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WO2011151620A1 - Compounds for the treatment of clostridium difficile associated disease - Google Patents

Compounds for the treatment of clostridium difficile associated disease Download PDF

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Publication number
WO2011151620A1
WO2011151620A1 PCT/GB2011/000830 GB2011000830W WO2011151620A1 WO 2011151620 A1 WO2011151620 A1 WO 2011151620A1 GB 2011000830 W GB2011000830 W GB 2011000830W WO 2011151620 A1 WO2011151620 A1 WO 2011151620A1
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WIPO (PCT)
Prior art keywords
pyridin
bibenzo
compound
imidazole
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2011/000830
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French (fr)
Inventor
Peter David Johnson
Richard Vickers
Francis Xavier Wilson
Colin Richard Dorgan
Olivier De Moor
Stephen Paul Wren
Renate Van Well
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Summit Therapeutics Ltd
Original Assignee
Summit Corp PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1009095.9A external-priority patent/GB201009095D0/en
Priority claimed from GBGB1106972.1A external-priority patent/GB201106972D0/en
Application filed by Summit Corp PLC filed Critical Summit Corp PLC
Publication of WO2011151620A1 publication Critical patent/WO2011151620A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds which are of use in the treatment of infection with, and diseases caused by, Clostridium difficile, to compositions containing these compounds and to methods of treating Clostridium difficile-associated diseases (CDAD) using the compounds.
  • CDAD Clostridium difficile-associated diseases
  • Bacterial spores (endospores) are dormant, non-reproductive structures formed by bacteria in response to environmental stress. Once environmental conditions become favourable, the spores germinate and the bacteria proliferate. In the case of pathogenic bacteria, germination in a human host may result in disease.
  • Bacterial spores are extremely tolerant to many agents and environmental conditions including radiation, desiccation, temperature, starvation and chemical agents. This natural tolerance to chemical agents allows spores to persistent for many months in key environments such as hospitals, other healthcare centres and food production facilities, where standard cleaning agents, germicides and sterilisation processes do not eradicate the bacteria. In the case of food production, the presence of spores can have significant consequences ranging from simple food spoilage through to the spread of food-borne pathogens and food poisoning. More recently, attention has been drawn to the risks associated with the spores of Bacillus anthracis, the causative agent of anthrax.
  • the spores can be readily prepared as a dry powder that can be disseminated by numerous methods and used as a bioterrorist agent.
  • Anthrax is considered the single most worrying bioterrorism agent (CDC Emerg. Infect. Dis., 2004, 5 (4), 552-555). This can be highlighted by the postal anthrax attacks in the United States in 2001. There were 22 confirmed infections resulting in 5 deaths with the cost of cleanup and decontamination following the attacks estimated at $1 billion.
  • Important spore-forming bacteria are the Gram-positive endospore-forming bacteria of the genera Bacillus and Clostridium. Examples of the genus Bacillus of health concern to humans include, but are not limited to, B. anthracis and B. cereus. Bacillus anthracis is of particular concern as the causative agent of anthrax. Anthrax infection can occur through ingestion, inhalation or cutaneous contact with Bacillus anthracis spores resulting in three distinct clinical forms. Cutaneous infection accounts for about 95% of all infections and is generally well controlled with the use of suitable antibiotics. Around 20% of untreated cases of cutaneous anthrax will result in death.
  • Intestinal infection is characterized by an acute inflammation of the intestinal tract resulting in nausea, loss of appetite, vomiting, fever, abdominal pain, vomiting of blood and severe diarrhoea. Intestinal anthrax results in death in 25% to 60% of cases. The most severe form of the disease is pulmonary anthrax which is often fatal, even with aggressive and timely antibiotic administration. The ability to readily disperse anthrax spores through the air and over a wide area to induce pulmonary anthrax makes anthrax the primary bioterrorism agent.
  • Clostridium are Gram-positive, spore-forming, obligate anaerobes.
  • Example species causing human disease include, but are not limited to, C. perfringens, C. tetani, C. botulinium, C. sordellii and C. difficile.
  • Clostridial species are associated with diverse human diseases including tetanus, gas gangrene, botulism and
  • pseudomembraneous colitis can be a causative agent in food poisoning.
  • Clostridium difficile causes Clostridium dfficffe-associated diseases (CDAD) and there has been a ten-fold increase in the number of cases within the last 10 years, with hyper-virulent and drug resistant strains now becoming endemic.
  • CDAD Clostridium dfficffe-associated diseases
  • Recent HPA figures show there were 55,681 cases of C. difficile infection in patients aged 65 years and above in England in 2006 (up 8% on the previous year). Perhaps most worrying are the cases of CDAD with no underlying antibiotic use now being reported.
  • Clostridium difficile is a commensal enteric bacterium, the levels of which are kept in check by the normal gut flora.
  • the bacterium is the causative agent of C, difficile - associated disease (CDAD) and has been identified as the primary cause of the most serious manifestation of CDAD, pseudomembraneous colitis.
  • CDAD is associated with a wide range of symptoms ranging from mild diarrhoea through to pseudomembraneous colitis, toxic megacolon and death.
  • the primary risk factor for the development of CDAD is the use of antibiotics disrupting the normal enteric bacterial flora causing an overgrowth of Clostridium difficile.
  • clindamycin is the major antibiotic associated with CDAD, the disease is now associated with nearly all antibiotics including members of the
  • CDAD is primarily of concern in the hospital setting and is of particular concern amongst elderly patients where mortality rates are particularly high. Reported rates of CDAD have increased dramatically in recent years with over 55,000 cases reported in the UK in 2006 (Health Protection Agency Surveillance of Healthcare Associated Infections Report 2007).
  • a critical factor associated with clostridial species is the high rates of bacterial spores present in hospital environments. It has recently been shown that many of the standard hospital cleaning agents in use are ineffective at eradicating clostridial spores for the environment resulting in ineffective disease control (Infect Cont. Hosp. Epidemiol., 2007, 28, 920-5). The hyper-sporulation characteristics of strains such as BI/NAP1 contribute significantly to the issue.
  • gastric acid suppressive agents such as proton pump inhibitors (PPIs) and histamine H2 - receptor antagonists (H2RAs) is associated with an increased risk of C. difficile colonisation and subsequent development of CDAD.
  • PPIs proton pump inhibitors
  • H2RAs histamine H2 - receptor antagonists
  • the use of PPIs and H2RAs has previously been associated with other enteric infections such as traveller's diarrhoea, salmonellosis and cholera.
  • Dial ef a/ have reported that the risk of CDAD increases with the use of gastric acid suppressive agents in both the community (JAMA, 2005, 294(23). 2989-2995) and hospital settings (CMAJ, 2004, 171 (1 ), 33-38).
  • PPIs include, but are not limited to, omeprazole (Losec, Prilosec, Zegerid), lansoprazole (Prevacid, Zoton, Inhibitol), esomeprazole (Nexium), pantoprazole (Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan) and rabeprazole ( abecid, Aciphex, Pariet, Rabeloc).
  • H2RAS include, but are not limited to, cimetidine (Tagamet), ranitidine (Zinetac, Zantac), famotidine, (Pepcidine, Pepcid), roxatidine (Roxit) and nizatidine (Tazac, Axid).
  • Typical antibacterials used to treat Helicobacter pylori infections are a combination of agents selected from, but not limited to metronidazole, amoxicillin, levofloxacin and clarithromycin - many of which are strongly associated with the development of CDAD, Current therapies are extremely limited; particularly in view of the fact nearly all antibiotic classes are associated with causing the disease.
  • the only FDA approved drug for treatment of CDAD is vancomycin although metronidazole is also extensively used.
  • the primary therapy option for the treatment of CDAD is discontinuation of any current antimicrobial treatment followed by appropriate use of either vancomycin or metronidazole. Both agents are usually administered orally although metronidazole may also be administered intravenously and in severe cases, vancomycin may also be administered via numerous other routes including intracolonic, through nasal gastric tube or as a vancomycin-retention enema. Additional antibiotics agents that have been reported to be used in the treatment of CDAD include fusidic acid, rifamycin and its analogues, teicoplanin and bacitracin although none show particular efficacy over vancomycin or metronidazole.
  • antiperistaltic agents In addition to halting any offending antibacterial treatment, the use of antiperistaltic agents, opiates, or loperamide should be avoided since they can reduce clearance of the C. difficile toxins and exacerbate toxin-mediated colonic injury. Such agents may also precipitate ileus and cause toxic dilation of the colon (J. Med. Microbiol., 2005, 54, 101-111 ; JAMA, 1993, 269. 71-5; Postgrad. Med. J, 1990, 66(777), 582).
  • Alternative therapies used as standard alone agents or in conjunction with antibacterials, are aimed at either trying to re-establish the native gut microorganism population, reducing the levels of C.
  • CDAD therapies include provision of Saccheromyces boulardii or Lactobacillus acidophilus in conjunction with antibiotics, faecal transplantation and in severe cases where all other therapy options have failed, surgery. Although rates of colectomy are low (up to 3% of cases) it is associated with high mortality rates (up to 60%).
  • Clostridium and Bacillus and in particular disease associated with Clostridium difficile infection This need is particularly acute in the light of the refractory nature of Clostridium difficile to many broad spectrum antibiotics (including ⁇ -lactam and quinolone antibiotics) and the frequency with which resistance emerges (Antimicrob. Agents Chemother., 1985, 28(6): 842-844).
  • WO2007056330 disclose various 2-amino benzimidazoies as antibacterial agents.
  • WO2007148093 discloses various 2-amino benzothiazoles as antibacterial agents.
  • WO2006076009, WO2004041209 and Bowser et al disclose various substituted benzimidazole compounds useful as anti- infectives that decrease resistance, virulence, or growth of microbes. The compounds are said not to exhibit intrinsic antimicrobial activity in vitro.
  • US 5,824,698 discloses various dibenzimidazoles as broad-spectrum antibiotics, disclosing activity against both Gram-negative and Gram-positive bacteria, including Staphylococcus spp.and Enterococcus spp. However, this document does not disclose activity against anaerobic spore-forming bacteria and in particular does not disclose activity against any Clostridium spp. (including C. difficile).
  • triarylamidines as broad-spectrum antibiotics, disclosing activity against both Gram- negative and Gram-positive bacteria, including Staphylococcus spp., Enterococcus spp. and Clostridium spp.
  • Staphylococcus spp. Enterococcus spp.
  • Clostridium spp. this document does not disclose compounds of general formula (I) as described herein.
  • L is a direct bond, O, N or C C 3 alkyl
  • R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocydyl group, the optional substitution being with one or more
  • R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
  • R and R is an optionally substituted heteroaryl or heterocydyl group, the optional substitution being with one or more substituents selected from halo,
  • R is selected from H, C,-C e alkyl, C 2 -C e alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 carbocydyl, C 4 -C 7 heterocyclyl and S- or 6- membered aryl or heteroaryl, any of which may be optionally substituted with one or more substituents selected from halo, ON, N0 2 ,
  • R is selected from hydrogen, C,-C e 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 the treatment of Clostridium d/f7/c//e-associated disease (CDAD).
  • CDAD Clostridium d/f7/c//e-associated disease
  • L is a direct bond, O, N or C C 3 alkyl
  • R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more substituents selected from halo, CN, N0 2 , R , OR , (R ) 2 , COR 3 , C0 2 R 3 ,
  • R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
  • R and R is an optionally substituted heteroaryl or heterocyclyl group, the optional substitution being with one or more substituents selected from halo,
  • R and R are not both or ⁇
  • R is selected from H, C,-C e alkyl, C 2 -C e alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 carbocyclyl,
  • R is selected from hydrogen, C,-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.
  • the compound as defined above may be for use in therapy or prophylaxis, for example in the treatment of a bacterial infection or disease (for example, in the treatment of CDAD).
  • a method of treating a bacterial infection or bacterial disease comprising administering an effective amount of a compound as defined above to said subject.
  • a method of killing a bacterium or inhibiting, reducing or preventing the growth thereof comprising contacting said bacterium with a compound as defined above.
  • the bacterium is preferably Clostridium difficile.
  • combinations comprising the compound of the invention as defined above with various adjunctive agents as defined below.
  • “comprising,” are to be read to indicate the inclusion of any recited integer ⁇ e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers.
  • the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
  • the term "consisting” is used to indicate the presence of the recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) alone.
  • disease * is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms.
  • the term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.
  • bacterial disease refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a bacterium residing and/or replicating in the body and/or cells of a subject.
  • the term therefore includes diseases caused or exacerbated by bacterial toxins (which may also be referred to herein as “bacterial intoxication”).
  • bacterial intoxication which may also be referred to herein as "bacterial intoxication”
  • Clostridium difficile disease is to be interpreted accordingly.
  • Clostridium d/ffiele-associated disease is used to define any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) Clostridium difficile residing and/or replicating in the body of a subject.
  • CDAD Clostridium d/ffiele-associated disease
  • the term covers any disease, disorder, pathology, symptom, clinical condition or syndrome in which bacteria of the species Clostridium difficile act as aetiological agents or in which infection with one or more strains of Clostridium difficile is implicated, detected or involved.
  • the term therefore includes the various forms of colitis, pseudomembranous colitis, diarrhoea and antibiotic-associated disease.
  • the term 'selective Clostridium difficile agent is used herein to define a compound which exhibits bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but which does not exhibit bacteriostatic and/or bacteriocidal activity against one or more representative(s) of the normal gut flora selected from: (a) Escherichia spp. (for example, Escherichia co/i); (b) Bacteroides spp. (for example, B. fragilis); (c) Fusobacterium spp.; (d) Eubacterium spp.
  • Enterococcus spp. for example, E. faecium
  • clostridial species other than C. difficile for example C. perfringens
  • Enterobacter spp. for example, E. faecium
  • Serratia spp. for example, S. perfringens
  • Klebsiella spp. for example, S. perfringens
  • Proteus spp. for example, Proteus spp.
  • Pseudomonas spp. and
  • Veillonella spp. Veillonella spp.
  • Preferred selective Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity against: (a) Escherichia coli ; or (b) B. fragilis.
  • certain preferred selective Clostridium difficile agents of the invention exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity against B. fragilis.
  • bacterial infection * is used to define a condition in which a subject is infected with a bacterium.
  • the infection may be symptomatic or asymptomatic.
  • the subject may be identified as infected on the basis of various tests, including for example biochemical tests, serological tests, microbiological culture and/or microscopy.
  • bacteriostatic and bacteriocidal are terms of art used to define the ability to prevent (or reduce the rate of) bacterial growth and to mediate (directly or indirectly) the cellular destruction of bacterial cells, respectively.
  • the terms are not mutually exclusive, and many agents exert both bacteriostatic and bacteriocidal effects (in some cases in a dose-specific or target-specific manner). In general, bacteriocidal agents yield better therapeutic results and are preferred.
  • MDR multi-drug resistant
  • treatment refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the causative bacterium).
  • the term is used synonymously with the term "therapy”.
  • the treatment of infection according to the invention may be characterized by the (direct or indirect) bacteriostatic and/or bacteriocidal action of the compounds of the invention.
  • treatment refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population.
  • intervention e.g. the administration of an agent to a subject
  • treatment is used synonymously with the term “prophylaxis”.
  • subject (which is to be read to include “individual”, “animal”, “patient” or “mammal” where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated.
  • Mammalian subjects include, but are not limited to, humans, primates, domestic animals, farm animals, pet animals and rodents such as mice, rats, hamsters and guinea pigs.
  • the subject is a human.
  • Gram-positive bacterium is a term of art defining a particular class of bacteria that are grouped together on the basis of certain cell wall staining characteristics.
  • tow G+C Gram-positive bacterium is a term of art defining a particular subclass class of evolutionarily related bacteria within the Gram-positives on the basis of the composition of the bases in the DNA,
  • the subclass includes Streptococcus spp.
  • Staphylococcus spp. Listeria spp., Bacillus spp., Clostridium spp., Enterococcus spp. and Lactobacillus spp.
  • MIC minimum inhibitory concentration
  • a common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the test compound that are then inoculated with the bacterial isolate of interest. Following incubation at appropriate atmosphere and temperature, the MIC of an antibiotic can be determined from the tube with the lowest concentration that shows no turbidity.
  • association of the two or more compounds/agents in a combination may be physical or non-physical.
  • Examples of physically associated combined compounds/agents include:
  • compositions ⁇ e.g. unitary formulations) comprising the two or more
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);
  • compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets); • pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds/agents are co-packaged or co-presented (e.g. as part of an array of unit doses); Examples of non-physically associated combined compounds/agents include:
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents
  • material e.g. a non-unitary formulation
  • material comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents
  • material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;
  • compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or
  • each of the two or more compounds agents in a combination therapy may also differ with respect to the route of administration. 18
  • the term "pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging.
  • dosing means e.g. measuring device
  • delivery means e.g. inhaler or syringe
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical kit may optionally further comprise instructions for use.
  • the term "pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging.
  • pharmaceutical packs comprising a combination of two or more compounds/agents
  • the individual compounds/agents may unitary or non-unitary formulations.
  • the unit dose(s) may be contained within a blister pack.
  • the pharmaceutical pack may optionally further comprise instructions for use.
  • patient pack defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment.
  • Patient packs usually contain one or more blister pack(s).
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • an effective amount or a therapeutically effective amount of a compound defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition.
  • the amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors.
  • a therapeutic result in this context 1? includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement.
  • a prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • efficacious includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity or improved performance or activity.
  • an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity, whilst producing and/or maintaining the same therapeutic effect.
  • a synergistic effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the components of the combination when presented individually.
  • An additive effect in the present context refers to a therapeutic effect produced by the combination which is larger than the therapeutic effect of any of the components of the combination when presented individually.
  • ancillary compound (or “ancillary agent”) as used herein is intended to define any compound which yields an efficacious combination (as herein defined) when combined with a compound of the invention.
  • the ancillary compound may therefore act as an adjunct to the compound of the invention, or may otherwise contribute to the efficacy of the combination (for example, by producing a synergistic or additive effect or by potentiating the activity of the compound of the invention).
  • adjunctive as applied to the use of the compounds and combinations of the invention in therapy or prophylaxis defines uses in which the materials are administered together with one or more other drugs, interventions, regimens or treatments (such as surgery and/or irradiation). Such adjunctive therapies may comprise the concurrent, separate or sequential administration/application of the materials of the invention and the other treatment(s). Thus, in some embodiments, adjunctive use of the materials of the invention is reflected in the formulation of the pharmaceutical compositions of the invention.
  • adjunctive use may be reflected in a specific unit dosage, or in formulations in which the compound of the invention is present in admixture with the other drug(s) with which it is to be used adjunctively (or else physically associated with the other drug(s) within a single unit dose).
  • adjunctive use of the compounds or compositions of the invention may be reflected in the composition of the pharmaceutical kits of the invention, wherein the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the other daig(s) with which it is to be used adjunctively.
  • adjunctive use of the compounds of the invention may be reflected in the content of the information and/or instructions co-packaged with the compound relating to formulation and/or posology.
  • pharmaceutically acceptable derivative as applied to the compounds of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent compounds of the invention.
  • the pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with mammalian tissues without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio).
  • Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of the parent compounds of the invention.
  • the derivatives may be active perse, or may be inactive until processed in vivo. In the latter case, the derivatives o the invention act as prodrugs.
  • Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo.
  • Other preferred prodrugs are covalently bonded
  • pharmaceutically acceptable derivatives of the invention retain some or all of the activity of the parent compound. In some cases, the activity is increased by derivatization. Derivatization may also augment other biological activities of the compound, for example bioavailability.
