Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

✍ Scribed by Peter Chiba; Barbara Tell; Walter Jäger; Elisabeth Richter; Manuela Hitzlera; Gerhard Ecker

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 510 KB
• Volume: 330
• Category: Article
• ISSN: 0365-6233
• DOI: 10.1002/ardp.19973301105

✦ Synopsis

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3. Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a-d. Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a-d. Structure activity relationship studies showed, that the 5-hydroxy derivates 6a-d fit the log Pllog potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a-d showed almost identical EC5o values, independent of their log P value.