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  High-purity texaphyrin metal complexesUSPTO Application #: 20070072838Title: High-purity texaphyrin metal complexes Abstract: Disclosed herein are the methods and compositions for the improved synthesis of texaphyrin metal complexes. The improved synthesis results in high-purity compositions of texaphyrin metal complexes in which more than about 98% of the texaphyrin metal complexes in the composition have the same structure and/or the same molecular weight. Further described herein are pharmaceutical compositions comprising such high-purity compositions, and the use of such high-purity compositions in the treatment of cancer and cardiovascular diseases and disorders. (end of abstract) Agent: Wilson Sonsini Goodrich & Rosati - Palo Alto, CA, US Inventors: Hugo Madden, Greg Hemmi, Tarak Mody USPTO Applicaton #: 20070072838 - Class: 514185000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Heavy Metal Containing (including Salts), Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20070072838. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] Disclosed herein are high-purity texaphyrin metal complexes, methods for making such complexes, and the use of such high-purity texaphyrin metal complexes to treat diseases, disorders and conditions, including cancer and atherosclerosis. BACKGROUND OF THE INVENTION [0002] Cancer is a serious threat to modern society. Worldwide, more than 10 million people are diagnosed with cancer every year and it is estimated that this number will grow to 15 million new cases every year by 2020. Cancer causes six million deaths every year or 12% of the deaths worldwide. Current treatment options are often limited but widely employed. Of the 1.2 million patients newly diagnosed with cancer in the United States annually, approximately 50% will be treated with radiation therapy as part of initial disease management. Approximately 150,000 additional patients with recurrent cancer may receive radiation therapy each year in the U.S. Chemotherapy is administered to about 350,000 cancer patients in the U.S. annually. [0003] High levels of circulating cholesterol are associated with atherosclerosis, which may result in life-threatening blockages of blood vessels to the heart and brain. Unstable angina, myocardial infarction (heart attack) and sudden ischemic death remain the leading cause of morbidity and mortality in developed nations. Current estimates indicate that 1.1 million people in the U.S. annually will have a new or recurrent coronary attack, and over 45 percent of these patients may die from the coronary attack. [0004] Texaphyrins are small molecules having a ring-shaped chemical structure containing one of several metal atoms. The physical and chemical characteristics of texaphyrin molecules are determined by the properties of the ring and the type of metal atom inserted into the ring. Texaphyrins are designed to selectively concentrate in diseased tissue such as tumor cells and atherosclerotic plaque inside blood vessels. Inside diseased cells, texaphyrins block crucial steps in cellular metabolism and disrupt bioenergetic processes. Texaphyrins are designed to provide a valuable therapeutic approach to a broad range of diseases. These can be used for the treatment of a variety of diseases, including cancer, atherosclerosis and cardiovascular diseases, and potentially neurodegenerative diseases, inflammatory diseases, and HIV/AIDS. SUMMARY OF THE INVENTION [0005] Disclosed herein are compositions comprising high-purity texaphyrin metal complexes, wherein the identity of the substituents on the texaphyrin complex are at least about 98% identical on all texaphyrin complexes in a sample. Also disclosed herein are compositions comprising high-purity synthetic precursors to high-purity texaphyrin complexes. Also disclosed herein are methods for synthesizing such high-purity texaphyrin metal complexes and such high-purity precursors. Also disclosed herein are methods for pegylating an aromatic moiety, wherein the identity of the poly(ethylene glycol) substituents on the aromatic moiety are at least about 98% identical on all aromatic moieties in a sample. Also disclosed herein are pharmaceutical compositions comprising such high-purity texaphyrin metal complexes. Also disclosed herein are methods for treating a disorder, disease or condition in a human patient comprising administering to the patient an effective amount of such high-purity texaphyrin metal complexes. [0006] A first aspect disclosed herein are high-purity compositions comprising a compound of Formula 1 [0007] wherein: M is a trivalent metal cation selected from the group consisting of Gd.sup.+3, and Lu.sup.+3; each X is independently selected from the group consisting of OH.sup.-, AcO.sup.-, Cl.sup.-, Br.sup.-, I.sup.-, F.sup.-, H.sub.2PO.sub.4.sup.-, ClO.sup.-, ClO.sub.2.sup.-, CLO.sub.3.sup.-, ClO.sub.4.sup.-, HCO.sub.3.sup.-, HSO.sub.4.sup.-, NO.sub.3.sup.-, N.sub.3.sup.-, CN.sup.-, SCN.sup.-, and OCN.sup.-; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently H, OH, C.sub.nH.sub.(2n+1)O.sub.y or OC.sub.nH.sub.(2n+1)O.sub.y and R.sub.1, R.sub.2 are independently H or C.sub.1-C.sub.6 alkyl where at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 is C.sub.nH.sub.(2n+1)O.sub.y or OC.sub.nH.sub.(2n+1)O.sub.y, having at least one hydroxyl substituent; n is a positive integer from 1 to 11; y is zero or a positive integer less than or equal to n; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; wherein at least about 98.4% of compounds of Formula 1 in the composition have the same structure. In one embodiment, M is Gd.sup.+3. In one embodiment, R.sub.4 and R.sub.7 are C.sub.3H.sub.6OH; R.sub.5 and R.sub.6 are C.sub.2H.sub.5; R.sub.3 and R.sub.8 are CH.sub.3; R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. In one embodiment, each X is AcO.sup.-. In another embodiment, M is Lu.sup.+3. In one embodiment, R.sub.4 and R.sub.7 are C.sub.3H.sub.6OH; R.sub.5 and R.sub.6 are C.sub.2H.sub.5; R.sub.3 and R.sub.8 are CH.sub.3; R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. In one embodiment, each X is AcO.sup.-. In a further or alternate embodiment, each X is selected from the group consisting of sugar derivatives, cholesterol derivatives, PEG acids, organic acids, organosulfates, organophosphates, phosphates or inorganic ligands. In a further or alternate embodiment, X is derived from an acid selected from the group consisting of gluconic acid, glucoronic acid, cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid, formic acid, propionic acid, butyric acid, pentanoic acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, and p-toluene-sulfonic acid. [0008] In one embodiment, at least about 98.4% of compounds of Formula 1 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 1 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of compounds of Formula 1 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of compounds of Formula 1 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of compounds of Formula 1 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99% of compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99.3% of compounds of Formula 1 in the composition have the same structure. In one embodiment, at least about 99.5% of compounds of Formula 1 in the composition have the same structure. [0009] A second aspect disclosed herein are high-purity compositions comprising a compound of Formula 2: [0010] wherein: R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently H, OH, C.sub.nH.sub.