C-Substituted Azepanes for Novel Organic Synthesis and Drug Discovery Research

On account of their continuing pharmacological significance azepane ring containing structures attract considerable attention in organic synthesis and drug discovery.^1-2

There are several naturally occurring azepane derivatives possessing a number of biological activities. For example, azepane ring containing metabolite (-)-balanol 1³ (Figure 1) showed the potency as an ATP-competitive inhibitor of the protein kinase. This natural compound has since been used as a scaffold for development of a series of analogues as potential antitumor agents.⁴ Presently there are 5 approved and ca. 20 experimental drugs that have the azepane substructure.⁵ Among them, Tolazamide 2 is an oral blood glucose lowering drug used for people with type 2 diabetes. Another azepane containing marketed drug Azelastine 3 represents an example of a potent, second-generation, selective histamine antagonist.

Noteworthy, substituted azepanes have flexible ring structures and this conformational diversity is often decisive for their bioactivity.⁶ Therefore, the ability to introduce specific substituents into the azepane ring to bias it to one major conformation is important for effective drug design.

Figure 1. Examples of bioactive azepane-ring containing compounds

The full list of the functionalized azepanes offered by Life Chemicals can be obtained upon request at orders@lifechemicals.com. Please see some representative compounds below:

References

1. (a) Barbero, A.; Diez-Varga, A.; Pulido, F. J.; González-Ortega, A.Org. Lett. 2016, 18, 1972–1975. (b) Zhou, J.; Yeung, Y.-Y. Org. Lett. 2014, 16, 2134–2137.
2. Bremner, J. B.;Samosorn, S. In Comprehensive Heterocyclic Chemistry III, Eds. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Pergamon, Oxford, 2008. Vol. 13, p. 1.
3. Kulanthaivel, P.; Hallock, Y.; Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.; Katz, B.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1993, 115, 6452.
4. Breitenlechner, C. B.; Friebe, W. G.; Brunet, E.; Werner, G.; Graul, K.; Thomas, U.; Kunkele, K. P.; Schafer, W.; Gassel, M. Bossemeyer, D.; Huber, R.; Engh, R. A.; Masjost, B.; J. Med. Chem. 2005, 48, 163.
5. www.drugbank.ca; accessed in March 2019.
6. (a) Patel, A. R.; Liu, F. Tetrahedron 2013, 69, 744–752. (b) Patel, A. R.; Ball, G.; Hunter, L.; Liu, F. Org. Biomol.