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. 2023 Dec 18;62(51):e202311583.
doi: 10.1002/anie.202311583. Epub 2023 Nov 14.

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

Alexander A Kirichok  1   2 , Hennadii Tkachuk  1 , Yevhenii Kozyriev  1   3 , Oleh Shablykin  1   4 , Oleksandr Datsenko  1 , Dmitry Granat  1 , Tetyana Yegorova  2 , Yuliya P Bas  2 , Vitalii Semirenko  1 , Iryna Pishel  1 , Vladimir Kubyshkin  1 , Dmytro Lesyk  5 , Oleksii Klymenko-Ulianov  5 , Pavel K Mykhailiuk  1   2
Affiliations

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

Alexander A Kirichok et al. Angew Chem Int Ed Engl. .

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.

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