Benzazepinone calcium channel blockers. 5. Effects on antihypertensive activity associated with N1 and aromatic substituents

Abstract

We have shown that the pyrrolidinylmethyl substituent on the lactam nitrogen (N1) of benzazepinone and benzothiazepinone calcium channel blocking agents is resistant to metabolic deamination and generally increases the duration and potency of antihypertensive activity in spontaneously hypertensive rats (SHR) relative to (N,N-dimethylamino)ethyl analogs. Additionally, compounds possessing a substituent on the fused aromatic ring are more resistant to metabolic deacylation of the C3 hydroxy function, which may explain why aromatic substituents also frequently increase the potency and/or duration of antihypertensive activity. Our data also indicate the increased antihypertensive activity associated with these structural modifications is independent of any effects of potency in vitro. Overall, we interpret these results to indicate that these structural modifications improve antihypertensive activity as a result of increased metabolic stability and, consequently, oral bioavailability.

Ethylene in Organic Synthesis: A New Route to Anticholenergic Pyrrolidinoindolines, and Other Molecules with All Carbon-Quaternary Centers via Asymmetric Hydrovinylation

“…At room temperature only one stereoisomer of the oxime, presumably the ( E )-form, is seen in both 1 H and 13 C NMR. Predictably, the corresponding Schmidt reaction, which relies on the intermediacy of a hydroxy-azide, where no such stereochemical constraint is possible, is a much less selective reaction, giving a mixture of benzazepinones 20 and 28 (eq ) …”

First Direct Reductive Amination of Mucochloric Acid: A Simple and Efficient Method for Preparing Highly Functionalized α,β-Unsaturated γ-Butyrolactams

“…Furthermore, the γ-butyrolactam can be converted to pyrrolidine by reduction . Pyrrolidines are ubiquitous structural motifs in drugs and potential drug candidates such as antidepressants, antimicrobials, antihypertensives, antiarthritics, antivirals, and antinociceptive agents . Singaram and co-workers recently reported the facile reduction of N -alkyl lactams to the corresponding pyrrolidines in excellent yields using lithium aminoborohydrides …”