Optically Pure Isoproterenol Analogues With Side Chains Containing an Amide Bond: Synthesis and biological properties

Abstract

The isoproterenol analogues 4a and 4b, synthesized as mixtures of diastereoisomers, were shown to possess very potent 8-adrenoceptor agonistic activity. Therefore, the four possible diastereoisomers of 4a have been synthesized and tested for inotropic activity. The (6R,2'R)-diastereoisomer turned out to be the most interesting one. Consequently, also (6R,2'R)-4b has been prepared and tested. For the diastereoselective synthesis, three variants have been elaborated: i ) coupling of epoxides 12 with amines 27 (Scheme 6) ; iz) coupling of the activated glycol 17 with the amine 22 (Scheme 8) ; iii) diastereoselective hydrogenation of the amino ketone 31 (Scheme 7). Both (6R,2'R)-4a and (6R,2'R)-4h show long lasting positive inotropic activity after intravenous as well as oral administration and are at least three times as potent as rue-isoproterenol. In the anesthetized dog, a good separation of positive inotropic and positive chronotropic effects is observed. In conscious dogs, however, heart rate and contractile force increase to the same extent (possibly due to reflex tachycardia).1. Introduction. -Within the scope of studies [ 1-91, the final objective of which is to improve the therapeutic index of drugs by covalent conjugation to carrier molecules, particularly to peptides, Goodman and Melmon and their coworkers investigated numerous compounds which have the skeleton of isoproterenol(2) and can be described by the general formula 3 (Scheme I ) [ 14][7-91. These compounds were synthesized starting from ruc -norepinephrine (1) by reductive amination and, therefore, obtained as mixtures of diastereoisomers. Separation into pure components could not be achieved [l]. In comparison with 2 in four in-vitro test systems, the preparations 4a and 4b attracted particular attention as very potent b-adrenoceptor agonists First, the four diastereoisomers of 4a were synthesized and biologically evaluated. Since (6R,2'R)-4a turned out to be by far the most interesting compound; subsequently, of the more complex structure 4b, only the (6R,2'R)-isomer was prepared and biologically studied.In the following, we report on our synthetic work (Chupt. 2) and on the pharmacological investigation of the optically pure stereoisomers mentioned in comparison to the corresponding mixtures of racemic diastereoisomers (Chupt. 3 ) .

Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor

“…The synthetic scheme for the catecholamine epoxide 12 was performed according to the procedure described by Marki et al (1988). The epoxide was reacted neat with phenteramine and the adduct purified by column chromatography.…”

Isolation, Total Synthesis, and Absolute Configuration Determination of Renoprotective Dimeric N-Acetyldopamine–Adenine Hybrids from the Insect Aspongopus chinensis

“…The nucleophilic substitution between fragment 7b and common intermediate 6 which was accessed from known compound 8 provided diaryl ether 13b . Reaction of 13b with sodium azide afforded the desired Mitsunobu precursor 5b .…”

Rhodium‐Catalyzed Enantioselective Hydrogenation of Functionalized Ketones

“…· · · · The (R)-amino ketone is hydrogenated enantioselectively by a neutral complex [{(S)-(R)-BPPFOH}RhCl] 2 to give the (R,R)-isoproterenol analogue, a compound which has been shown to possess very potent b-adrenoreceptor agonistic activity [33].…”