A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.

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In most of the methods which are in common laboratory use for assessing analgesic activities the pain threshold is measured from the response to superficial heat stimulation. The effect of analgesics on pain involving the deeper structures is equally if not more important. Methods for this purpose have been described by Eddy (1928), Haffner (1929, Molitor andLatven (1937), andFriend andHarris (1948). We describe here a simple pressure method, which does not suffer from certain of the disadvantages of these earlier techniques, and compare the results with those obtained by radiant heat stimulation. METHODSPressure method.-The apparatus shown in Fig. 1 was designed to give a uniformly increasing pressure on the tail of the rat. The vertical syringe (A) is connected by transparent "Portex" tubing to the horizontal syringe (B) and to the mercury manometer (C). All air in the system is displaced by a mixture of equal volumes of liquid paraffin and kerosene. At rest, the distance between the head of the plunger of syringe A and the surface of the base of the stand D should be approximately equal to the mean diameter of the tails of the rats. The manometer scale is then adjusted to give zero reading.With the tail of the rat under syringe A the pressure on it is increased by a uniform depression of syringe B. Readings which are estimates of pain threshold are taken from the manometer when the rat responds-first by struggling, then by squeaking. The pressure is then immediately released.The nature of the syringe head will have its effect on the observed threshold. In the experiments to be described it was 25 mm. in diameter, slightly concave at the centre, and so rounded that only about 20 mm. of tail was actually in contact with it.For convenience and standardization we have incorporated a mechanical drive for the horizontal syringe. For the design and construction of this device, which is described in the appendix, we are indebted to Mr. E. I. Godfrey, of these Laboratories. It provides a uniform increase of pressure of 2 cm. mercury per second and an instantaneous release.Heat method.-The apparatus described by Thorp (1946) for thermal irradiation of the tip of the rat's tail was used; but instead of obtaining thresholds in terms of minimal heat intensity required for a response, we have measured reaction times to a

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

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