PH26729A - Benzoxazines useful as antibacterial preparation thereof and pharmaceutical composition containing them - Google Patents
Benzoxazines useful as antibacterial preparation thereof and pharmaceutical composition containing them Download PDFInfo
- Publication number
- PH26729A PH26729A PH38419A PH38419A PH26729A PH 26729 A PH26729 A PH 26729A PH 38419 A PH38419 A PH 38419A PH 38419 A PH38419 A PH 38419A PH 26729 A PH26729 A PH 26729A
- Authority
- PH
- Philippines
- Prior art keywords
- oxo
- carbon atoms
- amino
- acid
- dihydro
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 11
- 230000000844 anti-bacterial effect Effects 0.000 title description 5
- 150000005130 benzoxazines Chemical class 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 105
- 239000000203 mixture Substances 0.000 claims description 59
- 239000002253 acid Substances 0.000 claims description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 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 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 77
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 50
- -1 amine salt Chemical class 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- 238000001914 filtration Methods 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
- 235000019341 magnesium sulphate Nutrition 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 125000004494 ethyl ester group Chemical group 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000012280 lithium aluminium hydride Substances 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical group 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 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
- 150000003857 carboxamides Chemical group 0.000 description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 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
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- 150000004985 diamines Chemical class 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- BLZVPYLBVJENNU-UHFFFAOYSA-N 1-benzyl-n-methyl-5-oxopyrrolidine-3-carboxamide Chemical compound O=C1CC(C(=O)NC)CN1CC1=CC=CC=C1 BLZVPYLBVJENNU-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 239000011152 fibreglass Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 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
- 239000007788 liquid Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 3
- 229960005141 piperazine Drugs 0.000 description 3
- 150000003141 primary amines Chemical group 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
- 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
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 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
- 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
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 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
- 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
- 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
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-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
- 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052774 Proactinium Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical group CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229910003480 inorganic solid Inorganic materials 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 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 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- BUQMHUKZYMREQT-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)ethanamine Chemical compound CCNCC1CCNC1 BUQMHUKZYMREQT-UHFFFAOYSA-N 0.000 description 2
- VJPYEYRKXXVWNA-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)propan-2-amine Chemical compound CC(C)NCC1CCNC1 VJPYEYRKXXVWNA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AMRNWWPARHIDHZ-UHFFFAOYSA-N n-[(1-benzylpyrrolidin-3-yl)methyl]ethanamine Chemical compound C1C(CNCC)CCN1CC1=CC=CC=C1 AMRNWWPARHIDHZ-UHFFFAOYSA-N 0.000 description 2
- ATVZOUGWKFEKFL-UHFFFAOYSA-N n-[(1-benzylpyrrolidin-3-yl)methyl]propan-2-amine Chemical compound C1C(CNC(C)C)CCN1CC1=CC=CC=C1 ATVZOUGWKFEKFL-UHFFFAOYSA-N 0.000 description 2
- JVODWNWKCOVKTO-UHFFFAOYSA-N n-methyl-1-pyrrolidin-3-ylmethanamine Chemical compound CNCC1CCNC1 JVODWNWKCOVKTO-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 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
- 229940043237 diethanolamine Drugs 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
- QTTDHHKBHTUYCK-UHFFFAOYSA-L dilithium;propanedioate Chemical compound [Li+].[Li+].[O-]C(=O)CC([O-])=O QTTDHHKBHTUYCK-UHFFFAOYSA-L 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910001651 emery Inorganic materials 0.000 description 1
- 239000000839 emulsion Substances 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
- 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
- HISNMGFYFJXXJW-UHFFFAOYSA-N ethyl 4-[6-(cyclopropylamino)-3-fluoropyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C1=NC(NC2CC2)=CC=C1F HISNMGFYFJXXJW-UHFFFAOYSA-N 0.000 description 1
- OQLZLQOQVVLZGK-UHFFFAOYSA-N ethyl 4-[6-[acetyl(cyclopropyl)amino]-3-fluoropyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C1=NC(N(C2CC2)C(C)=O)=CC=C1F OQLZLQOQVVLZGK-UHFFFAOYSA-N 0.000 description 1
- ONQDAESGZUODFI-UHFFFAOYSA-N ethyl 6,7,8-trifluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound FC1=C(F)C=C2C(=O)C(C(=O)OCC)=CNC2=C1F ONQDAESGZUODFI-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
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- OSTIHFXUTPZJQL-UHFFFAOYSA-N fluoro benzoate Chemical compound FOC(=O)C1=CC=CC=C1 OSTIHFXUTPZJQL-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel 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
- 150000004678 hydrides Chemical class 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 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
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- KYOLWTXOYMKDRP-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)propan-1-amine Chemical compound CCCNCC1CCNC1 KYOLWTXOYMKDRP-UHFFFAOYSA-N 0.000 description 1
- GBBWFNQLKOWTGS-UHFFFAOYSA-N n-[(1-benzylpyrrolidin-3-yl)methyl]-2,2,2-trifluoroethanamine Chemical compound C1C(CNCC(F)(F)F)CCN1CC1=CC=CC=C1 GBBWFNQLKOWTGS-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
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 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
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000573 polyethylene 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- VMPYTOIPVPQDNX-UHFFFAOYSA-N pyrrolidin-1-ylmethanamine Chemical compound NCN1CCCC1 VMPYTOIPVPQDNX-UHFFFAOYSA-N 0.000 description 1
- OQCUGPQOZNYIMV-UHFFFAOYSA-N pyrrolidin-3-ylmethanamine Chemical class NCC1CCNC1 OQCUGPQOZNYIMV-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
- 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
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-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
-L = “a . { : id. 26727
This application is a divisional application of application serial number 35962 filed October 20, 19R7, h BACKGROUND OF THE INVENTION ; ! US Patent 4,341,784 discloses certain ; substituted 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6- i fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3- : © 10 carboxylic acids having the general formula: o : > no” oN !
NHR
: The compounds are disclosed to have antibacterial activity.
The Journal of Medicinal Chemistry, 23, 1358 (1980) discloses certain substituted quinoline-3- carboxylic acids having the structural formula 0
Cr ) :
C, He enn —————— a » 1&4 y= Yad . 2 0 / J / wherein Cw- 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 benzoxazine derivatives having the : structural formula : 0
AN _-CO,H _T ory 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 Therapeutica, 29, 27 (1977). US
Patents 3,753,993 and 3,907,808 disclose certain 7-pyridylquinolones.
The references teach that these compounds possess antibacterial activity.
:
The invention in a first generic chemical compound aspect are compounds having the structural formula I and II
-4- 7 a :
Jud 7¢ / ro Y © 4 CO,R il
F ) Oe] 21 Fs Soi
IS li 2 7 xT ¢ JK, s ! 0h. 2 CHy
I IT wherein 2Z is ala ~N J tergng use, ot . (CHL)
CH "
Ya 2) a (CRsRe 0 -N N—R, :
Nn, (chy -
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 one to four carbon atoms or cycloalkyl having three to six carbon atoms; R, is ee _5- Jet 26727 hydrogen, alkyl from one to four carbon atoms, hydroxyalkyl having two to four carbon atoms, trifluoroethyl 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 (at —N erg Ry - Nth)
Also preferred connounds of this invention are those wherein 2 is ~ ECT —N N—R \ 3 ~— (cH, (ch) ° = :
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 those wherein R, is ethyl, vinyl, 2-fluoroethyl, or cyclopropyl.
