Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-06
2003-09-30
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000
Reexamination Certificate
active
06627649
ABSTRACT:
This is a national stage application of PCT/FR 99/00450,International filing date Mar. 1, 1999.
The object of the present invention is pharmaceutical compositions containing a combination of (2S)-1-{(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl}pyrrolidine-2-carboxamide, a selective V
1a
arginine vasopressin receptor antagonist and the equatorial isomer of 1-{4-(N-tert-butyl-carbamoyl)-2-methoxybenzenesulfonyl}-5-ethoxy-3-spiro{4-(2-morpholinoethyloxy) cyclohexane}indol-2-one or one of its salts, a selective V
2
arginine vasopressin receptor antagonist and the use of such compositions for the production of medicines designed to treat all diseases in which either arginine vasopressin or the V2 receptors are implicated or to treat all diseases related to a water overlead.
Vasopressin is a hormone known for its antidiuretic effect and its effect on the reOgulation of arterial blood pressure. It stimulates several types of receptors: V
1
(V
1a
, V
1b
or V
3
), V
2
. These receptors are localized on the liver, blood vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal, glands, central nervous system, hypophysis. 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 Shizume K., ed., Experta Medica, Amsterdam, 1988, 1183-1188, as well as in the following articles: Presse Médicale, 1987 16 (10) 481-485, J. Lab. Clin. Med., 1989, 114 (6) 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108. In particular, vasopressin exerts hormonal, cardiovascular, hepatic, renal, antidiuretic, aggregating effects and effects on the central and peripheral nervous systems, on the intestinal and uterine organs and on the pulmonary and ocular system.
The vasopressin receptor antagonists make it possible to inhibit the hormonal effects selectively. They may intervene in the regulation of the central and peripheral blood circulation, in particular the coronary, renal and gastric circulations, as well as on water balance and the release of the adrenocorticotrophic hormone (ACTH) (F. A. Laszlo et al., Pharmacol. Rev.,1991, 43, 73-108). Vasopressin itself as well as certain of its peptide analogues are used therapeutically and have shown their efficacy. Several reviews and many articles in the literature may be cited which demonstrate the potential therapeutic value of vasopressin receptor antagonists presently in clinical study: Vasopressin : P. Gross et al., ed. John Libbey Eurotext, 1993, in particular 243-257 and 549-562. F. A. Laszlo and F. A. Laszlo Jr., Clinical perspectives for vasopressin antagonists, Drug News Perspect., 1993, 6 (8); W. G. North, J. Clin. Endocrinol., 1991, 73, 1316-1320. J. J. Legros et al., Prog. Neuro-Pharmacol. Biol. Psychiat., 1988, 12, 571-586; K. E. Andersson et al., Drugs Today, 1988, 24, (7), 509-528; D. L. Stump et al., Drugs, 1990, 39, 38-53; S. Caltabiano et al., Drugs Future, 1988, 13, 25-30; Y. Mura et al., Clin. Nephrol. 1993, 40, 60-61; Faseb J., 1994, 8 (5), A 587:3398.
Furthermore, a recent review by J. D. Albright et al. (Current Pharmaceutical Design, 1997, 3, 615-632) reviews arginine vasopressin receptors and their antagonists and presents pharmacological studies and potential applications in human therapy. The V
1a
receptor antagonists are particularly to be recommended in diseases of the cardiovascular system. Moreover, the V
2
vasopressin receptor antagonists (also called “AVP-2 antagonists” or “V
2
antagonists”) are particularly to be recommended in diseases of the cardiovascular system, the central and peripheral nervous system, the endocrine and hepatic system, the gastric and intestinal organs, the lungs and in ophthalmology. They act as potent aquaretics which act specifically on the renal resorption of water without leading to loss of electrolytes (Na
+
, K
+
) as do the diuretics traditionally used in the clinic such as furosemide or hydrochlorothiazide.
(2S)-1-{(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl}pyrrolidine-2-carboxamide, the code name of which is SR 49059 of formula:
designated hereafter as compound A, has been described in the literature as being a potent and selective V
1a
arginine vasopressin receptor antagonist in various species, in particular towards human V
1a
receptors (C. Serradeil-Le Gal et al., J. Clin. Invest., 1993, 92 224-231). It possesses only a low affinity for the V
2
receptors. Compound A is the most potent antagonist selective for the human V
1a
receptors presently known.
The equatorial isomer of 1-{4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl}-5-ethoxy-3-spiro{4-(2-morpholino-ethyloxy)cyclohexane}indol-2-one, the code name of which is SR 121463, or one of its salts of formula:
designated hereafter as compound B, has been described in the literature as being a potent and selective antagonist of V
2
arginine vasopressin receptor in various species, in particular towards human V
2
receptors (C. Serradeil-Le Gal et al., J. Clin. Invest., 1996, 98, 2729-2738). Compound B is the most potent antagonist selective for human V
2
receptors presently known.
It has now been found that the combination of compound A, a selective V
1a
arginine vasopressin receptor antagonist with compound B, a selective V
2
arginine vasopressin receptor antagonist, potentiates the effects produced by compound B used alone.
Thus the pharmaceutical compositions containing such a combination may be useful in particular for the treatment of diseases of the central and peripheral nervous system, the cardiovascular system, the endocrine and hepatic system, the renal domain, the gastric and intestinal domain, the pulmonary domain, oedematous states, hydroelectrolytic disorders, glaucoma, cataract and disorders of sexual behaviour in man and animals.
According to one of its features the object of the present invention is pharmaceutical compositions containing in combination:
(2S)-1-{(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl}pyrrolidine-2-carboxamide (compound A), and the equatorial isomer of 1-{4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl}-5-ethoxy-3-spiro{4-(2-morpholinoethyloxy)cyclohexane}indol-2-one (compound B) or one of its pharmaceutically acceptable salts, hydrates or solvates.
The salts of compound B are salts formed with classical pharmaceutically acceptable organic or mineral acids such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, maleate, fumarate, succinate, naphthalene-2-sulfonate, glyconate, gluconate, citrate, isethionate, benzenesulfonate, para toluenesulfonate.
The compounds A and B contained in the pharmaceutical compositions according to the invention are prepared according to known methods such as those described in EP-0 526 348 A or U.S. Pat No. 5 338 755 and WO 97/15 556, respectively.
The synergistic effect of the combination of compound A and compound B according to the invention has been demonstrated in particular by using the in vivo assay of water diuresis induced in the normally hydrated conscious rat according to the procedure described by C. Serradeil-Le Gal et al., J. Clin. Invest. 1996, 98, 2729-2738.
EXPERIMENTAL CONDITIONS
1) Experimental Protocol
The various assays are performed on Sprague Dawley male rats (280+/−20 g) obtained from Iffa Credo (France).
Twenty four hours before the start of the study, the rats were randomized and placed in metabolic cages with food and water ad libitum. They received orally 3 ml/kg of a 0.6% aqueous solution of methylcellulose. The urines were collected over a 24 hour period, i.e. day D-1.
The next morning the rats are treated orally (solvent or products alone or in combination) and returned individually to their metabolic cage for a period of 24 hours with food
Lacour Colette
Nisato Dino
Alexander Michael D.
Bahar Mojdeh
Dupont Paul E.
Padmanabhan Sreeni
Sanofi-Synthelabo
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