BENZOISOTHIAZOLONES AS INHIBITORS OF PHOSPHOMANNOSE ISOMERASE

• US 20110257233A1
• Filed: 03/18/2011
• Published: 10/20/2011
• Est. Priority Date: 03/19/2010
• Status: Abandoned Application

• Current Assignee: Sanford-Burnham Medical Research Institute (Sanford Burnham Prebys Medical Discovery Institute)
• Original Assignee: Sanford-Burnham Medical Research Institute (Sanford Burnham Prebys Medical Discovery Institute)
• Inventors: Sharma, Vandana, Bravo, Yalda, Freeze, Hudson H., Ichikawa, Mie, Cosford, Nicholas D. P., Dahl, Russell
• Application Number:
  US13/051,910
• Publication Number:
  US 20110257233A1
• Time in Patent Office: Days
• US Class Current: 514/373
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/10 for accommodation disorders, e.g. myopia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 275/04 condensed with carbocyclic rings or ring systems

Abstract

The disclosure provides new compounds and compositions thereof, and methods for treating or ameliorating a disorder relating to CDG-Ia. In particular, the disclosure provides benzoisothiazolone inhibitors of PMI, which have been synthesized and their ability to drive glycosylation has been demonstrated. The disclosure provides two synthetic routes for these compounds, including a new copper-catalyzed N-arylation reaction amenable to parallel derivitization. The disclosed compounds represent potent inhibitors of PMI, and their dose-dependent efficacy in cell-based models of glycosylation have been demonstrated. In addition, the disclosed compounds are selective over PMM and therefore, are useful in treating or ameliorating a disorder relating to CDG-Ia.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein Ar is phenyl;

each R¹ is independently selected from hydrogen and halogen; and

each R² is independently selected from hydrogen, alkyl, trifluoroalkyl, halogen, OR³, C(O)R³, C(O)OR³; and

NR³R⁴.

3. The compound of claim 2, wherein R¹ is independently selected from hydrogen, fluoro, chloro, bromo, and iodo;

and each R² is independently selected from hydrogen, CH₃, CF₃, fluoro, chloro, bromo, iodo, OCH₃, C(O)CH₃, C(O)OCH₃; and

N(CH₃)₂.

4. The compound of claim 3, wherein the compound is:

5. The compound of claim 3, wherein the compound is:

6. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

7. A method of modulating the activity of phosphomannomutase 2 (PMM) and phosphomannose isomerase (PMI), the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

8. A method of modulating the activity of phosphomannomutase 2 (PMM), the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

9. A method of modulating the activity of phosphomannose isomerase (PMI), the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

10. A method of inhibiting the activity of phosphomannose isomerase (PMI), the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

11. A method of treating Congenital Disorder of Glycosylation Type Ia (CDG-Ia), the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

12. The method of claim 10, wherein the CDG-Ia is ataxia, seizures, retinopathy, liver fibrosis, coagulapathies, failure to thrive, dysmorphic features, strabismus.

13. The method of claim 10, wherein the CDG-Ia is myopia, infantile esotropia, delayed visual maturation, low vision, optic pallor, and reduced rod function on electrotinography.

14. The method of claim 10, wherein the CDG-Ia is congenital hyperinsulinism with hyperinsulinemic hypoglycemis in infancy.

15. A method of treating an microbial infection, the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6.

16. The method of claim 15, wherein the microbial infection is a bacterial infection.

17. The method of claim 16, wherein the bacterial infection is a Gram negative bacterial infection.

18. The method of claim 17, wherein the Gram negative bacterial infection is Pseudomonas aeruginosa infection.

19. The method of claim 15, wherein the microbial infection is a fungal infection.

20. The method of claim 19, wherein the fungal infection is a Candida albicans or Cryptococcus neoformans infection.

21. A method for killing bacteria or fungi, wherein the bacteria or fungi are selected from gram-negative bacteria, gram-positive bacteria and yeast, the method comprising the step of administering to a subject in need thereof, a therapeutically effective amount of the compound of Formula I of claim 1 or the pharmaceutical composition of claim 6, wherein the contacting is for a time and under conditions effective to kill bacteria or fungi.

22. The method of claim 21, wherein the bacteria are Gram-negative bacteria.

23. The method of claim 22, wherein the Gram-negative bacteria are selected from Pseudomonas aeruginosa and Escherichia coli.

24. The method of claim 21, wherein the bacteria are Gram-positive bacteria.

25. The method of claim 24, wherein the Gram-positive bacteria are selected from Staphylococcus aureus and Streptococcus faecalis.

26. The method of claim 21, wherein the fungi are Candida albicans or Cryptococcus neoformans.