The most preferred compounds are those wherein X is MN, CF, or CCl, 2 is
° nd AC 725 (CH, ) “NHR, N=R
Ry is hydrogen, R, is ethyl, vinyl, 2-fluorocethyl or cyclopropyl: n" is 0 or 1 and Ry 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: 8-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; 8-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-oxo-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}-1l-pyrrolidinyl]-7-oxo-2,3-dihydre-7H-pyrido {1,2,3-de][1,4]benzoxazine-6-carboxylic acid; 8-amino-9-fluoro-3-methyl-10-[3-( (2~-hydroxyethyl) - amino)methyl]-1-pyrrolidinyl}-7-oxo-2,3~-dihydro-7H- pyrido[1l,2,3-de][1l,4)benzoxazine-6-carboxylic acid; 8-amino-9-fluoro=-3-methyl-10-[3-{(2-propylamino)- . methyl]-1-pyrrolidinyl}-7-oxo~-2,3~-dihydro-7H-pyrido [1,2,3-del(1,4)benzoxazine-6-carboxylic acid; 8-amino-9-flucro-3-methyl-10-(3-((2,2,2-trifluocro- ethyl)amino)methyl)-1-pyrrolidinyl]-7-oxo-2,3- dihydro-7H-pyrido(1l,2,3-dej(l,4]benzoxazine~6-~ carboxylic acid; 8-amino-9-fluoro-3-methyl-10-[(3-{{ethylamino)methyl]- l-pyrrolidinyl)-7-oxo-2,3-dihydro-7H-pyrido(1l,2,3~-de] (1,4)benzoxazine-6~-carboxylic acid;
a -7- Jif 7677] 8-amino-9-fluoro-3-methyl-10-(2,7-diazaspiro(4.4]non- 2-y1]-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de](1, 4] benzoxazine-6-carboxylic acid; 8-amino-9-fluoro-3-methyl-10-[7-(7-methyl-2,7- diazaspiro(4.4lnon-2-yl]-7-oxo-2,3-dihydro-7H-pyrido (1,2,3-de}(1,4]benzoxazine-6§-carboxylic acid; 8-amino-9-fluoro-3-methyl-10-{7-(7-ethyl-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;
L-ethyl-5-amino-6,8-difluoro-7-(3-amino-1- byrrolidinyl)-4-oxo-1,4-dihydraquinoline-3-carboxylic acid hydrochloride; -ethyl-5-amino-6,8-difluoro-7-(3=-(ethylamino)methyl-
L-pyrrolidinyl) )-4-oxo-1,4-dihydroquinoline=3- carboxylic acid; -ethyl-5-amino-6,8-difluoro-7-3-(aminomethyl)-1-
Syrrolidinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; -ethyl-5-amino-6,8-difluoro-7-(3-(propylamino- nethyl)-1-pyrrolidinyl]-d-oxo-1,d-dinydroquinoline=3- carboxylic acid; -ethyl-5-amino-6,8-difluoro-7-[3-(2-propylamino= ethyl) -1-pyrrolidinyl]-4-oxo-1,4-dihydroguinoline=3- carboxylic acid; | -ethyl-5-amino-6,8-difluoro=7-[3-(cyclopropylamino ‘ methyl) -1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline=3- carboxylic acid; —ethyl-5-amino-6,8-difluoro-T-[2,7-diazaspirold. 4] “on-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; -ethyl-5-amino-6,8-difluoro=7-[7-(7-methyl-2,7" diazaspirol(4.4]non-2-yl]-4-oxo-1,4-dihydroquinoline j-carboxylic acid; -ethyl-5-amino-6,8-difluoro=7-[7-(7-ethyl-2,7 diazaspiro(4.4]non-2-yl]-4-oxo-1,4-dinydroquinoline= j-carboxylic acid;
6- Jad 76727 l-ethyl-5-amino-6,8-difluoro~7-[3-[((2-hydroxyethyl)- amino]methyl)-1-pyrrolidinyl)-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid; l-ethyl-5-amino-6,8-difluocro-7-({3-{((2,2,2-trifluoro- ethyl)amino]methyl])-1-pyrrolidinyl)-4-oxo-1, 4- dihydroquinoline-3-carboxylic acid; 5-amino-7-(3-amino-1-pyrrolidinyl)-l-ethyl-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; 5-amino-7-(3-amino-1-pyrrolidinyl)-8-chloro~1-cyclo-
Propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid;
S-amino-8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro- 7-{3-{(methylamino)methyl]-1l-pyrollidinyl)-4-oxo-3- tL 15 quinolinecarboxylic acid; 5-amino-7-(3-amino-l-pyrrolidinyl)-8-bromo-1-cyclo- propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid; and
S5~amino-7-(3-amino~1-pyrrolidinyl)-1l-cyclopropyl-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
The following process for preparing compounds of the formula :
CC — 9 a “ge (if 26177 y 0 Y 0
F CO,R
Ye Or 271 ~ NS 777 7x u Z yon or oI
R, CH, 111 Illa wherein Ry, R,, X, and Z are as defined for formula I which comprises reacting a compound having the "following structural formula
Y © Y Ni
CO,R ’
Ea CO,Ry F ~~ 271 || BE
LN L N
1 oO
R, E CH 4 1v Vv ‘ with an amine corresponding to the group 2 wherein 2 is the compound having the structural formula
Chal ,
HN : Stern, NR3Ry or
Ne ‘ (CHy) via .
Hala (CRgRe ~
HN Pa
NCH.) .
Vib
- - .? .
He Jaf. FEAT 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
Fx 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 and the pharmaceutically acceptable acid addition or base salts tha2reof. The preferred compounds are those wherein X is cCl, CBr, or CF and Y is NH, , NHR, or
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-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid; and 5-amino-1l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid.
The invention also includes a pharmaceutical composition which comprises an antibacterially effective amount of a compound having structural formula I and the pharmaceutically acceptable salts
—
Co ——————————————————————————— eee eee eee eee eee -11- 7 or 0
Jat Se 27 thereof in combination with a pharmaceutically acceptable carrier.
The invention further includes a method for treating bacterial infections in a mammal which 5s 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 III 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 groups such as the following may be utilized: carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, 8,B,B-trichloroethoxycarbonyl,
B-iodoethoxycarbonyl; aryloxycarbonyl groups such as penzyloxycarbonyl, p-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.
-12- Jaf 2727
The reaction between the compound of structural formula IV or Vv and a suitably protected compound of formula VIa or VIb, may be performed with or without a solvent, preferably at elevated temperature for a sufficient time so that the reaction is substantially complete. The reaction ls preferably carried out in the presence of an acid acceptor such as an alkali metal or alkaline earth 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, ethanol, 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, if new, may be prepared from known starting materials by standard procedures or by variations thereof. Thus
Co 30. the following compounds are disclosed in the noted references:
-13- NN Lo 7 7
NH, 0 :
F CO,H a 2 . ! cl ON
F Er
Js 8174 367A
NH, 0
OL
F > N 0. J ’ 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 sequence shown pelow wherein L is a leaving group as previously defined.
oD oa faf 76777 -14-
HH, 0 CF yCONH 0 i ry YY
Teme JL)
L «Nu (CFyC0),0 “yg )
Ry R,
NaH{or other base)
R H A
~n” o Fy 0
F CO,R
F COR, + XN 271 a ~~
L X ’ L X
R Ry .
Ry Ry
R'L (optional) - Be COR,
L GY
[
IVa
The S5-amino group is preferably acylated by trifluoroacetic acid anhydride although other acyl moieties may be employed. The alkylation of R proceeds with the presence of sodium hydride or other nonnucleophilic bases. 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 S-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.
Jog 24777 -1o-
HH,
F No COM RCHO —_— = i R R
Lox Hy or Nn 0 Ho R ! CO,H r ~~
Or ’ —_— [V
L x AL
NO
2
CO,H
Tr 2 RCHO rr ————————— ~ H
Lx TN 2 catalyst
Using appropriate control of the aldehyde (RCHO) equivalents mono and disubstituted amines may be . obtained. The substituted amino acids may be 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:
L OR, OR, - F CO,R F CO H
F COR) “OR, x 271 ad i — 1 — ig
L x7 L LL L oo
OR, 0
F Xx C0 ry 1) ~~ . L x~ NM
R)
IVb
A/ 7c” 7 -16- Jaf
Other compounds of formula IV wherein X is CH,
CCl, CBr, COR, COH, 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 F CO.,H 1 . _— ~~
L ay L x71 1. (cociy, 2. Malonate dianion
No, i 0 Ac,0 NO, 0 i
F (EtO) ,CH F j ~~,
L xFNp L Xx~ LU
R NH,
NO,O0 © NO, ’ i
F __C-OEt
F x Mee Base A : _ | ’ ~
L XSL TNNHR) L X "
R) , v »
NH, O NH, ©O ‘
CO.,H — J - | = .
L X N- L -X N
Ry Ry oo ————————————————————————— ful 2727
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 3-nitro-1,4,5,6-tetrafluoro-p-oxo-benzene propanoic acid ethyl ester. This product can be converted to 5-njtro-1-cyclopropyl-6,7,8-trifluoro- 1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester by a three step 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 t-butoxide to form -nitro-l-cyclopropyl-6,7,8- erifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. This product is hydrogenated to form the corresponding 5-amino compound. This is then hydrolyzed to form 1-cyclopropyl-5-amino-6,7,8~- erifluoro-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-tetrafluoroanthranilic acid. The acid is reacted with acetic anhydride and acetic acid to form
J-acetylamino-3,4,5,6-tetrafluorobenzoic acid. This compound is reacted with oxalyl chloride and dichloromethane in the presence of N,N-dimethyl- : formamide catalyst to form J-acetylamino-3,4,5,6- tetrafluorobenzoyl chloride. This product is treated with n-butyl lithium and malonic half acid ester to form 5-acetylamino-3,4,5,6-tetraf luoro-p-oxobenzene= propanoic acid ethyl ester.
This product can be converted to 5-acetylamino- 1-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-B-oxobenzene-propanoic acid ethylester is first treated with triethylorthoformate and acetic anhydride. After removal of the solvent the residue i’ - r 47 4) (3 -18- fat. 26777 is treated with a solution of cyclopropylamine in t-butanol. After the reaction is complete a solution of potassium t-butoxide in t-butanol is added. The resulting product is S-acetylamino-1l-cyclopropyl- 6,7,8-trifluoro-1,4-dihydro~4-oxo-quinoline-3- carboxylic acid ethyl ester. The ester is hydrolyzed to form l-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.
The compounds of the invention having structural formula VIa or Vib are either known compounds or they
Tay be prepared from known starting materials by standard procedures or by variations thereof. For example, 3-pyrrolidinemethanamines having the structural formula D
N-H
WF 0
CH, NHR 4 may be readily prepared from the known starting material methyl 5-oxo-1-(phenylmethyl)-3~pyrrolidine- carboxylate, A, (J. Org. Chem., 26, 1519 (1961)] by the following reaction sequence.
CO,CHy nur, CONHR
BPE
0 y © 0 °N
CH, Clg CH, CH
A 2] v
CH, NHR 4 CH, NHR 4
J J
N 0
H
. CH, Cty 0 : c
Ce —— — — -19- fof 26729
The compound wherein Rq 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 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 R, 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-diazabicyclo(5.4.0]Jundec-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
LL . structural formula I or Ia. The -CO,Et group may be removed by standard procedures.
Likewise spiroamino compounds represented by structural formula VIb may be readily prepared from the known starting material 3-ethoxycarbonyl-5-oxo- j-pyrrolidineacetic acid ethyl ester (J. org. Chem., 46, 2757 (1981)) by the following reaction sequence.
