Description
Afatinib dimaleate (Tovok; BIBW2992; Gilotrif) is a salt form of Afatinib. Afatinib is a second-generation, orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases.
Mechanism of Action
Afatinib (850140-73-7) downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-na?ve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US.
Description
Afatinib dimaleate was approved by the U.S. Food and Drug
Administration (FDA) in 2013 for the treatment of non-small cell
lung cancer (NSCLC). Specifically, it was approved for patients
presenting with metastatic NSCLC tumors which contain epidermal
growth factor receptor (EGFR) exon deletions or exon 21
mutations. Afatinib dimaleate is a covalent inhibitor of ErbB tyrosine
kinases (tyk), which downregulates ErbB signaling by irreversible
binding of EGFR tyk binding sites. While no
manufacturing route has been disclosed to date, the most scalable
published route likely derives from two Boehringer Ingelheim
patents.
Uses
Afatinib Dimaleate is a salt of Afatinib {BIBW 2992), an aminocrotonylamino-substituted quinazoline derivative used for treating cancer and diseases of the respiratory tract, lungs, gastrointestinal tract, bile duct, and gallbladder. An anilino-quinazoline that irreversibly inhibits EGFR and HER2 kinase activity.
Definition
ChEBI: Afatinib dimaleate is a maleate salt obtained by combining afatinib with two molar equivalents of maleic acid. Used 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 contains an afatinib.
General Description
Afatinib dimaleate is the dimaleate form of afatinib. It is a tyrosine kinase inhibitor of epidermal growth factor receptors (ERBB RECEPTORS) and an anti-angiogenic agent. Afatinib dimaleate has anti-tumour activity and is mainly used for the treatment of patients with metastatic non-small cell lung cancer (which has metastasised or spread to other parts of the body), or certain tumours with mutations in the EGFR gene and patients whose disease has worsened after platinum-based chemotherapy. It is also used for the treatment of esophageal squamous cell carcinoma (ESCC) and gastric cancer.
Biological Activity
Afatinib dimaleate is an orally bioavailable and irreversible dual-specific inhibitor of the ErbB family (EGFR and HER2). IC50 are 0.4, 0.5, 10, 14, 1 nM for EGFR
L858R, EGFR
wt, EGFR
L858R/T790M, ErbB2 (HER2) and ErbB4 (HER4), respectively. Afatinib dimaleate is available for cancer (esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC) and gastric cancer) studies.
Side effects
Afatinib dimaleate is similar to afatinib in terms of side effects. Common side effects include: diarrhoea, fever, difficulty urinating, burning or pain, redness, swelling or pain in the skin, discharge or excessive tearing, burning, dryness or itching of the eyes, and skin ulcers. Occasional symptoms of coughing and difficulty breathing. A very small number of patients may have bloody stools, black stools or tarry stools, indigestion, nausea, severe abdominal pain, cramping or burning sensation, and vomiting of a substance that looks like coffee grounds. Please contact your doctor promptly if any serious adverse reactions occur.
Synthesis
Nitroquinazolinone (6), which is commercially available, was
first chlorinated with phosphorous oxychloride (POCl3) followed
by treatment with commercial 3-chloro-4-fluoroaniline (7) to
afford SNAr adduct 8 in 90% yield over two steps. Sulfonylation to afford 9 (86%) and subsequent displacement with (S)-tetrahydrofuran-
3-ol gave 10 in 90% yield. Raney¨CNickel reduction
of the nitro group delivered 11 in 97% yield, which set the stage
for the final side-chain functionalization. 2-(Diethoxyphosphoryl)
acetic acid and N,N0-carbonyldiimidazole (CDI) were pre-mixed
and added to aniline 11 to afford 12 in 70% isolated yield. Next, a
Horner¨CWadsworth¨CEmmons homologation gave the (E)-olefin
13 in quantitative yield, followed by maleate salt formation
(92%) to deliver the final API. The final five steps of this synthesis
have been successfully demonstrated on multi-kilogram scale.
