HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Sorafenib
sorafenib · Nexavar · BAY 43-9006 · SORAFENIB-D3 · 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide · N-[4-Chloro-3-(trifluoromethyl)phenyl]-({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)-carboxamide · Sorafenib Free Base · Sorafenib free base for research
Identifikatoren & physikalische Daten
| CAS No. | 284461-73-0 |
|---|---|
| Summenformel | C21H16ClF3N4O3 |
| Durchschnittliche Molmasse | 464,8 g/mol |
| Monoisotopische Masse | 464,08630271 g/mol |
| SMILES | CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1 |
| InChIKey | MLDQJTXFUGDVEO-UHFFFAOYSA-N |
| PubChem CID | 216239 |
| ChEMBL | CHEMBL1336 |
| ChEBI | CHEBI:50924 |
| EC No. | 608-209-4 |
| DTXSID | DTXSID7041128 |
Chemische & physikalische Eigenschaften
| XLogP | 4,1 |
|---|---|
| Polarare Oberfläche (TPSA) | 92,4 |
| H-Brücken-Donoren | 3 |
| H-Brücken-Akzeptoren | 7 |
| Frei drehbare Bindungen | 5 |
| Schwere Atome | 32 |
| Formalladung | 0 |
| Komplexität | 646 |
| PFAS | PFAS -> PFAS identified in REACH Regulation EC No. 1272/2008PFAS -> Suspected persistent, mobile, toxic (PMT) PFAS or PFAS-like compounds |
| Arzneimittel | Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agentsPharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 3.8 |
| Color/Form | White solid |
| Löslichkeit | < 0.01 g/L1.71e-03 g/LChloroform (Slightly), DMSO (Slightly)100μg/L at 20℃ |
| Human Drugs | Breast FeedingLactationAntineoplastic AgentsEnzyme InhibitorsProtein Kinase InhibitorsSignal Transduction InhibitorsTyrosine Kinase InhibitorsEMA approved medicines: Human medicine |
| Decomposition | Dangerous products of decomposition: thermal ecomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. /Sorafenib tosylate/ |
| Schmelzpunkt | 187-226205.6 °C202-204°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable if stored as directedavoid strong oxidizing agents. /Sorafenib tosylate/ |
| Other Experimental Properties | White to yellowish or brownish solid. Practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400 /Sorafenib tosylate/ |
| Siedepunkt | 523.3±50.0 °C(Predicted) |
| Dichte | 1.454±0.06 g/cm3(Predicted) |
| Dampfdruck | 0Pa at 25℃ |
| Lagerbedingungen | Sealed in dry,Store in freezer, under -20°C |
| pKa (Säurekonstante) | 12.89±0.70(Predicted) |
| Aggregatzustand | White to off-white solid. |
| Farbe | White to Off-White |
| InChI | InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31) |
| InChIKey | MLDQJTXFUGDVEO-UHFFFAOYSA-N |
| SMILES | C1(C(NC)=O)=NC=CC(OC2=CC=C(NC(NC3=CC=C(Cl)C(C(F)(F)F)=C3)=O)C=C2)=C1 |
| LogP (Verteilungskoeffizient) | 3.3 at 25℃ |
| CAS Datenbank | 284461-73-0(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH351 (40%): Suspected of causing cancer [Warning Carcinogenicity]P203, P260, P263, P264, P270, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Regulatorische Informationen | Status: Active Update: 27-02-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/6884 |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sorafenib tosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sorafenib tosylate/Drug Name: NexavarFDA Application No.: (NDA) 021923Active Ingredient: Sorafenib tosylateCompany: Bayer HealthcareOriginal Approval or Tentative Approval Date: December 20, 2005Chemical Type: 1 New molecular entity (NME)Review Classification: Priority review drug, orphan drug. /Sorafenib tosylate/ |
| Toxic Combustion Products | Unusual fire hazard: emits toxic fumes such as carbon monoxide, etc. /Sorafenib tosylate/ |
| Hazard Classes and Categories | Carc. 2 (40%) |
| Brandbekämpfungsverfahren | Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes. /Sorafenib tosylate/ |
| Lagerbedingungen | Store at 25 °C (77 °F)excursions permitted to 15-30 °C (59-86 °F) |
| Reinigungsverfahren | Accidental release measures: After Inhalation: cordon off area of spillwear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders)decontaminate surfaces and equipment by scrubbing with alcoholdispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/. /Sorafenib tosylate/ |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash. |
| Preventive Measures | Information for safe handling: avoid inhalation and contact with skin, eyes and clothingmaterial may be an irritant. /Sorafenib tosylate/ |
| Personal Protective Equipment (PPE) | Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles. /Sorafenib tosylate/ |
| Treatment | There is no specific treatment for NEXAVAR (Sorafenib ) overdose. (L1712) |
| Wechselwirkungen | Sorafenib does not appear to affect the metabolism of warfarin (a CYP2C9 substrate) in vivomean changes from baseline in prothrombin time (PT)/international normalized ratio (INR) did not appear to be greater in patients receiving sorafenib as compared with placebo. However, infrequent bleeding events or elevations in INR have been reported in some patients receiving concomitant therapy with warfarin and sorafenib.Potential pharmacokinetic interaction with doxorubicin and irinotecan (increased area under the serum concentration-time curve (AUC) of doxorubicin and of irinotecan and its active metabolite SN-38). The clinical importance of these findings is not known. Caution is advised.In vitro studies indicate that sorafenib inhibits glucuronidation by the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and 1A9 pathwayspotential pharmacokinetic interaction (increased systemic exposure to UGT 1A1 or 1A9 substrates). Caution is advised when sorafenib is used concomitantly with drugs predominantly metabolized by the UGT 1A1 pathway (e.g., irinotecan, whose active metabolite SN-38 is metabolized by UGT 1A1).In vitro studies using human hepatic microsomes indicate that sorafenib inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4however, sorafenib does not appear to alter exposure to dextromethorphan (a CYP2D6 substrate), midazolam (a CYP3A4 substrate), or omeprazole (a CYP2C19 substrate). The manufacturer states that it is unlikely that sorafenib will alter the metabolism of substrates of CYP isoenzymes 2C19, 2D6, or 3A4 in vivo or induce CYP isoenzymes 1A2 or 3A4. However, sorafenib may increase systemic exposure to CYP2B6 or CYP2C8 substratescaution is advised when substrates of CYP2B6 or CYP2C8 are used concomitantly with sorafenib.For more Interactions (Complete) data for Sorafenib (6 total), please visit the HSDB record page. |
| Gesundheitliche Auswirkungen | Hand-foot skin reaction and rash represent the most common adverse reactionsmay increase the risk of bleeding (L1712) |
| Hepatotoxicity | In large clinical trials of sorafenib, elevations in serum aminotransferase levels were common, occurring in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurred in only 1% to 3% of treated subjects. In addition, there have been several single case reports of clinically apparent liver injury arising during sorafenib therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to 8 weeks of starting sorafenib, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once sorafenib was stopped, but some cases were associated with progressive liver injury and hepatic failure. Most of the reports of severe liver injury occurred in patients being treated for hepatocellular carcinoma who also had cirrhosis or in patients receiving other potentially hepatotoxic drugs31. |
| Expositionspfade | The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state. |
| Toxizitätsübersicht | Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited. |
| Signs and Symptoms | The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. |
| Human Toxicity Excerpts | /HUMAN EXPOSURE STUDIES/ Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). /The authors/ performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumor type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.2695% CI 1.03-4.99P= 0.043) and renal cancer (RR 1.8495% CI 1.15-2.94P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer./CASE REPORTS/ Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFbeta and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. ... /The authors/ report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial./CASE REPORTS/ Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. ... /The authors/ report the case of a HCC patient that developed a liver abscess while being treated with sorafenib./OTHER TOXICITY INFORMATION/ Possible increased risk of bleeding. In clinical studies, bleeding (regardless of causality) was reported in 15.3 or 8.2% of patients receiving sorafenib or placebo, respectively. The incidences of grade 3 and 4 bleeding were 2 and 0%, respectively, in patients receiving sorafenib compared with 1.3 and 0.2%, respectively, in patients receiving placebo. Fatal hemorrhage occurred in one patient in each treatment group. Permanent discontinuance of sorafenib should be considered if any bleeding episode requires medical intervention./OTHER TOXICITY INFORMATION/ Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and International Normalized Ratio (INR) may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Nexavar. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)sorafenibDILI PositiveOralDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ The toxicity of single doses of sorafenib has been investigated via the oral route in mice, rats and dogs. The highest single oral sorafenib dose of 1460 mg/kg was tolerated in mice and rats without any sign of toxicity. In Beagle dogs, vomiting was observed after a single oral dose of 120 mg/kg solution, and 1000 mg/kg powder (1370 mg/kg of the tosylate salt) After administration of two times 24 hours i.p doses of 125-500 mg/kg of sorafenib in mice, apathy, roughened fur, hard abdomen, spasm, periodically stretching of body and difficulty in breathing were observed but mortality was not induced. At 500 mg/kg one male died. At the 1000 mg/kg dose, all males and one female died./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 4-week study in dogs with initial twice-daily administration of 10, 30, or 60 mg/kg, both 30 mg/kg bid and 60 mg/kg bid of sorafenib induced emesis, bloody diarrhea and reduced body weight gain. Dosing was therefore reduced to once daily after one week of treatment. After the administration of 30 mg/kg of sorafenib, once-daily for 3 or 12 months in dogs, effects on the GI tract (bloody diarrhoea) and on the skin (hair loss, inflammation) were observed. At histopathology, degenerative and regenerative processes were seen dose-dependently in multiple tissues including kidneys, lymphoreticular / hematopoetic system, GI tract, adrenals, teeth and bone. Marked morphological changes were observed in the liver and skin. The morphological no-effect-level after 3 or 12 months treatment was below 10 mg/kg/day./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 6 month toxicity study, 20 male and 20 female Wistar rats were treated daily orally by gavage at 0 -2.5 mg/kg dose of sorafenib. The lowest dose causing significant toxicity (LOAEL) was 1 mg/kg/day. A NOAEL was not established for females./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A group of 10 male and 10 female Wistar rats were treated orally for 4 weeks at 0 -125 mg/kg dose of sorafenib. Mortalities prior to the end of 4 weeks treatment included 3 males and 9 females at 25 mg/kg, 3 males and 1 female at 125 mg/kg. Dose-dependent clinical signs of toxicity were noted at 5 mg/kg and above. In the clinico-chemical investigations, increases were seen in AST, ALT (beginning at 1 mg/kg), GLDH and LDH (at 25 and 125 mg/kg), cholesterol and bilirubin (beginning at 5 mg/kg). An increase was seen in alkaline phosphatase (ALP) at 5 mg/kg with decreases at 25 and 125 mg/kg. In urine, increases were seen in protein, urine creatinine (in females only), NAG, and LDH, particularly at 25 and 125 mg/kg. Histopathological evaluation revealed treatment-related findings in the majority of animals treated at 25 or 125 mg/kg. Overall, the changes were classified as degenerative in the adrenal glands, liver, stomach, duodenum, pancreas, kidneys, heart, and ovaries. Regenerative changes were observed in the liver (bile duct proliferation), pancreas, duodenum and kidneys. Necrosis was observed in the spleen, lymph nodes, and thymus. Effects in male reproductive organs included retardation in testes, epididymides, prostate and seminal vesicles. Most of the findings could be shown to be reversible. However, bile duct proliferation, liver fibrosis, effects on lymphoreticular system were still visible at the end of the 1-month recovery period. A NOAEL was not established.For more Non-Human Toxicity Excerpts (Complete) data for Sorafenib (8 total), please visit the HSDB record page. |
| Antidote and Emergency Treatment | /SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B//SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B//SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/ |
| Wassergefährdungsklasse (WGK) | WGK 3 |
| Zollcode | 29350090 |
| R-Sätze (R) | 68/20/21/22-37/38 |
| Sicherheitshinweise (S) | 36-37-39 |
| Lagerklasse | 6.1D - Non-combustible acute toxic Cat.3toxic hazardous materials or hazardous materials causing chronic effects |
| Gefahrstoffdaten | 284461-73-0(Hazardous Substances Data) |
| Gefahrenklasse | Aquatic Acute 1Aquatic Chronic 1Lact.Repr. 1BSTOT RE 1 |
Anwendungen & Verwendung
Beschreibung
Sorafenib is a small molecular inhibitor of several kinases involved in tumor angiogenesis and proliferation, including, but not limited to, Raf (IC50=12nM for Raf-1), VEGFR (IC50=90nM for VEGFR-2 and IC50=12nM for VEGFR-3), and platelet derived growth factor receptor (IC50=57nM for PDGFR-b). Specifically, sorafenib blocks tumor progression by inhibiting cellular proliferation that is dependent on activation of the MAPK pathway (Raf) and/or inhibiting tumor angiogenesis through VEGFR and/or PDGFR. While it may be effective in the treatment of a variety of tumors, the first approvable indication is for renal cell carcinoma. Overall, the drug appears to be well tolerated by the majority of patients at the 400 mg b.i.d. continuous dosing. As an inhibitor of multiple kinases vital for tumor progression, sorafenib may possess wide-spectrum antitumor properties and may emerge as an effective weapon against a variety of solid tumors.
Verwenden
Sorafenib Tosylate (Bay 43-9006, Nexavar) is a small molecular inhibitor of VEGFR, PDGFR, c-Raf and B-Raf with IC50s of 18 nM, 10 nM, 3 nM and 15 nM, respectively.