  • pharmaceutically acceptable salt as applied to the compounds of the invention defines any non-toxic organic or inorganic acid addition salt of the free base compound which is suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit risk ratio.
  • Suitable pharmaceutically acceptable salts are well known in the art. Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxy enzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p-toluenesulfonic acid).
  • inorganic acids for example hydrochloric, hydrobromic, sulphuric and phosphoric acids
  • organic carboxylic acids for example acetic, propionic, glycolic
  • the compounds of the invention may also be converted into salts by reaction with an alkali metal halide, for example sodium chloride, sodium iodide or lithium iodide.
  • an alkali metal halide for example sodium chloride, sodium iodide or lithium iodide.
  • the compounds of the invention are converted into their salts by reaction with a stoichiometric amount of sodium chloride in the presence of a solvent such as acetone.
  • salts and the free base compounds can exist in either a hydrated or a substantially anhydrous form.
  • Crystalline forms of the compounds of the invention are also contemplated and in general the add addition salts of the compounds of the invention are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility.
  • solvate as applied to the compounds of the invention defines any pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water (hydrates), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture.
  • the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone.
  • the structural formulae include compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • pharmaceutically acceptable prodrug as applied to the compounds of the invention defines any pharmaceutically acceptable compound that may be converted under physiological conditions or by solvolysis to the specified compound, to a pharmaceutically acceptable salt of such compound or to a compound that shares at least some of the antibacterial activity of the specified compound (e.g. exhibiting activity against Clostridium difficile).
  • pharmaceutically acceptable metabolite as applied to the compounds of the invention defines a pharmacologically active product produced through metabolism in the body of the specified compound or salt thereof. Prodrugs and active metabolites of the compounds of the invention may be identified using routine techniques known in the art (see for example, Bertolini et a/., J. Med. Chem., 1997, 40, 2011-2016).
  • compositions in which the compound of the invention forms a component part are compounds or compositions in which the compound of the invention forms a component part.
  • the complexes of the invention include derivatives in which the compound of the invention is physically associated (e.g. by covalent or non-covalent bonding) to another moiety or moieties.
  • the term therefore includes multimeric forms of the compounds of the invention. Such multimers may be generated by linking or placing multiple copies of a compound of the invention in close proximity to each other (e.g. via a scaffolding or carrier moiety).
  • bioisostere (or simply isostere) is a term of art used to define drug analogues in which one or more atoms (or groups of atoms) have been substituted with replacement atoms (or groups of atoms) having similar steric and/or electronic features to those atoms which they replace.
  • the substitution of a hydrogen atom or a hydroxy! group with a fluorine atom is a commonly employed bioisosteric replacement.
  • Sila-substitution (C/Si-exchange) is a relatively recent technique for producing isosteres. This approach involves the replacement of one or more specific carbon atoms in a compound with silicon (for a review, see Tacke and Zilch (1986) Endeavour, New Series 10: 191-197).
  • sila-substituted isosteres may exhibit improved pharmacological properties, and may for example be better tolerated, have a longer half-life or exhibit increased potency (see for example Englebienne (2005) Med. Chem., 1(3): 215-226). Similarly, replacement of an atom by one of its isotopes, for example hydrogen by deuterium, may also lead to improved pharmacological properties, for example leading to longer half-life (see for example Kushner et al (1999) Can J Physiol Pharmacol. 77(2):79-88). In its broadest aspect, the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention.
  • the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the compounds described herein.
  • the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • references to the compounds of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers. Therefore, the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g.
  • the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted.
  • the invention contemplates use of an isolated eutomer.
  • alkyl * defines a straight or branched saturated hydrocarbon chain.
  • d-d alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n- propyl, isopropyl, t-butyl, n-hexyl.
  • d-d alkyl * refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms.
  • * d-ds alkyl refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms.
  • the alkyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • d-d alkyl has a similar meaning except that it contains from one to four carbon atoms.
  • d-d alkenyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl, and 3-hexenyl.
  • C r C 6 haloalkyl refers to a C h alky! group as defined above substituted by one or more halogen atoms.
  • alkenyl defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon double bond.
  • d-Ce alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • CrC 9 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • Ci-C 15 alkenyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • Preferred is CrC 6 alkenyl. Examples include ethenyl, 2-propenyl, and 3-hexenyl.
  • the alkenyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • alkynyl * defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon triple bond.
  • B Ci-C 8 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms.
  • C 1 -C 9 alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms.
  • C Ci S alkynyl refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms.
  • Ci-Ce alkynyl examples include ethynyl, 2-propynyl, and 3-hexynyl.
  • the alkynyl groups of the invention may be optionally substituted by one or more halogen atoms.
  • heterocyclyl defines a saturated or partially saturated 3 to 14 membered ring system (except when alternative numbers of ring atoms are specified) similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O, S, SO or S0 2 .
  • Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine.
  • carbocyclyl means a mono- or poiycyclic residue containing 3 or more (e.g. 3-14, 3-10 or 3-8) carbon atoms.
  • the carbocyclyl residues of the invention may be optionally substituted by one or more halogen atoms.
  • Mono- and bicyclic carbocyclyl residues are preferred.
  • the carbocyclyl residues can be saturated or partially unsaturated and include fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and also bridged systems such as norbornyl and adamantyl.
  • cycloalkyls Saturated carbocyclyl residues are preferred and are referred to herein as "cycloalkyls" and the term “cycloalkyl” is used herein to define a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl and also bridged systems such as norbomyl and adamantyl.
  • the cycloalkyl residues of the invention may be optionally substituted by one or more halogen atoms.
  • aryl defines a 5-14 (e.g. 5-10) membered aromatic mono-, bi- or tricyclic group at least one ring of which is aromatic.
  • bicyclic aryl groups may contain only one aromatic ring.
  • aromatic moieties are benzene, naphthalene, imidazole and pyridine.
  • the term also includes bicyclic or tricyclic systems in which one or more of the rings has aromatic character. Indane is an example of this type of system.
  • heteroaryl are aryl moieties as defined above which contain heteroatoms (e.g. nitrogen, sulphur and/or oxygen).
  • the term also includes systems in which a ring having aromatic character is fused to a saturated or partially saturated ring.
  • Examples include pyridine, pyrimidine, furan, thiophene, indole, isoindole, indoline, benzofuran, benzimidazole, benzimidazoline quinoline, isoquinoline,
  • aryl * is to be interpreted to include heteroaryl groups as defined above.
  • aryl and heteroaryl groups of the invention may optionally be substituted by one or more halogen atoms.
  • halo refers to fluoro, chloro, bromo or iodo.
  • the bond orders of the specified rings may vary when the various possible heteroatom(s) imply specific requirements in order to satisfy aromaticity, prevent antiaromaticity and stabilize tautomeric forms due to localization.
  • the appropriate bond orders of the ring structures in the structural formulae of the present invention are contemplated herein.
  • the term "symmetrical" as applied to the compounds of formula (I) may define compounds in which the substituents R 1 and R 2 are the same.
  • the invention contemplates pharmaceutically acceptable salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs of each of the listed
  • the invention contemplates those compounds of general formula (I) which are novel as compounds per se, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals.
  • the invention contemplates a compound selected from:
  • Preferred compounds of the invention may be selective Clostridium difficile agents, as hereinbefore defined,
  • Particularly preferred selective Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit
  • bacteriostatic and/or bacteriocidal activity (MIC >64 pg/mL) against B. fragilis ATCC25285.
  • Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity (MIC >64 pg/mL) against both Bacteroides fragilis ATCC25285 and Escherichia coli ATCC25922.
  • Clostridium difficile agents can therefore be used to treat CDAD without disturbing the existing gut flora to a clinically significant extent.
  • such compounds may be used as antimicrobial agents without causing antibiotic-associated disease (as defined herein) and/or the spread of antibiotic resistant strains of gut pathogens.
  • Compounds of the invention which act as selective Clostridium difficile agents may be identified by determining the relative antibacterial activities of the compound for Clostridium difficile and one or more indicator organism(s) representative of the normal gut flora.
  • Suitable indicator organisms for this purpose include: (a) Escherichia spp. (for example, Escherichia coli); (b) Bacteroides spp. (for example, B, fragilis); (c) Fusobactenum spp.; (d) Eubacterium spp. (e) Ruminococcus spp.; (f) Peptococcus spp. ; (g) Peptostreptococcus spp,; (h) Bifidobacterium spp.; (i) Lactobacillus spp,; 0) Enterococcus spp. (for example, E faecium); (k) clostridial species other than C. difficile (for example C. periringens); (I) Enterobacter spp.; (m) Serratia spp.; (n) Klebsiella spp.; (o) Proteus spp.; (p)
  • compounds of the invention which act as selective Clostridium difficile agents may be identified by performing quantitative stool cultures on serial stool samples obtained from subjects dosed with the a test compound.
  • An in vitro variant of this approach is based on determining whether the test compound produces major floral shifts when incubated with diluted and filtered faecal samples in vitro.
  • floral shifts may be detected by determining the effect of the test compound on the relative numbers of bacteria representative of two or more of the following genera: (a) Escherichia spp. ⁇ for example, Escherichia colt); (b) Bacteroides spp. (for example, B. fragilis); (c)
  • Enterococcus spp. for example, E faecium
  • clostridial species other than C. dlffic/fe for example C. perfringens
  • Enterobacter spp. for example, E faecium
  • Serratia spp. for example, S. spp.
  • Klebsiella spp. for example, S. spp.
  • Proteus spp. for example, Pseudomonas spp.
  • q Veillonella spp.
  • the invention contemplates a selective Clostridium difficile agent selected from:
  • the compounds of the invention may inhibit or prevent spore germination.
  • the compounds of the invention may inhibit or prevent spore outgrowth.
  • the compounds of the invention may be bacteriocidal and/or bacteriostatic.
  • bacteriocidal compounds as hereinbefore defined. Such bacteriocidal compounds may also be bacteriostatic (e.g. depending on target bacterium and concentration). "I ⁇ Medical applications fa) Treatment of C, difficile infection The compounds of the invention find application in the treatment of Clostridium difficile infection or disease.
  • CDAD Clostridium difficile-associated disease
  • CDAD defines a set of symptoms and diseases associated with C. difficile infection and/or intoxication.
  • CDAD includes diarrhoea, bloating, flu-like symptoms, fever, appetite loss, abdominal pain, nausea, dehydration and bowel inflammation (colitis).
  • PMC pseudomembraneous colitis
  • the compounds of the invention find application in the treatment of all forms of CDAD, including diarrhoea, bloating, flu-like symptoms, fever, appetite loss, abdominal pain, nausea, dehydration, colitis and pseudomembraneous colitis.
  • the invention also finds application in the treatment of intoxication with clostridial exotoxins, including Clostridium difficile toxin A (TcdA), toxin B (TcdB) and/or binary toxin CDT.
  • TcdA Clostridium difficile toxin A
  • TcdB toxin B
  • binary toxin CDT binary toxin CDT.
  • Antibiotic-associated disease defines conditions arising from changes in the relative amounts of the microorganisms constituting the normal gut flora caused by (partial) elimination of the flora by antibiotic administration. Such diseases arise when the administration of antibiotics (particularly broad-spectrum antibiotics) permits the growth of pathogenic organisms (either by overgrowth from endogenous populations usually kept in check by the normal gut flora or by opportunistic colonization of sites cleared of the normal gut flora by the antibiotic). Antibiotic-associated diseases is typically manifested by diarrhoea (and associated dehydration), abdominal cramps, tenesmus and fever. It may also lead to various forms of colitis, including pseudomembraneous colitis (PMC). Thus, antibiotic-associated disease includes antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC).
  • AAD antibiotic-associated diarrhoea
  • AAC antibiotic-associated colitis
  • Antibiotic-associated disease is often caused by toxin-producing strains of Clostridium difficile. Staphylococcus aureus (including methicillin-resistant S. aureus) and Clostridium perfringens. Clostridium difficile is the most common cause of nosocomial AAD and causes the majority of cases of AAC. The bacterium proliferates in the colon of patients who have been given broad-spectrum antibiotics or cancer chemotherapy.
  • the compounds of the invention therefore find application in the treatment of antibiotic- associated disease, including AAD and AAC. Particularly preferred for use in such applications are compounds of the invention which are selective (as hereinbefore defined), since such compounds substantially spare the normal gut flora.
  • the compounds of the invention find particular application in the prophylaxis of antibiotic- associated disease, including AAD and AAC.
  • the compounds of the invention may be co-administered with other antibiotics or treatments which can induce changes in the relative amounts of the microorganisms constituting the normal gut flora.
  • the compounds of the invention may be used to treat subjects treated (or undergoing treatment) with broad-spectrum antibiotics.
  • Treatment of colitis, pseudomembraneous colitis and diarrhoea Treatment of colitis, pseudomembraneous colitis and diarrhoea
  • bacteria selected from Clostridium difficile are implicated in colitis, pseudomembraneous colitis (PMC) and diarrhoea.
  • the compounds of the invention find application in the treatment of colitis, pseudomembraneous colitis (PMC) or diarrhoea.
  • compositions comprising the compound of the invention in combination with one or more adjunctive agents selected from those described below.
  • auxiliary antiviral agents may be selected from one or more of: (a) viral enzyme inhibitors (for example selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors); (b) nucleoside/nucleotide reverse transcriptase inhibitors; (c) non- nucleoside reverse transcriptase inhibitors; (d) integrase inhibitors; (e) maturation inhibitors; (f) cytokines or cytokine stimulatory factors; (g) viral entry inhibitors, for example selected from: (i) an attachment inhibitor; (ii) a co-receptor binding inhibitor; and (iii) a membrane fusion inhibitor.
  • viral enzyme inhibitors for example selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors
  • nucleoside/nucleotide reverse transcriptase inhibitors for example selected from (i) protease inhibitors, (
  • the compounds of the invention may be used in combination with various antibacterial agents, including, but not limited to one or more antibiotic(s) selected from the following:
  • Aminoglycosides for example amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin.
  • Ansamycins for example geWanamycin and herbimycin.
  • Carbacephems for example loracarbef.
  • Carbapenems for example ertapenem, doripenem, imipenem/cilastatin and meropenem
  • Cephalosporins (first generation), including for example cefadroxil, cefazolin, cefalotin/cefalothin and cephalexin). • Cephalosporins (second generation), including for example cefaclor, cefamandole, cefoxitin, cefprozil and cefuroxime.
  • Cephalosporins (third generation), including for example cefixirne, cefdinir,
  • cefditoren cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone and cefdinir.
  • Cephalosporins (fourth generation), including for example cefepime.
  • Glycopeptides for example vancomycin and teicoplanin.
  • Macrolides for example azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin.
  • Monobactams for example aztreonam
  • Penicillins for example amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin).
  • Polypeptides for example bacitracin, polymixin B and colistin.
  • Sulfonamides for example mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim- sulfamethoxazole (co-trimoxazole, T P-S X)).
  • Tetracyclines for example demeclocycline, doxycycline, minocycline
  • Aminocoumarins for example novobiocin, albamycin, coumermycin and
  • Oxazolidinones for example linezolid and AZD2563
  • Lipopeptides for example daptomycin
  • Streptogramins for example quinupristin/dalfopristin
  • Glycylcyclines for example tigecycline
  • Lantibiotics for example Type A Lantibiotics (such as nisin, subtilin, epidermin, mutacin II, mutacin I & II! and Type B Lantibiotics (such as mersacidin, actagardine and cinnamycin).
  • antibiotics useful as adjunctive agents include one or more antibiotic(s) selected from the following: arsphenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampin/rifampicin and imidazole.
  • antibiotic(s) selected from the following: arsphenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfo
  • the compounds of the invention may be used in combination with one or more antibiotics selected from: penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, capreomycin, cycloserine, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, ethambutol, ethionamide, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolones (for example levofloxacin, moxafloxacin and gatifloxacin, ciprofloxacin, enoxacin,
  • grepafloxacin kanamycin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, p- aminosalicylic acid, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimethoprim- sulfamethoxazole, co-amoxyclav, cephalothin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, streptomycin, nitrofurantoin, co- trimoxazole, rifamycin and derivatives thereof (for example rifampicin, rifabutin and rifapentine), isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococcin, fusidic acid, thiolactomycin and fosmidomycin.
  • antibacterial adjunctive agents may be selected from those listed in the table below:
  • Antifungal adjunctive agents The compounds of the invention may be used in combination with various antifungal agents (antimycotics).
  • Antiprotozoal adjunctive agents may be used in combination with various antiprotozoal agents, including but not limited to, chloroquine, doxycycline, mefloquine, metronidazole, eplomithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate,
  • the compounds of the invention may be co-administered with a variety of other co- therapeutic agents which treat or prevent side effects arising from the antiinfective treatment and/or presenting as sequelae of the infection.
  • Adjunctive agents of this type may or may not have antiinfective activity and include, for example, PPIs and H2RAs (as hereinbefore described).
  • the compounds of the invention may be used adjunctively with PPIs including, but are not limited to, omeprazole (Losec, Prilosec, Zegerid), lansoprazole (Prevacid, Zoton, Inhibitol), esomeprazole (Nexium), pantoprazole (Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan) and rabeprazole (Rabecid, Aciphex, Pariet, Rabeloc).
  • PPIs including, but are not limited to, omeprazole (Losec, Prilosec, Zegerid), lansoprazole (Prevacid, Zoton, Inhibitol), esomeprazole (Nexium), pantoprazole (Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan) and rabeprazole (Rabecid, Aciphex, Pariet, Rabeloc).
  • H2RAs including, but are not
  • the compounds of the invention may be used adjunctively with triple therapy with PPIs or H2RAs together with a combination of two antibiotics ⁇ including, but not limited to, antibiotics selected from metronidazole, amoxicillin, levofloxacin and clarithromycin).
  • probiotics may be used as adjunctive agents, including for example
  • Saccharomyces boulardii or Lactobacillus acidophilus cells Probiotics are mono or mixed cultures of live microorganisms which are proposed to help re-establish the natural gut microflora of the patient that has been disrupted by the offending antimicrobial that induced CDAD or even the agent used to treat CDAD. In addition, such microorganisms may act to stimulate the patient's immune system and to elicit production of enzymes that degrade the toxins associated with C. difficile.
  • Particular microorganisms of interest are, but not limited to, Saccharomyces spp. (Tor example Saccharomyces boulardii and Saccharomyces cerevisiae) and Lactobacillus spp.
  • Lactobacillus rhamnosus for example Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaris and Lactobacillus plantarum.
  • Any other common probiotic composition or microorganism that is a normal member of the human intestinal tract may also be considered.
  • agents aimed at stimulating the growth of the intestinal flora may also be used as adjunctive agents.
  • agents aimed at stimulating the growth of the intestinal flora may also be used as adjunctive agents.
  • the use of oligofructose has been shown to increase levels of Bifidobacterium spp. and reduce subsequent relapse rates in patients.
  • any antibacterial agent with a narrow spectrum of activity targeted at Clostridium species would have significant benefit when dosed in combination with therapies aimed at reestablishing the normal enteric microorganism population.
  • Faecal bacteriotherapy may therefore also be used adjunctively with the compounds of the invention.
  • absorbents which bind and sequester bacteriotoxins of various different types may be used as adjunctive agents.
  • Ion exchange resins such as the bile acid sequestrants cholsetyramine or colestipol, bind to the C, difficile cytotoxins and thus aim to reduce the degree of toxic challenge to the gut.
  • ion exchange resins are known to bind to agents such as vancomycin and therefore may lead to suboptimal levels of antibacterial agent at the site of infection.
