HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Leflunomide
Leflunamide · LeflunoMida · 5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)ISOXAZOLE-4-CARBOXAMIDE · efL · Arava · Leflunomide for peak identification CRS · SU101 · HWA 486
Identifikatoren & physikalische Daten
| CAS No. | 75706-12-6 |
|---|---|
| Summenformel | C12H9F3N2O2 |
| Durchschnittliche Molmasse | 270,21 g/mol |
| Monoisotopische Masse | 270,06161219 g/mol |
| SMILES | Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1 |
| InChIKey | VHOGYURTWQBHIL-UHFFFAOYSA-N |
| PubChem CID | 3899 |
| ChEMBL | CHEMBL960 |
| ChEBI | CHEBI:6402 |
| EC No. | 616-254-6 |
| DTXSID | DTXSID9023201 |
Chemische & physikalische Eigenschaften
| XLogP | 2,5 |
|---|---|
| Polarare Oberfläche (TPSA) | 55,1 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 6 |
| Frei drehbare Bindungen | 2 |
| Schwere Atome | 19 |
| Formalladung | 0 |
| Komplexität | 327 |
| Arzneimittel | Pharmaceuticals -> Antineoplastic and immunomodulating agents -> ImmunosuppressantsPharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | log Kow = 2.43 /Estimated/2.83.9 |
| Color/Form | Crystals from toluene |
| Löslichkeit | In water, 153 mg/L at 25 °C /Estimated/8.44e-02 g/LPractically insoluble in water, freely soluble in methanol, sparingly soluble in methylene chloride. |
| Human Drugs | Breast FeedingLactationMilk, HumanAntirheumatic AgentsImmunosuppressive AgentsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Schmelzpunkt | 165-166 °C166.5 °C165 - 166 °C |
| Dampfdruck | 1.25X10-6 mm Hg at 25 °C /Estimated/ |
| Henry-Konstante | Henry's Law constant = 1.23X10-10 atm-cu m/mol at 25 °C /Estimated/8.0×104 mol/(m3Pa) at 25℃, HSDB (2015) |
| Physical Description | Solid |
| Other Experimental Properties | Hydroxyl radical reaction rate constant = 7.33X10-12 cu cm/molc-sec at 25 °C /Estimated/ |
| Siedepunkt | 289.3±40.0 °C(Predicted) |
| Dichte | 1.392±0.06 g/cm3(Predicted) |
| Lagerbedingungen | 2-8°C |
| pKa (Säurekonstante) | 10.8(at 25℃) |
| Aggregatzustand | Solid |
| Farbe | White |
| Merck | 14,5432 |
| Stabilität | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month. |
| Hauptanwendungen | pharmaceuticalpharmaceutical small molecule |
| InChI | 1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18) |
| InChIKey | VHOGYURTWQBHIL-UHFFFAOYSA-N |
| SMILES | Cc1oncc1C(=O)Nc2ccc(cc2)C(F)(F)F |
| CAS Datenbank | 75706-12-6(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (99.3%): Toxic if swallowed [Danger Acute toxicity, oral]P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 134 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leflunomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Hazard Classes and Categories | Acute Tox. 3 (99.3%) |
| Lagerbedingungen | Commercially available leflunomide tablets should be stored at a controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C. The tablets should be protected from light. |
| Entsorgungsverfahren | SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations. |
| Wechselwirkungen | Concurrent use with rifampin may increase the plasma concentration of leflunomidecaution is recommended.Concurrent use with these medications /hepatotoxic medications or methotrexate/ may increase the risk of side effects and medication-induced hepatic toxicityin a small study evaluating the concurrent use of leflunomide (100 mg/day followed by 10 to 20 mg/day) and methotrexate (10 to 25 mg/week with folate), an increased risk of hepatotoxicity was reporteddosage adjustment may be needed.In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.M1 was shown to cause increases ranging from 13-50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro.Concurrent use with these medications /activated charcoal, or cholestyramine/ will significantly decrease the plasma concentration of M1 by inhibiting gastrointestinal absorption. /M1 metabolite/ |
| Hepatotoxicity | Up to 15% of subjects treated with leflunomide develop transient serum aminotransferase elevations that are usually asymptomatic and mild, in the range of 1 to 3 times the upper limit of normal (ULN). Elevations above 3 times the ULN occur in 1% to 4% of patients. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,300(SRC), determined from a structure estimation method(2), indicates that leflunomide is expected to have slight mobility in soil(SRC). Volatilization of leflunomide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.23X10-10 atm-cu m/mole(3), using a fragment constant estimation method(3). Leflunomide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.25X10-6 mm Hg(4), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2004).