-20- vod. 76799
Oo % CO, Et SN W NR
CH,CO, Et _ SN)
E _ E 0
I 3
CgHgCH,-N N 2 gent 0
G t
H—N
J
The compound 2,7-diazaspiro(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 RyNH,, for example, methyl amine in water followed by benzylation which may be carried out with sodium 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,
—————
RES Jaf 26727
The compounds of the invention are capable of forming both pharmaceutically acceptable acid, addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
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 either 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, . potassium carbonate, ammonia, and sodium bicarbonate © 25 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 equivalent
7 4
Cy. fof, 26779 to the unsolvated forms for purposes of the invention.
The alkyl groups contemplated by the invention comprise both straight and branched carbon chains of
S 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 those having three to six carbon 10 atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The alkoxy groups contemplated by the invention comprise both straight and branched carbon chains of from one to about six carbon atoms unless otherwise 15 specified. Representative of such groups are . methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxy, and the like.
The term, haloalkyl, is intended to include halogen substituted straight and branched carbon 20 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
B~-fluorcethyl, B-chloroethyl, 8,B-dichloroethyl, 25 f-chloropropyl, B-chloro-2-propyl, _-iodobutyl, and the like.
The term halogen is intended to include fluorine, chlorine, bromine, and iodine unless otherwise specified. 30 Certain compounds of the inventicn 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.
Additional asymmetric carbon atoms may be present in 35 a substitutent such as an alkyl group. All such isomers as well as mixtures thereof are intended to be included in the invention.
ee ————— eer reer rrr mm
I. -23- jad. 2 0727
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.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include 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 and size desired. The powders and tablets preferably ° contain from 5 or 10 to apout 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl 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 carriers) is surrounded by carrier, which is thus in association with it. similarly, cachets are included. Tablets, powders, cachets, and capsules
-24- Jad. (7729 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 be acceptable to biological systems (isotonicity, 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, 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.
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.
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 ee ——————— —— -25- J JA. 2 229 about 497 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 5S severity of the condition being treated, and the compound being employed. petermination of the proper dosage for a particular gituation 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 is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The following nonlimiting examples jllustrate the inventors’ preferred methods for preparing the compounds of the invention.
PREPARATION OF STARTING MATERIALS
EXAMPLE A
|-Ethenyl-6,7,8-trifluoro-1,8-dihydro-4-0x0=3- quinolinecarboxylic acid ] 6.7,8-Trifluoro-1,4-dihydro-4-oxo=3-quinolines carboxylic acid ethyl ester was treated with dibromo ethane to afford the 1-ethenyl-6,7,8-trifluoro-1,4~ dihydro-4-oxo-3-quinolinecarboxylic acid ester, mp 134-135°C. Subsequent hydrolysis with hydrochloric acid gave |-ethenyl-6,7,8-trifluoro-1,4-dihydro=4- oxo-3-quinolinecarboxylic acid, mp 186-187°C.
EXAMPLE B
. 30 6.7,8-Trifluoro-1-(2-fluoroethyl)=1,4-dihydre=d-o%e- j-quinolinecarboxylic acid
In identical fashion, 6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester
Jud 26777 was converted to 6,7,8-trifluoro-1-(2-fluorcethyl)- 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 100 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 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 IN sodium ; hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 88.3 g of N-methyl-5-oxo-1-(phenyl- methyl)-3-pyrrolidinecarboxamide as a white solid, mp 82.5-83.0°C.
Analysis calculated for C 3H gN,05
Cc, 67.22; H, 6.94; N, 12.06 .
Found C, 66.98; H, 6.69; N, 12.02.
This material was used in the next step. :
N-Methyl-1l-(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 tetrafuran dropwise under nitrogen.
The reaction was then refluxed overnight. The : 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
CC ——————————————— ———
N fut. 26171 solids were fil-ered 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 68.7 g of N-methyl-1- (phenylmethyl)-)-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-i- (phenylmethyl) -3-pyrrolidinemethanamine, 3 g of 20% 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 4.9% 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-pyrrolidii. nethanamine. ’ 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-5-0x0- 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 removed under reduced pressure. The residue was taken up in dichloromethane and washed 1
BN Jot A 77 9 x 150 ml 1N 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 suspension of 108.8 g (2.86 mole) lithium aluminum hydride in 800 ml tetrahydrofuran, was added 0 a solution of 194.5 g (0.79 mole) of N-ethyl-5-oxo-1- (phenylmethyl)-3-pyrrolidinecarboxamide in 600 ml 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 w th hot ethancl. The combined filtrates were concentrated, thea 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- metharamine as an oil. : This material was used without further purification in the next step. :
N-Ethyl-3-pyrrolidinemethanamine
Q A mixture of 151.6 g (0.69 mole) of N-ethyl-1- (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 102 pa and at room temperature for 21.6 hours.
Another 5 g of 20% palladium on carbon was added and the hydrogenation continued €or 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled ee
Co ———— EE ——— eee eer
Cone Jad 26771 pder vaccum (B8-91°C, 11.5 mm Hg) to give 66.0 g \-ethyl-3-pyrrolidinemethanamine.
EXAMPLE E
\-(2,2,2-Trifluoroethyl]-3-pyrrolidinenethananine <oxo-1- (phenylmethyl) -N=(2,2,2-trifluoroethyLl- 3-pyrrolidine carboxamide :
A mixture of 21.9 g (0.10 mole) methyl 5-0ox0o- BN - (phenylmethyl) -3-pyrrolidinecarboxyiate in 150 ml tetrahydrofuran, was cooled to o°C in an ice bath under nitrogen and 24.3 @ {0.15 mole) carbonyl diimidazole was added. The reaction was stirred at oec for 30 minutes, then at room temperature for 10 ‘ minutes. A solution of 13.6 g (0.10 mole) of 5.2,2-trifluoroethylamine nydrochloride, 15.2 g (0.10 mole) ) 8-diazabicyclo(5.4.0]undec-7-ene and 100 ml tetrihydrofuran 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 ix 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 « -oxo-1- (phenylmethyl) -N-(2,2,2-trifluore” ethyl) -3-pyrrolidinecarboxamide, mp 110-112°C. q } This material was used in the next step.
L- (phenylmethyl) -N-(2,2,2-trifluoroethyl) == pyrrolidinemethanamine
A mixture of 8.50 g (28.3 mole) of 5-oxo-1- phenylmethyl) -N-(2,2,2-trifluoroethyl) =” pyrrolidinecarboxamide in 100 ml tetrahydrofuran was added dropwise to 3.22 g (84.9 mmole) of lithium aluminum hydride in 50 ml tetrahydrofuran. The reaction was refluxed two hours, then stirred at room
Jaf 20777 -30- (mperature overnight. The reaction was cooled in an ce bath and 3.2 ml of water, 3.2 ml of 15% sodium wdroxide, 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-Trifluorcethyl)-3-pyrrolidinemethanamine
A mixture of 7.15 g (26.3 mmole) 1-{phenyl- methyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidine- methanamine 100 ml of methanol and 0.7 g of 20% palladium on carbon was shaken in an atmosphere oO” 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- ethyl)-3-pyrrolidinemethanamine. :
EXAMPLE F
: 25 N-Propyl-3-pyrrolidinemethanamine a 5-Oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidine- . carboxamide
To a solution of 10.9 g (50 mmole) of 5-oxo-1l- phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 9.73 ¢ {60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60°C for one hour, cooled to room temperature and : treated with 4.13 g (70 mmole) of n-propylamine. . After stirring for two hours, the solvent was removed r oy
BAD ORIGINAL i . .
eo -31- Jad. 26777 4 vacuo and the residue partitioned petween ether nd water. The organic jayer was washed with water,
IN hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo ro give 12.0 9 of er timed) prop} PIECE carboxamide, mp g6-87°C. oneppineth cpr BIEESLSBEST
To a suspension of 8.2 @ (0.2 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was 0 added pertionwise, 12.0 9 (45.6 mmole) of solid de Emery) -proPt BITE AC carboxamide. when the addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then at reflux for two nours. Afcer 13 cooling to room temperature. the mixture was rreated dropwise, successively. with 8 ml of water, g ml of 15% aqueous sodium hydroxide and 24 ml f water, titrating the final addition ro produce a granular precipitate: The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated jn vacuo to give 9.6 9 of or prapyi prea as a heavy SYrup-
This material was used for the next step without further purification. q © sropy)-3-pyrolidinenetnananice
A mixture of 14.0 9 (60.0 mmole) of prop a-pyEzol dene TT 1.0 g of 20% palladium on carbon and 140 ml of - methanol was shaken in an atmosphere of hydrogen at about 4.9 % 10° pa and room temperature for 24 hours.
The cata.yst was removed bY filtering through celite, the filtrate concentrated and distilled in vacuo to give 7.1 9 of or yi-3-pyrrolidinenecnansnin®: bp 49-50°C/0.25 mm. ; f
BAD ORIGINAL J)
-32- Jaf 26727
EXAMPLE G y-Cyclopropyl-3-pyrrolidinemethanamine 5-0xo-1-(phenylmethyl)-N-cyclopropyl-3- : pyrrolidinecarboxamide
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was adied 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60°C for one hour, cooled to room temperature and i0 treated with 4.85 g (85 mmole) of cyclopropylamine.
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, 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) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise 18.0 g (70.0 mmole) of solid 5-oxo-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, 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, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 16.0 g of 1-(phenyl- methyl)-N-cyclopropyl-3-pyrrolidinemethanamine, as a ” “in WT oy » .
Cee oe —————————————————————————— 2 -33- Jat 26177 : avy oil. This was used for the next step without qrther purification. \-cyclopropyl-1-pyrrolidinenethananing
A mixture of 13.6 g (59.0 mmol) of 1-(phenyl- thyl)-N-cyclopropyl-3-pyrrolidinenethananine, 0.549 of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5 Xx 10° pa and room temperature for 24 hours. The ] catalyst was removed by filtering through Cellite, the ; filtrate concentrated and distilled in vacuo to give 6.3 g of 4-cyclopropyl-3-pyrrolidinemethananing, bp 88-90°/13 mm.
