Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N′-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons–Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald–Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK_a of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74±0.05, which is 1.3 pK_a units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules.

哌嗪和修饰的哌嗪，例如高哌嗪和2-甲基哌嗪，存在于多种药物和生物活性分子中。在该研究中，将2,5-二氮杂双环[4.1.0]庚烷描述为修饰的哌嗪类似物，其中环丙烷环稠合在哌嗪环上。差分Ñ，Ñ '二取代和Ñ使用1,2,3,4-四氢吡嗪与二乙基锌和二碘甲烷的Simmons-Smith反应形成关键的环丙烷环，只需几个步骤即可轻松地从2-ketopiperazine制备单取代化合物。氟喹诺酮类抗菌药环丙沙星的类似物是通过钯催化的布赫瓦尔德-哈特维格交叉偶联合成的，将二氮杂双环[4.1.0]庚烷核连接到氟喹诺酮核的7位上。所得的类似物被证明具有与母体药物环丙沙星相似的抗菌活性。该类似物的X射线晶体学分析显示，二氮杂双环[4.1.0]庚烷核中的哌嗪环变形。N的共轭酸的p K _a测定-Cbz-单保护的2，5-二氮杂双环[4.1.0]庚烷为6.74±0.05，这比相应的N -Cbz-单保护的哌嗪化合物低1.3p K _a单位。二氮杂双环[4.1.0]庚烷的碱性较低是由于相邻环丙烷环的吸电子特性。相对于哌嗪，修饰的二氮杂双环[4.1.0]庚烷的物理化学和结构性质有望导致这些分子的药代动力学和生物学活性变化。