CYPHOMYCIN, COMPOSITIONS AND USES THEREOF

• US 20200131220A1
• Filed: 10/25/2019
• Published: 04/30/2020
• Est. Priority Date: 10/26/2018
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Bugni, Timothy S., Pupo, Monica Tallarico, Andes, David R., Currie, Cameron R., Ortega Dominguez, Humberto Enrique
• Granted Patent: US 11,028,113 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: C07H 17/04 Heterocyclic radicals containing only oxygen as ring hetero atoms
• CPC Class Codes: C12N 1/20 Bacteria; Culture media therefor

Abstract

Cyphomycin, an isolated compound of Formula I or IA is provided. A compound isolated from insect Streptomyces and having a chemical formula of C₇₇H₁₂₂O₂₆ is also provided. Compositions including Cyphomycin, such as pharmaceutical compositions including effective amounts of Cyphomycin for treating fungal infections such as Candida and Aspergillus, including drug-resistant strains thereof, are also disclosed. Methods of treating fungal infections with Cyphomycin and compositions thereof are disclosed.

Claims

1. An isolated compound having the structure of Formula I:

2. The isolated compound of claim 1, having the structure of Formula IA:

3. An isolated compound having the formula, C₇₇H₁₂₂O₂₆ and exhibiting one or more of the following spectral features:

one or more ¹³C NMR peaks at or about the chemical shifts in Table 2, herein;

one or more ¹H NMR peaks at or about the chemical shifts in Table 2, herein,

one or more UV λ

_max at about 204, about 248, about 254, or about 334 nm.

13. A method of treating a fungal infection comprising administering to a mammal in need thereof an effective amount of a compound, or a pharmaceutical composition of claim 3, wherein:

the compound is a compound of Formula I or IA, or

the compound has the formula, C₇₇H₁₂₂O₂₆ and exhibits one or more of the following spectral features;

one or more ¹³C NMR peaks at or about the chemical shifts in Table 2, herein;

one or more ¹H NMR peaks at or about the chemical shifts in Table 2, herein,

one or more UV λ

_max at about 204, about 248, about 254, or about 334 nm.

14. The method of claim 13, wherein the mammal is human.

15. The method of claim 13, wherein the fungal infection is caused by one or more of Candida or Aspergillus.

16. The method of claim 13, wherein the fungal infection is caused by one or more of Candida albicans, Candida glabrata, Candida auris, Aspergillus fumigatus, and drug-resistant strains thereof.

17. The method of claim 13, wherein a second antifungal other than the compound of Formula I is administered to the mammal in need thereof simultaneously, sequentially or separately with the compound of Formula I, or the pharmaceutical composition.

18. The method of claim 17, wherein the second antifungal is a selected from the group consisting of amphotericin B, flucytosine, fluconazole, micafungin, and forazoline.

19. The method of claim 13, wherein the effect amount of the compound is about 0.01 mg/kg/day to 100 mg/kg/day.

20. The method of claim 13, wherein the effect amount of the compound is about 0.1 mg/kg/day to 5 mg/kg/day.

4. A pharmaceutical composition comprising an effective amount of a compound for treating a fungal infection and a pharmaceutically acceptable carrier, wherein:

the compound is a compound of Formula I or IA, or

the compound has the formula, C₇₇H₁₂₂O₂₆ and exhibits one or more of the following spectral features;

one or more ¹³C NMR peaks at or about the chemical shifts in Table 2, herein;

one or more ¹H NMR peaks at or about the chemical shifts in Table 2, herein,

one or more UV λ

_max at about 204, about 248, about 254, or about 334 nm.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated for oral, parenteral, nasal, or topical administration.

6. The pharmaceutical composition of claim 4 further comprising a second antifungal agent or combination of agents different from cyphomycin.

7. The pharmaceutical composition of claim 6, wherein the second antifungal agent or combination of agents is selected from the group consisting of azoles, echinocandins, and polyenes.

8. The pharmaceutical composition of claim 6, wherein the second antifungal is selected from the group consisting of amphotericin B, flucytosine, fluconazole, micafungin, and forazoline.

9. The pharmaceutical composition of claim 4, wherein the compound is isolated from Streptomyces.

10. The pharmaceutical composition of claim 4, wherein the compound is isolated and has a purity of at least 90 wt %.

11. The method of claim 4, wherein the effect amount of the compound is about 0.01 mg/kg/day to 100 mg/kg/day.

12. The method of claim 4, wherein the effect amount of the compound is about 0.1 mg/kg/day to 5 mg/kg/day.