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2,300(SRC), determined from a structure estimation method(2), indicates that leflunomide is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.23X10-10 atm-cu m/mole(4), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 15(SRC), from an estimated log Kow of 2.43(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Biodegradation data were not available(SRC, 2004).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), leflunomide, which has a an estimated vapor pressure of 1.25X10-6 mm Hg at 25 °C(2), is expected to exist in both the vapor and the particulate phases in the ambient atmosphere. Vapor-phase leflunomide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 2.2 days, calculated from its rate-constant of 7.33X10-12 cu cm/molecule sec(SRC), that was derived using a structure estimation method(3). Particulate-phase leflunomide may be removed from the air by wet and dry deposition(SRC). |
| Unerwünschte Wirkungen | Common adverse effects of leflunomide include: |
| Toxizitätsübersicht | Cholestyramine |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc for leflunomide can be estimated to be 2,300(SRC). According to a classification scheme(2), this estimated Koc value suggests that leflunomide is expected to have slight mobility in soil. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ During postmarketing surveillance, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiform have been reported rarely in patients receiving leflunomide./SIGNS AND SYMPTOMS/ Allergic reaction has occurred in 2% of patients receiving leflunomide in clinical studies. Drug rechallenge resulted in an anaphylactic reaction in at least one patient who had experienced rash while receiving leflunomide in a phase II study. Angioedema has been reported rarely. |
| Artificial Pollution Sources | Leflunomide's production and use as an antirheumatic(1) may result in its release to the environment through various waste streams. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)LeflunomidevMost-DILI-concern8Box warningDOI:10.1016/j.drudis.2016.02.015 |
| Environmental Bioconcentration | An estimated BCF of 15 was calculated for leflunomide(SRC), using an estimated log Kow of 2.43(1) and a regression-derived equation(2). The BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). |
| Volatilization from Water/Soil | The Henry's Law constant for leflunomide is estimated as 1.23X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that leflunomide is expected to be essentially nonvolatile from water surfaces(2). Leflunomide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.25X10-6 mm Hg(SRC), determined from a fragment constant method(3). |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg . However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied. Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg .../LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). ... Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. ... At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival./GENOTOXICITY/ Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN 2811 6.1/PG 3 |
| Zollcode | 2934990002 |
| RTECS-Nr. | NY2354200 |
| R-Sätze (R) | 22-36/37/38 |
| Gefahrensymbole | Xn,Xi |
| Sicherheitshinweise (S) | 26-36 |
| Gefahrenklasse | 6.1Acute Tox. 3 OralEye Irrit. 2Skin Irrit. 2STOT SE 3 |
| Verpackungsgruppe | III |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 75706-12-6(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Leflunomide is an orally-available disease-modifying antirheumatic drug and was launched as Arava in the US for the treatment of rheumatoid arthritis (RA) ; it is the first and only drug to be indicated to slow down structural joint damage of RA, so addressing an unmet medical need. Leflunomide is prepared in 3 steps from the appropriate acetoacetic anilide using a nitrile oxide- enamine cycloaddition reaction to assemble the isoxazole ring. Leflunomide is a prodrug, being extensively metabolized in vivo into the corresponding 2-cyano-3-hydroxy-2-butenamide resulting from fragmentation of the isoxazole ring. This cyanoenol is actually the active metabolite and several experiments in animals have demonstrated that after oral administration, substantial and sustained levels of this metabolite were delivered to the systemic circulation. In vitro, Leflunomide’s active metabolite inhibits dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidine nucleotides, probably accounting for its immunosuppressive effect in vivo. Other mechanisms of action such as inhibition of tyrosine kinase and inhibition of responsiveness to interleukin-2 have been proposed. In diverse models of autoimmune or allergic diseases, Leflunornide showed efficacy both prophylactically and therapeutically.
Verwenden
By virtue of its immunosuppressant effects, leflunomide has found use in organ transplantation and treatment of rheumatoid arthritis and other autoimmune diseases.