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

The isoproterenol analogues 4a and 4b, synthesized as mixtures of Diastereoisomers, were shown to possess very potent β‐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); (ii) 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)‐4b show long lasting positive inotropic activity after intravenous as well as oral administration and are at least three times as potent as rac‐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).