# US 8,772,295 B2 · Modulators of aldehyde dehydrogenase and methods of use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,772,295 B2
- Document ID: US8772295B2
- Status: Granted
- Kind: B2
- Application number: 13/747,106
- Filed: 2013-01-22
- Published: 2013-10-10
- Granted: 2014-07-08
- Earliest claimed: 2008-10-28
- Assignees: The Board of Trustees of the Leland Stanford Junior University
- Applicants: The Board of Trustees of the Leland Stanford Junior University
- Inventors: Daria Mochly-Rosen; Che-Hong Chen; Wenjin Yang
- Web page: https://patentgrep.com/patent/US8772295B2

## CPC

- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/16: Emollients or protectives, e.g. against radiation
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/32: Alcohol-abuse
- A61P 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 39/02: Antidotes
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 233/29: having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
- C07D 241/18: Oxygen or sulfur atoms
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/14: Nitrogen atoms
- C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52)
- C07D 317/60: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure provides compounds that function as modulators of aldehyde dehydrogenase (ALDH) enzymatic activity, as well as compositions and formulations comprising the compounds. The present disclosure provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition.

## Claims

### Claim 1

A compound of Formula Ic:
wherein Xn and Xy are each independently H, C, N, O, or a halogen; where n is the integer 0 or 1; where y is the integer 0 or 1;
wherein (dotted line) is an optional bond;
wherein z is the integer 0, 1, or 2, with the provisos that: 1) z =0 when X =halogen and is not a bond; and 2) when z =0, X =O, is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group;
where Ar is selected from a substituted phenyl and a substituted thiophene group; wherein the phenyl group is substituted with one or more C1 to C7 alkyl and an isoxazolyl group, and the thiophene group is substituted with C(O)NH2;
or a pro-drug, a pharmaceutically acceptable salt, or a derivative thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Xn and Xy are both O.

### Claim 3 (depends on 1)

The compound of claim 1, wherein z is 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ar is a substituted phenyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the phenyl is substituted with a methyl group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the isoxazolyl group is substituted with one or more methyl groups.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Ar is a substituted thiophene group.

### Claim 8

A compound having a structure selected from:

### Claim 9 (depends on 1)

A pharmaceutical composition comprising:
a) a compound of claim 1; and
b) a pharmaceutically acceptable excipient.

### Claim 10 (depends on 8)

A pharmaceutical composition comprising:
a) a compound of claim 8; and
b) a pharmaceutically acceptable excipient.

### Claim 11 (depends on 1)

A method of reducing a level of aldehyde present at a toxic level in an individual to below the toxic level comprising administering to an individual an effective amount of a compound of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the individual has alcohol intolerance, alcohol addiction, or an alcohol abuse disorder.

### Claim 13 (depends on 1)

A method of treating a disease or disorder selected from alcohol intolerance, alcohol addiction, alcohol abuse disorder, methanol poisoning, ethylene glycol monomethyl ether poisoning, and poisoning due to other xenogenic or biogenic aldehyde compounds, comprising administering to an individual an effective amount of a compound of claim 1.

### Claim 14 (depends on 13)

The method of claim 13, wherein the disease or disorder is alcohol addiction.

### Claim 15 (depends on 13)

The method of claim 13, wherein the disease or disorder is alcohol intolerance.

### Claim 16 (depends on 13)

The method of claim 13, wherein the individual is heterozygous or homozygous for the ALDH2*2 allele.

### Claim 17 (depends on 13)

The method of claim 13, wherein the compound is administered parenterally or orally.

### Claim 18 (depends on 1)

A method of detoxifying alcohol in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of claim 1.

### Claim 19

A pharmaceutical composition comprising:
a) a compound having the structure:
and
b) a pharmaceutically acceptable excipient.

### Claim 20 (depends on 19)

A method of reducing a level of aldehyde present at a toxic level in an individual to below the toxic level comprising administering to an individual an effective amount of a pharmaceutical composition of claim 19.

### Claim 21 (depends on 19)

A method of treating a disease or disorder selected from alcohol intolerance, alcohol addiction, alcohol abuse disorder, methanol poisoning, ethylene glycol monomethyl ether poisoning, and poisoning due to other xenogenic or biogenic aldehyde compounds, comprising administering to an individual an effective amount of a pharmaceutical composition of claim 19.