WO2016067009A1 - Composés présentant une activité contre les bactéries et les mycobactéries - Google Patents

Composés présentant une activité contre les bactéries et les mycobactéries Download PDF

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Publication number
WO2016067009A1
WO2016067009A1 PCT/GB2015/053212 GB2015053212W WO2016067009A1 WO 2016067009 A1 WO2016067009 A1 WO 2016067009A1 GB 2015053212 W GB2015053212 W GB 2015053212W WO 2016067009 A1 WO2016067009 A1 WO 2016067009A1
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compound
independently
alkyl
haloalkyl
aryl
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PCT/GB2015/053212
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English (en)
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Ian Cooper
Mark Pichowicz
Neil STOKES
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Redx Pharma Plc
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Priority claimed from GBGB1419175.3A external-priority patent/GB201419175D0/en
Priority claimed from GBGB1511642.9A external-priority patent/GB201511642D0/en
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2016067009A1 publication Critical patent/WO2016067009A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • 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
    • C07D498/22—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 four or more hetero rings

Definitions

  • This invention relates to antibacterial drug compounds containing a tricyclic ring system. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the compounds in treating bacterial and mycobacterial infections, and particularly tuberculosis (TB). The invention is also directed to antibacterial drug compounds that are capable of treating bacterial and mycobacterial infections that are currently hard to treat with existing drug compounds. Such infections are frequently referred to as being caused by resistant strains.
  • MRSA methicillin-resistant S. aureus, a Gram-positive bacterium
  • antibiotic-resistant Gram-negative strains such as either Escherichia coli NDM-1 (New Delhi Metallo ⁇ -lactamase-1) or Klebsiella pneumoniae NDM-1 , are also very difficult to treat. Often, only a very limited number of antibiotics such as vancomycin and colistin are effective against these strains.
  • a disease in which the development of resistance and multidrug resistance is of particular concern is TB.
  • TB A disease in which the development of resistance and multidrug resistance is of particular concern.
  • TB From the 17 th century to the early-20 th century TB was one of the most common causes of death, particularly amongst the urban poor.
  • Mycobacterium tuberculosis is usually caused by Mycobacterium tuberculosis.
  • Mycobacteria are aerobic bacteria and, as a result, tuberculosis infections most often develop in the lungs (pulmonary tuberculosis), although this is not always the case.
  • Mycobacteria lack an outer cell membrane and as such they are often classified as Gram-positive bacteria, although they are in many ways atypical. They have a unique cell wall that provides protection against harsh conditions (e.g. acidic, oxidative) but also provides natural protection against many antibiotics. Other antibiotics, such as ⁇ -lactams, are inactive against M. tuberculosis due to the intrinsic lack of activity of the compounds in the mycobacteria.
  • a drug molecule may have excellent activity against other bacterial strains but no activity against M. tuberculosis. Nevertheless, a number of antibiotics which are effective against TB have been developed. Examples include isoniazid, rifampicin, pyrazinamide and ethambutol and these are typically used in combination.
  • MDR-TB multidrug-resistant TB
  • MDR-TB often arises when a treatment for TB has been interrupted.
  • MDR-TB is the term typically used to refer to TB that has developed resistance to isoniazid and rifampicin.
  • MDR-TB can also be resistant to the fluoroquinolones and also to the so-called 'second-line' injectable anti-TB drugs, kanamycin, capreomycin and amikacin, with such resistances again commonly developing due to interruptions in treatment regimes. Where a strain of M.
  • tuberculosis is resistant to isoniazid and rifampicin as well as one fluoroquinolone and one of the injectable anti-TB drugs, it is known as extensively drug-resistant (XDR-TB).
  • XDR-TB extensively drug-resistant MDR- TB and XDR-TB are often found in those who have been previously treated for TB, but these forms of TB are just as infectious as wild-type TB and the incidence of MDR-TB and XDR-TB around the world is increasing.
  • infections arising from XDR-TB had at that time been identified in 84 different countries.
  • There have even been some reports of strains of M. tuberculosis that were resistant to all drugs tested against them (so-called 'totally drug-resistant tuberculosis', TDR-TB).
  • the 'second-line' anti-TB drugs and other antibiotics typically used to treat resistant infections can have unfavourable side-effects.
  • WO2012/125746 and WO2014/043272 disclose a range of tricyclic compounds with some antibacterial activity. No mention is made of the compounds having anti-mycobacterial activity.
  • M. tuberculosis is exposed to microaerophilic and anaerobic conditions within granulomatous lesions.
  • Granulomatous lesions contain various physiological states of M. tuberculosis including actively-replicating bacilli, non-replicating bacilli and dormant or latent cells in the hypoxic core of solid and caseous granulomas as well as in sputum.
  • M. avium infections are particularly prevalent amongst AIDS sufferers and other patient groups with compromised immune systems. Infection can occur in a variety of locations, including the pulmonary system, in which case the symptoms are similar to TB, or in the gastrointestinal tract, in which case severe diarrhoea can result. In children, M. avium can be the causative pathogen in cervical lymphadenitis. Mycobacterium abscessus is a rapidly-growing mycobacterium often found as a contaminant in water sources.
  • M. abscessus can also contaminate medications and other medical products, including medical devices.
