Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-18
2003-07-08
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S264000
Reexamination Certificate
active
06589966
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to chelators and their use as therapeutic agents. More particularly, the present invention relates to metal chelators and their use as chemotherapeutic agents in the treatment of cancer.
Biomolecules responsible for oxygen transport, electron transport, oxidation, reduction, and diverse other functions contain iron (“Fe”) at their active sites. Iron is also essential for the catalytic activity of numerous critical enzymes, including respiratory chain enzymes and ribonucleotide reductase. Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxynucleotides, the rate limiting step in DNA synthesis. Given the role of iron at the cellular level, in particular DNA synthesis, modulation of iron metabolism at the cellular level may play a key role in the treatment of various pathological conditions, for example, systemic iron overload and oxidative stress.
Iron deprivation strategies may indeed be useful in the treatment of cancer, a disease characterized by uncontrolled cell division. In fact, several strategies have been explored for applying iron deprivation therapy to treat cancer. For example, antibodies against transferrin receptors, which are responsible for the cellular uptake of circulating iron, have been used in the treatment of both hematopoetic and non-hematopoetic tumors. Gallium nitrate, which binds to the transferrin receptor, has been studied for use in the treatment of lymphoma and bladder cancers [Miller, R.,
Cancer Chemotherapy, and Pharmacology
30
Suppl.
S99 (1992); Chitambar, C.,
Amer. J. Clin. Oncol.
20:173 (1997)]. Bladder cancer has been studied as a potential clinical target of iron depletion therapy [Seymour, G.,
Urol. Res.
15:341 (1987); and Seligman, P.,
Amer. J. Hematol.
41:232 (1992)].
Iron chelators have been used diagnostically and as agents in the treatment of various disorders. Iron chelators are molecules that bind tightly to metal ions, rendering them chemically inert. The chemical bond formed between the chelator and the metal involves the donation of electrons present in the molecular orbital of the chelator to the vacant metal orbital. In general, a chelator can be characterized by the identity and number of donor atoms it contains, and its binding geometry. The most stable chelator metal complexes, or chelates, are formed when the denticity of the chelator is sufficient to coordinately saturate the metal. Iron occurs as a di- or trivalent cation with a coordinate number of six. Thus, stable iron chelators are advantageously hexadentate.
Iron chelators are commonly used to treat iron overload associated with genetic disorders and transfusion-dependent anemias (see U.S. Pat. No. 5,430,058). Iron chelators have also been used as contrast agents for diagnostic imaging, including X-ray and ultrasound, radiotherapy, and heavy metal detoxification (see U.S. Pat. No. 5,446,145). However, iron chelators have been developed primarily for use as agents to treat iron overload, and their effectiveness as well as the theories for their development have been based on this application. For this application, the desirable characteristics for iron chelators include chelation of Fe(III) with high stability, ability to mobilize iron for excretion, oral availability, and low chronic toxicity.
Representative iron chelators for the treatment of iron overload include members of the following five classes: hydroxamates, amine carboxylates, catechols, hydroxpyridinones and pyridoxal isonicotinoly hydrazones. Desferrioxamine (DFO), a member of the hydroxamate class of iron chelators, is the present clinical standard for the treatment of iron overload. DFO fulfills some but not all of the above-mentioned criteria for the treatment of iron overload. In particular, DFO exhibits a high and selective affinity for Fe(III). DFO is hexadentate so its effectiveness in binding iron is only weakly dependent on its concentration [Nathan, D.,
N. Eng. J. Med.
332(14) (1995)]. DFO is also able to mobilize iron for excretion. However, DFO suffers from serious limitations. Like most hydorxymates, DFO is acid labile, displays some chronic toxicity, and cannot be given orally. Parenteral administration is required, causing both compliance problems and further limiting the drug's utility in third world nations where iron overload is common, and facilities and supplies for parenteral administration are lacking. Further, the high cost of DFO, which must be isolated from Streptomyces cultures, further limits this drug's utility [Hoffbrand, A.,
J. Lab. Clin. Med
123:492 (1994)].
The hydroxpyridinone family of chelators has recently been developed, and is currently being used in clinical trials for the treatment of iron overload. Deferiprone, also known as LI (a 1,2 dimeth-3-hydroxypyrid-4,1 compound), is a hydroxpyridinone, which has been the target of considerable study. Deferiprone is an orally active iron chelator [Olivieri, N.,
N. Engl. J. Med
14:918-922 (1995)] that mobilizes iron. However, deferiprone's affinity for Fe(III) is only moderate, and this affinity has a strong dependence on the concentration of deferiprone [Loebstein, R.,
Clin. Drug. Invest,
13(6):345-349 (1997)]. Deferiprone has its limitations. Generally, deferiprone has a much lower therapeutic ratio than DFO. It is considerable more toxic, and has known serious side effects including agranulocytosis.
Another class of iron chelators, pyridoxal isonicotinoyl hydrazone (PIH) and its derivatives, has also been studied. PIH derivatives and their iron complexes exhibit good intracellular mobility, but their affinity for Fe(III) is only moderate [PCT WO 960253 1, Jul. 10, 1995].
Chemotherapeutic agents which exploit iron deprivation mechanisms represent a relatively unexplored field of study. These agents are considered antimetabolites, since they interfere with DNA synthesis. Some iron(III) chelators have also been studied for use as chemotherapeutic agents. Desferrioxamine (DFO) is currently being tested in clinical trials as a combination chemotherapeutic agent for treating neuroblastoma and prostate cancer [Donfranesco, A.,
Acta, Haematol.
95:66 (1996); and Frantz, C.,
Proc. Acad. Soc. Clin. Oncol.:
416 (abstr) (1994)]. Chelators of the pyridoxal isonicotinoyl hydrazide (PIH) family have also been studied as anti-proliferative agents. Members of the PIH family are tridentate ligands having both oxygen and nitrogen donor atoms. Several members of the PIH family have been identified with an IC
50
(1-7 &mgr;M) lower than desferioxamine (70 &mgr;M), and a potential correlation between lipophilicity and cytotoxicity [Richardson, D.,
Blood
86:4295 (1995)].
Most chelators selectively favor iron (III), (“Fe (III)”), due to the stronger binding and lower toxicity of iron (III) over iron (II), (“Fe(II)”). While all of the above chelators bind iron(III), chelators of iron(II) are relatively unexplored due in part to their relative lack of metal specificity and the potential toxicity of Fe(II). Fe(II) may reduce H
2
O
2
, resulting in the production of the highly reactive, tissue-damaging hydroxyl radical. Not all chelators yield toxic Fe(II) complexes, however, because structural features of the chelator, such as steric effects, may interfere in the mechanism of hydroxyl radical formation. Also, a chelator such as phenanthroline affords a redox potential of Fe(II) (+1.15 V/NHE) too positive to allow reduction of H
2
O
2
.
Chelators of iron(II) that are redox-active may also draw on bound iron(II), if they can reduce it to iron(II). The property of redox may, therefore, confer advantages on iron(II) chelators relative to iron(III) chelators for several reasons. First, there is a pool of intracellular iron accessible to iron(II) chelators, and, second, there are cellular stores of iron(III) that may be accessed by reduction to iron(II). Thus, there is a need for chelators of greater versatility, that may access both Fe(III) and Fe
Brechbiel Martin W.
Planalp Roy P.
Torti Frank M.
Torti Suzy V.
Davis Zinna Northington
Kilpatrick & Stockton LLP
Wake Forest University Health Sciences
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