WO2017046603A1 - Composés antibactériens et nouvelles utilisations de ceux-ci - Google Patents

Composés antibactériens et nouvelles utilisations de ceux-ci Download PDF

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WO2017046603A1
WO2017046603A1 PCT/GB2016/052896 GB2016052896W WO2017046603A1 WO 2017046603 A1 WO2017046603 A1 WO 2017046603A1 GB 2016052896 W GB2016052896 W GB 2016052896W WO 2017046603 A1 WO2017046603 A1 WO 2017046603A1
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methyl
alkyl
mmol
cyclopropyl
bromo
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PCT/GB2016/052896
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English (en)
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Neil STOKES
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Redx Pharma Plc
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Priority claimed from GBGB1516610.1A external-priority patent/GB201516610D0/en
Priority claimed from GBGB1610412.7A external-priority patent/GB201610412D0/en
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2017046603A1 publication Critical patent/WO2017046603A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • This invention relates to a series of compounds for use in treating infections caused by obligate anaerobic bacteria, including strains of Clostridium, e.g. Clostridium difficile.
  • the compounds can be used against strains of obligate anaerobic bacteria that have developed resistance to other antibiotics.
  • Many compounds used in the invention contain a tricyclic ring system.
  • Obligate anaerobic bacteria are important human pathogens. They are the aetiological agents of a wide range of infectious diseases including gastro-intestinal disorders, skin and soft tissue infections, bacteraemia, abdominal infections, endocarditis, osteomyelitis, periodontitis, as well as infections of the respiratory system, central nervous system and genital-urinary tract. Examples of clinically-significant Gram-positive obligate anaerobes are pathogenic species of the Bifidobacterium, Clostridium, Eubacterium, Finegoldia, Parvimonas, Peptoniphilus, Peptostreptococcus and Propionibacterium genera.
  • Examples of medically-important Gram-negative obligate anaerobes include pathogenic species of the Bacteroides, Fusobacterium, Porphyromonas, Prevotella and Veillonella genera. As with aerobic bacteria, the increasing occurrence of antibiotic resistance within the anaerobic bacteria is a serious global health concern.
  • C. difficile is a spore-forming obligate anaerobic Gram- positive bacterium of the genus Clostridium and is the major cause of hospital-acquired diarrhoea (N. Engl. J. Med. 370: 1 198-1208).
  • CDI causes mild-to-life-threatening infections such as diarrhoea (also referred to as C. difficile-associated diarrhoea, CDAD), severe pseudomembranous colitis, toxic megacolon, colonic perforations and sepsis.
  • CDI is an increasingly virulent disease and has emerged as a common and significant problem in community hospitals, surpassing MRSA as the leading cause of hospital-acquired infection (Inf. Control Hosp. Epidemiol. 34:387-390).
  • C. difficile was estimated to cause almost half a million infections in the United States in 201 1 and was recently classified by the CDC as an 'Urgent' threat to human health (Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention).
  • C. difficile is also a common pathogen in chili
  • C. difficile spores are resistant to antibiotic treatment, heat and alcohol-based disinfectants and can persist in the environment for long periods (J. Microbiol. Methods 87: 133-138). Therefore hospitalised patients are at an increased risk of acquiring C. difficile spores from contaminated surfaces, which germinate into vegetative forms, colonise the large intestine and produce toxins.
  • the clostridial enterotoxin toxin A (TcdA) and the cytotoxin toxin B (TcdB) constitute the main virulence factors and cause damage to the intestinal epithelial barrier and mucosal inflammation in the colonised individual, leading to intestinal fluid loss and diarrhoea (Trends Microbiol. 20:21-29).
  • a third toxin (binary toxin or CDT) has been associated with severe diseases and hyper-virulent strains such as BI/NAP1/027 and ribotype 078 isolates (Gut Microbes 5:6-18).
  • CDI also affects individuals with disturbances in the gut following oral antibiotic treatment, which alters the normal microbiota with long-lasting alterations to the structure of the human gastrointestinal tract microbiota thereby allowing C. difficile to colonise and cause disease (Gut Microbes 5:86-95).
  • Antibiotics commonly associated with CDI and antibiotic- associated diarrhoea (AAD) include the quinolones, clindamycin, cephalosporins, and penicillins (Future Microbiol. 3:563-578).
  • CDI can also occur without exposure to antimicrobials, particularly in individuals suffering from inflammatory bowel disease or in immunocompromised persons and is associated with significant mortality and morbidity especially among elderly patients, with renal insufficiency and transplants (Am. J. Geriatr. Pharmacother. 10: 14-24; J. Infect. Chemother. 21 :230-237).
  • Fidaxomicin which was recently approved for the treatment of C. difficile, also shows high recurrence rates of up to 24% for infections involving the hyper- virulent strains BI/NAP1/027 and up to 20% for CDAD (Clin. Infect. Dis. 55:S154-S161 ; J. Med. Chem. 58:5164-5185). Fidaxomicin shows a significant treatment failure in 12% of cases and resistance to this antibiotic has already been observed (Antimicrob. Agents Chemother. 55:5194-5199). Considering the rapid spread of hyper-virulent C. difficile strains, the high recurrence rates and therapeutic failure associated with the limited choice of antibiotic therapies, there is an urgent need for the development of antibiotics that can provide an effective treatment in a reliable manner.
  • Antibiotics of the quinolone class which target the bacterial type II topoisomerases DNA gyrase and topoisomerase IV, have generally shown poor-to-moderate in vitro antibacterial potency against anaerobic bacteria relative to other classes of antibiotics and compared with their potency against aerobic bacteria.
  • a study by Nord reported MICgo values of 8 and 16 ⁇ g/mL for ciprofloxacin versus sets of Bacteroides fragilis and Clostridium difficile clinical isolates, respectively (Clin. Infect. Dis. 23:S15-S18).
  • metronidazole gave M ICgo values of 1 and 0.25 ⁇ g/mL against the same strains.
  • PCT/GB2015/051 107 discloses a series of tricyclic antibacterial compounds as having antibacterial activity against a range of bacterial and mycobacterial _
  • pathogens including against resistant strains of Staphylococcus aureus and Escherichia coli.
  • compounds for use in treating obligate anaerobic bacterial infections e.g. those caused by C. difficile.
