Aminoglycosides and uses thereof in the treatment of genetic disorders

Patent metadata

Field	Value
Publication number	US-10159689-B2
Application number	US-201715817412-A
Country	US
Kind code	B2
Filing date	Nov 20, 2017
Priority date	Apr 3, 2006
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

A new class of paromomycin-derived aminoglycosides, which exhibit efficient stop-codon mutation suppression activity, low toxicity and high selectivity towards eukaryotic cells are provided. Also provided are chemical and chemo-enzymatic processes of preparing these paromomycin-derived aminoglycosides and intermediates thereof, as well as pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders.

First claim

What is claimed is:

1. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, said premature stop codon mutation being associated with a genetic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, at least one of R 1 , R 2 and R 3 being a monosaccharide moiety having the general Formula II:

wherein each of R 6 , R 7 and R 8 is independently selected from the group consisting of hydroxyl and amine, or R 1 being an oligosaccharide moiety,
whereas when R 2 is said monosaccharide moiety having said Formula II, R 6 is amine;
X is oxygen or sulfur;
R 4 is (S)-4-amino-2-hydroxybutyryl (AHB);
R 5 is hydroxyl;
Y is hydrogen or alkyl; and
each of the dashed lines indicates independently an R configuration or an S configuration,
the method further comprising administering to the subject another agent useful in the treatment of said genetic disorder.

2. The method of claim 1 , wherein said compound is:

3. The method of claim 1 , wherein X is oxygen.

4. The method of claim 1 , wherein Y is hydrogen.

5. The method of claim 1 , wherein at least one of R 1 , R 2 and R 3 is a disaccharide moiety.

6. The method of claim 1 , wherein Y is alkyl.

7. The method of claim 1 , 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 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.

8. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, said premature stop codon mutation being associated with a genetic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, hydroxyl, amine or an oligosaccharide moiety, and at least one of R 1 , R 2 and R 3 being a monosaccharide moiety having the general Formula II:

wherein each of R 6 , R 7 and R 8 is independently selected from the group consisting of hydroxyl and amine, or R 1 being an oligosaccharide;
X is oxygen or sulfur;
R 4 is hydrogen;
R 5 is hydroxyl;
Y is hydrogen; and
each of the dashed line indicates independently an R configuration or an S configuration,
with the proviso that said compound is not selected from the group consisting of

and paromomycin,
the method further comprising administering to the subject another agent useful in the treatment of said genetic disorder.

9. The method of claim 8 , wherein X is oxygen.

10. The method of claim 8 , wherein said compound is:

11. The method of claim 7 , 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 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.

12. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, said premature stop codon mutation being associated with a genetic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety,
X is oxygen or sulfur;
R 4 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB);
R 5 is hydroxyl or amine;
Y is alkyl; and
each of the dashed line indicates independently an R configuration or an S configuration,
and wherein:
at least one of R 1 , R 2 and R 3 is selected from a monosaccharide moiety and an oligosaccharide moiety; and/or
R 4 is (S)-4-amino-2-hydroxybutyryl (AHB),
with the proviso that said compound is not G-418,
the method further comprising administering to the subject another agent useful in the treatment of said genetic disorder.

13. The method of claim 12 , wherein X is oxygen.

14. The method of claim 12 , wherein R 5 is hydroxyl.

15. The method of claim 12 , wherein at least one of R 1 , R 2 and R 3 is a monosaccharide moiety.

16. The method of claim 15 , wherein R 4 is AHB.

17. The method of claim 12 , wherein said compound is:

18. The method of claim 12 , 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 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.

19. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, said premature stop codon mutation being associated with a genetic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide m

Assignees

• Technion Res & Dev Foundation

Inventors

• Baasov Timor
• Ben-Yosef Tamar
• Nudelman Igor
• Rebibo-Sabbah Annie
• Shallom-Shezifi Dalia
• Hainrichson Mariana

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P21/04

  for myasthenia gravis · CPC title

• C07H5/06

  Aminosugars · CPC title