(19) TZZ_ ___T (11) EP 1 945 211 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) A61K 31/4439 (2006.01) 21.10.2015 Bulletin 2015/43 A61P 31/04 (2006.01) (21) Application number: 06808472.2 (86) International application number: PCT/GB2006/004178 (22) Date of filing: 08.11.2006 (87) International publication number: WO 2007/054693 (18.05.2007 Gazette 2007/20) (54) USE OF PYRROLOQUINOLINE COMPOUNDS TO KILL CLINICALLY LATENT MICROORGANISMS VERWENDUNG VON PYRROCHINOLIN-VERBINDUNGEN ZUR ABTÖTUNG VON KLINISCH LATENTEN MIKROORGANISMEN UTILISATION DE DÉRIVÉS DE PYRROLOQUINOLINE POUR L’ÉLIMINATION DE MICRO- ORGANISMES PERSISTANTS AU NIVEAU CLINIQUE (84) Designated Contracting States: • LONDESBROUGH, Derek, John AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Sunderland SR5 2TQ (GB) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • MILLS, Keith SK TR Hertfordshire SG12 0PT (GB) Designated Extension States: • PALLIN, Thomas, David AL BA HR MK RS Essex CM19 5TR (GB) • REID, Gary, Patrick (30) Priority: 08.11.2005 GB 0522715 Sunderland SR5 2TQ (GB) • STODDART, Gerlinda (43) Date of publication of application: Oxfordshire OX7 3RR (GB) 23.07.2008 Bulletin 2008/30 (74) Representative: D Young & Co LLP (73) Proprietor: Helperby Therapeutics Limited 120 Holborn Selby London EC1N 2DY (GB) North Yorkshire YO8 4PW (GB) (56) References cited: (72) Inventors: EP-A1- 0 307 078 EP-A1- 1 238 979 • BECK, Petra, Helga WO-A-99/09029 WO-A-2005/105802 Oxfordshire OX7 3RR (GB) US-A- 725 745 US-A- 2 691 023 • BROWN, Marc, Barry US-A- 2 714 593 Oxfordshire OX7 3RR (GB) • CLARK, David, Edward • DATABASE CAPLUS CHEMICAL ABSTRACTS Essex CM19 5TR (GB) SERVICE, COLUMBUS, OHIO, US; 1957, • COATES, Anthony XP002419062 accession no. 1957:47059 cited in Cranmer Terrace the application & OZAWA, T ET AL.: YAKUGAKU London SW17 0RE (GB) ZASSHI, vol. 77, 1957, pages 90-93, cited in the • DYKE, Hazel, Joan application Essex CM19 5TR (GB) • DATABASE CAPLUS CHEMICAL ABSTRACTS • HU, Yanmin SERVICE, COLUMBUS, OHIO, US; 1957, Cranmer Terrace XP002419063 accession no. 1957:47058 & London SW17 0RE (GB) OZAWA ET AL.: YAKUGAKU ZASSHI, vol. 77, 1957, pages 85-89, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 945 211 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 945 211 B1 • PARSONS P J ET AL: "The Facile Construction • BROWN T H ET AL: "REVERSIBLE INHIBITORS of Indole Alkaloid Models: A Tandem Cascade OF THE GASTRIC (H+/K+)-ATPASE. 1. 1- ARYL-4- Approach for the Synthesis of a Model for METHYLPYRROLE3,2-CQUINOLINES AS Pseudocopsinine" TETRAHEDRON, ELSEVIER CONFORMATIONALLY RESTRAINED SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. ANALOGUES OF 4-(ARYLAMINO)QUINOLINES" 52, no. 2, 8 January 1996 (1996-01-08), pages JOURNAL OF MEDICINAL CHEMISTRY, 647-660, XP004104539 ISSN: 0040-4020 cited in AMERICAN CHEMICAL SOCIETY. the application WASHINGTON, US, vol. 33, 1990, pages 527-533, • IFE R J ET AL: "Reversible Inhibitors of the XP000919165 ISSN: 0022-2623 cited in the Gastric(H+/K+)-ATPase" JOURNAL OF application MEDICINALCHEMISTRY, AMERICAN CHEMICAL • JI H Y ET AL: "Characterization of human liver SOCIETY. WASHINGTON, US, vol. 38, no. 14, cytochrome P450 enzymes involved in the 1995, pages 2763-2773, XP002121213 ISSN: metabolism of a new H<+>/K<+>-ATPase 0022-2623 inhibitor KR-60436" TOXICOLOGY LETTERS, • BADAWEYE- SET AL: "Potential antineoplastics. ELSEVIER BIOMEDICAL PRESS, AMSTERDAM,, Synthesis and cytotoxicity of certain 4-chloro- NL, vol. 155, no. 1, 15 January 2005 (2005-01-15), 3-(2-chloroethyl)-2-methylquinolines and related pages 103-114, XP004673494 ISSN: 0378-4274 derivatives" EUROPEAN JOURNAL OF • HEIDEMPERGHER F ET AL: "PYRROLO3,2- MEDICINAL CHEMISTRY, EDITIONS CQUINOLINE DERIVATIVES: A NEW CLASS OF SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 32, no. KYNURENINE-3-HYDROXYLASEINHIBITORS" IL 10, October 1997 (1997-10), pages 815-822, FARMACO, ROME, IT, vol. 54, no. 3, 1999, pages XP004172152 ISSN: 0223-5234 cited in the 152-160, XP002934253 ISSN: 0014-827X application • LEACH COLIN A ET AL: "Reversible inhibitors of the gastric (H+/K+)-ATPase. 2. 1-Arylpyrrolo[3,2- c]quinolines: effect of the 4-substituent" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 35, no. 10, 1992, pages 1845-1852,XP002184101 ISSN: 0022-2623 cited in the application 2 EP 1 945 211 B1 Description [0001] This invention relates to the use of compounds based upon the pyrrolo[3,2- c]quinoline ring system to kill clinically latent microorganisms. The invention further relates to the use of such compounds to treat microbial infections, as well 5 as, inter alia, certain of the compounds per se. [0002] The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. [0003] Before the introduction of antibiotics, patients suffering from acute bacterial infections (e.g. tuberculosis or pneumonia) had a low chance of survival. For example, mortality from tuberculosis was around 50%. 