Antibacterial compounds
Disclosed are compounds of formula (I), which are of use in the treatment of bacterial diseases and infections, to compositions containing those compounds and to methods of treating bacterial diseases and infections using the compounds. In particular, the compounds are useful for the treatment of infection with, and diseases caused by, Clostridium difficile .
1. A method of treating Clostridium difficile -associated disease (CDAD) in a subject in need thereof, the CDAD selected from the group consisting of diarrhoea caused by Clostridium difficile , bloating caused by Clostridium difficile , flu-like symptoms caused by Clostridium difficile , fever caused by Clostridium difficile , appetite loss caused by Clostridium difficile , abdominal pain caused by Clostridium difficile , nausea caused by Clostridium difficile , dehydration caused by Clostridium difficile , colitis caused by Clostridium difficile and pseudomembraneous colitis caused by Clostridium difficile , which method comprises
a) detecting infection and/or intoxication of the subject with one or more strains of Clostridium difficile;
b) administering to the subject an effective amount of a compound of formula (I):
wherein:
L1 is a direct bond or a linker group;
R 1 and R 2 are each independently selected from H and optionally substituted C 1-6 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl, the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 6 , OR 6 , N(R 6 ) 2 , COR 6 , CO 2 R 6 , SO 2 R 6 , NR 7 COR 6 , NR 7 CO 2 R 6 , NR 7 SO 2 R 6 , NR 7 CONR 6 R 7 , CONR 6 R 7 and SO 2 NR 6 R 7 , provided that at least one of R 1 and R 2 is cyclic;
each R 5 is independently selected from H, halo, C 1-6 alkyl, OR 7 , N(R 7 ) 2 , CN and NO 2 ;
X 1 and X 2 are each independently selected from N and CR 3 ;
X 3 is selected from NR 4 , O and S;
X 4 is NH; and
R 3 is selected from H, halo and C 1-6 alkyl; R 4 is selected from H and C 1-6 alkyl; R 6 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 7 carbocyclyl, C 4 -C 7 heterocyclyl and 5- or 6-membered aryl or heteroaryl, any of which may be optionally substituted with one or more halo atoms; and R 7 is selected from hydrogen and C 1 -C 4 alkyl, each of which C 1 -C 4 alkyl is optionally substituted with one or more halo atoms;
or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate; and
c) preventing or reducing the rate of bacterial growth, and/or mediating the cellular destruction of bacterial cells, of the one or more strains of Clostridium difficile.
2. The method of claim 1 wherein X 1 and/or X 2 is N.
3. The method of claim 1 wherein X 3 is NR 4 .
4. The method of claim 1 wherein R 1 and R 2 are each independently selected from H and aryl.
5. The method of claim 1 wherein R 1 and R 2 are each independently selected from H and aryl optionally substituted with OR 5 and N(R 6 ) 2 .
6. The method of claim 1 wherein R 1 and R 2 are each cyclic.
7. The method of claim 1 wherein R 6 is selected from H and C 1 -C 6 alkyl.
8. The method of claim 1 wherein each R 5 is H.
9. The method of claim 1 wherein L1 is a direct bond between the 5 and/or 6 positions of each cycle.
10. The method of claim 1 wherein L1 is selected from O, S, SO 2 , NR 7 , C(R 7 ) 2 and C═O.
11. The method of claim 1 wherein R 1 and R 2 are the same.
12. The method claim 1 wherein R 1 and R 2 are different.
13. The method of claim 1 wherein R 1 and/or R 2 is (are) heterocyclyl or heteroaryl.
14. The method of claim 1 wherein R 1 and/or R 2 is (are): (a) heterocyclyl substituted with one or more substituents selected from halo, CN, NO 2 , R 6 , OR 6 , N(R 6 ) 2 , COR 6 , CO 2 R 6 , SO 2 R 6 , NR 7 COR 6 , NR 7 CO 2 R 6 , NR 7 SO 2 R 6 , NR 7 CONR 6 R 7 , CONR 6 R 7 and SO 2 NR 6 R 7 ; or (b) heteroaryl substituted with one or more substituents selected from halo, CN, NO 2 , R 6 , OR 6 , N(R 6 ) 2 , COR 6 , CO 2 R 6 , SO 2 R 6 , NR 7 COR 6 , NR 7 CO 2 R 6 , NR 7 SO 2 R 6 , NR 7 CONR 6 R 7 , CONR 6 R 7 and SO 2 NR 6 R 7 .
15. The method of claim 13 wherein R 1 and/or R 2 is (are) pyridyl.
16. The method of claim 15 wherein R 1 and R 2 are pyridyl.
17. The method of claim 14 wherein R 1 and/or R 2 is (are) pyridyl and the pyridyl is substituted with one or more substituents selected from halo, CN, NO 2 , R 6 , OR 6 , N(R 5 ) 2 , COR 6 , CO 2 R 6 , SO 2 R 6 , NR 7 COR 6 , NR 7 CO 2 R 6 , NR 7 SO 2 R 6 , NR 7 CONR 6 R 7 , CONR 6 R 7 and SO 2 NR 6 R 7 .
18. The method of claim 1 wherein the compound of formula (I) is 2,2′-di(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole, or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate or prodrug thereof.
