Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-12
2000-02-22
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546186, 546187, 546188, 546189, 546194, 514318, 514326, A61K 31445, C07D21108
Patent
active
060280824
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR 96/01416 filed Sep. 13, 1996, now WO 97/10211, published Mar. 20, 1997.
The present invention relates to novel selective human NK.sub.3 receptor antagonist compounds for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin, hypertension and, in general, any central or peripheral pathological condition in which neurokinin B and the NK.sub.3 receptor are involved in the interneuronal regulatory processes, to a method of obtaining said compounds and to the pharmaceutical compositions in which they are present as the active principle.
Diseases of psychosomatic origin are understood as meaning diseases which originate in the central nervous system (CNS) and have pathological consequences on the peripheral nervous system.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both the central nervous system and the peripheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK.sub.1, NK.sub.2, NK.sub.3. Substance P (SP) is the endogenous ligand of the NK.sub.1 receptors, neurokinin A (NK.sub.A) that of the NK.sub.2 receptors and neurokinin B (NK.sub.B) that of the NK.sub.3 receptors.
The NK.sub.1, NK.sub.2 and NK.sub.3 receptors have been identified in different species. Thus the NK.sub.3 receptors have been identified in the guinea-pig, the rat and the monkey (Br. J. Pharmacol., 1990, 99, 767-773); Neurochem. Int., 1991, 18, 149-165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90-95).
A review by C. A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the specific NK.sub.1 receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212) and SR140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
In the case of the NK.sub.2 receptor, the non-peptide selective antagonist SR48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the human NK.sub.3 receptor is concerned, the non-peptide selective antagonist (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenyl piperid-4-yl]-N-methylacetamide hydrochloride, or SR142801, has been described (EP-A-0 673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, Jul. 31-August 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0.9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, 1995, Apr. 6-8; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, 1995, Jun. 16-19).
Patent applications EP 474 561 and EP 512 901 describe neurokinin antagonists, more particularly NK.sub.1 or NK.sub.2 receptor antagonists. Pharmacological studies of peptide and non-peptide NK.sub.1 and NK.sub.2 receptor antagonists have shown that their affinities for these receptors, and their pharmacological activities, are very dependent on the species; this is very probably the result of small differences in the amino acid sequences, inducing very slight structural variations in these receptors from one species to another (J. Autonomic Pharmacol., 1993, 13, 23-93). Some experimental data, confirmed by pharmacological characterization of the compounds forming the subject of the present invention, seem to indicate that a comparable situation exists for the NK.sub.3 receptor. In particular, the human NK.sub.3 receptor differs from the NK.sub.3 receptor of the rat.
Non-peptide compounds have now been found which have a very strong affinity for the human NK.sub.3 receptor and a high specificity for said receptor. These compounds can be used for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin and an
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Emonds-Alt et al., Life Sciences, 56(1), 1995, pp. PL27-32.
Chemical Abstracts, No. 123:132661j.
Derwent Patent Abstract of EP 673928 (Abstract No. 95-329808/43).
Bichon Daniel
Broeck Didier Van
Emonds-Alt Xavier
Gueule Patrick
Proietto Vincenzo
Alexander Michael D.
Aulakh Charanjit S.
Kight John
Sanofi-Synthelabo
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