Synthesis and murine antineoplastic activity of bis[carbamoyloxymethyl] derivatives of pyrrolo[2,1-a]isoquinoline

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Abstract
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(hydroxymethyl)-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(cyclohexylcarbamate) (11b), 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 active against B16 melanocarcinoma, CD8F1 mammary, L1210 lymphoid leukemia, colon 38 and MX-1 human tumor breast xenograft systems.