Desferrioxamine-B salts and their use as orally effective iron c

Details Desferrioxamine-B salts and their use as orally effective iron c Desferrioxamine-B salts and their use as orally effective iron c

1994-11-30

1998-04-14

Shaver, Paul F.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

562623, 564191, 564193, 564197, A01N 3718

Patent

active

057391670

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/GB 93/00940, filed May 6, 1993.
This invention relates to salts of desferrioxamine-B, and to pharmaceutical compositions containing such salts as active ingredients.
The preparations of desferrioxamine-B and pharmaceutically acceptable addition salts thereof are described in U.S. Pat. No. 3,247,197. The amine and salts thereof such as those described in the above mentioned U.S. patent exhibit a marked ability to form stable complexes with trivalent metal ions, especially Fe.sup.3+. Consequently, desferrioxamine-B (as the methanesulphonate salt) is of immense importance as a pharmacological iron-chelator in the treatment of iron-overload diseases such as beta-thalassemia. As the only currently marketed drug which is available for the treatment of thalassemia, desferrioxamine-B is vital to the survival of patients suffering from this disease.
Administration of desferrioxamine-B (as the methane sulphonate salt) via slow (8 to 12 hour) subcutaneous infusion is now widely accepted as the route necessary to control transfusional iron overload in beta-thalassemics. However, such a mode of treatment is laborious, uncomfortable and inconvenient for the patient, and involves high costs. Patient compliance is poor: non-compliance with iron-chelation therapy has been suspected to be the most important cause of death amongst British thalassemics. Hence there is a great need for simpler, more convenient and cheaper iron-chelation therapy, criteria which would be met via an oral dosage form.
This need has been apparent for a long time, and numerous attempts have been made over many years to obtain a form of desferrioxamine-B which is effective in iron-overload therapy when administered orally. Such attempts have included formulations based on the methanesulphonate salt, other known salts and other derivatives. All of these attempts have proved unsuccessful.
It has now been found, in accordance with the present invention, that novel salts of desferrioxamine-B having enhanced lipophilicity provide a means of improving the clinical efficiency of the drug to such an extent that it is effective when administered orally. These salts can exhibit unexpectedly high lipophilicity under physiological conditions, whilst at the same time having good stability and effective iron-chelating properties.
Accordingly, the present invention provides, in one aspect, a salt of formula ##STR2## where X denotes a group of formula ##STR3## Y denotes a group of formula ##STR4## and R denotes the residue of an aliphatic or cycloaliphatic sulphonic acid having at least three carbon atoms after removal of a --SO.sub.3 H group therefrom.
R may contain up to 30 carbon atoms. Preferably it contains at least 6 carbon atoms, more preferably 6 to 20 carbon atoms, especially 6 to 12 carbon atoms, more especially 8 to 12 carbon atoms, most especially 8 to 10 carbon atoms. R may be, for example, a hydrocarbyl group, i.e. the residue after removal of the --SO.sub.3 H group from an alphatic or cycloaliphatic hydrocarbyl sulphonic acid, for example an alkanesulphonic, cycloalkanesulphonic, alkenesulphonic or alkynesulphonic acid such as propane-1-sulphonic acid, propane-2-sulphonic acid, butane-1-sulphonic acid, 2-methyl-1-propanesulphonic acid, pentane-1-sulphonic acid, 3-methyl-1-butanesulphonic acid, 2-methyl-1-butanesulphonic acid, pentane-2-sulphonic acid, hexane-1-sulphonic acid, 2-ethyl-butanesulphonic acid, 4-methyl-2-pentanesulphonic acid, hexane-2-sulphonic acid, heptane-1-sulphonic acid, heptane-2-sulphonic acid, octane-1-sulphonic acid, octane-2-sulphonic acid, nonane-1-sulphonic acid, nonane-2-sulphonic acid, decane-1-sulphonic acid, dodecane-1-sulphonic acid, tetradecane-1-sulphonic acid, hexadecane-1-sulphonic acid, octadecane-1-sulphonic acid, cyclopentanesulphonic acid, cyclohexane sulphonic acid, allylsulphonic acid, 2-methyl-2-propene-1-sulphonic acid, hexene-1-sulphonic acid, octene-1-sulphonic acid, decene-1-sulphonic acid, dodecene-1-sulphonic acid, tetradecene-1-sulphonic acid, hexadecene-1-sulphonic acid, cyclopenten

REFERENCES:
patent: 3247197 (1966-04-01), Gaeumann
patent: 3652411 (1972-03-01), Commichau
patent: 3679660 (1972-07-01), Magnus
patent: 5185368 (1993-02-01), Peter et al.
Calendar et al "Iron chelating with oral desferrioxamine" Chem Abs. #94:58388q vol. 96, No. 9 Mar. 1981.
Lancet vol. 2, No. 816q, 1980 p. 689.

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