Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-09-19
2002-10-22
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S470000, C540S472000, C540S473000
Reexamination Certificate
active
06469162
ABSTRACT:
The present invention lies in the field of metal cation chelators (ligands) and their use for purposes of decreasing the bioavailability of elements of the first transition series, and/or the removal from the body of these elements or those with similar chemical properties. First transition series elements are components of enzymes required for nucleic acid replication as well as general cell replication. By inhibiting nucleic acid replication these agents are useful in inhibiting growth of DNA and RNA viruses. By inhibiting bacterial and fungal cell replication these agents are useful in vitro as preservatives, and employing topical or systemic in vivo administration they are useful in treating bacterial and fungal infections and in wound care. By inhibiting protozoan cell replication these agents are useful in treatment of protozoan infections. By inhibiting mammalian cell replication, these agents are useful in treating neoplastic disease, in suppression of the immune response, in inhibition of osteoclast activity, and in termination of pregnancy. Iron, a first transition element, is involved in free radical mediated tissue damage. By decreasing the body free iron content, these agents inhibit free radical mediated tissue damage. Excess of body iron characterizes hemochromatosis/-hemosiderosis, and excess of the first transition series element, copper, characterizes Wilson's disease. By removing either excess iron or copper from the body these agents are useful in treating these diseases. When combined with elements possessing paramagnetic properties, the chelating agents described herein also find diagnostic utility as contrast enhancing agents in magnetic resonance imaging. When combined with radioactive elements, these chelating agents find utility in nuclear medical imaging.
BACKGROUND OF THE INVENTION
Metal cations belonging to the first transition series are known to play important coenzymatic roles in metabolism. Zinc is known to be a coenzyme for over eighty different enzyme systems including those directly involved with DNA and RNA synthesis such as thymidine kinase, DNA and RNA polymerases, reverse transcriptase and terminal deoxynucleotide transferase. Among its other coenzyme functions, iron is the coenzyme for myoglobin, the cytochromes and catalases and is thus essential for oxidative metabolism. Manganese and copper also play significant coenzyme roles, and other metal cations in the first transition series are considered to be essential trace elements although their metabolic role is less well defined.
Compounds capable of forming complexes with metal cations, which compounds are commonly referred to as chelators or ligands, are known to have a variety of uses in medicine. These include their use as pharmaceuticals in treating heavy metal poisoning, in treating diseases associated with trace metal excess such as iron storage and copper storage diseases (hemosiderosis and Wilson's disease, respectively), as radiopharmaceutical agents in nuclear medical imaging when forming complexes with radioactive metals, as contrast enhancement agents in magnetic resonance imaging (MRI) when forming complexes with paramagnetic metals, and as contrast enhancement agents in radiography when forming complexes with heavy metals.
Examples of ligands employed in treating heavy metal poisoning such as that due to lead, mercury, and other metals, are ethylenediamine tetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA). The ligand desferrioxamine is used in treating iron storage disease, and the ligand penicillamine is used in the mobilization of copper in the treatment of Wilson's disease.
Examples of complexes used to form radiopharmaceuticals useful in evaluations of the kidneys, bone and liver are complexes of technetium-99m (
99m
Tc) with diethylenetriamine pentaacetic acid (DTPA), dimercaptosuccinic acid (DMSA), methylene diphosphonate (MDP) and derivatives of iminodiacetic acid (IDA).
Complexes of paramagnetic metal cations which are useful as MRI contrast agents operate by accelerating proton relaxation rates. Most commonly a metal cation, such as gadolinium (III), having a large number of unpaired electrons is complexed by a ligand suitable for complexation of that cation. An example is gadolinium (III) complexed by DTPA.
Chelators with affinity for iron cations have been shown to inhibit cell proliferation. Desferrioxamine is one example of such a chelator. This effect is thought to be a consequence of the complexation of tissue iron by the chelator, which thereby deprives the proliferating cells of a source of iron for critical enzyme synthesis. Moreover, it is believed that certain types of tissue damage are mediated by the formation of free radicals. It is also appreciated that catalytically active iron catalyzes formation of the highly active hydroxyl free radical. Based on such relationships chelators (ligands) for iron such as desferrioxamine and the experimental iron chelator “L1” (1,2-dimethyl-3-hydroxypyrid-4-one) have been examined in management of conditions where free radical mediated tissue damage is believed to play a role, as well as in clinical management of conditions in which control of cell proliferation is desired. Conditions where the administration of iron chelators has been evaluated include: rheumatoid arthritis, anthracycline cardiac poisoning, reperfusion injury, solid tumors, hematologic cancers, malaria, renal failure, Alzheimer's disease, myelofibrosis, multiple sclerosis, drug-induced lung injury, graft versus host disease, and transplant rejection and preservation (Voest, E. E., et al., “Iron Chelating Agents in Non-Iron Overload conditions,”
Annals of Internal Medicine
120(6): 490-499 (Mar. 15, 1994)).
Agents which inhibit cell replication have found use in the prior art as chemotherapeutic agents for treatment of neoplasia and infectious disease, for suppression of the immune response, and for termination of pregnancy. Such agents usually act by inhibiting DNA, RNA or protein synthesis. This results in a greater adverse effect on rapidly proliferating cell populations than on cells “resting” in interphase or proliferating less rapidly.
Such agents may possess a degree of selectivity in treating the rapidly proliferating offending cell population, particularly in the case of certain neoplasias and infectious processes. These agents also inhibit replication of normal cells of the host organism, to varying degrees. Cells of the immune system proliferating in response to antigenic challenge are sensitive to such agents, and accordingly these agents are useful in suppressing the immunological response. Examples are the suppression of the homograft rejection response following tissue transplantation and the treatment of autoimmune disorders. Replication of protozoan, bacterial and mycotic microorganisms are also sensitive to such agents, which makes the agents useful in treating infections by such microorganisms.
Agents which suppress cell replication by inhibiting DNA or RNA synthesis have primarily found utility in treatment of neoplastic diseases. The glutamine antagonists azaserine, DON, and the anti-purines such as 6-mercaptopurine and 6-thioguanine principally inhibit DNA synthesis by their action on phosphoribosylpyrophosphate amidotransferase, the enzyme involved in the first step in purine nucleotide synthesis. The folic acid antagonists aminopterin arid methotrexate inhibit DNA synthesis (and other synthetic processes involving one carbon transport) by inhibiting the dihydrofolate reductase enzyme system, thereby interfering with formation of tetrahydrofolate, which is necessary in transfer of one-carbon fragments to purine and pyrimidine rings. Hydroxyurea inhibits DNA synthesis by inhibiting ribonuclease reductase, thereby preventing reduction of ribonucleotides to their corresponding deoxyribonucleotides. The anti-pyrimidines such as 5-fluorouracil inhibit DNA synthesis by inhibiting thymidylate synthetase. 5-Fluorouracil may also be incorporated into fraudulent RNA molecules. Bleomycin appea
Cyjon Rosa L.
Klein Joseph Y.
Klein Ofer
Simhon Elliot D.
Winchell Harry S.
Concat, Ltd.
Raymond Richard L.
Townsend and Townsend / and Crew LLP
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