EXAMPLE H
N-(2-Propyl)-3-pyrrolidinemethananine «oxo- 1-(phenylmethy: ) -N-(2-propyl) --pyErolidine: carboxamide
To a solution of 16.4 g (75.0 mmole) of <-oxo-1- (phenylmethyl) -3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1-'carbonyldiimidazole. The reaction was " ’ heated to 60°C for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room : temperature for 18 hours, the solvent removed in ¢ 25 vacuo and the residue partitioned petween 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 5-oxo-1l-
Sr enyimethyl)-N-(2-propyl) -3-pyrrolidinecarboxanids: mp 122-124°C.
BAD ORIGINAL PN
Ce i be
. Jaf 74777 (phenylmethyl) -N-(2-propyl)-3-pyrrolidine- ethanamine
To a suspension of 2.2 g (0.2 mole) of lithium’ ;luminum hydride in 150 ml of dry tetrahydrofuran was added portionwise, 18.3 g (70.0 mmole) of solid s-oxo0-1-phenylmethyl) -N-(2-propyl)-3-pyrrolidine- carboxamide. When the addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then refluxed 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, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 15.6 g 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 1-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 room temperature for 24 hours. , The q 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.
BAD ORIGINAL 9
3s fod 76TH
EXAMPLE I
-pinethylethyl(3-pyrroLldinyLIcEtbansES -piseshylethyl 1- (phenylnethy)) pela carbamate
A solution of 771.0 9 (0.44 mole) of j-amino-1- (phenylmethyl)pyrrolidine (J. Med. Chem., 24. 1229 (1981)), 440 ml (0.44 mole) 1.0 N sodium hydroxide and 600 ml of rertiarybutyl alcohol was treated dropwise with 98.2 9 (0.45 mole) of 4i-tertiarybutyl 0 dicarbomate. The reaction was stirred at room temperature for 18 hours and the solvent removed in 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 (MgSO, ) ,. 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 L1-dimethylethyl{1-(phenyi™ tnyl)-3-pyrrolidinyl]carbamate, mp 114-115°C. A second Crop (16.7 g) was obtained by concentrating the gilerate. © \-pimechylethyl (3-pysrolidinyLicarbensee -
A mixture of 101.5 4 (0.37 mole) of ep 1- (pany neti) 3-BYEEO AY 4 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 filtrate was concentrated in vacuo to give 6.8 g of 1,1-dimethylethyl . (3-pyrrolidinyl)carbamace which solidified upon standing and was of sufficient purity to pe used as is for the ensuing steps: :
jad. 76177
EXAMPLE J
-[(3-Pyrrolidinylmethyl)amino]ethanol 4-(2-Hydroxyethyl) -5-oxo-1-(phenylmethyl)-3- pyrrolidinecarboxamide u
A mixture of 46.7 g (0.2 mole) of methyl 5-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 dichloromethane and extracted 3 x 100 ml 1 N sodium hydroxide. The aqueous layer was taken to pH S. extracted 3 x 150 ml dichloromethane, then taken to pH 8 and again extracted 3 Xx 150 ml dichloromethane. . : The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in : dichloromethane. The salts were filtered off. ‘The combined organic layers 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 used in the next step without further purification. 2-[([1-{Phenylmethyl)-3-pyrrolidinyl]methyljamino] ethanol q 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 refluxed three hours, then cooled in an ice bath. The work up consisted of sequential addition of 20 ml water, 20 ml 15% sodium hydroxide then 60 ml water. The reaction was filtered and the precipitate washed with ethanol. The filtrate was ro
BAD ORIGINAL oN»
Loose. ’
Ce ————————————————————e eee -31"Jit. 26177 pcentrated at reduced pressure, the residue taken p In dichloromethane, dried over magnesium sulfate, nd the solvent removed at reduced pressure to give j2.31 g of 2-([{1-(phenylmethyl)-3-pyrrolidinyl] nethyl)amino)ethanol as an oil. This material was used in the next step without further purification. 2-[(3-pyrrolidinylmethyl)aninole aano
A mixture of 32.3 g of 5-[((1-(phenylmethyl)=-3- syirolidinyl]methyl)aminojethanol, 330 ml of methanol ; and 3 ¢ 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.% mm Hg) to v give 11.43 g of 2-1 (3-pyrrolidinylmethyljaminol= ethanol. © :
EXAMPLE K
2-Methyl-2,7-diazaspiro(d.4]nonane pihydrochloride -wethyl-2,7-diazaspiro(4.4]nonanesl,, B-trione
A solution of 20.3 g (0.084 mole) 3-ethoxy- 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 path and gradually 4 25 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 rethyl-2,7-diazaspiro(4.4]nonanesl,3 B-Eriones mp . 201-204°C.
Analysis calculated for CgHy N03" : c, 52.74; H, 5.53; N, 15.38 ’
Found C, 52.87; H, 5.60; N, 15.25. —
Cg BAD ORIGINAL J a
SoLoe he
Jid 7727 .penzyl-2-methyl-2,7-diazaspiro(4.4]nonane-1,3,8-
A solution of 1.82 g (10 mmol) of 2-methyl-2,7- jiazaspiro(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 sodium hydride which had been previously washed twice wich toluene and covered with ml N,N-dimethylformamide. After stirring one hour , 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 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-methy'-2,7-diazaspiro(4.4] nonane-1,3,8-trione, mp 157-158°C.
Analysls calculated for CigHygN204
Cc, 66.16; H, 5.92; N, 10.27
Found C, 66.45; H, 5.79; N, 10.09. 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]nonane-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 chloride in
LL oo
BAR CrGINAL }
————— eee ———— -39- ’ 7 . fad. 76779 opropanol. crystallization afforded 0.97 g of the tle compound, MP 233-234°C. nalysis calculated for c,gHpaM2tt c, 59.40: u, 7.98: N, 9.24: Cl, 23.38 found C, 59.37: H 7.98; N, 9.03; Cl. 23.09.
J-ethyl-2,1-dlazaspirold. A10ORE0 pihydrochloride
A solution of ontyl-2-methyl-2,7-diazaspize {4.4)nonane dihydrochloride in 150 ml of methanol with 1.0 9 20% palladium on carbon catalyst was
J hydrogenated at 4.5 Xx 10° pa for two days. After filtration, the filtrate was concentrated to a thick syrup which crystallized on addition of acetonitrile to give 11.5 ¢ of athyl-2,7-diazaspirold. 41nonane dihydrochloride, softened at 164°C and melted at 168-170°C.
Analysis calculated for CigaCla’ : ¢, 45.08; H, 8.51; N, 13.15: Cl, 33.27 found C, 45.24; H, 8.77; N, 13.18; Cl, 33.26.
EXAMPLE L oo } 20 1-gthyl-2,1-dtazaspirold.dlnonsns pihydrochloride . -pupy1-,1-diszaspizold.lnenanesb SEER .
A suspension of 24.3 9 (0.10 mmole) 3-ethoXxy-~ : rbomy1-5-oxo-3-pyrrotidineacetic acid, ethyl ester ‘ in an excess of 2 N sodium hydroxide, was stirred : . 25 three hours at room temperature, acidified with dilute hydrochloric acid, and evaporated to dryness in vacuo. The product, 3-carboxy-5-0x0-3~ pyrrolidineacetic acid, was raken up in isopropyl alcohol, separated from insoluble sodium chloride by’ giltration, concentrated to a SYYJUP and dissolved in 100 ml 70% ethylamine. The solution was gradually heated in an oil bath uP to 230°C allowing volatiles to distill and then aintained at 230-240°C for ten minutes. After cooling, the product was crystallized
FS
SU oo BAD ORIGINAL J
—4u- , | di fit 76777 -om isopropyl alcohol to afford 10.1 g of ;-ethyl-2,7-diazaspiro(4.4]nonane-1,3,8-trione, mp 168-169°C. . analysis calculated for CoH, N,04: c, 55.09; H, 6.177 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-
A suspension of sodium hydride (2.20 g of 60% 0 oil suspension (0.055 mole) washed with toluene) in 50 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, concen*rated 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,gH1gN203¢
Cc, 67.11; H, 6.34; N, 9.79
Found C, 67.41; H, 6.33; N, 9.79. , 2-Benzyl-7-ethyl-2,7-diazaspiro{4.4]nonane pihydrochloride 4 A solution of 11.0 g (0.038 mole) 2-ethyl-7- benzyl-2,7-diazaspiro(4.4]nonane-1,3,8-trione in 100 ml tetrahydrofuran was added dropwise to a suspension of 6.00 g (0.158 mole) lithium aluminum hydride in 250 ml tetrahydrofuran. After stirring overnight, the mixture was refluxed one hour, cooled, and treated dropwise with 6 ml water, 6 ml 15% sodium hydroxide, and 18 ml water. Inorganic solids were . separated by filtration and the filtrate was concentrated, taken up in ether, dried with magnesium
Ce ———— -41-
Jd 72777 fate, and reevaporated. The resulting Syrup was yssolved in isopropyl alcohol and treated with
JXCRSS hydrogen chloride in isopropyl alcohol tc : afford 9.63 g of the title compound, MP 196-198°C (dec). ” analysis calculated for Cc, gHaeM2Ct2°
Cc, 60.56; H, 8.26; N, 8.83; Cl, 22.35 found C, 60.51: 4, 8.08; N, 8.69; Cl, 22.26. )-Ethyl-2.7-diazaspirol4.4lnonans pihydrochloride 0 A solution of 9.5 g (0.03 mole) 2-benzyl-7- ethyl-2,7-dlazaspirol4.4]nonane dihydrochloride in 100 ml methanol was hydrogenated with 1.0 g 20% palladium on carbon catalyst at 4.5 x 10° pa for 22 hours. After filtration, the solution was concentrated to a Syrup and crystallized from . acetonitrile ro afford 6.7 g of the title compound, mp 168-172°C.