  • the invention provides a compound of formula (I), or a pharmaceutically
  • X 1 , X 2 and X 3 are each independently selected from N and CR 1 ;
  • L 1 is independently selected from -CR 5 R 5 NR 6 - and -S(0) justify-;
  • R 1 is independently at each occurrence selected from: H, halo, nitro, cyano, NR 7 R 7 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C(0)R 8 , NR 8 C0 2 R 8 , OR 8 , O-aryl, SR 8 , S-aryl, SOR 8 , SO3R 8 , SO2R 8 , S0 2 NR 8 R 8 CO2R 8 , C(0)R 8 , CONR 8 R 8 , aryl, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and Ci-C 4 -haloalkyl;
  • R 2 , R 6 and R 8 are each independently at each occurrence selected from: H, Ci-C 4 -alkyl, and Ci-C 4 -haloalkyl;
  • R 3 is independently selected from (CR 5 R 5 ) m -aryl and (CR 5 R 5 ) m -heteroaryl;
  • R 4 is independently selected from: -(CR 5 R 5 ) m -3-io-heterocycloalkyl, -(CR 5 R 5 ) m -aryl, - (CR 5 R 5 )m-heteroaryl, -(CR 5 R 5 ) m -C 3 -Cio-cycloalkyl, O-aryl and O-heteroaryl;
  • R 7 is independently at each occurrence selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, S(0) 2 - Ci-C 4 -alkyl and C(0)-Ci-C 4 -alkyl; n is an integer independently selected from 1 and 2; m is an integer independently selected from 0, 1 and 2; wherein each of the aforementioned alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl (e.g.
  • the compound of formula (I) is a compound of formula (II), or a reof:
  • R 1 , R 2 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 are as defined above for formula (I) and wherein R 9 is independently selected from aryl and heteroaryl.
  • R 9 may be a group selected from thiazole, oxazole, isothiazole, or isoxazole. of formula (I) is a compound of formula (III):
  • R 1 , R 2 , R 4 , X 1 , X 2 and X 3 are as defined above for formula (I) and wherein R 9 is as defined above for formula (II).
  • R 9 may be a group selected from thiazole, oxazole, isothiazole, or isoxazole.
  • formula (I) is a compound of formula (IV):
  • R 5 is independently at each occurrence selected from H, F, Ci-C4-alkyl, Ci-C4-haloalkyl.
  • the compound of formula (I) is a compound of formula (VI):
  • R 1 is as defined above for formula (I) and wherein R 9 is independently selected from aryl and heteroaryl, R 5 is independently at each occurrence selected from H and C1-C4- alkyl; R 4 is a N-heterocycloalkyl group that is attached to the rest of the molecule via the nitrogen or, where there is more than one nitrogen in the ring, via one of the nitrogens in the ring system; and R 10 , R 11 and R 12 are each independently at each occurrence selected from: H, halo and Ci-C4-alkyl.
  • R 9 may be a group selected from thiazole, oxazole, isothiazole, or isoxazole.
  • I la (I) is a compound of formula (VII):
  • R 1 is as defined above for formula (I) and wherein R 9 is independently selected from aryl and heteroaryl, R 4 is a N-heterocycloalkyl group that is attached to the rest of the molecule via the nitrogen or, where there is more than one nitrogen in the ring, via one of the nitrogens in the ring system; and R 10 , R 11 and R 12 are each independently at each occurrence selected from: H, halo and Ci-C4-alkyl.
  • R 9 may be a group selected from thiazole, oxazole, isothiazole, or isoxazole.
  • X 1 , X 2 , X 3 , R 1 , R 2 , R 3 and R 4 are as described above for compounds of formula (I) and wherein L 2 is independently selected from O and S.
  • the invention may provide a method of treating a mycobacterial infection, the method comprising treating a subject in need thereof with a therapeutically effective amount of a compound of formula (VIII).
  • X 1 may be N. Alternatively, X 1 is CR ⁇ e.g. CR 10 . It may be that X 2 is N. Alternatively, it may be that X 2 is CR 1 , e.g. CR 11 . It may be that X 3 is N. Alternatively, it may be that X 3 is CR 1 , e.g. CR 12 .
  • R 10 , R 11 and R 12 are each independently at each occurrence selected from: H, halo, Ci-C 4 -haloalkyl and Ci-C 4 -alkyl. R 10 , R 11 and R 12 are each independently at each occurrence selected from: H, halo and Ci-C 4 -alkyl.
  • X 1 is CH
  • X 2 is CF
  • X 3 is CH
  • L 1 may be -CR 5 R 5 NR 6 -.
  • L 1 may be -CR 5 R 5 NH-.
  • R 5 may be, at each occurrence in -L 1 - , selected from H and Ci-C 4 -alkyl.
  • L 1 may be -CH2NR 6 -. In some preferred embodiments,
  • L 1 may be -S(0) n -.
  • L 1 is -SO2-.
  • L 2 may be S.
  • L 2 may be O.
  • R 1 may be H.
  • R 1 may be selected from: halo, nitro, cyano, NR 7 R 7 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C(0)R 8 , NR 8 C0 2 R 8 , OR 8 , SR 8 , SOR 8 , SO3R 8 , SO2R 8 , S0 2 NR 8 R 8 , C0 2 R 8 , C(0)R 8 , CONR 8 R 8 , aryl, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and Ci- C 4 -haloalkyl.
  • R 1 may be selected from: halo, NR 7 R 7 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C(0)R 8 , NR 8 C0 2 R 8 , OR 8 , O-aryl, SR 8 and S-aryl.
  • R 1 may be selected from NR 7 R 7 , NR 8 S(0) 2 R 8 , NR 8 CONR 8 R 8 , NR 8 C(0)R 8 and NR 8 C0 2 R 8 .
  • R 1 may be selected from halo, NR 8 R 8 , OR 8 , O-aryl, SR 8 and S-aryl.
  • R 1 is NR 7 R 7 , e.g. NR 8 R 8 .
  • R 1 is NHR 7 , e.g. NHR 8 .
  • R 1 is NH-Ci-C 4 -alkyl, e.g. NHMe.
  • R 2 is preferably H.
  • R 3 may be (CR 5 R 5 )-R 9 , wherein R 9 is independently selected from aryl (e.g. phenyl) and heteroaryl.
