JP4370002B2 - Quinolone carboxylic acid derivative or salt thereof - Google Patents
Quinolone carboxylic acid derivative or salt thereof Download PDFInfo
- Publication number
- JP4370002B2 JP4370002B2 JP51197899A JP51197899A JP4370002B2 JP 4370002 B2 JP4370002 B2 JP 4370002B2 JP 51197899 A JP51197899 A JP 51197899A JP 51197899 A JP51197899 A JP 51197899A JP 4370002 B2 JP4370002 B2 JP 4370002B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- dihydro
- nmr
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000003839 salts Chemical class 0.000 title description 21
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title description 6
- -1 1,3- Dihydroisobenzofuranyl Chemical group 0.000 claims description 182
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 claims 1
- 125000005956 isoquinolyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 36
- 239000002904 solvent Substances 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000013078 crystal Substances 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 125000000217 alkyl group Chemical group 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 229910052763 palladium Inorganic materials 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 239000003480 eluent Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 239000012046 mixed solvent Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 125000004414 alkyl thio group Chemical group 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 150000002940 palladium Chemical class 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000002411 adverse Effects 0.000 description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 7
- 125000000547 substituted alkyl group Chemical group 0.000 description 7
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 150000003462 sulfoxides Chemical class 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000004673 fluoride salts Chemical class 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- FIEKWZGCKWZJHQ-UHFFFAOYSA-N 1-(3-bromophenyl)-2-hydroxyiminopropan-1-one Chemical compound ON=C(C)C(=O)C1=CC=CC(Br)=C1 FIEKWZGCKWZJHQ-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- UFPZBVCVXDUOPY-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-6-yloxyboronic acid Chemical compound O1CCOC2=CC(OB(O)O)=CC=C21 UFPZBVCVXDUOPY-UHFFFAOYSA-N 0.000 description 2
- HZTBIWQKKWRJIG-UHFFFAOYSA-N 2-bromo-6-(chloromethyl)naphthalene Chemical compound C1=C(Br)C=CC2=CC(CCl)=CC=C21 HZTBIWQKKWRJIG-UHFFFAOYSA-N 0.000 description 2
- LFCURAJBHDNUNG-UHFFFAOYSA-N 6-bromo-2,3-dihydro-1,4-benzodioxine Chemical compound O1CCOC2=CC(Br)=CC=C21 LFCURAJBHDNUNG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- MLRPCIPYHCAIJP-UHFFFAOYSA-N CC(=O)OCC1=C(C=C(C=C1[N+](=O)[O-])Br)C(=O)OC Chemical compound CC(=O)OCC1=C(C=C(C=C1[N+](=O)[O-])Br)C(=O)OC MLRPCIPYHCAIJP-UHFFFAOYSA-N 0.000 description 2
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical group CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical group C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000005885 boration reaction Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- SQIVIQODEXTXDF-UHFFFAOYSA-N cyclohexane;1,2-dimethoxyethane Chemical compound COCCOC.C1CCCCC1 SQIVIQODEXTXDF-UHFFFAOYSA-N 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- BCBMYVCFZJTEEU-UHFFFAOYSA-N ethyl 1-cyclopropyl-7-fluoro-8-methyl-4-oxoquinoline-3-carboxylate Chemical compound C12=C(C)C(F)=CC=C2C(=O)C(C(=O)OCC)=CN1C1CC1 BCBMYVCFZJTEEU-UHFFFAOYSA-N 0.000 description 1
- NSAIANPWRHILKT-UHFFFAOYSA-N ethyl 7-bromo-1-cyclopropyl-8-methyl-4-oxoquinoline-3-carboxylate Chemical compound C12=C(C)C(Br)=CC=C2C(=O)C(C(=O)OCC)=CN1C1CC1 NSAIANPWRHILKT-UHFFFAOYSA-N 0.000 description 1
- AOUDSRSOXFMPNL-UHFFFAOYSA-N ethyl 7-chloro-1-cyclopropyl-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(Cl)=CC=C2C(=O)C(C(=O)OCC)=CN1C1CC1 AOUDSRSOXFMPNL-UHFFFAOYSA-N 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- UPBDNPCJIJAMPI-UHFFFAOYSA-N methyl 5-bromo-2-methyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC(Br)=CC([N+]([O-])=O)=C1C UPBDNPCJIJAMPI-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical group C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- LJRGBERXYNQPJI-UHFFFAOYSA-M sodium;3-nitrobenzenesulfonate Chemical compound [Na+].[O-][N+](=O)C1=CC=CC(S([O-])(=O)=O)=C1 LJRGBERXYNQPJI-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
技術分野
本発明は、グラム陽性菌およびグラム陰性菌、とりわけＭＲＳＡに対して強力な抗菌作用を発揮し、かつ安全性の高い一般式［１］
Ｒ3およびＲ4は、上記したと同様の意味を有する。)である場合は除く。」
で表されるキノロンカルボン酸誘導体またはその塩に関する。
背景技術
キノロンカルボン酸骨格を有する化合物は、キノロン系合成抗菌剤として感染症の治療に用いられている。しかし、キノロンカルボン酸骨格の7位にベンゼン縮合環、6位に水素原子を有する化合物は知られていない。また、キノロン系合成抗菌剤として広く臨床に用いられているノルフロキサシン、シプロフロキサシンおよびオフロキサシンなどは、グラム陽性菌とりわけＭＲＳＡに対する活性が十分ではない。そのため、これらの菌に対しても有効で広範囲な抗菌スペクトルを有する合成抗菌剤の開発が望まれている。
発明の開示
このような状況下において、本発明者らは鋭意研究を行った結果、キノロンカルボン酸骨格の7位にベンゼン縮合環、6位に水素原子を有する次の一般式［１］の化合物またはその塩が優れた抗菌活性を有し、かつ従来のキノロン系合成抗菌剤に比べて高い安全性を有することを見出し、本発明を完成するに至った。
本明細書において特に断らない限り、ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を；アルキル基とは、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、ヘキシル、ヘプチルおよびオクチルなどの直鎖状または分枝鎖状Ｃ1-10アルキル基を；低級アルキル基とは、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチルおよびペンチルなどの直鎖状または分枝鎖状Ｃ1-5アルキル基を；アルケニル基とは、例えば、ビニル、アリル、イソプロペニル、ブテニル、ペンテニル、ヘキセニル、ヘプテニルおよびオクテニルなどの直鎖状または分枝鎖状Ｃ2-10アルケニル基を；低級アルケニル基とは、例えば、ビニルおよびアリルなどの直鎖状または分枝鎖状Ｃ2-5アルケニル基を；シクロアルキル基とは、例えば、シクロプロピル、シクロブチル、シクロペンチルおよびシクロヘキシルなどのＣ3-6シクロアルキル基を；シクロアルカン環とは、例えば、シクロプロパン、シクロブタン、シクロペンタンおよびシクロヘキサンなどのＣ3-6シクロアルカン環を；アルコキシ基とは、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシ、ヘキシルオキシ、ヘプチルオキシおよびオクチルオキシなどの直鎖状または分枝鎖状Ｃ1-10アルコキシ基を；低級アルコキシ基とは、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシおよびペンチルオキシなどの直鎖状または分枝鎖状Ｃ1-5アルコキシ基を；アルキルチオ基とは、例えば、メチルチオ、エチルチオ、n-プロピルチオ、イソプロピルチオ、n-ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、ヘキシルチオ、ヘプチルチオおよびオクチルチオなどの直鎖状または分枝鎖状Ｃ1-10アルキルチオ基を；低級アルキルチオ基とは、例えば、メチルチオ、エチルチオ、n-プロピルチオ、イソプロピルチオ、n-ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオおよびペンチルチオなどの直鎖状または分枝鎖状Ｃ1-5アルキルチオ基を；アルキルスルホニル基とは、例えば、メチルスルホニル、エチルスルホニル、n-プロピルスルホニル、イソプロピルスルホニル、n-ブチルスルホニル、イソブチルスルホニル、sec-ブチルスルホニル、tert-ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル、ヘプチルスルホニルおよびオクチルスルホニルなどの直鎖状または分枝鎖状Ｃ1-10アルキルスルホニル基を；低級アルキルスルホニル基とは、例えば、メチルスルホニル、エチルスルホニル、n-プロピルスルホニル、イソプロピルスルホニル、n-ブチルスルホニル、イソブチルスルホニル、sec-ブチルスルホニル、tert-ブチルスルホニルおよびペンチルスルホニルなどの直鎖状または分枝鎖状Ｃ1-5アルキルスルホニル基を；低級アルキルアミノ基とは、例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ブチルアミノ、ペンチルアミノ、ヘキシルアミノ、ジメチルアミノ、ジエチルアミノ、メチルエチルアミノ、ジプロピルアミノ、ジブチルアミノおよびジペンチルアミノなどの直鎖状または分枝鎖状Ｃ1-5アルキル基で置換されたアミノ基を；アシル基とは、例えば、ホルミル基、アセチルおよびエチルカルボニルなどの直鎖状または分枝鎖状Ｃ2-5アルカノイル基並びにベンゾイルおよびナフチルカルボニルなどのアロイル基を；アルコキシカルボニル基とは、アルコキシ−ＣＯ−基(アルコキシは、上記したアルコキシ基を示す。)を；低級アルコキシカルボニル基とは、低級アルコキシ−ＣＯ−基(低級アルコキシは、上記した低級アルコキシ基を示す。)を；アリール基とは、例えば、フェニルおよびナフチル基を；アリールスルホニル基とは、例えば、フェニルスルホニルおよびナフチルスルホニル基を；アルアルキル基とは、例えば、ベンジル、フェネチルおよびトリチル基を；複素環式基とは、該環を形成する異項原子として酸素原子、窒素原子および硫黄原子から選ばれる１つ以上の異項原子を含む４員、５員もしくは６員環またはそれらの縮合環、例えば、オキセタニル、チエタニル、アゼチジニル、フリル、ピロリル、チエニル、オキサゾリル、イソオキサゾリル、イミダゾリル、チアゾリル、イソチアゾリル、ピロリジニル、ベンゾフラニル、ベンゾチアゾリル、ピリジル、キノリル、ピリミジニルおよびモルホリニル基をそれぞれ意味する。
Ｄにおける５員または６員環の複素環としては、該環を形成する異項原子として酸素原子、窒素原子および硫黄原子から選ばれる１つ以上の異項原子を含む複素環、例えば、トリアジン、ピリダジン、ピリミジン、ピラジン、ピリジン、フラン、チオフェン、ピロール、オキサゾール、チアゾール、イミダゾール、イソオキサゾール、イソチアゾール、ピラゾール、ピラン、フラザンなどの５員または６員の芳香族複素環；テトラヒドロ−２Ｈ−ピラン、テトラヒドロ−２Ｈ−チオピラン、ピペリジン、ジオキサン、オキサチアン、モルフォリン、チオモルフォリン、ジチアン、ピペラジン、ピロリジン、テトラヒドロチオフェン、テトラヒドロフラン、ピラゾリジン、イミダゾリジン、テトラヒドロイソチアゾール、１,３−チアゾラン、テトラヒドロイソオキサゾール、１,３−オキサゾラン、ジチオラン、オキサチオラン、ジオキソランなどの5員もしくは6員環の脂肪族複素環が挙げられる。
Ｄにおける５員または６員環の炭化水素環としては、ベンゼン、シクロヘキセン、シクロペンテンなどの５員または６員環不飽和炭化水素環；シクロヘキサンおよびシクロペンタンといった飽和炭化水素環が挙げられる。
Ｒ2におけるアルキル基、アルケニル基、シクロアルキル基、アリール基または複素環式基；Ｒ3におけるアルキル基、アルケニル基、シクロアルキル基、アリール基、アルコキシ基、アルキルチオ基またはアミノ基；Ｒ4におけるアルキル基、アルケニル基、シクロアルキル基、アルアルキル基、アリール基、アルコキシ基、アルキルチオ基またはアミノ基；Ｒ5におけるアルキル基、アルコキシ基またはアルキルチオ基；Ｒ6におけるアルキル基、アルコキシ基またはアルキルチオ基の置換基としては、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基、保護されていてもよいヒドロキシル基、保護されていてもよいアミノ基、保護されていてもよい低級アルキルアミノ基、低級アルキル基、低級アルコキシ基、低級アルコキシカルボニル基、アリール基、シクロアルキル基、低級アルケニル基、ハロゲン原子で置換された低級アルキル基が挙げられ、これら一種または二種以上の置換基で置換されていてもよい。
カルボキシル基の保護基としては、通常のカルボキシル基の保護基として使用し得るすべての基を含み、例えば、メチル、エチル、n-プロピル、iso-プロピル、１,１−ジメチルプロピル、n-ブチルおよびtert-ブチルなどの低級アルキル基；フェニルおよびナフチルなどのアリール基；ベンジル、ジフェニルメチル、トリチル、p-ニトロベンジル、p-メトキシベンジルおよびビス(p-メトキシフェニル)メチルなどのアルアルキル基；アセチルメチル、ベンゾイルメチル、p-ニトロベンゾイルメチル、p-ブロモベンゾイルメチルおよびp-メタンスルホニルベンゾイルメチルなどのアシル低級アルキル基；２−テトラヒドロピラニルおよび２−テトラヒドロフラニルなどの含酸素複素環式基；２,２,２−トリクロロエチルなどのハロゲノ低級アルキル基；２−(トリメチルシリル)エチルなどの低級アルキルシリルアルキル基；アセトキシメチル、プロピオニルオキシメチルおよびピバロイルオキシメチルなどのアシルオキシアルキル基；フタルイミドメチルおよびスクシンイミドメチルなどの含窒素複素環式−低級アルキル基；シクロヘキシルなどのシクロアルキル基；メトキシメチル、メトキシエトキシメチルおよび２−(トリメチルシリル)エトキシメチルなどの低級アルコキシ−低級アルキル基；ベンジルオキシメチルなどのアルアルキルオキシ−低級アルキル基；メチルチオメチルおよび２−メチルチオエチルなどの低級アルキルチオ−低級アルキル基；フェニルチオメチルなどのアリールチオ−低級アルキル基；１,１−ジメチル−２−プロペニル、３−メチル−３−ブテニルおよびアリルなどの低級アルケニル基；並びにトリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、tert-ブチルジメチルシリル、tert-ブチルジフェニルシリル、ジフェニルメチルシリルおよびtert-ブチルメトキシフェニルシリルなどの置換シリル基などが挙げられる。
アミノ基の保護基としては、通常のアミノ保護基として使用し得るすべての基を含み、例えば、トリクロロエトキシカルボニル、トリブロモエトキシカルボニル、ベンジルオキシカルボニル、p-ニトロベンジルカルボニル、o-ブロモベンジルオキシカルボニル、(モノ−、ジ−、トリ−)クロロアセチル、トリフルオロアセチル、フェニルアセチル、ホルミル、アセチル、ベンゾイル、tert-アミルオキシカルボニル、tert-ブトキシカルボニル、p-メトキシベンジルオキシカルボニル、３,４−ジメトキシベンジルオキシカルボニル、４−(フェニルアゾ)ベンジルオキシカルボニル、２−フルフリルオキシカルボニル、ジフェニルメトキシカルボニル、１,１−ジメチルプロポキシカルボニル、イソプロポキシカルボニル、フタロイル、スクシニル、アラニル、ロイシル、１−アダマンチルオキシカルボニルおよび８−キノリルオキシカルボニルなどのアシル基；ベンジル、ジフェニルメチルおよびトリチルなどのアルアルキル基；２−ニトロフェニルチオおよび２,４−ジニトロフェニルチオなどのアリールチオ基；メタンスルホニルおよびp-トルエンスルホニルなどのアルキル−もしくはアリール−スルホニル基；Ｎ,Ｎ−ジメチルアミノメチレンなどのジ低級アルキルアミノ−低級アルキリデン基；ベンジリデン、２−ヒドロキシベンジリデン、２−ヒドロキシ−５−クロロベンジリデンおよび２−ヒドロキシ−１−ナフチルメチレンなどのアル−低級アルキリデン基；３−ヒドロキシ−４−ピリジルメチレンなどの含窒素複素環式アルキリデン基；シクロヘキシリデン、２−エトキシカルボニルシクロヘキシリデン、２−エトキシカルボニルシクロペンチリデン、２−アセチルシクロヘキシリデンおよび３,３−ジメチル−５−オキシシクロヘキシリデンなどのシクロアルキリデン基；ジフェニルホスホリルおよびジベンジルホスホリルなどのジアリール−もしくはジアル−低級アルキルホスホリル基；５−メチル−２−オキソ−２Ｈ−１,３−ジオキソール−４−イル−メチルなどの含酸素複素環式アルキル基；並びにトリメチルシリルなどの置換シリル基などが挙げられる。
ヒドロキシル基の保護基としては、通常のヒドロキシル保護基として使用し得るすべての基を含み、例えば、ベンジルオキシカルボニル、４−ニトロベンジルオキシカルボニル、４−ブロモベンジルオキシカルボニル、４−メトキシベンジルオキシカルボニル、３,４−ジメトキシベンジルオキシカルボニル、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル、１,１−ジメチルプロポキシカルボニル、イソプロポキシカルボニル、イソブチルオキシカルボニル、ジフェニルメトキシカルボニル、２,２,２−トリクロロエトキシカルボニル、２,２,２−トリブロモエトキシカルボニル、２−(トリメチルシリル)エトキシカルボニル、２−(フェニルスルホニル)エトキシカルボニル、２−(トリフェニルホスホニオ)エトキシカルボニル、２−フルフリルオキシカルボニル、１−アダマンチルオキシカルボニル、ビニルオキシカルボニル、アリルオキシカルボニル、Ｓ−ベンジルチオカルボニル、４−エトキシ−１−ナフチルオキシカルボニル、８−キノリルオキシカルボニル、アセチル、ホルミル、クロロアセチル、ジクロロアセチル、トリクロロアセチル、トリフルオロアセチル、メトキシアセチル、フェノキシアセチル、ピバロイルおよびベンゾイルなどのアシル基；メチル、tert-ブチル、２,２,２−トリクロロエチルおよび２−トリメチルシリルエチルなどの低級アルキル基；アリルなどの低級アルケニル基；ベンジル、p-メトキシベンジル、３,４−ジメトキシベンジル、ジフェニルメチルおよびトリチルなどのアルアルキル基；テトラヒドロフリル、テトラヒドロピラニルおよびテトラヒドロチオピラニルなどの含酸素および含硫黄複素環式基；メトキシメチル、メチルチオメチル、ベンジルオキシメチル、２−メトキシエトキシメチル、２,２,２−トリクロロエトキシメチル、２−(トリメチルシリル)エトキシメチルおよび１−エトキシエチルなどの低級アルコキシ−および低級アルキルチオ−低級アルキル基；メタンスルホニルおよびp-トルエンスルホニルなどのアルキル−およびアリール−スルホニル基；並びにトリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジエチルイソプロピルシリル、tert-ブチルジメチルシリル、tert-ブチルジフェニルシリル、ジフェニルメチルシリルおよびtert-ブチルメトキシフェニルシリルなどの置換シリル基などが挙げられる
一般式［１］の化合物の塩としては、通常知られているアミノ基などの塩基性基またはヒドロキシルもしくはカルボキシル基などの酸性基における塩を挙げることができる。塩基性基における塩としては、例えば、塩酸、臭化水素酸および硫酸などの鉱酸との塩；酒石酸、ギ酸、クエン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩；並びにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩を、また、酸性基における塩としては、例えば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；並びにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ−ベンジル−β−フェネチルアミン、１−エフェナミンおよびＮ,Ｎ’−ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などを挙げることができる。一般式［１］の化合物の塩としては、好ましくは、薬理学的に許容される塩が挙げられる。
