Synthesis and Class III antiarrhythmic activity of (phenyl-2-butenyl)ammonium salts. Effect of conformation on activity
| Autor: | Mark E. Sullivan, Ronald A. Wohl, Chung Nan Wan, Anthony J. Marisca, David D. Davey, Thomas Kenneth Morgan, William C. Lumma, Samuel S. Wong, Robert P. Gomez, Martha Briggs |
|---|---|
| Rok vydání: | 1986 |
| Předmět: |
Allylic rearrangement
Tertiary amine Stereochemistry Molecular Conformation Action Potentials Biological Availability Blood Pressure Alkenes Purkinje Fibers Structure-Activity Relationship chemistry.chemical_compound Dogs Heart Rate Hydrogenolysis Drug Discovery medicine Animals Moiety Ammonium Chemistry Meerwein arylation Clofilium Electrophysiology Quaternary Ammonium Compounds Molecular Medicine Aliphatic compound Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 29:1398-1405 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00158a014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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