Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof

#The present application is a National Entry Application of PCT application no. PCT/CA2013/050730 filed on Sep. 25, 2013 and published in English under PCT Article 21(2), which is herein incorporated by reference in its entirety.

#Pursuant to 37 C.F.R. 1.821(c), a sequence listing is submitted herewith as an ASCII compliant text file named 12810_575-Seq listing_ST25.txt, created on Mar. 10, 2016 and having a size of 2 kilobytes. The content of the aforementioned file is hereby incorporated by reference in its entirety.

#The present invention generally relates to polynucleotide repeat disorders such as trinucleotide repeat disorders, and more particularly to compounds and uses thereof such as for the treatment of diseases associated with the presence of polynucleotide repeats, such as myotonic dystrophy.

#In the appended drawings:

#FIG. 1 shows the symptoms of myotonic dystrophy;

#FIG. 2 shows DM1 patient fibroblasts with a 2000 CUG-triplet repeat expansion in the 3′UTR of the DMPK mRNA. This mutant mRNA forms nuclear foci which can be detected by fluorescent in situ hybridisation (FISH) (arrows);

#In the studies described herein, the present inventors have demonstrated that compounds having the structure of formula (1) and (2) defined below reduce the formation of mutant DMPK mRNA foci in DM1 patient myoblasts, have the capacity to correct the stabilization of the CUGBP1 alternative splicing factor in DM1 myoblasts, and correct the mis-splicing of specific mRNAs in DM1 cells. These compounds may thus be useful for the treatment of diseases associated with the accumulation of RNA foci (RNA aggregates), such as expanded polynucleotide (e.g, trinucleotide) repeat disorders.

#Accordingly, in a first aspect, the present invention provides method for treating a polynucleotide repeat disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (1), (2), or (3):

#wherein: R1 is: aryl, heteroaryl, arylmethyl, or heteroarylmethyl, said aryl, heteroaryl, arylmethyl, and heteroarylmethyl being optionally substituted on the aryl ring or on the methyl group by alkyl, alkenyl, or alkynyl, and said heteroaryl and heteroarylmethyl comprising only oxygen and/or nitrogen atoms as heteroatom(s), or alkyl, alkenyl or alkynyl, said alkyl, alkenyl and alkynyl being substituted by cycloalkyl, cycloalkenyl or cycloalkynyl, R2 and R3 are: a hydrogen atom, alkyl, alkenyl, or alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, an aryl free of heteroatom, aralkyl, or an aliphatic heterocycle, with the proviso that at least one of R2 and R3 is not a hydrogen atom or a C1-C2 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a 6- or more membered, optionally substituted, aromatic or aliphatic heterocycle, optionally comprising one or more additional nitrogen atom, R4 and R5 are: a hydrogen atom, alkyl, alkenyl, or alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, an aryl free of heteroatom, aralkyl, or an aliphatic heterocycle, with the proviso that at least one of R4 and R5 is not a hydrogen atom or a C1-C2 alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, form a 6 membered, optionally substituted, aromatic or aliphatic heterocycle, optionally comprising one or more additional nitrogen or oxygen atom, R6 is H, halogen, or C1-C8 alkyl optionally substituted with one or more halogen atoms, R7 is C1-C8 alkyl optionally substituted with one or more halogen atoms, R8 and R9 are independently alkyl, alkenyl, or alkynyl, said alkyl, alkenyl, and alkynyl being substituted by optionally substituted aryl or optionally substituted thioaryl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5- or more membered, optionally substituted, aromatic or aliphatic heterocycle, optionally comprising one or more additional nitrogen atom, and substituted with optionally substituted aryl, with the proviso that when R7 is C1 alkyl, R8 and R9 are independently alkyl, alkenyl, or alkynyl, said alkyl, alkenyl, and alkynyl being substituted by aryl or thioaryl, or a pharmaceutically acceptable salt thereof.