Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-08-19
1999-11-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548235, 548236, 5462714, 544137, 544369, 514252, 514340, C07D26332, C07D41304, A61K 3142
Patent
active
059943815
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel heterocyclic aromatic oxazole compounds. More particularly, the present invention relates to heterocyclic aromatic oxazole compounds having antipyretic activity, analgesic activity, anti-inflammatory activity, and in particular, selective inhibitory activity against cyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof, intermediates for producing them and pharmaceuticals useful as anti-inflammatory agents causing less side-effects such as disorders in the digestive tract, which comprise these heterocyclic aromatic oxazole compounds.
BACKGROUND OF THE INVENTION
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 structure and induction by various factors have been clarified [Yokoyama, 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 [Holtzman, M. J. et al.: J. Biol. Chem., 267: 21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88: 2692-2696 (1991); Kujubu, 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 follows therefrom that selective inhibition, without inhibition of COX-1, of solely COX-2 which is specifically induced at the inflammatory sites, would enable provision of a superior anti-inflammatory drug free of side-effects such as disorders in the digestive t
REFERENCES:
patent: 3901908 (1975-08-01), Fitzi et al.
patent: 4782058 (1988-11-01), Griffith
patent: 4849007 (1989-07-01), Rempfler et al.
patent: 5219731 (1993-06-01), Sih
patent: 5380738 (1995-01-01), Norman et al.
patent: 5474995 (1995-12-01), Ducharme et al.
patent: 5541080 (1996-07-01), Sih
patent: 5719163 (1998-02-01), Norman et al.
Noh, T J. Am. Chem Soc vol. 113 pp. 3105-3110,1993.
Berks, S J. Org. Chem vol. 53 pp. 5789-5791, 1988.
Seemuth, p J. Org Chem vol. 43 pp. 3063-3065, 1978.
P. Seemuth et al., J. Org. Chem., 43(15), 3063-3065 (1978).
S. Berk et al., J. Org. Chem., 53(24), 5789-5791 (1988).
T. Noh et al., J. Am. Chem. Soc., 115(8), 3105-3110 (1993).
Chemische Berichte vol. 67, 1934, Weinheim De, pp. 1617-1623, XP002026184; Hermann Bergs et al.; Zur Darstellung von alpha,beta-ungesattigten cyclischen Ketonen und Keto-sauren.
European Journal of Medicinal Chemistry Chimica Therapeutica.; vol. 28, 1993, Paris, Fr. pp. 715-720 XP00206185, M. Artico et al., "Antifungal agents.5.Chloro and amino derivatives of 1k,20-diaryl-1-(1H-imidazol-1-yl)ethane with potent antifungal activities", p. 716, compounds 4a-j, p. 719.
Journal of Medicinal Chemistry, vol. 15, No. 12, 1972, Washington U.S. pp. 1243-1247, XP002026186; Robert Bruce Moffett et al.; "Central nervous system agents.4.Analogs of 3-amino-2-phenylpropiophenone", pp. 1245-1247.
Journal of the American Chemical Society, vol. 83, N9. 19, Oct. 20, 1961, DC US, pp. 4208-4210, XP00206187; A. Fischer et al., "Dissociation constants of the conjugate acids of substituted benzyl phenyl ketones and of alkyl-substituted benzophenones".
Journal of Organic Cheimstry, vol. 28, No. 12, Feb. 1963, Easton US, pp. 307-311.
Haruta Jun-ichi
Hashimoto Hiromasa
Matsushita Mutsuyoshi
Coleman Brenda
Japan Tobacco Inc.
Shah Mukund J.
LandOfFree
Heterocyclic aromatic oxazole compounds and use thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic aromatic oxazole compounds and use thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic aromatic oxazole compounds and use thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1673162