Absolute configuration of glycerol derivatives. 4. Synthesis and pharmacological activity of chiral 2-alkylaminomethylbenzodioxans, competitive .alpha.-adrenergic antagonists

• Published in: Journal of medicinal chemistry 1977-07, Vol.20 (7), p.880-885
• Main Authors: Nelson, Wendel L, Wennerstrom, John E, Dyer, Donald C, Engel, Michael
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-Antagonists - chemical synthesis; Animals; Aorta - drug effects; Circular Dichroism; Dioxanes - chemical synthesis; Dioxanes - pharmacology; Dioxins - chemical synthesis; In Vitro Techniques; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Rabbits; Stereoisomerism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00217a002

The optical isomers of alpha-adrenergic receptor antagonists prosympal (2), piperoxan (3), and dibozane (4) were prepared by methods establishing the absolute configuration of each. (2S)-3(2'-Hydroxyphenoxy)-1,2-propanediol ditosylate (10) was prepared from (2R)-3-tosyloxy-1,2-propanediol acetonide (6). Intramolecular displacement afforded (2S)-tosyloxymethylbenzodioxan [(2R)-11]. Reaction of (2R)-11 with the appropriate amine (diethylamine, piperidine, or piperazine) afforded the 2S isomers of 2, 3, and 12, respectively. Reaction of (2S)-12 with (2R)-11 afforded the SS isomer of 4. Reaction of (2S)-3-benzyloxy-1,2-propanediol ditosylate (14) with catechol (NaOMe) afforded (2R)-benzyloxymethylbenzodioxan (15). Subjecting 15 to hydrogenolysis, tosylation, and displacement with the appropriate amine afforded 2R isomers of 2, 3, and 12. Reaction of (2R)-12 with (2S)-11 afforded (RR)-4. Reaction of (2R)-12 with (2R)-11 afforded meso-4. The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4. meso-4 was as effective as the SS isomer of 4. The results are interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen, and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.