Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-15
2003-11-18
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S141000, C546S139000, C546S089000, C514S307000, C514S291000
Reexamination Certificate
active
06649626
ABSTRACT:
The present invention relates to N-substituted 1-(2-butyrolactones and 2-thiobutyrolactones)-isoquinolines, their preparation, pharmaceutical compositions containing them and their use as stimulant of &ggr;-aminobutyric acid activity and as medicament preferably intended for treating nervous disorders.
&ggr;-aminobutyric acid (or GABA (I)) is the most important inhibiting neurotransmitter of the central nervous system. It acts at the level of three distinct classes of receptors called GABA-A, GABA-B and GABA-C receptors. The GABA-A receptor, whose amino acid sequence has been determined by cloning techniques is a pentameric structure composed of &agr;, &bgr;, &ggr;, &dgr; and/or &rgr; subunits. So far, 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
) assemble to form a channel which is 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, a very high heterogeneity of the GABA-A receptor is observed in the brain of mammals and various structures of the brain generally show a preponderance for certain combinations of subunits.
The search for ligands selective for one of these various subunits of GABA-A receptors is a major objective of clinical medical research in this field.
Apart from GABA, a large number of various classes of compounds are known which bind to the GABA-A receptor. 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 manner as GABA itself. Unlike 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 may be modulated by compounds which interact with a variety of allosteric sites on the GABA-A receptor which are 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-relaxing activities of these products which are widely used in the clinical field. Other classes of compounds which are structurally unrelated to the 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, certain derivatives inhibit, rather than increase, 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, which are generally convulsant, are called inverse agonists (or negative allosteric modulators) of BZR, to distinguish them from agonists (or positive allosteric modulators) of BZR which are therapeutically useful. Some of these products demonstrate selectivity on various subclasses of GABA-A/benzodiazepine receptors. Thus, zolpidem, which is clinically used as a hypnotic, is selective for the subclass of benzodiazepine receptors which are predominantly found in the cerebellum (BZ1 receptors) (S. Arbilla, H. Depoortere, P. George, S. Z. Langer, Naunyn-Schmiedeberg's Arch. Pharmacol., 1985, 330, 248). This selectivity results in a narrower activity spectrum (for example anxiolysis without hypnotic effect) or in a reduction in the undesirable effects of this type of product (addiction, dependence, amnesia and the like).
Other sites exist on the GABA-A receptor which also make it possible, depending on its binding with an appropriate molecule, to modulate the activity of GABA. Among these sites, there may be mentioned those for neurosteroids (for example 3&agr;-OH-5&agr;-pregnan-20-one), barbiturates (for example pentobarbital), anesthetics (for example propofol), cage convulsants t-butyl-bicyclophosphorothionate 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. Fiedgecock, Prog. Neurobiol., 1993, 40, 1). Other binding sites, which are less well characterized but which are apparently distinct, are those for loreclezole and &ggr;-butyrolactones. Such compounds also positively modulate the action of GABA and this effect results in an anticonvulsant and/or anxiolytic action in vivo.
It is thus clear that a large number of allosteric modulatory sites, which can increase the action of GABA and thus demonstrate a therapeutic efficacy in a wide range of central nervous system disorders, exist on the GABA-A receptor. It can thus be reasonably concluded that novel chemical structures can discover other allosteric modulatory sites not yet characterized on the GABA-A receptor or bind to known sites with higher affinities or higher selectivities. Such compounds may, as a result, demonstrate a potent and/or highly specific activity as well as lower undesirable side effects in the treatment of such disorders.
Wyeth laboratories claim that compound 17, which is obtained according to scheme 1 (and related compounds) are antagonists of the GABA autoreceptor and are thus useful for the treatment of central nervous system disorders and of pain (European patent No. EP0419247A2). The GABA autoreceptor is considered as being a pharmacological entity distinct from the GABA-A receptor itself. Type 17 compounds thus have no action or have a very weak action on GABA-A receptors. The GABA autoreceptor ligands exhibit different structural requirements from those of the GABA-A receptor.
Bicuculline 2, whose molecular structure has been used as the starting point for designing the compounds of the present invention, is a natural product which was isolated from Dicentra cucullaria in 1932 by Manske (R. H. Manske, Can. J. Res., 1932, 7, 265). This compound, a potent convulsant, is a competitive antagonist of the GABA-A receptor which binds to the same site as GABA itself (M. A. Simmonds, Br. J. Pharmacol., 1978, 63, 495). Because of the convulsant nature of bicuculline, very few structure-function studies have been carried out on this molecule. Allan and Apostopoulos (R. D. Allan, C. Apostopoulos, Aust. J. Chem., 1990, 43, 1259) have described the preparation of bicuculline derivatives modified at the C-9 position starting from 9-hydroxymethylbicuculline whose synthesis has been described by Bhattacharyya et al. (A. Bhattacharyya, K. M. Madyastha, P. K. Bhattacharyya, M. S. Devanandan, Indian J. Biochem. Biophys., 1981, 18, 171). No biological data has been reported. Simonyi et al. (J. Kardos, G. Blasko, P. Kerekes, I. Kovacs, M. Simonyi, Biochem. Pharmacol., 1984, 33, 3537) have determined the GABA-A receptor activities of 45 phthalideisoquinoline alkaloids related to (+)-bicuculline. No compound was more active than bicuculline, but in all cases, the erythro stereoisomer (that is to say that of bicuculline) was more active than the threo isomer. This conclusion was confirmed by the same authors in related studies published in 1996 (J. Kardos, T. Blandl, N. D. Luyen, G. Dornyei, E. Gacs-Baitz, M. Simonyi, D. J. Cash, G. Blasko, C. Szantay, Eur. J. Med. Chem., 1996, 31, 761). The importance of the fused ring “A” of bicuculline for the GABA-A receptor activity has never been demonstrated, except in the present invention. W
Dodd Robert
Furtmuller Roman
Jursky Frantisek
Potier Pierre Jean-Paul
Razet Rodolphe
Aulakh C. S.
Centre National de la Recherche Scientifique "CNRS"
Finnegan Henderson Farabow Garrett & Dunner LLP
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