Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-06
1999-01-19
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514418, 514509, 548452, 549 76, 558480, 558482, 558483, 534660, 534798, C07D48704, C07D33322, A61K 3140, A61K 31405, C07C20304
Patent
active
058614265
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).
It is known that the anti-inflammatory and anti-thrombotic efficacy, but most of all the tolerance, of NSAIDs (Non Steroid Anti-Inflammatory Drugs), also known as FANS, seem to be considerably affected by their cyclo-oxygenase (COX)-inhibiting activity 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 more potent 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 related 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; piroxicam, sudoxicam, tenoxicam, isoxicam, meloxicam.
See patents U.S. Pat. No. 3,558,690; U.S. Pat. No. 3,755,427; U.S. Pat. No. 3,641,127; FR 2,112,111; U.S. Pat. No. 4,035,376; U.S. Pat. No. 3,997,669; U.S. Pat. No. 3,784,701; U.S. Pat. No. 3,896,145; U.S. Pat. No. 3,600,437; U.S. Pat. No. 3,843,681; U.S. Pat. No. 3,904,682; U.S. Pat. No. 3,228,831; U.S. Pat. No. 4,161,538; U.S. Pat. No. 4,233,299; U.S. Pat. No. 3,591,584; DE 2,537,070; U.S. Pat. No. 3,161,654; U.S. Pat. No. 4,061,779; U.S. Pat. No. 4,556,672; U.S. Pat. No. 4,089,969.
The disadvantage of these products is that they are very effective but highly toxic.
The importance of the acidic function lies in the fact that a masking of this function in COX inhibitors results in a virtually complete loss of its prostanoid-inhibiting properties. See Drugs 35, 504, 1988.
Also known are products 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 PCT WO 94/04484, which describes a particular group of compounds including the well known commercial product diclofenac; PCT/EP 93/03193, which describes another specific group of compounds including the commercial products flurbiprofen and indoprofen.
The Applicant has unexpectedly found that other compounds having the termination group --ONO.sub.2, when X.sub.1 =--YO--, as defined hereinafter, have anti-inflammatory, analgesic and anti-thrombotic activities when used as medicaments with high efficacy in cyclo-oxigenase inhibition and have low toxicity.
A further object of the invention is that the known products as reported in PCT WO 94/04484 and PCT/EP 93/03193 and the new compounds found by the Applicant having X.sub.1 =--YO-- have a pharmaco-dynamic disadvantage. In fact, in the biochemical test evaluating the cyclo-oxygenase-inhibiting activity, experiments conducted by the applicant showed a high response variability, in the order of 10-40%.
This generally results in an erratic and unpredictable efficacy, so that the determination of a correct dosage is difficult.
In practice, higher doses must be administered to limit the above variability. The disadvantage lies in the risks of a higher incidence of side effects.
Another disadvantage is that these products are difficult from a formulation point of view because oral or parenteral preparations are more difficult to prepare than traditional preparations based on acidic FANS.
Molecule solubility is known be one of the most important properties affecting the molecule pharmacokinetic and dynamic processes.
For example, for
Del Soldato Piero
Sannicolo Francesco
Higel Floyd D.
Nicox S.A.
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