J. Med. Chem. 1991,34, 1314-1328
1314
Optical Isomers of Rocastine and Close Analogues: Synthesis and H1 Antihistaminic Activity of Its Enantiomers and Their Structural Relationship to the Classical Antihistamines Mark C. Sleevi,*ptd Albert D. Cale, Jr.,t Thomas W. Gero,tJ Larry W. Jaques,' William J. Welstead,' Ashby F. Johnson,t Brian F. Kilpatrick,: Iulia Demian,f Joseph C. Nolan,ll* and Herndon Jenkinsl Research Laboratories, A. H . Robins Company, Inc., Richmond, Virginia 23261 -6609. Received January 24,1990 The enantiomers of 2-[2-(dimethylamino)ethyl]-3,4-dihydr~4-methylpyrido[3,2-~-1,4-oxazap~e-5(~-thione (rocastine) and two of its more potent analogues were prepared with an enantiomeric purity of >99.9%. The antihistaminic activity of these compounds was assessed by their ability to block histamine-induced lethality in guinea pigs and to inhibit [aH]mepyramine binding to guinea pig cortex. In this series, compounds having the R configuration at the 2-position are at least 300 times more potent than the S hmers. Conformational analysis and molecular modeling suggest that rocastine can adopt a conformation in which the pyridine ring, ether oxygen, and protonated amine functions are positioned similarly to the corresponding elementa of the probable binding conformers of some of the more classical antihistamines. This conformation, boatlike in the oxazepine ring with the side chain quasi-equatorial and folded back toward the ring, is the likely binding conformer at the histamine H1 receptor, and the available structure-activity relationship data is consistent with this interpretation.
Many histamine H1 antagonists contain chiral centers, and those that do often show marked differences in the antihistaminic potency of their optical is0mers.l This paper describes the synthesis and pharmacological activity of the enantiomers of rocastine (1) and two of its more potent analogues (2 and 3). The racemic compounds are
Scheme I
