Fabi inhibitors for gram-negative pathogens

Patent metadata

Field	Value
Publication number	US-2024190872-A1
Application number	US-202218548580-A
Country	US
Kind code	A1
Filing date	Mar 2, 2022
Priority date	Mar 3, 2021
Publication date	Jun 13, 2024
Grant date	—

Abstract

A FabI inhibitor called fabimycin that has impressive activity against >200 clinical isolates of E. coli, K. pneumoniae, and A. baumannii. Fabimycin has activity in multiple mouse models of infection caused by Gram-negative bacteria, including a model of urinary tract infection. Fabimycin has translational promise, and its discovery provides data indicating that antibiotics whose spectrum of activity is restricted to Gram-positive bacteria can be systematically modified to accumulate in Gram-negative bacteria and be effective against these problematic pathogens.

First claim

What is claimed is:

1 . A compound of Formula I or II:

or a salt thereof;
wherein
G 1 is —CH(C 0 -C 6 )alkyl-NH 2 , CH 2 , —CH(C 3 -C 6 )cycloalkyl-NH 2 , —CHN(H)(C 2 -C 6 )alkyl-NH 2 , or G 2 ;
G 2 is

wherein G 3 is NH, —CH(C 0 -C 6 )alkyl-NH 2 , or —CH 2 CH(C 0 -C 6 )alkyl-NH 2 ;
J is —(CH 2 ) m —; and
m is 1-3;

Q is CHR a , NH, —NHCH 2 —, —CH 2 CH 2 —, —C(═O)N—, or absent, wherein R a is H or halo;
X is C═O or CH 2 ;
R 1 is H or halo;
R 2 is —(C 1 -C 6 )alkyl, H, or —(C 1 -C 6 )alkyl-NH 2 ;
R 3 is H or —(C 1 -C 6 )alkyl-NH2; and
R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, or —(C 3 -C 6 )cycloalkyl;

wherein for Formula I, R 2 and R 4 taken together optionally form a heterocycle; and
wherein at least one of G 1 , R 2 , or R 3 comprises an amine moiety and each alkyl moiety is optionally substituted.

2 . The compound of claim 1 wherein G 1 is G 2 .

3 . The compound of claim 1 wherein the compound is represented by Formula I, Q is absent, and R 2 or R 3 is —(C 1 -C 6 )alkyl-NH 2 .

4 . The compound of claim 1 wherein R 1 is fluoro.

5 . The compound of claim 1 wherein the compound is represented by Formula IA:

wherein
R 5 is —(C 0 -C 6 )alkyl-NH 2 or —NH(C 2 -C 6 )alkyl-NH 2 .

6 . The compound of claim 5 wherein Q is CH 2 or CHF.

7 . The compound of claim 5 wherein Q is CH 2 , R 1 is H or fluoro, R 2 is methyl, R 3 is H, and R 5 is NH 2 or CH 2 NH 2 .

8 . The compound of claim 5 wherein the compound is:

9 . The compound of claim 1 wherein Q is absent, R 1 is fluoro, R 2 is methyl, R 3 is H, and R 5 is —NHCH 2 CH 2 NH 2 or —NHCH 2 CH 2 CH 2 NH 2 .

10 . The compound of claim 1 wherein the compound is represented by Formula IB:

wherein
Q is NH, or —C(═O)N— wherein the carbonyl moiety of the amide group is at the position alpha to the tertiary carbon that is substituted with R 5 ; and
R 5 is —(C 0 -C 6 )alkyl-NH 2 or —NH(C 2 -C 6 )alkyl-NH 2 .

11 . The compound of claim 1 wherein the compound is represented by Formula IC:

12 . The compound of claim 11 wherein G 3 is NH.

13 . The compound of claim 1 wherein the compound is represented by Formula ID:

14 . The compound of claim 13 wherein G 3 is NH.

15 . The compound of claim 13 wherein G 3 is —CH(C 0 -C 6 )alkyl-NH 2 .

16 . The compound of claim 13 wherein G 3 is NH, —CHNH 2 , or —CHCH 2 NH 2 , R 1 is fluoro, R 2 is methyl, and R 3 is H.

17 . The compound of claim 1 wherein the compound is:

18 . A compound of Formula III:

or a salt thereof;
wherein
R 3 is H or —(C 1 -C 6 )alkyl;
R 6 is

wherein R 1 is H or halo, and n is 1-4; and
R 7 is H or —(C 0 -C 6 )alkyl-NH 2 .

19 . The compound of claim 18 wherein the compound is:

20 . A compound of Formula IV:

or a salt thereof;
wherein
G 4 is O, NH, CH 2 , —CH(C 0 -C 6 )alkyl-NH 2 , —N(C═O)(C 1 -C 6 )alkyl-NH 2 ;
X is C═O or CH 2 ;
R 1 is H or halo;
R 2 is H, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkyl-NH 2 ;
R 3 is H or —(C 1 -C 6 )alkyl-NH 2 ; and
R 4 is methyl, ethyl, or propyl;

wherein at least one of G 4 , R 2 , or R 3 comprises an amine moiety.

21 . The compound of claim 20 wherein the compound is:

22 . (canceled)

23 . A method of antimicrobial treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of at least a portion of a plurality of microorganisms in the subject.

24 - 27 . (canceled)

Assignees

• Univ Illinois
• Massachusetts Gen Hospital
• Broad Inst Inc

Inventors

• Hergenrother Paul J
• Parker Erica Nicole
• Hung Deborah
• Serrano-Wu Michael
• Lee Katie Kyungae

Classifications

• C07D471/20

  Spiro-condensed systems · CPC title

• A61K47/44

  Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14) · CPC title

• A61K47/38

  Cellulose; Derivatives thereof · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title