Compounds for the treatment of clostridium difficile associated disease

Abstract

Disclosed are compounds of formula (I): and pharmaceutically acceptable N-oxides, salts, hydrates, solvates, complexes, bioisosteres, metabolites, and prodrugs thereof, which are of use in the treatment of infection with, and diseases caused by, Clostridium difficile.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         R 1  is selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 ; 
         R 2  is an optionally substituted aromatic 8-14 membered fused bicyclic or tricyclic ring system in which one or more of the carbon atoms may be replaced by N, O, S, SO or SO 2  and the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 ; 
         R 3  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -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 substituents selected from halo, CN, NO 2 , R 4 , OR 4 , N(R 4 ) 2 , COR 4 , CO 2 R 4 , C(═O)SR 4 , SR 4 , S(═O)R 4 , SO 2 R 4 , NR 4 C(═O)R 4 , NR 4 CO 2 R 4 , OC(═O)NR 4 ) 2 , NR 4 SO 2 R 4 , C(═NR 4 )N(R 4 ) 2 , C(═S)N(R 4 ) 2 , NR 4 C(═NR 4 )N(R 4 ) 2 , NR 4 C(═S)N(R 4 ) 2 , NR 4 C(═O)N(R 4 ) 2 , CON(R 4 ) 2  and SO 2 N(R 4 ) 2 ; 
         R 4  is selected from hydrogen, C 1 -C 6  alkyl and C 3 -C 7  carbocyclyl, optionally substituted with one or more halo atoms; 
       
       or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof for use in a method for the treatment of  Clostridium difficile -associated disease (CDAD). 
     
     
         2 . The compound of  claim 1  wherein R 1  is: (a) a pyridyl group; or (b) a thiazole group. 
     
     
         3 . The compound of  claim 1  or  claim 2  wherein R 2  is an optionally substituted aromatic 8-10 membered fused bicyclic ring system in which one or more of the carbon atoms may be replaced by N, O, S, SO or SO 2  and the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 . 
     
     
         4 . The compound of  claim 3  wherein R 2  is an optionally substituted aromatic 9-membered bicyclic ring system in which one or more of the carbon atoms may be replaced by N, O, S, SO or SO 2  and the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 . 
     
     
         5 . The compound of any one of the preceding claims wherein R 2  is an optionally substituted aromatic fused 5- and 6-membered bicyclic ring system. 
     
     
         6 . The compound of  claim 5  wherein R 2  is: (a) a thienopyridyl group; or (b) a benzothiophene group; or (c) a benzofuran group; or (d) a pyridyl imidazole group; or (e) a benzodioxol group; or (f) an indole group. 
     
     
         7 . The compound of any one of  claims 1  to  3  wherein R 2  is an optionally substituted aromatic fused 6- and 6-membered bicyclic ring system. 
     
     
         8 . The compound of  claim 7  wherein R 2  is: (a) a isoquinolone group; or (b) a quinoxaline group; or (c) an isoquinoline group; or (d) a quinoline group; or (e) a naphthyridine group. 
     
     
         9 . The compound of any one of the preceding claims which is symmetrical, for example wherein R 1  and R 2  are the same. 
     
     
         10 . The compound of any one of  claims 1  to  8  which is unsymmetrical, for example wherein R 1  and R 2  are different. 
     
     
         11 . The compound of  claim 1  which is selected from compounds 1 to 13 as listed in Table 1 herein. 
     
     
         12 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         R 1  is selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 ; 
         R 2  is an optionally substituted aromatic 8-14 membered fused bicyclic or tricyclic ring system in which one or more of the carbon atoms may be replaced by N, O, S, SO or SO 2  and the optional substitution being with one or more substituents selected from halo, CN, NO 2 , R 3 , OR 3 , N(R 3 ) 2 , COR 3 , CO 2 R 3 , C(═O)SR 3 , SR 3 , S(═O)R 3 , SO 2 R 3 , NR 4 C(═O)R 3 , NR 4 CO 2 R 3 , OC(═O)NR 3 R 4 , NR 4 SO 2 R 3 , C(═NR 4 )NR 3 R 4 , C(═S)NR 3 R 4 , NR 4 C(═NR 4 )NR 3 R 4 , NR 4 C(═S)NR 3 R 4 , NR 4 C(═O)NR 3 R 4 , CONR 3 R 4  and SO 2 NR 3 R 4 ; 
         R 3  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -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 substituents selected from halo, CN, NO 2 , R 4 , OR 4 , N(R 4 ) 2 , COR 4 , CO 2 R 4 , C(═O)SR 4 , SR 4 , S(═O)R 4 , SO 2 R 4 , NR 4 C(═O)R 4 , NR 4 CO 2 R 4 , OC(═O)NR 4 ) 2 , NR 4 SO 2 R 4 , C(═NR 4 )N(R 4 ) 2 , C(═S)N(R 4 ) 2 , NR 4 C(═NR 4 )N(R 4 ) 2 , NR 4 C(═S)N(R 4 ) 2 , NR 4 C(═O)N(R 4 ) 2 , CON(R 4 ) 2  and SO 2 N(R 4 ) 2 ; 
         R 4  is selected from hydrogen, C 1 -C 6  alkyl and C 3 -C 7  carbocyclyl, optionally substituted with one or more halo atoms; 
       
       or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof, optionally for use in therapy or prophylaxis, for example in a method for the treatment of a bacterial infection or disease. 
     
     
         13 . The compound of  claim 12  which is as defined in any one of  claims 2  to  11 . 
     
     
         14 . The compound of  claim 12  which is selected from
 2-(2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)thieno[2,3-b]pyridine 
 2-(benzo[b]thiophen-2-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 2-(benzofuran-5-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 6-(2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazol-2-yl)benzo[d]imidazole 
 2-(benzo[b]thiophen-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole 
 2-(1H-indol-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole 
 2-(2,3-dihydrobenzofuran-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole 
 2-(imidazo[1,2-a]pyridin-6-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 2-(benzo[d][1,3]dioxol-5-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 2-(benzofuran-2-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 2-(2′-(pyridin-4-yl)-1H,1′H-[5,5′-bibenzo[d]imidazol]-2-yl)thieno[2,3-c]pyridine 
 2-(imidazo[1,2-a]pyridin-6-yl)-2′-(pyridin-3-yl)-1H,1′H-5,5′-bibenzo[d]imidazole 
 2-(2′-(pyridin-3-yl)-1H,1′H-[5,5′-bibenzo[d]imidazol]-2-yl)thieno[2,3-b]pyridine 
 or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof. 
 
     
     
         15 . The compound of any one of the preceding claims which is a selective  Clostridium difficile  agent, for example being selected from
 2-(2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazol-2-yl)thieno[2,3-b]pyridine   2-(benzo[b]thiophen-2-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   2-(benzofuran-5-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   6-(2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazol-2-yl)benzo[d]imidazole   2-(benzo[b]thiophen-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole   2-(1H-indol-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole   2-(2,3-dihydrobenzofuran-5-yl)-2′-(pyridin-4-yl)-1H,3′H-5,5′-bibenzo[d]imidazole   2-(imidazo[1,2-a]pyridin-6-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   2-(benzo[d][1,3]dioxol-5-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   2-(benzofuran-2-yl)-2′-(pyridin-4-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   2-(2′-(pyridin-4-yl)-1H,1′H-[5,5′-bibenzo[d]imidazol]-2-yl)thieno[2,3-c]pyridine   2-(imidazo[1,2-a]pyridin-6-yl)-2′-(pyridin-3-yl)-1H,1′H-5,5′-bibenzo[d]imidazole   2-(2′-(pyridin-3-yl)-1H,1′H-[5,5′-bibenzo[d]imidazol]-2-yl)thieno[2,3-b]pyridine   or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof.   
     
     
         16 . A combination comprising a compound as defined in any one of the preceding claims and an adjunctive agent selected from those described herein. 
     
     
         17 . A combination of  claim 16  comprising a compound as defined in any one of the preceding claims and an adjunctive agent selected from: (a) vancomycin; (b) metronidazole; (c) a probiotic; (d) a pre-biotic; (e) a bacteriotoxin sequestrant (e.g. ion exchange resin); (f) intravenous immunoglobulin; and (g) an anti-diarrhoeal agent. 
     
     
         18 . The combination of  claim 16  or  claim 17  comprising a compound as defined in any one of the preceding claims and a probiotic selected from  Saccharomyces  spp. and/or  Lactobacillus  spp. 
     
     
         19 . The combination of any one of  claims 16  to  18  wherein the compound as defined in any one of the preceding claims and adjunctive agent are physically or non-physically associated. 
     
     
         20 . A method of treating a  Clostridium difficile  infection or  Clostridium difficile  disease in a subject comprising administering an effective amount of a compound as defined in any one of  claims 1  to  15  or a combination as defined in any one of  claims 16  to  19  to said subject. 
     
     
         21 . A method of killing  Clostridium difficile  or inhibiting, reducing or preventing the growth thereof, comprising contacting said bacterium with a compound as defined in any one of  claims 1  to  15  or a combination as defined in any one of  claims 16  to  19 . 
     
     
         22 . A pharmaceutical composition comprising a compound as defined in any one of  claims 1  to  15  or a combination as defined in any one of  claims 16  to  19 . 
     
     
         23 . The invention of any one of the preceding claims for use in a method for the treatment of CDAD whilst sparing normal gut flora. 
     
     
         24 . The invention of any one of the preceding claims wherein the CDAD is selected from: (a) colitis; (b) pseudomembranous colitis; (c) diarrhoea; and (d) antibiotic-associated disease. 
     
     
         25 . The invention of  claim 24  wherein the antibiotic-associated disease is selected from: (a) antibiotic-associated diarrhoea; and (b) antibiotic-associated colitis for use in the treatment of 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.