PH27114A - Antibacterial agents II - Google Patents
Antibacterial agents II Download PDFInfo
- Publication number
- PH27114A PH27114A PH41163A PH41163A PH27114A PH 27114 A PH27114 A PH 27114A PH 41163 A PH41163 A PH 41163A PH 41163 A PH41163 A PH 41163A PH 27114 A PH27114 A PH 27114A
- Authority
- PH
- Philippines
- Prior art keywords
- oxo
- amino
- acid
- dihydro
- methyl
- Prior art date
Links
- 239000003242 anti bacterial agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 description 102
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 77
- 239000000243 solution Substances 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 61
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 239000002253 acid Substances 0.000 description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- 239000002904 solvent Substances 0.000 description 35
- 229910052739 hydrogen Inorganic materials 0.000 description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- -1 amine salt Chemical class 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- 238000001914 filtration Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- 239000001257 hydrogen Substances 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- 239000007787 solid Substances 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 25
- 239000000725 suspension Substances 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 17
- 125000004494 ethyl ester group Chemical group 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 150000003839 salts Chemical class 0.000 description 17
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- 239000012280 lithium aluminium hydride Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 6
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910052774 Proactinium Inorganic materials 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 150000004985 diamines Chemical class 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- ODXGUKYYNHKQBC-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)cyclopropanamine Chemical compound C1CNCC1CNC1CC1 ODXGUKYYNHKQBC-UHFFFAOYSA-N 0.000 description 4
- BUQMHUKZYMREQT-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)ethanamine Chemical compound CCNCC1CCNC1 BUQMHUKZYMREQT-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 3
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 3
- NSCCOUBDHCHVHL-UHFFFAOYSA-N 2-(pyrrolidin-3-ylmethylamino)ethanol Chemical compound OCCNCC1CCNC1 NSCCOUBDHCHVHL-UHFFFAOYSA-N 0.000 description 3
- LFABDWGLTKFHFD-UHFFFAOYSA-N 2-ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione Chemical compound O=C1N(CC)C(=O)CC11CC(=O)NC1 LFABDWGLTKFHFD-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000011152 fibreglass Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- KYOLWTXOYMKDRP-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)propan-1-amine Chemical compound CCCNCC1CCNC1 KYOLWTXOYMKDRP-UHFFFAOYSA-N 0.000 description 3
- JVODWNWKCOVKTO-UHFFFAOYSA-N n-methyl-1-pyrrolidin-3-ylmethanamine Chemical compound CNCC1CCNC1 JVODWNWKCOVKTO-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 150000003141 primary amines Chemical group 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- KEAYESYHFKHZAL-OUBTZVSYSA-N sodium-24 Chemical compound [24Na] KEAYESYHFKHZAL-OUBTZVSYSA-N 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 2
- ZSYALYBRMVKYAS-UHFFFAOYSA-N 1-(1-benzylpyrrolidin-3-yl)-n-methylmethanamine Chemical compound C1C(CNC)CCN1CC1=CC=CC=C1 ZSYALYBRMVKYAS-UHFFFAOYSA-N 0.000 description 2
- OCMQLNXULHLWBT-UHFFFAOYSA-N 1-benzyl-n-ethyl-5-oxopyrrolidine-3-carboxamide Chemical compound O=C1CC(C(=O)NCC)CN1CC1=CC=CC=C1 OCMQLNXULHLWBT-UHFFFAOYSA-N 0.000 description 2
- QHMPADKXXHRBCB-UHFFFAOYSA-N 2,2,2-trifluoro-n-(pyrrolidin-3-ylmethyl)ethanamine Chemical compound FC(F)(F)CNCC1CCNC1 QHMPADKXXHRBCB-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- JQGBMYKEWLSLCI-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-6-nitrobenzoic acid Chemical compound OC(=O)C1=C(F)C(F)=C(F)C(F)=C1[N+]([O-])=O JQGBMYKEWLSLCI-UHFFFAOYSA-N 0.000 description 2
- RUGZVPRCKQMYAZ-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-6-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=C(F)C(F)=C(F)C(F)=C1C(Cl)=O RUGZVPRCKQMYAZ-UHFFFAOYSA-N 0.000 description 2
- SFKRXQKJTIYUAG-UHFFFAOYSA-N 2,3,4,5-tetrafluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(F)=C1F SFKRXQKJTIYUAG-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- IWVZYQDULBTRBE-UHFFFAOYSA-N 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoyl chloride Chemical compound CN(C)C1=C(F)C(F)=C(F)C(F)=C1C(Cl)=O IWVZYQDULBTRBE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-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
- CCNVWYREYGBKHQ-UHFFFAOYSA-N 2-ethyl-2,7-diazaspiro[4.4]nonane;dihydrochloride Chemical compound Cl.Cl.C1N(CC)CCC11CNCC1 CCNVWYREYGBKHQ-UHFFFAOYSA-N 0.000 description 2
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 2
- HPJWOUAYEPSZEF-UHFFFAOYSA-N 3-(cyclopropylamino)-2-(2,3,4,5-tetrafluorobenzoyl)prop-2-enoic acid Chemical compound C=1C(F)=C(F)C(F)=C(F)C=1C(=O)C(C(=O)O)=CNC1CC1 HPJWOUAYEPSZEF-UHFFFAOYSA-N 0.000 description 2
- AQXKNIXHFPOZFL-UHFFFAOYSA-N 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid Chemical compound OC(=O)C1=C(F)C(Cl)=C(F)C(F)=C1[N+]([O-])=O AQXKNIXHFPOZFL-UHFFFAOYSA-N 0.000 description 2
- XCTXHWBTYGOGBK-UHFFFAOYSA-N 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propanoic acid Chemical compound OC(=O)CC(=O)C1=CC(F)=C(F)C(F)=C1F XCTXHWBTYGOGBK-UHFFFAOYSA-N 0.000 description 2
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical compound CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 2
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- GHFIDWVBARCCNS-UHFFFAOYSA-N ethyl 1-(2-ethoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate Chemical compound CCOC(=O)CN1CC(C(=O)OCC)CC1=O GHFIDWVBARCCNS-UHFFFAOYSA-N 0.000 description 1
- PRNXYRWUZSNSFK-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7,8-trifluoro-5-nitro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C([N+]([O-])=O)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 PRNXYRWUZSNSFK-UHFFFAOYSA-N 0.000 description 1
- QFAMZRUPUPZYSB-UHFFFAOYSA-N ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C(=O)OCC)C(=O)C1=C(F)C(Cl)=C(F)C(F)=C1[N+]([O-])=O QFAMZRUPUPZYSB-UHFFFAOYSA-N 0.000 description 1
- GKONDLRZGSAWIZ-UHFFFAOYSA-N ethyl 3-(2-ethoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate Chemical compound CCOC(=O)CC1(C(=O)OCC)CNC(=O)C1 GKONDLRZGSAWIZ-UHFFFAOYSA-N 0.000 description 1
- XMSGWEPSTPUTJE-UHFFFAOYSA-N ethyl 5-acetamido-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(NC(C)=O)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 XMSGWEPSTPUTJE-UHFFFAOYSA-N 0.000 description 1
- BOFBKJLYZUFZMV-UHFFFAOYSA-N ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(N)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 BOFBKJLYZUFZMV-UHFFFAOYSA-N 0.000 description 1
- SFCAQECGKHEYEP-UHFFFAOYSA-N ethyl 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(F)=C(F)C(N)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 SFCAQECGKHEYEP-UHFFFAOYSA-N 0.000 description 1
- PPUPERUOTYGCFJ-UHFFFAOYSA-N ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-5-nitro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(F)=C(F)C([N+]([O-])=O)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 PPUPERUOTYGCFJ-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000295 fuel oil Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WTRWSSDZHQOPJI-UHFFFAOYSA-N methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate Chemical compound O=C1CC(C(=O)OC)CN1CC1=CC=CC=C1 WTRWSSDZHQOPJI-UHFFFAOYSA-N 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- BMFDRCPVKBNLAA-UHFFFAOYSA-N n-[(1-benzylpyrrolidin-3-yl)methyl]cyclopropanamine Chemical compound C1CN(CC=2C=CC=CC=2)CC1CNC1CC1 BMFDRCPVKBNLAA-UHFFFAOYSA-N 0.000 description 1
- FJYAGSRZOYKZCA-UHFFFAOYSA-N n-[(1-benzylpyrrolidin-3-yl)methyl]propan-1-amine Chemical compound C1C(CNCCC)CCN1CC1=CC=CC=C1 FJYAGSRZOYKZCA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- KFTZCNLLRKFMQH-UHFFFAOYSA-N pyrrolidin-3-ylcarbamic acid Chemical compound OC(=O)NC1CCNC1 KFTZCNLLRKFMQH-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- PHOIDJGLYWEUEK-UHFFFAOYSA-N tert-butyl n-(1-benzylpyrrolidin-3-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CCN1CC1=CC=CC=C1 PHOIDJGLYWEUEK-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 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
- 239000011345 viscous material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Description
a
This application is a divisional of application serial number 35962 filed October 20, 1987 .
US Patent 4,341,784 discloses certain substituted 7-(3-amino-l-pyrrolidinyl)-1-ethyl-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-Z- carboxylic acids having the general formula: 0
F I .COLH
Try - , n N tM [Ly - C Hg
NHR
The compounds are disclosed to have antibacterial . oo activity.
The Journal of Medicinal Chemistry, 23, 1358 (1980) discloses certain substituted quinoline-3- carboxylic acids having the structural formula 0 - E ry Co, H
C7
C, He i
. ~ -3- wherein (Ch- may be pyrrolidinyl. See also US
Patent 4,146,719. The compounds are disclosed to have antibacterial activity.
European Patent Application 81 10 6747,
Publication Number 047,005, published March 10, 1982, discloses certain banzoxazine derivatives having the structural formula } . 0
A yr
B N wherein A is halogen and B may be a cyclic amine substituent such as pyrrolidine, or pirzridine.
Certain 7-heterocyclic substituted 1,8-naphthyridines are disclosed in Eur. J. Med.
Chem. - Chimica Therapeutics, 29, 27 (1977). US
Patents 3,753,993 and 3,907,808 disclose certain 7-pyridylquinolones.
Pa The references teach that these compounds posséss antibacterial activity.
The invention in a first generic chemical compound aspect arc compounds having the structural formula I and II i
: . \ . . -g- : .
Y 0 Y 0 . | }
IP 4 COR, F CO, Ry : 3 “0 8 | ok.
R, CH,
I II wherein 2 is
C2) -N Sterne, or
A ' (cH, ys icaln (CRgRe I = -N - N—Ry ' - ' (ci) Ne (CH) 4 } rn
Y is NH, , NHR, NRR', OR, or OH wherein R and R' are each independently an alkyl of from one to six carbon . atoms or a cycloalkyl of from three to six carbon atoms; X is CH, CF, CCl, CBr, COR, COH, CCF,, or N; n is 1, 2, 3, or 4; n' is 1, 2, 3, or 4 wherein n + n' is a total of 2, 3, 4, or 5, and n" is 0, 1, or 2; Ry is hydrogen, alkyl having from one to six carbon atoms or a cation; R, is alkyl having from one to ; four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having from two to four carbon atoms, or cycloalkyl having three to six carbon atoms; R, is hydrogen, alkyl having from sne to four carbon atoms or cycloalkyl having threa t . six carbon atoms; R, is hydrogen, alkyl from one to four carbon atoms, hydraxyalkyl having two to four carbon atoms, trifluorcethyl or R.CO- wherein R, is alkyl having from one to four carbon atoms, Or alkoxy having from one to four carbon atoms; Re is hydrogen, or alkyl . having from one to three carbon atoms; Rg is hydrogen or alkyl having from one to three carbon atoms; and the pharmaceutically acceptable acid addition or base salts thereof.
The preferred compounds of this invention are those wherein 2 is vo Hal —— (CRcR.) "NR3R, (CH, J,
Also preferred compounds of this invention are those wherein 2 is
CH,) — " a 2)n (CRsRe In" a N—R, : ,
Other preferred compounds of this invention are those wherein Ry is hydrogen or a pharmaceutically acceptable base salt such as a metal or amine salt. other preferred compounds of this invention are \ 20 those wherein R, is ethyl, vinyl, 2-fluorcethyl, or cyclopropyl.
The most preferred compounds are those wherein X , is N, CF, or CCl, 2 is j
I
N
C : _p- . Co (CH,) "NHR, N—R,
AY or LOK - Ry is hydrogen, Ry is ethyl, vinyl, 2-fluoroethyl or oo cyclopropyl: n" is 0 or 1 and R, is hydrogen, methyl, ethyl, 1- or 2-propyl, Y is NH, or a pharmaceutically acceptable acid addition or base salt thereof.
