Nilotinib

Bezeichnung:Nilotinib

CAS-Nr641571-10-0

Englisch Name:Nilotinib

CBNumberCB5966228

SummenformelC28H22F3N7O

Molgewicht529.52

MOL-Datei641571-10-0.mol

Nilotinib physikalisch-chemischer Eigenschaften

Schmelzpunkt	231-233 °C
Dichte	1.36
storage temp.	-20°C Freezer
Löslichkeit	Soluble in DMSO (up to 50 mg/ml)
Aggregatzustand	Beige powder.
Farbe	Off-white
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
InChIKey	HHZIURLSWUIHRB-UHFFFAOYSA-N
SMILES	N1(C=C(C)N=C1)C1C=C(C=C(C=1)NC(=O)C1C=CC(C)=C(NC2=NC=CC(C3=CC=CN=C3)=N2)C=1)C(F)(F)F
CAS Datenbank	641571-10-0(CAS DataBase Reference)

Sicherheit

HS Code	29335990
Giftige Stoffe Daten	641571-10-0(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Nilotinib Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Chronic myeloid leukemia (CML), a hematological stem-cell disorder, is definitively diagnosed by the detection of the Philadelphia chromosome, a truncated version of chromosome 22 resulting from the reciprocal translocation of chromosomes 9 and 22 induced by a single mutagenic event. The consequence is the juxtaposition of two genes creating a fusion gene BCR-ABL. This gene leads to the translation of a fusion protein with increased tyrosine kinase activity that contributes to the pathogenesis of CML. Targeting the BCR-ABL protein has led to the successful intervention of the disease. Now established as first-line therapy for CML, imatinib was the first selective tyrosine kinase inhibitor of BCR-ABL. Since imatinib only binds to an inactive conformation of the ABL kinase portion, the conformational restrictions contribute to its selectivity.
Chemische Eigenschaften
Off-White Solid
Originator
Novartis (Switzerland)
Verwenden
Nilotinib, an orally active signal transduction inhibitor that selectively inhibits the tyrosine kinase Bcr-Abl, was discovered and developed by Norvartis and was launched for the treatment of chronic myeloid leukemia (CML) in patients with Philadelphia chromosome-positive (Ph+) disease who are resistant or intolerant to imatinib mesilate. Additional clinical trials are currently underway for the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GISTs).
Verwenden
Nilotinib-d6, is the labeled analogue of Nilotinib, which might be useful in treatment of chronic myelogenous leukemia.
Verwenden
Nilotinib (AMN-107) is a Bcr-Abl inhibitor with IC50 less than 30 nM.
Definition
ChEBI: Nilotinib is a member of (trifluoromethyl)benzenes, a member of pyrimidines, a member of pyridines, a member of imidazoles, a secondary amino compound and a secondary carboxamide. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor and an anticoronaviral agent.
Trademarks
Tasigna
Clinical Use
Tyrosine kinase inhibitor:
Treatment of chronic myelogenous leukaemia (CML)
Synthese
The first step in the synthesis of nilotinib involves the nucleophilic aromatic substitution of 3-fluoro-5-(trifluoromethyl)benzonitrile with 2-methylimidazole. The nitrile is then hydrolyzed with sodium hydroxide in aqueous dioxane. A Curtius rearrangement employing diphenylphosphoryl azide in tert-butanol affords the tert-butyl carbamate. Deprotection of the Boc group provides the 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline piece for the convergent synthesis. Construction of the other half begins with the condensation of 3-amino-4- methylbenzoic acid methyl ester with cyanamide in refluxing ethanolic HCl to generate the 3-guanidinobenzoate. An enamino ketone, prepared by a Claisen condensation of 3-acetylpyridine with ethyl formate in the presence of sodium metal in hot toluene, is then cyclized with the guanidine to yield the pyridylpyrimidine. Following saponification of the ethyl ester, the resultant 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]benzoic acid is finally coupled with the aniline utilizing diethyl cyanophosphate to provide nilotinib.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: avoid with clarithromycin, rifampicin (concentration reduced) and telithromycin.
Antifungals: avoid with itraconazole, ketoconazole (concentration increased) and voriconazole.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: avoid with boceprevir and ritonavir (concentration possibly increased).
Grapefruit juice: avoid concomitant administration.
Avoid concomitant use with other inhibitors or inducers of CYP3A4. Dose alterations may be required.
Stoffwechsel
Nilotinib is metabolised in the liver via oxidation and hydroxylation, in which cytochrome P450 isoenzyme CYP3A4 plays an important role. Most of an oral dose is eliminated unchanged in the faeces within 7 days.
Einzelnachweise
1) Weisberg?et al.?(2006),?AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL; Br J. Cancer,?94?1765 2) Verstovsek?et al.?(2006),?Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells; Ann. Neurol.,?75?209

Nilotinib Upstream-Materialien And Downstream Produkte

Nilotinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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