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Vandetanib structure
Vandetanib structure

Vandetanib

Iupac Name:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
CAS No.: 443913-73-3
Molecular Weight:475.362
Modify Date.: 2022-11-12 07:04
Introduction: In April 2011, the U.S. FDA approved vandetanib (ZD6474) for the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in adult patients with inoperable advanced ormetastatic disease. Vandetanib inhibits KDR/VEGFR2, VEGFR3, EGFR, and RET kinases with IC50's of 40, 110, 500, and <100 nM, respectively. In athymic mice bearing MTC tumors, a 14.5-fold reduction of tumor volume was observed after 45 days of treatment with vandetanib at 50 mg/kg/day. The decrease in tumor volume was accompanied by decreases in mitotic index (Ki67) and tumor angiogenesis in treated xenografts. Key steps in the synthesis of vandetanib include the displacement of the chlorine atom from 7-benzyloxy-4-chloro-6-methoxyquinazoline with 4-bromo-2- fluoroaniline under acidic conditions in a protic solvent and a Mitsunobu reaction of a N-protected piperidine alcohol with a phenol. View more+
1. Names and Identifiers
1.1 Name
Vandetanib
1.2 Synonyms

4-(4-Bromo-2-fluoroanilino)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline 4-Quinazolinamine, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]- 7-((4-aminocyclohexyl)methoxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine AZD 6474 AZD6474 AZD-6474 Caprelsa CH 331 N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-amine N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine N-(4-BroMo-2-fluorophenyl)-6-Methoxy-7-[(1-Methylpiperidin-4-yl)Methoxy]-4-aMino-quinazoline N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Vandetanib (ZactiMa) Vandetanib base Vandetanib(Zactima),ZD6474 Vandetanib(ZactiMa,AZD6474) ZACTIMA ZD 6474 ZD6474

1.3 CAS No.
443913-73-3
1.4 CID
3081361
1.5 Molecular Formula
C22H24BrFN4O2 (isomer)
1.6 Inchi
InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
1.7 InChkey
UHTHHESEBZOYNR-UHFFFAOYSA-N
1.8 Canonical Smiles
CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC
1.9 Isomers Smiles
CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC
2. Properties
2.1 Density
1.406
2.1 Melting point
240-243oC
2.1 Boiling point
538.2 °C at 760 mmHg
2.1 Refractive index
1.629
2.1 Flash Point
279.3 °C
2.1 Precise Quality
474.10700
2.1 PSA
59.51000
2.1 logP
5.01510
2.1 Appearance
White solid
2.2 Storage
-20?C Freezer
2.3 Chemical Properties
Yellow Solid
2.4 Decomposition
Thermal decomposition may produce toxic gases such as carbon monoxide;, carbon dioxide;, and nitrogen oxides.
2.5 pKa
8.92±0.10(Predicted)
2.6 Water Solubility
Soluble in DMSO
2.7 Stability
Vandetanib; solid is found to be stable to both thermal and hydrolytic degradation but a small degree of degradation is observed under stressed photolytic conditions. In solution, vandetanib; is degraded under acidic, oxidative and light stress conditions but it is stable under basic conditions.
2.8 StorageTemp
-20?C Freezer
2.9 Toxicity Summary
IDENTIFICATION AND USE: Vandetanib; is a white to off white powder that is formulated into film-coated tablets. Vandetanib; is a multitargeted tyrosine; kinase inhibitor used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Because of the risk of QT prolongation, torsades de pointes, and sudden death, the US Food and Drug Administration (FDA) requires a Risk Evaluation and Mitigation Strategy (REMS) for vandetanib;. Under the terms of the REMS program, vandetanib; is available only under a restricted distribution program. It was granted orphan drug status by the FDA. HUMAN EXPOSURE AND TOXICITY: Vandetanib; prolongs the QT interval in a concentration-dependent manner. Torsades de pointes (a distinctive polymorphic ventricular tachycardia in which the QRS amplitude varies and the QRS complexes appear to twist around), ventricular tachycardia, and sudden death have all been reported in patients receiving vandetanib;. Vandetanib; should not be used in patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, or in patients with electrolyte disturbances. Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to the administration of vandetanib;. Other toxicities that are associated with the use of vandetanib; and have resulted in fatalities include: severe skin reactions (including Stevens-Johnson syndrome), interstitial lung disease or pneumonitis, ischemic cerebrovascular events, serious hemorrhagic events and heart failure. Vandetanib; may also cause fetal harm if administered to pregnant women. Pregnancy should therefore be avoided during vandetanib; therapy. Vandetanib; was not clastogenic to cultured human lymphocytes. ANIMAL STUDIES: In the rat, a single oral dose at 2000 mg/kg was not tolerated and all animals died or were killed for humane reasons by Day 4. Histopathological findings in these rats included hepatocyte vacuolation, fat deposition and necrosis in the liver, ulceration in the stomach, mucosal single cell necrosis and erosion in the duodenum, and macrophage vacuolation in the spleen. There were no adverse effects in rats dosed at 1000 mg/kg. A single oral dose of vandetanib; at 2000 mg/kg to mice was not tolerated and all animals died or were killed for humane reasons on Day 1. A single oral dose of 1000 mg/kg resulted in the death of 1 out of 10 mice. There were no salient histopathology findings except for ulceration in the stomach in 1 animal dosed at 2000 mg/kg. In 1, 6 and 9 month studies, the dose limiting toxicities included gastrointestinal effects in dogs (including loose/abnormal feces, emesis and body weight loss), and skin toxicity and hepatotoxicity in rats. Vandetanib; had no effect on copulation or fertility in male rats, while in female rats there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy and an increase in post-implantation loss. In rats, vandetanib; demonstrated the potential to cause embryo-fetal loss, delayed fetal development, heart vessel abnormalities and precocious ossification of some skull bones. In a rat pre- and post-natal development study, at doses producing maternal toxicity during gestation and/or lactation, vandetanib; increased pre-birth loss and reduced post-natal pup growth. Vandetanib; showed no mutagenic potential in 4 strains of Salmonella typhimurium (TA1535, TA1537, TA98 and TA100) and 2 strains of Escherichia coli (WP2P and WP2 uvrA) with or without metabolic activation.
3. Use and Manufacturing
3.1 GHS Classification
Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 4 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H360 (100%): May damage fertility or the unborn child [Danger Reproductive toxicity]
H373 (100%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]
H410 (100%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P260, P264, P270, P273, P281, P301+P312, P308+P313, P314, P330, P391, P405, and P501
3.2 Methods of Manufacturing
Preparation: L. F. A. Hennequin et al., World Intellectual Property Organization patent 01032651; eidem, United States of America patent 7173038 (2001, 2007 both to AstraZeneca).
3.3 Usage
Vandetanib (Zactima, ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM.
4. Safety and Handling
4.1 Specification

