Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-05-17
1998-03-10
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544367, 544373, A61K 31495, C07D40312, C07D41714
Patent
active
057261776
DESCRIPTION:
BRIEF SUMMARY
The present application is a U.S. national application filed under 35 USC 371 of PCT/FR94/01343, filed Nov. 17, 1994, which in turn is based upon the priority of French application 9313875, filed Nov. 19, 1993.
The present invention relates to new indole-derived arylpiperazines, to processes for their preparation and to their therapeutic uses.
The compounds according to the present invention are ligands having a very high affinity and a very good selectivity for the receptors commonly known as 5HT.sub.1 -like receptors and more particularly for the receptors known as 5HT.sub.1B and 5HT.sub.1D receptors, according to the new nomenclature recently proposed by P. Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 233-236, 1993).
Medicaments including (alone or in association with other therapeutic agents) the active principles of the present invention are employed in the treatment, both curative and preventive, of diseases related to dysfunctioning of 5HT.sub.1-like receptors, including 5HT.sub.1B, 5HT.sub.1D.alpha. and 5HT.sub.1D.beta. receptors, to their deregulation or to modifications in the activity of the endogenous ligand (generally serotonin).
It has moreover been demonstrated that serotonin could play a role in certain diseases such as depression, pain, obsessional convulsive disorders, panic attacks, obesity, schizophrenia, anxiety, certain sexual disfunctionings or alternatively certain forms of degeneration such as Brunello, G. Racagni and J. Mendlecvicz, "Serotonin receptors subtypes: pharmacological significance and clinical implications", edited by Karger (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 and G. Fillion, Pharmacological Reviews, 44, 401-458 (1992), and R. W. Fuller, J. Clin. Psychiatry, 53, 36-45 (1992)!.
The compounds of the present invention are powerful and selective ligands of 5HT.sub.1-like receptors which can act as agonists, partial agonists or antagonists as regards these receptors and can therefore be applied in the disorders related to serotonin mentioned above.
The majority of the compounds of the present invention are in addition powerful (as regards their affinity and as regards their intrinsic activity or effectiveness) and selective agonists of 5HT.sub.1B and 5HT.sub.1D receptors. Agonists of 5HT.sub.1-like receptors and more particularly of 5HT.sub.1D receptors have a selective vasoconstrictive activity and are used in the treatment of migraine and vasospastic (1988), M. D. Ferrari and 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 and E. T. Whalley, J. Neurol., 238, S57-S61 (1991) and A. V. Deligonis and S. J. Peroutka, Headache, 31, 228-231 (1991)!.
The compounds of the present invention, which are, for the most part, powerful and selective agonists of 5HT.sub.1-like receptors, are therefore more particularly employed in the curative and prophylactic treatment of "classic" (with aura) and "common" (without aura) migraine attacks, facial vascular pain, chronic vascular cephalalgias and vasospastic disorders.
The prior state of the art in this field is illustrated in particular by which describe new indole compounds derived respectively from piperazines and from arylamines as ligands of 5HT.sub.1B -5HT.sub.1D receptors. derivatives of tryptamine which have a good affinity for 5HT.sub.1D receptors. 0,497,512-A2, 0,501,568-A1, 0,464,558 and 0,548,813-A1 and Patent Application WO 92/13856, which describe heterocyclic derivatives derived from tryptamine as agonists of 5HT.sub.1-like receptors. claim benzamides derived from arylpiperazine as antagonists of the 5HT.sub.1D receptor.
Nevertheless, these patent applications do not in any case describe or suggest the indolic piperazine derivatives which form part of the present invention: the present invention describes a new class of indole-derived arylpiperazines which is distinguished
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TIPS 13 (1992), 307-311, Moskowitz.
Briley Michael
Halazy Serge
Pauwels Peter
Perez Michel
Bernhardt Emily
Pierre Fabre Medicament
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