1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine

Alexander A Kirichok; Hennadii Tkachuk; Yevhenii Kozyriev; Oleh Shablykin; Oleksandr Datsenko; Dmitry Granat; Tetyana Yegorova; Yuliya P Bas; Vitalii Semirenko; Iryna Pishel; Vladimir Kubyshkin; Dmytro Lesyk; Oleksii Klymenko-Ulianov; Pavel K Mykhailiuk

doi:10.1002/anie.202311583

1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine

Angew Chem Int Ed Engl. 2023 Dec 18;62(51):e202311583. doi: 10.1002/anie.202311583. Epub 2023 Nov 14.

Authors

Alexander A Kirichok^{1

2}, Hennadii Tkachuk¹, Yevhenii Kozyriev^{1

3}, Oleh Shablykin^{1

4}, Oleksandr Datsenko¹, Dmitry Granat¹, Tetyana Yegorova², Yuliya P Bas², Vitalii Semirenko¹, Iryna Pishel¹, Vladimir Kubyshkin¹, Dmytro Lesyk⁵, Oleksii Klymenko-Ulianov⁵, Pavel K Mykhailiuk^{1

2}

Affiliations

¹ Enamine Ltd, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
² Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Volodymyrska 60, 01601, Kyiv, Ukraine.
³ Oles Honchar Dnipro National University, Faculty of Chemistry, 72 Gagarina Ave., 49010, Dnipro, Ukraine.
⁴ V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Akademika Kukharya 1, 02094, Kyiv, Ukraine.
⁵ Bienta, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.

PMID: 37819253
DOI: 10.1002/anie.202311583

Abstract

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO₂ S-NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.

Keywords: 1-Azaspiro[3.3]Heptane; Bioisosteres; Drug Design; Medicinal Chemistry; Piperidine.

Grants and funding

101000893/HORIZON EUROPE European Research Council