? Zactima , with CAS number of 443913-73-3, can be called N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-4-piperidinyl)methoxy)-4-quinazolinamine ; N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine ; Vandetanib . It is a?yellow solid,?Zactima (CAS NO.443913-73-3) is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity.

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Reproductive toxicity, Category 1B

Specific target organ toxicity \u2013 repeated exposure, Category 2

Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 1

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word

Danger

Hazard statement(s)

H302 Harmful if swallowed

H360 May damage fertility or the unborn child

H373 May cause damage to organs through prolonged or repeated exposure

H410 Very toxic to aquatic life with long lasting effects

Precautionary statement(s)
Prevention

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P201 Obtain special instructions before use.

P202 Do not handle until all safety precautions have been read and understood.

P280 Wear protective gloves/protective clothing/eye protection/face protection.

P260 Do not breathe dust/fume/gas/mist/vapours/spray.

P273 Avoid release to the environment.

Response

P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell.

P330 Rinse mouth.

P308+P313 IF exposed or concerned: Get medical advice/ attention.

P314 Get medical advice/attention if you feel unwell.

P391 Collect spillage.

Storage

P405 Store locked up.

Disposal

P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

6. NMR Spectrum
9. Computational chemical data
  • Molecular Weight: 475.362g/mol
  • Molecular Formula: C22H24BrFN4O2
  • Compound Is Canonicalized: True
  • XLogP3-AA: 4.9
  • Exact Mass: 474.10667
  • Monoisotopic Mass: 474.10667
  • Complexity: 539
  • Rotatable Bond Count: 6
  • Hydrogen Bond Donor Count: 1
  • Hydrogen Bond Acceptor Count: 7
  • Topological Polar Surface Area: 59.5
  • Heavy Atom Count: 30
  • Defined Atom Stereocenter Count: 0
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
  • CACTVS Substructure Key Fingerprint: AAADceB7sQAAEAAAAAAAAAAAAAAAAAAAAAA8eIEAAAAAAACx9AAAHwBQAAABrQzhng439vfIFACgAyZjZACCiCkxIqQJ2CA+7LiNLuLE+duGPCru0BvK6jew0BMOIEAhAgACQABAgEIEAASAAAAAAAAAAA==
10. Question & Answer
  • Figure 1. Structural formula of vandetanib Vandetanib is a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity. Therefore, it has good anti...
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