本発明のうち、Ｒ2が置換されていてもよいシクロアルキル基；Ｒ3が水素原子、Ｒ4が水素原子または保護されていてもよいヒドロキシル基；Ｒ5が水素原子；Ｒ6が、水素原子、ハロゲン原子、置換されていてもよいアルキルまたはアルコキシ基である化合物が好ましい。
本発明化合物中、代表的化合物としては、例えば、表１〜２に示す化合物が挙げられる。なお、表中における省略記号は次の意味を有する。
cyclopropyl：シクロプロピル、fluoroethyl：２−フルオロエチル、2,4-diF-Ph：２,４−ジフルオロフェニル
【表１】
次に、本発明化合物の製造法について説明する。
本発明化合物は、例えば、次に示す製造法にしたがって合成することができる。
一般式［１ａ］、［２］、［３ａ］、［３ｂ］、［４］、［５］、［６］、［７］または［８］の化合物は塩として使用することもでき、それらの塩としては、一般式［１］の化合物の塩で説明したと同様の塩が挙げられる。
［製造法１］
(１−ａ)一般式［１ａ］の化合物は、酸化銀の存在下または不存在下、パラジウム触媒を用いて、一般式［２］の化合物と一般式［３ａ］の有機スズ化合物あるいは一般式［４］の有機スズ化合物と一般式［５］の化合物をカップリング反応に付すことによって得ることができる。
この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、例えば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類；アセトニトリルなどのニトリル類；Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；並びにジメチルスルホキシドなどのスルホキシド類などが挙げられ、また、これらの溶媒は混合して使用してもよい。
この反応で用いられるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム(0)、ビス(トリフェニルホスフィン)パラジウム(II)クロリド、１,１’−ビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリドなどの有機パラジウム錯体が挙げられる。
パラジウム触媒の使用量は、一般式［２］の化合物または一般式［４］の化合物に対して、0.00001倍モル以上、好ましくは、0.001〜0.05倍モルあればよい。
酸化銀の使用量は、一般式［２］の化合物または一般式［４］の化合物に対して、等モル以上、好ましくは、1〜10倍モルである。
一般式［３ａ］の有機スズ化合物の使用量は、一般式［２］の化合物に対して、等モル以上、好ましくは、1.0〜2.0倍モルであり、また、一般式［５］の化合物の使用量は、一般式［４］の有機スズ化合物に対して、等モル以上、好ましくは、1.0〜5.0倍モルである。
このカップリング反応は、通常、不活性気体(例えば、アルゴン、窒素)雰囲気下、50〜170℃で、１分〜24時間実施すればよい。
(１−ｂ)別法として一般式［１ａ］の化合物は、塩基の存在下または不存在下、パラジウム触媒を用いて、一般式［２］の化合物と一般式［３ｂ］の有機ホウ素化合物をカップリング反応に付すことによって得ることができる。
この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、例えば、水；メタノール、エタノールおよびプロパノールなどのアルコール類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；塩化メチレン、クロロホルムおよびジクロロエタンなどのハロゲン化炭化水素類；１,２−ジメトキシエタン、ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類；酢酸エチルおよび酢酸ブチルなどのエステル類；アセトンおよびメチルエチルケトンなどのケトン類；アセトニトリルなどのニトリル類；Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；並びにジメチルスルホキシドなどのスルホキシド類などが挙げられ、また、これらの溶媒は混合して使用してもよい。
この反応で用いられる塩基としては、例えば、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよびトリエチルアミンなどが挙げられ、塩基の使用量は、一般式［２］の化合物に対して、等モル以上、好ましくは、2〜5倍モルである。また、この反応で用いられるパラジウム触媒としては、例えば、パラジウム-活性炭素、パラジウム黒などの金属パラジウム、塩化パラジウムなどの無機パラジウム塩、酢酸パラジウムなどの有機パラジウム塩、テトラキス(トリフェニルホスフィン)パラジウム(0)、ビス(トリフェニルホスフィン)パラジウム(II)クロリド、１,１’−ビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリドなどの有機パラジウム錯体が挙げられる。
パラジウム触媒の使用量は、一般式［２］の化合物に対して、0.00001倍モル以上、好ましくは、0.001〜0.05倍モルあればよい。
一般式［３ｂ］の有機ホウ素化合物の使用量は、一般式［２］の化合物に対して、等モル以上、好ましくは、1.0〜1.5倍モルである。
このカップリング反応は、通常、不活性気体(例えば、アルゴン、窒素)雰囲気下、50〜170℃で、１分〜24時間実施すればよい。
［製造法２］
(２−ａ)一般式［７］の化合物は、一般式［６］の化合物に、無水酢酸中、オルトギ酸メチルまたはオルトギ酸エチルなどのオルトエステルを反応させた後、一般式［８］の化合物を反応させることによって得ることができる。
これらの反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、例えば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類；メタノール、エタノールおよびプロパノールなどのアルコール類；塩化メチレン、クロロホルムおよびジクロロエタンなどのハロゲン化炭化水素類；Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；並びにジメチルスルホキシドなどのスルホキシド類などが挙げられ、また、これらの溶媒は混合して使用してもよい。
無水酢酸の使用量は、一般式［６］の化合物に対して、等モル以上であればよく、好ましくは、１〜10倍モルであればよい。
オルトエステルの使用量は、一般式［６］の化合物に対して、等モル以上であればよく、好ましくは、１〜10倍モルであればよい。
これらの反応は、通常、0〜150℃、好ましくは、50〜150℃で、20分〜50時間実施すればよい。
次いで、一般式［８］の化合物を反応させるが、その際の一般式［８］の化合物の使用量は、一般式［６］の化合物に対して、等モル以上であり、またこの反応は、通常、0〜100℃、好ましくは、10〜60℃で、20分〜30時間実施すればよい。(２−ｂ)別法として、一般式［６］の化合物に、無水酢酸などの酸無水物の存在下あるいは不存在下に、Ｎ,Ｎ−ジメチルホルムアミドジメチルアセタールまたはＮ,Ｎ−ジメチルホルムアミドジエチルアセタールなどのアセタールを反応させた後、一般式［８］の化合物を反応させて、一般式［７］の化合物を得ることができる。
これらの反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、具体的には前述の(２−ａ)と同様の溶媒が挙げられる。アセタールの使用量は、一般式［６］の化合物に対して、等モル以上であればよく、好ましくは、約1〜5倍モルであればよい。
酸無水物の使用量は、一般式［６］の化合物に対して、等モル以上、好ましくは、1〜10倍モルである。
これらの反応は、通常、0〜100℃、好ましくは、20〜85℃で、20分〜50時間実施すればよい。
次いで、一般式［８］の化合物を反応させるが、その際の一般式［８］の化合物の使用量は、一般式［６］の化合物に対して、等モル以上であり、またこの反応は、通常、0〜100℃、好ましくは、10〜60℃で、20分〜30時間実施すればよい。
一般式［１ａ］の化合物は、一般式［７］の化合物を、フッ化塩もしくは塩基の存在下または不存在下に閉環反応に付すことによって得ることができる。
この反応で使用される溶媒としては、反応に悪影響を及ぼさない溶媒であれば特に限定されないが、例えば、Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；ジオキサン、アニソール、ジエチレングリコールジメチルエーテルおよびジメチルセロソルブなどのエーテル類；並びにジメチルスルホキシドなどのスルホキシドなどが挙げられ、また、これらの溶媒は混合して使用してもよい。
この反応で所望に応じて用いられるフッ化塩としては、例えば、フッ化ナトリウムおよびフッ化カリウムなどが挙げられる。
また、所望に応じて用いられる塩基としては、例えば、炭酸水素ナトリウム、炭酸カリウム、カリウムtert-ブトキシドおよび水素化ナトリウムなどが挙げられる。
フッ化塩および塩基の使用量は、一般式［７］の化合物に対して、それぞれ、等モル以上であればよく、好ましくは、1.0〜3.0倍モルであればよい。
この反応は、通常、0〜180℃で、5分〜30時間実施すればよい。
このようにして得られた一般式［１ａ］の化合物を、例えば、酸化、還元、転位、置換、ハロゲン化、脱水もしくは加水分解などの自体公知の反応に付すことによって、またはそれらを適宜組み合わせることによって、他の一般式［１ａ］の化合物に誘導することができる。
このようにして得られた一般式［１ａ］の化合物またはその塩は、抽出、晶出および／またはカラムクロマトグラフィーなどの常法にしたがって単離精製することができる。
上で述べた製造法における一般式［１ａ］、［２］、［３ａ］、［３ｂ］、［４］、［５］、［６］、［７］または［８］の化合物において、異性体(例えば、光学異性体、幾何異性体および互変異性体など)が存在する場合、これらの異性体も使用することができ、また、溶媒和物、水和物および種々の形状の結晶も使用することができる。
また、一般式［２］、［３ａ］、［３ｂ］、［４］、［５］、［６］、［７］、［８］または［１ａ］の化合物において、アミノ基、ヒドロキシル基またはカルボキシル基を有する化合物は、予めこれらの基を通常の保護基で保護しておき、反応後、自体公知の方法でこれらの保護基を脱離することもできる。
本発明化合物を製造するための原料である一般式［２］、［４］および［６］の化合物は、例えば、WO/96/05192、WO/97/29102、特願平10-110146号、US3984548、US39885882およびUS5457104などに記載の方法またはそれに準じた方法により製造することができる。
一般式［３ａ］の有機スズ化合物および一般式［３ｂ］の有機ホウ酸化合物は、例えば、以下の製法Ａのように製造できる。
一般式［３ａ］の有機スズ化合物は、一般式［５］をスズ化反応に付すことにより製造することができる。
スズ化反応は、例えば、ブレティン・オブ・ザ・ケミカル・ソサェティ・オブ・ジャパン(Bull．Chem．Soc．Jpn.)、第56巻、第3855-3856頁(1983年)に記載の方法に準じて、パラジウム触媒とヘキサアルキルジスタナンを用いればよい。
この反応で使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、例えば、ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；１,２−ジメトキシエタン、ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類；アセトニトリルなどのニトリル類；Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；並びにジメチルスルホキシドなどのスルホキシド類などが挙げられ、また、これらの溶媒は混合して使用してもよい。
この反応で用いられるパラジウム触媒としては、例えば、パラジウム-活性炭素、パラジウム黒などの金属パラジウム、塩化パラジウムなどの無機パラジウム塩、酢酸パラジウムなどの有機パラジウム塩、テトラキス(トリフェニルホスフィン)パラジウム(0)、ビス(トリフェニルホスフィン)パラジウム(II)クロリド、１,１’−ビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリドなどの有機パラジウム錯体が挙げられる。
パラジウム触媒の使用量は、一般式［５］の化合物に対して、0.00001倍モル以上、好ましくは、0.001〜0.05倍モルあればよい。
ヘキサアルキルジスタナンの使用量は、一般式［５］の化合物に対して、等モル以上、好ましくは、1.0〜3.0倍モルであればよい。
この反応は、通常、40〜160℃で1時間〜72時間実施すればよい。
ホウ酸化反応は、例えば、第4版実験化学講座、24巻、第61〜90頁(1992年)、特願平10-140586号に記載の方法に準じて行えばよい。
具体的には、一般式［５］の化合物をリチオ化あるいはグリニャール反応に付した後、ホウ酸トリアルキルと反応させればよい。
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであれば特に限定されないが、例えば、n-ヘキサンおよびシクロヘキサンなどの脂肪族炭化水素類；１,２−ジメトキシエタン、ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類などが挙げられ、また、これらの溶媒は混合して使用してもよい。
この反応に使用されるリチオ化剤としては、例えば、n-ブチルリチウム、tert-ブチルリチウム、フェニルリチウムおよびメチルリチウムなどのアルキル金属試薬；リチウムジイソプロピルアミドおよびリチウムビス(トリメチルシリル)アミドなどのアミド塩基が挙げられる。また、グリニャール試薬は、金属マグネシウムを反応させることにより得ることができる。
この反応に使用されるホウ酸トリアルキルとしては、例えば、ホウ酸トリメチル、ホウ酸トリエチル、ホウ酸トリイソプロピルおよびホウ酸トリブチルなどが挙げられる。
リチオ化剤、金属マグネシウムおよびホウ酸トリアルキルの使用量は、一般式［５］の化合物に対して、それぞれ、等モル以上、好ましくは、1〜2倍モルである。
この反応は通常、-70℃〜50℃、好ましくは、-60〜0℃で10分〜24時間実施すればよい。
ホウ酸化の別法として、塩基の存在下、パラジウム触媒とジアルコキシボランまたはアルコキシボランを反応させる方法を用いてもよい。
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよく、例えば、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；n-ヘキサンおよびシクロヘキサンなどの脂肪族炭化水素類；塩化メチレン、クロロホルムおよびジクロロエタンなどのハロゲン化炭化水素類；ジオキサン、テトラヒドロフラン、アニソール、ジエチレングリコールジエチルエーテルおよびジメチルセロソルブなどのエーテル類；酢酸エチルおよび酢酸ブチルなどのエステル類；アセトンおよびメチルエチルケトンなどのケトン類；アセトニトリルなどのニトリル類；Ｎ,Ｎ−ジメチルホルムアミドおよびＮ,Ｎ−ジメチルアセトアミドなどのアミド類；並びにジメチルスルホキシドなどのスルホキシド類などが挙げられ、これらの溶媒は、混合して使用してもよい。
この反応で所望に応じて用いられる塩基としては、例えば、酢酸カリウム、カリウムtert-ブトキシド、ジイソプロピルエチルアミン、ピリジン、１,８−ジアザビシクロ［５.４.０］−７−ウンデセン、トリブチルアミンおよびトリエチルアミンなどが挙げられる。その使用量は、一般式［５］の化合物またはその塩に対して等モル以上、好ましくは1〜3倍モルである。
この反応で用いられるパラジウム触媒としては、例えば、パラジウム-活性炭素、パラジウム黒などの金属パラジウム、塩化パラジウムなどの無機パラジウム塩、酢酸パラジウムなどの有機パラジウム塩、テトラキス(トリフェニルホスフィン)パラジウム(0)、ビス(トリフェニルホスフィン)パラジウム(II)クロリド、１,１−ビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリドなどの有機パラジウム錯体が挙げられる。
パラジウム触媒の使用量は、一般式［５］の化合物に対して、0.00001倍モル以上、好ましくは、0.001〜0.05倍モルあればよい。
この反応に使用されるジアルコキシボランとしては、例えば、４,４,５,５−テトラメチル−１,３,２−ジオキサボロラン、カテコールボランなどが挙げられ、アルコキシジボランとしては、例えば、４,４,５,５−テトラメチル−１,３,２−ジオキサボロラン−２−イル−４’,４’,５’,５’−テトラメチル−１’,３’,２’−ジオキサボロランなどが挙げられる。
その使用量は、一般式［５］の化合物に対して等モル以上、好ましくは1.0〜1.5倍モルである。
この反応は通常、不活性気体(例えば、アルゴン、窒素)雰囲気下、0〜150℃、好ましくは、80〜11O℃で1〜24時間実施すればよい。
一般式［５］の化合物は、市販品の購入もしくは公知の方法により製造される文献記載の化合物を使用することができ、また、文献記載の方法もしくはそれに準じた方法で製造される化合物を使用すればよい。以下に参考となる文献を挙げる。
(1)イソインドリン環を有するもの
Organic Syntheses,5,1064-1066
Arzniem.Forsh./Drug Res.30(II),1487-1493(1980)
特開昭63-179872号
特開平2-62875号
特開平3-52888号
(2)イソキノリン環を有するもの
J.Org.Chem.,45(26),5312-5315(1980)
Synthesis 70-72(1980)
(3)キノリン環を有するもの
新実験化学講座14[IV],2069(1978)
Chemical Abstracts Vol.80:108331
(4)キナゾリン環を有するもの
Chemical Abstracts Vol.60:524d
(5)3,4-ジヒドロ−２Ｈ−１,４−ベンゾオキサジン環を有するもの
特開昭61-215381号
(6)ベンゾ［ｂ］チオフェン環を有するもの
J.Org.Chem.,60(7),1936-1938(1995)
(7)１,４−ベンゾジオキサン環を有するもの
Chemical Abstracts Vol.53:6234c
(8)１,３−ジヒドロ−イソベンゾフラン環を有するもの
Chemical Abstracts Vol.47:8692h
Tetrahedron,953-958(1962)
特表昭63-501361号
(9)ヒドロキシアルキル置換ナフチル
特開昭60-155140号
(10)ヒドロキシイミノ置換インデン
WO96/36596
本発明化合物を医薬として用いる場合、通常製剤化に使用される賦形剤、担体および希釈剤などの製剤補助剤を適宜混合してもよく、これらは常法にしたがって、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、粉体製剤、坐剤、軟膏剤または注射剤などの形態で経口または非経口で投与することができる。また投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができ、通常成人に対しては、経口または非経口(例えば、注射、点滴および直腸部位への投与など)的投与により、１日、0.15〜100mg/kgを１回から数回に分割して投与すればよい。
次ぎに、本発明の代表的化合物についての薬理作用を説明する。
抗菌作用
［試験方法］
日本化学療法学会標準法［ケモテラピー(CHEMOTHERAPY)第29巻、第1号、第76〜79頁(1981年)］に従い、ミュラーヒントン・ブロース(Mueller Hinton broth)［ディフコ(Difco)社製］で37℃、20時間培養し、菌量を106個／プレート(108個／ml)に調整した菌液１白金耳を、薬剤を含むミュラーヒントン・アガー(Mueller Hinton agar)培地［ディフコ(Difco)社製］に接種し、37℃で20時間培養した後、菌の発育の有無を観察し、菌の発育が阻止された最小濃度をもってMIC(μg/ml)とした。
その結果を表３に示す。表３のａ〜ｄの記号は以下の菌株を示す。また、番号は、実施例の化合物を示す。
ａ：黄色ブドウ球菌(S.aureus FDA209P)
ｂ：β−ラクタマーゼ産生黄色ブドウ球菌(S.aureus F-137)
ｃ：メチシリン(Methicillin)耐性黄色ブドウ球菌(S.aureus F-597)
ｄ：大腸菌(E.coli NIHJ JC-2)
【表３】
次に本発明を参考例および実施例を挙げて説明するが、本発明はこれらに限定されるものではない。
なお、溶離液における混合比は、全て用量比であり、また、カラムクロマトグラフィーにおける担体は、BW-127ZH(富士シリシア化学製)を用いた。また、参考例および実施例中で用いられる記号は、次の意味を有する。
Ａｃ：アセチル基
Ｃｂｚ：ベンジルオキシカルボニル基
ｄ1−ＴＦＡ：重トリフルオロ酢酸
また、ＮＭＲにおける数値は、δ値を示す。
参考例１
１−シクロプロピル−７−フルオロ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル6.80gをジメチルスルホキシド136mlに懸濁し、1.5時間を要してナトリウムメトキシドのメタノール溶液(28%溶液)10.89gを滴下する。40℃で1.5時間撹拌後、水500mlおよび酢酸エチル300mlの混合溶媒に加え、6mol/L塩酸でpH1に調製した後、析出晶を濾取すれば、無色結晶の１−シクロプロピル−７−メトキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸1.94gを得る。
IR(KBr)cm-1:1723
NMR(CDCl3):0.8-1.4(4H,m),2.70(3H,s),3.9-4.3(1H,m),4.02(3H,s),7.16(1H,d,J=8.8Hz),8.37(1H,d,J=8.8Hz),8.91(1H,s)
参考例２
１−シクロプロピル−７−メトキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸2.40gを47%臭化水素酸48mlに懸濁し、5時間加熱還流する。反応混合物を室温まで冷却後、水200mlを加え析出晶を濾取すれば、無色結晶の１−シクロプロピル−７−ヒドロキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸・１水和物2.11gを得る。
IR(KBr)cm-1:1718
NMR(d1-TFA):1.1-1.8(4H,m),2.99(3H,s),4.5-4.9(1H,m),7.60(1H,d,J=8.8Hz),8.54(1H,d,J=8.8Hz),9.48(1H,s)
参考例３
１−シクロプロピル−７−ヒドロキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸・１水和物500mgをエタノールに懸濁し、これにパラトルエンスルホン酸・1水和物185mgを加え、45時間共沸脱水する。反応混合物を室温まで冷却後、水50mlおよびクロロホルム50mlの混合溶媒に加え、有機層を分取する。分取した有機層を無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；クロロホルム：エタノール=30:1］で精製すれば、無色結晶の1−シクロプロピル−７−ヒドロキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル300mgを得る。
IR(KBr)cm-1:1728
NMR(CDCl3):0.8-1.8(7H,m),2.70(3H,s),3.8-4.2(1H,m),4.42(2H,q,d=6.8Hz),7.37(1H,d,J=8.8Hz),8.26(1H,d,J=8.8Hz),8.71(1H,s)
参考例４
１−シクロプロピル−７−ヒドロキシ−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル300mgを塩化メチレン6mlに懸濁し、氷冷下、ジイソプロピルアミン202mgおよびトリフルオロメタンスルホン酸無水物364mgを加え、室温で3時間撹拌する。反応混合物を水30mlおよびクロロホルム30mlの混合溶媒に加え、1mol/L塩酸でpH1に調製した後有機層を分取する。分取した有機層を飽和炭酸水素ナトリウム水溶液、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=1：1］で精製すれば、無色結晶の１−シクロプロピル−８−メチル−４−オキソ−７−［［(トリフルオロメチル)スルホニル］オキシ］−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル270mgを得る。
