Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-10-01
2000-11-14
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514517, A61K 31255
Patent
active
061471127
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the use of derivatives of dihydroxybenzenesulfonic acids and their physiologically acceptable salts for the manufacture of medicaments intended for the normalization of the endothelial function, for the treatment of sexual dysfunction, of vascular complications of diabetes and of vascular disorders of endothelial origin.
BACKGROUND OF THE INVENTION
Recent studies have demonstrated that calcium dobesilate, ethamsylate and persilate exert effects on the endothelium in the sense of facilitating endothelium-dependent vascular relaxation. This effect is observed both in normal animals and in those in which vascular aging has been produced experimentally by means of the administration of high doses of vitamin D.sub.2. This activity of calcium dobesilate, of ethamsylate and of persilate may be reflected in man by effects which are therapeutically useful. In particular, it has been demonstrated that the erection of the penis is modulated by nitric oxide produced in the endothelium (A. L. Burnett et al., Science, 1992, 257, 401-403; J. Rajfer et al., N. Engl. J. Med., 1992, 326, 90-94; Editorial, Lancet, 1992, 340, 882-883) and that, under circumstances where the endothelial function is detrimentally affected, as in hyperlipidemias (K. Kugiyama et al., Nature, 1990, 344, 160-162), correction of the detrimental change normalizes the erectile function, measured with accuracy during nocturnal sleep (J.-B. Kostis et al., J. Clin. Pharmacol., 1994, 34, 989-996; R. C. Rosen, "The Pharmacology of Sexual Function and Dysfunction", edited by J. Bancroft, Elsevier Sc., 1995, pages 277-287). The normalization of the endothelial function obtained with calcium dobesilate, ethamsylate and persilate can represent an entirely novel therapeutic approach to the problem of impotence (I. Saenz de Tejada et al., N. Engl. J. Med., 1989, 320, 1025-1030), both in patients with vascular disorders with various causes (diabetes, arteriosclerosis, and the like) and in patients where only a functional disorder can be detected.
Furthermore, the normalizing effect on the endothelial function can also offer therapeutic opportunities in vascular spasm processes, in complications of diabetes (W. Durante et al., Br. J. Pharmacol., 1988, 94, 463-468) and in all disorders, including premature ejaculation (E. M. Hull et al., Neuropharmacology, 1994, 33, 1499-1504), where a deficit in the formation of nitric oxide for the vascular endothelium appears evident.
BRIEF SUMMARY OF THE INVENTION
The compounds recommended in the context of the present invention correspond to the general formula I: ##STR1## in which: R represents a hydrogen atom (H) or a sulfonic group (SO.sub.3 --) N+(C.sub.2 H.sub.5).sub.2 ]
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the examples which are shown below are prepared according to the processes described subsequently:
EXAMPLE 1
Calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate). "The Merck Index", 11th edition, Merck & Co., Rahway, N.J., USA, 1989.
EXAMPLE 2
Diethylamine 2,5-dihydroxybenzenesulfonate (ethamsilate). "The Merck Index", 11th edition, Merck & Co., R. Rahway, N.J., USA, 1989.
EXAMPLE 3
Bis(diethylamine) 2,5-dihydroxybenzene-1,4-disulfonate (bis(diethylamine) persilate). French Patent FR 73/17709 (Publication No. 2,201,888).
In order to study the normalizing effect on the endothelial function of the products which are the subject-matter of the present invention, various "in vitro" and "in vivo" studies have been carried out. A description is given below of the results obtained, as non-limiting example, with one of the products which are the subject-matter of the present invention, calcium dobesilate, it being demonstrated that it has an endothelium-dependent relaxing activity.
The studies were carried out by using the aortas isolated from male rabbits according to the techniques described by A. Quintana et al. (Europ. J. Pharmacol., 1978, 53, 113-116) and by the group from the University of Edinburgh (Pharmacological Experime
REFERENCES:
patent: 3947448 (1976-03-01), Esteve-Subirana
patent: 4038390 (1977-07-01), Esteve-Subirana
patent: 4513007 (1985-04-01), Courten et al.
Burnett, Arthur, L., et al., Nitric Oxide: A Physiologic Mediator Of Penile Erection, Science, 257:401-403, (1992).
Durante, William, et al., Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats, Br. J. Pharmacol, 94:463-468, (1988).
J. Hladovec, Vasotropic Drugs, A Survey Based on Unifying Concept of their Mechanism of Action, Arzneim. Forsch/Drug Res., 25:(5):1073-1076, XP 00615253 (1989).
Hull, E.M., et al., The Roles of Nitric Oxide in Sexual Function of Male Rats, Neuropharmacology, 33(11):1499-1504, (1994).
Huguet, Par, G., et al., Action d'un hemostatique, la cyclonamine, sur la permeabilite et la resistance capillaires. Etude comp lementaire, Therapie, 24:429-450, (1969).
Kostis,, John B., M.D., et al., Central Nervous System Effects of HMG CoA Reductase Inhibitors: Lovastatin and Pravastatin on Sleep and Cognitive Performance in Patients with Hypercholesterolemia, J. Clin Pharmacol, 34:989-996, (1994).
Kugiyama, K., et al., Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins, NATURE, 344:160-162, (1990).
Rajfer, J. et al., Lancet editorial, 1992, 340, 882-883.
Rajferm J., et al., Nitric Oxide As A Mediator of Relaxation of the Corpus Cavernosum In Response to Nonadrenergic, Noncholinergic Neurotransmission, The New England Journal of Medicine, 326:90-94, (1992).
Rosen, Raymond, M.D., Pharmacological Effects on Nocturnal Penil Tumescence (NPT), The Pharmacology of Sexual Function and Dysfunction, edited by J. Bancroft, Elsevier, Science, 277-287, (1995).
Saenz de Tejada, I, et al., Impaired Neurogenic and Endothelium-Mediated Relaxation of Penile Smooth Muscle form Diabetic Men with Impotence, The New England Journal of Medicine, 320:1025-1030, (1989).
Sim, A.K., et al., The Evaluation of the Effect of the Venous Tonic 263-E on Capillary Permeability in the Rabbit after Administration by Intradermal and Intravenous Routes, Arzneim-Forsch./Drug Res., 31(I):962-965, (1990).
Standl, Rudolf, Diabetische Mikroangiopathie XP 000615251, Innere Medisin, 48:140-149, (1993).
Thomas, J. et al., Action du dobesilate de calcium sur la resistance et la permeabilite capillaires et sur le temps de saignement et l'adhesivite plaquettaire modifies par le dextran, Annales pharmaceutiques francaises, 30(6):415-427, (1972).
Mathieu, et al., Effect of quinones and phenols on noradrenalinic hypertension in the rat, Chemical Abstracts, 84(1), p. 34, 310K Janvier (1976).
Criares Theodore J.
Laboratorios Del Dr. Esteve, S.A.
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