Pyrazole derivatives and COX inhibitors containing them

Details Pyrazole derivatives and COX inhibitors containing them Pyrazole derivatives and COX inhibitors containing them

1999-10-07

2000-10-24

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514375, 514394, 548152, 548178, 548217, 5483061, A61K 314184, A61K 31423, A61K 31428, C07D41704, C07D40304

Patent

active

061368318

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives which inhibit cyclooxygenase-2 (COX-2), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same. The compounds of the present invention are useful in treating inflammation and a variety of diseases associated therewith.


BACKGROUND OF THE INVENTION

It has been known that conventional non-steroidal anti-inflammatory drugs (NSAIDs), representatives of which include aspirin, indomethacin, etc., control the biosynthesis of prostaglandins, certain chemical mediators for inflammation, via the inhibition of cyclooxygenase (COX) which is a synthase responsible for the formation of prostaglandins from arachidonic acid, thereby exerting anti-inflammatory action. However, prostaglandins are involved in a variety of physiological actions including not only inflammation but also the inhibition of gastric secretion and the increase of mucosal blood flow. Since the conventional NSAIDs also inhibit the biosynthesis of certain prostaglandins responsible for other physiological roles than inflammation, they frequently have a high potential for raising adverse side effects such as attacks on gastric mucosa and kidney. Accordingly, the clinical usefulness of the NSAIDs is often restricted.
Recently, it has been found that there are isozymes of COX. Thus, one form of COX, named "COX-1", which has been known in the art up until recently, exists systemically and constantly in stomach, kidney, etc. Another form of COX, named "COX-2", which has been discovered newly, is inducible at the site of an inflammatory stimulus. It is believed that the conventional NSAIDs inhibit both COX-1 and COX-2, with the result that such side effects appear. When selective COX-2 inhibitors are available, it is therefore expected that such selective COX-2 inhibitors would exert predominantly desirable anti-inflammatory action whereby they would reduce the aforementioned side effects entailed by the conventional NSAIDs with non-selective COX inhibiting activity.
From such an angle, up until now, some compounds have been synthesized with a view to exploring selective COX inhibitors. For anti-inflammatory pyrazole derivatives among them, those disclosed in JP, 1-52758, A (1989); JP, 3-141261, A (1991); JP, 5-246997, A (1993); etc., have been known. Further, WO, 95/15315, Al (1995); WO, 95/15316, Al (1995); WO, 95/15318, Al (1995); etc., disclose pyrazole derivatives, part of which have selective COX-2 inhibitory and anti-inflammatory activity.
However, these compounds are not satisfactory medicaments for solving the above problems, so the development of anti-inflammatory drugs with significantly selective COX-2 inhibiting activity together with more advantageous pharmacological action and safety is still desired.


DISCLOSURE OF THE INVENTION

The present inventors have conducted an extensive research on various compounds in order to solve the above problems. As a result, the present inventors have succeeded in producing novel pyrazole derivatives with a nitrogen-containing heterocyclic group such as a benzothiazole moiety which exert selective inhibition against COX-2. Further, the present inventors have found that the compounds of the present invention are unexpectedly superior to the conventional NSAIDs and they are qualified as COX inhibitors from aspects of pharmacological action and safety and succeeded in accomplishing this invention.
Thus, the present invention provides a compound of the formula (1): ##STR1## wherein R.sup.1 is hydrogen or halogen, R.sup.2 and R.sup.3 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or lower alkanoyloxy, R.sup.4 is lower haloalkyl or lower alkyl, X is sulfur, oxygen or NH, and Y is lower alkylthio, lower alkylsulfonyl or sulfamoyl, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising said compound (1) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.


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