sporanox, Itraconazolum, Itraconazol, Itrizole |
Dampfdruck |
2.6X10-20 mm Hg at 25 °C (est) |
Herkunft des Produkts |
United States |
Vorbereitungsmethoden
Traditional Synthesis Using Triazole Intermediates
The foundational synthesis of this compound involves constructing its triazole core through multi-step reactions. A pivotal intermediate, 2,4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (Formula III), is purified using methanol and dimethylformamide (DMF) to achieve >98% purity. Subsequent condensation with 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolane-4-methanol-4-methyl sulfonate (Formula II) yields crude cis-itraconazole (Formula IV), which undergoes recrystallization in ethanol or acetonitrile.
Key Reaction Parameters
Improved Intermediate Synthesis via One-Step Alkylation
Patent CN101391994B introduces a streamlined method for synthesizing triazole intermediates, replacing hazardous sodium hydride with polyethylene glycol catalysts. This approach reduces production steps from three to one, achieving 80–85% yield while maintaining isomer impurities <11%.
Advantages Over Traditional Methods
- Eliminates explosive hydrogenation steps
- Reduces production costs by 40%
- Enhances scalability for industrial manufacturing
Purification and Crystallization Techniques
Supercritical Fluid Crystallization
GB2551672A details a supercritical CO₂-assisted crystallization method that enhances this compound’s solubility and bioavailability. The process involves:
- Dissolving this compound and L-ascorbic acid in methanol:dichloromethane (1:1–1:9 v/v)
- Adding hydroxypropyl methylcellulose and pluronic F-127 as stabilizers
- Spraying the solution into a CO₂-saturated autoclave at 50–130 Bar
Results
Recrystallization Solvent Optimization
Comparative studies show that ethyl acetate produces this compound crystals with optimal polymorphic Form I, critical for consistent dissolution rates. Ethanol and acetonitrile are preferred for intermediate purification, reducing residual solvents to <0.1%.
Analytical Methods for Quality Control
High-Performance Liquid Chromatography (HPLC)
The FDA mandates HPLC with UV detection (λ=263 nm) to quantify this compound and its metabolites. Column: C18, 5 μm; Mobile phase: acetonitrile:phosphate buffer (pH 3.0) (55:45).
Critical Quality Attributes
X-Ray Diffraction for Polymorph Characterization
XRD analysis confirms the dominance of the bioactive Form I crystal, exhibiting peaks at 2θ=12.8°, 15.4°, and 21.7°. Amorphous content is controlled to <5% via optimized annealing at 80°C for 24 hrs.
Formulation Strategies for Enhanced Delivery
Oral Solution Pharmacokinetics
The FDA-approved oral solution (SPORANOX®) uses hydroxypropyl-β-cyclodextrin to enhance solubility, achieving Cₘₐₓ=2 μg/mL after 200 mg dosing. Steady-state concentrations require 15 days of administration due to this compound’s nonlinear pharmacokinetics (t₁/₂=34–42 hrs).
Excipient Composition
| Component | Function | Concentration (%) |
|---|---|---|
| Hydrochloric acid | pH adjustment | 0.1–0.3 |
| Propylene glycol | Solubilizer | 15–20 |
| Sodium saccharin | Sweetener | 0.05–0.1 |
Nanoparticle Encapsulation
Recent advances utilize PLGA nanoparticles (150–220 nm) loaded via emulsion-diffusion:
- Encapsulation efficiency: 88–92%
- Sustained release over 72 hrs in simulated gastric fluid
- 3-fold increase in mucosal adhesion compared to conventional capsules
Comparative Analysis of Industrial Methods
| Method | Yield (%) | Purity (%) | Cost ($/kg) | Scalability |
|---|---|---|---|---|
| Traditional | 72–78 | 98.5–99.2 | 12,500 | Moderate |
| Supercritical | 89–93 | 99.8–99.9 | 8,200 | High |
| One-Step Alkylation | 80–85 | 99.1–99.4 | 7,800 | High |
Analyse Chemischer Reaktionen
Types of Reactions: Itraconazole undergoes several types of chemical reactions, including oxidation, reduction, and substitution.
Common Reagents and Conditions:
Reduction: Specific reduction reactions of this compound are less common in the literature.
