Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-02
1997-06-24
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514255, 514323, 514339, 544373, 544405, 546201, 5462781, 548492, A61K 3140, C07D20912
Patent
active
056418027
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage application of PCT/EP93/03387, filed Dec. 2, 1993 and published on Jun. 23, 1994 as WO 94/13694.
FIELD OF THE INVENTION
The present invention refers to tachyquinine antagonists, their preparation and use in pharmaceutical formulations.
In particular, the present invention refers to compounds having general formula (I) ##STR2## wherein: ##STR3## where R.sub.8 is selected out of a group consisting of H, a linear or branched alkyl radical containing 1 to 6 carbon atoms, a linear or branched alkenyl radical containing 2 to 7 carbon atoms, a linear or branched alkynyl radical containing 3 to 7 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, possibly substituted with at least one atom selected out of a group consisting of N, S, and O, an aryl-, aryl-alkyl-, alkyl-aryl-radical containing 7 to 12 carbon atoms; R.sub.1 and R.sub.2 are selected out of a group consisting of hydrogen, hydroxyl and halogen or are joined to form an epoxide; if the bond is double, they are hydrogen or halogen; A and B stand for N or CH; R.sub.3 and R.sub.4 are selected out of the group consisting of hydrogen, a linear or branched alkyl radical containing 1 to 6 carbon atoms, a linear or branched alkenyl radical containing 2 to 7 carbon atoms, a linear or branched alkynyl radical containing 3 to 7 carbon atoms, or are joined together to form a --(CH.sub.2).sub.n -- bridge, where n stands for a whole number from 1 to 3; 15 carbon atoms max.; alkyl -, aryl-, aryl-alkyl- or alkyl-aryl-radical as defined above.
Symbol means that the configuration of the asymmetric carbon atoms of 2-amino-cyclohexanecarboxylic acid is S or R, with the provisio that such configuration can not be S or R for both the asymmetric carbon atoms.
Tachyquinine antagonist compounds as per formula (I) prove to be effective in the treatment of diseases where tachyquinines play a pathogenic role, in particular in the treatment of arthritis, asthma, inflammations, tumoral growth, gastrointestinal hypermotility, Huntington's disease, neuritis, neuralgia, migraine, hypertension, incontinence of urine, urticaria, carcinoid syndrome symptoms, influenza, and cold.
Tachyquinines are a family of three peptides at least, known as substance P (SP), neuroquinine A (NKA) and neuroquinine B (NKB).
Research in the field of tachyquinine antagonists, initially directed toward single or multiple replacement of amino acids of the peptide agonists sequence of Substance P and of the other tachyquinines, brought to the discovery of nonapeptides containing one or more D-tryptophan units [Regoli et al., Pharmacol., 28, 301 (1984)].
On the other hand, the problems related to the use of high-molecular-weight peptides as drugs (multiplicity of enzymatic hydrolytic attack sites, poor bioavailability, rapid excretion from the liver and kidneys) spurred to search for the minimum peptide fragment still capable of exerting an antagonist action. These studies brought to the singling out of suitably derivatized SP antagonists tripeptides and dipeptides (European patents Nos. 333174 and 394989, in the latter .alpha.-amino-acids wherein the N-atom is s member of a ring-structure are described).
In Br J Pharmacol 107 (1992) 785-9, an high affinity dipeptide NK.sub.1 receptor antagonist, i.e.: N.sup.2 -[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methyl-N-p henylmethyl-3-(2-naphthyl)-L-alaninamide, is described.
In Science 251 (1991) 435, (2S,3C)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2 .2.2.]octan-3-amine is described as potent non-peptide antagonist of the Substance P (NK.sub.1) receptor.
DETAILED DESCRIPTION OF THE INVENTION
It has surprisingly been found--and this finding constitutes a fundamental feature of the present invention--that non-peptidic compounds of general formula (I) as defined above are good inhibitors of the tachyquinines bond to NK.sub.1 receptor and have a sufficient metabolic stability.
Particularly preferred products are compounds of general formula (I) wherein: ##STR4## and R.sub.
REFERENCES:
patent: 5164372 (1992-11-01), Matsuo et al.
R.M. Snider et al., A Potent Nonpeptide Antagonist of the Substance P (NK.sub.1) Receptor, Science, vol. 25, 25 Jan. 1991, pp. 435-447.
T. Fujii et al., Pharmacological Profile of a High Affinity Dipeptide NK.sub.1 Receptor Antagonist, FK888 Br. J. Pharmacol. (1992) 107, pp. 785-789.
D.G. Payan, et al., Stereospecific Receptors For Substance P On Cultured Human IM-9 Lymphoblasts. The Journal of Immunology, vol. 133, Dec. 6, 1984, pp. 3260-3265.
D. Regoli et al, Substance P -- Structure-Activity Studies and the Development of Antagonists, Pharmacology 28:301-320 (1984).
Arcamone Federico
Lombardi Paolo
Manzini Stefano
Potier Edoardo
Sisto Alessandro
A. Menarini Industrie Farmaceutiche Reiunite S.r.l.
Haley Jacqueline
Malesci Istituto Farmacobiologico S.p.A.
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