338992-12-4

Basic information

• Product Name: N-DeMethyl Vandetanib
• Synonyms: N-DeMethyl Vandetanib;4-(4-BroMo-2-fluoroanilino)-6-Methoxy-7-[(piperidin-4-yl)Methoxy]quinazoline;N-(4-BroMo-2-fluorophenyl)-6-Methoxy-7-(4-piperidinylMethoxy)-4-quinazolinaMine;N-DesMethyl Vandetanib;N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine
• CAS NO: 338992-12-4
• Molecular Formula: C₂₁H₂₂BrFN₄O₂
• Molecular Weight: 461.3273832
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics, Heterocycles, Inhibitors, Pharmaceuticals, Intermediates & Fine Chemicals
• Mol File: 338992-12-4.mol
• Article Data: 5

Chemical Properties

• Appearance: /
• CAS DataBase Reference: N-DeMethyl Vandetanib(CAS DataBase Reference)
• NIST Chemistry Reference: N-DeMethyl Vandetanib(338992-12-4)
• EPA Substance Registry System: N-DeMethyl Vandetanib(338992-12-4)

Safety Data

• Hazardous Substances Data: 338992-12-4(Hazardous Substances Data)

Usage

Uses

A major metabolite of Vandetanib (V097100).

Upstream product

• 338992-20-4 4-(((4-((4-bromo-2-fluorophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 
• 166815-96-9 N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine 
• 196603-96-0 4-(4-bromo-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline 
• 367-24-8 4-bromo-2-fluoroaniline 
• 162364-72-9 7-benzyloxy-4-chloro-6-methoxyquinazoline 
• 768350-54-5 7-(benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride 
• 723283-25-8 (E)-tert-butyl 4-((4-cyano-5-(((dimethylamino)methylene)amino)-2-methoxyphenoxy)methyl)piperidine-1-carboxylate 
• 123855-51-6 tert-butyl 4-(hydroxymethyl)piperidin-1-carboxylate 
• 4421-08-3 3-methoxy-4-hydroxybenzonitrile 
• 52805-34-2 4-(benzyloxy)-3-methoxybenzonitrile 
• 385784-84-9 4-(benzyloxy)-5-methoxy-2-nitrobenzonitrile 
• 385785-02-4 2-amino-4-(benzyloxy)-5-methoxybenzonitrile 

Downstream Products

• 443913-73-3 vandetanib 
• 1174683-46-5 N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-d3-methyl-piperidin-4-yl)methoxy)quinazolin-4-amine 
• 1312806-27-1 N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-[11C]methylpiperidin-4-yl)methoxy)quinazolin-4-amine 
• 910298-60-1 4-((4-bromo-2-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-ol 

Relevant articles and documents

An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement

Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).

SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES

The present invention relates to new substituted quinazoline inhibitors of vascular endothelial growth factor receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and/or REarranged during Transfection tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.

Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC50 0.02 μM, range 0.001-0.04 μM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC50 0.55 μM, range 0.02-1.6 μM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC50 0.2 μM, range 0.075-0.8 μM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC50 2.5 μM, range 0.9-19 μM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC50 0.06 μM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC50 0.04 μM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRβ, and AKT (IC50 range: 1.1 to > 100 μM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 μM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 μM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P 0.02) was evident with 12.5 mg/kg/day.