  • Other absorbents that may be used adjunctively with the compounds of the invention include polymers such as Synsorb 90 and Toievamer.
  • intravenous immunoglobulin J. Antimicrob. Chem., 2004, 53, 882-884
  • the compounds of the invention may be used adjunctively with various immunoglobulins.
  • agents aimed at reducing diarrhoea are generally avoided in CDAD patients, in certain cases it may be envisaged that the use of such agents in conjunction with an antibacterial may be of benefit when trying to increase levels of an antimicrobial agent at the site of infection and/or when trying to increase the length of time an antibacterial agent is in contact with the enteric pathogen.
  • agents may include, but are not limited to, loperamide (Lopex, Imodium, Dimor, Pepto) diphenoxylate (Lomotil, Co- phenotrope) difenoxin ( otofen), and racecadotril.
  • the compounds of the invention may be used adjunctively with various anti-diarrhoeal agents, including any of those listed above.
  • Co-therapeutic agents which treat or prevent any of the following side effects may be used as part of the same treatment regimen as the compounds of the invention: (a) lipodystrophy and wasting; (b) facial lipoatrophy; (c) hyperlipidemia; (d) fatigue; (e) anaemia; (f) peripheral neuropathy; (g) nausea; (h) diarrhoea; (i) hepatotoxicity; (j) osteopenia; (k) dehydration and (I) osteoporosis.
  • the treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:
  • Topical antimycottc therapy for example with an antimycotic agent selected from azoles, allylamines (e.g. terbinafine) or a morpholine (e.g. amorolfine);
  • an antimycotic agent selected from azoles, allylamines (e.g. terbinafine) or a morpholine (e.g. amorolfine);
  • the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (a) to (o) are being (or have been) carried out.
  • the treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:
  • Anti-inflammation therapy e.g. with steroids
  • the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (1) to (15) are being (or have been) carried out.
  • the compounds of the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway
  • the amount of the compound administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular compound selected.
  • the effective amount of the compound administered will generally range from about 0.01 mg/kg to 10000 mg/kg daily.
  • a unit dosage may contain from 0.05 to 500 mg of the compound, and can be taken one or more times per day.
  • the compound can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally, parenterally or topically, as described below.
  • the preferred route of administration is oral administration.
  • a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 1000 mg per kilogram body weight per day and most preferably in the range 1 to 5 mg per kilogram body weight per day.
  • the desired dose is preferably presented as a single dose for daily administration.
  • sub-doses administered at appropriate intervals throughout the day may also be employed. These sub-doses may be employed.
  • unit dosage forms for example, containing 0.001 to 100 mg, preferably 0.01 to 10 mg, and most preferably 0.5 to 1.0 mg of active ingredient per unit dosage form.
  • a number of factors are considered by the attending physician, including, but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
  • dosages can also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
  • a formulation intended for oral administration to humans can contain about 0.5 mg to about 7 g of active agent compounded optionally with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms for the compounds of the invention generally contain about 1 mg to about 500 mg of the active ingredient, for example 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the effectiveness of a particular dosage of the compound of the invention can be determined by monitoring the effect of a given dosage on the progression of the disease or its prevention.
  • the compound of the invention may take any form. It may be synthetic, purified or isolated from natural sources using techniques described in the art.
  • Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycoltc, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxy benzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
  • Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts.
  • Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ha) salts and other physiologically acceptable metal tons. Such salts can be made from the ions of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N, '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.
  • compositions can include stabilizers, antioxidants, colorants and diluents.
  • Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not compromised to such an extent that treatment is ineffective.
  • compositions may be administered enterally and/or parenterally.
  • Oral intra-gastric
  • Pharmaceutically acceptable carriers can be in solid dosage forms, including tablets, capsules, pills and granules, which can be prepared with coatings and shells, such as enteric coatings and others well known in the art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • Parenteral administration includes subcutaneous, intramuscular, intradermal, intravenous, and other routes known in the art.
  • Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
  • the pharmaceutical composition When administered, can be at or near body temperature.
  • compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • Tablets can be uncoated or they can be coated by known techniques, for example to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellutose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellutos
  • Aqueous suspensions can also contain one or more preservatives, for example, ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring - agents, or one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example, ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring - agents, or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavouring agents can be added to provide a palatable oral preparation.
  • These compositions can be preserved by addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., a suspending agent
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • Additional excipients for example sweetening, flavouring and colouring agents, can also be present.
  • Syrups and elixirs containing the compound of the invention can be formulated with sweetening agents, for example glycerol, sorbitol, or sucrose. Such formulations can also contain a demulcent, a preservative and flavouring and colouring agents.
  • the compound of the invention can be administered parenterally, for example
  • sterile injectable aqueous or oleaginous suspensions Such suspensions can be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above or other acceptable agents.
  • a sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1 ,3- butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any Wand fixed oil may be employed, including synthetic mono-or diglycerides.
  • omega-3 polyunsaturated fatty acids can find use in preparation of injectables.
  • Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperature, but liquid at rectal" temperature and will therefore, melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperature, but liquid at rectal" temperature and will therefore, melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • buccal and sub-lingual administration including administration in the form of lozenges, pastilles or a chewable gum comprising the compounds set forth herein.
  • the compounds can be deposited in a flavoured base, usually sucrose, and acacia or tragacanth.
  • Other methods for administration of the compounds of the invention include dermal patches that release the medicaments directly into and/or through a subject's skin.
  • Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, co!lyriums, solutions or suspensions.
  • compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers.
  • Viscosity-building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropylmethylcellulose,
  • hydroxyethylcellulose carboxymethylcellulose, hydroxypropylcellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition.
  • Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.
  • Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition.
  • cosolvents include polysorbates 20,60 and 80, polyoxyethylene/polyoxypropylene surfactants (e. g., Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
  • cosolvents are employed at a level of about 0.01% to about 2% by weight of a
  • compositions and carriers encompass all the foregoing and the like.
  • the above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See for example Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott. Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et a/., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).
  • any suitable excipient may be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while cornstarch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the pharmaceutical compositions may take any suitable form, and include for example tablets, elixirs, capsules, solutions, suspensions, powders, granules, nail lacquers, varnishes and veneers, skin patches and aerosols.
  • the pharmaceutical composition may take the form of a kit of parts, which kit may comprise the composition of the invention together with instructions for use and/or a plurality of different components in unit dosage form.
  • the compound of the invention can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, granules, solutions, suspensions, dispersions or emulsions (which solutions, suspensions).
  • dispersions or emulsions may be aqueous or non-aqueous).
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablets for oral use may include the compound of the invention, either alone or together with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the compound of the invention is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • the compounds of the invention are tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, colouring agents, and flavouring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch,
  • Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanoi, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent or emulsifying agent.
  • the compounds of the invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally.
  • the compound is provided as injectable doses in a physiologically acceptable diluent together with a pharmaceutical carrier (which can be a sterile liquid or mixture of liquids).
  • Suitable liquids include water, saline, aqueous dextrose and related compound solutions, an alcohol (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1 ,3-dioxolane-4- methanol), ethers (such as poly(ethylene-glycol) 400), an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or a detergent), suspending agent (such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
  • carboxymethylcellulose or emulsifying agent and other pharmaceutically adjuvants.
  • Suitable oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, com oil, olive oil, petrolatum, and mineral oil.
  • Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyt ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulphonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulphosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and
  • polyoxyethylenepolypropylene copolymers for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • amphoteric detergents for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • compositions of this invention will typically contain from about 0.5 to about 25% by weight of the compound of the invention in solution. Preservatives and buffers may also be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the compounds of the invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Topical formulations may contain a concentration of the compound from about 0.1 to about 10% w/v (weight per unit volume).
  • the compounds of the invention may be formulated for use with one or more other drug(s).
  • the compounds of the invention may be used in combination with analgesics, anti-inflammatories ⁇ e.g. steroids), immunomodulatory agents and anti-spasmodics.
  • adjunctive use may be reflected in a specific unit dosage designed to be compatible (or to synergize) with the other drug(s), or in formulations in which the compound is admixed with one or more antiinflammatories, cytokines or immunosuppressive agents (or else physically associated with the other drug(s) within a single unit dose).
  • Adjunctive uses may also be reflected in the composition of the pharmaceutical kits of the invention, in which the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the antimicrobial agents and/or antiinflammatories.
  • Adjunctive use may also be reflected in information and/or instructions relating to the co-administration of the compound with antimicrobial agents and/or antiinflammatories.
  • HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode.
  • the HPLC column used is a Phenomenex Gemini C18 150x4.6mm or a Phenomenex Gemini C18 50x4.6mm 3 ⁇ .
  • Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector.
  • the preparative HPLC column used is a Phenomenex Gemini C18 150x10mm and the mobile phase is acetonitrile/water.
  • DMSO dimethylsu!foxide
  • DMF dimethylformamide
  • IMS industrial methylated spirits
  • I PA isopropyl alcohol
  • TLC thin layer chromatography
  • Boc rerf-butyloxycarbon l
  • RT retention time
  • DCM diichloromethane
  • TFA driftuoroacetic acid
  • LCMS liquid chromatography-mass spectrometry
  • NMR nuclear magnetic resonance
  • DME 1- ,2-dimethoxyethane
  • MIC data were determined by broth microdiiution according to CLSl protocols described in Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard- Seventh Edition ⁇ M1 1 -A7, Vol. 27, No2, Jan 2007] and Methods for Dilution Antimicrobial
  • the bacterial strains used were:
  • the indicator strains are representatives of the normal gut flora and therefore act as surrogates for the microbial gut flora.
  • the compounds of the invention are selective Clostridium difficile agents (as hereinbefore defined) which exhibit bacteriostatic and/or bacteriocidal activity against C. difficile but which spare the normal gut flora.
  • the compounds of the invention therefore find utility in the treatment of CDAD without causing pathological disturbance of the normal gut flora.

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Abstract

Disclosed are compounds of formula (I): or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof, which are of use in the treatment of infection with, and diseases caused by, Clostridium difficile.

Description

COMPOUNDS FOR THE TREATMENT OF
CLOSTRIDIUM P/FF/C/LE-ASSOCIATED DISEASE Field of the Invention
The present invention relates to compounds which are of use in the treatment of infection with, and diseases caused by, Clostridium difficile, to compositions containing these compounds and to methods of treating Clostridium difficile-associated diseases (CDAD) using the compounds.
Background to the Invention (a) Antibacterial drugs and Clostridium difficile The development of antibacterial drugs represents one of the most important medical advances of the 20* Century, Previously unbeatable diseases could now be readily controlled and it was felt that many diseases would be eradicated with these new wonder drugs. Despite these significant advances in treatment, infectious diseases are the third major cause of mortality in the USA (Clin. Infect. Dis., 2004, 38, 1279-1286) and remain one of the most significant global healthcare problems. Rates of resistance in all of the major pathogenic bacteria are rising dramatically and of particular concern is the increasing number and severity of nosocomial infections (Infectious Disease Society of America, 2004, Sad Bugs, No Drugs). The emergence of multi-drug resistant pathogens has rendered many of the current frontline drugs completely ineffective in controlling many diseases.
A particular subset of bacterial pathogens of concern is those classified as spore-forming bacteria. Bacterial spores (endospores) are dormant, non-reproductive structures formed by bacteria in response to environmental stress. Once environmental conditions become favourable, the spores germinate and the bacteria proliferate. In the case of pathogenic bacteria, germination in a human host may result in disease.
Bacterial spores are extremely tolerant to many agents and environmental conditions including radiation, desiccation, temperature, starvation and chemical agents. This natural tolerance to chemical agents allows spores to persistent for many months in key environments such as hospitals, other healthcare centres and food production facilities, where standard cleaning agents, germicides and sterilisation processes do not eradicate the bacteria. In the case of food production, the presence of spores can have significant consequences ranging from simple food spoilage through to the spread of food-borne pathogens and food poisoning. More recently, attention has been drawn to the risks associated with the spores of Bacillus anthracis, the causative agent of anthrax. The spores can be readily prepared as a dry powder that can be disseminated by numerous methods and used as a bioterrorist agent. Anthrax is considered the single most worrying bioterrorism agent (CDC Emerg. Infect. Dis., 2004, 5 (4), 552-555). This can be highlighted by the postal anthrax attacks in the United States in 2001. There were 22 confirmed infections resulting in 5 deaths with the cost of cleanup and decontamination following the attacks estimated at $1 billion.
Important spore-forming bacteria are the Gram-positive endospore-forming bacteria of the genera Bacillus and Clostridium. Examples of the genus Bacillus of health concern to humans include, but are not limited to, B. anthracis and B. cereus. Bacillus anthracis is of particular concern as the causative agent of anthrax. Anthrax infection can occur through ingestion, inhalation or cutaneous contact with Bacillus anthracis spores resulting in three distinct clinical forms. Cutaneous infection accounts for about 95% of all infections and is generally well controlled with the use of suitable antibiotics. Around 20% of untreated cases of cutaneous anthrax will result in death. Intestinal infection is characterized by an acute inflammation of the intestinal tract resulting in nausea, loss of appetite, vomiting, fever, abdominal pain, vomiting of blood and severe diarrhoea. Intestinal anthrax results in death in 25% to 60% of cases. The most severe form of the disease is pulmonary anthrax which is often fatal, even with aggressive and timely antibiotic administration. The ability to readily disperse anthrax spores through the air and over a wide area to induce pulmonary anthrax makes anthrax the primary bioterrorism agent.
Members of the genus Clostridium are Gram-positive, spore-forming, obligate anaerobes. Example species causing human disease include, but are not limited to, C. perfringens, C. tetani, C. botulinium, C. sordellii and C. difficile. Clostridial species are associated with diverse human diseases including tetanus, gas gangrene, botulism and
pseudomembraneous colitis and can be a causative agent in food poisoning.
Of particular concern is disease caused by Clostridium difficile. Clostridium difficile causes Clostridium dfficffe-associated diseases (CDAD) and there has been a ten-fold increase in the number of cases within the last 10 years, with hyper-virulent and drug resistant strains now becoming endemic. Recent HPA figures show there were 55,681 cases of C. difficile infection in patients aged 65 years and above in England in 2006 (up 8% on the previous year). Perhaps most worrying are the cases of CDAD with no underlying antibiotic use now being reported.
Clostridium difficile is a commensal enteric bacterium, the levels of which are kept in check by the normal gut flora. However, the bacterium is the causative agent of C, difficile - associated disease (CDAD) and has been identified as the primary cause of the most serious manifestation of CDAD, pseudomembraneous colitis. CDAD is associated with a wide range of symptoms ranging from mild diarrhoea through to pseudomembraneous colitis, toxic megacolon and death. The primary risk factor for the development of CDAD is the use of antibiotics disrupting the normal enteric bacterial flora causing an overgrowth of Clostridium difficile. Although clindamycin is the major antibiotic associated with CDAD, the disease is now associated with nearly all antibiotics including members of the
fluoroquinolone, cephalosporin, macrolide, β-lactam and many others classes.
CDAD is primarily of concern in the hospital setting and is of particular concern amongst elderly patients where mortality rates are particularly high. Reported rates of CDAD have increased dramatically in recent years with over 55,000 cases reported in the UK in 2006 (Health Protection Agency Surveillance of Healthcare Associated Infections Report 2007).
Mortality rates in the USA have risen from 5.7 per million of population in 1999 to 23.7 per million in 2004. Colonisation rates of C. difficile in the general population are up to 3% although hospitalisation dramatically increases the rates of colonisation up to 25%. Of particular concern is the emergence of new endemic strains. A particularly pertinent example is the hyper-virulent BI/ AP1 (also known as ribotype 027) strain which shows increased toxin A and B production as well as the production of additional novel binary toxins.
A critical factor associated with clostridial species is the high rates of bacterial spores present in hospital environments. It has recently been shown that many of the standard hospital cleaning agents in use are ineffective at eradicating clostridial spores for the environment resulting in ineffective disease control (Infect Cont. Hosp. Epidemiol., 2007, 28, 920-5). The hyper-sporulation characteristics of strains such as BI/NAP1 contribute significantly to the issue.
Although the primary risk factors associated with CDAD are underlying antibiotic use and age (CMAJ, 2008, 179 (8), 767-772; J. Antimicrob. Chem., 2003, 51 , 1339-1350) there are numerous other associated factors including for example the use of proton pump inhibitors, use of H2 receptor antagonists, use of diuretics, length of hospital stay, use of feeding tubes, mechanical ventilation and underlying co-morbidity. Gastric acidity is part of the natural defence mechanism against ingested pathogens and any reduction in the acidity of the stomach can result in colonisation of the normally sterile upper gastrointestinal tract which can result in a disturbance of the normal enteric microflora. As such, the use of gastric acid suppressive agents, such as proton pump inhibitors (PPIs) and histamine H2 - receptor antagonists (H2RAs) is associated with an increased risk of C. difficile colonisation and subsequent development of CDAD. The use of PPIs and H2RAs has previously been associated with other enteric infections such as traveller's diarrhoea, salmonellosis and cholera. Dial ef a/, have reported that the risk of CDAD increases with the use of gastric acid suppressive agents in both the community (JAMA, 2005, 294(23). 2989-2995) and hospital settings (CMAJ, 2004, 171 (1 ), 33-38).
PPIs include, but are not limited to, omeprazole (Losec, Prilosec, Zegerid), lansoprazole (Prevacid, Zoton, Inhibitol), esomeprazole (Nexium), pantoprazole (Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan) and rabeprazole ( abecid, Aciphex, Pariet, Rabeloc). H2RAS include, but are not limited to, cimetidine (Tagamet), ranitidine (Zinetac, Zantac), famotidine, (Pepcidine, Pepcid), roxatidine (Roxit) and nizatidine (Tazac, Axid).
Triple therapy with PPIs or H2RAs together with a combination of two antibiotics is a recognised treatment for the eradication of Helicobacter pylori infections (Aliment.
Pharmacol. Ther., 2001 , 15(5), 613-624; Helicobacter., 2005, 10(3), 157-171 ). However, there are a few reports that this triple therapy regimen can lead to CDAD side effects ( Am. J. Gastroenterol., 1998, 93(7), 1 175-1 176; J. Int. Med., 1998, 243(3). 251-253;
Aliment. Pharm. Ther., 2001 , 15(9), 1445-1452; Med. Sci. Moni , 2001 , 7(4), 751-754). Typical antibacterials used to treat Helicobacter pylori infections are a combination of agents selected from, but not limited to metronidazole, amoxicillin, levofloxacin and clarithromycin - many of which are strongly associated with the development of CDAD, Current therapies are extremely limited; particularly in view of the fact nearly all antibiotic classes are associated with causing the disease. The only FDA approved drug for treatment of CDAD is vancomycin although metronidazole is also extensively used.
Widespread vancomycin use for the treatment of CDAD is of concern due to its
bacteriostatic action against Clostridia, relatively high cost and the possible selection of resistant C. difficile strains as well as other bacteria (particularly Enterococcus spp.). A key issue with both metronidazole and vancomycin is the high relapse rate with at least 20% of patients experiencing at least one recurrent episode. Relapse is proposed to occur due to the inability to eradicate the Clostridium spores during therapy resulting in subsequent outgrowth to a pathogenic state. This inability to control spore formation allows for continued contamination of the hospital environment. As such, agents able to eradicate vegetative cells and control endospores would be of significant advantage.
