Ceritinib (LDK378)

Bezeichnung:Ceritinib (LDK378)

CAS-Nr1032900-25-6

Englisch Name:Ceritinib (LDK378)

CBNumberCB82652832

SummenformelC28H36ClN5O3S

Molgewicht558.14

MOL-Datei1032900-25-6.mol

Ceritinib (LDK378) physikalisch-chemischer Eigenschaften

Schmelzpunkt	173-175°C
Siedepunkt	720.7±70.0 °C(Predicted)
Dichte	1.251±0.06 g/cm3(Predicted)
storage temp.	-20°C Freezer
Löslichkeit	Chloroform (Slightly), Methanol (Slightly)
pka	10.16±0.10(Predicted)
Aggregatzustand	Off-white solid.
Farbe	White to Off-White

Gefahreninformationscode (GHS)

Ceritinib (LDK378) Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Ceritinib (previously LDK378l, brand name Zykadia; Novartis Pharmaceuticals) is an oral small molecule tyrosine kinase inhibitor of ALK [87]. Preclinical studies suggested that it would inhibit ROS1 as well [88, 89].
Verwenden
5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine, is a Anaplastic lymphoma kinase (ALK) inhibitor.
Indications
Ceritinib (Zykadia(R), Novartis), approved in 2014, was developed as a second-generation ALK inhibitor for patients with NSCLC who have developed crizotinib resistance. Ceritinib addresses two of the most common ALK mutants that lead to crizotinib resistance, L1196M andG1269A, but is ineffective for G1202R and F1174C variants of ALK.
Definition
ChEBI: A member of the class of aminopyrimidines that is 2,6-diamino-5-chloropyrimidine in which the amino groups at positions 2 and 6 are respectively carrying 2-methoxy-4-(piperidin-4-yl)-5-methylphenyl and 2-(isopropylsulfonyl)phenyl substituents. Used for the treatment of ALK-positive metastatic non-small cell lung cancer.
Allgemeine Beschreibung
Class: receptor tyrosine kinase; Treatment: NSCLC; Elimination half-life = 41 h; Protein binding = 97%
Handelsname
Zykadia?
Clinical Use
ALK-inhibitor:
Treatment of anaplastic lymphoma kinase (ALK)- positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib
Synthese
The critical step in the synthesis of ceritinib involves a latestage Buchwald¨CHartwig coupling of two advanced intermediates, anilino piperidine 50 and arylsulfonyl chloro-pyrimidine 51. While these conditions utilize microwave-mediated conditions (as does another Suzuki coupling within the sequence), which are not commonly employed for process-scale routes, to our knowledge no other conditions to have been reported to date which facilitate the construction of ceritinib.
Construction of anilino piperidine 50 commenced with 2- chloro-4-fluoro-1-methylbenzene (45). Nitration with KNO3/ H2SO4 and subsequent reaction with i-PrOH/Cs2CO3 at elevated temperatures provided the 5-isopropoxy chloride intermediate 46 in 67% over 2 steps. Suzuki coupling of 46 with 4-pyridine boronic acid (47) furnished 49 in 73% yield, which was then subjected to platinum oxide-catalyzed hydrogenation conditions in the presence of acetic acid and trifluoroacetic acid, affording the corresponding piperidinyl aniline intermediate. Immediate Bocprotection of the crude aniline provided the Buchwald¨CHartwig coupling precursor 50 in 60% over 2 steps. Next, the critical union of 50 and 51 via Buchwald¨CHartwig coupling furnished the framework of ceritinib. This was followed by removal of the Boc group with TFA and subsequent precipitation with 1 M HCl to yield ceritinib (VII) as the HCl salt in 35% yield from 50.
target
ALK
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Anti-arrhythmics: possibly increased risk of ventricular arrhythmias with amiodarone, disopyramide, dronedarone and flecainide.
Antibacterials: possibly increased risk of ventricular arrhythmias with bedaquiline, clarithromycin, delamanid, IV erythromycin, moxifloxacin and telavancin; concentration reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: risk of QT prolongation with citalopram, escitalopram, venlafaxine and tricyclics that prolong the QT interval - avoid; concentration possibly reduced by St John’s wort - avoid.
Anti-emetics: possibly increased risk of ventricular arrhythmias with domperidone and ondansetron.
Antiepileptics: possibly increased concentration with carbamazepine - avoid; concentration possibly reduced by fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid or reduce ceritinib dose
Antihistamines: avoid with hydralazine due to risk of QT prolongation.
Antimalarials: possibly increased risk of ventricular arrhythmias with artemether and lumefantrine, piperaquine with artenimol, chloroquine and quinine - avoid.
Antipsychotics: possibly increased risk of ventricular arrhythmias with droperidol and haloperidol; avoid with other antipsychotics that prolong the QT interval; increased risk of agranulocytosis with clozapine - avoid.
Antivirals: concentration possibly increased by atazanavir, fosamprenavir, lopinavir, ritonavir, saquinavir and tipranavir - avoid or reduce dose; risk of QT prolongation with dasatinib - avoid.
Apomorphine: risk of QT prolongation - avoid.
Beta-blockers: possibly increased risk of ventricular arrhythmias with sotalol.
Ciclosporin: may increase ciclosporin concentration - avoid.
Cobicistat: concentration of ceritinib increased - avoid or adjust ceritinib dose.
Cytotoxics: risk of QT prolongation with arsenic trioxide, bosutinib, cabozantib, crizotinib, eribulin, lapatinib, nilotinib, osimertinib, panobinostat, pazopanib, sorafenib, sunitinib, vandetanib, vemurafenib, vinflunine - avoid; concentration possibly increased by idelalisib - avoid or adjust ceritinib dose
Enzalutamide: increases ceritinib concentration - avoid.
Methadone: possibly increased risk of ventricular arrhythmias.
Pasireotide: possibly increased risk of ventricular arrhythmias - avoid.
Ranolazine: possibly increased risk of ventricular arrhythmias - avoid.
Sirolimus: avoid concomitant use.
Tacrolimus: avoid concomitant use.
Tetrabenazine: possibly increased risk of ventricular arrhythmias - avoid.
Tizanidine: possibly increased risk of ventricular arrhythmias - avoid.
Warfarin - avoid concomitant use.
Stoffwechsel
In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. The main route of excretion of ceritinib and its metabolites is via the faeces. Recovery of unchanged ceritinib in the faeces accounts for a mean of 68% of a dose.
Lager
Store at +4°C
Einzelnachweise
[1]chen j, jiang c, wang s. ldk378: a promising anaplastic lymphoma kinase (alk) inhibitor. j med chem. 2013 jul 25;56(14):5673-4. doi: 10.1021/jm401005u. epub 2013 jul 9.
[2]marsilje th, pei w, chen b, lu w, uno t, jin y, jiang t, kim s, li n, warmuth m, sarkisova y, sun f, steffy a, pferdekamper ac, li ag, joseph sb, kim y, liu b, tuntland t, cui x, gray ns, steensma r, wan y, jiang j, chopiuk g, li j, gordon wp, richmond w, johnson k, chang j, groessl t, he yq, phimister a, aycinena a, lee cc, bursulaya b, karanewsky ds, seidel hm, harris jl, michellys py. synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (alk) inhibitor 5-chloro-n2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-n4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (ldk378) currently in phase 1 and phase 2

Ceritinib (LDK378) Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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