JP3745433B2 - Heterocyclic compounds - Google Patents
Heterocyclic compounds Download PDFInfo
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- JP3745433B2 JP3745433B2 JP01626096A JP1626096A JP3745433B2 JP 3745433 B2 JP3745433 B2 JP 3745433B2 JP 01626096 A JP01626096 A JP 01626096A JP 1626096 A JP1626096 A JP 1626096A JP 3745433 B2 JP3745433 B2 JP 3745433B2
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- carbon atoms
- compound
- alkyl
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- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 100
- -1 acetoxymethyl group Chemical group 0.000 claims description 49
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000003277 amino group Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical group C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 53
- 239000000243 solution Substances 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
- 239000002904 solvent Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000013078 crystal Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 230000000844 anti-bacterial effect Effects 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 150000007660 quinolones Chemical class 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- IJHTZGBRXSYOMG-UHFFFAOYSA-N tert-butyl n-(3-azabicyclo[3.1.0]hexan-1-yl)carbamate Chemical compound C1NCC2(NC(=O)OC(C)(C)C)C1C2 IJHTZGBRXSYOMG-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FFOYMNCZNJJCSO-UHFFFAOYSA-N 4-(carboxymethyl)-3,5,6-trifluorophthalic acid Chemical compound OC(=O)CC1=C(F)C(F)=C(C(O)=O)C(C(O)=O)=C1F FFOYMNCZNJJCSO-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 206010028470 Mycoplasma infections Diseases 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 206010040047 Sepsis Diseases 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 201000003146 cystitis Diseases 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 3
- CISXRFRLKWCFJS-UHFFFAOYSA-N 2,4,5-trifluoro-3-methylbenzoic acid Chemical compound CC1=C(F)C(F)=CC(C(O)=O)=C1F CISXRFRLKWCFJS-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 206010039438 Salmonella Infections Diseases 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 3
- 125000004391 aryl sulfonyl group Chemical group 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 3
- YKDASBAWJFXNAV-UHFFFAOYSA-N dimethyl 3,4,5,6-tetrafluorobenzene-1,2-dicarboxylate Chemical compound COC(=O)C1=C(F)C(F)=C(F)C(F)=C1C(=O)OC YKDASBAWJFXNAV-UHFFFAOYSA-N 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- SFYYMUUQGSQVFT-UHFFFAOYSA-N ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate Chemical compound CCOC(=O)CC(=O)C1=C(F)C(F)=C(F)C(F)=C1F SFYYMUUQGSQVFT-UHFFFAOYSA-N 0.000 description 3
- LAEMJDGOUPEDRU-NKWVEPMBSA-N ethyl 5,6,7,8-tetrafluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(F)=C2C(=O)C(C(=O)OCC)=CN1[C@@H]1C[C@@H]1F LAEMJDGOUPEDRU-NKWVEPMBSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 206010039447 salmonellosis Diseases 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 3
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 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 3
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 2
- TUKJTSUSKQOYCD-STHAYSLISA-N (1r,2s)-2-fluorocyclopropan-1-amine Chemical compound N[C@@H]1C[C@@H]1F TUKJTSUSKQOYCD-STHAYSLISA-N 0.000 description 2
- XUWZMHVPMZXIRU-LMLSDSMGSA-N (1r,2s)-2-fluorocyclopropan-1-amine;4-methylbenzenesulfonic acid Chemical compound N[C@@H]1C[C@@H]1F.CC1=CC=C(S(O)(=O)=O)C=C1 XUWZMHVPMZXIRU-LMLSDSMGSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- MYCPRDKWFULFIU-CRCLSJGQSA-N 6,7,8-trifluoro-1-[(1r,2s)-2-fluorocyclopropyl]-5-hydroxy-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(F)=C(F)C(O)=C2C(=O)C(C(=O)O)=CN1[C@@H]1C[C@@H]1F MYCPRDKWFULFIU-CRCLSJGQSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- 206010061190 Haemophilus infection Diseases 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010041925 Staphylococcal infections Diseases 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 150000003248 quinolines Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229940021506 stye Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
【0001】
【発明の属する技術分野】
本発明は医薬、動物薬、水産用薬または抗菌性の保存剤として有用な抗菌性化合物に関し、さらにこの化合物を含有する抗菌薬または抗菌性製剤に関する。
【0002】
【従来の技術】
1−アミノ−3−アザビシクロ[3.2.0]ヘプタン−3−イル基を有するキノロン誘導体は特開昭64−56673号公報および特開平3−86875号公報に記載があるが、このアミノ置換縮合二環性へテロ環式化合物から導かれた置換基を有し、かつ1位にハロゲノシクロプロピル基を有する本発明に係わるキノロン誘導体は知られていない。
【0003】
【発明が解決しようとする課題】
キノロン系合成抗菌剤は、近年、抗菌活性のみならず、経口吸収性、臓器への移行性あるいは尿中排泄率などの体内動態が優れたものが見い出されており、多くの感染症に有効な化学療法剤として多くの化合物が臨床の場に供されている。しかしながら、最近、臨床の場ではこれらの薬剤に対する低感受性菌が増加しつつある。また、例えばβ−ラクタム系抗生物質に非感受性の黄色ブドウ球菌(MRSA)の如く、キノロン系合成抗菌剤以外の薬剤に耐性の菌のなかにもキノロン系合成抗菌剤に低感受性の菌が増加している。したがって、臨床の場で有効性がさらに高い薬剤が望まれている。
【0004】
【課題を解決するための手段】
キノロン系合成抗菌剤の抗菌活性、有効性、安全性には7位および1位の置換基の構造が大きく関与すると本願発明者は考えている。本願発明者はキノロン耐性菌を含む広範な細菌に対して高い抗菌活性を有する化合物を得るべく鋭意研究した結果、アミノ置換縮合二環性ヘテロ環式化合物から導かれる置換基を7位に有するキノロン誘導体がグラム陰性菌およびグラム陽性菌、とりわけMRSAを含むキノロン耐性菌に対し強力な抗菌活性を示すことを見出し、そして1位にハロゲノシクロプロピル基、特にフルオロシクロプロピル基を置換したキノロン誘導体であれば抗菌活性と共に有効性、安全性に優れたキノロン誘導体が得られることを見いだした。
【0005】
本発明に係わるキノロン誘導体は、他の部位の置換基に立体異性がなくとも、1位のハロゲノシクロプロパン環部分だけで一対の対掌体が存在する。これはシクロプロパン環上でのピリドンカルボン酸部分とハロゲン原子との立体的な関係に由来している。このようにして生ずる異性体がラセミ体の関係の場合は、対掌体の混合物でありこのままで医薬として応用することは不可能ではない。
【0006】
一方、ハロゲノシクロプロパン環部分の立体異性に加え他の部位、特に7位の置換基にも立体異性が存在する場合にはジアステレオマーが存在することとなり、4種以上の立体異性体が存在することになる。ジアステレオマーの混合物は物性の異なった化合物の混合物であって、混合物のままでは医薬としての応用は困難である。
【0007】
本発明者は、ジアステレオマーが存在する1−(1,2−シス−2−ハロゲノシクロプロピル)置換キノロン誘導体であっても、単一な立体異性体からなるキノロン化合物が得られるべく鋭意努力した。
【0008】
その結果、本発明者はシス−2−フルオロシクロプロピルアミンの対掌体の各々を純粋な化合物として得ることに成功した。そしてこのシス−フルオロシクロプロピルアミンを原料として、フルオロシクロプロパン環の立体配置のみに由来した対掌体のキノロン誘導体の各々を単一な異性体からなる化合物として得ることに成功した。さらに、不斉炭素を有し、ヘテロ原子が窒素原子からなるアミノ置換縮合二環性ヘテロ環式化合物においても異性体の各々を純粋な化合物として得ることにも成功した。
【0009】
中間体として有用なこのキノロン誘導体およびヘテロ原子が窒素原子からなるアミノ置換縮合二環性ヘテロ環式化合物を得たことによって、単一のジアステレオマーからなる立体化学的に単一なキノロン誘導体を合成することが可能となった。
【0010】
そして、本発明に係わる、アミノ置換縮合二環性ヘテロ環式化合物から導かれる基を7位に、そしてハロゲノシクロプロピル基を1位に有することを特徴とする新規なキノロン誘導体が、キノロン耐性菌を含む広範な細菌に対する優れた活性と高い安全性を有する化合物であることを見い出し本発明を完成した。
【0011】
すなわち本発明は、一般式(I)
【0012】
【化4】
【0013】
[式中、X1はハロゲン原子または水素原子を表し、
X2はハロゲン原子を表し、
R1は水素原子、水酸基、チオール基、ハロゲノメチル基、アミノ基、炭素数1から6のアルキル基または炭素数1から6のアルコキシル基を表すが、このうちのアミノ基は置換基として、ホルミル基、炭素数1から6のアルキル基または炭素数2から5のアシル基を有していてもよい(ただし、置換基がアルキル基の場合はジアルキル置換となってもよく、この場合にアルキル基は同一でも異なっていてもよい。)、
R2は式(II)
【0014】
【化5】
【0015】
(式中、R3およびR4は各々独立に、水素原子または炭素数1から6のアルキル基を表し、nは1の整数を表す。)
で表される、アミノ置換縮合二環性ヘテロ環式化合物から導かれる構造の基を表し、
Aは窒素原子または式(III)
【0016】
【化6】
【0017】
[X3は水素原子、ハロゲン原子、シアノ基、アミノ基、炭素数1から6のアルキル基、ハロゲノメチル基、炭素数1から6のアルコキシル基、またはハロゲノメトキシ基を表すが、このうちのアミノ基は置換基として、ホルミル基、炭素数1から6のアルキル基または炭素数2から5のアシル基を有していてもよい(ただし、置換基がアルキル基の場合はジアルキル置換となってもよく、この場合にアルキル基は同一でも異なっていてもよい。)]
の部分構造を表し、
Rは水素原子、フェニル基、アセトキシメチル基、ピバロイルオキシメチル基、エトキシカルボニル基、コリン基、ジメチルアミノエチル基、5−インダニル基、フタリジニル基、5−アルキル−2−オキソ−1,3−ジオキソール−4−イルメチル基、3−アセトキシ−2−オキソブチル基、炭素数1から6のアルキル基、炭素数2から7のアルコキシメチル基または、炭素数1から6のアルキレン基とフェニル基とから構成されるフェニルアルキル基を表す。]
で表されるN1−(ハロゲノシクロプロピル)置換ピリドンカルボン酸誘導体およびその塩に関する。
【0018】
さらに本発明は、一般式(I)中、ハロゲノシクロプロピル基が1,2−シス−2−ハロゲノシクロプロピル基である上記の化合物およびその塩に関する。
【0019】
また本発明は、一般式(I)中、R2が立体化学的に単一な置換基である上記の化合物およびその塩に関する。
【0020】
そして本発明は、一般式(I)中、ハロゲノシクロプロピル基が立体化学的に単一な置換基である上記の化合物およびその塩に関する。
【0021】
さらに本発明は、ハロゲノシクロプロピル基が(1R,2S)−2−ハロゲノシクロプロピル基である上記の化合物およびその塩に関する。
【0022】
また本発明は、X2がフッ素原子である上記の化合物およびその塩に関する。
【0023】
そして本発明は、上記の一般式(I)の化合物またはその塩を有効成分として含有する抗菌薬に関するものである。
【0024】
【発明の実施の態様】
本発明の式(I)で表される化合物が有する置換基について以下に述べる。
【0025】
X1、X2およびX3が各々ハロゲン原子の場合、X1およびX2はフッ素原子が特に好ましく、X3はフッ素原子または塩素原子が好ましい。
【0026】
R1は水素原子、水酸基、チオール基、ハロゲノメチル基、アミノ基、炭素数1から6のアルキル基または炭素数1から6のアルコキシル基を表すが、このうちのアミノ基は置換基として、ホルミル基、炭素数1から6のアルキル基または炭素数2から5のアシル基を有していてもよい(ただし、置換基がアルキル基の場合はジアルキル置換となってもよく、この場合にアルキル基は同一でも異なっていてもよい。)。
【0027】
置換基R1としてのアルキル基としては、炭素数1から6の直鎖状または分枝鎖状のものでよいが、好ましくはメチル基、エチル基、ノルマルプロピル基またはイソプロピル基である。
【0028】
ハロゲノメチル基のハロゲン原子としては特にフッ素原子が好ましく、その数は1から3でよい。ハロゲノメチル基として好ましいものは、フルオロメチル基またはジフルオロメチル基である。
【0029】
R1がアミノ基、水酸基またはチオール基の場合に、これらは通常使用されている保護基によって保護されていてもよい。
【0030】
これらの保護基の例としては例えば、第三級ブトキシカルボニル基、2,2,2−トリクロロエトキシカルボニル基等のアルコキシカルボニル基類、ベンジルオキシカルボニル基、パラメトキシベンジルオキシカルボニル基、パラニトロベンジルオキシカルボニル基等のアラルキルオキシカルボニル基類、アセチル基、メトキシアセチル基、トリフルオロアセチル基、クロロアセチル基、ピバロイル基、ホルミル基、ベンゾイル基等のアシル基類、第三級ブチル基、ベンジル基、パラニトロベンジル基、パラメトキシベンジル基、トリフェニルメチル基等のアルキル基類又はアラルキル基類、メトキシメチル基、第三級ブトキシメチル基、テトラヒドロピラニル基、2,2,2−トリクロロエトキシメチル基等のエーテル類、トリメチルシリル基、イソプロピルジメチルシリル基、第三級ブチルジメチルシリル基、トリベンジルシリル基、第三級ブチルジフェニルシリル基等のシリル基類を挙げることができる。
【0031】
これらの保護基のうちエーテル類およびシリル基類は、水酸基およびチオール基の保護基として使用するのが好ましく、これら以外の保護基はアミノ基、水酸基またはチオール基のいずれの保護基としても使用することができる。
【0032】
X3は水素原子、ハロゲン原子、シアノ基、アミノ基、炭素数1から6のアルキル基、ハロゲノメチル基、炭素数1から6のアルコキシル基、またはハロゲノメトキシ基を表すが、このうちのアミノ基は置換基として、ホルミル基、炭素数1から6のアルキル基または炭素数2から5のアシル基を有していてもよい(ただし、置換基がアルキル基の場合はジアルキル置換となってもよく、この場合にアルキル基は同一でも異なっていてもよい。)。
【0033】
置換基X3としてのアルキル基としては、炭素数1から6の直鎖状または分枝鎖状のものでよいが、好ましくはメチル基、エチル基、ノルマルプロピル基またはイソプロピル基である。
【0034】
ハロゲノメチル基のハロゲン原子としては特にフッ素原子が好ましく、その数は1から3でよい。ハロゲノメチル基として好ましくは、フルオロメチル基またはジフルオロメチル基である。
【0035】
アルコキシル基としては炭素数1から6のものでよいが、好ましくはメトキシル基である。
【0036】
ハロゲノメトキシル基のハロゲン原子としては特にフッ素原子が好ましく、その数は1から3でよい。
【0037】
Aが
【0038】
【化7】
【0039】
で示される部分構造である場合、R1とX3の組み合わせとして好ましいのは、R1がアミノ基、水素原子、水酸基または炭素数1から6のアルキル基で、X3が炭素数1から6のアルキル基、炭素数1から6のアルコキシル基、ハロゲン原子、ハロゲノメトキシ基または水素原子の場合である。
【0040】
さらに好ましい組み合わせとしては、R1がアミノ基、水素原子、水酸基またはメチル基で、X3がメチル基、メトキシ基、フッ素原子、塩素原子、ジフルオロメトキシ基または水素原子の場合である。
【0041】
特に、好ましい組み合わせとしては、R1がアミノ基、水素原子、水酸基またはメチル基で、X3がメチル基またはメトキシ基の場合である。
【0042】
これらのR1およびX3に対して、X1およびX2はフッ素原子が好ましい。
【0043】
R2は化8
【0044】
【化8】
【0045】
で表されるアミノ置換縮合二環性ヘテロ環式化合物(ここでは五員環の窒素原子が水素置換のものを示したが、これは他の置換基、例えば窒素原子の保護基等、によって置換されていてもよい。)から導かれる、式(II)
【0046】
【化9】
【0047】
で表される基を意味する。この基は、ブリッジヘッドの炭素原子に置換基としてアミノ基を有している。したがって、この部分についてみれば小員環の脂環式環状アミン構造を有しているとも考えられ、この構造が本発明化合物の優れた特性の発現に大きく関与していると本発明者らは考えた。
【0048】
縮合二環性ヘテロ環式化合物とは、縮合二環性炭化水素化合物の環状構造を形成している炭素原子が窒素原子等の複素原子に置き換わって生ずる構造の化合物である。
【0049】
ここで、R3およびR4は各々独立に、水素原子または炭素数1から6のアルキル基である。アルキル基としては炭素数1から6の直鎖状または分枝鎖状いずれでもよいが、好ましくはメチル基である。また、R3およびR4は一体化して炭素数2から6のメチレン鎖を形成し、R3およびR4が結合している窒素原子を含んで環状構造を形成してもよい。
【0050】
R3およびR4の好ましい組み合わせは、R3およびR4が水素原子の場合、R3またはR4のいずれかが水素原子で、他方が炭素数1から6のアルキル基の場合である。
【0051】
さらに好ましい組み合わせは、R3およびR4が水素原子の場合、R3またはR4のいずれかが水素原子で、他方がメチル基またはエチル基の場合である。
【0052】
R2に立体異性が存在する場合、キノロン母核化合物との反応に際して、置換基R2の導入源である式R2−Hで表される化合物を、立体異性体の混合物のままで反応させると、1位の1,2−シス−2−ハロゲノシクロプロピル基との関係から、生成するキノロン誘導体はジアステレオマーの混合物となる。それ故に、置換基R2に立体異性が存在する場合には、キノロン母核化合物に反応させる式R2−Hで表される化合物は、異性体のうちの一種を単独で反応させるのが好ましい。
