Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-11-29
1996-01-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546113, C07D47104, C07D47106, A61K 3144
Patent
active
054847931
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR92/00480, filed 29 May 1992.
The invention relates to new 6-azaindole derivatives as ligands of the benzodiazepinee receptor, to the pharmaceutical compositions containing these compounds, to the processes for producing said compounds and also to the compounds which are useful in particular as intermediates in the processes of preparation.
1,4-Benzodiazepines (for example Valium) constitute a class of widely-prescribed medicaments due to their anxiolytic, anticonvulsant, sedative/hypnotic and muscle relaxant activities. The mechanism of action of the benzodiazepines remained unrecognized for a long time until the discovery of specific binding sites (or "receptors") for these molecules on the neuronal membranes of the central nervous system. The physiological importance of these receptors was demonstrated by the existence of good correlation between, on the one hand, the value of the affinity of the various benzodiazepines for the receptor (measured by displacement of a radioactive benzodiazepine) and, on the other hand, their therapeutic effectiveness.
Likewise, it was found that certain .beta.-carbolines behaved as agonists of the benzodiazepine receptor.
Thus, Abecarnil, developed by Schering as an anxiolytic, ##STR1## is in the course of clinical trials. Other related .beta.-carboniles such as ZK 93423 and ZK 91296 also possess properties analogous to those of diazepam in vivo (anxiolytic, anticonvulsant, and the like).
While searching for an endogenous ligand of the benzodiazepine receptor, Braestrup et al. (Proc. Natl. Acad. Sci., USA, 77, 2288-2292, 1980) discovered a molecule, the ethyl ester of .beta.-carboline-3-carboxylic acid (.beta.-CCE), extracted from human urine, which binds with very good affinity to the central receptors of benzodiazepines (IC.sub.50 =4 nM, in vitro, rat brain). On the other hand, .beta.-CCE has pharmacological effects in vivo which are opposite to those of the benzodiazepines. Thus, .beta.-CCE is a proconvulsant in mice, facilitating the convulsions caused by other agents such as pentylenetetrazole. ##STR2##
The term "inverse agonist" is now used to denote these ligands of the benzodiazepine receptor which have activities completely or partially opposed to those of the benzodiazepines.
The therapeutic advantage of the .beta.-carbolines lies at several levels. Thus, the team which is the author of the present invention was the first to demonstrate that such molecules (for example .beta.-CCM below), ##STR3## inverse agonists of the benzodiazepine receptor, have a positive effect on learning and memory (Venault et al., Nature, 321, 864-866, 1986). Although .beta.-CCM could not be tested in man for its memory-enhancing effects due to its highly convulsant activity, other analogues such as ZK 93426 or Flumazenil, which are antagonists of the benzodiazepine receptor, were tested in man where their memory-enhancing properties were revealed (Duka et al., Psychopharmacology, 93, 42-427, 1987 and Lal et al., Pharmacol, Biochem. Behav., 35, 747-750, 1990). ##STR4##
Thus, it would seem that antagonists or partial inverse agonists of the benzodiazepine receptor are useful in the treatment of certain cognitive problems such as Alzheimer's disease.
Moreover, 6-azaindole derivatives are known, some of which have been tested for their suitability on the central nervous system.
Thus, the authors of the present invention have described the synthesis of 2,5-dicarbethoxy-6-azaindole by the Frydman method (Dodd et al., Heterocycles, 28, 1101-1113, 1989). This molecule only has a very weak affinity for the benzodiazepine receptor in vitro (IC.sub.50 =84,000 nM).
Other compounds have been described by some of the authors of the invention in collaboration with other researchers (Dodd et al., J. Med. Chem., 32, 1272-1276, 1989 and Dellouve-Courillon et al., Tetrahedron, 46, 3245-3266, 1990).
However, no indication regarding their properties with respect to benzodiazepine receptors was reported.
For example, the compound of formula: ##STR5## was described in the a
REFERENCES:
Tetrahedron, vol. 46, No. 9, 1990, pp. 3245-3266.
Dellouve-Courillon, "Synthesis of B-Carboline-Benzodiazepine . . . ", Tetrahedron, vol. 46, No. 9, pp. 3245-3266, 1990.
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De Carvalho Lia P.
Dodd Robert H.
Doisy Xavier
Potier Pierre
Rossier Jean
Centre National de la Recherche Scientifique "CNRS"
Ivy C. Warren
M. Mach D. Margaret
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