# US 10,870,658 B2 · Aldose reductase inhibitors and methods of use thereof

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- Number: US 10,870,658 B2
- Document ID: US10870658B2
- Status: Granted
- Kind: B2
- Application number: 16/835,876
- Filed: 2020-03-31
- Published: 2020-09-10
- Granted: 2020-12-22
- Earliest claimed: 2016-06-21
- Assignees: The Trustees of Columbia University in the City of New York
- Applicants: The Trustees of Columbia University in the City of New York
- Inventors: Andrew Wasmuth; Donald W. Landry
- Web page: https://patentgrep.com/patent/US10870658B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61K 8/4986: {with sulfur as the only hetero atom}
- 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 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/02: for peripheral neuropathies
- A61Q 19/08: Anti-ageing preparations
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.

## Claims

### Claim 1

A method for inhibiting aldose reductase activity in a subject, comprising administering to a subject who has neuropathy a therapeutically effective amount of a compound of Formula (I)
wherein,
R1 is CO2R2;
R2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl;
X1 is H or halogen;
X2 is H or halogen;
Y is a bond, C═O, C═S, C═NH, or C═N(C1-C4)-alkyl;
Z is
A1 is NR7, O, S or CH2;
A2 is N or CH;
A3 is NR7, O, or S;
R3 through R6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl;
R7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein
Z is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein
R2 is hydrogen or (C1-C6)-alkyl;
Y is C═O;
A1 is NR7, O, or S;
A2 is N;
R3 through R6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and
R7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein
Z is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein
R2 is hydrogen or (C1-C6)-alkyl;
Y is C═O;
R3 through R6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and
R7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

### Claim 6

A method for inhibiting aldose reductase activity in a subject, comprising administering to a subject who has neuropathy a therapeutically effective amount of a compound of Formula (I)
wherein,
R1 is CO2R2;
R2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl;
X1 is H;
X2 is H;
Y is C═O;
Z is
A1 is S;
A2 is N; and
R3 through R6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein R2 is (C1-C6)-alkyl.

### Claim 8 (depends on 7)

The method of claim 7, wherein R3 through R6 are independently hydrogen, halogen, or haloalkyl.

### Claim 9 (depends on 6)

The method of claim 6, wherein R2 is (C1-C6)-hydroxyalkyl.

### Claim 10 (depends on 9)

The method of claim 9, wherein R3 through R6 are independently hydrogen, halogen, or haloalkyl.

### Claim 11 (depends on 6)

The method of claim 6, wherein R2 is (C1-C6)-aminoalkyl.

### Claim 12 (depends on 11)

The method of claim 11, wherein R3 through R6 are independently hydrogen, halogen, or haloalkyl.

### Claim 13 (depends on 6)

The method of claim 6, wherein R2 is H.

### Claim 14 (depends on 13)

The method of claim 13, wherein R3 through R6 are independently hydrogen, halogen, or haloalkyl.

### Claim 15 (depends on 6)

The method of claim 6, wherein R3, R5, and R6 are each hydrogen; and R4 is hydrogen, halogen, or haloalkyl.

### Claim 16 (depends on 7)

The method of claim 7, wherein R3, R5, and R6 are each hydrogen; and R4 is hydrogen, halogen, or haloalkyl.

### Claim 17 (depends on 9)

The method of claim 9, wherein R3, R5, and R6 are each hydrogen; and R4 is hydrogen, halogen, or haloalkyl.

### Claim 18 (depends on 11)

The method of claim 11, wherein R3, R5, and R6 are each hydrogen; and R4 is hydrogen, halogen, or haloalkyl.

### Claim 19 (depends on 13)

The method of claim 13, wherein R3, R5, and R6 are each hydrogen; and R4 is hydrogen, halogen, or haloalkyl.

### Claim 20 (depends on 6)

The method of claim 6, where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 21 (depends on 6)

The method of claim 6, where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 22 (depends on 6)

The method of claim 6, where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 23 (depends on 6)

The method of claim 6, where the compound of Formula (I) is
or a pharmaceutically acceptable salt or solvate thereof.