Compounds, compositions, and methods for the treatment and prevention of avian pathogenic E. coli (APEC)

Patent metadata

Field	Value
Publication number	US-11660294-B2
Application number	US-201917260140-A
Country	US
Kind code	B2
Filing date	Jul 15, 2019
Priority date	Jul 13, 2018
Publication date	May 30, 2023
Grant date	May 30, 2023

Abstract

Disclosed are anti-avian pathogenic E. coli (APEC) agents as well as methods of using thereof.

First claim

What is claimed is:

1. A method of treating or preventing a bacterial infection in an avian subject, the method comprising administering a therapeutically effective amount of an anti-APEC agent to the avian subject, wherein the anti-APEC agent is a growth inhibitor defined by Formula I,
wherein Formula I is defined by the structure below

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
X 1 and X 2 are independent selected from —O— and —S—;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl-C 1-4 alkylene, 6-10 membered aryl-C 1-4 alkylene, 5-10 membered heteroaryl-C 1-4 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl-C 1-4 alkylene, 6-10 membered aryl-C 1-4 alkylene, and 5-10 membered heteroaryl-C 1-4 alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected R X groups;
R 2 is —(CR 7 R 7′ ) n R 8 ;
R 3 , R 3′ , R 4 , R 4′ , R 5 , and R 5′ are each selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
R 6 is selected from a C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
each R 7 and R 7′ , when present, are each independently selected from H, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;
R 8 is selected from C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
each R X , when present, are each independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino; and
n is 0, 1, 2, 3, 4, or 5.

2. The method of claim 1 , wherein the bacterial infection comprises avian pathogenic E. coli (APEC).

3. The method of claim 1 , wherein the method further comprises administering an antibiotic selected from a tetracycline, a sulfonamide, an aminoglycoside, a β-lactam antimicrobial, a quinolone, and a combination thereof to the avian subject.

4. The method of claim 1 , wherein the method further comprises administering a therapeutically effective amount of a quorum sensing inhibitor.

5. The method of claim 1 , wherein administering the therapeutically effective amount of the anti-APEC agent to avian subject comprises adding the therapeutically effective amount of the anti-APEC agent to feed consumed by the avian subject.

6. The method of claim 1 , wherein administering the therapeutically effective amount of the anti-APEC agent to the avian subject poultry flock comprises adding the therapeutically effective amount of the anti-APEC agent to water consumed by the avian subject.

7. The method of claim 1 , wherein the avian subject comprises a chicken.

8. The method of claim 7 , wherein the chicken comprises a broiler.

9. The method of claim 7 , wherein the chicken comprises a layer.

10. The method of claim 1 , wherein the avian subject comprises a turkey.

11. The method of claim 1 , wherein X 1 and X 2 are both O.

12. The method of claim 1 , wherein R 1 is C 1-6 alkyl.

13. The method of claim 12 , wherein R 1 is methyl.

14. The method of claim 1 , wherein R 3 , R 3′ , R 5 , and R 5′ are all H.

15. The method of claim 1 , wherein R 4 is selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino; and R 4′ is H.

16. The method of claim 15 , wherein R 4 is OH and R 4′ is H.

17. The method of claim 1 , wherein R 6 comprises a C 5 cycloalkyl group or a 5-membered heterocycloalkyl group.

18. The method of claim 17 , wherein R 6 comprises a pyrrolidine ring.

19. The method of claim 1 , wherein
n is 1 or 2;
R 7 and R 7′ are H in all occurrences;
R 8 comprises a C 6-10 aryl ring optionally substituted by 1, 2, 3, or 4 independently selected R X groups; and
R X , when present, is selected from halo, C 1-6 alkyl, and C 1-4 haloalkyl.

20. The method of claim 19 , wherein R 8 comprises a phenyl ring optionally substituted by 1, 2, 3, or 4 independently selected R X groups.

21. The method of claim 1 , wherein the anti-APEC agent comprises SM7, the structure of which is shown below

Assignees

• Ohio State Innovation Foundation

Inventors

• Rajashekara Gireesh
• Kathayat Dipak
• Helmy Yosra A
• Deblais Loïc

Classifications

• A61K31/10

  Sulfides; Sulfoxides; Sulfones · CPC title

• A01N43/52

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A01N43/50

  1,3-Diazoles; Hydrogenated 1,3-diazoles · CPC title

• A61K31/4525

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title