Antibiotic conjugates

Patent metadata

Field	Value
Publication number	US-12544384-B2
Application number	US-201817054054-A
Country	US
Kind code	B2
Filing date	Aug 9, 2018
Priority date	May 9, 2018
Publication date	Feb 10, 2026
Grant date	Feb 10, 2026

Abstract

Provided are antibiotic conjugate compounds of formula (I) and pharmaceutical compositions thereof. Also provided are methods of treating treat bacterial infection, including infections caused by Gram-negative bacteria, by administering compounds of formula (I).

First claim

The invention claimed is:

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Sid is a siderophore moiety selected from the group consisting of

L is a bond, —C(O)—, —C(O)NHCH(R 1 )—C(O)—, —C(O)OCH(R 2 )—C(O)—, or

R 1 and R 2 are each hydrogen, C 1-6 alkyl, cyano, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, OH, oxo, and cyano;
R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or Rand R 4 together with the C atom to which they are attached form a 3- to 8-membered ring;
Cyc 1 is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein the 6- to 12-membered aryl or 5- to 12-membered heteroaryl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, OH, oxo, and cyano;
Y is O or NH;
G is -G 1 or —X—(CH 2 ) p C(O)-G 1 ;
X is O or S;
p is 0, 1, 2, 3, 4, or 5; and
G 1 is a drug moiety attached through an oxygen or nitrogen atom,
a wherein G 1 is an oxazolidinone antibiotic.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is bond, —C(O)—, or —C(O)NHCH(R 1 )—C(O)—.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —C(O)NHCH(R 1 )—C(O)—.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently hydrogen or C 1-6 alkyl.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the C atom to which they are attached form a 3- to 8-membered ring.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the C atom to which they are attached form

wherein t is 0, 1, 2, 3, 4, or 5.

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

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is NH.

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

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is —OC(O)-G 1 .

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is bond, —C(O)—, or —C(O)NHCH(R 1 )—C(O)—, R 1 is phenyl; and G is G 1 or —OC(O)-G 1 .

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is

15 . A compound of formula (A):

wherein
Siderophore is selected from the group consisting of

Drug is an oxazolidinone antibiotic;
n is 0 or 1; and
m is 0 or 1,
or a pharmaceutically acceptable salt thereof.

16 . The compound of claim 1 , having a structure of

or a pharmaceutically acceptable salt thereof.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Sid is a siderophore moiety

18 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19 . A method of treating bacterial infection, wherein the infection is caused by Acinetobacter, Pseudomonas , Enterobacteria, or combinations thereof, comprising administering to a subject infected by a bacterium an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20 . The method of claim 19 , wherein the bacterium is a Gram-negative bacterium.

21 . The method of claim 19 , wherein the bacterium is an antibiotic-resistant bacterium.

22 . The method of claim 19 , wherein the bacterium produces a β-lactamase.

23 . The method of claim 19 , wherein the infection is caused by Acinetobacter baumannii.

24 . A method of killing or inhibiting the growth of a bacterium, wherein the bacterium is Acinetobacter, Pseudomonas , Enterobacteria, or combinations thereof, comprising contacting the bacterium with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

25 . The method of claim 24 , wherein the bacterium is a Gram-negative bacterium.

26 . The method of claim 24 , wherein the bacterium is an antibiotic-resistant bacterium.

27 . The method of claim 24 , wherein the bacterium produces a β-lactamase.

28 . The method of claim 24 , wherein the bacterium is by Acinetobacter baumannii.

Assignees

• Univ Notre Dame Du Lac

Inventors

• Miller Marvin J
• Liu Rui
• Miller Patricia
• Vakulenko Sergei
• Stewart Nichole K
• Boggess Jr William

Classifications

• C07D501/16

  with a double bond between positions 2 and 3 · CPC title

• A61P31/04 Primary

  Antibacterial agents · CPC title

• A61K47/547

  Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent · CPC title

• A61K47/552

  one of the codrug's components being an antibiotic · 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