The primary therapy option for the treatment of CDAD is discontinuation of any current antimicrobial treatment followed by appropriate use of either vancomycin or metronidazole. Both agents are usually administered orally although metronidazole may also be administered intravenously and in severe cases, vancomycin may also be administered via numerous other routes including intracolonic, through nasal gastric tube or as a vancomycin-retention enema. Additional antibiotics agents that have been reported to be used in the treatment of CDAD include fusidic acid, rifamycin and its analogues, teicoplanin and bacitracin although none show particular efficacy over vancomycin or metronidazole. In addition to halting any offending antibacterial treatment, the use of antiperistaltic agents, opiates, or loperamide should be avoided since they can reduce clearance of the C. difficile toxins and exacerbate toxin-mediated colonic injury. Such agents may also precipitate ileus and cause toxic dilation of the colon (J. Med. Microbiol., 2005, 54, 101-111 ; JAMA, 1993, 269. 71-5; Postgrad. Med. J, 1990, 66(777), 582). Alternative therapies, used as standard alone agents or in conjunction with antibacterials, are aimed at either trying to re-establish the native gut microorganism population, reducing the levels of C. difficile toxins or stimulating the immune system (for reviews see Antibiotic Treatment for Clostridium difficile- Associated Diarrhea in Adults, Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004610.; Clin. Inf. Dis., 2008, 4§(S1 ), S32- S42; Clin. Inf. Dis., 2007, 45(S2), S122-S128; J. Med. Microbiol., 2005, 54, 101 -1 1 1 and references therein). Thus, alternative CDAD therapies include provision of Saccheromyces boulardii or Lactobacillus acidophilus in conjunction with antibiotics, faecal transplantation and in severe cases where all other therapy options have failed, surgery. Although rates of colectomy are low (up to 3% of cases) it is associated with high mortality rates (up to 60%).
As such, there is a pressing need for new and effective agents to treat diseases associated with spore forming bacteria, particularly those caused by members of the genera
Clostridium and Bacillus and in particular disease associated with Clostridium difficile infection. This need is particularly acute in the light of the refractory nature of Clostridium difficile to many broad spectrum antibiotics (including β-lactam and quinolone antibiotics) and the frequency with which resistance emerges (Antimicrob. Agents Chemother., 1985, 28(6): 842-844).
(b) Prior art
WO2007056330, WO2003105846 and WO2002060879 disclose various 2-amino benzimidazoies as antibacterial agents.
WO2007148093 discloses various 2-amino benzothiazoles as antibacterial agents.
WO2006076009, WO2004041209 and Bowser et al, (Bioorg. Med. Chem. Lett., 2007, 17, 5652-5655) disclose various substituted benzimidazole compounds useful as anti- infectives that decrease resistance, virulence, or growth of microbes. The compounds are said not to exhibit intrinsic antimicrobial activity in vitro.
US 5,824,698 discloses various dibenzimidazoles as broad-spectrum antibiotics, disclosing activity against both Gram-negative and Gram-positive bacteria, including Staphylococcus spp.and Enterococcus spp. However, this document does not disclose activity against anaerobic spore-forming bacteria and in particular does not disclose activity against any Clostridium spp. (including C. difficile).
US 2007/0112048 A1 discloses various bi- and triarylimidazolidines and bi- and
triarylamidines as broad-spectrum antibiotics, disclosing activity against both Gram- negative and Gram-positive bacteria, including Staphylococcus spp., Enterococcus spp. and Clostridium spp. However, this document does not disclose compounds of general formula (I) as described herein.
Chaudhuri et al. (J. Org. Chem., 2007, 72, 1912-1923) describe various bis-2-(pyridyl)-1 H- benzimidazoles (including compounds of formula I as described herein) as DNA binding agents. This document is silent as to potential antibacterial activity.
Summary of the Invention
Therefore, in a first aspect of the present invention, there is provided a compound of general formula (I):
Figure imgf000008_0001
L is a direct bond, O, N or C C3 alkyl;
1 2
R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocydyl group, the optional substitution being with one or more
3 3 3 3 3
,
Figure imgf000008_0002
4 3 4 3 4 3 4
NR C(=0)NR R , CONR R and S02NR R , with the proviso that: (a) at least one of
1 2
R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
1 2
least one of R and R is an optionally substituted heteroaryl or heterocydyl group, the optional substitution being with one or more substituents selected from halo,
3 3 3 3 3 3 3 3 3
CN, N02, R , OR , N(R )2l COR , C02R , C(=0)SR , SR , S(=0)R , S02R , p
Figure imgf000009_0001
rovided that R and R are not both or ;
3
R is selected from H, C,-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, C3-C7carbocydyl, C4-C7 heterocyclyl and S- or 6- membered aryl or heteroaryl, any of which may be optionally substituted with one or more substituents selected from halo, ON, N02,
R4, OR4, N(R4)2, COR4, CO2R4, C{=O)SR4, SR4, S(=O)R4, SO2R4, NR C(=O)R4, NR4C02R4, OC(=0)NR4)2, NR4S02R4, C(=NR4)N(R4)2> C(=S)N(R4)2,
NR4C(=NR4)N(R4)2, NR4C(=S)N(R4)2. NR4C(=0)N(R4)2L CON(R4)2and S02N(R )2;
R is selected from hydrogen, C,-Cealkyl and C3-C7carbocyclyl, optionally substituted with one or more halo atoms; or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof, for the treatment of Clostridium d/f7/c//e-associated disease (CDAD).
Certain of the compounds of general formula (I) are novel. Thus, according to the invention, we also provide those compounds of general formula (I) which are novel, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals.
Thus, in another aspect, there is provided a compound of general formula (I):
Figure imgf000009_0002
(I)
wherein: L is a direct bond, O, N or C C3 alkyl;
1 2
R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more substituents selected from halo, CN, N02, R , OR , (R )2, COR3, C02R3,
3 3 3 3 4 3 4 3 3 4
=0)SR » SR , S(=0)R , S02R , NR C(=0)R , NR C02R » OC(=0)NR R ,
Figure imgf000010_0001
4 3 4 3 4 3 4
NR C(=0)NR R , CONR R and S02NR R , with the proviso that: (a) at least one of
1 2
R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
1 2
least one of R and R is an optionally substituted heteroaryl or heterocyclyl group, the optional substitution being with one or more substituents selected from halo,
3, OR3, N(R3)2, COR3, C02R3, C(=0)SR3, SR3, S(=0)R3, S02R3,
Figure imgf000010_0002
4 4 3 4 4 5 3 4 3 4 3 4
NR C(=NR )NR R , NR C(=S)NR R , NR C(=0)NR R , CONR R and S02NR R ,
provided that R and R are not both
Figure imgf000010_0003
or ·
3
R is selected from H, C,-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl,
C4-C7 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, N02>
R4 OR4, N(R4)2( COR4, C02R4, C(=0)SR4, SR4, S(=0)R4, S02R4, N C(=0)R ,
NR4C02R4, 0C(=0)NR4)2> NR4S02R , C(=NR4)N(R )2, C(=S)N(R4)2,
NR C(=NR )N(R )2l NR4C{=S)N(R4)2l NR4C(=0)N(R4)2, CON(R )2 and S02N(R4)2;
4
R is selected from hydrogen, C,-C6 alkyl and C3-C7 carbocyclyl, optionally substituted with one or more halo atoms; or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof.
The compound as defined above may be for use in therapy or prophylaxis, for example in the treatment of a bacterial infection or disease (for example, in the treatment of CDAD).
In another aspect, there is provided a method of treating a bacterial infection or bacterial disease (for example CDAD) in a subject comprising administering an effective amount of a compound as defined above to said subject.
In another aspect, there is provided a method of killing a bacterium or inhibiting, reducing or preventing the growth thereof, comprising contacting said bacterium with a compound as defined above. In such embodiments the bacterium is preferably Clostridium difficile. Also contemplated are combinations comprising the compound of the invention as defined above with various adjunctive agents as defined below.
Yet other aspects of the invention are defined in the claims set out below.
Detailed Description of the Invention
All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.
I. Definitions and general preferences
Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art; Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term "a" or "an" used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.
As used herein, the term "comprise," or variations thereof such as "comprises" or
"comprising," are to be read to indicate the inclusion of any recited integer {e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term "comprising" is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
The phrase "consisting essentially of is used herein to require the specified integer(s) or steps as well as those which do not materially affect the character or function of the claimed invention.
As used herein, the term "consisting" is used to indicate the presence of the recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) alone.
As used herein, the term "disease* is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.
As used herein, the term "bacterial disease" refers to any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) a bacterium residing and/or replicating in the body and/or cells of a subject. The term therefore includes diseases caused or exacerbated by bacterial toxins (which may also be referred to herein as "bacterial intoxication"). The more specific term "Clostridium difficile disease" is to be interpreted accordingly.
As used herein, the term Clostridium d/ffiele-associated disease (CDAD) is used to define any disease that involves (e.g. is caused, exacerbated, associated with or characterized by the presence of) Clostridium difficile residing and/or replicating in the body of a subject. Thus, the term covers any disease, disorder, pathology, symptom, clinical condition or syndrome in which bacteria of the species Clostridium difficile act as aetiological agents or in which infection with one or more strains of Clostridium difficile is implicated, detected or involved. The term therefore includes the various forms of colitis, pseudomembranous colitis, diarrhoea and antibiotic-associated disease.
As used herein, the term 'selective Clostridium difficile agent" is used herein to define a compound which exhibits bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but which does not exhibit bacteriostatic and/or bacteriocidal activity against one or more representative(s) of the normal gut flora selected from: (a) Escherichia spp. (for example, Escherichia co/i); (b) Bacteroides spp. (for example, B. fragilis); (c) Fusobacterium spp.; (d) Eubacterium spp. (e) Ruminococcus spp.; (f) Peptococcus spp.; (g) Peptostreptococcus spp.; (h) Bifidobacterium spp.; (i) Lactobacillus spp.; (j)
Enterococcus spp. (for example, E. faecium); (k) clostridial species other than C. difficile (for example C. perfringens), (I) Enterobacter spp.; (m) Serratia spp.; (n) Klebsiella spp.; (o) Proteus spp.; (p) Pseudomonas spp. and (q) Veillonella spp..
Preferred selective Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity against: (a) Escherichia coli ; or (b) B. fragilis.
Thus, certain preferred selective Clostridium difficile agents of the invention exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity against B. fragilis.
As used herein, the term "bacterial infection* is used to define a condition in which a subject is infected with a bacterium. The infection may be symptomatic or asymptomatic. In the latter case, the subject may be identified as infected on the basis of various tests, including for example biochemical tests, serological tests, microbiological culture and/or microscopy.
The terms bacteriostatic and bacteriocidal are terms of art used to define the ability to prevent (or reduce the rate of) bacterial growth and to mediate (directly or indirectly) the cellular destruction of bacterial cells, respectively. The terms are not mutually exclusive, and many agents exert both bacteriostatic and bacteriocidal effects (in some cases in a dose-specific or target-specific manner). In general, bacteriocidal agents yield better therapeutic results and are preferred.
As used herein, the term "broad spectrum antibiotic" defines an agent which is
bacteriocidal and/or bacteriostatic for a range of bacteria including both Gram-positive and Gram-negative bacteria. The "term multi-drug resistant" (MDR) as applied herein to a bacterium defines a bacterium which is resistant to two or more classes of antibiotics including, but not limited to, antibiotics selected from penicillin, methicillin, quinolone, macrolide and/or vancomycin.
As used herein, the term "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the causative bacterium). In this case, the term is used synonymously with the term "therapy". Thus, the treatment of infection according to the invention may be characterized by the (direct or indirect) bacteriostatic and/or bacteriocidal action of the compounds of the invention.
Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term "prophylaxis".
The term "subject" (which is to be read to include "individual", "animal", "patient" or "mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, primates, domestic animals, farm animals, pet animals and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human. The term Gram-positive bacterium is a term of art defining a particular class of bacteria that are grouped together on the basis of certain cell wall staining characteristics. The term tow G+C Gram-positive bacterium is a term of art defining a particular subclass class of evolutionarily related bacteria within the Gram-positives on the basis of the composition of the bases in the DNA, The subclass includes Streptococcus spp.,
Staphylococcus spp., Listeria spp., Bacillus spp., Clostridium spp., Enterococcus spp. and Lactobacillus spp.
The term "minimum inhibitory concentration" or "MIC" defines the lowest concentration of a test compound that is needed to inhibit growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the test compound that are then inoculated with the bacterial isolate of interest. Following incubation at appropriate atmosphere and temperature, the MIC of an antibiotic can be determined from the tube with the lowest concentration that shows no turbidity.
As used herein, the term "combination", as applied to two or more compounds and/or agents (also referred to herein as the components), is intended to define material in which the two or more compounds/agents are associated. The terms "combined" and
"combining" in this context are to be interpreted accordingly.
The association of the two or more compounds/agents in a combination may be physical or non-physical. Examples of physically associated combined compounds/agents include:
• compositions {e.g. unitary formulations) comprising the two or more
compounds/agents in admixture (for example within the same unit dose);
• compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);
• compositions comprising material in which the two or more compounds/agents are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets); • pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds/agents are co-packaged or co-presented (e.g. as part of an array of unit doses); Examples of non-physically associated combined compounds/agents include:
• material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of the at least one compound/agent to form a physical association of the two or more compounds/agents;
• material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents;
• material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered;
• material comprising at least one of the two or more compounds/agents in an
amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds/agents.
As used herein, the term 'combination therapy" is intended to define therapies which comprise the use of a combination of two or more compounds/agents (as defined above). Thus, references to "combination therapy", "combinations** and the use of
compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or
simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. The posologies of each of the two or more compounds agents in a combination therapy may also differ with respect to the route of administration. 18
As used herein, the term "pharmaceutical kit" defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging. In pharmaceutical kits comprising a combination of two or more
compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical kit may optionally further comprise instructions for use.
As used herein, the term "pharmaceutical pack" defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging. In pharmaceutical packs comprising a combination of two or more compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical pack may optionally further comprise instructions for use.
As used herein, the term "patient pack" defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment. Patient packs usually contain one or more blister pack(s). Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds/agents when administered separately. As used herein, an effective amount or a therapeutically effective amount of a compound defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective'' amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context 1? includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure. As used herein, a "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
The term "efficacious" includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity or improved performance or activity.
Advantageously, an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity, whilst producing and/or maintaining the same therapeutic effect. A synergistic effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the components of the combination when presented individually. An additive effect in the present context refers to a therapeutic effect produced by the combination which is larger than the therapeutic effect of any of the components of the combination when presented individually.
The term "ancillary compound" (or "ancillary agent") as used herein is intended to define any compound which yields an efficacious combination (as herein defined) when combined with a compound of the invention. The ancillary compound may therefore act as an adjunct to the compound of the invention, or may otherwise contribute to the efficacy of the combination (for example, by producing a synergistic or additive effect or by potentiating the activity of the compound of the invention).
The term "adjunctive" as applied to the use of the compounds and combinations of the invention in therapy or prophylaxis defines uses in which the materials are administered together with one or more other drugs, interventions, regimens or treatments (such as surgery and/or irradiation). Such adjunctive therapies may comprise the concurrent, separate or sequential administration/application of the materials of the invention and the other treatment(s). Thus, in some embodiments, adjunctive use of the materials of the invention is reflected in the formulation of the pharmaceutical compositions of the invention. For example, adjunctive use may be reflected in a specific unit dosage, or in formulations in which the compound of the invention is present in admixture with the other drug(s) with which it is to be used adjunctively (or else physically associated with the other drug(s) within a single unit dose). In other embodiments, adjunctive use of the compounds or compositions of the invention may be reflected in the composition of the pharmaceutical kits of the invention, wherein the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the other daig(s) with which it is to be used adjunctively. In yet other embodiments, adjunctive use of the compounds of the invention may be reflected in the content of the information and/or instructions co-packaged with the compound relating to formulation and/or posology.
The term pharmaceutically acceptable derivative as applied to the compounds of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent compounds of the invention. The pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with mammalian tissues without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio). Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of the parent compounds of the invention. The derivatives may be active perse, or may be inactive until processed in vivo. In the latter case, the derivatives o the invention act as prodrugs. Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo. Other preferred prodrugs are covalently bonded
compounds which release the active parent drug according to general formula (I) after cleavage of the covalent bond(s) in vivo. The pharmaceutically acceptable derivatives of the invention retain some or all of the activity of the parent compound. In some cases, the activity is increased by derivatization. Derivatization may also augment other biological activities of the compound, for example bioavailability. The term pharmaceutically acceptable salt as applied to the compounds of the invention defines any non-toxic organic or inorganic acid addition salt of the free base compound which is suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit risk ratio.
Suitable pharmaceutically acceptable salts are well known in the art. Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxy enzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p-toluenesulfonic acid). The compounds of the invention may also be converted into salts by reaction with an alkali metal halide, for example sodium chloride, sodium iodide or lithium iodide. Preferably, the compounds of the invention are converted into their salts by reaction with a stoichiometric amount of sodium chloride in the presence of a solvent such as acetone.
These salts and the free base compounds can exist in either a hydrated or a substantially anhydrous form. Crystalline forms of the compounds of the invention are also contemplated and in general the add addition salts of the compounds of the invention are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility.
The term pharmaceutically acceptable solvate as applied to the compounds of the invention defines any pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water (hydrates), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone. Also included are miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture. In a preferred embodiment, the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone. Thus, the structural formulae include compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
The term pharmaceutically acceptable prodrug as applied to the compounds of the invention defines any pharmaceutically acceptable compound that may be converted under physiological conditions or by solvolysis to the specified compound, to a pharmaceutically acceptable salt of such compound or to a compound that shares at least some of the antibacterial activity of the specified compound (e.g. exhibiting activity against Clostridium difficile). The term pharmaceutically acceptable metabolite as applied to the compounds of the invention defines a pharmacologically active product produced through metabolism in the body of the specified compound or salt thereof. Prodrugs and active metabolites of the compounds of the invention may be identified using routine techniques known in the art (see for example, Bertolini et a/., J. Med. Chem., 1997, 40, 2011-2016).
The term pharmaceutically acceptable complex as applied to the compounds of the invention defines compounds or compositions in which the compound of the invention forms a component part. Thus, the complexes of the invention include derivatives in which the compound of the invention is physically associated (e.g. by covalent or non-covalent bonding) to another moiety or moieties. The term therefore includes multimeric forms of the compounds of the invention. Such multimers may be generated by linking or placing multiple copies of a compound of the invention in close proximity to each other (e.g. via a scaffolding or carrier moiety).
The term bioisostere (or simply isostere) is a term of art used to define drug analogues in which one or more atoms (or groups of atoms) have been substituted with replacement atoms (or groups of atoms) having similar steric and/or electronic features to those atoms which they replace. The substitution of a hydrogen atom or a hydroxy! group with a fluorine atom is a commonly employed bioisosteric replacement. Sila-substitution (C/Si-exchange) is a relatively recent technique for producing isosteres. This approach involves the replacement of one or more specific carbon atoms in a compound with silicon (for a review, see Tacke and Zilch (1986) Endeavour, New Series 10: 191-197). The sila-substituted isosteres (silicon isosteres) may exhibit improved pharmacological properties, and may for example be better tolerated, have a longer half-life or exhibit increased potency (see for example Englebienne (2005) Med. Chem., 1(3): 215-226). Similarly, replacement of an atom by one of its isotopes, for example hydrogen by deuterium, may also lead to improved pharmacological properties, for example leading to longer half-life (see for example Kushner et al (1999) Can J Physiol Pharmacol. 77(2):79-88). In its broadest aspect, the present invention contemplates all bioisosteres (and specifically, all silicon bioisosteres) of the compounds of the invention. In its broadest aspect, the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the compounds described herein. Those skilled in the art will appreciate that, owing to the asymmetrically substituted carbon atoms present in the compounds of the invention, the compounds may be produced in optically active and racemic forms. If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of the invention containing a chiral centre (or multiple chiral centres) may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. Thus, references to the compounds of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers. Therefore, the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g. by use of dash-wedge structural formulae) the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted. In cases where the stereochemical form of the compound is important for pharmaceutical utility, the invention contemplates use of an isolated eutomer.
