Poziotinib

Poziotinib (HM781-36B) is an irreversible pan-HER inhibitor with IC50 of 3.2 nM, 5.3 nM and 23.5 nM for HER1, HER2, and HER4, respectively. Phase 2. Poziotinib [1. {4. [4. (3,4. Dichloro.2.monofluoroaniline) -7-methoxyquinazoline-6. Oxygen]. 1. Piperidinyl} propan-2-ene-1one (1)] is a novel oral cancer cell inhibitor developed by Seoul Medical University in South Korea in 2008. It is used for the treatment of breast and gastric cancer, and has targeted Small molecule inhibitor of tyrosine kinas

Poziotinib has been used in trials studying the treatment of Breast Cancer, Metastatic Breast Cancer, Increased Drug Resistance, Adenocarcinoma of Lung Stage IV, and Adenocarcinoma of Lung Stage IIIB, among others.|Poziotinib is an orally bioavailable, quinazoline-based, irreversible pan-epidermal growth factor receptor (EGFR or HER) inhibitor, with potential antineoplastic activity. Upon oral administration, poziotinib inhibits EGFR (HER1 or ErbB1), HER2 and HER4, thereby inhibiting proliferation of tumor cells in which these receptors are overexpressed and/or mutated. EGFRs, cell surface receptor tyrosine kinases upregulated or mutated in a variety of cancer cell types, play key roles in cellular proliferation and survival.

4-(3, 4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (12 g, 34 mmol) prepared in Preparation Example 1, l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), KThe procedure of Step (1-2) of was repeated, except l-(3- chloropropanoyl)piperidin-4-yl 4-methylbenzenesulfonate (13 g, 35 mmol) prepared in step (2-1) above was used instead of 1 -aery toy lpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), to obtain the target compound (7.4 g, yield: 58percent). 1H-NMR (300 MHz, DMSO-dExample 5 Example 5 Preparation of 1-(4-(4-(3, 4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (the Compound of Formula (II)) N-(3, 4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0 C. with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0 C. for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1-(4-(4-(3, 4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40 C. in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield=57%). 1H-NMR (CDCl3, 300 MHz, ppm) 68.68 (s, 1H), 8.39 (t, 3H), 7.31 (m, 3H), 6.61 (m, 1H), 6.29 (m, 1H), 5.72 (m, 1H), 4.75 (m, 1H), 4.02 (s, 3H), 3.89 (m, 2H), 3.60 (m, 2H), 1.86 (m, 4H).Example 6 Preparation of The procedure of Step (1-2) of was repeated, except l-(3- chloropropanoyl)piperidin-4-yl 4-methylbenzenesulfonate (13 g, 35 mmol) prepared in step (2-1) above was used instead of 1 -aery toy lpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), to obtain the target compound (7.4 g, yield: 58%). 1H-NMR (300 MHz, DMSO-d6) delta 9.65 (bs, IH), 8.40 (s, IH), 7.88 (s, IH), 7.64-7.56 (m, 2H), 7.24 (s, IH), 6.89-6.80 (m, IH), 6.15-6.08 (m, IH), 5.70-5.66 (m, IH), 4.78 (m, IH), 3.94 (s, 3H), 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, IH).4-(3, 4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (12 g, 34 mmol) prepared in Preparation Example 1, l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), K2CO3 (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 mL) were admixed. The reaction temperature was raised to 70C, and the mixture was stirred for 24 hours. Upon completion of the reaction, the mixture was cooled down to room temperature, extracted with ethyl ester (300 mL), and then washed with water (300 mL). The organic layer was separated, and distilled under a reduced pressure. The residue thus obtained was solidified by adding ethyl ester, filtered, and dried to obtain the target compound (12.8 g, yield: 77%). 1H-NMR (300 MHz, DMSO-d6) delta 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.64-7.56 (m, 2H), 7.24 (s, 1H), 6.89-6.80 (m, 1H), 6.15-6.08 (m, 1H), 5.70-5.66 (m, 1H), 4.78 (m, 1H), 3.94 (s, 3H), 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, 1H).(12 g, 34 mmol) synthesized in Production and 4- (3, 4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin- (16 g, 51 mmol), K2CO3 (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 ml) were mixed and the mixture was stirred at room temperature for 1 hour. Was heated to 70 DEG C and stirred for 24 hours. After completion of the reaction, the temperature of the reaction mixture was cooled to room temperature, extracted with ethyl ester (300 ml), and washed with water (300 ml). The organic layer was separated and distilled under reduced pressure. Ethyl ester was added to the residue to solidify it, followed by filtration and drying to obtain the title compound (12.8 g, yield 77%).

Poziotinib is suitable for the treatment of patients with advanced NSCLC with exon 20 mutations in EGFR. Multiple patients have proven effective. Poziotinib is also valuable for patients with advanced NSCLC who are resistant to first-generation EGFR TKI and T790M / MET negative. There are no clinical data on the treatment of patients with brain metastases by Poziotinib. One patient with advanced NSCLC with exon 20 mutation in EGFR had meningeal metastases. This patient has been taking Poziotini

Molecular Weight:491.3
XLogP3:5.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:490.0974741
Monoisotopic Mass:490.0974741
Topological Polar Surface Area:76.6
Heavy Atom Count:33
Complexity:684
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes