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Ep 2097400 B1 (19) TZZ ZZZ_T (11) EP 2 097 400 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: C07D 401/04 (2006.01) C07D 401/14 (2006.01) of the grant of the patent: C07D 491/052 (2006.01) C07D 498/04 (2006.01) 03.07.2013 Bulletin 2013/27 A61K 31/47 (2006.01) A61P 31/04 (2006.01) (21) Application number: 07860629.0 (86) International application number: PCT/JP2007/075434 (22) Date of filing: 28.12.2007 (87) International publication number: WO 2008/082009 (10.07.2008 Gazette 2008/28) (54) FUSED SUBSTITUTED AMINOPYRROLIDINE DERIVATIVE ANELLIERTES SUBSTITUIERTES AMINOPYRROLIDINDERIVAT DÉRIVÉ D’AMINOPYRROLIDINE SUBSTITUÉ LIÉ PAR FUSION (84) Designated Contracting States: • TSUDA, Toshifumi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Edogawa-ku HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE Tokyo 134-8630 (JP) SI SK TR • NAKAYAMA, Kiyoshi Edogawa-ku (30) Priority: 05.01.2007 JP 2007000667 Tokyo 134-8630 (JP) 22.03.2007 JP 2007074991 • TAKEMURA, Makoto Edogawa-ku (43) Date of publication of application: Tokyo 134-8630 (JP) 09.09.2009 Bulletin 2009/37 • YOSHIDA, Kenichi Edogawa-ku (60) Divisional application: Tokyo 134-8630 (JP) 12186361.7 / 2 540 715 • MIYAUCHI, Rie Edogawa-ku (73) Proprietor: Daiichi Sankyo Company, Limited Tokyo 134-8630 (JP) Chuo-ku • NAGAMOCHI, Masatoshi Tokyo 103-8426 (JP) Edogawa-ku Tokyo 134-8630 (JP) (72) Inventors: • TAKAHASHI, Hisashi (74) Representative: Fairbairn, Angus Chisholm Edogawa-ku Marks & Clerk LLP Tokyo 134-8630 (JP) 90 Long Acre • KOMORIYA, Satoshi London Edogawa-ku WC2E 9RA (GB) Tokyo 134-8630 (JP) • KITAMURA, Takahiro (56) References cited: Edogawa-ku EP-A- 0 343 524 EP-A- 0 812 838 Tokyo 134-8630 (JP) WO-A-96/23782 WO-A-96/39407 • ODAGIRI, Takashi WO-A-2005/049602 JP-A- 1 056 673 Edogawa-ku Tokyo 134-8630 (JP) • INAGAKI, Hiroaki Edogawa-ku Tokyo 134-8630 (JP) 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 2 097 400 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 097 400 B1 • OGATA M ET AL: "SYNTHESIS AND • CIANCHETTA G. ET AL: "Chemometric studies ANTIBACTERIAL ACTIVITY OF NEW on the bacterial activity of quinolones via an 7-(AMINOAZABICYCLOALKANYL ) extended volsurf approach" JOURNAL OF QUINOLONECARBOXYLIC ACIDS" EUROPEAN MEDICINAL CHEMISTRY, vol. 47, 2004, pages JOURNAL OF MEDICINAL CHEMISTRY, 3193-3201, XP002494591 EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 26, no. 9, 1 December 1991 (1991-12-01), pages 889-906, XP000647511 ISSN: 0223-5234 • MA Z ET AL: "SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-4-OXOQUINOLIZINE DERIVATIVES: CONSEQUENCES OF STRUCTURAL MODIFICATION AT THE C-8 POSITION" JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 42, 1 January 1999 (1999-01-01), pages 4202-4213, XP002936065 ISSN: 0022-2623 2 EP 2 097 400 B1 Description BACKGROUND OF THE INVENTION 5 Field of the Invention [0001] The present invention relates to quinolone compounds useful as medicines, veterinary medicines, fishery med- icines, or antibacterial preservatives. 10 Description of the Related Art [0002] Since the discovery of norfloxacin, quinolone synthetic antibacterial agents (including those having a pyrido- benzoxazine skeleton) with improved antibacterial activity and pharmacokinetics have been developed into chemother- apeutic agents effective for almost all systemic infections, and many of them are now clinically used (see Japanese 15 Patent Laid-Open No. 61-282382 or Japanese Patent Laid- Open No. 63-45261 and Clinical Microbiology and Infection, Vol.11, No.4, p.256 (2005)). [0003] However, the number of types of bacteria having low sensitivity to quinolone synthetic antibacterial agents has tended to increase in the clinical field in recent years. For example, the number of types of bacteria resistant to drugs other than quinolone synthetic antibacterial agents, which are so-called multidrug-resistant bacteria, such as Gram- 20 positive cocci including Staphylococcus aureus (methicillin- resistant Staphylococcus aureus: MRSA) and pneumococcus (penicillin-resistant Streptococcus pneumonia: PRSP) having low sensitivity toβ -lactam antibiotics; and enterococci having low sensitivity to aminoglycoside antibacterial agents (vancomycin- resistant enterococcus: VRE) and having also low sensitivity to quinolone synthetic antibacterial agents has increased. Bacterial infections caused by such resistant Gram-positive bacteria are known to be generally severe (fatal) and intractable. Accordingly, drugs more effective to 25 Gram-positive cocci are particularly desired in the clinical field (see Drugs, Vol. 66, No.6, p.751 (2005)). [0004] On the