IP Library › Granted Patent US 8,691,511
Granted Patent B2
US 8,691,511 · App. 13/327,816 · Granted Apr 8, 2014

Hydroxylated 1,2,4-oxadiazole benzoic acid compounds, compositions thereof and their use in bioassays

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Quick Facts
Patent No.
US 8,691,511
App. No.
13/327,816
Granted
Apr 8, 2014
Kind
B2
Abstract

Novel hydroxylated 1,2,4-oxadiazole benzoic acid compounds, methods of using and pharmaceutical compositions comprising a hydroxylated 1,2,4-oxadiazole benzoic acid derivative are disclosed. The methods include methods of treating or preventing a disease ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, or ameliorating one or more symptoms associated therewith.

Claims (133)

1. A method for testing whether a compound increases the amount or activity of a protein encoded by an mRNA that contains a premature stop codon, comprising:

(a) contacting in vitro a composition comprising a cell extract or cell lysate and the mRNA with an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein:

Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, or aryloxyalkyl; and

X 1 ,X 2 , X 3 and X 4 are independently H or OH, and at least one of X 1 , X 2 , X 3 or X 4 is OH; and

(b) detecting the amount or activity of the protein, wherein a compound that increases the amount or activity of the protein is detected if there is an increase in the amount or activity of the protein in the presence of the compound relative to the absence of the compound or the presence of a control.

2. The method of claim 1 , wherein the compound is:

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-5-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,6-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,5-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,3-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,5-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,5,6-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,6-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,5-trihydroxybenzoic acid;

5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,3,4-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,5,6tetrahydroxybenzoic acid;

3-[5-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxyl-benzoic acid;

3-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxyl-benzoic acid;

4-Hydroxy-3-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-(5-phenyl-[1,2,4]oxadiazol-3-yl)-4-benzoic acid;

3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxyl-benzoic acid;

4-Hydroxy-3-(5-phenyl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

3-[5-(4-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-yl]-hydroxy-benzoic acid;

3-[5-(4-tert-Butyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(Ethyl-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2,4-Dichloro-5-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(4-Cyano-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(4-Dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(5-Bromo-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2,3-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(5-Chloro-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

4-Hydroxy-3-(5-phenoxymethyl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

4-Hydroxy 3-[5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(3,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2-Fluoro-4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-hydroxy-benzoic acid;

3-[5-(2-Fluoro-5-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2,4,6-trichloro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(3-Cyano-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-(5-Biphenyl-4-yl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

3-[5-(2-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-(5-naphthalen-1-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

4-Hydroxy-3-[5-(3-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-(5-Butyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(3-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-(5-Butyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-(5-But-2-enyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-trifluoromethly-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

4-Hydroxy-3-[5-(3-sulfo-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(4-Bromo-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,

4-Hydroxy-3-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-benzoic acid, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

3. The method of claim 1 , wherein the compound is a compound having the structure:

4. A method for increasing the amount or activity of a protein encoded by an mRNA that contains a premature stop codon, comprising:

(a) contacting in vitro a cell containing the mRNA with an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein:

Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl, or aryloxyalkyl; and

X 1 , X 2 , X 3 and X 4 are independently H or OH, and at least one of X 1 , X 2 , X 3 or X 4 is OH; and

(b) detecting the amount or activity of the protein, wherein a compound that increases the amount or activity of the protein is detected if there is an increase in the amount or activity of the protein in the presence of the compound relative to the absence of the compound or the presence of a control.

5. The method of claim 4 , wherein the compound is:

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2-hydroxybenzoic acid;

5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-5-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,5-dihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4-dihydroxybenzoic acid;

5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroxybenzoic acid;

5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4-dihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]4,5-dihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,5,6-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,6-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,5-trihydroxybenzoic acid;

5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,3,4-trihydroxybenzoic acid;

3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2,4,5,6-tetrahydroxybenzoic acid;

3-[5-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hdyroxy-benzoic acid;

4-Hydroxy-3-(5-phenyl-[1,2,4]oxadiazol-3-yl)-4-benzoic acid;

3-[5-(4-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-3-Bromo-phenyl-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(4-tert-Butyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

3-[5-2,4-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-2,4-Dichloro-5-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(4-Cyano-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(4-Dimethylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(5-Bromo-pyridin-3-yl)-[1,2.4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2,3-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(5-Chloro-pyridin-3-yl)-[1,2.4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-hydroxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

4-Hydroxy-3-(5-phenoxymethyl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

4-Hydroxy-3-[5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(2,5-Difluoro-phenyl)-[1,2.4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(3,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2-Fluoro-4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-[5-(2-Fluoro-5-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2,4,6-trichloro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(3-Cyano-phenyl)-[1,2.4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-(5-Biphenyl-4-yl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

3-[5-(2-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

4-Hydroxy-3-(5-naphthalen-1-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;

4-Hydroxy-3-[5-(3-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-(5-Butyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-(5-But-2-enyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

4-Hydroxy-3-[5-(3-sulfo-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;

3-[5-(4-Bromo-phenyl)-[1,2,4]oxadiazol-3-yl]-4-hydroxy-benzoic acid;

3-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-4-hydroxy-benzoic acid;

4-Hydroxy-3-[5-(4-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid,

4-Hydroxy-3-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-benzoic acid, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

6. The method of claim 4 , wherein the compound is a compound having the structure:

7. The method of claim 1 , wherein the cell is from a patient.

8. The method of claim 4 , wherein the cell is from a patient.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Jul 14, 2020
From: MIDCAP FINANCIAL TRUST, AS AGENT
To: PTC THERAPEUTICS, INC.
Reel/Frame 053209/0872 →
CORRECTIVE ASSIGNMENT TO CORRECT THE INCLUSION OF 6420591,6583309,6503713, 5843995,7029846,7056656, 6468969,6486305,6630294, 6989256,6627398,8247167, 9017935 PREVIOUSLY RECORDED ON REEL 042418 FRAME 0774. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 24, 2017
From: PTC THERAPEUTICS, INC.
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 043672/0096 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2017
From: ALMSTEAD, NEIL G.; HWANG, PETER SEONGWOO; MOON, YOUNG-CHOON; WELCH, ELLEN M.
To: PTC THERAPEUTICS, INC.
Reel/Frame 043141/0715 →
SECURITY INTEREST Recorded May 8, 2017
From: PTC THERAPEUTICS, INC.
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 042418/0774 →