Analysis calculated for CqH,oN, C12" ‘ c, 47.58; H, 8.86; N, 12.33; Cl, 31.21 50 found C, 47.70; H, 8.58; Ni 12.39; Cl, 30.92. \
EXAMPLE M cyeropropyl<6,7,8-trifluorosl AdinyarozizonS IE quinolinecarboxylic acid : 2.3,4,5-Tetraf luorobenzoylacetis Acid, Ethyl Ester q 25 ro 25.2 g (0.117 mol) of sqdium 2,3,4,5-tetra-. fluorobenzoate, prepared as a dry powder from 2 3,4,5-tetraf luorobenzoic acid [J. org. Chem., 29, 7381 (1961)) and aqueous sodium hydroxide with concentration to dryness, was added 400 ml of dry 30 ether and the suspension was cooled to 0°C. Slowly, 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 ¢iltered and concentrated to remove low r
Co. BAD ORIGINAL 9d fot. 24777 iling impurities. The residue was dissolved in ml of ether and placed in an addition funnel.
Meanwhile, 2.9 g (0.119 mol) of magnesium rurnings 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 175 ml of ether at a rate to keep the temperature just: below reflux. When addition was complete, the reaction was refluxed for two hours. At -20°C, the etheral acid chloride was slowly added. When addition was complete, the reaction was brought to 0°C over 18 hours. The mixture was poured into dilute hydrochloric acid and was extracted into dichloromethane which was dried (MgSO, ) and concentrated. The residue was then treated with : . 340 mg of p-toluenesulfonic 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 (silita gel, using toluene:hexane: ether, 4:5:1), to give 18.5 g of a reddish oil. This material was triturated with pentane to give 10.2 g of 2,3,4,5-tetrafluorobenzoylacetic acid, ethyl nster, mp 49-51°C. 2-(2,3,4,5-Tetrafluorobenzoyl)-3-cyclopropylamino=- acrylic Acid, Ethyl Ester ¢ To 10.2 g (38.5 mmol) of the 2-(2,3,4,5-tetra- fluorobenzoylacetic acid, ethyl ester was added 8.4 g (57.0 mmol) of triethylorthoformate 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 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 nN
BAD ORIGINAL D enn ~43- , : ( af 20771 ylumn chromatography (silica gel 70-200, using exane:chloroform: isopropyl alcohol, 80:15:5). The sroduct of f the column 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. \-cyclopropyl-6,7,8-trifluoro-1, 4-dihydro= d7oxe=3- quinolinecarboxylic Acid
To 2.0 g (6.0 mmol) of the 2-(2,3,4,5-tetra- 0 ¢ Juorobenzoyl)-3-cyclopropylaminoacrylic acid, ethyl ester in 60 ml of dry dioxane was added 0.29 g of sodium hydride 50% dispersion) that was prewashed with pentane. The sodium hydride was delivered in ml of dry tetrahydrofuran at 0°c. When evolution of hydrogen began to glow, the mixture was refluxed for two hours. It was concentrated, and the residue - taken up in dichloromethane, which was water extracted, dried (MgSO, ) 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 1-cyclopropyl-6,7,8- :
Lt luoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, mp 168-169°C. This material was dissolved in acetic acid at 100°C and was treated te 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 © eyclopropyl-1, d-dihydro-4-oxo-6,7,8-trifluores” . quinolinecarboxylic acid, mp 226-228°C. : . rr il Orig... 3
A ] Ce . 3
~ 4 4 -
Sof 76771
EXAMPLE N
-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- i,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)-1-piperazinecarboxylic acid, : ethyl ester (prepared as described in European Patent
Publication No. 9425), 76.1 g (0.5 mole) of 0 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU), 28.6 g (0.5 mole) of cyclopropylamine and 500 ml of absolute 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-(Acetylcyclopropylamino)-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}-1-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 m.uxture of ethanol and toluene which was also evaporated in vacuo to give 68.3 g of the title compound, mp . 30 90-93°C. - 4-[6-(Acetylcyclopropylaming)-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
BAD ORIGINAL 9 ee -45-
Jaf 26771 arboxylic 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.
J+ (4- (Ethoxycarbonyl)-1-piperazinyl]-6-(acetylevelos propylamino)-3-pyridinediazonium Tetrafluoroborate
A solution of 20.8 g (60 mmole) of 4-(6-acetyl- ~yclopropylamino)-3-amino-2-pyridinyl)-1-piperazine 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 oo of anhydrous ether keeping the temperature below . 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 ¢@ of the title ‘compound, mp 100-105°C (dec). t \-[6- (Acetylcyclopropylanino)=3-fluoro-2-pyridinyliz 1-piperazinecarboxylic Acid, Ethyl Ester € To 800 ml of refluxing toluene was added in portions, as a solid, 46.2 g (0.1 mole) of 1- {4 (ethoxycarbonyl) -1-piperazinyl]-6-acetyleyeior 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 ’ patween chloroform and water. The chloroform layer 15 was washe. with 5% aqueous sodium bicarbonate, water, : : BAD ORIGINAL 9
~46~ ’ ) - : : Jaf. P77] ried over magnesium sulfate, and evaporated in vacuo 0 give 13.7 g of the title compound, as a viscous sil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction ) was also a viscous oil which did not crystallize upon standing. Both fractions wer" of sufficient purity to be used as is in the ensuing steps. 4-[6-(Cyclopropylamino)-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]-1-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 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- plperazinyl)-1,8-naphthyridine-3-carboxylic Acid
Route A [ [Cyclopropyl[6-[4-(ethoxycarbonyl)-1-piperazinyl]- 5-fluoro-2-pyridinyl)amino]methylene]propanedioic
Acid, Diethyl Ester
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclo- propylamino)-3-fluoro-2-pyridinyl]-1l-piperazine — AN
BAD ORIGINAL
Ce ————— -47- jaf. 70027 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 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 | -cyclopropyl-6-fluoro-1,4-dihydro-d-oxo=]- +- (ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine- 3-carboxylate
A solution of 2.3 g (4.8 mmole) of [[cyclo- sropyl(6-[4-(ethoxycarbonyl)-1-piperazinyl]-3-fluoro »-pyridinyl]aminolmethylene]propanediolc acid, diethyl ester, in 15 ml of acetic anhydride was treated dropwise with 5 ml of 98% sulfuric acid keeping the temperature g5-60°C. When the addit_.on was complete, the reaction was stirred for one hour and poured onto 50 g of ice. The aqueous suspension wag extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was } 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 . v original aqueous fraction, mp 184-186°C.
L-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-
Lopiperazinyl)-1,8-naphthyridine-3-carboxylic Acid
A suspension of 0.7 9 (1.6 mmole) of ethyl -eyclopropyl-6-£luoro-1, 4-dihydro-4-oxo-7-{4- othoxycarbonyl) -1-piperazinyl]-1,8-naphthyridine=3- carboxylate, 6 ml of 10% aqueous sodium hydroxide and 2 ml of ethanol was refluxed for three hours. The reaction was filtered through a fiber glass pad to
———— _..- ; clarify and acidified to PH 1.5 with 6.01 AL : nydrochloric acid and Jyophilized: The residue was : aissolved jp 10 ml of ammonium nydroxide and the | h : solution concentrated in vacuo. The precipitate BN] g which formed was removed PY filtration. washed with B aqueous ethanol, ether, and dried in vacuo to give , 0.04 g, TP 274-276°C- \
Route B on 8 ropa me EE \
S5- jidine amino _3-£luoro=2- ridinyl -1-pi erazine- MN eo carboxylic Acid, Ethyl Ester \
A solution of 17.6 9 (57 mmole) of 4-(6-(cyclo” v propylamine) _3-fluoro-2-P¥F jdinyl} -1-piperaz ine ’ carboxylic acid, ethyl ester, 11.6 @ (63 mmole) of + rie se J ame 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 9d of the title compound, mp 177-178°C- pe EE (ethoX carponyl -1-pi erazinyl -1,8-naphth ridine- . 3-carboxylic Acid " » solution of 17.0 g (37.0 mmole) of ! sent ET — tetera er man VEIT : carboxylic acid, ethyl ester in 125 ml of acetic anhydride was treated dropwise with 35 ml of 98% sulfuric acid keepind the temperature 50-60°C- when the addition was complete. the reaction was stirred for two hours and poured onto 600 4g of ice. The mixture was scirred for one hour and the resulting precipitate was removed by giltration, washed with water, and dried in yacuo to give 10.2 9 of the title compound, ®P 277-279°C-
ee cas fuk, 26777 cyclopropyl -6=fluoro-l, d-dihydro=izose=ts ee erazinyl-l,8-naphthyridines3-carboxrts Acid
A solution of 10.2 g (25 mmole) of l-cyclo- ropyL-6- fluoro-1, d-dihydroa-oxe-T (4 SHY
DE oyl)-1-piperazinyl] 1 8-naphenyridiness” 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 0 resulting precipitate was removed by giltration, washed with 50% aqueous ethanol, ether and dried in vacuo to give 7.2 g of the title compound, mp 274-276°C. cyolopropy)-6-flusro=1, d-dinydroc] ArerEstEs 15 |_8-naphithyridine-3-carboxylic Acid : To a solution of 2 ml of 70% nitric acid in ml of 98% sulfuric acid wes added in portions 1.0 g (3.0 mmole) of | -cyclopropyl-6-fluoro=1,4 co Lower 1-plperazinyl)-},B-napnERY Eine carboxylic acid, keeping the temperature petween : 75-30°C. The resulting solution was stirred at room temperature for 18 houcs and poured onto 40 g of ice.
