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  Texaphyrin coordination compounds and uses thereofUSPTO Application #: 20060128638Title: Texaphyrin coordination compounds and uses thereof Abstract: Novel coordination polymers, their pharmaceutical formulations, useful for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress, are disclosed. (end of abstract)
Agent: Wilson Sonsini Goodrich & Rosati - Palo Alto, CA, US Inventors: Darren Magda, Dale Miles, Nikolay Gerasimchuk, Cheryl Lepp USPTO Applicaton #: 20060128638 - Class: 514023000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Carbohydrate (i.e., Saccharide Radical Containing) Doai The Patent Description & Claims data below is from USPTO Patent Application 20060128638. Brief Patent Description - Full Patent Description - Patent Application Claims
CLAIM OF PRIORITY INFORMATION [0001] This application is the National Stage of International. Application No. PCT/US01/43590, filed Nov. 16, 2001, published in English under PCT Article 21(2) as Publication No. WO 02/39953, on May 23, 2002, which claimed the benefit of priority from U.S. Provisional Application No. 60/249,523, filed Nov. 17, 2000, both of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to novel compounds and their pharmaceutical formulations, and their uses to treat atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress. [0004] 2. Background Information [0005] Treatment of solid mammalian tumors with ionizing radiation involves the in situ generation of hydroxyl radicals and other reactive oxygen species that, due to the focusability of the ionizing radiation are primarily located in the tumor, i.e., in tumor cells. These reactive species possess extreme oxidizing properties which oxidize biomolecules in vivo thereby interfering with cellular metabolism, as discussed by Buettner et al., "Catalytic Metals, Ascorbate and Free Radicals: Combinations to Avoid," Radiation Research, vol. 145. pp. 532-541 (1996). [0006] Tumor treatment via the use of ionizing radiation can be enhanced by increasing the radio sensitivity of the tumor cells. One method suggested for enhancing radio sensitivity has been the external administration of a compound having a high affinity for electrons, which ideally localizes in the tumor. Proposed radiation sensitizers include compounds such as halogenated pyrimidines, nitroimidazoles and gadolinium (III) complexes of the pentadentate macrocycle texaphyrin, as described by Sessler et al., "One-Electron Reduction and Oxidation Studies of the Radiations Sensitizer Gadolinium (III) Texaphyrin (PCI-120) and Other Water Soluble Metallotexaphyrins," J. Phys. Chem. A., vol. 103, pp. 787-794 (1999). [0007] Texaphyrins are known to be useful as radiation sensitizers, and also for the treatment of plaque caused by atherosclerosis, retinal diseases, for the destruction of retroviruses, especially HIV and the like. [0008] Efficacy of texaphyrins is dependent on its ability to penetrate cellular membranes and thereby increase its intracellular concentration. Thus intracellular availability of texaphyrin is a key to its biological activity and effectiveness. Texaphyrins are known to penetrate cell membranes and are known to have an effective intracellular concentration to have beneficial biological activity. An improvement in the ability of a drug substance to enter cellular membranes is however always welcome. It has been surprisingly discovered that premixing texaphyrins with an oxalate salt or an oxalate precursor, for example ascorbic acid, gives rise to a compound whose structure differs from that of a texaphyrin, but is seen to accumulate more rapidly in tumor cells, plaque, etc. SUMMARY OF THE INVENTION [0009] This invention relates to a method of treating tumors and other neoplastic tissue, plaque caused by atherosclerosis, viruses, including HIV, and retinal diseases using the polymeric complex of the present invention. [0010] The present invention also relates to polymeric complexes formed by treating texaphyrins with oxalate salts or oxalate precursors and their pharmaceutical compositions. [0011] The present invention thus provides a method for treating a disease or condition in a mammal resulting from the presence of neoplastic tissue, neovascularization, or an atheroma, said method comprising: [0012] administering to a mammal in need of such treatment a therapeutically effective amount of a coordination polymer comprising structural units "A": wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B" [0013] Another aspect of the present invention provides a coordination polymer comprising structural units "A": wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B" [0014] Provided in yet another aspect is a coordination polymer wherein structural unit "A" is represented by wherein M independently at each occurrence represents Gd(III) or Lu(III); and structural unit "B" is represented by [0015] Yet another aspect provides a process of making a coordination polymer comprising structural units "A": wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 to 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; and structural unit "B" said process comprising contacting a compound of Formula A wherein M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 to 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, to form a coordination polymer comprising structural units "A" and "B". [0016] Also provided is a coordination polymer prepared by contacting a compound of Formula A wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 to 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, optionally in the presence of oxygen. BRIEF DESCRIPTION OF THE DRAWINGS [0017] FIG. 1 depicts the time course showing changes in optical spectra occurring upon incubation of Motexafin Gadolinium (GdTex) with dihydroascorbate (DHA) in a buffer (see Example 2). [0018] FIG. 2 refers to cellular uptake of GdTex oxalate complex as measured by absorbance (see Example 7). [0019] FIG. 3 refers to cellular uptake of GdTex oxalate complex as measured by dichlorofluoroscin acetate (DCFA) oxidation to form dichlorofluoresin (DCF) (see Example 7). [0020] FIG. 4 depicts uptake in A549 cells as measured using flow cytometry (see Example 8). Continue reading... Full patent description for Texaphyrin coordination compounds and uses thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Texaphyrin coordination compounds and uses thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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