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Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antogonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD4 than the standard (aerosol route of administration, guinea pig bronchoconstriction model). Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB4 whereas 1 did not. Attempts to establish structure--activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system. All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7. Optical resolution of 7 was achieved by two methods. Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer. Although the enantiomers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC4 and LTD4 when administered by the aerosol route (S antipode 15-fold more potent). The properties of 7 have been compared with several recently reported leukotriene antagonists.

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9-Chloro-7-(2-chlorophenyl)pyrimido [5,4-d][2]benzazepine, a potent anxiolytic agent, was synthesized in three steps from 4-chloro-5-methylpyrimidine and 2-iodo-2',5-dichlorobenzophenone In the key step these materials were coupled in an unsymmetrical biaryl synthesis mediated with zerovalent nickel. The methyl group of the resulting product was brominated with NBS, and the seven-membered ring was closed with ammonia. Three byproducts of the coupling reaction were isolated and characterized. They proved to be 5,5'-dimethyl-4,4'-bipyrimidinyl, 4,4'-dichloro-2,2'-bis(o-chlorobenzoyl)biphenyl, and 2-chloro-9-fluorenone. An improved procedure for the Sandmeyer conversion of aminobenzophenones to iodobenzophenones is also described. Under conditions for palladium-catalyzed coupling of the ketone with terminal acetylenes, the oximes of 2-iodo-2',5-dichlorobenzophenone undergo cyclization to a 1,2-benzisoxazole or reductive loss of iodine, depending on whether the Z or E oxime is used.

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