IE84193B1 - 7-(1-Pyrrolidinyl)-3-quinolone and naphthyridone carboxylic acid derivatives, method for their preparation and for substituted mono- and bicyclic pyrrolidine intermediates, and their antibacterial and feed additive compositions - Google Patents
7-(1-Pyrrolidinyl)-3-quinolone and naphthyridone carboxylic acid derivatives, method for their preparation and for substituted mono- and bicyclic pyrrolidine intermediates, and their antibacterial and feed additive compositions Download PDFInfo
- Publication number
- IE84193B1 IE84193B1 IE1997/0856A IE970856A IE84193B1 IE 84193 B1 IE84193 B1 IE 84193B1 IE 1997/0856 A IE1997/0856 A IE 1997/0856A IE 970856 A IE970856 A IE 970856A IE 84193 B1 IE84193 B1 IE 84193B1
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- IE
- Ireland
- Prior art keywords
- oxo
- dihydro
- acid
- methyl
- diazabicyclo
- Prior art date
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- -1 naphthyridone carboxylic acid derivatives Chemical class 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 title abstract description 246
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract description 27
- 230000000844 anti-bacterial Effects 0.000 title abstract description 9
- 239000003674 animal food additive Substances 0.000 title abstract description 7
- 239000000543 intermediate Substances 0.000 title abstract description 7
- OBNVVQVZIMRUGW-UHFFFAOYSA-N 7-pyrrolidin-1-yl-2H-quinolin-3-one Chemical compound C1=CC2=CC(=O)CN=C2C=C1N1CCCC1 OBNVVQVZIMRUGW-UHFFFAOYSA-N 0.000 title 1
- 125000002619 bicyclic group Chemical group 0.000 title 1
- 125000002950 monocyclic group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 173
- 239000002253 acid Substances 0.000 claims abstract description 96
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 61
- 239000011780 sodium chloride Substances 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 23
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 239000000460 chlorine Substances 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 20
- 150000002367 halogens Chemical group 0.000 claims abstract description 20
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 19
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- 239000011737 fluorine Substances 0.000 claims abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 238000007792 addition Methods 0.000 claims abstract description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 14
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 10
- 230000001681 protective Effects 0.000 claims abstract description 10
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims abstract description 9
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 7
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 5
- 230000001580 bacterial Effects 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims abstract description 4
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 4
- 235000008957 cocaer Nutrition 0.000 claims abstract description 4
- 150000004677 hydrates Chemical class 0.000 claims abstract description 4
- 239000011630 iodine Chemical group 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000654 additive Substances 0.000 claims abstract description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 235000019730 animal feed additive Nutrition 0.000 claims abstract 6
- 235000019770 animal feed premixes Nutrition 0.000 claims abstract 4
- 125000006414 CCl Chemical group ClC* 0.000 claims abstract 2
- FAKRCMADVNJVKV-UHFFFAOYSA-N NN(F)C Chemical compound NN(F)C FAKRCMADVNJVKV-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical class NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 claims abstract 2
- 125000005059 halophenyl group Chemical group 0.000 claims abstract 2
- 239000004332 silver Substances 0.000 claims abstract 2
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052709 silver Inorganic materials 0.000 claims abstract 2
- 125000001544 thienyl group Chemical group 0.000 claims abstract 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- LWZDUZOSIKVXAA-UHFFFAOYSA-N COC1=C(C(=C(C=C1)SF)SC)S Chemical compound COC1=C(C(=C(C=C1)SF)SC)S LWZDUZOSIKVXAA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 241000735552 Erythroxylum Species 0.000 claims 1
- 230000000996 additive Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 195
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 181
- 238000002844 melting Methods 0.000 abstract description 177
- 238000009835 boiling Methods 0.000 abstract description 154
- 239000000243 solution Substances 0.000 abstract description 149
- 238000000354 decomposition reaction Methods 0.000 abstract description 127
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 124
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 121
- 238000010992 reflux Methods 0.000 abstract description 118
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 86
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 74
- 239000000706 filtrate Substances 0.000 abstract description 73
- 235000019441 ethanol Nutrition 0.000 abstract description 72
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 66
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 abstract description 65
- 238000006243 chemical reaction Methods 0.000 abstract description 65
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 60
- 239000000047 product Substances 0.000 abstract description 58
- 239000002244 precipitate Substances 0.000 abstract description 56
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 50
- 235000011167 hydrochloric acid Nutrition 0.000 abstract description 47
- 229960000443 hydrochloric acid Drugs 0.000 abstract description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 47
- 239000000284 extract Substances 0.000 abstract description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 42
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 abstract description 40
- KWIUHFFTVRNATP-UHFFFAOYSA-N Trimethylglycine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract description 36
- 238000001816 cooling Methods 0.000 abstract description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 33
- TVMXDCGIABBOFY-UHFFFAOYSA-N Octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 abstract description 32
- 239000000126 substance Substances 0.000 abstract description 32
- 239000003054 catalyst Substances 0.000 abstract description 31
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 abstract description 30
- 239000003921 oil Substances 0.000 abstract description 30
- 235000019198 oils Nutrition 0.000 abstract description 30
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 30
- 235000015320 potassium carbonate Nutrition 0.000 abstract description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 27
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 27
- 239000001184 potassium carbonate Substances 0.000 abstract description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 24
- 239000003610 charcoal Substances 0.000 abstract description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 abstract description 24
- 239000000725 suspension Substances 0.000 abstract description 24
- 201000009910 diseases by infectious agent Diseases 0.000 abstract description 23
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 abstract description 22
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 abstract description 22
- 239000012074 organic phase Substances 0.000 abstract description 22
- 235000011121 sodium hydroxide Nutrition 0.000 abstract description 22
- 239000003826 tablet Substances 0.000 abstract description 22
- 229960001701 Chloroform Drugs 0.000 abstract description 21
- 239000012043 crude product Substances 0.000 abstract description 20
- 239000007787 solid Substances 0.000 abstract description 20
- 239000007858 starting material Substances 0.000 abstract description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 19
- 229960003237 betaine Drugs 0.000 abstract description 18
- 239000005457 ice water Substances 0.000 abstract description 18
- 244000052769 pathogens Species 0.000 abstract description 18
- 239000000741 silica gel Substances 0.000 abstract description 18
- 229910002027 silica gel Inorganic materials 0.000 abstract description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 abstract description 16
- 230000001717 pathogenic Effects 0.000 abstract description 16
- KIWWEIOFOPULSX-UHFFFAOYSA-N 6-oxa-3-azabicyclo[3.1.0]hexane Chemical class C1NCC2OC12 KIWWEIOFOPULSX-UHFFFAOYSA-N 0.000 abstract description 14
- AYJRCSIUFZENHW-UHFFFAOYSA-L Barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 abstract description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 14
- 239000008346 aqueous phase Substances 0.000 abstract description 14
- 238000004587 chromatography analysis Methods 0.000 abstract description 14
- 239000000843 powder Substances 0.000 abstract description 14
- 150000003254 radicals Chemical class 0.000 abstract description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 14
- 239000001117 sulphuric acid Substances 0.000 abstract description 14
- 235000011149 sulphuric acid Nutrition 0.000 abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 abstract description 13
- 239000000839 emulsion Substances 0.000 abstract description 12
- 239000000499 gel Substances 0.000 abstract description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract description 12
- 238000001819 mass spectrum Methods 0.000 abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 abstract description 12
- 235000011152 sodium sulphate Nutrition 0.000 abstract description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 abstract description 11
- 229910052763 palladium Inorganic materials 0.000 abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 11
- 206010039447 Salmonellosis Diseases 0.000 abstract description 10
- 239000002775 capsule Substances 0.000 abstract description 10
- 238000010410 dusting Methods 0.000 abstract description 10
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 10
- 239000011734 sodium Substances 0.000 abstract description 10
- MKRBAPNEJMFMHU-UHFFFAOYSA-N 1-benzylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CC=CC=C1 MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 abstract description 9
- KSCPLKVBWDOSAI-UHFFFAOYSA-N 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine Chemical compound N1CCCC2CNCC21 KSCPLKVBWDOSAI-UHFFFAOYSA-N 0.000 abstract description 9
- 229960000583 Acetic Acid Drugs 0.000 abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 9
- WVMSAVCBJVBMGC-UHFFFAOYSA-N ethyl 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c][1,2]oxazole-5-carboxylate Chemical compound C1ONC2CN(C(=O)OCC)CC21 WVMSAVCBJVBMGC-UHFFFAOYSA-N 0.000 abstract description 9
- 235000019253 formic acid Nutrition 0.000 abstract description 9
- 238000010438 heat treatment Methods 0.000 abstract description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 9
- 229910052708 sodium Inorganic materials 0.000 abstract description 9
- YETODIXQMRZKEG-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropyrrolo[2,3-c]pyrrole Chemical compound C1NCC2NCCC21 YETODIXQMRZKEG-UHFFFAOYSA-N 0.000 abstract description 8
- 241000282412 Homo Species 0.000 abstract description 8
- 239000011230 binding agent Substances 0.000 abstract description 8
- 239000003085 diluting agent Substances 0.000 abstract description 8
- 239000008187 granular material Substances 0.000 abstract description 8
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;N-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 8
- 239000002674 ointment Substances 0.000 abstract description 8
- 239000003208 petroleum Substances 0.000 abstract description 8
- 239000012071 phase Substances 0.000 abstract description 8
- 239000006187 pill Substances 0.000 abstract description 8
- 239000007921 spray Substances 0.000 abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 abstract description 8
- YYKNVQTUDLJKGI-RNFRBKRXSA-N (3R,4R)-N-ethyl-4-methylsulfanylpyrrolidin-3-amine Chemical compound CCN[C@@H]1CNC[C@H]1SC YYKNVQTUDLJKGI-RNFRBKRXSA-N 0.000 abstract description 7
- ZHFGWIOLVRSZNQ-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(Cl)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ZHFGWIOLVRSZNQ-UHFFFAOYSA-N 0.000 abstract description 7
- 241000282414 Homo sapiens Species 0.000 abstract description 7
- 239000005662 Paraffin oil Substances 0.000 abstract description 7
- 235000011054 acetic acid Nutrition 0.000 abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 7
- 238000004821 distillation Methods 0.000 abstract description 7
- 238000004817 gas chromatography Methods 0.000 abstract description 7
- 239000008079 hexane Substances 0.000 abstract description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 abstract description 7
- 235000019341 magnesium sulphate Nutrition 0.000 abstract description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 7
- 229920001817 Agar Polymers 0.000 abstract description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 abstract description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract description 6
- 241001465754 Metazoa Species 0.000 abstract description 6
- 206010034674 Peritonitis Diseases 0.000 abstract description 6
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 abstract description 6
- 235000010419 agar Nutrition 0.000 abstract description 6
- 238000009632 agar plate Methods 0.000 abstract description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 abstract description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract description 6
- 235000012216 bentonite Nutrition 0.000 abstract description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 6
- 230000037396 body weight Effects 0.000 abstract description 6
- 201000004813 bronchopneumonia Diseases 0.000 abstract description 6
- 239000007795 chemical reaction product Substances 0.000 abstract description 6
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 abstract description 6
- LBLQPBVEGKLIEU-UHFFFAOYSA-N ethyl N-(2,2-dimethoxyethyl)carbamate Chemical compound CCOC(=O)NCC(OC)OC LBLQPBVEGKLIEU-UHFFFAOYSA-N 0.000 abstract description 6
- 239000008098 formaldehyde solution Substances 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- 244000005700 microbiome Species 0.000 abstract description 6
- 230000002829 reduced Effects 0.000 abstract description 6
- 235000012239 silicon dioxide Nutrition 0.000 abstract description 6
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- QNIXILGOUVOCEP-UHFFFAOYSA-N N-methyl-N-(2-methylprop-2-enylideneamino)methanamine Chemical compound CN(C)N=CC(C)=C QNIXILGOUVOCEP-UHFFFAOYSA-N 0.000 description 1
- VDTCYKQQQXJJGA-UHFFFAOYSA-M NC1CCCN1C([O-])=O Chemical compound NC1CCCN1C([O-])=O VDTCYKQQQXJJGA-UHFFFAOYSA-M 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 102100006888 POU3F2 Human genes 0.000 description 1
- 101710023958 POU3F2 Proteins 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 241000588912 Pantoea agglomerans Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000093692 Prosthemadera novaeseelandiae Species 0.000 description 1
- 229940055033 Proteus mirabilis Drugs 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-M Sodium 2-anthraquinonesulfonate Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)[O-])=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-M 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N Sulfur dichloride Chemical class ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229940040944 Tetracyclines Drugs 0.000 description 1
- KKIOSFKOGSMUAC-UHFFFAOYSA-N [4-(dimethylamino)pyrrolidin-3-yl] acetate Chemical compound CN(C)C1CNCC1OC(C)=O KKIOSFKOGSMUAC-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- UCYRHKZMNROTDG-UHFFFAOYSA-N amino pyrrolidine-1-carboxylate Chemical compound NOC(=O)N1CCCC1 UCYRHKZMNROTDG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical group [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WOBLPDAWNVAVAS-UHFFFAOYSA-M butoxycarbonyl carbonate Chemical compound CCCCOC(=O)OC([O-])=O WOBLPDAWNVAVAS-UHFFFAOYSA-M 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- QMZLCHBVQNZKKS-UHFFFAOYSA-N ethyl 1-(2,4-difluorophenyl)-5,6,7,8-tetrafluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(F)=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F QMZLCHBVQNZKKS-UHFFFAOYSA-N 0.000 description 1
- MVNQINIRVJCBTQ-UHFFFAOYSA-N ethyl N-(2,2-dimethoxyethyl)-N-(2-methylprop-2-enyl)carbamate Chemical compound CCOC(=O)N(CC(C)=C)CC(OC)OC MVNQINIRVJCBTQ-UHFFFAOYSA-N 0.000 description 1
- SXIOXBYMPVICFV-UHFFFAOYSA-N ethyl N-(2,2-dimethoxyethyl)-N-prop-2-enylcarbamate Chemical compound CCOC(=O)N(CC=C)CC(OC)OC SXIOXBYMPVICFV-UHFFFAOYSA-N 0.000 description 1
- IQQODTFRDRREIO-UHFFFAOYSA-N ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate Chemical compound CCOC(=O)N(CC=C)CC=O IQQODTFRDRREIO-UHFFFAOYSA-N 0.000 description 1
- PSQPCOVSACYBOX-UHFFFAOYSA-N ethyl N-but-2-enyl-N-(2,2-dimethoxyethyl)carbamate Chemical compound CCOC(=O)N(CC=CC)CC(OC)OC PSQPCOVSACYBOX-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 239000000174 gluconic acid Chemical class 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Chemical class 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- DUGNFQGRDJUREQ-UHFFFAOYSA-N methyl N-(4-methoxypyrrolidin-3-yl)carbamate Chemical compound COC1CNCC1NC(=O)OC DUGNFQGRDJUREQ-UHFFFAOYSA-N 0.000 description 1
- DDCYYCUMAFYDDU-UHFFFAOYSA-N methyl thiohypochlorite Chemical compound CSCl DDCYYCUMAFYDDU-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical group CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrugs Drugs 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- DASZTFGYDXJWBT-UHFFFAOYSA-N quinoline-2-carboxylic acid;hydrochloride Chemical compound Cl.C1=CC=CC2=NC(C(=O)O)=CC=C21 DASZTFGYDXJWBT-UHFFFAOYSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 102220007331 rs111033633 Human genes 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- KAGVQRIRFSJQHD-UHFFFAOYSA-N sodium;hydride;oxolane Chemical compound [H-].[Na+].C1CCOC1 KAGVQRIRFSJQHD-UHFFFAOYSA-N 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000001384 succinic acid Chemical class 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RVUGUSZSDYIZMS-CABCVRRESA-N tert-butyl N-[(3R,4S)-1-benzyl-4-methoxypyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)[C@@H](OC)CN1CC1=CC=CC=C1 RVUGUSZSDYIZMS-CABCVRRESA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
Abstract
ABSTRACT 7-(1-Pyrrolidinyl)-3-quinolone- and —naphthyridone- carboxylic acid derivatives, processes for their preparation and substituted (oxa)diazabicyclooctanes and -nonanes as intermediate products for their preparation, and antibacterial agents and feed additives containing them. This invention relates to 7—(l-pyrrolidinyl)-3- quinolone- and -naphthyridone—carboxylic acid derivatives of the formula I T2 ° x1\V/;-‘\"/I \/coon? (I) I I I 33/*§A;L\N in which X1, X2, R1, R2, R3 and A have the meanings given in the description, processes for their preparation and substituted (oxa)diazabicyclooctanes and ~nonanes as intermediate products for their preparation, and antibacterial agents and feed additives containing them. PATENTS ACT, 1992 7—(1—PYRROLIDINYL)-3-QUINOLONE— AND -N§§hTHYRIDONEcARBOxILIc ACID DERIVATIVES, PROCESSES FOR THEI§9PREPARATION AND SUBSTITUTED (OXA)DIAZABICYCLO0CTANES AND -NON%§§S As INTERMEDIATE PRODUCTS FOR THEIR PREPARATION, AND ANTIBAcTg§IAL AGENTS AND FEED ADDITIvEs cON3$ENING THEM I;-—-:_‘~:,,e~ -;~—-.».E. _. -. OP'.'.."I, ' ' " _ 'H’)N Sr_"“Y‘ ~_ yryl ‘_:.“-r,: '45-.’ 2‘ JNL .'~§O......:.\.'.§1......OF.....g..i'f3..{....;._‘3" . Im ct g ‘r '., ., I‘ (L: BAYER AKTIENGESELLSCHAF M114“ 3: /W7. ")1 /SZL’ 3D5$lfl23kQfl? ‘Q C/ A‘ /-(-.'S//—( IE 970856 The invention relates to new 7-(1-pyrro1idiny1)—3-quino- lone- and -naphthyridonecarboxylic acid derivatives, processes for their preparation and antibacterial agents and feed additives containing them. A number of 3-quinolone- and naphthyridonecarboxylic acids which are substituted in the 7-position by a pyrro- lidinyl ring have already been disclosed. German Patent Application 3,318,145 and European Patent Applications 106,489 and 153,826. It has been found that the 7-(1—pyrro1idinyl)-3—quino- lone- and naphthyridonecarboxylic acid derivatives of the formula (I) I2 3 xi _, x./coosz I if | R3 ~;y.~,, in which X‘ represents halogen, X2 represents hydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 10 R’ IE 970856 carbon atoms, arylthio or halogen, represents alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethy1- amino or phenyl which is optionally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2—oxo-1,3-dioxol-4-y1)—methy1, represents a radical of the structure R‘ Z-R4 3- R x~+- H-—-z r+—,—~,;».~ . N\ ’ 5 ’ - N D ' N /Y R~\1‘ , l coon? (VI) R3‘/l§A N in which X’, X2, R3, R2 and A have the abovementioned meaning and 10 R“ represents a radical having the structure R‘ z-R4 54“ B‘ -N /w~ r ,4v \ 3 " ,- ‘-r-- ' or ’ T’. I Y P” N‘ *1 IV I 9” [ _ 11 - IE 970856 wherein R5’ R5’ R1’ Ru’ Ru!’ meaning, Y and 2 have the abovementioned is reacted with compounds of the formula (VII) R‘-x‘ (VII) in which R‘ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine, hydroxyl or acyloxy, if appropriate in the presence of acid entrainers (method If, for A example, 1-cyclopropyl-6,7,8-trifluoro—1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methy1- octahydropyrrolo[3,4-b]pyridine are used as starting substances, the course of the reaction can be represented by the following equation: -12- IE 970856 F-‘\.V,_/, \ / ~.‘,r L .,:o,{ \/’ \ E 2 9 2- | !] | a [ I H H -—‘ — I r ‘»u/ 3 *», - If, for example, 7-ch1oro-6-f1uoro-1-(4-fluorophenyl)- 1,4-dihydro-4-oxo-1,B—naphthyrid1ne-3-carboxylicacidand cia-3—tert.—butoxycarbonylamino-4—methoxy-pyrrolidine are used as starting substances, the course of the reaction can be represented by the following equation: - 13 _ IE 970856 (CH3)3C-O-CO-NH cnao COOH ‘-“\ Base I + NH ———————~ c1 N ,———/ -HC1 CH3O (CH3)3C-O-CO-NH <9 0 9 coon 3: RC1 -14- IE 970856 If, for example, 1-cyclopropyl-5,6,8-trif1uoro-1,4- dihydro-7-(2-methyl—2,7-diazbicyclo[3.3.o]oct-3-yl)-4- oxo-3-quinolinecarboxylic acid and ammonia are used as starting substances, the course of the reaction can be represented by the following equation: If, for example, 1—cyc1opropy1-7-(2,7-diazabicyclo— [3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid and ethanool/hydrogen chloride are used as starting substances, the course of the reaction can be represented by the following equation: -15- IE 970856 p\vé?\\/J\\/’COOH HC1 | if - C2}-l5OH —?' ,.x‘\ 2: 1 x HC1 The compounds of the formula (II) used as starting substances are known or can be prepared by known methods. Examples which may be mentioned are: 7-ch1oro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,142,854), 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3~quino1ine- carboxylic acid (European Patent Application 113,091), 6-chloro-1-cyclopropyl-7,8-df1uoro—1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), - 15 _ IE 970856 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro—4—oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydro-4-oxo-3-quino- linecarboxylic acid (German Patent Application 3,318,145), 6,B-dichloro-1—cyclopropy1-7-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (German Patent Application 3,420,743), 1-cyclopropyl-6,7—dif1uoro-1,4-dihydro-8-methy1-4-oxo-3- quinolinecarboxylic acid, 1-cyclopropyl-7—ch1oro-6-fluoro-1,4-dihydro-8-nitro-4- oxo-3-quinolinecarboxylic acid, 6,7—dif1uoro-1—ethyl—1,4-diyydro-4-oxo-3~quino1ine- carboxylic acid,’ 7—chlorc—6-fluoro-1-ethyl-1,4-dihydro-4—oxo-3—quino1ine- carboxylic acid, 7—ch1oro-6-fluoro—1,4-dihydro—1-(2-hydroxyethyl)-4-oxo- 3—quinolinecarboxy1ic acid, 6,7-difluoro-1-(2—f1uoroethyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, -17- IE 970856 8-chioro-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Patent Application 235,762), (European 7-chloro-6-fluoro-1,4-dihydro—1-methoxy-4-oxo-3-quino- linecarboxylic acid, 7-chloro-6-fluoro-1,4-dihydro-1-methy1amino-4-oxo-3- quinolinecarboxylic acid, 6,7-difluoro-1,4-dihydro-4-oxo—1-pheny1-3—quino1ine- carboxylic acid, 7-chloro-1-cyc1opropy1-6-f1uoro-1,4-dihydro-4-oxo—1,8- naphthyridine—3-carboxylic acid, 6,7-dich1oro-1-cyc1opropy1-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid, ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4—dihydro-4-oxo—3- quinolinecarboxylate Patent 3,319,145), (German Application 9,10-dif1uoro—2,3-dihydro-3-methyl~7—oxo-7H-pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid (European Patent Application 47,005), 8,9-diflnoro-6,7-dihydro-5-methy1-1—oxo-1H,SH-benzo[i,j}- quinolizine-2-carboxylic acid, -13- IE 970856 7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naph- thyridine-3-carboxylic acid (European Patent Application 153,580), 7-chloro-6-fluoro-1—(4-fluorophenyl)-1,4-dihydro-4—oxo— 1,B-naphthyridine-3-carboxylic acid (European Patent Application 153,580), 6,7,8-trifluoro-1,4-dihydro-1—methylamino-4-oxo—3-quino- linecarboxylic acid (German Patent 3,409,922), Application 1-amino-6,7,8—triflnoro-1,4-dihydro-4-oxo-3-quino1ine— carboxylic acid (German Patent Application 3,409,922), 6,7,8—trif1uoro-1,4-dihydro-1—dimethy1amino—4-oxo—3- quinolinecarboxylic acid (German Patent Application 3,409,922), 7-chloro-6-fluoro-1,4-dihydro-8-nitro-4—oxo—1-pheny1-3- quinolinecarboxylic acid, 7-chloro-6-fluoro~l-(4-fluorophenyl)-1,4-dihydro-8-nitro- 4-oxo-3-quinolinecarboxylic acid, 6,7-difluoro-1-(4-fluorophenyl)-l,4—dihydro~B-methyl-4- oxo-3-quinolinecarboxylic acid, 6—chloro-7-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid (European Patent Application - 19 - 131,839), 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-d1hydro- 4-oxo-3-quinolinecarboxylic acid, S,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid, 5,7—dich1oro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, 6-chloro-7-£luoro-1-(2,4-difluorophenyl)-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid (European Patent Applica- tion 131,839), 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid (European Patent Application 154,780), 6,7,B-trifluoro-1-(2,4-difluorophenyl)-1,4—dihydro-4-oxo- 3-quinolinecarboxylic acid (European Patent Application 154,790), 6,7,8-trifluoro—1,4-dihydro-4-oxo-1-phenyl-3-quinoline- carboxylic acid (European Patent Application 154,780), 7-ch1oro-1—ethy1-6-fluoro-1,4-dihydro-4-oxo-1,B—naph— thyridine-3-carboxylic acid, 6,7-difluoro-1,4-dihydro-4-oxe-1-vinyl-3-qnino1ine- - 20 - IE 970856 carboxylic acid, 1-cyclopropl-5,6,7,3-tetrafluoro-1,4-dihydro-4-oxo-3- quinoinecarboxylic acid, 5-amino-1-cyclopropy1~6,7,8-trifluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy-4- oxo-3-quinolinecarboxylic acid, and 1-cyclopropyl-6,7—dif1uoro-1,4-dihydro-8-methoxy-4-oxo- 3-quinolinecarboxylic acid. The compounds of the formula (III) used as starting compounds are new in some cases. They can be prepared by the following processes. 1. Starting from the N-protected 3,4—epoxypyrrolidine (1) (German Offenlegungsschrift (German Published Specification) 1,929,237 and u.s. Patent 4,254,135), which can optionally also carry one or two methyl or phenyl radicals, the starting compounds of the formula (IIIa)-(IIIe) are prepared. -21- K E] . ,., .l"’ ‘x‘:L .____‘_/ R“ = x3 — C Ht; /R5 , . ‘\\R6 removal cf protective groups nrotcctiuu qrounr IE 970856 removal of HO,’ /R5 ‘ I \\R5 (IIIa) "- N \\R5 (IIIb) benzyl, acyl, alkoxycarbonyl, benzyloxycarbonyl, trialkylsilyl or sulphonyl (examples of protec- tive groups), a leaving group, arylsulphonyloxy - 22 _ such as halogen, or alkyl- or __ H0». 3 N R4x3 (1) T-0 N T--0 I Base IE 970856 ”Ir:; 3 N ———-. R40”mI:fi;T(NH2 R4O“T:—:](NH-COOC(CH3)3 N —————~ N IE 970856 4 §I:_:]4NH-R5 R‘oL.__:]4N//Rs P40>T:f-I4“//R N_ N H2IPd T/ ' L‘ , w L\nf\\ H I L J .. ;~\ \\, \.IIP.) H2/F1! R‘0\I:f:](NH-R6 | (X1Id) 2. Starting compounds of the formula (IIIf) are obtained from 2-(1,2-dichloroethyl)-oxirane via the following reaction sequence: __'| . \\ ,, \ . IE 970856 / -RS R40 N P40 N .- \. \nt: [___ _]/ \R6 __\N’_,I '2 \“N'_, I, . ' -.,g m‘ H I . ‘J *1. ( I II I J 3. By addition of azidea onto N—henzylmaleimidea which are optionally substituted by one or two methyl or phenyl radicals, starting compounds of the formula 5 (III g) can be prepared: N¢N\N-R9 M W O a4om,.,,,o_ Jrlfi-R9 R“o#m, H-R10 I reduction 'fx‘H I - e——» - N i’ ‘an ‘ - 25 - YE L‘© R‘0fi~Er:JtNH-R10 (IIIg) R” = H, alkyl or benzyl. 4. From the 3,4-epoxypyrrolidines (1), the starting compounds of the formula (III h) are obtained via 5 cyclization with thionyl chloride: H0”T:_:]4NH2 H0~«[___,4uH.c0-9" f 1 J ""'—'—’ T ‘ ‘\N/J SOC ‘- 3 - . :2 :77 (111 h) 5. By reaction of the 3,4-epoxypyrrolidines (1) with ethanolamines, the starting compounds of the formula (III 1) are-obtained by intramolecular etherifica- 10 tiona _ 25 _ IE 970856 I//A\v/OH //A\v/NH-R6 HO N HO r ——- H9 (1) [ } ____ r--\ »\ N-R6 0 N_Re \L‘u‘ {III i). The starting compounds of the formula (III j) are obtained from aminoacetaldehyde dimethyl acetal via intramolecular 1,3-dipolar cycloaddition. CH3 OCH3 I 3 HZN OCH3 ~—--* R9-NH,/“xaciocna H2c;“\v/X Base ’\ OCH3 6_ _ 9 ., .ocH3 Ho 9 ,/*\cHo R NH on R -N /CH2 --*-* R -N /CH2 \_.._< _ ¥:°‘ 5°60 o"‘Q. i Q ' ' ' 0 Q2‘ 2 2 0 = O I :: o : o : Q‘ \_/ \ / I 3: I I : IE 970856 ...u .....:z ... _I ll: : ulfll mu m u &£w Ilz : u Q. @T \_ 0% __ : .._ Bu 1 u Qox — z .ooe.z/\/\_ O : u Ox 2 :u : .. : ..TA V1 .2 Ave 1 90, u._ Illlivl ncomumacwucouv F odamp -54- IE 970856 ' |I|-1 - I H. : .._ zQU m:._. = .._ : raw 2 k Q z§€lf7iTL// «$5 mzu /04 I HID I.- go -2 : I h AW ¢s6\ OQ : nzo .... I “AV I um I / :6? .._ __ rmv _U ... - m .z wx _x mm ~ ncowumacmacouv p oaamp -55- IE 970856 ...u u t._ : mum! Cu : x._ : mum! .8 : u : \ m‘ ... < NM _X Nm .2 ncomumacwucouv p 322 IE 970856 .....m .m Acoznacmucouw .p|M..Hm...m: -67.. IE 970856 ...u 'II'II|| .... ,_ fiv , .Q ._ XWY ._ .Q mm .m acomunacmucouv w canon -58.. IE 970856 ...—U Acomumacmucouv — udmah. IE 970856 a tab e ccord to e 'nven Each tablet contains: Compound of Example 1 583.0 mg Microcrystalline cellulose 55.0 mg Maize starch 72.0 mg Insoluble poly~(1-vinyl-2-pyrrolidone) 30.0 mg Highly disperse silica 5.0 mg Magnesium stearate 5,9 mg 750.0 mg The lacquer shell contains: Poly-(O-hydroxypropyl—0-methyl)- cellulose 15 cp 6.0 mg Macrogol 4000, recommended INN polyethylene glycols (DAB) 2.0 mg Titanium(IV) oxide 2.0 mg 10.0 mg The compounds according to the invention, while having a low toxicity, exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs, in par- ticular against Enterobacteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cepha1o- sulphonamides and tetra- sporins, aminoglycosides, cyclines. - 70 _ IE 970856 These useful properties enable them to be used as chemo- therapeutic active compounds in medicine and as sub- stances for preserving inorganic and organic materials, in particular all types of organic materials, for example polymers, lubricants, paints, fibres, leather, paper and wood, and foodstuffs and water. The compounds according to the invention are active against a very broad spectrum of microorganisms. Gram- negative and Gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, alleviated and/or cured with the aid of these compounds. The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these patho- gens. For example, local and/or systemic diseases caused by the following pathogens or by’ mixtures of the following pathogens can be treated and/or prevented: Gram-positive cocci, for example Staphylococci (Staph. aureus and Staph. epidermidis) and streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes); Gram-negative cocci (Neisseria gonor- rhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemo- _ 71 - IE 970856 philus influenzae, Citrobacter (Citrob. freundii and Citrob. divernis), Salmonella and Shigella; and further- more Klebsiella (xlebs. pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mira- bilis, Pr. rettgeri and Pr. vulgaris), Providencia and Yersinia, and the genus Acinetobacter. The antibacterial spectrum moreover includes the genus Pseudomonas (Ps. aeruginosa and Ps. maltophilia) as well as strictly anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; and fur- thermore Hycoplasma (M. pneumoniae, M. hominis and M. urealyticum) and Mycobacteria, for example Hycobacterium tuberculosis. The above list of pathogens is to be interpreted merely as examples and in no way as limiting. Examples which may be mentioned of diseases which are caused by the patho- gens or mixed infections mentioned and can be prevented, alleviated or cured by the compounds according to the invention are: infectious diseases in humans, such as, for example, otitis, pharyngitis, pneumonia, peritonitis, nephritis, cystitis, endocarditis, systemic infections, bronchitis (acute and chronic), diseases of the upper respiratory tract, diffuse panbron- chiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, pyelo— septic infections, _ 72 - IE 970856 cystic fibrosis, skin infections, postoperative wound infections, phlegmons, wound infections, infected burns, burn. wounds, infections in the oral region, infections following dental operations, osteomye- litis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsil- litis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections. abscesses, As well as in humans, bacterial infections can also be treated in other species. Examples which may be mentioned are: Pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, mastitis—metritis-agalactia syndrome and mastitis; Ruminants (cattle, sheep and goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, myco- plasmosis and genital infections; Horses: bronchopneumonias, joint ill, puerperal and postpuerperal infections and salmonellosis; Dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections and prostatitis; Poultry (chickens, turkeys, quails, pigeons, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory tract infections, salmonellosis, pasteurellosis and psittacosis. Bacterial diseases in the rearing and keeping of stock -73- IE 970856 and ornamental fishes can also be treated, the antibac- terial spectrum extending beyond the abovementioned pathogens to further pathogens, such as, for example, Pasteurella, Brucella, Campylobacter, Listeria, Erysi- pelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia. The present invention includes pharmaceutical formula- tions which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more com- pounds according to the invention or consist of one or more active compounds according to the invention, and processes for the preparation of these formulations. The present invention also includes pharmaceutical formulations in dosage units. This means that the for- mulations are present in the form of individual parts, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, the active compound content of which corresponds to a fraction or a multiple of an individual dose. The dosage units can contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is adminis- tered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily dose. Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, -74- IE 970856 fillers and formulation auxiliaries of all types. Preferred pharmaceutical formulations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emul- sions, pastes, ointments, gels, creams, lotions, dusting powders and sprays. Tablets, coated tablets, capsules, pills and granules can contain the active compound or compounds in addition to the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example gly- cerol, (d) disintegrating agents, for example agar—agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary amonium compounds, (g) wetting agents, for example cetyl alcohol and gly- cerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate and solid polyethyl- ene glycols, or mixtures of the substances listed under (a) to (1). The tablets, coated tablets, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of a composition such that they release the active - 75 _ IE 970856 compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes. If appropriate, the active compound or compounds can also be present in microencapsulated form with one or more of the abovementioned excipients. Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C“-alcohol with C“-fatty acid) or mixtures of these substances. Ointments, pastes, creams and gels can contain, in addition to the active compound or compounds, the cus- tomary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose deriva- tives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances. Dusting powders and sprays can contain, in addition to the active compound or compounds, the customary excipi- ents, for example lactose, talc, silicic acid, aluminium hydroxide, calcium. silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain the customary propellants, for example chloro- -76- IE 970856 fluorohydrocarbons. Solutions and emulsions can contain, in addition to the active compound or compounds, the customary excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, di- methylformamide, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances. For parenteral administration, the solutions and emul- sions can also be in a sterile form which is isotonic with blood. Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl alcohol and propylene glycol, and suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, alumin- ium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. The formulation forms mentioned can also contain colour- ing agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyp- -77- IE 970856 tus oil, and sweeteners, for example saccharin. The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture. The abovementioned pharmaceutical formulations can also contain other pharmaceutical active compounds in addition to the compounds according to the invention. The abovementioned pharmaceutical formulations are prepared in the customary manner by known methods, for example by mixing the active compound or compounds with the excipient or excipients. The formulations mentioned can be used on humans and animals either orally, rectally, parenterally (intra- venously, intramuscularly or subcutaneously), intra- cisternally, intravaginally, intraperitoneally'or locally (dusting powder, ointment, drops) and for the therapy of infections in hollow spaces and body cavities. Possible suitable formulations are injection solutions, solutions and suspensions for oral therapy and gels, infusion formulations, emulsions, ointments or' drops. Ophthal- mological and dermatological formulations, silver salts and other salts, eardrops, eye ointments, dusting powders or solutions can be used for local therapy. In the case of animals, intake can also be in suitable formulations via the feed or drinking water. Gels, powders, dusting - 73 _ IE 970856 powders, tablets, delayed release tablets, premixes, concentrates, granules, pellets, boli, capsules, aero- sols, sprays and inhalants can furthermore be used on humans and animals. The compounds according to the invention can moreover be incorporated into other carrier materials, such as, for example, plastics (chains of plastic for local therapy), collagen or bone cement. In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably contains the active com- pound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to deviate from the dosages mentioned, and in particular to do so as a function of the nature and body weight of the object to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament and the period or interval within which administration takes place. Thus in some cases it can suffice to manage with less than the abovementioned amount of active compound, whilst in other cases the abovementioned amount of active compound must be exceeded. The particular optimum dosage and mode of administration required for the active - 79 - IE 970856 compounds can easily be determined by any expert on the basis of his expert knowledge. The new compounds can be administered in the customary concentrations and formulations together with the feed or with feed formulations or with the drinking water. Infection by Gram-negative or Gram-positive bacteria can in this way be prevented, alleviated and/or cured and promotion of growth and an improvement in feed utiliza- tion can in this way be achieved. The minimum inhibitory concentrations (MIC) were deter- mined by the series dilution method on Iso—Sensitest agar (Oxoid). For each test substance, a series of agar plates which contained concentrations of the active compound which decreased by a dilution factor of two each time was prepared. The agar plates were inoculated with a multi- point inoculator (Denley). Overnight cultures of the pathogens which had first been diluted so that each inoculation point contained about 10‘ colony-forming particles were used for the inoculation. The inoculated agar plates were incubated at 37°C and the germ growth was read off after about 20 hours. The MIC value (pg/ml) indicates the lowest active compound concentration at which no germ growth was to be detected with the naked eye. The MIC values of some of the compounds according to the invention are shown in comparison with ciprofloxacin in the following table. - go - 0 N m~.o 3.5 36 .35 m~.o m.o mmio comm 7: m m~.o m-.o mm.c oo.o m~_.o - m~_.o _o_n~ w_~muoa. n3 mfluuououwacm mm m~_.o eo.o mo.o m-.o m_a.ow mo.o mm_.o o:.o mm. mm_.o oo.o no.0 m~_.o m_o.ow eo.o mm_.o a:.o om». mm_.o eo.o no.0 w~_.o m~o.ow oo.o m~_.a oo.o Nmv xx msmgsm msu :uouo_>£amgw Nmo~_ Mwggmagm co mm c v m.o N u _ -mmu:wu_>ogm Nma mmCflmLDE m.o m.o oo.o m_o.ow m~o.ow no.o mo.o m_o.ow m__u:mmgoz n_o_ magma _ m.o oo.o mo.o m~o.ow m_o.ow m~_.o m.:.ow -.:> wsoguhm mum» w__«n o. m N N m.o a c _ INLmE msmaoum CCGESWZ ~00 mm_.o m~.o mHo.ow m_o.ow m~o.ow m#o.ow m~o.ow m_o.ow mdzu_Lw;umw cwmguw «mow udaloxw nummm am V . uuwmcum omm .Loum.:uocm ucmoamugafi xvacoou umwu :owa=._u Lama u;. »n uu:_s.ouuu ,.\m:v nu:.a> um: 81 - IE 970856 mm.o m~.o mm.o m_o.ow m_o.ow m_o.oV cmumxO—uoLumU mm.o mmA.o mm_.o mm_.o eo.o u m.o 0 m.o m.o m~_.o m.o m~_.o who m~_.o 0 mm m.o 00.0 m.o 00.0 m~_.o oo.o B. o, mo.o mo.o no.0 mo.o mo.o 00.0 m_o.ow Agmmw umwu_mcumuom_ comu:._u gums wnu xa vozmsgwuwt a_\mEu meson: uaz mm.o m~.o mm.o m~.o ;:.: ugoumgzuocm m~.o mm~.o oo.o $0.0 oo.o mm~.o mo.o co.o omma _o_nm m__mumm. msuuououmgcm emm_ mwv zu uawgam mau auouo_>:am4w ~mo~_ _ouLm=4m :w_U:mt_>OLm N09 _mcwmLoE m__w:mmuoZ hqou wmumm nH=> wawaoum HNND mm_mn smL_E mawaoum ccmfizwz «_ou mmcumuwzuum cwmgum «mu» ucwonwu.:E xudcvov umwu IE 970856 The following examples illustrate the invention: Preparation of the intermediate products: am le A tert.—Butyl N-(cis-4-methoxy-pyrrolidin-3-yl)—carbamate a) trans-1—Benz 1- -h dro -4-metho rro1'dine 34.9 g (0.2 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0}- hexane (U.S. Patent 4,254,135) are heated with 3.6 g (20 mol) of sodium methylate solution (30% strength) at 120°C in 200 ml of absolute methanol in an autoclave for 10 hours. After cooling, the mixture is neutralized with 1.2 g (20 mmol) of acetic acid and the solvent is removed on a rotary evaporator. The residue is taken up in tetrahydrofuran and the sodium acetate is filtered off. The filtrate is concentrated and the residue is dis- tilled. Yield: 40.9 g (91% of theory) Boiling point: 112-116°C/0.1 mbar Content: 92% pure b) cis-3—Amino-1-benzyl—4—metho§y-Qyrrolidine 5.6 g (25 mmol) of trans-1-benzyl-3-hydroxy-4-methoxy- pyrrolidine and 8.6 g (33 mol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydro- -83- IE 970856 furan and a solution of 6 g (34 moi) of diethyl azodi- carboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at NT. 3.9 g (27 mol) of phthalimide are then added in small portions at VT in the course of one hour. The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 80 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize out overnight and the crystals (triphenylphosphine oxide and diethyl hydrazine- dicarboxylate) are filtered off. The filtrate is con- centrated and the residue is heated under reflux with 60 ml of concentrated hydrochloric acid overnight. The undissolved residues are decanted and the solution is concentrated. The residue is taken up in a little water and the solution is rendered alkaline with solid potas- sium carbonate and extracted five times with 50 ml of chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled. Yield: 3.4 g (65.9% of theory) Boiling point: 95°C/0.2 mbar c) tert.-Butyl .{-«H.-C N-(cis-1—benzyl-4—methoxypyrrolidin-3- 3 g (l4.S mnol) of cis-3-amino-1-benzy1-4-methoxy-pyr- rolidine and 11 ml of tert.-butanol are added to a solution of 0.65 g of NaOH in 8 ml of water. 3.5 g (16 mmol) of di-tert.-butyl dicarbonate are added dropwise. The mixture is stirred at room temperature overnight, the -34- IE 970856 inorganic salts are filtered off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled. Yield: 3.8 g (85.5% of theory) Boiling point: 130-140°C/0.05 mbar d) tert.-Butyl N-(cis-4-methoxypyrrolidin-3-yl)- carbamate _ 3.5 g (11.4 mol) of tert.-butyl N-(cis-1-benzy1—4- methoxypyrrolidin-3-yl)-carbamate are hydrogenated in 100 ml of methanol (n1 2 g of palladium-on-active charcoal (10% of Pd) at 100%: under 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled. Yield: 1.9 g (81.6% of theory) Boiling point: 84°C/0.1 mbar Exam le B tert.-Butyl N-(trans-4-methoxy-pyrro1idin-3-yl)- carbamate a) ans- ~ o-1-ben - -metho - o d 27 g (0.41 mol) of sodium azide are dissolved in 50 ml of _ 35 _ IE 970856 water, and 17.5 g (0.1 mol) of 3—benzy1-6-oxa-3-azabi- cyclo[3.1.0]hexane in 300 ml of dioxane are added. The mixture is heated under reflux for 72 hours and con- centrated, the inorganic salts are dissolved in water and the mixture is extracted with chloroform. The extract is dried over potassium carbonate and concentrated. The residue is dissolved in 50 ml of absolute tetrahydrofuran and the solution is added dropwise to 4 g of sodium hydride (80% strength in paraffin oil) in 200 ml of absolute tetrahydrofuran. The mixture is heated under reflux for one hour and 15 g (0.1 mol) of methyl iodide are then added dropwise. The mixture is subsequently heated under reflux overnight and concentrated, the residue is taken up in water and the mixture is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled. 13.1 g of a material which is 73% pure according to the gas chromatogram are obtained. 12.7 g of this material in 40 ml of absolute tetrahydrofuran are added dropwise to a suspension of 4 g of lithium aluminium hydride in 150 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. Excess lithium aluminium hydride is decomposed by careful dropwise addition of 4 ml portions of water and 15% strength potassium hydroxide solution and again 4 ml of water. The inorganic salts are filtered off with suction and washed several times with chloroform. The organic phases are dried over potassium carbonate and concentrated and the residue is distilled. Yield: 9 g (32.8% of theory) - 35 _ IE 970856 Boiling point: 91°C/0.07 mbar The product has a content of 75%, determined by gas chromatography (area method). b) ‘x-3;‘: .—i.'.u'.:',/2 N- r_*_2'<;.'!:4 1-—In‘;;'._'y'.-11--mu!iuruzc;/)1-{Irraliuiixt i— 8.2 g (30 mol) of trans-3-amino-l—benzyl-4-methoxy— pyrrolidine and 21 ml of tart.-butanol are added to a solution of 1.3 g of NaOH in 15 ml of water. 7.1 g (31 mmol) of di-tert.-butyl dicarbonate are added drop- wise and the mixture is then stirred at room temperature overnight. Inorganic salts are filtered off with suction, the filtrate is extracted with chloroform, the extract is dried over potassium carbonate and concentrated and the residue is distilled. Yield: 7.7 g (84.4% of theory) Boiling point: 148°C/0.1 mbar Melting point: 88-90°C c) tert.-Butyl N-(trans-4-methoxypyrrolidin-3-yl)- carhaate_ 6.7 g (22 mmol) of tert.—buty1 N-(trans-1-benzyl-4— methoxypyrrolidin-3-yl)carbamate are hydrogenated in 150 ml of methanol on 2 g of palladium-on-active charcoal (10% of Pd) under 100 bar at 100°C. The catalyst is filtered off with suction, the filtrate is concentrated -87- IE 970856 and the residue is distilled. Yield: 2.2 g (46% of theory) Boiling point: 94°C/0.05 mbar £rs2l2_§ trans-3-Amino-4-hydroxy—pyrro1idine a) 3- — o-1-benz 1- - - rolidine 8.9 g (50 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hex- ane are heated in 75 ml of ammonia solution (25% strength) at 120°C in an autoclave for 8 hours. The solution is concentrated and the residue is distilled. Yield: 6 g (62.4% of theory) Boiling point: 130-140°C/0.1 mbar Melting point: B2—84°C b) gran;-3-Aing-5—hyg;Q§y—py;rolidine 5.2 g (27 mmol) of trans-3-amino-1-benzy1-4-hydroxy- pyrrolidine are hydrogenated in 40 ml of methanol on 1 g of palladium-on-active charcoal (10% of Pd) at 100%:under 100 bar. The catalyst is filtered off with auction, the filtrate is concentrated and the residue is distilled. Yield: 1 g (36.3% of theory) - 33 - IE 970856 Boiling point: 110°C/0.3 mbar figggple D trans-4—Hydroxy-3-(2-hydroxyethylamino)-pyrrolidine a) trans-1-Benzy1~4-hydroxy-3-(2-hydroxyethylamino)- pygrolidine 40 g (0.22 mol) of 3-benzyl-6-oxa-3—azabicyc1o[3.1.0]hex— ane are heated under reflux with 42 g (0.68 mol) of 2- aminoethanol in 450 ml of water overnight. The solution is extracted once with tert.-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled. Yield: 34.1 g (65.6% of theory) Boiling point: 190°C/0.1 mbar b) trans-4-Hvgzggv-3-(2-hv o eth lamino - rolid'ne trans—1—Benzyl-4-hydroxy-3-(2-hydroxyethylamino)-pyr- rolidine is hydrogenated analogously to Example C b) to give the reaction product as an oil. - 39 - IE 970856 gxamgle E trans-4-Hydroxy—3-(2-hydroxyethy1-methyl-amino)- pyrrolidine a) trans-1-Benzyl-4—hydroxy-3-(2-hydroxyethyl-methyl- 9I_:1..rl.rr:a.<'a) -1_>.y.rr9.1..i::!.i.uv , 17.5 g (0.1 mol) of 3-benzy1-6-oxa-3—azabicyc1o[3.1.0]- hexane are reacted with 17 g (0.1 mol) of methy1amino- ethanol in 200 ml of water analogously to Example D a). Yield: 18.2 g (73% of theory) Boiling point: 180-190°C/0.1 mbar b) trans-4-Hydroxy-3-(2-hydroxyethyl-methyl-amino)- pyrrolidine trans-1-Benzy1-4-hydroxy~3-(2-hydroxyethyl-methyl-amino)- pyrrolidine is hydrogenated analogously to Example C b) to give the reaction product as an oily compound. Examgle F 2—0xa—5,8—diazabicyc1o[4.3.0]nonane dihydrochloride a) 8-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane _ 90 - IE 970856 15.6 g (66 mol) of 1-benzyl-4—hydroxy-3—(2—hydroxyethyl- amino)-pyrrolidine are heated under reflux in a mixture of 60 ml of concentrated sulphuric acid and 20 ml of water for 6 hours. The mixture is rendered alkaline with concentrated sodium hydroxide solution, the sodium sulphate which has precipitated is filtered. off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and con- centrated and the residue is distilled. Yield: 4.1 g (28.5% of theory) Boiling point: 122-128°C (0.08 mbar) b) 2- xa- -diazabic clo 4. .0 nonane d'h drochloride A solution of 4 g (18.2 mmol) of 8-benzy1-2-oxa-5,8- diazabicyc1o[4.3.0]nonane in 100 ml of methanol and 3.5 ml of concentrated hydrochloric acid is hydrogenated on 2 g of palladium-on-active charcoal (10% of Pd) at 80%: under 100 bar. The catalyst is filtered off and washed with water. The filtrates are concentrated and the product is crystallized by trituration with a little methanol. The crystals are filtered off with suction, washed with acetone and dried in air. Yield: 1.85 g (51% of theory) Melting point: 280°C with decomposition -91.. IE 970856 c) 2-Oxa-§,8-dia;abicygloL443-Olnonane 7.2 g (33 mol) of [4.3.0]nonane are hydrogenated in 400 ml of methanol with 8-benzyl-2—oxa-5,B-diazabicyclo— 2.5 g of palladium-on-active charcoal (10% of Pd) under 50 bar at 100°C. The catalyst is filtered off with suc- tion, the filtrate is concentrated and the residue is distilled. Yield: 3.1 g (73.4% of theory) Boiling point: 58°C/9.1 mbar. d) trans-2-Oxa-5,8-diazabicyclo/5.3.07nonane 3-benzyl-6-oxa-3-azabicyclo[3.l.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example D a), to give trans-l-benzyl-3-[N-benzyl~N-(2-hydroxy- ethyl)—amino]-4-hydroxypyrrolidine which is then reac- ted analogously to Example F a) to give 5,8-dibenzyl— 2—oxa-5,87diazabicyclo[4.3.0]nonane which is purified by chromatography (silica gel, cyclohexane/tert.-butyl methyl ether/ethyl acetate l:l:l). The hydrogenolytic debenzylation is carried out analo- gously to Example F c) to give trans—2-oxa-5,B-diaza- bicyclo[4.3.0]—nonane, boiling point: 60'C/0.1 mbar. IE 970856 Exam le 5-Methyl-2-oxa-5,B-diazabicyclo[4.3.0]nonane dihydrochloride a) -Benz 1- — th 1-2-oxa-S 8-diaz ‘c clo 4.3.0 nonane 18 g (71.9 mol) of 1-benzyl-4-hydroxy—3-(2-hydroxyethyl- methyl—amino)-pyrrolidine are reacted in 60 ml of con- centrated sulphuric acid and 30 ml of water as in Example F a). Yield: 10 g (60% of theory) Boiling point: 122°C/0.08 mbar b) 5-Methyl-2-oxa-S,8-diazabicyclo[4.3.0]nonane dihvdrochloride A solution of 9.4 g (40 mmol) of 8-benzyl-5-methy1-2-oxa- 5,8-diazabicyclo[4.3.0]nonane in 150 ml of methanol and 7.4 ml of concentrated hydrochloric acid is hydrogenated on 3 g of palladium-on-active charcoal (10% of Pd) at 80°C under 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P‘Om in a desiccator. The product is very hygroscopic. Yield: 8.2 g (95% of theory) Mass spectrum: m/e 142 (M’), 112 (1-1’-CI-I20), 100 (M’—CHz- N=CHz), 32 (C.H.No*), 68 (c.H5N*) Exam le H 2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane a) Ethyl N-(2.2-dimethogyethyl1-carbamate 214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in - 93 - IE 970856 1 1 of toluene and 90 g of Nabfl in 500 ml of water at 10°C. The mixture is stirred at room temperature for a further 2 hours and the aqueous phase is separated off, saturated with sodium chloride and extracted with tol- uene. The toluene solutions are dried over magnesium sulphate and concentrated and the residue is distilled. Yield: 338 g (95.4% of theory) Boiling point: 60°C/0.03 mbar b) Ethyl N-allvl-N-(2.2-dimethoxvethvll-carbamate 20 g of sodium hydride (80% strength in paraffin oil) are initially introduced into 500 ml of toluene and 89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 80°C. The mixture is stirred at 80°C for one hour and 73 g (0.6 mol) of allyl bromide are then added dropwise in the course of three hours. The mixture is stirred at 80°C.overnight, the salts are dissolved with water and the organic phase is separated off. The aqueous phase is extracted with toluene, the organic phases are dried over potassium carbonate and concentrated and the residue is distilled. Yield: 68 g (62.5% of theory) Boiling point: 65°C/0.09 mbar c) Ethvl N-allvl-N~(2-oxoethvl)-carbamate 68 g (0.313 mol) of ethyl N—ally1-N-(2,2-dimethoxyethyl)- carbamate are heated with 150 ml of formic acid at 100°C organic phases are washed with sodium bicarbonate solu- for one hour. The mixture is poured onto ice extracted several times with methylene chloride, tion, dried over magnesium sulphate and concentrated and the residue is distilled. Yield: 46.7 g (87.2% of theory) IE 970856 Boiling point: 58°C/0.09 mbar d) Ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane—7- sarbozylgis 10 g (0.12 mol) of methylhydroxylamine hydrochloride are dissolved in 50 ml of methanol, the solution is cooled in an ice-bath and 22 g (0.12 mol) of 30% strength sodium methylate solution in methanol are added dropwise. The sodium chloride is filtered off with suction and the salt is washed with 80 ml of toluene. The methylhydroxylamine solution is added dropwise in the course of one hour to 20 g (0.117 mol) of ethyl N—(2-(oxoethyl)-carbamate, which is heated under reflux in 160 ml of toluene, using a water separator. The mixture is heated under reflux overnight and the product is extracted twice with 80 ml of 10% strength hydrochloric acid each time. The hydro- chloric acid solutions are saturated with potassium carbonate and extracted six times with 200 ml of chloro- form each time. The extract is dried over KZCO3 and concentrated and the residue is distilled. Yield: 18.6 g (79.5% of theory) Melting point: 93°C/0.09 mbar e) 2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane 13 g (65 mmol) of ethyl 2-methyl-3—oxa-2,7-diazabicyclo- [3.3.0]octane-7-carhoxylate are heated under reflux in 300 ml of water with 41 g of Ba(0H)z.8I-I20 overnight. _ 95 _ IE 970856 Potassium carbonate is added, the barium carbonate which has precipitated out is filtered off with suction and the filtrate is extracted ten times with 100 ml of chloroform each time. The extract is dried over potassium carbonate and concentrated and the residue is distilled. Yield: 5.4 g (65% of theory) Boiling point: 80°C/10 mbar Exam le 1-Methyl-octahydropyrrolo[3,4-b]pyrrole diazabicyclo[3.3.0]octane) (2-methyl-2,7- a) 1-Benzyl—3—(2—ch1oroethyl~methyl—amino)—pyrrolidine— 245-dione 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 1Q_, 489 (l975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methy1- amine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20°C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice—water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. -95- IE 970856 1% value: 0.33 (silica gel, ethyl acetate/petroleum ether = 1:2) b) 5-Benzyl-4,6-dioxo-1-methyl-octahydropyrrolo{3,4-b]- pyrrole 7.2 g (0.24 mol) of an 80% strength sodium hydride suspension in mineral oil are suspended in 150 ml of absolute dimethylformamide (dried over calcium hydride), and 62 g (0.22 mol) of 1-benzyl-3-(2—ch1oroethyl-methy1- amino)-pyrrolidine-2,5-dione are added dropwise as a solution in 50 ml of absolute dimethylformamide at room temperature. During this, an exothermic reaction takes place with foaming. The mixture is diluted with a further 50 ml of absolute dimethylformamide and subsequently stirred at room temperature for 1 hour and is then poured into ice-water and extracted with methylene chloride. The extract is washed with water, dried with sodium sulphate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel using ethyl acetate:petro- leum ether (1:2) and later (1:1). 16.4 g of educt are initially recovered here, and 17.2 g (44% of theory, based on the educt reacted) of an oily product are then isolated. Rf value = 0.26 (silica gel, ethyl acetate:petro1eum ether = 1:1). - 97 _ IE 970856 c) -Ben -1-me h 1-oc ah d o rro 4- role 1.52 g (40 mol) of lithium aluminium hydride are initially introduced into 30 ml of anhydrous tetrahydro- furan, and 4.9 g (20 mmol) of 5~benzyl-4,6-dioxo-1- methyl-octahydropyrrolo[3,4-bjpyrrole are added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is then subsequently stirred at the boiling point for 3 hours. 1.5 ml of water, 1.5 ml of 15% strength potassium hydroxide solution and 4.5 ml of water are added dropwise in succession to the batch and the pre- cipitate is then filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a rotary evaporator and the residue is distilled. 3.1 g (72% of theory) of a colourless distillate of boiling point 80°C/0.07 mbar are obtained. d) 1-Methyl-Qggghyggopyrrolo[3,4-b]pyr;g1g 6.49 g (30 mmol) of 5-benzyl-1-methyl-octahydropyrrolo- [3,4-b]—pyrrole are dissolved in 100 ml of absolute ether, and 5.2 g of hydrogen chloride dried over phos- phorus pentoxide.are passed in. The hydrochloride suspen- sion formed is concentrated in vacuo and the residue is taken up in 100 ml of methanol. It is then hydrogenated with 2 g of Pd-on-C (50 strength) at 80%: under 50 bar for 4 hours. The catalyst is subsequently filtered off, the filtrate is concentrated and 30 ml of 40% strength sodium hydroxide solution and 50 ml of ether are added to the residue. The ethereal phase is separated off and the -98- IE 970856 aqueous phase is extracted with 2 x 50 ml of ether. The combined organic phases are dried over sodium sulphate and concentrated and the residue is distilled. 1.3 g (34% of theory) of a colourless oil of boiling point 65-66°C/ 12 mbar are obtained. Purity: >99% Example J Octahydropyrrolo[3,4-b]pyrrole (2,?-diazabicyclo[3.3.0]- octane) a) l-Benzyl-§-[2-chloroethylamino)-pgrr0lidine—2,5-dione 74.8 g (0.4 mol) of N—benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an R, value of 0.24 (on silica gel using ethyl acetate: petroleum ether = 1:1) are obtained. b) 5-Benzvl-446-dioxo—octahvdropvrrolo[3,4-blpvrrole 17.4 g (0.58 mol) of sodium hydride suspension are reacted with 119 g (0.45 mol) of 1-benzyl-3—(2-ch1oro- ethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instruc- tions of Example Ib. After the mixture has been left to - 99 _ IE 970856 stand overnight, it is worked up under aqueous condi- tions. on purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetateamethanol (3:1) (R,value 0.55). 57.7 g of product (56% of theory) are isolated. c) -Benz 1-octah dro rolo 4- re e 57.7 g (0.25 mol) of crude 5-benzyl-4,6-dioxo-octahydro- pyrrolo[3,4-b]pyrrole are reduced with 21.4 g (0.56 mol) of lithium aluminium hydride by boiling in 700 ml of absolute tetrahydrofuran for 10 hours in accordance with the working instructions of Example Ic. Working up by distillation gives 21.0 g (41.1% of theory) of an oil of boiling point 95°C/0.1 mbar. d) cta o rolo 4-b role 21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo- [3,4-bjpyrrole are initially introduced into 180 ml of ice-cooled methanol, and 17.3 ml (0.208 mol) of concen- trated hydrochloric acid are added. The mixture is then hydrogenated with 2 g of Pd-on-C (5% strength) at 90%: under 100 bar for 4 hours. The catalyst is filtered off, 37.4 g (0.208 mol) of 30% strength sodiumm methylate solution are added to the filtrate, the mixture is filtered again and the filtrate is concentrated. The residue is distilled through a small Vigreux column. 5.6 g of a colourless oil (48% of theory) of boiling point 93-95°C/30 mbar, which fumes in air and slowly solidifies -100- IE 970856 in the receiver (melting point 40°C) are obtained. Eggmple 5 0ctahydropyrrolo[3,4—b]pyridine (2,B~diazabicyclo[4.3.0]— nonane) a) - enz -5 7-dio o-octah dro rrolo 3 4-b idine 47.6 g (0.2 mol) of pyridine—2,3-dicarboxylic acid N- benzylimide (British Patent 1,086,637; Chem. Abstr. gg, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90%: under 100 bar until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is concentrated on a rotary evaporator. 44 g of an oily crude product are obtained. The corresponding hydrogenation with palladium-on-active charcoal (5% strength) gives a quantitative yield of a pure product of melting point 67-69°C. b) 6-Benzyl-octahydropyrrolo[3.4-b]py;idine 44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7- dioxo-octahydropyrro1o[3,4-b]pyridine are reduced with 15.2 g (0.40 mol) of lithium aluminium hydride in 390 ml of absolute tetrahydrofuran in the course of 10 hours in — 101 - IE 970856 accordance with the working instructions of Example Ic. 24.4 g of a colourless oil having a boiling point of 93- 95°C/0.06 mbar are obtained on distillation. c) Qctahgdropg;rolo[3.4-b]Q1;idige 69 g (0.32 mol) of 6—benzyl—octahydropyrrolo[3,4-b]pyri— dine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal (5% strength) at 90°C/90 bar in the course of 3 hours. The catalyst is then filtered off, the filtrate is concentrated and the residue is distilled. 33.8 g (84% of theory) of a colourless solid having a melting point of 65-67°C and a boiling point of 78°C/9 mbsr are obtained. fixgmgle L 1-Methyl-octahydropyrrolo[3,4-b]pyridine (2-methyl—2,8- diazabicyclo[4.3.0]nonane) I; ;:-_~:.zyl- 190.5 g (0.8 mol) of pyridine~2,3-dicarboxylic acid N- benzylimide are dissolved in 800 ml of nitromethane, while heating, and 136 g (0.96 mol) of methyl iodide are added dropwise. The mixture is then boiled for 8 hours while cooling under reflux (cooling water OWZ). After cooling, the solid is filtered. off with suction and - 102 - IE 970856 washed with methylene chloride. 123 g of dark red crys- tals having a melting point of 162-165°C (decomposition) are obtained. b) 6-Benzy1~1-methyl-5,7-dioxo-octahydropyrrolo[3,4-b]- pyridine _ 38 g (0.1 mol) of 1-methyl-pyridinium-2,3-dicarboxylic acid N-benzylimide iodide are hydrogenated over 1 g of platinum oxide in 450 ml of glycol monomethyl ether at 30°C under 70 bar until the uptake of hydrogen has ended (51 hours). The catalyst is then filtered off, the filtrate is concentrated, the residue is taken up in 300 ml of chloroform and the solution is washed 2 x with 300 ml of 10% strength sodium carbonate solution each time and with 300 ml of water. After drying over sodium sulphate, it is concentrated. 27 g of an oily residue remain. c) 6-Benzy;-1-methyl—Qg§ahyg;opy;ro1o[3,4-b]pyridine 19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxo- octahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g (0.16 mol) of lithium aluminium hydride in absolute tetrahydrofuran in accordance with the working instruc- tions of Example 1c. Yield: 9.5 g (52% of theory), Boiling point: 93-96°C/0.1 mbar. - 103 - IE 970856 d) - h 1-octah o rro o -b ‘dine 11.7 g (54 mol) of 6-benzyl-1-methyl-octahydropyrrolo- [3,4-b]pyridine as the dihydrochloride are hydrogenated in 100 ml of methanol over palladium-on-active charcoal in accordance with the working instructions of Example Id. Working up by distillation gives 2.6 g (34% of theory) of a colourless oil of boiling point B3-85°/12 mbar). xam 1e trans-4-Methoxy-3-methylamino-pyrrolidine dihydrochloride a) trans-l-Benzy1-3-benzylmethylamino-4-hydroxy- pygrglidine ~ 19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3- azabicyclo[3.1.0]hexane are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHC13, the extracts are dried with R5C03 and concentrated and the residue is subjected to incipient distillation up to 160°C (oil bath temperature). Crude yield: 18.3 g Content: 100% (determined by gas chromatography) - 104 - IE 970856 trans-1-Benzyl-3-benzylmethylamino-4-methoxy- Qgrrolidine 17.3 g (58 mmol) of crude trans-1-benzyl-3-benzyl— methylamino-4-hydroxy-pyrrolidine in 80 ml of abso- lute tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol) of 30% strength sodium hydride in 40 ml of absolute tetrahydrofuran and the mixture is heated under reflux at the same time. When the evolution of hydrogen has ended, 8.7 g (61 mol) of methyl iodide are added dropwise and the mixture is then heated under reflux overnight. It is poured into ice—water and extracted with toluene, the extracts are dried with RQCO, and concentrated and the residue is distilled. Yield: 9.7 g (52% of theory) Boiling point: 140—1SWC/0.1 mbar trans-4-Methoxy-3-methylamino-pyrrolidine gihydrochloridgr 9.3 g (29 mmol) of trans-1-benzyl-3-benzylmethy1- amino-4—methoxy-pyrrolidine are dissolved in 100 ml of methanol, 4.8 ml of concentrated hydrochloric acid are added and the mixture is hydrogenated on 4 g of 10% strength Pd-on-active charcoal at 90%: under 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is recrystallized from isopropanol/methanol. Yield: 3.7 g (62.8% of theory) - 105 - Exam IE 970856 Melting point: 157-162°C 2,5-Dimethyl-3—oxa-2,7-diazabicyc1o[3.3.0]octane N-(2-Methy1prop—2—enyl)-N-(2,2-dimethoxyethy1)— ureghane _ 89 g (0.5 mol) of N-(2,2-dimethoxyethyl)-urethane are added dropwise to 20 g of sodium hydride (80% strength) in 500 ml of absolute toluene at 90°C. When 54 g (0.6 mol) of and the The sodium no further hydrogen is formed, methallyl chloride are added dropwise mixture is stirred overnight at 90%L chloride which has precipitated out is dissolved with a little water, the organic phase is separated off, dried over xgco, and concentrated and the residue is distilled. Yield: 71.3 g (61.7% of theory) Boiling point: 60°C/0.08 mbar N- 2—Meth 1 ro -2—en -N- -oxoeth -urethane 11.5 g (50 mol) of N-(2-methylprop-2-enyl)-N-(2,2- dimethoxyethy1)—urethane and ]”25 g (5 mmol) of pyridinium p-toluenesulphate in 100 ml of acetone and 10 ml of water are heated under reflux for two days. The mixture is concentrated and the residue is — 106 - IE 970856 distilled. Yield: 5.3 g (61.2% of theory) Boiling point: 73°C/0.1 mbar Ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]— Qctane-7-carboxvlate 21.7 g of 30% strength sodium methylate solution are added. dropwise to 10 g (0.12 mol) of N~methyl- hydroxylamine hydrochloride in 26 ml of methanol. The sodium chloride is filtered off with suction and washed with 8 ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N-(2-methyl—prop-2-enyl)—N-(2—oxoethyl)-urethane, which is heated under reflux in 160 ml of toluene using a water separator. The mixture is heated under reflux overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydro- chloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHC13. The extracts are dried over Kgxr and concentrated and the residue is distilled. Yield: 13 g (55% of theory) Boiling point: 88-95°C/0.08 mbar 2 5-Dimeth 1- -oxa-2 7-diazabic clo . . octane 13 g (60.6 mmol) of ethyl 2,S-dimethyl-3-oxa-2,7- diazabicyclo[3.3.0]octane-7—carboxylate are heated under reflux with 33 g of Ba(0H)2.8Hg3 in 330 ml of - 107 - IE 970856 water overnight. The BaC03 is filtered off with suction, xzco, is added to the filtrate; the solid is filtered off with suction again and the filtrate is extracted ten times with 100 ml of CHCI3 each time. The extracts are dried over K200, and concentrated and the residue is distilled. Yield: 5.9 g (63.7% of theory) Boiling point: 64°C/5 mbar Ex_an;p.le_Q 2,8-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane - 1 1-D etho — - 1 - rethane 80 g (0.73 mol) of ethyl ohloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropion- aldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred at room temperature for a further 2 hours, the organic phase is separated off, the aqueous phase is extracted with toluene and the toluene solutions are dried over xgxr. The solution is concentrated and the residue is distilled. Yield: 132 g (95% of theory) Boiling point: 55°C/0.06 mbar - 108 - IE 970856 - 1- - 1- et r - - -ur ane 131 g (0.686 mol) of N-(1,1-dimethoxyprop-2-yl)- urethane are added dropwise to 25 g of sodium hydride (80% strength) in 700 ml of absolute toluene at 90°C. when the evolution of hydrogen has ended, 61.2 g (0.8 mol) of allyl chloride are added drop- wise at 90°C and the mixture is stirred overnight at 90°C, The sodium chloride which has precipitated out is dissolved with water, the organic phase is separated off, dried over KZCO, and concentrated and the residue is distilled. Yield: 78 g (31.7% of theory) Boiling point: 62-69°C/0.06 rnbar. Content: 64.5% pure (determined by gas chromato- graphy) - l-N- -o o -2- 1 - t ane 76.5 g (0.213 mol) of 64.5% pure N-a1ly1-N-(1,1- dimethoxyprop-2-yl)-urethane are heated in 180 ml of formic acid at 100°C for one hour. The mixture is poured into ice-water and extracted with cH,C1,, the extracts are washed neutral with Nal-ICO, solution, dried over ngso. and concentrated and the residue is distilled. Yield: 36 g (80.9% of theory) Boiling point: 97-102°C/8 mbar Content: 88.8% pure (determined by gas chromato- 91'5PhY) -109- IE 970856 Ethyl 2,8-dimethyl-3—oxa-2,7-diazabicyclo[3.3.0]- 0 ne-7-c ate A methanolic methylhydroxylamine solution is pre- pared from 16.4 g (0.2 mol) of N-methylhydroxylamine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30% strength sodium methyiate solution, and the solution formed is diluted with 130 ml of toluene and added dropwise to 354 g (0.17 mol) of N-allyl-N-(1-oxoprop-2—yl)-urethane in 250 ml of toluene, which is heated under reflux using a water separator. The mixture is heated under reflux overnight, the product is extracted. with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K,CO3 and extracted with CI-ICl,. The extract is dried over KZCO3 and concentrated and the residue is distilled. Yield: 18.5 g (50.8% of theory) Boiling point: 95-105°C/0.1 mbar 2 8—Dimeth - -o a-2 7- azabic clo . .0 octane 9.2 g (42.9 mmol) of ethyl 2,8-dimethyl-3-oxa—2,7- diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 23.5 g of Ba(OH)2.8HgD in 235 ml of water’ overnight. The BaC03 is filtered off with suction, Kgxx is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHCl, each time, the extracts are dried over KZCO, and concentrated - 110 - IE 970856 and the residue is distilled. Yield: 1.7 g Boiling point: B7-92°C/10 mbar The product is a mixture of the possible stereo- isomers in a ratio of 3:1 (‘H-NMR). 4 g of starting material could to be recovered in the after-runnings. Hmpfii 2-Methyl-4-oxa—2,8-diazabicyclo[4.3.0]nonane 7 4 .V|I jj. Ethyl 4-hydroxymethyl-3-methylaminopyrrolidine-1- carboxvlate 10 g (50 mol) of ethyl 2-methyl-3-oxa-2,7-diazabi- cyclo[3.3.0]octane-7—carboxylate (Example H d)) are hydrogenated in 200 ml of ethanol on 3 g of Pd-on- active charcoal (10% of Pd) at 50%: under 50 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled. Yield: 8.1 g (80% of theory) Boiling point: 135-IANT/0.1 mbar Ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane- ,c,_,,c as _, 10.1 g (50 mmol) of ethyl 4-hydroxymethyl-3-methy1- amino—pyrrolidine-1-carboxylate and 8 g (0.1 mol) of - 111 - IE 970856 37% strength formaldehyde solution are dissolved in 100 ml of butanol and the solution is stirred at room temperature overnight. It is then concentrated and the residue is distilled. Yield: 9.5 g (88.7% of theory) Boiling point: 110°C/0.1 mbar -Met --4-o - - c o 4. ane 9 g (42 mmol) of ethyl 2-methyl-4-oxa-2,8-diaza— bicyclo[4.3.0]nonane-8-carboxylate are heated under reflux with 28 g of Ba(OH),.8l-I20 in 280 ml of water overnight. The saco, is filtered off with auction, the filtrate is concentrated and the residue is boiled up with dioxane. The dioxane solution is concentrated and the residue is distilled. Yield: 1.3 g (21.8% of theory) Boiling point: 115°C/3 mbar 4-fl1dro;ygethyl-3-gethylaygigopyzrolidige 34 g (0.168 mol) of ethyl 4-hydroxymethyl—3-methy1- aminopyrrolidine-1-carboxylate are heated under reflux with 100 g of Ba(OH)2.8Hzo in 400 ml of water overnight. The BaCO, is filtered off with suction, the filtrate is concentrated and the residue is boiled up ten times with 100 ml of dioxane each time. The dioxane filtered, the filtrate is concentrated and the residue is dis- tilled. solutions are -112- Exam IE 970856 Yield: 13 g (60.3% of theory) Boiling point: 85-88°C/0.08 mbar - t l—4-oxa- -d abic clo 4. . e 8.1 g (0.1 mol) of 37% strength formaldehyde solu- tion in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylamino- pyrrolidine in 100 ml of n-butanol at room tempera- ture. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled. Yield: 8.7 g (61.2% of theory) Boiling point: 84°C/6 mbar 3-Oxa-2,7-diazabicyc1o[3.3.0]octane "40- Ethyl cyclo[3.3,p1octane-7-carbogylgte 2-(tetrahydropyran-2-yl)-3-oxa-2,7-diazabi— 18.1 g (0.106 mol) of ethyl N~allyl-N-(2-oxoethyl)- carbamate (Example H c)) are heated under reflux in 220 ml of toluene, and 14.2 g (0.12 mol) of 5- hydroxypentanal oxime (Acts Chim. Acad. Sci. Hung., lg, 333 (1958)), dissolved in 55 ml of hot toluene, are added dropwise. The mixture is heated under reflux overnight and concentrated and the residue is - 113 - IE 970856 distilled. Yield: 15.5 g (54% of theory) Boiling point: 160°C/0.01 mbar Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7- carboxylate 15 g (55.5 mmol) of ethyl 2-(tetrahydropyran-2-yl)- 3-oxa~2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 8.25 g (56 mol) of 70% strength perchloric acid in 100 ml of ethanol for 30 minutes. 10.5 g (58 mmol) of 30 strength sodium methylate solution are added, the mixture is con- centrated, the residue is taken up in water and the solution is saturated with K300, and extracted with CHCl,. The extract is dried over xzco, and concentra- ted and the residue is distilled. Yield: 7.6 g (73.5% of theory) Boiling point: 125-130°C/0.1 mbar Eth 1 3-oxa-2 7-d'az c clo . . octan -7—carbo — leis 8.5 g (50 mmol) of ethyl N-(2-oxoethy1)-N-allyl- carbamate are heated under reflux with 5.5 g (50 mmol) of o-trimethylsilylhydroxylamine in 100 ml of xylene overnight. The mixture is concentrated and the residue is distilled. Yields 6.8 g (73% of theory) Boiling point: 120-122°C/0.05 mbar - 114 - IE 970856 d) - a- 7-diazabic c . ta e This substance is obtained analogously to Example N d) by hydrolysis of ethyl 3-oxa-2,7-diazabicyclo— [3.3.0]octane-7-carboxylate with Ba(OH)2.8Hg3. Boiling point: 75°C/10 mbar. Exgggle R 3-Methyl-2,7-diazabicyclo[3.3.0]octane 3-Methyl-2,7-diazabicyclo[3.3.0]octane is obtained analogously to Example 1. Boiling point: 68-70°C/6 mbar. xam 1e 2,3—Dimethyl-2,7-diazabicyclo[3.3.0]octane 2,3-Dimethyl-2,7—diazabicyc1o[3.3.0]octane is obtained analogously to Example 1. Boiling point: 72-74°C/10 mbar. ggggple T 1,2-Dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]octane — 115 - l_!I IE 970856 N-Ally;-Q-(3,g-dimethggyproggl)-aceggmide 119 g (74 mol) of 2,2-dimethoxypropylacetamide are added. dropwise to 29.6 g (0.987 mol) of sodium hydride (80% strength in paraffin oil) in 750 ml of absolute toluene at 80%L The mixture is then stirred for one hour and 100 g (0.83 mol) of allyl bromide are subsequently added dropwise at BOYL The mixture is stirred overnight at 80°C and cooled and the salts are dissolved with water. The aqueous phase is separated off and extracted twice with 100 ml of toluene each time. The toluene solutions are dried over KZCO3 and concentrated and the residue is distilled. Yield: 112 g (75.6% of theory) Boiling point: 70°C/0.08 mbar. N-A1111-N-(2-oxogroggl)-acetamide 85.5 g (0.425 mol) of N-al1yl-N-(2,2-dimethoxy- propyl)-acetamide are heated under reflux with 212 ml of formic acid for one hour. The mixture is poured onto 500 g of ice and extracted several times with. methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled. Yield: 50 g (75.8% of theory) Boiling point: 79°C/0.25 mbar. - 116 - IE 970856 7-Acety1- 1 , 2-dimethyl-3-oxa-2 , 7-diazabicyclo [ 3 . 3 . 0 3- 9911599, 15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acet- amide are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N- methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and xzco, is added. The mixture is extracted with CHCl,, the extract is dried over KZCO3 and concentrated and the residue is distilled. Yield: 15.9 g (86.3% of theory) Boiling point: 75°C/0.1 mbar. - - -oxa-2 7-d . a 11.8 g (64 mmol) of '7-acetyl-1,2-dimethyl—3—oxa-2,7- diazabicyclo[3.3.0]octane are heated under reflux with 12 g of Naol-I in 36 ml of water overnight. The mixture is saturated with xzco, and extracted several times with CI-{C13, the extract is dried over x,co, and concentrated and the residue is distilled. Yield: 4.7 g (51.6% of theory) Boiling point: 40°C/0.2 mbar. -117- IE 970856 E2:2m2J..e_Q 2,4-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane Ethyl bamate N-(but-2-enyl)~N-(2,2-dimethoxyethy1)—car— 89 g (0.5 mol) of ethyl N—(2,2-dimethoxyethy1)- carhamate are added dropwise to 17.5 g (0.58 mol) of Nan (80% strength in paraffin oil) in 500 ml of absolute toluene at 80°C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at B0%L The mixture is stirred at 30%: overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over KZCO3 and concentra- ted and the residue is distilled. Yield: 90 g (77.8% of theory) Boiling point: 65°C/0.1 mbar. gthvl N-(but-2-envl1-N-I2-oxoethglj-cagggmggg 90 g (0.39 mol) of ethyl N-(but—2-eny1)-N-(2,2- dimethoxyethyl)-carbamate are heated under reflux with 200 ml of formic acid for one hour. The mixture is poured onto 500 g of ice and extracted with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over mag- - 118 - IE 970856 nesium sulphate and concentrated and the residue is distilled. Yield: 33.6 g (46.5% of theory) Boiling point: 65°C/0.1 mbar. Ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]- 9cLen¢~2r9a§§yxxinre 1 , 18.4 g (0.1 mol) of ethyl N-(but-2-enyl)-N-(2-oxo- ethyl)-carbamate are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and race, is added. The mixture is extracted with CI-ICl,, the extract is dried over Kzco, and concentrated and the residue is distilled. Yield: 15.0 g (70% of theory) Boiling point: '74-87°C/0.1 mbar. 13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,’h diazabicyc1o[ 3 . 3 . 0 Joctane-7-carboxylate are heated under reflux with 39 g of Ba(0H)z . 81120 in 200 ml of water overnight. xzco, is added, the saco, is fil- tered off with suction and the filtrate is extracted several times with CHCl,. The extract is dried over -119- IE 970856 BQCO3 and concentrated and the residue is distilled. Yield: 4.8 g (54.8? of theory) Boiling point: 74°C/8 mbar. Exggple V Ethyl 2,7—diazabicyc1o[3.3.0]octane-2-carboxylate 7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example 0a) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane- 2-carboxylate, and this is then debenzylated hydrogeno- lytically analogously to Example Jd). A.oo1our1ees oil of boiling point 90°C/0.1 mbar is obtained. Example W 2-Pheny1—2,7-diazabicyclo[3.3.0]octane The preparation is carried out analogously to Example I); Boiling point: 103°C/0.08 mbar. - 120 - IE 970856 ma=.n.2J.§_X 4-Oxa-2,8-diazabicyclo[4.3.0]nonane Ethyl 3-amino—4-hydroxymethyl-pyrrolidine-1- carbogylate Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7-car- boxylate (Example Qc) is hydrogenated analogously to Example Pa). Boiling point: l63—168°C/0.8 mbar 3—Amino-4-hydrogyggghyl-pygrolidgge Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-1-car- boxylate is hydrolyzed analogously to Example Pd). Boiling point: 78°C/0.06 mbar. 4- xa-2 —di zabic . . ne 3-Amino-4-hydroxymethyl-pyrrolidine is reacted with formaldehyde solution analogously to Example Pa). Boiling point: 50-60°C/0.07 mbar - 121 - IE 970856 1.’.sm2l9_Z trans-3-Ethylamino-4-methylthio-pyrrolidine 1-Benzoyl-trans-3-ethylamino—4-methylthio- 91n:ro_1 tgne 8.65 g (50 mmol) of 1-benzoyl-2,5-dihydropyrrole [Chem. Ber. gg, 2521 (1889)] are initially intro- duced into 30 ml of methylene chloride, and 4.94 g (60 mol) of methanesulphonyl chloride in 20 ml of methylene chloride are added dropwise at OWE. The mixture is subsequently stirred at 20-25%: for 16 hours and concentrated under 8 mbar and the residue is dissolved in 50 ml of tetrahydrofuran. 18 g (0.2 mol) of 50% strength aqueous ethylamine solu- tion are then added. The batch is boiled for 18 hours, while cooling under reflux, poured into water and extracted with methylene chloride. On concen- trating, 11.1 g of crude product are obtained, and the crude product is chromatographed. with. ethyl acetate/ethanol 5:1 on silica gel (RF value 0.34). Yield: 7.4 g (56% of theory). thic- 6.0 g (22 mmol) of 1-benzoyl-trans-3-ethylamino-4- methylthio-pyrrolidine are stirred vigorously with 22 ml of SN Naofi at 100%: for 24 hours, until the - 122 - IE 970856 conversion is The mixture is then extracted with 3 x 80 ml of ether and the extract is dried over sodium sulphate and concentrated on a homogeneous. rotary evaporator. The crude product is distilled through a micro-puncture column. Yield: 1.56 g (44% of theory) of colourless liquid, Boiling point: 52°C/0.1 mbar Exam le Z trans-3—amino-4—methylthio-pvrrolidine 1—Benzoyl-2,5-dihydropyrrole is reacted with methylsu1fe- nyl chloride analogously to Example Y to give 1-benzyl—3— chloro-4-methylthiopyrrolidine which is reacted as a crude product with ammonia to give 3-amino-l-benzoyl—4-methyl- thio-pyrrolidine and the benzoyl radical is removed with sodium hydroxide solution. Yield over 3 stages: 47 % of theory Boiling point: 108-110°C/11 mbar. Example ZA 4—Methyl-2,B-diazabicyclojé.3.0jnonane a) 5-Methyl-l,4-dihydropyridine-2,3-dicarboxylic acid N-benzvlimido 33 g (0.29 mol) zone and 55 g of 2-methyl-2-propenal-dimethylhydra~ (0.29 mol) stirred in 225 ml of acetonitrile for 3 hours at 60°C. of N-benzylmaleinimide are - 123 - IE 970856 Then the solvent is removed in a rotary evaporator, the residue is taken up in 600 ml of toluene and, after adding 150 g of boiled for 1 hour under reflux. silica gel, the mixture is Then the mixture is filtered while hot and the silica boiled out with ethanol. The combined organic phases are concentrated in a rotary gel is several times evaporator. 17.5 g (24 % of theory) point of 184-186'C are obtained. of red crystals of a melting 5-MethylLhexahydropyridine-2,3-dioarboxylic acid N-benzylimide 17.5 g (70 mmol) of 5—methyl-1,4-dihydropyridine-2,3- dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70°C and under 100 bar Then the catalyst is filtered off and the filtrate is over palladium on active charcoal. concentrated by (13.0 g) is used evaporation. The solid oily residue as a crude product in the next stage. 13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarb— oxylic acid N-benzylimide are added in the form of a solution in 50 ml of absolute tetrahydrofuran to 4.6 g (0.12 mol) absolute of lithium aluminium hydride in 100 ml of tetrahydrofuran, already present in the vessel. Then the mixture is boiled for 17 hours under reflux. 4.6 g of water in 14 ml of tetrahydrofuran, 4.6 g of 10 % strength sodium hydrox- ide solution and 13.8 g of water are added dropwise The salts are filtered off, the one after the other. filtrate is concentrated by and residue is distilled. evaporation - 124 - IE 970856 Yield: 8.7 g (54 %, based on 5-methyl-1,4-dihydropyri- dine-2,3-dicarboxylic acid N-benzylimide); boiling point: 95-98'C/0.1 mbar. 4-Methyl-2,8-diazabicvQlo[4.3.0]nonane 8.0 g (35 mmol) of 8-benzyl-4—methyl—2,8—diaza- bicyclo[4.3.0]nonane are dissolved in 60 ml of methanol and hydrogenated over palladium on acitive charcoal at 100'C and under 100 bar. Then the cata- lyst is filtered off, evaporation and the residue is distilled. the filtrate is concentrated by Yield: 3.3 g (67 % of theory) boiling point: 88-B9’C/llmbar. The 1H-NMR spectrum shows the compound to be a mixture of two stereoisomers in a ratio of 7:2. Example AA 5,6,7,8-Tetrafluoro-1-(2,4—difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Ethyl 2-(2,3,4,5,6—pentafluorobenzoyl)-3-(2,4- difluorophenglamino]-acrvlate 44.3 g of 2,4—difluoroani1ine are added dropwise to a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6- pentafluorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is 380 ml of and the washed stirred at room temperature for 1 hour, water are added, while cooling with ice, precipitate is filtered off with suction, with ethanol/Hg) (1:1) 135.4 g of the title compound of melting point 97-99°C are obtained. - 125 - and dried. IE 970856 b) Ethyl 5,6,7,8-tetrafluoro-1-(2,4—difluorophenyl)- 1.4-dihgdro-4—oxo-§—guinolinecarboxylate A mixture of 135.4 g of ethyl 2-(2,3,4,5,6— pentafluorobenzoyl)-3-(2,4-dif1uoropheny1amino)- acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide is heated at 140-150%: 10 for 3 hours. The suspension is poured hot onto 2 kg of ice and the precipitate is filtered off with suction, washed with water and dried. 122 g of the title compound of melting point 160-162°C are obtained. c) 5,6,7,8-Tetraf1uoro—l-(2,4-difluoropheny1)-1,4- dihgdro-4-oxo-§-gginolinecarboxvlic acid 40.1.g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluoro- go phenyl)-1,4-dihydro-4-oxo—3-quinolinecarboxylate are added to a mixture of 28.5 ml of concentrated sulphuric acid, 250 ml of glacial acetic acid and 200 ml of water and the mixture is heated under reflux for 2 hours. The hot solution is poured onto ice and the precipitate is filtered off with suc- tion, washed with water and dried. 34.5 g of the title compound of melting point 250-252°C are obtained. 30 Example AB 5,7—Dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro—4-oxo-3- gyinolinecarboxyllc acid 35 a) h 2 4-d'ch1oro- -d uorobenzovl)-acetate — 126 - 2.1 g of magnesium filings are suspended in 5 ml of anhydrous ethanol. 0.5 ml of carbon tetrachloride is added and, when the reaction has started, a mixture of 14 g of ethyl malonate, 10 ml of absolute ethanol and 41 ml of toluene is added dropwise. The mixture is then heated at 70°C for a further 1.5 hours and cooled to -5°C to -10°C with acetone/dry ice, and a solution of 21.5 g of 2,4-dichloro-3,6-difluoro- benzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at O%2for 1 hour and allowed to come to room temper- ature overnight, and a mixture of 35 ml of ice-water and 5 ml of concentrated sulphuric acid is allowed to run in, while cooling with ice. The phases are separated and subsequent extraction is carried out twice with toluene. The combined toluene solutions are washed once with saturated sodium chloride solution and dried with Nazso. and the solvent is stripped off in vacuo. 34.7 g of diethyl (2,4- dichloro-3 , 6-difluorobenzoyl ) -malonate are obtained as a crude product. 0.04 g of p-toluenetoluenesulphonic acid is added to an emulsion of 34.7 g of crude diethyl (2,4-di- chloro-3,6—difluorobenzoyl)-malonate in 40 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emulsion is extracted several times with methylene chloride, the combined CH2C1z solutions are washed once with saturated sodium chloride solution and -127- IE 970856 dried with Na3S0,, and the solvent is distilled off in vacuo. Fractionation of the residue (33.9 g) in vacuo gives 13.9 g of ethyl (2,4-dichloro-3,6- difluorobenzoyl)-acetate of boiling point 110-115°C/ 0.05 mbar, n35: 1,5241. Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) -3-ethoxy- '~. <3 1'"/1 e: 1: «:4 13.7 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)- acetate are heated under reflux with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride for 2 hours. The mixture is then concentrated in vacuo up to a bath temperature of 140°C and 15.7 g of ethyl 2-(2,4-dichloro-3,6—d.i.fluorobenzoy1)-3- ethoxy-acrylate are obtained as an oil, nD Ethyl 2- ( 2 , 4-dichloro-3 , 6-difluorobenzoyl ) -3-cyclo- nronvlamino-acrvl ate 15.6 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)- 3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H20 (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro- 3 , 6-difluorobenzoyl ) -3-cyc lopropylamino-acrylate of melting point 106-107°C are obtained. -128~ 1,5302. IE 970856 Ethyl 5,7-dichloro—1-cyclopropyl-6-fluoro-1,4- dro- -oxo- - 1 ho ate 6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)- 3-cyclopropylamino-acrylate are heated in 100 ml of dimethylformamide at 150°C with 2.75 g of potassium carbonate for 2.5 hours. The mixture is poured into 600 ml of ice-water and the precipitate is filtered off with suction, washed with water_and dried. 5.2 g of ethyl 5,7-dich1oro-l-cyclopropyl-6—f1uoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 227-229°C are obtained. S,7-Dichloro-1-cyclopropy1-6-fluoro-1,4-dihydro-4- oxo-3-gginoigeggggogglic acid 5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-f1uoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated under reflux in a mixture of 38 ml of acetic acid, 30 ml of water and 4.3 ml of concentrated sulphuric acid for 2.5 hours. After cooling, the mixture is poured into 250 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 4.8 g of 5,7-dichloro-1-cyclopropyb6-f1uoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 277-278°C are obtained. - 129 - IE 970856 5,7—Dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Ethyl 2-(2.4-dichloro-3,6—difluorobenzoy1)-3-(2,4- §!i...f1.uoeropheny.1ame.ino) -acrxlafi __e 35.3 g of ethyl 2-(2,4-dichloro-3,6-dif1uoro- benzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added dropwise, while cooling with ice. The mixture is stirred at room temperature for 1.5 hours, 120 ml of water are added, while cooling, and the precipitate is filtered off with suction, rinsed with ethanol/- I50 (1:1) and dried. 40.5 g of ethyl 2-(2,4—dichloro- 3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)- acrylate are obtained, melting point: 84-86°C. Ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)- 1 4- ' o-4-ox - - no ineca b te 43.6 g of ethyl 2-(2,4-dichloro-3,6-difluoro- benzoyl)-3-(2,4-difluorophenylamino)-acrylate are heated in 260 ml of dimethylformamide at 150°C with 15.2 g of potassium carbonate for 2.5 hours. The mixture is poured into 1 litre of ice-water and the precipitate is filtered off with suction, washed with water and dried. 38.6 g of ethyl 5,7-dichloro- - 130 - IE 970856 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4—oxo— 3-quinolinecarboxylate are obtained. c) 5,7-Dichloro-6-fluoro-1-(2,4-difluoropheny1)-1,4- di - -ox - - o1‘ e o lic acid 41.6 g of ethyl 5,7-dich1oro-6-fluoro-1-(2,4—di- fluorophenyl)-1,4-dihydro-4—oxo-3-quinolinecar- boxylate are heated under reflux with 250 ml of acetic acid, 200 ml of water and 28.5 ml of con- centrated sulphuric acid for 3 hours. After cooling, the mixture is poured into 2 litres of ice-water and the precipitate is filtered off with suction, washed with water and dried. 35.5 g of 5,7-dichloro-6- fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo—3- quinolinecarboxylic acid are obtained, me1ting point: 244-246°C. E.2¢A-El1P.l§._.l. A. 855 mg (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide in the presence of 330 mg (3.3 mmol) of 1,4-diazabicyclo[2.2.2]octane and 750 mg' of IE 970856 trans-3-tert.-butoxycarbonyl-amino-4-methoxy-pyrrolidine for 1 hour. The mixture is evaporated, the residue is stirred with water and the mixture is dried. Yield: 1.3 g (90.5% of theory) of 7-(trans-3-tert.- butoxycarbony1amino—4-methoxy-1-pyrrolidinyl)—1—cyc1o- propyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid. Melting point: 222-224°C (with decomposition) (from glycol monomethyl ether). B. 1.2 g (3.5 mmol) of the product from stage A are introduced into 10 ml of 3N hydrochloric acid, the mixture is stirred until a solution is obtained and the solution is concentrated. The residue is triturated with ethanol, filtered off with suction and dried at 60° under a high vacuum. Yield: 0.73 g (70% of theory) of 7-(trans-3-amino-4— methoxy—l—pyrrolidinyl)-l-cyclopropyl—6,8—difluoro-4-oxo- 3-quinolinecarboxylic acid hydrochloride. Melting point: 279°C (with decomposition). -132’- IE 970856 1-Cyclopropyl-6,7-dif1uoro—l,4-dihydro-4-oxo-3—quino1ine- carboxylic acid is reacted analogously to Example 1 to 5 give: A. 7-(trans-3-tert.-Butoxycarbonylamino-4-methoxy—l- pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, melting point: 247-249°C (with decomposition). 10 B. 7-(trans-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclo- propyl-6-fluoro-4-oxo-3—quinolinecarboxylic acid hydro- chloride, melting point: from 293°C (with decomposition). Exam le ‘-£;.r—."-5 " x HC1 47:‘ I ' /' 15 A reaction is carried out analogously to Example 1 with - 133 - IE 970856 cis—3—tert.-butoxycarbonylamino-4-methoxy-pyrrolidine‘to give: A. 7-(cis—3-tert.-Butoxycarbonylamino-4-methoxy-1- pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro—4- oxo-3—quinolinecarboxy1ic acid, melting point: 230-231°C (with decomposition). B. 7-(cis-3-Amino-4—methoxy-1-pyrrolidinyl)-1-cyc1o- propyl-6,8-difluoro—4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point 201-203°C (with decomposi- tion). Exam le 4 E-‘\4’\\//l\«’CO0H /it-\\_k;J H2513‘/Ax}; x CF'3COOl-I '1 I : c1-:3-3. ’*'*' e’ A. 1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-di- fluoro-1,4—dihydro-4—oxo-3—quinolinecarboxylic acid are heated under reflux in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide with 550 mg (5 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol) of cia-3—tert.-butoxycarbonylamino-4-methoxy-pyrrolidine for 2 hours. The mixture is allowed to cool and the precipit- ate which has separated out is filtered off with suction, rinsed thoroughly with water and dried at 100°C in vacuo. - 134 - IE 970856 Yield: 2.0 g (80.7%) of 7-(cis-3-tert.-butoxycarbonyl- amino—4-methoxy-1-pyrrolidinyl)-8-ch1oro—1-cyclopropyl- 6-fluoro’-1,4-dihydro-4-oxo-3-quinolinecarboxylic ac id, melting point: 222-225°C (with decomposition). B. 1.9 g (3.8 mmol) of the product from stage A are stirred in 10 ml of trifluoroacetic acid at room tempera— ture for 20 minutes, the solution is concentrated, the oil which remains is evaporated twice with methylene chloride and the residue is stirred. with ether. The precipitate which has separated out is filtered off with suction, washed with ether and dried at 60°C in vacuo. Yield: 1.9 g (97% of theory) of 7-(cis-3-amino-4-methoxy- 1-pyrrolidinyl)-B-chloro-1-cyclopropyl-6—£luoro-1,4- dihydro—4-oxo-3-quinolinecarboxylic acid trif1uoro- acetate, melting point: 235-239°C (with decomposition). xam 1e h.Hm_-"$4 V J X551 cis—3-tert.-Butoxycarbonylamino-4-methoxy-pyrrolidine is reacted with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid analogously to Example 1 to give: - 135 — IE 970856 A. 7-(cis-3-tart.-Butoxycarbonylamino—4-methoxy-1- pyrrolidinyl)-1-cyclopropyl-6—f1uoro-1,4-dihydro-4-oxo- 3-quinoiinecarboxylic acid, melting point 232-233°C (with decomposition). B. 7-(cis-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyc1o- propyl-6-fluoro-1,4-dihydro-4-oxo-3—quinolinecarboxylic acid hydrochloride, melting point 252-256°C (with decom- position) (sintering beforehand). Es.4zmp.le_6. H>N\~/”\N xHCl - _ _ . " -2 _\_. cis-3-tert.-Butoxycarbonylamino-4-methoxypyrrolidine is reactedwith7-chloro-1-cyclopropyl-6-fluoro-1,4—dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid analogously to Example 1 to give: A. 7-(cis-tert.-Butoxycarbonylamino-4-methoxy-1- pyrrolidinyl)-1-cyc1opropy1—6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, melting point 214- 216°C (with decomposition). B. 7-(cia-3-Amino-4—methoxy-1-pyrrolidinyl)-1-cyclopro- pyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- - 136 - IE 970856 carboxylic acid hydrochloride, melting point 205-210° (with decomposition). Mass spectrum: m/e 362 (1-1*), 330 (M*-32), 318 (M“-C02), 286, 250, 41 (c3H,), 35 (ncl). Exam le 7 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.55 g (5.4 mmol) of trans-3-amino-4-hydroxy-pyrrolidine are added to 1.33 g (5 mmol) of l-cyclopropyl-6,7—di- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 30 ml of acetonitrile and 5 ml of dimethyl- formamide and the mixture is heated under reflux for 1 hour. The suspension is concentrated, water is added to the residue and the undissolved product is filtered off with suction and recrystallized from dimethylformamide. Yield: 1.2 g (73% of theory) of 7-(trans-3-amino-4- hydroxy—1-pyrrolidinyl}-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid, Melting point: 274-278°C (with decomposition). - 137 - IE 970856 850 mg’ (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.are heated under reflux in 9 ml of pyridine with 630 mg (3.1 mol) of 2- oxa—S,8—diazabicyclo{4.3.0]nonane dihydrochloride and 500 mg (4.5 mmol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. The mixture is concentrated, the residue is stirred with. water and the precipitate is filtered off with suction, washed with water, dried and recrystallized from glycol monomethyl ether. Yield: 840 mg (72% of theory) of 1-cyc1opropyl—6,8- difluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non- B-yl)-4-oxo-3-quinolinecarboxylic acid, Melting point: 289-291°C (with decomposition); Mass spectrum: m/e 391 (M+), 347 (If-CO2), 331, 306, 294, 262, 234, 98, 41 (CJQ). - 138 - IE 970856 The reaction is carried out analogously to Example 8 with 5-methyl-2-oxa-5,8-dia2nbicyclo[4.3.0}nonane dihydro— chlorideeto give: 1-cyclopropyl-6,8-difluoro-1,4-dihydro- 7-(5-methyl-2-oxa—5,8-diazabicyc1o[4.3.0]non-8-yl)-4-oxa- 3-quinolinecarboxylic acid, melting point: from 270°C (with decomposition); Mass spectrum: m/e 405 (M"), 361 (If-C02), 331, 112, (100%). Exggple 10 N\cr-13 795 mg (3 mmol) of 1-cyclopropyl-6,7-dif1uoro-1,4-di- hydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 9 ml of acetonitrile and 4.5 ml of dimethylformamide with 890 mg (4.1 mmol) of 5-methy1-2- oxa-5,3-diazabicyc1o[4.3.0]nonane dihydtochloride and - 139 - IE 970856 860 ng (7.8 mol) of 1,4-diazabicyc1o[2.2.2]octane for 2 hours. The mixture is evaporated, the residue is stirred with water and the undissolved product is filtered off with suction, washed with water, dried and recrystallized from dimethylformamide. Yield: 0.8 g (69% of theory) of 1-cyclopropyl-6-fluoro- 1,4-dihydro-7—(5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]non- 8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 340°C (with decomposition) (on heating up, the substance already becomes dark from about 300°). Mass spectrum: rule (if), 343 (M*-coz), 313, 244, 112 (100%). Examgle 11 ./’.__.._.N‘,r‘ \\.‘/I\.h, 1:-—\ J I 1 I: 4‘ \ //\~\ \. " ‘ , ‘ ‘\ L _.. \cH3 The reaction is carried out analogously to Example 10 with B-chloro-1-cyclopropyl-6,7—difluoro-1,4-dihydro—4— oxo-3-quinolinecarboxylic acid to give 8-chloro—1-cyclo- propyl-6-f1uoro—1,4-dihydro-7-(5-methyl-2-oxa-5,8-diaza- bicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 258-262°C (with decomposition) (recrystal- lized from dimethylformamide). IE 970856 Eggmple 12 .:'\~/\\/jL\~//C OOH I ll 1 —— -N/-~> ,/\-.-;»J ‘l ‘IA V _ r . A\-CH3 The reaction is carried out analogously to Example 10 with 1—ethyl-6,7,8-trifluoro-1,4-dihydro—4—oxo-3-quino- linecarboxylic acid to give 1—ethy1-6,8-difluoro-1,4- dihydro-7-(5-methyl-2-oxa-5,8-diazabicyc1o[4.3.0]non-8- yl)-4-oxo-3-quinolinecarboxylic acid, melting point 279- 281°C (with decomposition). Example 13 O F / C00 \ I1 :1 r~“N/A\v/A\N/’ 1 I i ( '. . ./ \c1-13 0.84 g (3 mol) of 1-cyclopropyl-6,7,8—trif1uoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid are heated.under reflux in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide with 0.66 g (6 mmol) of 1,4—diazabi- cyc1o[2.2.2]octane and 0.49 g (3.5 mmol) of 2-methy1-2,B- diazabicyc1o[4.3.0]nonane for 2 hours. The suspension is concentrated, the residue is stirred with 20 ml of water, - 141 - IE 970856 the mixture is brought to pH 7 with 2N hydrochloric acid and the precipitate is filtered off with suction, washed with water, dried and recrystallized from glycol mono- methyl ether. Yield: 0.? g (58% of theory) of 1-cyc1opropy1-6,8-di- fluoro-1,4-dihydro-7-(2-methyl-2,8-dia2abicyc1o[4.3.0]- non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point 204-207°C. gxamgle 14 :7“ .,/,‘-‘\/’ ‘xx’ //*—N/" KN ._ $ I /r-1’ 1' Qk__N> J /”\\ \c1-:3 "coca Analogously to Example 13, 1-cyclopropyl—6-fluoro-1,4- dihydro-7-(2-methyl-2,8-diazabicyclo[4.3.0]non-8-y1)-4- oxo-3-quinolinecarboxylic acid, melting point 234—236°, is obtained with 1-cyclopropyl-6,7-dif1uoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid. - 142 - IE 970856 Example 1§ A. 1~Cyc1opropyl-6,7,B-trifluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid is reacted. with 2,8-diazabi- cyclo[4.3.0]nonane analogously to Example 13 to give 1- cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-y1)-6,8- difluoro-1,4-dihydro-4—oxo-3-quinolinecarboxylic acid, melting point 265-267° (with decomposition) (recrystal- lized from dimethylformamide). B. If the reaction of Example 15 A) is carried out in a mixture of acetonitrile/1-methyl-2-pyrrolidinone and the crude product is recrystallized from dimethy1- formamide, 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non- 8-yl)-6,8-difluoro-1,4-dihydro—4-oxo-3-quinoline- carboxylic of melting point 269-271°C (with decomposition) is obtained. According to a comparison by chromatography and spectroscopy, the product is identical to the product prepared according to process A). C. 65 g (167 mmol) of the betaine (stage A) are dis- solved in 330 ml of half-concentrated hydrochloric acid by heating, the solution is concentrated and the residue is stirred with 300 ml of ethanol. The undissolved - 143 - IE 970856 precipitate is filtered off with suction, washed with ethanol and dried at 100°C in vacuo. Yield: 66.3 g (93% of theory) of 1-cyclopropy1-7-(2,8- diazabicyclo[4.3.0]non-8-y1)~6,8—dif1uoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 303-305°C (with decomposition). le 1 Analogously to Example 13, 1-cyclopropyl-7-(2,7-diazabi- cyclo[3.3.0]oct-7-y1)—6-fluoro-1,4-dihydro-4—oxo-3- quinolinecarboxylic acid, melting point: 260-282° (with decomposition), is obtained with 1-cyc1opropy1—6,7-di- fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,7-diazabicyc1o[3.3.0]octane. Mass spectrum: m/e 357 (if), 313 (1oo%, 11*.-coz), 259, 257, 244, 82, 23. - 144 — IE 970856 Analogously to Example 13, 1-cyclopropyl-6-f1uoro—1,4- dihydro-7-(2-methyl-2,7-diazabicyc1o[3.3.0]oct-7-y1)—4— oxo-3-quinolinecarboxylic acid, melting point: 206—208°C (with decomposition), is obtained with 1-cyclopropy1-6,7- difluoro-1,4—dihydro-4-oxo-3—quinolinecarboxy1icacidand 2-methyl-2,7-diazabicyclo[3.3.0]octane. §.2F.QJ2l£_l_3 A F V‘//\\'/)\ "OCH! Jifi [\\ I II Analogously to Example 13, 1-cyc1opropy1—6,8-difluoro- 1,4-dihydro-7-(2-methyl—2,7-diazabicyclo[3.3.0]oct-7-y1)- 4-oxo-3-quinolinecarboxylic acid, melting point 193- 200°C (with.decomposition), is obtained with 2-methyl-2,7- diazabicyc1o[3.3.0]octane. — 145 - IE 970856 Example 13 F~ ‘”«¢/‘x 1”” I H 1’. -"\—p.-' A mixture of 2.83 g (10 mol) of 1-cyclopropy1—6,7,8- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4—diazabicyc1o[2.2.2)octane and 1.4 g (11 mol) of 2—methy1-3-oxa-2,7-diazabicyc1o[3.3.- 0]octane in 20 ml of acetonitrile and 10 ml of l-methy1- 2-pyrrolidinone is heated under reflux for 1 hour. It is concentrated in vacuo, the residue is stirred with water (pH 7) and the precipitate is filtered off with suction, washed with water and dried at 60° in vacuo. The crude product (3.7 g) is recrystallized from dimethylformamide. Yield: 1.9 g (49% of theory) of 1—cyclopropyl-6,8-di- fluoro-1,4-dihydro—7—(2-methyl-3-oxa-2,7-diazabicyclo- [3.3.0]oct—7—yl)-4-oxo-3-quinolinecarboxylic acid, melting point 221-223°C (with decomposition). - 146 - IE 970856 The reaction is carried out analogously to Example 19 with 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,5- dimethyl-3-oxa-2,7-diazabicyc1o[3.3.0]oct-7-yl)-4-oxo-3- quinolinecarboxylic acid of melting point 237-238°C (with decomposition). Example 2 ; ';\_ _,/ ~-.\ /" \\/f“"‘.,".'..:‘ . .“ The reaction is carried out analogously to Example 19 with 2,8-dimethyl-3-oxa-2,7—diazabicyclo[3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,8- dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]oct-7-y1)-4—oxo-3- quinolinecarboxylic acid of melting point 197-199°C. - 147 - IE 970856 Example 22 A. 3 g (10 mol) of 8—chloro-1-cyclopropyl~6,7-di- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux in a mixture of 30 ml of acetonitrile and 15 ml of 1-methyl-2-pyrrolidinone with 1.4 g (11 mmol) of 2,8-diazabicyc1o[4.3.0]nonane and 1.65 g (15 mol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. After cooling, the suspension is stirred with about 150 ml of water and the undissolved precipitate is filtered off with suction, washed with water and ethanol and dried at 80°C/12m bar. The crude product is recrystallized from 40 ml of glycol monomethyl ether. Yield: 2.3 g (57% of theory) of 3-chloro-1-cyclopropyl- 7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4-dihydro- 4—oxo-3-quinolinecarboxylic acid, melting point: 224- 226°C (with decomposition). B. The crude betaine is prepared analogously to Example 22 A. and is suspended in 50 ml of water and dissolved by addition of 17 ml of 1N hydrochloric acid and heating. After cooling in an ice-bath, the precipitate which has separated out is filtered off with suction, washed with ethanol and dried at 100°C in vacuo. - 148 — IE 970856 Yield: 2.7 g (61% of theory) of 8-chloro-1-cyclopropyl- 7-(2,8—diazabicyc1o[4.3.0]non—8-yl)-6-fluoro-1,4-dihydro— 4-oxo-3—quinolinecarboxylic acid hydrochloride, melting point: from 225°C decomposition. Example 23 The reaction is carried out analogously to Example 22 with 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo—7H-pyrido- [l,2,3-de][1,4]benzoxazine-6-carboxylic acid and the reaction product obtained is purified by chromatography on silica gel using methylene chloride/methanol/17% strength aqueous ammonia solution (30:8:1) as the mobile phase. 10-(2,8-Diazabicyclo[4.3.0]non—8—yl)—9—fluoro—2,3- dihydro—3-methyl-7-oxo-7H-pyrido[1,2,3—de][l,4]benzoxa- zine-6—carboxylic acid of melting point 291-292°C (with decomposition) is obtained. -149- IE 970856 Egggple 24 6 g (20 mmol) of 1-cyclopropyl-S,6,7,8-tetrafluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.are heated under reflux in 30 ml of 1-methyl-2-pyrrolidinone and 60 ml of acetonitrile with 2.2 g (20 mmol) of 1,4-diazabicyc1o- [2.2.2]octane and 2.7 g (21.4 mmol) of 2,8-diazabicyclo- [4.3.0]nonane for 1 hour. The mixture is concentrated to a substantial degree in vacuo, the residue is stirred with 200 ml of water and the undissolved crystals are filtered off with suction, washed with water and dried. Yield: 6.3 g (77.4% of theory) of 1-cyclopropyl-7-(2,8- diazabicyc1o[4.3.0]non—8-yl]—5,6,8-trifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid Melting point: 266-269°C (with decomposition); after recrystallization from dimethylformamide: melting point: 272-273°C (with decomposition). - 150 - IE 970856 :7 ,.‘ 20 ml of saturated ethanolic ammonia solution are added to 4.1 g (10 mol) of the product from Example 24 in 40 ml of pyridine, and the mixture is heated at 120°C in an autoclave for 12 hours. The suspension is evaporated, the residue is stirred with water and the pH is brought to 7 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction and recrys- tallized from glycol monomethyl ether. Yield: 0.? g (17% of theory) of 5-amino-l-cyclopropyl-7- (2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 275-277°C (with decomposition). Mass spectrum: m/e 404 (M’), 384 flf-HF), 290, 249, 96 (100%). - 151 — IE 970856 A. Analogously to Example 13, 1—cyclopropyl~7-(2,7- diazabicyc1o[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4- oxoo3-quinolinecarboxylic acid, melting point: 277-280” (with decomposition), is obtained with 2,7-diazabicyc1o— [3.3.0]octane. B. 370 mg of the betaine are dissolved in 13 ml of half-concentrated hydrochloric acid, the solution is concentrated and the residue is treated with 10 ml of ethanol. The undiasolved product is filtered off with suction, washed with ethanol and dried. Yield: 290 mg of l-cyclopropyl-7-(2,7-diazabicyclo- [3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid hydrochloride, melting point: 269- 271FC (with decomposition). - 152 - IE 970856 Exam e 27 ‘if ‘A K‘ CH3‘ NH\\‘ The reaction is carried out analogously to Example 8 with trans-4-methoxy-3-methylamino-pyrrolidine chloride. (trans-4-methoxy-3-methylamino—1-pyrrolidinyl)-4-oxo—3- dihydro- 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- quinolinecarboxylic acid, melting point: 268-270°C (with decomposition) is obtained. Example 28 ;—_' F) '.;~s§‘_,;"\\/ /’ \\- '/’/“‘:\/'1 N cH30L~ ? I . HZNWW xCF3C0OH A. 1.4 g (2.9 mmol) of the product from Example 3 A) and 1.98 ml (1.7 g, 12 mol) of dimethylformamide di- ethyl acetal are heated at 120%: in 15 ml of absolute dimethylformamide for 2 hours. The mixture is then concentrated in vacuo. The residue which remains is stirred with acetonitrile. The precipitate is filtered - 153 — IE 970856 off with suction, washed with a little acetonitrile and dried. Yield: 0.8 g (54.4% of theory) of ethyl 7-(cis-3-tert.- butoxycarbonylamino-4-methoxy-1-pyrrolidinyl)-1-cyclo- propyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylate, melting point: 151-152°C. B. 0.3 g (0.6 mmol) of the product from Example 28 A) are stirred in 10 ml of trifluoroacetic acid at 20°C for 10 minutes. The trifluoroacetic acid is then removed in vacuo. The residue solidifies on addition. of diethyl ether. The solid is isolated, washed with diethyl ether and dried. Yield: 0.25 g (80.6% of theory) of ethyl 7—(cis-3-amino- 4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro—4-oxo—3-quinolinecarboxylate trifluoroacetate Melting point: 124-126°C. Example 29 H3C\ Analogously to Example 13, 1-cyclopropyl-6,8-difluoro- 1,4—dihydro-7-(2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]non— 8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point IE 970856 258-260°C (with decomposition), is obtained with 2-methyl- 4-oxo-2,8-diazabicyc1o[4.3.0]nonane. Examgle 3Q Analogously to Example 19, 1-cyclopropyl-6,B-dif1uoro- 1,4-dihydro-7-(3-oxa-2,7-diazabicyclo[3.3.0]octan-7-yl)- 4-oxo-3-quinolinecarboxylic acid is obtained with 3-oxa- 2,7-diazabicyc1o[3.3.0]octane. E am le 1 xHC1 A. 1.1 g (10 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 1.4 g (11 mol) of 2,8—diazabicyclo[4.3.0]nonane are added to 2.53 g (10 mmol) of 1-ethyl-6,7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of acetonitrile and 15 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. The mixture is - 155 - IE 970856 concentrated, the residue is stirred with water and the precipitate is filtered off with suction, washed with water and dried. Yield: 3.1 g (86% of theory) of 7-(2,B-diazabicyc1o- [4.3.0]non-8-yl)-l-ethyl-6-fluoro-4-oxo-3-quinoline- carboxylic acid, melting point: 259-261°C (with decom- position). B. 2.9 g (B mmol) of the betaine from stage A are dissolved in 20 ml of half-concentrated hydrochloric acid under the influence of heat, the solution is filtered hot and the hydrochloride is precipitated from the filtrate by addition of ethanol. This hydrochloride is filtered off with suction, washed with ethanol and dried at l20°C/ 12 mbar. Yield: 1.8 g (57% of theory) of 7-(2,8-diazabicyclo- [4.3.0]non-8-yl)-1-ethyl-6-fluoro—4-oxo-3-quinoline- carboxylic acid hydrochloride, melting point, with decom- position: 299%: (dark coloration already starting from about 215°C). Example 32 Reaction analogously to Example 31 with 1-cyclopropy1- - 156 - IE 970856 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid gives: A. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-B-yl)- 6-fluoro-4-oxo-3-quinolinecarboxylic acid, melting point: 249-257°C (with decomposition) B. 1—Cyclopropyl-7—(2,B-diazabicyclo[4.3.0]non-8-yl)- 6-fluoro-4—oxo-3-quinolinecarboxylic acid hydrochloride, melting point with decomposition: 320°C (dark coloration already starting from about 288°C). Examgle 33 F\jf7\n/)\r/COQH "“N/*§,/*\g/J }w—~< l i If Fe: F //\\\ _ it 1.1 g (3 mmol) of 1-cyclopropyl-7-(2,8-dia2abicyclo- [4.3.0]non—8-yl)-6,8-difluoro-1,4-dihydro—4-oxo-3-quino- linecarboxylic acid are heated under reflux in 10 ml of dimethylformamide and 1 ml of formic acid for 4 hours. The mixture is evaporated, the residue is stirred with 4 ml of water and the precipitate is filtered off with suction, dried (crude yield: 1 g, content: 99.5%) and recrystallized from dimethylformamide. Yield: 0.8 g (64% of theory) of 1-cyclopropy1-6,8—di- iluoro-7-(2-formyl-2,8-diazabicyclo[4.3.0]non-8-yl)-1,4- — 157 - IE 970856 dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 276-278°C. Example 34 C}'I3C0\ V’: I ‘|" 1.1 g (3 mmol) of 1—cyclopropyl-7-(2,8-diazabicyclo— [4.3.0]non-8-yl)-6,8—difluoro-1,4-dihydro—4-oxo-3~quino- linecarboxylic acid are dissolved in a mixture of 8 ml of dioxane and a solution of 120 mg of sodium hydroxide in 1 ml of water, and at the same time 3 ml of 1N sodium hydroxide solution and 260 mg of acetyl chloride are added, while cooling with ice. The mixture is subse- quently stirred at room temperature for 2 hours and diluted with 30 ml of water and the precipitate which has separated out is filtered off with suction. The crude product is recrystallized from glycol monomethyl ether. Yield: 0.6 g (46% of theory) of 7-(2-acetyl—2,8-diaza- bicyclo[4.3.0]non-8-yl)-1-cyclopropyl-6,B-difluoro—1,4- dihydro-4-oxo—3-quinolinecarboxylic acid, melting point: 261-263°C (with decomposition) — 158 - IE 970856 §_x_aLm_..;2 1.9. 3.2 A. Analogously to Example 13, B-chloro-1-cyclopropyl- 6-fluoro-1,4-dihydro-7~(2-methyl-2,7-dia2abicyclo[3.3.0]— oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 222-227°C (with decomposition), is obtained with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid and 2-methyl-2,7-diazabicyclo- [3.3.0]octane. B. 2.3 g (5.8 mmol) of the betaine from stage A are dissolved in 15 ml of 1N hydrochloric acid under the influence of heat, the solution is evaporated and the residue is treated with ethanol. The precipitate is filtered off with suction, washed with water and dried. Yield: 2.2 g (87.7% of theory) of B-chloro-1-cyclopropyl- 6-fluoro-1,4-dihydro-7-(2—methyl-2,7-diazabicyc1o[3.3.0]- oct-7-yl)-4-oxo—3—quinolinecarboxylicacidhydrochloride, melting point: 303-305°C (with decomposition). - 159 - IE 970856 Egample 3§ c}-:3 Analogously to Example 13, 1-cyclopropyl-6,8-dif1uoro- 1,4-dihydro-7-(3-methyl-2,7-diazabicyc1o[3.3.0]oct-7-y1)- 4—oxo-3-quinolinecarboxylic acid is obtained with 3- methyl-2,7-diazabicyclo[3.3.0]octane, and is converted into 1-cyclopropyl-6,B-difluoro-1,4-dihydro-7-(3-methyl- 2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecar- boxylic acid hydrochloride, melting point: 216-221°C (with decomposition), analogously to Example 15 C. with half- concentrated hydrochloric acid. Examgle 37 A. A mixture of 1.45 g (5 mol) of 1-cyclopropy1-6,7,3- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.85 g (7.5 mmol) of 1,4-diazabicyc1o[2.2.2]octane and 0.77 g (5.5 mol) of 2,3-dimethyl-2,7—diazabicyc1o- — 160 - IE 970856 [3.3.0]octane in 15 ml of acetonitrile and 7.5 ml of dimethylformamide is heated under reflux for 1 hour. After cooling, the precipitate is filtered off with suction, washed with water and recrystallized from glycol monomethyl ether. Yield: 1 g (47% of theory) of 1-cyclopropy1-7—(2,3- dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8—difluoro- 1,4—dihydro—4-oxo-3-quinolinecarboxylic acid, melting point: 203-209°C (with decomposition). B. 0.7 g (1.7 mmol) of the betaine from stage A are dissolved in 6 ml of hot half-concentrated hydrochloric acid and the solution is filtered and concentrated to a substantial degree in vacuo. About 15 ml of ethanol are added, the mixture is cooled in an ice-bath and the salt is filtered off with suction, washed with ethanol and dried at 100°C/1 mbar. Yield: 0.64 g (84% of theory) of 1—cyclopropy1—7-(2,3- dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8-difluoro— hydro- chloride, melting point: 233-236°C (with decomposition). 1,4-dihydro-4-oxo-3—quinolinecarboxy1ic acid -161 - IE 970856 Egamgle 33 1-13c\‘ .~ xi-[Cl Analogously to Example 37 A. and B., 8—ch1oro-1-cyclo- propyl-7-(2,3—dimethy1-2,7-diazabicyc1o[2.2.2]oct-7-y1)- 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 240-2419C (with decomposi- tion), is obtained with 8-chloro-1-cyclopropyl-6,7- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Exam le 9 P\/5‘\v/u\,/Coon 1 H H z*._\ ‘ 5}.’ \T/‘\—,’1~<'—. The reaction is carried out analogously to Example 19 with 1,2—dimethyl-3-oxa-2,7-diazabicyc1o{3.3.0]octane to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1,2- dimethyl—3-oxa-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3- quinolinecarboxylic acid of melting point 269-271°C (with decomposition). - 162 - IE 970856 Example 40 xHCl 1.45 g’ (13 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.23 g (9.6 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane are added to 2.6 g (8.7 mol) of 8-chloro-1—cyclopropyl- 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 25 ml of acetonitrile and 12.5 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. It is concentrated, the residue is stirred with water and the undissolved precipitate is filtered off with suction and washed with water. This crude 1- cyclopropyl-B-chloro—6-fluoro-1,4-dihydro-7—(2-oxa-5,8- diazabicyclo[4.3.0]non-8-yl)-4-oxo-3~quinolinecarboxylic acid is introduced into 85 ml of 1N hydrochloric acid, and 6 ml of concentrated hydrochloric acid are added. The hydrochloride which has precipitated out is filtered off with suction, washed with ethanol and dried. Yield: 3.0 g (77.7% of theory) of B-chloro-1-cyclopropyl- 6~fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non— 8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, melting point: from 29¢? decomposition. — 163 - IE 970856 Example 41 , ”*»~:ooH H3C\ Analogously to Example 13, 8-chloro-1-cyclopropyl-6- fluoro-7-(2-methyl—4-oxa-2,8-diazabicyclo[4.3.0]non-8- yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 202- 203°C (with decomposition), is obtained with 8-chloro-1- cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo—3-quino1ine- carboxylic acid and 2-methyl-4-oxa-2,8-diazabicyclo- [4.3.0]nonane. FAB mass spectrum: m/e 422 ([M+H]U, 404 (422-Hgn. Example 42 P-.: . *~ H ‘cozczns A. The reaction is carried out analogously to Example 13 with ethyl 2 , 7-diazabicyclo [ 3 . 3 . 0 ]octane-2-carboxylate to give 1-cyclopropyl-7-(2-ethoxycarbonyl-2,7-diazabi- cyc1o[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid of melting point 191—192°C. - 164 - IE 970856 B. 1.8 g (4 mmol) of the product from Example 42A are heated in 30 ml of concentrated hydrochloric acid under gentle reflux for 15 hours. The solution is concentrated, the residue is stirred with ethanol and the precipitate is filtered off with suction, washed with ethanol and dried at 120°C/12 mbar. Yield: 1.1 g (67% of theory) of 1-cyclopropyl—7-(2,7- diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4—dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride, melting point: 273-275°C (with. decomposition). The product is identical to the compound obtained according to Example 26B. Example 43 A. 7.8 g (20 mmol) of 1-cyclopropyl-7-(2,8-diazabi- cyclo[4.3.0]non-8-yl)-6,B-difluoro-1,4—dihydro-4—oxo-3- quinolinecarboxylic acid are introduced into 175 ml of ethanol, and 2.4 g (25 mmol) of methanesulphonic acid are added at about 70°C. The betaine dissolves, and on cool- ing the salt precipitates out, this being filtered off with suction, washed with ethanol and dried at 120°C/12 mbar. It is readily soluble in water. Yield: 8.6 g (88.6% of theory) of 1-cyclopropyl-7-(2,8- diazabicyclo[4.3.0]non-8-yl)-6,8—difluoro—1,4-dihydro-4- oxo-3-quinolinecarboxylic acid mesylate, melting point: 262—265°C (with decomposition). The following compounds are obtained analogously: — 165 - IE 970856 B. 1—Cyclopropyl-7—(2,8-diazabicyc1o[4.3.0]non-8—yl)- 6,8-difluoro-1,4—dihydro-4—oxo—3-quinolinecarboxylic acid tosylate, melting point: 248-250°C (with decomposition). C. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-B—yl)- 6,8-difluoro-1,4-dihydro—4-oxo-3—quinolinecarboxylic acid lactate, melting point: 205°C-215°C, after sintering beforehand. Example 44 3.9 g (10 mmol) of 1-cyclopropyl-7-(2,8—diazabicyclo- [4.3.0]non-8-yl)-6,8-difluoro—1,4—dihydro-4-oxo-3-quino- linecarboxylic acid are suspended in 50 ml of water, and 10 ml of 1N sodium hydroxide solution are added at room temperature, whereupon the product largely dissolves. A slight turbidity is removed by filtration through a membrane filter, the filtrate is concentrated under a high vacuum and the residue is stirred with ether, filtered off with suction and dried. Yield: 3.4 g (82.7% of theory) of sodium 1-cyclopropyl- 7-(2,8-diazabicyclo[4.3.0]non-8—yl)-6,8-difluoro-1,4-di- hydro-4-oxo—3—quinolinecarboxylate; the salt decomposes slowly above 210°C without melting. - 166 - IE 970856 Egample 45 A mixture of 3.9 g (10 mmol) of 1-cyclopropyl-7-(2,8- diazabicyclo [ 4 . 3 . 0 ] non-8-yl ) -6 , 8-difluoro-1 , 4-dihydro-4w oxo-3-quinolinecarboxylic acid in 100 ml of dimethyl- formamide is heated at 80-100°C with 4.2 g of triethyl- amine and 2.8 g of 2-bromoethanol for 20 hours. The solution is then concentrated in vacuo and the residue obtained is purified by chromatography on 200 g of silica gel (mobile phase: CI-Izclz/CH3OI-I/17% strength NH, = 30:B:1) . The eluate is concentrated and the residue is stirred with ethanol, filtered off with suction and dried. Yield: 1.8 g (41.6% of theory) of 1-cyclopropy1-6,8- difluoro-1,4—dihydro-7-[2-(2-hydroxyethyl)—2,8-diazabi- cyclo[4.3.0]non—8-yl]-4-oxo-3-quinolinecarboxylic acid, melting point: 200-206°C (with decomposition). Mass spectrum: m/e 433 (M7), 402 (M+ -cngnn, 140, 110 (100%), 96 -167- |,_i IE 970856 32H5NHaw " 2-“.v‘«yp Cl-I35 ,2 The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine to give 1-cyc 1op:r:opy1-7- ( trans-3-ethylamino—4-methylthio) -6 , 8- difluoro-1 , 4-clihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 215-216°C (with decomposition). Egamgle 47 The reaction is carried out analogously to Example 13 with 2-phenyl-2,7-diazabicyc1o[3.3.0]octane to give 1- cyclopropyl-6 , 8-difluoro-1 , 4-dihyd.ro-4-oxo—7- ( 2—pheny1- 2,7-diazabicyclo[3.3.0]0ct—7-yl)-3-quinolinecarboxylic acid, melting point: 259-260°C (with decomposition). -168- IE 970856 Examgle 43 F CH3 .1 Analogously to Example 13, 5,6,8-trifluoro-1—(2,4-di- fluorophenyl)-1,4-dihydro-7-(2-methyl-2,8-diazabicyc1o- [4.3.0]non-8-yl)—4-oxo-3-quinolinecarboxylic acid is obtainedwith5,6,7,8-tetrafluoro-1~(2,4-difluoropheny1)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. Example 49 .Ana1ogously to Example 24, 7-(2.8-diazabicyc1o[4.3.0]non- 8—yl)-5,6,8-trifluoro-1~(2,4-difluorophenyl)-1,4-dihydro- 4-oxo—3-quinolinecarboxylic acid is obtained with 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)—1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid. - 169 — IE 970856 ggamgle 50 Analogoualy to Example 25, 5-amino-7-(2,B-diazabicyclo- [4.3.0]non-8~yl)-6,8-difluoro-1-(2,4-dif1uoropheny1)-l,4- dihydro-4—oxo—3-quinolinecarboxylic acid is obtained‘with 7-(2.8-diazabicyclo[4.3.0]non-8-yl)-5,6,8-trifluoro-1- (2,4—difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecar- boxylic acid. Examgle 51 Analogously to Example 15 A, 5-chloro-1-cyclopropyl-7- (2,8-diazabicyclo[4.3.0]non-B-yl)-6—fluoro-1,4-dihydro- 4-oxo-3—quinolinecarboxylic acid, melting point: 270°C (decomposition), is obtained with 5,7-dichloro-1-cyc1o- propyl-6-fluoro-1,4—dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours). - 170 - IE 970856 Analogously to Example 3, 5-ch1oro-1-cyc1opropyl-6- fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyc1o[4.3.0]non- 8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7—dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo—3- quinolinecarboxylic acid (reflux for 5 hours). Examgle 53 Analogous1y' to Example 15 A, 5~chloro~7—(2,8-diazabi- cyclo[4.3.0]non-8-yl)-6-fluoro-1-(2,4-difluorophenyl)— 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours). — 171 - IE 970856 Examgle 54 Analogously to Example 8, 5—chloro-6-f1uoro-1-(2,4- difluorophenyl)-1,4-dihydro-7-(2-oxa-S,8-diazabicyclo- [4.3.0]non-8-yl)-4-oxo—3-quinolinecarboxylic acid is 5,7-dichloro-6-fluoro-1-(2,4-dif1uoro- phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5 hours). obtained with gxamgle 55 The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine and B- chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid to give B-chloro-1-cyclopropy1— 7-(trans-3-ethylamino-4-methylthio-1-pyrrolidinyl)-6- fluoro-1,4—dihydro-4-oxo—3-quinolinecarboxylic acid, melting point: 217—218°C (with decomposition). - 172 - IE 970856 Example 56 XHCI CH3S 7-(trans-3-Amino-4—methylthio-1-pyrrolidinyl)-1-cyclopro~ pyl-6,B-difluoro-1,4-dihydro—4-oxo-3-quinolinecarboxylic, melting point: 208-21l'C (with decomposition) and 7-(trans- 3-amino-4-methylthio-1-pyrrolidinyl)-l-cyclopropyl—6,8—di- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro? chloride, 255-257'C obtained with trans-3-amino-4-methylthio-pyrrolidine analogously to Examples 13 and 15. melting‘ point: (with decomposition), Example 57 XHCI 1—Cyclopropyl-6,8-difluoro-l,4—dihydro-7—(4-methyl-2,8- diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 213-215'C (with decomposition) (recrystallised from glycol monomethyl ether), and 1-cyclo~ propyl-6,B-difluoro-1,4-dihydro-7-(4-methyl-2,B-diazabi- cyclo[4.3.0]non—8—yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride, 204-2l2'C melting’ point: (with decomposi- - 173 - IE 970856 tion) are obtained with 4—methyl-2,8—diazabicyclo[4.3.Q7- nonane analogously to Examples 13 and 15. The product consists of a mixture of 2 stereoisomers. — 174 - IE 970856 Patent Qlaims: 1. 7-(1-Pyrrolidinyl)-3-quinolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) X1 .. . 1 "COOR2 (I) in which represents halogen, represents hydrogen, amino, alkylamino having 1 dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio to 4 carbon atoms, having 1 to 4 carbon atoms, arylthio or halogen, represents alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, cycloalkyl 2-hydroxyethyl, 2- fluoroethyl, methoxy, amino, methylamino, ethyl- having 3 to 6 carbon atoms, amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atomsor(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, - 175 - IE 970856 R’ represents a radical of the structure *3 .2-R‘ _. 3,5 . P6 wherein R‘ can represent C1-C.-alkyl, aryl or C,- C.-acyl, R’ can represent H, C,-C.-alkyl, OH or OCH3, R5 can represent H, optionally hydroxy1-aub- etituted C,-C.~elky1, as well as aryl, heteroary1, benzyl, C,-C.-alkoxycarbonyl, C1-C.-ecyl, (S-methyl-2-oxo-1 , 3-dioxol-4-yl ) -methyl , or C,-C,-cycloallcyl, R’ can represent H or C1-C.-alkyl, R’ can represent H, CH, or phenyl, R" can represent H, CH, or phenyl, R"' can represent H or CI-I3, Y can represent 0, CH2, CHzC!-I3 or CH,-0, it being possible for the CI-I2-O group to be linked to the nitrogen either via 0 or via CH1, and Z can represent 0 or S, and -176- IE 970856 A represents N or C-R‘, wherein R‘ represents H, halogen, methyl, cyano, nitro, hydroxyl or methoxy or, together with R‘, can form a bridge having the structure ‘CH2'CH2‘CH‘CH3 and pharmaceutically usable hydrates and acid addition salts thereof and the alkali. metal, 10 alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids. with the exception of compounds of the formula N} 4;, 0 wherein 15 R1 is C1-C4 alkyl, R2/R3 are each hydrogen or C1-C4 alkyl, R4 is cyclopropyl, phenyl, halophenyl or thienyl, which may be substituted by C1-C4 alkyl or halogen, and 20 R5 is halogen. 2. Compounds of the formula (I) according to Claim 1, in which X‘ represents fluorine or chlorine, X‘ represents hydrogen, amino, alkylamino having 1 - 177 - IE 970856 or 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, ‘fluorine or chlorine, represents alkyl having 1 to 3 carbon. atoms, alkenyl having 2 or 3 carbon atoms, cycloalkyl having 3 to 5 carbon atoms, 2-hydroxyethyl, 2- fluoroethyl, methoxy, amino, methylamino, ethyl- amino, dimethylamino or phenyl which is option- ally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 3 carbon atomsor(5-methyl-2-oxo-1,3~dioxol-4—yl)-methyl, represents a radical having the structure R‘,Z-R‘ 4h, I . ?T‘~<““ ‘:-,é. wherein R‘ can represent C1-C,-alkyl or C,-C,-acyl, R’ can represent H, C¢4g-alkyl, OH or OCH3, it also being possible for, R‘ and R5 together to denote a Crxh-alkylene bridge which is optional1y'mono- or disubstituted by methyl, - 178- IE 970856 can represent H, optionally hydroxy1— substituted C1-C3-alkyl, as well as phenyl, benzyl, C,-C.-alkoxycarbonyl, C1-C2-acyl. (S- methyl-2-oxo-1,3-dioxol-4-yl)-methyl, or C3-C5-cycloalkyl, can represent H or Cfmg-alkyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCH, or C!-I2-O, it being possible for the can-0 group to be linked to the nitrogen either via 0 or via CH2, and can represent 0 or S, and represents N or C-R‘, wherein represents H, fluorine, chlorine, bromine or hydroxyl or together with R’ can form a bridge having the structure - 179- IE 970856 Compounds of the formula (I) according to Claim 1, in which represents fluorine, represents hydrogen, amino, methylamino fluorine, represents alkyl having 1 or 2 carbon atoms, vinyl, cyclopropyl, 2-hydroxyethyl, 2-f1uoro- ethyl, methoxy, methylamino, 4-fluorophenyl or 2,4-difluorophenyl, represents hydrogen or alkyl having 1 or 2 carbon atoms, represents a radical having the structure e /Z-*‘ wherein R‘ can represent C,-C2-alkyl, R’ can represent H or C,-C,-alkyl, it also being possible for R‘ and R’ together to form a C,-C,-alkylene bridge which is - 180 - IE 970856 optionally substituted by methyl, can represent H, CH3, C211,, HOCHZCHZ, benzyl, C1-C.-alkoxycarbonyl or C,-C,-acyl, can represent H or CH“ can represent H or CH3, can represent H or CH3, can represent H or CH3, can represent 0, CH2, CHZCI-I, or CH2-0, it being possible for the CH2-0 group to be linked to the nitrogen either via 0 or via CH2 , and can represent 0 or S, and represents N or C-R”, wherein represents H, fluorine or chlorine, or together with R’ also can form a bridge having the structure -0-CHz—|C1-I-CI-I3 . 4. Process for the preparation of the compounds of the formula (I) according to Claim 1, characterized in -181- IE 970856 that compounds of the formula (II) V;.pf;_fi/~_\ m__FL (II) in which 1 2 1 A, R , R , X and X2 have the abovementioned meaning and X3 represents halogen, in particular fluorine or chlorine, are reacted with compounds of the formula (III) R’-H (III) in which R3 has the meaning given in Claim 1, if appropriate in the presence of acid entrainera, and if appropriate protective groups contained in R3 are removed. “Process for the preparation of the compounds of the formula (I) according to Claim 1 - 182 - IE 970856 ,~T®o&9 (1) in which X‘, R’, R’, R3 and A have the abovementioned meaning X’ represents amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms or arylthio, characterized in that a compound of the formula (IV) (IV) in which X‘, R’, R’, R’ and A have the abovementioned meaning, is reacted with compounds of the formula (V) - 183 - IE 970856 x‘-H (V) in which X2 has the abovementioned meaning, if appropriate in the presence of acid entrainers. 6. Process for the preparation of compounds of the formula (Ia) X 2 II’! ‘ ;« 2 / -_/ \‘ R3/*\A/“x? (Ia) in which X1, X2, R‘, R2 and A have the abovementioned meaning 10 and R3 represents a radical having the structure wherein R‘, R5, R5, R’, R", R"', Y and Z have the abovemen- tioned meaning, - 184 - IE 970856 characterized in that a compound of the formula (VI) X2 0 I 1| . L 'i 2 if‘ .x‘ ~ .-"coon 1’ H U \ ‘; _. (VI) in which X1, X‘, R‘, R2 and A have the abovementioned meaning R“ represents a radical having the structure 13- 2-124 ’“\ Q or ‘N -+—« /F‘ ‘—L———— H N’ P 1 Q :1:——‘.: \< wherein R‘, R’, R‘, R", R"', Y and Z have the abovementioned meaning, is reacted with compounds of the formula (VII) R°—x' (VII) in which - 185 - IE 970856 R“ has the abovementioned meaning and X‘ represents chlorine, bromine, iodine or acyloxy, if appropriate in the presence of acid entrainers. 7-(1-Pyrrolidinyl)-3-qu1nolone- and -naphthyridone— carboxylic acid derivatives of the formula (I) according to Claim 1 for use in a method for thera- peutic treatment of the human or animal body. Medicaments containing compounds of the formula (I) according to Claim 1. Use of compounds of the formula (I) according to Claim 1 for the preparation of medicaments. Use of compounds of the formula (I) according to Claim 1 as animal feed additives. Animal feeds or animal feed additives and premixes containing compounds of the formula (I) according to Claim 1. - 186 - IE 970856 Carboxylic acid derivatives in the S,S—configuration of the formula wherein A is C—Cl, C-F or C—OCH3 and pharmaceutically acceptable salts thereof. Medicaments containing a compound according to Claim Use of compounds according to Claim 12 for the preparation of animal feeds, animal feed additives and premixes. Use of compounds according to Claim 12 as antibacterial agents. Use of compounds according to Claim 12 for the ‘preparation of a medicament for the treatment of bacterial diseases. A compound according to Claim 1, which is any one of those specifically hereinbefore mentioned. A process for the preparation of a compound according to Claim 1, substantially as hereinbefore described and exemplified. - 187 - IE 970856 19. A compound according to Claim 1, whenever prepared by a process claimed in a preceding claim. 20 . A medicament according to Claim 8, substantially as hereinbefore described and exemplified. 21. An animal feed or animal feed additive or premix according to Claim 11, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. - 188 —
Description
PATENTS ACT, 1992
97/0856
*(I-PYRROLIDINYL)~3—QUINOLONE AND NAPHTHYRIDONE
CARBOXYLIC ACID DERIVATIVES, METHOD FOR THEIR
PREPARATION AND FOR SUBSTITUTED MONO- AND BICYCLIC
RYRROLIDINE INTERMEDIATES, AND THEIR ANTIBACTERIAL AND
FEED ADDITIVE COMPOSITIONS
BAYER AKTIENGESELLSCHAET
Description
The invention relates to new 7—(l—pyrrolidinyl)—
—quinolone— and —naphthyridonecarboxylic acid deriva-
their
bacterial agents and feed additives containing them.
tives, processes for preparation and anti—
A number of 3—guinolone— and naphthyridonecarboxylic
acids which are substituted in the 7—position by a
pyrrolidinyl ring has already been disclosed. German
Patent Application 3,318,145, European Patent
Applications lO6,489 and 153,826.
It has been found that the 7-(l-pyrrolidinyl)—3—quino—
lone— and naphthyridonecarboxylic
the formula (I)
acid derivatives of
in which
X1 represents halogen,
X2 represents hydrogen, amino, alkylamino having 1 to
carbon atoms,
dialkylamino having l to 3 carbon
atoms per alkyl group, hydroxyl, alkoxy having 1 to
carbon atoms, mercapto, alkylthio having 1 to 4
carbon atoms, arylthio or halogen,
R1 represents
alkyl having 1 to 4 carbon atoms,
alkenyl having 2 to 4 carbon atoms, cycloalkyl
having 3 to 6 carbon atoms, 2—hydroxyethyl,
2—fluoroethyl, methoxy, amino, methylamino, ethyl-
amino, dimethylamino or phenyl which is optionally
substituted by l or 2 fluorine atoms,
R!!!
represents hydrogen, alkyl
(5—methyl—2—oxo—l,3—dioxo3—4—yl)—me:hyl,
having 1 to 4 carbon
atoms or
represents a radical of the structure
wherein
represents H, Cy{Q—alkyl, aryl, Cy{g—acyl,
represents H, C;{g—alkyl, OH, OCH3, wherein R4 and
R5 together may also denote a Cy%g—alkylene bridge
optionally mono— or disubstituted by methyl,
can represent H, optionally hydroxyl—substituted
C;—C4—alkyl, and aryl, heteroaryl, benzyl, C1—C4—
alkoxycarbonyl, C1—C4—acyl, (5—methyl—2—oxo—l,3—
dioxol—4—yl)—methyl, or C3—C6—cycloalkyl,
can represent H or C1-C4-alkyl,
can represent H, CH3 or phenyl,
can represent H, CH3 or phenyl,
can represent H or CHy
represent 0, CH2, CHZCH2 or CH2—O,
possible for the C}b—O group to be linked to the
it being
nitrogen either via 0 or via CH2, and
can represent 0 or S, and
represents N or C—R8, wherein
R8 represents H, halogen, methyl, oyano, nitro,
__3_
hydroxyl or methoxy or, together‘ with R5 can
form a bridge of the structure
CH2-¢]:H~cH3, —s-CR2-<':H-CH3
'CH2"CH2'(“:H'CH3
hydrates and acid
alkali
and guanidiniun
and pharmaceutically usable
thereof and the
earth metal,
addition salts metal,
alkaline silver
salts of the underlying carboxylic acids, have a
high antibacterial action, in particular in the
Gram—positive region.
Preferred compounds are those of the formula (I)
(I),
which
represents fluorine or chlorine,
represents hydrogen, amino, alkylamino having 1 or
2 carbon atoms, dimethylamino, hydroxyl, methoxy,
mercapto, methylthio, phenylthio, fluorine or
chlorine,
represents alkyl having l to 3 carbon atoms,
alkenyl having 2 or 3 carbon atoms, cycloalkyl
having 3 to 5 carbon atoms, 2-hydroxyethyl,
2—fluoroethyl, methoxy, amino, methylamino,
ethylamino, dimethylamino or phenyl which is
optionally substituted by l or 2 fluorine atoms,
represents hydrogen, alkyl having l to 3 carbon
atoms or (5—methyl—2—oxo—l,3—dioxol—4—yl)—methyl,
represents a radical of the structure
wherein
R4 represents H, C1—C3—alkyl, C1—C2—acyl,
R5 represents H, C;—C3—alkyl, OH, OCH3, wherein R4
and R5 together may also denote a Cy<5—alkylene
bridge
methyl,
optionally mono- or disubstituted by
R6 can represent H, optionally hydroxyl—substituted
C1—C3—alkyl benzyl, C1-C4—alkoxy—
carbonyl, (5—methyl—2—oxo—l,3-dioxol-
4—yl)—methyl or Cy(g—cycloalkyl,
and phenyl,
C1—C2—acyl ,
R can represent H or C1-C2-alkyl,
R‘ can represent H or CHM
R" can represent H or CHm
R"'can represent H or CH3
Y can represent 0, CH2,
possible for the CH2-O group to be linked to the
CHZCHZ or CH2—O, it being
nitrogen either via 0 or via CH2, and
Z can represent 0 or S, and
represents N or C—R8, wherein
R8 represents H, fluorine, chlorine, bromine,
methyl, nitro, hydroxyl or methoxy or, together
with R1, also can form a bridge of the structure
—O—CH;—CH—CH3
Particularly preferred compounds are those of the
formula (I)
x2 o
x‘ , cook?
I I 11>.
R3 ‘
I
R1
in which
X1 represents fluorine,
X2 represents hydrogen, amino, methylamino or
fluorine,
R1 represents alkyl having 1 or 2 carbon atoms, vinyl,
cyclopropyl, 2-hydroxyethyl, 2—fluoroethyl,
methoxy, methylamino, 4—f1uorophenyl or
2,4—difluorophenyl,
R2 represents hydrogen or alkyl having 1 or 2 carbon
atoms,
R3 represents a radical of the structure
R’ ,2-R4 R‘ R‘
-N/.+-‘ 9 ‘N l_—“/>"R7 5 "X/+-‘___*f
‘2:’»<“ ‘:7
wherein
R4 represents H, C1—C2—alkyl, acetyl,
R5 represents H, C1—C2—alkyl, wherein R4 and R5
together may also denote a Cfi—C2-alkylene bridge
optionally substituted by methyl,
R6 can represent H, CH3, Cfih, HOCHZCHZ, benzyl,
C1—C4—alkoxycarbonyl or C1—C2—acy1,
R can represent H or CHM
R‘ can represent H or CH&
R" can represent H or CHw
R"'can represent H or CH3
lO Y can represent 0, CH” <3bCH2 or CH2—O, it being
possible for the CH2—O group to be linked to the
nitrogen either via 0 or via CH2, and
Z can represent 0 or S, and
A represents N or C—R8, wherein
R8 represents H, fluorine or chlorine, or, together
with R1, also can form a bridge of the structure
—o—cnz~cH—cH3
l
It has furthermore been found that the compounds of the
formula (I) are obtained by a process in which compounds
of the formula (II)
X2 0
X1 , coca?
