Neumeyer J L, Granchelli F E, Filer C N, Soloway A H, Law S J
J Med Chem. 1980 Sep;23(9):1008-13. doi: 10.1021/jm00183a009.
A series of aporphine nitrogen mustards and their congeners (1b-g) has been prepared. N-[[Bis(2-chloroethyl)-amino]-2,11-dihyroxy-10-methoxynoraporphine (1b) and its mono- and diacetyl ester derivatives (1c-d) were prepared from N-(chloroacetyl)-2,11-diacetoxy-10-methoxynoraporphine (2). Reaction of 2 with diethanolamine under various conditions and different solvents resulted in the corresponding N-[[bis(2-hydroxyethyl)amino]acetyl] precursors, which were subsequently treated with SOCl2 to yield the target compounds. N-(2-Choroethyl)norapocodeine (1e) was obtained from the chlorination of N-(2-hydroxyethyl)norapocodeine (9) with SOCl2. Prolonging such treatment was found to result in the formation of N-[2-(chloroethoxy)ethyl]norapocodeine (1f) at the expense of 1e. N-[[[N'-(2-Chloroethyl)carbamyl]oxy]ethyl]norapocodeine (1g) and its 11-(2-chloroethyl)carbamyl derivative (1h) were also prepared. All the double-armed aporphine amide nitrogen mustards (ab-d) were found to have antitumor activity. The single-armed aporphine nitrogen mustard (1e) was also active in P388 but the activity was less than that observed with 1b-d. The lead compound 1a was inactive in the LE1210 and P388 systems at the doses tested. Similarly, the two aporphine mustard congeners (1f,g) were also inactive in the P388 system. All the activity was observed in the intraperitoneally innoculated tumor systems.
