Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-21
1998-12-22
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514419, 548504, 548506, A61K 3140, C07D20916
Patent
active
058520490
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR95/01220 field Sep. 22, 1995.
The present invention relates to new aromatic ethers derived from indols, as well as the processes for preparing them, the pharmaceutical compositions containing them and their use as medicaments.
Serotonin or 5-hydroxytryptamine (5HT) plays an important role both at the level of the nervous system and at the level of the cardiovascular system and serotoninergic receptors have been identified either at the central or peripheral level. It is generally accepted that serotonin may play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, panic attacks, obsessive compulsive disorders, schizophrenia, suicidal tendency), certain neurodegenerative disorders (Alzheimer's disease, Parkinsonism), migraine, cephalalgia and disorders linked to alcoholism (cf. E. Zifa and G. Fillion, Pharm. Reviews, 44, 401, 1992; A. Moulignier, Rev. Neuro. (Paris) 150, 3-15, 1994; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, "Serotinin receptors subtypes: pharmacological significance and clinical implications" Karger ed.; 1992; B. E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21, 1992; D. G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, Suppl. 4, 6-13, 1992; E. Zifa, G. Fillion, Pharmacological Reviews, 44, 401-458, 1992; R. W. Fuller, J. Clin. Psychiatry, 53, 36-45, 1992).
The compounds according to the present invention are new compounds having a very high affinity and a very good selectivity for the receptors commonly called 5HT.sub.1-like and more particularly for the receptors called 5HT.sub.1B and 5HT.sub.1D, according to the new nomenclature recently proposed by P. Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 233-236, 1993).
The medicaments including (alone or in combination with other therapeutic agents) the active ingredients of the present invention find use in the treatment, both curative and preventive, of diseases linked to the dysfunction of the 5HT.sub.1-like receptors including the 5HT.sub.1B, 5HT.sub.1D.alpha. and 5HT.sub.1D.beta. receptors, to their deregulation or to modifications of the activity of the endogenous ligand (generally serotonin).
The compounds of the present invention are potent and selective ligands of the 5HT.sub.1-like receptors which can act as agonists, partial agonists or antagonists at the level of these receptors, and may therefore find application in the abovementioned disorders linked to serotonin.
Most of the compounds of the present invention are more particularly potent agonists (both at the level of their affinity and at the level of their intrinsic activity or efficacy) and selective agonists of the 5HT.sub.1B and 5HT.sub.1D receptors. The agonists of the 5HT.sub.1-like receptors and more particularly of the 5HT.sub.1D receptors exhibit a selective vasoconstrictive activity and find use in the treatment of migraine and 1309-1311, 1988; M. D. Ferrari, P. R. Saxena, Cephalalgia, 13, 151-165, 1993; S. J. Peroutka, Headache, 30, 5-11, 1990; M. A. Moskowitz, TiPS, 13, 307-311, 1992; W. Feniuk, P. P. Humphrey, M. S. Perren, H. E. Connor, E. T. Whalley, J. Neurol., 238, S57-S61, 1991; A. V. Deligonis, S. J. Peroutka, Headache, 31, 228-231, 1991)!.
The compounds of the present invention which are, for the most part, potent and selective agonists of the 5HT.sub.1-like receptors therefore find more particularly use in the curative and prophylactic treatment of "conventional" (with aura) or "common" (without aura) migraine attacks, vascular facial pain, chronic vascular cephalalgia and vasospastic disorders.
The prior state of the art in this domain is illustrated especially by: and U.S. Pat. No. 4,839,377, GB 2,124,210A and GB 2,162,532A which describe sulfonamides derived from tryptamines (including sumatriptan) as antimigraine drugs. describe alkylamides derived from tryptamine. which describe new indole compounds derived from piperazines and arylamines respectively as ligands of the 5HT.sub.1B -5HT.sub.1D receptors. 5-O-carboxymethylat
REFERENCES:
Glennon, Richard A. et al., Drug Dev. Res., vol. 22, No. 1, pp. 25-36 (1991).
Glennon et al., Chemical Abstracts, 114:178477 (1991).
Gordeev et al., Chemical Abstracts, 118:233816 (1993).
Halazy Serge
John Gareth
Pauwels Peter
Perez Michel
Valentin Jean-Pierre
Pierre Fabre Medicament
Powers Fiona T.
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