Polycyclic N-Heterocyclic Compounds, Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Abstract

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

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GRAPHICAL ABSTRACT

Keywords:

• Antiplatelet aggregation
• cyclization
• Thorpe–Ziegler reaction
• Truce–Smiles rearrangement
• Vilsmeier reagent

ACKNOWLEDGMENTS

We are grateful to the Superconducting (SC)-NMR Laboratory of Okayama University for 200-MHz ¹H NMR experiments. We also thank Hiromi Ohtomo, Kaori Ueda, Yoko Ohkuma (Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University), and Taiji Nakayama (deceased) (Faculty of Pharmaceutical Sciences, Okayama University) for their experimental assistance, and K. L. Kirk (National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health) for helpful comments on the manuscript.