3 \ (I ) ,
R A ‘
R1
in which
R1, R2, X1 and X2 have the abovementioned meaning and
X’ represents halogen, in particular fluorine or
chlorine, are reacted with compounds of the formula
(III)
R3—H (III)
in which
R3 has the abovementioned meaning,
if appropriate in the presence of acid scavengers, and
if appropriate protective contained in R3
(method A).
groups are
removed
Compounds of the formula (1) according to the invention
X3 o
x1 , con?
3 \ I I (1),
R A
R1
in which
X1, R1, R2, R3 and A have the abovementioned meaning and
X“ represents amino, alkylamino having 1. to 4 carbon
atoms, dialkylamino having 1 to 3 carbon atoms per
alkyl group, hydroxyl, alkoxy having 1 to 4 carbon
atoms, mercapto, alkylthio having 1 to 4 carbon
atoms or arylthio,
can also be obtained by reacting a compound of the
formula (IV)
F 0
xi , coca?
\ (IV),
R3 A
31
in which
X1, R1, R2, R3 and A have the abovementioned meaning,
with compounds of the formula (V)
in which
Xzhas the abovementioned meaning, if appropriate in the
presence of acid scavengers (method B).
Compounds of the formula (la) according to the invention
X2 o
X1 , coon?
R3 \A I (13);
R1
in which
X1, X2, R1, R2 and A have the abovementioned meaning and
R3 represents a radical of the structure
R‘ ,2.-R4 R-
-“ v ' _N I: R
\+__. 5 ‘ I?
an (R ' u -—'N
‘A R6 R w,'6
wherein
R4, R5, R6, R’, R", R"', Y and Z have the abovementioned
meaning,
can also be obtained by a process in which a compound of
the formula (VI)
x2 o
x‘ , coon?
" I
R1
in which
X1, X2, R1, R2 and A have the abovementioned meaning and
R*’ represents a radical of the structure
Ra ’Z_R4 E?» A’
/I '
‘N 5 or ‘N Y
‘*5 *7/“ ‘*1-R..~*~’,
3 H
wherein
R3 R5, R‘, R", R"', Y ands Z have the abovementioned
meaning,
is reacted with compounds of the formula (VII)
R6—Xa (VII)
in which
R6 has the abovementioned meaning and
Xa represents chlorine, bromine, iodine, hydroxyl or
acyloxy,
if appropriate in the presence of acid scavengers
(method C).
If, for example, l—cyclopropyl—6,7,8—trifluoro—
l,4—dihydro~4—oxo—3—quinolinecarboxylic acid and
l—methyloctahydropyrrolo[3,4—b]pyridine are used as
starting substances, the course of the reaction can be
represented by the following equation:
COOH Base
I o NH --—---°
3 -HF‘
7'' ‘!“a
_ 10 _
0
O0
F A
If, for example, 7—chloro—6-fluoro—l-(4—fluorophenyl)—
\\
CH3
l,4—dihydro—4—oXo—l,8—naphthyridine—3~carboxylic acid
and cistert—butoxycarbonylamino—4—methoxypyrrolidine
are used as starting substances, the course of the
reaction can be re resented b the following e uation:
P Y 4 Q
cngo
COOH Base
6 mi"-—-*
C1 —HC1
(CH3)3C’0’CO’NH
o
coon
I HC1
cH3::I::: N ---——-+
‘ -F
o
’ cboH
CH3 -
me E:
F .
x H01
If, for example, l—cyclopropyl—5,6,8—trifluoro—l,4-di-
hydro—7—(2—methyl-2,7—diazbicyclo[3.3.0]oct—3—yl)—
4—oxo—3—quinolinecarboxylic acid and ammonia. are used
as starting substances, the course of the reaction can
be represented by the following equation:
H3C'
NHZO
O0
F A
If, for example, l—cyclopropyl—7—(2,7—diazabicyclo—
[3.3.0]oct-7—yl)fluoro~l,4—dihydro—4—oxo—3—
guinolinecarboxylic acid and ethanol/hydrogen chloride
are used as starting substances, the course of the
reaction can be represented by the following equation:
coon Hal
1 + czusou --——-—+
A
Q
xucz
The compounds of the formula (11) used as starting
substances are known or can be prepared by known
methods. Examples which may be mentioned are:
—chloro—l—cyclopropyl-6—fluoro—l,4—dihydra—4—oxo—3—
quinolinecarboxylic acid (German Patent Application
3,142,854),
_’_)_2_
—cyclopropyl—6,7—difluoro—l,4—dihydro—4—oxo—3—
quinolinecarboxylic acid
113,091),
(European Patent Application
—chlorocyclopropyl-7,8~difluoro—l,4—dinydro—4—oxo—
3—quinolinecarboxylic acid
,420,743),
(German Patent Application
—chloro—l—cyclopropyl—6,7-difluoro—l,4—dihydro—4—oxo—
3—quinolinecarboxylic acid
3,420,743),
(German Patent Application
l—cyclopropyl—6,7,8—trifluoro—1,4—dihydro—4—oxo—3—qumKk
linecarboxylic acid (German Patent
,318,145),
Application
,8—dichloro—l—cyclopropyl—7-fluoro—l,4—dihydro—4—oxo—
3—quinolinecarboxylic acid
3,420,743),
(German Patent Application
l—cyclopropyl—6,7—difluoro—l,4—dihydro—8—methyl—4—oxo—
—quinolinecarboxylic acid,
l—cyclopropyl~7—chloro—6—fluoro~l,4—dihydro-8—nitro—
—oxo—3—quinolinecarboxylic acid,
,7—difluoro—l—ethyl—l,4—diyydro—4—oxo-3—quinoline—
carboxylic acid,
—cnloro—6—fluoro—1—ethyl—1,4—dihydro—4—oxo-3—quino—
linecarboxylic acid,
—cnloro—6—fluoro—l,4—dihydro—l—(2—hydroxyethyl)—4—oxo—
—quinolinecarboxylic acid,
,7—difluoro—l—(2—fluoroethyl)—1,4—dihydro—4—oxo—
—quinolinecarboxylic acid,
—cnloro—l—(2,4—difluorophenyl)—6,7—difluoro—l,4—di-
_ 13 _
hydro-4—oxo—3—quinolinecarboxylic acid
Application 235,762),
(European Patent
—chloro—6—fluoro—1,4—dihydro—l—methoxy—4—oxo-3—quino-
linecarboxylic acid,
—chloro—6—fluoro—1,4—dihydro—l—methylamino—4-oxo—3—
quinolinecarboxylic acid,
,7—difluoro—l,4—dihydro—4—oxo—l—phenyl—3—quinoline—
carboxylic acid,
—chloro—l—cyclopropyl—6—fluoro—l,4—dihydro—4—oxo—
1,8—naphthyridine—3—carboxylic acid,
,7—dichloro—1—cyclopropyl—l,4—dihydro—4—oxo—l,8—naph—
thyridine—3—carboxylic acid,
ethyl l—cyclopropyl—6,7,8—trifluoro—l,4—dihydro—4—oxo-
3—quinolinecarboxylate 7Patent
,318,145),
(German Application
,l0—difluoro—2,3—dihydro—3—methyl—7—oxo—7H—pyrido—
[1,2,3—de][1,4]benzoxazine—6—carboxylic acid
Patent Application 47,005),
(European
,9—difluoro—6,7—dihydro—5—methyl—l—oxo—lH,5H—benzo—
[i,j]quinolizinecarboxylic acid,
—chloro—6—fluoro—l—phenyl—l,4—dihydro—4—oxo—l,8—naph—
tnyridine—3—carboxylic acid
Application 153,580),
(European Patent
—chloro—6-fluoro—l—(4—fluorophenyl)—1,4—dihydro—4—oxo—
l,8—naphthyridine—3—carboxylic acid
Application 153,580),
(European Patent
,7,8—trifluoro—l,4—dihydro—l—methylamino—4—oxo—3—quhKr
linecarboxylic acid (German Patent Application
,409,922),
l~amino—6,7,8—trifluoro—l,4—dihydro-4—oxo—3—quinoline—
carboxylic acid (German Patent Application 3,409,922),
6,7,8—t:ifluoro—l,4—dihydro—1—dimethylamino—4—oxo~
3—quinolinecarboxylic acid
3,409,922),
(German Patent Application
—chloro—6—fluoro—l,4—dihydro-8—nitro—4-oxo~l—phenyl—3—
quinolinecarboxylic acid,
—cnloro—6—fluoro—l—(4—fluorophenyl)—l,4—dihydro—8—
nitro—4—oxo~3—quinolinecarboxylic acid,
,7—difluoro—1—(4—fluorophenyl)—l,4-dihydro—8—methyl—
—oxo-3—quinolinecarboxylic acid,
—chloro—7—fluoro—l—(4—fluorophenyl)—1,4—dihydro—4—oxo—
3—quinolinecarboxylic acid
131,839),
(European Patent Application
,6,7,8—tetrafluoro—l—(2,4—difluorophenyl)—l,4—dihydro—
—oxo—3—quinolinecarboxylic acid,
,7—dichloro—6—fluoro—l—(2,4—difluorophenyl)—l,4—di—
hydro—4—oxo—3—quinolinecarboxylic acid,
,7—dichloro—1—cyclopropyl—6—fluoro-1,4—dihydro—4—oxo—
—quinolinecarboxylic acid,
—chloro—7—fluoro—l—(2,4—difluorophenyl)—l,4—dihydro—4—
oxo—3—quinolinecarboxylic acid Patent
Application l31,839),
(European
,7,8—trifluoro—1—(4—fluorophenyl)—l,4—dihydro—4-oxo—3—
quinolinecarboxylic acid
l54,780),
(European Patent Application
_ 15 _
,7,8-trifluoro—1—(2,4—difluorophe:yl)~1,4—dihydro—4—
oxo—3—quinolinecarboxy1ic
Application 154,780),
acid (European Patent
,7,8—trifluoro—1,4—dihydro—4—oxo—1-phenyl-3—quino;ine—
carboxylic acid (European Patent Application 154,780),
7—ch;oro—1—ethyl—6—fluoro—1,4—dihydro—4—oxo—1,8—naph—
thyridine—3—carboxylic acid,
,7—difluoro—1,4—dihydro—4—oxo—1—vinyl-3—quinoline-
carboxylic acid,
—cyc1oprop1—5,6,7,8—tetraf1uoro—1,4—dihydro—4—oxo—
—quinoinecarboxylic acid,
—amino—1-cyclopropyl~6,7,8-trifluoro—1,4—dihydro~
—oxo—3—quino1inecarboxy1ic acid,
—cyc1opropyl—6,7,8—trifluoro—1,4—dihydro—5—hydroxy—
4—oxo—3—quino1inecarboxylic acid, and
1—cyc1opropyl—6,7—difluoro—1,4—dihydro—8—methoxy—4—oxo—
3-quinolinecarboxylic acid.
of the formula used as
The compounds (III)
compounds are new in some cases.
starting
They can be prepared
by the following processes.
. Starting from the N—protected 3,4—epoxypyrrolidine
(German Published
U.S. Patent
(1) (German Offenlegungsschrift
1,929,237
which can optionally also carry one or
radicals, the
(IIIa)—(IIIe)
Specification) and
4,254,135),
two
methyl or phenyl
starting
compounds of formulae are
prepared.
_l6._
H 5 elimination of 5
/g5 /R protective groups H04’. /R
+ HN "“"‘ \\R6 Q g \R5
1 i 1
R9 R9 H
(1) (Illa)
4 3 . 4 5
R X HE'S emmnamnof R %. ’/R
R49? /R5 protective groups l \g6
~> N
\R5 1
H
R9 (1 1 11:)
R9 2 benzyl, acyl, alkoxycarbonyl, benzyloxy—
carbonyl, trialkylsilyl or sulphonyl (examples
of protective groups),
X3 : a leaving group, such as halogen, or alkyl— or
(1)-—--
arylsulphonyloxy
-- H0041 R40”/II; ‘ 3
R‘): 3
.__.___._..... _____,____________.
“I Base’ - ” I‘
R9 R9
R9 . H
(IIIC)
, s
R4 H-R5 R40 /R ' R4 /R
“U” '*[;j‘“\R«. N\R6
H2/Pd
H
(I119)
(1111!)
Starting compounds of the formula (IIIf) are
obtained from 2-(l,2—dichloroethyl)oxirane via the
following reaction sequence:
Hi) "
(III!)
By addition reaction of azides with N—benzyl—
maleimides which. are optionally substituted. with
one or two methyl and/or phenyl radicals it is
possible to prepare starting compounds of the
formula (lIIg):
H
(1119)
RNC = H, alkyl, benzyl.
4. FIOHI the 3,4—epoxypyrrolidines (1), the starting
compounds of the formula (IIIh) are obtained via
cyclization with thionyl chloride:
H0WT:;:]lNH2 Hem» -co-R7
<1) ~-—--* I —————~ soczz
R9
| -—-—————--o
R9
R9 H
A (111 ha
5. By reaction of the 3,4—epoxypyrrolidines (1) with
ethanolamines, the starting compounds of the
formula (IIIi) are obtained by intramolecular
etherification:
(III i).
. The starting compounds of the formula (IIIj) are
obtained from aminoacetaldehyde dimethyl acetal
via intramolecular l,3—dipolar cycloaddition.
R.
gcua 9 ocaa N3
c-———-—-———-—-O
Base
OCH3 _ .
. /\4ocH3 H+ /\cHo Rb-NH-OH
529-»: /cnz --—-4 39-14 Hz —--—-——v
x_._( \_4R:
N-R5 N-R5
R‘ ----* R’
I I
R9 H
(111 j)
/. Starting from pyridine—2,3—dicarboxylic acid
N—benzylimide, starting compounds (lllk) or (I111)
are prepared via the reaction steps shown.
alkyiiodide I o 32/are or
I Pdéc
N-CH2-‘C685 N—cH2—c6H5
“ o
JLiA1H4 or
NBBH I
BF3‘?C2H5)2O
alkyl
lLiA1H4 ‘ ]H2IPd-C
| H
alkyl
(HI 1)
H2IPd-C
CO"
I
alkyl
(III k)
_ 22 _
. N—Benzyl—maleimide adds onto 2—ch1o:oethy1amines
to give 3-(2—chloroethylamino)—succinimides, which
are converted into the starting compounds of the
formula (IIIm):
[ N-CH2-C6H5 + c1—cu2cH2-NH~R5 —————-—~
~--{
C1 0
I -——( Nan
CH2 “‘c“2‘C6H5 —“*——”‘“*
I z*'(
cH2—? 0
R6
0
N‘CH2‘C6H5 LiA1H4 N'CH2'C6H5
I 1
R5 R5
NH
H2/Pd'C
---——--—-—-9
I
R6
(III m)
9. 2—Methyl—2—propenal—dimethylhydrazone reacts with
N—benzylmaleimide to give a cycloadduct, which can
be converted into the starting compound (IIIn) by
the reaction sequence shown.
_23._
o 0
CH3 ,CH2 CH3
E + I N-CH2-Ph —————~ I N-CH2-Ph
I I
N o N 0
/"\ /"\
CH3 CH3 CH3 CH3
0 o
—(CH3)2NH CH3 H2; CH3
~———-————v 1‘ I N-CH2-Pb N-C_H2—Ph
N catalyst N
H H
o 0
LiA1H4 CH3 H2IPd-C CH3
-——--—-¢ N-CH2-Pn————-——- V NH
N N
H - H
(II! :1)
l0. Starting compounds of the formulae (lllo), (lllp)
or (lllq) can be obtained starting from
N—protected. 2,5—dihydropyrroles (3—pyrrolines) by
addition reaction sulphenoyl chlorides in the
following ways:
R9 R9
1. +R_6-_NI-lg (R119 = CH2C}-I2-Hal) R5\
2- ehmmatnon ofR + NH
Ii R6/
/""\ R6\
525-}; s s-R“
9: WU
I
H R9
(1110) "J
R5‘ 11 R5‘ 11
}»: ' ‘ ' —
R6/WU/. ehmmatnon of R R6/mg/s R
H> (R11= acyl, R
alkoxycarbonyl)
(I119) (IIIq)
Rll = optionally halogen—substituted Cy%h—alkyl,
optionally halogen—, nitro—, alkyl— and alkoxy-
substituted phenyl, and also acyl, alkoxy-
carbonyl.
The following starting compounds, for example, can be
prepared in accordance with these general equations.
They can be prepared and employed as diastereomer
enantiomerically pure form.
mixtures or in diastereomerically pure or
-amino-3—hydroxypyrrolidine,
3—hydoxy—4—methylaminopyrrolidine,
4—dimethylamino—3—hydroxypyrrolidine,
4—ethylamino—3—hydroxypyrrolidine,
3—amino—4—methoxypyrrolidine,
4—methoxy—3—methylaminopyrrolidine,
3-dimethylamino—4—methoxypyrrolidine,
3—ethylamino—4—methoxypyrrolidine,
-amino—4—ethoxypyrrolidine,
_25..
—ethoxy—3—methylaminopyrrolidine,
3—dimethylaminO—4—ethoxypyrrolidine,
4—ethoxy—3—ethylaminopyrrolidine,
3—hydroxy—4—hydroxyaminopyrrolidine,
3—hydroxy—4—methoxyaminopyrrolidine,
3—hydroxyamino—4—methoxypyrrolidine,
4—methoxy—3—methoxyaminopyrrolidine,
3—benzylamino—4—methoxypyrrolidine,
4—methoxy—3—((5—methyl—2—oxo—l,3—dioxol—4—yl)me:hyl~
amino>pyrrolidine,
—amino—4-methylmercaptopyrrolidine,
3—acetoXy—4—dimethylaminopyrrolidine,
3—acetamido—4—methoxypyrrolidine,
4—methoXy—3—methoxycarbonylaminopyrrolidine, 3—formami—
do—4—methoxypyrrolidine, 3—amino—4—methoxy—2—methyl—
pyrrolidine, 3—amino—4—methoxy—5—methylpyrrolidine,
4—methoxy—2—methyl—3—methylaminopyrrolidine, 4—methoxy—
—methyl—3—methylaminopyrrolidine, 3—amino—4—methoxy—
2—phenylpyrrolidine, 4—methoxy—3—methylamino—5—phenyl—
p rrolidine, 3—methyl—2,7—diazabicyclo[3.3.0]octane,
—methyl—
3,5—dimethyl—2,7—dia—
l,5—dimethyl—2,7—diazabicy—
—methyl—2,7—diazabicyclo[3.3.0]octane,
2,7—diazabicyclo[3.3.0]octane,
zabicyclo[3.3.0]octane,
clo[3.3.0]octane, 2—oxa—4,7—diazabicyclo[3.3.0]octane,
3,3—dimethyl—2—oxa—4,7—diazabicyclo[3.3.0]octane,
l,2—dimethyl—3—
2,5-dimethyl—3—oxa—
2,8—dimethyl—3—oxa—2,7—
—methyl—3—oxa—2,7—diazabi—
—oxa-2,7—diazabicyclo[3.3.0]octane,
oxa—2,7—diazabicyclo[3.3.0]octane,
,7—diazabicyclo[3.3.0]octane,
diazabicyclo[3.3.0]octane,
cyclo[3.3.0]octane, 2—oxa—4,7—diazabicyclo[3.3.0]oct—
3—ene, 3—methyl—2—oxa—4,7—diazabicyclo[3.3.0]oct—3—ene,
6—me—
8—methyl—
3—methyl—
4—methyl—2,8—diazabi—
—methyl—2,8—diazabicyclo[4.3.0]—
6—methyl—2,8—diazabicyclo[4.3.0]nonane,
—phenyl—2—oxa—4,7—diazabicyclo[3.3.0]oct—3—ene,
thyl—2-oxa—4,7—diazabicyclo[3.3.0]oct—3—ene,
2—oxa—4,7—diazabicyclo[3.3.0]oct—3—ene,
,8—diazabicyclo[4.3.0]nonane,
cyclo[4.3.0]nonane,
nonane,
3—methyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane, 4—methyl—
—oxa—5,8—diazabicyclo[4.3.0]nonane, 1—methy1—2—oxa—
,8—diazabicyclo[4.3.0]nonane,
3,5—dimethyl—2—oxa-5,8—diazabicyclo[4.3.0]nonane,
2—thia—5,8—diazabicyclo[4.3.0]nonane,
—methyl—2—thia—5,8—diazabicyclo[4.3.0)nonane,
3,5—dimethyl—2—thia—5,8—diazabicyclo[4.3.0]ncnane,
3—oxa-2,8—diazabicyclo[4.3.0]nonane,
2—methyl—9—oxa—2,8-diaZabicyclo[4.3.0]nonane,
4~methyl—3—oxa—2,8—diazabicyclo[4.3.0]nonane,
2,5—dimethyl—3—oxa—2,8—diazabicyclo[4.3.0]nonane,
3—oxa—5,8—diazabicyclo[4.3.0]nonane,
—methyl—3—oXa-5,8—diazabicyclo[4.3.0]nonane,
l,5—dimethyl—3—oxa—5,8—diazabicyclo[4.3.0]nonane and
4,4—dimethyl—3—oxa—5,8—diazabicyclo[4.3.0]nonane.
with
The reaction of (II)
in which the compounds
(III)
(III)
the form of their hydrochlorides,
according to method A,
can also be employed in
is preferably carried
N,N—
hexamethyl-
out in a diluent, such as dimethyl sulphoxide,
dimethylformamide, N—methylpyrrolidone,
phosphoric acid triamide, sulpholane, acetonitrile,
water, an alcohol, such as methanol, ethanol, n-
propanol or isopropanol, glycol monomethyl ether or
pyridine. Mixtures of these diluents can also be used.
Acid—binding agents which can be used are all the cus-
tomary inorganic and organic acid—binding agents. These
the alkali
alkali metal carbonates,
include, preferably, metal hydroxides,
organic amines and amidines.
Particularly suitable acid—binding agents which may be
mentioned specifically are: triethylamine, 1,4—diaza—
bicyclo[2 2.2]octane (DABCO), l,8—diazabicyclo[5,4,0]—
undec—7—ene (DBU) or excess amine (III).
The reaction temperatures can be Varied within a
substantial range. The reaction
out between about 20 and 200°C,
and 180°C.
is in general carried
preferably between 80
The reaction can be carried out under normal pressure,
_ 27 _
but also under elevated pressure. It is in general
carried out under pressures between about 1 and 100
bar, preferably between 1 and 10 bar.
In carrying out the process according to the invention,
to 15 nml, preferably 1 ix) 6 mol, of the compound
(III) are employed per mol of the carboxylic acid (:1).
Free hydroxyl groups can be protected during the
reaction by 23 suitable hydroxyl—protective group, for
example by the tetrahydropyranyl radical, and can be
liberated again when the reaction has ended (see
J.F.W. McOmie, Protective Groups in Organic Chemistry
(1973), page 104).
Free amino functions can be protected during the
reaction by a suitable amino—protective group, for
example by the ethoxycarbonyl or tert.—butoxycarbonyl
radical, and liberated again when the reaction has
ended by treatment with a suitable acid, such as
hydrochloric acid or trifluoroacetic acid (see Houben—
Weyl, Methoden der organischen Chemie (Methods of
Organic Chemistry), Volume E4, page 144 (1983); and
J.F.W. McOmie, Protective Groups in Organic Chemistry
(1973), page 43).
The reaction of (IV) with (V) according to method B is
preferably carried out in a diluent, such as dimethyl
sulphoxide, dioxane, N,N—dimethylformamide, N—methyl—
pyrrolidone, hexamethyl—phosphoric acid triamide,
sulpholane, water, an alcohol, such as methanol,
ethanol, n—propanol or isopropanol, glycol monomethyl
ether or pyridine. Mixtures of these diluents can also
be used.
Acid—binding agents which can be used are all the
customary inorganic and organic acid—binding agents.
These include, preferably, the alkali metal hydroxides,
alkali metal carbonates, organic amines and amidines.
_ 28 _
Particularly suitable acid—binding agents which may be
mentioned specifically are: triethylamine, 1,4—di—
azabicyclo[2.2.2]octane (DABCO) or l,8—diazabicyclo—
[5,4,0]undec—7—ene (DBO).
The reaction temperatures can be varied within a
substantial range. The reaction is in general carried
out between about 70 and about 200°C, preferably
between 100 and 180°C.
The reaction can be carried out under normal pressure,
but also under increased pressure. It is in general
carried out under pressures of between about 1 bar and
about 100 bar, preferably between l and l0 bar.
In carrying out the process according to the invention
by method B, 1 to 50 mol,
the compound (V)
(IV).
preferably 1 to 30 mol, of
are employed per mol of the compound
the
carboxylic acid on which they are based is preferably
To prepare the esters according to the invention,
reacted in excess alcohol in the presence of strong
acids, such as sulphuric acid, anhydrous hydrochloric
acid, methanesulphonic acid, p—toluenesulphonic acid or
acid ion exchangers, at temperatures from about 20° to
200°C, preferably about 60° to 120°C. The water of reac-
tion formed can also be removed by azeotropic distilla-
benzene or
tion with chloroform, carbon tetrachloride,
toluene.
The esters are also advantageously prepared by heating
the acid on which they are based with dimethylformamide
dialkyl acetal in a solvent, such as dimethylformamide.
The 5—methyloxo—l,3-dioxol—4-yl—methyl esters used
as a prodrug are obtained. by reaction of an alkali
metal salt of the carboxylic acid on which. they are
based with 4-bromomethyl— or 4—chloromethyl—5—methyl—
_ 29 _
,3-dioxol—2—one in a solvent, such as dimethyl—
formamide, dimethylacetamide, N—methylpyrrolidone,
dimethyl sulphoxide or tetramethylurea at
of about 0° to 10 °C, preferably 0° to 50°C.
temperatures
The acid addition salts of the compounds according to
the invention are prepared in the customary manner, for
example by dissolving the betaine in excess aqueous
acid and precipitating the salt with a water—miscible
organic solvent, such as methanol, ethanol, acetone or
acetonitrile. It is also possible to heat equivalent
amounts of the betaine and acid in water or an alcohol,
and then
the mixture to dryness or filter off the
such as glycol monomethyl ether, to evaporate
precipitated
salt with suction.
Pharmaceutically usable salts are to
be understood as, for example, the salts of hydro-
chloric acid, sulphuric acid, acetic acid, glycolic
acid, lactic acid, succinic acid, citric acid, tartaric
acid, methanesulphonic acid, 4—toluenesulphonic acid,
galacturonic acid, gluconic acid, embonic acid,
glutamic acid or aspartic acid.
The alkali metal or alkaline earth metal salts of the
the
by dissolving the betaine in
carboxylic acids according to invention are
obtained, for example,
excess alkali metal or alkaline earth metal hydroxide
solution, filtering fronl the undissolved betaine and
evaporating the filtrate to dryness. Sodium, potassium
or calcium. salts are pharmaceutically suitable. The
corresponding silver salts are obtained by reaction of
an alkali metal or alkaline earth metal salt with a
suitable silver salt, such as silver nitrate.
The compounds listed by way of example in Table 1 can
also be prepared, in addition to the active compounds
mentioned in the examples, it being possible for these
compounds to be present both as diastereomer mixtures
or as the diastereomerically pure or enantiomerically
pure compounds.
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ACOHMMDCHQCOUV a QHQQH
Example of a tablet according to the invention
Each tablet contains:
Compound of Example 1 583.0 mg
Microcrystalline cellulose 55.0 mg
Maize starch 72.0 mg
Insoluble poly-(l—vinyl—2—pyrrolidone) 30.0 mg
Highly disperse silica 5.0 mg
Magnesium stearate 5.0 mg
750.0 mg
The lacquer shell contains:
Poly—(O-hydroxypropyl—O—methyl)cellulose 6.0 mg
Macrogel 4000, recommended INN polyethylene
glycol (DAB) 2.0 mg
Titanium(lV) oxide 2.0 mg
.0 mg
The compounds according to the invention, while having
a low toxicity, exhibit a broad antibacterial spectrum
against Gram—positive and Gram—negative germs, in par-
all
various
Enterobacteriaceae; above also
which
such as,
ticular against
against those are resistant towards
antibiotics, for example, penicillins,
cephalosporins, aminoglycosides, sulphonamides and
tetracyclines.
enable them to be used as
These useful properties
chemotherapeutic active compounds in medicine and as
substances for preserving inorganic and organic mater-
ials, in particular all types of organic materials, for
example polymers, lubricants, paints, fibres, leather,
paper and wood, and foodstuffs and water.
The compounds according to the invention are active
against a very broad spectrum of microorganisms. Gram-
negative and Gram—positive bacteria. and bacteria—like
microorganisms can be combated and the diseases caused
by these pathogens can be prevented, alleviated and/or
cured with the aid of these compounds.
The the
particularly active against bacteria and bacteria—like
They
compounds according to invention are
microorganisms. are therefore particularly
suitable in human and veterinary medicine for the
prophylaxis and chemotherapy of local and systemic
infections caused by these pathogens.
For example, local and/or systemic diseases caused by
the following pathogens or by mixtures of the following
pathogens can be treated and/or prevented:
Gram—positive cocci,
Staph.
agalactiae,
for example Staphylococci (Staph.
aureus and epidermidis) and
Strept.
