# US 8,772,250 B2 · Compositions and methods for treating ischemia and ischemia-reperfusion injury > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,772,250 B2 - Document ID: US8772250B2 - Status: Granted - Kind: B2 - Application number: 13/319,839 - Filed: 2010-05-13 - Published: 2012-05-31 - Granted: 2014-07-08 - Earliest claimed: 2010-05-13 - Assignees: Ischemix LLC - Applicants: Alexander B. Baguisi; Reinier Beeuwkes; Ralph Casale; Steven A. Kates; Alan S. Lader - Inventors: Alexander B. Baguisi; Reinier Beeuwkes; Ralph Casale; Steven A. Kates; Alan S. Lader - Web page: https://patentgrep.com/patent/US8772250B2 ## CPC - C07K 5/06104: {with the first amino acid being acidic} - A61K 31/381: having five-membered rings - A61K 31/385: having two or more sulfur atoms in the same ring - A61K 38/05: Dipeptides - A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics - A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 11/00: Drugs for disorders of the respiratory system - A61P 13/12: of the kidneys - A61P 21/00: Drugs for disorders of the muscular or neuromuscular system - A61P 25/00: Drugs for disorders of the nervous system - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates, in some embodiments, to compositions comprising a substantially pure compound represented by Structural Formula (I) and methods of using such compounds to activate cytoprotective kinases. In additional embodiments, the invention relates to methods for treating an ischemia or an ischemia-reperfusion injury in a subject, comprising administering to the subject an effective amount of a compound of the invention (e.g., in multiple doses). The values and preferred values of the variables in Structural Formula (I) are defined herein. ## Claims ### Claim 1 A method for treating an ischemic injury or an ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject at least two doses of a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein R1 and R2 in the compound are each independently H or a hydrolyzable group and the compound, or pharmaceutically acceptable salt thereof, is at least 90% enantiomerically pure, the method comprising: administering to the subject a non-final dose of the compound, or a pharmaceutically acceptable salt thereof, and a final dose of the compound, or a pharmaceutically acceptable salt thereof, prior to the injury, wherein: (a) the final dose is administered immediately prior to the injury; and (b) the non-final dose and the final dose are administered at a dosage interval that potentiates the efficacy of the compound for treating the injury relative to a single-dose administration of the compound. ### Claim 2 (depends on 1) The method of claim 1, wherein the dosage interval between the non-final dose and the final dose is at least about 4 hours. ### Claim 3 (depends on 2) The method of claim 2, wherein the dosage interval between the non-final dose and the final dose is at least about 6 hours. ### Claim 4 (depends on 3) The method of claim 3, wherein the dosage interval between the non-final dose and the final dose is at least about 8 hours. ### Claim 5 (depends on 1) The method of claim 1, wherein the final dose is administered to the subject at a time point in the range of about 0 minutes to about 90 minutes prior to the injury. ### Claim 6 (depends on 5) The method of claim 5, wherein the final dose is administered to the subject at least about 30 minutes prior to the injury. ### Claim 7 (depends on 6) The method of claim 6, wherein the final dose is administered to the subject at least about 60 minutes prior to the injury. ### Claim 8 (depends on 1) The method of claim 1, wherein the compound, or pharmaceutically acceptable salt thereof, has a concentration that is less than 10% of its Cmax in a blood sample obtained from the subject after administration of the non-final dose and immediately prior to administration of the final dose. ### Claim 9 (depends on 1) The method of claim 1, wherein the non-final dose is administered to the subject at a time point within about 48 hours prior to the injury. ### Claim 10 (depends on 1) The method of claim 1, further comprising administering one or more additional