Patent Evaluation: Acridine Multidrug Resistance Inhibitiors

Summary

Novelty: A novel group of compounds which sensitize multidrug resistant (MDR) cancer cells to chemotherapy is disclosed. In contrast to similar known agents, the claimed compounds are non-toxic at their effective dose levels.

Biology: The efficacy of compounds as inhibitors of MDR is evaluated in the CHO cell line CH^RC5, treated with doxorubicin (5 mg/ml). EC₅₀ data (0.018 − 0.72 mM) refer to cell viability relative to doxorubicin-treated controls. The EC₅₀ for the known agent verapamil was 3mM. Oral toxicity in mice is said to be negligible at 300mg/kg.

Chemistry: Procedures are outlined for the synthesis of one hundred and thirty-seven named examples of which thirty-six are specifically claimed, including 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-diethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridinecarboxamide. Thirteen novel compounds are amongst 101 named intermediates.

Structure: