Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-05
2004-11-30
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S318000, C546S281400, C546S193000, C546S046000, C546S261000
Reexamination Certificate
active
06825204
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel N-substituted 3-hydroxy-4-pyridinones and metal chelates, methods of preparing N-substituted 3-hydroxy-4-pyridinones and metal chelates, and pharmaceutical compositions containing new N-substituted 3-hydroxy-4-pyridinones and/or their metal chelates. This invention also relates to the use of N-substituted 3-hydroxy-4-pyridinones and their metal chelates as pharmaceutical agents for the treatment of diseases, such as parasitic and viral infections, conditions associated with inflammation and infection, and conditions mediated by cell-proliferation or collagen formation. This invention particularly relates to the N-substituted 3-hydroxy-4-pyridinones as chelators for chelation therapy of iron overload. This invention also relates to the use metal chelates of N-substituted 3-hydroxy-4-pyridinones as NMR contrast agents or radiopharmaceuticals.
BACKGROUND OF THE INVENTION
There are a number of inherited diseases, which are associated with the gradual accumulation of iron. These include &bgr;-thalassaemia major and thalassaemia intermedia. Due to its facile redox chemistry, excess iron in human body often results in irreversible damage to endocrine organs and lethal cardiac toxicity. In humans such excess iron can not be excreted via normal routes, namely, the urine and the bile, and consequently chelation therapy is essential (
J. Med. Chem
. 1998, 41: 3347-3359
; Inorg. Chem. Acta
1999, 291: 238-246).
The objectives of iron-chelation therapy for iron overload are two fold: first, to produce negative iron balance by removing excess body iron; and second, to detoxify the excess iron while, and until, the first objective is achieved (
Drug Safety
1997, 17: 407-421). In order to be considered harmless, iron must be fully coordinated. If any of its six coordination sites remain uncoordinated, iron will participate in Fenton reactions, resulting in lipid peroxidation with organelle and cell damage from hydroxyl radicals (
Baillieres Clin. Haematol
. 1989, 2: 195-256). Therefore, the iron chelator has to be able to form the iron complex with extremely high stability. Specificity of iron binding over other metals (e.g., zinc and copper) is also necessary to avoid chelation of these metals, which are needed for normal physiological activities.
Ideally, an iron chelator should have a low degree of penetration into the central nerve system and should produce a high degree of extraction of iron from hepatic cells, where iron is present in high levels (
Drug Safety
1997, 17: 407-421
; Acta Haematol
. 1996, 95: 6-12). A second constraint of chelator design is that iron must not be redistributed from liver to other parts (e.g., heart and joint) of the body where it may be harmful. This requires that the iron complex be extremely stable. For a chelator to be efficiently absorbed from the gut, the molecular weight of the chelator has to be about 400 Dalton.
There has been considerable interest in the design of orally active iron chelators over the last two decades and many high-affinity iron chelators have been prepared (
J. Med. Chem
. 1990, 33: 1749-1755
; J. Med. Chem
. 1993, 36: 2448-2458
; J. Med. Chem
. 1993, 36: 2448-2458
; J. Med. Chem
. 1994, 37: 461-466
; J. Med. Chem
. 1994, 37: 93-98
; J. Med. Chem
. 1998, 41: 3347-3359
; Eur. J. Med. Chem
. 1999, 34: 475-485
; J. Med. Chem
. 2000, 43: 1467-1475
, J. Pharm. Pharmacol
. 2000, 52: 263-272
; Bioorg. Med. Chem
. 2001, 9: 563-573
; Bioorg. Med. Chem
. 2001, 9: 3041-3047
; Tetrahedron
2001, 57:3479-3486). As a result, 1,2-dimethyl-3-hydroxypyridin-4-one (DMHP, CP20, Deferiprone) has been selected as the clinical candidate for the treatment of iron overload. One of the problems with such an N-alkyl-3-hydroxypyridin-4-one is the ability of the free ligand and the resulting iron complex to rapidly penetrate cell membranes and other biological barriers (
Drug Met. Disp
. 1992, 20: 256-261). A second problem is that N-alkyl-3-hydroxypyridin-4-ones are rapidly metabolized by glyceronidation of the 3-hydroxy group, which will lead to disappearance of iron-chelating properties of the molecule. Despite recent developments, there is a continuing need for new iron chelators, which have high binding affinity for iron and are able to accumulate in liver, the major storage organ in iron-overload conditions.
