NOVEL DEPSIPEPTIDE AND USES THEREOF

• US 20140194345A1
• Filed: 12/03/2013
• Published: 07/10/2014
• Est. Priority Date: 12/03/2012
• Status: Active Grant

• Current Assignee: NovoBiotic Pharmaceuticals, LLC
• Original Assignee: Losee Lucy Ling
• Inventors: Hughes, Dallas, Ling, Losee Lucy, Lewis, Kim, Peoples, Aaron J., Millett, William, Nitti, Anthony, Spoering, Amy, Steadman, Victoria Alexandra, Chiva, Jean-Yves Christophe, Lazarides, Linos, Jones, Michael Kenyon, Poullenec, Karine Gaelle
• Granted Patent: US 9,163,065 B2
• Time in Patent Office: Days
• US Class Current: 514/2.6
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: A61P 33/12 Schistosomicides
• CPC Class Codes: C07K 11/02 cyclic, e.g. valinomycins ; Derivatives thereof
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid
• CPC Class Codes: C12N 1/205 Bacterial isolates
• CPC Class Codes: C12P 17/14 Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
• CPC Class Codes: C12P 21/02 : having a known sequence of two or more amino acids, e.g. glutathione
• CPC Class Codes: C12R 2001/01 : Bacteria or Actinomycetales ; using bacteria or Actinomycetales
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates generally to novel depsipeptides, to methods for the preparation of these novel depsipeptides, to pharmaceutical compositions comprising the novel depsipeptides; and to methods of using the novel depsipeptides to treat or inhibit various disorders.

Claims

1. An isolated compound of Formula (I):

2. The compound of claim 1, wherein the compound is a natural product of bacterial isolate ISO1862.

3. The compound of claim 1, wherein the compound is producible from bacterial isolate ISO1862.

5. The compound of claim 1, wherein the compound is characterized by at least ten ¹³C nuclear magnetic resonance peaks at chemical shifts in DMSO-d₆ selected from 36.3 ppm, 36.5 ppm, 36.9 ppm, 37.4 ppm, 52.1 ppm, 52.2 ppm, 52.7 ppm, 53.5 ppm, 55.7 ppm, 56.1 ppm, 56.4 ppm, 56.7 ppm, 57.3 ppm, 57.8 ppm, 57.9 ppm, 61.8 ppm, and 71.1 ppm.

6. The compound of claim 1, wherein the compound is characterized by ¹³C nuclear magnetic resonance peaks at chemical shifts in DMSO-d₆ of 36.3 ppm, 36.5 ppm, 36.9 ppm, 37.4 ppm, 52.1 ppm, 52.2 ppm, 52.7 ppm, 53.5 ppm, 55.7 ppm, 56.1 ppm, 56.4 ppm, 56.7 ppm, 57.3 ppm, 57.8 ppm, 57.9 ppm, 61.8 ppm, and 71.1 ppm.

7. A compound of claim 1, wherein the compound is characterized by at least one of:

(a) a molecular weight of about 1242.47 g/mol;

(b) a proton nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 1;

(c) a carbon 13 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 2;

(d) a COSY nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 3;

(e) a DEPT-135 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 4;

(f) a HSQC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 5; and

(e) a HMBC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 6.

8. A compound of claim 1, wherein the compound is characterized by:

(a) a molecular weight of about 1242.47 g/mol;

(b) a proton nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 1;

(c) a carbon 13 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 2;

(d) a COSY nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 3;

(e) a DEPT-135 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 4;

(f) a HSQC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 5; and

(e) a HMBC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 6.

14. A method for producing a compound of Formula (I) of claim 1,

the method comprising:

cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;

thereby producing a compound of Formula (I).

20. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) of claim 1

thereby treating the disorder in said subject.

46. A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (I) of claim 1

thereby inhibiting the growth of the infectious agent.

4. An isolated compound of Formula (II):

12. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically-acceptable excipient, carrier, or diluent.