doses of the compound to the subject prior to administering the non-final dose. ### Claim 11 (depends on 10) The method of claim 10, wherein three doses of the compound are administered to the subject prior to the injury. ### Claim 12 (depends on 1) The method of claim 1, further comprising administering one or more additional doses of the compound to the subject after the injury. ### Claim 13 (depends on 1) The method of claim 1, wherein each dose is equivalent. ### Claim 14 (depends on 1) The method of claim 1, wherein the compound is administered intravenously and each dose has a concentration ranging from about 0.5 mg/kg to about 5.0 mg/kg. ### Claim 15 (depends on 1) The method of claim 1, wherein the ischemic injury is a myocardial ischemic injury. ### Claim 16 (depends on 1) The method of claim 1, wherein the ischemic injury is consequent to an ischemia selected from the group consisting of a cardiovascular ischemia, a cerebrovascular ischemia, a renal ischemia, a hepatic ischemia, a ischemia -reperfusion cardiomyopathy, a cutaneous ischemia, a bowel ischemia, an intestinal ischemia, a gastric ischemia, a pulmonary ischemia, a pancreatic ischemia, a skeletal muscle ischemia, an abdominal muscle ischemia, a limb ischemia, an ischemia-reperfusion colitis, a mesenteric ischemia and a silent ischemia. ### Claim 17 (depends on 1) The method of claim 1, wherein the ischemia-reperfusion injury is a myocardial ischemia-reperfusion injury. ### Claim 18 (depends on 17) The method of claim 17, wherein the myocardial ischemia-reperfusion injury is consequent to a myocardial infarction. ### Claim 19 (depends on 18) The method of claim 18, wherein the myocardial infarction is an acute myocardial infarction. ### Claim 20 (depends on 1) The method of claim 1, wherein the ischemia-reperfusion injury is a cerebral ischemia-reperfusion injury. ### Claim 21 (depends on 20) The method of claim 20, wherein the cerebral ischemia-reperfusion injury is consequent to a stroke. ### Claim 22 (depends on 1) The method of claim 1, wherein the ischemia-reperfusion injury is selected from the group consisting of a cerebrovascular ischemia-reperfusion injury, a renal ischemia-reperfusion injury, a hepatic ischemia-reperfusion injury, an ischemia-reperfusion cardiomyopathy, a cutaneous ischemia-reperfusion injury, a bowel ischemia-reperfusion injury, an intestinal ischemia-reperfusion injury, a gastric ischemia-reperfusion injury, a pulmonary ischemia-reperfusion injury, a pancreatic ischemia-reperfusion injury, a skeletal muscle ischemia-reperfusion injury, an abdominal muscle ischemia-reperfusion injury, a limb ischemia-reperfusion injury, ischemia-reperfusion colitis, a mesenteric ischemia-reperfusion injury and a silent ischemia-reperfusion injury. ### Claim 23 (depends on 1) The method of claim 1, wherein the ischemic injury or the ischemia-reperfusion injury includes peri-operative cardiac damage. ### Claim 24 (depends on 1) The method of claim 1, wherein the ischemic injury or the ischemia-reperfusion injury is consequent to a therapeutic intervention. ### Claim 25 (depends on 24) The method of claim 24, wherein the therapeutic intervention is selected from the group consisting of a coronary artery bypass graft surgery, a coronary angioplasty surgery, a transplant surgery and a cardiopulmonary bypass surgery. ### Claim 26 (depends on 1) The method of claim 1, wherein the subject is a human. ### Claim 27 A method for treating an ischemic injury or an ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject at least two doses of a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein R1 and R2 in the compound are each independently H or a hydrolyzable group and the compound, or pharmaceutically acceptable salt thereof, is at least 90% enantiomerically pure, the method comprising: administering to the subject a non-final dose of the compound, or a pharmaceutically acceptable salt thereof, and a final dose of the compound, or a pharmaceutically acceptable salt thereof, prior to the injury, wherein: (a) the final dose is administered to the subject at a time point within about two half-lives of the compound prior to the injury; and (b) the non-final dose is administered to the subject at a time point that is at least about four half-lives of the compound prior to administration of the final dose. ### Claim 28 (depends on 27) The method of claim 27, wherein the final dose is administered to the subject at a time point in the range of about 0.25 half-lives to about 2 half-lives of the compound prior to the injury. ### Claim 29 (depends on 28) The method of claim 28, wherein the final dose is administered to the subject about one half-life of the compound prior to the injury. ### Claim 30 (depends on 27) The method of claim 27, wherein the compound, or pharmaceutically acceptable salt thereof, has a concentration that is less than 10% of its Cmax in a blood sample obtained from the subject after administration of the non-final dose and immediately prior to administration of the final dose. ### Claim 31 (depends on 27) The method of claim 27, further comprising administering one or more additional doses of the compound to the subject prior to the non-final dose. ### Claim 32 (depends on 27) The method of claim 27, further comprising administering one or more additional doses of the compound to the subject after the injury. ### Claim 33 (depends on 27) The method of claim 27, wherein each dose is equivalent. ### Claim 34 (depends on 27) The method of claim 27, wherein the compound is administered intravenously and each dose has a concentration ranging from about 0.5 mg/kg to about 5.0 mg/kg. ### Claim 35 (depends on 27) The method of claim 27, wherein the ischemic injury is a myocardial ischemic injury. ### Claim 36 (depends on 27) The method of claim 27, wherein the ischemic injury is consequent to an ischemia selected from the group consisting of a cardiovascular ischemia, a cerebrovascular ischemia, a renal ischemia, a hepatic ischemia, a ischemia-reperfusion cardiomyopathy, a cutaneous ischemia, a bowel ischemia, an intestinal ischemia, a gastric ischemia, a pulmonary ischemia, a pancreatic ischemia, a skeletal muscle ischemia, an abdominal muscle ischemia, a limb ischemia, an ischemia-reperfusion colitis, a mesenteric ischemia and a silent ischemia. ### Claim 37 (depends on 27) The method of claim 27, wherein the ischemia-reperfusion injury is a myocardial ischemia-reperfusion injury. ### Claim 38 (depends on 37) The method of claim 37, wherein the myocardial ischemia-reperfusion injury is consequent to a myocardial infarction. ### Claim 39 (depends on 38) The method of claim 38, wherein the myocardial infarction is an acute myocardial infarction. ### Claim 40 (depends on 27) The method of claim 27, wherein the ischemia-reperfusion injury is a cerebral ischemia-reperfusion injury. ### Claim 41 (depends on 40) The method of claim 40, wherein the cerebral ischemia-reperfusion injury is consequent to a stroke. ### Claim 42 (depends on 27) The method of claim 27, wherein the ischemia-reperfusion injury is selected from the group consisting of a cerebrovascular ischemia-reperfusion injury, a renal ischemia-reperfusion injury, a hepatic ischemia-reperfusion injury, an ischemia-reperfusion cardiomyopathy, a cutaneous ischemia-reperfusion injury, a bowel ischemia-reperfusion injury, an intestinal ischemia-reperfusion injury, a gastric ischemia-reperfusion injury, a pulmonary ischemia-reperfusion injury, a pancreatic ischemia-reperfusion injury, a skeletal muscle ischemia-reperfusion injury, an abdominal muscle ischemia-reperfusion injury, a limb ischemia-reperfusion injury, ischemia-reperfusion colitis, a mesenteric ischemia-reperfusion injury and a silent ischemia-reperfusion injury. ### Claim 43 (depends on 27) The method of claim 27, wherein the injury includes peri-operative cardiac damage. ### Claim 44 (depends on 27) The method of claim 27, wherein the injury is consequent to a therapeutic intervention. ### Claim 45 (depends on 44) The method of claim 44, wherein the therapeutic intervention is selected from the group consisting of a coronary artery bypass graft surgery, a coronary angioplasty surgery, a transplant surgery and a cardiopulmonary bypass surgery. ### Claim 46 (depends on 27) The method of claim 27, wherein the subject is a human.