IR(KBr)cm-1:1724,1214
NMR(CDCl3):0.8-1.7(7H,m),2.81(3H,s),3.8-4.1(1H,m),4.40(2H,q,J=7.6Hz),7.29(1H,d,J=8.8Hz),8.41(1H,d,J=8.8Hz),8.71(1H,s)
参考例５
４−ブロモ−１,２−ベンゼンジオール2.00gをエタノール10mlに溶解し、これにジブロモエタン3.56gおよび水酸化カリウム1.44gを加えた後、15時間加熱還流する。反応混合物を室温まで冷却し不溶物を濾去後、濾液を減圧下に濃縮する。得られた残留物をカラムクロマトグラフィー［溶離液；トルエン］で精製すれば、無色油状の６−ブロモ−１,４−ベンゾジオキサン0.92gを得る。
IR(ニート)cm-1:1601,1490,1302,1286,1251
NMR(CDCl3):4.23(4H,s),6.6-7.1(3H,m)
参考例６
４−ブロモアニリン2.00g、硫酸鉄(II)7水和物7.86g、３−ニトロベンゼンスルホン酸ナトリウム1.26g、ホウ酸0.60g、グリセリン3.56gを混合し、これに濃硫酸2.14mlを加え120℃で6時間撹拌する。反応混合物を室温まで冷却後、水50mlおよびクロロホルム50mlの混合溶媒に加え、5mol/L水酸化ナトリウム水溶液でpH12に調整し、次いで、不溶物を濾去後、濾液の有機層を分取する。分取した有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；トルエン:酢酸エチル=15:1］で精製すれば、褐色油状の６−ブロモキノリン1.14gを得る。
IR(ニート)cm-1:1490,830
NMR(CDCl3):7.40(1H,dd,J=4.4Hz,J=8.5Hz),7.7-8.2(4H,m),8.91(1H,dd,J=1.7Hz,J=4.4Hz)
同様にして次の化合物を得る。
・６−ブロモ−８−フルオロキノリン
IR(KBr)cm-1:1765,1532
NMR(CDCl3):5.70(2H,s),8.39(lH,bs),8.64(1H,bs)
参考例７
６−ブロモ−１,３−ジヒドロ−１−イソベンゾフラノン10.00gをテトラヒドロフラン500mlに溶解し、この溶液に10℃で三フッ化ホウ素ジエチルエーテル錯体200gおよび水素化アルミニウムリチウム3.56gを加え窒素雰囲気下、氷冷で30分間撹拌後、さらに4時間加熱還流する。反応混合物を室温まで冷却後、酢酸エチル300mlおよび5%食塩水400mlの混合溶媒に加え1mol/L塩酸でpH1に調整し有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン:酢酸エチル=20:1］で精製すれば、無色結晶の５−ブロモ−１,３−ジヒドロイソベンゾフラン2.00gを得る。
IR(KBr)cm-1:2854,1474,1050,808
NMR(CDCl3):5.05(4H,s),7.0-7.5(3H,m)
参考例８
(１)(６−ブロモ−２−ナフチル)メタノール0.70gを塩化メチレン7mlに懸濁し、これに氷冷下、塩化チオニル0.42gを加え、室温で2時間撹拌する。反応混合物にジイソプロピルエーテルを加え濾取すれば、無色結晶の２−ブロモ−６−(クロロメチル)ナフタレン0.42gを得る。
NMR(CDCl3):4.93(2H,s),7.50-7.75(2H,m),7.88(1H,d,J=1.8Hz),7.9-8.1(2H,m),8.22(1H,bs)
(２)２−ブロモ−６−(クロロメチル)ナフタレン0.20gをエタノール1mlに溶解し、これにジメチルアミン溶液(約50%)0.5mlを加え、室温で3時間撹拌する。反応混合物に水10mlおよびクロロホルム10mlを加え、有機層を分取する。分取した有機層を水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=5:1］で精製すれば、油状のＮ,Ｎ−ジメチル−(６−ブロモ−２−ナフチル)メタンアミン0.16gを得る。
NMR(CDCl3):2.28(6H,s),3.56(2H,s),7.4-8.4(6H,m)
参考例９
(１)５−ブロモ−２−メチル−３−ニトロ安息香酸メチルエステル3.00gを四塩化炭素30mlに溶解し、これにＮ−ブロモコハク酸イミド2.34gおよび触媒量の過酸化ベンゾイルを加え、12時間加熱還流する。反応混合物を室温まで冷却し不溶物を濾去後、濾液に水30mlを加え、1mol/L水酸化ナトリウム水溶液でpH9に調整し有機層を分取する。分取した有機層を無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=20:1］で精製すれば、油状の５−ブロモ−２−(ブロモメチル)−３−ニトロ安息香酸メチルエステル3.49gを得る。
NMR(CDCl3):4.01(3H,s),5.09(2H,s),8.09(1H,d,J=1.4Hz),8.23(1H,d,J=1.4Hz)
(２)５−ブロモ−２−(ブロモメチル)−３−ニトロ安息香酸メチルエステル4.56gをジメチルスルホキシド13.7mlに溶解し、これに酢酸ナトリウム3.22gを加え、室温で1時間撹拌する。反応混合物を水100mlおよび酢酸エチル100mlの混合溶媒に加え、有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物にn-ヘキサンを加え濾取すれば、無色結晶の２−［(アセチルオキシ)メチル］−５−ブロモ−３−ニトロ安息香酸メチルエステル3.62gを得る。
IR(KBr)cm-1:1749,1728,1532
NMR(CDCl3):2.00(3H,s),3.97(3H,s),5.55(2H,s),8.05(1H,d,J=1.4Hz),8.15(1H,d,J=1.4Hz)
(３)２−［(アセチルオキシ)メチル］−５−ブロモ−３−ニトロ安息香酸メチルエステル3.60gをエタノール18mlに懸濁し、これに1mol/L水酸化ナトリウム水溶液18mlを加え50℃で2時間撹拌する。反応混合物を減圧下に濃縮し、得られた残留物に水100mlおよび酢酸エチル50mlを加え1mol/L塩酸でpH1.0に調整した後、析出晶を濾取すれば、無色結晶の６−ブロモ−４−ニトロ−１,３−ジヒドロ−１−イソベンゾフラノン1.79gを得る。
IR(KBr)cm-1:1765,1532
NMR(CDCl3):5.70(2H,s),8.39(1H,bs),8.64(1H,bs)
(４)６−ブロモ−４−ニトロ−１,３−ジヒドロ−１−イソベンゾフラノン0.50gをトルエン40mlに溶解し、これに−70℃で5分間を要して水素化ジイソブチルアルミニウムのトルエン溶液(1.01M溶液)2.88mlを滴下した後、同温度で1時間撹拌する。反応混合物を水50mlおよび酢酸エチル50mlの混合溶媒に加え、6mol/L塩酸でpH1.0に調整した後、有機層を分取する。分取した有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物を塩化メチレン10mlに懸濁し、これに−60℃でトリフルオロ酢酸0.65gを加え、同温度で15分間撹拌する。次いで、同温度でトリエチルシラン0.67gを加え、同温度で20分間撹拌後、5℃まで昇温する。反応混合物を水20mlおよび酢酸エチル20mlの混合溶媒に加え、5mol/L水酸化ナトリウム水溶液でpH8.0に調整した後、不溶物を濾去し、濾液の有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物にジイソプロピルエーテルを加え濾取すれば、黄色結晶の６−ブロモ−４−ニトロ−１,３−ジヒドロイソベンゾフラン0.13gを得る。
IR(KBr)cm-1:1532,1334
NMR(CDCl3):5.18(2H,brs),5.46(2H,brs),7.69(1H,brs),8.27(1H,brs)
(５)６−ブロモ−４−ニトロ−１,３−ジヒドロイソベンゾフラン0.74gをメタノールに懸濁し、これに塩酸2.2mlを加えた後、鉄粉0.51gを5分間を要して加える。室温で1時間撹拌する。反応混合物を水50mlおよび酢酸エチル50mlの混合溶媒に加え、炭酸カリウムでpH8.0に調整した後、不溶物を濾去し、濾液の有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=3:1］で精製すれば、橙色結晶の６−ブロモ−１,３−ジヒドロ−４−イソベンゾフランアミン0.56gを得る。
IR(KBr)cm-1:3365
NMR(CDCl3):3.60(2H,brs),4.8-5.2(4H,m),6.72(1H,brs),6.78(1H,brs)
(６)６−ブロモ−１,３−ジヒドロ−４−イソベンゾフランアミン0.53gを塩化メチレン6mlに懸濁し、氷冷下、トリエチルアミン0.33gを加えた後、塩化アセチル0.25gの塩化メチレン3ml溶液を5分間を要して滴下し、同温度で30分間撹拌する。反応混合物に水10mlを加え、飽和炭酸水素ナトリウム水溶液でpH5.0に調整した後、有機層を分取する。分取した有機層を無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物にジイソプロピルエーテルを加え濾取すれば、無色結晶のＮ1(６−ブロモ−１,３−ジヒドロ−４−イソベンゾフラニル)アセトアミド0.57gを得る。
IR(KBr)cm-1:1670
NMR(CDCl3):2.06(3H,s),4.8-5.1(4H,m),7.26(1H,brs),7.78(1H,brs)
参考例１０
５−ブロモ−１−インダノンオキシム2.00gをメタノール80mlに溶解し、これに塩化ニッケル(II)六水和物4.21gを加え、-40℃で水素化ホウ素ナトリウム2.00gを30分間を要して分割添加した後、-25℃まで昇温し、1時間撹拌する。反応混合物を減圧下に濃縮し、得られた残留物に水150mlおよび酢酸エチル150mlを加え、セライト濾過した後有機層を分取する。分取した有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物を塩化メチレン32mlに溶解し、トリエチルアミン0.91gを加え、氷冷下、塩化カルボベンゾキシ1.54gを滴下し、室温で2時間撹拌する。反応混合物に水50mlを加え、1mol/L塩酸でpH1に調整し有機層を分取する。分取した有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=4:1］で精製すれば、無色結晶のＮ−(５−ブロモ−２,３−ジヒドロ−１Ｈ−インデニル)カルバミン酸ベンジルエステル0.81gを得る。
IR(KBr)cm-1:3307,1681,1531,1248
NMR(CDCl3):1.6-2.1(1H,m),2.4-2.8(1H,m),2.8-3.1(2H,m),4.7-5.1(1H,m),5.1-5.3(1H,m),5.16(2H,s),7.0-7.5(8H,m)
参考例１１
(１)１−(３−ブロモフェニル)−１−プロパノン1.00gをジエチルエーテル2mlに溶解し、これに濃塩酸0.022mlおよび亜硝酸エチルアルコール溶液(約15%w/w)4.89mlを加えた後、50℃で５時間撹拌する。反応混合物を減圧下に濃縮し、得られた残留物に水およびn-ヘキサンを加え、結晶を濾取すれば、無色結晶の１−(３−ブロモフェニル)−２−ヒドロキシイミノ−１−プロパノン0.95gを得る。
IR(KBr)cm-1:3300,1649
NMR(CDCl3):2.17(3H,s),7.2-8.1(4H,m),8.40(1H,brs)
(２)、１−(３−ブロモフェニル)−２−ヒドロキシイミノ−１−プロパノン0.50gを酢酸2.5mlに溶解し、無水酢酸0.31gを加えた後、亜鉛末0.41gを30分間を要して加え、室温で2時間撹拌する。反応混合物に水20mlおよび酢酸エチル20mlを加え、飽和炭酸水素ナトリウム水溶液でpH7.5に調整した後、不溶物を濾去し、濾液の有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=1:1］で精製すれば、油状のＮ1−［２−(３−ブロモフェニル)−１−メチル−２−オキソエチル］アセトアミド0.36gを得る。
IR(ニート)cm-1:1697,1656
NMR(CDCl3):1.42(3H,d,J=4.7Hz),2.06(3H,s),5.3-5.7(1H,m),6.50(1H,brs),7.2-8.2(4H,m)
(３)Ｎ1−［２−(３−ブロモフェニル)−１−メチル−２−オキソエチル］アセトアミド0.33gをエタノール3mlに溶解し、これに5℃で水素化ホウ素ナトリウム23mgを加え、同温度で30分間撹拌する。反応混合物を減圧下に濃縮し、得られた残留物に水10mlおよび酢酸エチル10mlを加え有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去すれば、無色油状のＮ1−［２−(３−ブロモフェニル)−２−ヒドロキシ−１−メチルエチル］アセトアミド0.29gを得る。
IR(ニート)cm-1:3304,1648
NMR(CDCl3):1.00(3H,d,J=4.6Hz),2.00(3H,s),3.8-4.7(2H,m),4.80(1H,brs),5.75(1H,brs),7.1-7.6(4H,m)
(４)Ｎ1［２−(３−ブロモフェニル)−２−ヒドロキシ−１−メチルエチル］アセトアミド0.28gをデカリン2mlに懸濁し、これに五酸化二燐0.44gを加え、1.5時間加熱還流する。反応混合物を室温まで冷却後、水10mlおよびクロロホルム10mlの混合溶媒に加え、1mol/Lに水酸化ナトリウム水溶液でpH10に調整した後、不溶物を濾去し、濾液の有機層を分取する。分取した有機層を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=3:1］で精製すれば、黄色結晶の６−ブロモ−１,３−ジメチル−イソキノリン0.05gを得る。
IR(KBr)cm-1:1614,1562
NMR(CDCl3):2.65(3H,s),2.92(3H,s),7.26(1H,s),7.57(1H,dd,J=1.3Hz,J=6.0Hz),7.88(1H,d,J=1.3Hz),7.94(1H,d,J=6.0Hz)
参考例１２
６−ブロモ−１,４−ベンゾジオキサン0.69gをテトラヒドロフラン3.5mlに溶解し、この溶液に-70℃で、15分間を要してn-ブチルリチウムのヘキサン溶液(1.54M溶液)2.5mlを滴下する。同温度で1時間撹拌後、5分間を要してホウ酸トリイソプロピル0.73gを滴下する。さらに同温度で30分間撹拌後、水3.5mlを加え30分間を要して0℃まで昇温する。反応混合物に酢酸エチル10mlを加え、1mol/L塩酸でpH2に調製した後有機層を分取する。分取した有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物にn-ヘキサンを加え濾取すれば、淡黄色固体の１,４−ベンゾジオキサン−６−イルホウ酸0.36gを得る。
IR(KBr)cm-1:1066,1121,1314,1420
NMR(CDCl3):4.2-4.5(4H,m),6.95(1H,d,J=8.3Hz),7.6-7.9(2H,m)
同様にして次の化合物を得る。
・１,３−ベンゾジオキソール−５−イルホウ酸
NMR(d6-DMSO):5.98(4H,s),6.8-7.0(1H,m),7.2-7.5(2H,m)
参考例１３
２−アセトキシ−６−ブロモナフタレン0.90gをトルエン13.5mlに溶解し、ヘキサブチルジスタナン3.94gおよびビス(トリフェニルホスフィン)パラジウム(II)クロリド72mgを加えた後、窒素雰囲気下、3時間加熱還流する。反応混合物を減圧下に濃縮し、得られた残留物をカラムクロマトグラフィー［溶離液；n-ヘキサン：酢酸エチル=20.1］で精製すれば、油状の２−アセトキシ−６−トリブチルスタニルナフタレン0.89gを得る。
IR(ニート)cm-1:1765
NMR(CDCl3):0.6-1.8(27H,m),2.35(3H,s),7.0-8.0(6H,m)
同様にして次の化合物を得る。
・トリブチル(１,３−ジヒドロ−５−イソベンゾフラニル)スタナン
IR(ニート)cm-1:1464,1354,1049,906,804
NMR(CDCl3):0.8-2.0(27H,m),5.11(4H,s),7.2-7.5(3H,m)
・６−(１,１,１−トリブチルスタニル)キノリン
IR(ニート)cm-1:1560,1488,1458,1340,1058,831
NMR(CDCl3):0.7-2.0(27H,m),7.3-7.5(1H,s),7.7-8.2(4H,m),8.8-9.0(1H,m)
・ベンゾ［ｂ］チオフェン−５−イル(トリブチル)スタナン
IR(ニート)cm-1:1458,1040,797,692
NMR(CDCl3):0.7-1.8(27H,m),7.3-7.5(3H,m),7.8-8.0(2H,m)
・Ｎ−［５−(１,１,１−トリブチルスタニル)−２,３−ジヒドロ−１Ｈ−１−インデニル］カルバミン酸ベンジルエステル
NMR(CDCl3):0.7-1.7(31H,m),2.8-3.0(1H,m),5.17(2H,s),7.2-7.5(8H,m)
・６−(１,１,１−トリブチルスタニル)キナゾリン
・８−フルオロ−６−(１,１,１−トリブチルスタニル)キノリン
・５−(１,１,１−トリブチルスタニル)−１Ｈ−インドール
NMR(CDCl3):0.7-2.0(27H,m),6.5-6.6(1H,m),7.1-7.5(3H,m),7.74(1H,s)
・６−(１,１,１−トリブチルスタニル)イソキノリン
NMR(CDCl3):0.8-1.8(27H,m),7.6-8.0(4H,m),8.52(1H,d,J=5.86Hz),9.22(1H,s)
・Ｎ,Ｎ−ジメチル−Ｎ−［［６−(１,１,１−トリブチルスタニル)−２−ナフチル］メチル］アミン
NMR(CDCl3):0.8-2.0(27H,m),2.28(6H,s),3.57(2H,s),7.4-8.0(6H,m)
・７−(１,１,１−トリブチルスタニル)−３,４−ジヒドロ−２Ｈ−１.４−ベンズオキサジン−４−カルボン酸ベンジルエステル
IR(ニート)cm-1:1718,1493,1406,1342,1282,1224,1141,1063,1026
NMR(CDCl3):0.8-1.6(27H,m),3.8-4.0(2H,m),4.2-4.4(2H,m),5.26(2H,s),6.9-7.0(1H,m),7.2-7.5(6H,m),7.7-7.9(1H,m)
・１,３−ジメチル−６−(１,１,１−トリブチルスタニル)イソキノリン
IR(ニート)cm-1:1612,1561,1458,1388,1046
NMR(CDCl3):0.7-1.8(27H,m),2.65(3H,s),2.92(3H,s),7.3-8.1(4H,m)
・Ｎ1−［６−(１,１,１−トリブチルスタニル)−１,３−ジヒドロ−４−イソベンゾフラニル］アセトアミド
IR(ニート)cm-1:1664,1542,1459,1401,1293,1041
NMR(CDCl3):0.8-1.7(27H,m),2.17(3H,s),5.07(2H,s),5.10(2H,s),7.0(1H,br),7.1(1H,brs),7.4(1H,brs)
実施例１
７−ブロモ−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル4.40gをトルエン66mlに懸濁し、これに６−(１,１,１−トリブチルスタニル)キノリン7.80gおよびビス(トリフェニルホスフィン)パラジウム(II)クロリド0.18gを加えた後、窒素雰囲気下、3時間加熱還流する。反応混合物を室温まで冷却後、ジエチルエーテル70mlを加え、析出物を濾取する。析出物をカラムクロマトグラフィー［溶離液；クロロホルム:エタノール=50:1］で精製後、ジエチルエーテルを加え析出晶を濾取すれば、無色結晶の１−シクロプロピル−８−メチル−４−オキソ−７−(６−キノリル)−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル4.71gを得る。
IR(KBr)cm-1:1718
NMR(CDCl3):1.0-1.5(7H,m),2.66(3H,s),3.9-4.2(1H,m),4.42(2H,q,J=7.08Hz),7.4-7.6(2H,m),7.7-7.9(2H,m),8.2-8.5(3H,m),8.76(1H,s),8.9-9.0(1H,m)
実施例２〜１５
実施例１と同様にして表４ａおよび表４ｂの化合物を得る。
【表４ａ】
No.2:１−シクロプロピル−７−(１,３−ジヒドロ−５−イソベンゾフラニル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
No.3:７−［６−(アセチルオキシ)−２−ナフチル］−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1760,1731
NMR(CDCl3):1.0-1.7(7H,m),2.39(3H,s),2.63(3H,s),3.9-4.1(1H,m),4.42(2H,q,J=7.08Hz),7.2-8.0(7H,m),8.39(1H,d,J=8.05Hz),8.75(1H,s)
No.4:７−(ベンゾ［ｂ］チオフェン−５−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1687
NMR(CDCl3):1.0-1.6(7H,m),2.64(3H,s),3.9-4.2(1H,m),4.42(2H.q,J=7.08Hz),7.3-7.6(4H,m),7.81(1H,s),7.97(1H,d,J=8.30Hz),8.37(1H,d,J=8.06Hz),8.74(1H,s)
No.5:１−シクロプロピル−７−(１,３−ジヒドロ−５−イソベンゾフラニル)−８−メトキシ−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1729
NMR(CDCl3):1.0-1.3(4H,m),1.42(3H,t,J=7.08Hz),3.37(3H,s),3.9-4.1(1H,m),4.41(2H,q,J=7.08Hz),5.20(4H,s),7.3-7.5(4H,m),8.30(1H,d,J=8.30Hz),8.67(1H,s)
No.6:７−［４−(ベンジルオキシカルボニル)−３,４−ジヒドロ−２Ｈ−１,４−ベンズオキサジン−７−イル］−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
NMR(CDCl3):0.9-1.6(7H,m),2.63(3H,s),3.9-4.1(3H,m),4.2-4.6(4H,m),5.30(2H,s),6.8-7.0(2H,m),7.2-7.5(6H,m),8.01(1H,d,J=8.55Hz),8.32(1H,d,J=8.05Hz),8.72(1H,s)
No.7:１−シクロプロピル−７−［６−［(ジメチルアミノ)メチル］−２−ナフチル］−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
NMR(CDCl3):1.0-1.6(7H,m),2.32(6H,s),2.65(3H,s),3.62(2H,s),3.9-4.2(1H,m),4.42(2H,q,J=7.08Hz),7.4-8.0(7H,m),8.39(1H,d,J=8.06Hz),8.75(1H,s)
No.8:７−［７−(アセチルアミノ)−１,３−ジヒドロ−５−イソベンゾフラニル］−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
No.9:７−(１−［［(ベンジルオキシ)カルボニル］アミノ］−２,３−ジヒドロ−１Ｈ−５−インデニル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
NMR(CDCl3):0.8-1.4(7H,m),2.5-3.1(7H,m),3.9-4.3(3H,m),4.8-5.2(3H,m),7.0-7.6(10H,m),8.34(1H,d,J=7.8Hz),8.73(1H,s)
No.10:１−シクロプロピル−７−(１Ｈ−５−インドリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1718
NMR(CDCl3):1.0-1.5(7H,m),2.64(3H,s),3.8-4.2(1H,m),4,41(2H,q,J=7.6Hz),6.5-6.7(1H,m),7.1-7.7(5H,m),8.3-8.5(1H,m),8.74(1H,s)
No.11:１−シクロプロピル−７−(８−フルオロ−６−キノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1716