Streptococci
(Strept. faecalis, Strept.
pneumoniae and. Strept. pyogenes); Gram—negative cocci
(Neisseria
bacilli,
Escherichia
(Citrob.
Shigella;
and Klebs.
Ent.
gonorrhoeae) and Gram—negative rod—shaped
such as Enterobacteriaceae, for example
coli, Haemophilus influenzae, Citrobacter
Salmonella and
(Klebs.
(Ent.
(Serr.
freundii and Citrob. divernis),
and furthermore Klebsiella pneumoniae
oxytoca), Enterobacter aerogenes and
agglomerans), Serratia
(Pr.
Hafnia, marcescens),
Proteus mirabilis, Pr. rettgeri and Pr. vulgaris),
Providencia and Yersinia, and the genus Acinetobacter.
The antibacterial spectrum moreover includes the genus
Pseudomonas (Ps. aeruginosa and Ps. maltophilia) as
well as strictly anaerobic bacteria, such as, for
example, Bacteroides fragilis, representatives of the
genus Peptococcus, Peptostreptococcus and the genus
Clostridium; and furthermore Mycoplasma (M. pneumoniae,
M. hominis and M. urealyticunn and. Mycobacteria, for
example Mycobacterium tuberculosis.
The above list of pathogens is to be interpreted merely
as examples and in no way as limiting. Examples which
may be Hentioned of diseases which are caused by the
can be
mentioned and
pathogens or mixed infections
prevented, alleviated or cured by compounds
according to the invention are:
_62_
infectious diseases in humans, such as, for example,
otitis, pharyngitis, pneumonia, peritonitis, pyelo—
nephritis, cystitis, endocarditis, systemic infections,
bronchitis (acute and chronic), septic infections,
diseases of the upper diffuse
pulmonary
respiratory tract,
panbronchiolitis, emphysema, dysentery,
enteritis, liver abscesses, urethritis, prostatitis,
epididymitis, gastrointestinal infections, bone and
joint infections, cystic fibrosis, skin infections,
postoperative wound infections, abscesses, phlegmons,
wound infections, infected burns, burn wounds, infec-
tions in the oral region, infections following dental
operations, osteomyelitis, septic arthritis, chole-
cystitis, peritonitis with appendicitis, cholangitis,
intraabdominal abscesses, pancreatitis, sinusitis,
mastoiditis, mastitis,
of the
genital
tonsillitis, typhoid, meningitis
and infections nervous system, salpingitis,
endometritis, infections, pelveoperitonitis and
eye infections.
As well as in humans, bacterial infections can also be
treated in other species. Examples which may be
mentioned are:
Pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery,
salmonellosis, mastitis—metritis—agalactia syndrome and
mastitis;
Ruminants (cattle, sheep and goats): diarrhoea, sepsis,
bronchopneumonia, salmonellosis, pasteurellosis, myco—
plasmosis and genital infections;
Horses: bronchopneumonias, joint ill, puerperal and
postpuerperal infections and salmonellosis;
Dogs and cats: bronchopneumonia, diarrhoea, dermatitis,
otitis, urinary tract infections and prostatitis;
Poultry (chickens, turkeys, guails, pigeons, ornamental
birds and others): mycoplasmosis, E. coli infections,
chronic respiratory tract infections, salmonellosis,
pasteurellosis and psittacosis.
Bacterial diseases in the rearing and keeping of stock
_63_
and ornamental fishes can also be treated, the anti-
bacterial spectrum extending beyond the abovementioned
pathogens to further pathogens, such as, for example,
Pasteurella, Brucella, Campylobacter, Listeria,
Erysipelothrix, Corynebacteria, Borrelia, Treponema,
Nocardia, Rickettsia and Yersinia.
The present invention includes pharmaceutical formula-
tions which contain, in addition to non—toxic, inert
pharmaceutically suitable excipients, one or more com-
pounds according to the invention or consist of one or
more active compounds according to the invention, and
processes for the preparation of these formulations.
The present invention also includes pharmaceutical
formulations in dosage units. This means that the for-
mulations are present in the form of individual parts,
for example tablets, coated tablets,
capsules, pills,
suppositories and ampoules, the active compound content
of which corresponds to a fraction or a multiple of an
individual dose. The dosage units can contain, for
example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or
l/4 of an individual dose. An individual dose
preferably contains the amount of active compound which
is administered in one application and which usually
corresponds to a whole, one half, one third or a
quarter of a daily dose.
Non—toxic inert pharmaceutically suitable excipients
are to be understood as solid, semi—solid. or liquid
diluents, fillers and formulation auxiliaries of all
types.
Preferred pharmaceutical formulations which may be
mentioned are tablets, coated tablets, capsules, pills,
granules, suppositories,i solutions, suspensions and
emulsions, pastes, ointments, gels, creams, lotions,
dusting powders and sprays.
-64..
Tablets, coated tablets, capsules, pills and granules
can contain the active compound or compounds in
addition to the customary excipients, such as (a)
fillers and extenders, for example starches, lactose,
sucrose, glucose, mannitol and silicic acid, (b)
binders, for example carboxymethylcellulose, alginates,
gelatine and polyvinylpyrrolidone, (C) humectants, for
example glycerol, (d) disintegrating agents, for
example agar—agar, calciunt carbonate and sodium car-
bonate, (e)
and (f)
ammonium
solution retarders, for example paraffin,
absorption accelerators, for example quaternary
compounds, (g) wetting agents, for example
cetyl alcohol and glycerol monostearate, (h) adsor-
bents, for example kaolin and bentonite, and (i) lubri-
cants, for example talc, calcium stearate, magnesium
stearate and solid polyethylene glycols, or mixtures of
the substances listed under (a) to (i).
The tablets, coated tablets, capsules, pills and
granules can be provided with the customary coatings
and shells, optionally containing opacifying agents,
and can also be of a composition such that they release
the active compound or compounds only or preferentially
the
appropriate in a delayed manner,
in a certain part of intestinal tract, if
examples of embedding
compositions which can be usedr being polymeric sub-
stances and waxes.
If appropriate, the active compound or compounds can
also be present in microencapsulated form with one or
more of the abovementioned excipients.
Suppositories can contain, in addition to the active
compound or compounds, the customary water—soluble or
water—insoluble for
fats,
excipients, example polyethylene
glycols, for example cacao fat, and higher esters
(for example CM—alcohol with Cm—fatty acid) or mixtures
of these substances.
._65_.
Ointments, pastes, creams and gels can contain, in
addition to the active compound or compounds, the cus~
tomary excipients, for example animal and vegetable
fats, waxes, paraffins, starch, tragacanth, cellulose
derivatives, polyethylene glycols, silicones, ben-
tonites, silicic acid, talc and zinc oxide, or mixtures
of these substances.
Dusting powders and sprays can contain, in addition to
the active compound or compounds, the customary excipi—
ents, for example lactose, talc, silicic acid,
aluminium hydroxide, calcium silicate and polyamide
powder, or mixtures of these substances. Sprays can
additionally contain the customary propellants, for
example chlorofluorohydrocarbons.
Solutions and emulsions can contain, in addition to the
active compound or compounds, the customary excipients,
such as solvents, solubilizing agents and emulsifiers,
for example water, ethyl alcohol,
ethyl
propylene
isopropyl alcohol,
ethyl carbonate, acetate, benzyl alcohol,
,3—butylene
benzyl
benzoate, glycol, glycol,
dimethylformamide, oils, in particular cottonseed oil,
groundnut oil, Haize germ oil, olive oil, castor oil
and sesame oil, glycerol, glycerol formal, tetra-
hydrofurfuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, or Huxtures of these
substances.
For parenteral administration, the solutions and emul-
sions can also be in a sterile form which is isotonic
with blood.
Suspensions can contain, in addition to the active
compound or compounds, the customary excipients, such
as liquid. diluents, for example water, ethyl alcohol
and propylene and for
ethoxylated
glycol, suspending agents,
polyoxy—
ethylene sorbitol and sorbitan esters, microcrystalline
example isostearyl alcohols,
_ 66 _
cellulose, aluminium metahydroxide, bentonite, agar-
agar and tragacanth, or mixtures of these substances.
The contain
which
formulation forms mentioned can also
colouring agents, preservatives and additives
improve the smell and taste, for example peppermint oil
and eucalyptus oil, and sweeteners, for example
saccharin.
The therapeutically active compounds should preferably
the
formulations in a concentration of about O.l to 99.5,
preferably about 0.5 to 95% by weight of the
be present in abovementioned
pharmaceutical
total
mixture.
The abovementioned pharmaceutical formulations can also
contain other pharmaceutical active compounds in
addition to the compounds according to the invention.
The abovementioned pharmaceutical formulations are
prepared in the customary manner by known methods, for
example by mixing the active compound or compounds with
the excipient or excipients.
The formulations mentioned can be used on humans and
animals either orally, rectally, parenterally (intra-
venously, intramuscularly or subcutaneously), intra-
cisternally, intravaginally, intraperitoneally or
and for the
body
locally ointment,
hollow
(dusting powder, drops)
therapy of infections in spaces and
cavities. Possible suitable formulations are injection
solutions, solutions and suspensions for oral therapy
and gels, infusion formulations, emulsions, ointments
or drops. Ophthalmological and dermatological formu-
lations, silver‘ salts and other‘ salts, eardrops, eye
ointments, dusting powders or solutions can be used for
local therapy. In the case of animals, intake can also
be in suitable formulations via the feed or drinking
water. Gels, powders, dusting powders, tablets, delayed
_.67_
release
tablets, premixes, concentrates, granules,
pellets, boli, capsules, aerosols, sprays and inhalants
can furthermore be used on humans and animals. The
compounds according to the invention can moreover‘ be
incorporated into other carrier materials, such as, for
example, plastics (chains of plastic for local
therapy), collagen or bone cement.
In general, it has proved advantageous both in human
and in veterinary medicine to administer the active
compound or compounds according to the invention in
total amounts of about 0.5 to about 500, preferably 5
to lOO mg/kg of body weight every 24 hours, if appro-
in the form. of several
priate individual doses, to
desired results. An individual dose
achieve
preferably contains active compound or compounds
according to the invention in amounts of about l to
about 80, in particular 3 to 30 mg/kg of body weight.
However, it may be necessary to deviate from the
dosages mentioned, and in particular to do so as a
function of the nature and body weight of the object to
be treated, the
nature of the formulation and of the administration of
the nature and severity of the disease,
the medicament and the period or interval within which
administration takes place.
Thus in some cases it can suffice to manage with less
than the abovementioned amount of active compound,
whilst in other cases the abovementioned amount of
active compound must be exceeded. The particular
optimum dosage and mode of administration required for
the active compounds can easily be determined by any
expert on the basis of his expert knowledge.
The new compounds can be administered in the customary
concentrations and formulations together with the feed
or with feed formulations or with the drinking water.
bacteria
Infection by Gram-negative or Gram—positive
can in this way be prevented, alleviated and/or cured
_ 6g _
and promotion of growth and an improvement in feed
utilization can in this way be achieved.
The minimum inhibitory concentrations (MIC)
dilution method on Iso—Sensitest
were deter-
mined. by the series
agar (Oxoid). For each test substance, a series of agar
plates which contained concentrations of the active
compound which decreased by a dilution factor of two
each time was prepared. The agar plates were inoculated
with a multipoint inoculator (Denley). Overnight
cultures of the pathogens which had first been diluted
so that about 104
colony—forming particles were used for the inoculation.
each inoculation point contained
The inoculated agar plates were incubated at 37°C and
the germ growth was read off after about 20 hours. The
MIC value (ug/ml)
concentration at
indicates the lowest active compound
which no
detected with the naked eye.
germ growth was to be
The MIC values of some of the compounds according to
the invention are shown in comparison with
ciprofloxacin in the following table.
N m~.o m~«.o mN.O oo.o mm.o m.o m~«.o oosm
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ubuuouououcw
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ummu COHu3HfiU Mmmm map >2 U®CHEH®H®U Aa\mEv m@3Hm> UHZ
_ 71 -
The following examples illustrate the invention:
Preparation of the intermediate products:
Example A
tert—Butyl N—(cis—4—methoxypyrrolidin—3—yl)carbamate
a) trans-l-Benzyl—3—hydroxy—4—methoxypyrrolidine
.9 g (0.2 mol) of 3—benzyl—6—oxa—3—azabicyclo(3.1.0]-
hexane (US Patent 4 254 l35) are heated with 3.6 g
(20 mmol) of sodium methylate solution (30%) in 200 ml
of absolute methanol at l20°C in an autoclave for
the batch is neutralized with
and the
hours.
1.2 g
removed on a rotary evaporator.
After cooling,
(20 mmol) of acetic acid solvent is
The residue is taken up
in tetrahydrofuran and the sodium acetate is filtered
off. The filtrate is concentrated and the residue is
distilled.
Yield: 40.9 g
Boiling point:
(91% of theory)
ll2-ll6°C/O.l mbar
Purity: 92%
b) cis-3—Amino—l—benzyl—4—methoxypyrrolidine
.6 g (25 mmol)
pyrrolidine and 8.6 g
in 40 ml
into a vessel and at 0°C a solution of 6 g (34 mmol) of
diethyl
of trans-l—benzyl—3—hydroxy—4—methoxy—
(33 mmol)
tetrahydrofuran
of triphenylphosphine
of absolute are introduced
azodicarboxylate in 40 ml of absolute tetra-
hydrofuran is added dropwise. Subsequently at 0°C 3.9 g
(27 mmol) of phthalimide are added in small portions
over the course of one hour. The mixture is stirred
overnight at room. temperature and concentrated. The
residue is dissolved in 80 ml of ethyl acetate, and
ml of petroleum ether are added. The batch is left
and the
diethyl
to crystallize out overnight crystals
(triphenylphosphine oxide and hydrazine-
_ 72 _
dicarboxylate) are filtered off.
residue is
The filtrate is
concentrated and the heated under reflux
with 60 ml of concentrated hydrochloric acid overnight.
Decanting is carried out to remove undissolved
and the solution is concentrated. The residue
and the
residues,
is taken up in a little water, solution is
rendered alkaline with solid potassium Carbonate and
with 50 ml of The
extracts are dried over potassium carbonate and concen-
extracted five times chloroform.
trated and the residue is distilled.
Yield: 3.4 g (65.9% of theory)
95°C/0.2 mbar
Boiling point:
c) tert—Butyl N-(cis-l—benzyl—4—methoxypyrrolidin—
—yl)carbamate
A solution of 0.65 g of NaOH in 8 ml of water is
(14.5 mmol)
4-methoxypyrrolidine and ll ml of tert—butanol.
admixed with 3 g of cis—3—amino—l—benzyl—
Added
dropwise to this are 3.5 g (16 mmol) of di—tert~butyl
dicarbonate. The mixture is stirred at room temperature
overnight, inorganic salts are removed by suction
filtration and the filtrate is extracted with chloro-
form. The extracts are dried over potassium carbonate
and concentrated and the residue is distilled.
Yield: 3.8 g (85.5% of theory)
Boiling point: l30—l40°C/0.05 mbar
d) tert—Butyl N-(cis-4—methoxypyrrolidin—3—yl)—
carbamate
3.5 g (ll.4 mmol) of tert-butyl N—(cis—l—benzyl—
4—methoxypyrrolidin—3—yl)carbamate in 100 ml of
methanol are hydrogenated at 100°C and 100 bar over 2 g
of palladium on active carbon (lO% Pd). The catalyst is
filtered off, the and the
residue is distilled.
Yield: l.9 g (81.6% of theory)
Boiling point: 84°C/0.1 mbar
filtrate is concentrated
_ 73 _
Example B
tert—Butyl N-(trans—4-methoxypyrrolidin—3—yl)carbamate
a) trans—3—amino—1—benzyl—4—methoxypyrrolidine
(0.41 mol)
of sodium azide are dissolved in 50 ml
17.5 g (0.1 mol) of
3—azabicyclo[3.1.0]hexane in 300 ml of
g
of water, 3—benzyl—6—oxa—
dioxane are
added. The mixture is heated under reflux for 72 hours
and concentrated, inorganic salts are dissolved in
water, and extraction is carried out with chloroform.
are dried over and
The extracts potassiunm carbonate
50 ml of
absolute tetrahydrofuran and added dropwise to 4 g of
(80% in 200 ml of
absolute tetrahydrofuran.
concentrated. residue is dissolved in
sodium hydride in liquid paraffin)
The mixture is heated under
(0.1 mol) of methyl
Subsequently the mixture is
reflux for an hour and then 15 g
iodide are added dropwise.
heated under reflux overnight and concentrated, and the
residue is taken up in water and extracted with
chloroform. The extracts are dried over potassium
carbonate, concentrated and distilled. This gives
.1 g of a material with a purity of 73% according to
12.7 g of this material in 40 ml of
added
gas chromatogram.
absolute tetrahydrofuran are dropwise to a
suspension of 4 g of lithium aluminium hydride in
ml of absolute tetrahydrofuran and the Hdxture is
heated under reflux for 2 hours. Excess lithium
aluminium hydride is
addition of 4 ml
decomposed by careful dropwise
each of water, of 15% strength
potassium hydroxide solution and, again, 4 ml of water.
The inorganic salts are filtered off with suction and
washed repeatedly with chloroform. The organic phases
are dried over potassium carbonate and concentrated and
the residue is distilled.
Yield: 9 g (32.8% of theory)
Boiling point: 91°C/0.07 mbar
_ 74 _
The product has a purity as determined by gas chromato-
graphy (area method) of 75%.
b) tert—Butyl H-(trans—l—benzyl—4—methoxypyrrolidin—
—yl)carbamate
A solution of 1.3 g of NaOH in 15 ml of water is
admixed with 8.2 g (30 mmol) of trans—3—amino—l—benzyl—
4—methoxypyrrolidine and 21 ml of tert—butanol. 7.1 g
(31 mmol) of di—tert-butyl dicarbonate are added
dropwise and then the mixture is stirred at room
It is filtered with suction to
the filtrate is extracted with
temperature overnight.
remove inorganic salts,
chloroform, dried over potassium carbonate and concen-
trated and the residue is distilled.
Yield: 7.7 g (84.4% of theory)
°C/0.1 mbar
—90°C
Boiling point:
Melting point:
c) tert—Butyl N-(trans—4—methoxypyrrolidin—3—yl)—
carbamate
6.7 g (22 mmol) of tert—butyl N—(trans—1—benzyl—
4-methoxypyrrolidinyl)carbamate in 150 ml of
methanol are hydrogenated at 100 bar and 100°C over 2 g
of palladium on active carbon (10% Pd). The catalyst is
removed by suction filtration, the filtrate is concen-
trated and the residue is distilled.
Yield: 2.2 g (46% of theory)
Boiling point: 94°C/0.05 mbar
Example C
trans-3—Amino—4—hydroxy—pyrrolidine
a) trans—3-Amino—l—benzyl—4—hydroxy—pyrrolidine
.9 g (50 mmol) of 3—benzyl—6—oxa—3—azabicyclo(3.1.0)—
_ 75 _
(25%
are heated. in 75 ml of ammonia solution
at 120°C
solution is concentrated and the residue is distilled.
hexane
strength) in an autoclave for 8 hours.
Yield: 6 g (62.4% of theory)
Boiling point: 130—140°C/0.1 mbar
Melting point: 82—84°C
b) trans-3—Amino—4—hydroxy—pyrrolidine
.2 g (27 mmol) of trans—3—amino—1-benzyl—4—hydroxy—
pyrrolidine in 40 ml of nethanol are hydrogenated at
100°C and 100 bar over 1 g of palladium on active
carbon (10% Pd). The catalyst is removed by suction
filtration, the filtrate is concentrated and the
residue is distilled.
Yield: 1 g (36.3% of theory)
Boiling point: 110°C/0.3 mbar
Example D
trans—4-Hydroxy—3—(2—hydroxyethylamino)—pyrrolidine
a) trans—1—Benzyl-4—hydroxy—3—(2—hydroxyethylamino)—
pyrrolidine
g (0.22 mol) of 3—benzyl—6—oxa—3—azabicyclo[3.1.0]—
hexane are heated under reflux with 42 g (0.68 mol) of
2~aminoethanol in 450 ml of water overnight. The
solution is extracted once with tert.—butyl methyl
ether and the aqueous phase is— concentrated. The
residue is distilled.
Yield: 34.1 g (65.6% of theory)
Boiling point: 190°C/0.1 mbar
b) trans—4—Hydroxy—3—(2-hydroxyethylamino)—pyrrolidine
In the same way as in Example C b), trans-l—benzyl—
—hydroxy—3—(2-hydroxyethylamino)—pyrrolidine is hydro—
genated and the reaction product is obtained as an oil.
_ 76 _
Example E
trans—4—Hydroxy~3—(2—hydroxyethy1—methyl—amino)—
pyrrolidine
a) trans—1—Benzy1—4—hydroxy—3—(2—hydroxyethyl—methyl—
amino)—pyrrolidine
.5 g (0.1 mol) of 3—benzyl—6—oxa—3—azabicyclo[3.1.0]-
(0.1 mol)
ethanol in 200 ml of water analogously to Example D a).
Yield: 18.2 g (73% of theory)
Boiling point: 180—190°C/0.1 mbar
hexane are reacted with 17 g of methylamino—
b) trans-4—hydroxy—3—(2—hydroxyethyl—methyl—amino)—
pyrrolidine
In the same way as for Example C b), trans—l—benzyl—
-hydroxy—3—(2—hydroxyethyl-methyl—amino)—pyrrolidine
is hydrogenated and the reaction product is obtained as
an oily compound.
Example F
—Oxa—5,8—diazabicyclo[4.3.0]nonane dihydrochloride
a) 8—Benzyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane
.6 g (66 mmol) of
ethylamino)—pyrrolidine are heated. under reflux in a
—benzyl—4—hydroxy(2—hydroxy—
mixture of 60 nfl. of concentrated sulphuric acid and
ml of water for 6 hours. The mixture is rendered
alkaline with concentrated sodiunl hydroxide solution,
the sodium sulphate which has precipitated is filtered
Off with
chloroform.
suction and the filtrate is extracted with
The extract is dried over‘ potassiunx car-
bonate and concentrated and the residue is distilled.
Yield: 4.1 g (28.5% of theory)
_7'7_.
Boiling point: l22—l28°C (0.08 mbar)
b) 2—Oxa—5,8—diazabicyclo[4.3.0)nonane dihydrochloride
A solution of 4 g (l8.2 mmol) of 8—benzyl—2—oxa—5,8—di—
lOO ml of
concentrated hydrochloric
azabicyclo[4.3 O]nonane in methanol and
.5 ml of acid is hydro-
genated on 2 g of palladium—on—active charcoal ( 0% of
Pd) at 80°C under l0O bar. The catalyst is filtered off
The filtrates
and the product is crystallized by trituration with a
little methanol. filtered off with
suction, washed with acetone and dried in air.
Yield: l.85 g (51% of theory)
and washed with water. are concentrated
The crystals are
Melting point: 280°C with decomposition
c) 2—Oxa-5,8—diazabicyclo[4.3.0]nonane
.2 g (33 mmol) of
[4.3.0]nonane are hydrogenated in 400 ml of methanol
—benzyl—2—oxa—5,8-diazabicyclo—
with 2.5 g of palladium—on—actiVe charcoal (10% of Pd)
under‘ 50 bar at lOO°C. The catalyst is filtered off
with suction, the filtrate is concentrated and the
residue is distilled.
Yield: 3.l g (73.4% of theory); cis—trans isomer
mixture l:7
Boiling point: 58°C/0.1 mbar.
d) trans—2—Oxa—5,8—diazabicyclo(4.3.0]nonane
Analogously to Example D a), 3—benzyl—6-oxa—3—aza—
bicyclo—[3.l.O]hexane is reacted with 2~(benzylamino)—
ethanol to give trans—l—benzyl[N—benzyl—N—(2—hydroxy—
the product is then
,8—di—
ethyl)amino]—4~hydroxypyrroldine,
reacted analogously to Example F a) to give
benzyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane and
product is purified by chromatography (silica
methyl ether/ethyl
gel,
cyclohexane/tert—butyl acetate
lzlzl).
-78..
Hydrogenolytic debenzylation is carried out analogously
to Example F c) to give trans—2—oxa—5,8—diazabicyclo—
[4.3.0]nonane, boiling point: 60°C/0.1 mbar.
Example G
—Methyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane dihydro—
chloride
a) 8—Benzyl—5—methyl—2—oxa—5,8—diazabicyclo[4.3.0]—
nonane
g
ethyl—methyl—amino)—pyrrolidine are reacted in 60 ml of
(71.9 mmol) of 1—benzyl—4—hydroxy—3—(2—hydroxy—
concentrated sulphuric acid and 30 ml of water as in
Example F a).
Yield: 10 g (60% of theory)
Boiling point: 122°C/0.08 mbar
b) 5—Methyl—2—oxa—5,8—diazabicyclo[4.3 O]nonane
dihydrochloride
A solution of 9.4 g (40 mmol) of 8—benzy1—5—methy1-
2—oxa—5,8—diazabicyc1o[4.3.0]nonane in 150 ml of
methanol and 7.4 ml of concentrated hydrochloric acid
is hydrogenated on 3 g of palladium—on—active charcoal
(10% of Pd) at 80°C under 100 bar. The catalyst is
filtered off with suction and the filtrate is
concentrated. The residue is triturated with
butanol/acetone 1:1 and the crystals are filtered off
with suction and dried over Pfiho in a desiccator. The
product is very hygroscopic.
Yield: 8.2 g (95% of theory)
Mass spectrum: m/e 142 (MW, 112 (M*—cH2o), 100 (M*—cH2—
N=CH2), 82 (C41-14NO+), 68 (C4H6N+)
-79..
Example H
—Methyl—3—oxa—2,7-diazabicyclo(3.3.0]octane
a) Ethyl N-(2,2—dimethoxyethyl)—carbamate
g (2 mol) of ethyl chloroformate are added dropwise
to 214 g (2 mol)
in 1 l of toluene and 90 g of NaOH in 500 ml of water
at 10°C.
of aminoacetaldehyde dimethyl acetal
The mixture is stirred at room temperature for
a further 2 hours and the aqueous phase is separated
off,
toluene. The toluene solutions are dried over magnesium
saturated with sodium chloride and extracted with
sulphate and concentrated and the residue is distilled.
Yield: 338 g (95.4% of theory)
Boiling point: 60°C/0.03 mbar
b) Ethyl N—allyl—N—(2,2—dimethoxyethyl)—carbamate
g of sodium hydride (80% strength in paraffin oil)
are initially introduced into 500 ml of toluene and
g (0.5 ethyl N—(2,2—dimethoxyethyl)—
carbamate are added dropwise at 80°C.
mol) of
The nuxture is
(0.6 mol) of
allyl bromide are then added dropwise in the course of
stirred. at 80°C for one hour and 73 g
three hours.
the
The mixture is stirred at 80°C overnight,
salts are dissolved with water and the organic
phase is separated off. The aqueous phase is extracted
with toluene, the organic phases are dried over
potassium carbonate and concentrated and the residue is
distilled.
Yield: 68 g
Boiling point:
(62.5% of theory)
65°C/0.09 mbar
c) Ethyl N-allyl—N—(2—oxoethyl)—carbamate
g (0.313 mol) of ethyl
ethyl)—carbamate are heated with 150 ml of formic acid
at 100°C for one hour.
N-allyl—N—(2,2—dimethoxy—
The mixture is poured onto ice
_ 80 -
and extracted several times with methylene chloride,
the organic phases are washed with sodium bicarbonate
solution, dried over magnesium sulphate and
concentrated and the residue is distilled.
Yield: 46.7 g (87.2% of theory)
Boiling point: 58°C/0.09 mbar
d) Ethyl 2—methyl—3—oxa—2,7—diazabicyclo[3.3.0]—
octane—7—carboxylate
g (0.12 mol)
are dissolved. in 50 ml of methanol,
ice—bath 22 g (0.12 mol) of
solution in
of methylhydroxylamine hydrochloride
the solution is
%
cooled in an and
strength sodium methylate methanol
added dropwise. The
with and the
are
sodium. chloride is filtered off
suction washed with 80 ml of
The added
dropwise in the course of one hour to 20 g (0.117 mol)
heated
salt is
toluene. methylhydroxylamine solution is
of ethyl N—(2—(oxoethyl)—carbamate, which is
160 ml
separator. The mixture is heated under reflux overnight
under reflux in of toluene, using a water
and the product is extracted twice with 80 ml of 10%
strength hydrochloric acid each time. The hydrochloric
acid solutions are saturated with potassium carbonate
and extracted six times with 200 ml of chloroform each
time. The extract is dried over EQCO3 and concentrated
and the residue is distilled.
Yield: 18.6 g (79.5% of theory)
Melting point: 93°C/0.09 mbar
e) 2—Methyl—3—oxa—2,7—diazabicyclo[3.3.0]octane
g (65 mmol) of 2—methy1—3—oxa—2,7—diaza—
bicyclo[3.3.0]octane—7—carboxylate heated
in 300 ml of water with 41 g of Ba(OH)2.8H2O
overnight. added, the
carbonate which has precipitated out is filtered off
ethyl
are under
reflux
Potassium carbonate is barium
with suction and the filtrate is extracted ten times
with 100 ml of chlorofornm each time. The extract is
-81..
dried over potassium carbonate and concentrated and the
residue is distilled.
Yield: (65% of theory)
80°C/1O mbar
.4 g
Boiling point:
Example I
—Methyl—octahydropyrrolo[3,4—b]pyrrole (2—methyl—
,7—diazabicyclo[3.3.0]octane)
a) l—Benzyl(2—chloroethyl—methyl—amino)—pyrrolidine—
,5—dione
74.8 g (0.4 mol) of N—benzylmaleimide [Arch. Pharm.
