# US 2024/0189291 A1 · Prevention And Treatment Of Atrial Fibrillation/Flutter With Gamma-Ketoaldehyde Scavengers

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- Number: US 2024/0189291 A1
- Document ID: US20240189291A1
- Status: Published application
- Kind: A1
- Application number: 18/414,316
- Filed: 2024-01-16
- Published: 2024-06-13
- Earliest claimed: 2016-07-07
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Katherine T. Murray; L Jackson Roberts, II; Venkataraman Amarnath
- Web page: https://patentgrep.com/patent/US20240189291A1

## CPC

- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- 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 31/4415: Pyridoxine, i.e. Vitamin B6 (pyridoxal phosphate A61K31/675)
- A61P 9/06: Antiarrhythmics
- 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

Methods and compositions for use in treating atrial fibrillation in a subject. The compounds of the present invention are gamma-ketoaldehyde scavengers.

## Claims

### Claim 1

A method for treating, or ameliorating atrial arrhythmias to a subject with or at risk of an atrial arrhythmia, comprising the step of administrating to said subject an effective amount of a compound of the following formula:
wherein:
R is C;
R2 is independently H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R2, R3 and R4, and may cyclize with to one or more R2, R3, or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R3 is H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2 or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R4 is H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2, R3, or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R5 is a bond, H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2, R3, or R4 to form an optionally substituted C3-8 membered ring containing C, O, S or N; and stereoisomers and analogs thereof.
In certain embodiments, the compound may be selected from the compounds disclosed herein. In a preferred embodiment, the compound may be salicylamine.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is of the following formula:
wherein:
R2 is independently H, substituted or unsubstituted alkyl;
R3 is H, halogen, alkoxy, hydroxyl, nitro;
R4 is H, substituted or unsubstituted alkyl, carboxyl; and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is salicylamine (2-hydroxybenzylamine or 2-HOBA).

### Claim 4 (depends on 1)

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

### Claim 5

A method for treating, preventing, or ameliorating atrial fibrillation to a subject with or at risk of atrial fibrillation, thereby inhibiting or treating the atrial fibrillation, comprising the step of co-administering to the subject at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a compound of the following formula:
wherein:
R is C;
R2 is independently H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R2, R3 and R4, and may cyclize with to one or more R2, R3, or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R3 is H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2 or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R4 is H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2, R3, or R5 to form an optionally substituted C3-8 membered ring containing C, O, S or N;
R5 is a bond, H, hydroxy, halogen, nitro, CF3, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize with to one or more R2, R3, or R4 to form an optionally substituted C3-8 membered ring containing C, O, S or N; and stereoisomers and analogs thereof; with a drug having a known side effect of treating, preventing, or ameliorating atrial fibrillation.

### Claim 6 (depends on 5)

The method of claim 5, wherein the compound is selected from the formula:
wherein:
R is N or C;
R2 is independently H, substituted or unsubstituted alkyl;
R3 is H, halogen, alkoxy, hydroxyl, nitro;
R4 is H, substituted or unsubstituted alkyl, carboxyl; and pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 5)

The method of claim 5, wherein the compound is salicylamine (2-hydroxybenzylamine or 2-HOBA).

### Claim 8 (depends on 5)

The method of claim 5, wherein the compound is selected from the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 9

A method for treating, preventing, or ameliorating atrial arrhythmias in a subject with atrial stretch, comprising the step of administering to said subject an effective amount of a compound of the following formula:
wherein:
R is C;
R2 is independently H or C1-6 alkyl;
R3 is H, or C1-6 alkyl;
R4 is H;
R5 is H, or C1-6 alkyl;
and stereoisomers and analogs thereof; or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein the compound is 2-hydroxybenzylamine, ethyl-2-hydroxybenzylamine, or methyl-2-hydroxybenzylamine.

### Claim 11 (depends on 9)

The method of claim 9, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 9)

The method of claim 9, wherein the risk factor is at least one of obesity or hypertension.

### Claim 13 (depends on 9)

The method of claim 9, wherein the risk factor is obesity.