Novel series of diaryl indenes and benzofurans have been shown to be potent and selective COX-2 inhibitors. A structuro-actlvity relationship study suggests that the conversion of sulfones to sulfonamides affords potent, but slightly less selective COX-2 lnhibitors, and that for benzofurans the 3-halo-4-methoxyphe~yl sulfonamide analogs are more selective than the corresponding 4-fluorophenyl analog.
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, have been widely used to treat chronic inflammation such as arthritis. 1 Major side effects, such as gastrointestinal (GI) hemorrhage and ulceration1,2 have greatly limited the thempoutic potential of all the NSAIDs. It has been hypothesized that constitutive COX-1 protects the GI tract, whereas inducible COX-2 mediates inflammation.3,4 Two structurally distinct compounds were reported to be selective COX-2 inhibitors (DuP 697 and NS-398).5
Since then, several novel classes of potent and selective COX-2 inhibitors, such as SC-57666 (1)6a and SC-58451 (2),6b have been publisbed.6 Herein we now report the discovery of diaryl indenes and benzofurans as potent and selective COX-2 inhibitors. F 697 NS-398 SC-57666 SC-58451 Chemistry Diaryl indene 3 was prepared readily according to Scheme I. The starting chloroindanone 4 was obtained from the chlorination of the silyl enol ether of 1-indanone (TMSC1, Et3N, and then NCS). The treatment of chloroindanone 4 with 4-methylthiophenyl magnesium bromide, followed by the rearrangement