Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

Abstract

The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.

Carbon‐14 radiosynthesis of 4‐(5‐chloro‐2‐hydroxyphenyl)‐3‐(2‐hydroxyethyl)‐6‐(trifluoromethyl)‐[4‐14C]quinolin‐2(1H)‐one (XEN‐D0401), A novel BK channel activator

“…The 500 MHz proton NMR‐spectrum of [ 14 C]XEN‐D0401 was consistent with the molecular structure 3. One feature of interest in the proton‐NMR spectrum of [ 14 C]XEN‐D0401 was that multiplets at δ 2.75 and 2.71 were assigned to the diastereotopic methylene protons (C H 2 CH 2 OH) on the 2‐hydroxyethyl moiety, an interpretation consistent with the reported atropisomerism of XEN‐D0401 3–10…”

Review and Modeling of Crystal Growth of Atropisomers from Solutions

“…Therefore, historically, equilibration between conformers was rarely considered as impacting nucleation and crystallization kinetics [50]. However, there is steady growing evidence that improved potency of specific conformers under physiological conditions led to an increase in the focus on relatively stable conformers, as evidenced by recent reports [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Since crystallization is the main purification and separation unit operation in the development of new medicines, studies about molecular flexibility and the effect of the presence of conformation stability and conversion in solution on nucleation, crystal growth and polymorphism has also been steadily increasing [50,[69][70][71][72][73][74][75][76][77][78][79][80][81][82].…”