The mixture was stirred at room remperature for 24 hours, concentrated in vacuo, the pH adjusted to 12 26 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to pH ¢ 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. -chioro-L-cyclopropyl=6-fluore-l, A-aIhVaEestzSEEn ' 8-naphthyridine-3-carboxylic Acid
A suspension of 0.19 ¢ (0.72 mmole) of yeroppapy1-6-Fluoro-1 A-dihydrorT-myaroxy TATE r .
BAD ORIGINAL J hoa
A _
Jat. 2077] ,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 0.11 g of the title compound, mp 209-212°C.
EXAMPLE O
3-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, 4712, (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 usud as is without further purification. '
EXAMPLE P
2-Nitro-3,4,5,6-tetrafluoro--oxobenzenepropanolc
Acid, Ethyl Ester
To a solution of 7.5 g (56.8 mmoles) of malonic i 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 for 15 minutes. The 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- 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
’ . Cte madi ” ff 70771 18 ml of concentrated hydrochloric acid in 50 ml of ice 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 (MgsSO,), and evaporated in vacuo to give 7.3 g of the 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 g {22 mmoles) of 2-nitro- 3 4,5,6-tetrafluoro-p-oxobenzenepropanolc 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 go°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 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 oil which was used without further purification.
EXAMPLE R :
Ethyl 5 -Amino-1-cyclopropyl-6,7,8-trifluoro-1,4= dihydro-4-oxo-3-quinolinecarboxylate
A suspension of 1.9 g (5.3 mmoles) of ethyl
J -eyclopropyl-5-nitro-6,7,8-trifluoro-1, 4-dihydro=d-
Je Bd 7.72 ¢
Jaf J 6727 sjx0-3-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. i0 EXAMPLE S
S-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic Acid
A solution of 0.5 g (1.5 mmoles) of ethyl } 5-amino-1l-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 mg 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.O. 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-trilfuoro-6-nitrobenzoic acid.
BAD ORIGINAL I)
Reps «cet
Ce — — -53- fal 7677]
EXAMPLE U chlora-2,4,5-trifluoro-6=nitrobenzelt chloride
To a suspension of 25.6 ¢@ (100 mmol) of -chloro-2,4,5-trif luoro-g-nitrobenzole 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 rapiuly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 0 27.0 g of the title compound which was used without purification in the next step.
EXAMPLE V
Ethyl (3-Chloro-2,4, 5-trifluoros6-niEro) shoes phenylpropanoate
To 26.4 9 {200 mmol) of malonic half ethyl ester in 500 ml of dry tetrahydrofuran at -35°C was added : g1 ml of n-butyllithium (2.2 M, 200 mmol) drrpwise.
A catalytic amount of pipyridyl {10 mg) was added, and the suspension was warmed to -5°C. Another : 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 hloro-2,4,5-trifluoro-6-nitrobenzovl chloride in 50 ml of tetrahydrofuran was added dropwise. The : © 25 reaction mixture was kept at -78°c for one hour, then warmed to -35°C and poured into a mixture of ice v water (400 ml) and concentrated hydrochloric acid (17 ml). The solution was extracted with dichloromethane; the extracts were combined and washed with 5% sodium bicarbonate, 2M hydrochloric acid, and water. The dichloromethane was dried over magnesium sulfate and concentrated to give 27.4 3g of the title compound. :
B
AD ORIGINAL 9
=-24- if 24727
EXAMPLE W gthyl 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)-g-oxophenyl propanoate was added 18.7 g (126 mmol) of triethyl orthoformate and 100 ml of acetic anhydride. The mixture was refluxed for two hou i, then cooled to ghec, and concentrated to give 31.5 g of the title 0 compound.
EXAMPLE Y
Ethyl 8-Chloro-1l-cyclopropyl-6,7-difluoro-1,4- dihydro-5-nltro-4-oxo-3-quinolinecarhoxylate
The ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitro- : penzoyl)-3-ethoxyacrylate prepared in the previous step was dissolved in 200 ml of t-butanol and treated with 5.0 g (88 mmol) of cyclopropy amine. The reaction mixture was warmed to 45°C and stirred for three hours at that temperature. 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 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 §-Amino-8-chloro-l-cyclopropyl-6,7-difluoro= 1,4-dihydro-4-oxo-3-quinolinecarboxylate ‘ A suspension of 21.7 g (58.2 mmol) of ethyl g-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 the mixture was diluted with dichloromethane and the ee catalyst was removed by filtration. The filtrate was concentrated to give 17.2 9 of the title compound.
EXAMPLE AA
« -Amino-8-chloro-1-cyclopropyl-6,7-difluoro=1, 32 dihydro-4-oxo-3-quinolinecarboxyllc Acid
A suspension of 17.2 g (50.2 mmol) of ethyl « - amino-8-chloro-1-cyclopropyl-6,7-difluoro-l 4- dihydro-4-oxo-3-quinolinecarboxylate in 100 ml of 6 M hydrochloric acld 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: c - amino-8-bromo-1-cyclopropyl=6,7-difluoro=i, 4 dihydro-4-oxo-3-quinolinecarboxylic acid: : c -amino-1-cyclopropyl-6,7-difluoro-g-trifiuoros ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;
C. umino-1-cyclopropyl-6,7-difluoro-1,a-dihydro=8” ethoxy-4-oxo-3-quinolinecarboxylic acid; -. amino: 1-cyclopropyl-6,7-difluoro-1, 4-dihydro=8- hydroxy-4-oxo-3-quinc,.necarboxylic acid; c §-diamino-1-cyclopropyl-6,7-difluoro-l, d-dihydror
A-oxc-3-quinolinecarboxylic acid; Lo : -. omino-1-cyclopropyl-6,7-difluoro-1, 4-dihydro=d- oxo-3-quinolinecarboxylic acid; and ! SN no-7-chloro-1-cyclopropyl-6=fluoro-l, 4-dihydro” 4-oxo-1,8-naphthyridine-3-carboxylic acid.
EXAMPLE BB
| cyclopropyl-6,1,8-trifluoro-l, 4-dihydro=5: (Reshii: amino) -4-oxo-3-quinolinecarboxylic Acid ,
A solution of 5.9 g (20 mmol) of 5-amino-1l- <yelopropyl-6,7,8-trifluoro-1,4-dihydro=d-oxe 3” quinolinecarboxylic acid, 20 ml of trifluoroacetic anhydride, and 100 ml of trifluoro acetic acid was !
BAD ORIGINAL 9
: 77. 2 LU 7 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 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 g (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 iodomethane with continued stirring at 50-55°C for two hours and for three hours at room temperature. The reaction mixture was evaporated and the residue was triturated 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 compound, mp 205-207°C.
In a similar manner, the following compounds were prepared: 8-chloro-l-cyclopropyl-6,7-difluoro- 1, 4-dihydro-5S-(methylamino)-4-oxo-3-quinoline- carboxylic acid: 8-bromo-1-cyclopropyl-6,7-difluoro- 1,4-dihydro-5-(methylamino)-4-oxo-3-quinoline- carboxylic acid; and 1-cyclopropyl-6,7-difluoro-8- trifluorémethyl-1,4-dihydro-S-(methylamino)-4-oxo-3- Co quinolinecarboxylic acid. '
EXAMPLE CC
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-dimethyl- amino-4-oxo-3-quinolinecarboxylic Acid 2-(Dimethylamino)-3,4,5,6-tetrafluorobenzoic Acid
A solution of 10.0 g (41.8 mmol) of 2-nitro- 3,4,5,3-tetrafluorobenzoic acid, 10 ml of 37%
EE
= 2 2671
Jif 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. ‘
J- (pimethylamino)-3,4,5,6-tetrafluorobenzoyt Chloride
To a suspension of 4.22 g (17.8 mmol} of »- (4imethylamino)-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. : -
Co - (pinethylanino)-1,4,5,6-tetrafluoro-B-oxshenaens> ~propanoic Acid, Ethyl Ester oe ee ee
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 remaining 25 ml (40 mmol) of 1.5N putyllithium solution was added at 0°. After cooling to -78°C, a solution of the 4.8 g of 2-(dimethyl- v amino) -3,4,5,6-tetrafluorobenzoyl chloride in 50 ml of THF was added to the dilithio 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 jce, 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 Mgso, the ether solution was concentrated to 4.4 g of oil product.
NMR spectra indicated the desired product.
-98- 3 did 20077
J-(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-[ (Cyclopropylamino)methylene]-2-(dimethylamino)- 10 3,4,5,6-tetrafluoro-p-oxobenzenepropanoic Acid,
Ethyl Ester
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 15 was stirred for 18 hours at room temperature. The reaction mixture 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. (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) 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 reaction 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 3%. compounds were prepared: 8-chloro-1l-cyclopropyl-6,7-
ee or id 2177 oro dines quinolinecarboxyLic acid, and + -promo-1-cycloProPyL” pinot] ro samen quinolinecarboxytic acid.
