284461-73-0 Usage
Uses
1. Used in Oncology:
Sorafenib tosylate is used as an antineoplastic agent for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. It targets multiple kinases, including RAF, VEGFR-2, VEGFR-3, PDGFR-β, KIT, and FLT-3, which are involved in tumor cell proliferation and tumor angiogenesis.
2. Used in Phase III Trials:
Sorafenib tosylate is being jointly developed by Bayer and Onyx in phase III trials as a single agent for the treatment of advanced hepatocellular carcinoma and in combination with carboplatin and paclitaxel for patients with advanced metastatic melanoma.
3. Used in Phase II Trials:
Sorafenib tosylate is under investigation in phase II trials in combination with doxorubicin for the treatment of advanced hepatocellular carcinoma. Additional phase II trials are ongoing for non-small cell lung cancer (NSCLC) and in postmenopausal women with estrogen receptor and/or progesterone receptor-positive metastatic breast cancer.
4. Used in National Cancer Institute (NCI) Trials:
The NCI is evaluating Sorafenib tosylate both as a single therapy agent and in combination with other oncology agents in phase II trials for several cancer indications.
Indications
It is indicated for the treatment of hepatocellular carcinoma and the treatment of advanced renal cell carcinoma (primary kidney cancer).
Indications
Sorafenib (Nexavar(R), Bayer) was the first approved inhibitor targeting the vascular endothelial growth factor (VEGF) family kinases, which include VEGFR1, VEGR2, and VEGFR3. Sorafenib was originally approved for the treatment of renal cell carcinoma (RCC) in 2005, hepatocellular carcinoma in 2007, and locally recurrent or metastatic thyroid carcinoma refractory to radioactive iodine treatment in 2013. Six other approved inhibitors with VEGFRs as the main targets are sunitinib (Sutent(R), Pfizer) for RCC, soft tissue sarcoma, thyroid cancer,metastatic pancreatic tumors, gastrointestinal stromal tumor, and several other types of carcinomas; pazopanib (Votrient(R), GlaxoSmithKline) for RCC, soft tissue sarcoma, and thyroid cancer; axitinib (Inlyta(R), Pfizer) for RCC,thyroid cancer, and aplastic anemia, as well as T315I-mutant Bcr–Abl1-driven leukemia; regorafenib (Stivarga(R), Bayer) for gastrointestinal stromal tumors and colorectal cancer; nintedanib (Ofev(R), Boehringer Ingelheim) for the non-oncological indication of idiopathic pulmonary fibrosis; and lenvatinib (Lenvima(R), Eisai Inc.) for RCC and different types of thyroid cancers. Sunitinib, pazopanib, and lenvatinib bind to the “DFG-in”conformation of VEGFRs, while axitinib, regorafenib, and nintedanib bind to inactive VEGFRs adopting the “DFG-out”conformation.
Mechanism of action
The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits both cell surface tyrosine kinase receptors and downstream intracellular serine/threonine kinases in the Ras/MAPK cascade.[2-4] Receptor tyrosine kinases inhibited by sorafenib include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-b, c-KIT, FMS-like tyrosine kinase 3 (FLT-3) and RET. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf and mutant B-Raf.[3, 4] These kinases are involved in tumour cell proliferation and tumour angiogenesis.[3, 4]
The antiproliferative activity of sorafenib is variable in different tumor types and largely depends on the oncogenic signaling pathways that mediate tumor proliferation. Sorafenib has also been shown to induce apoptosis in several tumor cell lines. Although the mechanism through which sorafenib induces apoptosis is not fully elucidated and may vary between cell lines, a commonly observed theme is the inhibition of phosphorylation of the initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukemia-1 (MCL-1)[5]. Recently, sorafenib was shown to inhibit hepatitis C viral replication in vitro[6], and in vitro studies have also shown some direct effects on immune cells [7]. Whether these effects
Side effects
The most common adverse reactions (20%), considered to be related to sorafenib, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain [12].
Across all tumor types, common side effects (> 10%) include hypertension (9 -13%, grade 4: < 1%; onset: ~ 3 weeks), fatigue (37 -46%), sensory neuropathy (13%), pain (11%), rash/desquamation (19 -40%; grade 3: 1%), handfoot syndrome (21 -30%; grade 3: 6 -8%), alopecia (14 -27%), pruritis (14 -19%), dry skin (10 -11%), hypoalbuminemia (59%), hypophosphatemia (35 -45%; grade 3: 11 -13%; grade 4: < 1%), diarrhea (43 -55%; grade 3: 2 -10%; grade 4: < 1%), lipase increased (40 -41%, usually transient), amylase increased (30 -34, usually transient), abdominal pain (11 -31%), weight loss (10 -30%), anorexia (16 -29%), nausea (23 -24%), vomiting (15 -16%), constipation (14 -15%), muscle pain, weakness, dyspnea (14%), cough (13%) and hemorrhage (15 -18%; grade 3: 2 -3%; grade 4: 2%). Laboratory abnormalities attributable to sorafenib use are also seen and include lymphopenia (23 -47%; grades 3/4: 13%), thrombocytopenia (12 -46%; grades 3/4: 1 -4%), international normalized ration (INR) increased (42%), neutropenia (18%; grades 3/4: 5%), leucopenia, liver dysfunction (11%; grade 3: 2%; grade 4: 1%).
Less frequent side effects (> 1 -10) include cardiac ischemia/infarction (3%), flushing, headache (10%), depression, fever, acne, exfoliative dermatitis, decreased appetite, dyspepsia, dysphagia, esophageal varices bleeding (2%), glossodynia, mucositis, stomatitis, xerostomia, erectile dysfunction, anemia, transaminases increased (transient), joint pain (10%), arthralgia, myalgia, hoarseness and flu-like syndrome.
Rare (< 1%) side effects of sorafenib include acute renal failure, alkaline phosphatase increased, arrhythmia, bilirubin increased, bone pain, cardiac failure, cerebral hemorrhage, congestive heart failure, dehydration, eczema, epistaxis, erythema multiforme, folliculitis, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal reflux, gynecomastia, hypersensitivity (skin reaction, urticaria), hypertensive crisis, hyponatremia, hypothyroidism, infection, jaundice, myocardial infarction (MI), mouth pain, myocardial ischemia, pancreatitis, pleural effusion, preeclampsialike syndrome (reversible hypertension and proteinuria), renal failure, respiratory hemorrhage, reversible posterior leukoencephalopathy syndrome (RPLS), rhinorrhea, skin cancer (squamous cell/keratoacanthomas), thromboembolism, tinnitus, transient ischemic attack, tumor lysis syndrome, tumor pain and voice alteration.
References
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007 Jun; 132 (7): 2557-76
Adnane L, Trail PA, Taylor I, et al. Sorafenib (BAY 439006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2005; 407: 597-612
Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006 Oct; 5 (10): 835-44
Wilhelm SM, Carter C, Tang LY, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004 Oct 1; 64 (19): 7099-109
Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005;24:6861-9
Himmelsbach K, Sauter D, Baumert TF, et al. New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication. Gut 2009;58:1644-53
Molhoek KR, McSkimming CC, Olson WC, et al. Apoptosis of CD4(+) CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2. Cancer Immunol Immunother 2009;58:867-76
Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965-72
Clinical Pharmacology and Biopharmaceutics NDA Review for Sorafenib Tosylate (NDA 21 923), F.C.F.D.E.A. RESEARCH, Editor, 2005
BAY 43-9006 (sorafenib) Investigator’s Brochure. Bayer Healthcare AG,Version 10.0, July 1, 2009
European Medicines Agency. Sorafenib (Nexavar): summary of product characteristics [online].
Blanchet B, Billemont B, Barete S, et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf 2010;9:275-87
https://www.drugs.com/cdi/sorafenib.html
Originator
Bayer/Onyx (Germany)
Flammability and Explosibility
Nonflammable
Clinical Use
Protein kinase inhibitor:
Treatment of advanced renal cell carcinoma
Treatment of hepatocellular carcinoma
Treatment of thyroid cancer
Synthesis
An improved, four-step synthesis in 63% overall yield
was published recently and is illustrated in the scheme.
Picolinic acid (127) was heated with Vilsmeier reagent for
16 hr to give 128 in 89% yield as an off-white solid. The
acid chloride 128 was treated with methylamine in methanol
at low temperature to give amide 129 in 88% yield as paleyellow
crystals after its crystallization from ethyl acetate.4-Aminophenol anion was generated under a basic condition
and compound 129 was added to the anion solution to give
corresponding addition compound 131 in 87% yield. For an
unknown reason, potassium carbonate used in the reaction
increased the reaction rate significantly. Finally, compound
131 was condensed with isocyanate 132 in methylene chloride
to give sorafenib (XVIII) in 92% yield as a white solid.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: may enhance effect of coumarins.