Particularly preferred species of the invention are the compounds having the names: go g8-amino-9~fluoro-3-methyl-10-[ (3~-cyclopropylamino- methyl)-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido- {1,2,3-de][1,4]benzoxazine-6-carboxylic acid; g-amino-9-fluoro-3-methyl-10-(3-amino-1-pyrroli- dinyl)-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de](1,4] benzoxazine-6-carboxylic acid hydrochloride; 8-amino-9-fluoro-3-methyl-10-[3-(aminomethyl)-1- pyrrolidinyl}-7-oxn-2,3-dihydro-7H-pyrido(1,2,3-de] [1,4]benzoxazine-6-carboxylic acid; 8-amino-9-fluoro-3-methyl-10-(3-( (propylamino)- methyl]-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido on {1,2,3-del}(1,4]benzoxazine-6-carboxylic acid; © 20 8-amino-9-fluoro-3-methyl-10-[3-[(2-hydroxyethyl)- amino)methyl]~-1~-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-~ pyrido(1,2,3-de](1,4]benzoxazine-6-carboxylic acid; g8-amino-9-fluoro-3-methyl-10-[3-{(2-propylamino)- methyl ]j-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido (1,2,3-del(1,4)benzoxazine-6-carboxylic acid; : 8~amino-9-fluoro-3-methyl-10-(3-((2,2,2-trifluoro- ethyl)amino]methyl]-1-pyrrolidinyl]-7-oxo-2,3- dihydro-7H-pyrido(1,2,3-de}(1,4]benzoxazine-6-~ - carboxylic acid; ! 30 g8-amino-9-fluoro-3-methyl-10~(3-((ethylamino)methyl]- 1-pyrrolidinyl]-7-oxo-2,3~-dihydro-7H-pyrido(1,2,3-de] (1,4]benzoxazine-6-carboxylic acid;
oo -7- 8-amino-9-fluoro-3-methyl-10-[2,7-diazaspirc[4.4]non- c 2-yl]-7-oxo-2,3-dihvdro-7H-pyrido(1,2,3-de][1,4] benzoxazine-6-carboxylic acid; g-amino-9-fluoro-3-methyl-10-(7-(7-methyl-2,7- diazaspiro(4.4)non-2-yl)-7-oxo-2,3-dihydro~-7H-pyrido” (1,2,3-de}(1,4]lbenzoxazine-6~carboxylic acid; g-amino-9-fluoro-3-methyl-=10~(7-(7-ethyl-2,7~
Co diazaspiro(4.4]}non-2-yl]-7-ox0-2,3~-dihydro-7H-pyrido [1,2,3-de](1,4)benzoxazine-6-carboxylic aclic; : 10 1-ethyl-5-amino-6,8~difluoro-7-(3-amino-1- pyrrolidinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride; ) : 1-ethyl-5-amino-6,8-difluoro-7-[3-(ethylamino)methyl- 1-pyrrolidinyl) J-4-oxo-1,4-dihydroquinoline-3- : carboxylic acid; l1-ethyl-5-amino-6,8-difluoro-7-[3-(aminomethyl)-1- pyrrolidinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; l-ethyl-5-amino-6,8-difluoro-7-(3-(propylamino- : 20 methyl) ~-1-pyrrolidinyl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acid; 1-ethyl-5-amino-6,8-difluoro-7-[3-(2-propylamino- methyl) -1-pyrrolidinyl)-4-oxo-1,4-dihydrogquinoline-3- carboxylic acid: l1-ethyl-5-amino-6,8-dLifluoro-7-[3-(cyclopropylamino- methyl) -1l-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline=-3- carboxylic acid; l1-ethyl-S5-amino-6,8-difluoro-7-(2,7-diazaspiro(4.4] non-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; : 1-ethyl-5-amino-6,8~difluoro-7-{7-(7-methyl-2,7- diazaspiro(4.4]non-2-yl)-4-oxo~1,4-dihydroquinoline- 3-carboxylic acid; i-ethyl-5-amino-6,8-difluoro=-7-[7-(7-ethyl-2,7~ diazaspiro(4.4)non-2-yl]l-4-oxo-1,4-dihydroquinoline-~ 3-carboxylic acid;
- C- ’ . -g- F. . - 1-ethyl-5-amino-6,8-difluoro=7-(3-([(2-hydroxyethyl)- amino)methyl)-1-pyrrolidinyl)-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid; 1-ethyl-5-amino-6,8-difluoro-7-{3-{[(2,2,2-trifluoro- ; 5 ethyl)aminolmethyl)-1-pyrrolidinyl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid; 5-amino-7-(3-amino-1-pyrrolidinyl)-i-ethyl-6-fluoro- 1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; : 10 5-amino-7-(3-amino-1l-pyrrolidinyl)-8-chloro-l-cyclo- : propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid;
FT 5-amino-8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro- 7-[3-[(methylamino)methyl)~1-pyrollidinyl])-4-oxo-3- quinolinecarboxylic acid; : §-amino-7-(3-amino-1-pyrrolidinyl)-8-bromo-1-cyclo- propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid; and ) $-amino-7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
The following process for preparing compounds of - © the formula . rN f = i
-z- . Y 0 Y 0
F CO,R : . F7# 7) CO.Ry Ay Ry i : 2 X \ Z .
R or oJ 2 CH, 111 Illa wherein R,, R,, X, nd 2 are as defined for formula I : which comprises reacting a compound having the . - following structural formula
Y O Y i
CO,R
F ~ CO,Ry F Zz | 271 5, | | “
LX N L TL
R, CH 3 iv Vv ~ with an amine corresponding to the group Z wherein 2 is the compound having the structural formula i
Mala
HN (CRgRg)"NR3Ry op ) 1
N—(cHy)
Via ,
Ca) (CRgRg) ~ 1 HN N—R, , \
N~dcH,) (CH, _/
Vib wherein all of the above terms are as defined in formulae I and II and L is a leaving group which is preferably fluorine or chlorine. © This invention also includes novel intermediates. In a second generic chemical aspect’ are compounds having the structural formula VII
Y 0
FN 1 wherein X is CH, N, CF, CCl, CBr, CCF,, COH, or COR;
Y is NH, , NHR, NRR', OR or OH wherein R and R" are each independently an alkyl of from one to six carbon atoms or a cycloalkyl of from three to six carbon atoms; Ry is as defined above ahd the pharmaceutically acceptable acid addition or base : salts thereof. The preferred compounds are those wherein X is CCl, CBr, or CF and Y is NH,, NHR, or a NRR'.
Particularly preferred species of the invention are compounds having the names: 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid; 5-amino-8-bromo-1-oyclopropyl-6,7-difluoro-~1,4- dihydro-4-oxo-3-quinolinecarboxylie acid; and
S-amino-1l-cyclopropyl=-6,7,8-triflucro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid.
The invention also includes a pharmacsutical composition which comprises an antibacterially effective amount of a compound having structural formula I and the pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier.
The invention further includes a method for treating bacterial infections in a mammal which comprises administering an antibacterially effective’ amount of the above defined pharmaceutical composiiton to a mammal in need thereof.
The compounds of the invention having the structural formula II or IIIa may be readily prepared by treating a corresponding compound having the structural formula IV or V with the desired cyclic amine VIa or VIb. For purposes of this reaction, the alkylamine substituent of compound VIa or VIb may, if desired, be protected by a group which renders it substantially inert to the reaction conditions. Thus, for example, protecting ¢roups such as the following may be utilized: carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, pB,P,B-trichloroethoxycarbonyl, ay A~-lodoethoxycarbonyl; aryloxycarbonyl groups such as benzyloxycarbonyl, pn-methoxybenzyloxycarbonyl, phenoxycarbonyl; silyl groups such as trimethylsilyl; and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl, may all be utilized. The protecting group may be removed, after the reaction between compound IV or V and compound VIa or VIb if desired, by procedures known to those skilled in the art. For example, the ethoxycarbonyl group may be removed by acid or base hydrolysis and the trityl group may be removed by hydrogenolysis. :
7 CLT «ld- .
The reaction batween the compound of structural formula IV or V and a suitably protected compound of formula VIa or VIb, may be performed with or without a solvent, preferably at elevated temperature for a gufficient time so that the reaction is substantially complete. The reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal or alkaline eirth metal carbonate or bicarbonate, a tertiary amine such as triethylamine, pyridine, or picoline. Alternatively an excess of the compound of formula VI may be utilized as the acid acceptor. | : ; Convenient solvents for this reaction are nonreactive solvents such as acetonitrile, tetrahydrofuran, etianol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, picoline, water, and the like. Solvent mixtures may : also be utilized. :
Convenient reaction temperatures are in the range of from about 20° to about ‘150°C; higher temperatures usually require shorter reaction times.
The removal of the protecting group R, may be accomplished either before or after isolating the ~~ product, III. Alternatively, the protecting group R, need not be removed.
Some of the starting compounds having structural formulae IV and V are known in the art or, Lf new, may be prepared from known starting materials by standard procedures or by variations thereof. Thus the following compounds are disclosed in the noted references:
‘ NH, 0
F CO, H cl "
F Et Cs
JS 8174 367A
NH, 0
F~ p CO, H
F ~ X N o oA .
JS 7149 286
Other starting compounds having structural formula IV wherein Y is NRR' and R and/or R' are not hydrogen may be prepared from the known S-amino quinolines or naphthyridines by an alkylation a sequence shown below wherein L is a leaving group as previously defined. { j
. : ~14~ .
F,CONH O
NH, O CFyC
F CO,R terres r———————— : : Lo . o v (CF4C0),0 L X » ’ R.
Ry 2
NaH(or other base)
RL
R H A
~un~ 0 CFjCON N i i F _CO4R : F XN ! CO,Ry nt | ANN | 271 [OT — ) . L X " L X i» R | Ra
R'L (optional)
F N CO.Ry
L <> X2 ON . . Iva
The S-amino group is preferably acylated by trifluoroacetic acid anhydride although other acyl a moieties may be employed. The alkylation of R proceeds with the presence of sodium hydride or other nonnucleophilic basns. Removal of the acyl activating group is accomplished with acid or base , hydrolysis such as 2N hydrochloric acid in acetic acid. A second alkylation, if desired, with R'L, again in the presence of base such as, for example, potassium carbonate provides compounds of formula IV where both R and R' are not hydrogen.
Alternatively, the 5-alkylamino compounds of formula II may be prepared from the nitro or amino acids IV through reductive amination procedures as illustrated in the following scheme.
~1l>- oo :
NH. ~ RCHO rrr : ~ R R
L X L Hoy or ~~
H™ or R x CO,H — IV ~~,
NO L X L
2
CO,H
F X 2 RCHO z Hoy
L X L catalyst
Using appropriate control of the aldehyde (RCHO) equivalents mono and disubstituted amines may be obtained. The substituted amino acids may he converted to the desired compounds of formula II by methods described in the references cited in the
The compounds of formula IV wherein Y is OR may be prepared from the polysubstituted acids or esters by displacement of an ortho leaving group with OR as shown: 7 L ORj, OR3 - F CO,R F O.,H
Oe OR. TY 271 ut TY 2
Ew errs 5 <
Lx NL L RING LANRPN
OR 4 oO
Lx? o : Ry
IVb
Other compounds of formula IV wherein X is CH, ccl, CBr, COR, CCH, CCF, or N are made by the sequence shown below according to the general methods in the references cited in the background of the invention. - 0 NO,
F Oe HNO, YOY —————
L x7 L L x” L iL. (cocl), . | 2. Malonate dianion
NO, O © Ac,0 No, 0 0
F (EtO) ,CH F PY 2
LO RENL L x7 ate . 0
NO, O IY i "Oz |) i
C-0Et
F x OEt Base ~r 8 | —_— P
L XZ SL SNHR) L xX \ :
Rl
NH, 0 NH. 0
CO,H
F N 2 at F N CO, Et lL — LJ
Lo Lo NIN LX ) ’
J . -Li= .
The general pathway to the compounds of formula
IV is illustrated with 2-nitro-3,4,5,6-tetrafluoro- benzoyl chloride. This starting material is treated with n-butyl lithium and malonic half acid ester to form 2-nitro-3,4,5,6-tatrafluoro-p-oxo-benzene - propancic acid ethyl ester. This product can be converted to S5-nitrn-l-cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-quinoline~-3~-carboxylic acid ethyl ester by a three stnp reaction. The starting material is first treated with triethylorthoformate and subsequently with cyclopropyl amine in t-butyl alochol. The product is ring closed with potassium a t-butoxide to form 5-nitro-l-cyclopropyl-6,7,8- trifluoro-1,4-dihydro-4-oxoquinocline-3-carboxylic acid ethyl ester. This product 1s hydrogenated to form the corresponding S5-aminoc compound. This is then hydrolyzed to form l-cyclopropyl-5-amino-6,7,8- trifluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid. Alternatively compounds of the formula IV may be prepared by a series of reactions illustrated with : 3,4,5,6-tetrafluorcanthranilic acid. The acid is reacted with acetic anhydride and acetic acid to form 2-acetylamino-3,4,5,6~tetrafluorobenzoic acid. This - — compound is reacted with oxalyl chlorlde and dichloromethane in the presence of N,N-dimethyl- formamide catalyst to form 2-acetylamino-3,4,5,6- tetrafluorobenzoyl chloride. This product is treated with n-butyl lithium and malonic half acid ester to form 2-acetylamino-3,4,5,6~tetrafluoro~-f-oxobenzene- propanoic acid ethyl ester. ; This product can be converted to 5-acetylamino- l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid ethyl ester by a three step reaction. The 2-acetylamino-3,4,5,6-tetra- fluoro~-f-oxobenzene-propanoic acid ethylestoer is first treated with triethylorthoformate and acetic anhydride. After removal of the solvent the residue i oo -18- © is treated with a solution of cyclopropylamine in t-butanol. After the reaction ls complete a solution of potassium t-butoxide in t-butanol is added. The resulting product is S5-acetylamino-l-cyclopropyl- . : 5 6,7,8-trifluoro-1,4~dihydro-4-oxo-quinoline-3- carboxylic acid ethyl ester. The ester is hydrolyzed to form l-cyclopropvyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxyllic acid.
The compounds of the invention having structural formula VIa or VIb are elther known compounds or they may be prepared from known starting materials by standard procedures or by variations thereof. For - example, 3-pyrrolidinemethanamines having the structural formula D : N-H ) 15 . D
CH,NHR 4 ’ may be readily prepared from the known starting material methyl S5-oxo-1-(phenylmethyl)-3-pyrrolidine- carboxylate, A, [J. Org. Chem., 26, 1519 (1361)] by : Fa the following reaction sequence. ~COLCHy u,R, ~~ CONHR, 0” \ 07 Nn
CH,C.H - . 265 CH,C He
A 2 v y CH, NHR, CH, NHR, eee ttre ne. » LJ
H
: CH, CH, . Nn
. C o19- .
The compound wherein R, is hydrogen, namely j-pyrrolidinemethanamine, has been reported in J.
Org. Chem., 26, 4955 (1961).
Thus compound A may be converted to the corresponding amide B by treatment with RyNH,; for . example, a saturated solution of ethylamine in an alkanol such as methyl alcohol may be utilized. The diamide B may next be reduced to produce the corresponding diamine C. This reduction may be carried out using lithium aluminum hydride, for example, in a convenient solvent such as tetrahydrofuran. Compound C may next be oT debenzylated, for example using hydrogen and 20% palladium on carbon catalyst to produce the diamine
D. Alternatively, when R = H in C, the primary amine function may be protected with a group Ry as defined, hereinabove. For example, the primary amine function may be acylated with an acyl halide such as ace:yl chloride by well known procedures. The primary amine function of C may also be converted to a carbamate ester such as the ethyl ester by treatment with ethyl chloroformate in the presence of a strong base such as 1,8-dlazabicyclo(5.4.0}undec-7-ene in a convenient ~~ solvent such as methylene chloride. The benzyl group may next be removed, for example as described above for compound C, thereby producing compound D where R is -CO,Et, which after conversion to a compound of the type VIa or VIb may be reacted with a compound having the structural formula IV or V to thereby produce a corresponding compound having the structural formula I or Ia. The -CO,Et group may be removed by standard procedures.
Likewise spliroamino compounds represented by . . structural formula VIb may be readily prepared from the known starting material 3-ethoxycarbonyl-5-oxo- l-pyrrolidineacetic acid ethyl ester [J. Org. Chem., 46, 2757 (1981)] by the following reaction sequence.
: 0
XN CO, Et CE :
Ee —— aX H-N
CH, CO, Et _ 0 : 0
IY ~N-R
Pt pent OC
CgHgCH,=N , CoHgCHy—N c 1
H~—N
J
The compound 2,7-dlazaspiro(4.4)nonane where Ry is H is described in the above reference. Thus ~~ ‘compound E may be converted to the corresponding amide F by treatment with R4NH,, for example, methyl amine in water followed by benzylation which may be carried out with sndium hydride and benzyl chloride to give G. Reduction to the diamine H may be accomplished with lithium aluminum hydride.
Subsequent debenzylation, for example, with hydrogen and 20% palladium on carbon catalyst produces the diamine J. : The compounds of the invention display antibacterial activity when tested by the microtitration dilution method as described in
Heifetz, et al, Antimicr. Agents & Chemoth., 6, 124 (1974), which is incorporated herein by reference. i oo | | -21-
The compounds of the inventlon are capable of forming both pharmaceutically acceptable acid " addition and/or bare salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or orcanic amines. Examples of metals’ used as cations arn sodium, potassium, magnesium, - calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chlorcprocaine, choline, diethanolamine, ethylenediamine,
N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids. co Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce aither a mono or di, etc salt in the conventional manner. The free base forms may be regenerated by treating the salt form with a base.
For example, dilute solutions of aqueous base may be . utilized. Dilute aqueous soldium hydroxide, a potassium carbonate, ammonia, ,and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base where R' is hydrogen gives the corresponding : basic salt.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the like are aquivalent
Ce -22- to the unsolvated forms for purposes of the invention. : The alkyl groups contemplated by the invention } comprise both straicht and branched carbon chains of from one to about six carbon atoms. Representative . of such groups are methyl, ethyl, propyl, isopropyl, and the like. :
The cycloalkyl groups contemplated by the invention comprise “hose having three to si» carbon atoms such as cyclonropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The alkoxy groups contemplated by the invention
So comprise both straight and branched carbon chains of ~ from one to about six carbon atoms unless otherwise specified. Representative of such groups are methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxy, and the 1ikAn.
The term, haloalkyl, is intended to include halogen substituted straight and branched carbon chains of from two to four carbon atoms. Those skilled in the art will recognize that the halogen substitutent may not be present on the a-carbon atom of the chain. Representative of such groups are ro p-fluoroethyl, B-chloroethyl, B,B-dichloroethyl,
A-chloropropyl, P-~chloro~2-propyl, _-iodobutyl, and the like.
The term halognan is intended to include fluorine, chlorine, bromine, and iodine unless otherwise specified.
Certain compounds of the invention may exist in : optically active forms. The pure D isomer, pure L isomer as well as mixtures thereof; including the racemic mixtures, are contemplated by the invention. i Additional asymmetric carbon atoms may be present in a substitutent such as an alkyl group. All such i isomers as well as mixtures thereof are intended to be included in the lnvention.
: © =23-
The compounds of the invention can be prepared : and administered in a wide variety of oral and : parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a . compound of formula I or a corresponding pharmaceutically acceptable salt of a compound of : formula I. i
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. €olid form preparations include : ah powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as } diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.” In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape a and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Sultable solld carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl : 30 cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other ; 35 carriers) is surrounded by carrier, which is thus in - association with it. Similarly, cachets ara included. Tablets, powders, cachets, and capsules
- | —24- i can be used as solid dosage forms suitable for oral administration. : Liquid form preparations include solutions, ) suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions - for parenteral injection. Such solutions are . prepared so as to ba acceptable to biological systems (1sotonicity, pH, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, yo flavors, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active : component in water with viscous material, i.e., - natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. : 20 Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage - form can be a packaged preparation, the package °° containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to . 100 mg according to the particular application and the potency of the active ingredient.
NE In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to
“ . : 25a about 40 mg per kilogram daily. A daily dose range of about 6 mg to about 14 mg per kilogram is : preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the : compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage lis increased by small increments until the optimum effect under the circumstances ls reached. For convenience, the ‘ total daily dosage may be divided and administered in portions during the day if desired.
The following nonlimiting examples illustrate the inventors' preferred methods for preparing the : compounds of the invention.
PREPARATION OF STARTING MATERIALS
EXAMPLE A
1-Ethenyl-6,7,8-trifluoro-1,8-dihydro-4--oxn=-3- quinolinecarboxylic acid 6,7,8-Trifluoro-1,4-dihydro-4-oxo~3-quinoline- : carboxyiic acid ethyl ester was treated with dibromo ethane to afford the l-ethenyl-6,7,8-trifluoro-1,4- a 25 dihydro-4-oxo-3-quinolinecarboxylic acid ester, mp 134-135°C. Subsequent hydrolysis with hydrochloric acid gave l-ethenyl-6,7,8-trifluoro-1,4~-dihydro-4- oxo-3-quinolinecarboxylic acid, mp 186-187°C.
EXAMPLE B
300 6,7,8-Trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid
In identical fashion, 6,7,8-trifluoro-1,4- dihydro-4-oxo~3-quinolinecarboxylic acid ethyl ester { . ’
was converted to 6,7,8-trifluoro-1-(2-fluoroethyl)- 1,4-dihydro-4-oxo-l-quinolinecarboxylic acid, mp 207-211°C. .
EXAMPLE C
N-Methyl-3-pyrrolidinemethanamine : N-Methyl-5-oxo-1=(phenylmethyl)-3-pyrrolidine=- carboxamide
A mixture of 1.00 g (0.43 mole) of methyl 5-oxo-1-(phenylmethyl)=-3-pyrrolidinecarboxylate (J.
Org. Chem., 26, 1519 (1961)]), 500 ml methanol and 100 g (3.2 mole) of methylamine was heated at 100°C i in a pressure reactor for 16 hours. The reaction : mixture was cooled and the ammonia and methanol were removed under pressure. The residue was taken up in dichloromethane and washed 3 x 100 ml 1N sodium hydroxide. The orrianic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 8.3 g of N-methyl-5-oxc-1-(phenyl- methyl) -3-pyrrolidinecarboxamide as a white solid, mp 82.5-83.0°C.
Analysis calculated for CyyH N05
Cc, 67.22; H, 6.94; N, 12.06 ro Found C, 66.98; H, 6.69; N, 12.02.
This material was used in the next step.
N-Methyl-l-(phenylmethyl)-3-pyrrolidinemethanamine
To a suspension of 37.4 g (1.00 mole) lithium aluminum hydride in 1000 ml tetrahydrofuran, was . added a solution of 88.3 ¢g (0.380 mole) of
N-methyl-5-oxo-~1-(phenylmethyl)-3-pyrrolidine- carboxamide in tetvafuran dropwise under nitrogen.
The reaction was then refluxed overnight. The
I reaction flask was cooled in an ice bath and 37.4 ml of water, 37.4 ml of 15% sodium hydroxide and 112.2 ml of water were added. The precipitated solids were filtered and washed with hot ethanol.
The combined filtrates were concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate, and the solvent evaporated under reduced pressure tc give 68.7 ¢ of N-methyl-1- . (phenylmethyl)-3-pyrrolidinemethanamine as an oil.
This material was used without further purification in the step.
N-Methyl-3-pyrrolidinemethanamine
A mixture of 67.3 g (0.32 mole) of N-methyl-1- (phenylmethyl)-3-pyrrolidinemethanamine, 3 g of 20% on palladium on carbon, and 600 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5 x 10° Pa and at room temperature for 18 hours.
Another 3 g of 20% palladium on carbon was added and the hydrogenation continued for 6.5 hours. Another 3.0 g of 20% palladium Hn charcoal was added and the hydrogenation continued for another 4.5 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (72-76°C, 10.5 mm Hg) to give 8.32 g
N-methyl-3-pyrrolidinemethanamine. rN
EXAMPLE D
N-Ethyl-3-pyrrolidinemethanamine
N-Ethyl-5-oxo-1-{phenylmethyl)-3-pyrrolidine- carboxamide
A. mixture of 200 g (0.86 mole) of methyl-5-oxo- : 1-(phenylmethyl)pyrrolidinecarboxylate (J. Org.
Chem., 26, 1519 (1961)], 1000 ml methanol and 200 g (4.4 mole) of ethylamine was heated at 100°C in a : pressure reactor for 17.2 hours. The reaction mixture was cooled and the excess ethylamine and methanol were remcved tnde reduced pressure. The residue was 'ak nn np i= di ‘hlororethane and washed 3 x 150 ml IN sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 104.6 g of N-ethyl-5- } oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 97-99°C. ’ This materials was used in the next step. ;
N-Ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine
To a suspensicn of 108.8 g (2.86 mole) lithium aluminum hydride in 800 ml tetrahydrofuran, was added a solution of 194.5 ¢g (0.79 mole) of N-ethyl-5-oxo-1- (phenylmethyl)-3-pyrrolidinecarboxamide in 600 ml
LL tetrahydrofuran dropwise under nitrogen. The " reaction was then refluxed four hours. The reaction flask was cooled in an ice bath and 108 ml of water, 108 ml of 15% sodium hydroxide, and 324 ml of water were added. The precipitated solids were filtered and washed with hot. ethanol. The combined filtrates were concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to give 151.9 g of N-ethyl-1-(phenylmethyl)-3-pyrrolidine- methanamine as an oil.
This material was used without further ro purification in tho next step.
N-Ethyl-3-pyrrolidinemethanamine
A mixture of 151.6 ¢g (0.69 mole) of N-ethyl-1l- (phenylmethyl)-3-pyrrolidinemethanamine, 5 g of 20% palladium on carbon, and 1100 ml of ethanol was shaken in an atmosphere of hydrogen at about 4.5 x 10° Pa and at room temperature for 21.6 hours. ! Another 5 g of 20% palladium on carbon was added and the hydrogenation continued for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled
. : A : under vaccum (88-91°C, 11.5 mm Hg) to give 66.0 g
N-ethyl-3-pyrrolidinemethanamine.
EXAMPLE E
N-{2,2,2-Trifluoroethyl)-3-pyrrolidinemethanamine °° + 5 5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-
J-pyrrolidine carboxamide
A mixture of 21.9 g (0.10 mole) methyl 5-oxo- 1-(phenylmethyl)-3-pyrrolidinecarboxylate in 150 ml tetrahydrofuran, was cooled to 0°C in an ice bath under nitrogen and 24.3 g (0.15 mole) carbonyl oo diimidazole was added. The reaction was stirred at : 0°C for 30 minutes, then at room temperature for 30 minutes. A solution of 13.6 g (0.10 mole) of 2,2,2-trifluorcethylamine hydrochloride, 15.2 g (0.10 mole) 1,8-dlazabicyclo[5.4.0]Jundec-7-ene and 100 ml ’ tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed 3 x 150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under ~ reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give ‘ 8.50 g of 5-oxo~1~(phanylmethyl)-N-(2,2,2~-trifluoro- 2S ethyl)-3-pyrrolidinecarboxamide, mp 110-112°C.
This material was used in the next step. 1-(Phenylmethyl)-N-(2,2,2-trifluorcethyl)-3- pyrrolidinemethanamnine
A mixture of 8.50 ¢ (28.3 mole) of S5-oxo-1- {phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-~ pyrrolidinecarboxamide in 100 ml tetrahydrofuran was added dropwise to 1.22 g (84.9 mmole) of lithium aluminum hydride in 50 ml tetrahydrofuran. The reaction was refluxed two hours, then stirred at room.
. : -30-~ temperature overnight. The reaction was cooled in an ice bath and 3.2 ml of water, 3.2 ml of 15% sodium hydroxide, and 9.6 ml of water were added. The precipitated salts were filtered and washed with hot ethanol. The combined filtrates were concentrated under reduced pressure. The residue was taken up in dichloromethane, filtered, and dried over magnesium sulfate. The solvent was removed at reduced pressure to give 7.15 g of 1-(phenylmethyl)-N-(2,2,2~ trifluorocethyl)-3-pyrrolidinemethanamine.