  • compounds for treating obligate anaerobic bacterial infections e.g. those caused by C. difficile
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection caused, at least in part, by acterium:
  • X 1 is independently selected from: N and CR 5 ;
  • X 2 is independently selected from: N and CR 2 ;
  • R 1 is independently selected from: H, F, NR 6 R 7 , NR 6 NR 6 R 7 and Ci-C 4 -alkyl;
  • R 2 is independently selected from: H and F;
  • R 5 is independently selected from: H, O-d-Cs-alkyl, halo, d-Cs-alkyl, d-Cs-alkenyl, d-Cs- alkynyl, Ci-Cs-haloalkyI, O-d-Cs-haloalkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, d-d- halocycloalkyl; or R 4 and R 5 together form an alkylene or heteroalkylene chain of the form - (CR 8 R 8 )rW 1 -(CR 8 R 8 )s-W 2 -(CR 8 R 8 )t- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 1 and W 2 are each independently selected from: a bond, O, S and NR 9 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of
  • R 6 , R 9 and R 13 are independently at each occurrence selected from: H, Ci-C 4 -alkyl, and Ci- C 4 -haloalkyl;
  • R 7 and R 14 are each independently at each occurrence selected from: H, Ci-C 4 -alkyl, Ci-C 4 - haloalkyl, S(0) 2 -Ci-C 4 -alkyl, C(0)-Ci-C 4 -alkyl, C(0)-0-Ci-C 4 -alkyl and CH 2 -phenyl;
  • R 8 is independently at each occurrence selected from: H, Me, CF3 and F;
  • R 11 where the nitrogen to which R 11 is attached has a formal double bond to one of its neighbouring atoms in the heteroaromatic ring, R 11 is absent; or, where the nitrogen to which R 11 is attached is attached via formal single bonds to both of its neighbouring atoms in the heteroaromatic ring, R 11 is independently selected from: H, Ci-C 4 -alkyl, and Ci-C 4 - haloalkyl;
  • R 12 may be independently at each occurrence selected from: H, halo, nitro, cyano, NR 13 R 14 , NR 13 S(0) 2 R 13 , NR 13 CONR 13 R 13 , NR 13 C0 2 R 13 , OR 13 ; SR 13 , SOR 13 , SO3R 13 , SO2R 13 , S0 2 NR 13 R 13 CO2R 13 C(0)R 13 , CONR 13 R 13 , Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 - haloalkyl, CR 13 R 13 OR 13 , CR 13 R 13 OC(0)R 13 and CR 13 R 13 NR 13 R 14 ; doctrine
  • n is an integer independently selected at each occurrence from 0, 1 , 2 and 3; and wherein each of the aforementioned aryl, heteroaryl, C3-Cio-heterocycloalkyl or C3-C10- cycloalkyl groups is monocyclic or bicyclic; and
  • R 1 , R 4 , R 6 , R 7 , R 9 and R 15 is an alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl (e.g.
  • a method of treating a bacterial infection caused, at least in part, by an obligate anaerobic bacterium comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a bacterial infection caused, at least in part, by an obligate anaerobic bacterium.
  • R 1 , R 2 , R 3 , R 4 , X 1 , A are as defined above for formula (I) and Z Z 2 and Z 3 , together with the carbon atoms to which Z 1 and Z 3 are attached form a 5-membered heteroaromatic ring as described above.
  • Z 1 and Z 3 may each be independently selected from O, S, S(O), NR 11 and CR 12 ;
  • R 1 , R 2 , R 3 , R 4 and R 5 and are as defined above for formula (I) and Z Z 2 and Z 3 are as defined above for formula (II). It may be that Z Z 2 and Z 3 are selected such that the 5- membered ring which comprises Z Z 2 and Z 3 is an imidazole, pyrazole, oxazole, thazole, isoxazole or thioxazole ring. It may be that Z Z 2 and Z 3 are selected such that the 5- membered ring which comprises Z Z 2 and Z 3 is an oxazole, thazole, isoxazole or thioxazole ring.
  • the remaining Z 1 , Z 2 or Z 3 is selected from O and S.
  • the compound of formula (I) is a compound of formula (VI):
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 12 are as defined above for formula (I) and wherein Z 1 is selected from NR 11 , S and O. It may be that Z 1 is selected from S and O. It may be that Z 1 is O.
  • the compound of formula (I) is a compound of formula (VII):
  • R 1 , R 3 , R 4 , R 12 , X 1 , X 2 and A are as defined above for formula (I) and wherein Z 1 is selected from NR 11 , S and O. It may be that Z 1 is selected from S and O.
  • the compound may be a compound of formula (Vila):
  • the compound of formula (I) is a compound of formula (VIII):
  • R 1 , R 3 , R 4 , X 1 and X 2 are as defined above for formula (I).
  • the compound of formula (I) has a structure according to any more of formulae IX) to (XXXXXVI):
  • R 1 , R 2 , R 3 , R 4 , R 11 , R 12 , W, X 1 , X 2 and A are as defined above for formula (I).
  • X 1 may be N.
  • X 1 may be CR 5 .
  • X 2 may be N.
  • X 2 is CR 2 .
  • A may be selected from O or S.
  • A is O.
  • R 1 is independently selected from: H , N R 6 R 7 , and Ci-C4-alkyl.
  • R 1 may be H .
  • R 1 may be N R 6 R 7 , e.g. N H R 7 .
  • R 1 may be Ci-C 4 -alkyl, e.g. methyl.
  • R 2 may be H .
  • R 2 may be F.
  • R 3 may be -(CR 8 R 8 ) n -3-io-heterocycloalkyl, e.g. 3-10-heterocycloalkyl.
  • R 3 will be an N-heterocycloalkyl group.
  • N-heterocycloalkyl groups may be monocyclic or bicyclic and comprise 1 to 3 nitrogen atoms in the heterocyclic ring system and R 3 may be attached to the rest of the molecule via a carbon or a nitrogen in the ring system. It may be that the N- heterocycloalkyl group is attached to the rest of the molecule via the or each nitrogen in the ring system.
  • N R 17 is independently selected from: H , Ci-C 4 alkyl.
  • R 17 is independently selected from: H , Ci-C 4 alkyl.
