No abstract

A general synthesis to the title compounds 1, substituted in the 6-position and on the phenyl ring, is outlined. Eighteen analogues were compared with respect to in vitro activity against rhinovirus types 1A, 9, and 64. Compounds 1c and 1h, the 6-bromo- and 6-(methylsulfonyl)-3',4'-dichlorophenyl analogues, afforded median MIC50 values against 23 rhinovirus serotypes of 0.05 and 0.13 micrograms/mL, respectively. Mice dosed orally with 200 mg/kg of 1c or 1h exhibited serum levels well in excess of each compound's MIC50, indicating that some analogues have the potential to be orally effective drugs.

The title compounds, 7a and its 9‐chloro analog 7b, were prepared in three steps from methyl N‐phenylanthranilates. Thus, methyl N‐phenylanthranilate (3a) was treated with oxalyl chloride to yield 2‐[(2‐chloro‐1, 2‐dioxoethyl) phenylamino]benzoic acid methyl ester (4a). Treatment of 4a with methylhydrazine gave 2‐([2‐(1‐methylhydrazino)‐1,2‐dioxoethyl]phenylamino) benzoic acid methyl ester (6a), which was cyclized with sodium hydride in dimethylformamide to produce 7a. Alkylation of 7a and 7b with iodomethane afforded the respective 5‐methyl derivatives 8a and 8b. A survey of the known literature benzotriazocines is presented.

Complementary approaches to the synthesis of the title compounds 1 are described. Metallation of 3,5‐di‐bromo‐2‐methoxypyridine (5b) by bromine/lithium exchange gave selectively the 3‐lithio intermediate 6 which was trapped with substituted cinnamaldehydes 7, providing allylic alcohols 8 in good yields. Methyl ether cleavage and concomitant cyclization occurred on exposure to concentrated hydrobromic acid in hot acetic acid. The resulting 2‐phenyl‐2H‐pyrano[2,3‐b]pyridines were hydrogenated over Raney nickel to the title compounds which had antiviral activity. Alternatively, 1 were synthesized by Heck reaction of appropriately substituted 3‐halo‐2‐methoxypyridines (5 or 24) with vinyl carbinol 15 to furnish ketones 16 or 26 which, upon reduction of the carbonyl group, were cyclized directly to 1.

Die 2‐Methoxy‐pyridine (I) werden über die Brom‐ (II) und Lithioverbindungen (III) mit den Zimtaldehyden (IV) in die Allylalkohole (V) übergeführt, die mit HBr/ Eisessig zu den Bicyclen (VI) kondensiert werden.