Halogenated quinoline derivatives as antimicrobial agents

Patent metadata

Field	Value
Publication number	US-11008290-B2
Application number	US-201615762456-A
Country	US
Kind code	B2
Filing date	Sep 23, 2016
Priority date	Sep 24, 2015
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

The present invention provides halogenated quinoline derivatives, such as compounds of Formula (I) or (I′), and pharmaceutically acceptable salts thereof, and methods of preparing the halogenated quinoline derivatives. The halogenated quinoline derivatives are expected to be antimicrobial agents and may act through an iron(II)-dependent mode of action. The present invention also provides pharmaceutical compositions, kits, uses, and methods that involve the halogenated quinoline derivatives and may be useful in preventing or treating a microbial infection (e.g., a bacterial infection) in a subject, inhibiting the growth and/or reproduction of a microorganism (e.g., a bacterium), killing a microorganism (e.g., a bacterium), inhibiting the formation and/or growth of a biofilm, reducing or removing a biofilm, and/or disinfecting a surface.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R H is:
CO 2 R L , wherein R L is substituted or unsubstituted, C 1-6 alkyl or an oxygen protecting group;
(substituted or unsubstituted C 1-6 -alkylene)-0H;
CN;
NR M 2 ;

R A′ is substituted methyl, substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted, monocyclic heteroaryl, or unsubstituted bicyclic heteroaryl;
R A is substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R B is H, halogen, or substituted or unsubstituted C 1-6 alkyl;
R D is H, halogen, or substituted or unsubstituted C 1-6 alkyl;
R I is H, halogen, or substituted or unsubstituted C 1-6 alkyl;
R J is H, halogen, or substituted or unsubstituted C 1-6 alkyl;
R K′ is H, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R K is substituted or unsubstituted C 1-6 alkyl or a nitrogen protecting group;
each R M is independently H, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R C is H or CH 3 ;
R E is halogen; and
R G is halogen;
provided that at least one of R E and R G is Br or I.

2. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
each instance of R a is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR 1 , —N(R 1 ) 2 , —SR 1 , —CN, —SCN, —C(═NR 1 )R 1 , —C(═NR 1 )OR 1 , —C(═NR 1 )N(R 1 ) 2 , —C(═O)R 1 , —C(═O)OR 1 , —C(═O)N(R 1 ) 2 , —NO 2 , —NR 1 C(═O)R 1 , —NR 1 C(═O)OR 1 , —NR 1 C(═O)N(R 1 ) 2 , —OC(═O)R 1 , —OC(═O)OR 1 , or —OC(═O)N(R 1 ) 2 , wherein each instance of R 1 is independently H, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R 1 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
n is 0, 1, 2, 3, 4, or 5.

4. The compound of claim 3 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is of the formula:

wherein:
each instance of Ra is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR 1 , —N(R 1 ) 2 , —SR 1 , —CN, —SCN, —C(═NR 1 )R 1 , —C(═NR 1 )OR 1 , —C(═NR 1 )N(R 1 ) 2 , —C(═O)R 1 , —C(═O)OR 1 , —C(═O)N(R 1 ) 2 , —NO 2 , —NR 1 C(═O)R 1 , —NR 1 C(═O)OR 1 , —NR 1 C(═O)N(R 1 ) 2 , —OC(═O)R 1 , —OC(═O)OR 1 , or —OC(═O)N(R 1 ) 2 , wherein each instance of R 1 is independently H, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R 1 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
n is 1, 2, 3, 4, or 5.

7. The compound of claim 1 , wherein the compound is of Formula (I′-a):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A′ is substituted methyl, substituted or unsubstituted C 2-6 alkyl, or substituted or unsubstituted aryl.

9. The compound of claim 7 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C is H.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R E is Br or I.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R G is Br or I.

13. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

14. A method of preparing a compound of claim 1 , the method comprising contacting a compound of Formula (B):

or a salt thereof, with an amine of Formula (C):

or a salt thereof, in the presence of a reductant to provide the compound of claim 1 .

15. A composition comprising a compound of cla

Assignees

• Univ Florida

Inventors

• Huigens Iii Robert William
• Basak Akash
• Abouelhassan Yasmeen

Classifications

• C07D215/28

  with halogen atoms or nitro radicals in positions 5, 6 or 7 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title