  • R 3 may be a monocyclic C3-C7-N-heterocycloalkyl group.
  • R 3 may be a piperazine ring.
  • R 3 may thus be a piperazine ring substituted with a methyl group, e.g. an N-methyl piperazine ring, a 3-methyl piperazine ring, or a 2-methyl piperazine ring.
  • R 3 may be an unsubstituted piperizine group. Any piperazine group will typically be attached to the rest of the molecule via one of the nitrogens in the ring system.
  • R 3 is an azetidine, pyrrolidine or piperidine ring, optionally wherein the ring nitrogen attaches the aziridine, pyrrolidine or piperidine ring to the rest of the compound.
  • R 3 may be an azetidine, pyrrolidine or piperidine ring wherein the ring nitrogen attaches the azetidine, pyrrolidine or piperidine ring to the rest of the compound and which is substituted with a single hydroxyl group.
  • R 3 may be a piperidine ring substituted with a single hydroxyl group, e.g. a 4- hydroxy-piperidine ring.
  • R 3 may be a pyrrolidine substituted with a single hydroxyl group, e.g. a 3-hydroxypyrrolidine.
  • R 3 is a 3-hydroxy azridine group.
  • R 3 may be a bicylic C7-C10-N- heterocycloalkyl group. Specific examples of R 3 groups include:
  • R 3 may be a bicyclic C7-Cio-N-heterocycloalkyl group.
  • the bicyclic N-heterocycloalkyl group may be attached to the rest of the molecule via either a carbon or a nitrogen in the ring system.
  • R 3 is wherein R 16 is R 15 ; or wherein two R 16 groups together with the carbon or carbons to which they are attached form a 3-6 membered cycloalkyl, a 3- 6 membered heterocycloalkyi ring or a 6-membered aryl or 5- or 6-membered heteroaryl ring. Where two R 16 groups form a heterocycloalkyi ring, that ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system.
  • m is an integer independently selected from 0, 1 , 2 and 3.
  • R 15 may be NR 6 R 7 .
  • Each R 6 and R 7 in R 15 may be H (e.g. R 15 may be NH 2 ).
  • Each R 6 and R 7 in R 15 may independently be Ci-C 4 alkyl, e.g. each R 6 and R 7 in R 15 may independently be methyl (e.g. R 15 may be NMe 2 ).
  • R 15 may be OR 6 .
  • R 6 may be H and thus, R 15 may be OH.
  • R 15 may be CR 6 R 6 NR 6 R 7 .
  • R 15 may be CMe 2 NR 6 R 7 .
  • R 15 may be CR 6 R 6 NH 2 .
  • R 15 may be CMe 2 NH 2 .
  • m may be 2.
  • Two R 16 groups may form a 3-6 membered heterocycloalkyl ring, e.g. a 6-membered heterocycloalkyl ring, e.g. a vicinally fused 6 membered heterocycloalkyl ring.
  • a specific example of a 6-membered heterocycloalkyl ring would be a morpholine ring.
  • the two R 16 groups may also form a 3-6 membered cycloalkyl ring, e.g. a 3-membered ring.
  • two R 16 groups may form a vicinally fused 3-membered ring or a spiro fused 3-membered ring. That 3-membered ring (e.g.
  • the 3-membered ring (e.g. that vicinally fused 3-membered ring) may be substituted with an NR 6 R 7 group, e.g. a NH 2 group.
  • R 16 groups In cases in which two R 16 groups form a 3 to 6-membered cycloalkyl or 3 to 6-membered heterocycloalkyl ring, there may be one or more other R 16 groups, e.g. m may be 4. Such additional R 16 groups will generally not form a 3 to 6-membered cycloalkyl or a 3 to 6- membered heterocycloalkyl ring and will thus be R 15 groups.
  • R 15 may be Ci-C 4 alkyl, e.g. methyl.
  • R 15 may be NR 6 R 7 , e.g. NH 2 .
  • R 3 groups include:
  • R 3 may be an aryl group, e.g. a phenyl group.
  • R 3 may be a phenyl group with at least one NR 6 R 7 , CONR 6 R 6 , CR 6 R 6 OR 6 or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl, e.g. a phenyl group with at least one NR 6 R 7 , CONR 6 R 6 , or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1 to 3 halo groups (e.g. fluoro groups).
  • halo groups e.g. fluoro groups
  • R 3 may be a phenyl group with at least one NR 6 R 7 or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1-3 groups independently selected from halo, Ci-C4-haloalkyl and Ci- C4-alkyl, e.g. a phenyl group with at least one NR 6 R 7 or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1-3 halo groups (e.g. fluoro groups).
  • R 3 may be a group selected from:
  • R 3 may also be a heteroaryl group.
  • R 3 may be a heteroaryl group comprising at least one nitrogen atom in the ring system.
  • R 3 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one NR 6 R 7 , CONR 6 R 6 , or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl.
  • R 3 may be a heteroaryl group comprising at least one nitrogen atom in the ring system and substituted with at least one NR 6 R 7 group.
  • R 3 groups include:
  • R 3 may be a 9-membered bicyclic heteroaryl group.
  • R 3 may be a 9-membered heteroaryl group comprising 1 , 2 or 3 (e.g. 1 or 2 nitrogen atoms in the ring system.
  • R 3 may be an
  • R 3 may b
  • R 3 may be a
  • benzimiazole e.g. R 3 may be may be a benzoxadiazole e.g.
  • R 3 may be indole, e.g. R 3 may be and It may be that R 3 is not a benzotriazole.
  • R 3 may comprise a pyridine ring fused to a 5 membered heteroaryl ring, e.g. a 5-membered heteroaryl ring comprising 1 or 2 nitrogen atoms in the ring.
  • further exemplary R 3 groups include
  • R 3 may be a 6-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system.
  • R 3 may be a group selected from pyridinyl, pyrimidine, pyrazine.
  • R 3 may be substituted with at least one N R 6 R 7 , CONR 6 R 6 , or CR 6 R 6 NR 6 R 7 group and optionally further substituted with from 1 to 3 groups independently selected from halo, Ci-C4-haloalkyl and Ci-C4-alkyl.
  • R 3 is a 6-membered monocyclic heteroaryl group, it may be substituted with at least one NR 6 R 7 group.
