Aminoglycosides and uses thereof in treating genetic disorders

Patent metadata

Field	Value
Publication number	US-9943533-B2
Application number	US-201715453990-A
Country	US
Kind code	B2
Filing date	Mar 9, 2017
Priority date	Nov 18, 2010
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

A new class of pseudo-trisaccharide aminoglycosides having an alkyl group at the 5″ position, exhibiting efficient stop codon mutation readthrough activity, low cytotoxicity and high selectivity towards eukaryotic translation systems are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders, as well as processes of preparing these aminoglycosides. The disclosed aminoglycosides can be represented by the general formula I:

or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of alkyl, cycloalkyl and aryl; and all other variables and features are as described in the specification.

First claim

What is claimed is:

1. A method for treating a genetic disorder 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 in a subject in need thereof, the method comprising co-administering to the subject a therapeutically effective amount of a compound having the general formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of alkyl, cycloalkyl and aryl;
R 2 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB);
R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; and
a stereo-configuration of each of position 6′ and position 5″ is independently an R configuration or an S configuration,
and an additional agent usable in treating said genetic disorder.

2. The method of claim 1 , wherein R 1 is alkyl.

3. The method of claim 2 , wherein said alkyl is methyl.

4. The method of claim 1 , wherein R 2 and R 3 are each hydrogen.

5. The method of claim 1 , wherein R 2 is AHB and R 3 is hydrogen.

6. The method of claim 1 , wherein R 2 is hydrogen and R 3 is alkyl.

7. The method of claim 1 , wherein R 2 is AHB and R 3 is alkyl.

8. The method of claim 7 , wherein said alkyl is methyl.

9. The method of claim 1 , wherein said compound is selected from the group consisting of:

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

11. The method of claim 1 , wherein said compound is characterized by a ratio of IC 50 translation inhibition in eukaryotes to IC 50 translation inhibition in prokaryotes lower than 15.

12. The method of claim 11 , wherein said ratio is lower than 1.

13. The method of claim 1 , wherein said compound is characterized by a MIC in Gram-negative bacteria higher than 200 μM and a MIC in Gram-positive bacteria higher than 20 μM.

14. A pharmaceutical composition packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a genetic disorder 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, the composition comprising a compound having the general formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of alkyl, cycloalkyl and aryl;
R2 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB);
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; and
a stereo-configuration of each of position 6′ and position 5″ is independently an R configuration or an S configuration,
and an additional agent usable in treating said genetic disorder.

15. The composition of claim 14 , wherein R 1 is alkyl.

16. The composition of claim 15 , wherein said alkyl is methyl.

17. The composition of claim 14 , wherein R 2 and R 3 are each hydrogen.

18. The composition of claim 14 , wherein R 2 is AHB and R 3 is hydrogen.

19. The composition of claim 14 , wherein R 2 is hydrogen and R 3 is alkyl.

20. The composition of claim 19 , wherein said alkyl is methyl.

21. The composition of claim 14 , wherein R 2 is AHB and R 3 is alkyl.

22. The composition of claim 21 , wherein said alkyl is methyl.

23. The composition of claim 14 , being selected from the group consisting of:

24. The composition of claim 14 , wherein said compound is:

25. The composition of claim 14 , wherein said compound is characterized by a ratio of IC 50 translation inhibition in eukaryotes to IC 50 translation inhibition in prokaryotes lower than 15.

26. The composition of claim 25 , wherein said ratio is lower than 1.

27. The composition of claim 14 , wherein said compound is characterized by a MIC in Gram-negative bacteria higher than 200 μM and a MIC in Gram-positive bacteria higher than 20 μM.

Assignees

• Technion Res & Dev Foundation

Inventors

• Baasov Timor
• Atia-Glikin Dana
• Kandasamy Jeyakumar
• Belakhov Valery

Classifications

• A61P43/00

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

• A61P7/04

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

• A61P21/04

  for myasthenia gravis · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title