Basic information Indications and Usage Mechanisms of Action Patents Chemical Synthesis Safety Related Supplier
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Ceritinib (LDK378)

Basic information Indications and Usage Mechanisms of Action Patents Chemical Synthesis Safety Related Supplier
Ceritinib (LDK378) Basic information
Ceritinib (LDK378) Chemical Properties
  • Boiling point:720.7±70.0 °C(Predicted)
  • Density 1.251±0.06 g/cm3(Predicted)
  • pka10.16±0.10(Predicted)
  • form Off-white solid.
Ceritinib (LDK378) Usage And Synthesis
  • Indications and UsageCeritinib is a new ALK gene inhibitor (ALKi) developed by Novartis Pharmaceuticals; its commercial name is Zykadia, and its previous code was LDK378. It was approved by the FDA for sale on April 29, 2014, and it is used to treat anaplastic lymphoma kinase (ALK) positive transfer of crizotinib (CRZ) progress or intolerance of non-small cell lung cancer (NSCLC).
  • Mechanisms of ActionCrizotinib resistance is a major issue for patients undergoing treatment for ALK gene rearrangement positive non-small cell lung cancer. Ceritinib is a kind of ALK tyrosine kinase inhibitor. Ceritinib does not target the MET proto-oncogene, but instead inhibits the insulin-like growth factor 1 receptor and blocks proteins from promoting cancer cell development, thus inhibiting the expression of EML4-ALK and NPM-ALK fusion protein cells. It is used to treat ALK rearrangement positive NSCLC patients who have previously used Crizotinib and can overcome Crizotinib resistance. Compared to Crizotinib, Ceritinib does not inhibit MET kinase activity, but inhibits IGF-1 receptors. Whether in terms of enzyme reaction, cell analysis or Crizotinib resistant animal models, research results all show that Ceritinib is more effective than Crizotinib. Additionally, regardless of any ALK resistance mutation, Ceritinib is still highly effective. In clinical models, Ceritinib’s ALK inhibition has 20 times the tumor-fighting effect of Crizotinib. Ceritinib also has the same effect on Crizotinib resistant central nervous system lesion NSCLC. Clinical trials show that Ceritinib can effectively inhibit ALK targets, potentially affecting an unknown kinase related to drug resistance, thus overcoming Crizotinib resistance.
  • PatentsAmerican patent numbers: US7153964,US7893074,US7964592,US8039474,US8039479,US8377921,US8703787.
    Patent expiration dates:
    February 26, 2021 (US7153964)
    April 25, 2026 (US7893074)
    January 13, 2027 (US7964592)
    June 29, 2030 (US8039474, US8039479)
    November 20, 2027 (US8377921)
    April 29, 2032 (US8703787)
    Patents belong to Novartis
  • Chemical SynthesisCeritinib can be synthesized using a highly convergent synthetic route that consist two sequential amination reactions on 2,4,5-trichloropyrimidine itself (Scheme 6.1). In the first amination step, 2-(isopropylsulfonyl)aniline can be isolated in three steps from fluoronitrobenzene, and in the second step, 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline is easily isolated in four steps from 2-chloro-4-fluorotoluene. Overall yields are >28% from 2-fluoronitrobenzene and >22% from 2-chloro-4-fluorotoluene.
    Synthesis of Ceritinib
    Scheme 6.1 Synthesis of LDK378 (1, ceritinib). Reagents and conditions: (a) propane-2-thiol, K2CO3, DMF, 45°C ON. (b) NaBO3, AcOH, 60°C. (c) H2/Pd/C, EtOAc/MeOH (10/1). (d) NaH, DMF/DMSO, 0–20 °C. (e) KNO3, H2SO4, 0–20°C. (f ) IPA, Cs2CO3, 60°C, 24 h. (g) 4-Pyridineboronic acid, 1-BuOH (Pd2(dba)3, 2-dicyclohexylphosphine-2′-6′-dimethoxy biphenyl, MW, 150 °C. (h) AcOH/TFA; PtO2, H2, RT, 3 h. (i) Anh. HCl-dioxane, 0.1M anh. 2-methoxy ethanol, 135 °C, 2 h.
  • DescriptionCeritinib (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].
  • DefinitionChEBI: 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.
  • IndicationsCeritinib (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.
  • Chemical SynthesisThe critical step in the synthesis of ceritinib involves a latestage Buchwald–Hartwig 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–Hartwig coupling precursor 50 in 60% over 2 steps. Next, the critical union of 50 and 51 via Buchwald–Hartwig 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.

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