【0053】
キノロンの7位にR2を導入する際、式R2−Hで表される化合物にアミノ基が存在する場合にこのアミノ基は、通常使用されている保護基に変換した化合物として反応させてもよい。
【0054】
このような保護基としては例えば、第三級ブトキシカルボニル基、2,2,2−トリクロロエトキシカルボニル基等のアルコキシカルボニル基類、ベンジルオキシカルボニル基、パラメトキシベンジルオキシカルボニル基、パラニトロベンジルオキシカルボニル基等のアラルキルオキシカルボニル基類、アセチル基、メトキシアセチル基、トリフルオロアセチル基、クロロアセチル基、ピバロイル基、ホルミル基、ベンゾイル基等のアシル基類、第三級ブチル基、ベンジル基、パラニトロベンジル基、パラメトキシベンジル基、トリフェニルメチル基等のアルキル基類又はアラルキル基類、メタンスルホニル基、トリフルオロメタンスルホニル基等のアルキルスルホニル基類あるいはハロゲノアルキルスルホニル基類、そしてベンゼンスルホニル基、トルエンスルホニル基等のアリールスルホニル基類を挙げることができる。
【0055】
次にN1位のハロゲノシクロプロピル基について述べる。
【0056】
置換するハロゲン原子としてはフッ素原子および塩素原子を挙げることができるが、特にフッ素原子が好ましい。
【0057】
この部分での立体的な環境は、シクロプロパン環に対しハロゲン原子とピリドンカルボン酸部分がシス配置であるのが特に好ましい。
【0058】
この1位のシス−2−ハロゲノシクロプロピル部分だけで、他の部位の置換基とりわけ7位のR2の立体異性の如何に拘らず、いわゆる対掌体関係の異性体が存在するが、いずれの異性体にも強い抗菌活性と高い安全性が認められた。
【0059】
本発明化合物である式(I)の化合物がジアステレオマーの存在する構造のものである場合、本発明化合物をヒトや動物に投与する際は単一のジアステレオマーからなるものを投与することが好ましい。この、『単一のジアステレオマーからなる』とは、他のジアステレオマーを全く含有しない場合だけではなく、化学的に純粋な程度の場合をも含むと解される。つまり、物理定数や、生理活性に対して影響がない程度であれば他のジアステレオマーが含まれていてもよいと解釈されるのである。
【0060】
また『立体化学的に単一な』とは、化合物等において不斉炭素原子が含まれるために、異性体関係となる複数種が存在する場合にそれらのうちの一種のみにて構成されたものであることを意味する。この場合においてもこの『単一』については上記と同様に考えればよい。
【0061】
本発明のピリドンカルボン酸誘導体は遊離体のままでもよいが、酸付加塩としてあるいはカルボキシル基の塩としてもよい。酸付加塩とする場合の例としては、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩等の無機酸塩類、あるいは酢酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、乳酸塩等の有機酸塩類を挙げることができる。
【0062】
またカルボキシル基の塩としては、例えばリチウム塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アンモニウム塩、またトリエチルアミン塩やN−メチルグルカミン塩、トリス−(ヒドロキシルメチル)アミノメタン塩等で無機塩類、有機塩類の何れでもよい。
【0063】
またこれらのピリドンカルボン酸誘導体の遊離体や酸付加塩、カルボキシル基の塩は水和物として存在することもある。
【0064】
一方、カルボン酸部分がエステルであるキノロン誘導体は合成中間体やプロドラッグとして有用である。例えば、アルキルエステル類やベンジルエステル類、アルコキシアルキルエステル類、フェニルアルキルエステル類およびフェニルエステル類は合成中間体として有用である。
【0065】
また、プロドラッグとして用いられるエステルとしては、生体内で容易に切断されてカルボン酸の遊離体を生成するようなエステルであり、例えば、アセトキシメチルエステル、ピバロイルオキシメチルエステル、エトキシカルボニルエステル、コリンエステル、ジメチルアミノエチルエステル、5−インダニルエステルおよびフタリジニルエステル、5−アルキル−2−オキソ−1,3−ジオキソール−4−イルメチルエステルそして3−アセトキシ−2−オキソブチルエステル等のオキソアルキルエステルを挙げることができる。
【0066】
式(I)で表される本発明の化合物は種々の方法により製造されるが、その好ましい一例を挙げれば例えば式(VI)
【0067】
【化10】
【0068】
[式中、Xは例えばフッ素原子、塩素原子、臭素原子、炭素数が1から3のアルキルスルホニル基、またはベンゼンスルホニル基やトルエンスルホニル基等のアリールスルホニル基等の脱離基としての機能を有する置換基であり、Rは一般式(I)で定義したRと同義であるか、式(VII)
【0069】
【化11】
【0070】
(式中、R11およびR12はフッ素原子あるいは低級アルキルカルボニルオキシ基を示す)
のホウ素含有の置換基であり、X1、X2、R1およびAは一般式(I)に関して定義した通りである]
で表される化合物(キノロン母核化合物)を、式R2−H(式中R2の定義において、アミノ基の置換基が保護基Rxとなってもよい以外は、R2は式(I)に関して定義した通りである。)である化合物あるいはその酸付加塩と反応させることによって製造することができる。
【0071】
窒素原子の保護基Rxは、この分野で通常使用されている保護であればよく、これらの保護基の例としては例えば、第三級ブトキシカルボニル基、2,2,2−トリクロロエトキシカルボニル基等のアルコキシカルボニル基類、ベンジルオキシカルボニル基、パラメトキシベンジルオキシカルボニル基、パラニトロベンジルオキシカルボニル基等のアラルキルオキシカルボニル基類、アセチル基、メトキシアセチル基、トリフルオロアセチル基、クロロアセチル基、ピバロイル基、ホルミル基、ベンゾイル基等のアシル基類、第三級ブチル基、ベンジル基、パラニトロベンジル基、パラメトキシベンジル基、トリフェニルメチル基等のアルキル基類又はアラルキル基類、メタンスルホニル基、トリフルオロメタンスルホニル基等のアルキルスルホニル基類あるいはハロゲノアルキルスルホニル基類、そしてベンゼンスルホニル基、トルエンスルホニル基等のアリールスルホニル基類を挙げることができる。
【0072】
Rが炭素数1から6のアルキル基、炭素数2から7のアルコキシメチル基または炭素数1から6のアルキレン基とフェニル基で構成されるアラルキル基であって、カルボン酸エステルとなっているとき、相当するカルボン酸への変換はカルボン酸エステルの加水分解に用いられる一般的な酸性るいは塩基性条件下で行い、さらに他の置換基が保護されていて脱保護が必要な場合は、その保護基に対応した適当な条件で保護基を除去して一般式(I)で示される目的化合物を得ることができる。
【0073】
式(IV)の化合物においてRが化14で表される基である場合には、化合物R2−Hとの置換反応を行った後に酸性または塩基性化合物で処理すことにより相当するカルボン酸に変換することができる。
【0074】
化13の化合物とR2−Hの化合物との置換反応は溶媒を用いてまたは用いずに行うことができる。溶媒を使用するとき、溶媒は反応条件下で不活性であればよい。適した溶媒としてたとえばジメチルスルホキシド、ピリジン、アセトニトリル、エタノール、クロロホルム、ジメチルホルムアミド、ジメチルアセトアミド、N−メチルピロリドン、テトラヒドロフラン、水、3−メトキシブタノールまたはこれらの混合物をあげることができる。
【0075】
反応温度は通常室温から200℃の温度範囲で実施でき、好ましくは25℃から150℃の範囲である。反応時間は30分から48時間でよく、通常は30分から2時間程度で完結する。
【0076】
反応は無機または有機塩基のような酸受容体、たとえばアルカリ金属、アルカリ土類金属炭酸塩もしくは炭酸水素塩、あるいはトリエチルアミンもしくはピリジン等の有機塩基性化合物の存在下で行うのが有利である。
【0077】
アミノ置換縮合二環性ヘテロ環式化合物の合成例を以下に示す。立体的に単一の異性体からなる1−第三級ブトキシカルボニルアミノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサンは、例えば以下の方法で得ることができる。
【0078】
【化12】
【0079】
すなわち、(S)−(−)−フェニルエチルアミンをエタノールを溶媒として用いてグリシドールと反応した後、アクリロニトリルと反応させてN−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−プロパンジオールとする。この化合物をトリフェニルフォスフインおよび四臭化炭素と反応させてN−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−ジブロモプロパンとする。この化合物を強塩基存在下に反応させて1−シアノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサンとする。この化合物は3位にフェニルエチル基、そして1位に不斉炭素を有するためにジアステレオマーの混合物として得られる。それぞ
れの異性体はシリカゲルカラムクロマトグラフィーあるいは高速液体クロマトグラフィーで分離できる。このようにして得られる異性体それぞれを通常用いられる方法により塩基と反応させて3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン−1−カルボン酸とする。この化合物を三級ブタノールの存在下でクルチウス反応を行なうと、一気に保護された3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン−1−カルボン酸に変換することができる。この反応ではジフェニルホスホリルアジドを使用すると簡便に実施できるが、中間体のアジド体の合成はこれに限定されず通常の合成法が適用できる。この化合物を通常用いられる方法により接触水素添加によりフェニルエチル基を除去すれば単一の異性体からなる1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサンとなる。
【0080】
一方、光学活性なシス−2−フルオロシクロプロピルアミン誘導体を原料とする、単一の異性体からなる式(VIII)の化合物の合成は例えば、特開平2−231475号記載の方法によって実施することができる。
【0081】
【化13】
【0082】
式(VIII)で表わされる化合物に含まれる6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−5−ヒドロキシ−4−オキソキノリン−3−カルボキシラートは例えば、次のように合成することができる。
【0083】
エチル 2,3,4,5,6−ペンタフルオロベンゾイルアセタートをN,N−ジメチルホルムアミド ジメチルアセタールと反応した後、トリエチルアミン等の酸除去剤の存在下に(1R,2S)−2−フルオロシクロプロピルアミン・p−トルエンスルホン酸塩を反応させ、エチル 5,6,7,8−テトラフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキシラートとする。
【0084】
この化合物とベンジルアルコールを塩基存在下に反応させ、エチル 5−ベンジルオキシ−6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキシラートとする。この反応は当業界において公知の方法で実施することができる。ここで使用できる塩基としては水素化ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウムを例示することができる。
【0085】
この化合物を酸性条件で処理すれば、6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−5−ヒドロキシ−4−オキソキノリン−3−カルボキシラートとなる。
【0086】
式(VIII)の化合物の中でR1がアミノ基であり、かつX3が低級アルキル基である化合物は3位に低級アルキルを有する2,4,5−トリフルオロ安息香酸を通常の方法によってニトロ化して得られる3位に低級アルキル基を有する2,4,5−トリフルオロ−6−ニトロ安息香酸を出発原料として上記の方法にしたがって製造することができる。
【0087】
【化14】
【0088】
3−メチル−2,4,5−トリフルオロ安息香酸は特開昭61−205240号公報、特開平3−95176号公報記載の方法で製造することができるが、以下の方法によってより簡便に合成することができる。
【0089】
【化15】
【0090】
すなわち、3,4,5,6−テトラフルオロフタル酸ジエステルをマロン酸ジエステルと塩基を用いて反応し、例えばジエチル 4ージエトキシカルボニルメチル−3,5,6−トリフルオロフタラートを得る。
【0091】
ここで使用できる塩基は無機塩基、有機塩基のいずれでも良いが、例えば無機塩基としては水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の水酸化物、炭酸塩または炭酸水素塩等を挙げることができる。さらにこの反応には四級アンモニウム塩等の相間移動触媒を用いることができる。
【0092】
有機塩基としてはトリエチルアミン、トリプロピルアミン、トリブチルアミン、N,N−ジイソプロピルエチルアミン等のトリアルキルアミン類、ジエチルアニリン、ジメチルアニリン等のジアルキルアニリン類、N−メチルモルホリン、ピリジン、N,N−ジメチルアミノピリジン等の飽和あるいは芳香族の複素環化合物類を例示することができる。
【0093】
溶媒を使用するとき、溶媒は反応条件下で不活性であればよい。適した溶媒としてたとえばジメチルスルホキシド、ピリジン、アセトニトリル、エタノール、クロロホルム、ジメチルホルムアミド、ジメチルアセトアミド、N−メチルピロリドン、テトラヒドロフラン、ベンゼン、トルエン、水またはこれらの混合物を挙げることができる。
【0094】
反応温度は通常0℃から150℃の温度範囲で実施でき、好ましくは25℃から100℃の範囲である。
【0095】
次に、ジメチル 4−ジエトキシカルボニルメチル−3,5,6−トリフルオロフタラートを酸性あるいは塩基性条件下で加水分解し4−カルボキシメチル−3,5,6−トリフルオロフタル酸とする。
【0096】
ここでは酸として濃硫酸、あるいは濃塩酸を例示することができる。また塩基としては水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の水酸化物、炭酸塩または炭酸水素塩等の無機塩基を挙げることができる。
【0097】
得られた、4−カルボキシメチル−3,5,6−トリフルオロフタル酸をジメチルスルホキシド中で塩基存在下に加熱して3−メチル−2,4,5−トリフルオロ安息香酸を得ることができる。
【0098】
ここで使用できる有機塩基としてはトリエチルアミン、トリプロピルアミン、トリブチルアミン、N,N−ジイソプロピルエチルアミン等のトリアルキルアミン類、ジエチルアニリン、ジメチルアニリン等のジアルキルアニリン類、N−メチルモルホリン、ピリジン、N,N−ジメチルアミノピリジン等の飽和あるいは芳香族の複素環化合物類を例示することができる。
【0099】
反応温度は通常100℃から200℃の温度範囲で実施でき、好ましくは100℃から150℃の範囲である。反応時間は1時間から96時間でよいが、通常は5時間から48時間で完結する。
【0100】
本製造法において3,4,5,6−テトラフルオロフタル酸ジエステルの代わりに3,4,5,6−テトラフルオロフタロニトリルを出発原料として用いても同様に実施できる。また、マロン酸ジエステルの代わりにマロノニトリルを使用してもよく、アルキルマロン酸ジエステルやアルキルマロノニトリルはメチル基以外のアルキル基を有する3−アルキル−2,4,5−トリフルオロ−6−ニトロ安息香酸の製造に有用である。
【0101】
本発明化合物は強い抗菌作用を有することから人体、動物、および魚類用の医薬として或は農薬、食品の保存剤として使用することができる。
【0102】
本発明化合物を人体用の医薬として使用する場合、投与量は成人一日当たり 50mgから1g、好ましくは100mgから300mgの範囲である。
【0103】
また動物用としての投与量は、投与の目的(治療或は予防)、処置すべき動物の種類や大きさ、感染した病原菌の種類、程度によって異なるが、一日量として一般的には動物の体重1kg当たり1mgから200mg、好ましくは5mgから100mgの範囲である。
【0104】
この一日量を一日1回、あるいは2から4回に分けて投与する。また一日量は必要によっては上記の量を超えてもよい。
【0105】
本発明化合物は各種の感染症の原因となる広範囲の微生物類に対して活性であり、これらの病原体によって引き起こされる疾病を治療し、予防し、または軽減することができる。
【0106】
本発明化合物が有効なバクテリア類又はバクテリア様微生物類としてブドウ球菌属、化膿レンサ球菌、溶血レンサ球菌、腸球菌、肺炎球菌、ペプトストレプトコッカス属、淋菌、大腸菌、シトロバクター属、シゲラ属、肺炎桿菌、エンテロバクター属、セラチア属、プロテウス属、緑膿菌、インフルエンザ菌、アシネトバクター属、カンピロバクター属、トラコーマクラミジア等を例示することができる。
【0107】
またこれらの病原体によって引き起こされる疾病としては、毛嚢炎、せつ、よう、丹毒、蜂巣炎、リンパ管(節)炎、ひょう疽、皮下膿瘍、汗腺炎、集簇性ざ瘡、感染性粉瘤、肛門周囲膿瘍、乳腺炎、外傷・熱傷・手術創などの表在性二次感染、咽喉頭炎、急性気管支炎、扁桃炎、慢性気管支炎、気管支拡張症、びまん性汎細気管支炎、慢性呼吸疾患の二次感染、肺炎、腎盂腎炎、膀胱炎、前立腺炎、副睾丸炎、淋菌性尿道炎、非淋菌性尿道炎、胆のう炎、胆管炎、細菌性赤痢、腸炎、子宮付属器炎、子宮内感染、バルトリン腺炎、眼瞼炎、麦粒腫、涙嚢炎、瞼板腺炎、角膜潰瘍、中耳炎、副鼻腔炎、歯周組織炎、歯冠周囲炎、顎炎、腹膜炎、心内膜炎、敗血症、髄膜炎、皮膚感染症等を例示することができる。
【0108】
また動物の感染症の原因となる各種の微生物、例えばエシエリキア属、サルモネラ属、パスツレラ属、ヘモフィルス属、ボルデテラ属、スタヒロコッカス属、マイコプラズマ属等に有効である。具体的な疾病名を例示すると鳥類では大腸菌症、ひな白痢、鶏パラチフス症、家禽コレラ、伝染性コリーザ、ブドウ球菌症、マイコプラズマ感染症等、豚では大腸菌症、サルモネラ症、パスツレラ症、ヘモフィルス感染症、萎縮性鼻炎、滲出性表皮炎、マイコプラズマ感染症等、牛では大腸菌症、サルモネラ症、出血性敗血症、マイコプラズマ感染症、牛肺疫、乳房炎等、犬では大腸菌性敗血症、サルモネラ感染症、出血性敗血症、子宮蓄膿症、膀胱炎等、そして猫では滲出性胸膜炎、膀胱炎、慢性鼻炎、ヘモフィルス感染症、仔猫の下痢、マイコプラズマ感染症等を挙げることができる。
【0109】
本発明化合物からなる抗菌製剤は投与法に応じ適当な製剤を選択し、通常用いられている各種製剤の調製法にて調製できる。本発明化合物を主剤とする抗菌製剤の剤型としては例えば錠剤、散剤、顆粒剤、カプセル剤や、溶液剤、シロップ剤、エリキシル剤、油性ないし水性の懸濁液等を経口用製剤として例示できる。
注射剤としては製剤中に安定剤、防腐剤、溶解補助剤を使用することもあり、これらの補助剤を含むこともある溶液を容器に収納後、凍結乾燥等によって固形製剤として用時調製の製剤としても良い。また一投与量を容器に収納しても良く、また多投与量を同一の容器に収納しても良い。
【0110】
また外用製剤として溶液剤、懸濁液、乳濁液、軟膏、ゲル、クリーム、ローション、スプレー等を例示できる。
【0111】
固形製剤としては活性化合物とともに製剤学上許容されている添加物を含み、例えば充填剤類や増量剤類、結合剤類、崩壊剤類、溶解促進剤類、湿潤剤類、潤滑剤類等を必要に応じて選択して混合し、製剤化することができる。
【0112】
液体製剤としては溶液、懸濁液、乳液剤等を挙げることができるが添加剤として懸濁化剤、乳化剤等を含むこともある。
【0113】
本発明化合物を動物に投与する方法としては直接あるいは飼料中に混合して経口的に投与する方法、また溶液とした後、直接もしくは飲水、飼料中に添加して経口的に投与する方法、注射によって投与する方法等を例示することができる。
【0114】
本発明化合物を動物に投与するための製剤としては、この分野に於いて通常用いられている技術によって適宜散剤、細粒剤、可溶散剤、シロップ剤、溶液剤、あるいは注射剤とすることができる。
【0115】
製剤処方例を次に示す。
【0116】
製剤例1.(カプセル剤):
実施例2の化合物 100.0 mg
コーンスターチ 23.0 mg
CMC カルシウム 22.5 mg
ヒドロキシメチルセルロース 3.0 mg
ステアリン酸マグネシウム 1.5 mg
総計 150.0 mg
【0117】
製剤例2.(溶液剤):
実施例2の化合物 1 - 10 g
酢酸又は水酸化ナトリウム 0.5 - 2 g
パラオキシ安息香酸エチル 0.1 g
精製水 88.9 - 98.4 g
計 100 g
【0118】
製剤例3.(飼料混合用散剤):
実施例2の化合物 1 - 10 g
コーンスターチ 98.5 - 89.5 g
軽質無水ケイ酸 0.5 g
計 100 g
【0119】
【実施例】
次に本発明を実施例と参考例により説明するが、本発明はこれに限定されるものではない。また、光学活性な目的化合物の抗菌活性の試験方法は日本化学療法学会指定の標準法に準じて行い、その結果を表1にMIC(μg/ml)で示した。
【0120】
参考例A−1
N−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−プロパンジオール
(S)−(−)−フェニルエチルアミン(75ml、0.58mmol)のエタノール(500ml)溶液に、氷冷下、グリシドール(37g、0.5mol)を加え室温で20分間撹拌後、62時間加熱還流した。アクリロニトリル(40ml)を加えさらに45時間加熱還流した後反応液を濃縮した。残留物をシリカゲルカラムクロマトグラフィーに付し、5%メタノール−クロロホルムの溶出部より標記の化合物121g(84%)を得た。
【0121】
1H-NMR(CDCl3) δ:
1.41 - 1.48(3H, m), 2.39 - 2.50(2H, m), 2.60 - 3.25(4H, m),
3.41 - 3.46(1H, m), 3.68 - 3.78(2H, m), 3.93 - 4.02(1H, m),
7.27 - 7.40(5H, m).
