Synthesis and .beta.-adrenergic blocking activity of new aliphatic and alicyclic oxime ethers

Abstract

We describe the synthesis and pharmacological properties of two new series of aliphatic and alicyclic beta-adrenergic blockers, most of them containing a cyclopropyl ring. They belong either to 2-hydroxy-3-(tert-butylamino)propyl ether A or 2-hydroxy-3-tert-(butylamino)propyl ketoxime ether B derivatives. The O-[2-hydroxy-3-(tert-butylamino)propyl] dicyclopropyl ketoxime 5 exhibited a beta-adrenergic antagonist activity comparable to that of propranolol. It was found that ketoxime ethers B generally showed higher potency than the corresponding ethers A. We confirm that the presence of an aromatic nucleus is not crucial for the beta-adrenergic activity. Structure-activity relationships among these series are discussed.

Membrane Permeation by Multidrug-resistance-modulators and Non-modulators: Effects of Hydrophobicity and Electric Charge

“…Where these data were available in the literature, the experimental logP values (Craig 1990) were similar to the predicted ones, except in the case of verapamil (3Á79 vs 5Á52 predicted). Also, the experimental logD values (Bouzoubaa et al 1984;Zamora et al 1988;Betageri & Dipali 1993) were in agreement with the predicted ones, except in the case of quinine. The predicted value for this compound (logD À0Á06) was obviously inaccurate compared with the experimental value (logD 2Á1 at pH 7Á4) determined by Zamora et al (1988).…”

Role of 1,4-Benzothiazine Derivatives in Medicinal Chemistry

“…An oxypropanolamine side chain linked to an aromatic ring are the chemical features required for β-blocking activity. However, the alteration of these features as the intercalation of an imino group in the side chain does not abolish the interaction on β-adrenoceptors but can lead, in some cases, to potent β-antagonists [28,29]. To evaluate the effect caused by a different type of insertion of pharmacophore oxypropanolamine chain in the 1,4-BT moiety that possesses short-lived blood pressure reducing effects in experimental animals [30], 6-, 7-, 8-oxypropanolamine and 6-, 7-, 8-acetimidoyloxypropanolamine of 3,4-dihydro-3-oxo-2H-1,4-benzothiazine were prepared [31].…”

Synthesis, Docking Study and β-Adrenoceptor Activity of Some New Oxime Ether Derivatives

“…Based on the chemical structure of the classical aryloxypropanolamine β-adrenoceptor blockers, Imbs et al [2] showed that the insertion of an oxime ether in place of the typical ether linkage retained β 2 -antagonist activity; e.g., IPS 339 (Figure 1). Other oxime ethers were also synthesized and reported to have β 2 -blocking activity with high potency, e.g., falintolol (Figure 1) [3,4]. Although the above mentioned cardiovascular effects are mainly attributed to β 1 -blockage, β 2 -adrenoceptor antagonists might be potentially interesting as experimental tools [5], or for testing in pulmonary arterial hypertension [6].…”