other hand, quinolone synthetic antibacterial compounds created in recent years have antibacterial activities that are much higher than those of previous ones (see Japanese Patent Laid- Open No. 2-231475 or Japanese Patent Laid-Open No. 3-95176). However, many of such quinolone compounds having high antibacterial activity cause side effects based on their physiological and pharmacological effects not observed for previous quinolone synthetic 30 antibacterial agents. [0005] Examples of the side effects of quinolone synthetic antibacterial agents include conventionally reported side effects such as induction of convulsion by use in combination with non-steroidal anti-inflammatory drugs (NSAIDs), central actions (mild central nervous system disorders such as sway, headache, and insomnia, and serious side effects such as the onset of fatal convulsion), and phototoxicity (photosensitivity); as well as recently disclosed side effects such 35 as hepatotoxicity (serious allergic hepatitis), cardiotoxicity (electrocardiographic abnormality inducing fatal arrhythmia, observed as QT or QTc prolongation), delayed drug eruption (skin rash), and blood glucose level abnormality (see Hiroyuki Kobayashi (ed.), Clinical Application of New Quinolone Agents, Iyaku (Medicine and Drug) Journal Co., Ltd.; Drugs, Vol.62, No.1, p.13 (2002); Toxicology Letters, Vol. 127, p.269 (2002); Clinical Infectious Diseases, Vol.41, p. 1269 (2005)); and International Journal of Antimicrobial Agents, Vol. 23, No.5, p.421 (2004)). 40 [0006] The clinical onset of cardiotoxicity among such side effects is a particular problem in recent years. Distinct QT or QTc prolongation is reported and some serious conditions (electrocardiographic abnormality inducing fatal arrhythmia) are also reported for some commercially available quinolone synthetic antibacterial agents (such as grepafloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and gemifloxacin). Serious side effects such as the onset of serious allergic hepatitis accompanying liver transplantation (trovafloxacin: see Clinical Infectious Diseases, Vol. 41, p.1269 (2005)) and 45 blood glucose level abnormality including fatal hypoglycemia (gatifloxacin: see International Journal of Antimicrobial Agents, Vol.23, No.5, p.421 (2004)) are also clinical problems. Further, delayed drug eruption (skin rash) caused by repeated administration of a quinolone agent in a clinical test (gatifloxacin: see Clinical Infectious Diseases, Vol.41, p. 1269 (2005)) is reported. In such circumstances, the administration of some quinolone synthetic antibacterial agents has been limited, and the development and use as human medicines of some quinolone synthetic antibacterial agents 50 has been abandoned. That is, some quinolone synthetic antibacterial agents have been observed which have strong antibacterial activity but which in terms of side effects are not sufficiently suitable as medicines. [0007] Accordingly, there is a need for safer quinolone synthetic antibacterial agents for use as human medicines, having only low side effects such as induction of convulsion by use in combination with non- steroidal anti-inflammatory drugs, central actions, and phototoxicity (photosensitivity) which are conventionally known as side effects; as well as 55 cardiotoxicity, hepatotoxicity, delayed drug eruption (skin rash), and blood glucose level abnormality which are clinical problems in recent years. Therefore, there is a need for the development of compounds conceptually different from conventional compounds that have high antibacterial activity but cause side effects and thus cannot be used as medicines. That is, there is a need for quinolone compounds having both strong antibacterial activity and high safety (see The 3 EP 2 097 400 B1 Japanese Journal for History of Pharmacy, Vol.38, No.2, p.161 (2003)). [0008] Antibacterial activity, pharmacokinetics, and safety of a quinolone synthetic antibacterial agent are known to be influenced by the structure of the substituents at each position of the quinolone skeleton, in particular, the structure of the substituent at the 7-position (corresponding to the 10-position of the pyridobenzoxazine skeleton) (see Clinical 5 Microbiology and Infection, Vol.11, No.4, p.256 (2005), for example). [0009] The characteristic feature of the compounds of the present invention is that they have, at the 7- position of the quinolone mother skeleton, a substituent represented by the following formula 1: 10 15 20 wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in claim 1. That is, the 7-position substituent in the compounds
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