【0122】
参考例A−2
N−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−ジブロモプロパン
N−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−プロパンジオール(24.8g、0.1mol)のベンゼン(400ml)溶液にトリフェニルフォスフィン(57.71g、0.22mol)および四臭化炭素(73g、0.22mol)を加えた後、撹拌しながら90℃まで昇温した。上澄み液を分取して溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィーに付した。n−ヘキサン:酢酸エチル=4:1の溶出部より標記の化合物を38g(100%)得た。
【0123】
1H-NMR(CDCl3) δ:
1.43 - 1.46(3H, m), 2.35 - 2.44(2H, m), 2.82 - 2.96(3H, m),
3.14 - 3.27(1H, m), 3.67 - 4.15(4H, m), 7.27 - 7.40(5H, m).
【0124】
参考例A−3
1−シアノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン
N−(2−シアノエチル)−N−[(1S)−フェニルエチル]−3−アミノ−1,2−ジブロモプロパン(37.4g、0.1mol)のトルエン(700ml)溶液に、氷冷下、ナトリウム(ビストリメチルシリル)アミドの1モル−テトラヒドロフラン溶液(220ml、0.22mol)を滴下し、そのまま20分間撹拌した。反応終了後、反応溶液に飽和塩化アンモニウム水溶液(100ml)を滴下し、室温まで昇温した。有機層を分取して飽和食塩水で洗った後、硫酸ナトリウムで乾燥した。溶媒を留去して残留物をシリカゲルカラムクロマトグラフィーに付した。n−ヘキサン:酢酸エチル=9:1の溶出部より低極性の標記の化合物(Fr.1)を7.93g(37%)得、次いで高極性の標記の化合物(Fr.2)を7.85g(36%)得た。
【0125】
Fr.1;
1H-NMR(CDCl3) δ:
1.09(1H, dd, J = 4.5, 8.3 Hz), 1.29(3H, d, J = 6.4 Hz),
1.57(1H, t, J = 4.5 Hz), 1.95 - 1.99(1H, m),
2.27(1H, dd, J = 3.9, 9.8 Hz), 2.61(1H, d, J = 8.8 Hz),
2.68(1H, d, J = 9.8 Hz), 3.33 - 3.38(2H, m), 7.21 - 7.31(5H, m).
【0126】
Fr.2;
1H-NMR(CDCl3) δ:
1.09(1H, dd, J = 4.9, 8.3 Hz), 1.29(3H, d, J = 6.4 Hz),
1.55 - 1.58(1H, m), 2.04 - 2.09(1H, m), 2.35(1H, d, J = 8.8 Hz),
2.53(1H, dd, J = 3.9, 9.3 Hz), 2.86(1H, d, J = 9.3 Hz),
3.18(1H, d, J = 9.3 Hz), 3.32 - 3.37(1H, m), 7.21 - 7.32(5H, m).
【0127】
参考例A−4
3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン−1−カルボン酸(Fr.1)
1−シアノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン(Fr.1、5.6g、26.4mmol)のメタノール(50ml)溶液に2規定水酸化ナトリウム水溶液(50ml)を加え、30時間加熱還流した。メタノールを留去して残留物をクロロホルム(30ml×2)で洗浄後、濃塩酸でpH3としてn−ブタノール(80ml×3)で抽出した。抽出液を硫酸ナトリウムにて乾燥後、溶媒を留去して粗製の標記の化合物を6.11g(100%)得た。これは、そのまま次の反応に用いた。
【0128】
参考例A−5
3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン−1−カルボン酸
Fr.2についても同様に反応を行った。
【0129】
参考例A−6
1−第三級ブトキシカルボニルアミノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン(Fr.1)
3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン−1−カルボン酸(Fr.1、6.11g、26.4mmol)の第三級ブタノール(200ml)溶液にジフェニルリン酸アジド(9.99g、34.3mmol)、トリエチルアミン(4.23g、36.9mmol)を加えた後、4時間加熱還流した。反応液を冷却後、溶媒を留去して残留物に酢酸エチル200mlを加えて飽和食塩水(50ml×2)で洗浄し、硫酸ナトリウムにて乾燥した。溶媒を留去して残留物をシリカゲルカラムクロマトグラフィーに付した。n−ヘキサン:酢酸エチル=4:1の溶出部より標記の化合物を3.19g(40%)得た。
【0130】
1H-NMR(CDCl3) δ:
0.67 - 0.71(1H, m), 1.25 - 1.31(4H, m), 1.45(9H, s), 1.60(1H, brs.),
2.30 - 2.38(1H, m), 2.51 - 2.58(2H, m),3.20 - 3.35(2H, m),
4.96(1H, brs.), 7.20 - 7.29(5H, m).
【0131】
参考例A−7
1−第三級ブトキシカルボニルアミノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン(Fr.2)
1H-NMR(CDCl3) δ:
0.69 - 0.71(1H, m), 1.25(3H, d, J = 6.4 Hz), 1.39(9H, s),
1.50 - 1.72(2H, m), 2.29(1H, d, J = 8.3 Hz), 2.58 - 2.82(2H, m),
3.08 - 3.15(1H, m), 3.30 - 3.38(1H, m), 4.82(1H, brs.),
7.19 - 7.37(5H, m).
【0132】
参考例A−8
1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(Fr.1)
1−第三級ブトキシカルボニルアミノ−3−[(1S)−フェニルエチル]−3−アザビシクロ[3.1.0]ヘキサン(Fr.1、3.1g、10.26mmol)のエタノール(50ml)溶液に10%パラジウム炭素(3g)を加え、赤外線ランプで照射して反応容器を加温しながら4気圧で3時間接触水素添加を行った。触媒を濾別後、溶媒を留去して標記の化合物を2.04g(100%)得た。
【0133】
1H-NMR(CDCl3) δ:
0.85 - 1.14(2H, m), 1.44(9H, s), 1.44 - 1.70(1H, m),
2.95 - 3.34(4H, m), 5.08(1H, brs.).
【0134】
実施例1
5−アミノ−7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6,8−ジフルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(fr.1)
【0135】
【化16】
【0136】
5−アミノ−6,7,8−トリフルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(316mg、1mmol)のアセトニトリル(15ml)溶液に、1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(fr.1)(396mg、2mmol)およびトリエチルアミン(5ml)を加え22時間加熱還流した。溶媒を留去して残留物にクロロホルム(20ml)を加え10%クエン酸(10ml×2)で洗浄後、硫酸ナトリウムにて乾燥して溶媒を留去した。残留物に濃塩酸(5ml)を加え室温で5分間撹拌後、反応液をクロロホルム(5ml×2)で洗浄した。20%水酸化ナトリウム水溶液でpH7.3としてクロロホルム(30ml×3)で抽出した。硫酸ナトリウムにて乾燥して溶媒を留去し、粗製の標記の化合物を190mg(48%)得た。クロロホルム−メタノール−エタノールから再結晶して標記の化合物を111mg得た。
【0137】
1H-NMR(0.1N-NaOD) δ:
0.61 - 0.64(1H, m), 0.80 - 0.83(1H, m), 1.21 - 1.83(3H, m),
3.23 - 3.79(5H, m), 4.87 - 4.98(0.5H, m), 8.21(1H, s).
元素分析 C18H18F3N4O3・0.25H2Oとして:
計算値:C, 54.07; H, 4.66; N, 14.01.
分析値:C, 53.98; H, 4.54; N, 13.82.
融点(℃):191 - 203 (分解)
[α]D +72.37 °(T = 22.4 ℃, c = 0.665, 0.1N-NaOH)
【0138】
実施例2
7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6−フルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メチル−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(fr.1)
【0139】
【化17】
【0140】
6,7−ジフルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メチル−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸BF2 キレート(345mg、1mmol)のスルホラン(4ml)溶液に1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(fr.1)(298mg、1.5mmol)およびトリエチルアミン(0.2ml)を加え室温で200時間撹拌した。トリエチルアミンを留去後、残留物に水(10ml)を加えて室温で30分間撹拌した。析出した結晶を水洗後濾取し、これをエタノール:水=4:1の混合溶媒(50ml)に溶解してトリエチルアミン(5ml)を加え、3時間加熱還流した。溶媒を留去して残留物にクロロホルム(50ml)を加え10%クエン酸(20ml×2)で洗浄後、硫酸マグネシウムにて乾燥して溶媒を留去した。残留物に濃塩酸(5ml)を加え室温で5分間撹拌後、反応液をクロロホルム(5ml×2)で洗浄した。20%水酸化ナトリウム水溶液でpH7.3としてクロロホルム(30ml×3)で抽出した。硫酸ナトリウムにて乾燥し溶媒を留去した。残留物をプレパラテイブTLC(クロロホルム:メタノール:水=7:3:1の下層で展開)で分離精製して粗製の標記の化合物を35mg得た。クロロホルム−エタノールから再結晶して標記の化合物を18mg得た。
【0141】
1H-NMR(0.1N-NaOD) δ:
0.78 - 0.83(2H, m), 1.12 - 1.21(1H, m), 1.38 - 1.39(1H, m),
1.51 - 1.62(1H, m), 2.36(3H, s), 3.03(1H, d, J = 9.3 Hz),
3.31(1H, d, J = 9.3 Hz), 3.56(1H, d, J = 9.3 Hz),
3.72 - 3.74(1H, m), 3.99 - 4.04(1H, m), 5.00 - 5.08(0.5H, m),
7.60(1H, d, J = 13.67 Hz), 8.44(1H, d, J = 2.4 Hz).
元素分析 C19H19F2N3O3・0.75H2Oとして:
計算値:C, 58.68; H, 5.31; N, 10.81.
分析値:C, 59.01; H, 5.15; N, 10.65.
融点(℃):189 - 210 (分解)
【0142】
実施例3
7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6−フルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メチル−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(fr.2)
【0143】
【化18】
【0144】
実施例2と同様の方法で、1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(fr.2)についても合成した。
1H-NMR(0.1N-NaOD) δ:
0.75 - 0.83(2H, m), 1.13 - 1.17(1H, m), 1.39 - 1.41(1H, m),
1.55 - 1.61(1H, m), 2.39(3H, s), 3.26(1H, d, J = 9.3 Hz),
3.35(1H, d, J = 9.3 Hz), 3.47 - 3.49(1H, m), 3.55 - 3.60(1H, m),
3.98 - 4.04(1H, m), 5.01 - 5.08(0.5H, m), 7.62(1H, d, J = 13.67 Hz),
8.45(1H, d, J = 1.9 Hz).
元素分析 C19H19F2N3O3・0.25H2Oとして:
計算値:C, 60.07; H, 5.17; N, 11.06.
分析値:C, 59.87; H, 5.33; N, 10.46.
融点(℃):200 - 217 (分解)
【0145】
実施例4
7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6−フルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メトキシ−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(fr.1)
【0146】
【化19】
【0147】
6,7−ジフルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メトキシ−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸BF2キレート(217mg、0.6mmol)のジメチルスルホキシド(2.5ml)溶液に1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(fr.1)(170mg、0.86mmol)およびトリエチルアミン(0.2ml)を加え室温で150時間撹拌した。トリエチルアミンを留去後、残留物に水(10ml)を加え室温で30分間撹拌した。析出した結晶を水洗後濾取し、これをエタノール:水=4:1の混合溶媒(20ml)に溶解してトリエチルアミン(3ml)を加え、2時間加熱還流した。溶媒を留去して残留物にクロロホルム(30ml)を加えて10%クエン酸(10ml×2)で洗浄後、硫酸マグネシウムにて乾燥して溶媒を留去した。残留物に濃塩酸(5ml)を加えて室温で5分間撹拌後、反応液をクロロホルム(5ml×2)で洗浄した。20%水酸化ナトリウム水溶液でpH7.3としてクロロホルム(30ml×3)で抽出した。硫酸ナトリウムにて乾燥して溶媒を留去し、粗製の標記の化合物を175mg(74%)得た。クロロホルム−エタノール−エーテルから再結晶して標記の化合物を80mg得た。
【0148】
1H-NMR(0.1N-NaOD) δ:
0.67 - 0.69(1H, m), 0.82 - 0.85(1H, m), 1.40 - 1.66(3H, m),
3.42 - 3.61(4H, m), 3.54(3H, s), 3.98 - 4.03(1H, m),
4.98 - 5.05(0.5H, m), 7.64(1H, d, J = 13.67 Hz), 8.47(1H, s).
元素分析 C19H19F2N3O4・0.25H2Oとして:
計算値:C, 57.65; H, 4.96; N, 10.61.
分析値:C, 57.53; H, 5.03; N, 10.57.
