Absolute configuration of glycerol derivatives. 4. Synthesis and pharmacological activity of chiral 2-alkylaminomethylbenzodioxans, competitive alpha-adrenergic antagonists.
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.
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002942:Circular Dichroism; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004147:Dioxins / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011817:Rabbits; D013237:Stereoisomerism
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins