Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-26
1997-04-15
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514423, 514448, 514509, 548432, 548444, 548472, 548532, 549 72, 558482, A61K 3140, C07D20988
Patent
active
056210000
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage Application of PCT/EP93/03193 filed Nov. 15, 1993 and published as WO 94/12463 on Jun. 9, 1994.
Object of the present invention are nitric esters with an anti-inflammatory and/or anti-platelet aggregation activity, their pharmaceutical utilization and the process for their preparation.
PRIOR ART
Some derivatives of propionic acid, such as for instance 2-(-3-benzoylphenyl)propionic acid, commonly known as ketoprofen, have been used for a long time as pharmaceutical preparations for their anti-inflammatory activity and are sold on the different international markets since many years. The process for the preparation of 2-(3-benzoylphenyl)propionic acid has been described in the South African patent no. 68 00,524, corresponding to the US Pat. No. 3,641,127; in the French patent no. M6444 and also in C.A. 75,5528m (1971); G. A. PINNA et al., FARMACO Ed. Sci. 35,684 (1980); while the pharmacokinetics in humans is described in T. ISHIZAKI et al., Eur. J. Clin. Pharmacol. 18,407 (1980). The use of derivatives of propionic acid, such as, for instance, keptofren, as well as the use of other products which are utilized as anti-inflammatory agents, involves, as known, severe adverse reactions, for instance in the gastrointestinal apparatus, as well as possible damages to the liver and the kidneys.
There is much experimental evidence [S. MONCADA, R. M. J. PALMER, E. A. HIGGS, Pharmacological Reviews, 43(2), 109 (1991); T. H. LUSHER, C. M. BOUGLANGER, Y. DOHI, Z. YANG, Hypertension, 19,117 (1992)], on whose basis the integrity of vasal endothelium is thought to be a basic barrier against the onset of pathological processes in several organs and apparatuses.
Such protection barrier, and therefore the integrity of the vasal endothelium, is ensured physiologically by the presence of nitric oxide and prostacyclin. The treatment with non steroid drugs having an anti-inflammatory activity, such as, for instance, 2-(3-benzoylphenyl)propionic acid or ketoprofen, causes the inhibition of cyclo-oxygenase, an enzyme which syntesizes the precursor of prostacyclin.
As a consequence, having so inhibited the production of prostacyclin, the reserve of same in the tissues is markedly depauperated, and therefore the integrity of vasal endothelium is compromised.
As said, because of this endothelial damage due to the reduction of prostacyclin, diffuse pathological process break out which affect the gastrointestinal apparatus, liver and kidneys.
OBJECTS OF THE INVENTION
Object of the present invention is that to provide a group of products which, while ensuring the maintenance of the pharmacological activity characteristic of the known anti-inflammatory agents, are capable of eliminating the adverse reactions caused by the treatment with said agents.
Another object of the present invention is the realization of a process for the preparation of a group of products having an anti-inflammatory activity while being exempt from the adverse reactions which are typical of anti-inflammatory agents.
DESCRIPTION OF THE INVENTION
These and still other objects and associated advantages which will appear from the following description, are obtained with nitric esters having the following general formula: ##STR2## where: A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, R is chosen among ##STR3## R.sub.2 is chosen among hydrogen, methyl, ethyl, alkyl chains linear or branched by 3 to 12 carbon atoms, substituted or non substituted, Y is chosen among oxygen, NH, NR.sub.1, where R.sub.1 is a linear or branched alkyl group and n is comprised between 1 and 10.
In fact, it has been observed that the introduction of a group such as a terminal nitric ester in the general formula derivatives (I) allows to maintain the pharmacological activity characteristic of non steroid anti-inflammatory agents, while eliminating the adverse reactions caused by the treatment with such agents. Besides, it has been observed that derivatives (I) are useful also in the treatment of var
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Arena Barbara
Del Soldato Piero
Haley Jacqueline
Nicox S.A.
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