Antineoplastic agents LXIV: 1,4-Bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dihydrogen dimaleate

The 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dication (II) exhibits remarkable antineoplastic activity. Detailed evaluation of several dianion derivatives showed a curative response level against the murine P-388 lymphocytic leukemia, colon 26, CD8F1 mammary, and the Walker 256 carcinosarcoma (rat) tumor systems. In addition, significant cancer chemotherapeutic activity was found against the murine L-1210 lymphoid leukemia, colon 38, and B16 melanocarcinoma tumor systems. The bicyclo dication (II) first was isolated, evaluated, and stored as the diperchlorate derivative (IIa). Because of the promising anticancer activity of IIa, procedures were developed for obtaining other anion derivatives for comparative biological purposes. Several naturally occurring substances were evaluated, and the dihydrogen dimaleate derivative (IIi) obtained by an ion-exchange technique was the most suitable.