  • R 3 may be an amino-pyridinyl group (e.g. a 6-amino-pyridin-3-yl group) or an amino pyrimidine (e.g. 2-amino-pyrimidin-5-yl group).
  • R 3 may be a 5-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a thiazole or pyrazole.
  • R 3 is selected from phenyl, pyridinyl, pyrimidine, pyrazine and 9-membered heteroaryl group comprising 1 or 2 nitrogen atoms in the ring system.
  • R 3 is selected from phenyl or 6-membered heteroaryl (e.g. pyridine or pyrimidine) and has an NR 6 R 7 (e.g. an NH2) group situated para to the position at which the R 3 group is attached to the rest of the molecule.
  • phenyl or 6-membered heteroaryl e.g. pyridine or pyrimidine
  • NR 6 R 7 e.g. an NH2
  • R 4 may independently be selected from: Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, -(CR 8 R 8 ) n -C3-C 6 - cycloalkyl, -(CR 8 R 8 ) n -C 3 -C 6 -halocycloalkyl; -(CR 8 R 8 ) n -phenyl and -(CR 8 R 8 ) n -pyridyl. _
  • R 4 may independently selected from Ci-C6-alkyl, Ci-C6-haloalkyl, -(CR 8 R 8 ) n -C3- C6-cycloalkyl and -(CR 8 R 8 ) n -C3-C6-halocycloalkyl.
  • n is 0.
  • R 4 may be selected from Ci-C6-alkyl and -(CH2)n-C3-C6-cycloalkyl, wherein n is an integer selected from 0, 1 , 2 and 3.
  • R 4 may be selected from Ci-C 6 -haloalkyl and -(CR 8 R 8 ) n -C3-C 6 - halocycloalkyl, wherein n is an integer selected from 0, 1 , 2 and 3.
  • R 4 may be selected from Ci-C6-alkyl (e.g. C2-C4-alkyl) and C3-C6-cycloalkyl (e.g. C3-C4-cycloalkyl).
  • R 4 may be selected from C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
  • R 4 may be C3-C6- cycloalkyl.
  • R 4 is ethyl.
  • R 4 is cyclopropyl.
  • R 5 may be independently selected from: H, 0-Ci-C4-alkyl, halo, Ci-C4-alkyl, Ci-C4-haloalkyl and 0-Ci-C4-haloalkyl.
  • R 5 is independently selected from: 0-Ci-C4-alkyl, C1-C4- alkyl, Ci-C4-haloalkyl and 0-Ci-C4-haloalkyl.
  • R 5 may be H.
  • R 5 may be CI or F.
  • R 5 may be methyl.
  • R 5 may be OMe.
  • R 2 is F and R 5 is H. It may be that R 2 is H and R 5 is C1-C4 alkyl, (e.g. Me). It may be that R 2 is F and R 5 is CI.
  • R 4 and R 5 together form an alkylene or heteroalkylene chain of the form -(CR 8 R 8 ) r -W 1 -(CR 8 R 8 ) s -W 2 -(CR 8 R 8 ) t - and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively; wherein W 1 and W 2 are each independently selected from: a bond, O, S and NR 9 ; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W 1 and W 2 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms.
  • r, s, t, W 1 and W 2 are chosen such that the total length of the alkylene or heteroalkylene chain is 3 atoms. It may be that r is 0 and W 1 is O.
  • R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -W 1 -(CR 8 R 8 ) S -.
  • W 1 is attached to the rest of the molecule at the substitution point for R 5 and the CR 8 R 8 at the opposite end of the chain to W 1 is attached to the rest of the molecule at the substitution point for R 4 .
  • s is 2.
  • W 1 is O.
  • R 5 is independently selected from: CI, 0-Ci-C4-alkyl, Ci-C4-alkyl, C1-C4- haloalkyl and 0-Ci-C4-haloalkyl; or R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 8 R 8 )2- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively.
  • R 5 is Me and R 4 is cyclopropyl. It may be that n is always 0.
  • A is O; R 1 is independently selected from: H, NR 6 R 7 , and Ci-C4-alkyl; X 1 is CR 5 ; X 2 is CR 2 ; R 4 is independently selected from Ci-Ce-alkyl, Ci-Ce-haloalkyl, -(CR 8 R 8 ) n - C3-C6-cycloalkyl and -(CR 8 R 8 ) n -C3-C6-halocycloalkyl and R 5 is independently selected from: CI, 0-Ci-C 4 -alkyl, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl and 0-Ci-C 4 -haloalkyl; or R 4 and R 5 may together form an alkylene or heteroalkylene chain of the form -0-(CR 8 R 8 )2- and which is attached at its respective ends to the substitution point for R 4 and R 5 respectively. Furthermore, it may be that R 1 is H. It
  • Y 1 and Y 2 are both C.
  • Y 1 and Y 2 are not both N.
  • Z Z 2 and Z 3 are each independently selected from O, S, NR 11 and CR 12 .
  • Y 1 and Y 2 are each independently selected from C and N;
  • Z 1 , Z 2 and Z 3 are each independently selected from O, S, NR 11 and CR 12 ; with the proviso that the ring formed by Z 1 , Z 2 , Z 3 , Y 1 and Y 2 contains two endocyclic double bonds; and with the further proviso that at least one of Z ⁇ Z 2 , Z 3 , Y 1 and Y 2 is O, S, N or NR 11 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, tetrazole, pyrazole or pyrole ring. It may be that one of Y 1 and Y 2 is N and the other is C. Thus, it may be that Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form an imidazole, tetrazole, pyrazole or pyrole ring in which one of Y 1 and Y 2 is N. It may be that Y 1 is N. It may be that Y 2 is N. _
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a thiophene, furan, or pyrrole ring.
  • a single one of Z 1 , Z 2 and Z 3 is independently selected from O, S and NR 11 and the remaining two of Z 1 , Z 2 and Z 3 are each CR 12 .
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a pyrazole, oxazole, imidazole, thiazole, isoxazole or isothiazole ring.
  • a single one of Z Z 2 and Z3 is independently CR 12 and the remaining two of Z 1 , Z 2 and Z 3 are selected from O, S and
  • Z 1 , Z 2 , Z 3 , Y 1 and Y 2 together form a oxazole, thiazole, isoxazoleor isothiazole ring.
  • the remaining Z 1 , Z 2 or Z 3 is selected from O and S.
  • R 12 may be independently at each occurrence selected from: H, halo, nitro, cyano, S(0)R 13 , S(0) 2 OR 13 , S(0) 2 R 13 , S(0) 2 NR 13 R 14 C0 2 R 13 C(0)R 13 , CONR 13 R 13 , d-C 4 -alkyl, C 2 - C 4 -alkynyl, C 2 -C 4 -alkenyl, Ci-C 4 -haloalkyl, CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently at each occurrence selected from: halo, nitro, cyano, S(0)R 13 , S(0) 2 OR 13 , S(0) 2 R 13 , S(0) 2 NR 13 R 13 C0 2 R 13 , C(0)R 13 , CONR 13 R 13 , d-C 4 -alkyl, C 2 -C 4 -alkynyl, C 2 -C 4 - alkenyl, Ci-C 4 -haloalkyl, CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently at each occurrence selected from: H, halo, nitro, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci- C 4 -haloalkyl.
  • R 12 may be independently at each occurrence selected from: halo, nitro, Ci- C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently at each occurrence selected from: Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 - C 4 -alkynyl, Ci-C 4 -haloalkyl CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently at each occurrence selected from: H. Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 -haloalkyl Q R 13 R 13 0 R13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently at each occurrence selected from: H, Ci-C 4 -alkyl, CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be independently selected from CR 13 R 13 OR 13 and CR 13 R 13 NR 13 R 14 .
  • R 12 may be CR 13 R 13 NR 13 R 14 .
  • W is preferably O.
  • the compound of formula (I) may be any one of the final compounds formed in Examples 1 to 1 12 below.
  • the compound of formula (I) may be selected from:
  • the compound may be selected from:
  • R 1 , R 3 , R 4 , R 13 , X 1 and X 2 are as described above for formula (I); and Z 1 is independently selected from O and S.
  • R 13 is in at least one occurrence H. It may be that R 13 is in each occurrence
  • the invention may provide a compound of formula (XXXXXVM) for medical use.
  • the invention may provide a compound of formula (XXXXXVM) for use in treating a bacterial or mycobacterial infection.
  • the invention may provide a method of treating a bacterial or mycobacterial infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (XXXXXVM).
  • the bacterial infection may be caused by a Gram-positive bacterium (e.g. S. aureus).
  • the bacterial infection may be caused by a Gram-negative bacterium (e.g. N. gonorrhoeae).
  • the infection may be a mycobacterial infection (e.g. TB).
  • the infection may be caused by a bacterial or mycobacterial strain that is resistant to at least one known antibiotic.
  • a bacterial or mycobacterial strain that is resistant to at least one known antibiotic.
  • all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counter ion is optically active for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
  • tautomeric isomerism ('tautomerism') can occur.
  • This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted into the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 _
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • Aryl groups have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements.
  • Aryl groups satisfy the Huckel rule.
  • Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups. Equally, aryl groups may include non- aromatic carbocyclic portions.
  • a 5-membered heteroaromatic ring may be an aromatic ring with 1-4 (e.g.1-3) heteroatoms selected from O, S and N in the ring system, e.g. pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, triazole or tetrazole.
  • 1-4 e.g.1-3
  • heteroatoms selected from O, S and N in the ring system, e.g. pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, triazole or tetrazole.
  • the ring contains a nitrogen in the ring system
  • that nitrogen may be attached via a double bond to one of the neighbouring atoms, in which case the nitrogen will be unsubstituted or it may be attached via a single bond to both of the neighbouring atoms, in which case the nitrogen will be substituted with an R 9 group.
  • Heteroaryl groups may be 5- or 6-membered heteroaryl groups. Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 heteroatoms selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-2 nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 _
  • heteroaryl groups may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • the aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(0) 2 R a , NR a CONR a R a , NR a C0 2 R a , OR a ; SR a , SOR a , S0 3 R a , S0 2 R a , S0 2 NR a R a , C0 2 R a C(0)R a , CONR a R a , Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, Ci-C 4 haloalkyl and CR b R b NR a R a ; wherein R a is independently at each occurrence selected from H, Ci-C 4 -alkyl and Ci-C 4
  • the present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXXXVI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • the compounds of the present invention may be used in the treatment of a wide range of anaerobic bacterial infections.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of obligate anaerobic bacteria.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-positive obligate anaerobic bacteria.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of obligate anaerobic Gram-negative bacteria.
  • the bacterial infection may be caused by a bacterium selected from Bacteroides spp., Bifidobacterium spp., Clostridium spp., Eubacterium spp., Finegoldia spp., Fusobacterium spp., Parvimonas spp., Peptoniphilus spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp. and Veillonella spp.
  • a bacterium selected from Bacteroides spp., Bifidobacterium spp., Clostridium spp., Eubacterium spp., Finegoldia spp., Fusobacterium spp., Parvimonas spp., Peptoniphilus spp., Peptostreptococcus spp., Porphyromonas spp.,
  • the bacterial infection may be caused by a bacterium selected from Bacteroides spp., Bifidobacterium spp., Clostridium spp., Eubacterium spp., Fusobacterium spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp. and Veillonella spp.
  • the bacterial infection may be caused by a bacterium selected from Bacteroides spp., Clostridium spp., Finegoldia spp., Peptoniphilus spp., Peptostreptococcus spp., Prevotella spp.
  • the bacterial infection may be caused by a bacterium selected from: Bacteroides spp., Clostridium spp., Peptostreptococcus spp., Prevotella spp. and Propionibacterium spp.
  • the infection may be caused, at least in part by, Clostridium spp.
  • the bacterial infection may be caused, at least in part, by Clostridium difficile.
  • the compounds of the invention may be used to treat CDI and CDAD.
  • the compounds of the invention may be used to treat infections caused by bacteria that are in the form of a biofilm.
  • the term 'resistant' is intended to refer to strains of bacteria that have shown non- susceptibility to one or more known antibacterial drug.
  • a non-susceptible strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a higher number than for corresponding susceptible strains.
  • it may refer to strains that are non-susceptible to ⁇ -lactam antibiotics, strains that are non-susceptible to one or more fluoroquinolones and/or strains that are non-susceptible to one or more other antibiotics (i.e. antibiotics other than ⁇ -lactams and fluoroquinolones).
