Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-29
1997-06-24
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544373, A61K 31495, C07D24136
Patent
active
056417799
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new indole compounds derived from piperazine, to processes for their preparation and to their therapeutic uses.
During the last twenty years, considerable progress has been made in understanding the biochemistry and physiology of serotonin or 5-hydroxytryptamine (5-HT), both at the level of the central nervous system and at the cardiovascular level. Thus it has been demonstrated that serotonin could play a role in certain illnesses such as depression, pain, compulsive obsessional disorders, obesity, schizophrenia, anxiety, certain sexual dysfunctionings, migraine and other vasospastic disorders. The discovery of the various subclasses of the receptors for serotonin has stimulated the search for selective ligands (cf. R. A. Glennon, Neuroscience & Biobehavioral Reviews, 14, 35-47, 1990; A. W. Schmidt and S. J. Peroutka, FASEB J., 3, 2242-2249, 1989) in order better to determine the pharmacological meaning of each of these receptor subtypes and to be able to identify new therapeutic agents which are selective, non-toxic and devoid of undesirable side effects (S. Langer, N. Brunello, G. Racagni and J. Mendlewicz, "Serotonin receptor 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)).
The compounds according to the present invention are powerful and selective ligands of receptors for 5-hydroxytryptamine and more particularly of the receptor recently described as 5-HT.sub.1B and/or 5-HT.sub.1D receptor. The medicaments according to the present invention find their use in both the curative and preventive treatment of disorders related to serotonin.
Patent Application FR 2,671,971 describes a class of 5-O-carboxymethylated derivatives of tryptamine which possess good affinity for 5-HT.sub.1D receptors and can consequently act as therapeutic agents in the treatment of migraine. Nevertheless, Application FR 2,671,971 does formula: ##STR2## to their preparation and to the medicaments containing them.
In the formula (I): phenyl, benzyl, cycloalkyl, polycycloalkyl, dibenzocycloalkyl, dibenzooxepine, dibenzoazepine, dibenzothiepine, benzopyrrolocycloalkyl, benzothienocycloalkyl or naphthyl radical, optionally substituted by one or a number of substituents chosen from halogen atoms and alkyl, aryl, acyl, alkoxy and alkyl thio radicals.
Z represents C=O, SO.sub.2 or (CH.sub.2).sub.n in which n is between 1 and 5. benzyl, cycloalkyl, pyrrole, furan, pyridinyl or thiophenyl radical, optionally substituted by one or a number of substituents chosen from halogen atoms and alkyl, aryl, acyl, alkoxy and alkylthio radicals. a phenyl radical. benzyl or phenethyl radical. linear or branched alkyl radical. benzyl or phenethyl radical. acyl (COR.sub.7), acyloxy (CO.sub.2 R.sub.7) or acylamino (CONHR.sub.7) radical in which R.sub.7 represents a linear or branched alkyl radical, or a variously substituted phenyl radical.
In the preceding definitions and those which will be mentioned below, except when otherwise stated, the alkyl, alkoxy or alkylthio radicals contain 1 to 6 straight-or branched-chain carbon atoms, the cycloalkyl portions contain 3 to 7 carbon atoms and the polycycloalkyl portions contain 7 to 12 carbon atoms. In the formula (I), the halogen atoms are preferentially chlorine, fluorine and bromine atoms.
The compounds of formula (I) containing 1 or a number of asymmetric centers have isomeric forms. The racemates and the pure enantiomers of these compounds also form part of this invention.
The invention also comprises the salts, solvates (for example hydrates) and bioprecursors of these compounds which are acceptable in therapeutic use.
Mention will be made, among the salts of the indoles of general formula (I) which are acceptable in therapeutic use, of the salts formed by addition with organic or inorganic acids and for example hydrochlorides, hydrobromides, sulfates, fumarates and maleates. Other salts can
REFERENCES:
patent: 3929793 (1975-12-01), Popelak et al.
M.J. Millan, S 14671: A Naphtylpiperazine 5HT Angonist, Journal of Pharmacology and Experimental Therapeutics, vol. 262 (2), pp. 451-463.
Briley Michael
Halazy Serge
Perez Michel
McKane Joseph
Myers, Jr. Richard S.
Pierre Fabre Medicament
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