Compounds for Nonsense Suppression, and Methods for Their Use

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.

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 system disease, heart disease, kidney disease, a muscular dystrophy, macular degeneration, retinitis pigmentosa, amyloidosis, giantism, dwarfism, hypothyroidism, hyperthyroidism, aging or obesity. 
       
     
     
         94 . The method of  claim 93 , wherein the autoimmune disease is immunodeficiency, severe combined immunodeficiency, rheumatoid arthritis or graft versus host disease; wherein the blood disease is familial polycythemia, hemophilia, Von Willebrand disease, ataxia-telangiectasia or β-thalassemia; wherein the collagen disease is epidermolysis bullosa, Marfan syndrome, osteogenesis imperfecta or cirrhosis; wherein the inflammatory disease is arthritis, rheumatoid arthritis or osteoarthritis; wherein the central nervous system disease is multiple sclerosis, classical late infantile neuronal ceroid lipofuscinosis, Alzheimer's disease or Tay Sachs disease; wherein the lysosomal storage disorder is tuberous sclerosis, Niemann Pick disease, mucopolysaccharidosis type VII, metachromatic leukodystrophy, Sandhoff disease, mucopolysaccharidosis type IIIA or mucopolysaccharidosis type VI; wherein the kidney disease is kidney stones; wherein the cardiovascular disease is familial hypercholesterolemia or atherosclerosis; wherein the pulmonary disease is cystic fibrosis; and, wherein the muscular dystrophy is Duchenne muscular dystrophy. 
     
     
         95 . The method of  claim 93 , wherein the disease is cancer associated with a genetic or a somatic nonsense mutation in a tumor suppressor gene in a human subject in need thereof. 
     
     
         96 . The method of  claim 95 , wherein the tumor suppressor gene is selected from the group consisting of PTEN, BRCA1, BRCA2, Rb, and p53. 
     
     
         97 . The method of  claim 95 , wherein the cancer is of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenals. 
     
     
         98 . The method of  claim 95 , wherein the cancer is a solid tumor cancer selected from sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma or retinoblastoma. 
     
     
         99 . The method of  claim 95 , wherein the cancer is a blood-born tumor selected from acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma. 
     
     
         100 . The method of  claim 93 , for inhibiting the growth of a cancer cell or for selectively producing a protein in a mammal by the suppression of a genetic or somatic nonsense mutation. 
     
     
         101 . The method of  claim 93 , wherein the compound of Formula 1-A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salt, hydrate, solvate, clathrate, polymorph, racemate or stereoisomer thereof.