  • the term 'resistant' may refer to one in which the MIC of a given compound or class of compounds for that strain has shifted to a significantly higher number than for corresponding susceptible strains.
  • a bacterial strain might be said to be resistant to a given antibiotic when it is inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic failure.
  • the bacterial strain may be resistant to one or more fluoroquinolone antibiotics, e.g. one or more antibiotics selected from levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.
  • fluoroquinolone antibiotics e.g. one or more antibiotics selected from
  • the compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Also included are acid
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the compounds of the invention may be administered in combination with other active compounds (e.g. antifungal compounds, oncology compounds) and, in particular, with other antibacterial compounds.
  • active compounds e.g. antifungal compounds, oncology compounds
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • the compound of the invention and the other active e.g. the other antibacterial compound
  • Examples of other bacterial compounds which could be administered with the compounds of the invention are penems, carbapenems, fluoroquinolones, ⁇ -lactams, vancomycin, erythromycin or any other known antibiotic drug molecule.
  • penems carbapenems
  • fluoroquinolones e.g., ⁇ -lactams
  • vancomycin e.g., vancomycin
  • erythromycin erythromycin
  • the compounds of the invention can be administered with fluoroquinolone antibiotics, e.g. one or more antibiotics selected from: levofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, pefloxacin, moxifloxacin, ofloxacin, delafloxacin, zabofloxacin, avarofloxacin, finafloxacin.
  • fluoroquinolone antibiotics e.g. one or more antibiotics selected from:
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or by inhalation (i.e. in the form of an aerosol or by nebulisation).
  • oral administration in the form of tablets, capsules, syrups, powders, suspensions, solutions or granules
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories; or
  • a compound with an in vitro MIC of, for example, 16-64 ⁇ g/mL may still provide an effective treatment against certain bacterial infections.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for _
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.
  • DMSO dimethyl sulfoxide
  • dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
  • FBS Foetal Bovine Serum
  • THF tetrahydrofuran
  • W represents a halogen
  • Amine (1) can be converted into a-keto-amide (2) using chloral hydrate (e.g. in the presence of HCI and Na2S0 4 in water followed by NH2OH.HCI).
  • a-Keto-amide can subsequently alkylated with R 4 W, where W is a halogen in the presence of a base (e.g. K2CO3 optionally with heating) to form a-keto-amide (3).
  • a-Keto-amide (3) can alternatively be made from amine (4) via a reaction with oxalyl chloride (e.g. in DCM optionally with heating) followed by a ring closing Friedel-Crafts reaction (e.g. with AlC optionally at 0°C).
  • Key intermediate (5) can be obtained from amide (3) by reaction with H2O2 and aq NaOH (e.g. at room temperature).
  • Acid amine (5) can be converted into diamine (6) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 'BuOH and treating the product with TFA).
  • a condensation reaction e.g. using EtOH as a solvent optionally with heating
  • a-ester-aldehyde e.g. EtOaCCHO
  • Tetrazole formation can be effected by reaction with H2O2 and aq NaOH and then by POC in DCM (optionally at a temperature of from 0°C to 45°C) followed by azide displacement of the resultant halide (e.g. with NaN3 in acetonitrile optionally at room temperature).
  • tetrazole (8) can be converted into tetrazole (9) (a subset of compounds of formula (XXXXVIII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3- C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • the amide can be made for example by treatment with thionyl chloride and DMF in THF (optionally with heating) to form the acid chloride and subsequent reaction with ammonia gas (e.g. in THF at 0°C) and the dehydration can be achieved by treating the amide with P2O5 (optionally at room temperature initially and then heating to 75°C).
  • Carbamate formation e.g. using CIC(0)OEt with NaHC03 in 2-butanone
  • Cyclisation with formic hydrazide e.g.
  • Triazole (14) can be prepared from intermediate (7) by reaction with H2O2 and aq NaOH and then with POC in DCM (optionally at a temperature of from 0°C to 45°C) followed by hydrazine displacement of the resultant halide (e.g. in EtOH).
  • the resultant hydrazide product can be converted into triazole (14) by reaction with triethylorthoformate.
  • Triazole (14) can then be converted into 1 ,2,4-triazole (15) (a subset of compounds of formula (XXXXXIII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (5) can be acetylated (e.g. with AcCI, EtzN optionally in dioxane at room temperature).
  • Acid (16) can be converted into amine (17) via a Curtius rearrangement (e.g. using diphenylphosphorylazide in dioxane and heat followed by 'BuOH and treating the product with TFA).
  • Diazotisation reaction e.g. with HCI and NaNC>2 optionally in EtOH at 0- 5°C
  • reaction with ethyl-2-chloroacetoacetate e.g. in the presence of NaOAc
  • treatment of the product with NH3 (g) e.g. in THF
  • CIC(0)C02Et e.g.
  • Addition of ethyldiazoacetate (e.g. with Et2NH and EtOH) to intermediate (3) can provide alcohol (23) which, upon treatment with a Lewis acid and t-BuOH (e.g. BF3.0Et2 in acetonitrile and t-BuOH optionally at room temperature) can ring open to form alkyne (24).
  • a Lewis acid and t-BuOH e.g. BF3.0Et2 in acetonitrile and t-BuOH optionally at room temperature
  • 1 ,3-dipolar cycloaddition with benzyl azide (e.g. with heating in toluene) can provide triazole (25).
  • carbamate removal e.g. with TFA
  • heating triazole (25) can cyclise to form tricycle (26).
  • Tricycle (26) can then finally be converted into 1 ,2,3-triazole (27) (a subset of compounds of formula (XXXXXV)).
  • R 3 aryl or heteroaryl
  • this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • the triazole can be deprotected by removing the benzyl group (e.g. with Pd/C and H2 optionally in EtOH) to provide triazole (27).
  • Reaction of urea with intermediate (5) can provide bicycle (28).
  • Treatment with Lawesson's reagent e.g. in dioxane
  • subsequent methylation e.g. by heating with Mel in acetone
  • thiane e.g. by heating with Mel in acetone
  • Displacement of the SMe group with hydrazide e.g. by heating in EtOH
  • hydrazide (31) can produce hydrazide (31) which, upon reaction with triethylorthoformate (e.g. with TFA) can give triazole (32).
