Synthesis and Murine Antineoplastic Activity of Bis[(carbamoyloxy)methy 1] Derivatives of Pyrrolo[2,1-a]isoquinoline

The synthesis of 4,5-dihydropyrrolo[2, 1-a]isoquinolines is reported. A key intermediate in the synthesis of 8-methoxy-4,5-dihydropyrrolo[2,1-a]isoquinolines, 6-hydroxy-1, 2, 3,4-tetrahydroisoquinoline-1-carboxylic acid (6), was prepared by using a regiospecific phenolic cyclization reaction. The P388 lymphocytic activity is reported for 1.2-bis(hydroxymethy)-5, 6-dihydro-8-methoxy-3-methylpyrrolo[2,1-a]isoquinoline bis(isopropylcarbamate) (11a), 1.2-bis(hydroxymethyl)-5, 6-dihydro-8-methoxy-3-methylpyrrolo[2,1-a]isoquinoline bis(cyclohexylcarbaniate) (lib), 1.2-bis(hydroxymethyl)-5, 6-dihydro-3-methylpyrrolo[2,1-a]isoquinoline bis(methylcarbamate) (13a), 1,2-bis(hydroxymethyl)-5, 6-dihydro-3-methylpyrrolo[2,1-a]isoquinoline bis(ethylcarbamate) (13b), and 1, 2-bis(hydroxymethyl)5, 6-dihydroxy-3-methylpyrrolo[2,1-a]isoquinoline bis(cyclohexylcarbamate) (13c); all of the compounds were active. Compound 11a was tested in an expanded tumor panel and was shown to be active against B16 melanocarcinoma, CD8F₁ mammary, L1210 lymphoid leukemia, colon 38, and MX-1 human tumor breast xenograft systems.