Compounds for Nonsense Suppression, and Methods for Their Use

Patent metadata

Field	Value
Publication number	US-2016229818-A1
Application number	US-201615130318-A
Country	US
Kind code	A1
Filing date	Apr 15, 2016
Priority date	Oct 13, 2004
Publication date	Aug 11, 2016
Grant date	—

Abstract

The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

First claim

1 - 84 . (canceled)

85 . A compound of Formula 1-A:

wherein:
n is 0, 1, 2, or 3;
R a is hydrogen or a C 1 -C 4 alkyl group;
R 1 is a cyano group; a carbamoyl which is optionally substituted with one or two C 1 -C 4 alkyl groups; or a carbonyl group which is substituted with a hydroxy, a C 1 -C 4 alkyl, or a C 1 -C 4 alkoxy group;
R is independently selected from a hydroxy group; a halogen; a C 1 -C 4 alkyl which is optionally substituted with one or more independently selected halogen or hydroxy groups; a C 1 -C 4 alkoxy which is optionally substituted with one or more independently selected halogen or phenyl groups; a C 4 -C 8 cycloalkyl which is optionally substituted with one or more independently selected C 1 -C 4 alkyl groups; an —R b group; an —O—R b group; a five to six-membered heterocycle which is optionally substituted with one or more independently selected C 1 -C 4 alkyl, oxo, or —R b groups; a nine to ten membered heterocycle having two ring structures; a carbonyl which is substituted with a hydroxy, a C 1 -C 4 alkyl, or a C 1 -C 4 alkoxy group; a carbamoyl which is optionally substituted with one or two C 1 -C 4 alkyl groups; a nitro group; a cyano group; a thio which is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or —R b group; a sulfonyl which is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or —R b group; an amino which is optionally substituted with one or two independently selected C 1 -C 4 alkyl, sulfonyl, or carbonyl groups, wherein the aminosulfonyl group is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or an —R b group and wherein the aminocarbonyl group is optionally substituted with a C 1 -C 4 alkyl, a C 1 -C 4 haloalkyl, a benzoxy, or an amino group which is optionally substituted with an —R b group; or two R groups together with the phenyl ring to which they are attached form a benzo[1,3]dioxole or a 2,3-dihydro-benzo[1,4]dioxinyl group; wherein
—R b is a C 6 -C 8 aryl which is optionally substituted with one or more of the following: a hydroxy, a halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 alkoxy group, or an amino group which is optionally substituted with one or more C 1 -C 4 alkyl groups;
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof.

86 . The compound of claim 85 , wherein
n is 0, 1 or 2; R a is hydrogen or a C 1 -C 4 alkyl group, R 1 is a cyano group; a carbamoyl; or a carbonyl group which is substituted with a hydroxy; R is independently selected from a hydroxy group; a halogen; a C 1 -C 4 alkyl which is optionally substituted with one or more independently selected halogen; a C 1 -C 4 alkoxy which is optionally substituted with one or more independently selected halogen groups; an —R b group; a five to six-membered heterocycle; an amino which is optionally substituted with one or two independently selected C 1 -C 4 alkyl; or two R groups together with the phenyl ring to which they are attached form a benzo[1,3]dioxole or a 2,3-dihydro-benzo[1,4]dioxinyl group; wherein —R b is a C 6 -C 8 aryl; or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof.

87 . The compound of claim 86 , wherein R 1 is a carboxy group, and is located in a meta or para position.

88 . The compound of claim 86 , wherein R is independently selected from chloro, fluoro, bromo, methyl, isopropyl, tert-butyl, trifluromethyl, methoxy, ethoxy, trifluoromethoxy, amino, dimethylamino, or two R groups together with the phenyl ring to which they are attached form a 2,3-dihydro-benzo[1,4]dioxinyl group.

89 . The compound of claim 88 , wherein R is selected from methyl, fluoro, methoxy, ethoxy or trifluoromethyl.

90 . The compound of claim 86 , wherein R a is hydrogen or methyl.

91 . The compound of claim 89 , wherein R is located in one or more ortho position, one or more meta position, or a para position.

92 . The compound of claim 85 , wherein the compound of Formula 1-A is selected from the group consisting of:

and a pharmaceutically acceptable salt, hydrate, clathrate, polymorph, racemate or stereoisomer thereof.

93 . A method for preventing or treating a disease associated with a gene having a nonsense mutation encoding a premature stop codon in mRNA in a patient in need thereof, comprising administering to said patient a compound of Formula 1-A

wherein:
n is 0, 1, 2, or 3;
R a is hydrogen or a C 1 -C 4 alkyl group;
R 1 is a cyano group; a carbamoyl which is optionally substituted with one or two C 1 -C 4 alkyl groups; or a carbonyl group which is substituted with a hydroxy, a C 1 -C 4 alkyl, or a C 1 -C 4 alkoxy group;
R is independently selected from a hydroxy group; a halogen; a C 1 -C 4 alkyl which is optionally substituted with one or more independently selected halogen or hydroxy groups; a C 1 -C 4 alkoxy which is optionally substituted with one or more independently selected halogen or phenyl groups; a C 4 -C 8 cycloalkyl which is optionally substituted with one or more independently selected C 1 -C 4 alkyl groups; an —R b group; an —O—R b group; a five to six-membered heterocycle which is optionally substituted with one or more independently selected C 1 -C 4 alkyl, oxo, or —R b groups; a nine to ten membered heterocycle having two ring structures; a carbonyl which is substituted with a hydroxy, a C 1 -C 4 alkyl, or a C 1 -C 4 alkoxy group; a carbamoyl which is optionally substituted with one or two C 1 -C 4 alkyl groups; a nitro group; a cyano group; a thio which is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or —R b group; a sulfonyl which is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or —R b group; an amino which is optionally substituted with one or two independently selected C 1 -C 4 alkyl, sulfonyl, or carbonyl groups, wherein the aminosulfonyl group is optionally substituted with a hydroxy, a C 1 -C 4 alkyl, or an —R b group and wherein the aminocarbonyl group is optionally substituted with a C 1 -C 4 alkyl, a C 1 -C 4 haloalkyl, a benzoxy, or an amino group which is optionally substituted with an —R b group; or two R groups together with the phenyl ring to which they are attached form a benzo[1,3]dioxole or a 2,3-dihydro-benzo[1,4]dioxinyl group;
wherein —R b is a C 6 -C 8 aryl which is optionally substituted with one or more of the following: a hydroxy, a halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 alkoxy group, or an amino group which is optionally substituted with one or more C 1 -C 4 alkyl groups;
or a pharmaceutically acceptable salt, hydrate or solvate, clathrate, racemate, stereoisomer or polymorph thereof,
wherein the premature stop codon results in either or both premature mRNA translation termination or nonsense-mediated mRNA decay, and wherein the disease is selected from cancer, a lysosomal storage disorder, an autoimmune disease, a blood disease, a collagen disease, diabetes, a cardiovascular disease, a pulmonary disease, an inflammatory disease, a central nervous syst

Assignees

• Ptc Therapeutics Inc

Inventors

• Almstead Neil
• Karp Gary M
• Wilde Richard
• Welch Ellen
• Ren Hongyu

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title