Synthesis of N-[3,4-Dihydro-4-(acetoxymethyl)-2,2,4-trimethyl-2H-1-benzothiopyran-6-yl]-N′-(4-nitrophenyl)thiourea and N-[3,4-dihydro-4-(hydroxymethyl)-2,2,4-trimethyl-2H-1-benzothiopyran-6-yl]-N′-(4-nitrophenyl)thiourea, a Major Metabolite of N-(3,4-Dihydro-2,2,4,4-tetramethyl-2H-1-benzothiopyran-6-YL)-N′-(4-nitrophenyl)thiourea

Abstract The compound N-(3,4-dihydro-2,2,4,4-tetramethyl-2H-1-benzothiopyran-6-yl)-N′-(4-nitrophenyl)thiourea [NSC 726189] has exhibited strong anticancer activity in several assays and cell lines and is under consideration for clinical trials for the possible treatment of kidney cancer. Since the heterocycle has not shown any significant toxicity in animal studies, it is conceivable that a metabolite could be the active agent. In a previous study, major metabolites were tentatively identified via analyses of materials extracted from rat and human liver microsomes, as well as extracts from rat urine, by the use of HPLC-UV and MS/MS. However, no metabolite has been obtained in pure form. This article outlines a de novo synthesis of a primary metabolite, namely N-[3,4-dihydro-4-(hydroxymethyl)-2,2,4-trimethyl-2H-1-benzothiopyran-6-yl]-N′-(4-nitrophenyl)thiourea. A prodrug of the metabolite was also prepared, namely N-[3,4-dihydro-4-(acetoxymethyl)-2,2,4-trimethyl-2H-1-benzothiopyran-6-yl]-N′-(4-nitrophenyl)thio-urea. GRAPHICAL ABSTRACT