Enopeptins, uses thereof, and methods of synthesis thereto

• US 10,106,580 B2
• Filed: 10/27/2015
• Issued: 10/23/2018
• Est. Priority Date: 03/30/2011
• Status: Active Grant

• Current Assignee: Brown University
• Original Assignee: Brown University
• Inventors: Sello, Jason K.
• Primary Examiner(s): Reynolds, Fred H
• Application Number:
  US14/924,667
• Publication Number:
  US 20160046674A1
• Time in Patent Office: 1,092 Days
• Field of Search: None
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• 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 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07D 498/14 Ortho-condensed systems
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07K 7/56 the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

Provided herein are inventive enopeptin compounds of Formula (I):

and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Further provided are methods of preparation, use, and treatment.

Claims

1. A compound of Formula (III-a):

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein x is 1.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each of R^10a and R^10b is hydrogen;

and R⁹ is optionally substituted alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2 and the group:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and the group:

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is halogen, optionally substituted c_2-6 alkyl, substituted C₁ alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is halogen.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is optionally substituted C_2-6 alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is halogen, —

OH, —

SH, —

NH₂, —

CN, —

NO₂, —

N₃, —

SO₂H, —

SO₃H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted C_2-6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is substituted C₁ alkyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is fluoro or chloro.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is halogen, —

OH, —

SH, —

NH₂, —

CN, —

NO₂, —

N₃, —

SO₂H, —

SO₃H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is fluoro.

14. A pharmaceutical composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of preparing a compound of claim 1, the method comprising providing a compound of Formula (G):

16. A method of treating a microbial infection in a subject comprising administering an effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof, to the subject.

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

18. The method of claim 17, further comprising administering the compound, or pharmaceutically acceptable salt thereof, in combination with an antibiotic.

19. The method of claim 18, wherein the antibiotic is a ribosome-targeting antibiotic.

20. The method of claim 17, wherein the bacterial infection is resistant to other treatments.

21. The method of claim 17, wherein the bacterial infection is multi-drug tolerant or multi-drug resistant.

22. A method of treating microbial virulence comprising contacting an effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof, to a microorganism.

23. The method of claim 22, wherein the compound, or pharmaceutically acceptable salt thereof, blocks virulence factor production.