Rosabulin

We report herein the SAR studies of a series of indole- and indolizine-glyoxylamides that demonstrate substantial in vitro anti-proliferative activities against cancer cell lines, including multidrug resistance (MDR) phenotypes. The in vitro cytotoxic effects have been demonstrated across a wide array of tumor types of various origins (e.g., breast, colon, uterine).

An efficient synthesis of the novel microtubule inhibitor STA-5312 (3-[(4-cyanophenyl)methyl]-N-(3-methyl-5-isothiazolyl)-α-oxo-1-indolizineacetamide) was developed.A novel DMF/Me₂SO₄ directed regioselective synthesis of the 3-(4-cyanobenzoyl)-indolizine (4) was a critical transformation within the four-step process.Alternatively, a CuCl mediated synthesis of 3-(4-cyanobenzyl)indolizine (5) was also developed.All intermediates were obtained in high quality and were used directly for the next step without extensive purificationThe drug substance itself was purified by recrystallization from a mixture of THF and water, resulting in a high purity product (HPLC >98%).The process was applied successfully in the manufacturing of kilograms of GMP API.