In the present specification the term "alkyl* defines a straight or branched saturated hydrocarbon chain. The term "d-d alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n- propyl, isopropyl, t-butyl, n-hexyl. The term "d-d alkyl* refers to a straight or branched saturated hydrocarbon chain having one to nine carbon atoms. The term *d-ds alkyl" refers to a straight or branched saturated hydrocarbon chain having one to fifteen carbon atoms. The alkyl groups of the invention may be optionally substituted by one or more halogen atoms.
"d-d alkyl" has a similar meaning except that it contains from one to four carbon atoms.
"d-d alkenyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl, and 3-hexenyl. The term "CrC6 haloalkyl" refers to a Ch alky! group as defined above substituted by one or more halogen atoms. In the present specification the term "alkenyl" defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon double bond. The term "d-Ce alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "CrC9 alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "Ci-C15 alkenyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is CrC6 alkenyl. Examples include ethenyl, 2-propenyl, and 3-hexenyl. The alkenyl groups of the invention may be optionally substituted by one or more halogen atoms.
In the present specification the term "alkynyl* defines a straight or branched hydrocarbon chain having containing at least one carbon-carbon triple bond. The term BCi-C8 alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to six carbon atoms. The term "C1-C9 alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to nine carbon atoms. The term "C CiS alkynyl" refers to a straight or branched unsaturated hydrocarbon chain having one to fifteen carbon atoms. Preferred is Ci-Ce alkynyl. Examples include ethynyl, 2-propynyl, and 3-hexynyl. The alkynyl groups of the invention may be optionally substituted by one or more halogen atoms.
The term "heterocyclyl" defines a saturated or partially saturated 3 to 14 membered ring system (except when alternative numbers of ring atoms are specified) similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O, S, SO or S02. Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine.
As used herein, the term "carbocyclyl" means a mono- or poiycyclic residue containing 3 or more (e.g. 3-14, 3-10 or 3-8) carbon atoms. The carbocyclyl residues of the invention may be optionally substituted by one or more halogen atoms. Mono- and bicyclic carbocyclyl residues are preferred. The carbocyclyl residues can be saturated or partially unsaturated and include fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and also bridged systems such as norbornyl and adamantyl. Saturated carbocyclyl residues are preferred and are referred to herein as "cycloalkyls" and the term "cycloalkyl" is used herein to define a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl and also bridged systems such as norbomyl and adamantyl. The cycloalkyl residues of the invention may be optionally substituted by one or more halogen atoms.
In the present specification the term "aryl" defines a 5-14 (e.g. 5-10) membered aromatic mono-, bi- or tricyclic group at least one ring of which is aromatic. Thus, bicyclic aryl groups may contain only one aromatic ring. Examples of aromatic moieties are benzene, naphthalene, imidazole and pyridine. The term also includes bicyclic or tricyclic systems in which one or more of the rings has aromatic character. Indane is an example of this type of system. As used herein, the term "heteroaryl" are aryl moieties as defined above which contain heteroatoms (e.g. nitrogen, sulphur and/or oxygen). The term also includes systems in which a ring having aromatic character is fused to a saturated or partially saturated ring. Examples include pyridine, pyrimidine, furan, thiophene, indole, isoindole, indoline, benzofuran, benzimidazole, benzimidazoline quinoline, isoquinoline,
tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole and imidazole ring systems. Unless otherwise indicated, the term "aryl* is to be interpreted to include heteroaryl groups as defined above.
The aryl and heteroaryl groups of the invention may optionally be substituted by one or more halogen atoms.
In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.
In the general formulae of the present invention (and in particular in general formula (I) as described below), the bond orders of the specified rings may vary when the various possible heteroatom(s) imply specific requirements in order to satisfy aromaticity, prevent antiaromaticity and stabilize tautomeric forms due to localization. In such cases, the appropriate bond orders of the ring structures in the structural formulae of the present invention are contemplated herein. The term "symmetrical" as applied to the compounds of formula (I) may define compounds in which the substituents R1 and R2 are the same.
The term "unsymmetnca as applied to the compounds of formula (I) may define
compounds in which the substituents R1 and R2 are different.
II. Compounds according to the invention
(a) Structural considerations
Particularly preferred compounds of general formula (I) are listed in Table 1 (below);
Table 1
Compound
Compound Name
number
1 2-(6-methoxypyridin-3-yl)-2'-(pyridin-4-yl)-1 H,1 ,H-5,5'-bibenzo[d]imidazole
2 N-(4-(2'-(pyridin-4-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazol-2-yl)phenyl)acetamide
3 2,2'-di(pyridin-3-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
2,2'-di(thiazol-5-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
5 4-(2'-(pyridin-4-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
6 2-{pyridin-4-yl)-2'-(thioprten-2-yl)-1 Hl1'H-5,5'-bibenzo[d]imidazole
7 5-{2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
8 2-{3-fluoropyrk.in-4-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
9 4-<2'-(pyridin-4-yl)-1 H,1 'H-5,5,-bibenzo(d]imidazol-2-yl)phenol
10 2-phenyl-2'-(pyridin-4-yl)-1H,1,H-5,5'-bibenzo[d]imidazote
11 2-<5-chlorothiophen-2-y1)-2'-(pyridin-4-yl)-1 H,1 ,H-5l5'-bibenzo[d]imidazole
12 N,N-dimethyI-4 2'-(pyridin^-yl)-1H 'H-5»5'-bibenzo[d]imidazol-2-yI)aniline
13 2-{3-methoxyphenyl)-2'-(pyridin-4-yl)-1 H,1,H-5,5'-bibenzo[d]imidazole
14 2-{pyridin-4-yl)-2'-(3-(trifluoromethyl)phenyl)-1 H, 1 'H-5,5'-bibenzoId]imidazole
15 5- 2'-(thiophen-2-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
16 2-{pyridin-4-yi)-2'-(4-(trifluoromethoxy)phenyl)-1 H, 1 Ή-5,5'- bibenzo[dJimidazole
17 4-(2'-(thiazol-5-yl)-1 H, 1 'H-5,5*-bibenzo[d]imidazol-2-yl)oxazole
18 2-(5-chlorofuran-2-yl)-2'-(pyridin-4-yl)-1 H, 1'H-5,5'-bibenzo[d]imidazole
19 2,2'-di{pyridirv-2-yl)-1 H,1,H-5,5,-bibenzo[d]imidazole 20 4-(2'-(thiazol-4-yl)-1 H , 1'H-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
21 2,2'-di(thiazol-4-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazole
22 2-(pyridin-4-yl)-2'-(6-(trifluoromethyl)pyridin-3-yl)-1 H, 1 Ή-5,5'- bibenzo[dJtmidazoIe
23 2-(pyridin-2-yl)-2'-(pyr(din-4-yl)-1 H,1'H-5,5'-bibenzo[d]irriidazole
24 2-(pyridin-3-yl)-2'-(pyridin-4-yl)-1 H,1,H-5,5'-bibenzo[dlimidazole
25 2-(6-(methylsulfonyl)pyridin-3-yl)-2,-{pyridin-4-yl)-1Hl 1'H-5,5'- bibenzo[d]imidazole
26 4-(2'-{pyridin-4-yl)-1H,1,H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
2? 4-(2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazol-2-yl)oxazole
28 2-(5-methylthiophen-2-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
29 5-(2'-(6-methoxypyridin-3-yl)-1 H, 1 ,H-[5,5,-bibenzo[d]imidazoIJ-2-yl)thiazole
30 5-(2'-{pyridin-3-yl)-1 H,1'H-[5,5,-bibenzo[dlimidazol]-2-yl)thiazole
31 2-{6-methoxypyridin-3-yl)-2'-(pyridin-3-yl)-1 H, 1 Ή-5, 5'-bibenzo[d]imidazole
32 N-(4-(2'-(pyridin-3-yl)-1 H, 1 'H-[5,5'-bibenzo[d]imidazol]-2-yl)phenyl)acetamide
In each case, the invention contemplates pharmaceutically acceptable salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs of each of the listed
compounds.
References to particular compound numbers herein refer to the numbers in Table 1.
Certain of the compounds of general formula (I) are novel. Thus, according to the invention, the invention contemplates those compounds of general formula (I) which are novel as compounds per se, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals.
Thus, the invention contemplates a compound selected from:
2-{6-methoxypyridin-3-yl)-2,-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
N-(4-(2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)phenyl)acetamide
2,2'-di(thiazol-5-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazole
4- (2,-{pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
2-(pyridin-4-yl}'2'-(thiophen-2-yl)-1 H,1*H-5,5,-bibenzo[d]imidazole
5- (2'-{pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazol-2-yl)thiazole 2-(3-fluoropyridin-4-yl)-2'-(pyridin^^
4- (2'-(pyridin-4-yl)-1H,1 'H-5,5'-bibenzo[d]imidazol-2-yl)phenol
2-phenyI-2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzotd]imidazole
2-{5-chlorothiophen-2-yl)-2'-(pyrkjin-4^
N,N-dimethy1-4-(2'-(pyridin^
2-(3-methoxyp lenyl)-2,-(pyridin- -yl)-1 H!1Ή-5,5,-biber^zo[d]imidazole
2-(pyridin-4-yl)-2,^3 trifluoromethyl)phenyl)-1 H,1Ή-5,5,-biDenzo[d]imidazole
5- (2'-{thiophen-2-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
2-(pyridin-4-yl)-2H4-(trifluoromethoxy)pheny ^
4-(2'-(thiazol-5-yl)-1 H,1'H-5,5'-bjbenzo[d]imidazol-2-yl)oxazole
2-(5-chiorofuran-2-yl)-2'-(pyridin^-yl)-1H,1'H-5)5,-bibenzo(d]imidazoie
4-(2'-(thiazol-4-yl)-1 H,1'H-5,5,-bibenzo[d]irnidazol-2-yl)pyridine 1 -oxide
2,2'-di(thiazol-4-yl)-1 H,1 'H-5,5'-bibenzo[dlimidazole
2-(pyridin-4-y1)-2'-(6-(trifluoromethy ^^
2-(pyridin-2-yl)-2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo(d]imidazole
2-(pyridirv3-yl)-2,-(pyridin-4-yl)-1 H,1'H-5,5,-bibenzo[d]imidazole
2-(6-(methylsulfonyl)pyridin-3-yl)-2'-(pyridir»-4-yl)-1 H, 1 *H-5,5'-bibenzo(d]imidazo)e 4-(2'-(pyridin-4-yl)-1H,1'HI-5,5,-bibenzo[d]imidazol-2-yI)thiazole
4- (2'-(pyridin-4-yl)-1H,rH-5,5*-bibenzo[d]imidazol-2-yl)oxazole
2 5-meth ithio hen-2- l)-2,^ ridin-4- i)-1H,1Ή-5f5,- i enzo[d]im!dazoIe
5- {2'-(6-methoxypyridin-3-yl)-1 H, 1 'H-l5,5*-bibenzo[d]imidazoll-2-yl)thiazole
5-(2'-(pyridin-3-yl)-1 H,1 ^[5,5'-bibenzo|;d]imidazo)]-2-yt)thiazoIe
2-{6-metho ypyridin-3-yl)-2 pyridin-3-yl)-1H Ή-5,5'-b(benzo[d]imidazole
N-(4-(2'-(pyridin-3-yl)-1 H, 1 'H-[5,5'-bibenzo[d]imidazol]-2-yl)phenyl)acetamide or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof, as well as compositions (for example pharmaceutical compositions) comprising said compounds.
(b) Functional considerations
(i) Effect and Selectivity against strains of Clostridium difficile 2?
Preferred compounds of the invention may be selective Clostridium difficile agents, as hereinbefore defined,
Particularly preferred selective Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit
bacteriostatic and/or bacteriocidal activity (MIC >64 pg/mL) against B. fragilis ATCC25285.
Yet more particularly preferred selective Clostridium difficile agents exhibit bacteriostatic and/or bacteriocidal activity against one or more strains of C. difficile but do not exhibit bacteriostatic and/or bacteriocidal activity (MIC >64 pg/mL) against both Bacteroides fragilis ATCC25285 and Escherichia coli ATCC25922.
The preferred compounds of the invention which are selective Clostridium difficile agents can therefore be used to treat CDAD without disturbing the existing gut flora to a clinically significant extent. Thus, such compounds may be used as antimicrobial agents without causing antibiotic-associated disease (as defined herein) and/or the spread of antibiotic resistant strains of gut pathogens.
Compounds of the invention which act as selective Clostridium difficile agents may be identified by determining the relative antibacterial activities of the compound for Clostridium difficile and one or more indicator organism(s) representative of the normal gut flora.
Suitable indicator organisms for this purpose include: (a) Escherichia spp. (for example, Escherichia coli); (b) Bacteroides spp. (for example, B, fragilis); (c) Fusobactenum spp.; (d) Eubacterium spp. (e) Ruminococcus spp.; (f) Peptococcus spp. ; (g) Peptostreptococcus spp,; (h) Bifidobacterium spp.; (i) Lactobacillus spp,; 0) Enterococcus spp. (for example, E faecium); (k) clostridial species other than C. difficile (for example C. periringens); (I) Enterobacter spp.; (m) Serratia spp.; (n) Klebsiella spp.; (o) Proteus spp.; (p)
Pseudomonas spp. and (q) Veillonella spp.. Alternatively, or in addition, compounds of the invention which act as selective Clostridium difficile agents may be identified by performing quantitative stool cultures on serial stool samples obtained from subjects dosed with the a test compound. An in vitro variant of this approach is based on determining whether the test compound produces major floral shifts when incubated with diluted and filtered faecal samples in vitro. In this case, floral shifts may be detected by determining the effect of the test compound on the relative numbers of bacteria representative of two or more of the following genera: (a) Escherichia spp. {for example, Escherichia colt); (b) Bacteroides spp. (for example, B. fragilis); (c)
Fusobaclerium spp.; (d) Eubacterium spp. (e) Ruminococcus spp.; (f) Peptococcus spp.; (g) Peptostreptococcus spp.; (h) Bifidobacterium spp.; (i) Lactobacillus spp.; (j)
Enterococcus spp. (for example, E faecium); (k) clostridial species other than C. dlffic/fe (for example C. perfringens); (I) Enterobacter spp.; (m) Serratia spp.; (n) Klebsiella spp.; (o) Proteus spp.; (p) Pseudomonas spp. and (q) Veillonella spp..
Thus, the invention contemplates a selective Clostridium difficile agent selected from:
2-(6-memoxypyridin-3-yl)-2,-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazole
^.^2«-(pyiidin-4-yl)-1 H,1*H-5,5'-bibenzotd]imidazol-2-yl)phenyl)acetamide
2,2,-di(pyridin-3-yl)-1 H, 1,H-5,5'-bibenzo[d]imidazole
2,2'-di(thiazol-5-yl)-1 H, 1 ^5,5'-bibenzo[d]imidazole
4-(2'-(pyridin- -yl)-1 H,1'H-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
2-(pyridin-4-yrl)-2'-(thiophen-2-yl)-1 H, 1 Ή-5, 5*-bibenzo[d]imidazole
5-(2'-(pyridin-4-yl)-1 H,1,H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
2-(3-fluoropyridin-4-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazote
4-(2'-(pyridin-4-yl)-1 H,1,H-5,5*-bibenzo[d]imidazol-2-yl)phenol
2-phenyl-2'-(pyridin-4-y I)- 1 H.I'H-S.S'-bibenzoldJimidazole
2-{5-chlorothiophen-2-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5*-bibenzo[d]imidazole
N,N-dimethyl-4-{2,-(pyridin-4-yl)-1 Hl1'H-5,5'-bibenzo[d]imidazol-2-yl)aniline
2-(3-methoxyphenyl)-2'-(pyridin-4-yl)-1 H, 1 "H-S.^-bibenzotdJimidazole
2-(pyridin-4-yl)-2,-(3-(trifluoromethyl)phenyl)-1H,1,H-5l5'-bibenzo[d]imidazole
5-(2,-(thiophen-2-yl)-1H,1,H-5,5'-bibenzo[d]imidazol-2-yl)thiazole
2-(pyridin-4-yl)-2'-(4-(trifluoromethoxy)phenyl)-1 H , 1 'H-5,5'-bibenzo[dlimidazole
4-(2,-(thiazol-5-yl)-1 H,1,H-5,5,-bibenzo[d]imidazol-2-yl)oxazole
2-(5-chlorofuran-2-yl)-2'-(pyridin-4-yl)-1 H,1,H-5l5'-bibenzo[d]imidazole
2,2*-di(pyridin-2-yl)-1H,1 'H-5,5'-bibenzo[dlimidazole
4-(2*-(thiazol-4-yl)-1 H,rH-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
2,2'-di(thiazol-4-yl)-1 H, 1 "H-5,5'-bibenzo[d]imidazole
2-(pyridin-4-yl)-2'-(6-(trifluoromethyl)pyridin-3-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
2-(pyridin-2-yl)-2'-(pyridin-4-yl)-1 H, 1,H-5,5,-bibenzo[d]imidazole
2-(pyridin-3-yl)-2,-(pyridin-4-yl)-1 H, 1,H-5,5,-bibenzo[d]imidazole
2-(6-(methylsulfonyl)pyridin-3-yl)-2'-(pyridin-4-yl)-1 H,1'H-5.5,-bibenzo[d]imidazole 4-(2^ ridin^-yl)-1H»1Ή-5)5,- ibenzo[d]im!clazoI-2·-yI)thίazoIe
4- (2'-(pyridin-4-yl)-1 H,1 'H-5,5'-biben20[d]irnida2ol-2-yl)oxazole
2-(5-methylthiophen-2-yl)-2'-(pyrid!n-4-yI)-1 H,1^-5,5*-bibenzo[d]imi
5- (2,-{6-mβthoxypyιidin-3-yl)-1 H,1Ή-[5,5,-biben2o[d]imidazol]-2-yl)thiazolβ
5-(2·-(p ridin-3-yl)-1 H,1Ή-[5,5,-bίDenzo[d]imidazol]-2-yl)thia2ole
2-(6-metho y ridin-3-yl)-2,-( ridΐn-3-yI)-1H,1Ή-5,5" ibenzofd]irnidazole
N-^-^^pyridin-S-y -IH ^^S -bibenzoIdlim ^ or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere, metabolite or prodrug thereof,
(ii) Effect on spore germination
The compounds of the invention may inhibit or prevent spore germination.
Compounds which inhibit spore germination can be identified by in vitro detection of alterations in endospore refractivity, heat resistance and staining: germinating endospores become phase dark, susceptible to heat and stainable with certain dyes. (iii) Effect on spore outgrowth
The compounds of the invention may inhibit or prevent spore outgrowth.
Compounds which inhibit spore outgrowth can be identified by microscopic examination of spores exposed to germinants in vitro.
(iv) Bacteriocidal and/or bacteriostatic effect
The compounds of the invention may be bacteriocidal and/or bacteriostatic.
Preferred are bacteriocidal compounds as hereinbefore defined. Such bacteriocidal compounds may also be bacteriostatic (e.g. depending on target bacterium and concentration). "I· Medical applications fa) Treatment of C, difficile infection The compounds of the invention find application in the treatment of Clostridium difficile infection or disease.
