120329-95-5Relevant articles and documents
Synthesis of the leukotriene antagonist ablukast
Manchand,Micheli,Saposnik
, p. 9391 - 9398 (1992)
An efficient synthesis of the leukotriene antagonist ablukast (5) has been achieved starting from 2,4-dihydroxyacetophenone. The latter, on a Claisen condensation with ethyl oxalate, followed by hydrogenation, gave the chromane ester 7, which was subjected to a Fries rearrangement (AcOH/BF3·OEt2) and the product, after transesterification with methanol, was alkylated with 5-bromo-1-pentanyl acetate to afford the acetate 9. A novel methanolysis of 9 with methanol in the presence of tetra-n-butylammonium hydroxide followed by mesylation of the derived alcohol furnished the mesylate 10. Alkylation of the acetophenone derivative 16 with 10 using K2CO3 in the presence of tris(3,6-dioxaheptyl)amine and saponification gave 5.
3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids and Related Compounds as Leukotriene Antagonists
Cohen, Noal,Weber, Giuseppe,Banner, Bruce L.,Lopresti, Rocco J.,Schaer, Beatrice,et al.
, p. 1842 - 1860 (2007/10/02)
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 antagonist 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 enantiommers 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.
