Aminoglycoside derivatives and uses thereof in treating genetic disorders

Abstract

Novel pseudo-disaccharide and pseudo-trisaccharide aminoglycosides, represented by Formulae I or Ia, as defined in the instant specification, designed to exhibit stop codon mutation readthrough activity, are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic diseases and disorders, such as diseases and disorders associated with stop codon mutations.

1 . A compound represented by general formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         the dashed lines indicates a stereo-configuration of position 6′ being an R configuration or an S configuration; 
         R 1  is alkyl, cycloalkyl or aryl; 
         R 2  is selected from a substituted or unsubstituted alkyl, OR′ and NR′R″, wherein each of R′ and R″ is independently selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkaryl, and an acyl; 
         R 4  is selected from hydrogen, acyl, an amino-substituted alpha-hydroxy acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkaryl and a cell-permealizable; and 
         R 3  is hydrogen or a monosaccharide moiety represented by Formula II: 
       
       
         
           
           
               
               
           
         
         wherein the curved line denotes a position of attachment; and 
         R 5  and R 6  are each independently selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted heteroaryl, acyl, and a cell-permealizable group, or, alternatively, R 5  and R 6  form together a heterocyclic ring, 
         provided that: 
         the compound is not gentamycin, geneticin, fortimycin; and 
         when R 2  is hydroxy or NR′R″, and R and R″ are each hydrogen, R 4  is not hydrogen, AHB or AHP, and/or at least one of R 5  and/or R 6 , if present, is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein R 3  is said monosaccharide moiety, the compound being represented by Formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is alkyl. 
     
     
         4 . The compound of  claim 3 , wherein said alkyl is methyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is OR′. 
     
     
         6 . The compound of  claim 5 , wherein R′ is hydrogen. 
     
     
         7 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein R 3  is hydrogen. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein R 5  and R 6  are each hydrogen. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein one of R 5  and R 6  is said cell-permealizable group. 
     
     
         18 . The compound of  claim 17 , wherein said cell-permealizable group is guanidinyl. 
     
     
         19 . The compound of  claim 17 , wherein R 4  is (S)-4-amino-2-hydroxybutyryl (AHB). 
     
     
         20 . The compound of  claim 17 , being selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . The pharmaceutical composition of  claim 21 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a genetic disorder. 
     
     
         23 . The compound of  claim 1 , for use in the treatment of a genetic disorder. 
     
     
         24 . Use of the compound of  claim 1  in the manufacture of a medicament for treating a genetic disorder. 
     
     
         25 . The composition, use or compound of  claim 22 , wherein said genetic disorder is associated with a premature stop codon mutation and/or a protein truncation phenotype. 
     
     
         26 . The composition, use or compound of  claim 13 , wherein said genetic disorder is selected from the group consisting of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome, Tay-Sachs disease, Becker muscular dystrophy (BMD), Congenital muscular dystrophy (CMD), Factor VII deficiency, Familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, Mucopolysaccharidosis, Nephropathic cystinosis, Polycystic kidney disease, Rett syndrome, Spinal muscular atrophy (SMA), X-linked nephrogenic diabetes insipidus (XNDI) and X-linked retinitis pigmentosa.