NMR(CDCl3):1.0-1.6(7H,m),2.67(3H,s),3.9-4.2(1H,m),4.42(2H,q,J=7.08Hz),7.3-7.7(4H,m),8.27(1H,d,J=8.30Hz),8.40(1H,d,J=8.30Hz),8.76(1H,s),9.0-9.1(1H,m)
No.12:１−シクロプロピル−７−(６−イソキノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1728
NMR(CDCl3):1.0-1.5(7H,m),2.64(3H,s),3.9-4.1(1H,m),4.42(2H,q,J=7.08Hz),7.2-7.8(4H,m),8.1(1H,d),8.41(1H,d,J=8.06Hz),8.61(1H,d,J=5.86Hz),8.76(1H,s),9.34(1H,s)
No.13:１−シクロプロピル−７−(１,３−ジメチル−６−イソキノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1733
NMR(CDCl3):1.0-1.6(7H,m),2.63(3H,s),2.69(3H,s),3.00(3H,s),3.9-4.1(1H,m),4.42(2H,q,J=7.08Hz),7.2-7.7(4H,m),8.17(1H,d,J=8.30Hz),8.40(1H,d,J=8.05Hz),8.76(1H,s)
No.14:１−シクロプロピル−８−メチル−４−オキソ−７−(６−キナゾリニル)−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
IR(KBr)cm-1:1732
NMR(CDCl3):1.0-1.6(7H,m),2.65(3H,s),4.0-4.2(1H,m),4.42(2H,q,J=7.08Hz),7.39(1H,d,J=8.31Hz),7.9-8.3(3H,m),8.42(1H,d,J=8.06Hz),8.76(1H,s),9.41(1H,s),9.49(1H,s)
No.15:１−シクロプロピル−８−メトキシ−４−オキソ−７−(６−キノリル)−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
NMR(CDCl3):1.0-1.6(7H,m),3.36(3H,s),3.9-4.2(1H,m),4.42(2H,q,J=7.08Hz),7.4-7.6(2H,m),8.0-8.4(5H,m),8.70(1H,s),8.9-9.0(1H,m)
実施例１６
１−シクロプロピル−８−メチル−４−オキソ−７−(６−キノリル)−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル4.50gをエタノール45mlに懸濁し、これに1mol/L水酸化ナトリウム水溶液22.6mlを加えた後、室温で5時間撹拌する。反応混合物を濾過後、炭酸ガスを吹き込む。析出晶を濾取すれば、無色結晶の１−シクロプロピル−８−メチル−４−オキソ−７−(６−キノリル)−１，４−ジヒドロ−３−キノリンカルボン酸3.97gを得る。
IR(KBr)cm-1:1707
NMR(d1-TFA):1.3-1.8(4H,m),3.00(3H,s),4.7-5.0(1H,m),8.0-8.9(6H,m),9.2-9.4(2H,m),9.73(1H,s)
実施例１７〜３０
実施例１６と同様にして表５ａおよび表５ｂの化合物を得る。
【表５ａ】
No.17:１−シクロプロピル−７−(１,３−ジヒドロ−５−イソベンゾフラニル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1730
NMR(d1-TFA):1.2-2.0(4H,m),3.00(3H,s),4.6-5.0(1H,m),5.48(4H,s),7.4-7.7(3H,m),7.96(1H,d,J=8.5Hz),8.68(1H,d,J=8.5Hz),9.68(1H,s)
No.18:１−シクロプロピル−７−［６−(ヒドロキシ)−２−ナフチル］−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1706
NMR(d1-TFA):1.3-1.9(4H,m),3.0-3.2(3H,m),4.7-5.0(1H,m),7.3-8.2(7H,m),8.6-8.8(1H,m),9.6-9.8(1H,m)
No.19:７−(ベンゾ［ｂ］チオフェン−５−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1725
NMR(d1-TFA):1.1-1.9(4H,m),3.02(3H,s),4.6-5.0(1H,m),7.3-7.7(3H,m),7.9-8.2(3H,m),8.68(1H,d),9.67(1H,s)
No.20:１−シクロプロピル−７−(１,３−ジヒドロ−５−イソベンゾフラニル)−８−メトキシ−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1724
NMR(CDCl3):1.0-1.4(4H,m),3.42(3H,s),4.0-4.3(1H,m),5.21(4H,s),7.3-7.6(4H,m),8.31(1H,d,J=8.3Hz),8.94(1H,s),14.75(1H,s)
No.21:１−シクロプロピル−７−(３,４−ジヒドロ−２Ｈ−１,４−ベンズオキサジン−７−イル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1722
NMR(d6-DMSO):0.9-1.4(4H,m),2.70(3H,s),3.2-3.5(2H,m),4.1-4.5(3H,m),6.11(1H,s),6.7-6.9(3H,m),7.44(1H,d,J=8Hz),8.15(1H,d,J=8Hz),8.87(1H,s)
No.22:１−シクロプロピル−７−［６−(ジメチルアミノ)メチル］−２−ナフチル］−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1718
NMR(d1-TFA):1.2-2.0(4H,m),3.03(3H,s),3.13(6H,s),4.5-5.0(3H,m),7.6-8.6(7H,m),8.75(1H,d,J=7.3Hz),9.73(1H,s)
融点:228℃
No.23:７−(７−アミノ−１,３−ジヒドロ−５−イソベンゾフラニル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1716
NMR(d1-TFA):1.2-1.9(4H,m),2.97(3H,s),4.6-5.0(1H,m),5.4-5.8(4H,m),7.3-8.2(3H,m),8.72(1H,d,J=6.5Hz),9.69(1H,s)
融点:>270℃
No.24:７−(１−アミノ−２,３−ジヒドロ−１Ｈ−５−インデニル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1610
NMR(d1-TFA):1.1-1.9(4H,m),2.1-3.2(2H,m),2.97(3H,s),3.2-3.5(2H,m),4.6-5.0(1H,m),5.0-5.4(1H,m),7.0-7.7(4H,m),7.85(2H,dd,J=8.4Hz,J=11.8Hz),8.68(1H,d,J=8.4Hz),9.67(1H,s)
融点:187-188.5℃
No.25:１−シクロプロピル−７−(１Ｈ−５−インドリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1610
NMR(d1-TFA):1.2-1.9(4H,m),3.01(3H,s),4.7-5.0(1H,m),6.1-6.3(1H,m),7.4-8.2(5H,m),8.6-8.8(1H,m),9.66(1H,s)
融点:279-280.5℃
No.26:１−シクロプロピル−７−(８−フルオロ−６−キノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1711
NMR(d1-TFA):1.2-1.9(4H,m),3.04(3H,s),4.6-5.0(1H,m),7.9-8.6(4H,m),8.80(1H,d),9.2-9.6(2H,m),9.73(1H,s)
No.27:１−シクロプロピル−７−(６−イソキノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1718
NMR(d1-TFA):1.2-1.9(4H,m),3.05(3H,s),4.7-5.0(1H,m),7.9-9.0(7H,m),9.7-10.0(1H,m),9.78(1H,s)
融点:259℃
No.28:１−シクロプロピル−７−(１,３−ジメチル−６−イソキノリル)−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1724
NMR(d1-TFA):1.2-1.9(4H,m),2.95(3H,s),3.02(3H,s),3.39(3H,s),4.5-5.0(1H,m),7.8-8.4(4H,m),8.5-9.0(2H,m),9.73(1H,s)
融点233℃(分解)
No.29:１−シクロプロピル−８−メチル−４−オキソ−７−(６−キナゾリニル)−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1727
NMR(d1-TFA):1.2-1.9(4H,m),3.05(3H,s),4.7-5.0(1H,m),8.02(1H,d,J=9.1Hz),8.5-8.9(3H,m),8.81(1H,d,J=9.1Hz),9.7-9.9(2H,m),10.30(1H,s)
No.30:１−シクロプロピル−８−メトキシ−４−オキソ−７−(６−キノリル)−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1724
NMR(d1-TFA):1.5-1.9(4H,m),3.62(3H,s),4.6-5.0(1H,m),8.1-8.4(2H,m),8.6-8.8(4H,m),9.2-9.5(2H,m),9.62(1H,s)
実施例３１
１−シクロプロピル−８−メチル−４−オキソ−７−［［(トリフルオロメチル)スルホニル］オキシ］−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル200mgを１,２−ジメトキシエタン2mlに溶解し、これに１,４−ベンゾジオキサン−６−イルホウ酸103mg、ビス(トリフェニルホスフィン)パラジウム(II)クロリド10mgおよび2mol/L炭酸ナトリウム水溶液0.5mlを加えた後、窒素雰囲気下、2時間加熱還流する。反応混合物を室温まで冷却後、水20mlおよび塩化メチレン20mlの混合溶媒に加え有機層を分取する。分取した有機層を無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去する。得られた残留物をカラムクロマトグラフィー［溶離液；トルエン：酢酸エチル=2:1］で精製後、ジイソプロピルエーテルを加え結晶を濾取すれば、７−(１,４−ベンゾジオキサン−６−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル140mgを得る。
IR(KBr)cm-1:1724
NMR(CDCl3):0.9-1.6(7H,m),2.64(3H,s),3.9-4.1(1H,m),4.2-4.6(6H,m),6.8-7.0(3H,m),7.29(1H,d,J=8.06Hz),8.31(1H,d,J=8.06Hz),8.72(1H,s)
実施例３２
実施例３１と同様にして次の化合物を得る。
・７−(１,３−ベンゾジオキソール−５−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル
実施例３３
７−(１,４−ベシゾジオキサン−６−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸エチルエステル130mgをエタノール1.3mlに懸濁し、1mol/L水酸化ナトリウム水溶液1.3mlを加えた後室温で1時間撹拌する。反応混合物に1mol/L塩酸2.6mlを加え結晶を濾取すれば、無色結晶の７−(１,４−ベンゾジオキサ−６−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸120mgを得る。
IR(KBr)cm-1:1718
NMR(d1-TFA):1.1-1.9(4H,m),3.00(3H,s),4.52(4H,s),4.6-5.0(1H,m),7.0-7.3(3H,m),7.95(1H,d,J=7.8Hz),8.63(1H,d,J=7.8Hz),9.65(1H,s)
実施例３４
実施例３３と同様にして次の化合物を得る。
・７−(１,３−ベンゾジオキソール−５−イル)−１−シクロプロピル−８−メチル−４−オキソ−１,４−ジヒドロ−３−キノリンカルボン酸
IR(KBr)cm-1:1727
NMR(d1-TFA):1.2-1.8(4H,m),3.00(3H,s),4.7-4.9(1H,m),6.12(2H,s),7.06(3H,s),7.96(1H,d,J=8.5Hz),8.64(1H,d,J=8.5Hz),9.66(1H,s)
実施例３５
７−クロロ−１−シクロプロピル−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸エチルエステル1.00gをキシレン40mlに懸濁し、２−［(４−メチルフェニル)スルホニル］−５−(１,１,１−トリブチルスタニル)イソインドリン3.84gおよびビス(トリフェニルホスフィン)パラジウム(II)クロリド0.12gを加えた後、窒素雰囲気下、3時間加熱還流する。反応混合物を減圧下に濃縮し、得られた残留物をカラムクロマトグラフィー［溶離液；クロロホルム］で精製後、ジエチルエーテルを加え結晶を濾取すれば、淡黄色の１−シクロプロピル−７−［２−［(４−メチルフェニル)スルホニル］-２,３-ジヒドロ−１Ｈ−５−イソインドリル］−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸エチルエステル1.22gを得る。
IR(KBr)cm-1:1676
NMR(CDCl3):0.8-1.8(7H,m),2.40(3H,s),3.5-4.0(1H,m),4.1-4.9(6H,m),7.1-8.9(10H,m)
実施例３６
１−シクロプロピル−７−［２−［(４−メチルフェニル)スルホニル］-２,３-ジヒドロ−１Ｈ−５−イソインドリル］−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸エチルエステル1.20gをエタノール12mlおよび１,４−ジオキサン12mlの混合溶媒に懸濁し、1mol/L水酸化ナトリウム水溶液4.5mlを加えた後、40℃で2時間撹拌する。反応混合物に1mol/L塩酸9.0mlを加え結晶を濾取すれば、１−シクロプロピル−７−［２−［(４−メチルフェニル)スルホニル］-２,３-ジヒドロ−１Ｈ−５−イソインドリル］−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸1.10gを得る。
実施例３７
１−シクロプロピル−７−［２−［(４−メチルフェニル)スルホニル］-２,３-ジヒドロ−１Ｈ−５−イソインドリル］−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸1.00gを臭化水素酸10.0mlに懸濁し、フェノール0.56gおよびプロピオン酸6.0mlを加えた後、窒素雰囲気下、100℃で10時間撹拌する。反応混合物を減圧下に濃縮し、得られた残留物にエタノールを加え結晶を濾取すれば、１−シクロプロピル−７−(２,３-ジヒドロ−１Ｈ−５−イソインドリル)−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸の臭化水素酸塩0.85gを得る。
得られた臭化水素酸塩をエタノール15.8mlおよび水20.8mlの混合溶媒に懸濁し、1mol/L水酸化ナトリウム水溶液10.8mlを加え溶解した後、炭酸ガスを吹き込む。析出晶を濾取すれば、淡黄色結晶の１−シクロプロピル−７−(２,３-ジヒドロ−１Ｈ−５−イソインドリル)−４−オキソ−１,４−ジヒドロ［１,８］ナフチリジン−３−カルボン酸0.54gを得る。
IR(KBr)cm-1:1618
NMR(d1-TFA):1.0-1.9(4H,m),4.2-4.7(1H,m),5.04(4H,brs),7.65(1H,d,J=8.8Hz),8.2-8.6(3H,m),9.12(1H,d,J=8.8Hz),9.55(1H,s)
産業上の利用可能性
本発明のキノロンカルボン酸誘導体またはその塩は、グラム陽性菌およびグラム陰性菌、とりわけＭＲＳＡに対して強力な抗菌作用を発揮し、かつ安全性の高い化合物であり各種感染症の治療剤として有用である。Technical field
The present invention is a general formula [1] that exhibits a strong antibacterial action against Gram-positive and Gram-negative bacteria, particularly MRSA, and is highly safe.
R Three And R Four Has the same meaning as described above. ) Is excluded. "
It is related with the quinolone carboxylic acid derivative represented by these, or its salt.
Background art
A compound having a quinolone carboxylic acid skeleton is used as a quinolone synthetic antibacterial agent for the treatment of infectious diseases. However, a compound having a benzene fused ring at the 7-position and a hydrogen atom at the 6-position of the quinolone carboxylic acid skeleton is not known. In addition, norfloxacin, ciprofloxacin, and ofloxacin, which are widely used clinically as quinolone synthetic antibacterial agents, do not have sufficient activity against gram-positive bacteria, particularly MRSA. Therefore, it is desired to develop a synthetic antibacterial agent that is effective against these bacteria and has a broad antibacterial spectrum.
Disclosure of the invention
Under such circumstances, the present inventors have conducted intensive research. As a result, the compound of the following general formula [1] or a salt thereof having a benzene condensed ring at the 7-position and a hydrogen atom at the 6-position of the quinolonecarboxylic acid skeleton. Has superior antibacterial activity and has higher safety than conventional quinolone synthetic antibacterial agents, and has completed the present invention.
Unless otherwise specified in the present specification, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, linear or branched C such as sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl 1-10 An alkyl group; a lower alkyl group is, for example, linear or branched C such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl 1-5 An alkyl group; an alkenyl group is, for example, linear or branched C, such as vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl 2-10 An alkenyl group; a lower alkenyl group is, for example, linear or branched C, such as vinyl and allyl 2-5 An alkenyl group; a cycloalkyl group is, for example, a C such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 3-6 A cycloalkyl group; a cycloalkane ring means, for example, C, such as cyclopropane, cyclobutane, cyclopentane and cyclohexane 3-6 A cycloalkane ring; an alkoxy group means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy Linear or branched C 1-10 An alkoxy group; a lower alkoxy group is, for example, linear or branched C such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentyloxy 1-5 An alkoxythio group is a straight chain such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio Branched chain C 1-10 An alkylthio group; a lower alkylthio group is, for example, linear or branched C such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and pentylthio 1-5 An alkylthio group; an alkylsulfonyl group is, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, Linear or branched C such as heptylsulfonyl and octylsulfonyl 1-10 An alkylsulfonyl group; a lower alkylsulfonyl group includes, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and pentylsulfonyl Linear or branched C 1-5 An alkylsulfonyl group; a lower alkylamino group means, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and dipentylamino Linear or branched C such as 1-5 An amino group substituted with an alkyl group; an acyl group is, for example, a linear or branched C, such as formyl group, acetyl and ethylcarbonyl 2-5 An alkanoyl group and an aroyl group such as benzoyl and naphthylcarbonyl; an alkoxycarbonyl group is an alkoxy-CO— group (alkoxy is an alkoxy group as described above); a lower alkoxycarbonyl group is a lower alkoxy-CO— group. A group (lower alkoxy represents the lower alkoxy group described above); an aryl group, for example, phenyl and naphthyl groups; an arylsulfonyl group, for example, phenylsulfonyl and naphthylsulfonyl groups; Represents, for example, a benzyl, phenethyl and trityl group; a heterocyclic group is a 4-membered member containing one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom as the hetero atoms forming the ring 5- or 6-membered rings or fused rings thereof, such as oxetanyl, thie Tanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl and morpholinyl groups, respectively.
