Uses
BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models.
Definition
ChEBI: Copanlisib is an imidazoquinazoline that is 2,3-dihydroimidazo[1,2-c]quinazoline substituted by (2-aminopyrimidine-5-carbonyl)amino, methoxy, and 3-(morpholin-4-yl)propoxy groups at positions 5, 7 and 8, respectively. It is a intravenous pan-class I PI3K inhibitor used for the treatment of relapsed follicular lymphoma in patients who have received at least 2 prior systemic therapies. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of morpholines, an aromatic ether, a diether, a tertiary amino compound, a secondary carboxamide, a pyrimidinecarboxamide, an aminopyrimidine and an imidazoquinazoline.
General Description
Class: lipid kinase;
Treatment: FL (IV infusion);
Other name: BAY 80-6946;
Elimination half-life = 52 h (IV);
Protein binding = 84.2%
Pharmacokinetics
Copanlisib has poor oral bioavailability due to
low permeability and poor solubility, and therefore, it
is not suitable for an oral medication. Consequently,
it was developed as an IV drug. IV infusion of
copanlisib resulted in rapid distribution throughout
the body and a prolonged elimination half-life (52 h).
Synthesis
Example 10: Step A9: Preparation of copanlisib (10). 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine, 20.3 kg of N,N-dimethylformamide, 531 g of 2-amino-pyrimidine-5-carboxylic acid, 425 g of N,N-dimethylaminopyridine, and 1000 g of N-[3-(dimethylamino)propyl]-N'-ethylcarbodi N'-ethylcarbodiimide hydrochloride were mixed and the reaction was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was filtered and the solid was collected. The solid was washed with N,N-dimethylformamide followed by ethanol and dried at 50 °C to give 1.6 kg of the target product in 96% yield. The resulting product was directly converted to its dihydrochloride form.
Metabolism
Copanlisib was the predominant component in
human plasma, accounting for 84% of total
radioactivity AUC, and the morpholinone metabolite
6 was the only circulating metabolite (about 5%).
References
[1] Patent: WO2016/71435, 2016, A2. Location in patent: Page/Page column 55
[2] Patent: WO2016/71426, 2016, A1. Location in patent: Page/Page column 37
[3] Patent: WO2008/70150, 2008, A1. Location in patent: Page/Page column 85
[4] ChemMedChem, 2016, p. 1517 - 1530
![7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-](/CAS/20200611/GIF/1032570-74-3.gif)
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