Particularly preferred is the treatment of Clostridium difficile-associated disease (CDAD) defines a set of symptoms and diseases associated with C. difficile infection and/or intoxication. CDAD includes diarrhoea, bloating, flu-like symptoms, fever, appetite loss, abdominal pain, nausea, dehydration and bowel inflammation (colitis). The most serious manifestation of CDAD is pseudomembraneous colitis (PMC), which is manifested histologically by colitis with mucosal plaques, and clinically by severe diarrhoea, abdominal cramps and systemic toxicity.
The compounds of the invention find application in the treatment of all forms of CDAD, including diarrhoea, bloating, flu-like symptoms, fever, appetite loss, abdominal pain, nausea, dehydration, colitis and pseudomembraneous colitis. The invention also finds application in the treatment of intoxication with clostridial exotoxins, including Clostridium difficile toxin A (TcdA), toxin B (TcdB) and/or binary toxin CDT. Thus, the compounds of the invention find application in the treatment of a disease caused (or exacerbated) by the presence of Clostridium difficile toxins A (TcdA), B (TcdB) and/or binary toxin CDT.
(b) Treatment of antibiotic-associated disease
Antibiotic-associated disease defines conditions arising from changes in the relative amounts of the microorganisms constituting the normal gut flora caused by (partial) elimination of the flora by antibiotic administration. Such diseases arise when the administration of antibiotics (particularly broad-spectrum antibiotics) permits the growth of pathogenic organisms (either by overgrowth from endogenous populations usually kept in check by the normal gut flora or by opportunistic colonization of sites cleared of the normal gut flora by the antibiotic). Antibiotic-associated diseases is typically manifested by diarrhoea (and associated dehydration), abdominal cramps, tenesmus and fever. It may also lead to various forms of colitis, including pseudomembraneous colitis (PMC). Thus, antibiotic-associated disease includes antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC).
Antibiotic-associated disease is often caused by toxin-producing strains of Clostridium difficile. Staphylococcus aureus (including methicillin-resistant S. aureus) and Clostridium perfringens. Clostridium difficile is the most common cause of nosocomial AAD and causes the majority of cases of AAC. The bacterium proliferates in the colon of patients who have been given broad-spectrum antibiotics or cancer chemotherapy.
The compounds of the invention therefore find application in the treatment of antibiotic- associated disease, including AAD and AAC. Particularly preferred for use in such applications are compounds of the invention which are selective (as hereinbefore defined), since such compounds substantially spare the normal gut flora.
The compounds of the invention find particular application in the prophylaxis of antibiotic- associated disease, including AAD and AAC. In such applications, the compounds of the invention may be co-administered with other antibiotics or treatments which can induce changes in the relative amounts of the microorganisms constituting the normal gut flora.
Thus, the compounds of the invention may be used to treat subjects treated (or undergoing treatment) with broad-spectrum antibiotics. (c) Treatment of colitis, pseudomembraneous colitis and diarrhoea
As explained above, bacteria selected from Clostridium difficile. Staphylococcus aureus and Clostridium perfringens are implicated in colitis, pseudomembraneous colitis (PMC) and diarrhoea.
Accordingly, the compounds of the invention find application in the treatment of colitis, pseudomembraneous colitis (PMC) or diarrhoea.
Particularly preferred is the treatment of pseudomembraneous colitis. IV. Adjunctive agents for use in the combinations of the invention
(a) General In addition to the compound of the invention, the invention also contemplates the use of one or more of the following adjunctive agents as further components of the invention.
Thus, the invention provides compositions comprising the compound of the invention in combination with one or more adjunctive agents selected from those described below.
(b) Antiviral adjunctive agents
The combinations preferably further comprise one or more auxiliary antiviral agent(s). Such auxiliary antiviral agents may be selected from one or more of: (a) viral enzyme inhibitors (for example selected from (i) protease inhibitors, (ii) helicase inhibitors and (iii) polymerase inhibitors); (b) nucleoside/nucleotide reverse transcriptase inhibitors; (c) non- nucleoside reverse transcriptase inhibitors; (d) integrase inhibitors; (e) maturation inhibitors; (f) cytokines or cytokine stimulatory factors; (g) viral entry inhibitors, for example selected from: (i) an attachment inhibitor; (ii) a co-receptor binding inhibitor; and (iii) a membrane fusion inhibitor.
(c) Antibacterial adjunctive agents
The compounds of the invention may be used in combination with various antibacterial agents, including, but not limited to one or more antibiotic(s) selected from the following:
Aminoglycosides (for example amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin).
Ansamycins (for example geWanamycin and herbimycin).
Carbacephems (for example loracarbef).
Carbapenems (for example ertapenem, doripenem, imipenem/cilastatin and meropenem)
Cephalosporins (first generation), including for example cefadroxil, cefazolin, cefalotin/cefalothin and cephalexin). • Cephalosporins (second generation), including for example cefaclor, cefamandole, cefoxitin, cefprozil and cefuroxime.
• Cephalosporins (third generation), including for example cefixirne, cefdinir,
cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone and cefdinir.
• Cephalosporins (fourth generation), including for example cefepime.
• Glycopeptides (for example vancomycin and teicoplanin).
• Macrolides (for example azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin).
• Monobactams (for example aztreonam).
• Penicillins (for example amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin).
• Polypeptides (for example bacitracin, polymixin B and colistin).
• Quinolones (for example ciprofloxacin, enoxacin, gatifloxacin, levofloxacin,
lomefloxacin, moxifloxacin, norfloxacin, ofloxacin and trovafloxacin).
• Sulfonamides (for example mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim- sulfamethoxazole (co-trimoxazole, T P-S X)).
• Tetracyclines (for example demeclocycline, doxycycline, minocycline,
oxytetracycline and tetracycline).
• Aminocoumarins (for example novobiocin, albamycin, coumermycin and
clorobiocin).
• Oxazolidinones (for example linezolid and AZD2563).
• Lipopeptides (for example daptomycin).
• Streptogramins (for example quinupristin/dalfopristin).
• Glycylcyclines (for example tigecycline).
• Lantibiotics (for example Type A Lantibiotics (such as nisin, subtilin, epidermin, mutacin II, mutacin I & II!) and Type B Lantibiotics (such as mersacidin, actagardine and cinnamycin).
Other suitable antibiotics useful as adjunctive agents include one or more antibiotic(s) selected from the following: arsphenamine, chloramphenicol, clindamycin, lincoamycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampin/rifampicin and imidazole. Thus, the compounds of the invention may be used in combination with one or more antibiotics selected from: penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, capreomycin, cycloserine, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, ethambutol, ethionamide, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolones (for example levofloxacin, moxafloxacin and gatifloxacin, ciprofloxacin, enoxacin,
grepafloxacin), kanamycin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, p- aminosalicylic acid, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimethoprim- sulfamethoxazole, co-amoxyclav, cephalothin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, streptomycin, nitrofurantoin, co- trimoxazole, rifamycin and derivatives thereof (for example rifampicin, rifabutin and rifapentine), isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococcin, fusidic acid, thiolactomycin and fosmidomycin.
Other suitable antibacterial adjunctive agents may be selected from those listed in the table below:
Compound Class
DU-6859 Fluoroquinolone
Erythromycin stinoprate acrolide
Oritavancin Glycopeptide
Telavancin Glycopeptide
Dalbavancin Glycopeptide
Ceftobiprole medocaril Cephalosporin
Tebipenem pivoxil Carbapenem
Iclaprim DHFR
OPT-80 Difimicin
Ceftaroline fosamil Cephalosporin
RX-3341 Fluoroquinolone
Cethromycin Ketolide
TD-1792 Glycopeptide - β-lactam dimer cnD A n Macrolide
RX-1741 Oxazolidinone
MK-2764 Glycycline
Nemonoxacin Fluoroquinolone
Flopristin + Linopristin Streptogramin
Tomopenem Carbapenem
Ramoplanin Glycolipodepsipeptide
Linezolid Oxazolidinone
Cefditoren pivoxil Cephalosporin Ertapenem Carbapenem
Gemifloxacin Fluoroquinolone
Daptomycin Upopetide
Telithromycin Lipopetide
Tigecy!ine Glycylcycline
(d) Antifungal adjunctive agents The compounds of the invention may be used in combination with various antifungal agents (antimycotics).
(e) Antiprotozoal adjunctive agents The compounds of the invention may be used in combination with various antiprotozoal agents, including but not limited to, chloroquine, doxycycline, mefloquine, metronidazole, eplomithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine and sulfadiazine.
{f Other adjunctive agents
The compounds of the invention may be co-administered with a variety of other co- therapeutic agents which treat or prevent side effects arising from the antiinfective treatment and/or presenting as sequelae of the infection. Adjunctive agents of this type may or may not have antiinfective activity and include, for example, PPIs and H2RAs (as hereinbefore described).
Thus, the compounds of the invention may be used adjunctively with PPIs including, but are not limited to, omeprazole (Losec, Prilosec, Zegerid), lansoprazole (Prevacid, Zoton, Inhibitol), esomeprazole (Nexium), pantoprazole (Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan) and rabeprazole (Rabecid, Aciphex, Pariet, Rabeloc). The compounds of the invention may also be used adjunctively with H2RAs including, but are not limited to, cimetidine (Tagamet), ranitidine (Zinetac, Zantac), famotidine,
(Pepcidine, Pepcid), roxatidine (Roxit) and nizatidine (Tazac, Axid). The compounds of the invention may be used adjunctively with triple therapy with PPIs or H2RAs together with a combination of two antibiotics {including, but not limited to, antibiotics selected from metronidazole, amoxicillin, levofloxacin and clarithromycin).
Various probiotics may be used as adjunctive agents, including for example
Saccharomyces boulardii or Lactobacillus acidophilus cells. Probiotics are mono or mixed cultures of live microorganisms which are proposed to help re-establish the natural gut microflora of the patient that has been disrupted by the offending antimicrobial that induced CDAD or even the agent used to treat CDAD. In addition, such microorganisms may act to stimulate the patient's immune system and to elicit production of enzymes that degrade the toxins associated with C. difficile. Particular microorganisms of interest are, but not limited to, Saccharomyces spp. (Tor example Saccharomyces boulardii and Saccharomyces cerevisiae) and Lactobacillus spp. (for example Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaris and Lactobacillus plantarum). Any other common probiotic composition or microorganism that is a normal member of the human intestinal tract may also be considered.
Pre-biotics, agents aimed at stimulating the growth of the intestinal flora, may also be used as adjunctive agents. For example, the use of oligofructose has been shown to increase levels of Bifidobacterium spp. and reduce subsequent relapse rates in patients. As such, any antibacterial agent with a narrow spectrum of activity targeted at Clostridium species would have significant benefit when dosed in combination with therapies aimed at reestablishing the normal enteric microorganism population.
Other approaches aimed at reestablishing the normal enteric flora include faecal biotherapy and faecal enemas prepared from the stools of healthy individuals which contain the normal microorganisms of the gut. Faecal bacteriotherapy may therefore also be used adjunctively with the compounds of the invention.
In order to sequester the toxins produced by C. difficile, absorbents which bind and sequester bacteriotoxins of various different types may be used as adjunctive agents. Ion exchange resins, such as the bile acid sequestrants cholsetyramine or colestipol, bind to the C, difficile cytotoxins and thus aim to reduce the degree of toxic challenge to the gut. However, ion exchange resins are known to bind to agents such as vancomycin and therefore may lead to suboptimal levels of antibacterial agent at the site of infection. Other absorbents that may be used adjunctively with the compounds of the invention include polymers such as Synsorb 90 and Toievamer.
Although probiotic therapy is suggested to improve immune system response in CDAD patients, intravenous immunoglobulin (J. Antimicrob. Chem., 2004, 53, 882-884), for example, may also be used to treat CDAD patients, particularly recurrent cases where any further antimicrobial treatment would further exacerbate gut flora disturbance. Thus, the compounds of the invention may be used adjunctively with various immunoglobulins.
Although the use of agents aimed at reducing diarrhoea are generally avoided in CDAD patients, in certain cases it may be envisaged that the use of such agents in conjunction with an antibacterial may be of benefit when trying to increase levels of an antimicrobial agent at the site of infection and/or when trying to increase the length of time an antibacterial agent is in contact with the enteric pathogen. Such agents may include, but are not limited to, loperamide (Lopex, Imodium, Dimor, Pepto) diphenoxylate (Lomotil, Co- phenotrope) difenoxin ( otofen), and racecadotril. Thus, the compounds of the invention may be used adjunctively with various anti-diarrhoeal agents, including any of those listed above.
Co-therapeutic agents which treat or prevent any of the following side effects may be used as part of the same treatment regimen as the compounds of the invention: (a) lipodystrophy and wasting; (b) facial lipoatrophy; (c) hyperlipidemia; (d) fatigue; (e) anaemia; (f) peripheral neuropathy; (g) nausea; (h) diarrhoea; (i) hepatotoxicity; (j) osteopenia; (k) dehydration and (I) osteoporosis. The treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:
(a) Cancer therapy;
(b) AIDS therapy;
(c) Immunosuppressive interventions; (d) Post-transplantation graft/implant management;
(e) Onychomycotic nail surgery or debridement;
(f) Topical antimycottc therapy (for example with an antimycotic agent selected from azoles, allylamines (e.g. terbinafine) or a morpholine (e.g. amorolfine);
(g) Systemic antimycotic therapy;
(h) Antibacterial therapy;
(i) Antiviral therapy;
(j) Anti-inflammation therapy (e.g. with steroids);
(k) Analgesic administration;
(I) Antipruritic administration;
(m) Probiotic administration;
(n) Faecal bacteriotherapy; or
(o) Skin grafting. Thus, the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (a) to (o) are being (or have been) carried out.
(g) Adjunctive treatments
The treatment or prophylaxis may comprise the administration of a compound as defined herein as an adjunctive to one or more of the following treatments or interventions:
1 Cancer therapy;
2. Immunosuppressive interventions;
3. Immunostimulatory interventions;
4. Post-transplantation graft/implant management;
5. Onychomycotic nail surgery or debridement;
6. Anti-inflammation therapy (e.g. with steroids);
7. Analgesic administration;
8. Antipruritic administration;
9. Surgery;
10. Cell or tissue ablation;
11. Radiotherapy;
12. Cryotherapy; 13. Faecal transplantation therapy (faecal bacteriotherapy);
14. Probiotic tehrapy; or
15. Skin grafting. Thus, the invention may comprise the treatment or prophylaxis of a patient population in which one or more of the treatment or interventions (1) to (15) are being (or have been) carried out.
(V) Posologv
The compounds of the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway
(aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. The amount of the compound administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular compound selected.
In general, the effective amount of the compound administered will generally range from about 0.01 mg/kg to 10000 mg/kg daily. A unit dosage may contain from 0.05 to 500 mg of the compound, and can be taken one or more times per day. The compound can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally, parenterally or topically, as described below. The preferred route of administration is oral administration. In general a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 1000 mg per kilogram body weight per day and most preferably in the range 1 to 5 mg per kilogram body weight per day. The desired dose is preferably presented as a single dose for daily administration.
However, two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day may also be employed. These sub-doses may be
administered in unit dosage forms, for example, containing 0.001 to 100 mg, preferably 0.01 to 10 mg, and most preferably 0.5 to 1.0 mg of active ingredient per unit dosage form. In determining an effective amount or dose, a number of factors are considered by the attending physician, including, but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages can also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
The amount of the compound that can be combined with carrier materials to produce a single dosage form varies depending upon the subject to be treated and the particular mode of administration. For example, a formulation intended for oral administration to humans can contain about 0.5 mg to about 7 g of active agent compounded optionally with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95 percent of the total composition. Dosage unit forms for the compounds of the invention generally contain about 1 mg to about 500 mg of the active ingredient, for example 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
The effectiveness of a particular dosage of the compound of the invention can be determined by monitoring the effect of a given dosage on the progression of the disease or its prevention.
(VI) Formulation
The compound of the invention may take any form. It may be synthetic, purified or isolated from natural sources using techniques described in the art.
Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycoltc, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxy benzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids. Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts. Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ha) salts and other physiologically acceptable metal tons. Such salts can be made from the ions of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc. Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N, '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.
Pharmaceutical compositions can include stabilizers, antioxidants, colorants and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not compromised to such an extent that treatment is ineffective.
The pharmaceutical compositions may be administered enterally and/or parenterally. Oral (intra-gastric) is a typical route of administration. Pharmaceutically acceptable carriers can be in solid dosage forms, including tablets, capsules, pills and granules, which can be prepared with coatings and shells, such as enteric coatings and others well known in the art. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
Parenteral administration includes subcutaneous, intramuscular, intradermal, intravenous, and other routes known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
When administered, the pharmaceutical composition can be at or near body temperature.
Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. Tablets can be uncoated or they can be coated by known techniques, for example to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellutose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
Aqueous suspensions can also contain one or more preservatives, for example, ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring - agents, or one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents can be added to provide a palatable oral preparation. These compositions can be preserved by addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavouring and colouring agents, can also be present.
Syrups and elixirs containing the compound of the invention can be formulated with sweetening agents, for example glycerol, sorbitol, or sucrose. Such formulations can also contain a demulcent, a preservative and flavouring and colouring agents.
The compound of the invention can be administered parenterally, for example
subcutaneously, intravenously, or intramuscularly, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. Such suspensions can be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above or other acceptable agents. A sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1 ,3- butanediol. Among acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any Wand fixed oil may be employed, including synthetic mono-or diglycerides. In addition, omega-3 polyunsaturated fatty acids can find use in preparation of injectables. Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperature, but liquid at rectal" temperature and will therefore, melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Also encompassed by the present invention is buccal and sub-lingual administration, including administration in the form of lozenges, pastilles or a chewable gum comprising the compounds set forth herein. The compounds can be deposited in a flavoured base, usually sucrose, and acacia or tragacanth.
Other methods for administration of the compounds of the invention include dermal patches that release the medicaments directly into and/or through a subject's skin.
Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, co!lyriums, solutions or suspensions.
Compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers. Viscosity-building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition. Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.
Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition. Such cosolvents include polysorbates 20,60 and 80, polyoxyethylene/polyoxypropylene surfactants (e. g., Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art. Typically, such cosolvents are employed at a level of about 0.01% to about 2% by weight of a
pharmaceutical composition.
Pharmaceutically acceptable excipients and carriers encompass all the foregoing and the like. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See for example Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott. Williams and Wilkins), 2000; Lieberman et al., ed. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980) and Kibbe et a/., ed. , Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).
Thus, in embodiments where the compound of the invention is formulated together with a pharmaceutically acceptable excipient, any suitable excipient may be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while cornstarch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. The pharmaceutical compositions may take any suitable form, and include for example tablets, elixirs, capsules, solutions, suspensions, powders, granules, nail lacquers, varnishes and veneers, skin patches and aerosols.
The pharmaceutical composition may take the form of a kit of parts, which kit may comprise the composition of the invention together with instructions for use and/or a plurality of different components in unit dosage form.
For oral administration the compound of the invention can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, granules, solutions, suspensions, dispersions or emulsions (which solutions, suspensions
dispersions or emulsions may be aqueous or non-aqueous). The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch. Tablets for oral use may include the compound of the invention, either alone or together with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral use include hard gelatin capsules in which the compound of the invention is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
The compounds of the invention may also be presented as liposome formulations.
In another embodiment, the compounds of the invention are tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, colouring agents, and flavouring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanoi, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent or emulsifying agent.
