Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

• Published in: Tetrahedron Vol. 66; no. 18; pp. 3370 - 3377
• Main Authors: Taylor, Rivka R.R., Twin, Heather C., Wen, Wendy W., Mallot, Rebecca J., Lough, Alan J., Gray-Owen, Scott D., Batey, Robert A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2010; Elsevier
• Subjects: 2,5-Diazabicyclo[4.1.0]heptanes; Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Analogue; Antiinfectives and antibacterials; Basicity; Biological; Chemistry; Chemistry, Organic; Cross coupling; Cyclopropanation; Cyclopropane; Drugs; Enamide; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Organic chemistry; Parents; Physical Sciences; Piperazine heterocycle analogues; Preparations and properties; Quinolone antibiotic; Science & Technology; Cyclopropanation; Enamide; Quinolone antibiotic; Piperazine heterocycle analogues; 2,5-Diazabicyclo[4.1.0]heptanes; QUINOLONES; ELECTROCHEMICAL REDUCTION; BARBARALANES; GRAM-NEGATIVE BACILLI; ANTIBACTERIALS; FLUOROQUINOLONES; RESISTANCE; INHIBITORS; Cyclopropane derivatives; Nitrogen heterocycle; Enamine; Palladium complex; Distortion; Fluoroquinolone derivatives; Simmons Smith reaction; Chemical synthesis; Quinolone derivatives; Drug; Catalytic reaction; Quinoline derivatives; Ketone; X ray diffraction; Biological activity; Antibiotic; Analog; Alkalinity; Piperazine derivatives; Antibacterial agent; Ciprofloxacin; Pharmacokinetics; Electron acceptor
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2010.02.046

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 p K 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 p K 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. [Display omitted]