1-氮杂螺[3.3]庚烷作为哌啶的生物电子等排体。
1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine.
作者信息
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
机构信息
Enamine Ltd, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Volodymyrska 60, 01601, Kyiv, Ukraine.
出版信息
Angew Chem Int Ed Engl. 2023 Dec 18;62(51):e202311583. doi: 10.1002/anie.202311583. Epub 2023 Nov 14.
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, ClO 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.
1-氮杂螺[3.3]庚烷被合成、表征，并作为哌啶的生物电子等排体进行了生物学验证。关键的合成步骤是环内烯烃与格拉夫异氰酸酯ClO S-NCO之间的热[2+2]环加成反应，生成螺环β-内酰胺。用铝烷还原β-内酰胺环得到1-氮杂螺[3.3]庚烷。将这个核心结构引入麻醉药物布比卡因中，取代哌啶片段，得到了一种具有高活性的无新专利类似物。
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