Cyclo-oxygenase inhibitor and amidine derivatives salts, prepara

Details Cyclo-oxygenase inhibitor and amidine derivatives salts, prepara Cyclo-oxygenase inhibitor and amidine derivatives salts, prepara

1998-01-06

2000-05-16

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514423, 548500, 549 77, 549499, 562428, 562439, 558414, A61K 3140, C07D20926, C07D33322, C07C32302

Patent

active

060638079

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns novel compounds exhibiting dual biological activity, namely the simultaneous inhibition of the formation of nitrogen monoxide (NO) as well as the cyclo-oxygenase activity, a procedure for their preparation, pharmaceutical compositions comprising them and their use notably as inhibitors of NO synthase and cyclo-oxygenase.
The cyclo-oxygenase inhibitors or the medications analogous to asprin, for example acetylsalicylic acid and salicylic acid, the methyl indoline derivatives, such as indometacine (DCI of [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl] acetic acid and sulindac (DCI of [5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]-methylene-1H-indene-3-yl] acetic acid, the derivatives of the N-phenylanthranilic acids (meclofenamate, fenamates), the derivatives of propionic acid such as ibuprofen (DCI of p-isobutylhydratropic acid), naproxyn, fenoprofen, are widely used and have proved themselves sufficiently as efficacious medications in the treatment of inflammation, however, with several undesirable secondary effects at increased doses (R. Flower, S. Moncada and J. Vane, Mechanism of action of asprin-like drugs--In the pharmacological basis of therapeutics Goodman and Gilman, 1985, 29, 674-715). Moreover, these compounds were used at the same time in the acute and prophylactic treatment of migraines. The value of these medications is undeniable, even though their therapeutic responses are often incomplete and, in certain patients, the treatment with such compounds is not appropriate. Because of their anti-inflammatory and antiplatelet aggregate properties, these compounds are used as well for thrombosis with an evident reduction of edema, in the ischemic models of the brain and consequently are proposed in the treatment and the prevention of infarctions, concussions, and cerebrovascular diseases (W. Armstrong Recent trends in research and treatment of stroke, SCRIP, PJB Publications, 1991).
The biological activity of the NO-synthase inhibitors has only been recently discovered and their potential therapeutic function is only now in the investigative stage. These substances, in which the structures are represented by analogues of L-arginine and described in the Danish Patent 3041/90, are inhibitors of nitric oxide (NO) production. Our current knowledge of NO was revised in 1991, by Monacada et al., (S. Monacada, R. M. J. Palmer, E. A. Higgs: Nitric oxide: physiology, pathophysiology and pharmacology--Pharmacological reviews 43, 2, 109-142) and more recently by Kerwin et al. (Kerwin J., Lancaster J., Feldman P., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. (1995), vol 38, 22, 4343-4362). In summary, it appears that NO serves as a transduction mechanism for soluble guanylate cyclase in platelets, the nervous system, and as effector molecule in immunological reactions in many cells and tissues, comprising macrophages and neutrophiles. NO is produced enzymatically from L-arginine by an enzyme called NO synthase. This enzyme exists in two forms: one constitutive (endothelial and neuronal) and the other inducible. In certain pathologies excessive production of NO can occur, as has already been demonstrated to occur in the course of a shock, and such as has already been described in the previously cited patent. In this context, the NO synthase inhibitors are medications effective in preventing the vascular consequences and mortality caused by an illness, particularly when they are combined with cyclo-oxygenase inhibitors such as asprin, indometacine or meclofenamate.
The beneficial effects of the combination of two active ingredients in the same molecule are open to occur for patients suffering from other pathologies, such as for example: atherosclerosis, migraine, arterial hypertension, septic shock, cardiac or cerebral infarctions of ischemic or hemorragic origins, ischemias and thrombus; neurodegenerative illnesses where notably cerebral infarctions, senile dementias, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld

REFERENCES:
patent: 4324801 (1982-04-01), Matsuzaki et al.
Patent Abstracts of Japan JP61143320 (1 page) Jul. 1, 1986, Akinori et al.
Patent Abstracts of Japan (1 page) JP56147761 Nov. 16, 1981, Akinori et al.

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