  • Triazole (32) can then be converted into 1 ,2,4-triazole (33) (a subset of compounds of formula (XXXXXI)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Intermediate (31) can be converted into tetrazole (34) (e.g. using NaNC>2 and HCI optionally in EtOH at 0-5°C). Tetrazole (34) can then be converted into tetrazole (35) (a subset of compounds of formula (XXXXIX)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Amine (40) can be obtained from intermediate (4).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Bromination e.g. using B3 ⁇ 4 in acetic acid and sodium acetate optionally at room temperature
  • an appropriate acylating agent e.g. the acid chloride, exemplary conditions being with EtzN optionally in THF with heating
  • a intramolecular cross- coupling reaction e.g. using CU2O, 4,7-dimethoxy-1 , 10-phenanthroline, CS2CO3, PEG, n- PrCN, ⁇
  • imidazole (43) a subset of compounds of formula (XXXII)).
  • Intermediate (6) can be converted into chloride (45) by treatment with oxalyl chloride (e.g. in DCM at room temperature) followed by treatment with POC (optionally with heat).
  • Chloride displacement with aminoacetaldehyde diethyl acetal can provide acetal (46), which in the presence of acid (e.g. tosic acid in isopropyl alcohol) can cyclise to form imidazole (47).
  • Imidazole (47) can then be converted into imidazole (48) (a subset of compounds of formula (XXXIII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • Intermediate (5) can be converted to enol (49) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl nitroacetate (e.g. heating with EtzN in THF).
  • Enol (49) can be converted into enamine (51) by chlorination (e.g. by heating with POC ), displacement of the resultant chlorine with a protected amine (e.g. 4-methoxybenzylamine optionally in DMF at room temperature) and then deprotecting the amine (in the case of 4- methoxybenzylamine this can be achieved using TFA, e.g. in DCM at room temperature).
  • Reduction of the nitro group e.g.
  • Intermediate (5) can be converted into bicycle (55) by reaction with phosgene (e.g. in THF at room temperature) followed by ethyl 2-(benzyloxy)acetate (e.g. by heating with EtsN in THF).
  • phosgene e.g. in THF at room temperature
  • ethyl 2-(benzyloxy)acetate e.g. by heating with EtsN in THF.
  • a similar chlorination, amination, deprotection sequence to that used in Scheme K above can generate amine (57).
  • the benzyl protecting group of amine (57) can be removed (e.g. using Pd/C and H2 in MeOH at room temperature) to provide aminoenol (58) which can be converted into the oxazole (59) by reaction with tnethylorthoformate (e.g. by heating with tnethylorthoformate).
  • Oxazole (59) can be converted into oxazole (60) (a subset of compounds of formula (XII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Certain com ounds of formula (XXXIV) can be made via Scheme M:
  • Reaction of intermediate (41) with an appropriate acylating agent e.g. 2H-pyrazole-3- carboxylic acid, exemplary conditions being to do so by heating with propylphosphonic anhydride and diisopropylamine in THF
  • an appropriate acylating agent e.g. 2H-pyrazole-3- carboxylic acid, exemplary conditions being to do so by heating with propylphosphonic anhydride and diisopropylamine in THF
  • amide (65) which can undergo an intramolecular cross-coupling reaction (e.g. using CU2O, 4,7-dimethoxy-1 , 10- phenanthroline, CS2CO3, PEG, n-PrCN, ⁇ ) to provide pyrazole (66) (a subset of compounds of formula (XXXI)).
  • Boc protection of amine (41) can provide carbamate (67).
  • a sequential palladium coupling of intermediate (41) to bis(pinacolato)diboron e.g. using Pd(dppf)Cl2 and KOAc in 1 ,4 dioxane at 80°C
  • Boc-protected 4-bromo-1 H-pyrazole-5-carboxylic acid methyl ester e.g. using Pd(dppf)Cl2 and CS2CO3 in a 10: 1 dioxane: H2O mixture at 70°C
  • Boc deprotection e.g. using TFA in DCM at room temperature
  • ester hydrolysis e.g. using aq. NaOH in EtOH
  • lactam formation e.g. by heating with propylphosphonic anhydride and diisopropylamine in THF
  • pyrazole (71) (a subset of compounds of formula (XXI)).
  • Intermediate (5) can be converted into ⁇ -ketoamide (72) by reaction with phosgene (e,g, in THF at room temperature) followed by ethyl 3-(benzyloxy)propanoate (e.g with heating in DMF following deprotonation of ethyl 3-(benzyloxy)propanoate with NaH).
  • ⁇ -Ketoamide (72) can be converted into ⁇ -ketoamide (73).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl
  • this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Removal of the benzyl protecting group e.g. using Pd/C and H2 optionally in MeOH at room temperature
  • oxidation e.g. using Dess-Martin Periodinane optionally in DCM at room temperature
  • aldehyde (75) Treatment of aldehyde (75) with hydrazine (e.g. as hydrazine hydrate in TH F in the presence of acetic acid) can provide pyrazole (76) (a subset of compounds of formula (XXX)).
  • Intermediate (5) can be converted into oxazole (77) by treating with triphosgene (e.g. in THF at room temperature) and reacting the product with ethyl isocyanate (e.g. by heating in the presence of EtzN in THF). Cyclisation (e.g. by heating with NaH in DMF) can provide oxazole (78) which can be converted into oxazole (79) (a subset of compounds of each of formulae (VI), (VII) and (VIII)).
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Intermediate (4) can be converted into iodide (83) (e.g. by treating with iodine and NaHCC>3 optionally in EtOAc at room temperature).
  • Acylation with an acid chloride (84) e.g. using ⁇ in THF at room temperature
  • amide (85) which, following an intramolecular Heck reaction (e.g. by heating amide (85) with Pd(PP i3) 4 and EtzN in acetonitrile) can give tricycle (86).
  • Tricycle (86) can be converted into tricycle (87) (e.g.
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3-C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Reaction of fluoride (92) with NHR 4 can provide amine (93) (e.g. by heating in DMSO).
  • Acylation of amine (93) with acyl chloride (94) e.g. using EtzN in THF at room temperature
  • amide (95) which upon deprotection (e.g. using TFA in DCM at room temperature) can give pyrrole (96).
