Compounds for nonsense suppression, and methods for their use
AssigneePTC Therapeutics, Inc.
InventorsJeffrey A. Campbell, Atiyya Kahn, James Takasugi, Ellen Welch
Life of this patent
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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.
Claims39
A method of treating or preventing a disease resulting from a somatic mutation comprising administration to a patient in need thereof an effective amount of a compound of Formula 1:
- wherein:
- X is a halogen;
- R is a C1-C8 alkyl group;
- a C1-C4 haloalkyl group;
- an —OR1 group;
- or an amino group which is optionally substituted with one or two independently selected R2 groups;
- R1 is a C1-C8 alkyl group which is optionally substituted with one or more independently selected Ra groups;
- a —Rb group;
- a pyrrolidinyl group which is optionally substituted with one or more independently selected C1-C4 alkyl or oxo groups;
- a piperidyl group which is optionally substituted with one or more independently selected C1-C4 alkyl groups, benzyl groups, or carboxy groups optionally substituted with one or more C1-C4 alkyl or C1-C4 alkoxy groups;
- a tetrahydro-furyl group;
- a tetrahydro-pyranyl group;
- a tetrahydro-naphthyl group;
- or an indanyl group;
- R2 is a hydrogen, a C1-C6 alkyl group;
- a C1-C4 haloalkyl group;
- a C1-C4 alkoxy group;
- a —Rb group;
- a pyrimidinyl group;
- a pyridyl group;
- a sulfonyl group optionally substituted with an —Rb group;
- or two R2 groups together with the amino to which they are attached form a morpholinyl group, a pyrrolidinyl group, an isoindolinyl group, or a piperazinyl group which is optionally substituted with a phenyl group;
- wherein Ra is a halogen;
- a C1-C4 alkoxy group;
- a carbamoyl group which is optionally substituted with one or two independently selected C1-C4 alkyl or C1-C4 alkoxy groups;
- a phosphinoyl group which is optionally substituted with one or two independently selected C1-C4 alkyl or C1-C4 alkoxy groups;
- a morpholinyl group;
- a pyridyl group;
- or an —Rb group;
- and
- wherein Rb is a C6-C8 aryl which is optionally substituted with one or more of the following, independently selected:
- a hydroxy, a halogen, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, or an amino group which is optionally substituted with one or more independently selected C1-C4 alkyl groups;
- or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer of said compound of Formula 1.
A method of treating or preventing an autoimmune disease, a blood disease, a collagen disease, diabetes, a neurodegenerative disease, a cardiovascular disease, a pulmonary disease, or an inflammatory disease or central nervous system disease comprising administration to a patient in need thereof an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, racemate or stereoisomer thereof.
A method of treating or preventing familial polycythemia, immunodeficiency, kidney disease, kidney stones, heart disease, ataxia-telangiectasia, cystic fibrosis, muscular dystrophy, familial hypercholesterolemia, retinitis pigmentosa, amyloidosis, hemophilia, Alzheimer's disease, Tay Sachs disease, Niemann Pick disease, Parkinson's disease, atherosclerosis, giantism, dwarfism, hypothyroidism, hyperthyroidism, aging, obesity, Duchenne muscular dystrophy, epidermolysis bullosa or Marfan syndrome comprising administration to a patient in need thereof an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, racemate or stereoisomer thereof.
A method of treating or preventing cancer in a human comprising administration to a human in need thereof an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, racemate or stereoisomer thereof.
A method of treating or preventing a disease associated with a mutation of the p53 gene comprising administration to a patient in need thereof an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, racemate or stereoisomer thereof.
A method of inhibiting the growth of a cancer cell comprising contacting the cancer cell with an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof.
A method for selectively producing a protein in a mammal comprising, transcribing a gene containing a nonsense mutation in the mammal;
- and
- providing an effective amount of a compound of Formula 1 to said mammal, wherein said protein is produced from said gene containing a nonsense mutation.
A compound of Formula 1:
- wherein:
- X is a halogen;
- R is a C1-C8 alkyl group;
- a C1-C4 haloalkyl group;
- an —OR1 group;
- or an amino group which is optionally substituted with one or two independently selected R2 groups;
- R1 is a C1-C8 alkyl group which is optionally substituted with one or more independently selected Ra groups;
- a —Rb group;
- a pyrrolidinyl group which is optionally substituted with one or more independently selected C1-C4 alkyl or oxo groups;
- a piperidyl group which is optionally substituted with one or more independently selected C1-C4 alkyl groups, benzyl groups, or carboxy groups optionally substituted with one or more C1-C4 alkyl or C1-C4 alkoxy groups;
- a tetrahydro-furyl group;
- a tetrahydro-pyranyl group;
- a tetrahydro-naphthyl group;
- or an indanyl group;
- R2 is a hydrogen, a C1-C6 alkyl group;
- a C1-C4 haloalkyl group;
- a C1-C4 alkoxy group;
- a —Rb group;
- a pyrimidinyl group;
- a pyridyl group;
- a sulfonyl group optionally substituted with an —Rb group;
- or two R2 groups together with the amino to which they are attached form a morpholinyl group, a pyrrolidinyl group, an isoindolinyl group, or a piperazinyl group which is optionally substituted with a phenyl group;
- wherein Ra is a halogen;
- a C1-C4 alkoxy group;
- a carbamoyl group which is optionally substituted with one or two independently selected C1-C4 alkyl or C1-C4 alkoxy groups;
- a phosphinoyl group which is optionally substituted with one or two independently selected C1-C4 alkyl or C1-C4 alkoxy groups;
- a morpholinyl group;
- a pyridyl group;
- or an —Rb group;
- and
- wherein Rb is a C6-C8 aryl which is optionally substituted with one or more of the following, independently selected:
- a hydroxy, a halogen, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, or an amino group which is optionally substituted with one or more independently selected C1-C4 alkyl groups;
- or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer of said compound of Formula 1.
A compound having the formula (Compound NO:
- 1):
Dependencies are inferred from the claim text.