The compounds of the invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally. In such embodiments, the compound is provided as injectable doses in a physiologically acceptable diluent together with a pharmaceutical carrier (which can be a sterile liquid or mixture of liquids). Suitable liquids include water, saline, aqueous dextrose and related compound solutions, an alcohol (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1 ,3-dioxolane-4- methanol), ethers (such as poly(ethylene-glycol) 400), an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or a detergent), suspending agent (such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
carboxymethylcellulose), or emulsifying agent and other pharmaceutically adjuvants.
Suitable oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, com oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyt ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulphonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulphosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5 to about 25% by weight of the compound of the invention in solution. Preservatives and buffers may also be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The compounds of the invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of the compound from about 0.1 to about 10% w/v (weight per unit volume). When used adjunctively, the compounds of the invention may be formulated for use with one or more other drug(s). In particular, the compounds of the invention may be used in combination with analgesics, anti-inflammatories {e.g. steroids), immunomodulatory agents and anti-spasmodics.
Thus, adjunctive use may be reflected in a specific unit dosage designed to be compatible (or to synergize) with the other drug(s), or in formulations in which the compound is admixed with one or more antiinflammatories, cytokines or immunosuppressive agents (or else physically associated with the other drug(s) within a single unit dose). Adjunctive uses may also be reflected in the composition of the pharmaceutical kits of the invention, in which the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the antimicrobial agents and/or antiinflammatories. Adjunctive use may also be reflected in information and/or instructions relating to the co-administration of the compound with antimicrobial agents and/or antiinflammatories.
(VII) Exemplification
The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention. HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode. The HPLC column used is a Phenomenex Gemini C18 150x4.6mm or a Phenomenex Gemini C18 50x4.6mm 3μ. Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector. The preparative HPLC column used is a Phenomenex Gemini C18 150x10mm and the mobile phase is acetonitrile/water.
1H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained as CDCI3l CD3OD or DMSO- ¾ solutions (reported in ppm), using chloroform as the reference standard (7.26 ppm), methanol (3.35 ppm) or DMSO-c¾ (2.50 ppm). When peak multiplicities are reported, the following abbreviations are used s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), obsc. (obscured), app. (apparent). Coupling constants, when given, are reported in Hertz (Hz).
Column chromatography was performed either by flash chromatography (40-65pm silica gel) or using an automated purification system (SP1™ Purification System from Biotage®or CombiFlash Companion from ISCO). Reactions in the microwave were performed in an Initiator 8™ (Biotage) or in an Explorer 48 (CEM).
The abbreviations used are DMSO (dimethylsu!foxide), DMF (dimethylformamide), IMS (industrial methylated spirits), I PA (isopropyl alcohol), TLC (thin layer chromatography), Boc (rerf-butyloxycarbon l), RT (retention time), DCM (dichloromethane), TFA (triftuoroacetic acid), LCMS (liquid chromatography-mass spectrometry), NMR (nuclear magnetic resonance), DME (1 ,2-dimethoxyethane).
MIC data were determined by broth microdiiution according to CLSl protocols described in Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard- Seventh Edition {M1 1 -A7, Vol. 27, No2, Jan 2007] and Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Seventh Edition [M7-A7, Vol. 26, No2, Jan 2006].
Example 1: Preparation of compounds of general formula (I) Method 1
4-{2-(Pyridin-4-yl)-1 H-benzo[d]imidazol-5-yl)benzene-1 ,2-diamine (Intermediate A)
To a stirred solution of 3,3'-diaminobenzidine (3.857 g, 18 mmol) and 4- pyridinecarboxaldehyde (1.41 mL, 15 mmol) in I PA (22.5 mL) and H20 (7.5 mL), was added sodium metabisulfite (2.852 g, 15 mmol). The suspension was heated to reflux for 16 h. The resulting yellow suspension was poured into water (200 mL) and the precipitate collected through filtration. The yellow solid was triturated with hot methanol and filtered giving intermediate A (1.672 g, 5.5 mmol, 37%).
LCMS RT=1.05min, H* 302.1 ; 1H NMR (d6-D SO): 13.17 (1 H, br s), 8.76 (2 H, d, J 6.0), 8.09 (2 H, d, J 6.0), 7.64 (2 H, br s), 7.42 (1 H, d, J 8.4), 6.91 (1 H, d, J 1.9), 6.77 (1 H, dd, J 8.0 and 1.9), 6.60 (1 H, d, J 8.0) and 4.58 (4 H, br s).
4-(2-(thiazol-5-yl)-1 H-benzo[d]imidazol-5-yl)benzene-1 ,2-diamlne (Intermediate B) A mixture of 3,3'-diaminobenzidine (570 mg, 2.65 mmol), thiazole-5-carbaldehyde (250 mg, 2.21 mmol) and Na2S2Os (420 mg, 2.21 mmol) in I PA (22.5 mL) and H20 (7.5 mL) was heated to 160 °C for 10 minutes in the microwave. The solution was cooled to room temperature and poured into water. The resulting yellow precipitate was collected through filtration and washed with water. The solids were absorbed onto silica and purified by column chromatography eluting with (95:5 EtOAc-MeOH to 90: 10 EtOAc-MeOH) afforded intermediate B as a yellow solid (230 mg, 0.75mmol, 33%).
LCMS RT=1.08 min, H* 308.1 ; 1H NMR (de-DMSO): 13.08 (1 H, br s), 9.22 (1 H, s), 8.56 (1 H, s), 7.64-7.53 (2 H, m), 7.38 (1 H, d, J 8.5), 6.89 (1 H, d, J 2.0), 6.76 (1 H, dd, J 8.0 and 1.9), 6.60 (1 H, d. J 8.0) and 4.56 (4 H, br s).
4-(2-(pyridin-3-yl)-1 H-benzo[d]imidazol-5-yl)benzene-1,2-dlamine (Intermediate C)
To a stirred solution of 3,3'-diaminobenzidine (5.00 g, 23.36 mmol) and 3- pyridinecarboxaldehyde (1.98 mL, 21.02 mmol) in I PA (16 mL) and H20 (16 mL), was added sodium metabisulfite (4.44 g, 23.36 mmol). The suspension was heated to 160°C for 15 minutes in the CEM microwave then cooled to room temperature. The resulting yellow suspension was poured into water (150 mL) and the precipitate collected through filtration and dried. The solid was purified by silica column chromatography eluting with neat EtOAc to 9:1 (EtOAc-MeOH) affording intermediate C as a yellow solid (3.92 g, 13.03 mmol, 62%). LCMS RT=1.44 min, MH* 302.3; *H NMR (d«-DMSO): 13.05 (1 H, br s), 9.37 (1H, d, J 2.0), 8.69 (1 H, dd, J 4.7 and 1.5), 8.51 (1 H, dt, J 8.1 and 1.9), 7.70-7.58 (3H, m), 7.41 (1 H, dd, J 8.5 and 1.5), 6.93 (1 H, d, J 2.0), 6.79 (1 H, dd, J 8.0 and 2.0), 6.62 (1 H, d, J 8.0) and 4.58 (4H, br s).
2-{6-Methoxypyridin-3-yl)-2Xpyridin-4-yl)-1 H,1'H-5,5'-blbenzo[d]imidazole
(Compound 1)
A mixture of 4-(2-(Pyridin-4-yl)-1 H-benzo[d]imidazol-5-yl)benzene-1 ,2-diamine
(intermediate A) (50 mg, 0.17 mmol), 6-methoxynicotinaldehyde (27 mg, 0.20 mmol) and Na2S205 (38 mg. 0.20 mmol) in IPA-H20 (3:1 , 4 mL) was heated under microwave radiation for 160°C for 10min then cooled to room temperature. The resulting mixture was poured into water and the precipitate collected through filtration. The material was absorbed onto silica and purified by column chromatography eluting with EtOAc to 80:20 EtOAc- eOH) to afforded the title compound as a yellow solid (25 mg, 0.06 mmol, 36%).
LCMS: RT=1.21 min, H* 419.1 ; 1H NMR (MeOO): 8.92 (1 H, dd, J 2.5 and 0.6), 8.77 (2 H, dd, J 4.6 and 1 .7), 8.38 (1 H, dd, J 8.8 and 2.5), 8.13 (2 H, dd, J 4.6 and 1 .6), 7.97-7.62 (6 H, m), 7.01 (1 H, dd, J 8.7 and 0.7) and 4.03 (3 H, s).
The following compounds were prepared in a similar manner using the relevant intermediate and purifying by crystallization or column chromatography where necessary:
N-(4-(2,-(Pyrldin-4-yl)-1H,1'H-5,5,- ibenzo[dlimidazol-2-yl)phenyl)acetamide
(Compound 2)
LCMS: RT=1.14min, H+ 445.1 ; 1H NMR (MeOD): 8.62 (2 H, dd, J 4.7 and 1.5). 7.98 (2 H, dd, J 4.7 and 1.6), 7.94 (2 H, dd, J 6.9 and 1.9), 7.84-7.42 (8 H, m) and 2.05 (3 H, s).
2-(Pyridin-4-yl)-2'-(thiophen-2-yl)-1 H,1 'H-S.S'-bibenzoIdJ imidazole (Compound 6) LCMS RT=1.31min, H* 394.1 ; 1H NMR (d6-DMSO): 8.80 (2 H, d, J 6,0), 8.16 (2 H, d, J 6.0), 7.96-7.82 (3 H, m), 7.80-7.74 (2 H, m), 7.70-7.56 (3 H, m) and 7.26 (1 H, dd, J 5.0 and 3.7).
5-<2'-(pyridln-4-yl)-1 H»1 'H-5t5*-bibenzo|;€f|imidazol-2-yl)thiazole (Compound 7) 5*)
LCMS RT=1.25min. MH* 395.2; 1H NMR (d6-DMS0): 9.22 (1 H, s), 8.76 {2 H, dd, J 4.5 and 15), 8.58 {1 H, s), 8.10 (2 H, dd, J 4.5 and 1.5), 7.93 (1 H, s), 7.88 (1 H, s), 7.77 (1 H, d, J 8.4), 7.70 (1 H, d, J 8.4) and 7.67-7.59 (2 H, m). 2^3-Fluoro yr^dinH4-y|)-2'-<pyridin^-yl -1H,1Ή-5,5,-bibβnzo[cΠimida2olθ (Compound
8)
LCMS: RT=1.28 min, MH* 406.9; 1H NMR (MeOO): 8.66 (2 H, dd, J 4.8 and 1.3), 8.63 (1
H, d, J 2.9), 8.51 (1 H, dd, J 5.1 and 0.7), 8.13 (1 H, dd, J 6.4 and 5.2), 8.02 (2 H, dd, J 4.6 and 1.6) and 7.99-7.56 (6 H, m).
4-(2'-(Pyridin-4-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazol-2-yl)phenol (Compound 9)
LCMS: RT=1.13min, MH* 404.2; 1H NMR (MeOO): 8.77 (2 H, dd, J 4.7 and 1.4), 8.13 (2 H, dd, J 4.6 and 1.6), 7.99 (2 H, dd, J 6.8 and 1.9). 7.95-7.51 (6 H, m) and 6.97 (2 H, dd, J 6.7 and 2.0).
2-phenyl-2'-(pyridin-4-yl)-1H>1,H-5,5'-bibenzo[d]imidazote (Compound 10)
LCMS RT=1.20min, MH* 388.2; 1H NMR (MeOD): 8.75 (2 H, dd, J 4.6 and 1.7), 8.16-8.10
(4 H, m), 7.90 (2 H, d, J 9.7) and 7.80-7.51 {7 H, m). 2-(5-Chlorothiophen-2-yl)-2'-(pyridin-4-yl)-1 H,1 'H-S^-bibenzoIdJimidazole
(Compound 11)
LCMS: RT=1.46 min, MH* 428.0; 1H NMR (MeOD): 8.64 (2 H, dd, J 4.6 and 1.6), 8.00 (2 H, dd, J 4.6 and 1.7), 7.84-7.51 (6 H, m), 7.49 (1 H, d, J 4.0) and 7.02 (1 H, d, J 4.0). N,N-Dimethy -(2,-(pyridin-4-yl)-1H>rH-5,5'-bibenzo[d]imidazol-2-yl)aniline
(Compound 12)
LCMS: RT=1.19min, MH* 431.1 ; 1H NMR (D20): 8.75 (2 H, dd, J 4.7 and 1.6), 8.11 (2 H, dd, J 4.6 and 1.6), 7.97 (2 H, dd, J 7.1 and 2.0), 7.90-7.46 (6 H, m), 6.88 (2 H. dd, J 6.9 and 2.0) and 3.06 (6 H, s).
2-(3-Methoxyphenyl)-2'-(pyridin-4-yl)-1 H»1 'H-5,5'-bibenzo[d]imidazole (Compound 13) LCMS: RT=1.25min, MH* 418.2; 1H NMR (d6-DMSO): 13.35 (1 H, s), 13.00 (1 H, s), 8.79 (2 H, d, J 5.5), 8.14 (2 H, d, J 6.0), 8.06-7.96 (1 H, m), 7.88-7.73 (4 H, m), 7.73-7.54 (3 H, m), 7.49 (1 H, t, J 8.1), 7.09 (1 H, d, J 8.1 ) and 3.89 (3 H. s). 2-{ ridin^-yl^2M3-(trffluoromethyl)^^
(Compound 14)
LCMS: RT=1.56min, H* 456.0; 1H NMR (ds-OMSO): 13.31 (2 H, s), 8.79 (2 H, dd, J 4.5 and 1.5), 8.57 (1 H, br s), 8.52 (1 H, d, J .5), 8.14 (2 H, dd, J 4.5 and 1.6) and 8.10-7.57 (8 H, m).
5-{2'-{thiophen-2-yl)-1 H,1 ^5,S*-bibenzo[d]imidazol-2-yI)thiazol© Compound 15)
LCMS RT=1.34min, MH* 400.1 ; 1H NMR ( eOD): 9.08 (1 H, d, J 0.7), 8.45 (1 H, d, J 03),
7.82-7.67 (3 H, m), 7.64-7.48 (5 H, m) and 7.15 (1 H, dd, J 5.1 and 3.7).
2-(Pyridin-4-yl)-2'-<4-<trjfluoromethoxy)phenylHH,1'H-5,5''-bibenzo[d]imidazole
(Compound 16)
LCMS: RT=1.51min, MH+ 472.2; 1H NMR (MeOD): 8.78-8.68 (2 H, m), 8.18 (2 H, d, J 8.8), 8.07 (2 H, d, J 4.8), 7.95-7.56 (6 H, m) and 7.46 (2 H, d, J 8.1).
4-(2'-(thiazol-5-yl)-1 H,1'H-5»5*-bibenzo[dJimidazoI-2-yI)oxazoie (Compound 1 ) LCMS RT=1.27min, MH* 385.1; 1H NMR (d DMSO : 13.50-12.90 (2 H, m), 9.25 (1 H, s), 8.86 (1 H, d, J 1.0), 8.68 (1 H, d, J 1.0), 8.61 (1 H, s), 7.95-7,75 (2 H, m) and 7.72-7.54 (4 H, m).
2-(5-Chlorofuran-2-yl)-2'-(pyHdin-4-yl)-1H,1'H-5,5,-bibenzo[d]imidazole (Compound
18)
LCMS; RT=1.33 min, MH* 412.3; H NMR (MeOD); 8.65 (2 H, dd, J 4.7 and 1.4), 8.01 (2 H, dd, J 4.7 and 1.6), 7.86-7.49 (6 H, m), 7.14 (1 H, d, J 3.5) and 6.48 (1 H, d» J 3.5).
2^pyridin^-yI)-2Me-(trifluoromethyI)pyridin-3-yIHH,1,H-5»5,-bibenzo[d]imidazo!e (Compound 22)
LCMS: RT=1.58 min, MH* 457.2; 1H NMR (ds-DMSO); 9.52 (1 H, s), 8.82-8.75 (3H, m), 8.17-8.09 (3H, m), 7.96 (2 H, s), 7.83-7.74 (2H, m), 7.69 (1 H, s) and 7.66 (1 H, s).
2-(pyridin-2-yl)-2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazole (Compound 23)
LCMS: RT=1.26 min, MH* 389.2; 1H NMR (MeOD): 8.77 (4 H, d, J 6.1), 8.34 (1H, d, J 8.2), 8.14 (2 H, dd, J 4.7 and 1.6), 8.01 (2H, dt, J .6 and 1.6), 7.91-7.70 (4 H, m), 7.51 (1 H, dd, J 6.5 and 5.9). 2-{pyrfdin-3-yl)-2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazole (Compound 24)
LCMS: RT=1.20min, MH* 389,3; 1H NMR ( eOO): 9,17 (1 H, d, J 2.3), 8.61 (2 H, dd, J 4.7 and 1.7), 8.56 (1 H, dd, J 4.9 and 1.5), 8.39 (1 H, dt, J 8.0 and 1.8), 7.97 (2 H, dd, J 4.6 1.7) and 7.85-7.48 (7 H, m).
2-(6-(methylsulfonyl)pyridin-3-yl)-2MpyHdin-4-ylHH,1,H-5)5,-bibenzo[d]imidazole (Compound 25)
LCMS: RT= 1.31 min, 467.0 MH*; 1H NMR (MeOD): 9.48 (1 H, dd, J 2 2 and 0.8), 8.79- 8.74 (3 H. m), 8.29 (1 H, dd, J 8.2 and 0.8), 8.13 (2 H, dd, J 4.6 and 1.6). 8.00-7.70 (6 H, m) and 3.34 (3 H, s).
4-(2'-(pyrldln-4.yl)-1 H.I'H-S.S'-bibenzotflimidazol^-y thtazoIe (Compound 26) LCMS: RT=1.24 min, MH* 395.1 ; 1H NMR (D6-DMSO): 13.34 (1 H. s), 13.05 (1H, s), 9.36 (1H, d, J 2.0), 8 79 (2H, d, J 5.9), 8.49 (1 H, d, J 1.9), 8.13 (2H, d, J 5.9) and 8.06-7.54 (6H, m).
4-(2'-(pyridin-4-yl)-1 H(1*H-5,5'-bib6nzo[d]imidazoI-2-yl)oxazole (Compound 27) LCMS: RT=1.19 min, MH* 379.2; 1H NMR (D6-DMSO): 13.35 (1 H, s), 13.01 (1H, s), 8.87 (1H, s), 8.78 (2H, d, J 5.9), 8.68 (1 H, s), 8.13 (2H, d, J 5.9) and 8.05-7.55 (6H, m).
2-(5>methylthiophen-2-yl)-2,-(pyridln-4-yl)-1H,1'H-5,5,-biberizo(cr|imldazole
(Compound 28)
LCMS: RT=1.24 min, MH* 408.1 ; 1H NMR (MeOD): 8.79 (2H, d, J 4.9), 8.15 (2H. dd, J 4.6 and 1.6), 8.05-7.60 (7H, m), 6.95 (1 H, dd, J 3.7 and 1.2) and 2.62 (3H, s).