  • R 3 is (CR 5 R 5 )-R 9 and R 5 is independently at each occurrence selected from H, F, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl.
  • R 5 is at each occurrence H.
  • R 3 may be -(CR 5 R 5 ) m -aryl, e.g. (CR 5 R 5 ) m -phenyl. m may be 1. It may be that m is 1 and R 5 is independently at each occurrence selected from H, F, Ci-C 4 -alkyl, Ci-C 4 -haloalkyl. In some preferred embodiments, R 3 is substituted or unsubstituted CH 2 -phenyl, e.g. unsubstituted CH 2 -phenyl.
  • R 3 comprises a heteroaryl group
  • that heteroaryl group may be a monocyclic 5- or 6- membered heteroaryl group.
  • the heteroaryl group is a 5-membered heteroaryl group in which the heteroaromatic ring includes 1-4 heteroatoms selected from O, S and N.
  • the heteroaryl group is a 5-membered heteroaryl group in which the heteroaromatic ring includes a single nitrogen and a single heteroatom selected from O and S.
  • a preferred 5-membered heteroaryl group would be an oxazole.
  • heteroaryl group is a thiazole.
  • the heteroaryl group is a 6-membered heteroaryl group in which the heteroaromatic ring includes 1 -2 nitrogen atoms.
  • An exemplary 6- membered heteroaryl group would be a pyridine.
  • the heteroaryl group may be a bicyclic heteroaromatic group.
  • Heteroaryl groups may be substituted or unsubstituted. In some embodiments, they are unsubstituted. 3 may be selected from:
  • R 4 may be -(CR 5 R 5 ) m -3-io-heterocycloalkyl, e.g. 3-10-heterocycloalkyl.
  • R 4 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 4 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 nitrogen or, where there is more than one nitrogen in the ring, via one of the nitrogens in the ring system.
  • any nitrogen in the ring system that is not at a bridgehead or is not the point of attachment of R 4 to the rest of the molecule will be an NR 8 group.
  • R 4 may be a monocyclic 3-7-N-heterocycloalkyl group.
  • R 4 may be a piperazine ring.
  • R 4 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 4 may be an unsubstituted piperazine group. Any piperazine group will typically be attached to the rest of the molecule via one of the nitrogens in the ring system.
  • R 4 is an azetidine, pyrrolidine or piperidine ring, optionally wherein the ring nitrogen attaches the azetidine, pyrrolidine or piperidine ring to the rest of the compound.
  • R 4 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 that is substituted with a single hydroxyl group.
  • R 4 may be a piperidine ring substituted with a single hydroxyl group, e.g. a 4- hydroxy-piperidine ring.
  • R 4 may be a pyrrolidine substituted with a single hydroxyl group, e.g. a 3-hydroxypyrrolidine.
  • R 4 is a 3-hydroxy azetidine group.
  • R 4 groups include:
  • R 4 may be a bicyclic 7-10-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 13 groups form a heterocycloalkyi ring
  • that ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system.
  • two R 13 groups form a cycloalkyi or heterocycloalkyi ring
  • p is an integer independently selected from 0, 1 , 2, 3 and 4.
  • tw 13 groups do not form a cycloalkyi or heterocycloalkyi ring.
  • R 4 may be .
  • R 13 may be NR a R a .
  • Each R a in R 13 may be H (i.e. R 13 may be NH 2 ).
  • Each R a in R 13 may independently be C 1 -C 4 alkyl, e.g. each R a in R 13 may independently be methyl (i.e. R 13 may be NMe 2 ).
  • R 13 may be OR a .
  • R a may be H and thus, R 13 may be OH.
  • R 13 may be CR b R b NR a R a .
  • Each R b in R 13 may independently be Ci-C 4 -alkyl, e.g. each R b in R 13 may independently be methyl (e.g. R 13 may be CMe 2 NR a R a ).
  • Each R a in R 13 may be H (e.g. R 13 may be CR b R b NH 2 ).
  • R 13 may be CMe 2 NH 2 .
  • p may be 2.
  • Two R 13 groups may form a 3-6- membered heterocycloalkyi ring, e.g. a 6-membered heterocycloalkyi ring, e.g. a vicinally fused 6 membered heterocycloalkyi ring.
  • a specific example of a 6-membered heterocycloalkyl ring would be a morpholine ring.
  • the two R 13 groups may also form a 3-6 membered cycloalkyl ring, e.g. a 3-membered ring.
  • two R 13 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
  • R 13 may be Ci-C 4 -alkyl, e.g. methyl.
  • R 13 may be NR a R a , e.g. NH 2 .
  • R 4 groups include:
  • R 4 may be an aryl group, e.g. a phenyl group.
  • R 4 may be a phenyl group with at least one NR a R a , CONR a R a or CR b R b NR a R a 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 a R a , CONR a R a or CR b R b NR a R a group and optionally further substituted with from 1-3 halo groups (e.g. fluoro groups).
  • 1-3 halo groups e.g. fluoro groups
  • R 4 may be a phenyl group with at least one NR a R a or CR b R b NR a R a 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 a R a or CR b R b NR a R a group and optionally further substituted with from 1-3 halo groups (e.g. fluoro groups).
  • a group with at least one NR a R a or CR b R b NR a R a group and optionally further substituted with from 1-3 halo groups (e.g. fluoro groups).
  • embodime 4 may be a group with at least one NR a R a or CR b R b NR a R a group and optionally further substituted with from 1- 3 groups independently selected from halo, Ci-C4
  • R 4 may also be a heteroaryl group.
  • R 4 may be a heteroaryl group comprising at least one nitrogen atom in the ring structure.
  • R 4 may be a 9-membered bicyclic heteroaryl group comprisi gen atoms in the ring system, e.g. an indazole group, e.g. R 4
  • R 4 may be a 6-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a pyridinyl group, e.g.