融点(℃):188 - 185 (分解)
[α]D +138.73°(c = 0.395, 0.1N-NaOH)
【0149】
実施例5
7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6−フルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−8−メトキシ−1,4−ジヒドロ−4−オキソキノリン−3−カルボン酸(fr.2)
【0150】
【化20】
【0151】
実施例4と同様の方法で、1−第三級ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(fr.2)についても合成した。
【0152】
1H-NMR(0.1N-NaOD) δ:
0.72 - 0.74(1H, m), 0.86 - 0.89(1H, m), 1.44 - 1.67(3H, m),
3.39 - 3.44(2H, m), 3.58(3H, s), 3.72(1H, d, J = 7.8 Hz),
3.83(1H, d, J = 9.8 Hz), 4.01 - 4.06(1H, m), 5.03 - 5.06(0.5H, m),
7.66(1H, d, J = 14.16 Hz), 8.48(1H, s).
元素分析 C19H19F2N3O3・0.25H2Oとして:
計算値:C, 57.65; H, 4.96; N, 10.61.
分析値:C, 57.61; H, 4.93; N, 10.72.
融点(℃):189 - 188 (分解)
[α]D +45.52 °(c = 0.303, 0.1N-NaOH)
【0153】
参考例H−1
ジメチル 3,4,5,6−テトラフルオロフタラート
3,4,5,6−テトラフルオロフタル酸300g( 1.26mol) のメタノール溶液に、氷冷下、硫酸300mlを加え、反応液を3日間還流した。室温まで冷却後、析出した結晶をろ取した。ろ液のメタノールを留去した後、残査に氷水(2リットル) を加え、析出した結晶をろ取した。合わせた結晶を水で洗浄後乾燥し、標記の化合物294.86gを粗精製物として得た。
【0154】
1H-NMR (400MHz,CDCl3) δ:
0.95(6H,s).
【0155】
参考例H−2
ジメチル 4−ジエトキシカルボニルメチル−3,5,6−トリフルオロフタラート
ジメチル 3,4,5,6−テトラフルオロフタラート286.4g(1.077mol)のジメチルホルムアミド750ml溶液に、マロン酸ジエチル164ml(1.08mol)および炭酸カリウム414.63g(3mol)を加え、室温にて26時間撹拌した。混合物をろ過後、ろ液を4規定塩酸(1200ml)に注いだ。エーテル(1リットル×2)で抽出した。有機層を水(1リットル×2)、飽和食塩水(1リットル)で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を留去し、標記の化合物433.61g(1.068mol,99.2%)を粗精製物として得た。
【0156】
1H-NMR (400MHz,CDCl3)δ:
1.29(6H,t,J=7.5Hz), 3.92(3H,s), 3.96(3H,s), 4.28(4H,q,J=7.5Hz),
4.98(1H,s).
【0157】
参考例H−3
4−カルボキシメチル−3,5,6−トリフルオロフタル酸
ジメチル 4ージエトキシカルボニルメチル−3,5,6−トリフルオロフタラート433.6g(1.068mol)に60%硫酸2リットルを加えて110℃で40時間撹拌した。室温に冷却後、水1リットル に注いだ。酢酸エチル(1リットル×3)で抽出した。有機層を水1リットル、飽和食塩水1リットルで洗浄後、硫酸ナトリウムで乾燥した。溶媒を留去し、標記の化合物304.35gを粗生成物として得た。
【0158】
1H-NMR (400MHz,D2O)δ:
3.77(2H,s).
【0159】
参考例H−4
2,4,5−トリフルオロ−3−メチル安息香酸
4−カルボキシメチル−3,5,6−トリフルオロフタル酸304.35gのジメチルスルホキシド(1.5リットル)溶液にトリエチルアミン(0.5リットル)を加えて140℃で64時間撹拌した。室温に冷却後、ジメチルスルホキシドを留去した。残査に1規定塩酸1リットルを加えエーテル(1リットル×3)抽出した。有機層を水1リットル、飽和食塩水1リットルで洗浄後、硫酸ナトリウムで乾燥した。溶媒を留去し、標記の化合物177.94g(0.64mol,60%)を粗生成物として得た。
【0160】
1H-NMR (400MHz,CDCl3)δ:
2.29(3H,t,J=1.5Hz), 7.70(1H,dt,J=6.5,9.5Hz).
【0161】
参考例H−5
2,4,5−トリフルオロ−3−メチル−6−ニトロ安息香酸
濃硫酸120mlに氷冷下2,4,5−トリフルオロ−3−メチル安息香酸43.4g(0.21mol)を加え、反応温度が30℃を越えないように発煙硝酸(d1.52)を滴下した。滴下終了後、室温にて1時間撹袢した。反応終了後、反応溶液を氷1.5リットルに注ぎ生じた結晶を濾取し、得られた結晶を水洗(100ml×3)後、酢酸エチル500mlに溶解し無水硫酸ナトリウムにて乾燥した。濾液をクロロホルム抽出(300ml×4)し無水硫酸ナトリウムにて乾燥した。合わせた有機層を濃縮し50.3g(定量的)の標記の化合物を得た。
【0162】
1H-NMR (400MHz,CDCl3)δ:
2.36(3H,t,J=2.44Hz).
【0163】
参考例H−6
エチル 2,4,5−トリフルオロ−3−メチル−6−ニトロベンゾイルアセタート
2,4,5−トリフルオロ−3−メチル−6−ニトロ安息香酸をベンゼン 490mlに懸濁し室温にてチオニルクロリド30.4ml(0.42mol)を滴下した。滴下終了後、反応溶液を22時間加熱還流した。ベンゼンを留去し残留物をベンゼン200mlにて2回共沸し粗製の2,4,5−トリフルオロ−3−メチル−6−ニトロベンゾイルクロリドを得た。マグネシウム6.13g(0.25mol)にエタノール200mlを加え、室温にて四塩化炭素10mlを滴下し、同温にて6時間撹袢した。マグネシウムが溶解したところでジエチル マロナート44ml(0.29mol)のテトラヒドロフラン溶液150mlを1時間かけて滴下した。滴下終了後、室温にて2時間撹袢した。反応終了後、溶媒を留去し残留物を減圧乾燥した。得られた固体にテトラヒドロフラン300mlを加え、先に得られた酸クロリドのテトラヒドロフラン溶液150mlを1.5時間かけて滴下した。滴下終了後、反応溶液を室温にて2時間撹袢した。反応終了後、反応溶液に酢酸エチル400mlを加え、10%クエン酸(500ml×1)、水(500ml×1)、飽和食塩水(500ml×1)の順に洗浄した。有機層を無水硫酸ナトリウムにて乾燥し溶媒を留去した。残留物に水1.5リットル、p−トルエンスルホン1.5gを加え、1.5時間加熱還流した。反応終了後、反応溶液を放冷し、ベンゼン抽出(500ml×5)した。合わせた有機層を飽和食塩水500mlで洗浄し無水硫酸ナトリウムにて乾燥した。溶媒を留去後、残留物をシリカゲルカラムクロマトグラフィーに付しヘキサン:酢酸エチル=95:5溶出部より37.65g(44%)の標記の化合物を得た。
【0164】
1H-NMR (400MHz,CDCl3)δ:
1.26 and 1.34(3H,each t,J=7.33Hz), 2.33 and 2.35(3H,each t,J=2.44Hz),
3.90(1.35H,s), 4.20 and 4.28(2H,each q,J=7.33Hz), 5.48(0.325H,s),
12.34(0.325H,s).
【0165】
参考例H−7
エチル 6,7−ジフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−8−メチル−5−ニトロ−4−オキソキノリン−3−カルボキシラート
エチル 2,4,5−トリフルオロ−3−メチル−6−ニトロベンゾイルアセタート16.4g(53.8mmol)にオルトギ酸エチル17.9ml(107.6mmol)および無水酢酸29mlを加え、100℃にて2時間撹袢した。溶媒を留去し、残留物をトルエン200mlに溶解し、(1R,2S)−2−フルオロシクロプロピルアミンのp−トルエンスルホン酸塩16g(64.7mmol)を加えた。氷冷下トリエチルアミン10.87ml(78mmol)のトルエン溶液30mlを滴下した。滴下終了後、同温にて2時間撹袢した。反応溶液に酢酸エチル200mlを加え、水(500ml×1)、飽和食塩水(500ml×2)の順に洗浄した。有機層を無水硫酸ナトリウムにて乾燥し溶媒を留去した。残留物を1,4−ジオキサン150mlに溶解し、氷冷下、水素化ナトリウム3.23g(80.7mmol)を少量づつ加え、室温にて1時間撹袢した。反応終了後、反応溶液を氷冷した0.5規定塩酸に注いだ。生じた結晶を濾取し水洗(100ml×3)した。得られた結晶をクロロホルム−エタノールより再結晶し13.9g(70%)の標記の化合物を得た。
【0166】
融点:230−231℃
1H-NMR (400MHz,CDCl3)δ:
1.38(3H,t,J=7.33Hz), 1.35-1.45(1H,m), 1.58-1.70(1H,m),
2.75(3H,d,J=3.42Hz), 3.85-3.93(1H,m), 4.37(2H,q,J=7.33Hz),
4.80-4.83 and 4.95-4.99(1H,m), 8.57(1H,d,J=2.93Hz).
【0167】
参考例H−8
エチル 5−アミノ−6,7−ジフルオロ−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−1−8−メチル−4−オキソキノリン−3−カルボキシラート
エチル 6,7−ジフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−8−メチル−5−ニトロ−4−オキソキノリン−3−カルボキシラート3.91g(37.6mmol)をメタノール−1,4−ジオキサン=1:1混合液1リットルに懸濁し、ラネーニッケル200mlを加え室温にて10分間撹袢した。反応終了後、反応液を濾過し、濾液を濃縮した。残留物をクロロホルム300mlに溶解しセライト濾過した。濾液を濃縮し12.5g(98%)の標記の化合物を得た。
【0168】
1H-NMR (400MHz,CDCl3)δ:
1.25-1.38(1H,m), 1.39(3H,t,J=7.33Hz), 1.45-1.59(1H,m),
2.46(3H,d,J=2.44Hz), 3.73-3.79(1H,m), 4.38(2H,q,J=7.33Hz),
4.73-4.75 and 4.88-4.92(1H,m), 6.99(2H,br s), 8.40(1H,d,J=3.42Hz).
【0169】
元素分析値 C16H13F3N2O5・1/4H2Oとして
計算値 C 51.28 H 3.63 N 7.47
実測値 C 51.51 H 3.58 N 7.43
【0170】
参考例H−9
5−アミノ−6,7−ジフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−8−メチル−4−オキソキノリン−3−カルボン酸
エチル 5−アミノ−6,7−ジフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−8−メチル−4−オキソキノリン−3−カルボキシラート10.43g(30.6mmol)に酢酸150ml、濃塩酸150mlを加え、1時間加熱還流した。反応終了後、反応溶液を放冷し、水700mlを加えた。生じた結晶を濾取し、水(100ml×2)、エタノール(300ml×1)、エーテル(300ml×1)の順に洗浄後乾燥して7.52g(79%)の標記の化合物を得た。
【0171】
融点:293−297℃(分解).
1H-NMR (400MHz,0.1N NaOD)δ:
1.31-1.42(1H,m), 1.53-1.68(1H,m), 2.52(3H,s), 4.03-4.10(1H,m),
4.85-4.93 and 5.05-5.10(1H,m), 8.32(1H,s).
【0172】
参考例I−1
エチル 2,3,4,5,6−ペンタフルオロベンゾイルアセタート
ペンタフルオロ安息香酸100g(0.47mol)、ベンゼン900mlおよび塩化チオニル350ml(4.80mol)の混合物を40時間加熱還流した。反応終了後、反応液を減圧下に濃縮した。ベンゼン(900ml×2)により留去をくり返した後、残渣をエーテル500mlに溶解さた。マグネシウム11.5g(0.47mol)、エタノール450mlおよび四塩化炭素20mlの混合物を室温にて1時間撹拌後、ジエチル マロナート71.6ml(0.47mol)のエーテル(900ml)溶液を滴下し同温で17時間撹拌した。反応液を減圧乾固し、残渣をエーテル1,500mlに溶解した。これに上記の酸クロライドを室温にて滴下し、同温で63時間撹拌した。反応終了後、反応液を10%クエン酸次いで水で洗浄し無水硫酸ナトリウムにて乾燥後、溶媒を留去した。残渣に水300mlおよびp−トルエンスルホン酸1.00g(5.81mmol)を加え6時間加熱還流した後、ベンゼン2,500mlを加え水で洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、溶媒を留去した。減圧蒸留(10mmHg、118−120℃)にて精製し、89.7g(67%)の標記の化合物を得た。
【0173】
参考例I−2
エチル 5,6,7,8−テトラフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキシラート
エチル 2,3,4,5,6−ペンタフルオロベンゾイルアセタート14.4g(51.0mmol)のベンゼン(150ml)溶液にN,N−ジメチルホルムアミド ジメチルアセタール28.8ml(204mmol)を加え3時間加熱還流した。反応終了後、溶媒を留去した。残留物にトルエン120mlおよび(1R,2S)−2−フルオロシクロプロピルアミン p−トルエンスルホン酸塩12.6g(51.0mmol)を加え氷冷しトリエチルアミン8.54ml(61.2mmol)のトルエン(39ml)溶液を滴下した。滴下終了後、室温にて1時間撹拌した。反応終了後、反応液を吸引濾過し、濾液を水(50ml×3)で洗浄後、水層を酢酸エチル(100ml×3)で抽出した。有機層を合わせ飽和食塩水で洗浄し無水硫酸ナトリウムにて乾燥後、溶媒を留去した。残留物に1,4−ジオキサン100mlを加え氷冷後、60%水素化ナトリウム2.04g(51.0mmol)を加え室温に昇温後2時間撹拌した。反応終了後、10%クエン酸中に反応液を注ぎジクロロメタン(200ml×2)にて抽出した。有機層を飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥、溶媒を留去した。残渣をジクロロメタン−イソプロピルエーテルより結晶化した。結晶を濾取しエーテルで十分に洗浄した後、減圧乾燥し12.6g(71%)の標記の化合物を得た。
【0174】
1H-NMR (400MHz,CDCl3)δ:
8.46(1H,s), 5.02-4.80(1H,m), 4.37(2H,q,J=7.32Hz), 3.83-3.75(1H,m),
1.75-1.55(2H,m), 1.40(3H,t,J=7.32Hz).
【0175】
参考例I−3
エチル 5−ベンジルオキシ−6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキシラート
エチル 5,6,7,8−テトラフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキシラート2.35g(6.77mmol)のトルエン(20ml)溶液にベンジルアルコール0.70ml(6.77mmol)を加え0℃に冷却し、60%水素化ナトリウム280mg(6.99mmol)のトルエン(10ml)懸濁液を加え同温で2時間、さらに室温にて2時間撹拌した。反応終了後、反応液に10%クエン酸を加えクロロホルム(100ml×2)で抽出した。有機層を無水硫酸ナトリウムにて乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフ法[ヘキサン−酢酸エチル(1:1)]により精製し1.68g(57%)の標記の化合物を得た。
【0176】
1H-NMR (400MHz,CDCl3)δ:
8.41(1H,s), 7.62-7.28(5H,m), 5.25 and 5.19(2H,ABd,J=10.25Hz),
5.00-4.77(1H,m), 4.39(2H,q,J=7.33Hz), 3.82-3.72(1H,m),
1.70-1.53(2H,m), 1.39(3H,t,J=7.33Hz).
【0177】
参考例I−4
6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−5−ヒドロキシ−4−オキソキノリン−3−カルボキシラート
エチル 5−ベンジルオキシ−6,7,8−トリフルオロ−1−[(1R,2S)−2−フルオロシクロプロピル]−1,4−ジヒドロ−5−ヒドロキシ−4−オキソキノリン−3−カルボン酸1.68g(3.86mmol)に酢酸−水−硫酸(8:6:1)15mlを加え100℃で1 時間加熱した。反応液を室温まで冷却した後、水20mlを加え析出した結晶を濾取し水で十分に洗浄した後、減圧乾燥し1.04g(85%)の標記の化合物を得た。
【0178】
1H-NMR (400MHz,CDCl3)δ:
13.11(1H,s), 13.10-12.75(1H,br), 8.82(1H,s), 5.09-4.83(1H,m),
3.99-3.88(1H,m), 1.86-1.69(2H,m).