The 5- or 6-membered heterocyclic ring in D is a heterocyclic ring containing one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom as the hetero atoms forming the ring, for example, triazine, 5- or 6-membered aromatic heterocycles such as pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyran, furazane; tetrahydro-2H-pyran, Tetrahydro-2H-thiopyran, piperidine, dioxane, oxathiane, morpholine, thiomorpholine, dithiane, piperazine, pyrrolidine, tetrahydrothiophene, tetrahydrofuran, pyrazolidine, imidazolidine, tetrahydroisothiazole, 1,3-thiazolane, te Examples include 5- or 6-membered aliphatic heterocycles such as trahydroisoxazole, 1,3-oxazolane, dithiolane, oxathiolane, and dioxolane.
Examples of the 5- or 6-membered hydrocarbon ring in D include 5-membered or 6-membered unsaturated hydrocarbon rings such as benzene, cyclohexene and cyclopentene; and saturated hydrocarbon rings such as cyclohexane and cyclopentane.
R 2 An alkyl group, an alkenyl group, a cycloalkyl group, an aryl group or a heterocyclic group in R; Three An alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, alkylthio group or amino group in R; Four Alkyl group, alkenyl group, cycloalkyl group, aralkyl group, aryl group, alkoxy group, alkylthio group or amino group in R; Five An alkyl group, an alkoxy group or an alkylthio group in R; 6 As the substituent of the alkyl group, alkoxy group or alkylthio group, a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a protected group And a lower alkylamino group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, and a lower alkyl group substituted with a halogen atom. It may be substituted with one or more substituents.
The carboxyl-protecting group includes all groups that can be used as ordinary carboxyl-protecting groups, such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl, and the like. lower alkyl groups such as tert-butyl; aryl groups such as phenyl and naphthyl; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; acetylmethyl Acyl lower alkyl groups such as benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; Halogeno lower alkyl groups such as 2,2-trichloroethyl; 2 Lower alkylsilylalkyl groups such as (trimethylsilyl) ethyl; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl and succinimidomethyl; cyclohexyl and the like Cycloalkyl groups; lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; aralkyloxy-lower alkyl groups such as benzyloxymethyl; lower groups such as methylthiomethyl and 2-methylthioethyl Alkylthio-lower alkyl groups; arylthio-lower alkyl groups such as phenylthiomethyl; 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl and allyl Any lower alkenyl group; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl .
The amino-protecting group includes all groups that can be used as ordinary amino-protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl. , (Mono-, di-, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxy Benzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, ara Acyl groups such as nyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; aralkyl groups such as benzyl, diphenylmethyl and trityl; arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio Alkyl- or aryl-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chloro; Ar-lower alkylidene groups such as benzylidene and 2-hydroxy-1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene, 2-ethoxycarbo Cycloalkylidene groups such as nylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxycyclohexylidene; diaryl- or dialls such as diphenylphosphoryl and dibenzylphosphoryl A lower alkylphosphoryl group; an oxygen-containing heterocyclic alkyl group such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl; and a substituted silyl group such as trimethylsilyl.
Examples of the protecting group for the hydroxyl group include all groups that can be used as usual hydroxyl protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbo 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, Acyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; lower alkyls such as methyl, tert-butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl Groups; lower alkenyl groups such as allyl; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; tetrahydrofuryl, tetrahydro Oxygen- and sulfur-containing heterocyclic groups such as ranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxy Lower alkoxy- and lower alkylthio-lower alkyl groups such as methyl and 1-ethoxyethyl; alkyl- and aryl-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, and substituted silyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.
Examples of the salt of the compound of the general formula [1] include salts that are generally known in basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups. Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and methane Salts with sulfonic acids such as sulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid, mesitylene sulfonic acid and naphthalene sulfonic acid, and as salts in acidic groups, for example, salts with alkali metals such as sodium and potassium Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine , Jiben Triethanolamine, N- benzyl -β- phenethylamine, 1-Efenamin and N, N'and salts with nitrogen-containing organic bases such as di-dibenzylethylenediamine and the like. The salt of the compound of the general formula [1] is preferably a pharmacologically acceptable salt.
Of the present invention, R 2 Is an optionally substituted cycloalkyl group; R Three Is a hydrogen atom, R Four Is a hydrogen atom or an optionally protected hydroxyl group; R Five Is a hydrogen atom; R 6 Are preferably a hydrogen atom, a halogen atom, an optionally substituted alkyl or alkoxy group.
Among the compounds of the present invention, representative compounds include, for example, compounds shown in Tables 1 and 2. The abbreviations in the table have the following meanings.
cyclopropyl: cyclopropyl, fluoroethyl: 2-fluoroethyl, 2,4-diF-Ph: 2,4-difluorophenyl
[Table 1]
Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention can be synthesized, for example, according to the following production method.
Compounds of general formula [1a], [2], [3a], [3b], [4], [5], [6], [7] or [8] can also be used as salts, Examples of the salt include the same salts as described for the salt of the compound of the general formula [1].
[Production Method 1]
(1-a) The compound of the general formula [1a] is obtained by using a palladium catalyst in the presence or absence of silver oxide and the organotin compound of the general formula [3a] or the general formula [3a]. It can be obtained by subjecting the organotin compound of [4] and the compound of general formula [5] to a coupling reaction.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, and these solvents are mixed. May be used.
Examples of the palladium catalyst used in this reaction include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II). ) Organic palladium complexes such as chloride.
The amount of the palladium catalyst used may be 0.00001 times mol or more, preferably 0.001 to 0.05 times mol for the compound of the general formula [2] or the compound of the general formula [4].
The usage-amount of silver oxide is equimolar or more with respect to the compound of General formula [2], or the compound of General formula [4], Preferably, it is 1-10 times mole.
The amount of the organotin compound of the general formula [3a] used is equimolar or more, preferably 1.0 to 2.0 times the mol of the compound of the general formula [2]. The amount to be used is equimolar or more, preferably 1.0 to 5.0 times the molar amount of the organotin compound of the general formula [4].
This coupling reaction may be usually performed at 50 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, argon, nitrogen) atmosphere.
(1-b) As an alternative, the compound of the general formula [1a] can be obtained by using a palladium catalyst in the presence or absence of a base to convert a compound of the general formula [2] and an organoboron compound of the general formula [3b]. It can be obtained by subjecting it to a coupling reaction.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene, toluene and xylene Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; Ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and dimethyl sulfoxide Include such as sulfoxides, it may also be used These solvents are mixed.
Examples of the base used in this reaction include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and triethylamine. The amount of the base used is equimolar or more with respect to the compound of the general formula [2], preferably 2-5 moles. Examples of the palladium catalyst used in this reaction include palladium-activated carbon, metal palladium such as palladium black, inorganic palladium salts such as palladium chloride, organic palladium salts such as palladium acetate, tetrakis (triphenylphosphine) palladium ( 0), organic palladium complexes such as bis (triphenylphosphine) palladium (II) chloride and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride.
The usage-amount of a palladium catalyst should just be 0.00001 times mole or more with respect to the compound of General formula [2], Preferably, what is necessary is just 0.001-0.05 times mole.
The usage-amount of the organoboron compound of General formula [3b] is equimolar or more with respect to the compound of General formula [2], Preferably, it is 1.0-1.5 times mole.
This coupling reaction may be usually performed at 50 to 170 ° C. for 1 minute to 24 hours in an inert gas (eg, argon, nitrogen) atmosphere.
[Production Method 2]
(2-a) The compound of the general formula [7] is obtained by reacting the compound of the general formula [6] with an ortho ester such as methyl orthoformate or ethyl orthoformate in acetic anhydride, It can be obtained by reacting a compound.
The solvent used in these reactions is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether And ethers such as dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; In addition, sulfoxides such as dimethyl sulfoxide and the like can be mentioned, and these solvents may be used in combination.
The usage-amount of acetic anhydride should just be equimolar or more with respect to the compound of General formula [6], Preferably, what is necessary is just 1-10 times mole.
