A New Bromination Method for Phenols and Anisoles: NBS/HBF4·Et2O in CH3CN

Acylketene O-prop-2-ynyl S-methylmonothioketals 3a–e, easily obtained through displacement on β-oxosulfonium salts 2a–e by prop-2-ynol, are shown to undergo facile rearrangement under neutral (toluene-xylene) and basic conditions (K2CO3-EtCOMe) to afford the diene esters 5a–e and the substituted furans 4a–e, respectively. The probable mechanism for the formation of the various products involving initial Claisen rearrangement of compounds 3a–e has been described.

Rearrangement studies on acylketene O-prop-2-ynyl S-methylmonothioketals

Process development of potassium channel opener, TCV-295, based on convenient ring formation of 2H-1,3-benzoxazine and selective N-oxidation of the pyridyl moiety

Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists.

Publisher Summary This chapter discusses recent advances in studies of structure-activity relationships (SAR) of the various types of potassium channel activators (KCAs), reports on the compounds known to be in development, and highlights how structurally similar KCAs can have diverse pharmacological effects. The pharmacological methods and the various animal models used for the screening of KCAs are outlined, and differences between the compounds in the screens are noted in the chapter. The second generation KCAs and prospects for future research are also discussed in the chapter. Potassium channel activators (KCAs), or openers, are a group of compounds that have aroused considerable pharmaceutical interest during the last decade as smooth muscle relaxants. In developing screens for KCAs, the primary objective is to identify the general KCA mechanism of action, and to distinguish this from other mechanisms of action. Unlike many screening protocols where binding experiments are often the primary screen, in the KCA area very little progress has been made because of the lack of useful radioactive ligands and the lack of binding to membrane fractions or cultured cells. Studies showed that with a diverse range of KCAs, all the compounds bound to a common site in rat aortic tissue—but surprisingly did not bind to membrane fractions. There is little doubt that the investigation of the class of KCAs for the amelioration of a variety of disease states is gathering pace, and that selectivity for different tissues and organs is being sought by three approaches.

Ian Churcher

Papers

Synthesis of the potent potassium channel opener Ro 31-6930 via claisen rearrangement and tandem regiocontrolled cyclisation.