【0179】
参考例J−1
ジメチル 4−(1,1−ビスエトキシカルボニルエチル)−3,5,6−トリフルオロフタラート
80%水素化ナトリウム(8.0g,0.20mol)をジメチルホルムアミド(300ml)に懸濁し、ジメチル マロナート(34.84g,0.20mol)を滴下した後10分間撹拌した。氷冷下、ジメチル テトラフルオロフタラート(53.23g,0.20mol)を加えた後、室温にて24時間撹拌した。反応液を酢酸エチル(1000ml)に溶解し、水洗(3×500ml)した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を留去し、83.7gの標記の化合物を淡黄色油状物として得た。
【0180】
1H-NMR(400MHz,D2O)δ:
1.27(6H,t,J=7Hz), 1.85(3H,s), 3.91(3H,s), 3.97(3H,s),
4.26(2H,q,J=7Hz), 4.27(2H,q,J=7Hz)
【0181】
参考例J−2
4−(1−カルボキシエチル)−3,5,6−トリフルオロフタル酸
ジメチル 4−(1,1−ビスエトキシカルボニルエチル)−3,5,6−トリフルオロフタラート(12.9g,30.7mmol)、塩酸(120ml)、酢酸(120ml)を混合し24時間加熱乾留した。反応液を減圧乾固し9.0gの標記の化合物を無色結晶として得た。
1H-NMR(400MHz,D2O)δ:
1.45(3H,d,J=7.4Hz), 4.25-4.32(2H,m)
【0182】
参考例J−3
3−エチル−2,4,5−トリフルオロ安息香酸
4−(1−カルボキシエチル)−3,5,6−トリフルオロフタル酸(14.9g,47.9mmol)、ジメチルスルホキシド(100ml)、トリエチルアミン(30ml)を混合し、140℃で4日間加熱撹拌した。反応液を減圧乾固し、残渣に1規定塩酸(100ml)を加えエーテル抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後溶媒を留去し9.27gの標記の化合物を黄色結晶として得た。
【0183】
1H-NMR(400MHz, CDCl3)δ:
1.24(3H,7,J=7Hz), 2.78(2H,q,J=7Hz), 7.67-7.73(1H,m), 8.5-9.3(1H, br)
【0184】
参考例K−1
エチル 5−アミノ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−4−オキソキノリン−3−カルボキシレート
エチル 1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−5−ニトロ−4−オキソキノリン−3−カルボキシレート(1.72g,4.45mmol)を、テトラヒドロフラン(40ml)−エタノール(40ml)の混合溶媒に溶解し、ラネーニッケル(1ml)を加え、常温常熱にて1.5時間接触水素添加を行った。触媒を濾別後、溶媒を留去し残査をシリカゲルカラムクロマトグラフィーに付した。3%メタノール−クロロホルム溶出部より標記の化合物を1.33g(84%)得た。
【0185】
1H-NMR(400MHz, CDCl3)δ:
1.39(3H, t, J=6.84Hz), 1.40-1.60(2H, m), 3.76-3.82(1H, m),
3.86(3H, s), 4.38(2H,q, J=6.84Hz), 4.72-4.76(0.5H, m),
4.88-4.92(0.5H, m), 8.40(1H, s).
【0186】
参考例K−2
5−アミノ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−4−オキソキノリン−3−カルボン酸
エチル 5−アミノ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−4−オキソキノリン−3−カルボキシレート(1.33g,3.73mmol)を、エタノール(10ml)−メタノール(5ml)混合溶媒の懸濁液に1規定水酸化ナトリウム水溶液(8ml)を加えた後、室温にて2.5時間撹拌した。溶媒を留去し残査に氷冷下濃塩酸を加え酸性とした後、析出した結晶を水洗後エタノールで洗い濾取し、標記の化合物を1.0g(82%)得た。
【0187】
実施例6
5−アミノ−7−(1−アミノ−3−アザビシクロ[3.1.0]ヘキサン−3−イル)−6−フルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−4−オキソキノリン−3−カルボン酸
5−アミノ−6,7−ジフルオロ−1−[(2S)−フルオロ−(1R)−シクロプロピル]−1,4−ジヒドロ−8−メトキシ−4−オキソキノリン−3−カルボン酸(335mg,1.02mmol)のジメチルスルホキシド(8ml)溶液に、1−tert−ブトキシカルボニルアミノ−3−アザビシクロ[3.1.0]ヘキサン(Fr.1)(350mg,1.77mmol)、トリエチルアミン(2ml)を加え100℃にて24時間加熱した。溶媒を留去し残査にクロロホルム(20ml)を加え濾過し不溶物を除き、濾液を10%クエン酸(10ml×2)で洗浄後硫酸ナトリウムにて乾燥し溶媒を留去した。残査に濃塩酸(5ml)を加え室温で5分間撹拌後、反応液をクロロホルム(10ml×2)で洗浄した。20%水酸化ナトリウム水溶液でpH7.3としクロロホルム(30ml×3)で抽出した。硫酸ナトリウムにて乾燥し溶媒を留去して、粗製の標記の化合物を240mg(58%)得た。エタノール−28%アンモニア水溶液から再結晶して標記の化合物を120mg得た。
【0188】
融点:219−230℃(分解)
1H-NMR(400MHz, 0.1N-NaOD)δ:
0.62-0.65(1H, m), 0.78-0.82(1H, m), 1.21-1.52(3H, m), 3.37(3H,s),
3.42(1H, d, J=9.28Hz),3.52(2H, brs), 3.63-3.69(1H, m),
3.83-3.90(1H, m), 4.75-4.81(0.5H, m), 4.90-4.95(0.5H, m),
8.26(1H, s).
【0189】
【表1】
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to antibacterial compounds useful as pharmaceuticals, veterinary drugs, marine products or antibacterial preservatives, and further relates to antibacterial drugs or antibacterial preparations containing this compound.
[0002]
[Prior art]
Quinolone derivatives having a 1-amino-3-azabicyclo [3.2.0] heptan-3-yl group are described in JP-A Nos. 64-56673 and 3-86875. There is no known quinolone derivative according to the present invention having a substituent derived from a fused bicyclic heterocyclic compound and having a halogenocyclopropyl group at the 1-position.
[0003]
[Problems to be solved by the invention]
In recent years, quinolone synthetic antibacterial agents have been found not only to have antibacterial activity, but also have excellent pharmacokinetics such as oral absorption, transferability to organs and urinary excretion rate, and are effective for many infectious diseases. Many compounds are used in clinical settings as chemotherapeutic agents. However, recently, in the clinical field, low-sensitivity bacteria to these drugs are increasing. In addition, for example, S. aureus insensitive to β-lactam antibiotics (MRSA), among bacteria resistant to drugs other than quinolone synthetic antibacterial agents, bacteria that are less sensitive to quinolone synthetic antibacterial agents are increasing. is doing. Therefore, there is a demand for a drug that is more effective in clinical settings.
[0004]
[Means for Solving the Problems]
The inventor of the present application considers that the structure of the substituent at the 7-position and the 1-position is greatly involved in the antibacterial activity, effectiveness and safety of the quinolone synthetic antibacterial agent. As a result of earnest research to obtain compounds having high antibacterial activity against a wide range of bacteria including quinolone-resistant bacteria, the present inventor has found that a quinolone having a substituent derived from an amino-substituted fused bicyclic heterocyclic compound at the 7-position It is found that the derivatives show strong antibacterial activity against gram-negative and gram-positive bacteria, particularly quinolone-resistant bacteria including MRSA, and quinolone derivatives substituted at the 1-position with a halogenocyclopropyl group, particularly a fluorocyclopropyl group. It was found that a quinolone derivative excellent in effectiveness and safety as well as antibacterial activity can be obtained.
[0005]
In the quinolone derivative according to the present invention, a pair of enantiomers exists only at the 1-position halogenocyclopropane ring portion even if the substituents at other sites do not have stereoisomerism. This is due to the steric relationship between the pyridonecarboxylic acid moiety and the halogen atom on the cyclopropane ring. When the isomers thus produced are in a racemic form, it is a mixture of enantiomers, and it is not impossible to apply it as a medicine as it is.
[0006]
On the other hand, in addition to stereoisomerism of the halogenocyclopropane ring moiety, diastereomers exist when stereoisomerism is present at other sites, particularly the substituent at the 7-position, and there are four or more stereoisomers. Will do. A mixture of diastereomers is a mixture of compounds having different physical properties and is difficult to be applied as a medicine if the mixture is left as it is.
[0007]
The present inventor has made extensive efforts to obtain a quinolone compound consisting of a single stereoisomer even if it is a 1- (1,2-cis-2-halogenocyclopropyl) -substituted quinolone derivative in which a diastereomer exists. did.
[0008]
As a result, the present inventor succeeded in obtaining each enantiomer of cis-2-fluorocyclopropylamine as a pure compound. Using this cis-fluorocyclopropylamine as a raw material, each enantiomer quinolone derivative derived only from the configuration of the fluorocyclopropane ring was successfully obtained as a compound consisting of a single isomer. Furthermore, each of the isomers was successfully obtained as a pure compound even in an amino-substituted fused bicyclic heterocyclic compound having an asymmetric carbon and a hetero atom consisting of a nitrogen atom.
[0009]
This quinolone derivative, which is useful as an intermediate, and an amino-substituted fused bicyclic heterocyclic compound in which the heteroatom is a nitrogen atom have been obtained, thereby producing a stereochemically single quinolone derivative consisting of a single diastereomer. It became possible to synthesize.
[0010]
A novel quinolone derivative having a group derived from an amino-substituted fused bicyclic heterocyclic compound according to the present invention at the 7-position and a halogenocyclopropyl group at the 1-position is a quinolone-resistant bacterium. The present invention was completed by discovering that it is a compound having excellent activity against a wide range of bacteria and high safety.
[0011]
That is, the present invention relates to the general formula (I)
[0012]
[Formula 4]
[0013]
[Where X1Represents a halogen atom or a hydrogen atom,
X2Represents a halogen atom,
R1Represents a hydrogen atom, a hydroxyl group, a thiol group, a halogenomethyl group, an amino group, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms. Among these, the amino group is a formyl group, It may have an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms (however, when the substituent is an alkyl group, it may be dialkyl substituted, and in this case, the alkyl groups are the same) But it may be different.)
R2Is the formula (II)
[0014]
[Chemical formula 5]
[0015]
(Wherein R3And R4Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,n is an integer of 1Represents. )
A group having a structure derived from an amino-substituted fused bicyclic heterocyclic compound represented by:
A is a nitrogen atom or formula (III)
[0016]
[Chemical 6]
[0017]
[X3Represents a hydrogen atom, a halogen atom, a cyano group, an amino group, an alkyl group having 1 to 6 carbon atoms, a halogenomethyl group, an alkoxyl group having 1 to 6 carbon atoms, or a halogenomethoxy group, of which the amino group is substituted The group may have a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms (however, when the substituent is an alkyl group, it may be dialkyl-substituted, In some cases, the alkyl groups may be the same or different.)]
Represents the substructure of
R is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3 -Dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group Represents a composed phenylalkyl group. ]
N represented by1The present invention relates to a-(halogenocyclopropyl) -substituted pyridonecarboxylic acid derivative and a salt thereof.
[0018]
Furthermore, this invention relates to said compound and its salt whose halogenocyclopropyl group is 1,2-cis-2-halogenocyclopropyl group in general formula (I).
[0019]
Further, the present invention relates to a compound represented by R in the general formula (I).2Relates to the above compounds and salts thereof wherein is a stereochemically single substituent.
[0020]
And this invention relates to said compound and its salt whose halogenocyclopropyl group is a stereochemical single substituent in general formula (I).
[0021]
Furthermore, the present invention relates to the above-mentioned compounds and salts thereof in which the halogenocyclopropyl group is a (1R, 2S) -2-halogenocyclopropyl group.
[0022]
The present invention also provides the X2Relates to the above compounds and salts thereof, wherein is a fluorine atom.
[0023]
And this invention relates to the antibacterial agent which contains the compound or its salt of said general formula (I) as an active ingredient.
[0024]
BEST MODE FOR CARRYING OUT THE INVENTION
The substituents which the compound represented by the formula (I) of the present invention has will be described below.
[0025]
X1, X2And X3When each is a halogen atom, X1And X2Is particularly preferably a fluorine atom, and X3Is preferably a fluorine atom or a chlorine atom.
[0026]
R1Represents a hydrogen atom, a hydroxyl group, a thiol group, a halogenomethyl group, an amino group, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms. Among these, the amino group is a formyl group, It may have an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms (however, when the substituent is an alkyl group, it may be dialkyl substituted, and in this case, the alkyl groups are the same) But it can be different.)
[0027]
Substituent R1The alkyl group as may be linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
[0028]
The halogen atom of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. A preferable halogenomethyl group is a fluoromethyl group or a difluoromethyl group.
[0029]
R1When is an amino group, a hydroxyl group or a thiol group, these may be protected by a commonly used protecting group.
[0030]
Examples of these protecting groups include, for example, tertiary butoxycarbonyl group, alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxy Aralkyloxycarbonyl groups such as carbonyl groups, acetyl groups, methoxyacetyl groups, trifluoroacetyl groups, chloroacetyl groups, pivaloyl groups, formyl groups, benzoyl groups and other acyl groups, tertiary butyl groups, benzyl groups, para Alkyl groups or aralkyl groups such as nitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group, etc. Ethers of trimethylsilyl Group, an isopropyl dimethyl silyl group, tert-butyldimethylsilyl group, and tribenzylsilyl group, a silyl group such as tert-butyldiphenylsilyl group.
[0031]
Of these protecting groups, ethers and silyl groups are preferably used as protecting groups for hydroxyl groups and thiol groups, and other protecting groups are used as protecting groups for amino groups, hydroxyl groups or thiol groups. be able to.
[0032]
X3Represents a hydrogen atom, a halogen atom, a cyano group, an amino group, an alkyl group having 1 to 6 carbon atoms, a halogenomethyl group, an alkoxyl group having 1 to 6 carbon atoms, or a halogenomethoxy group, of which the amino group is substituted The group may have a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms (provided that when the substituent is an alkyl group, it may be dialkyl-substituted, In some cases, the alkyl groups may be the same or different.)
[0033]
Substituent X3The alkyl group as may be linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
[0034]
The halogen atom of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The halogenomethyl group is preferably a fluoromethyl group or a difluoromethyl group.
[0035]
The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group.
[0036]
The halogen atom of the halogenomethoxyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3.
[0037]
A is
[0038]
[Chemical 7]
[0039]
In the case of a partial structure represented by R1And X3Preferred as a combination of R1Is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms,3Is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a halogenomethoxy group or a hydrogen atom.
[0040]
A more preferred combination is R1Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3Is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a difluoromethoxy group or a hydrogen atom.
[0041]
Particularly preferred combinations include R1Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3Is a methyl group or a methoxy group.
[0042]
These R1And X3X1And X2Is preferably a fluorine atom.
[0043]
R2Hachi 8
[0044]
[Chemical 8]
[0045]
An amino-substituted fused bicyclic heterocyclic compound represented by the formula (here, the five-membered nitrogen atom is hydrogen-substituted, but this is substituted by other substituents such as a protecting group of the nitrogen atom, etc. From the formula (II)
[0046]
[Chemical 9]
[0047]
Means a group represented by This group has an amino group as a substituent on the carbon atom of the bridge head. Therefore, it can be considered that this portion has a small-membered alicyclic amine structure, and the present inventors consider that this structure is greatly involved in the expression of the excellent properties of the compound of the present invention. Thought.
[0048]
The condensed bicyclic heterocyclic compound is a compound having a structure formed by replacing the carbon atom forming the cyclic structure of the condensed bicyclic hydrocarbon compound with a hetero atom such as a nitrogen atom.
[0049]
Where R3And R4Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group. R3And R4Unite to form a methylene chain having 2 to 6 carbon atoms, and R3And R4A cyclic structure may be formed including a nitrogen atom to which is bonded.
[0050]
R3And R4Preferred combinations of R are3And R4R is a hydrogen atom, R3Or R4One of these is a hydrogen atom and the other is an alkyl group having 1 to 6 carbon atoms.
[0051]
A more preferred combination is R3And R4R is a hydrogen atom, R3Or R4Is a hydrogen atom and the other is a methyl group or an ethyl group.
[0052]
R2In the reaction with the quinolone mother nucleus compound, the substituent R2The source of the formula R2When the compound represented by -H is reacted as a mixture of stereoisomers, the resulting quinolone derivative is diastereomeric due to the relationship with the 1,2-cis-2-halogenocyclopropyl group at the 1-position. It becomes a mixture. Therefore, the substituent R2In the case where stereoisomerism exists in the compound, the compound of formula R reacted with the quinolone mother nucleus compound2The compound represented by —H is preferably obtained by reacting one of isomers alone.
[0053]
R in seventh place of quinolone2When introducing R2When an amino group is present in the compound represented by -H, this amino group may be reacted as a compound converted into a commonly used protecting group.
[0054]
Examples of such protecting groups include tertiary butoxycarbonyl groups, alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl groups, benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, paranitrobenzyloxycarbonyl groups. Aralkyloxycarbonyl groups such as acetyl groups, acetyl groups, methoxyacetyl groups, trifluoroacetyl groups, chloroacetyl groups, pivaloyl groups, formyl groups, benzoyl groups and other acyl groups, tertiary butyl groups, benzyl groups, paranitro Alkyl groups or aralkyl groups such as benzyl group, paramethoxybenzyl group, triphenylmethyl group, alkylsulfonyl groups such as methanesulfonyl group, trifluoromethanesulfonyl group or halogenoalkylsulfonyl groups, and benzenesulfo Group, may be an arylsulfonyl group such as a toluenesulfonyl group.
[0055]
Then N1The halogenocyclopropyl group at the position is described.
[0056]
Examples of the halogen atom to be substituted include a fluorine atom and a chlorine atom, and a fluorine atom is particularly preferable.
[0057]
The steric environment at this part is particularly preferably such that the halogen atom and the pyridonecarboxylic acid part are in cis configuration with respect to the cyclopropane ring.
[0058]
Only the cis-2-halogenocyclopropyl moiety at the 1-position can be substituted at other sites, particularly the R-position at the 7-position.2Regardless of the stereoisomerism, there are so-called enantiomer-related isomers, but strong antibacterial activity and high safety were recognized for all isomers.
