776-16-9Relevant articles and documents
Synthesis and Optimization of Kv7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity
Liu, Ruiting,Tzounopoulos, Thanos,Wipf, Peter
supporting information, p. 929 - 935 (2019/06/13)
Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5, resulting in a selectivity index SI > 10. RL-56 is remarkably potent, EC2x 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for Kv7.4/Kv7.5 over Kv7.2/Kv7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF3, and SF5, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.
Continuous flow synthesis of difluoroamine systems by direct fluorination
McPake, Christopher B.,Murray, Christopher B.,Sandford, Graham
, p. 145 - 150 (2013/04/10)
Continuous flow methodology for the synthesis of perfluoroaryl difluoroamine derivatives by reaction of fluorine gas with an appropriate perfluoroaniline substrate is described, further demonstrating the efficient use of flow regimes for reactions involvi
Fluorinated 1,3λ4δ2,2,4-benzodithiadiazines - A synthetic, structural and theoretical study
Makarov, Alexander Yu.,Bagryanskaya, Irina Yu.,Blockhuys, Frank,Van Alsenoy, Christian,Gatilov, Yuri V.,Knyazev, Vladimir V.,Maksimov, Alexander M.,Mikhalina, Tatiana V.,Platonov, Vyacheslav E.,Shakirov, Makhmut M.,Zibarev, Andrey V.
, p. 77 - 88 (2007/10/03)
The series of title compounds has been prepared through both electrophilic (C6HnF5-n-N=S=N-SiMe3 + SCl2) and nucleophilic (C6HF4_S-N=S=N-SiMe3 + CsF) intramolecular ortho-cyclisation reactions, and the former route seems to be the more effective. High regioselectivity of the ring-closing procedures is observed in both cases. The compounds were characterised by X-ray crystallography and multinuclear (1H, 13C, 15N and 19F) NMR spectroscopy. In accordance with GIAO calculations, 15N{1H} experiments and the effects observed on complete substitution of hydrogen by fluorine, the high-field signal in the 15N NMR spectra can be assigned to N-4 and the low-field signal to N-2. In the crystal, 5,6,7-trifluoro-(5) and 5,6,8-trifluoro-1,3λ4δ22,4- benzodithiadiazine (6) are planar, whereas the 6,8-difluoro derivative 3 is bent along the S1...N4 line by 8.3°. According to NICS calculations the heterocycle moiety in this compound class is antiaromatic while the carbocycle is aromatic. The fluorine substituents increase the aromaticity - and in some cases (especially when a fluorine atom is present in the 8-position) the antiaromaticity - of the corresponding rings. The ortho-fluoro-containing starting material C6HnF5-n-N=S=N-SiMe3 (n = 2: 10) cyclises to the fluorinated 2,1,3-benzothiadiazole 27 upon treatment with CsF instead of SCl2. For starting compound 6-HC6F4-S-N=S=N-SiMe3 (14) the planar (Z,E) configuration features a short intramolecular H...N contact, as evidenced by X-ray diffraction. Both the reaction pathways mentioned are also discussed. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2003.
