Alkenyl and beta-substituted phosphonates as antimicrobial agents

Patent metadata

Field	Value
Publication number	US-11098072-B2
Application number	US-201816627004-A
Country	US
Kind code	B2
Filing date	Jun 27, 2018
Priority date	Jun 27, 2017
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present disclosure relates to novel compounds, pharmaceutical compositions, and methods for treating or preventing microbial infection caused by parasites or bacteria, such as Plasmodium falciparum or related Plasmodium parasite species and Mycobacterium tuberculosis or related Mycobacterium bacteria species. The compounds are α,β-unsaturated analogs of fosmidomycin and can inhibit deoxyxylulose phosphate reductoisomerase (Dxr) in many microbes, such as P. falciparum.

First claim

We claim:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein
each R 1 is independently C 1-6 haloalkyl, C 3-6 cycloalkyl, (CR a R b ) m -aryl, (CR a R b ) m -O(C═O)—C 1-6 alkyl, (CR a R b ) m -O(C═O)—C 3-6 cycloalkyl, (CR a R b ) m -O(C═O)-aryl, (CR a R b ) m -O(C═O)O—C 1-6 alkyl, or (CR a R b ) m —O(C═O)O—C 3-6 cycloalkyl, wherein the atom at the left is attached to the oxygen atom; or
two R 1 taken together with the oxygen atoms and the phosphorus atom to form a 5-to 6-membered optionally substituted ring;
R 2 is (CR c R d ) n -aryl, wherein the atom at the left is attached to the oxygen atom;
R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, or (CR e R f ) p -aryl;
each R a , R b , R c , R d , R e , and R f is independently H, halogen, methyl, or ethyl; m and n is independently 1, 2, 3, or 4;
p is 0, 1, 2, 3, or 4;
each aryl is optionally substituted with up to five R 4 selected from the group consisting of halogen, hydroxyl, cyano, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-6 cycloalkoxy.

2. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.

3. The compound of claim 2 , wherein the salt is a Na + , K + , or quaternary ammonium salt.

4. The compound of claim 3 , wherein the salt is a Na + or NH 4 + salt.

5. The compound of any one of claims 1 to 4 , wherein the compound is a mono- or di-salt.

6. The compound of claim 1 , wherein R 1 is (CR a R b ) m -O(C═O)—C 1-6 alkyl.

7. The compound of claim 6 , wherein R 1 is CH 2 —O(C═O)—C(CH 3 ) 3 .

8. The compound of claims 1 , 4 , 6 , or 7 , wherein R 2 is (CR a R b )-aryl.

9. The compound of claim 8 , wherein R 2 is CH 2 -aryl.

10. The compound of claim 9 , wherein the aryl is optionally substituted phenyl, biphenyl, or naphthyl.

11. The compound of claims 1 , 4 , 6 , 7 , 9 , or 10 , wherein R 3 is H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or (CH 2 ) p -aryl.

12. The compound of claim 11 , wherein R 3 is H, CH 3 , CF 3 , OCH 3 , phenyl, or benzyl.

13. The compound of claim 12 , wherein R 3 is H, CH 3 , or phenyl.

14. The compound of claim 13 , wherein R 3 is H.

15. The compound of claim 13 , wherein R 3 is CH 3 .

16. A compound selected from the group consisting of:

17. A compound that is:

18. A pharmaceutical composition comprising the compound of claims 1 , 4 , 6 , 7 , 9 , 10 , 12 - 16 , or 17 and a pharmaceutically acceptable excipient.

19. A method for treating or preventing a microbial infection in a subject in need thereof comprising administering to the subject an effective amount of the compound of claims 1 , 4 , 6 , 7 , 9 , 10 , 12 - 16 , or 17 .

20. The method of claim 19 , wherein the microbial infection is malaria.

21. The method of claim 19 , wherein the microbial infection is tuberculosis.

22. The method of claim 19 , wherein the subject is a human.

Assignees

• Univ George Washington
• Univ Washington
• Univ George Mason
• Univ Saint Louis
• The George Washington Univ A Congressionally Chartered Not For Profit Corporation
• St Louis Univ

Inventors

• Dowd Cynthia
• Wang Xu
• Brothers Robert Carl
• John Audrey Ragan Odom
• Edwards Rachel
• Meyers Marvin
• Arnett Stacy
• Couch Robin
• Heidel Kenneth

Classifications

• C07F9/4015

  Esters of acyclic unsaturated acids · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07F9/3826 Primary

  Acyclic unsaturated acids · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title