84417-40-3Relevant articles and documents
Synthesis and β-Adrenergic Antagonist Activity of Stereoisomeric Practolol and Propranolol Derivatives
Leftheris, Katerina,Goodman, Murray
, p. 216 - 223 (2007/10/02)
A series of stereoisomeric practolol and propranolol derivatives has been synthesized in which the N-isopropyl group of the drug was replaced by an asymmetric heptanoic acid terminated by a substituted p-toluidide of p-(tri-fluoromethyl)anilide.The asymmetric epoxide, 3-(p-acetamidophenoxy)-1,2-epoxypropane, was allowed to react with a preformed enantiomeric 6-aminoheptanoic acid amide to yield the stereoisomeric practolol congener derivatives.An asymmetric drug precursor epoxide was prepared from p-acetamidophenol and enantiomeric 3-(tosyloxy)-1,2-epoxypropane (the Sharpless epoxide).For the propranolol congener derivatives, the preformed asymmetric 6-aminoheptanoic acid amides were allowed to react with one of the enantiomers of 3-(1-naphthyloxy)-1,2-epoxypropane.This drug precursor epoxide was prepared either by combining 1-naphthol with enantiomeric 3-(tosyloxy)-1,2-epoxypropane (the Sharpless epoxide) or by combining 1-naphthol with enantiomeric 3-(tosyloxy)-1,2-propanediol followed by epoxidation.Pharmacological studies carried out for the practolol derivatives demonstrated a significant dependence of enhanced potency and tissue/subreceptor specificity on both the configuration of the drug asymmetric carbon and the configuration of the spacer asymmetric carbon.The compounds containing the S configuration at the drug asymmetric center and the R configuration at the spacer asymmetric carbon exhibited an increase in potency over the other stereoisomeric congener derivatives and the progenitor drug.For the propranolol congener derivatives, a large decrease in potency was observed for all of the stereoisomers over the progenitor drug.The propranolol stereoisomers containing the S configuration at the drug asymmetric center were more active than those containing the R configuration at that center.
Conjugates of Catecholamines. 1. N-Alkyl-Functionalized Carboxylic Acid Congeners and Amides Related to Isoproterenol
Jacobson, Kenneth A.,Marr-Leisy, Debra,Rosenkranz, Roberto P.,Verlander, Michael S.,Melmon, Kenneth L.,Goodman, Murray
, p. 492 - 499 (2007/10/02)
A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide.The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide.An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams.In vitro evaluation of these compounds as potential β-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide.In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency.The implications of these studies, in terms of general β-adrenergic drug design and also the attachment of the carboxylic acid congeners to carries, are discussed
