Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-26
2003-12-09
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S445000, C549S321000, C549S068000
Reexamination Certificate
active
06660769
ABSTRACT:
The present invention relates to N-substituted 3-amino-2,2-di(C-alkyl)-1,4-butyrolactones and -1,4-thiobutyrolactones, to their preparation, to the pharmaceutical compositions comprising them and to their use as stimulant of the activity of &ggr;-aminobutyric acid and as medicament preferably intended for the treatment of nervous disorders.
The GABA-A Receptor
&ggr;-Aminobutyric acid (or GABA (1)) is the most important inhibitory neurotransmitter of the central nervous system. It acts at the level of three separate classes of receptors known as GABA-A, GABA-B and GABA-C receptors. The GABA-A receptor, the amino acid sequence of which has been determined by cloning techniques, is a pentameric structure composed of &agr;, &bgr;, &ggr;, &dgr; and/or &rgr; subunits. To date, 6 &agr; subunits, 3 &bgr; subunits, 3 &ggr; subunits, 1 &dgr; subunit and 2 &rgr; subunits have been identified and sequenced. Five of these subunits (for example 2&agr;
1
2&bgr;
2
&ggr;
2
) combine together to form a channel permeable to chloride ions. By binding to this GABA-A receptor, GABA increases the permeability of the channel to chloride ions, thus inhibiting neuronal transmission. In the light of the large number of possible permutations of the various subunits, the GABA-A receptor is observed to be extremely heterogeneous in the brain of mammals and different structures in the brain generally show a preference for certain combinations of subunits.
The search for ligands which are selective for one of these various subclasses of GABA-A receptors is a major object of clinical medical research in this field.
Apart from GABA, a large number of various classes of compounds which bind to the GABA-A receptor are known. Some products, such as muscimol and isoguvacine, bind directly to the same site as GABA on the GABA-A receptor and stimulate the receptor in the same way as GABA itself. In contrast to these agonists, some substances, such as bicuculline (2), competitively inhibit the action of GABA. Such antagonists of the GABA receptor show convulsant properties in vivo (P. Krogsgaard-Larsen, B. Frolund, F. S. Jorgensen, A. Schousboe, J. Med. Chem., 1994, 37, 2489).
The inhibitory action of GABA can be modulated by compounds which interact with a variety of allosteric sites on the GABA-A receptor distinct from the GABA recognition site. One of the best known classes of allosteric modulators of the GABA-A receptor is that of the benzodiazepines (for example diazepam (3)). By thus binding to their own recognition site on the GABA-A receptor (the benzodiazepine receptor or BZR), these compounds improve the action of GABA by increasing the frequency of opening of the chloride channel (R. E. Study, J. L. Barker, Proc. Natl. Acad. Sci. USA, 1981, 78, 7180). This results in the anticonvulsant, anxiolytic, sedative-hypnotic and muscle-relaxant activities of these products, widely used clinically. Other classes of compounds structurally unrelated to benzodiazepines, such as triazolopyridazines (for example Cl 218872 (4)), imidazopyridines (for example zolpidem (5)), cyclopyrrolones (for example zopicolone (6)) and &bgr;-carbolines (for example &bgr;-CCM (7)), can also bind to the benzodiazepine receptors. In the case of the latter, some derivatives inhibit, rather than enhance, the neuroinhibitory action of GABA (R. L. Macdonald, R. E. Twyman in “Ion Channels” ed. by T. Narahashi, Vol. 3, pp. 315-343, Plenum Press, New York, 1992). In this case, the compounds, generally convulsant, are referred to as inverse agonists (or negative allosteric modulators) of the BZR, in order to distinguish them from the therapeutically useful agonists (or positive allosteric modulators) of the BZR. Some of these products show selectivity at the level of the various subclasses of GABA-A/benzodiazepine receptors. Thus, zolpidem, used clinically as hypnotic, is selective for the subclass of benzodiazepine receptors which is found predominantly in the cerebellum (BZ1 receptors) (S. Arbilla, H. Depoortere, P. George, S. Z. Langer, Naunyn-Schmiedeberg's Arch. Pharmacol., 1985, 330, 248). This selectivity is reflected either by a narrower spectrum of activity (for example, anxiolysis without a hypnotic effect) or by a reduction in the undesirable effects of this type of product (habituation, dependency, amnesia, and the like).