  • R 4 may be a 5-membered monocyclic heteroaryl group comprising from 1 to 2 nitrogen atoms in the ring system, e.g. a thiazole.
  • R 6 may be Ci-C4-alkyl. Preferably, however, R 6 is H.
  • R 7 may be R 8 .
  • R 7 may independently at each occurrence be selected from: H, Ci-C4-alkyl, and Ci-C4-haloalkyl.
  • R 7 is preferably selected from H and Ci-C4-alkyl.
  • R 8 may be Ci-C4-alkyl.
  • R 8 may be H.
  • R 9 may be a monocyclic 5- or 6-membered heteroaryl group.
  • the heteroaryl group is a 5-membered heteroaryl group in which the heteroaromatic ring includes 1-4 heteroatoms selected from O, S and N.
  • the heteroaryl group is a 5- membered heteroaryl group in which the heteroaromatic ring includes a single nitrogen and a single heteroatom selected from O and S.
  • a preferred 5-membered heteroaryl group would be an oxazole.
  • An alternative preferred heteroaryl group is a thiazole.
  • R 9 may be a 6-membered heteroaryl group in which the heteroaromatic ring includes 1-2 nitrogen atoms.
  • An exemplary 6-membered heteroaryl group would be a pyridine.
  • R 9 may be a bicyclic heteroaromatic group.
  • R 9 may be a group selected from thiazole, oxazole, isothiazole, or isoxazole. It may be that R 9 is a group selected from thiazole or oxazole.
  • R 9 may be substituted or unsubstituted. In some embodiments, R 9 is unsubstituted.
  • R 9 may be substituted with a Ci-C4-alkyl group.
  • R 9 may be aryl, e.g. phenyl.
  • the aryl group e.g. phenyl group, may be substituted or unsubstituted. In some preferred embodiments, aryl groups, e.g. phenyl groups, are unsubstituted.
  • R 4 has at least one NR a R a or CR b R b NR a R a substituent. It may be that R 4 has a single NR a R a or CR b R b NR a R a substituent. It may be that R 4 has at least one NR a R a substituent. It may be that R 4 has a single NR a R a substituent. In these embodiments, R 4 may have other substituent groups, e.g. from 0 to 2 groups selected from oxo, Ci-C4-alkyl and F.
  • R 10 may be selected from H and Ci-C4-alkyl.
  • R 10 is H.
  • R 11 may be selected from F and Ci-C4-fluoroalkyl.
  • R 11 is F.
  • R 12 may be selected from H and Ci-C4-alkyl.
  • R 12 is H.
  • the compound of formula (I) has a structure selected from:
  • the compound of formula (I) has a structure selected
  • 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 that 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 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • 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).
  • C m -C n refers to a group with m to n carbon atoms.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • Ci-C6-alkyl may refer to methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, te/f-butyl, n-pentyl and n- hexyl.
  • the alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, OR a or NHR a .
  • haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • Ci-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1- chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • a halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom.
  • alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • C2-C6-alkenyl may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, OR a or NHR a .
  • alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • C2-C6-alkynyl may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, OR a or NHR a .
  • cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms.
  • C3-C6-cycloalkyl may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, OR a or NHR a .
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "aryl” may be phenyl and naphthyl.
  • the aryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each aryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • heteroaryl may refer to any aromatic (i.e. a ring system containing (4n + 2) ⁇ - electrons or n- electrons in the ⁇ -system) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N).
  • any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms.
  • heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.
  • Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones.
  • the heteroaryl system itself may be substituted with other groups.
  • the heteroaryl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each heteroaryl group independently may be Ci-C4-alkyl, Ci-C4-haloalkyl, cyano, halogen, OR a or NHR a .
  • Vnheterocycloalkyl may refer to a m-n membered monocyclic or bicyclic saturated or partially saturated groups comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N).
  • partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 8 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom.
  • An N-heterocycloalkyl group is a heterocycloalkyl group comprising at least one N in the ring system.
  • heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine.
  • Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms.
  • the heterocycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, OR a or NHR a .
  • the compound of the invention may be an N-oxide. Where the compound of the invention is an N-oxide, it will typically be a pyridine N-oxide, i.e. where the compound of the invention comprises a pyridine ring, the nitrogen of that pyridine may be N + -0 ⁇ Alternatively, it may be that the compound of the invention is not an N-oxide.
  • a carbocyclic group consists of one or more rings that are entirely formed from carbon atoms.
  • a carbocylic group can be a mono- or bicyclic cycloalkyl group, or it can comprise at least one phenyl ring.
  • a heterocyclic group consists of one or more rings wherein the ring system includes at least one heteroatom.
  • a heterocyclic group comprises at least one heteroaryl or heterocyclic rings.
  • a heterocyclic ring is a saturated ring comprising at least one heteroatom selected from O, S and N.
  • a ring system is described as being an x-membered bicyclic group, that is intended to mean that the skeleton of the bicyclic ring system is formed from x atoms (i.e. the total number of atoms across the two rings of the bicycle is x).
  • Aryl and heteroaryl groups are optionally substituted with 1 to 5 substituents that 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 , NR a C(0)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
  • R b may be selected from H, Ci-C 4 -alkyl and Ci-C 4 -haloalkyl.
  • the present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (VIII) 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.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • 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.
  • Each of the compounds of the present invention may be used as a medicament.
  • a compound as defined above for the treatment of bacterial or mycobacterial infections there is provided a compound as defined above for the treatment of bacterial or mycobacterial infections.
  • the compounds and formulations of the present invention may be used in the treatment of a wide range of bacterial or mycobacterial infections.
  • the compounds can be used to treat bacterial infections caused by one or more resistant strains of bacteria. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-positive bacteria. In a further embodiment, the compounds can be used to treat bacterial infections caused by one or more resistant strains of Gram-negative bacteria.
