Synthesis and class III antiarrhythmic activity of (phenylbut-2-enyl)ammonium salts. Effect of conformation on activity.
J Med Chem
; 29(8): 1398-405, 1986 Aug.
Article
en En
| MEDLINE
| ID: mdl-3735308
ABSTRACT
The syntheses of seven 4-(substituted phenyl)but-2-en(or yn)yl quaternary ammonium salts and four related tertiary amines are described. The Meerwein arylation reaction was the preferred synthetic method for the required intermediate 1-aryl-4-halo-2-butenes (15a-c, 18). In the case of 18, the trans stereochemistry of the Meerwein adduct of 2,3-dimethylbutadiene was established unambiguously by 2D NMR and X-ray studies. The title compounds represent conformationally restricted analogues of the class III antiarrhythmic agent clofilium (1) and exhibit comparable potency and efficacy in the in vitro evaluation using isolated canine Purkinje fibers. These results suggest that the alkylene chain in 1 is extended in the active conformation. Computer-aided conformational analysis (MM2) supports this conclusion. Selective catalytic hydrogen conditions were developed for the conversion of the unsaturated analogue 2 to clofilium (1) with minimal hydrogenolysis of the allylic quaternary ammonium moiety, thus completing a novel and efficient synthesis of this substance.
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Banco de datos:
MEDLINE
Asunto principal:
Alquenos
/
Compuestos de Amonio Cuaternario
/
Antiarrítmicos
Límite:
Animals
Idioma:
En
Año:
1986
Tipo del documento:
Article