# US 10,500,177 B2 · Glutarate compounds for treating ischemia-reperfusion injuries

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- Number: US 10,500,177 B2
- Document ID: US10500177B2
- Status: Granted
- Kind: B2
- Application number: 16/297,599
- Filed: 2019-03-09
- Published: 2019-07-04
- Granted: 2019-12-10
- Earliest claimed: 2016-05-01
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Jing Huang; Xudong Fu; Xiang Yin; Mansoureh Eghbali; Jingyuan Li; Karen Reue; Laurent Vergnes
- Web page: https://patentgrep.com/patent/US10500177B2

## CPC

- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/365: Lactones
- A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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

Disclosed herein are methods of preventing, inhibiting, reducing, or treating ischemia and reperfusion injury to tissues with glutarate compounds such as α-ketoglutarate.

## Claims

### Claim 1

A method of treating or reducing an ischemia-reperfusion (IR) injury to a tissue in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising:
a therapeutically effective amount of a compound of Formula II:
or a salt thereof, wherein:
R1 is hydrogen, halogen, —CHO, —OR7, —NR8R9, —COOR7, —CONR8R9, —SR10, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 and R3 are each independently hydrogen,
halogen, —CN, —CHO, —OR7, —NR8R9, —COOR7, —CONR8R9, —NO2, —SR10, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
or R2 and R3, together with the atom to which they are bound, form an oxo;
R4 and R5 are each independently hydrogen,
halogen, —CN, —CHO, —OR7, —NR8R9, —COOR7, —CONR8R9, —NO2, —SR10, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R6 is halogen, —CN, —CHO, —OR7, —NR8R9, —COOR7, —CONR8R9, —NO2, —SR10, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and
each R7, R8, R9, and R10 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein each R7 substituent is independently selected when two or more R7 substituents are present, each R8 substituent is independently selected when two or more R8 substituents are present, each R9 substituent is independently selected when two or more R9 substituents are present, and each R10 substituent is independently selected when two or more R10 substituents are present;
wherein the pharmaceutical composition is administered to the subject to treat or reduce IR injury to a tissue in the subject; and
wherein the therapeutically effective amount is about 5-20 mg of the compound of Formula II, or the salt thereof, per kilogram weight of the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is —OH, —O—(C1-20 substituted alkyl) or —O—(C1-20 unsubstituted alkyl).

### Claim 3 (depends on 2)

The method of claim 2, wherein R1 is —O-(n-octyl).

### Claim 4 (depends on 2)

The method of claim 2, wherein R1 is —OH.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2 is —OR7 or —NR8R9.

### Claim 6 (depends on 5)

The method of claim 5, wherein R2 is —OH or —NH2.

### Claim 7 (depends on 1)

The method of claim 1, wherein R3 is hydrogen.

### Claim 8 (depends on 1)

The method of claim 1, wherein R2 and R3, together with the atom to which they are bound, form an oxo.

### Claim 9 (depends on 1)

The method of claim 1, wherein R4 and R5 are each independently hydrogen or —CH3.

### Claim 10 (depends on 1)

The method of claim 1, wherein R6 is —COOH, —COO—(C1-20 unsubstituted alkyl), —CONH2, or —CONH-(C1-20 unsubstituted alkyl).

### Claim 11 (depends on 10)

The method of claim 10, wherein R6 is —COOH or —COO-(n-octyl).

### Claim 12 (depends on 1)

The method of claim 1, wherein:
R1 is hydrogen, —OH, —O-(C1-20 substituted alkyl) or —O-(C1-20 unsubstituted alkyl);
R2 and R3 are each independently hydrogen, —OR7, or —NR8R9; or R2 and R3 form an oxo together with the atom to which they are bound;
R4 and R5 are each independently hydrogen or —CH3; and
R6 is —COOH, —COO-(C1-20 unsubstituted alkyl), —COO-(C1-20 substituted alkyl), CONH2, —CONH-(C1-20 unsubstituted alkyl), or —CONH-(C1-20 substituted alkyl).

### Claim 13 (depends on 12)

The method of claim 12, wherein R1 is —OH and R6 is —COO-(C1-20 unsubstituted alkyl); or R1 is —O-(C1-20 unsubstituted alkyl) and R6 is —COOH.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound of Formula II is administered during or after an event that causes IR injury or reperfusion injury.

### Claim 15 (depends on 14)

The method of claim 14, wherein the compound of Formula II is administered within 1 to 2 hours of the event.

### Claim 16 (depends on 14)

The method of claim 14, wherein the event is a myocardial infarction.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound of Formula II is administered as a single dose.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound of Formula II is administered to the subject in combination with an additional therapeutic agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein the additional therapeutic agent is oligomycin or aspirin.

### Claim 20 (depends on 1)

The method of claim 1, wherein the tissue is cardiac tissue.