A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-1H-pyrrol izin-5- yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the alpha-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer composition, and ionic strength. The 4- and 5-pyrrolizinyl-2-halopyridinium iodides and the corresponding pyridones were evaluated against P388 lymphocytic leukemia in vivo. The alpha-fluoropyridinium compounds were active but the alpha-chloro compounds were not. This activity was correlated with the rates of hydrolysis of the alpha-halopyridinium compounds to the active pyridone. Compounds that were active in the P388 screen were evaluated in L1210 leukemia, M5076 carcinoma, and MX-1 mammary xenograft assays in mice.

A series of bis[[(carbamoyl)oxy]methyl]-substituted pyrrole-fused tricyclic heterocycles were synthesized by using 1,3-dipolar cycloaddition reactions with a trifluoromethanesulfonate salt of an appropriate Resissert compound or with a mesoionic oxazolone intermediate. All of the bis(carbamates) were active in vivo against P388 lymphocytic leukemia with 5,6-dihydro-8-methoxy-1,2- bis(hydroxymethyl)pyrrolo[2,1-a]isoquinoline bis[N-(2-propyl)carbamate] (3c) showing the highest level of activity.

Treatment of N-acylproline derivatives, 2, with acetic anhydride--dimethyl acetylenedicarboxylate (DMAD) gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (5). The reaction proceeds via a 1,3-dipolar addition of DMAD with the mesoionic oxazalone intermediate 3, generated in situ, with concomitant elimination of carbon dioxide. Reduction of 5 gave the diols 6 which upon subsequent acylation gave 1. The bis(N-methylcarbamate) 1d and the diacetate li show a modest level of in vivo antileukemia activity in the L1210 assay. A majority of the diesters, 1, showed significant antileukemic activity in the in vivo P-388 assay. The bis(carbamate) 1d afforded "cures" at dose levels as low as 12.5 mg/kg; 1 q showed potent activity at doses as low as 0.78 mg/kg. Several other compounds showed potent activity against P-388 over a greater than fourfold dose range with no acute toxicity. Half-lives for several diacetate derivatives of 1 were determined for aqueous Me2SO solutions. The preparation of 7 and 8 shows that 1 may react by O-alkyl ester cleavage.

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