  • the compounds and formulations of the invention may be used to treat infections caused by bacteria that are in the form of a biofilm.
  • resistant strains is intended to mean strains of bacteria or mycobacteria that have shown resistance to one or more known antibacterial or antimycobacterial drugs. For example, it may refer to bacterial strains that are resistant to methicillin, strains that are resistant to one or more other ⁇ -lactam antibiotics, strains that are resistant to one or more fluoroquinolones and/or strains that are resistant to one or more other antibiotics (i.e. antibiotics other than ⁇ -lactams and fluoroquinolones).
  • a resistant strain is one in which the MIC (minimum inhibitory concentration) of a given compound or class of compounds for that strain has shifted to a significantly higher number than for the parent (susceptible) strain.
  • 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.
  • one or more antibiotics selected from levofloxacin, enoxacin,
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-positive bacteria.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-positive bacteria that are resistant to one or more fluoroquinolone antibiotics.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria.
  • the compounds of the invention may be particularly effective at treating infections caused by Gram-negative bacteria that are resistant to one or more fluoroquinolone antibiotics.
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by bacterial strains associated with biowarfare. These may be strains that are Category A pathogens as identified by the US government (e.g. those that cause anthrax, plague, etc.) and/or they may be strains that are Category B pathogens as identified by the US government (e.g. those that cause Glanders disease, mellioidosis, etc).
  • the compounds and formulations of the present invention can be used to treat or to prevent infections caused by Gram-positive bacterial strains associated with biowarfare (e.g. anthrax). More particularly, the compounds and formulations may be used to treat Category A and/or Category B pathogens as defined by the US government on 1 st January 2014.
  • the compounds of the invention can be used to treat or prevent mycobacterial infections, e.g. mycobacterial infections caused by resistant strains of mycobacteria. Thus, for example, they can be used to treat TB or leprosy. Thus, it may be that the mycobacterial infection is caused by M. tuberculosis. It may also be that the mycobacterial infection is caused by a mycobacterium selected from: M. avium complex, M. abscessus, M. leprae, M. bovis, M. kansasii, M. chelonae, M. africanum, M. canetti and M. microti. The compounds may be used to treat resistant forms of TB, e.g. MDR-TB (i.e.
  • TB infections caused by strains that are resistant to isoniazid and rifampicin TB infections caused by strains that are resistant to isoniazid and rifampicin
  • XDR-TB i.e. TB infections caused by strains that are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin
  • TDR-TB i.e. TB infections caused by strains that have proved resistant to every drug tested against it with the exception of a compound of the invention.
  • the TB may be caused by a mycobacterial strain that is resistant to at least one approved antimycobacterial compound.
  • the at least one approved antimycobacterial compound may be selected from: rifampicin, isoniazid, kanamycin, capreomycin, amikacin and a fluoroquinolone.
  • the at least one approved antimycobacterial compound may be selected from: rifampicin, moxifloxacin, isoniazid, ciprofloxacin and levofloxacin.
  • the compounds of the invention may be used to treat non-replicating TB.
  • the compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic infections and/or viral infections.
  • 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.
  • the compounds of the invention may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt.
  • 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.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. Also included are 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.
  • 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 that could be administered with the compounds of the invention are fluoroquinolones, ⁇ -lactams, vancomycin, erythromycin or any other known antibiotic drug molecule.
  • antimycobacterial compounds examples include isoniazid, rifampicin, pyrazinamide, ethambutol, fluoroquinolones, kanamycin, capreomycin, amikacin or any other known antimycobacterial drug molecule.
  • the pharmaceutical composition that 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, 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).
  • high-dosages of the compounds of the invention can be administered.
  • 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 that may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution 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 tablets.
  • 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 the 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.
  • the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the formulation may further comprise one or more other antibiotics, e.g. one or more fluoroquinolone antibiotics.
  • fluoroquinolone antibiotics include 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
  • a method of treating a bacterial or mycobacterial infection comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.
  • the subject may be a human or an animal.
  • the compounds of the present invention can be used in the treatment of the human body.
  • the compounds of the invention may be for use in treating human bacterial or mycobacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin, the throat, soft tissue, bone and joints (including infections caused by Staphylococcus aureus).
  • the compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, infections caused by Escherichia coli, prophylaxis before dental surgery, cellulitis, acne, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, abdominal infection, bacteraemia, septicaemia, leprosy, sexually-transmitted bacterial infection (e.g.
  • the compounds of the present invention may also be used in treating other conditions treatable by eliminating or reducing a bacterial infection. In this case they will act in a secondary manner alongside, for example, a chemotherapeutic agent used in the treatment of cancer.
  • a compound for use in the preparation of a medicament may be for use in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • a compound of the invention for medical use.
  • the compound may be used in the treatment of any of the diseases, infections and indications mentioned in this specification.
  • the compounds of the present invention may be used in the treatment of the animal body.
  • the compounds of the present invention can be used to treat commercial animals such as livestock.
  • the livestock may be mammal (excluding humans), e.g. cows, pigs, goats, sheep, llamas, alpacas, camels and rabbits.
  • the livestock may be birds (e.g. chickens, turkeys, ducks, geese, etc.).
  • the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.
  • the veterinary use may be to treat wild populations of animals in order to prevent the spread of disease to humans or to commercial animals.
  • the animals may be rats, badgers, deer, foxes, wolves, mice, kangaroos and monkeys and other apes.
  • a compound of the invention for veterinary use.
  • the compound may be used in the treatment of any of the animal diseases and infections and indications mentioned in this specification.
  • the present invention provides a veterinary formulation comprising a compound of the invention and a veterinarily acceptable excipient.
  • the methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly, intravenously or into an udder), or as an implant.
  • Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
  • the formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal.
  • typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
  • the veterinary practitioner, or the skilled person will be able to determine the actual dosage that will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds when treating animals the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
  • 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.
  • RaNi Raney NickelTM (a nickel sponge)
  • Certain compounds of the invention can be made according to the following general schemes. Certain compounds of the invention can be made according to or analogously to the methods described in Examples 1 to 4.
  • Tricycle (1) wherein Gi and G2 are leaving groups independently selected from CI, Br, F, S02CH2aryl and tosylate, can be treated with amine (2) (where the R groups can be taken together with the nitrogen of attachment to form a C3-C10 heterocycle optionally substituted with R13) in the presence of a base, such as K2CO3, in a solvent, such as EtOH, at a temperature of 75°C to 100°C to provide tricyclic amine (3).
  • Nitrile (4) can be formed from (3) via a second displacement reaction with an alkali metal cyanide, such as NaCN or KCN, in a solvent, such as DMF, at a temperature of 70°C to 120°C. Nitrile (4) can be converted to amine (5).
  • the reaction can be carried out with a reducing agent, such as RaNi in the presence of H2, in a solvent, such as EtOH, at room temperature.
  • Amine (5) can be converted to amide (7) (a subset of compounds of formula II) through coupling with acid (6).
  • the reaction can be performed with a peptide coupling agent, such as N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in the presence of a base, such as ⁇ , in a solvent, such as DCM, at a temperature of 0°C to room temperature.
  • amide (7) can be formed from treatment with the acid chloride of (6).
  • the reaction can be carried in a solvent, such as diisopropyl ether, in the presence of a base, such as ⁇ , at a temperature from room temperature to 70°C.
  • a base such as ⁇
  • the acid chloride of (6) can be formed from its acid via treatment with oxalyl choride or SO2CI2, in a solvent, such as DCM, at room temperature.
  • Ri or R13 is an amine
  • this may be protected throughout the synthetic sequence with either a carbobenzyloxy (Cbz) or BOC.
  • Cbz carbobenzyloxy
  • Removal of the Cbz group to release the free amine can be effected using Pd/C and H2 in an alcoholic solvent, such as EtOH, at room temperature.
  • Removal of the BOC group to release the free amine can be effected by treatment with TFA in DCM at room temperature or hydrogen chloride in dioxane at room temperature.
  • NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AVIII 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) or 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, washed with MeOH (10 ml_) and concentrated in vacuo to furnish tert-butyl N-[2-(aminomethyl)-4-(3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ pyrrolidin-1-yl)-6-fluoro-9H-pyrimido[4,5-b]indol-8-yl]-N- methylcarbamate 1c (18 mg, 35%) as a pale brown solid, which was used without any further purification.
  • reaction mixture was poured into 1 M HCI (20 mL) and extracted with DCM (2 ⁇ 10 mL). The combined organics were washed with H2O (10 mL), 2M NaOH (10 mL), H2O (10 mL), brine (10 mL), dried (MgSCU) and concentrated under reduced pressure to give a yellow oil (35 mg).
  • the crude product was purified by chromatography using petroleum ether 40- 60/EtOAc gradient 70:30 to 30:70, to furnish tert-butyl N-[4-(3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ pyrrolidin-1-yl)-6-fluoro-2-[(1 ,3-oxazol-5-ylformamido)methyl]-9H- pyrimido[4,5-b]indol-8-yl]-N-methylcarbamate 1d (13 mg, 37%) as a pale yellow solid.
  • dihydrochloride B was prepared as a pale yellow solid.
  • Example 1 step (e) Using the method described in Example 1 step (e) and N-[4-(3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ pyrrolidin-1-yl)-6-fluoro-2-[(pyridine-2-ylformamido)methyl]-9H- pyrimido[4,5-b]indol-8-yl]-N-methylcarbamate 3a, N- ⁇ [4-(3-aminopyrrolidin-1-yl)-6-fluoro-8- (methylamino)-9H-pyrimido[4,5-b]indol-2-yl]methyl ⁇ pyridine-2-carboxamide dihydrochloride C was prepared as an orange-brown solid.
  • Example 1 step (e) Using the method described in Example 1 step (e) and tert-butyl N-[4-(3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ pyrrolidin-1-yl)-6-fluoro-2-phenylmethanesulphonyl-9H-pyrimido[4,5- b]indol-8-yl]-N-methylcarbamate 1a (prepared as described in Example 1 step (a)), 1-[6- fluoro-8-(methylamino)-2-phenylmethanesulphonyl-9H-pyrimido[4,5-b]indol-4-yl]pyrrolidin-3- amine D was prepared as a yellow solid.
  • MICs Minimum Inhibitory Concentrations versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition. CLSI document M07-A9, 2012) and by the agar dilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes, Approved Standard-Second Edition. CLSI document M24-A2, 201 1).
  • the broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of typically 0.004-128 ⁇ g/mL and a maximum final concentration of 1 % DMSO.
  • the agar dilution method involves a two-fold serial dilution of compounds in 24-well microtitre plates, giving a final concentration range of typically 0.004- 32 ⁇ / ⁇ . and a maximum final concentration of 1 % DMSO.
  • the bacterial strains tested include Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Mycobacterium smegmatis ATCC 19420 and Mycobacterium tuberculosis ATCC 25177 (H37Ra). Strains are grown in cation-adjusted Muller-Hinton broth (supplemented with 2% w/v NaCI in the case of methicillin-resistant S. aureus strains), on Muller-Hinton agar at 37°C in an ambient atmosphere for 16-20 h or on Middlebrook 7H9 broth with ADC enrichment and Middlebrook 7H 11 agar with OADC enrichment at 37°C, 5% C0 2 for up to four weeks.
