ABSTRACT
Since the disclosure of antihypertensive activity in a series of 4-amido benzopyran-3-ols (Ashwood eta/., 1986), and the emergence of cromakalim (CRK 1) as the prototype (Hamilton eta/., 1986) of a new class of smooth muscle relaxant offering therapeutic potential (Longman and Hamilton, 1992), the literature in the potassium channel activator (KCA) area has increased-dramatically.
Not only has the scientific literature grown over the last few years but from the patent literature it is evident that a large number of organisations have been, or are still, involved in the search for similar entities, and numerous compounds based on the CRK lead have undergone further development. Thus compounds where the aromatic ring has been variously substituted or replaced by other aromatic moieties (pyranopyridines, thienopyrans) have been investigated. Similarly benzothiapyran, indane, benzoxepine, tetralin (tetralone), tetrahydroquinoline and benzoxazine analogues of the benzopyran have been explored and have given rise to active derivatives. Positional substitution of the non-aromatic ring has shown that the C-2 and C-3 positions of CRK are relatively intolerant to structural change whereas C-4 is remarkably flexible in the type of substituent it can accommodate; the cyclic lactam being just one example of a multitude of both cyclic and acyclic amide moieties, or their equivalents, which confer KCA activity. Details of structureactivity relationships (SAR) brought about by such changes have been reviewed recently (Evans eta/., 1992; Buckle and Smith, 1993) and have been updated in Chapter 2 of this book.