The usage-amount of orthoester should just be equimolar or more with respect to the compound of General formula [6], Preferably, what is necessary is just 1-10 times mole.
These reactions are usually carried out at 0 to 150 ° C., preferably 50 to 150 ° C., for 20 minutes to 50 hours.
Next, the compound of the general formula [8] is reacted, and the amount of the compound of the general formula [8] used at that time is equimolar or more with respect to the compound of the general formula [6]. Usually, it may be carried out at 0 to 100 ° C., preferably 10 to 60 ° C., for 20 minutes to 30 hours. (2-b) Alternatively, N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl is added to the compound of general formula [6] in the presence or absence of an acid anhydride such as acetic anhydride. After reacting acetal such as acetal, the compound of general formula [8] can be reacted to obtain the compound of general formula [7].
The solvent used in these reactions is not particularly limited as long as it does not adversely influence the reaction, and specific examples thereof include the same solvents as those described in the above (2-a). The usage-amount of acetal should just be equimolar or more with respect to the compound of General formula [6], Preferably, it may be about 1-5 times mole.
The usage-amount of an acid anhydride is equimolar or more with respect to the compound of General formula [6], Preferably, it is 1-10 times mole.
These reactions are usually carried out at 0 to 100 ° C., preferably 20 to 85 ° C. for 20 minutes to 50 hours.
Next, the compound of the general formula [8] is reacted, and the amount of the compound of the general formula [8] used at that time is equimolar or more with respect to the compound of the general formula [6]. Usually, it may be carried out at 0 to 100 ° C., preferably 10 to 60 ° C., for 20 minutes to 30 hours.
The compound of the general formula [1a] can be obtained by subjecting the compound of the general formula [7] to a ring-closing reaction in the presence or absence of a fluoride salt or a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dioxane, anisole, diethylene glycol Examples include ethers such as dimethyl ether and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide. These solvents may be used in combination.
Examples of the fluoride salt used as desired in this reaction include sodium fluoride and potassium fluoride.
Examples of the base used as desired include sodium bicarbonate, potassium carbonate, potassium tert-butoxide and sodium hydride.
The usage-amount of a fluoride salt and a base should just be an equimolar or more with respect to the compound of General formula [7], respectively, Preferably, what is necessary is just 1.0-3.0 times mole.
This reaction may be usually carried out at 0 to 180 ° C. for 5 minutes to 30 hours.
The compound of the general formula [1a] thus obtained is subjected to a reaction known per se such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or an appropriate combination thereof. Can be derived into other compounds of the general formula [1a].
The thus obtained compound of the general formula [1a] or a salt thereof can be isolated and purified according to conventional methods such as extraction, crystallization and / or column chromatography.
In the compound of the general formula [1a], [2], [3a], [3b], [4], [5], [6], [7] or [8] in the production method described above, the isomer If present (for example, optical isomers, geometric isomers and tautomers, etc.), these isomers can also be used, and solvates, hydrates and crystals of various shapes are also used. can do.
In the compounds of the general formula [2], [3a], [3b], [4], [5], [6], [7], [8] or [1a], an amino group, hydroxyl group or carboxyl In the case of a compound having a group, these groups can be protected in advance by an ordinary protecting group, and these protecting groups can be removed by a method known per se after the reaction.
The compounds of the general formulas [2], [4] and [6] which are raw materials for producing the compounds of the present invention include, for example, WO / 96/05192, WO / 97/29102, Japanese Patent Application No. 10-110146, It can be produced by the method described in US3984548, US39885882, US5457104 and the like, or a method analogous thereto.
The organotin compound of the general formula [3a] and the organoboric acid compound of the general formula [3b] can be produced, for example, by the following production method A.
The organotin compound of the general formula [3a] can be produced by subjecting the general formula [5] to a stannation reaction.
The stannous reaction is carried out in accordance with, for example, the method described in Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.), Volume 56, pages 3855-3856 (1983). Thus, a palladium catalyst and a hexaalkyl distanan may be used.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; 1,2-dimethoxyethane, dioxane, tetrahydrofuran Ethers such as anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, etc. These solvents may be used as a mixture.
Examples of the palladium catalyst used in this reaction include palladium-activated carbon, metal palladium such as palladium black, inorganic palladium salts such as palladium chloride, organic palladium salts such as palladium acetate, tetrakis (triphenylphosphine) palladium (0) And organic palladium complexes such as bis (triphenylphosphine) palladium (II) chloride and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride.
The usage-amount of a palladium catalyst should just be 0.00001 times mol or more with respect to the compound of General formula [5], Preferably, what is necessary is just 0.001-0.05 times mol.
The amount of hexaalkyldistanane used may be equimolar or more, preferably 1.0 to 3.0-fold mol with respect to the compound of general formula [5].
This reaction may be usually carried out at 40 to 160 ° C. for 1 to 72 hours.
The borated oxidation reaction may be carried out in accordance with, for example, the method described in the 4th edition Experimental Chemistry Course, Vol. 24, pp. 61-90 (1992), Japanese Patent Application No. 10-140586.
Specifically, the compound of the general formula [5] may be subjected to lithiation or Grignard reaction and then reacted with trialkyl borate.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aliphatic hydrocarbons such as n-hexane and cyclohexane; 1,2-dimethoxyethane, dioxane, tetrahydrofuran , Ethers such as anisole, diethylene glycol diethyl ether and dimethyl cellosolve, and the like, and these solvents may be used as a mixture.
Examples of the lithiating agent used in this reaction include alkyl metal reagents such as n-butyllithium, tert-butyllithium, phenyllithium and methyllithium; amide bases such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide. Can be mentioned. The Grignard reagent can be obtained by reacting magnesium metal.
Examples of the trialkyl borate used in this reaction include trimethyl borate, triethyl borate, triisopropyl borate, and tributyl borate.
The amount of the lithiating agent, metallic magnesium and trialkyl borate used is equimolar or more, preferably 1 to 2 times the molar amount of the compound of the general formula [5].
This reaction is usually performed at -70 ° C to 50 ° C, preferably -60 to 0 ° C for 10 minutes to 24 hours.
As another method of boration, a method of reacting a palladium catalyst with dialkoxyborane or alkoxyborane in the presence of a base may be used.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as n-hexane and cyclohexane; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile Nitriles such as; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide, and the like. May be used.
Examples of the base used as desired in this reaction include potassium acetate, potassium tert-butoxide, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, tributylamine and triethylamine. Is mentioned. The amount used is equimolar or more, preferably 1 to 3 times the molar amount of the compound of the general formula [5] or a salt thereof.
Examples of the palladium catalyst used in this reaction include palladium-activated carbon, metal palladium such as palladium black, inorganic palladium salts such as palladium chloride, organic palladium salts such as palladium acetate, tetrakis (triphenylphosphine) palladium (0) And organic palladium complexes such as bis (triphenylphosphine) palladium (II) chloride and 1,1-bis (diphenylphosphino) ferrocenepalladium (II) chloride.
The usage-amount of a palladium catalyst should just be 0.00001 times mol or more with respect to the compound of General formula [5], Preferably, what is necessary is just 0.001-0.05 times mol.
Examples of dialkoxyboranes used in this reaction include 4,4,5,5-tetramethyl-1,3,2-dioxaborolane and catecholborane. Examples of alkoxydiboranes include 4,4. , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4 ′, 4 ′, 5 ′, 5′-tetramethyl-1 ′, 3 ′, 2′-dioxaborolane and the like.
The amount used is equimolar or more, preferably 1.0 to 1.5 times the molar amount of the compound of the general formula [5].
This reaction is usually carried out in an atmosphere of inert gas (for example, argon or nitrogen) at 0 to 150 ° C., preferably 80 to 110 ° C. for 1 to 24 hours.
As the compound of the general formula [5], a commercially available product or a compound described in a literature produced by a known method can be used, and a compound produced by a method described in the literature or a method analogous thereto is used. do it. The following is a reference document.
(1) Having an isoindoline ring
Organic Syntheses, Five , 1064-1066
Arzniem.Forsh./Drug Res. 30 (II), 1487-1493 (1980)
JP 63-179872
JP-A-2-62875
JP 3-52888
(2) Having an isoquinoline ring
J.Org.Chem., 45 (26), 5312-5315 (1980)
Synthesis 70-72 (1980)
(3) Having a quinoline ring
New Experimental Chemistry Course 14 [IV], 2069 (1978)
Chemical Abstracts Vol.80: 108331
(4) Having a quinazoline ring
Chemical Abstracts Vol.60: 524d
(5) having a 3,4-dihydro-2H-1,4-benzoxazine ring
JP 61-215381
(6) having a benzo [b] thiophene ring
J.Org.Chem., 60 (7), 1936-1938 (1995)
(7) Having a 1,4-benzodioxane ring
Chemical Abstracts Vol.53: 6234c
(8) Having a 1,3-dihydro-isobenzofuran ring
Chemical Abstracts Vol.47: 8692h
Tetrahedron, 953-958 (1962)
Special Table Sho 63-501361
(9) Hydroxyalkyl-substituted naphthyl
JP-A-60-155140
(10) Hydroxyimino substituted indene
WO96 / 36596
When the compound of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be mixed as appropriate, and these can be mixed according to conventional methods, such as tablets, capsules, powders. , Syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, ointments or injections, and can be administered orally or parenterally. In addition, the administration method, dosage, and frequency of administration can be appropriately selected depending on the age, weight and symptoms of the patient, and usually for adults, oral or parenteral (for example, injection, infusion, and administration to the rectal site) The daily dose may be divided into 0.15 to 100 mg / kg divided into 1 to several times.
Next, the pharmacological action of representative compounds of the present invention will be described.
Antibacterial action
[Test method]
According to the Japanese Chemotherapy Standard Method [CHEMOTHERAPY Vol. 29, No. 1, pp. 76-79 (1981)], Mueller Hinton broth (Difco) 37 Incubate for 20 hours at ℃, 6 Piece / plate (10 8 1 ml of the bacterial solution adjusted to 1 / ml) was inoculated into Mueller Hinton agar medium (Difco) containing the drug and cultured at 37 ° C for 20 hours. The presence or absence of growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml).
The results are shown in Table 3. The symbols a to d in Table 3 indicate the following strains. Moreover, a number shows the compound of an Example.
a: Staphylococcus aureus (S.aureus FDA209P)
b: β-lactamase-producing S. aureus F-137
c: Methicillin-resistant Staphylococcus aureus (S. aureus F-597)
d: E. coli NIHJ JC-2
[Table 3]
Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.
The mixing ratios in the eluent are all dose ratios, and BW-127ZH (manufactured by Fuji Silysia Chemical) was used as the carrier in the column chromatography. Moreover, the symbol used in a reference example and an Example has the following meaning.
Ac: Acetyl group
Cbz: benzyloxycarbonyl group
d 1 -TFA: heavy trifluoroacetic acid
Moreover, the numerical value in NMR shows (delta) value.
Reference example 1
1-Cyclopropyl-7-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (6.80 g) is suspended in dimethyl sulfoxide (136 ml), and 1.5 hours are required for sodium methoxide. 10.89 g of methanol solution (28% solution) is added dropwise. After stirring at 40 ° C. for 1.5 hours, the mixture was added to a mixed solvent of 500 ml of water and 300 ml of ethyl acetate, adjusted to pH 1 with 6 mol / L hydrochloric acid, and the precipitated crystals were collected by filtration to give colorless crystals of 1-cyclopropyl-7-methoxy. 1.94 g of -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid are obtained.
IR (KBr) cm -1 : 1723
NMR (CDCl Three ): 0.8-1.4 (4H, m), 2.70 (3H, s), 3.9-4.3 (1H, m), 4.02 (3H, s), 7.16 (1H, d, J = 8.8Hz), 8.37 (1H, d, J = 8.8Hz), 8.91 (1H, s)
Reference example 2
1.40 g of 1-cyclopropyl-7-methoxy-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is suspended in 48 ml of 47% hydrobromic acid and heated to reflux for 5 hours. After cooling the reaction mixture to room temperature, 200 ml of water is added and the precipitated crystals are collected by filtration. As a result, colorless crystals of 1-cyclopropyl-7-hydroxy-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid are obtained. 2.11 g of acid monohydrate are obtained.
IR (KBr) cm -1 : 1718
NMR (d 1 -TFA): 1.1-1.8 (4H, m), 2.99 (3H, s), 4.5-4.9 (1H, m), 7.60 (1H, d, J = 8.8Hz), 8.54 (1H, d, J = 8.8 Hz), 9.48 (1H, s)
Reference example 3
500 mg of 1-cyclopropyl-7-hydroxy-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid monohydrate was suspended in ethanol, and paratoluenesulfonic acid monohydrate was added thereto. 185 mg of product is added and azeotropic dehydration is performed for 45 hours. The reaction mixture is cooled to room temperature, added to a mixed solvent of 50 ml of water and 50 ml of chloroform, and the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: chloroform: ethanol = 30: 1] to give colorless crystals of 1-cyclopropyl-7-hydroxy-8-methyl-4-oxo-1,4- 300 mg of dihydro-3-quinolinecarboxylic acid ethyl ester are obtained.
IR (KBr) cm -1 : 1728
NMR (CDCl Three ): 0.8-1.8 (7H, m), 2.70 (3H, s), 3.8-4.2 (1H, m), 4.42 (2H, q, d = 6.8Hz), 7.37 (1H, d, J = 8.8Hz) , 8.26 (1H, d, J = 8.8Hz), 8.71 (1H, s)
Reference example 4
300 mg of 1-cyclopropyl-7-hydroxy-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester is suspended in 6 ml of methylene chloride, and 202 ml of diisopropylamine and trifluoromethanesulfone are added under ice cooling. Add 364 mg of acid anhydride and stir at room temperature for 3 hours. The reaction mixture is added to a mixed solvent of 30 ml of water and 30 ml of chloroform, adjusted to pH 1 with 1 mol / L hydrochloric acid, and then the organic layer is separated. The separated organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 1: 1] to give colorless crystals of 1-cyclopropyl-8-methyl-4-oxo-7-[[( 270 mg of trifluoromethyl) sulfonyl] oxy] -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester are obtained.
IR (KBr) cm -1 : 1724,1214
NMR (CDCl Three ): 0.8-1.7 (7H, m), 2.81 (3H, s), 3.8-4.1 (1H, m), 4.40 (2H, q, J = 7.6Hz), 7.29 (1H, d, J = 8.8Hz) , 8.41 (1H, d, J = 8.8Hz), 8.71 (1H, s)
Reference Example 5
Dissolve 2.00 g of 4-bromo-1,2-benzenediol in 10 ml of ethanol, add 3.56 g of dibromoethane and 1.44 g of potassium hydroxide, and then heat to reflux for 15 hours. The reaction mixture is cooled to room temperature, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure. If the obtained residue is purified by column chromatography [eluent: toluene], 0.92 g of colorless oily 6-bromo-1,4-benzodioxane is obtained.
IR (neat) cm -1 : 1601,1490,1302,1286,1251
NMR (CDCl Three ): 4.23 (4H, s), 6.6-7.1 (3H, m)
Reference Example 6
2.00 g of 4-bromoaniline, 7.86 g of iron (II) sulfate heptahydrate, 1.26 g of sodium 3-nitrobenzenesulfonate, 0.60 g of boric acid, and 3.56 g of glycerin are mixed, and 2.14 ml of concentrated sulfuric acid is added to the mixture. For 6 hours. The reaction mixture is cooled to room temperature, added to a mixed solvent of 50 ml of water and 50 ml of chloroform, adjusted to pH 12 with a 5 mol / L aqueous sodium hydroxide solution, and then the insoluble material is filtered off, and the organic layer of the filtrate is separated. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent: toluene: ethyl acetate = 15: 1] to obtain 1.14 g of brown oily 6-bromoquinoline.
IR (neat) cm -1 : 1490,830
NMR (CDCl Three ): 7.40 (1H, dd, J = 4.4Hz, J = 8.5Hz), 7.7-8.2 (4H, m), 8.91 (1H, dd, J = 1.7Hz, J = 4.4Hz)
In the same manner, the following compound is obtained.
6-bromo-8-fluoroquinoline
IR (KBr) cm -1 : 1765,1532
NMR (CDCl Three ): 5.70 (2H, s), 8.39 (lH, bs), 8.64 (1H, bs)
Reference Example 7
10.00 g of 6-bromo-1,3-dihydro-1-isobenzofuranone is dissolved in 500 ml of tetrahydrofuran, and 200 g of boron trifluoride diethyl ether complex and 3.56 g of lithium aluminum hydride are added to this solution at 10 ° C. under a nitrogen atmosphere. After stirring for 30 minutes under ice cooling, the mixture is further heated under reflux for 4 hours. The reaction mixture is cooled to room temperature, added to a mixed solvent of 300 ml of ethyl acetate and 400 ml of 5% brine, adjusted to pH 1 with 1 mol / L hydrochloric acid, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography [eluent: n-hexane: ethyl acetate = 20: 1] to obtain 2.00 g of colorless crystals of 5-bromo-1,3-dihydroisobenzofuran.
IR (KBr) cm -1 : 2854,1474,1050,808
NMR (CDCl Three ): 5.05 (4H, s), 7.0-7.5 (3H, m)
Reference Example 8
(1) Suspend 0.70 g of (6-bromo-2-naphthyl) methanol in 7 ml of methylene chloride, add 0.42 g of thionyl chloride under ice cooling, and stir at room temperature for 2 hours. If diisopropyl ether is added to the reaction mixture and collected by filtration, 0.42 g of colorless crystals of 2-bromo-6- (chloromethyl) naphthalene is obtained.
NMR (CDCl Three ): 4.93 (2H, s), 7.50-7.75 (2H, m), 7.88 (1H, d, J = 1.8Hz), 7.9-8.1 (2H, m), 8.22 (1H, bs)
(2) 0.20 g of 2-bromo-6- (chloromethyl) naphthalene is dissolved in 1 ml of ethanol, 0.5 ml of dimethylamine solution (about 50%) is added thereto, and the mixture is stirred at room temperature for 3 hours. 10 ml of water and 10 ml of chloroform are added to the reaction mixture, and the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 5: 1] to give 0.16 g of oily N, N-dimethyl- (6-bromo-2-naphthyl) methanamine. obtain.