  • the MIC is determined as the lowest concentration of compound that inhibits growth following a 16-20 h incubation period for S. aureus and E. coli, following a 72 h incubation for M. smegmatis and following a 3-4 weeks incubation for M. tuberculosis H37Ra.
  • the antibacterial activity of compounds against M. tuberculosis H37Rv grown under aerobic conditions was assessed by measuring bacterial growth after five days in the presence of compounds.
  • Compounds were prepared as 20-point two-fold serial dilutions in DMSO and diluted into 7H9-Tw-OADC medium in 96-well plates with a final DMSO concentration of 2 %. The highest concentration of compound was 200 ⁇ where compounds were soluble in DMSO at 10 mM.
  • Bacterial growth was measured by OD590 nm and fluorescence (Ex 560/Em 590) using a BioTekTM Synergy 4 plate reader.
  • the dose- response curve was plotted as percentage growth and fitted to the Gompertz model using GraphPad Prism 5.
  • the MIC was defined as the minimum concentration at which growth was completely inhibited and was calculated from the inflection point of the fitted curve to the lower asymptote (zero growth).
  • the strains tested include: M. tuberculosis H37Rv; two isoniazid-resistant strains, INH-R1 (a KatG Y155 truncation mutant derived from H37Rv) and INH-R2 (strain ATCC 35822); two rifampicin-resistant strains, RIF-R1 (a RpoB S522L mutant derived from H37Rv) and RIF-R2 (strain ATCC 35828); and a fluoroquinolone-resistant strain, FQ-R1 , derived from H37Rv (GyrB D94N mutant).
  • Antibacterial activity under low oxygen conditions The antibacterial activity of compounds against M. tuberculosis H37Rv grown under hypoxic conditions was assessed using the low oxygen recovery assay (LORA). Bacteria were first adapted to low oxygen conditions and then exposed to compounds under hypoxia. The method used was as described above for aerobic conditions with the following modifications: M. tuberculosis constitutively expressing the luxABCDE operon was inoculated into DTA medium in gas-impermeable glass tubes and incubated for 18 days to generate hypoxic conditions (Wayne model of hypoxia). At this point, bacteria are in a non-replicating state (NRP stage 2) induced by oxygen depletion.
  • NTP stage 2 non-replicating state
  • Oxygen-deprived bacteria were inoculated into compound assay plates and incubated under anaerobic conditions for 10 days followed by incubation under aerobic conditions (outgrowth) for 28 h. Growth was measured by luminescence. Oxygen-deprived bacteria were also inoculated into compound assay plates and incubated under aerobic conditions for five days.
  • THP-1 cells The activity of compounds against intracellular bacteria was determined by measuring viability in infected THP-1 cells (macrophage-like cells) after three days in the presence of compounds. Compounds were prepared as 10-point three-fold serial dilutions in DMSO. The highest concentration of compound tested was 50 ⁇ where compounds were soluble in DMSO at 10 mM.
  • THP-1 cells were cultured in complete RPMI medium and differentiated into macrophage-like cells using 80 nM PMA overnight at 37°C, 5% CO2. THP-1 cells were infected with a luminescent strain of H37Rv (that constitutively expresses luxABCDE) at a multiplicity of infection of one and incubated overnight at 37°C, 5% CO2.
  • Infected cells were recovered using Accutase/EDTA solution, washed twice with PBS to remove extracellular bacteria and seeded into assay pates. Compound dilutions were added to a final DMSO concentration of 0.5%. Assay plates were incubated for 72 h at 37°C, 5% CO2. Relative luminescent units (RLU) were measured using a Biotek Synergy 2 plate reader. The dose- response curve was fitted using the Levenberg-Marquardt algorithm. The IC50 was defined as the compound concentrations that produced 50% inhibition of microbial growth.
  • M. abscessus plates were inoculated and incubated for three days at 37°C; growth was measured by OD590 nm.
  • the dose-response curve was plotted as percentage growth and fitted to the Gompertz model and the MIC was defined as the minimum concentration at which growth was completely inhibited and was calculated from the inflection point of the fitted curve to the lower asymptote (zero growth).
  • Compounds A, B, C and E showed good activity against both E. coli and S. aureus and all five compounds A to E tested exhibited excellent activity against M. smegmatis.
  • Three compounds (A, B and C) showed excellent activity against M. tuberculosis H37Ra and compounds A, B, C and E showed excellent activity against the virulent strain M. tuberculosis H37Rv.
  • Compounds A, B, C and E also showed excellent activity against M. tuberculosis H37Rv under low oxygen conditions, suggesting that the compounds are effective against non-replicating TB.
  • Compounds A, B, C and E also showed excellent activity against intracellular bacteria.
  • Compounds A, B, C and E retained excellent activity against antibiotic-resistant M.
  • a MIC (in ⁇ ) of less than or equal to 0.1 is assigned the letter A; a MIC of from 0.1 to 1 is assigned the letter B; a MIC of from 1 to 10 is assigned the letter C; a MIC of from 10 to 100 is assigned the letter D; and a MIC of over 100 is assigned the letter E.
  • Example 6 Human cell viability assay
  • Compounds are assessed for potential non-specific cytotoxic effects against a human hepatic cell line (HepG2, ATCC HB-8065) and a human monocytic cell line (THP-1 , ATCC TI B-202).
  • HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10 % FBS and 1 mM sodium pyruvate. After 24 h compound dilutions are prepared in Dulbecco's minimum essential media (DMEM) supplemented with final concentrations of 0.001 % FBS, 0.3 % bovine albumin and 0.02 % HEPES and added to cells. Compounds are tested in two-fold serial dilutions over a final concentration range of 1-128 ⁇ g/mL in a final DMSO concentration of 1 % vol/vol. Chlorpromazine is used as a positive control.
  • MEM minimal essential medium
  • DMEM Dulbecco's minimum essential media
  • Luminescence is measured on a BMG Omega plate reader. Data are analysed using GraphPad Prism software to determine the concentration of compound that inhibits cell viability by fifty percent (IC50).
