Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-04-29
2000-03-21
Barts, Samuel
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
558482, A61K 3121
Patent
active
060403411
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new products having anti-inflammatory, analgesic and anti-thrombotic activities.
In particular it relates to inhibitors of cyclo-oxygenase (COX) of the class of Aspirin, i.e. of acetylsalicidic acid or its derivatives in general.
It is known that the anti-inflammatory and anti-thrombotic efficacy of NSAIDs (Non Steroid Anti-Inflammatory Drugs), also known as FANS, but above all their tolerance, seem to be markedly affected by their inhibitor activity of the cyclo-oxygenase (COX) in the inflammatory site as well as in healthy tissue. See for example FASEB Journal 1, 89, 1987; Bioch. Biophys. Acta 1083, 1, 1991. It is generally believed that the stronger a COX inhibitor is the more effective it is.
The disadvantage of these products is that they are toxic.
Furthermore, it is also known that the COX-inhibiting properties seem to depend on some factors bound to the physico-chemical and structural characteristics of the molecules themselves, such as for example the acidic function. See for example J. Pharmacol. Exp. Therap. 196, 226, 1976; Arch. Toxicol. 60, 261, 1987.
The known cyclo-oxygenase inhibitors are generally acids which can be brought back to general structures, including: triflusal, or nonacetylated such as, for example, salycilate, diflunisal, salsalate; etodolac, ketorolac; tiaprofenic acid, loxoprofen, indoprofen, oxaprozin, ketoprofen, fenoprofen, fenbufen, flurbiprofen, carprofen, suprofen.
See for example a previous patent application in the name of the applicant PCT/EP 95/01233, herein incorportated by reference, which describes the prior art of the above products.
As said, the disadvantage of these products is that they are very effective but highly toxic.
The importance of the acidic function resides in the fact that the masking of this function in COX inhibitors results in a virtually complete loss of its prostanoid-inhibiting properties. See Drugs 35, 504, 1988.
Products are also known which are highly effective in inhibiting cyclooxygenase and have a low toxicity even though they do not contain the acidic function in their molecule.
These products are known as nitric esters with nonacidic ending. See for example patents WO 94/04484, which describes a particular group of compounds including the well known commercial product diclofenac; WO 94/12463, which describes another specific group of compounds including the commercial products flurbiprofen and indoprofen, PCT/EP 94/03182, which describes another specific group of compounds including the commercial products naproxen and ketorolac.
In a previous patent application in the name of the applicant PCT/EP 95/01233 other nitric esters having a nonacidic termination have been described with various linking groups X.sub.1 as specified below. The new linking groups therein described showed advantages from the pharamcological and pharmaceutical viewpoint, in particular pharmaco-cinetic and pharmaco-dynamic viewpoint, since they showed a lower variability of the response. The products described in said patent application were also able to exert an inhibition effect of the inflammation produced by lyposaccaride (LPS) and therefore useful in the septic shock. This result was unexpected since it is well known that the anti-inflammatory products in general do not significantly modify the activity of the nitrosynthetase induced by lypopolysaccarides in the rat and therefore they are not useful in the septic shock.
The technical problem to be solved by the present invention relates to inhibitor products of the COX much more effective in inhibiting the piastrine aggregation induced by arachidonic acid and trombin, the latter having a well known primary patogenetic role even superior to arachidonic acid and other aggregant stimulus, said products having contemporaneously a high gastric tolerability, without provoking adhesions of the gastric intestinal mucose on the treated animals.
The applicant has unexpectedly and surprisingly found a specific class of anti-inflammatory products, as described hereinbelow, having an imp
REFERENCES:
patent: 5621000 (1997-04-01), Arena et al.
patent: 5700947 (1997-12-01), Soldato
Del Soldato Piero
Sannicolo Francesco
Barts Samuel
Nicox S.A.
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