Improved Procedure for the Preparation of Bosentan, an Endothelin Receptor Antagonist

摘要

Endothelins are a family of structurally related 21-amino acid peptides with two cysteine-cysteine disulfide bridges. Endothelin itself has recently been shown to play a pivotal role in the development of pulmonary hypertension and elevated endothelin concentrations have been found to be strongly correlated with the severity of the disease. Endothelin antagonists, especially 4-(1,1-dimethyl ethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-pyrimidin]-4-yl] benzenesulfonamide monohydrate (bosentan), represent a new approach for the treatment of pulmonary hypertension. Bosentan (Tracleer~R) became the first endothelin antagonist to reach the market for the treatment of pulmonary hypertension and to date, only a few drugs such as sitaxentan and ambrisen-tan have been specifically approved for this indication. Bosentan can also be used for the treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris and offers a new strategy for the treatment of patients with cardiovascular pathology and in particular, congestive heart failure. We sought to establish a new manufacturing process for bosentan, free of impurities.