Substitution: Substitution reactions involving this compound typically occur during its synthesis rather than in its metabolic pathways.
Major Products Formed: The major metabolites of this compound include hydroxy-itraconazole, keto-itraconazole, and N-desalkyl-itraconazole .
Wissenschaftliche Forschungsanwendungen
Systemic Fungal Infections
Itraconazole is primarily indicated for the treatment of several serious fungal infections, including:
- Blastomycosis : Effective in both pulmonary and extrapulmonary forms.
- Histoplasmosis : Particularly useful for chronic cavitary pulmonary disease and disseminated forms.
- Aspergillosis : Recommended for patients intolerant to or refractory to amphotericin B therapy .
Superficial Fungal Infections
This compound is also used to treat superficial fungal infections, notably:
- Onychomycosis : The treatment has a cure rate of approximately 63% .
- Seborrheic Dermatitis : Although not FDA-approved for this indication, this compound has shown efficacy when administered in pulse therapy .
Prophylactic Use
This compound is utilized as a prophylactic agent in immunocompromised patients, including those with:
- HIV/AIDS
- Patients undergoing chemotherapy
- Individuals who have received organ transplants
The broad-spectrum coverage and safety profile make this compound a preferred choice for preventing systemic fungal infections in these populations .
Oncological Applications
Recent research has highlighted this compound's potential in cancer treatment:
- Inhibition of Tumor Growth : this compound has been shown to inhibit the Hedgehog signaling pathway, which is involved in cancer cell proliferation. Studies indicate that this compound can induce autophagy-mediated cell death in colon cancer cells, leading to significant tumor growth suppression in animal models .
- Enhanced Chemosensitivity : A clinical retrospective study found that combining this compound with platinum-based chemotherapy improved progression-free survival and overall survival rates in ovarian cancer patients compared to chemotherapy alone .
Formulation and Bioavailability
The pharmacological advancements surrounding this compound have led to the development of various formulations:
- Oral Solutions and Intravenous Formulations : These formulations enhance solubility and bioavailability, making this compound accessible for patients with systemic fungal infections who may have variable absorption from capsule formulations .
Efficacy in Immunocompromised Patients
A study involving patients with HIV demonstrated that those receiving this compound prophylaxis had significantly lower incidences of systemic fungal infections compared to those who did not receive prophylaxis.
Cancer Treatment Trials
Clinical trials exploring the use of this compound in combination with standard chemotherapy regimens have shown promising results, particularly in improving patient outcomes in ovarian cancer.
Summary Table of Applications
| Application Area | Specific Uses | FDA Approval Status |
|---|---|---|
| Systemic Fungal Infections | Blastomycosis, Histoplasmosis, Aspergillosis | Yes |
| Superficial Fungal Infections | Onychomycosis, Seborrheic Dermatitis | Partial (Onychomycosis only) |
| Prophylaxis | HIV/AIDS, Chemotherapy, Organ Transplants | Yes |
| Oncology | Tumor growth inhibition | Research Phase |
Wirkmechanismus
Itraconazole exerts its antifungal effects by inhibiting the enzyme lanosterol 14α-demethylase, a cytochrome P450 enzyme involved in the conversion of lanosterol to ergosterol. Ergosterol is a crucial component of fungal cell membranes. By inhibiting this enzyme, this compound disrupts the synthesis of ergosterol, leading to increased membrane permeability and ultimately fungal cell death .
Vergleich Mit ähnlichen Verbindungen
Itraconazole is often compared with other triazole antifungal agents such as fluconazole, voriconazole, and posaconazole:
Fluconazole: this compound has a broader spectrum of activity, particularly against Aspergillus species, which fluconazole does not cover.
Voriconazole: Voriconazole has a broader spectrum of activity than this compound but is associated with more severe side effects.
Posaconazole: Posaconazole is similar to this compound in terms of spectrum but has better bioavailability and fewer drug interactions.
This compound’s unique properties, such as its broad-spectrum activity and potential use in cancer treatment, make it a valuable compound in both clinical and research settings.
Q & A
Basic Research Questions
Q. What chromatographic methods are validated for simultaneous quantification of itraconazole with other antifungals, and how are critical parameters optimized?
- Methodological Answer : Reverse-phase high-performance liquid chromatography (RP-HPLC) with a Zorbax Eclipse C18 column is recommended. Optimize parameters (e.g., mobile phase pH, flow rate) using a 2³ factorial design to assess resolution, tailing, and theoretical plates. Validation includes robustness testing via fractional factorial design . For example, Roshdy et al. (2021) resolved this compound alongside fluconazole and terbinafine by analyzing interactions between independent variables (e.g., acetonitrile percentage) and responses (e.g., resolution R1–R4) .
Q. How should researchers design in vitro release studies for this compound-loaded nanoparticles to ensure reproducibility?
- Methodological Answer : Use phosphate-buffered saline (pH 6.8) at 37°C with sink conditions. Employ a minimum of five replicates (n=5) and report mean ± SEM. For example, in vitro release profiles of this compound from PLGA nanoparticles (F4, F7, F8) showed sustained release over 24 hours, with formulation variables (e.g., PLGA concentration) impacting release kinetics .
Q. What are the standard protocols for assessing this compound’s antifungal activity in preclinical models?
- Methodological Answer : Use broth microdilution assays per CLSI guidelines (e.g., MIC determination against Aspergillus or Candida). Include controls for pH-dependent solubility and serum protein binding, as this compound’s efficacy is influenced by physiological conditions. Liu et al. (2011) demonstrated improved antifungal activity of pyridine-substituted analogues under standardized testing .
Advanced Research Questions
Q. How can response surface methodology (RSM) optimize this compound multiparticulate systems for enhanced dissolution and reduced adhesion?
- Methodological Answer : Apply central composite design (CCD) to variables like drug-carrier mass ratio and core weight gain. Use response variables (e.g., accumulative dissolution rate, adhesion rate) to generate polynomial equations. For example, Sadalge et al. (2024) optimized this compound pellets using CCD, validated by SEM and XRD to confirm amorphous dispersion .
Q. What experimental design principles are critical for formulating this compound-loaded PLGA nanoparticles with high encapsulation efficiency?
- Methodological Answer : Employ a 2³ factorial design to evaluate PLGA concentration (X1), benzyl benzoate (X2), and drug loading (X3). Use ANOVA to identify significant factors (e.g., PLGA% impacts particle size, F-test p < 0.05) and derive regression models for response optimization (e.g., ITRAe = 250.5 + 25.3X1 – 18.7X2) .
Q. How can pharmacokinetic-pharmacodynamic (PK-PD) modeling resolve contradictions in this compound’s concentration-dependent antitumor effects?
- Methodological Answer : Perform noncompartmental PK analysis to quantify plasma/tumor this compound levels. Correlate with pharmacodynamic endpoints (e.g., tumor perfusion via MRI, cytokine levels) using Spearman rank correlation. Gerber et al. (2020) linked higher tumor this compound concentrations to reduced Ktrans (perfusion) and IL1b/GM-CSF levels (ρ = -0.71, p < 0.05) .
Q. What statistical strategies address robustness in HPLC method validation for this compound impurity profiling?
- Methodological Answer : Use fractional factorial design (e.g., 2⁴⁻¹) to test factors like column temperature and mobile phase composition. Assess system suitability parameters (e.g., tailing factor, theoretical plates). Kasagić et al. (2013) validated a method for this compound impurities B/F, confirming robustness via controlled variability in retention times (<2% RSD) .
Q. How should window-of-opportunity trials be designed to evaluate this compound’s antivascular effects in non-small cell lung cancer (NSCLC)?
- Methodological Answer : Administer this compound (300 mg BID) pre-surgically for 10–14 days. Use dynamic contrast-enhanced MRI for tumor perfusion (Ktrans) and collect paired biopsies for biomarker analysis (e.g., microvessel density). Gerber et al. (2020) demonstrated dose-dependent reductions in tumor volume and perfusion, validated by metabolic profiling .
Key Methodological Considerations
- Experimental Design : Prioritize factorial designs (e.g., 2³, CCD) over one-factor-at-a-time approaches to capture interactions .
- Statistical Analysis : Use ANOVA for factorial experiments and Spearman correlations for nonparametric PK-PD relationships .
- Characterization Techniques : SEM, XRD, and DSC are critical for confirming drug-polymer interactions in formulations .
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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