[0059]
When the compound of the formula (I) which is a compound of the present invention has a structure in which a diastereomer exists, when the compound of the present invention is administered to humans or animals, a compound consisting of a single diastereomer should be administered. Is preferred. The term “consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also the case where it is chemically pure. That is, it is interpreted that other diastereomers may be included as long as they do not affect physical constants and physiological activities.
[0060]
In addition, “stereochemically single” means that a compound or the like contains an asymmetric carbon atom, so that when there are multiple types of isomers, only one of them is formed. It means that. Even in this case, this “single” may be considered in the same manner as described above.
[0061]
The pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be an acid addition salt or a carboxyl group salt. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, methanesulfonate, benzene Examples thereof include organic acid salts such as sulfonate, toluenesulfonate, citrate, maleate, fumarate, and lactate.
[0062]
Examples of the carboxyl group salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt, Any of inorganic salts and organic salts such as tris- (hydroxylmethyl) aminomethane salt may be used.
[0063]
In addition, free forms, acid addition salts, and carboxyl group salts of these pyridonecarboxylic acid derivatives may exist as hydrates.
[0064]
On the other hand, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthetic intermediates.
[0065]
In addition, the ester used as a prodrug is an ester that is easily cleaved in vivo to generate a free form of carboxylic acid, such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, Oxo such as choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester Mention may be made of alkyl esters.
[0066]
The compound of the present invention represented by the formula (I) can be produced by various methods. Preferred examples thereof include, for example, the formula (VI)
[0067]
Embedded image
[0068]
[Wherein X has a function as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, an alkylsulfonyl group having 1 to 3 carbon atoms, or an arylsulfonyl group such as a benzenesulfonyl group or a toluenesulfonyl group. Is a substituent, and R has the same meaning as R defined in formula (I), or is represented by formula (VII)
[0069]
Embedded image
[0070]
(Wherein R11And R12Represents a fluorine atom or a lower alkylcarbonyloxy group)
A boron-containing substituent of1, X2, R1And A are as defined for general formula (I)]
A compound represented by the formula (quinolone mother nucleus compound) is represented by the formula R2-H (wherein R2In the definition of R, except that the substituent of the amino group may be a protective group Rx, R2Is as defined for formula (I). ) Or a compound thereof or an acid addition salt thereof.
[0071]
The protecting group Rx for the nitrogen atom may be any protection usually used in this field. Examples of these protecting groups include tertiary butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like. Alkoxycarbonyl groups, benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, aralkyloxycarbonyl groups such as paranitrobenzyloxycarbonyl groups, acetyl groups, methoxyacetyl groups, trifluoroacetyl groups, chloroacetyl groups, pivaloyl groups , Acyl groups such as formyl group and benzoyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, alkyl group such as triphenylmethyl group or aralkyl group, methanesulfonyl group, trifluoro Alkyls such as lomethanesulfonyl group Honiru group such or halogenoalkyl alkylsulfonyl groups, and benzenesulfonyl group, and an arylsulfonyl group such as a toluenesulfonyl group.
[0072]
When R is an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an aralkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, and is a carboxylic acid ester The conversion to the corresponding carboxylic acid is carried out under the general acidic or basic conditions used for hydrolysis of carboxylic acid esters, and when other substituents are protected and deprotection is required, The target compound represented by the general formula (I) can be obtained by removing the protecting group under appropriate conditions corresponding to the protecting group.
[0073]
In the compound of formula (IV), when R is a group represented by the formula 14,2Substitution with -H followed by treatment with an acidic or basic compound can be converted to the corresponding carboxylic acid.
[0074]
Compound of formula 13 and R2The substitution reaction with the compound of —H can be carried out with or without a solvent. When using a solvent, the solvent may be inert under the reaction conditions. Suitable solvents include, for example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol or mixtures thereof.
[0075]
The reaction temperature can usually be carried out in the temperature range of room temperature to 200 ° C, preferably in the range of 25 ° C to 150 ° C. The reaction time may be 30 minutes to 48 hours, and is usually completed in about 30 minutes to 2 hours.
[0076]
The reaction is advantageously carried out in the presence of an acid acceptor such as an inorganic or organic base, for example an alkali metal, alkaline earth metal carbonate or bicarbonate, or an organic basic compound such as triethylamine or pyridine.
[0077]
Synthesis examples of amino-substituted fused bicyclic heterocyclic compounds are shown below. 1-Tertiary butoxycarbonylamino-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane consisting of a sterically single isomer can be obtained, for example, by the following method. Can do.
[0078]
Embedded image
[0079]
That is, (S)-(−)-phenylethylamine was reacted with glycidol using ethanol as a solvent and then reacted with acrylonitrile to give N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3. -Amino-1,2-propanediol. This compound is reacted with triphenylphosphine and carbon tetrabromide to give N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3-amino-1,2-dibromopropane. This compound is reacted in the presence of a strong base to give 1-cyano-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane. This compound is obtained as a mixture of diastereomers because it has a phenylethyl group at the 3-position and an asymmetric carbon at the 1-position. That
These isomers can be separated by silica gel column chromatography or high performance liquid chromatography. Each of the isomers thus obtained is reacted with a base by a commonly used method to give 3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid. When this compound is subjected to a Curtius reaction in the presence of tertiary butanol, it is converted into 3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid protected at once. be able to. In this reaction, diphenylphosphoryl azide can be used conveniently, but the synthesis of the intermediate azide is not limited to this, and ordinary synthesis methods can be applied. If the phenylethyl group is removed by catalytic hydrogenation by a method usually used, 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane consisting of a single isomer is obtained.
[0080]
On the other hand, the synthesis of a compound of formula (VIII) consisting of a single isomer using an optically active cis-2-fluorocyclopropylamine derivative as a raw material is carried out, for example, by the method described in JP-A-2-231475. Can do.
[0081]
Embedded image
[0082]
6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-5-hydroxy-4-oxoquinoline contained in the compound represented by the formula (VIII) -3-Carboxylate can be synthesized, for example, as follows.
[0083]
Ethyl 2,3,4,5,6-pentafluorobenzoyl acetate is reacted with N, N-dimethylformamide dimethyl acetal and then (1R, 2S) -2-fluorocyclo is present in the presence of an acid remover such as triethylamine. Propylamine p-toluenesulfonate is reacted with ethyl 5,6,7,8-tetrafluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-4-oxo Quinoline-3-carboxylate.
[0084]
This compound is reacted with benzyl alcohol in the presence of a base, and ethyl 5-benzyloxy-6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro- 4-oxoquinoline-3-carboxylate. This reaction can be carried out by methods known in the art. Examples of the base that can be used here include sodium hydride, potassium carbonate, sodium hydroxide, and potassium hydroxide.
[0085]
If this compound is treated under acidic conditions, 6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-5-hydroxy-4-oxoquinoline- 3-carboxylate.
[0086]
Among the compounds of formula (VIII) R1Is an amino group and X3Is a lower alkyl group, a 2,4,5-tribenzoic acid having a lower alkyl group at the 3-position obtained by nitrating 2,4,5-trifluorobenzoic acid having a lower alkyl at the 3-position by a conventional method. It can be produced according to the above-mentioned method using fluoro-6-nitrobenzoic acid as a starting material.
[0087]
Embedded image
[0088]
3-Methyl-2,4,5-trifluorobenzoic acid can be produced by the methods described in JP-A-61-205240 and JP-A-3-95176, but it can be more easily synthesized by the following method. can do.
[0089]
Embedded image
[0090]
That is, 3,4,5,6-tetrafluorophthalic acid diester is reacted with malonic acid diester using a base to obtain, for example, diethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate.
[0091]
The base that can be used here may be either an inorganic base or an organic base. For example, as the inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate Alkali metal hydroxides, carbonates, bicarbonates, and the like. Further, a phase transfer catalyst such as a quaternary ammonium salt can be used for this reaction.
[0092]
Examples of organic bases include trialkylamines such as triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dialkylanilines such as diethylaniline and dimethylaniline, N-methylmorpholine, pyridine, N, N-dimethylamino. Examples thereof include saturated or aromatic heterocyclic compounds such as pyridine.
[0093]
When using a solvent, the solvent may be inert under the reaction conditions. Suitable solvents include, for example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, water or mixtures thereof.
[0094]
The reaction temperature can usually be carried out in the temperature range of 0 ° C. to 150 ° C., preferably in the range of 25 ° C. to 100 ° C.
[0095]
Next, dimethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate is hydrolyzed under acidic or basic conditions to give 4-carboxymethyl-3,5,6-trifluorophthalic acid.
[0096]
Here, examples of the acid include concentrated sulfuric acid and concentrated hydrochloric acid. In addition, as a base, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, an inorganic such as carbonate or hydrogen carbonate A base can be mentioned.
[0097]
The obtained 4-carboxymethyl-3,5,6-trifluorophthalic acid can be heated in dimethyl sulfoxide in the presence of a base to obtain 3-methyl-2,4,5-trifluorobenzoic acid. .
[0098]
Examples of the organic base that can be used here include trialkylamines such as triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, dialkylanilines such as diethylaniline and dimethylaniline, N-methylmorpholine, pyridine, N, Saturated or aromatic heterocyclic compounds such as N-dimethylaminopyridine can be exemplified.
[0099]
The reaction temperature can usually be carried out in the temperature range of 100 ° C. to 200 ° C., preferably in the range of 100 ° C. to 150 ° C. The reaction time may be 1 hour to 96 hours, but is usually completed in 5 hours to 48 hours.
[0100]
In this production method, the same process can be carried out using 3,4,5,6-tetrafluorophthalonitrile as a starting material instead of 3,4,5,6-tetrafluorophthalic acid diester. In addition, malononitrile may be used instead of malonic acid diester, and alkylmalonic acid diester and alkylmalononitrile are 3-alkyl-2,4,5-trifluoro-6-nitrobenzoic acid having an alkyl group other than methyl group. Useful for the production of acids.
[0101]
Since the compound of the present invention has a strong antibacterial action, it can be used as a medicine for human bodies, animals and fish, or as a preservative for agricultural chemicals and foods.
[0102]
When the compound of the present invention is used as a pharmaceutical for the human body, the dosage is in the range of 50 mg to 1 g, preferably 100 mg to 300 mg per adult day.
[0103]
The dose for animals varies depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and degree of the infectious pathogen, but the daily dose is generally It is in the range of 1 mg to 200 mg, preferably 5 mg to 100 mg per kg body weight.
[0104]
This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above amount if necessary.
[0105]
The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases, and can treat, prevent, or alleviate diseases caused by these pathogens.
[0106]
The bacterium Staphylococcus, Streptococcus pyogenes, Streptococcus haemolyticus, Enterococcus, Streptococcus pneumoniae, Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, Citrobacter, Shigella, Neisseria pneumoniae , Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, Trachoma chlamydia and the like.
[0107]
Diseases caused by these pathogens include folliculitis, illness, erysipelas, cellulitis, lymphangiosis (nodal), hail cancer, subcutaneous abscess, sweat glanditis, congestive acne, infectious mass, anus Peripheral abscess, mastitis, superficial secondary infection such as trauma / burn / surgical wound, sore throat, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, chronic respiratory disease Secondary infection, pneumonia, pyelonephritis, cystitis, prostatitis, accessory testicularitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, enteritis, uterine adnexitis, intrauterine Infection, bartholin adenitis, blepharitis, stye, lacrimal cystitis, pleurisy, corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jawitis, peritonitis, endocarditis, sepsis, Meningitis, skin infection, etc. can be illustrated.
[0108]
It is also effective for various microorganisms that cause infectious diseases in animals, such as Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma. Specific examples of disease names include colibacillosis, chick dysentery, chicken paratyphoid fever, poultry cholera, infectious coryza, staphylococci, and mycoplasma infections in swine, and colibacillosis, salmonellosis, pasteurellosis, and hemophilus infections in swine. , Atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc., cattle with colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine pneumonia, mastitis, etc., dogs with colibacillary sepsis, salmonella infection, bleeding Septicemia, uterine empyema, cystitis, etc., and in cats, exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection, kitten diarrhea, mycoplasma infection, and the like.
[0109]
The antibacterial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations which are usually used. Examples of the dosage form of the antibacterial preparation comprising the compound of the present invention as the main ingredient include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. .
As injections, stabilizers, preservatives, and solubilizing aids may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be prepared as a solid preparation by lyophilization or the like. It may be a preparation. One dose may be stored in a container, and multiple doses may be stored in the same container.
[0110]
Examples of external preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.
[0111]
Solid preparations include pharmaceutically acceptable additives as well as active compounds, such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants, etc. It can be selected and mixed as necessary to prepare a formulation.
[0112]
Examples of liquid preparations include solutions, suspensions, emulsions and the like, but additives may include suspending agents, emulsifiers and the like.
[0113]
As a method of administering the compound of the present invention to animals, it can be administered directly or mixedly in feed and orally, or after it has been made into a solution, it can be directly or directly added to drinking water or feed and administered orally. The method of administration can be illustrated by.
[0114]
As a preparation for administering the compound of the present invention to an animal, a powder, a fine granule, a soluble powder, a syrup, a solution, or an injection may be appropriately used according to techniques commonly used in this field. it can.
[0115]
Formulation formulation examples are shown below.
[0116]
Formulation Example 1 (Capsule):
Compound of Example 2 100.0 mg
Corn starch 23.0 mg
CMC Calcium 22.5 mg
Hydroxymethylcellulose 3.0 mg
Magnesium stearate 1.5 mg
Total 150.0 mg
[0117]
Formulation Example 2 (Solution):
Compound of Example 2 1-10 g
Acetic acid or sodium hydroxide 0.5-2 g
Ethyl paraoxybenzoate 0.1 g
purified water 88.9-98.4 g
100 g total
[0118]
Formulation Example 3 (Feed mixing powder):
Compound of Example 2 1-10 g
Corn starch 98.5-89.5 g
Light anhydrous silicic acid 0.5 g
100 g total
[0119]
【Example】
EXAMPLES Next, although an Example and a reference example demonstrate this invention, this invention is not limited to this. The test method for the antibacterial activity of the optically active target compound was performed according to the standard method designated by the Japanese Society of Chemotherapy, and the results are shown in Table 1 as MIC (μg / ml).
[0120]
Reference Example A-1
N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3-amino-1,2-propanediol
Glycidol (37 g, 0.5 mol) was added to a solution of (S)-(−)-phenylethylamine (75 ml, 0.58 mmol) in ethanol (500 ml) under ice cooling, and the mixture was stirred at room temperature for 20 minutes and then heated to reflux for 62 hours. did. Acrylonitrile (40 ml) was added and the mixture was further heated under reflux for 45 hours, and then the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography, and 121 g (84%) of the title compound was obtained from the eluate of 5% methanol-chloroform.
[0121]
1H-NMR (CDClThree) δ:
1.41-1.48 (3H, m), 2.39-2.50 (2H, m), 2.60-3.25 (4H, m),
3.41-3.46 (1H, m), 3.68-3.78 (2H, m), 3.93-4.02 (1H, m),
7.27-7.40 (5H, m).
[0122]
Reference Example A-2
N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3-amino-1,2-dibromopropane
To a solution of N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3-amino-1,2-propanediol (24.8 g, 0.1 mol) in benzene (400 ml) was added triphenylphosphine ( 57.71 g, 0.22 mol) and carbon tetrabromide (73 g, 0.22 mol) were added, and the temperature was raised to 90 ° C. with stirring. The supernatant was collected, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the eluate of n-hexane: ethyl acetate = 4: 1, 38 g (100%) of the title compound was obtained.
[0123]
1H-NMR (CDClThree) δ:
1.43-1.46 (3H, m), 2.35-2.44 (2H, m), 2.82-2.96 (3H, m),
3.14-3.27 (1H, m), 3.67-4.15 (4H, m), 7.27-7.40 (5H, m).
[0124]
Reference Example A-3
1-cyano-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane
To a solution of N- (2-cyanoethyl) -N-[(1S) -phenylethyl] -3-amino-1,2-dibromopropane (37.4 g, 0.1 mol) in toluene (700 ml) was cooled with ice. A 1 mol-tetrahydrofuran solution (220 ml, 0.22 mol) of sodium (bistrimethylsilyl) amide was added dropwise, and the mixture was stirred as it was for 20 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution (100 ml) was added dropwise to the reaction solution, and the temperature was raised to room temperature. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography. From the eluate of n-hexane: ethyl acetate = 9: 1, 7.93 g (37%) of the title compound (Fr. 1) having a low polarity was obtained, and then the title compound (Fr. 2) having a high polarity was obtained. 85 g (36%) were obtained.
[0125]
Fr. 1;
1H-NMR (CDClThree) δ:
1.09 (1H, dd, J = 4.5, 8.3 Hz), 1.29 (3H, d, J = 6.4 Hz),
1.57 (1H, t, J = 4.5 Hz), 1.95-1.99 (1H, m),
2.27 (1H, dd, J = 3.9, 9.8 Hz), 2.61 (1H, d, J = 8.8 Hz),
2.68 (1H, d, J = 9.8 Hz), 3.33-3.38 (2H, m), 7.21-7.31 (5H, m).
