Afatinib (BIBW 2992)

Bezeichnung:Afatinib (BIBW 2992)

CAS-Nr439081-18-2

Englisch Name:Afatinib (BIBW 2992)

CBNumberCB12470923

SummenformelC24H25ClFN5O3

Molgewicht485.94

MOL-Datei439081-18-2.mol

Afatinib (BIBW 2992) physikalisch-chemischer Eigenschaften

Siedepunkt	676.9±55.0 °C(Predicted)
Dichte	1.380
storage temp.	Store at -20°C
Löslichkeit	≥24.3 mg/mL in DMSO; insoluble in H2O; ≥42.1 mg/mL in EtOH with ultrasonic
pka	12.06±0.43(Predicted)
Aggregatzustand	solid
Farbe	White to off-white
InChIKey	ULXXDDBFHOBEHA-INIZCTEOSA-N
SMILES	C(NC1C(O[C@H]2CCOC2)=CC2C(C=1)=C(NC1=CC=C(F)C(Cl)=C1)N=CN=2)(=O)C=CCN(C)C
CAS Datenbank	439081-18-2

Sicherheit

HS Code

29349990

Gefahreninformationscode (GHS)

Afatinib (BIBW 2992) Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
In July 2013, the US FDA approved afatinib (also referred to as BIBW- 2992), for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) and with tumors that have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution. Afatinib functions as an irreversible inhibitor by covalently binding directly to the ATP-binding site in the kinase domains of both EGFR(Cys 773) andHER2 (Cys 805;HER-2 is the preferred dimerization partner of EGFR) resulting in downregulation of EGFR signaling. Afatinib is a potent inhibitor of wild-type and mutant forms (L858R) of EGFR (IC_50s of 0.5 and 0.4 nM, respectively), and HER2 (IC₅₀=14 nM), but about 100-fold more active against the gefitinib resistant L858R– T790M EGFR double mutant, with an IC₅₀ of 10 nM. Consistent with its in vitro activity, afatinib induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. A synthetic route to afatinib that employs the displacement of a phenylsulfonyl group to install the (S)-3-hydoxytetrahydrofuran ring and a modified Horner–Wadsworth–Emmons reaction with {[4-(3-chloro-4- phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]- methyl}-phosphonate and dimethylaminoacetaldehyde-hydrogen sulfite adduct to install the eneamide moiety, has been reported.
Originator
Boehringer-Ingelheim (United States)
Verwenden
BIBW2992 (Afatinib, Tomtovok, Tovok) irreversibly inhibits EGFR/HER2 including EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively.
Definition
ChEBI: Afatinib is a quinazoline compound having a 3-chloro-4-fluoroanilino group at the 4-position, a 4-dimethylamino-trans-but-2-enamido group at the 6-position, and an (S)-tetrahydrofuran-3-yloxy group at the 7-position. Used (as its dimaleate salt) for the first-line treatment of patients with metastatic non-small cell lung cancer. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of quinazolines, a member of furans, an organofluorine compound, an enamide, an aromatic ether, a tertiary amino compound, a member of monochlorobenzenes and a secondary carboxamide.
Trademarks
Gilotrif
Synthese
Afatinib (BIBW 2992) is synthesized through a sequence starting from KI, NaIO4 and NaCl in AcOH/H2O, followed by formamide acetate in ethylene glycol monomethyl ether under reflux, (3S)-tetrahydrofuran-3-ol with NaH at 130 °C, SOCl2 in DMF at 90 °C, 3-chloro-4-fluoroaniline with trans-N,N'-dimethyl-1,2-cyclohexanediamine in dioxane at 100 °C, and finally CuI with K3PO4 in i-PrOH at 90 °C[1].
target
EGFRwt
Einzelnachweise
[1] Kovacevic, T., Mesic, M., Avdagic, A., & Zegarac, M. (2018). An alternative synthesis of the non-small cell lung carcinoma drug afatinib. Tetrahedron Letters, 59(47), 4180–4182. https://doi.org/10.1016/j.tetlet.2018.10.026

Afatinib (BIBW 2992) Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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