NMR (CDCl Three ): 2.28 (6H, s), 3.56 (2H, s), 7.4-8.4 (6H, m)
Reference Example 9
(1) Dissolve 3.00 g of 5-bromo-2-methyl-3-nitrobenzoic acid methyl ester in 30 ml of carbon tetrachloride, and add 2.34 g of N-bromosuccinimide and a catalytic amount of benzoyl peroxide for 12 hours. Heat to reflux. The reaction mixture is cooled to room temperature, insolubles are removed by filtration, 30 ml of water is added to the filtrate, the pH is adjusted to 9 with a 1 mol / L aqueous sodium hydroxide solution, and the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 20: 1] to give 3.49 g of oily 5-bromo-2- (bromomethyl) -3-nitrobenzoic acid methyl ester. Get.
NMR (CDCl Three ): 4.01 (3H, s), 5.09 (2H, s), 8.09 (1H, d, J = 1.4Hz), 8.23 (1H, d, J = 1.4Hz)
(2) 4.56 g of 5-bromo-2- (bromomethyl) -3-nitrobenzoic acid methyl ester is dissolved in 13.7 ml of dimethyl sulfoxide, 3.22 g of sodium acetate is added thereto, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is added to a mixed solvent of 100 ml of water and 100 ml of ethyl acetate, and the organic layer is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If n-hexane is added to the obtained residue and filtered, 3.62 g of 2-[(acetyloxy) methyl] -5-bromo-3-nitrobenzoic acid methyl ester as colorless crystals is obtained.
IR (KBr) cm -1 : 1749,1728,1532
NMR (CDCl Three ): 2.00 (3H, s), 3.97 (3H, s), 5.55 (2H, s), 8.05 (1H, d, J = 1.4Hz), 8.15 (1H, d, J = 1.4Hz)
(3) 2-[(Acetyloxy) methyl] -5-bromo-3-nitrobenzoic acid methyl ester (3.60 g) is suspended in ethanol (18 ml), and 1 mol / L aqueous sodium hydroxide solution (18 ml) is added to the suspension at 50 ° C. for 2 hours. Stir. The reaction mixture was concentrated under reduced pressure, and 100 ml of water and 50 ml of ethyl acetate were added to the resulting residue. After adjusting the pH to 1.0 with 1 mol / L hydrochloric acid, the precipitated crystals were collected by filtration to give colorless crystals of 6-bromo. 1.79 g of -4-nitro-1,3-dihydro-1-isobenzofuranone are obtained.
IR (KBr) cm -1 : 1765,1532
NMR (CDCl Three ): 5.70 (2H, s), 8.39 (1H, bs), 8.64 (1H, bs)
(4) 0.50 g of 6-bromo-4-nitro-1,3-dihydro-1-isobenzofuranone is dissolved in 40 ml of toluene, and this takes 5 minutes at -70 [deg.] C. and a toluene solution of diisobutylaluminum hydride. (1.01M solution) 2.88 ml is added dropwise and stirred at the same temperature for 1 hour. The reaction mixture is added to a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, adjusted to pH 1.0 with 6 mol / L hydrochloric acid, and the organic layer is separated. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is suspended in 10 ml of methylene chloride, 0.65 g of trifluoroacetic acid is added thereto at −60 ° C., and the mixture is stirred at the same temperature for 15 minutes. Next, 0.67 g of triethylsilane is added at the same temperature, and the mixture is stirred at the same temperature for 20 minutes and then heated to 5 ° C. The reaction mixture is added to a mixed solvent of 20 ml of water and 20 ml of ethyl acetate, adjusted to pH 8.0 with 5 mol / L sodium hydroxide aqueous solution, insoluble matter is removed by filtration, and the organic layer of the filtrate is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Diisopropyl ether is added to the obtained residue and filtered to obtain 0.13 g of yellow crystalline 6-bromo-4-nitro-1,3-dihydroisobenzofuran.
IR (KBr) cm -1 : 1532,1334
NMR (CDCl Three ): 5.18 (2H, brs), 5.46 (2H, brs), 7.69 (1H, brs), 8.27 (1H, brs)
(5) Suspend 0.74 g of 6-bromo-4-nitro-1,3-dihydroisobenzofuran in methanol, add 2.2 ml of hydrochloric acid thereto, and then add 0.51 g of iron powder over 5 minutes. Stir at room temperature for 1 hour. The reaction mixture is added to a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, adjusted to pH 8.0 with potassium carbonate, insoluble matter is removed by filtration, and the organic layer of the filtrate is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 3: 1] to obtain 0.56 g of orange crystals of 6-bromo-1,3-dihydro-4-isobenzofuranamine. obtain.
IR (KBr) cm -1 : 3365
NMR (CDCl Three ): 3.60 (2H, brs), 4.8-5.2 (4H, m), 6.72 (1H, brs), 6.78 (1H, brs)
(6) Suspend 0.53 g of 6-bromo-1,3-dihydro-4-isobenzofuranamine in 6 ml of methylene chloride, add 0.33 g of triethylamine under ice cooling, and then add 3 ml of methylene chloride in 0.25 g of acetyl chloride. Add dropwise over 5 minutes and stir at the same temperature for 30 minutes. 10 ml of water is added to the reaction mixture, and the pH is adjusted to 5.0 with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If diisopropyl ether is added to the obtained residue and collected by filtration, colorless crystals of N 1 0.57 g of (6-bromo-1,3-dihydro-4-isobenzofuranyl) acetamide is obtained.
IR (KBr) cm -1 : 1670
NMR (CDCl Three ): 2.06 (3H, s), 4.8-5.1 (4H, m), 7.26 (1H, brs), 7.78 (1H, brs)
Reference Example 10
Dissolve 2.00 g of 5-bromo-1-indanone oxime in 80 ml of methanol, add 4.21 g of nickel (II) chloride hexahydrate, and add 2.00 g of sodium borohydride at -40 ° C for 30 minutes. Then, heat up to -25 ° C and stir for 1 hour. The reaction mixture is concentrated under reduced pressure, 150 ml of water and 150 ml of ethyl acetate are added to the resulting residue, and the mixture is filtered through celite, and the organic layer is separated. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in 32 ml of methylene chloride, 0.91 g of triethylamine is added, 1.54 g of carbobenzoxy chloride is added dropwise under ice cooling, and the mixture is stirred at room temperature for 2 hours. Add 50 ml of water to the reaction mixture, adjust to pH 1 with 1 mol / L hydrochloric acid, and separate the organic layer. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When the obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 4: 1], colorless crystals of N- (5-bromo-2,3-dihydro-1H-indenyl) carbamine were obtained. 0.81 g of acid benzyl ester is obtained.
IR (KBr) cm -1 : 3307,1681,1531,1248
NMR (CDCl Three ): 1.6-2.1 (1H, m), 2.4-2.8 (1H, m), 2.8-3.1 (2H, m), 4.7-5.1 (1H, m), 5.1-5.3 (1H, m), 5.16 (2H , s), 7.0-7.5 (8H, m)
Reference Example 11
(1) 1.00 g of 1- (3-bromophenyl) -1-propanone was dissolved in 2 ml of diethyl ether, and 0.022 ml of concentrated hydrochloric acid and 4.89 ml of ethyl nitrite solution (about 15% w / w) were added thereto. Thereafter, the mixture is stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water and n-hexane were added to the resulting residue, and the crystals were collected by filtration to give colorless crystals of 1- (3-bromophenyl) -2-hydroxyimino-1-propanone. 0.95g is obtained.
IR (KBr) cm -1 : 3300,1649
NMR (CDCl Three ): 2.17 (3H, s), 7.2-8.1 (4H, m), 8.40 (1H, brs)
(2) 0.50 g of 1- (3-bromophenyl) -2-hydroxyimino-1-propanone was dissolved in 2.5 ml of acetic acid, 0.31 g of acetic anhydride was added, and 0.41 g of zinc powder was required for 30 minutes. Add and stir at room temperature for 2 hours. 20 ml of water and 20 ml of ethyl acetate are added to the reaction mixture, and the pH is adjusted to 7.5 with a saturated aqueous sodium hydrogen carbonate solution. The insoluble matter is removed by filtration, and the organic layer of the filtrate is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: n-hexane: ethyl acetate = 1: 1] to give oily N 1 -0.36 g of [2- (3-bromophenyl) -1-methyl-2-oxoethyl] acetamide is obtained.
IR (neat) cm -1 : 1697,1656
NMR (CDCl Three ): 1.42 (3H, d, J = 4.7Hz), 2.06 (3H, s), 5.3-5.7 (1H, m), 6.50 (1H, brs), 7.2-8.2 (4H, m)
(3) N 1 -0.33 g of [2- (3-bromophenyl) -1-methyl-2-oxoethyl] acetamide is dissolved in 3 ml of ethanol, 23 mg of sodium borohydride is added thereto at 5 ° C., and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, 10 ml of water and 10 ml of ethyl acetate are added to the resulting residue, and the organic layer is separated. The separated organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove colorless oily N 1 0.29 g of [2- (3-bromophenyl) -2-hydroxy-1-methylethyl] acetamide is obtained.
IR (neat) cm -1 : 3304,1648
NMR (CDCl Three ): 1.00 (3H, d, J = 4.6Hz), 2.00 (3H, s), 3.8-4.7 (2H, m), 4.80 (1H, brs), 5.75 (1H, brs), 7.1-7.6 (4H, m)
(4) N 1 Suspend 0.28 g of [2- (3-bromophenyl) -2-hydroxy-1-methylethyl] acetamide in 2 ml of decalin, add 0.44 g of diphosphorus pentoxide, and heat to reflux for 1.5 hours. The reaction mixture is cooled to room temperature, added to a mixed solvent of 10 ml of water and 10 ml of chloroform, adjusted to pH 10 with 1 mol / L sodium hydroxide aqueous solution, insoluble matter is removed by filtration, and the organic layer of the filtrate is separated. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent: n-hexane: ethyl acetate = 3: 1] to obtain 0.05 g of 6-bromo-1,3-dimethyl-isoquinoline as yellow crystals.
IR (KBr) cm -1 : 1614,1562
NMR (CDCl Three ): 2.65 (3H, s), 2.92 (3H, s), 7.26 (1H, s), 7.57 (1H, dd, J = 1.3Hz, J = 6.0Hz), 7.88 (1H, d, J = 1.3Hz ), 7.94 (1H, d, J = 6.0Hz)
Reference Example 12
0.69 g of 6-bromo-1,4-benzodioxane was dissolved in 3.5 ml of tetrahydrofuran, and 2.5 ml of n-butyllithium hexane solution (1.54 M solution) was added dropwise to this solution at -70 ° C. over 15 minutes. To do. After stirring for 1 hour at the same temperature, 0.73 g of triisopropyl borate is added dropwise over 5 minutes. After stirring at the same temperature for 30 minutes, 3.5 ml of water is added and the temperature is raised to 0 ° C. over 30 minutes. Add 10 ml of ethyl acetate to the reaction mixture, adjust to pH 2 with 1 mol / L hydrochloric acid, and separate the organic layer. The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If n-hexane is added to the obtained residue and collected by filtration, 0.36 g of 1,4-benzodioxan-6-ylboric acid as a pale yellow solid is obtained.
IR (KBr) cm -1 : 1066,1121,1314,1420
NMR (CDCl Three ): 4.2-4.5 (4H, m), 6.95 (1H, d, J = 8.3Hz), 7.6-7.9 (2H, m)
In the same manner, the following compound is obtained.
1,3-benzodioxol-5-yl boric acid
NMR (d 6 -DMSO): 5.98 (4H, s), 6.8-7.0 (1H, m), 7.2-7.5 (2H, m)
Reference Example 13
Dissolve 0.90 g of 2-acetoxy-6-bromonaphthalene in 13.5 ml of toluene, add 3.94 g of hexabutyl distanane and 72 mg of bis (triphenylphosphine) palladium (II) chloride, and then heat to reflux for 3 hours in a nitrogen atmosphere To do. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by column chromatography [eluent: n-hexane: ethyl acetate = 20.1] to give 0.89 g of oily 2-acetoxy-6-tributylstannylnaphthalene. Get.
IR (neat) cm -1 : 1765
NMR (CDCl Three ): 0.6-1.8 (27H, m), 2.35 (3H, s), 7.0-8.0 (6H, m)
In the same manner, the following compound is obtained.
Tributyl (1,3-dihydro-5-isobenzofuranyl) stannane
IR (neat) cm -1 : 1464,1354,1049,906,804
NMR (CDCl Three ): 0.8-2.0 (27H, m), 5.11 (4H, s), 7.2-7.5 (3H, m)
・ 6- (1,1,1-tributylstannyl) quinoline
IR (neat) cm -1 : 1560,1488,1458,1340,1058,831
NMR (CDCl Three ): 0.7-2.0 (27H, m), 7.3-7.5 (1H, s), 7.7-8.2 (4H, m), 8.8-9.0 (1H, m)
Benzo [b] thiophen-5-yl (tributyl) stannane
IR (neat) cm -1 : 1458,1040,797,692
NMR (CDCl Three ): 0.7-1.8 (27H, m), 7.3-7.5 (3H, m), 7.8-8.0 (2H, m)
N- [5- (1,1,1-tributylstannyl) -2,3-dihydro-1H-1-indenyl] carbamic acid benzyl ester
NMR (CDCl Three ): 0.7-1.7 (31H, m), 2.8-3.0 (1H, m), 5.17 (2H, s), 7.2-7.5 (8H, m)
・ 6- (1,1,1-tributylstannyl) quinazoline
. 8-Fluoro-6- (1,1,1-tributylstannyl) quinoline
5- (1,1,1-tributylstannyl) -1H-indole
NMR (CDCl Three ): 0.7-2.0 (27H, m), 6.5-6.6 (1H, m), 7.1-7.5 (3H, m), 7.74 (1H, s)
・ 6- (1,1,1-tributylstannyl) isoquinoline
NMR (CDCl Three ): 0.8-1.8 (27H, m), 7.6-8.0 (4H, m), 8.52 (1H, d, J = 5.86Hz), 9.22 (1H, s)
N, N-dimethyl-N-[[6- (1,1,1-tributylstannyl) -2-naphthyl] methyl] amine
NMR (CDCl Three ): 0.8-2.0 (27H, m), 2.28 (6H, s), 3.57 (2H, s), 7.4-8.0 (6H, m)
7- (1,1,1-tributylstannyl) -3,4-dihydro-2H-1.4-benzoxazine-4-carboxylic acid benzyl ester
IR (neat) cm -1 : 1718,1493,1406,1342,1282,1224,1141,1063,1026
NMR (CDCl Three ): 0.8-1.6 (27H, m), 3.8-4.0 (2H, m), 4.2-4.4 (2H, m), 5.26 (2H, s), 6.9-7.0 (1H, m), 7.2-7.5 (6H) , m), 7.7-7.9 (1H, m)
1,3-dimethyl-6- (1,1,1-tributylstannyl) isoquinoline
IR (neat) cm -1 : 1612,1561,1458,1388,1046
NMR (CDCl Three ): 0.7-1.8 (27H, m), 2.65 (3H, s), 2.92 (3H, s), 7.3-8.1 (4H, m)
・ N 1 -[6- (1,1,1-tributylstannyl) -1,3-dihydro-4-isobenzofuranyl] acetamide
IR (neat) cm -1 : 1664,1542,1459,1401,1293,1041
NMR (CDCl Three ): 0.8-1.7 (27H, m), 2.17 (3H, s), 5.07 (2H, s), 5.10 (2H, s), 7.0 (1H, br), 7.1 (1H, brs), 7.4 (1H, brs)
Example 1
7-Bromo-1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (4.40 g) was suspended in 66 ml of toluene, and 6- (1,1,1- After adding 7.80 g of tributylstannyl) quinoline and 0.18 g of bis (triphenylphosphine) palladium (II) chloride, the mixture is heated to reflux for 3 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, 70 ml of diethyl ether is added, and the precipitate is collected by filtration. After purification of the precipitate by column chromatography [eluent: chloroform: ethanol = 50: 1], diethyl ether was added and the precipitated crystals were collected by filtration to give colorless crystals of 1-cyclopropyl-8-methyl-4-oxo- 4.71 g of 7- (6-quinolyl) -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester are obtained.
IR (KBr) cm -1 : 1718
NMR (CDCl Three ): 1.0-1.5 (7H, m), 2.66 (3H, s), 3.9-4.2 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.4-7.6 (2H, m), 7.7- 7.9 (2H, m), 8.2-8.5 (3H, m), 8.76 (1H, s), 8.9-9.0 (1H, m)
Examples 2-15
The compounds of Table 4a and Table 4b are obtained in the same manner as in Example 1.
