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 ß-lactams. Reduction of the ß-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.
ABSTRACT
The synthesis of multifunctional spirocycles was achieved from common cyclic carboxylic acids (cyclobutane carboxylate, cyclopentane carboxylate, l-proline, etc.). The whole sequence included only two chemical steps-synthesis of azetidinones, and reduction into azetidines. The obtained spirocyclic amino acids were incorporated into a structure of the known anesthetic drug Bupivacaine. The obtained analogues were more active and less toxic than the original drug. We believe that this discovery will lead to a wide use of spirocyclic building blocks in drug discovery in the near future.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacology , Drug Discovery , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Anesthetics/chemistry , Azetidines/chemistry , Bupivacaine/chemistry , Carboxylic Acids/chemistry , Cyclopentanes/chemistry , Proline/chemistry , Spiro Compounds/chemistryABSTRACT
The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and a demonstration of their validation in drug discovery.
