Tandem free-radical addition/substitution chemistry and its application to the preparation of novel AT₁receptor antagonists

Abstract

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT(1) receptor antagonists, with pK(B) estimates of 7.2-9.5.

Rate coefficients for intramolecular homolytic substitution of oxyacyl radicals at selenium

“…Homolytic substitution chemistry is particularly effective for the preparation of chalcogen-containing rings and has been used for the preparation of a number of biologically im- portant molecules [3][4][5]. For example, the antihypertensive drug candidate selenomilfasartan was prepared through a strategy that employed the use of intramolecular attack of a vinyl radical at selenium in the key synthetic step (Scheme 1) [6].…”

Intramolecular Homolytic Substitutions in Synthesis

“…20 However, because of the increased reactivity of the selenium atom toward radicals, that include chain-carrying radicals such as n-tributylstannyl, 2 synthetically useful homolytic chemistry carried out at selenium has utilized the (more reactive) iodide (over the bromide) as radical precursor, or has made use of precursors that do not require chain-carriers. 30,31,[33][34][35][36][37][38][39] In contrast, there are relatively few examples of intramolecular homolytic substitution reactions at tellurium, and this can be attributed to a number of factors that include (i) the intrinsic photolability of organic tellurides, (ii) the propensity for organic tellurides to react with oxygen, and (iii) their intrinsic reactivity toward chain-carrying radicals; indeed organic tellurides are often more reactive toward radicals such as n-tributylstannyl, than are the corresponding iodides. 2,21 Nevertheless, there are some examples of this chemistry (see below), and success required the invention of new ways of generating radicals in the presence of tellurium, in particular, the use of aryl iodides together with sodium n-butyltellurolate.…”

“…33 Staples was able to extend this novel tandem addition/substitution methodology to the preparation of benzo[b]selenophenes, an example of which is depicted in Scheme 26. 34 It should be noted that this chemistry requires the involvement of an alkane bearing an electron-withdrawing group and was inspired by the contributions of Zanardi and coworkers toward the construction of benzo[b]thiophenes. 48 Presumably, the diazonium salt (61) …”

Fluorescent Angiotensin AT1 Receptor Antagonists

“…4) also proved to be effective sartans. [8] Furthermore, the phenanthrene-substituted comKeywords: anthracenes · AT 1 receptor antagonists · coumarins · fluorescent probes · sartans Abstract: Fluorescent selective angiotensin AT 1 receptor antagonists (sartans) that contain naphthalene (6,7,10, and 11), anthracene (12 and 14), acenaphthene (13 and 15), and coumarin (8 and 9) substituents have been prepared and their preliminary pharmacology evaluated in Chinese hamster ovary (CHO) cell based assays. Compounds 6-15 proved to be effective sartans with pK B estimates in the range of 6.7-10.5; their potential as cellular imaging agents is also discussed.…”