Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-07-26
2002-06-11
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S517000
Reexamination Certificate
active
06403643
ABSTRACT:
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
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. Kajfer 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, cages 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:
in which:
R represents a hydrogen atom (H) or a sulfonic group (SO)
3
—)
B represents a calcium atom (Ca++) or a diethylamine group [H
2
N+(C
2
H
5
)
2]
n represents 1 or 2
m represents 1 or 2.
REFERENCES:
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patent: 4038390 (1977-07-01), Esteve-Subirana
patent: 4513007 (1985-04-01), Courten et al.
patent: 6147112 (2000-11-01), Esteve-Soler
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).
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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.,Lanceteditorial, 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 Penile 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 from 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 dobésilate de calcuim sur la résistance et la perméabilité capillaires et sur le temps de saignement et l'adhésivité plaquettaire modifiés par le dextran,Annales pharmaceutiques francaises,30(6):415-427, (1972).
Mathieu, et al., Effect of Quinones and phenols on noradrenalinic hypertension in the ratChemical Abstracts,84(1), p. 34, 310KJanvier(1976).
Criares Theodore J.
Laboratories del Dr. Esteve S.A.
Wood Phillips Katz Clark & Mortimer
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