10 [0004] Although the introduction of antibacterial agents in the 1940s and 1950s rapidly changed this picture, bacteria have responded by progressively gaining resistance to commonly used antibiotics. Now, every country in the world has antibioticresistant bacteria. Indeed, more than 70% of bacteria that give rise to hospital acquired infections in the USA resist at least one of the main antimicrobial agents that are typically used to fight infection (see Nature Reviews, Drug Discover 1, 895-910 (2002)). 15 [0005] One way of tackling the growing problem of resistant bacteria is the development of new classes of antimicrobial agents. However, until the introduction of linezolid in 2000, there had been no new class of antibiotic marketed for over 37 years. Moreover, even the development of new classes of antibiotic provides only a temporary solution, and indeed there are already reports of resistance of certain bacteria to linezolid (see Lancet 357, 1179 (2001) and Lancet 358, 207-208 (2001)). 20 [0006] In order to develop more long-term solutions to the problem of bacterial resistance, it is clear that alternative approaches are required. One such alternative approach is to minimise, as much as is possible, the opportunities that bacteria are given for developing resistance to important antibiotics. [0007] Thus, strategies that can be adopted include limiting the use of antibiotics for the treatment of non-acute infections, as well as controlling which antibiotics are fed to animals in order to promote growth. 25 [0008] However, in order to tackle the problem more effectively, it is necessary to gain an understanding of the actual mechanisms by which bacteria generate resistance to antibiotic agents. To do this requires first a consideration of how current antibiotic agents work to kill bacteria. [0009] Antimicrobial agents target essential components of bacterial metabolism. For example, theβ -lactams (e.g. penicillins and cephalosporins) inhibit cell wall synthesis, whereas other agents inhibit a diverse range of targets, such 30 as DNA gyrase (quinolones) and protein synthesis (e.g. macrolides, aminoglycosides, tetracyclines and oxazolidinones). The range of organisms against which the antimicrobial agents are effective varies, depending upon which organisms are heavily reliant upon the metabolic step(s) that is/are inhibited. Further, the effect upon bacteria can vary from a mere inhibition of growth (i.e. a bacteriostatic effect, as seen with agents such as the tetracyclines) to full killing (i.e. a bact ericidal effect, as seen, for example, with penicillin). 35 [0010] Bacteria have been growing on Earth for more than 3 billion years and, in that time, have needed to respond to vast numbers of environmental stresses. It is therefore perhaps not surprising that bacteria have developed a seemingly inexhaustible variety of mechanisms by which they can respond to the metabolic stresses imposed upon them by antibiotic agents. Indeed, mechanisms by which the bacteria can generate resistance include strategies as diverse as inactivation of the drug, modification of the site of action, modification of the permeability of the cell wall, overproduction of the targe t 40 enzyme and bypass of the inhibited steps. [0011] Nevertheless, the rate of resistance emerges to a particular agent has been observed to vary widely, depending upon factors such as the agent’s mechanism of action, whether the agent’s mode of killing is time- or concentration- dependent, the potency against the population of bacteria and the magnitude and duration of the available serum concentration. 45 [0012] It has been proposed (see Science 264, 388-393 (1994)) that agents that target single enzymes (e.g. rifampicin) are the most prone to the development of resistance. Further, the longer that suboptimal levels of antimicrobial agent are in contact with the bacteria, the more likely the emergence of resistance. [0013] Moreover, it is now known that many bacterial infections include sub-populations of bacteria that arepheno- typically resistant to antimicrobials (see, for example: J. Antimicrob. Chemother. 4, 395-404 (1988); J. Med. Microbiol. 50 38, 197-202 (1993); J. Bacteriol. 182, 1794-1801 (2000);ibid. 182, 6358-6365 (2000); ibid. 183, 6746-6751 (2001); FEMS Microbiol. Lett. 202, 59-65 (2001); and Trends in Microbiology 13, 34-40 (2005)). There appear to be several types of such phenotypically resistant bacteria, including persisters, stationary-phase bacteria, as well as those in the depths of biofilms.