Design, Synthesis, Antineoplastic Activity, and Chemical Properties of Bis(carbamate) Derivatives of 4,5-Bis(hydroxymethyl)imidazole

A series of bis (carbamate) derivatives of 1,2-substituted 4,5-bis(hydroxymethyl)imidazoles were prepared and evaluated against murine P388 lymphocytic leukemia. Electron-withdrawing substituents at either N-l or C-2 gave rise to inactive compounds. However, electron-donating substituents gave active compounds and the 2-(methylthio)-l-methyl derivative 2i (carmethizole), as the bis(N-methylcarbamate) was found to be very active. The derivative 2i, referred to by the name carmethizole, was also shown to be active against the MX-1 mammary xenograft, the human amelanotic melanoma cell line (LOX) xenograft, the M5076 sarcoma, and L1210 lymphocytic leukemia. The solution stability, water solubility, pK_a, and log P of carmethizole are also reported.