Pyrrolomycins and methods of using the same

Patent metadata

Field	Value
Publication number	US-10414725-B2
Application number	US-201615743427-A
Country	US
Kind code	B2
Filing date	Jul 15, 2016
Priority date	Jul 16, 2015
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

Provided herein are pyrrolomycin derivatives, which can be used to modulate Mcl-1, inhibit proliferation of bacteria and pathogens, as well as to treat infectious diseases and cancers.

First claim

What is claimed is:

1. A compound, or pharmaceutically acceptable salt thereof, having a structure of formula (I):

wherein
R 1 is H, C 1-10 alkyl, or COR 9 ;
R 2 is OH, C 1-10 alkoxy, NHC(O)R 9 , or NHSO 2 R 10 ;
A, D, and E are selected as indicated in one of groups (i)-(iv):
(i) A and D are each independently CR 3 and E is N;
(ii) A is CR 3 , D is N, and E is CH;
(iii) A is CR 3 , and D and E are each N; and
(iv) A is N, D is CR 3 , and E is CH

each R 3 is H, halogen, C 1-10 haloalkyl, C 1-10 haloalkoxy, CN, CONHR 9 , SO 2 R 10 , or SO 2 NHR 9 ;
R 5 is F or Cl;
R 6 , R 7 , and R 8 are each H, halogen, CF 3 , or OCF 3 ;
R 9 is H, C 1-10 alkyl, or C 6-10 aryl; and
R 10 is C 1-10 alkyl or C 6-10 aryl,

with the proviso that at least one R 3 is other than H, and at least one of R 5 , R 6 , R 7 , and R 8 is other than H.

2. The compound or salt of claim 1 , wherein A and D are each CR 3 , and E is N.

3. The compound or salt of claim 1 , wherein A is CR 3 , D is N, and E is CR 4 .

4. The compound or salt of claim 1 , wherein A is CR 3 , and D and E are N.

5. The compound or salt of claim 1 , wherein A is N, D is CR 3 , and E is CR 4 .

6. The compound or salt of claim 1 , wherein R 3 is halogen, CF 3 , OCF 3 , CN, CONHR 9 , SO 2 R 10 , or SO 2 NHR 9 .

7. The compound or salt of claim 1 , wherein R 2 is NHC(O)R 9 , or NHSO 2 R 10 .

8. The compound or salt of claim 1 , wherein R 1 is H or C 1-10 alkyl.

9. The compound or salt of claim 1 , wherein R 6 and R 8 are each independently F or Cl.

10. A compound or pharmaceutically acceptable salt thereof having a structure selected from the group consisting of:

11. A method of inhibiting the growth or proliferation of bacteria or pathogen in a subject, comprising contacting the bacteria with the compound or salt of claim 1 , wherein the bacteria or pathogen is Staphylococcus, Enterococcus, Bacillus, Streptococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter, Escherichia, Clostridium, Citrobacter, Serratia, Neisseria, Corynebacterium, Cyanobacterium, Salmonella, Shigella, Helicobacter, Brucella, Borrelia, Bordetella, Bartonella, Bacteroides, Burkholderia, Mycobacterium, Mycoplasma, Campylobacter, Chlamydia, Chlamydophila, Francisella, Haemophilus, Legionella, Leptospira, Listeria, Rickettsia, Vibrio, Ureaplasma, Yersinia, Treponema, Proteus, Stenotrophomonas, Plesiomonas, Nocardia, Actinomyces, Moraxella, Erysipelothrix, Actinobacillus, Anaplasma, Pasteurella, Alcaligenes, Achromobacter , or Candida.

12. The method of claim 11 , wherein the pathogen or bacteria is methicillin-resistant, carbapenem-resistant, fluoroquinone-resistant, vancomycin-resistant, or multidrug-resistant.

13. The compound or salt of claim 1 , wherein R 7 is F or Cl.

14. The compound or salt of claim 1 , wherein R 6 and R 8 are each H.

Assignees

• Univ Nebraska

Inventors

• Bayles Kenneth
• Li Rongshi
• Liu Yan

Classifications

• C07D233/64

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D233/68

  Halogen atoms · CPC title

• C07D231/16

  Halogen atoms or nitro radicals · CPC title

• C07D233/90

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title