# US 8,772,249 B2 · Compositions and methods for treating ischemia and ischemia-reperfusion injury

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- Number: US 8,772,249 B2
- Document ID: US8772249B2
- Status: Granted
- Kind: B2
- Application number: 13/041,001
- Filed: 2011-03-04
- Published: 2011-06-30
- Granted: 2014-07-08
- Earliest claimed: 2009-05-14
- Assignees: Ischemix LLC
- Applicants: Alexander Baguisi; Reinier Beeuwkes; Ralph Casale; Steven A. Kates; Alan Lader
- Inventors: Alexander Baguisi; Reinier Beeuwkes; Ralph Casale; Steven A. Kates; Alan Lader
- Web page: https://patentgrep.com/patent/US8772249B2

## 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 to compositions comprising a substantially pure compound represented by Structural Formula I: and methods of using such compounds to activate cytoprotective kinases. 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 an effective amount 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 wherein the compound has a percent optical purity of at least 90% by weight relative to the other stereoisomers.

### Claim 2 (depends on 1)

The method of claim 1, wherein the hydrolyzable group is selected from the group consisting of (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkoxy(C1-C10)alkyl, (C1-C10)alkoxy(C1-C10)alkoxy(C1-C10)alkyl, aryl and aryl(C1-C10)alkyl, wherein each is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, morpholino, phenyl, and benzyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the hydrolyzable group is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, allyl, ethoxymethyl, methoxyethyl, methoxyethoxymethyl, methoxyethoxyethyl, benzyl, pentafluorophenyl, 2-N-(morpholino)ethyl, dimethylaminoethyl and para-methoxybenzyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt comprises a monovalent cation or a divalent cation.

### Claim 5 (depends on 4)

The method of claim 4, wherein the monovalent cation is a monovalent metal cation and the divalent cation is a divalent metal cation.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is represented by the following structural formula:

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject in a composition comprising a pharmaceutically acceptable carrier or diluent.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound has a percent optical purity by weight of at least 99%.

### Claim 10 (depends on 1)

The method of claim 1, wherein the ischemic injury is a myocardial ischemic injury.

### Claim 11 (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, an 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 12 (depends on 1)

The method of claim 1, wherein the ischemia-reperfusion injury is a myocardial ischemia-reperfusion injury.

### Claim 13 (depends on 12)

The method of claim 12, wherein the myocardial ischemia-reperfusion injury is consequent to a myocardial infarction.

### Claim 14 (depends on 13)

The method of claim 13, wherein the myocardial infarction is an acute myocardial infarction.

### Claim 15 (depends on 1)

The method of claim 1, wherein the ischemia-reperfusion injury is a cerebral ischemia-reperfusion injury.

### Claim 16 (depends on 15)

The method of claim 15, wherein the cerebral ischemia-reperfusion injury is consequent to a stroke.

### Claim 17 (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 18 (depends on 1)

The method of claim 1, wherein the ischemic injury or ischemia-reperfusion injury includes peri-operative cardiac damage.

### Claim 19 (depends on 1)

The method of claim 1, wherein the ischemic injury or ischemia-reperfusion injury is consequent to a therapeutic intervention or a trauma.

### Claim 20 (depends on 19)

The method of claim 19, 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 21 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject orally.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject intravenously.

### Claim 24

A method for treating an ischemic injury or an ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject an effective amount 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 wherein the compound or pharmaceutically acceptable salt thereof is at least 90% enantiomerically pure.

### Claim 25 (depends on 24)

The method of claim 24, wherein the hydrolyzable group is selected from the group consisting of (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkoxy(C1-C10)alkyl, (C1-C10)alkoxy(C1-C10)alkoxy(C1-C10)alkyl, aryl and aryl(C1-C10)alkyl, wherein each is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, morpholino, phenyl, and benzyl.

### Claim 26 (depends on 24)

The method of claim 24, wherein the hydrolyzable group is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, allyl, ethoxymethyl, methoxyethyl, methoxyethoxymethyl, methoxyethoxyethyl, benzyl, pentafluorophenyl, 2-N-(morpholino)ethyl, dimethylaminoethyl and para-methoxybenzyl.

### Claim 27 (depends on 24)

The method of claim 24, wherein the pharmaceutically acceptable salt comprises a monovalent cation or a divalent cation.

### Claim 28 (depends on 27)

The method of claim 27, wherein the monovalent cation is a monovalent metal cation and the divalent cation is a divalent metal cation.

### Claim 29 (depends on 24)

The method of claim 24, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject in a composition comprising a pharmaceutically acceptable carrier or diluent.

### Claim 30 (depends on 24)

The method of claim 24, wherein the subject is a human.

### Claim 31 (depends on 24)

The method of claim 24, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject orally.

### Claim 32 (depends on 24)

The method of claim 24, wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject intravenously.

### Claim 33 (depends on 24)

The method of claim 24, wherein the compound or pharmaceutically acceptable salt thereof is applied to the eye.

### Claim 34 (depends on 1)

The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is applied to the eye.

### Claim 35

A method for treating a diabetic condition in a subject in need thereof, wherein the diabetic condition is selected from the group consisting of a diabetic neuropathy, a diabetic ulcer, a diabetic mephropathy and a diabetic retinopathy, comprising administering to the subject an effective amount 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 wherein the compound has a percent optical purity of at least 90% by weight relative to the other stereoisomers.

### Claim 36 (depends on 1)

The method of claim 1, wherein the method comprises administering to the subject a single dose of the compound, or pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 24)

The method of claim 24, wherein the method comprises administering to the subject a single dose of the compound, or pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 35)

The method of claim 35, wherein the method comprises administering to the subject a single dose of the compound, or pharmaceutically acceptable salt thereof.