Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-06-14
2000-07-18
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514418, 546 15, 548411, 544 70, C07D21304, C07D20910, A61K 31395, A61K 31404
Patent
active
060908181
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a filing under 35 U.S.C. .sctn.371 corresponding to International Application Ser. No. PCT/FR97/02270, filed Dec. 11, 1997, which claims priority of French Patent Application Ser. No. FR 96 15384, filed Dec. 13, 1996.
The present invention relates to novel derivatives of indolin-2-one, to a process for their preparation and to pharmaceutical compositions containing them. These novel derivatives are generally endowed with an affinity for vaso pressin and/or oxytocin receptors and can thus constitute active principles of pharmaceutical compositions.
Vasopressin is a hormone known particularly for its anti-diuretic effect and its effect in arterial pressure regulation. It stimulates a number of types of receptors: V.sub.1 (V.sub.1a, V.sub.1b or V.sub.2). Those receptors are located in the liver, vessels (coronary, renal, cerebral), platelets, kidneys, uterus, pancreas, adrenal glands, central nervous system and the pituitary gland. Oxytocin has a peptide structure which is close to that of vasopressin. Oxytocin receptors are also found in the smooth muscle of the uterus; they are essentially found in the myoepithelial cells of the mammary gland, in the central nervous system, in the kidneys, in the vessels and in the adipocytes. The location of the different receptors are described in: Jard S. et al., "Vasopressin and oxytocin receptors: and overview, in progress" in Endocrinology; Imura H. and Shizurne K., eds., 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 has hormonal, cardiovascular, hepatic, renal, antidiuretic, aggregating and effects on the central and peripheral nervous systems, on the uterine and intestinal spheres and the occular and pulmonary system. Oxytocin intervenes in parturition, lactation, sexual behaviour and in the regulation of fat metabolism.
Antagonists for 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 specifically intervene in renal re-absorption of water without causing electrolyte loss (Na.sup.+, K.sup.+) unlike diuretics which are conventionally used in clinical medicine, such as furosemide or hydrochlorothiazide. These latter cause hypokalemia and hyponatremia after prolonged treatment.
The first antagonist for the V.sub.2 receptors of arginine-vasopressin (hereinafter termed AVP), OPC-31260, is currently under clinical development. A comparison of the effects of OPC-31260 with conventional diuretics such as furosemide shows 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, Akihiro O. et al., J. Pharmacol. Exp. Ther., 1995, 272, 546-551), such a composition selectively favours aqueous diuresis and does not affect ion excretion, or only has a slight effect in high doses.
Indolin-2-one derivatives have been described in the literature. By way of example, the patent ZA 830952 describes derivatives for use as antihypertensors which inhibit the conversion enzyme, and French patent FR 1 509 373 which describes diuretic compounds endowed with an effect on potassium excretion.
A number of patent applications or patents also describe a series of non peptide compounds with an affinity for vasopressin and/or oxytocin receptors. This is the case, for example in European patent EP 382 185 which describes carbostyryl derivatives which are antagonists of vasopressin for use as vasodilators, hypotensors, diuretics and anti-platelet aggregating agents; EP 444 945 which describes spiropiperidine derivatives for use, notably, in dysmenorrhea; EP 514 667 which describes benzazepine derivatives for use, notably, in renal function disorders, in hyponatremia, diabetes or in the treatment and prophylaxis of hypertension and in inhibition of platelet aggregation; or in Japanese paten
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Foulon Loic
Gal Claudine Serradeil-Le
Valette Gerard
Alexander Michael D.
Richter Johann
Sanofi-Synthelabo
Wright Sonya N.
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