Other sites exist on the GABA-A receptor which also make it possible, according to the binding of the receptor with an appropriate molecule, to modulate the activity of GABA. Mention should be made, among these sites, of those for neurosteroids (for example 3&agr;-OH-5&agr;-pregnane-20-one), barbiturates (for example pentobarbital), anesthetics (for example propofol), t-butyl-bicyclophosphorothionate cage convulsants (for example TBPS, 8), which bind to the picrotoxin site of the GABA-A receptor (W. Sieghart, Pharmacol. Rev., 1995, 47, 181 and C. R. Gardner, W. R. Tully, C. J. R. Hedgecock, Prog. Neurobiol., 1993, 40, 1). Other binding sites, less well characterized but apparently distinct, are those of loreclezole and of &ggr;-butyrolactones. Such compounds also positively modulate the action of GABA and this effect is reflected by an in vivo anticonvulsant and/or anxiolytic action.
It has recently been demonstrated that gem-dialkylated &ggr;-butyrolactones (9a) and gem-dialkylated &ggr;-thiobutyrolactones (9b) can either reduce or enhance the action of GABA according to the position and the size of their alkyl substituents (K. D. Holland, M. G. Bouley, D. F. Covey, J. A. Ferrendelli, Brain Res., 1993, 615, 170). These compounds allosterically inhibit the binding of [S
35
]TBPS to rat brain membranes but do not displace [H
3
]-flunitrazepam from its binding site, not enhancing either the binding of benzodiazepines or of muscimol. This suggests that the compounds of type 9 may act on a different site from those already characterized on the GABA-A receptor complex.
Finally, loreclezole (10) is a novel compound which demonstrates both an anticonvulsant activity and an anxiolytic activity in various animal models (A. Wauquier et al., Drug Dev. Res., 1990, 19, 375 and G. R. Dawson, R. Curnow, P. Bayley, A. Rambridge, M. D. Tricklebank, Eur. J. Pharmacol., 1994, 252, 325). These compounds have only a negligible affinity for benzodiazepine recognition sites. Although the direct interaction of loreclezole with GABA-A receptors has been demonstrated in recombinant receptor studies, the relationship between the loreclezole binding sites and the other allosteric binding sites of this receptor is not clear to date. It has recently been demonstrated that the affinity of loreclezole for receptors comprising &bgr;
2
or &bgr;
3
subunits is 300 times greater than that for receptors comprising the &bgr;
1
subunit (P. B. Wingrove, K. A. Wafford, C. Bain, P. J. Whiting, Proc. Natl. Acad. Sci. USA, 1994, 91, 4569). This selectivity may explain the absence of sedative effects of loreclezole and suggests that the compounds interacting with the loreclezole binding site on the GABA-A receptor may have important therapeutic applications.
It is therefore clear that a large number of allosteric modulatory sites, which can enhance the action of GABA and thus show a therapeutic effectiveness in a wide range of disorders of the central nervous system, exist on the GABA-A receptor. It may therefore be reasonably concluded that novel chemical structures may discover other allosteric modulatory sites currently uncharacterized on the GABA-A receptor or may bind to known sites with greater affinities or greater selectivities. Such compounds may, as a result, show a powerful and/or highly specific activity and weaker undesirable side effects in the treatment of such disorders.
Covey et al. were the first to indicate the convulsant and anticonvulsant properties of gem-dialkyl-1,4-butyrolactones (W. E. Klunk, A. C. McKeon, D. F. Covey, J. A. Ferrendelli, Science, 1982, 217, 1040). They found that, whereas dialkyl substitutions in the &bgr; (that is to say C-3) position of butyrolactone (for example compound 54) produces con
Dodd Robert
El Hadri Ahmed
Furtmuller Roman
Jursky Frantisek
Potier Jean-Paul Pierre
Centre National de la Recherche Scientifique "CNRS"
Foley & Lardner
Owens Amelia
LandOfFree
N substituted 3-amino-2,2-di-c-alkyl-1,4-butyrolactones and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N substituted 3-amino-2,2-di-c-alkyl-1,4-butyrolactones and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N substituted 3-amino-2,2-di-c-alkyl-1,4-butyrolactones and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3125180