308, 489 (1975)) and 52.0 g (0.4 mol) of 2—chloroethyl—
methylamine hydrochloride are initially introduced into
400 ml of dioxane and 40.4 g (0.4 mol)
are added dropwise at 20°C. The mixture is then boiled
The batch is
of triethylamine
hours.
2 l of
400 ad of chloroforH1 and the extract is
dried
on a rotary evaporator.
(101.1 g) on silica
(1:2)
under reflux for subsequently
poured into ice—water and extracted with 3
portions of
washed with water, over sodium sulphate and
concentrated
the
Chromatography of
ethyl
(51% of
residue gel
.8 g
using
acetatezpetroleum ether gives
of an oil.
RF value: 0.33
ether = 1:2)
theory)
(silica gel, ethyl acetate/petroleum
b) 5—Benzyl—4,6—dioxo—l-methyl—octahydropyrrolo-
[3,4—b]—pyrrole
.2 g (0.24 mol) of an 80%
suspension in nuneral oil are suspended in 150 ml of
(dried
of 1—benzyl—3—(2-chloro-
added
dropwise as a solution in 50 ml of absolute dimethyl—
strength sodium. hydride
absolute dimethylformamide calcium
hydride), and 62 g (0.22 mol)
ethyl—methylamino)-pyrrolidine—2,5—dione
OVSI
formamide at room temperature. During this, an
exothermic reaction takes place with foaming. The
mixture is diluted with a further 50 ml of absolute
dimethylformamide and subsequently stirred at room
temperature for 1 hour and is then poured into
ice—water and extracted. with methylene chloride. The
extract is washed with water, dried with sodium
sulphate and concentrated on a rotary evaporator. The
residue is chromatographed on silica gel using ethyl
acetatezpetroleum ether (1:2) and later (1:1). 16.4 g
of educt are initially recovered here, and 17.2 g (44%
of theory, based on the educt reacted) of an oily
product are then isolated.
Rf value = 0.26
(silica gel, ethyl acetatezpetroleum ether = 1:1).
c) 5—Benzyl—1-methyl—octahydropyrrolo[3,4—b]pyrrole
1.52 g (40 mmol) of lithium aluminium hydride are
initially introduced into 30 ml of anhydrous tetra-
hydrofuran, and 4.9 g (20 mmol) of 5—benzyl—4,6—dioxo—
—methyl—octahydropyrrolo[3,4~b]pyrrole are added drop-
wise as a solution 1J1 15 Nd of anhydrous tetrahydro—
furan. The mixture is then subsequently stirred at the
1.5 ml of
% strength potassium hydroxide solution and 4.5 ml of
boiling point for 3 hours. 1.5 ml of water,
water are added dropwise in succession to the batch and
the precipitate is then filtered off with suction and
washed with tetrahydrofuran. The filtrate is concen-
trated on a rotary evaporator and the residue is
distilled. 3.1 g (72% of theory) of a colourless
distillate of boiling point 80°C/0.07 mbar are
obtained.
d) 1—Methyl—octahydropyrrolo[3,4—b]pyrrole
.49 g (30 mmol)
[3,4—b]—pyrrole
of 5—benzyl—1—methyl—octahydropyrrolo—
are dissolved in 100 ml of absolute
ether, and 5.2 g of hydrogen chloride dried over phos-
phorus pentoxide are passed in. The hydrochloride
_.83_
suspension formed is concentrated in vacuo and the
residue is taken up in 100 ml of methanol. It is then
hydrogenated with 2 g of Pd—on—C (5% strength) at 80°C
under 50 bar for 4 hours. The catalyst is subsequently
filtered off, the filtrate is concentrated and 30 ml of
40% solution and 50 ml of
strength sodium hydroxide
ether are added to the residue. The ethereal phase is
separated off and the aqueous phase is extracted with
x 50 ml of ether. The combined organic phases are
dried over sodium sulphate and concentrated and the
residue is distilled. 1.3 g (34% of theory) of a
colourless oil of boiling point 65—66°C/12 mbar are
obtained.
Purity: >99%
Example J
Octahydropyrrolo[3,4—b]pyrrole (2,7-diazabicyclo[3.3.0]~
octane)
a) l—Benzyl—3—(2—chloroethylamino)—pyrro1idine—
,5—dione
.8 g (0.4 mol) of N-benzylmaleimide are reacted with
58 g (0.5 mol) of 2—chloroethylamine hydrochloride and
50.5 g (0.5 mol)
the working instructions of Example Ia.
81.6 g (77%
with an Ry value of 0.24 (on silica gel using ethyl
of triethylamine in accordance with
After working
of an oil
up by chromatography, of theory)
acetate: petroleum ether = 1:1) are obtained.
b) 5—Benzy1—4,6—dioxo-octahydropyrrolo[3,4—b]pyrrole
.4 g
reacted with 119 g
(0.58 mmol) of
(0.45 mol)
ethylamino)—pyrrolidine—2,5—dione in 550 ml of absolute
with the
sodiunx hydride
of 1—benzyl—3—(2—chloro—
suspension are
dimethylformamide in accordance working
instructions of Example lb. After the mixture has been
left to stand overnight, it is worked up under aqueous
_ 84 _
conditions. On‘ purification by chromatography,
impurities are first eluted with ethyl acetate and the
product is then eluted with ethyl acetatezmethanol
(3:1) (RF value 0.55). 57.7 g of product (56% of theory)
are isolated.
c) 5—Benzyl—octahydropyrrolo[3,4—b]pyrrole
.7 g (0.25 mol) of
hydropyrrolo[3,4—b]pyrrole
(0.56 mol)
700 ml of
—benzyl—4,6—dioxo—octa—
with 21.4 g
of lithium aluminium hydride by boiling in
crude
are reduced
absolute tetrahydrofuran for 10 hours in
accordance with the working instructions of Example Tc.
21.0 g (41.1% of
theory) of an oil of boiling point 95°C/0.1 mbar.
Working up by distillation gives
d) Octahydropyrrolo[3,4—b]pyrrole
.0 g (0.104 mol) of
[3,4—b]pyrrole are initially introduced into 180 ml of
and 17.3 ml (0.208 mol)
trated hydrochloric acid are added. The mixture is then
hydrogenated with 2 g of Pd—on—C (5% strength) at 90°C
under 100 bar filtered
off, 37.4 g sodium
methylate the
filtrate is
—benzy1—octahydropyrrolo—
ice—cooled methanol, of concen-
for 4 hours.
(0.208
solution
filtered
The catalyst is
mol) of 30%
added to
again
strength
the filtrate,
the
The residue is distilled through a small
(48% of
which fumes
are
mixture is and
concentrated.
Vigreux column. oil
of boiling point 93—95°C/30 mbar,
in air and slowly solidifies in the receiver
.6 g of a colourless
theory)
(melting
point 40°C) are obtained.
Example K
Octahydropyrrolo[3,4—b]pyridine (2,8—diazabicyclo—
[4.3.0]nonane
a) 6—Benzyl—5,7—dioxo—octahydropyrrolo[3,4—b]pyridine
.6 g
N—benzylimide
6g, 95695w)
monomethyl
acid
Abstr.
(0.2 mol) of pyridine—2,3-dicarboxylic
(British Patent 1,086,637; Chem.
400 ml of
ruthenium-on~active
are hydrogenated in
g of
90°C under 100 bar until the
glycol
ether over
charcoal (5% strength) at
calculated amount of hydrogen has been taken up.
then filtered off and the
concentrated (H1 a rotary evaporator.
catalyst is filtrate is
g of an oily
crude product are obtained.
The corresponding hydrogenation with palladium—on-
active charcoal (5% strength) gives a quantitative
yield of a pure product of melting point 67—69°C.
b) 6—Benzyl-octahydropyrrolo[3,4—b]pyridine
g (about 0.18 mol) of crude or pure 6—benzyl—5,7—di—
oxooctahydropyrrolo[3,4—b]pyridine reduced with
.2 g (0.40 mol) of lithium
ml of absolute tetrahydrofuran
are
aluminium hydride in
in the course of
hours in accordance with the working instructions of
Example Ic. 24.4 g of a colourless oil having a boiling
93—95°C/0.06 mbar obtained on
point of are
distillation.
c) Octahydropyrrolo[3,4—b]pyridine
g (0.32 mol) of
pyridine are hydrogenated in 450 ml of methanol over
—benzyl—octahydropyrrolo[3,4—b]—
g of palladium—on—active charcoal (5% strength) at
°C/90 bar in the course of 3 hours. The catalyst is
then filtered off, the filtrate is concentrated and the
_ 86 _
residue is distilled. 33.8 g (84%
colourless solid having a melting point of 65—67°C and
of theory) of a
a boiling point of 78°C/9 mbar are obtained.
Example L
l—Methyl—octahydropyrrolo[3,4—b]pyridine (2—methyl—
2,8—diazabicyclo[4.3.0lnonane)
a) l—Methyl—pyridinium—2,3—dicarboxylic acid N—benzyl—
imide iodide
(0.8 mol)
N—benzylimide are dissolved in 800 ml of nitromethane,
and 136 g (0.96 mol)
added dropwise. The mixture is
.5 g of pyridine—2,3—dicarboxylic acid
while heating, of methyl iodide
then boiled for
(cooling water 0°C).
are
8 hours while cooling under reflux
the solid is filtered off with suction
123 g of dark red
162-165°C
After cooling,
and washed with methylene chloride.
crystals having a
melting point of
(decomposition) are obtained.
b) 6—Benzyl—l—methyl—5,7—dioxo—octahydropyrrolo[3,4—b]—
pyridine
g
acid N-benzylimide iodide are hydrogenated over 1 g of
(0.1 mol) of 1—methyl-pyridinium—2,3—dicarboxylic
platinum oxide in 450 ml of glycol monomethyl ether at
°C under 70 bar until the uptake
ended (51 hours).
the filtrate is concentrated,
in 300 ml of chloroform and the
2 x with 300 ml of lO%
solution each time and with 300 ml of water.
of hydrogen has
The catalyst is then filtered off,
the residue is taken up
solution is washed
carbonate
After
g
strength sodium
drying over sodium sulphate, it is concentrated.
of an oily residue remain.
_87_
c) 6—Benzyl—1—methy1—octahydropyrro1o[3,4—b]pyridine
19.2 g (0.08 mol) of crude 6—benzyl—1—methyl—5,7—d:oxo—
octahydropyrro1o[3,4—b]pyridine are reduced with 6.1 g
(0.16 mol)
of lithiuni aluminium hydride in absolute
tetrahydrofuran in accordance with the working instruc-
tions of Example Ic.
Yield: 9.5 g (52% of theory),
Boiling point: 93—96°C/0.1 mbar.
d) l—Methy1—oCtahydropyrrolo[3,4—b]pyridine
.7 g (54 mmol) of 6—benzylmethy1—octahydropyrrolo-
[3,4—b]pyridine as the dihydrochloride are hydrogenated
in 100 ml of methanol over palladium—on-active charcoal
in accordance with the working instructions of
Example Id. Working up by distillation gives 2.6 g (34%
oil of
of theory) of a colourless
~85°/12 mbar).
boiling point
Example M
trans—4—Methoxy—3—methylamino—pyrro1idine dihydro~
chloride
a) trans-1—Benzyl—3—benzylmethy1amino—4—hydroxy—
pyrrolidine
.4 g (0.1 mol) of 90% 3—benzyl—6—oxa—3—azabicyc1o—
[3.1.0]hexane are heated with 14.5 g (0.12 mol) of
benzylmethylamine in 100 ml of dioxane and 200 ml of
water under reflux overnight. The mixture is extracted
with CHC13 and the dried with KQCOL
concentrated and distilled at up to 160°C (oil bath
extracts are
temperature). Crude yield: 18.3 g
Purity: 100% (determined by gas chromatography)
_ 88 _
b) trans—l—Benzyl—3-benzylmethylamino-4—methoxy-
pyrrolidine
l7.3 g (58 mmol) of crude trans—l—benzyl—3—benzyl—
methylamino—4—hydroxy—pyrrolidine in 80 mm, of absolute
tetrahydrofuran are added dropwise to 2.8 g (93.3 mmol)
of 80% 40 ml of
tetrahydrofuran
sodium hydride in absolute
the simultaneously
heated under reflux. After the end of the
8.7 g (61 mmol) of methyl
dropwise and the ndxture is
and mixture is
evolution of
hydrogen, iodide are added
then heated under reflux
overnight. It ice-water‘ and extracted
is poured into
with toluene, and the extracts are dried with. KgCO@
concentrated and distilled.
Yield: 9.7 g (52% of theory)
Boiling point: l40—l50°C/0.1 mbar
c) trans—4—methoxy—3—methylamino—pyrrolidine dihydro—
chloride
9.3 g (29 mmol) of trans—l~benzyl—3—benzylmethylamino—
ml of
.8 ml of concentrated hydrochloric acid are
—methoxy—pyrrolidine are dissolved in
methanol,
added and the mixture is hydrogenated over 4 g of 10%
Pd on active carbon at 90°C and 100 mbar. The catalyst
off with the filtrate is
is filtered suction,
concentrated and the residue is recrystallized from
isopropanol/methanol.
Yield: 3.7 g (62.8% of theory)
Melting point: l57~l62°C
Example N
2,5—Dimethyl-3—oxa—2,7—diazabicyclo[3.3.0]octane
a) N-(2-Methylprop—2—enyl)—N—(2,2—dimethoxyethyl)—
urethane
g (0.5 mol) of N—(2,2—dimethoxyethyl)—urethane are
-89..
added dropwise to 20 g of sodium hydride (80% strength)
90°C.
mol) of
in 500 ml of absolute toluene at
(0.6
chloride are added dropwise and the mixture is stirred
90°C. The which
precipitated out is dissolved with a little water, the
when no further
hydrogen is formed, 54 g methallyl
overnight at sodium chloride has
organic phase is separated. off, dried over‘ KZCO3 and
concentrated and the residue is distilled.
Yield: 71.3 g (61.7% of theory)
Boiling point: 60°C/0.08 mbar
b) N-(2-Methylprop—2—enyl)—N—(2—oxoethyl)—urethane
.5 g (50 mmol) of N-(2—methylprop~2—enyl)-N-(2,2-
dimethoxyethyl)—urethane 1.25 g (5
pyridinium p—toluenesulphate in 100 ml of acetone and
and mmol) of
ml of water are heated under reflux for two days.
The mixture is concentrated and the residue is
distilled.
Yield: 5.3 g (61.2% of theory)
Boiling point: 73°C/0.1 mbar
c) Ethyl 2,5—dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]-
octane—7-carboxylate
.7 g of 30% strength sodium nethylate solution are
added dropwise to 10 g (0.12 mol) of N—methly—
hydroxylamine hydrochloride in 26 ml of methanol. The
sodium chloride is sucked off and washed with 8 ml of
methanol and 80 ml of toluene. This solution is added
19.2 g (0.11 mol)
-enyl)~N—(2—oxoethyl)-urethane,
dropwise to of N—(2—methyl—prop—
which is heated under
reflux in 160 ml of toluene using a water separator.
The heated under reflux the
with 160 ml of
hydrochloric acid and the hydrochloric acid solution is
mixture is overnight,
product is extracted 10% strength
and
The
potassium carbonate
of 200 ml of CHCl3.
and concentrated and the
rendered alkaline with
extracted. with six portions
extracts are dried over EQCO3
residue is distilled.
13 g (55% of theory)
Boiling point: 88—95°C/0.08 mbar
Yield:
d) 2,5—Dimethyl—3—oxa—2,7—diazabicyclo[3.3.0loctane
l3 g (60.6 mmol) of ethyl 2,5—dimethyl—3-oxa—2,7—diaza—
bicyclo[3,3.0]octane—7—carboxylate heated under
reflux with 33 g of Ba(OH)2.8H2O
are
in 330 IM_ of water
The BaCO3 is filtered off with suction, KZCO3
is added. to the filtrate, filtered off
overnight.
the solid is
with suction again and the filtrate is extracted ten
times with 100 ml of CHCl3
each time. The extracts are
dried over KZCO3 and concentrated and the residue is
distilled.
Yield: 5.9 g (63.7% of theory)
Boiling point: 64°C/5 mbar
Example 0
2,8—Dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]octane
a) N-(l,l—Dimethoxyprop—2—yl)—urethane
g (0.73 mol) of ethyl chloroformate are added drop-
(0.72 mol)
dimethyl acetal in 350 ml of toluene and 32 g
of NaOH in 300 ml of water.
wise to 86.2 g of 2-aminopropionaldehyde
(0.8 mol)
The mixture is stirred at
further 2 hours,
roon1 temperature for a the organic
phase is separated off, the aqueous phase is extracted
with toluene and the toluene solutions are dried over
KfiXh. The solution is concentrated and the residue is
distilled.
Yield: l32 g (95% of theory)
Boiling point: 55°C/0.06 mbar
b) N—Allyl—N—(l,l—dimethoxyprop—2—yl)—urethane
g (0.686 mol) of N-(1,l—dimethoxyprop—2—yl)—urethane
_9l_
are added dropwise to
in 700 ml of
the evolution of hydrogen has ended,
g of sodium hydride (80%
absolute toluene at 900C. When
61.2 g (0.8 mol)
of allyl chloride are added dropwise at 90°C and the
90°C, The
chloride which has precipitated out is dissolved with
strength)
mixture is stirred overnight at sodium
water, the organic phase is separated off, dried over
Kfixh and concentrated and the residue is distilled.
Yield: 78 g (31.7% of theory)
—69°C/0.06 mbar.
Content: 64.5% pure (determined by gas chromatography)
Boiling point:
c) N—Allyl—N-(1~oxoprop—2—yl)—urethane
.5 g (0.213 mol) of 64.5% pure N—allyl—N—(1,1—di—
methoxyprop—2—yl)-urethane are heated in 180 ml of
formic acid at 100°C for one hour. The mixture is
poured into ice—water and extracted. with CH2Cl2, the
extracts are washed neutral with NaHCO3 solution, dried
over MgSO4 and concentrated and the residue is
distilled.
Yield: 36 g (80.9% of theory)
-102°C/8 mbar _
Content: 88.8% pure (determined by gas chromatography)
Boiling point:
d) Ethyl 2,8—dimethyl—3—oxa—2,7—diazabicyclo[3 3.0]-
octane—7—carboxylate
A methanolic methylhydroxylamine solution
(0.2 mol) of N—methylhydroxy1amine hydro—
chloride in 33 ml of 36 g
(0.2 mol) of 30% sodiun1 methylate solution,
and the diluted with 130 ml of
(0.17 mol) of
ml of
is prepared
from 16.4 g
absolute methanol and
strength
solution formed is
toluene and added dropwise to 354 g
N—allyl—N-(l—oxoprop—2—yl)—urethane in
toluene, which is heated under reflux using’ a water
separator. The mixture is heated under reflux
overnight, the product is extracted with dilute
hydrochloric acid and the hydrochloric acid solution is
_ 92 _
rendered alkaline with EQCO3 and extracted with CHCl}
The extract is dried over KfiXb and concentrated and the
residue is distilled.
Yield: l8.5 g (50.8% of theory)
Boiling point: 95—lO5°C/O.l mbar
e) 2,8—Dimethyl~3—oxa—2,7-diazabicyclo[3.3.0]octane
.2 g (42.9 mmol) of ethyl 2,8—dimethyl—3—oxa—2,7—di—
azabicyclo[3.3 O]octane—7—carboxylate are heated under
reflux with 23.5 g of Ba(OH)2.8Hfi) in 235 ml
The BaCO3 is filtered off with suction,
of water
K2CO3
is added to the filtrate and the solid is filtered off
with suction again.
with 50 ml of CHCl3
overnight.
The filtrate is extracted ten times
each time, the extracts are dried
over EQCO3 and concentrated and the residue is
distilled.
Yield: 1.7 g
—92°C/lO mbar
The product is a mixture of the possible stereoisomers
in a ratio of 3:1 (lH—NMR).
Boiling point:
g of starting material could be recovered in the
after—runnings.
Example P
—Methyl—4—oxa—2,8-diazabicyclo[4.3.0]nonane
a) Ethyl 4—hydroxymethyl—3—methylaminopyrrolidine—
—carboxylate
l0 g (50 mmol) of
cyclo[3.3.0]octane—7—carboxylate
ethyl 2—methyl—3—oxa—2,7—diazabi—
(Example Hd))
hydrogenated in 200 ml of ethanol on 3 g of Pd—on—
(lO% of Pd) at 50°C under 50 bar. The
catalyst is filtered off, the filtrate is concentrated
are
active charcoal
and the residue is distilled.
Yield: 8.1 g (80% of theory)
Boiling point: l35—l40°C/0.1 mbar
_93_
b) Ethyl
nonane—8—carboxylate
—methyl—4—oxa—2,8—diazabicyclo(4.3.0]~
.1 g (50 mmol) of ethyl 4—hydroxymethyl—3—me:hyl~
amino—pyrrolidine—1—carboxylate and 8 g (0.1 mol) of
37% strength formaldehyde solution are dissolved in
ml
temperature overnight.
of butanol and the solution is stirred at room
It is then concentrated and the
residue is distilled.
Yield: 9.5 g (88.7% of theory)
Boiling point: 110°C/0.1 mbar
c) 2—Methyl—4—oxa—2,8—diazabicyclo[4.3.0]nonane
g (42 mmol)
[4.3.0]nonane—8—carboxylate
of ethyl 2—methyl—4—oxa—2,8-diazabicyclo—
heated reflux
with 28 g of Ba(OH)2.8H2O in 280 ml of water overnight.
The BaCO3 is filtered off with suction, the filtrate is
concentrated and the residue is boiled up with dioxane.
are under
The dioxane solution is concentrated and the residue is
distilled.
Yield: 1.3 g
Boiling point:
(21.8% of theory)
115°C/8 mbar
d) 4—Hydroxymethyl—3-methylaminopyrrolidine
g (0.168 mol) of
aminopyrrolidine—l—carboxylate are heated under reflux
with 100 g of Ba(OH)2.8H2O in 400 ml of water overnight.
The BaCO3 is filtered off with suction,
ethyl 4~hydroxymethyl—3—methyl—
the filtrate is
concentrated. and the residue is boiled up ten times
with 100 ml of dioxane each time. The dioxane solutions
are filtered, the filtrate is concentrated and the
residue is distilled.
Yield: 13 g (60.3% of theory)
Boiling point: 85—88°C/0.08 mbar
e) 2~Methy1—4—oxa—2,8—dia2abicyclo[4.3.0]nonane
8.1 g (0.1 mol)
in 20 ml of
(0.101 mol) of
of 37%
n—butanol
strength formaldehyde solution
are added dropwise to 13 g
4—hydroxymethyl—3—methylamino~pyrroli—
dine in 100 ml of n—butanol at room temperature. The
mixture is stirred at roon1 temperature overnight and
concentrated and the residue is distilled.
Yield: 8.7 g (61.2% of theory)
Boiling point: 84°C/6 mbar
Example Q
—Oxa—2,7—diazabicyclo[3.3.0]octane
a) Ethyl 2~(tetrahydropyran—2—yl)—3—oxa—2,7—diazabi—
cyclo(3.3.0]octane~7—carboxylate
.1 g (0.106 mol) of
carbamate
ml of
—hydroxypentanal oxime
13, 333 (1958)),
added dropwise.
ethyl N—a1lyl—N—(2—oxoethyl)—
heated
14.2 g
(Acta Chim.
dissolved in 55 ml of hot toluene,
under reflux in
(0.12
Acad.
(Example Mc)) are
toluene, and mol) of
Sci. Hung.,
are
reflux
mixture is heated under
overnight and concentrated and the residue is
distilled.
Yield: 15.5 g (54% of theory)
Boiling point: 160°C/0.01 mbar
b) Ethyl
—carboxylate
—oxa—2,7—diazabicyclo[3.3.0]octane—
g (55.5 mmol) of ethyl
3—oxa—2,7—diazabicyclo[3.3.0]octane—7—carboxylate are
heated 8.25 g (56 mmol) of 70%
strength perchloric acid in 100 ml of ethanol for 30
-(tetrahydropyran—2—yl)—
under reflux with
minutes. 10.5 g (58 mmol) of 30 strength sodium
methylate solution are added, the mixture is con-
centrated, the residue is taken up in water and the
_95_
solution is saturated with K;CO3 and extracted with
CHCL3. The extract is dried over Kfixh and concentrated
and the residue is distilled.
Yield: 7.6 g (73.5% of theory)
Boiling point: l25—130°C/O.l mbar
c) Ethyl 3—oxa—2,7—diazabicyclo(3.3.0]octane—7—car—
boxylate
8.5 g (50 mmol) of ethyl N—(2-oxoethyl)—N—allyl—
carbamate are heated under reflux with 5.5 g (50 mmol)
lOO ml of
The mixture is concentrated and the residue
is distilled.
Yield: 6.8 g
Boiling point:
of o-trimethylsilylhydroxylamine in xylene
overnight.
(73% of theory)
120—122°C/0.05 mbar
d) 3—Oxa—2,7—diazabicyclo[3 3.0]octane
This substance is obtained analogously to Example Nd)
of ethyl 3—oxa—2,7—diazabicyclo[3.3.0]—
octane—7—carboxylate with Ba(OH)2.8H2O.
°C/1O mbar.
by hydrolysis
Boiling point:
Example R
—Methyl—2,7-diazabicyclo[3.3.0]octane
—Methyl—2,7—diazabicyclo[3.3.0]octane is obtained
analogously to Example I.
Boiling point: 68—70°C/6 mbar.
Example S
,3-Dimethyl—2,7—diazabicyclo[3.3.0]octane
,3—Dimethyl—2,7—diazabicyclo[3.3.0]octane is obtained
analogously to Example 1.
Boiling point: 72—74°C/10 mbar.
_ 95 _
Example T
,2—Dimethy1—3—oxa—2,7—diazabicyclo(3.3.0]octane
a) N—Ally1—N-(2,2—dimethoxypropy1)—acetamide
g (74 mol) of
added dropwise to 29.6 g (0.987 mol)
(80% strength in paraffin oil)
toluene at 80°C. The Huxture is then stirred
100 g (0.83 allyl
subsequently added dropwise at 80°C. The
stirred overnight at 80°C and cooled and the salts are
,2—dimethoxypropylacetamide are
of sodium hydride
in 750 ml of absolute
for one
hour and
mol) of bromide are
mixture is
dissolved with water. The aqueous phase is separated
off and extracted twice with 100 ml of toluene each
time. and
The toluene solutions are dried over EQCO3
concentrated and the residue is distilled.
Yield: 112 g (75.6% of theory)
Boiling point: 70°C/0.08 mbar.
b) N—Al1yl—N—(2—oxopropyl)—acetamide
.5 g (0.425 mol)
acetamide are heated under reflux with 212 ml of formic
of N—al1y1-N-(2,2—dimethoxypropyl)—
acid for one hour. The mixture is poured onto 500 g of
ice and extracted several times with methylene
chloride, the organic phases are washed. with sodium
bicarbonate solution, dried over magnesium sulphate and
concentrated and the residue is distilled.
Yield: 50 g (75.8% of theory)
Boiling point: 79°C/0.25 mbar.
c) 7—Acety1—1,2—dimethyl—3—oxa—2,7—diazabicyclo—
[3.3.0]—octane
.5 g (0.1 mol) of N—allyl—N—(2—oxopropyl)—acetamide
are dissolved in 100 ml of dioxane, and 9 g of
anhydrous sodium acetate and 9 g (0.108 mol) of
_9'7_
N—methylhydroxylamine hydrochloride in 10 inl of water
are added. The mixture is heated under reflux overnight
and cooled and the salts are filtered off with suction
and washed with dioxane.
The filtrate is concentrated,
residue is taken up in l00 ml of water and KfiXh is
added. The mixture is extracted with CHCl3, the extract
is dried over Kgxg and concentrated and the residue is
distilled.
Yield: 15.9 g (86.3% of theory)
Boiling point: 75°C/0.1 mbar.
d) l,2—Dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]octane
ll.8 g (64 mmol)
azabicyclo[3.3.0]octane are heated under
of 7—acetyl—l,2—dimethyl—3-oxa—2,7—di—
reflux with
l2 g of NaOH in 36 ml of water overnight. The mixture
is saturated with K2CO3 and extracted several times with
CHCl%
and the residue is distilled.
Yield: 4.7 g (51.6% of theory)
Boiling point: 40°C/0.2 mbar.
the extract is dried over KZCO3 and concentrated
Example U
,4—Dimethyl—3—oxa—2,7-diazabicyclo[3.3.0]octane
a) Ethyl N-(but—2—enyl)—N—(2,2—dimethoxyethyl)—
carbamate
89 g (0.5 mol) of ethyl N-(2,2—dimethoxyethyl)—carba—
mate are added dropwise to 17.5 g (0.58 mol) of NaH
(80% strength in paraffin oil) in 500 ml of absolute
toluene at 80°C. The Hdxture is then stirred for one
hour and 80 g (0.59 mol) of l—bromo—2—butene are
The mixture is
the
at 80°C.
and cooled,
subsequently added dropwise
stirred. at 80°C overnight salts are
dissolved with water and the aqueous phase is separated
off and extracted with toluene. The toluene solutions
are dried over Kfixh and concentrated and the residue is
distilled.
Yield: 90 g
Boiling point:
(77.8% of theory)
65°C/0.l mbar.
b) Ethyl N-(but—2—enyl)—N—(2—oxoethyl)—carbamate
g (0.39 mol) of
methoxyethyl)—carbamate
ethyl
N-(but—2—enyl)—N—(2,2—di—
heated under reflux with
200 ml of formic acid for one hour. The mixture is
poured onto 500 g of ice and extracted with methylene
chloride, the organic phases are washed with sodium
bicarbonate solution, dried over magnesium sulphate and
concentrated and the residue is distilled.
Yield: 33.6 g (46.5% of theory)
Boiling point: 65°C/O.l mbar.
c) