Axitinib

Base Information

• Chemical Name: Axitinib
• CAS No.: 319460-85-0
• Deprecated CAS: 790713-39-2
• Molecular Formula: C22H18N4OS
• Molecular Weight: 386.477
• Hs Code.: 29333990
• European Community (EC) Number: 638-771-6
• NSC Number: 757441
• UNII: C9LVQ0YUXG
• DSSTox Substance ID: DTXSID3049049
• Nikkaji Number: J2.302.956A
• Wikipedia: Axitinib
• Wikidata: Q4830631
• NCI Thesaurus Code: C38718
• RXCUI: 1242999
• Pharos Ligand ID: C9S74HT6XVFD
• Metabolomics Workbench ID: 64845
• ChEMBL ID: CHEMBL1289926
• Mol file: 319460-85-0.mol

Synonyms:AG013736;Benzamide,N-methyl-2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]-;

Chemical Property of Axitinib

Chemical Property:

• Appearance/Colour: Off-white solid
• Vapor Pressure: 9.35E-18mmHg at 25°C
• Melting Point: 213-215 °C
• Refractive Index: 1.728
• Boiling Point: 668.9 °C at 760 mmHg
• PKA: 12.70±0.40(Predicted)
• Flash Point: 358.3 °C
• PSA: 95.97000
• Density: 1.35 g/cm³
• LogP: 5.03000
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO: ≥8mg/mL
• XLogP3: 4.2
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 4
• Rotatable Bond Count: 5
• Exact Mass: 386.12013238
• Heavy Atom Count: 28
• Complexity: 557

Purity/Quality:

99% ^*data from raw suppliers

AG013736 ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn,N
• Hazard Codes: Xn,N
• Statements: 22-50/53
• Safety Statements: 60-61

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CNC(=O)C1=CC=CC=C1SC2=CC3=C(C=C2)C(=NN3)C=CC4=CC=CC=N4
• Isomeric SMILES: CNC(=O)C1=CC=CC=C1SC2=CC3=C(C=C2)C(=NN3)/C=C/C4=CC=CC=N4
• Recent ClinicalTrials: A Study to Evaluate the Bioavailability of Pembrolizumab (MK-3475) Via Subcutaneous (SC) Injection of MK-3475A (Pembrolizumab Formulated With MK-5180) In Advanced Solid Tumors (MK-3475A-C18)
• Recent EU Clinical Trials: A RANDOMIZED OPEN LABEL PHASE II STUDY OF IMMUNE CHECKPOINT INHIBITOR COMBINATIONS WITH AXITINIB IN PATIENTS WITH PREVIOUSLY UNTREATED LOCALLY ADVANCED UNRESECTABLE OR METASTATIC RENAL CELL CARCINOMA
• Recent NIPH Clinical Trials: Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing
• Description: Axitinib is a VEGFR inhibitor (IC50s = 1.2, 0.25, and 0.29 nM for VEGFR1, -2, and -3, respectively). It also inhibits c-Kit and PDGFRβ (IC50s = 1.7 and 1.6 nM, respectively). It inhibits VEGF-induced migration of and tube formation by human umbilical vein endothelial cells (HUVECs). Axitinib (1-100 mg/kg) reduces microvessel density, a marker of angiogenesis, and tumor growth in MV522 colon carcinoma, A375 melanoma, SN12C-GFP renal carcinoma, and U87 glioma mouse xenograft models in a dose-dependent manner. Formulations containing axitinib have been used in the treatment of renal cell carcinoma. In January 2012, the US FDA approved axitinib (also referred to as AG-013736) for the treatment of advanced renal cell carcinoma (RCC) for patients who have not responded to prior therapy. Axitinib is a pan VEGF inhibitor and functions by binding to the intracellular tyrosine kinase catalytic domain of VEGF leading to blockade of signaling through this angiogenic pathway. Axitinib is50–400 times more potent for VEGF (enzyme Ki and cellular IC50s for VEGF 1, 2, and 3 are ～0.1 nM) than first-generation inhibitors like sorafenib and sunitinib. Axitinib also inhibits c-Kit and PDGFR(α/β) with enzyme Ki's of ～2 nM and was selective when tested against a broad panel of other protein kinases. Axitinib was discovered by a structure-based drug design approach and binds to the kinase domain of VEGF in a DFG-out conformation. Axitinib blocks VEGF-2 phosphorylation up to 7 h postdose in vivo and inhibits endothelial cell proliferation in xenograft tumors implanted in mice. Synthetic routes to axitinib employing a Migita coupling to form the diaryl sulfide and a Heck reaction to install the 2-styrylpyridine moiety have been reported.
• Uses: A tyrosine kinase inhibitor; used in cancer therapy. Axitinib (AG-013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively. Axitinib is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively. Axitinib is a tyrosine kinase inhibitor. Axitinib is used in cancer therapy.
• Clinical Use: Sold under the brand name Inlyta? by Pfizer, Inc., axitinib was approved by the FDA in January 2012 for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments. Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In particular, axitinib is a potent inhibitor of VEGF/RTK 1-3, which selectively slows angiogenesis, vascular permeability, and blood flow in solid tumors.
• Drug interactions: Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide. Concomitant use with strong CYP3A4/5 inhibitors: avoid; however, if concomitant use cannot be avoided then reduce the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability; if CYP3A4/5 inhibitor is discontinued, then increase the axitinib dose used prior to initiation of the strong inhibitor after 3-5 half-lives of the inhibitor (strong CYP3A4/5 inhibitors include ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, ritonavir, saquinavir, and voriconazole).

Technology Process of Axitinib

There total 76 articles about Axitinib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.0%

(E)-N-methyl-2-{[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide (885126-35-2) → axitinib (319460-85-0,885126-40-9)

Guidance literature:

With toluene-4-sulfonic acid; In neat (no solvent); for 0.75h; Milling;

DOI:10.3762/bjoc.14.66

Reference yield: 95.0%

C22H18N4OS*C4H4O4 → axitinib (319460-85-0,885126-40-9)

Guidance literature:

With 1,2-diaminopropan; In 1-methyl-pyrrolidin-2-one; at 40 - 70 ℃; for 1h;

Reference yield: 92.0%

6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole ethylacetate solvate → axitinib (319460-85-0,885126-40-9)

Guidance literature:

In methanol; acetic acid; at 60 ℃;

upstream raw materials:

2-vinylpyridine

2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide

N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide

(E)-N-methyl-2-{[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide

Refernces

• 1、 -. "PROCESS FOR PREPARING AXITINIB, PROCESS FOR PURIFYING THE INTERMEDIATE 2-((3-IODO-1H-INDAZOL-6-YL)THIO)-N-METHYLBENZAMIDE, PROCESS FOR PURIFYING AXITINIB VIA THE AXITINIB HCL SALT, SOLID FORM OF THE AXITINIB HCL SALT". Page/Page column 24-25. . Retrieved 2020/10/28.
• 2、 Heintze, Linda,Schmidt, Dorian,Rodat, Theo,Witt, Lydia,Ewert, Julia,Kriegs, Malte,Herges, Rainer,Peifer, Christian. "Photoswitchable azo‐ and diazocine‐functionalized derivatives of the vegfr‐2 inhibitor axitinib". . p. 1 - 23. Retrieved 2020/11/30.