For many years radical scavenging antioxidants have been successfully used to protect synthetic material and food products from degradating process of oxidation (
Cosmet. Sci. Technol. Ser
. 1997, 16: 159-179). Radical scavengers have been proposed as neuroprotective agents for the treatment of disorders known to involve oxidative stress, such as stroke, tramatic brain injury, spinal cord injury, cerebral tumor, subharrchnoid haemorrage/cerebral vasospam, cerebral ischaemia, stroke, Alzheimers' disease, Huntington's disease, Parkinson's disease, Friedrich ataxia, motor neuron disease or multiple sclerosis. However, the effectiveness of radical scavengers in reducing oxidative stress within living biological environment is often undermined by the continual production of free radicals mediated by iron. Since Fe is involved in the production of toxic free radicals, several radical scavenger-conjugated 3-hydroxy-4-pyridinones have been prepared and studied as potent inhibitors of lipid peroxidation and cell toxicity (
J. Med. Chem
. 2000, 43: 2779-2782). Some display a superior neuroprotective activity compared to dual administration of the radical scavenger, di-tert-butylphenol, and the iron chelator, Deferiprone, demonstrating the synergistic effect between the radical scavenger and the iron chelator.
Vanadium compounds, in vitro, stimulate glucose uptake and inhibit lipid break down, in a manner remarkably reminiscent of insulin's effect. Vanadium chelates with organic chelators present ways to fine tune the effect of vanadium, thereby minimizing any adverse effects without sacrificing important therapeutic benefits. Many compounds have been proposed as “insulin mimetics”. These include vanadium complexes of pyronates (
J. Med. Chem
. 1992, 35: 1489-1491
; J. Am. Chem. Soc
. 1995, 117: 12759-12770
; Can. J. Physiol. Pharmacol
. 1995, 73: 55-64
; Can. J. Physiol. Pharmacol
. 1996, 74: 1001-1009
; J. Inorg. Biochem
. 1997, 68: 109-116;), pyridinates (
Transition Metal Chem
. 2001, 26: 219-223), picolinates (
Inorg. Chem
. 1999, 38: 2288-2297), and cycteine ester (
Inorg. Chim. Acta
1980, 46: 2288-L119-L125), and have been recently reviewed (
J. Chem. Soc., Dalton Trans
. 2000, 2885-2892
; Coord. Chem. Rev
. 2001, 219-221: 1033-1053).
For vanadium to be useful as an orally available insulin mimetic agent, it must be able to cross biological membranes, both for the initial absorption process and intracellular uptake. Therefore, the metal chelate must have low molecular weight, neutral charge, and a fair degree of resistance to hydrolysis. The lipophilicity of the metal chelates must be balanced with its hydrophilicity, and possess adequate thermodynamic stability. As bidentate chelators for the design of vanadium chelates useful as insulin enhancing agents, 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones are exemplary. Both 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones form stable and neutrally charged vanadium chelates, which have an optimal combination of water solubility, reasonable hydrolytic stability, and significant lipophilicity (
J. Chem. Soc., Dalton Trans
. 2000, 2885-2892
; Coord. Chem. Rev
. 2001, 219-221: 1033-1053).
N-Alkyl-3-hydroxy-4-pyridinones form very stable six-coordinated gadolinium chelates (
Inorg. Chim. Acta
1992, 191: 57-63), potentially useful as MRI contrast agents. They also form very stable Zn(II) and Tin(II) complexes, which are useful in dental care formulations (
Polyhedron
2000, 19, 129-135
; Inorg. Chem
. 2001, 40, 4384-4388). In addition,
67
Ga,
111
In and
99m
Tc complexes of N-alkyl-3-hydroxy-4-pyridinones have been studied as potential radiopharmaceuticals either for imaging or for the radiolabeling of white blood cells (
Nucl. Med
Bristol--Myers Squibb Company
Robinson Binta
Seaman D. Margaret
Woodcock & Washburn LLP
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