Phenazine derivatives as antimicrobial agents

Patent metadata

Field	Value
Publication number	US-11053205-B2
Application number	US-201816486694-A
Country	US
Kind code	B2
Filing date	Feb 17, 2018
Priority date	Feb 17, 2017
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

The present invention provides novel phenazine derivatives, such as compounds of Formula (I) (e.g., Formulae (II)-(XIX)), and pharmaceutically acceptable salts thereof. The compounds of the invention are expected to be antimicrobial agents and may act by a microbial warfare strategy (e.g., a reactive oxygen species (ROS)-based competition strategy). The present invention also provides pharmaceutical compositions, kits, uses, and methods that involve the compounds of the invention and may be useful in preventing or treating a microbial infection (e.g., a bacterial infection or mycobacterial infection) in a subject, inhibiting the growth and/or reproduction of a microorganism (e.g., a bacterium or mycobacterium), killing a microorganism (e.g., a bacterium or mycobacterium), inhibiting the formation and/or growth of a biofilm, reducing or clearing a biofilm, and/or disinfecting a surface.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:
X is hydrogen or halogen;
Y is halogen;
Z is N or CR D ;
R A is hydrogen, halogen, 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, —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 hydrogen, 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;
R B is hydrogen, halogen, 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, —OR 2 , —N(R 2 ) 2 , —SR 2 , —CN, —SCN, —C(═NR 2 )R 2 , —C(═NR 2 )OR 2 , —C(═NR 2 )N(R 2 ) 2 , —C(═O)R 2 , —C(═O)OR 2 , —C(═O)N(R 2 ) 2 , —NO 2 , —NR 2 C(═O)R 2 , —NR 2 C(═O)OR 2 , —NR 2 C(═O)N(R 2 ) 2 , —OC(═O)R 2 , —OC(═O)OR 2 , or —OC(═O)N(R 2 ) 2 , wherein each instance of R 2 is independently hydrogen, 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 2 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R C is hydrogen, halogen, 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, —OR 3 , —N(R 3 ) 2 , —SR 3 , —CN, —SCN, —C(═NR 3 )R 3 , —C(═NR 3 )OR 3 , —C(═NR 3 )N(R 3 ) 2 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)N(R 3 ) 2 , —NO 2 , —NR 3 C(═O)R 3 , —NR 3 C(═O)OR 3 , —NR 3 C(═O)N(R 3 ) 2 , —OC(═O)R 3 , —OC(═O)OR 3 , or —OC(═O)N(R 3 ) 2 , wherein each instance of R 3 is independently hydrogen, 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 3 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R D is hydrogen, halogen, 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, —OR 4 , —N(R 4 ) 2 , —SR 4 , —CN, —SCN, —C(═NR 4 )R 4 , —C(═NR 4 )OR 4 , —C(═NR 4 )N(R 4 ) 2 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)N(R 4 ) 2 , —NO 2 , —NR 4 C(═O)R 4 , —NR 4 C(═O)OR 4 , —NR 4 C(═O)N(R 4 ) 2 , —OC(═O)R 4 , —OC(═O)OR 4 , or —OC(═O)N(R 4 ) 2 , wherein each instance of R 4 is independently hydrogen, 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 4 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R E is hydrogen, unsubstituted C 2-20 alkyl, unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═NR 5 )R 5 , —C(═NR 5 )OR 5 , or —C(═NR 5 )N(R 5 ) 2 ;
or R E is hydrogen, an oxygen protecting group, 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, —C(═NR 5 )R 5 , —C(═NR 5 )OR 5 , —C(═NR 5 )N(R 5 ) 2 , —C(═O)R 5 , —C(═O)OR 5 , or —C(═O)N(R 5 ) 2 ; provided that R A is not hydrogen, and/or R B is not hydrogen; and
each instance of R 5 is independently hydrogen, 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of R 5 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
provided that when R C and R E are both hydrogen, Z is CR D , and R D is hydrogen, then R A and R B are not the same.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Z is CR D .

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein both X and Y are halogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein each of X and Y is bromo.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled deriva

Assignees

• Univ Florida

Inventors

• Huigens Iii Robert William
• Garrison Aaron
• Abouelhassan Yasmeen
• Yang Hongfen
• Burch Gena

Classifications

• A61P31/06

  for tuberculosis · CPC title

• C07D241/46 Primary

  Phenazines · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K45/06

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

• C07D501/16

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