Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1984-02-07
1987-04-07
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548193, 548194, 548195, 548198, A61K 31425, C07D27750
Patent
active
046561846
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new therapeutic compositions containing N-substituted hydrazones as active ingredient. Said compositions are useful in the treatment of inflammatory phenomena and, in particular, in the treatment of ocular inflammatory phenomena.
The ocular inflammatory response is the sequence of events induced by a lesion or irritation of the tissues of the eye. It is reflected by an increase of the intraocular pressure, a leukocytic infiltration in the tissues and the liquids of the eye, an increase of the protein level in the aqueous humor and an uveitis.
Although the nature of the inflammatory response may be extremely varied, and it may have a multiplicity of mediators (kinines, histamine, etc.), there is always production of proinflammatory metabolites of arachidonic acid at the level of the injured tissue, i.e., prostaglandines (PG.sub.s) and hydroxy-eicosatetraenoic acids (HETE.sub.s). This production is increased by the infiltration of the polymorphonuclear leukocytes (PMN.sub.s) towards the site of the inflammation, which, in turn, produce PG.sub.s and HETE.sub.s in the course of the phagocytosis. The known biologic effects of the HETE.sub.s are, inter alia, chemokinetism and chemotactism with respect to the PMN.sub.s.
The PG.sub.s and HETE.sub.s are metabolites of arachidonic acid, a C.sub.20 fatty acid. They are synthetically produced according to two distinct routes, which are diagrammatically represented in FIG. 1:
the cyclooxygenase route leads successively to endoperoxides PGG.sub.2 and PGH.sub.2, precursors of various PG.sub.s of Series 2. Among them, PGE.sub.2 and PGI.sub.2 (prostacycline) possess in particular a vasodilator action.
the lipoxygenase route leads to un-cyclized mono- and -dihydroxyeicosatetraenoic acids (HETE.sub.s) most of which are proinflammatory acids, just as their precursors, the corresponding hydroxyperoxy acids (HPETE.sub.s) Thus, 5,12-diHETE or leucotriene B.sub.4 (LTB.sub.4) is the most potent chemotactic agent known in the case of human leukocytes. Additionally, metabolites of this route are involved in allergic phenomena such as asthma.
In contrast to the PG.sub.s which have common precursors, PGG.sub.2 and PGH.sub.2, the lipoxygenase products have different precursors:
12-HPETE, in the blood-platelets, synthetically formed under the action of a 12-lipoxygenase, leads to the formation of 12-HETE.
in the leukocytes, 5-HPETE and 15-HPETE are predominantly involved leading to 5-HETE, 5,12-diHETE and 15-HETE.
Research for therapeutic agents liable to oppose the inflammatory reaction was oriented towards the following routes:
inhibition of the release of arachidonic acid by the glucocorticoids. The major drawback of the glucocorticoids is to induce an increase of the intraocular pressure and to favor the formation of a glaucoma or a cataract.
inhibition of the cyclooxygenase route by nonsteroid anti-inflammatory agents (such as Aspirin, Indomethacin, Tanderil). Recent experimental investigations, however, show that Indomethacin increases leukocytic infiltration in the aqueous humor: by inhibiting the cyclooxygenase route, it favors the lipoxygenase route and, thus, the release of chemotactic products.
The simultaneous inhibition of the 5-lipoxygenase and of the cyclooxygenase route is liable to block the synthesis of the different pro-inflammatory mediators in the same manner as the glucocorticoids, but without exhibiting the detrimental effects thereof.
The present invention is precisely based on the discovery that certain hydrazones inhibit both the leukocytic lipoxygenase and the formation of blood-platelet prostanoids. Thus, they oppose the development of the vascular phase of inflammation (involving the HETE.sub.s).
Therefore, the present invention relates to therapeutic compositions which contain, as active ingredient, a compound of the formula: ##STR2## in which:
Z represents a 2-thiazolyl or phenyl group;
R.sub.1 represents a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.5-7 cycloalkyl group, a hydroxy group, a C.sub.1-6 alkoxy group, a carboxy gr
REFERENCES:
patent: 3786094 (1974-01-01), Perronnet et al.
Schilt et al., Talanta, vol. 27, pp. 55-58, (1980).
Beyer et al., Berichte, vol. 89, No. 5, pp. 1095-1099, (1956).
Yamada et al., Chemical Abstracts, vol. 73:78537g, (1970).
Bertez Chantal
Bonne Claude
Coquelet Claude
Sincholles Daniel
Gerstl Robert
Kapner Stephen M.
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