Synthesis and Structure‐Activity Relationship of Di‐(3, 8‐diazabicyclo[3.2.1]octane) Diquaternary Ammonium Salts as Unique Analgesics

Abstract

Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.

Rigid Scaffolds: Synthesis of 2,6‐Bridged Piperazines with Functional Groups in all three Bridges

“…MS: MicroTOFQII mass spectrometer (Bruker Daltonics, Bremen, Germany); deviations of the found exact masses from the calculated exact masses were 5 ppm or less; the data were analyzed with DataAnalysis® (Bruker Daltonics). NMR: NMR spectra were recorded in deuterated solvents on a AV300 (Bruker), DPX (Bruker), AV400 (Bruker), AS400 mercury plus NMR spectrometer (Varian), a 600 MHz unity plus NMR spectrometer (Varian), Agilent DD2 400 MHz and 600 MHz spectrometers (Agilent, Santa Clara CA, USA); chemical shifts (δ) are reported in parts per million (ppm) against the reference substance tetramethylsilane and calculated using the solvent residual peak of the undeuterated solvent; coupling constants are given with 0.5 Hz resolution; assignment of 1 H and 13 C NMR signals was supported by 2-D NMR techniques where necessary.IR: FT/IR IR Affinity®-1 spectrometer (Shimadzu, Düsseldorf, Germany) using ATR technique. Optical rotation: UniPol L1000 (Schmidt + Haensch); 1.0 dm tube; concentration c in g/100 mL; T = 20 °C; wavelength 589 nm (D-line of Na light); the unit of the specific rotation ([α] D T grad .…”

“…Subsequently a solution of pmethoxybenzylamine (1.51 mL, 11.60 mmol) in THF (10 mL) was added slowly over 30 min and the mixture was stirred for 60 min. 13…”

“…1 The signals for the CH 2 protons of the piperazine ring appear as very broad signals and are therefore not given. 13…”

“…The residue was purified by fc 26 (m, 3H, 2-CH benzyl , 4-CH benzyl , 6-CH benzyl ), 7.32 (t, J = 7.2 Hz, 2H, 3-CH benzyl , 5-CH benzyl ). 13 C NMR (101 MHz, DMSO-d 6 ): δ (ppm) = 24.6 (1C, CH 2 CH 2 CH 2 OH), 28.7 (1C, CH 2 CH 2 CH 2 OH), 41.3 (1C, NCH 2 Ph), 50.4 (1C, NCH 2 CO), 55.0 (1C, OCH 3 ), 56.5 (1C, NCH 2 PhOMe), 60.01 (1C, CH 2 CH 2 CH 2 OH), 61.9 (1C, NCHCO), 113.8 (2C, C-3 PMB , C-5 PMB ), 127.1 (1C, C-4 benzyl ), 127.3 (2C, C-2 benzyl , C-6 benzyl ), 128.3 (2C, C-3 benzyl , C-5 benzyl ), 128.9 (1C, C-1 PMB ), 130.0 (2C, C-2 PMB , C-6 PMB ), 137.2 (1C, C-1 benzyl ), 158.7 (1C, C-4 PMB ), 170.1(1C, NCH 2 CO), 172.7 (1C, NCHCO). IR (neat): v˜(cm À 1 ) = 3390 (OH), 2935 (C-H Benzyl-4-(4-methoxybenzyl)-3,5-dioxopiperazin-2-yl] propanal (31) The primary alcohol 29 (0.77 g, 2.0 mmol) was dissolved in CH 2 Cl 2 (50 mL) and Dess-Martin-Periodinane (1.02 g, 2.4 mmol) was added.…”

“…1 H NMR (300 MHz, CDCl 3 ): δ (ppm) = 3.39 (s, 4H, NCH 2 CO), 3.59 (s, 2H, NCH 2 Ph), 3.78 (s, 3H, OCH 3 ), 4.86 (s, 2H, NCH 2 Ar), 6.82 (d, J = 8.7 Hz, 2H, 3-H PMB , 5-H PMB ), 7.24 (dd, J = 6.1/ 4.4 Hz, 2H, 2-H benzyl , 6-H benzyl ), 7.28-7.39 (m, 3H, 3-H benzyl , 4-H benzyl , 5-H benzyl ), 7.34 (d, J = 8.7 Hz, 2H, 2-H PMB , 6-H PMB ). 13 C NMR (300 MHz, CDCl…”