19. The method of claim 1 wherein the compound is selected from:
4,4′-(1H,3′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline;
3,3′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline;
4,4′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)diphenol;
4,4′-(3′-methyl-1H,3′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline;
4,4′-(1-methyl-1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline;
4,4′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)bis(N-methylaniline);
2,2′-bis(4-methoxyphenyl)-1H,1′H-5,5′-bibenzo[d]imidazole;
4-(1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)aniline;
4-(2′-phenyl-1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)aniline;
2′-(4-methoxyphenyl)-2-phenyl-1H,3′H-5,5′-bibenzo[d]imidazole;
5,5′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2-′-diyl)dipyridin-2-amine; and
2,2′-di(pyridin-4-yl)-1H,1′H-5,5′-benzo[d]imidazole;
and pharmaceutically acceptable N-oxides, salts, hydrates, solvates and prodrugs thereof.
20. The method of claim 1 wherein CDAD is treated whilst sparing normal gut flora.
21. The method of claim 20 wherein the CDAD is selected from: (a) colitis caused by Clostridium difficile ; (b) pseudomembraneous colitis caused by Clostridium difficile ; and (c) diarrhoea caused by Clostridium difficile.
22. The method of claim 20 wherein the CDAD is selected from: (a) diarrhoea caused by Clostridium difficile ; and (b) colitis caused by Clostridium difficile.
23. A compound selected from:
4,4′-(3′-methyl-1H,3′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline
4,4′-(1-methyl-1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline
4,4′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)bis(N-methylaniline)
4-(1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)aniline
4-(2′-phenyl-1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)aniline
2′-(4-methoxyphenyl)-2-phenyl-1H,3′H-5,5′-bibenzo[d]imidazole and
5,5′-(1H,1′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dipyridin-2-amine
or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate or prodrug thereof.
24. The method of claim 1 wherein the subject is from a patient subgroup selected from: (a) subjects treated, or undergoing treatment, with proton pump inhibitors; (b) subjects treated, or undergoing treatment, with H2 receptor antagonists; (c) subjects treated, or undergoing treatment, with diuretics; (d) hospitalized subjects: (e) subjects with indwelling feeding tubes; (f) subjects undergoing mechanical ventilation; (g) subjects treated, or undergoing treatment, with probiotics; and (g) subjects treated, or undergoing treatment, with vancomycin and/or metronidazole.
25. A pharmaceutical composition comprising a compound as defined in claim 23 or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate or prodrug thereof and a pharmaceutically acceptable excipient.
26. A method of treating Clostridium difficile -associated disease (CDAD) in a subject in need thereof, the CDAD selected from the group consisting of diarrhoea caused by Clostridium difficile , bloating caused by Clostridium difficile , flu-like symptoms caused by Clostridium difficile , fever caused by Clostridium difficile , appetite loss caused by Clostridium difficile , abdominal pain caused by Clostridium difficile , nausea caused by Clostridium difficile , dehydration caused by Clostridium difficile , colitis caused by Clostridium difficile and pseudomembraneous colitis caused by Clostridium difficile , which method comprises administering to the subject an effective amount of a compound as defined in claim 23 or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate or prodrug thereof.
27. The method of claim 26 wherein the CDAD is treated whilst sparing normal gut flora.
28. The method of claim 26 wherein the CDAD is selected from: (a) colitis caused by Clostridium difficile ; (b) pseudomembraneous colitis caused by Clostridium difficile ; and (c) diarrhoea caused by Clostridium difficile.
29. The method of claim 26 wherein the CDAD is selected from: (a) diarrhoea caused by Clostridium difficile ; and (b) colitis caused by Clostridium difficile.
30. A method of treating Clostridium difficile -associated disease (CDAD) in a subject in need thereof, the CDAD selected from the group consisting of diarrhoea caused by Clostridium difficile , bloating caused by Clostridium difficile , flu-like symptoms caused by Clostridium difficile , fever caused by Clostridium difficile , appetite loss caused by Clostridium difficile , abdominal pain caused by Clostridium difficile , nausea caused by Clostridium difficile , dehydration caused by Clostridium difficile , colitis caused by Clostridium difficile and pseudomembraneous colitis caused by Clostridium difficile , which method comprises
a) detecting infection and/or intoxication of the subject with one or more strains of Clostridium difficile;
b) administering to the subject an effective amount of a compound 2,2′-di(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole or a pharmaceutically acceptable N-oxide, salt, hydrate, or solvate thereof; and
c) preventing or reducing the rate of bacterial growth, and/or mediating the cellular destruction of bacterial cells, of the one or more strains of Clostridium difficile,
wherein the compound does not exhibit bacteriostatic and/or bacteriocidal activity (minimum inhibitory concentration (MIC) >64 μg/mL) against Escherichia spp. Bacteroides spp., Fusobacterium spp., Eubacterium spp., Ruminococcus spp., Peptococcus spp., Peptostreptococcus spp., Bifidobacterium spp., C. perfringens, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Bacillus subtilis and/or Lactobacillus spp.
31. The method of claim 30 wherein the compound does not exhibit bacteriostatic and/or bacteriocidal activity against Bacteroides fragilis.
32. The method of claim 30 , wherein the compound does not exhibit bacteriostatic and/or bacteriocidal activity against both Bacteroides fragilis and Escherichia coli.