Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-11-02
1989-09-12
Davis, Curtis R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514188, A61K 31555
Patent
active
048660523
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the treatment of sickle cell disease and other conditions benefiting from the modification of haemoglobin to enhance its oxygen carrying characteristics.
Sickle cell disease comprises a group of disorders resulting from a hereditary defect which causes a modification of the normal AA haemoglobin to haemoglobin of the SS, SC, SD or S.beta.thal form and leads to a polymerisation of the haemoglobin when in the deoxy state to form a linear polymer of a sickle shape. The sickle cells are less readily able to pass through the capilliaries resulting in repeated painful crises for the patient.
Various treatments have been developed for sickle cell disease involving the oral administration to the patient of one of several drugs having an influence on the behaviour of the haemoglobin molecules, these drugs including cyanates, urea and zinc salts Although each of the drugs can have some beneficial effect, none of them is really satisfactory and there is still a need for an effective treatment for alleviation of the recurrent pain crises in sickle cell disease.
In UK Patent Application No. 8427485 (published as GB 2148896A) and in equivalent applications (European Patent Application No. 84307511.0, Japanese Patent Appliction No. 84/231136, U.S. Pat. No. 666905, now U.S. Pat. No. 4,665,064, etc.) a wide range of zinc complexes is described for administration to patients to treat zinc depletion but no mention is made therein of the donation of zinc from the complexes to haemoglobin and, indeed, it is indicated therein that when administered to a patient the zinc becomes predominantly bound to apotransferrin. We have now found that certain of this group of zinc complexes may be used with advantage for alleviating the effects of sickle cell disease in a treatment involving an extra-corporeal processing of the patient's blood.
Accordingly the present invention comprises the use of a neutral 2:1 ligand:zinc(II) complex in which at least one ligand is provided by a compound being 3-hydroxy-4-pyrone or a 3-hydroxy-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, for the manufacture of a medicament for use in the treatment of sickle cell disease.
The zinc complexes of the present invention are of particular interest in that they include several compounds which have previously been used either as the metal-free compound or as its iron complex in foodstuffs, thereby indicating their non-toxic nature and the consequent suitability for pharmaceutical use of the zinc complexes of these compounds.
The 2:1 zinc complexes used in the present invention contain zinc in the divalent state and are neutral, there being an internal balance of charges between the metal cation and the two monobasic, bidentate ligands bound covalently thereto. The hydroxypyrones described above will provide such a monobasic, bidentate ligand by the loss of a proton from the hydroxy group (OH.fwdarw.0.sup.-). Although the complexes used in the present invention are required to contain at least one hydroxypyrone ligand, the second ligand may if desired be derived from any alternative compound which will provide a physiologically acceptable, monobasic, bidentate ligand which is capable of binding to zinc. The inclusion in a complex of two different ligands can produce an added dimension to the design of complexes having optimised properties for uptake by erythrocytes. S However, both ligands are more conveniently derived from a hydroxypyrone and, in general, complexes containing two identical hydroxypyrone ligands are preferred by virtue of their greater simplicity of preparation and use.
It will be appreciated that the zinc complexes used in the present invention may exist in either a tetrahedral or an octahedral form since, although complexes containing a 2:1 proportion of monobasic, bidentate ligand:zinc(II) will usually have the tetrahedral form, it is possible for them to adopt the octahedral form by combination with two additional
REFERENCES:
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Hider Robert C.
Huehns Ernst R.
Davis Curtis R.
National Research Development Corporation
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