S^y^e-methoxypyrldi -S-yO-IH.I'H-IS.S'-bibenzotdlimidazon^-y thiazole
(Compound 29)
LCMS: RT=2.09 min, MH* 425.3; 1H NMR (Ds-DMSO): 13.25 (1 H, s), 13.02 (1 H, s), 9.26 (1H, s), 8.99 (1H, d, J 2.3), 8.62 (1H, d, J 4.5), 8.45 (1 H, dd, J 8.7 and 2.6), 7.95 (1H, d, J 9.3), 7.80-7.71 (2H, m), 7.66-7.53 (3H, m), 7.04 (1H, d, J 9.1 ) and 3.96 (3H, s). S-(2*-(pyridin-3-yl)-1H,1'H-[5,5'-bibenzo[dJimidazol]-2-yI)thiazoIe (Compound 30) LCMS: RT=1.83 min. MH* 395.6; H NMR (Ds-DMSO): 13.21 (2H, s), 9.39 (1 H, d, J 2.2), 9.25 (1 H, s), 8.70 (1 H, dd, J 4.8 and 1.5), 8.62 (1H, s), 8.54 (1H, dt, J 8.0 and 1.8), 7.95- 7.83 (2 H, m), 7.77-7.67 (2H, m) and 7.65-7.58 (3H, m). 2-{6^ethoxypyridin-3-yI)-2Mpyridin-3-yl)-1^
(Compound 31)
LCMS: RT=2.18 min, H* 420.0; H NMR (D«-DMSO): 13.18 (1 H, s), 12.99 (1 H, s), 9.39 (1H, s), 9.00 (1H, s), 8.70 (1H, d, J 4.2), 8.54 (1H, d, J 8.0), 8.46 (1H, dd, J 8.5 and 2.0), 8.04-7.53 (7H, m), 7.04 (1 H, d, J 8.6) and 3.96 (3H, s).
N^4^2 pyridin-3-yl)-1 H,1,H-[5,5'-bibenzo[d]imida2ol]-2-yl)phenyl)acetamide
(Compound 32)
LCMS: RT=1.72 min, H+ 446.1 ; 1H NMR (D6-DMSO): 10.25 (1H, s), 9.39 (1H, s), 8.71 (1 H, d, J 4.0), 8.54 (1 H, d, J 7.8), 8.15 (2H, d, J 8.2), 7.94-7.85 (2H, m), 7.83-7.68 (4H, m), 7.66-7.58 (3H, m) and 2.11 (3H, s).
Method 2
2,2'-Di(pyridin-3-ylM H.I'H-S.S'-bibenzoIdJimidazole (Compound 3)
Prepared by a similar procedure to method 1 , using a ratio of 2:1 of nicotinaldehyde to 3,3'- diaminobenzidine.
LCMS RT=1.20min, H* 389.3; 1H NMR (d«-OMSO): 13.20 (2 H, br s), 9.39 (2 H, d J, 2.1), 8.70 (2 H, dd, J 4.8 and 1.5), 8.54 (2 H, dt, J 8.1 and 1 9), 8.10-7.70 (4 H, m) and 7.66-7.58 (4 H, m).
The following compounds were prepared in a similar manner, purifying by
crystallization or column chromatography where necessary:
2,2'-Di(thiazol-5-yl)-1 H,1'H-5,5'-bibenzo[d]imidazole (Compound 4)
LCMS RT=1.37min, MH* 401.1 ; 1H NMR (d6-DMSO): 13.26 (2H, s), 9.25 (2H, s), 8.62 (2H, s) and 7.61-7.95 (6H, m).
2,2,-Di(pyrldin-2-yl)-1 H,1'H-5,5*-bibenzo[d]imidazole (Compound 19)
LCMS RT=1.39 min, H* 389.3; 1H NMR (d«-DMSO): 13.17 (2 H, br s), 8.76 (2 H, d, J 4.6), 8.36 (2 H. d, J 7.9), 8.03 (2 H, td, J 7.7 and 1.6) and 7.98-7.50 (8 H, m). 2,2'-Di(thiazol-4-yl)-1 H.I'H-S.S'-bibemoIdJimidazoie (Compound 21 )
LCMS RT=1.22min, MH* 401.1 ; 1H NMR (d6-DMSO): 13.03 (2H, s), 9.36 (2H, d, J 2.0 Hz),
8.48 (2H, d, J 2.0 Hz) and 7.55-7.93 (6H, m). Method 3
4^2,^thiazo -yl)-1H,1'H-5,5,-bibenzo[d]irnidazol-2-yl)pyridine-1 -oxide (Compound
20)
To a suspension of 4-{2,-(pyridin-4-yI)-1HtTH-[5,5'-bibenzo[d]imidazoi]-2-yl)thiazoIe (50mg 0.13 mmol) in DCM (10 mL) was added solid mCPBA (30 mg, 0.13 mmol) in one lot. The mixture was stirred and warmed to 40°C for 5 hours. The solids were filtered off and washed with DCM and dried. Purification by column chromatography eluting with (5:95 MeOH-DCM to 10:90 MeOH-DCM) afforded the title compound as a yellow solid (7 mg, 0.02 mmol, 13%)
LCMS RT=3.84min, MH* 411.1; 1H NMR (MeOD): 9.17 (1 H, d, J 1.8), 8.52-8.48 (2 H, m), 8.36 (1 H, d, J 1.9), 8.22-8.17 (2 H, m), 8.05-7.68 (5 H, br m) and 7.64 (1 H, dd, J 8.5 and
1.7).
The following compounds were prepared in a similar manner, purifying by
crystallization or column chromatography where necessary:
4-(2'-<Pyridin-4-yl)-1H,1,H-5,5,-bibenzo[d]imidazol-2-yl)pyridine-1-oxide (Compound 5) LCMS RT=2.44min, MH* 405.2; 1H NMR (d6-DMSO): 13.46-13.20 (2 H, m), 8.79 (2 H, d J
6.0), 8.43-8.37 (2 H, m), 8.18-8.11 (4 H, m) and 8.08-7.57 (6 H, m).
Example 2: Activity of the compounds of the invention
A list of preferred compounds of general formula (I) together with their minimum inhibitory concentration (MIC) against Clostridium difficile ATCC700057 and a panel of gut flora indicator bacteria is summarized in Table 2 (below).
Table 2
Figure imgf000058_0001
Figure imgf000059_0001
yl)p enyl)acetamide In the above table, the symbols used to indicate the MIC values are:
MIC≤ 1 Mg /ml = ++++
MIC≤ 4 pg/ml = +++
MIC≤ 32 pg/ml = ++
MIC≥ 54 pg/ml = +
The bacterial strains used were:
Bacteroides fragilis ATCC 25285
Escherichia coli ATCC25922
Lactobacillus paracasei Z1 83
Bifidobacterium dentium NCTC 11816
B. adotescentis MWR1 4
Staphylococcus aureus ATCC29213
Enterococcus faecalis ATCC29212 The indicator strains are representatives of the normal gut flora and therefore act as surrogates for the microbial gut flora. Thus, the data show that the compounds of the invention are selective Clostridium difficile agents (as hereinbefore defined) which exhibit bacteriostatic and/or bacteriocidal activity against C. difficile but which spare the normal gut flora. The compounds of the invention therefore find utility in the treatment of CDAD without causing pathological disturbance of the normal gut flora.
(VIII) Equivalents
The foregoing description details presently preferred embodiments of the present invention Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.

Claims

CLAIMS:
Figure imgf000061_0001
L is a direct bond, O, N or C1-C3 a!kyl;
1 2
R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more
3 3 3 3 3 substituents selected from halo, CN, N02, R , OR , N(R )2, COR , CO.R ,
C(=0)SR3, SR3, S(=0)R3, S02R3, NR*C(=0)R3, R4C02R3, OC(=0)NRV,
Figure imgf000061_0002
4 3 3 3 4
NR C(=0)NR R , CONR R and S02NR R , with the proviso that: (a) at least one of
1 2
R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
1 2
least one of R and R is an optionally substituted heteroaryl or heterocyclyl group, the optional substitution being with one or more substituents selected from halo,
3, OR3, N(R3)2, COR3, C02R3, C(=0)SR3, SR3, S(=0)R3, S02R3,
p
Figure imgf000061_0003
rovided that R and R are not both or ;
3
R is selected from H, C^Cg alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl,
C -C7 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, N02, R4. OR , (R )2T COR4, C02R , C(=0)SR4, SR* S(=0)R4, S02R4, NR4C(=0)R , 4C02R4, 0C(=0)NR4)2, R'SO^', C(=NR4)N(R4)2L C(=S)N<R4)2I
Figure imgf000062_0001
C0N(R4)2and S02N(R4)2;
4
5 R is selected from hydrogen, C^Cgalk l and C3-C7 carbocyclyl, optionally
substituted with one or more halo atoms;
or a pharmaceutically acceptable N-oxide, salt, hydrate, solvate, complex, bioisostere,0 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 wherein L is a direct bond. 5
3. The compound of claim 1 or claim 2 wherein R1 is a heteroaryl optionally substituted »th one or more suostituents sele ', OR , N(RJ), COR3, Co ,
C(=0)SR3, SR3, S(=0)R3, S02R3,
Figure imgf000062_0002
NR R3,
C{= 4) R3R , C(=S)NR3R4, N C{=NR ) R3R4, NR C(=S)NR3 4, N C(=0)NR3R4, CONRVand S02NR3R4.
0
1 2
4, The compound of any one of the preceding claims wherein R and/or R is an optionally substituted thiazole, thiophene, oxazole, phenyl, pyridyl, phenylamine or furan group.
5, The compound of any one of the preceding claims wherein R1 is a pyridyl group.
K
6, The compound of any one of the preceding claims wherein R2 is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from halo, CN, 3, OR3. N(R3)2, COR3, C02R3, C(=0)SR3, S 3, S(=0)R3, S02R3, NR4C(=0)R3,
Figure imgf000062_0003
0 NR4C(=S)NR3R4, NR C(=0)NR3R , CONRV and S02NR3R4.
7. The compound of claim 6 wherein R2 is a pyridyl group.
8. The compound of claim 6 wherein R2 is a phenyl group.
9. The compound of claim 7 wherein the pyridyl group is a pyridyl N-oxide group or a pyridyl group substituted with a: (a) methylsulfonyl group; or (b) a trifluoromethyl group; or (c) an acetamide group; or (d) a methoxy group; or (e) halo, for example F; or (f) a hydroxy group; or (g) C CE alkyl, for example methyl, group.
10. The compound of claim 8 wherein the phenyl group is substituted with a: {a) methylsulfonyl group; or (b) a trifluoromethyl group; or (c) an acetamide group; or (d) a methoxy group; or (e) halo, for example F; or (f) a hydroxy group; or (g) a C,-CE alkyl, for example methyl, group.
11. The compound of claim 1 which is selected from compounds 1 to 32 as listed in Table 1 herein.
12. A compound of formula (I):
Figure imgf000063_0001
(I)
wherein:
L is a direct bond, O, N or C,-C3 alkyl;
1 2
R and R are independently selected from an optionally substituted aryl, heteroaryl, carbocyclyl and heterocyclyl group, the optional substitution being with one or more
3 3 3 3 3 substituents selected from halo, CN, N02, R , OR , N{R )2L COR , C02R ,
C(=0)SR3, SR3, S(=0)R3, S02R3, NR4C(=0)R3, R'C02R3, OC(=0)NR3R4,
Figure imgf000063_0002
4 3 4 3 4 3 4
NR C(=0)NR R , CONR R and S02NR R , with the proviso that: (a) at least one of 1 2
R and R is not a substituted or unsubstituted six-membered aromatic ring; or (b) at
1 2
least one of R and R is an optionally substituted heteroaryl or heterocyclyl group, the optional substitution being with one or more substituents selected from halo,
3, OR , N(R3)2l COR3, C02R3, C(=0)SR3, SR', S(=0)R3, S02R3,
Figure imgf000064_0001
NR4C(=NR4)N 3R4, R C(=S)NR3R , 4C(*0)NRV, CONRVan S02NR3R4,
provided that R
Figure imgf000064_0002
R is selected from H, C^Cgalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7carbocydyl,
C -C7 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, N02,
R4, OR , N(R )2L COR4, C02R4, C(=0)SR4, SR , S(=0)R4, S02R4, C{=G)R , C02R4, 0C(=0)NR4)2| R4S02R", C(=NR4)N(R )2, C(=S)N(R4)2I
NR4C(=NR4)N(R4)2, NR C(=S)N(R4)2, NR4C(=0)N(R4)2I CON(R4)2and S02N(R4)2;
4
R is selected from hydrogen, C,-C3alkyl and C3-C7 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-(6-methoxypyridin-3-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
N-{4-(2'-(pyridin-4-yl)-1 H,1,H-5,5,-biben2o(d]imida20l-2-yl)phenyl)acetamide
2,2'-di(thiazol-5-yl)-1H,1'H-5,5'-bibenzo[dlimidazole
4-(2^pyridin-4-yl)-1H,rH-5,5'-bibenzotdlimidazol-2-yl)pyridine 1 -oxide 2-(pyridin-4-yl)-2'-(thiophen-2-yl)-1 H,1 'H-5,5'-bibenzo[d]imidazole
5-(2*-(pyridin-4-yl)-1 H, 1 *H-5,5,-bibenzo[d3imidazol-2-yl)thiazole
2-(3-fluoropyridin-4-yl)-2'-(pyridiri-4-yl)-1 H, 1 'H-5,5'-bibenzo[d)imidazole
4-(2'-{pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)phenol
2-phenyt-2'-(pyridin-4-yl)-1 H,1 'H-S.S'-bibenzotdJimidazoIe
2-(5-chlorothiophen-2-yt)-2'-(pyridin- -yl)-1 H Ή-5,5,-bibenzo[d]irnidazolθ
N.N-dimethyM-t -ipyridin^-yi)-! H, 1 ^-5,5'-bibenzo[d]imidazoi-2-yl)aniiine
2-(3-methoxyphenyl)-2'-(pyridin^-yl)-1 H 'H-5,5'-bibenzo[d]imidazole
2-(pyridin~4-yl)-2'-(3-(trifluoromethyl)phenyl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
5 2Mthiophen-2-yI)-1 H,1'H-5,5'-biberizoId|!midazol-2-yl)thiazoIe
2-(pyridin^-y))-2 4-(trifluoromethoxy)phenyl)-1 H,1^^
4-(2'-{thiazol-5-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)oxazole
2-(5-chlorofuran-2-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
4-(2*-{thiazol-4»yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazoI-2-yl)pyridine 1 -oxide
2,2'-di(thiazol-4-yl)-1 Η.1 Ή-5 ,5'-bibenzo[d]imidazole
2-(pyridin-4-yt)-2M6-(trifluoromethyt)pyridm^
2-(pyridin-2-yl)-2'-(pyridin-4-yl)-1 H,1'H-5,5,-bibenzo[d]imidazole
2-(pyridin-3-yl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
2-(6-(methylsulfonyl)pyridin-3-yl)-2 pyridin-4-yl)-1 H Ή-5,5'-bib nzo[d]imidazole 4-(2'-<pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[dlimidazol-2-yl)thiazole
4- (2'-(pyrkiin-4-yl)-1 Hl1 'H-5,5'-bibenzo[dJimidazol-2-yl)oxazole
2-(5-methylthiophen-2-yl)-2'-(pyridin-4-yi)-1 H, 1 'H-5,5'-bibenzo[d] imidazole
5- (2'-(6-methoxypyridin-3-yl)-1 H, 1 'H-[5,5'-bibenzo[d]imidazol]-2-yl)thiazole
S ^ pyndin-S-ytJ-I H.I'H-lS.S'-bibenzoIdjlimidazofl^-ylJthiazole
2-(6-methoxypyridin-3-yl)-2'-(pyridin-3-yl)-1Hl1 'H-5,5'-bibenzo[d]imidazole
N-(4-(2 pyridin-3-yl)-1H,1 ^[5,5'-bibenzo^ 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-(6-methoxypyridin-3-y1)-2'-(pyridin-4-yl)-1 Hl1 *H-5,5'-bibenzo[d]imidazole
N-(4-(2,-(pyridin-4-yl)-1H,1 ,H-5.5,-bibenzo[d]imidazol-2-yl)phenyl)acetamide 2,2'-di(pyridin-3-yl)-1H,1'H-5,5'-bib€n2o{d]imida2ole
2, 2'-di(thiazo!-5-yl)- 1 H , 1 *H-5,5'-bibenzo[d]imidazoIe
4-(2'-(pyridin-4-yl)-1 H,1'H-5,5'-bibenzo[d]imidazol-2-yl)pyridine 1 -oxide
2-{pyridin^-yl)-2' thiophen-2-yl)-1 H,1'H-5,5'-bibenzo[d]imidazole
5-<2*-(pyridin-4-yl)-1 H,1 'H-5.5'-bibenzo[d]imidazol-2-yl)thiazole
2-{3-fluoropyridin-4-yl)-2,-(pyridin^-yl)-1H,1,H-5,5,-bibenzotd]irn!dazole
4- {2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)pheno!
2-phenyl-2'-(pyridin-4-yl)-1 H,1 Ή-5,5 *»bibenzo[d]imidazote
2-(5-chlorothiophen-2-yl)-2'-(pyridin-4-yl)-1H 'H-5,5'-bibenzo[d]imidazole
N,N-dimethyl-4-(2'-(pyridin-4-y!)-1 H, 1 'H-5,5'-bibenzo[d]imidazol-2-yl)aniline
2-(3-methoxyp enyl)-2'-(pyridin-4-yl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
2-(pyridin-4-yl)-2'-(3-(trifluoromethyl)phenyl)-1 H, 1 'H-5,5'-bibenzo[d]imidazole
5- (2'-(thiophen-2-yl)-1 H,1,H-5,5,-bibenzo[d]imidazol-2-yl)thiazole
2-(pyridin-4-yl)-2'-(4-(trifluoromethoxy}phenyl)-1 H, 1 'H-5,5'-bibenzo[dlimidazole 4-(2'-(thiazol-5-yl)-1H,1 'H-5,5'-bib€nzo[d]imidazol-2-yl)oxazole
2-(5-chlorofuran-2-yl)-2'-{pyridin-4-yl)-1H,1 'H-5,5'-bibenzo[d]imidazote
2l2'-di(pyridin-2-yl)-1 H,1'H-5,5,-bibenzo[d]imidazole
4-(2'-(thiazoM-yl)-1H,1,H-5,5,-bibenzo[d]imidazol-2-yl)pyridine 1-oxide
2,2'-di(thiazol-4-yl)-1 H,1'H-5,5'-bibenzo[d]tmidazole
2-(pyridin-4.yl)-2'-(6-(trifluoromethyl)pyridin-3-yl)-1H,1 'H-5,5'-bibenzo[d]imidazole 2-(pyridin-2-yl)-2,-(pyridin-4-yl)-1 H, 1,H-5,5'-bibenzo[d]imidazole
2-(pyridin-3-yl)-2 -(pyridin-4-yl)-1 H,1'H-5,5,-bibenzo[d]inriidazole
2 6-(met lsuIfon !)pyΓidϊn-3- I)-2'-(pyridin^- I)-1Hl1Ή-5,5,-bibenzo[d]imidazoie
4- (2'-(pyridin-4-yf)-1H 'H-515'-bibenzo[dJimidazol-2-yl)thiazole
4-(2'-(pyridin-4-yl)-1 H,1"H-5,5'-bibenzo[d]imidazoI-2-yl)oxazole
2-(5-methyithio hen-2-yl)-2,-{ yridin-4- i)-1Ht1Ή-5,5,-bi enzotd]imidazole
5- (2'-(6-methoxypyridin-3-yl)-1 H, 1 'H-[5,5'-bibenzo[d]imidazol]-2-yl)thiazole
5-<2*-(pyridin-3-yl>-1 H , 1 ,H-[5,5'-bibenzoId]imidazol]-2-yl)thiazole
2-{6-methoxypyridin-3-yl)-2'-(pyridin-3-yl)-1 H, 1 Ή-5, 5'-bibenzo{d]imidazole
-(4-(2,-(p ridίn-3-yi)-1H,1Ή-[5,5'-b!benzo[dlimidazoi]-2-yi) henyi)acetamide 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
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.
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