Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1986-08-11
1988-08-16
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530323, A61K 3702, C07K 702
Patent
active
047645237
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel derivatives, acylated by carbonic acid monoesters, of hydroxamic acids, especially of trihydroxamic acids, which are known under the name ferrioxamines and specifically desferrioxamines as metabolites of microorganisms, especially actinomycetes, and among these especially N- and/or O-acylates, derived from carbonic acid monoesters, of desferrioxamine B of the general formula ##STR2## the symbols having the following meanings: each of AA.sup.1, AA.sup.2 and AA.sup.3, independently of the others, is hydrogen, an acyl radical, referred to as Ac, of a carboxylic acid having from 1 to 24 carbon atoms, or an esterified oxycarbonyl radical referred to as Cb (acyl radical of a carbonic acid monoester) having a total of from 2 to 25 carbon atoms, and AA.sup.1, AA.sup.2 and AA.sup.3 represents Cb, it may also be hydrogen or an amino-protecting group referred to as X,
The invention also relates to processes for the manufacture of the above-mentioned compounds and to pharmaceutical compositions containing these compounds and processes for their manufacture; also to the use of these compounds as chemical intermediates and the therapeutic use of these compounds and pharmaceutical compositions containing them in warm-blooded animals, including humans.
Desferrioxamine B, the basic material of the acylates of the present invention, has already been known for a relatively long time (H. Bickel, H. Keberle and E. Vischer: Helv. Chim. Acta 46, 1385-9 [1963]). Its chemical structure corresponds to the formula ##STR3## and, in accordance with Rule C-06 (replacement nomenclature) of the official IUPAC nomenclature, it has the systematic name 6,17,28-trihydroxy-7,10,18, 21,29-pentaoxo-6,11,17,22,28-pentaazatriacontylamine. (For the sake of simplicity, however, in the following the names of the acylates are derived from the trivial name, the position of individual acyl radicals in each case being related to the amino-nitrogen N or to the oxygen atoms, designated O, O' and O", of the hydroxy groups in positions 6, 17 and 28, respectively).
Among the most striking properties of desferrioxamine B and its addition salts, which are formed with one equivalent of acid, is the ability to link up especially with trivalent metal ions, such as chromium(III), aluminium and more especially iron(III) ions to form stable chelate-like metal complexes. This imparts to desferrioxamine B the valuable pharmacological activity of preventing the deposit of iron-containing pigments in tissue and, if there are existing iron deposits in the organism, of causing the iron to be excreted, for example in the case of haemochromatosis, haemosiderosis, liver cirrhosis and poisoning with compounds of trivalent iron. The broad therapeutic use of desferrioxamine B and its salts (for example especially methanesulphonate) therefore extends generally to diseases and pathological conditions of the human body (and of the body of other warm-blooded animals) which go hand in hand with excessive loading of the organism with iron(III) ions (Fe.sup.+++ ions), such as thalassaemia major, sickle cell anaemia, sideroachrestic anaemia, aplastic anaemia and other forms of anaemia in which haemosiderosis (that is to say a local or general increase in iron levels in otherwise undamaged body tissues) plays a part. This type also includes pathological conditions which develop in patients after several blood transfusions or repeated dialysis treatment when there is no kidney function or damaged kidney function. Owing to the complex-forming properties, desferrioxamine B has proved to have a significant activity in the case of diseases caused by iron(III)-dependent micro-organisms and parasites, such as, especially, malaria, which is of fundamental importance not only in human medicine but also in veterinary medicine. The complex formation with other trivalent metals can also be used for the excretion of those metals from the organism, for example for the removal of aluminium in the case of dialysis encephalopathy and osteomalacia, and in the case of Alzhei
REFERENCES:
patent: 3634407 (1972-01-01), Ernst et al.
patent: 4419365 (1983-12-01), McLachlan
patent: 4612122 (1986-09-01), Ambrus et al.
patent: 4671901 (1987-06-01), Green
Helv. Chim. Acta 46: pp. 1385-1389 (1963).
Merck Index, 10th Ed., No. 2839, pp. 412 (1983).
Ciba-Geigy Corporation
Fishman Irving M.
Phillips Delbert R.
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