This material was used without further purification in the next step. .
N-(2,2,2-Trifluoroethyl)-3-pyrrolidinemethanamine
A mixture of 7.15 ¢g (26.3 mmole) 1-(phenyl- methyl) -N-(2,2,2-trifluorcethyl)-3~pyrrolidine- methanamine 100 ml of methanol and 0.7 g of 20% palladium on carbon was shaken in an atmosphere oc hydrogen at about 4.5 x 10° Pa and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. ~The residue was distilled under vacuum (63-65°C, 2.8 mm Hg) to give 2.55 g of N-(2,2,2-trifluoro- ro ethyl)-3-pyrrolidiremethanamine.
EXAMPLE F
N-Propyl-3-pyrrolidinemethanamine 5-0xo-1-(phenylmethyl)~N-propyl-3-pyrrolidine- carboxamide : To a solution of 10.9 g (50 mmole) of 5-oxo-1- ! phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml : of acetonitrile was added 9.73 g (60 mmole) of aN 1,1'-carbonyldiimidazole. The reaction was heated to 60°C for one hour, cooled to room temperature and treated with 4.13 ¢ (79 mm>le) of n-propylamine.
After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water,
IN hydrochloric acid, dried over magnesium sulfate, : filtered, and evaporated in vacuo to give 12.0 g of 5-oxo~-1-(phenylmethyl)-N~propyl-3-pyrrolidine- . carboxamide, mp 86-87°C. : 1-(Phenylmethyl)=-N-propyl-3-pyrrolidinemethanamine
To a suspension of 8.2 g (0.2 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise, 12.0 g (45.6 mmole) of solid
S-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidine- oT carboxamide. When the addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then at reflux for two hours. After cooling to room temperature, the mixture was treated dropwise, successively, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml cf water, titrating the final addition to produce a granular precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 9.6 g of 1-(phenylmethyl)-N-propyl-3-pyrrolidinemethanamine,
Pa as a heavy syrup. .
This material was used for the next step without further purification.
N-Propyl-3-pyrrolidinemethanamine
A mixture of 14.0 g (60.0 mmole) of . 1-(phenylmethyl)-N-propyl=-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5 x 10° Pa and room temperature for 24 hours.
The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 7.1 g of N-propyl-3-pyrrolidinemethanamine, bp 49-50°C/0.25 mm. | :
EXAMPLE G oo N-Cyclopropyl-3-pyrrolidinemethanamine 5-0xo-1-(phenylmethyl)-N-cyclopropyl-3- pyrrolidinecarboxamide . » 5 To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)=-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60°C for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine.
The reaction was stirred at room temperature for 18 a hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo~-1- (phenylmethyl)-N-cyclopropyl-:-pyrrolidine- carboxamide, mp 94-96°C. 1-(Phenylmethyl)-N-cyclopropyl-3-pyrrolidine methanamine
To a suspension of 8.2 g (0.20 mole) cf lithium an aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise 18.0 g (70.0 mmole) of solid 5-0x0-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidine- carboxamide. When the addition was complete, the reaction mixture was stirred at room temperature for . 18 hours and then at reflux for two hours. After cooling to room temperature, the mixture was treated : dropwise, successi‘ely, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml cf water, titrating the final addition to produce a granular precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated in vacun to give 16.0 g of 1-(phenyl- methyl)-N-cycloyropyl-3-pyrrolidinemethanamine, as a i : -33-~ heavy oil. This was used for the next step without further purification.
N-Cyclopropyl-3-pyrrolidinemethanamine
A mixture of 13.6 ¢ (59.0 mmol) of 1-(phenyl- : 5 methyl)-N-cyclopropyl=-3-pyrrolidinemethanamine, 0.5 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosrhere of hydrogen at about 4.5 x 10° Pa and room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 6.3 g of N-cyclopropyl-3-pyrrolidinemethanamine, bp = 88-90°/13 mm.
EXAMPLE H
N-(2-Propyl)-3-pyrrolidinemethanamine 5-0xo-1-(phenylmethy!)-N-{(2-propyl)-3-pyrrolidine- carboxamide
To a solution of 16.4 g (75.0 mmole} of 5-0xo-1~(phenylmethyl)~3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1-'carhonyldiimlidazole. The reaction was ~ heated to 60°C for one hour, cooled to.room temperature and trrated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water,
IN hydrochloric acid, dried over magnesium sulfate, and evaporated in vacuo to give 18.6 g of S5-oxo-1- {phenylmethyl)-N-(2=-propyl)~-3-pyrrolidinecarboxamide, mp l122-124°C.
1-(Phenylmethyl)-N-(2-propyl)=-3-pyrrolidine- methanamine
To a suspension of 8.2 ¢g (0.2 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrcfuran was added portionwise, 18.3 g (70.0 mmole) of solid 5-ox0o-1-phenylmethyl)~N-(2=-propyl)~-3-pyrrolidine- carboxamide. When “he addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then rnfluxed for two hours. After cooling to room temperature, the mixture was treated dropwise, successively, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, — titrating the final addition to produce a granular precipitate. The solid was removed by filtration, : 15 washed with tetrahydrofuran and the filtrate x evaporated in vacuo to give 15.6 ¢ of 1-(phenylmethyl)-N~(2-propyl)-3-pyrrolidine- methanamine as a heavy syrup.
This materials was used for the next step without further purification.
N-(2-Propyl)-3-pyrrolidinemethanamine
A mixture of 13.4 g (58.0 mmol) of l-phenyl- methyl-N-(2-propyl)-3-pyrrolidinemethanamine, 1.0 g ~ of 20% palladium on carbon and 130 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5 x 10° Pa and ronm temperature for 24 hours. The catalyst was removed by filtration through Celite; the filtrate concentrated and distilled in vacuo to : give 6.3 g of N-(2=-propyl)-3-pyrrolidinemethanamine, bp 58-60°C/3.5 mm. !
~35-
EXAMPLE I
1,1-Dimethylethyl(3-pyrrolidinyl)carbamate 1,1-Dimethylethyl{1-(phenylmethyl)-3-pyrrolidinyl] carbamate .
A solution of 77.0 g (0.44 mole) of 3-amino-1- (phenylmethyl)pyrrolidine [J. Med. Chem., 24, 1229 (1981)), 440 ml (0.44 mole) 1.0 N sodium hydroxide and 600 ml of tertiarybutyl alcohol was treated dropwise with 98.2 g (0.45 mole) of di-tertiarybutyl dicarbomate. The reaction was stirred at room temperature for 18 hours and the solvent removed in oT vacuo. The residue was partitioned between ether and water. The aqueous layers were reextracted with ether, the combined ether layers were washed with water, dried (MgsSo,), filtered, and evaporated on a steam bath replacing the ether with petroleum ether.
The crystals which formed were removed by filtration, washed with ether/petroleum ether (1:1), and dried in vacuo to give 84.8 g of 1,1~dimethylethyl{1l-(phenyl- methyl) -3-pyrrolidinyl)carbamate, mp 114-115°C. A second crop (16.7 g) was obtained by concentrating the filtrate. . 1,1-Dimethylethyl(3-pyrrolidinyl)carbamate
A mixture of 101.5 ¢g (0.37 mole) of 1,1-dimethylethyl(1l~{(phenylmethyl)-3-pyrrolidinyl] carbamate, 5.0 g of 20% palladium on carbon and 1 liter of tetrahydrofuran was shaken in an atmosphere ; of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the flltrate was concentrated in vacuo to give 6.8 g of 1,l1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon i standing and was of sufficient purity to be used as is for the ensuing steps.
: -36~ :
EXAMPLE J
2-[(3-Pyrrolidinylmethyl)amino]ethanol
N-(2-Hydroxyethyl)-S-oxo-1-(phenylmethyl)-3- = pyrrolidinecarboxamide .
A mixture of 46.7 ¢g (0.2 mole) of methyl S5-oxo- 1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org.
Chem., 26, 1519 (1961)], 36.7 g (0.6 mole) of 2-aminoethanol and 500 ml methanol was refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in ro dichloromethane and extracted 3 x 100 ml 1 N sodium hydroxide. The aqueous layer was taken to pH 5, extracted 3 x 150 ml dichloromethane, then taken to 15 . pH 8 and again extracted 3 x 150 ml dichloromethane.
The aqueous layer was concentrated at reduced pressure and the rcsulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic lryers were dried over magnesium sulfate, the solvent removed at reduced pressure to yield 47.9 g of N-(2-hydroxyethyl)-5-oxo~-1-(phenyl- methyl) -3-pyrrolidinecarboxamide as an oil. This was os used in the next step without further purification. 2-[[[1-(Phenylmethyl)-3-pyrrolidinyl]methyl]jamino] ethanol
A mixture of 46.6 g (0.18 mole) of N-(2-hydroxy- ethyl) -5-oxo-1-(phenylmethyl)-3-pyrrolidine- carboxamide in 200 ml of tetrahydrofuran was added dropwise to a slurry of 20.25 g (0.534 mole) of lithium aluminum hydride in 150 ml tetrahydrofuran.
The reaction was rrfluxed three hours, then cooled in an ice bath. The work up consisted of sequential addition of 20 ml vater, 20 ml 15% sodium hydroxide then 60 ml water. The reaction was filtered and the precipitate washed with ethanol. The filtrate was
. oo -3/- concentrated at rediiced pressure, the residue taken up in dichloromethane, dried over magnesium sulfate, and the solvent removed at reduced pressure to give : 32.31 g of 2-[([1-(phenylmethyl)-3-pyrrolidinyl] maethyllamino)ethanol as an oil. This material was - used in the next step without further purification. 2-[(3-Pyrrolidinylmethyl)amino]ethanol
A mixture of 32.3 g of 2-[([{1-(phenylmethyl)-3- pyrrolidinyllmethyl Jamino)ethanol, 330 ml of methanol and 3 g of 20% palladium on charcoal was shaken in an atmosphere of hydrogen at about 4.5 x 10° Pa and at : room temperature for 18 hours. The solvents were then removed at reduced pressure. The residue was distilled under vacuum (bp 129-131°C, 1.5 mm Hg) to give 11.43 g of 2-[(3-pyrrolidinylmethyl)amino]- ethanol. : EXAMPLE K 2-Methyl-2,7-diazasoiro[4.4]nonane Dihydrochloride 2-Methyl-2,7-dlazaspirof[4.4]nonane~1,3,8~-trione
A solution of 20.3 ¢g (0.084 mole) 3-ethoxy-
Pa carbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester (J. Org. Chem., 46, 2757 (1981)] in 40 ml of 40% ) aqueous methylamine was stirred at room temperature overnight, then placed in an oil bath and gradually heated to 220°C over 30 minutes allowing volatiles to \ . distill from the open flask. The crude product was crystallized from ethanol to afford 12.6 g of 2-methyl-2,7-diazaspiro(4.4)nonane~1,3,8-trione, mp 201-204°C.
Analysis calculated for CgHyoN,05 3 Cc, 52.74; H, 5.53; N, 15.38
Found C, 52.87; H, 5.60; N, 15.25.
Co -38- 7-Benzyl-2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8- i trione : A solution of 1.82 ¢g (10 mmol) of 2-methyl-2,7- dlazaspiro(4.4)nonane-1,3,8~trione in 20 ml
N,N-dimethylformamide was added gradually under a nitrogen atmosphere to 0.05 g (10.4 mmol) of 50% oil : suspension of sodiitm hydride which had been previously washed twice with toluene and covered with ml N,N-dimethylformamide. After stirring one hour 10 there was added 1.40 g (11 mmol) of benzyl chloride and stirring was continued overnight at room : temperature. After concentrating to a small volume oo in vacuo, the residue was diluted with 40 ml water and extracted twice with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate, and evaporated to give a solid. Crystallization from toluene:hexane to afford 1.74 g of 7-benzyl-2-mathyl-2,7-diazaspiro(4.4)] : nonane-1,3,8~trione, mp 157-158°C.
Analysis calculated for Cy gH M505!
Cc, 66.16; H, 5.92; N, 10.27
Found C, 66.45; H, 5.79; N, 10.09.
Co 7-Phenylmethyl-2-methyl-2,7-diazaspiro[4.4]nonane
Dihydrochloride
A solution of 1.36 g (5.0 mmol) 7-phenylmethyl- 2-methyl-2,7-diazaspiro(4.4]1nonane-1,3,8-trione in 50 ml tetrahydrofuran was added dropwise to a suspension of 0.95 g (25 mmol) lithium aluminum ’ hydride in 30 ml tetrahydrofuran. The mixture was stirred overnight at room temperature, refluxed one hour, cooled, and treated dropwise with 0.95 ml water, 0.95 ml 15% sodium hydroxide solution, and 2.8 ml water. After removal of the inorganic solids by filtration, the filtrate was concentrated in vacuo to give a syrup which was dissolved in isopropanol ! and treated with excess 6N hydrogen chlorice in
. -dY= . isopropanol. Crystallization afforded 0.97 g of the : title compound, mp 233-234°C.
Analysis calculated for CygHyyNoCly: ' : Cc, 59.40; H, 7.98; N, 9.24; Cl, 23.38 ; 5 Found C, 59.37; H, 7.98; N, 9.03; Cl, 23.09. . : 2-Methyl-2,7-diazaspiro(4.4]nonane Dihydrochloride
A solution of 7-benzyl-2-methyl-2,7-diazaspiro (4.4])nonane dihydrochloride in 150 ml of methanol with 1.0 g 20% palladium on carbon catalyst was hydrogenated at 4.5 x 10° Pa for two days. After filtration, the filtrate was concentrated to a thick : oo syrup which crystallized on addition of acetonitrile to give 11.5 g¢ of 2-methyl-2,7-dlazaspiro(4.4]nonane dihydrochloride, softened at 164°C and melted at 168-170°C.
