Rogletimide Explained

Rogletimide, also known as pyridoglutethimide, is a medication which was never marketed.[1] It is related in chemical structure to the sedative/hypnotic drug glutethimide, but instead has pharmacological activity as a selective aromatase inhibitor similar to the related drug aminoglutethimide and has no significant sedative-hypnotic effect.[2] This makes it potentially useful in the treatment of breast cancer, and with fewer side effects than aminoglutethimide, but its lower potency caused it to be unsuccessful in clinical trials.[3]

Synthesis

Base catalyzed alkylation of ethyl 4-pyridylacetate [54401-85-3] (1) with iodoethane gives ethyl 2-(4-pyridyl)butyrate [76766-56-8] (2). Base catalyzed conjugate addition of the carbanion to acrylamide (3) gives (4). The last step is an intramolecular cyclization to rogletimide (5).

Notes and References

  1. Book: Frederick A. Luzzio. Imides: Medicinal, Agricultural, Synthetic Applications and Natural Products Chemistry. 17 May 2019. Elsevier Science. 978-0-12-815676-6. 361–.
  2. Vanden Bossche HV, Moereels H, Koymans LM . Aromatase inhibitors--mechanisms for non-steroidal inhibitors . Breast Cancer Research and Treatment . 30 . 1 . 43–55 . 1994 . 7949204 . 10.1007/bf00682740. 24414161 .
  3. MacNeill FA, Jones AL, Jacobs S, Lønning PE, Powles TJ, Dowsett M . The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer . British Journal of Cancer . 66 . 4 . 692–7 . October 1992 . 1419608 . 1977412 . 10.1038/bjc.1992.339.