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).