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Antivirals: avoid with boceprevir.
Metabolism
Sorafenib is metabolised primarily in the liver and
undergoes oxidative metabolism mediated by CYP3A4,
as well as glucuronidation mediated by UGT1A9. 8
metabolites have been identified, during in vitro studies
one has been shown to have equal activity to sorafenib.
About 96% of a dose is excreted within 14 days, with
77%, mostly as unchanged drug, recovered in the faeces,
and 19% in the urine as glucuronidated metabolites.
Check Digit Verification of cas no
The CAS Registry Mumber 284461-73-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,8,4,4,6 and 1 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 284461-73:
(8*2)+(7*8)+(6*4)+(5*4)+(4*6)+(3*1)+(2*7)+(1*3)=160
160 % 10 = 0
So 284461-73-0 is a valid CAS Registry Number.
InChI:InChI=1/C21H16ClF3N4O3.C7H8O3S/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;1-6-2-4-7(5-3-6)11(8,9)10/h2-11H,1H3,(H,26,30)(H2,28,29,31);2-5H,1H3,(H,8,9,10)
284461-73-0Relevant articles and documents
Catalytic Decarboxylative C?N Formation to Generate Alkyl, Alkenyl, and Aryl Amines
Zhang, Yipin,Ge, Xia,Lu, Hongjian,Li, Guigen
supporting information, p. 1845 - 1852 (2020/12/01)
Transition-metal-catalyzed sp2 C?N bond formation is a reliable method for the synthesis of aryl amines. Catalytic sp3 C?N formation reactions have been reported occasionally, and methods that can realize both sp2 and sp3 C?N formation are relatively unexplored. Herein, we address this challenge with a method of catalytic decarboxylative C?N formation that proceeds through a cascade carboxylic acid activation, acyl azide formation, Curtius rearrangement and nucleophilic addition reaction. The reaction uses naturally abundant organic carboxylic acids as carbon sources, readily prepared azidoformates as the nitrogen sources, and 4-dimethylaminopyridine (DMAP) and Cu(OAc)2 as catalysts with as low as 0.1 mol % loading, providing protected alkyl, alkenyl and aryl amines in high yields with gaseous N2 and CO2 as the only byproducts. Examples are demonstrated of the late-stage functionalization of natural products and drug molecules, stereospecific synthesis of useful α-chiral alkyl amines, and rapid construction of different ureas and primary amines.
Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
, p. 15651 - 15670 (2021/11/16)
A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
Synthesis, anticancer activity, and β-lactoglobulin binding interactions of multitargeted kinase inhibitor sorafenib tosylate (SORt) using spectroscopic and molecular modelling approaches
Tanzadehpanah, Hamid,Bahmani, Asrin,Hosseinpour Moghadam, Neda,Gholami, Hamid,Mahaki, Hanie,Farmany, Abbas,Saidijam, Massoud
, p. 117 - 128 (2020/08/19)
Sorafenib tosylate (SORt) is an oral multikinase inhibitor used for treatment of advanced renal cell, liver, and thyroid cancers. In this study, this drug was synthesized and its antiproliferative activities against HCT116 and CT26 cells were assessed. The interaction of SORt with β-lactoglobulin (BLG) was studied using different fluorescence techniques, circular dichroism (CD), zeta potential measurements, and docking simulation. The results of infrared (IR), mass, HNMR, and CNMR spectra demonstrated that the drug was produced with high quality, purity, and efficiency. SORt showed potent cytotoxicity against HCT116 and CT26 cells with IC50 of 8.12 and 5.42 μM, respectively. For BLG binding of SORt, the results showed that static quenching was the cause of the high affinity drug–protein interaction. Three-dimensional fluorescence and synchronous spectra indicated that SORt conformation was changed at different levels. CD suggested that the α-helix content remained almost constant in the BLG–SORt complex, whereas random coil content decreased. Zeta potential values of BLG were more positive after binding with SORt, due to electrostatic interactions between BLG and SORt. Thermodynamic parameters confirmed van der Waals and hydrogen bond interactions in the complex formation. Molecular modelling predicted the presence of hydrogen bonds and electrostatic forces in the BLG–SORt system, which was consistent with the experimental results.