Analysis calculated for CqHygN,Cly: c, 45.08; H, 0.51; N, 13.15; Cl, 33.27
Found C, 45.24; H, B.77; N, 13.18; Cl, 33.26.
EXAMPLE L
2-Ethyl-2,7-diazaspiro(4.4]nonane Dihydrochloride
Ia 2-Ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione
A suspension of 24.3 g (0.10 mmole) 3-ethoxy- carbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester in an excess of 2 N sodium hydroxide, was stirred } three hours at room temperature, acidified with dilute hydrochloric acid, and evaporated to dryness in vacuo. The product, 3-carboxy-5-oxo-3- pyrrolidineacetic acid, was taken up in isopropyl alcohol, separated from insoluble sodium chloride by filtration, concentrated to a syrup and dissolved in g 100 ml 70% ethylamine. The solution was gradually heated in an oil bath up to 230°C allowing volatiles to distill and then maintained at 230-240°C for ten minutes. After cooling, the product was crystallized
. : -4u- . from isopropyl alcohol to afford 10.1 g of 2-ethyl-2,7-diazaspiro{4.4]nonane-1,3,8-trione, mp 168-169°C. :
Analysis calculated for CgH,,N,0;:
Cc, 55.09; H, 6.17; N, 14.28 -
Found C, 55.03; H, 5.84; N, 14.01. 2-Ethyl-7-benzyl-2,7-diazaspiro{4.4]nonane-1,3,8- trione
A suspension of sodium hydride (2.20 g of 60% oil suspension (0.055 mole) washed with toluene) in
S50 ml N,N-dimethylformamide was treated gradually . © with a solution of 10.0 g (0.051 mole) 2-ethyl-2,7- diazaspiro(4.4)nonane-1,3,8-trione in 100 ml
N,N-dimethylformamide. After stirring 15 minutes, there was added dropwise 6.4 ml (0.055 mole) benzyl ) chloride and the mixture was stirred overnight, concentrated in vacuo and shaken with water-methylene chloride. The organic layers were dried, evaporated, and the product crystallized from toluene-hexane to afford 11.1 g of the title compound, mp 125-126.5°C.
Analysis calculated for C,6H18N203 Co
Cc, 67.11; H, 6.34; N, 9.79 rN Found C, 67.41; H, 6.33; N, 9.79. : 2-Benzyl-7-ethyl-2,7-diazaspiro[4.4]nonane
Dpihydrochloride
A solution of 11.0 ¢g {0.038 mole) 2-ethyl-7- benzyl-2,7-diazaspiro(4.4]nonane~1,3,8-tricne in 100 ml tetrahydrofuran was added dropwise to a suspension of 6.00 g (0.158 mole) lithium aluminum
JO hydride in 250 ml tetrahydrofuran. After stirring overnight, the mixture was refluxed one hour, cooled, : and treated dropwice with 6 ml water, 6 ml 15% sodium ; hydroxide, and 18 ml water. Inorganic solids were separated by filtration and the filtrate was : 35 concentrated, taken up in ether, dried with magnesium
. . . ~-41~ ’ . . sulfate, and reevaporated. The resulting syrup was dissolved in isopropyl alcohol and treated with excess hydrogen chloride in isopropyl alcohol to afford 9.63 g of the title compound, mp 196~-198°C (dec). .
Analysis calculated for C,gHogNCL5 c, 60.56; H, 8.26; N, 8.83; Cl, 22.35
Found C, 60.51; H, 8.08; N, 8.69; Cl, 22.26. 2-Ethyl-2,7-diazaspiro[4.4]nonane Dihydrochloride
A solution of 9.5 g (0.03 mole) 2-benzyl-7- ethyl-2,7-dlazaspiro{4.4]nonane dihydrochloride in ’ 100 ml methanol was hydrogenated with 1.0 g 20% "palladium on carbon catalyst at 4.5 Xx 10° Pa for 22 hours. After filtration, the solution was concentrated to a syrup and crystallized from acetonitrile to afford 6.7 g of the title compound, mp 168~-172°C.
Analysis calculaterl for CgHygN,Cly:
Cc, 47.58; H, 8.86; N, 12.33; C1, 31.21
Found C, 47.70; H, 8.58; N, 12.39; Cl, 30.92.
EXAMPLE M ro 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3- guinolinecarboxylic Acid 2,3,4,5-Tetrafluorobenzoylacetic Acid,, Ethyl Ester
To 25.2 g (0.117 mol) of sodium 2,3,4,5-tetra- fluorocbenzoate, prepared as a dry powder from 2,3,4,5-tetrafluornbenzolic acid (J. Org. Chem., 29, 2381 (1961)] and aqueous sodium hydroxide with concentration to dryness, was added 400 ml of dry ether and the suspnnsion was cooled to 0°C. Slowly,
To 25 ml (= 2.5 equivalents) of oxalyl chloride in 50 ml of ether was added and the mixture brought to room : temperature where it was maintained for 2.0 hours.
It was filtered and concentrated to remove low
. CL -42- : : boiling impurities. The residue was dissolved in 100 ml of ether ans placed in an addition funnel.
Meanwhile, 2.9 g (0.119 mol) of magnesium turnings were treated with 100 ml of absolute ethanol and 0.3 ml of carbon tetrachloride. To this mixture was added 18.6 ml (0.12 mol) of diethyl malonate in 75 ml of ether at a rate to keep the temperature just below reflux. Whan addition was complete, the reaction was refluxed for two hours. At -20°C,. the atheral acid chloride was slowly added. When addition was complete, the reaction was brought to ] 0°C over 18 hours. The mixture was poured into ro dilute hydrochloric acid and was extracted into dichloromethane which was dried (MgSO, ) and concentrated. The residue was then treated with 340 mg of p-toluenasulfonlc acid in 600 ml of water at 100°C for two hours with rapid stirring. The oil was extracted into dichloromethane, dried’ (MgSO,) and } concentrated. The residue was purified by column chromatography (silica gel, using toluene:hexane: ether, 4:5:1), to give 18.5 g of a reddish oil. This material was tritucated with pentane to give 10.2 g of 2,3,4,5-tetrafluorobenzoylacetic acid, ethyl ro ester, mp 49-51°C. 2-(2,3,4,5-Tetrafluorobenzoyl)-3-cyclopropvlamino- acrylic Acid, Ethyl Ester
To 10.2 g (38.5 mmol) of the 2-(2,3,4,5-tetra- fluorobenzoylacetis acid, ethyl ester was added 8.4 g {57.0 mmol) of triathylorthoformate and 9.3 g (91.5 mmol) of acetic anhydride. The mixture was heated to 150°C for two hours and was then placed under high vacuum at 75-85°C for one hour. The residue i dissolved, without purification, in 100 ml of isopropyl alcohol and treated with 2.4 ml of cyclopropylamine. The reaction was allowed to stand overnight. It was concentrated and purified by
. , ' -u §- . column chromatography (silica gel 70-200, using hexane:chloroform: isopropyl alcohol, 80:15:5). The product off the columh was recrystallized from pentane to give 6.16 g of 2-(2,3,4,5-tetrafluoro- benzoyl) -3-cyclopropylaminoacrylic acid, ethyl ester, mp 63-64°C. 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydrc-4-oxo-3- : quinolinecarboxylic Acid
To 2.0 g (6.0 mmol) of the 2-(2,3,4,5-tetra- f£luorobenzoyl)-3-cyclopropylaminoacrylic acid, ethyl aster in 60 ml of dry dioxane was added 0.29 g of oo sodium hydride 50% dispersion) that was prewashed with pentane. The 3odium hydrlde was delivered in 10 ml of dry tetrahydrofuran at 0°C. When evolution of hydrogen began t> slow, the mixture was refluxed for two hours. It was concentrated, and the residue taken up in dichloromethane, which was water extracted, dried (M3S0,), and concentrated. The residue was purified by column chromatography (silica gel 70-200 mesh, using chloroform: hexane: isopropanol, 4:5:1) to give 0.95 g of the l-cyclopropyl-6,7,8- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic ro acid, ethyl ester, mp 168-169°C. This material was : dissolved in acetic acid at 100°C and was treated with 10 ml of 0.5 N hydrochloric acid for 2.5 hours.
The mixture was cooled and water added. The solids ; were then collected to give 0.7 g of
L 1-ecyclopropyl-1l,4-dihydro~4-oxo~6,7,8~trifluoro-3- quinolinecarboxylic acid, mp 226-228°C. oH
J
C- : -44- oC | EXAMPLE N 7-Chloro-l-cyclopropyl=-6-fluoro-1,4-dihycro-4-oxo= 1,8-naphthyridine-3-carboxylic Acid 4-[6-(Cyclopropylamino)-3-nitro-2-pyridinyl)-1- . piperazinecarboxylic Acid, Ethyl Ester } A solution of 126.0 g (0.4 mole) of 4-(6-chloro- j-nitro-2-pyridinyl)-l-piperazinecarboxylic acid, ethyl ester (prepared as described in European Patent
Publication No. 9425), 76.1 g (0.5 mole) of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 28.6 g (0.5 mole) of cyclopropylamine and 500 ml of absolute
Co ethanol was stirred at room temperature for 48 hours.
The solution was then heated at reflux for four hours and concentrated in vacuo. The residue was partitioned between chloroform and water. The chloroform layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to give 64.0 g of the title compound, mp 100-103°C. 4-[6-(Acetylcyclopropylaminoc)-3-nitro-2-pyridinylj-1- piperazinecarboxylic Acid, Ethyl Ester
A solution of 64.0 g (0.19 mole) of 4-(6-(cyclo- ‘ propylamino)-3-nitro~2-pyridinyl]-l-piperazine- carboxylic acid, ethyl ester, 115 ml of acetic anhydride and 115 ml of acetic acid was heated on a steam bath for 36 hours. The solvents were removed in vacuo, the residue was triturated with a mixture of ethanol and toluene which was also evaporated in vacuo to give 68.3 g of the title compound, mp : . 30 90-93°C. ~~
Co 4-[6-(Acetylcyclopropylamino)-3-amino-2-pyridinyl)-1- : piperazinecarboxylic Acid, Ethyl Ester
A mixture of 17.0 g (45 mmole) of 4-(6-(acetyl- cyclopropylamino)-3-nitro-2-pyridinyl-l-piperazine
} R -45- oo carboxylic acid, ethyl ester, 1.5 g of Raney nickel and 180 ml of absolute ethanol was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for approximately 24 hours. The catalyst was removed by filtering through Celite and the solvent removed in vacuo to give 15.2 g of the title compound, mp 149-150°C. 2-[4-(Ethoxycarbonyl)-1-piperazinyl]-6-(acetylcyclo= propylamino)-3-pyridinediazonium Tetrafluoroborate
A solution of 20.8 g (60 mmole) of 4-(6-acetyl- cyclopropylamino)-3-amino-2-pyridinyl]-1-piperazine a carboxylic acid, ethyl ester, 44 ml of ethanol and 27 ml of 48% tetrafluoroboric acid was cooled to 0°C and treated dropwise with a solution of 4.56-g (66 mmol) of sodium nitrite in 8 ml of water under a nitrogen atmosphere keeping the temperature 0-5°C.
After the adiition was complete, the reaction was } stirred at 0-5°C for one hour and treated with 150 ml of anhydrous ether keeping the temperature helow 10°C. The solid was removed by filtration, the precipitate was washed with ethanol/ether (1:1), ether and dried in vacuo to give 24.5 g of the title a compound, mp 100-105°C (dec). 4~[6-(Acetylcyclopropylamino)-3-fluoro-2-pyridinyl]- l-piperazinecarboxylic Acid, Ethyl Ester
To 800 ml of refluxing toluene was added in : portions, as a solid, 46.2 g (0.1 mole) of 2-[4-(ethoxycarbonyl)-l-piperazinyl]-6-acetylcyclo- propylamino)=-3-pyridinediazonium tetrafluoroborate.
After the addition was complete, the reaction was refluxed for ten minutes and the toluene was decanted from the insoluble precipitate. The toluene was evaporated in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was washed with 5% aqueous sodium bicarbonate, water,
dried over magnesium sulfate, and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material : 5 in chloroform and water. The organic layer was . washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, cvaporated in vacuo and the residue was chromatngraphed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction was also a viscous oll which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps. { 4-[6-(Cyclopropylaminc)=-3-fluoro-2-pyridinyl]}-1- piperazinecarboxylic Acid, Ethyl Ester
A solution of 21.9 g (63 mmole) of 4-[6-(acetyl- cyclopropylamino)-3-fluoro-2-pyridinyl)-1l-piperazine- carboxylic acid, ethyl ester, 170 ml of 15% hydrochloric acid and 235 ml of methanol was refluxed for one hour and allowed to stir at room temperature for 18 hours. The methanol was removed in vacuo and the aqueous .acid was made basic with 1.0 N sodium hydroxide to pH 10.5. The mixture was extracted with “5 chloroform, the chloroform layer washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 17.6 g of the title compound, mp 68-70°C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1- piperazinyl)-1,8-naphthyridine-3-carboxylic Acid
Route A [[Cyclopropyl[6-[4-(ethoxycarbonyl)-l-piperazinyl]- 5-fluoro-2-pyridinyljamino]methylene]propan:zdioic
Acid, Diethyl Ester
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclo- propylamino)-3-fluoro-2-pyridinyll]l-l-pipaerazine carboxylic acid, ethyl ester, 2.7 g (12.3 mmole) of diethyl (ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed : in vacuo and the residue was chromatograhed over : : 5 silica gel eluting with chloroform/ethyl acetate . (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further . purification.