EXAMPLE DD meses SESE xo 3-quinolinecarborilis Acid ! To 22.4 9 {100 mmol) of the 5 -methoxy-3,4,5+8”
Let rafluorobenzoic acid prepared as in (J. Fluorine
Chem. 3g, 361 (1985) ) was added 400 ml of retrahydrofuran: 1 ml of 4imethylformamide: and 13 ml of oxalylchloride: The acid chloride mixture was concentrated, diluted with 100 ml of retrahydrofuran: and added to a solution of the dilithio anion of malonic acid monoethylester (200 mmol) in goo ml of retrrahydrofuran at -10°C- The reaction was stirred for one hour at -30°C, poured over jce and dilute nydrochloric acid and taken into dichloromethane:
The product was jgolated by an extraction at pH 7. . 20 followed by drying the dichloromethane (MgSO, and concentration. The crude product was then treated neat with 2.5 equivalents of +r ethylorthoformate and } 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 9) was added in 150 ml of t-.itanol. The ’ mixture was gtirred overnight. To this mixture was added 11.3 @ of potassium ¢-putoxide and the temperature prought t0 so*C. The mixture was A concentrated after 18 hours and the residue treated with 100 ml of acetic acid and 100 ml of 4N nydrochloric acid. From this mixture after four hours at 100°C, 12.7 9 of the title compound precipitated: in a similar manner, the following compounds were prepared: Ee eyetoprop1”S THI
Jif 26777 1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 8-bromo-1-cyclopropyl-6,7-difluoro-1,4- dinydro-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. s EXAMPLE EE : 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy- 4-oxo-3-quinolinecarboxylic Acid
To 1.5 g of 1-cyclopropyl-6,7,8-trifluoro-1,4- 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 rollowing compounds were prepared: g-chloro-1-cyclopropyl-6,7-difluoro-1,4- ’ 20 dihydro-5-hydroxy-4-oxo-3-quinolinecarboxylic acid: 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5- hydroxy-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-5-" hydroxy-4-oxo-3-quinolinecarboxylic acid and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-hydroxy-4- oxo-3-quinolinecarboxylic acid. {
Co EXAMPLE 1 1-Ethyl-5-amino-6,8-difluor8-7-[3-(t-butoxycarbonyl- amino)-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline~3- carboxylic Acid
A suspension of 3.02 g (10 mmole) of 1-ethyl-S-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
Ce ——— -61- if 26724 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 td give 1-ethyl-5-amino- 6. 8-di fluoro-1-[ 3-(t-butoxycarbonylamino) ~~
Ce rolidinyl])-d-oxo-1,4-dinydroquinoline-3-carboxyiic acid. Ce,
A
’ EXAMPLE 2 \-Ethyl-5-amino-6,8-difluoro=1={3-anino=i- rrolldinyl)-4-oxo-1,4-dihydroquinoline=3-carboryLic
Acid Hydrochloride
A near solution of 4.5 g (10 mmole) of 1-ethyl- <- amino-6, 8-41 luoro=T-[3- (t-butoxycarbonylamino) =~
Se rolidimyl]-d-oxo-1,4-dihydroquinoline-3-carboxy Le ls 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 remperature for 18 hours.
The solvent is removed in vacuo, the residue triturated with ethanol/ether (1:1), giltered, washed with ether, and dried in vacuo to give the title compound. :
EXAMPLE 3 -sthyl-5-anino-6,8-dif luoro=T=(3-(ethylaninolmethyis
I_pyrrolédinyl] |-4-oxo-1,4-dihydroquinoline=3- { 25 carboxylic Acid
A suspension of 3.02 g (10 mmole) of ‘ | -ethyl-5-amino-6,7,8-trifluoro-4-oxo=1, 4-dihydre quinoline-3-carboxylic acid, 1.93 g (15 mmole) of
N-ethyl-3-pyrrolidinemethananine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is 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= coc-
Wd. 26779 7-(3-(ethylamino)methyl-1-pyrrolidinyl))-4-oxo-1,4~ dihydroquinoline-3-carboxylic acid.
The following compounds may be prepared from l-ethyl-5-amino-6,7,8-trifluocro-4-oxo-1,4-dihydro- - quinoline-3-carboxylic acid and the desired amine or protected amine using the method above: l1-ethyl-5-amino-6,8-difluoro-7-(3-(aminomethyl)-1- pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 1-ethyl-S5-amino-6,8-difluoro-7-(3-(propylamino- methyl) -1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid; l-ethyl-S-amino-6,8-difluoro-7-(3- (2-propylaminomethyl)-1-pyrrolidinyl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid; l1-ethyl-S5-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]-A-oxo-1,4-dihydroquinoline-3- ‘ carboxylic acid; l-ethyl-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]non-2-yl]- 4-oxo-1,4~dihydroquinoline-3-carboxylic acids” . 1-ethyl-5-amino-6,8-difluoro-7-(3-([(2-hydroxyethyl)- amino]methyl]-1-pyrrolidinyl]-4-oxo-1,4-dihydro- quinoline-3j-carboxylic acid; and l-ethyl-5-amino- 6,8-d1fluoro-7-[3-[((2,2,2-trifluoroethyl)amino] methyl]-1-pyrrolidinyl]-4-oxo-1,4~-dihydroquinoline- ‘ ] J-carboxylic acid. ;
EXAMPLE 4 ¥ 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
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
————— of. 26777 (15 mmole) of J ( £-butoxycarbony amino) pYEroLidines 3.03 g (30 mmole) of triethylamine and 100 ml of
N,N-dimethyl formamide {gs heated at 100°C for four hours. The solvent is removed in vacuo and the ; residue 1s criturated with water. The aqueous 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 g-amino-
En pethyl-10-((3-t-puroxyeerbon LaninO an 1 Tooxo-, J-dihydro- Thrash 208 (1, 4]benzoxazine-6-carboxylic acid. ‘ EXAMPLE 5 + Amino=9-fluoro-3-methyl-10= (amines
Ce ronor2, -dihyaro-Tiopyridoll 2275S oevaosarine-g-carborylis Acid, BIareciotiSs
A suspension of 4.63 4 {10.0 mmole) of eoton1-nethyL-L0-{ (3 UOXICAE amino) -1-pyrrolidinyl ] -7-0%0-2, 3-dihydro-7H-pYT ido
LT 3-de](1,4]benzoxazine-6-carsoxIle acid 5 ml of 2p 6.0 M hydrochloric acid and 50 ml of glacial acetic acid is heated at go°c for four hours. The solvent is rpmoved in vacuo and the residue is triturated with ethanol/ether (1:1). The precipitate is removed : by filtration, washed with ether, and dried in vacuo to give NE o-9-E luoro-)-methyl-10=(3-aminoT” ro Le ire -ono-2, J-ainydro-TH-RYEAST LF TE { (1, 4]benzoxazine-6-carboxylic acid, hydrochloride. . EXAMPLE 6 ’ + inous- fluoro -methyl=10-((3-eyEloREeRLSN AC "
Ee diny }-7-oxo-2, dinar TPT : 3-de)(1,4)benzoxazine-6-careOTY LC Acid
A mixture of 2.96 g (10 mmole) of g-amino-9,10-
Lumen a-methyl--oxo-2,J-dinydro THIEVES
7 A) 7 - if 7771 [1,2,3-del)(1,4)benzoxazine-6-carboxylic acid, 2.1 g (15 mmole) of N-cyclopropyl-3-pytrolidinemethanamine, 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 hyurochloric acid. The solid is removed by filtration, washed with water, and dried in vacuo to give 8-amino-9-fluoro-3-methyl-10-[(3-cyclopropyl- aminomethyl)~-1-pyrrolidinyl)-7-oxo-2,3-dihydro-7H- pyrido(1,2,3-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-del[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; g8-amino-9-fluoro-3-methyl-10-(3-((propylamino)- methyl) -1-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-[(2-hydroxyethyl})- amino)methyl]-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H- pyrido(l,2,3-de)(1,4]benzoxazine-6-carboxylic acid: g8-amino-9-fluoro-3-methyl-10~[3~{(2~-propylamino)- methyl)-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]-l-pyrrolidinyl]-7-oxo-2,3~ dihydro-7H-pyrido(1l,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](1,4)benzoxazine-6- 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-h-carboxylic acid;
Ce ——————— -n3- Aga 5 fa) 777] +- amino-9-£luoro-3-methyl-10-(7-(7-metnyl)=2, 7” iro(d. d)non-2-yl]-T-oxo-2,3-dihydro-T-PYride (1.2,3-de)1,4]benzoxazine-6-carboxylic acid; and -omino-9-£Luoro-3-methyl-10-(7-(7-ethyl) 2, 7~ epirold. d]non-2-yl]-T-oxo-2,3-dihydro=TH-PYEide (1,2,3-de](1,4]benzoxazine-6-carboxylic acid.
EXAMPLE 7 q Amino-L-cyclopropyl-6,8-difluoro=7=[ (3-ethylanine: ethyl) -lopyrrolidinyl]-1,4-dihydro=4-0Xe=3: quinolinecarboxylic Acid
A solution of 0.43 g (1.5 mmoles) of «amino. 1-cyclopropyl-6.7,8-Erifluoro-l, 4-dibydroms oxo-3-quinolinecarboxylic acid, 0.61 g (6.0 mmoles) of triethylamine, 0.77 gq (6.0 mmoles) j-(ethylamino- : methyl)pyrrolidine and 25 ml of acetonitrile was heated at reflux for two hours. The solvent was reroved in vacuo and the residue w7sS 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 <-minoo7-(3-anino-l-pyrrolidinyl)-8-chlorosiocyeles ‘ © sopyl-6-fluoro-1,d-dihydro-4-oxo:d-dulnolines carboxylic Acid
To 1.57 g (5 mmol) of 5-amino-8-chloro-1-cyclo= ropyl-6,7-difluoro-1, 4-dihydro-4-oxo=dauine’ °° carboxylic acid in 20 ml of acetonitrile was added 0.93 g (5 mmol) of 3-{ (t-butoxycarbonyl) amino] pyrrolidine and 1.0 g (10 mmol) of triethylamine. :
So The mixture was refluxed for three hours, cooled, and filtered. The solids were washed with acetonitrile and ether, then dissolved in 10 ml of acetic acid and
- - ) - °° Jif 20779 2 ml of 3 N hydrochloric acid. The mixture was heated at 100°C for four hours, concentrated, and trriturated with 2-propanol. The solid that formed was filtered and washed with ether to give 1.2 g of the title compound.
