# US 2014/0194481 A1 · Novel Pyrrole Inhibitors of S-Nitrosoglutathione Reductase as Therapeutic Agents

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- Number: US 2014/0194481 A1
- Document ID: US20140194481A1
- Status: Published application
- Kind: A1
- Application number: 14/204,875
- Filed: 2014-03-11
- Published: 2014-07-10
- Earliest claimed: 2008-08-15
- Assignees: N30 Pharmaceuticals, Inc.
- Applicants: N30 Pharmaceuticals, Inc.
- Inventors: Jan Wasley; Gary J. Rosenthal; Xicheng Sun; Sarah Strong; Jian Qiu
- Web page: https://patentgrep.com/patent/US20140194481A1

## CPC

- C07D 409/14: containing three or more hetero rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 15/10: for impotence
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/06: Antiglaucoma agents or miotics
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.

## Claims

### Claim 1

A method of treatment of heart failure, atherosclerosis, degenerative neurologic disorders, arthritis and liver injury (ischemic or alcoholic) comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein
Ar1 and Ar2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
X is selected from the group consisting of C or N;
Y is C when X is N, and N when X is C; and
n is 0-3;
to a patient in need thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein:
Ar1 is a substituted phenyl; and
Ar2 is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl.

### Claim 3 (depends on 1)

The method of claim 1 wherein:
Ar1 is
wherein
R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, CF3, carbamoyl, C1-C6 alkylcarbamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl R2 is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, amino, CF3, carboxyl, ureido, sulfamoylamino, C1-C6 sulfonamido, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R3 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkyl sulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl; and
Ar2 is selected from the group consisting of phenyl, 4-chlorophenyl, 3-chlorophenyl, 4-chloro-2-methoxyphenyl, 4-bromophenyl, 4-bromo-2-methoxyphenyl, 3-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorothiophen-2-yl, 5-chlorothiophen-2-yl, 3-bromothiophen-2-yl, 4-bromothiophen-2-yl, 5-bromothiopheny-2-yl, 5-bromothiophen-3-yl,
wherein
R4 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl; and
R5 is selected from the group consisting of hydrogen, methyl, and ethyl.

### Claim 4 (depends on 1)

The method of claim 1 wherein:
Ar2 is selected from the group consisting of phenyl, 4-chloro-2-methoxyphenyl, 4-bromophenyl, 4-bromo-2-methoxyphenyl, 4-methoxyphenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, and 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl.

### Claim 5 (depends on 3)

The method of claim 3 wherein:
R1 is selected from the group consisting of hydrogen and methyl;
R2 is selected from the group consisting of hydroxyl, carboxyl, carbamoyl, methylsulfonamido, and tert-butyl-carboxy; and
R3 is hydrogen.

### Claim 6 (depends on 1)

The method of claim 1 wherein the compound of formula I is selected from the group consisting of:
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzamide;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzoic acid;
tert-butyl 4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzoate;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)phenol;
4-(2-(4-(1H-imidazol-1-yl)phenyl)-5-(2-(1H-tetrazol-5-yl)ethyl)-1H-pyrrol-1-yl)phenol;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-(4-(1H-imidazol-1-yl)phenyl)-5-((1H-tetrazol-5-yl)methyl)-1H-pyrrol-1-yl)phenol;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)phenol;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-1-yl)phenol;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromo-2-methoxyphenyl)-1H-pyrrol-1-yl)phenol;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromo-2-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-1-yl)phenol;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)-3-methylbenzamide;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)phenol;
4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;
N-(4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)-3-methylphenyl)methanesulfonamide;
4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide; and
4-(1-((1H-tetrazol-5-yl)methyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide

### Claim 7 (depends on 1)

The method of claim 1 comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.

### Claim 8

A method of making a pharmaceutical composition comprising the step of combining a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein
Ar1 and Ar2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
X is selected from the group consisting of C or N;
Y is C when X is N, and N when X is C; and
n is 0-3;
with a pharmaceutically accepted carrier or excipient.