  • THP-1 cells were cultured in complete RPMI and differentiated into macrophage-like cells using 80 nM PMA overnight at 37°C, 5% CO2. Compounds were prepared as 10-point three-fold serial dilutions in DMSO. The highest concentration of compound tested was 50 ⁇ where compounds were soluble in DMSO at 10 mM. Cells were inoculated into assay plates and cultured for 24 h before compound dilutions were added to a final DMSO concentration of 0.5%. Assay plates were incubated for 3 days at 37°C, 5% CO2. Growth was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) that uses ATP as an indicator of cell viability.
  • Relative luminescent units were measured using a Biotek Synergy 4 plate reader. The dose-response curve was fitted using the Levenberg-Marquardt algorithm. The IC50 was determined as the compound concentration causing a 50% loss in viability. The results are provided in Table 2.
  • compound A shows no detectable toxicity against the tested human hepatic and human monocytic cell lines and this indicates that the compound has the potential to have an excellent therapeutic benefit relative to its cytotoxicity.
  • Compounds B to E also demonstrate an acceptable level of cytotoxicity relative to therapeutic activity.
  • Compounds A and B both show reduced cytotoxicity when compared to prior art compound E.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des composés médicamenteux antibactériens contenant un système cyclique tricyclique, ainsi qu'à des compositions pharmaceutiques à base de ceux-ci. Ces composés se révèlent utiles dans le traitement des infections bactériennes et mycobactériennes et, en particulier, de la tuberculose (TB), y compris les infections provoquées par des souches résistantes de bactéries ou de mycobactéries.
PCT/GB2015/053212 2014-10-28 2015-10-27 Composés présentant une activité contre les bactéries et les mycobactéries WO2016067009A1 (fr)

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GBGB1419175.3A GB201419175D0 (en) 2014-10-28 2014-10-28 Compounds with activity against bacteria and mycobacteria
GB1511642.9 2015-07-02
GBGB1511642.9A GB201511642D0 (en) 2015-07-02 2015-07-02 Compounds with activity against bacteria and mycobacteria

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170369498A1 (en) * 2011-03-15 2017-12-28 Merck Sharp & Dohme Corp. Tricyclic gyrase inhibitors
WO2019148244A1 (fr) * 2018-02-01 2019-08-08 The University Of Sydney Composés anticancéreux
US11040945B2 (en) 2017-12-06 2021-06-22 Lin Bioscience Pty Ltd. Tubulin inhibitors
CN114763357A (zh) * 2021-01-15 2022-07-19 中国科学院上海药物研究所 吲哚并嘧啶三环类化合物及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037898A1 (fr) * 2001-10-31 2003-05-08 Bayer Healthcare Ag Derives de pyrimido [4,5-b] indole
WO2009029473A1 (fr) * 2007-08-27 2009-03-05 Duquesne University Of The Holy Ghost Composés tricycliques ayant une activité cytostatique et/ou cytotoxique et leurs procédés d'utilisation
WO2009085185A1 (fr) * 2007-12-19 2009-07-09 Amgen Inc. Composés condensés de pyridine, de pyrimidine et de triazine en tant qu'inhibiteurs du cycle cellulaire
WO2014043272A1 (fr) * 2012-09-12 2014-03-20 Trius Therapeutics Inc. Inhibiteurs tricycliques de gyrase utilisables comme agents antibactériens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037898A1 (fr) * 2001-10-31 2003-05-08 Bayer Healthcare Ag Derives de pyrimido [4,5-b] indole
WO2009029473A1 (fr) * 2007-08-27 2009-03-05 Duquesne University Of The Holy Ghost Composés tricycliques ayant une activité cytostatique et/ou cytotoxique et leurs procédés d'utilisation
WO2009085185A1 (fr) * 2007-12-19 2009-07-09 Amgen Inc. Composés condensés de pyridine, de pyrimidine et de triazine en tant qu'inhibiteurs du cycle cellulaire
WO2014043272A1 (fr) * 2012-09-12 2014-03-20 Trius Therapeutics Inc. Inhibiteurs tricycliques de gyrase utilisables comme agents antibactériens

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170369498A1 (en) * 2011-03-15 2017-12-28 Merck Sharp & Dohme Corp. Tricyclic gyrase inhibitors
US10858360B2 (en) * 2011-03-15 2020-12-08 Merck Sharp & Dohme Corp. Tricyclic gyrase inhibitors
US11040945B2 (en) 2017-12-06 2021-06-22 Lin Bioscience Pty Ltd. Tubulin inhibitors
WO2019148244A1 (fr) * 2018-02-01 2019-08-08 The University Of Sydney Composés anticancéreux
CN111741944A (zh) * 2018-02-01 2020-10-02 悉尼大学 抗癌化合物
JP2021512861A (ja) * 2018-02-01 2021-05-20 ザ・ユニバーシティ・オブ・シドニー 抗癌性化合物
AU2019215799B2 (en) * 2018-02-01 2022-04-14 The University Of Sydney Anti-cancer compounds
US11472774B2 (en) 2018-02-01 2022-10-18 The University Of Sydney Anti-cancer compounds
JP2022160635A (ja) * 2018-02-01 2022-10-19 ザ・ユニバーシティ・オブ・シドニー 抗癌性化合物
JP7184383B2 (ja) 2018-02-01 2022-12-06 ザ・ユニバーシティ・オブ・シドニー 抗癌性化合物
US11939296B2 (en) 2018-02-01 2024-03-26 The University Of Sydney Anti-cancer compounds
CN114763357A (zh) * 2021-01-15 2022-07-19 中国科学院上海药物研究所 吲哚并嘧啶三环类化合物及其制备方法和用途

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