The following compounds were also prepared by a similar procedure: §-amino-8-chloro-1-cyclopropyl-7- (3-[ (ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4- 'dihydro-4-oxo-3-quinolinecarboxylic acid; 10 5 -amino-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 7-{3-{ (methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3- quinolinecarboxylic acia? 5-amino-8~-chloro-l-cyclo- propyl-6-fluoro-1,4-dihydro-7-(3-{(dimethylamino) methyl ]-1-pyrrolidinyl]-4-oxo-3-quirolinecarboxylic 15 actdf’ s-amino-7-(3-(aminomethyl)-3-methy’" 1” . pyrfolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid 5-amino-8- bromo-1-cyclopropyl-7-[2-[(ethylamino)methyl]-1- pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinoline= 20 carboxylic acid}, 5-amino-8-bromo-1-cyclopropyl-6- fluoro-1,4-dihydro-7-[3-[ (methylamino)methyll-1- pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acidf/ - amino-B8-bromo-1-cyclopropyl-6-fluoro-1, 4-dihydro- 7-[3-[ (dimethylamino)methyl]-1-pyrrolidinyl]-4-oxo= 25 3-quinolinecarboxylic acidy/s-amino-7-(3-amino-1- pyrrolidinyl)-8-bromo-1-cyclopropyl-6-fiyoro-l, 4- ¢ dihydro-4-oxo-3-quinolinecarboxylic acid/’ 5-amino-7- (1-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8- trifluoromethyl-1,4-dihydro-4-oxo-3-quinoline= : 30 carboxylic acid} 5-amino-1-cyclopropyl-6-fluoro-8- trifluoromethyl-1,4-dihydro-7-(3-[(methylamino) methyl] -1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid; ¢-amino-1-cyelopropyl-7-[3-((ethylamino) methyl ]-1-pyrrolidinyl]-6-fluoro-8-trifluoromethyl- 4-oxo-3-quinolinecarboxylic acid/ S-amino-1l-cyclo- oropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro=7- . (3-[ (dimethylamino)methyl]-1-pyrrolidinyl]-4-oxo=3-
eC —— — -67- Cal fuf 20771 quinolinecarboxylic acid; 5-amino-l-cyclopropyl-7- (3-1 othylamino)methyl]-1-pyrrolidinyl]-6-£luoro=s ,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid: « - amino-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (3 | (methylamino)methyl]-1-pyrrolidinyl]-g-methoxy=4- oxo-3-quinolinecarboxylic acid) S-amino-1- : cyclopropyl-6-£luoro-1,4-dihydro-7-{ 3-[(dimethyl- + ino)methyl]-1-pyrrolidinyl]-8-methoxy-4-oxo=3" quinolinecarboxylic acid §-amino-7-(3-amino-1- erolidinyl)-1-cyclopropyl-6-fluoro-l,dzdihvdro-8- methoxy-4-oxo-3-quinolinecarboxylic acid) 5-amino-1- eyclopropyl-7-[3-{(ethylamino)methyl}=1- _yrrolidinyl]-6-fluoro-1,4-dihydro-8-hydroxy=4-oxor 3-quinolinecarboxylic acid] s-amino-1-cyclopropyl= +f 1uoro-1, 4-dlhydro-8-hydroxy-7-(3-( (methylanino) © thyll-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxyl e : reid) 's-amino-1-cyclopropyl-6-fluoro-l, d-dihydra-s re scoxy-1-(3-({dimethylanino methyl] -1-pyrrolidinyl ”
A-oxo-3-quinolinecarboxylic seid Samtne Te
Ca 29 oreroiidingl) -L-cyclopropyl-s-Eluoro-d, 4-aihydre- o-nydroxy-A4-oxo-3-quinolinecarboxylie acids Lat ee a
ST tno-1-pyrrolidinyl) -8-chloro-1-cyclopropyl=6- f1uoro-1, 4-dihydro-5-methoxy-4-oxo-3-quinoline” carboxylic acid} 7-(3-amino-1-pyrrolidinyl)-8-chloro=
Co elopropyl-6-Eluoro-1,4-dihydro-5-hydroxy-4-oxo-3” quinolinecarboxyllc acid] 7-(3-amino-1-pyrrolidinyl)= \ TR rare-T-cyclopropyl-6-fluoro-1, d-dinydro-Smethy.” amino-4-oxo-3-quinolinecarboxylic acidf/ 7-(3-anino-1- ’ rrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-d 4 bvdro-5-dimethylanino-4-oxo-3-quinolinecarboxyiie acid; s-onloro-1-cyclopropyl-7-(3-((dinethylanino} thyl]-1-pyrrolidinyl)-6-fluoro=1, 4-dihydro=s ethoxy-4-oxo-3-quinolinecarboxylic acid’ ne raro-1-cyclopropyl-7-[3-( (dimethylaninoimethy} |” | yrrolidinyl]-6-fluoro-1,d-dihydro-S-hydroxy=drorer j-quinolinecarboxylic acid.’
Claims (6)
1. A compound of the formula 3 Y o° F I CO,R Tig NY : 5 ~~ NceH 3 I1 wherein Z is Fla -N D— tergag, mame, or Ne C ' (CH), cH § Yah 270 (CRsRE I ~N N—R, Y is 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: 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; I, is hydrogen, alkyl having from one to six carbon atoms: Rs is hydrogen, alkyl having from one to four carbon atoms or cycloalkyl having three to six carbon atoms: Ra is hydrogen, alkyl from one to four carbon atoms, hydroxyalkyl having two to four carbon atoms, trifluorocethyl or R,CO- wherein R» is alkyl having from one to four carbon atoms, or alkoxy having from one to four carbon atoms; Res is hydrogen, or alkyl
Co — —
Td. 26127 ~- 69 having from one to Lhree carbon aloms; Re is hydrogen or alkyl having from one to three carbon atoms; and the pharmaceutically acceptable acid addition or base salts thereof.
5 .
A. A process for the preparation of a compound as claimed in Claim 1 which comprises reacting a compound of the formula Y 0 ry ZN oo Aer, wherein IL is fluorine or chlorine with an amine corresponding to the group 2 wherein 2 is (C45) n N-(chy) We wet Tag tees ee ae eee eee eT aN ee .“ n eM (CRgPe dy -N YC N—R, : Nach, ly Ne en y is NHR, NRR', OR, or OH wherein R and R' are each independently an atkyl of from one to six carbon atoms . or a cycloalkyl of from three to six carbon atoms: n is 1, 2, 3 or 4; n' is L, 2, 3, or 4 wherein n Ft ntois a Lotal of 2, 3, 4, ov 5, and nods 0, 1, or 2: Ry is hydrogen, alkyl having from one to six carbon atoms oY a cation; Ra is hydrogen, alkyl having from one to four carbon atoms oY cycloalkyl having three to six . 35 carbon atoms; Ra is hydrogen, alkyl from one to four carbon atoms, hydroxyalkyl having two to four carbon © atoms. trifluoroethyl or R-CO- wherein Rs is alkyl having from one to tour carbon atoms, or alkoxy having from one to four carbon atoms: Hs is hydrogen, or
.- ol Gad 20777 —- TY - oT alkyl having from one to three carbon atoms; Rs i= hydrogen or alkyl having from one to three carbon atoms; and, if desired, converting the resulting product Lo a pharmaceutically acceptable acid addition or base salt Lhereof by known melhods.
3. A pharmacentical composition comprising an anti-bacterially effective amount of a compound as claimed in Claim 1 together wilh a pharmaceutically acceptable carrier.
4. B8--Amino-9-fluoro-3-methyl-10-1(3-Lt-butoxy— carbonylamino)-1l-pyrrolidinyl}-7-oxo-2, 3-dihydro-7H- pyrido{l,2,3-del(l,4}benzoxazine-6—carboxylic acid.
5. B8-Amino-9-fluoro-3-methy1-10--(3-amino--1-- pyrrolidinyl)-7-oxo--2,3-dihydro -7H-pyrido(l,2,3-de}- : {1.4} benzoxazine-6-"carboxylic acid, hydrochloride.
6. 8-Amino-9-fluoro-3-methy!1-10-(3-cyclopropyl-—- aminomethyl)-1-pyrrolidiny!)-7-oxo-2,3-dihydro-7H-pyrido .
(1.2,3-del- 11,4)benzoxazine-6-carboxylic acid. JOHN M. DOMAGALA THOMAS F. MICH JOSEPH i". SANCHEZ (Inventors)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 |
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 |
PH35962A PH24199A (en) | 1986-10-20 | 1987-10-20 | Derivatives of quinoline carboxylic acid,pharmaceutical composition containing same and process of preparing same |
PH38419A PH26729A (en) | 1986-10-20 | 1989-04-03 | Benzoxazines useful as antibacterial preparation thereof and pharmaceutical composition containing them |
Publications (1)
Publication Number | Publication Date |
---|---|
PH26729A true PH26729A (en) | 1992-09-28 |
Family
ID=26652372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH38419A PH26729A (en) | 1986-10-20 | 1989-04-03 | Benzoxazines useful as antibacterial preparation thereof and pharmaceutical composition containing them |
Country Status (1)
Country | Link |
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PH (1) | PH26729A (en) |
-
1989
- 1989-04-03 PH PH38419A patent/PH26729A/en unknown
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