[0126]
Fr. 2;
1H-NMR (CDClThree) δ:
1.09 (1H, dd, J = 4.9, 8.3 Hz), 1.29 (3H, d, J = 6.4 Hz),
1.55-1.58 (1H, m), 2.04-2.09 (1H, m), 2.35 (1H, d, J = 8.8 Hz),
2.53 (1H, dd, J = 3.9, 9.3 Hz), 2.86 (1H, d, J = 9.3 Hz),
3.18 (1H, d, J = 9.3 Hz), 3.32-3.37 (1H, m), 7.21-7.32 (5H, m).
[0127]
Reference Example A-4
3-[(1S) -Phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid (Fr.1)
1N-Cyano-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (Fr.1, 5.6 g, 26.4 mmol) in methanol (50 ml) in 2N hydroxyl group A sodium aqueous solution (50 ml) was added, and the mixture was heated to reflux for 30 hours. Methanol was distilled off and the residue was washed with chloroform (30 ml × 2), adjusted to pH 3 with concentrated hydrochloric acid and extracted with n-butanol (80 ml × 3). The extract was dried over sodium sulfate, and the solvent was distilled off to obtain 6.11 g (100%) of the crude title compound. This was used as such for the next reaction.
[0128]
Reference Example A-5
3-[(1S) -Phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid
Fr. A similar reaction was carried out for 2.
[0129]
Reference Example A-6
1-Tertiary butoxycarbonylamino-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (Fr.1)
To a solution of 3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid (Fr.1, 6.11 g, 26.4 mmol) in tertiary butanol (200 ml). Diphenyl phosphoric acid azide (9.99 g, 34.3 mmol) and triethylamine (4.23 g, 36.9 mmol) were added, and the mixture was heated to reflux for 4 hours. After cooling the reaction solution, the solvent was distilled off, 200 ml of ethyl acetate was added to the residue, washed with saturated brine (50 ml × 2), and dried over sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography. From the eluate of n-hexane: ethyl acetate = 4: 1, 3.19 g (40%) of the title compound was obtained.
[0130]
1H-NMR (CDClThree) δ:
0.67-0.71 (1H, m), 1.25-1.31 (4H, m), 1.45 (9H, s), 1.60 (1H, brs.),
2.30-2.38 (1H, m), 2.51-2.58 (2H, m), 3.20-3.35 (2H, m),
4.96 (1H, brs.), 7.20-7.29 (5H, m).
[0131]
Reference Example A-7
1-Tertiary butoxycarbonylamino-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (Fr.2)
1H-NMR (CDClThree) δ:
0.69-0.71 (1H, m), 1.25 (3H, d, J = 6.4 Hz), 1.39 (9H, s),
1.50-1.72 (2H, m), 2.29 (1H, d, J = 8.3 Hz), 2.58-2.82 (2H, m),
3.08-3.15 (1H, m), 3.30-3.38 (1H, m), 4.82 (1H, brs.),
7.19-7.37 (5H, m).
[0132]
Reference Example A-8
1-tertiary butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (Fr.1)
1-tert-butoxycarbonylamino-3-[(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (Fr.1, 3.1 g, 10.26 mmol) in ethanol (50 ml) 10% palladium carbon (3 g) was added thereto, and catalytic hydrogenation was performed at 4 atm for 3 hours while heating the reaction vessel by irradiation with an infrared lamp. After the catalyst was filtered off, the solvent was distilled off to obtain 2.04 g (100%) of the title compound.
[0133]
1H-NMR (CDClThree) δ:
0.85-1.14 (2H, m), 1.44 (9H, s), 1.44-1.70 (1H, m),
2.95-3.34 (4H, m), 5.08 (1H, brs.).
[0134]
Example 1
5-Amino-7- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -6,8-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fr. 1)
[0135]
Embedded image
[0136]
5-Amino-6,7,8-trifluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316 mg, 1 mmol) 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (fr.1) (396 mg, 2 mmol) and triethylamine (5 ml) were added to a solution of styrene in acetonitrile (15 ml) and the mixture was heated to reflux for 22 hours. . The solvent was distilled off, chloroform (20 ml) was added to the residue, washed with 10% citric acid (10 ml × 2), dried over sodium sulfate and the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was washed with chloroform (5 ml × 2). The mixture was extracted with chloroform (30 ml × 3) to pH 7.3 with a 20% aqueous sodium hydroxide solution. Drying over sodium sulfate and evaporation of the solvent yielded 190 mg (48%) of the crude title compound. Recrystallization from chloroform-methanol-ethanol gave 111 mg of the title compound.
[0137]
1H-NMR (0.1N-NaOD) δ:
0.61-0.64 (1H, m), 0.80-0.83 (1H, m), 1.21-1.83 (3H, m),
3.23-3.79 (5H, m), 4.87-4.98 (0.5H, m), 8.21 (1H, s).
Elemental analysis C18H18FThreeNFourOThree・ 0.25H2As O:
Calculated values: C, 54.07; H, 4.66; N, 14.01.
Analytical values: C, 53.98; H, 4.54; N, 13.82.
Melting point (℃): 191-203 (decomposition)
[Α]D +72.37 ° (T = 22.4 ° C, c = 0.665, 0.1N-NaOH)
[0138]
Example 2
7- (1-Amino-3-azabicyclo [3.1.0] hexane-3-yl) -6-fluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methyl-1 , 4-Dihydro-4-oxoquinoline-3-carboxylic acid (fr. 1)
[0139]
Embedded image
[0140]
6,7-Difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF2 To a solution of chelate (345 mg, 1 mmol) in sulfolane (4 ml) was added 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (fr.1) (298 mg, 1.5 mmol) and triethylamine (0. 2 ml) was added and stirred at room temperature for 200 hours. Triethylamine was distilled off, water (10 ml) was added to the residue, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were washed with water and collected by filtration. The crystals were dissolved in a mixed solvent (50 ml) of ethanol: water = 4: 1, triethylamine (5 ml) was added, and the mixture was heated to reflux for 3 hours. The solvent was distilled off, chloroform (50 ml) was added to the residue, washed with 10% citric acid (20 ml × 2), dried over magnesium sulfate and the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was washed with chloroform (5 ml × 2). The mixture was extracted with chloroform (30 ml × 3) to pH 7.3 with a 20% aqueous sodium hydroxide solution. It dried with sodium sulfate and the solvent was distilled off. The residue was separated and purified by preparative TLC (developed in the lower layer of chloroform: methanol: water = 7: 3: 1) to obtain 35 mg of the crude title compound. Recrystallization from chloroform-ethanol gave 18 mg of the title compound.
[0141]
1H-NMR (0.1N-NaOD) δ:
0.78-0.83 (2H, m), 1.12-1.21 (1H, m), 1.38-1.39 (1H, m),
1.51-1.62 (1H, m), 2.36 (3H, s), 3.03 (1H, d, J = 9.3 Hz),
3.31 (1H, d, J = 9.3 Hz), 3.56 (1H, d, J = 9.3 Hz),
3.72-3.74 (1H, m), 3.99-4.04 (1H, m), 5.00-5.08 (0.5H, m),
7.60 (1H, d, J = 13.67 Hz), 8.44 (1H, d, J = 2.4 Hz).
Elemental analysis C19H19F2NThreeOThree・ 0.75H2As O:
Calculated values: C, 58.68; H, 5.31; N, 10.81.
Analytical values: C, 59.01; H, 5.15; N, 10.65.
Melting point (℃): 189-210 (decomposition)
[0142]
Example 3
7- (1-Amino-3-azabicyclo [3.1.0] hexane-3-yl) -6-fluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methyl-1 , 4-Dihydro-4-oxoquinoline-3-carboxylic acid (fr. 2)
[0143]
Embedded image
[0144]
In the same manner as in Example 2, 1-tertiary butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (fr. 2) was also synthesized.
1H-NMR (0.1N-NaOD) δ:
0.75-0.83 (2H, m), 1.13-1.17 (1H, m), 1.39-1.41 (1H, m),
1.55-1.61 (1H, m), 2.39 (3H, s), 3.26 (1H, d, J = 9.3 Hz),
3.35 (1H, d, J = 9.3 Hz), 3.47-3.49 (1H, m), 3.55-3.60 (1H, m),
3.98-4.04 (1H, m), 5.01-5.08 (0.5H, m), 7.62 (1H, d, J = 13.67 Hz),
8.45 (1H, d, J = 1.9 Hz).
Elemental analysis C19H19F2NThreeOThree・ 0.25H2As O:
Calculated values: C, 60.07; H, 5.17; N, 11.06.
Analytical values: C, 59.87; H, 5.33; N, 10.46.
Melting point (℃): 200-217 (decomposition)
[0145]
Example 4
7- (1-Amino-3-azabicyclo [3.1.0] hexan-3-yl) -6-fluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methoxy-1 , 4-Dihydro-4-oxoquinoline-3-carboxylic acid (fr. 1)
[0146]
Embedded image
[0147]
6,7-Difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF21-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (fr.1) (170 mg, 0.86 mmol) in a solution of chelate (217 mg, 0.6 mmol) in dimethyl sulfoxide (2.5 ml) And triethylamine (0.2 ml) was added and stirred at room temperature for 150 hours. Triethylamine was distilled off, water (10 ml) was added to the residue, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were washed with water and collected by filtration. This was dissolved in a mixed solvent (20 ml) of ethanol: water = 4: 1, triethylamine (3 ml) was added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off, chloroform (30 ml) was added to the residue, washed with 10% citric acid (10 ml × 2), dried over magnesium sulfate, and the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was washed with chloroform (5 ml × 2). The mixture was extracted with chloroform (30 ml × 3) to pH 7.3 with a 20% aqueous sodium hydroxide solution. Drying over sodium sulfate and evaporation of the solvent gave 175 mg (74%) of the crude title compound. Recrystallization from chloroform-ethanol-ether gave 80 mg of the title compound.
[0148]
1H-NMR (0.1N-NaOD) δ:
0.67-0.69 (1H, m), 0.82-0.85 (1H, m), 1.40-1.66 (3H, m),
3.42-3.61 (4H, m), 3.54 (3H, s), 3.98-4.03 (1H, m),
4.98-5.05 (0.5H, m), 7.64 (1H, d, J = 13.67 Hz), 8.47 (1H, s).
Elemental analysis C19H19F2NThreeOFour・ 0.25H2As O:
Calculated values: C, 57.65; H, 4.96; N, 10.61.
Analytical values: C, 57.53; H, 5.03; N, 10.57.
Melting point (° C): 188-185 (decomposition)
[Α]D + 138.73 ° (c = 0.395, 0.1N-NaOH)
[0149]
Example 5
7- (1-Amino-3-azabicyclo [3.1.0] hexan-3-yl) -6-fluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -8-methoxy-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid (fr.2)
[0150]
Embedded image
[0151]
In the same manner as in Example 4, 1-tertiary butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (fr. 2) was also synthesized.
[0152]
1H-NMR (0.1N-NaOD) δ:
0.72-0.74 (1H, m), 0.86-0.89 (1H, m), 1.44-1.67 (3H, m),
3.39-3.44 (2H, m), 3.58 (3H, s), 3.72 (1H, d, J = 7.8 Hz),
3.83 (1H, d, J = 9.8 Hz), 4.01-4.06 (1H, m), 5.03-5.06 (0.5H, m),
7.66 (1H, d, J = 14.16 Hz), 8.48 (1H, s).
Elemental analysis C19H19F2NThreeOThree・ 0.25H2As O:
Calculated values: C, 57.65; H, 4.96; N, 10.61.
Analytical values: C, 57.61; H, 4.93; N, 10.72.
Melting point (° C): 189-188 (decomposition)
[Α]D +45.52 ° (c = 0.303, 0.1N-NaOH)
[0153]
Reference Example H-1
Dimethyl 3,4,5,6-tetrafluorophthalate
To a methanol solution of 300 g (1.26 mol) of 3,4,5,6-tetrafluorophthalic acid, 300 ml of sulfuric acid was added under ice cooling, and the reaction solution was refluxed for 3 days. After cooling to room temperature, the precipitated crystals were collected by filtration. After the methanol in the filtrate was distilled off, ice water (2 liters) was added to the residue, and the precipitated crystals were collected by filtration. The combined crystals were washed with water and dried to obtain 294.86 g of the title compound as a crude product.
[0154]
1H-NMR (400MHz, CDClThree) δ:
0.95 (6H, s).
[0155]
Reference Example H-2
Dimethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate
To a solution of 286.4 g (1.077 mol) of dimethyl 3,4,5,6-tetrafluorophthalate in 750 ml of dimethylformamide was added 164 ml (1.08 mol) of diethyl malonate and 414.63 g (3 mol) of potassium carbonate at room temperature. For 26 hours. After the mixture was filtered, the filtrate was poured into 4N hydrochloric acid (1200 ml). Extracted with ether (1 liter x 2). The organic layer was washed with water (1 liter × 2) and saturated brine (1 liter) and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 433.61 g (1.068 mol, 99.2%) of the title compound as a crude product.
[0156]
1H-NMR (400MHz, CDClThree) δ:
1.29 (6H, t, J = 7.5Hz), 3.92 (3H, s), 3.96 (3H, s), 4.28 (4H, q, J = 7.5Hz),
4.98 (1H, s).
[0157]
Reference Example H-3
4-carboxymethyl-3,5,6-trifluorophthalic acid
To 433.6 g (1.068 mol) of dimethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate was added 2 liters of 60% sulfuric acid, and the mixture was stirred at 110 ° C. for 40 hours. After cooling to room temperature, it was poured into 1 liter of water. Extracted with ethyl acetate (1 liter x 3). The organic layer was washed with 1 liter of water and 1 liter of saturated brine, and then dried over sodium sulfate. The solvent was distilled off to obtain 304.35 g of the title compound as a crude product.
[0158]
1H-NMR (400MHz, D2O) δ:
3.77 (2H, s).
[0159]
Reference Example H-4
2,4,5-trifluoro-3-methylbenzoic acid
Triethylamine (0.5 liter) was added to a solution of 304.35 g of 4-carboxymethyl-3,5,6-trifluorophthalic acid in dimethyl sulfoxide (1.5 liter), and the mixture was stirred at 140 ° C. for 64 hours. After cooling to room temperature, dimethyl sulfoxide was distilled off. To the residue was added 1 liter of 1N hydrochloric acid and extracted with ether (1 liter × 3). The organic layer was washed with 1 liter of water and 1 liter of saturated brine, and then dried over sodium sulfate. The solvent was distilled off to obtain 177.94 g (0.64 mol, 60%) of the title compound as a crude product.
[0160]
1H-NMR (400MHz, CDClThree) δ:
2.29 (3H, t, J = 1.5Hz), 7.70 (1H, dt, J = 6.5,9.5Hz).
[0161]
Reference Example H-5
2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid
Add 4,3.4 g (0.21 mol) of 2,4,5-trifluoro-3-methylbenzoic acid to 120 ml of concentrated sulfuric acid under ice cooling, and add fuming nitric acid (d1.52) so that the reaction temperature does not exceed 30 ° C. It was dripped. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into 1.5 liters of ice, and the resulting crystals were collected by filtration. The obtained crystals were washed with water (100 ml × 3), dissolved in 500 ml of ethyl acetate, and dried over anhydrous sodium sulfate. The filtrate was extracted with chloroform (300 ml × 4) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated to give 50.3 g (quantitative) of the title compound.
[0162]
1H-NMR (400MHz, CDClThree) δ:
2.36 (3H, t, J = 2.44Hz).
[0163]
Reference Example H-6
Ethyl 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl acetate
2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid was suspended in 490 ml of benzene, and 30.4 ml (0.42 mol) of thionyl chloride was added dropwise at room temperature. After completion of the dropwise addition, the reaction solution was heated to reflux for 22 hours. Benzene was distilled off and the residue was azeotroped twice with 200 ml of benzene to obtain crude 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. 200 ml of ethanol was added to 6.13 g (0.25 mol) of magnesium, and 10 ml of carbon tetrachloride was added dropwise at room temperature, followed by stirring at the same temperature for 6 hours. When the magnesium was dissolved, 150 ml of a tetrahydrofuran solution of 44 ml (0.29 mol) of diethyl malonate was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dried under reduced pressure. To the obtained solid was added 300 ml of tetrahydrofuran, and 150 ml of the previously obtained tetrahydrofuran solution of acid chloride was added dropwise over 1.5 hours. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, 400 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with 10% citric acid (500 ml × 1), water (500 ml × 1), and saturated brine (500 ml × 1) in this order. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. To the residue were added 1.5 liters of water and 1.5 g of p-toluenesulfone, and the mixture was heated to reflux for 1.5 hours. After completion of the reaction, the reaction solution was allowed to cool and extracted with benzene (500 ml × 5). The combined organic layers were washed with 500 ml of saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography to obtain 37.65 g (44%) of the title compound from an eluate of hexane: ethyl acetate = 95: 5.
[0164]
1H-NMR (400MHz, CDClThree) δ:
1.26 and 1.34 (3H, each t, J = 7.33Hz), 2.33 and 2.35 (3H, each t, J = 2.44Hz),
3.90 (1.35H, s), 4.20 and 4.28 (2H, each q, J = 7.33Hz), 5.48 (0.325H, s),
12.34 (0.325H, s).