Sorafenib hemicamsylate and processes for preparation thereof
-
Paragraph 0082-0086, (2020/05/26)
The present invention relates to: novel sorafenib hemi camsylate salt for treating cancer (chemical formula III); a novel crystalline form thereof; and a method for manufacturing the same. More specifically, the present invention relates to: hemi camsylate salt having high stability, solubility, and purity; a crystalline form thereof; and a method for manufacturing the same. The problem to be solved by the present invention is to provide novel sorafenib salt which is easy to make various preparations, and the method for manufacturing novel salt.COPYRIGHT KIPO 2020
Preparation method of high-purity tosylate salt crystal III (by machine translation)
-
Paragraph 0050-0053, (2020/10/05)
The invention belongs to the field of pharmaceutical chemical engineering, and particularly relates to a preparation method of a high-purity tosylate salt crystal III. The method can effectively reduce the content of genotoxic impurities by controlling specific reaction conditions, and has a good technical effect. (by machine translation)
Method for preparing amine compounds based on novel catalytic Curtius rearrangement reaction
-
Paragraph 0076-0081, (2020/12/15)
The invention relates to a method for preparing amine compounds based on a novel catalytic Curtius rearrangement reaction. Transition metal catalyzed formation of sp C-N bond is an effective methodfor synthesizing arylamine, a coupling reaction for catalyzing sp C-N bond is also reported, but a method for simultaneously realizing generation of sp C-N bond and sp C-N bond is relativelynot fully developed. According to the method, organic carboxylic acid with rich resources is used as a carbon source, alkyl/aryloxy acyl azide easy to prepare is used as a nitrogen source, under thecatalysis of DMAP and Cu(OAc)2 as low as 0.1mol%, gas N2 and CO2 are used as unique byproducts, and protected alkyl, alkenyl and aryl amine compounds are generated through a one-pot method. The reaction can be applied to later functionalization of natural products and drug molecules, synthesis of chiral alkylamine and rapid construction of different ureas and primary amines. Mechanism research shows that the reaction is carried out through cascade carboxylic acid activation, azidation, Curtius rearrangement and nucleophilic addition reaction.
Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities
Zhong, Lili,Hou, Chenhui,Zhang, Liang,Zhao, Jianchun,Li, Feng,Li, Wenbao
, p. 341 - 350 (2018/10/02)
Deuterium substitution has been widely known that can improve the pharmacokinetic profiles due to isotope effect. Herein, a series of deuterated sorafenib derivatives have been synthesized and characterized by 1H NMR, 13C NMR and MS. Their antitumor activities were evaluated in vitro against human hepatoma cell line HepG2 and human cervical carcinoma cell line HeLa. The LogP values were detected by high-performance liquid chromatography. Subsequently, the metabolic stability and pharmacokinetics study were assessed in vitro and in vivo.
Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines via a C-H Activation Strategy Using Ethenesulfonyl Fluoride as Ethylene Provider
Li, Chen,Qin, Hua-Li
supporting information, p. 4495 - 4499 (2019/06/27)
A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for modification of Sorafenib was also accomplished.
Synthetic method and application of urea compound
-
Paragraph 0215-0217, (2019/06/07)
The invention relates to a synthetic method of a urea compound, comprising the following steps: adding substituted oxazolone and sodium acetate into a methanol solution, and adding substituted amine under the stirring condition, reacting and carrying out column chromatography to obtain the urea compound. The defect that dangerous compounds need to be used during existing synthetic process is overcome, and a one-pot method is adopted to replace an existing reaction with low yield. The method of the invention has mild reaction condition, the operation is simple, raw materials are easily available, and the substrate can be converted into various other useful molecules. The compound has strong practicality, and can be applied to synthesis of the pesticide daimuron, dieresis long and the anti-cancer drug Sorafenib. The invention relates to a green and environmentally-friendly unsymmetrical urea compound synthesis method with simple process and low cost.
Method for preparing sorafenib tosylate salt targeted anti-tumor drug
-
, (2019/06/08)
The invention discloses a method for preparing a sorafenib tosylate salt targeted anti-tumor drug. The method is characterized in that a synthesis route is as followings (please see the specificationsfor the synthesis route), wherein carbonate (M2CO3) in the synthesis route is sodium carbonate, potassium carbonate or cesium carbonate, and a solvent in the synthesis route is MDF or DMA. The carbonate is adopted to replace potassium tert-butoxide, reaction operation is greatly simplified, and the cost is lowered; and through repeated testing and condition screening, the problem of excessively long reaction time is solved finally through heating reflux.
