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

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, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with...

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Published in:Angewandte Chemie International Edition 2023-12, Vol.62 (51), p.e202311583-n/a
Main Authors: Kirichok, Alexander A., Tkachuk, Hennadii, Kozyriev, Yevhenii, Shablykin, Oleh, Datsenko, Oleksandr, Granat, Dmitry, Yegorova, Tetyana, Bas, Yuliya P., Semirenko, Vitalii, Pishel, Iryna, Kubyshkin, Vladimir, Lesyk, Dmytro, Klymenko‐Ulianov, Oleksii, Mykhailiuk, Pavel K.
Format: Article
Language:English
Subjects:
1-Azaspiro[3.3]Heptane
Bioisosteres
Drug Design
Medicinal Chemistry
Piperidine
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Summary: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, ClO2S−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. 1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine ring resulted in a patent‐free analogue with high activity.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202311583