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Optically Pure Isoproterenol Analogues With Side Chains Containing an Amide Bond: Synthesis and biological properties
Author(s) -
Märki Hans P.,
Crameri Yvo,
Eigenmann Rainer,
Krasso Anna,
Ramuz Henri,
Bernauer Karl,
Goodman Murray,
Melmon Kenneth L.
Publication year - 1988
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19880710204
Subject(s) - chemistry , chronotropic , diastereomer , inotrope , stereochemistry , amine gas treating , amide , biological activity , succinimide , ketone , enantiomer , heart rate , organic chemistry , in vitro , medicine , biochemistry , blood pressure
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 (6 R , 2′ R )‐diastereoisomer turned out to be the most interesting one. Consequently, also (6 R ,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 (6 R ,2′ R )‐ 4a and (6 R ,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).