NOVEL PRODRUGS VON 6-HYDROXY-2,3-DIHYDRO-1H-INDOLES, 5-HYDROXY-1,2-DIHYDRO-3H-PYRROLO3,2-EINDOLES AND 5-HYDROXY-1,2-DIHYDRO-3H-BENZO(E)INDOLES AS WELL AS OF 6-HYDROXY-1,2,3,4-TETRAHYDRO-BENZOFQUINOLINE DERIVATIVES FOR USE IN SELECTIVE CANCER THERAPY

摘要

Chemotherapy of malignant tumors is seriously restricted by the fact that available cytostatics are often not capable of differentiating between normal and malignant tissue. The aim of the invention is therefore to improve the selectivity of cytostatics used for cancer therapy. To this end, novel prodrugs of 6-hydroxy-2,3-dihydro-1H-indoles, 5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indoles and 5-hydroxy-1,2-dihydro-3H-benzo[e]indoles as well as of 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines have been developed which can be used in ADEP therapy (antibody directed enzyme prodrug therapy). The novel prodrugs are characterized by a marked difference in toxicity between the prodrug and the drug on which it is based and by a very high effectiveness of the drug. The high selectivity of the novel prodrugs is probably due to the fact that they contain, unlike the prodrugs of a similar kind produced so far, a secondary halide. Said halide reduces the direct alkylation of the DNA or RNA by the prodrugs and thereby the toxicity of the prodrug. Once the glycoside or acetal group on the phenolic hydroxy group of the prodrug is removed, a spirocyclopropacyclohexadiene is formed which, being a highly toxic group, brings about the alkylation of the DNA or RNA.