Halogenated salicylanilides for treating clostridium infections
The present invention relates to halogenated salicylanilides, or pharmaceutically acceptable salts or esters thereof, for use in the treatment of an infection in a subject caused by Clostridium bacteria, particularly a C. difficile infection. The halogenated salicylanilides are expected to be useful in the treatment of C. difficile associated diseases including C. difficile associated diarrhea and C. difficile associated colitis.
1. A method of treating an infection caused by Clostridium difficile bacteria in a subject, the method comprising administering to said subject an effective amount of a halogenated salicylanilide, or a pharmaceutically acceptable salt or ester thereof, wherein the halogenated salicylanilide is of the formula (I):
wherein
X is O or S;
R 1 and R 2 are each independently halo;
R 3 and R 4 are each independently selected from the group consisting of H, C 1-6 alkyl, —OR A1 , —NO 2 and —CN;
R 5 is H or -L 1 -R 7 ;
R 6 is H or —C(O)R A2 ;
L 1 is selected from the group consisting of a bond, O, S, and —(CR A3 R B ) o —, wherein subscript o is 1 or 2;
R 7 is phenyl, unsubstituted or substituted with 1, 2, or 3 groups each independently selected from the group consisting of halo, C 1-4 alkyl, —OR A4 , —NO 2 and —CN;
R A1 , R A2 , R A3 and R A4 are each independently selected from the group consisting of H and C 1-4 alkyl;
R B is selected from the group consisting of H, C 1-4 alkyl and —CN;
subscripts n and p are each independently 0, 1, 2, 3 or 4, with the proviso that n+p is at least 1; and
subscripts t and v are each independently 0, 1 or 2.
2. The method of claim 1 , wherein the Clostridum difficile infection is associated with a disease selected from the group consisting of diarrhea, colitis, pseudomembranous colitis and toxic megacolon.
3. The method of claim 1 , wherein the Clostridium difficile infection is an antibiotic induced Clostridium difficile infection, wherein the antibiotic which induced the infection is other than the halogenated salicylanilide.
4. The method of claim 3 , wherein the antibiotic which induced the infection is selected from clindamycin, a cephalosporin, cefotaxime, ceftazidime, ampicillin, amoxicillin, a quinolone, a fluoroquinolone, ciprofloxaxin and levofloxacin.
5. The method of claim 2 , wherein the Clostridium difficile infection is induced by a gastric acid suppressive agent.
6. The method of claim 5 , wherein the Clostridium difficile is resistant to an antibiotic agent other than the halogenated salicylanilide.
7. The method of claim 6 , wherein the Clostridium difficile is a Clostridium difficile strain that is resistant to an antibiotic agent selected from metronidazole, vancomycin, fidaxomicin and a rifamycin.
8. The method of claim 7 , wherein the Clostridium difficile infection has not been treated with an antibiotic prior to administration of the halogenated salicylanilide to the subject.
9. The method of claim 7 , wherein the subject has a recurrent Clostridium difficile infection.
10. The method of claim 9 , wherein the Clostridium difficile infection has recurred after being treated with an antibiotic selected from metronidazole, vancomycin, fidaxomicin and a rifamycin.
11. The method of claim 1 , wherein X is O.
12. The method of claim 1 , wherein R 6 is H.
13. The method of claim 1 , wherein R 3 and R 4 are at each occurrence independently selected from H, C 1-4 alkyl, —OR A1 and —NO 2 .
14. The method of claim 1 , wherein L 1 is selected from O, —CH 2 — and —CH(CN)—.
15. The method of claim 1 , wherein R 7 is phenyl unsubstituted or substituted with 1, 2 or 3 groups each independently selected from halo.
16. The method of claim 1 , wherein the halogenated salicylanilide is selected from:
or a pharmaceutically acceptable salt or ester thereof.
17. The method of claim 1 , wherein the halogenated salicylanilide is selected from the group consisting of niclosamide, clioxanide, closantel, oxyclozanide, rafoxanide, tribromosalan, or a pharmaceutically acceptable salt or ester thereof.
18. The method of claim 1 , wherein the halogenated salicylanilide is selected from the group consisting of the group consisting of clioxanide, closantel, oxyclozanide, rafoxanide and tribromosalan, or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the halogenated salicylanilide is selected from the group consisting of the group consisting of rafoxanide, oxyclozanide and clioxanide, or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the halogenated salicylanilide is rafoxanide, or a pharmaceutically acceptable salt thereof.
21. The method of claim 9 , wherein the recurrent Clostridium difficile infection has recurred following prior treatment with an antibiotic other than the halogenated salicylanilide.