Ethyl 1-Cyclopropyl-6-£luoro-1,4-dihydro-4-oxo-7- 4-(ethoxycarbonyl)-l-piperazinyl]-1,8-naphthyridine- 3-carboxylate ro A solution of 2.3 g (4.8 mmole) of [[cyclo~ propyl[6-(4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro- 2-pyridinyl}amino)methylene]propanedioic acid, diethyl ester, in 15 ml of acetic anhydride was treated dropwise with 5 ml of 98% sulfuric acid keeping the temperature 55-60°C. When the addit.on was complete, the reaction was stirred for one hour and poured onto 50 g of ice. The aqueous suspension was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was a triturated with several portions of ethanol/toluene which were also removed in vacuo to give 0.4 g of the title compound, mp 184-186°C. An additional 0.5 g of product could be obtained by concentrating the original aqueous fraction, mp 184-186°C. 1-Cyclopropyl-6-£luoro=1,4-dihydro-4-oxo-7- (1-piperazinyl)-1,8-naphthyridine-3-carboxylic Acid ; 30 A suspension of 0.7 g (1.6 mmole) of ethyl l-cyclopropyl-6~fluoro=-1,4-dihydro-4-oxo-7-{4- (ethoxycarbonyl)-l-piperazinyl]-1,8-naphthyridine-3-
I carboxylate, 6 ml cf 10% aqueous sodium hydroxide and : 2 ml of ethanol was refluxed for three hours. The reaction was filterad through a fiber glass pad to
. clarify and acidified to pH 1.5 with 6.0 M hydrochloric acid and lyophilized. The residue was dissolved in 10 ml of ammonium hydroxide and the solution concentrated in vacuo. The precipitate which formed was removed by filtration, washed with aqueous ethanol, ether, and dried in vacuo to give . 0.04 g, mp 274-276°C.
Route B 4-[6-[Cyclopropyl(2,2-dimethyl-4,6-dioxo-1,3-dioxan
S-ylidine)amino]~-3-fluoro-2-pyridinyl]-1-piperazine- carboxylic Acid, Ethyl Ester rr A solution of 17.6 g (57 mmole) of 4-[6-(cyclo- : propylamino)-3-fluoro-2-pyridinyl])-l-piperazine carboxylic acid, ethyl ester, 11.6 g (63 mmole) of 5~(methoxymethylene)-2,2-dimethyl-1,3-dioxane~-4,6- dione and 250 ml of methanol was stirred at room ; : temperature for four hours. The solid was removed by filtration, washed with methanol, ether and dried in vacuo to give 17.6 g of the title compound, mp 177-178°C. - 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7~[4- fg (ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine- 3-carboxylic Acid :
A solution of 17.0 g (37.0 mmole) of 4-[6~(cyclopropyl-(?,2-dimethyl-4,6-dioxo-1,3-dioxan~
S-ylidene)amino)-3-fluoro-2-pyridinyl]-1-piperazine- : carboxylic acid, ethyl ester in 125 ml of acetic
Co anhydride was treated dropwise with 35 ml of 98% sulfuric acid keeping the temperature 50-60°C. When the addition was complete, the reaction was stirred : for two hours and poured onto 600 g of ice. The ; mixture was stirred for one hour and the resulting i precipitate was removed by filtration, washed with water, and dried in vacuo to give 10.2 g of the title : 35 compound, mp 277-279°C. .
- . ’ ’ “N= . 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7= , {1-piperazinyl-1,8- 8-naphthyridine-3-carboxylic Acid
A solution of 10.2 ¢ (25 mmole) of l-cyclo- . propyl-6-fluoro-1,4-dihydro-4-oxo-7-[4- (ethoxy carbonyl) -l-piperazinyl]-1,8-naphthyridine-3- . carboxylic acid, 100 ml of 10% aqueous sodium hydroxide and 40 ml of ethanol was refluxed for three . hours. The solution was concentrated to 125 ml and acidified to pH 7.3 with glacial acetic acid. The resulting precipitate was removed by filtration, oo washed with 50% aqueous ethanol, ether and dried in vacuo to give 7.2 g of the title compound, mp ,~ 274-276°C. 1-Cyclopropyl-6-£luoro-1,4-dihydro-7-hydroxy/-4-0Xo=- 1,8-naphthyridine~3-carboxylic Acid
To a solution of 2 ml of 70% nitric acid in 10 ml of 98% sulfuric acid wis added in portions 1.0 ¢ (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7-(1l-piperazinyl)-1,8~naphthyridine-3- carboxylic acid, keeping the temperature between 25-30°C. The resulting solution was stirred at room temperature for 18 hours and poured onto 40 g of ice. pe The mixture was stirred at room temperature for 24 : hours, concentrated in vacuo, the pH adjusted to 12 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to pH i 3.5 with 6.0 M hydrochloric acid, the resulting precipitate removed by filtration, washed with water then ether and dried in vacuo to give 0.23 g of the title compound, mp 325-327°C. 7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic Acid oo A suspension of 0.19 g (0.72 mmole) of 1-cyclopropyl-6-flroro-1,4-dihydro-7-hydroxy-4-oxo-
. ‘ -50- SE : 1,8~naphthyridine-3-carboxylic acid in 2 ml of phosphorus oxychloride was heated at reflux for: one-half hour. The resulting solution was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with ice water and : the resulting solid was removed by filtration, washed with water, then ether, and dried in vacuo to give oo 0.11 g of the title compound, mp 209-212°C.
EXAMPLE O
2-Nitro-3,4,5,6-tetrafluorobenzoyl Chloride
A solution of 6.7 ¢g (28 mmoles) of 2-nitro- — 3,4,5,6-tetrafluorobenzoic acid [Tetrahedron, 23, 4719, (1967)], 3.8 g (30 mmoles) of oxalyl chloride and 50 ml of dichloromethane was treated with four drops of N,N-dimethylformamide and stirred at room temperature overnight. The solvent was removed and . the residue was usvi as is without further purification.
EXAMPLE P
2-Nitro-3,4,5,6-tetrafluoro-B-oxobenzenepropanoic
Acid, Ethyl Ester
To a solution of 7.5 g (56.8 mmoles) of malonic . ' half acid ester in 125 ml of dry tetrahydrofuran was added 20 mg of 2,2'-bipyridyl. The reaction mixture was cooled to -30°C and treated dropwise with 24 ml (57.6 mmoles) of 2.4 N n-butyl lithium. The reaction was then allowed to warm to -5°C where a second, equivalent, 24 ml (57.6 mmoles), of 2.4 N n-butyl : lithium was added until a light pink color persisted ; 30 for 15 minutes. Tre reaction mixture was then cooled to -75°C and treated dropwise with a solution of ! 7.2 g (28 mmoles) of 2-nitro-3,4,5,6-tetrafluoro-
Hd benzoyl chloride in 15 ml of tetrahydrofuran. The reaction was stirred at -75°C for one hour, warmed to 35°C, and quenched by pouring onto a solution of i
. , Co + =ol- : 28 ml of concentratnd hydrochloric acid in 50 ml of jce water. The reaction was extracted with dichloromethane (3 x 200 ml), the organic layer was washed with 5% aqueous sodium bicarbonate § (2 x 100 ml), and with 1.0 M hydrochloric acid " (1 x 100 ml), dried (MgSO, ), and evaporated in vacuo to give 7.3 g of thn title compound which was used for the ensuing step without further purification.
EXAMPLE Q
Ethyl 1-Cyclopropyl-5-nitro-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylate — A solution of 6.8 ¢ (22 mmoles) of 2-nitro- 3,4,5,6-tetrafluoro-p-oxobenzenepropanoic acid, ethyl ester, 4.9 g (33 mmoles) of triethylorthoformate and 50 ml of acetic anhydride was heated at reflux for two hours. The solvent was removed in vacuo and then in high vicuo at 80°C for 1.5 hours. The residue was dissolved in 25 ml of t-butanol and treated with : 1.43 g (25 mmoles) of cyclopropylamine. The mixture was heated at 45°C for four hours, cooled to room temperature and treated dropwise with a solution of 2.47 g (25 mmoles) of potassium t-butoxide in 25 ml po of t-butanol. The reaction was heated at 60°C for : six hours and the solvent was removed in vacuo. The residue was dissolved in chloroform, washed with water, dried (Mgso,), and evaporated in vacuo. The residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 1.9 g of the title compound as an oll which was used without further purification.
EXAMPLE R
Ethyl 5-Amino-l-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylate
A suspension of 1.9 g (5.3 mmoles) of ethyl 1-cyclopropyl-5-nitro-6,7,8-triflucro-1,4-dihydro-4-
oxo-3-quinolinecarboxylate, 0.5 g of Raney nickel and 100 ml of ethanol was shaken in a hydrogen atmosphere at pressures of 42.5-50 psi and temperatures of : 24-26.5°C for ten hours. The mixture was filtered through Celite and some insoluble product was dissolved in tetrahydrofuran with filtration. The ) combined filtrates were evaporated in vacuo and the } residue was chromatographed on silica gel to give 600 mg of the title compound, mp 223-225°C.
EXAMPLE S
5-Amino-1l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- - oxo-3-quinolinecarboxylic Acid
A solution of 0.5 ¢g (1.5 mmoles) of ethyl
S-amino-l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4~ oxo-3-quinolinecarboxylate, 5 ml of 6.0 M hydrochloric acid and 5 ml of ethanol was heated at reflux for two hours. The solvent was removed in vacuo to give 430 my of the title compound, mp 269-271°C.
EXAMPLE T
3-Chloro-2,4,5-trifluoro-6-nitrobenzoic Acid ~ To a solution of 42.1 g (200 mmol) of 3-chloro- : 2,4,5-trifluorobenzoic acid (E.P.O0. 0 183 129) in 100 ml of sulfuric acid was added concentrated nitric acid (50 ml) dropwise such that the reaction temperature stayed below 40°C. The reaction mixture was heated at 60°C for 18 hours, then poured cautiously onto 500 g of ice water. The aqueous solution was extracted with ether, and the ether extracts were washed with water, dried over magnesium : sulfate, and concentrated to give 26.5 g of 3-chloro-2,4,5-tril fuoro-6-nitrobenzoic acid.
EXAMPLE U
3-Chloro-2,4,5-trifluoro-6-nitrobenzoyl Chloride
To a suspension of 25.6 g (100 mmol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid in 75 ml of dichloromethane was added 14.0 g (110 mmol) of . oxalyl chloride. This mixture was treated with four drops of dry N,N-dimethylformamide, and the rapidly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 27.0 g of the title compound which was used without purification in the next step.
EXAMPLE V
Ethyl (3-Chloro-2,4,5-trifluoro-6-nitro)-pf-oxo- phenylpropanoate
To 26.4 g (200 mmol) of malonic half ethyl ester in 500 ml of dry tetrahydrofuran at -35°C was added ’ 91 ml of n-butyllithium (2.2 M, 200 mmol) dropwise.
A catalytic amount of bipyridyl (10 mg) was added, and the suspension was warmed to -5°C. Another . 20 equivalent of n-butyllithium (91 ml, 200 mmol) was added until the indicator turned pink. The mixture was cooled to -78°C, and a solution of 27 g of - 3-chloro-2,4,5-trifluoro-6-nitrobenzoyl chloride in : 50 ml of tetrahydrofuran was added dropwise. The . reaction mixture was kept at ~-78°C for one hour, then warmed to -35°C and poured into a mixture of ice water (400 ml) and concentrated hydrochloric acid (17 ml). The solution was extracted with dichloromethane; the extracts were combined and ! 30 washed with 5% sodium bicarbonate, 2 M hydrochloric acid, and water. The dichloromethane was dried over magnesium sulfate and concentrated to give 27.4 g of the title compound.
. , © =24-
EXAMPLE W
Ethyl 2-(3-Chloro-2,4,5-trifluoro-6-nitrobenzoyl)=3=- ethoxyacrylate
To 27.4 g (84.1 mmol) of the ethyl (3-chloro-2,4,5-trifluoro-6-nitro)-p-oxophenyl propanocate was added 18.7 g (126 mmol) of triethyl orthoformate and 100 ml of acetic anhydride. The" : mixture was refluxed for two hours, then cooled to 80°C, and concentrated to glve 31.5 g of the title compound. o EXAMPLE Y pe ‘Ethyl 8-Chloro-1l-cyclopropyl-6,7-difluoro-1,4- dihydro-5-nitro-4-oro-3-quinolinecarboxylate :
The ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitro- benzoyl) -3-ethoxyacrylate prepared in the previous step was dissolved in 200 ml of t-butanol and treated with 5.0 g (88 mmol) of cyclopropylamine. The reaction mixture was warmed to 45°C and stirred for three hours at that temparature. The solution was then cooled to room temperature and treated with a slurry of 9.4 g (84 mmol) of potassium t-butoxide in 50 ml of t-butanol. The mixture was stirred at 60°C pu for five hours; the suspension was filtered, and the : solid was washed with water and ether to give 21.7 g of the title compound. . EXAMPLE 2
Ethyl 5-Amino-8-chloro-1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylate
A suspension of 21.7 g (58.2 mmol) of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5- nitro-4-oxo-3-quinolinecarboxylate in 300 ml of ethanol and 300 ml of tetrahydrofuran was . catalytically reduced using 3 g of Raney nickel in a hydrogen atmosphere of 50 psi. After twelve hours + 35 the mixture was diluted with dichloromethane and the
. _ a ) catalyst was removed by filtration. The filtrate was . concentrated to give 17.2 g of the title compound.