15. A method for producing a compound of Formula (II) of claim 4,

the method comprising:

cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;

thereby producing a compound of Formula (II).

21. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (II) of claim 4,

thereby treating the disorder in said subject.

25. The method of claim 21, wherein the disorder is caused by a pathogen selected from the group consisting of a bacterium, a fungus, a virus, a protozoan, a helminth, a parasite, and combinations thereof.

26. The method of claim 25, wherein the pathogen is a bacterium.

27. The method of claim 26, wherein the bacterium is a Gram-positive bacterium.

28. The method of claim 27, wherein the Gram-positive bacterium is selected from the group consisting of Streptococcus, Staphylococcus, Enterococcus, Corynebacteria, Listeria, Bacillus, Erysipelothrix, Mycobacterium, Clostridium, and Actinomycetales.

29. The method of claim 27, wherein the Gram-positive bacterium is selected from the group consisting of methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, and coagulase-negative staphylococci), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), penicillin-susceptible and penicillin-resistant streptococci (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus and Streptococci Group C, Streptococci Group G and Viridans streptococci), enterococci (including vancomycin-susceptible and vancomycin-resistant strains such as Enterococcus faecalis and Enterococcus faecium), Clostridium difficile, Clostridium clostridiiforme, Clostridium innocuum, Clostridium perfringens, Clostridium tetani, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansaii, Mycobacterium gordonae, Mycobacteria sporozoites, Listeria monocytogenes, Bacillus subtilis, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium sporozoites, Erysipelothrix rhusiopathiae, and Actinomyces israelli.

30. The method of claim 25, wherein the disorder is caused by infection with Bacillus anthracis.

31. The method of claim 26, wherein the bacterium is a Gram-negative bacterium.

32. The method of claim 31, wherein the Gram-negative bacterium is selected from the group consisting of Helicobacter pylori, Legionella pneumophilia, Neisseria gonorrhoeae, Neisseria meningitidis, pathogenic Campylobacter sporozoites, Haemophilus influenzae, Pseudomonas aeruginosa, Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Pasteurella multocida, Bacteroides sporozoites, Bacteroides fragilis, Bacteroides thetaiotaomicron Bacteroides uniformis, Bacteroides vulgatus Fusobacterium nucleatum, Streptobacillus moniliformis, Leptospira, Escherichia coli, Salmonella enterica, Salmonella salamae, Salmonella arizonae, Salmonella diarizonae, Salmonella houtenae, Salmonella bongori, Salmonella indica, Salmonella Enteritidis, Salmonella typhi, and Citrobacter freundii.

33. The method of claim 25, wherein the pathogen is a virus.

36. The method of claim 25, wherein the pathogen is a protozoan.

38. The method of claim 25, wherein the pathogen is a helminth.

40. The method of claim 25, wherein the pathogen is a parasite.

43. The method of claim 25, wherein the pathogen is a fungus.

48. A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (II) of claim 4

thereby inhibiting the growth of the infectious agent.

9. (canceled)

10. An isolated compound of Formula (III):

16. A method for producing a compound of Formula (III) of claim 10

the method comprising:

cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;

thereby producing a compound of Formula (III).

22. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (III) of claim 10,

thereby treating the disorder in said subject.

50. A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (III) of claim 10,

thereby inhibiting the growth of the infectious agent.

11. An isolated compound of Formula (IV):

17. A method for producing a compound of Formula (IV) of claim 11,

the method comprising:

cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;

thereby producing a compound of Formula (IV).

23. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (IV) of claim 11,

thereby treating the disorder in said subject.

52. A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (IV) of claim 11

thereby inhibiting the growth of the infectious agent.

13. (canceled)

18. (canceled)

19. (canceled)

24. (canceled)

34. (canceled)

35. (canceled)

37. (canceled)

39. (canceled)

41. (canceled)

42. (canceled)

44. (canceled)

45. An isolated culture comprising a bacterial species, having the identifying characteristics of a ISO18629 isolate.

47. (canceled)

49. (canceled)

51. (canceled)

53. (canceled)