Oxazole derivatives and use thereof

Details Oxazole derivatives and use thereof Oxazole derivatives and use thereof

1997-06-18

1999-08-31

Owens, Amelia

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514374, C07D26330

Patent

active

059455390

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel oxazole derivatives. More particularly, the present invention relates to oxazole derivatives having antipyretic activity, analgesic activity, anti-inflammatory activity, and in particular, selective inhibitory activity against cyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof and pharmaceutical agents comprising these compounds, which are useful as anti-inflammatory agents causing less side-effects such as disorders in the digestive tract.


BACKGROUND ART

It has been conventionally known that arachidonic acid metabolites, prostaglandin E.sub.2 (PGE.sub.2), prostaglandin I.sub.2 (PGI.sub.2) and thromboxane B.sub.2 (TXB.sub.2) are deeply involved in inflammations. An important enzyme in this arachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase which produces prostaglandin H.sub.2 (PGH.sub.2) from arachidonic acid via prostaglandin G.sub.2 (PGG.sub.2), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
With respect to COX-1, cDNA cloning was performed in 1988 and its primary C. et al.: Biochem. Biophys. Res. Commun., 165: 888-894 (1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083: 1-17 (1991); DeWitt, D. L.: Biochim. Biophys. Acta, 1083: 121-134 (1991)!. On the other hand, the existence of an isozyme of COX-1, namely, COX-2, was suggested in 1989 cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 D. A. et al.: J. Biol. Chem., 266: 12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA, 89: 7384-7388 (1992)!. COX-2 is quickly induced by phorbol ester, lipopolysaccharide (LPS) and the like, and the relationship with inflammation and bronchial asthma has been inferred.
COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE.sub.2 and PGI.sub.2, which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused. With regard to a symptom associated with a decrease in renal blood flow, in general terms, the renal blood flow can be increased by promoting the production of vasodilative PGE.sub.2 in the body, thereby to appropriately maintain glomerular filtration rate. However, if the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
On the other hand, COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
Currently, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen and naproxen have been widely used in clinical situations. Most of these NSAIDs are anti-inflammatory drugs which selectively inhibit cyclooxygenase (COX) and are associated with side-effects such as disorders in the digestive tract. Such side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
It is therefore expected that a selective inhibition of COX-2, which is specifically induced at the inflammatory sites, would enable provision of an anti-inflammatory agent free of side-effects such as disorders in the digestive tract (e.g., ulcer).
There have recently been presented various reports on anti-inflammatory drugs having selective COX-2 inhibitory activity, which aim at reducing side-effects such as disorders in the digestive tract.
For example, WO94/15932 discloses, as COX-2 inhibitors, 5-membered cyclic compounds having one hetero atom, such as thiophene, furan and pyrrol

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