Synthesis of Bicyclic “Preactivated” Analogues of Cyclophospamide

Abstract

Abstract Studies on the metabolism of Cyclophosphamide (CPA), one of the most widely used anticancer agents, have shown that hydroxycyclophosphamide (4-hydroxy-CPA) is a major metabolite in the process which lead to the liberation of the ultimate cytostatic agent “phosphoramide mustard” in tumor cells (1). Unfortunately, hydroxycyclophosphamide itself is very unstable and many attemps have been made to synthesize more stable derivatives. One of the most successful was accomplished by ASTA GRUPPE who introduced Mafosfami.de (4-sulfoethylthio-cyclophosphamide) as a stable derivative of 4-hydroxy-CPA (2). We have ourselves undertaken the synthesis of bicyclic “preactivated” analogues of cyclophosphamide of the type : Two chemical ways, outlined below, were studied for this purpose.