Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-12-18
1997-12-16
Hill, Jr., Robert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514807, 514866, 930 21, 930150, 530315, A61K 3800, A61K 3811, C07K 500, C07K 700
Patent
active
056985169
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to biologically active vasopressin analogues. More precisely, the invention relates to vasopressin analogues having specific antidiuretic activity and much improved bioavailability compared to the widely used antidiuretic compound 1-desamino-8-D-arginine vasopressin, also known as desmopressin or DDAVP.
BACKGROUND
DDAVP has now been on the market for about 20 years as a pharmaceutical preparation with antidiuretic activity, at first mainly for the treatment of patients suffering from diabetes insipidus, but, since a few years, also for the treatment of enuresis, specially nocturnal enuresis. It has also successfully been used in the treatment of hemphilia type A, yon Willebrand's disease and prolonged bleeding times of unknown reasons.
The intravenous administration of DDAVP gives the best bioavailability of the compound, but is inconvenient to use at home. Therefore, a common way of administration of DDAVP has been by intranasal route. However, the bioavailability of the compound decreases about 10 times. DDAVP may also be administered oraly as is disclosed in the European Patent No. 0 163 723. However, the loss in bioavailability is even greater than by administration through the nasal mucosa.
Research efforts have been focused on improved DDAVP analogues. Numerous DDAVP derivatives have been synthesized and tested for bioavailability in the search for compounds with specific antidiuretic activity and with improved absorption through the nasal mucosa and absorption through the intestinal mucosa.
DESCRIPTION OF THE INVENTION
The present invention provides new vasopressin analogues of the formula ##STR2## wherein X is (S)-2-amino-2-methyl-butanoic acid (C.alpha.MeAbu) or Valine (Val), (D-Tyr)
As is evident from the testing of biological activity disclosed later in the text, the new compounds of the invention have, in addition to good antidiuretic activity, about 12 to 25 times higher values for gastrointestinal absorption than DDAVP, and 2 to 5 times higher intranasal absorption values. The blood clotting effect of the compounds of the invention has not yet been tested, but it is believed that in analogy with DDAVP, the compounds of the invention will also be useful for the treatment of hemphilia type A, yon Willebrand's disease and prolonged bleeding times of unknown reasons.
Another aspect of the invention is directed to a pharmaceutical preparation comprising a vasopressin analogue of the invention as active ingredient. This aspect of the invention is intended to comprise any useful pharmaceutical preparation as long as it contains a vasopressin analogue of the invention as active ingredient. The pharmaceutical preparation is preferably in the form of an oral preparation, such as a tablet or capsula, a nasal preparation, such as a nasal spray or nasal drops, or an intravenous preparation, such as an injectable solution. In a pharmaceutical preparation the active ingredient is in combination with pharmaceutically acceptable additives and/or diluents. A suitable pharmaceutically acceptable diluent is isotonic saline solution. As to the other pharmaceutically acceptable additives and diluents, such can be found in the literature, e.g. the European or US Pharmacopoeia, and these additives shall be chosen in conformity with the specific form of the preparation for a specific administration route.
A further aspect of the invention is directed to a vasopressin analogue of the invention for use as a medicament. The medicament is preferably an antidiuretic agent.
Another aspect of the invention is directed to the use of a vasopressin analogue according to the invention for the preparation of a medicament for the treatment of diabetes insipidus. The invention also comprises the use of a vasopressin analogue according to the invention for the preparation of a medicament for the treatment of enuresis, specially nocturnal enuresis.
Yet another aspect of the invention is directed to a method of treating a diabetes insipidus or enuresis patient comprising administering to said patie
REFERENCES:
Journal of Medicinal Chemistry, vol. 18, No. 8, 1975, Clark W. Smith, et al. p. 822-825.
Nilsson Anders
Olson H.ang.kan
Soderberg-Ahlm Christina
Trojnar Jerzy
Ferring B.V.
Harle Jennifer
Hill Jr. Robert J.
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