  • An addition-elimination cyclisation reaction e.g. by heating pyrrole (96) with K2CO3 in DMSO
  • Tricycle (97) can be converted into tricycle (98) by reduction of the nitro group (e.g.
  • R 3 aryl or heteroaryl, this can be achieved by cross coupling with arylB(OH)2 or heteroarylB(OH)2 using standard Suzuki coupling conditions.
  • R 3 C3- C10 heterocycloalkyl, this can be achieved by nucleophilic displacement of W using standard conditions or by standard Buchwald coupling conditions.
  • Amide (36) can, for example, be converted to thioamide (37) by heating with P2S5 in pyridine.
  • Amide (36) can, for example, be converted to amidine (38) by heating with POCI3 and heating the product with the primary amine NH2R 6 .
  • Amide (36) can, for example, be converted to oxime (39) by heating with POCI3 and heating the product with the O-substituted hydroxylamine NH2OR 6 .
  • NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AVI 11 400 Nanobay using a 5 mm BBFQ with z-gradients (Method B).
  • MS was carried out on a Waters ZQ MS (Method A and B) or ACQ-SQD2#LCA081 (Method C) using H 2 0 and ACN (0.1-0.05% formic acid - high pH; 0.05% ammonia - low pH). Wavelengths were 254 and 210 nM.
  • Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) Waters 2767 Sample Manager (Method B) using H 2 0 and ACN (0.1-0.05% formic acid high pH; 0.05% ammonia - low pH).
  • reaction mixture was filtered through Celite and concentrated to dryness.
  • the mixture was then re-dissolved in MeOH and purified by flash chromatography using a gradient eluent system of 100% Petroleum ether (40-60) to 100% EtOAc.
  • the fractions containing the desired product were concentrated in vacuo and triturated with ice cold Et20 to give 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl- oxazolo[4,5-c]quinolin-4-one A as a yellow solid (41 mg, 17 %).
  • lodoethane (7.61 ml_, 94.65 mmol) was added dropwise to a solution of 6-bromo-7-methyl- indoline-2,3-dione (11.36 g, 47.32 mmol) and anhydrous K 2 C0 3 (7.85 g, 56.79 mmol) in dry DMF (20 ml_) and the reaction mixture was heated to 100 ° C. After 1 h the reaction mixture was then diluted with EtOAc (100 ml_) and H2O (100 ml_) and the phases separated.
  • Glacial acetic acid (1.0 mL, 17.47 mmol) and trifluoroacetic acid (1.0 mL, 13.07 mmol) added to N-(7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide mg, 0.29 mmol) in a microwave vial.
  • the solution was then irradiated with microwaves at 200°C for 20 min, allowed to cool and solvent removed under vacuo.
  • EtOAc (20 mL) and the solution washed with aq. NaHCC>3 (5 mL) followed by brine (5 mL).
  • the organic layer was then dried over Na2S0 4 , filtered and the solvent removed under vacuo.
  • aqueous layer was acidified with 1 M aqueous HCI (80 mL) and extracted with Et20 (3 ⁇ 100 mL). The organic layer was washed with brine (50 mL), dried over Na2S04, filtered and solvent was removed in vacuo to give 4-bromo-2,5-difluoro benzoic acid (2.3 g, 97 %) as an off-white solid, which was used without further purification.
  • Example 1 10 one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f).
  • Example 80 step (a) Prepared using tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and 7-chloro-5-cyclopropyl-8- fluoro-oxazolo[4,5-c][1 ,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 80 step (b), followed by deprotection of the BOC group using the method described in Example 49 step (j).
  • Example 80 step (a) Prepared using N,N-dimethylpyrrolidin-3-amine and 7-chloro-5-cyclopropyl-8-fluoro- oxazolo[4,5-c][1 ,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 80 step (b).
  • ethyl 2,4,5-trifluoro-3-methoxy-benzoate (11.3 g, 99 % yield) as a colourless oil, which was used without further purification.

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Abstract

La présente invention se rapporte à une série de composés de formule (I) pour utilisation dans le traitement d'infections provoquées par des bactéries anaérobies strictes, comprenant Clostridium difficile, et à des méthodes de traitement desdites infections par administration desdits composés. Ces composés peuvent être utilisés contre des souches de bactéries anaérobies strictes qui ont développé une résistance à l'égard d'autres antibiotiques. De nombreux composés utilisés dans la présente invention contiennent un système de noyau tricyclique.
PCT/GB2016/052896 2015-09-18 2016-09-16 Composés antibactériens et nouvelles utilisations de ceux-ci WO2017046603A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2575490A (en) * 2018-07-12 2020-01-15 Recordati Ind Chimica E Farmaceutica Spa P2X3 receptor antagonists

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118583A1 (fr) * 2004-05-28 2005-12-15 Millennium Pharmaceuticals, Inc. Inhibiteurs de chk-1
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
US20130079337A1 (en) * 2011-09-26 2013-03-28 Sanofi Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof
US20130338139A1 (en) * 2012-06-18 2013-12-19 Dart Neuroscience (Cayman) Ltd Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6h)-ones
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens
WO2016024096A1 (fr) * 2014-08-11 2016-02-18 Redx Pharma Plc Composés antibactériens

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118583A1 (fr) * 2004-05-28 2005-12-15 Millennium Pharmaceuticals, Inc. Inhibiteurs de chk-1
EP1972629A1 (fr) * 2007-03-23 2008-09-24 Mutabilis SA Nouveaux dérivés d'imidazolo-hétéroaryle ayant des propriétés antibacteriaux
US20130079337A1 (en) * 2011-09-26 2013-03-28 Sanofi Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof
US20130338139A1 (en) * 2012-06-18 2013-12-19 Dart Neuroscience (Cayman) Ltd Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6h)-ones
WO2015155549A1 (fr) * 2014-04-10 2015-10-15 Redx Pharma Plc Composés antibactériens
WO2016024096A1 (fr) * 2014-08-11 2016-02-18 Redx Pharma Plc Composés antibactériens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2575490A (en) * 2018-07-12 2020-01-15 Recordati Ind Chimica E Farmaceutica Spa P2X3 receptor antagonists

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