Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-04-17
1999-11-30
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514409, 544 6, 544 70, 544230, 546 15, 348411, A61K 3140, A61K 31535, C07D20906, C07D41312
Patent
active
059943505
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is new indolin-2-one derivatives and a process for their preparation. These new derivatives possess an affinity for vasopressin and/or oxytocin receptors and can thus constitute active principles of pharmaceutical compositions.
Vasopressin is a hormone known for its antidiuretic effect and its effect in the regulation of arterial pressure. It stimulates a number of receptor types: V.sub.1 (V.sub.1a, V.sub.1b or V.sub.3), V.sub.2. These receptors are located in the liver, the vessels (coronary, renal or cerebral), the platelets, the kidney, the uterus, the suprarenal glands, the central nervous system or the hypophysis. Oxytocin has a peptide structure similar to that of vasopressin. The oxytocin receptors are also found on the smooth muscle of the uterus; they are also found on the myoepithelial cells of the mammary gland, in the central nervous system and in the kidney. The localization of the different receptors is described in: Jard S. et al., "Vasopressin and Oxytocin Receptors: an Overview in Progress" in Endocrinology, Imura H. and Shizurne K., published by Experta Medica, Amsterdam, 1988, 1183-1188 and in the following articles: Presse Medicale, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108. Vasopressin thus exerts hormonal, cardiovascular, hepatic, renal, antidiuretic and aggregant effects and effects on the central and peripheral nervous systems, on the uterine and intestinal areas and on the ocular and pulmonary system. Oxytocin is involved in parturition, lactation and sexual behaviour.
Antagonists of the V.sub.2 receptors of vasopressin (also known as "AVP-2-antagonists" or "V.sub.2 antagonists") can be recommended as powerful aquaretics which act specifically on renal reabsorption of water without resulting in losses of electrolytes (Na.sup.+ or K.sup.+), as induced by the diuretics conventionally used clinically, such as furosemide or hydrochlorothiazide. The latter result, after prolonged treatment, in hypokalaemias and hyponatraemias.
The first antagonist of the V.sub.2 receptors of arginine-vasopressin (hereinafter known as AVP), OPC-31260, is currently in the course of clinical development Comparison of the effects of OPC31260 with conventional diuretics, such as furosemide, demonstrates that both in animals (Yoshitaka Y. et al., Br. J. Pharmacol., 1992, 105, 787-791) and in man (Akihiro O. et al., J. Clin. Invest, 1993, 92, 2653-2659, and Akihiro O. et al., J. Pharmacol. Exp. Ther., 1995, 272, 546-551) such a compound selectively promotes aqueous diuresis and has no effect, or very little effect at high doses, on the excretion of ions,
Indolin-2-one derivatives have been described in the literature. Mention may be made, by way of example, of Patent ZA 830952, which describes derivatives which are useful as antihypertensives which inhibit the converting enzyme, or Patent FR 1,509,373, which describes diuretic compounds which have an effect on potassium excretion.
A number of patent applications or patents also describe series of non-peptide compounds having an affinity for vasopressin and/or oxytocin receptors. This is the case, for example, with EP 382,185, which describes carbostyryl derivatives, which are vasopressin antagonists, which are useful as vasodilators, hypotensives, diuretics and platelet antiaggregants; EP 444,945, which describes spiropiperidine derivatives which are useful in particular in dysmenorrhoea; EP 514,667, which describes benzazepine derivatives which are useful in particular in disorders of renal function, in hyponatraemia, diabetes or alternatively in the treatment and the prophylaxis of hypertension and in the inhibition of platelet aggregation: JP 03127732 which described indole derivatives as vasopressin antagonists.
Benzyl or sulphonylindoline derivatives and indole derivatives have also been described as vasopressin antagonists. To this end, mention may be made of the documents EP 469,984, EP 526,348, EP 636,608, EP 636,609, WO 93/15051 and WO 95/18105 but
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Foulon Loic
Gal Claudine Serradeil-Le
Garcia Georges
Valette Gerard
Alexander Michael D.
Ramsuer Robert W.
Sanofi-Synthelabo
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