(2n+1)O.sub.y or OC.sub.nH.sub.(2n+1)O.sub.y and R.sub.1, R.sub.2 are independently H or C.sub.1-C.sub.6 alkyl where at least one of R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 is C.sub.nH.sub.(2n+1)O.sub.y or OC.sub.nH.sub.(2n+1)O.sub.y, having at least one hydroxyl substituent; n is a positive integer from 1 to 11; y is zero or a positive integer less than or equal to n; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and acceptable acid addition salts thereof; wherein at least about 98.4% of compounds of Formula 2 in the composition have the same structure. In one embodiment, R.sub.4 and R.sub.7 are C.sub.3H.sub.6OH; R.sub.5 and R.sub.6 are C.sub.2H.sub.5; R.sub.3 and R.sub.8 are CH.sub.3; R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. In one embodiment, the acceptable acid addition salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In one embodiment, the acceptable acid addition salt is a hydrochloride salt. [0011] In one embodiment, at least about 98.4% of compounds of Formula 2 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 2 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of compounds of Formula 2 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of compounds of Formula 2 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of compounds of Formula 2 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 2 in the composition have the same structure. In one embodiment, at least about 99% of compounds of Formula 2 in the composition have the same structure. In one embodiment, at least about 99.3% of compounds of Formula 2 in the composition have the same structure. In one embodiment, at least about 99.5% of compounds of Formula 2 in the composition have the same structure. [0012] A third aspect disclosed herein are high-purity compositions comprising a compound of [0013] wherein R.sub.1 and R.sub.2 are independently H or C.sub.1-C.sub.6 alkyl; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and wherein at least about 98.4% of compounds of Formula 4 in the composition have the same structure. In one embodiment, R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. [0014] In one embodiment, at least about 98.4% of compounds of Formula 4 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 4 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of compounds of Formula 4 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of compounds of Formula 4 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of compounds of Formula 4 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 4 in the composition have the same structure. In one embodiment, at least about 99% of compounds of Formula 4 in the composition have the same structure. In one embodiment, at least about 99.3% of compounds of Formula 4 in the composition have the same structure. In one embodiment, at least about 99.5% of compounds of Formula 4 in the composition have the same structure. [0015] A fourth aspect disclosed herein are high-purity compositions comprising a compound of Formula 5 [0016] wherein R.sub.1 and R.sub.2 are independently H or C.sub.1-C.sub.6 alkyl; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and wherein at least about 98.4% of compounds of Formula 5 in the composition have the same structure. In one embodiment, R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. [0017] In one embodiment, at least about 98.4% of compounds of Formula 5 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 5 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of compounds of Formula 5 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of compounds of Formula 5 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of compounds of Formula 5 in the composition have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 5 in the composition have the same structure. In one embodiment, at least about 99% of compounds of Formula 5 in the composition have the same structure. In one embodiment, at least about 99.3% of compounds of Formula 5 in the composition have the same structure. In one embodiment, at least about 99.5% of compounds of Formula 5, in the composition have the same structure. [0018] A fifth aspect disclosed herein are methods for synthesizing a purified sample of a compound of Formula 4 [0019] wherein R.sub.1 and R.sub.2 are independently H or C.sub.1-C.sub.6 alkyl; each x is independently selected from the group consisting of 2, 3, 4, 5, and 6; and wherein at least about 98.4% of the compounds of Formula 4 in the purified sample have the same structure comprising: reacting a compound of Formula 5 with about 90% HNO.sub.3 in AcOH at about 0-5.degree. C. for at least 30 minutes, wherein at least about 98.4% of the compounds of Formula 4 formed in the purified sample have the same structure. In one embodiment, R.sub.1 and R.sub.2 are H. In one embodiment, each x is 3. [0020] In one embodiment, at least about 98.4% of compounds of Formula 4 in the purified sample have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 4 in the purified sample have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99% of compounds of Formula 4 in the purified sample have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.3% of compounds of Formula 4 in the purified sample have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 99.5% of compounds of Formula 4 in the purified sample have the same molecular weight, wherein the same molecular weight excludes isotopic variations. In one embodiment, at least about 98.7% of compounds of Formula 4 in the purified sample have the same structure. In one embodiment, at least about 99% of compounds of Formula 4 in the purified sample have the same structure. In one embodiment, at least about 99.3% of compounds of Formula 4 in the purified sample have the same structure. In one embodiment, at least about 99.5% of compounds of Formula 4 in the purified sample have the same structure. [0021] A sixth aspect disclosed are methods for synthesizing a purified sample of a compound of Formula 5 Continue reading... Full patent description for High-purity texaphyrin metal complexes Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this High-purity texaphyrin metal complexes patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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