EXAMPLE AA
5-Amino-8-chloro-l-cyclopropyl-6,7-difluoro-1,4- : 5 dihydro-4-oxo-3-quinolinecarboxylic Acid
A suspension nf 17.2 g (50.2 mmol) of ethyl } 5~amino-~-8-chloro-1-cyclopropyl-6,7-difluoro-1,4- dihydro~-4-oxo-3-quinolinecarboxylate in 100 ml of 6 M hydrochloric acid was refluxed for three hours. The mixture was cooled to room temperature, and the solids were filtered, washed with water and ether, — and dried to give 14.2 g of the title compound. : Using the same sequence of reactions the following compounds could be prepared: .
S-amino-8-bromo-l-cyclopropyl-6,7-difluoro-1, 4- dihydro~-4-oxo-3-quinolinecarboxylic acid; 5-amino-l~cyclopropyl=-6,7-difluoro-8-trifluoro- methyl-1l,4-dihydro~4~oxo-3-quinolinecarboxylic acid; 5-amino-l-cycloprepyl=-6,7-difluoro-1,4-4dihydro-8- methoxy-4-oxo-3-quinolinecarboxylic acid;
S5-amino-l-cyclopropyl-6,7-difluoro-1,4-dihydro-8- hydroxy-4-oxo-3-quinolinecarboxylic acid; 5,8-diamino~1~-cyclopropyl-6,7~difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid; . 5-amino-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid; and
S5-amino-7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8~-naphthyridine-3-carboxylic acid.
EXAMPLE BB
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-(methyl- amino) -4-oxo-3-quinolinecarboxylic Acid
A solution of 5.9 g (20 mmol) of S~amino-1- . cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, 20 ml of trifluoroacetic anhydride, and 100'ml of trifluoro acetic acid was
: , - -56= stirred at room temperature overnight. The solution was evaporated to dryness and the residue was triturated with water and filtered to give 7.55 g of i 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5- ((trifluoroacetyl)amino}-3-quinolinecarboxylic acid, mp 188°C.
A solution of 5.53 ¢ (14.0 mmol) of the ; trifluoroacetyl intermediate above, 55 ml of DMF and 1.42 g (30.9 mmol) of 50% sodium hydride was stirred at 50-55°C for 35 minutes. To this mixture was added 2.8 ml (45 mmol) of lodomethane with continued stirring at 50-55°C for two hours and for three hours a at room temperature, The reaction mixture was evaporated and the residue was trlturated with water and filtered. The solid was dissolved with 60 ml of acetic acid and 30 ml of 6N HCl was added and the solution was heated under reflux for two hours. The solution was concentrated and the residual oil was treated with isopropanol to give 3.0 g of the title } 20 compound, mp 205-207°C.
In a similar manner, the following compounds . were prepared: 8-chloro-l-cyclopropyl-6,7-difluoro- 1,4-dihydro-5~(methylamino)-4-oxo-3-quinoline- ba © carboxylic acid; 8-bromo-1-cyclopropyl-6,7-difluoro- ' 25 1,4-dihydro-5-(methylamino)-4-oxo~3-quinoline- carboxylic acid; and l-cyclopropyl-6,7-difluoro-8- trifluoromethyl-1,4~-dihydro~5=-(methylamino)-4-oxo~-3-
TL quinolinecarboxylic acid. : EXAMPLE CC 1-Cyclopropyl-6,7,8-trifluoro-~1,4~-dihydro-5-dimethyl~- amino-4-oxo-3-quinolinecarboxylic Acid ot 2-(Dimethylamino)=-3,4,5,6-tetrafluorobenzoic Acid
A solution of 10.0 g (41.8 mmol) of 2-nitro- 3,4,5,6-tetrafluorobenzoic acid, 10 ml of 37%
. ’ ' sors formaldehyde solution, 1.5 g of Raney nickel and 100 ml of ethanol was hydrogenated until TLC indicated absence of starting material. The reaction mixture was filtered and evaporated to an oil which was recrystallized with ethyl acetate-hexane to give 2.15 g of the title compound, mp 110-112°C. An additional 2.28 g, mp 90~100°C was isolated from the filtrate. 2-(Dimethylamino)-3,4,5,6-tetrafluorobenzoyl Chloride
To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoic acid and ~ 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF were added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification. - 2-(Dimethylamino)-3,4,5,6-tetrafluoro-g-oxobenzene- propanoic Acid, Ethyl Ester
To a solution of 4.76 ¢g (36 mmol) of malonic acid monoethyl ester and 75 ml of THF at -35°C was : added 25 ml (40 mmol) of 1.5N n-butyl lithium ‘ solution. The remalning.25 ml (40 mmol) of 1.5N butyllithium solution was added at 0°. After cooling to -78°C, a solution of the 4.8 g of 2-(dimethyl- amino)-3,4,5,6-tetrafluorobenzoyl chloride in 50 ml of THF was added tc the dilithlo malonate over a 15 minute period. The reaction mixture was stirred for 1.75 hours while the temperature came up to -30°C.
The reaction mixture was poured into ice, water, and 50 ml of 1N HCl. The mixture was extracted with ether and the ether extract was washed with H,0, 5%
NaHCO, and HCl. After drying over MgsoO, the ether solution was concentrated to 4.4 g of oil product.
NMR spectra indicated the desired product.
oo -58- : 2-(Dimethylamino)-a- (ethoxymethylene)-3,4,5,6-tetra- fluoro-p-oxobenzenepropanoic Acid, Ethyl Ester
A solution of 4.4 g (14.3 mmol) of the crude : ketoester, 3.57 ml (21.5 mmol) of triethylortho formate, and 25 ml of acetic anhydride was heated ) under reflux for two hours. The solution was evaporated to 5.2 g of oil which was used in the next step without purification. . a-[ (Cyclopropylaminc)methylene]-2-(dimethylamino)- 3,4,5,6-tetrafluoro-p-oxobenzenepropanoic Acid,
Ethyl Ester so To a solution of 5.2 g (14.3 mmol) of the above crude product in 50 ml of t-butanol was added 1.2 ml (17 mmol) of cyclopropylamine. The reaction solution was stirred for 18 hours at room temperature. The reaction mixtura was filtered to give 0.12 g of the title compound, mp 122-124°C. TLC of the filtrate showed it to be the same as the solid. 5- (Dimethylamino)-1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic Acid
To the above filtrate was added 1.7 g (15 mmol) so of potassium t-butoxide and the mixture was stirred ' at room temperature for 1.5 hours. TLC showed no change in reactants. An additional 1.7 g (15 mmol) of potassium t-butoxide was added and the reaction } mixture was heated at 50-55°C for two hours. After
TLC indicated the rnaction was complete, the solution was evaporated to 4 g of an oil. This oil was heated with 100 1 6N HCl for three hours on the steam bath.
The solution was evaporated and the residue was recrystallized from isopropanol to give 0.3 g of the : title compound, mp 160-163°C. An additional 1.0 g of solid was added from the filtrate.
Following the same sequence, the following compounds were prepired: B8-chloro-l-cyclopropyl-6,7-
' , -5Y- difluoro-1,4-dihydro-5-dimethylamino-4-oxo-3- quinolinecarboxylic acid, and 8-bromo-l-cyclopropyl- 6,7-difluoro-1,4-dihydro-5-dimethylamino-4-oxo-3- quinolinecarboxylic acid.
EXAMPLE DD
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methoxy- 4-oxo-3-quinolinecarboxylic Acid
To 22.4 g (100 mmol) of the 2-methoxy-3,4,5,6~ tetrafluorobenzoic acid prepared as in (J. Fluorine
Chem., 28, 361 (1985)] was added 400 ml of tetrahydrofuran, 1 rl of dimethylformamide, and 13 ml
Pa of oxalylchloride. The acid chloride mixture was concentrated, diluted with 100 ml of tetrahydrofuran, and added to a solution of the dilithio anion of malonic acid monoethylester (200 mmol) in 800 ml of tetrahydrofuran at -70°C. The reaction was stirred for one hour at ~30°C, poured over ice and dilute hydrochloric acid and taken into dichloromethane.
The product was isolated by an extraction at pH 7, followed by drying the dichloromethane (Mgs0,) and concentration. The crude product was then treated neat with 2.5 equivalents of triethylorthoformate and
So 2.8 equivalents of acetic anhydride at 150°C for two ' hours: The mixture was concentrated and at room : temperature a slight excess of cyclopropylamine (6.0 g) was added in 150 ml of t-butanol. The mixture was stirred overnight. To this mixture was added 11.3 g of potassium t-butoxide and the temperature brought to 50°C. The mixture was concentrated after 18 hours and the residue treated with 100 ml of acetic acid and 100 ml of 4N hydrochloric acid. From this mixture after four hours at 100°C, 12.7 g of the title compound precipitated.
In a similar manner, the following compounds were prepared: 8-chloro-l-cyclopropyl-6,7-difluoro-
1, 4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 8-bromo-l-cyclopropyl-6,7-difluorc-1,4- dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-5- methoxy-4-oxo-3-quinolinecarboxylic acid; and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4- : oxo-3-quinolinecarboxylic acid.
EXAMPLE EE
1-Cyclopropyl-6,7,8~trifluoro-1,4-dihydro-5-hydroxy- 4-oxo-3-quinolinecarboxylic Acid
To 1.5 g of l-cyclopropyl-6,7,8~trifluoro-1,4- pe dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid : was added 25 ml of hydrogen bromide in acetic acid (32%). The mixture was stirred at room temperature for 16 hours and concentrated to dryness. The residue was triturated with water:ethanol and filtered to give 1.15 g of the title compound.
In a similar manner the following compounds were prepared: B8-chloro-l-cyclopropyl-6,7-difluoro-1,4- dihydro-5-hydroxy-4-oxo-3-quinolinecarboxylic acid; 8-bromo-1l-cyclopropyl-6,7~difluoro-1,4-dihydro-5- hydroxy-4-oxo-3-quinolinecarboxylic acid;
Se l-cyclopropyl-6,7-difluoro-8-trifluoromethyl-5- . hydroxy-4-oxo-3-quinoclinecarboxylic acid and l-cyclopropyl-6,7-difluoro-1,4-dihydro-5-hydroxy-4- oxo-3-quinolinecarboxylic acid.
EXAMPLE 1 1-Ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonyl- amino) -1l-pyrrolidinylj-4-oxo-1,4-dihydrcquinoline-3- carboxylic Acid
A suspension of 3.02 g (10 mmole) of l-ethyl-5-amino-6,7,8-trifluoro-4-oxo~-1,4~-dihydro quinoline-3-carboxylic acid, 2.79 g (15 mmole) of 3-(t-butoxycarbonylamino) pyrrolidine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is
. , -61-~ refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ’ ether, and dried in vacuo to give l-ethyl-5-amino- 6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1- pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. : EXAMPLE 2 1-Ethyl-5-amino-6,8-difluoro-7-(3-amino-1- pyrrolidinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
Acid Hydrochloride — A near solution of 4.5 g (10 mmole) of l-ethyl- 5-amino-6,8-difluoro-7-{3-(t-butoxycarbonylamino)-1- pyrrolidinyl]-4-oxo-1,4-dLhydroquinoline-3-carboxylic acid, 10 ml of 6.0 M hydrochloric acid and 100 ml of glacial acetic acid is heated at 60°C for four hours and then stirred at room temperature for 18 hours.
The solvent is removed in vacuo, the residue triturated with ethanol/ether (1:1), filtered, washed : with ether, and dried in vacuo to give the title compound. = EXAMPLE 3 te 1-Ethyl-5-amino-6,8~-difluoro-7-[3-f{ethylamino)methyl- 1-pyrrolidinyl)]-4-oxo-1,4-dihydroquinoline-3- carboxylic Acid
A suspension of 3.02 g (10 mmole) of l-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1, 4-dihydro quinoline-3-carboxylic acid, 1.93 g (15 mmole) of
N-ethyl=3-pyrrolidinemethanamine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room
BN temperature and the pracipitate is removed by ! filtration, washed vith acetonitrile, ether, and dried in vacuo to give l-ethyl-S5-amino-6,8-difluocro-
* » : 0s" . 7-[3-(ethylamino)methyl-1-pyrrolidinyl)]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid.
The following compounds may be prepared from 1-ethyl-5-amino~6,7,8-trifluoro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid and the desired amine or protected amine using the method above: ; i 1-ethyl-5-amino-6,8-difluoro-7-[3-(aminomethyl)-1- pyrrolidinyll-4-oxo-1,4-dihydroquinoline-3-carboxylic acld; 1-ethyl-5-amino-6,8-difluoro-7-{3-(propylamino- methyl) -1l-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid; l-nthyl-5-amino-6,8-difluocro-7-(3- (2-propylaminomethyl)-1-pyrrolidinyl]-4-oxo-1,4- — dihydroquinoline-3-carboxylic acid; l-ethyl-5-amino- . . 6,8-difluoro-7-[3-(cyclopropylaminomethyl)-1- pyrrolidinyl]-4-oxo~1,4-dihydroquinoline-3-carboxylic acid; l-ethyl-5~-amino-6,8-difluoro-7-{2,7-diazaspiro (4.4)non-2-yl]-4-0x0-1,4-dihydroquinoline-3- carboxylic acid; 1-cthyl-5-amino-6,8-difluoro=-7- [7-methyl-2,7-diazaspiro{4.4]non-2-yl}-4-oxo-1,4- dihydroquinoline-3-carboxylic acid: l-ethyl-5~-amino- 6,8-difluoro-7-[7-ethyl-2,7-diazaspiro(4.4]lnon-2-yl)~ 4-ox0-1,4-dihydroquinoline~3-carboxylic acid; l-ethyl-5-amino-6,8-difluoro-7-[3~-[[(2-hydroxyethyl)- ~ amino)methyl]-1-pyrrolidinyl]-4-oxo-1,4-dihydro- . 25 quinoline-3-carboxylic acid; and l-ethyl-5-amino- 6,8-difluoro-7-{3-[((2,2,2-trifluorcethyl)amino] : methyl]-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-
J-carboxylic acid.
