Bis-cyclic guanidines as antibacterial agents

Patent metadata

Field	Value
Publication number	US-11214550-B2
Application number	US-201816629805-A
Country	US
Kind code	B2
Filing date	Jun 21, 2018
Priority date	Jul 24, 2017
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

Provided are novel bis-cyclic guanidine compounds, and the use thereof for treating bacterial infection.

First claim

What is claimed is:

1. A compound of formula (I), or a salt thereof

wherein
R1 at each occurrence is independently hydrogen, C1-C10 alkyl, aryl, aryl-C1-C6 alkyl, cycloalkyl, or cycloalkyl-C1-C6 alkyl;
R2 at each occurrence is independently hydrogen, C1-C10 alkyl, aryl, aryl-C1-C6 alkyl, cycloalkyl, or cycloalkyl-C1-C6 alkyl;
X is NH
L1 is —(CRxRy)n1;
L2 is —(CRxRy)n2;
L is —(CRxRy)n3-(CH2CH2O)m1-G-(CH2CH2O)m2-(CRxRy)n4-
Rx and Ry at each occurrence is independently hydrogen or C1-C4 alkyl;
G is a bond or -(G1)t-, wherein G1 at each occurrence is independently aryl, cycloakyl, heteroaryl, or heterocycle;
n1 and n2 are each independently 1-4;
m1, m2, n3, and n4 are each independently 0-10;
t is 1, 2, 3, or 4; and
wherein R1, R2, Rx, Ry, and G1 optionally are each independently substituted with one or more substituents selected from the group consisting of halogen, cyano, —OH, C1-C6 alkoxy, —COOH, C1-C6 alkoxycarbonyl, oxo, and amino.

2. The compound of claim 1 , having a structure of formula (I-a)

3. The compound of claim 1 , wherein L is —(CH2)n3- and n3 is 4-8.

4. The compound of claim 1 , wherein L is -(G1)t-, and wherein G1 is aryl and t is 1.

5. The compound of claim 4 , wherein L is

6. The compound of claim 1 , wherein R1 is C1-C10 alkyl or aryl-C1-C6 alkyl.

7. The compound of claim 1 , where in R1 is benzyl.

8. The compound of claim 1 , where in R2 is C1-C10 alkyl, aryl-C1-C6 alkyl, or cycloalkyl-C1-C6 alkyl.

9. The compound of claim 1 , wherein R1 is benzyl, R2 is C1-C6 alkyl, and L is

10. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .

11. A method of treating infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .

12. The method of claim 11 , wherein the infection is a bacterial infection.

13. The method of claim 12 , wherein the bacterial infection is caused by a bacteria selected from the group consisting of K. pneumoniae, P. aeruginosa, E. coli , vancomycin-resistant Enterococcus faecalis , Methicillin-resistant S. aureus (MRSA), and Methicillin-resistant S. epidermidis (MRSE).

14. The method of claim 12 , wherein the bacterial infection is caused by MRSA.

15. The method of claim 12 , wherein the bacterial infection is caused by bacteria that form a bacterial biofilm.

16. The method of claim 15 , wherein the bacterial biofilm is formed by MRSA or E. coli bacteria.

17. The method of claim 12 , wherein the bacterial infection is resistant to treatment with one or more antibiotics.

18. The method of claim 11 , wherein the compound is administered orally, intravenously, transdermally, or topically.

19. The method of claim 18 , wherein the compound is administered topically.

20. A compound selected from the group consisting of the compounds disclosed in the Table below:

and pharmaceutically acceptable salts thereof.

Assignees

• Univ South Florida

Inventors

• Cai Jianfeng
• Teng Peng
• Nimmagadda Alekhya

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D233/46 Primary

  with only hydrogen atoms attached to said nitrogen atoms · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title