New chiral and isomeric cyclopropyl ketoxime propanolamine derivatives with potent .beta.-adrenergic blocking properties

Abstract

The synthesis of R-(+) and S-(-) isomers of O-[3-tert-butylamino)-2-hydroxypropyl] cyclopropyl methyl ketone oxime (falintolol) is described. The syn and anti isomers of falintolol were obtained in two different ways from cyclopropyl methyl ketoxime or from falintolol. For comparison purposes, the enantiomers of the dicyclopropyl ketone oxime derivatives were also prepared. Structure-activity relationships are described.

Synthesis and Adrenergic Activity of a New Series ofN-Aryl Dicyclopropyl Ketone Oxime Ethers: SAR and Stereochemical Aspects

“…The (R)-and (S)enantiomers of 10 and 18 are equipotent, confirming our previous observations. 5,15 Very surprisingly the (R)and (S)-benzimidazole enantiomers differ markedly. For this pair only the (S)-enantiomer was found to be active, as is generally observed among β-blockers of the (aryloxy)propanolamine type.…”

“…Enantiomers of 10, 18, and 28 were prepared from (R)-and (S)-glycidyl tosylates and the sodium salt of dicyclopropyl oxime according to a previously described procedure. 5 The physicochemical properties of compounds 1-31 are recorded in Table 1.…”

“…The high yield of the product resulting from disubstitution 31 is probably related to employing a 2-fold excess of amine and to the long duration of the reaction (72 h). Enantiomers of 10 , 18 , and 28 were prepared from ( R )- and ( S )-glycidyl tosylates and the sodium salt of dicyclopropyl oxime according to a previously described procedure . The physicochemical properties of compounds 1 − 31 are recorded in Table .…”

“…4 This was exemplified by several cyclopropylketoxime propanolamines which displayed potent activities. 5 In particular, the dicyclopropyl analogue (falintolol) has been found to be useful in the clinical treatment of glaucoma. 6 It is also well-known that most of the initial β-blockers contained an isopropyl-or tert-butylamine.…”

O‐Alkylation of Pyridine Aldo‐ and Ketoximes with Dihalohydrins under Phase‐Transfer Conditions

“…The E configuration of oximes 1a-f was confirmed by the red brown color with ferrous salts and by green copper chelate with cupric ions. [28,29] The solvent and the catalyst used in the reaction also have an important effect on the Scheme 1. Synthesis of halohydrins (3 -14).…”