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US 7,247,741 B2Granted
Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
AssigneesPTC Therapeutics, Inc., Amgen Inc.
InventorsRichard G. Wilde, Ellen M. Welch, James Jan Takasugi, Neil G. Almstead, Steven Marc Rubenstein, Holger Beckmann
Life of this patent
Estimating the term…
Abstract
Novel acetylamino benzoic acid compounds, methods of using and pharmaceutical compositions comprising an acetylamino 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.
Claims9
A compound of the formula I:
- or pharmaceutically acceptable salts, hydrates, clathrates, prodrugs, polymorphs, stereoisomers, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, thereof wherein:
- X is oxygen, sulfur, SO or S(O)2;
- Y is oxygen or sulfur;
- Z is para or meta substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, acridinyl, oxazolyl, benzo[1,3]dioxole or 2,3-dihydro-benzo[1,4]dioxine, substituted or unsubstituted cycloalkyl;
- n is an integer from 0 to 4;
- R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, SO2R7, CF3, CN, COOH, COR7, or COOR7;
- R0 is hydrogen, or taken together with R1 and the atoms to which they are attached form an optionally substituted 5–7 membered heterocyclic, or heteroaryl ring;
- R2, R3, R4 and R5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF3, OCF3, OCHF2, CN, COOH, COOR7, SO2R7, NO2, NH2, or N(R7)2;
- R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or any biohydrolyzable group;
- and
- each occurrence of R7 is independently hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen or CF3;
- with the proviso that when X is O, Y is O, n is 0 and R1 is hydrogen, then Z is not 4-chlorophenyl, 4-methylphenyl, 3-chlorophenyl, or 2,4-dichlorophenyl;
- and with the proviso that when X is O, Y is O, n is O, R1 is hydrogen, and Z is phenyl at least one of R2–R5 is not hydrogen;
- and with the proviso that when R3 is COOH, R2, R4, and R5 are not all halogen.
14 more elements
A compound having the formula:
- or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, or stereoisomer thereof wherein:
- X is oxygen or sulfur;
- Z is para or meta substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinnolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, acridinyl, oxazolyl, benzo[1,3]dioxole or 2,3-dihydro-benzo[1,4]dioxine, substituted or unsubstituted cycloalkyl;
- R1 is hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, SO2R7, CF3, COOH, COR7, or COOR7;
- R2, R3, R4 and R5 are independently hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF3, OCF3, OCHF2, CN, COOH, COOR7, SO2R7, NO2, NH2, or NR72;
- and
- R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or any biohydrolyzable group;
- and
- each occurrence of R2 is independently hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen or CF3;
- with the proviso that when X is O and R1 is hydrogen, then Z is not 4-chlorophenyl, 4-methylphenyl, 3-chlorophenyl, or 2,4-dichlorophenyl;
- and with the proviso that when X is O, R1 is hydrogen, and Z is phenyl at least one of R2–R5 is not hydrogen;
- and with the proviso that when R3 is COOH, R2, R4, and R5 are not all halogen.
12 more elements
A compound having the formula:
- or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, or stereoisomer thereof wherein:
- X is oxygen or sulfur;
- Z is para or meta substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, acridinyl, oxazolyl, benzo[1,3]dioxole or 2,3-dihydro-benzo[1,4]dioxine, substituted or unsubstituted cycloalkyl;
- R1 is hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, SO2R2,CF3, CN, COOH, COR2, or COOR2;
- R′ is hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF3, OCF3, OCHF2, CN, COOR2, SO2, NO2, NH2, or NR22;
- R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or any biohydrolyzable group;
- and
- each occurrence of R2 is independently hydrogen, substituted or unsubsituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen or CF3;
- with the proviso that when R1 is hydrogen, then Z is not 4-chlorophenyl, 4-methylphenyl, 3-chlorophenyl, or 2,4-dichlorophenyl.
9 more elements
A compound having the formula:
- or pharmaceutically acceptable salts, hydrates, clathrates, prodrugs, polymorphs, stereoisomers, including enantiomers, diastereomers, racemates or mixtures of stereoisomers, thereof wherein:
- Z is para or meta substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzoquinazolinyl, acridinyl, oxazolyl, benzo[1,3]dioxole or 2,3-dihydro-benzo[1,4]dioxine, substituted or unsubstituted cycloalkyl;
- R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, SO2R7, CF3, CN, COOH, COR7, or COOR7;
- R0 is hydrogen, or taken together with R1 and the atoms to which they are attached form an optionally substituted 5–7 membered heterocyclic, or heteroaryl ring;
- R′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
- substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF3, OCF3, OCHF2, CN, COOH, COOR7, SO2R7, NO2, NH2, or N(R7)2;
- and
- R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or any biohydrolyzable group.
6 more elements
A compound selected from the group consisting of:
- 3-[2-(4-isopropyl-3-methyl-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(3-isopropyl-5-methyl-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(4-trifluoromethoxy-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(4-iodo-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(indan-5-ylpxy)-acetylamino]-benzoic acid;
- 3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetylamino]-benzoic acid;
- 3-{2-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-acetylamino}-benzoic acid;
- 3-[2-(4-tert-butyl-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(4-cyclopentyl-phenoxy)-acetylamino]-benzoic acid;
- 3-{2-[4-(1,1-dimethyl-propyl)-phenoxy]acetylamino)-benzoic acid;
- 3-[2-(4-propyl-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(4-trifluromethyl-phenoxy)-acetylamino-benzoic acid;
- 3-[2-(3,4-dichloro-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(4-Isopropyl-phenoxy)-acetylamino]-benzoic acid;
- 3-[2-(2′-methyl-biphenyl-4-yloxy)-acetylamino]-benzoic acid;
- 3-[2-(3′-methyl-biphenyl-4yloxy)-acetylamino-benzoic acid;
- 4-chloro-3-[2-(4-isopropyl-3-methyl-phenoxy)-acetylamino]-benzoic acid;
- 3-{N-[2-(4-isopropyl-3-methyl-phenoxy)-acetyl-N-methylamino]}-benzoic acid;
- 3-[2-(4-isopropyl-3-methyl-phenoxy)-thioacetylamino]-benzoic acid;
- 3-[3-(4-Isopropyl-phenoxy)-2-oxo-pyrrolidin-1-yl]-benzoic acid;
- 3-[3-(4-Isopropyl-phenoxy)-2-oxo-pyrrolidin-1-yl]-benzoic acid Sodium Salt;
- 3-[3-(Indan-5-yloxy)-2-oxo-pyrrolidin-1-yl]-benzoic acid;
- 3-[3-(Benzo[1,3]dioxol-5-yloxy)-2-oxo-pyrrolidin-1-yl]-benzoic acid;
- 3-{2-Oxo-3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-pyrrolidin-1-yl}-benzoic acid;
- 3-[3-(3-Ethyl-phenoxy)-2-oxo-pyrrolidin-1-yl]-benzoic acid;
- 3-[2-Oxo-3-(4-phenoxy-phenoxy)-pyrrolidin-1-yl]-benzoic acid and pharmaceutically acceptable salts, hydrates, solvates, clathrates and stereoisomers thereof.
23 more elements
Dependencies are inferred from the claim text.