Treatment of
Compounds, compositions, and methods for the treatment of infections caused by Acanthamoeba or Balamuthia mandrillaris trophozoites and/or cysts and for the disinfection of solids and/or liquids, such as medical and personal care items, for example contact lenses, that may harbor Acanthamoeba trophozoites and/or cysts are provided.
1. A compound of Formula 2 or Formula 3:
or a pharmaceutically acceptable salt thereof;
wherein:
R 3 and R 4 are independently selected from hydrogen, halo, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl, wherein at least one of R 3 and R 4 is not hydrogen;
R 5 is selected from halo, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl;
R 6 and R 7 are independently selected from hydrogen, halo, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl, wherein at least one of R 6 and R 7 is not hydrogen;
R 8 is selected from halo, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl;
R 9 and R 10 are independently selected from hydrogen, halo, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl, wherein at least one of R 9 and R 10 is not hydrogen;
R X and R Y are independently selected at each occurrence from halo, C 1-4 alkoxy, and C 1 -C 4 haloalkyl;
o and p are independently selected 0, 1, 2, and 3; and
R A and R B are independently C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein one of R 3 and R 4 is a halogen.
3. The compound of claim 1 , wherein two of R 3 and R 4 , R 5 , R 6 and R 7 are selected from a halogen.
4. The compound of claim 1 , wherein two of R 3 , R 4 , R 8 , R 9 and R 10 are selected from a halogen.
5. The compound of claim 1 , wherein one of R 3 , R 4 , R 8 , and R 9 is selected from C 1 -C 4 alkoxy.
6. The compound of claim 1 , wherein R A and R B are isopropyl.
7. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
9. A method for treating an eye infection caused by one or more Acanthamoeba species in a host in need thereof comprising administering an effective amount of a compound of claim 1 , optionally in a pharmaceutically acceptable carrier.
10. The method of claim 9 wherein the eye infection is Acanthamoeba keratitis.
11. The method of claim 9 , further comprising administering an effective amount of an additional therapeutic agent selected from alexidine, chlorhexidine, polyhexamethylene biguanide (PHMB), propamidine isethionate, hexamidine isethionate, natamycin, neomycin, ketoconazole, itraconazole, polymyxin B, gramicidin, voriconazole, miconazole nitrate, pentamidine, octamidine, fluconazole, miltefosine, and combinations thereof.
12. The method of claim 9 , wherein the one or more Acanthamoeba species are present as both cysts and trophozoites.
13. The method of claim 9 , wherein the host is treated with the compound for at least 1 day, at least 3 days, at least 5 days, at least 10 days, at least 20 days, at least 30 days, at least 40 days, or at least 50 days.
14. The method of claim 9 wherein the host is a human.
15. A method for disinfecting one or more Acanthamoeba species from a solid, liquid or gel object comprising administering an effective amount of a compound of claim 1 , optionally in a pharmaceutically acceptable carrier.
16. The method of claim 15 , wherein the object is selected from an application, a dressing, contact lens, an optical implant, a contact lens solution, an ocular solution and rewetting eye drops.
17. A method for treating an infection caused by Balamuthia mandrillaris in a host in need thereof comprising administering an effective amount of a compound of claim 1 , optionally in a pharmaceutically acceptable carrier.
18. The method of claim 17 , wherein the infection caused by Balamuthia mandrillaris is granulomatous amoebic encephalitis.
19. The method of claim 17 , wherein the Balamuthia mandrillaris is present as both cysts and trophozoites.
20. A disinfecting solution comprising an effective amount of a compound of claim 1 in an aqueous carrier.
21. A contact lens care solution comprising an effective amount of a compound of claim 1 in a suitable aqueous carrier.
22. A method for treating an infection caused by one or more Acanthamoeba species in a host in need thereof comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 wherein the infection is Acanthamoeba keratitis.
24. The method of claim 22 , wherein the one or more Acanthamoeba species are present as both cysts and trophozoites.
25. The method of claim 22 , wherein the host is treated with the compound for at least 1 day, at least 3 days, at least 5 days, at least 10 days, at least 20 days, at least 30 days, at least 40 days, or at least 50 days.
26. The method of claim 22 , wherein the host is a human.
27. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
28. A method for treating an infection caused by Balamuthia mandrillaris or a Acanthamoeba species in a host comprising administering an effective amount of a compound from the group consisting of:
or a pharmaceutically acceptable salt thereof.