[0165]
Reference Example H-7
Ethyl 6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate
To 16.4 g (53.8 mmol) of ethyl 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl acetate was added 17.9 ml (107.6 mmol) of ethyl orthoformate and 29 ml of acetic anhydride. And stirred for 2 hours. The solvent was distilled off, the residue was dissolved in 200 ml of toluene, and 16 g (64.7 mmol) of (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate was added. 30 ml of a toluene solution of 10.87 ml (78 mmol) of triethylamine was added dropwise under ice cooling. After completion of dropping, the mixture was stirred at the same temperature for 2 hours. 200 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with water (500 ml × 1) and saturated brine (500 ml × 2) in this order. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in 150 ml of 1,4-dioxane, and 3.23 g (80.7 mmol) of sodium hydride was added little by little under ice cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into 0.5N hydrochloric acid cooled with ice. The resulting crystals were collected by filtration and washed with water (100 ml × 3). The obtained crystals were recrystallized from chloroform-ethanol to obtain 13.9 g (70%) of the title compound.
[0166]
Melting point: 230-231 ° C
1H-NMR (400MHz, CDClThree) δ:
1.38 (3H, t, J = 7.33Hz), 1.35-1.45 (1H, m), 1.58-1.70 (1H, m),
2.75 (3H, d, J = 3.42Hz), 3.85-3.93 (1H, m), 4.37 (2H, q, J = 7.33Hz),
4.80-4.83 and 4.95-4.99 (1H, m), 8.57 (1H, d, J = 2.93Hz).
[0167]
Reference Example H-8
Ethyl 5-amino-6,7-difluoro-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-1-8-methyl-4-oxoquinoline-3-carboxylate
Ethyl 6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate 3.91 g ( 37.6 mmol) was suspended in 1 liter of a methanol-1,4-dioxane = 1: 1 mixed solution, 200 ml of Raney nickel was added, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in 300 ml of chloroform and filtered through celite. The filtrate was concentrated to give 12.5 g (98%) of the title compound.
[0168]
1H-NMR (400MHz, CDClThree) δ:
1.25-1.38 (1H, m), 1.39 (3H, t, J = 7.33Hz), 1.45-1.59 (1H, m),
2.46 (3H, d, J = 2.44Hz), 3.73-3.79 (1H, m), 4.38 (2H, q, J = 7.33Hz),
4.73-4.75 and 4.88-4.92 (1H, m), 6.99 (2H, br s), 8.40 (1H, d, J = 3.42Hz).
[0169]
Elemental analysis value C16H13FThreeN2OFive・ 1 / 4H2As O
Calculated value C 51.28 H 3.63 N 7.47
Found C 51.51 H 3.58 N 7.43
[0170]
Reference Example H-9
5-Amino-6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
10.43 g of ethyl 5-amino-6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate ( 30.6 mmol) was added 150 ml of acetic acid and 150 ml of concentrated hydrochloric acid, and the mixture was heated to reflux for 1 hour. After completion of the reaction, the reaction solution was allowed to cool and 700 ml of water was added. The resulting crystals were collected by filtration, washed with water (100 ml × 2), ethanol (300 ml × 1) and ether (300 ml × 1) in this order and dried to obtain 7.52 g (79%) of the title compound.
[0171]
Melting point: 293-297 ° C (decomposition).
1H-NMR (400MHz, 0.1N NaOD) δ:
1.31-1.42 (1H, m), 1.53-1.68 (1H, m), 2.52 (3H, s), 4.03-4.10 (1H, m),
4.85-4.93 and 5.05-5.10 (1H, m), 8.32 (1H, s).
[0172]
Reference Example I-1
Ethyl 2,3,4,5,6-pentafluorobenzoyl acetate
A mixture of 100 g (0.47 mol) of pentafluorobenzoic acid, 900 ml of benzene and 350 ml (4.80 mol) of thionyl chloride was heated to reflux for 40 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. After repeated distillation with benzene (900 ml × 2), the residue was dissolved in 500 ml of ether. A mixture of 11.5 g (0.47 mol) of magnesium, 450 ml of ethanol and 20 ml of carbon tetrachloride was stirred at room temperature for 1 hour, and then a solution of 71.6 ml (0.47 mol) of diethyl malonate in ether (900 ml) was added dropwise at the same temperature. Stir for 17 hours. The reaction solution was dried under reduced pressure, and the residue was dissolved in 1,500 ml of ether. The above acid chloride was added dropwise thereto at room temperature and stirred at the same temperature for 63 hours. After completion of the reaction, the reaction solution was washed with 10% citric acid and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. To the residue, 300 ml of water and 1.00 g (5.81 mmol) of p-toluenesulfonic acid were added and heated under reflux for 6 hours. Then, 2500 ml of benzene was added and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Purification by vacuum distillation (10 mmHg, 118-120 ° C.) gave 89.7 g (67%) of the title compound.
[0173]
Reference Example I-2
Ethyl 5,6,7,8-tetrafluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylate
Add 28.8 ml (204 mmol) of N, N-dimethylformamide dimethylacetal to a solution of 14.4 g (51.0 mmol) of ethyl 2,3,4,5,6-pentafluorobenzoyl acetate in benzene (150 ml) and heat for 3 hours. Refluxed. After completion of the reaction, the solvent was distilled off. To the residue were added 120 ml of toluene and 12.6 g (51.0 mmol) of (1R, 2S) -2-fluorocyclopropylamine p-toluenesulfonate, and the mixture was cooled with ice and 8.54 ml (61.2 mmol) of toluene (39 ml). ) The solution was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was subjected to suction filtration. The filtrate was washed with water (50 ml × 3), and the aqueous layer was extracted with ethyl acetate (100 ml × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. To the residue, 100 ml of 1,4-dioxane was added, and the mixture was cooled with ice. After completion of the reaction, the reaction solution was poured into 10% citric acid and extracted with dichloromethane (200 ml × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was crystallized from dichloromethane-isopropyl ether. The crystals were collected by filtration, washed thoroughly with ether, and dried under reduced pressure to obtain 12.6 g (71%) of the title compound.
[0174]
1H-NMR (400MHz, CDClThree) δ:
8.46 (1H, s), 5.02-4.80 (1H, m), 4.37 (2H, q, J = 7.32Hz), 3.83-3.75 (1H, m),
1.75-1.55 (2H, m), 1.40 (3H, t, J = 7.32Hz).
[0175]
Reference Example I-3
Ethyl 5-benzyloxy-6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylate
2.35 g (6.77 mmol) of ethyl 5,6,7,8-tetrafluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylate ) In toluene (20 ml), 0.70 ml (6.77 mmol) of benzyl alcohol is added and cooled to 0 ° C., and a suspension of 280 mg (6.9 ml) of 60% sodium hydride in toluene (10 ml) is added at the same temperature. The mixture was stirred for 2 hours and further at room temperature for 2 hours. After completion of the reaction, 10% citric acid was added to the reaction solution and extracted with chloroform (100 ml × 2). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1)] to give 1.68 g (57%) of the title compound.
[0176]
1H-NMR (400MHz, CDClThree) δ:
8.41 (1H, s), 7.62-7.28 (5H, m), 5.25 and 5.19 (2H, ABd, J = 10.25Hz),
5.00-4.77 (1H, m), 4.39 (2H, q, J = 7.33Hz), 3.82-3.72 (1H, m),
1.70-1.53 (2H, m), 1.39 (3H, t, J = 7.33Hz).
[0177]
Reference Example I-4
6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-5-hydroxy-4-oxoquinoline-3-carboxylate
Ethyl 5-benzyloxy-6,7,8-trifluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -1,4-dihydro-5-hydroxy-4-oxoquinoline-3-carboxylic acid To 1.68 g (3.86 mmol), 15 ml of acetic acid-water-sulfuric acid (8: 6: 1) was added and heated at 100 ° C. for 1 hour. After cooling the reaction solution to room temperature, 20 ml of water was added, and the precipitated crystals were collected by filtration, washed thoroughly with water, and dried under reduced pressure to obtain 1.04 g (85%) of the title compound.
[0178]
1H-NMR (400MHz, CDClThree) δ:
13.11 (1H, s), 13.10-12.75 (1H, br), 8.82 (1H, s), 5.09-4.83 (1H, m),
3.99-3.88 (1H, m), 1.86-1.69 (2H, m).
[0179]
Reference Example J-1
Dimethyl 4- (1,1-bisethoxycarbonylethyl) -3,5,6-trifluorophthalate
80% sodium hydride (8.0 g, 0.20 mol) was suspended in dimethylformamide (300 ml), and dimethyl malonate (34.84 g, 0.20 mol) was added dropwise, followed by stirring for 10 minutes. Dimethyl tetrafluorophthalate (53.23 g, 0.20 mol) was added under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction solution was dissolved in ethyl acetate (1000 ml) and washed with water (3 × 500 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 83.7 g of the title compound as a pale yellow oil.
[0180]
1H-NMR (400MHz, D2O) δ:
1.27 (6H, t, J = 7Hz), 1.85 (3H, s), 3.91 (3H, s), 3.97 (3H, s),
4.26 (2H, q, J = 7Hz), 4.27 (2H, q, J = 7Hz)
[0181]
Reference Example J-2
4- (1-carboxyethyl) -3,5,6-trifluorophthalic acid
Dimethyl 4- (1,1-bisethoxycarbonylethyl) -3,5,6-trifluorophthalate (12.9 g, 30.7 mmol), hydrochloric acid (120 ml) and acetic acid (120 ml) were mixed and heated to dry for 24 hours. . The reaction solution was dried under reduced pressure to obtain 9.0 g of the title compound as colorless crystals.
1H-NMR (400MHz, D2O) δ:
1.45 (3H, d, J = 7.4Hz), 4.25-4.32 (2H, m)
[0182]
Reference Example J-3
3-ethyl-2,4,5-trifluorobenzoic acid
4- (1-carboxyethyl) -3,5,6-trifluorophthalic acid (14.9 g, 47.9 mmol), dimethyl sulfoxide (100 ml) and triethylamine (30 ml) were mixed, and the mixture was heated and stirred at 140 ° C. for 4 days. did. The reaction mixture was evaporated to dryness, 1N hydrochloric acid (100 ml) was added to the residue, and the mixture was extracted with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 9.27 g of the title compound as yellow crystals.
[0183]
1H-NMR (400MHz, CDClThree) δ:
1.24 (3H, 7, J = 7Hz), 2.78 (2H, q, J = 7Hz), 7.67-7.73 (1H, m), 8.5-9.3 (1H, br)
[0184]
Reference Example K-1
Ethyl 5-amino-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate
Ethyl 1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (1.72 g, 4.45 mmol) Was dissolved in a mixed solvent of tetrahydrofuran (40 ml) -ethanol (40 ml), Raney nickel (1 ml) was added, and catalytic hydrogenation was performed at room temperature and normal temperature for 1.5 hours. After the catalyst was filtered off, the solvent was distilled off and the residue was subjected to silica gel column chromatography. From the eluate of 3% methanol-chloroform, 1.33 g (84%) of the title compound was obtained.
[0185]
1H-NMR (400MHz, CDClThree) δ:
1.39 (3H, t, J = 6.84Hz), 1.40-1.60 (2H, m), 3.76-3.82 (1H, m),
3.86 (3H, s), 4.38 (2H, q, J = 6.84Hz), 4.72-4.76 (0.5H, m),
4.88-4.92 (0.5H, m), 8.40 (1H, s).
[0186]
Reference Example K-2
5-Amino-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
Ethyl 5-amino-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (1.33 g, 3.73 mmol) After adding 1N aqueous sodium hydroxide solution (8 ml) to a suspension of a mixed solvent of ethanol (10 ml) -methanol (5 ml), the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off, and the residue was acidified with concentrated hydrochloric acid under ice-cooling. The precipitated crystals were washed with water and then with ethanol to obtain 1.0 g (82%) of the title compound.
[0187]
Example 6
5-Amino-7- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -6-fluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1 , 4-Dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
5-Amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (335 mg, 1 0.02 mmol) in dimethyl sulfoxide (8 ml) was added 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (Fr.1) (350 mg, 1.77 mmol) and triethylamine (2 ml). Heated at 100 ° C. for 24 hours. The solvent was distilled off, chloroform (20 ml) was added to the residue and filtered to remove insoluble matters. The filtrate was washed with 10% citric acid (10 ml × 2) and then dried over sodium sulfate, and the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue and stirred at room temperature for 5 minutes, and then the reaction solution was washed with chloroform (10 ml × 2). The pH was adjusted to 7.3 with a 20% aqueous sodium hydroxide solution, and the mixture was extracted with chloroform (30 ml × 3). Drying over sodium sulfate and evaporation of the solvent yielded 240 mg (58%) of the crude title compound. Recrystallization from ethanol-28% aqueous ammonia gave 120 mg of the title compound.
[0188]
Melting point: 219-230 ° C. (decomposition)
1H-NMR (400 MHz, 0.1 N-NaOD) δ:
0.62-0.65 (1H, m), 0.78-0.82 (1H, m), 1.21-1.52 (3H, m), 3.37 (3H, s),
3.42 (1H, d, J = 9.28Hz), 3.52 (2H, brs), 3.63-3.69 (1H, m),
3.83-3.90 (1H, m), 4.75-4.81 (0.5H, m), 4.90-4.95 (0.5H, m),
8.26 (1H, s).
[0189]
[Table 1]
Claims (7)
X2はハロゲン原子を表し、
R1は水素原子、水酸基、チオール基、ハロゲノメチル基、アミノ基、炭素数1から6のアルキル基または炭素数1から6のアルコキシル基を表すが、このうちのアミノ基は置換基として、ホルミル基、炭素数1から6のアルキル基または炭素数2から5のアシル基を有していてもよい(ただし、置換基がアルキル基の場合はジアルキル置換となってもよく、この場合にアルキル基は同一でも異なっていてもよい。)、
R2は式(II)
で表される基を表し、
Aは窒素原子または式(III)
の部分構造を表し、
Rは水素原子、フェニル基、アセトキシメチル基、ピバロイルオキシメチル基、エトキシカルボニル基、コリン基、ジメチルアミノエチル基、5−インダニル基、フタリジニル基、5−アルキル−2−オキソ−1,3−ジオキソール−4−イルメチル基、3−アセトキシ−2−オキソブチル基、炭素数1から6のアルキル基、炭素数2から7のアルコキシメチル基または、炭素数1から6のアルキレン基とフェニル基とから構成されるフェニルアルキル基を表す。]
で表されるN1−(ハロゲノシクロプロピル)置換ピリドンカルボン酸誘導体およびその塩Formula (I)
X 2 represents a halogen atom,
R 1 represents a hydrogen atom, a hydroxyl group, a thiol group, a halogenomethyl group, an amino group, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms. Group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms (provided that when the substituent is an alkyl group, the alkyl group may be dialkyl substituted. Can be the same or different.)
R 2 represents the formula (II)
Represents a group represented by
A is a nitrogen atom or formula (III)
Represents the substructure of
R is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3 -Dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group Represents a composed phenylalkyl group. ]
N 1- (halogenocyclopropyl) -substituted pyridonecarboxylic acid derivative represented by the formula:
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Cited By (3)
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US7868021B2 (en) | 1997-09-15 | 2011-01-11 | Warner Chilcott Company, Llc | Antimicrobial quinolones, their compositions and uses |
US8039485B2 (en) | 2006-03-28 | 2011-10-18 | Warner Chilcott Company, Llc | Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid |
US8158798B2 (en) | 2006-03-28 | 2012-04-17 | Taigen Biotechnology Co., Ltd. | Coupling process for preparing quinolone intermediates |
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PT919553E (en) * | 1996-07-12 | 2005-05-31 | Daiichi Seiyaku Co | CIS-SUBSTITUTED AMINOCYCLOPOPAN DERIVATIVES |
AU1040597A (en) * | 1996-12-04 | 1998-06-29 | Daiichi Pharmaceutical Co., Ltd. | Substituted aminomethylpyrrolidine derivatives |
WO1998052939A1 (en) * | 1997-05-21 | 1998-11-26 | Daiichi Pharmaceutical Co., Ltd. | Cis-disubstituted aminocycloalkyl-pyrrolidine derivatives |
ZA984527B (en) | 1997-05-30 | 1998-12-03 | Daiichi Seiyaku Co | Substituted cyclobutylamine derivative |
AU8038798A (en) * | 1997-06-24 | 1999-01-04 | Daiichi Pharmaceutical Co., Ltd. | Cis-substituted fluoromethylpyrrolidine derivatives |
JP4629973B2 (en) * | 2003-09-22 | 2011-02-09 | 第一三共株式会社 | Optically active cyclopropylamine derivative and method for producing the same |
EP1693364B1 (en) | 2003-12-12 | 2015-05-20 | Daiichi Sankyo Company, Limited | Intermediates for the production of optically active cyclopropylamine derivatives and process for the production of the intermediates |
TW201024283A (en) * | 2008-12-01 | 2010-07-01 | Targacept Inc | Synthesis and novel salt forms of (R)-3-((E)-2-(pyrrolidin-3-yl)vinyl)-5-(tetrahydropyran-4-yloxy)pyridine |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US7868021B2 (en) | 1997-09-15 | 2011-01-11 | Warner Chilcott Company, Llc | Antimicrobial quinolones, their compositions and uses |
US8039485B2 (en) | 2006-03-28 | 2011-10-18 | Warner Chilcott Company, Llc | Malate salts, and polymorphs of (3S,5S)-7-[3-amino-5-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid |
US8158798B2 (en) | 2006-03-28 | 2012-04-17 | Taigen Biotechnology Co., Ltd. | Coupling process for preparing quinolone intermediates |
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