EXAMPLE 4 ! : - 30 g-aAmino-9-fluoro-3-methyl=-10-[(3-t-butoxycarbonyl- amino)-1l-pyrrolidinyl}-7~oxo-2,3-dihydro-7H-pyrido (1,2,3-de][1,4)benzoxazine-6-carboxylic Acid . A solution of 2.9 g (10 mmole) of 8-amino-9,10- difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido (1,2,3-de])[1,4]benzoxazine-6~carboxylic acid, 2.8 ¢g
{15 mmole) of 3-(t-butoxycarbonylamino)pyrrolidine, 3.03 g (30 mmole) of triethylamine and 100 ml of
N,N-dimethylformamide is heated at 100°C for four hours. The solvent is removed in vacuo and the residue ls triturated with water. The agueous slurry is adjusted to pH 7.2 with 1.0 M hydrochloric acid °° and the precipitate is removed by filtration, washed with water, and dried in vacuo to give the f-amino- 9-fluoro-3-methyl-10-[ ( 3-t-butoxycarbonylamino)~-1- pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de] (1,4)benzoxazine-6~-carboxylic acid. _ EXAMPLE 5 8-Amino-9-fluoro-3-methyl-10-(3~amino-1- : pyrrolidinyl)-7-oxc-2,3-dihydro-7H-pyrido(1l,2,3-de] [1,4]benzoxazine-6-carboxylic Acid, Hydrochloride
A suspension of 4.63 g (10.0 mmole) of . g-amino-9-fluoro-3-methyl-10-[ (3-t-butoxycarbonyl amino)-1-pyrrolidinyl]-7-oxo~2,3-dihydro-7H-pyrido (1,2,3-de}(1,4]benzoxazine-6-carboxylic acid 5 ml of 6.0 M hydrochloric acid and 50 ml of glacial acetic acid is heated at 60°C for four hours. The solvent is removed in vacuc and the residue is triturated with ethanol/ether (1:1). The precipitate is removed
C- by filtration, washed with ether, and dried in vacuo to give 8-amino-9-fluoro-3-methyl-10~-(3-amino-1- pyrrolidinyl)-7-oxo-2,3~-dihydro-7H-pyrido(l,2,3~de] (1,4]benzoxazine-6-carboxylic acid, hydrochloride.
EXAMPLE 6 ; 8-Amino-9-fluoro-3-methyl-10-[(3-cyclopropylamino- methyl)-l-pyrrolidinyl)~7-oxo-2,3-dihydro-7H-pyrido (1,2,3-de)[1,4])benzoxazine-6-carboxylic Acid
A mixture of 7.96 ¢g (10 mmole) of 8-amino-9,10- difluoro-3-methyl-7-oxo0-2,3~-dihydro-7H-pyrido
. - i : Qa" . (1,2,3-de](1,4]benznxazine-6-carboxylic acid, 2.1 g (15 mmole) of N-cyclopropyl-3-pyrrolidinemethanamine, ' 3.03 g (30 mmole) of triethylamine and 100 ml of
N,N-dimethylformamide is heated at 100°C for four hours. The solvent is removed in vacuo and the residue triturated with water. The aqueous : suspension is adjusted to pH 7.2 with 1.0 M hydrochloric acid. The solld is removed by . filtration, washed with water, and dried in vacuo to give g8-amino-9-fluoro-3-methyl-10-[(3-cyclopropyl- aminomethyl)-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H- pyrido(1l,2,3-del[1,4]benzoxazine-6-carboxylic acid. — The following compounds may be prepared from g8-amino-9,10~-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- pyrido(l,2,3-de][1,4]benzoxazine-6-carboxylic acid and the desired amine or protected amine using the above method: 8-amino-9-fluoro-3-methyl-10- (3-(aminomethyl)-1-pyrrolidinyl)-7-oxo-2,3-dihydro- 7H-pyrido(1,2,3-de](1,4]benzoxazine-6-carboxylic acid; B8-amino-9-fluoro-3-methyl-10-[3-[(propylamino)- methyl) -1-pyrrolidinyl]=~7-oxo0-2,3-dihydro-7H-pyrido (1,2,3-de][1,4]benzoxazine-6-carboxylic acid; © g-amino-9-fluoro-3-methyl-10-{3~[(2-hydroxyethyl)- pe amino)methyl)-1-pyrrolidinyl]-7-oxo-2,3-dihvdro-7H-
CL 25 pyrido(l,2,3-de]([l,4]benzoxazine-6-carboxylic acid; g8-amino-9-fluoro-3-methyl-10-(3~((2-propylamino)- ; methyl]-1-pyrrolidinyl]-7-oxo-2,3-dihydro-71- pyrido(1,2,3-de](1,4])benzoxazine-6-carboxylic acid; oo g-amino-9-fluoro-3-methyl-10-(3~((2,2,2-trifluoro- ethyl)amino]methyl)-l-pyrrolidinyl]-7-oxo-2,3- dihydro-7H-pyrido(1,2,3-de](1,4]benzoxazine-6- carboxylic acid; 8-amino-9-fluoro-3-methyl-10-[3- } { (ethylamino)methyl]-1~pyrrolidinyl)-7-oxo-2,3- dihydro-7H-pyrido(1,2,3-de](1l,4])benzoxazine-6- 3s carboxylic acid; 8-amino-9-fluoro-3-methyl-10-(2,7- diazaspiro(4.4])non-2-yl]=7~oxo-2,3-dihydro-7H-pyrido {(1,2,3-de](1,4]benzoxazine-6-carboxylic acid;
. . -h5= 8-amino-9-fluoro-3-methyl-10-[7=(7-methyl)-2,7~ diazaspiro(4.4)non-2-y1)-7-oxo0-2,3~-dihydro-7H-pyrido (1,2,3-de](1,4]benzoxazine-6-carboxylic acid; and 8-amino-9-fluoro-3-methyl-10-(7-(7-ethyl)-2,7~ dlazaspiro(4.4)}non-2-yl]-7-ox0-2,3~-dihydro~7H-pyrido [1,2,3-del(1,4]benzoxazine-6-carboxylic acid. ’
EXAMPLE 7 5-Amino-1-cyclopropyl-6,8-difluoro-7-{(3-ethylamino- methyl) -1-pyrrolidinyl]-1,4-dihydro-4-oxo-3- quinolinecarboxylic Acid
A solution of 0.43 g (1.5 mmoles) of — S-amino-l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- : oxo-3-quinolinecarboxylic acid, 0.61 g (6.0 mmoles) of triethylamine, 0.77 g (6.0 mmoles) 3-(ethylamino- methyl)pyrrolidine and 25 ml of acetonitrile was heated at reflux for two hours. The solvent was removed in vacuo and the residue wns dissolved in water and filtered through a fiber glass pad to remove a trace of insoluble material. The filtrate was adjusted to pH 7.0 and the resulting precipitate removed by filtration, washed with water, and dried in vacuo to give 200 mg of the title compound, mp - 250~-252°C.
EXAMPLE 8 5-Amino-7-(3-amino-1-pyrrolidinyl)-8-chloro-l-cyclo- propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic Acid
To 1.57 g (5 mmol) of 5-amino-8-chloro-l-cyclo- propyl-6,7-difluocro~1,4-dihydro-4-oxo-3-quinoline carboxylic acid in 20 ml of acetonitrile was added 0.93 g (5 mmol) of 3-((t-butoxycarbonyl)amino] pyrrolidine and 1.0 ¢ (10 mmol) of triethylamine.
The mixture was refluxed for three hours, ccoled, and filtered. The solids were washed with acetonitrile and ether, then dissolved in 10 ml of acetic acid and
* » -66~ . . . . 2 ml of 3 N hydrochloric acid. The mixture was : heated at 100°C for four hours, concentrated, and triturated with 2-propanol. The solid that formed was filtered and washed with ether to give 1.2 g of the title compound. i
The following compounds were also prepared by a similar procedure: 5-amino-8-chloro-l-cyclopropyl-7- : (3-[{ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid; 100 5-amino-8-chloro-l--yclopropyl-6-fluoro-1,4-dihydro- 7-({3-( (methylamino)methyl]~1l-pyrrolidinyl]-4-oxo-3- quinolinecarboxylic acid; S-amino-8-chloro-l-cyclo- — propyl-6-fluoro-1,4-dihydro-7-(3-((dimethylamino) methyl)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid; 5-amino-7-[{3~(aminomethyl)-3-methyl-1- pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3~quinolinacarboxylic acid; S-amino-8- bromo-1l-cyclopropyl =7-(2~((ethylamino)methyl]-1~- pyrrolidinyl]-6-fluoro~1,4-dihydro-4-oxo-3-quinoline- carboxylic acid; S5-amino-8-bromo-l-cyclopropyl-6- fluoro-1,4-dihydro-7-[3-[ (methylamino)methyl]-1- pyrrolidinyl]-4-oxc-3-quinolinecarboxylic acid; 5-amino-8-bromo-1l-cyclopropyl-6~-£fluoro-1,4-dihydro- ~ 7-[3-[{(dimethylamino)methyl]-1-pyrrolidinyl]-4-oxo-
Co 25 J-quinolinecarboxylic acid; 5-amino-7-(3-amino-1- pyrrolidinyl)-8~bromo~1l-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid; 5-amino-7- {3-amino-1-pyrrolidinyl)-1l-cyclopropyl-6-fluoro-8- trifluoromethyl-1l,4-dihydro-4-oxo-3-quinoline- carboxylic acid; S-amino-1l-cyclopropyl-6-fluoro-8- trifluoromethyl=-1, A-dihydro~7~(3~[ (methylamino) methyl)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic "acid; 5-amino-l-cyclopropyl-7-(3-([(ethylamino)
Co methyl)-l-pyrrolidinyl)-6-fluoro-8~-trifluoromethyl- - 35 4-oxo-3-quinolinecarboxylic acid; S-amino-l-cyclo- propyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-7- [(3-[(dimethylamino)methyl]-1-pyrrolidinylj-4-oxo-3-
. oy -67- quinolinecarboxylic acid; §-amino-1-cyclopropyl-7- ] (3-[ (ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4- dihydro-8-methoxy-4-oxo=-3-quinolinecarboxylic acid; 5-amino-1-cyclopropyl-6-fluoro-1, 4-dihydro-7-(3- [ (methylamino)methyl]-1-pyrrolidinyl]-8-methoxy=-4- i oxo-3-quinolinecarboxylic acid; S~amino-l- cyclopropyl-6-fluoro-1,4-dihydro-7-(3-[(dimethyl- amino)methyl]-1-pyrrolidinyl]-8-methoxy-4-oxo-3- quinolinecarboxylic acid; 5-amino-7-(3-amino-1l- } pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8- methoxy-4-oxo-3-quinolinecarboxylic acid; 5-amino-1- cyclopropyl-7-(3-((ethylamino)methyl]-1- ~~ pyrrolidinyl)-6-fluoro-1,4-dihydro-8-hydroxy-4-oxo- 3-quinolinecarboxylic acld; S5-amino-l-cyclopropyl- 6-fluoro-1,4-dihydro-8-hydroxy=7-[3~-[ (methylamino) methyl]-1-pyrrolidiryl]-4-oxo=-3-quinolinecarboxylic acid; 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8- hydroxy-7-(3-[{dimethylamino)methyl]-1-pyrrolidinyl]- 4-oxo-3-quinolinecarboxylic acid, S-amino-7-(3-amino- 1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro- 8-hydroxy-4-oxo-3-quinolinecarboxylic acid; 7-(3-amino-1-pyrrolidinyl)-8-chloro-1l-cyclopropyl-6- fluoro-1,4-dihydro~5-methoxy-4-oxo-3-quinoline-
Pp carboxylic acid; 7-(3-amino-1-pyrrolidinyl)-8-chloro- 1-cyclopropyl-6-flunro-1,4-dihydro-5-hydroxy=-4-oxo-3- quinolinecarboxylic acid; 7-(3-amino-l-pyrrolidinyl)- : 8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-S-methyl- amino-4-oxo-3-quinolinecarboxylic acid; 7-(3~amino-1- ’ pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4- dihydro-5-dimethylamino-4-oxo~3-quinolinecarboxylic acid; 8-chloro-l-cynlopropyl-7-(3-((dimethylamino) : methyl] -1-pyrrolidinyl])-6~-fluoro-1,4-dihydro=-5-" : methoxy-4-oxo-3-quinolinecarboxylic acid; 8-chloro-l-cyclopropyl-7-[3-[(dimethylamino)methyl]- 1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-hydroxy=-4-oxo- 3-quinolinecarboxylic acid.
Claims (1)
1. 5-Amino-7-chloro-l-cyalopropyl-6- fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid. JOHN M. DOMAGALA } THOMAS F. MICH JOSEPH P. SANCHEZ } (Inventors)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PH41163A PH27114A (en) | 1986-10-20 | 1990-09-10 | Antibacterial agents II |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/920,536 US4822801A (en) | 1984-07-20 | 1986-10-20 | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
PH38419A PH26729A (en) | 1986-10-20 | 1989-04-03 | Benzoxazines useful as antibacterial preparation thereof and pharmaceutical composition containing them |
PH41163A PH27114A (en) | 1986-10-20 | 1990-09-10 | Antibacterial agents II |
Publications (1)
Publication Number | Publication Date |
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PH27114A true PH27114A (en) | 1993-03-16 |
Family
ID=26652389
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH41163A PH27114A (en) | 1986-10-20 | 1990-09-10 | Antibacterial agents II |
Country Status (1)
Country | Link |
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PH (1) | PH27114A (en) |
-
1990
- 1990-09-10 PH PH41163A patent/PH27114A/en unknown
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