[Table 4a]
No. 2: 1-cyclopropyl-7- (1,3-dihydro-5-isobenzofuranyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
No. 3: 7- [6- (Acetyloxy) -2-naphthyl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1760,1731
NMR (CDCl Three ): 1.0-1.7 (7H, m), 2.39 (3H, s), 2.63 (3H, s), 3.9-4.1 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.2-8.0 ( 7H, m), 8.39 (1H, d, J = 8.05Hz), 8.75 (1H, s)
No. 4: 7- (Benzo [b] thiophen-5-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1687
NMR (CDCl Three ): 1.0-1.6 (7H, m), 2.64 (3H, s), 3.9-4.2 (1H, m), 4.42 (2H.q, J = 7.08Hz), 7.3-7.6 (4H, m), 7.81 ( 1H, s), 7.97 (1H, d, J = 8.30Hz), 8.37 (1H, d, J = 8.06Hz), 8.74 (1H, s)
No. 5: 1-cyclopropyl-7- (1,3-dihydro-5-isobenzofuranyl) -8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1729
NMR (CDCl Three ): 1.0-1.3 (4H, m), 1.42 (3H, t, J = 7.08Hz), 3.37 (3H, s), 3.9-4.1 (1H, m), 4.41 (2H, q, J = 7.08Hz) , 5.20 (4H, s), 7.3-7.5 (4H, m), 8.30 (1H, d, J = 8.30Hz), 8.67 (1H, s)
No. 6: 7- [4- (Benzyloxycarbonyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] -1-cyclopropyl-8-methyl-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid ethyl ester
NMR (CDCl Three ): 0.9-1.6 (7H, m), 2.63 (3H, s), 3.9-4.1 (3H, m), 4.2-4.6 (4H, m), 5.30 (2H, s), 6.8-7.0 (2H, m ), 7.2-7.5 (6H, m), 8.01 (1H, d, J = 8.55Hz), 8.32 (1H, d, J = 8.05Hz), 8.72 (1H, s)
No. 7: 1-cyclopropyl-7- [6-[(dimethylamino) methyl] -2-naphthyl] -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
NMR (CDCl Three ): 1.0-1.6 (7H, m), 2.32 (6H, s), 2.65 (3H, s), 3.62 (2H, s), 3.9-4.2 (1H, m), 4.42 (2H, q, J = 7.08 Hz), 7.4-8.0 (7H, m), 8.39 (1H, d, J = 8.06Hz), 8.75 (1H, s)
No. 8: 7- [7- (acetylamino) -1,3-dihydro-5-isobenzofuranyl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinoline Carboxylic acid ethyl ester
No. 9: 7- (1-[[(Benzyloxy) carbonyl] amino] -2,3-dihydro-1H-5-indenyl) -1-cyclopropyl-8-methyl-4-oxo-1,4- Dihydro-3-quinolinecarboxylic acid ethyl ester
NMR (CDCl Three ): 0.8-1.4 (7H, m), 2.5-3.1 (7H, m), 3.9-4.3 (3H, m), 4.8-5.2 (3H, m), 7.0-7.6 (10H, m), 8.34 (1H , d, J = 7.8Hz), 8.73 (1H, s)
No. 10: 1-cyclopropyl-7- (1H-5-indolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1718
NMR (CDCl Three ): 1.0-1.5 (7H, m), 2.64 (3H, s), 3.8-4.2 (1H, m), 4,41 (2H, q, J = 7.6Hz), 6.5-6.7 (1H, m), 7.1-7.7 (5H, m), 8.3-8.5 (1H, m), 8.74 (1H, s)
No. 11: 1-cyclopropyl-7- (8-fluoro-6-quinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1716
NMR (CDCl Three ): 1.0-1.6 (7H, m), 2.67 (3H, s), 3.9-4.2 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.3-7.7 (4H, m), 8.27 ( 1H, d, J = 8.30Hz), 8.40 (1H, d, J = 8.30Hz), 8.76 (1H, s), 9.0-9.1 (1H, m)
No. 12: 1-cyclopropyl-7- (6-isoquinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1728
NMR (CDCl Three ): 1.0-1.5 (7H, m), 2.64 (3H, s), 3.9-4.1 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.2-7.8 (4H, m), 8.1 ( 1H, d), 8.41 (1H, d, J = 8.06Hz), 8.61 (1H, d, J = 5.86Hz), 8.76 (1H, s), 9.34 (1H, s)
No. 13: 1-cyclopropyl-7- (1,3-dimethyl-6-isoquinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1733
NMR (CDCl Three ): 1.0-1.6 (7H, m), 2.63 (3H, s), 2.69 (3H, s), 3.00 (3H, s), 3.9-4.1 (1H, m), 4.42 (2H, q, J = 7.08 Hz), 7.2-7.7 (4H, m), 8.17 (1H, d, J = 8.30Hz), 8.40 (1H, d, J = 8.05Hz), 8.76 (1H, s)
No. 14: 1-cyclopropyl-8-methyl-4-oxo-7- (6-quinazolinyl) -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
IR (KBr) cm -1 : 1732
NMR (CDCl Three ): 1.0-1.6 (7H, m), 2.65 (3H, s), 4.0-4.2 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.39 (1H, d, J = 8.31Hz) , 7.9-8.3 (3H, m), 8.42 (1H, d, J = 8.06Hz), 8.76 (1H, s), 9.41 (1H, s), 9.49 (1H, s)
No. 15: 1-cyclopropyl-8-methoxy-4-oxo-7- (6-quinolyl) -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
NMR (CDCl Three ): 1.0-1.6 (7H, m), 3.36 (3H, s), 3.9-4.2 (1H, m), 4.42 (2H, q, J = 7.08Hz), 7.4-7.6 (2H, m), 8.0- 8.4 (5H, m), 8.70 (1H, s), 8.9-9.0 (1H, m)
Example 16
1-Cyclopropyl-8-methyl-4-oxo-7- (6-quinolyl) -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (4.50 g) was suspended in 45 ml of ethanol, and 1 mol / L hydroxylated was added thereto. After adding 22.6 ml of an aqueous sodium solution, the mixture is stirred at room temperature for 5 hours. After filtering the reaction mixture, carbon dioxide gas is blown. The precipitated crystals are collected by filtration to obtain 3.97 g of colorless crystals of 1-cyclopropyl-8-methyl-4-oxo-7- (6-quinolyl) -1,4-dihydro-3-quinolinecarboxylic acid.
IR (KBr) cm -1 : 1707
NMR (d 1 -TFA): 1.3-1.8 (4H, m), 3.00 (3H, s), 4.7-5.0 (1H, m), 8.0-8.9 (6H, m), 9.2-9.4 (2H, m), 9.73 (1H , s)
Examples 17-30
Analogously to Example 16, the compounds of Table 5a and Table 5b are obtained.
[Table 5a]
No. 17: 1-cyclopropyl-7- (1,3-dihydro-5-isobenzofuranyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1730
NMR (d 1 -TFA): 1.2-2.0 (4H, m), 3.00 (3H, s), 4.6-5.0 (1H, m), 5.48 (4H, s), 7.4-7.7 (3H, m), 7.96 (1H, d , J = 8.5Hz), 8.68 (1H, d, J = 8.5Hz), 9.68 (1H, s)
No. 18: 1-cyclopropyl-7- [6- (hydroxy) -2-naphthyl] -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1706
NMR (d 1 -TFA): 1.3-1.9 (4H, m), 3.0-3.2 (3H, m), 4.7-5.0 (1H, m), 7.3-8.2 (7H, m), 8.6-8.8 (1H, m), 9.6 -9.8 (1H, m)
No. 19: 7- (Benzo [b] thiophen-5-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1725
NMR (d 1 -TFA): 1.1-1.9 (4H, m), 3.02 (3H, s), 4.6-5.0 (1H, m), 7.3-7.7 (3H, m), 7.9-8.2 (3H, m), 8.68 (1H , d), 9.67 (1H, s)
No. 20: 1-cyclopropyl-7- (1,3-dihydro-5-isobenzofuranyl) -8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1724
NMR (CDCl Three ): 1.0-1.4 (4H, m), 3.42 (3H, s), 4.0-4.3 (1H, m), 5.21 (4H, s), 7.3-7.6 (4H, m), 8.31 (1H, d, J = 8.3Hz), 8.94 (1H, s), 14.75 (1H, s)
No. 21: 1-cyclopropyl-7- (3,4-dihydro-2H-1,4-benzoxazin-7-yl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarbon acid
IR (KBr) cm -1 : 1722
NMR (d 6 -DMSO): 0.9-1.4 (4H, m), 2.70 (3H, s), 3.2-3.5 (2H, m), 4.1-4.5 (3H, m), 6.11 (1H, s), 6.7-6.9 (3H , m), 7.44 (1H, d, J = 8Hz), 8.15 (1H, d, J = 8Hz), 8.87 (1H, s)
No. 22: 1-cyclopropyl-7- [6- (dimethylamino) methyl] -2-naphthyl] -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1718
NMR (d 1 -TFA): 1.2-2.0 (4H, m), 3.03 (3H, s), 3.13 (6H, s), 4.5-5.0 (3H, m), 7.6-8.6 (7H, m), 8.75 (1H, d , J = 7.3Hz), 9.73 (1H, s)
Melting point: 228 ° C
No. 23: 7- (7-Amino-1,3-dihydro-5-isobenzofuranyl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1716
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 2.97 (3H, s), 4.6-5.0 (1H, m), 5.4-5.8 (4H, m), 7.3-8.2 (3H, m), 8.72 (1H , d, J = 6.5Hz), 9.69 (1H, s)
Melting point:> 270 ° C
No. 24: 7- (1-Amino-2,3-dihydro-1H-5-indenyl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1610
NMR (d 1 -TFA): 1.1-1.9 (4H, m), 2.1-3.2 (2H, m), 2.97 (3H, s), 3.2-3.5 (2H, m), 4.6-5.0 (1H, m), 5.0-5.4 (1H, m), 7.0-7.7 (4H, m), 7.85 (2H, dd, J = 8.4Hz, J = 11.8Hz), 8.68 (1H, d, J = 8.4Hz), 9.67 (1H, s)
Melting point: 187-188.5 ℃
No. 25: 1-cyclopropyl-7- (1H-5-indolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1610
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 3.01 (3H, s), 4.7-5.0 (1H, m), 6.1-6.3 (1H, m), 7.4-8.2 (5H, m), 8.6-8.8 (1H, m), 9.66 (1H, s)
Melting point: 279-280.5 ℃
No. 26: 1-cyclopropyl-7- (8-fluoro-6-quinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1711
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 3.04 (3H, s), 4.6-5.0 (1H, m), 7.9-8.6 (4H, m), 8.80 (1H, d), 9.2-9.6 (2H , m), 9.73 (1H, s)
No. 27: 1-cyclopropyl-7- (6-isoquinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1718
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 3.05 (3H, s), 4.7-5.0 (1H, m), 7.9-9.0 (7H, m), 9.7-10.0 (1H, m), 9.78 (1H , s)
Melting point: 259 ° C
No. 28: 1-cyclopropyl-7- (1,3-dimethyl-6-isoquinolyl) -8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1724
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 2.95 (3H, s), 3.02 (3H, s), 3.39 (3H, s), 4.5-5.0 (1H, m), 7.8-8.4 (4H, m ), 8.5-9.0 (2H, m), 9.73 (1H, s)
Melting point 233 ° C (decomposition)
No. 29: 1-cyclopropyl-8-methyl-4-oxo-7- (6-quinazolinyl) -1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1727
NMR (d 1 -TFA): 1.2-1.9 (4H, m), 3.05 (3H, s), 4.7-5.0 (1H, m), 8.02 (1H, d, J = 9.1Hz), 8.5-8.9 (3H, m), 8.81 (1H, d, J = 9.1Hz), 9.7-9.9 (2H, m), 10.30 (1H, s)
No. 30: 1-cyclopropyl-8-methoxy-4-oxo-7- (6-quinolyl) -1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1724
NMR (d 1 -TFA): 1.5-1.9 (4H, m), 3.62 (3H, s), 4.6-5.0 (1H, m), 8.1-8.4 (2H, m), 8.6-8.8 (4H, m), 9.2-9.5 (2H, m), 9.62 (1H, s)
Example 31
200 mg of 1-cyclopropyl-8-methyl-4-oxo-7-[[(trifluoromethyl) sulfonyl] oxy] -1,4-dihydro-3-quinolinecarboxylic acid ethyl ester to 2 ml of 1,2-dimethoxyethane After dissolution, 103 mg of 1,4-benzodioxan-6-yl boric acid, 10 mg of bis (triphenylphosphine) palladium (II) chloride and 0.5 ml of 2 mol / L aqueous sodium carbonate solution were added, and then under nitrogen atmosphere for 2 hours Heat to reflux. After cooling the reaction mixture to room temperature, it is added to a mixed solvent of 20 ml of water and 20 ml of methylene chloride, and the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: toluene: ethyl acetate = 2: 1], diisopropyl ether was added and the crystals were collected by filtration to give 7- (1,4-benzodioxan-6-yl. 140 mg of 1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester are obtained.
IR (KBr) cm -1 : 1724
NMR (CDCl Three ): 0.9-1.6 (7H, m), 2.64 (3H, s), 3.9-4.1 (1H, m), 4.2-4.6 (6H, m), 6.8-7.0 (3H, m), 7.29 (1H, d , J = 8.06Hz), 8.31 (1H, d, J = 8.06Hz), 8.72 (1H, s)
Example 32
The following compounds are obtained in the same manner as in Example 31.
7- (1,3-benzodioxol-5-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester
Example 33
130 mg of 7- (1,4-bezodioxan-6-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester was suspended in 1.3 ml of ethanol. After adding 1.3 ml of 1 mol / L aqueous sodium hydroxide solution, the mixture is stirred at room temperature for 1 hour. If 2.6 ml of 1 mol / L hydrochloric acid is added to the reaction mixture and the crystals are collected by filtration, 7- (1,4-benzodiox-6-yl) -1-cyclopropyl-8-methyl-4-oxo-1, 120 mg of 4-dihydro-3-quinolinecarboxylic acid are obtained.
IR (KBr) cm -1 : 1718
NMR (d 1 -TFA): 1.1-1.9 (4H, m), 3.00 (3H, s), 4.52 (4H, s), 4.6-5.0 (1H, m), 7.0-7.3 (3H, m), 7.95 (1H, d , J = 7.8Hz), 8.63 (1H, d, J = 7.8Hz), 9.65 (1H, s)
Example 34
The following compounds are obtained in the same manner as in Example 33.
7- (1,3-benzodioxol-5-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
IR (KBr) cm -1 : 1727
NMR (d 1 -TFA): 1.2-1.8 (4H, m), 3.00 (3H, s), 4.7-4.9 (1H, m), 6.12 (2H, s), 7.06 (3H, s), 7.96 (1H, d, J = 8.5Hz), 8.64 (1H, d, J = 8.5Hz), 9.66 (1H, s)
Example 35
1.00 g of 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid ethyl ester is suspended in 40 ml of xylene and 2-[(4-methylphenyl) sulfonyl ] After adding 3.84 g of 5- (1,1,1-tributylstannyl) isoindoline and 0.12 g of bis (triphenylphosphine) palladium (II) chloride, the mixture is refluxed for 3 hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by column chromatography [eluent: chloroform], diethyl ether is added, and the crystals are collected by filtration to give pale yellow 1-cyclopropyl-7- [ 1.22 g of 2-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid ethyl ester obtain.
IR (KBr) cm -1 : 1676
NMR (CDCl Three ): 0.8-1.8 (7H, m), 2.40 (3H, s), 3.5-4.0 (1H, m), 4.1-4.9 (6H, m), 7.1-8.9 (10H, m)
Example 36
1-cyclopropyl-7- [2-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro [1,8] naphthyridine-3 -Carboxylic acid ethyl ester (1.20 g) is suspended in a mixed solvent of ethanol (12 ml) and 1,4-dioxane (12 ml), 1 mol / L aqueous sodium hydroxide solution (4.5 ml) is added, and the mixture is stirred at 40 ° C for 2 hours. If 1 mol / L hydrochloric acid 9.0 ml is added to the reaction mixture and the crystals are collected by filtration, 1-cyclopropyl-7- [2-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1H-5-isoindolyl] 1.10 g of -4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid are obtained.
Example 37
1-cyclopropyl-7- [2-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro [1,8] naphthyridine-3 -1.00 g of carboxylic acid is suspended in 10.0 ml of hydrobromic acid, 0.56 g of phenol and 6.0 ml of propionic acid are added, and then the mixture is stirred at 100 ° C. for 10 hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, ethanol is added to the resulting residue, and the crystals are collected by filtration to give 1-cyclopropyl-7- (2,3-dihydro-1H-5-isoindolyl) -4-oxo- 0.85 g of 1,4-dihydro [1,8] naphthyridine-3-carboxylic acid hydrobromide is obtained.
The obtained hydrobromide is suspended in a mixed solvent of 15.8 ml of ethanol and 20.8 ml of water, and 10.8 ml of 1 mol / L sodium hydroxide aqueous solution is added and dissolved, and then carbon dioxide gas is blown into the solution. The precipitated crystals were collected by filtration to give pale yellow crystals of 1-cyclopropyl-7- (2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro [1,8] naphthyridine-3. -0.54 g of carboxylic acid is obtained.
IR (KBr) cm -1 : 1618
NMR (d 1 -TFA): 1.0-1.9 (4H, m), 4.2-4.7 (1H, m), 5.04 (4H, brs), 7.65 (1H, d, J = 8.8Hz), 8.2-8.6 (3H, m), 9.12 (1H, d, J = 8.8Hz), 9.55 (1H, s)
Industrial applicability
The quinolonecarboxylic acid derivative or salt thereof of the present invention exhibits a strong antibacterial action against gram-positive and gram-negative bacteria, particularly MRSA, and is a highly safe compound that is useful as a therapeutic agent for various infectious diseases. is there.
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| EP1885378A4 (en) * | 2005-05-09 | 2010-10-27 | Microbia Inc | Organometal benzenephosphonate coupling agents |
| WO2006137485A1 (en) * | 2005-06-24 | 2006-12-28 | Toyama Chemical Co., Ltd. | Novel nitrogenated heterocyclic compound and salt thereof |
| US8211908B2 (en) | 2006-05-26 | 2012-07-03 | Toyama Chemical Co., Ltd. | Heterocyclic compound or salt thereof and intermediate thereof |
| US8354426B2 (en) | 2007-11-26 | 2013-01-15 | Toyama Chemical Co., Ltd. | Naphthyridine derivative monohydrate and method for producing the same |
| CN102212056A (en) * | 2010-04-09 | 2011-10-12 | 山东轩竹医药科技有限公司 | Novel bicyclo-carbostyril compounds |
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| US5141931A (en) * | 1991-01-03 | 1992-08-25 | Sterling Winthrop Inc. | 5-Quinolinylpyridinones, cardiotonic compositions and methods |
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