443913-73-3 Usage
Anticancer drugs
Vandetanib is a kind of small molecule multi-targeted tyrosine kinase inhibitor studied and developed by the British AstraZeneca Company. In April 2011, it was approved the US FDA for entering into market under the trade name Zactima. The drug, as a tablet, can be applied to the treatment of advanced medullary thyroid cancer of adult patients.
Vandetanib is a multi-targeted tyrosine kinase inhibitor, and belongs to the Anilinoquinazoline compounds, called "second generation Iressa”. It not only acts on the tumor cells, EGFR, VEGFR and RET tyrosine kinases, but can also inhibit other kind of tyrosine kinases and serine/threonine kinases. Vandetanib is the first approved drugs approved for treatment of medullary thyroid carcinoma. It is suitable for treating unresectable, locally advanced or metastatic-symptoms or progressive medullary thyroid carcinoma. A randomized, placebo-controlled clinical trial results have showed that vandetanib can significantly delay the progression time of locally advanced or metastatic medullary thyroid cancer. The recommended daily dose is 300 mg (oral), when the patient exhibits tolerance to drugs or being not able to tolerate the toxicity, they should stop treatment immediately. Those most common adverse reactions of this medicine include diarrhea, rash, acne, nausea, hypertension, headache, fatigue, loss of appetite and abdominal pain.
The adverse reactions is dose-related; at <300 mg/d, the patient has a well tolerance with the maximum tolerated dose (MTD) being 300mg. There are many kinds disease types contained in the Ⅱ phase clinical study. The NSCLC clinical trials of vandetanib are currently under way for China.
British AstraZeneca Company, in May 2001 and October 2001, respectively, had obtained preferential access to the world's patent (WO2001032651, WO 2001074360) and applied corresponding protection on the formula, synthesis methods and pharmaceutical compositions of these compounds (including bonus salt). Vandetanib can inhibit the development of medullary thyroid carcinoma, and is the first FDA-approved drug for the treatment of the disease and will provide support for the treatment of advanced medullary thyroid cancer in adult patients.
The above information is edited by the lookchem of Dai Xiongfeng.
Treatment of advanced (non-small cell lung cancer) NSCLC
A study published in the [Journal of Clinical Oncology] have showed that compared with gefitinib which only has inhibitory effect on EGFR, vandetanib can effectively extend the progression-free survival period of the non-small cell lung cancer (NSCLC) patients.
In this phase II clinical trial conducted by doctors Ronald B. Natale from Los Angeles Cedars-Sinai Cancer Center, clinical study compared the treatment efficacy of vandetanib (300 mg/d) and gefitinib (250mg/d) on 168 cases of NSCLC patients who had been subject to failing first-line or second-line chemotherapy. Compared with gefitinib, vandetanib significantly increased efficiency and prolonged the progression-free survival, period respectively, by 8% and 1%, 11.9 weeks and 8.1 weeks, (P = 0.011). In clinical trials, if there is progression of the disease or if the patient can’t tolerate the toxicity, they allowed the patients to change the treatment regimen. Experimental results had shown that using gefitinib for replacing vandetanib in patients gave a disease control rate of 14% while using vandetanib to replace gefitinib gave a disease control rate of 32%. The overall survival period in the case of vandetanib → gefitinib was 6.1 months while it was 7.4 months in the cases of gefitinib → vandetanib.
Preparation method
Use 4-hydroxy-3-methoxy-benzoic acid ethyl ester as a starting material, go through substitution, reduction, nitrification, reduction, cyclization aromatization to give 4-chloro-6-methoxy--7-(N-methyl piperidin-4-ylmethoxy) quinazoline (A), A was then reacted with 4-bromo-2-aniline to obtain the targeted compound vandetanib.
Originator
Astra Zeneca (United Kingdom)
Clinical Use
Vandetanib, an oral VEGF, EGF, and RET receptor tyrosine kinase
inhibitor, was developed by AstraZeneca for the treatment of
symptomatic or aggressive medullary thyroid cancer (MTC) in patients
with advanced or metastatic disease. This is the first drug
approved for the treatment of MTC. Trials for other cancer indications
such as small-cell lung cancer (SCLC), breast cancer, head and
neck cancer, colorectal cancer, hormone-resistant prostate cancer,
and papillary thyroid cancer are currently being explored. While
AstraZeneca had previously developed ZD-4190 which displays
similar efficacy and pharmacokinetic profile to vandetanib, vandetanib
exhibited significantly improved solubility.
Synthesis
Vandetanib contains
a 4-anilinoquinazoline scaffold similar to other EGFR
inhibitors, and the synthesis described below is based on a recent
patent (Scheme).Commercially available vanillic acid (262) was treated with
benzyl bromide, DIPEA and Et3N to give ethereal ester 263 in 93%
yield. Arene 263 was then subjected to nitration conditions to provide
nitroarene 264 in 86% yield, which underwent immediate
reduction with sodium dithionite in acetonitrile and water to give
aniline 265 in 92% yield. Aniline 265 was then treated with foramidine
acetate in isobutanol which affected an intramolecular cyclization
reaction, giving rise to dihydroquinazolin-4-one 266 in 98%
yield. Heterocycle 266 was treated with phosphorous oxychloride
and the resulting quinazoline chloride was subsequently reacted
with 4-bromo-2-fluoroaniline 267 and trifluoroacetic acid to give
hydroxyaniline 268 in 90% for the three-step sequence. Phenolic
azacycle 268 was then alkylated with sulfonate 269 to furnish
piperidine 270 in 77% yield. Subsequent treatment with formic
acid and aqueous formaldehyde under elevated temperatures gave
vandetanib (XXIII) in 91% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: possibly increased risk of ventricular
arrhythmias with methadone - avoid.
