Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-01-24
1996-06-11
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 31555
Patent
active
055255981
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/01687, filed Jul. 23, 1992.
The present invention relates to gallium (III) complexes, to the processes useful for their obtention and to their use as antitumoral and antiviral agents.
In medicine, gallium (III) compounds play a role in the following fields of research:
Firstly, Ga-67, a low energy-gamma-emitting radionuclide, is a very useful tumor diagnostic agent and has been used extensively (mostly as gallium-67 citrate) in the detection of a great number of human malignancies, ["Metal-based Antitumour Drugs" edited by M. F. Gielen, Freund Publishing House Ltd., 1988, Chapter 1; Ward, S. G. and Taylor, R. C]
Secondly, antitumor activity of gallium (III) salts (especially gallium nitrate) has been evaluated in clinidal phase I and phase II trials [Foster et al. Cancer Treat. Rep. 70, 1311-1319, 1986]. Thereafter, gallium nitrate had shown antitumor activity in experimental animal tumors [Adamson et al. Cancer. Chemother. rep. 59, 599-610, 1975]. The phase II trials have shown that gallium nitrate exhibits antitumor activity in patients with refractory lymphomas [FOSTER et al. Cancer Treat. Rep. 70, 1311-1319, 1986].
Another property of gallium nitrate worth mentioning is the fact that it inhibits the reverse transcriptase (an enzyme found in retroviruses) of Rauscher murine leukemia virus in vitro, a virus which belongs to the same viral family as HIV (human immunodeficiency virus). [Waalkes, T. P. et al. Cancer Res. 34, 385-391, 1974].
However, the preclinical toxicology tests suggest that renal and hepatic damages might be expected with gallium nitrate.
On the other hand, gallium III, administered per os in the form of an aqueous formulation of GaCl.sub.3 at the therapeutical dosages involves no renal toxicity [EP-B.sub.1 -0059 148].
It has now been found that certain gallium (III) complexes have antitumor and antiviral activities.
The invention gallium (III) complexes comprise gallium (III) complexes of N-heterocycles.
More specifically, the gallium (III) complexes of the present invention are selected from the complexes of the following formulae:
1.) Gallium (III)complexes of N-heterocycles ##STR2##
The present invention also relates to the use of the above complexes of formulae I to V as pharmaceutical agents having antiviral and antitumor activities.
The present invention also relates to the use of the following complexes of formula VI as pharmaceutical agents having antiviral and antitumoral activities: ##STR3## wherein R.sub.1 represents hydrogen, a halogen or a sulfono group SO.sub.3 M, in which M is a metal ion, such as potassium or sodium and R.sub.2 represents Hydrogen or R.sub.1 is chlorine and R.sub.2 is iodo. Said compounds are also gallium III complexes of a N-heterocycle, namely of 8-hydroxy-quinoline.
The compound of formula VI in which R.sub.1 is a sulfono group and R.sub.2 is hydrogen is new and is a further object of the present invention.
The invention compounds I-V are water-soluble, stable solids, which may exist in the form of enantiomers. The enantiomers are also within the scope of the present invention.
In general, the invention compounds of formulae I to V may be prepared by reacting the ligand L with gallium (III) chloride. The ligand L is firstly dissolved in an inert solvent, optionally under reflux and thereafter a solution of gallium chloride is added; the reaction mixture is advantageously refluxed and cooled gradually to room temperature. If necessary, the so obtained reaction mixture is kept at low temperature, for example 0.degree.-5.degree. C., up to the end of the crystallization. The crystals so formed are then recovered by conventional means.
The compounds of formula VT are prepared by reacting, at room temperature, an appropriate derivative of 8-hydroxyquinoline with a gallium (III) salt, preferably the nitrate or sulfate, and recovering the crystals formed after optional addition of a base, such as potassium hydroxyde or ammonia.
The invention compounds are stable solids, which may exist in the form of enantiomers. The ena
REFERENCES:
patent: 4529593 (1985-07-01), Warrell et al.
Collery Philippe
Keppler Bernhard
Collery Phillippe
Jordan Kimberly
Keppler Bernhard
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