Antineoplastic Agents. 36. Acetylenic Carrier Groups

The development of experimentally facile routes to N-(2-chloroethyl)amines with multifunctional carrier groups was an initial objective of our efforts to design site specific² (e.g., central nervous system) cancer chemotherapeutic agents. Methods were eventually uncovered for utilizing N-bis(2-chloroethyl)amine in Mannich reactions with, for example, ketones and imides (for leading references see ref 3 and 4). Of the common active hydrogen type compounds generally employed in Mannich reactions the acetylenic carbinols 1 proved most resistant to reaction with N-bis(2-chloroethyl)amine. However, an appropriate copper-catalyzedt procedure was eventually found and acetylenic Mannich bases 2a-d were prepared.³ Subsequent biological evaluation of these substances under the direction of the National Cancer Institute led to the results shown in Table I.⁶ Because of the promising inhibition shown by the acetylenic Mannich base 2a against murine P-388 lymphocytic leukemia, the present study was undertaken to explore this structural lead and further scope of the copper-catalyzed reaction with N-bis(2-chloroethyl) amine.