Anti-arrhythmics: possibly increased risk of
ventricular arrhythmias with amiodarone or
disopyramide - avoid.
Antibacterials: possibly increased risk of ventricular
arrhythmias with parenteral erythromycin and
moxifloxacin - avoid; concentration reduced by
rifampicin - avoid.
Antihistamines: possibly increased risk of ventricular
arrhythmias with mizolastine - avoid.
Antimalarials: possibly increased risk of ventricular
arrhythmias with artemether with lumefantrine -
avoid.
Antipsychotics: possibly increased risk of ventricular
arrhythmias with amisulpiride, chlorpromazine,
haloperidol, pimozide, sulpiride and zuclopenthixol
- avoid; avoid concomitant use with clozapine, risk
of agranulocytosis.
Beta-blockers: possibly increased risk of ventricular
arrhythmias with sotalol - avoid.
Cytotoxics: possibly increased risk of ventricular
arrhythmias with arsenic trioxide - avoid.
Hormone antagonist: possibly increased risk of
ventricular arrhythmias with toremifene - avoid.
5HT3
-receptor antagonists: possibly increased risk of
ventricular arrhythmias with ondansetron - avoid.
Pentamidine: possibly increased risk of ventricular
arrhythmias - avoid.
Metabolism
N-desmethyl-vandetanib is primarily produced by
CYP3A4, and vandetanib-N-oxide is primarily produced
by flavin-containing monooxygenase enzymes FMO1
and FMO3.
Unchanged vandentanib and metabolites vandetanib
N-oxide and N-desmethyl vandetanib were detected in
plasma, urine (25%) and faeces (44%).
References
Wedge et al. (2002), ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis and tumor growth following oral administration; Cancer Res., 62 4645
Ciardiello et al. (2003), Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase; Clin. Cancer Res., 9 1546
Herbst et al. (2007), Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis; Expert Opin. Investig. Drugs, 16 239
Check Digit Verification of cas no
The CAS Registry Mumber 443913-73-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,4,3,9,1 and 3 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 443913-73:
(8*4)+(7*4)+(6*3)+(5*9)+(4*1)+(3*3)+(2*7)+(1*3)=153
153 % 10 = 3
So 443913-73-3 is a valid CAS Registry Number.
InChI:InChI=1/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)
443913-73-3Relevant articles and documents
Tyrosine kinase inhibitors implant he loni and its key intermediate for the preparation of
-
, (2018/10/19)
The invention discloses tyrosine kinase inhibitor implant he loni and its key intermediate of the preparation method, which belongs to the medicine, in the field of fine chemicals. The invention of the preparation method of gefitinib, is a brand-new preparation scheme, from whatever a intermediate starting, can be obtained in accordance with the requirements of the target compound. The method of the invention has short steps, the reaction operation is simple, safe and reliable, high yield, low cost, high purity, pollution little and simple operation and the like.
An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement
Brocklesby, Kayleigh L.,Waby, Jennifer S.,Cawthorne, Chris,Smith, Graham
, p. 1467 - 1469 (2017/03/23)
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).
Radiosynthesis of [11C]Vandetanib and [11C]chloro- Vandetanib as new potential PET agents for imaging of VEGFR in cancer
Gao, Mingzhang,Lola, Christian M.,Wang, Min,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
experimental part, p. 3222 - 3226 (2011/07/07)
Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [ 11C]Vandetanib and [11C]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555 GBq/μmol specific activity at end of bombardment (EOB).
A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: an improved synthesis of 4-anilinoquinazolines
Marzaro, Giovanni,Guiotto, Adriano,Pastorini, Giovanni,Chilin, Adriana
experimental part, p. 962 - 968 (2010/03/25)
A novel strategy to prepare 4-anilinoquinazoline derivatives based on the oxidation of the quinazoline ring is described. Quinazoline oxidation has been investigated and improved, thus leading to an efficient and high yielding method to quinazolin-4(3H)-ones. Efficiency of this approach has been evaluated synthesizing four well known tyrosine kinase inhibitors and comparing the obtained yields with those achievable through conventional synthetic methods.
SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES
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Page/Page column 23, (2010/04/23)
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.
CHEMICAL PROCESS
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Page/Page column 59; 60, (2008/06/13)
The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.
QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
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Page/Page column 21, (2010/11/08)
The invention relates to quinazoline derivatives of the formula I:- wherein: m is an integer from 1 to 3; R 1 represents halogeno or C 1-3 alkyl; X 1 represents -O-; R 2 is selected from one of the following three groups: 1) C 1-5 alkylR 3 (wherein R 3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; 2) C 2-5 alkenylR 3 (wherein R 3 is as defined hereinbefore); 3) C 2-5 alkynylR 3 (wherein R 3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
