Synthesis and adrenergic beta-blocking activity of ortho-, meta- and para-oxypropanolamino-substituted [(benzylideneamino)oxy]propanolamines.
The N-isopropyl- and N-t-butyl-substituted 1-[o-(3-amino-2-hydroxypropoxy)benzylideneaminoxy]-3-amino-2-propa nols (7a,b) and their meta (8a,b) and para (9a,b) isomers, in which a single aromatic ring is substituted both by the oxypropanolaminic chain of (aryloxy)propanolaminic beta-adrenergic antagonists (AOPAs) and the [(methyleneamino)oxy]propanolaminic chain of [(methyleneamino)oxy]-propanolaminic beta-blocking drugs (MAOPAs), were synthesized and assayed for their beta-adrenergic activity by functional tests on isolated preparations. Compounds 7-9 represent a new type of molecular duplication of beta-adrenergic drugs, formally deriving from the sharing of the aromatic portions of two different pharmacophoric subunits, namely the (aryloxy)propanolaminic portion of AOPAs and the [(benzylideneamino)oxy]propanolaminic portion of aryl-substituted MAOPAs. The pharmacological results showed that the beta-blocking activity of compounds 7-9 is closely related to the way in which the two subunits are linked by the aromatic nucleus: the activity decreases on passing from the ortho-compounds (7a,b) to the meta (8a,b) and then to the para (9a,b) isomers. A comparison of this activity trend with those found for series of both beta-blocking AOPAs and aryl-substituted MAOPAs seems to indicate that compounds 7-9 can be considered more as AOPAs substituted on the phenyl ring by a [(methyleneamino)oxy]propanolaminic chain rather than as aromatic MAOPAs substituted on the same phenyl moiety by an oxypropanolaminic portion.
Balsamo
A
A
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Italy.
Lapucci
A
A
Macchia
B
B
Macchia
M
M
Orlandini
E
E
Rossello
A
A
Ferni
G
G
Pinza
M
M
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006325:Heart Atria; D008297:Male; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects; D011412:Propanolamines / Q000737:chemistry* / Q000494:pharmacology; D014132:Trachea
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines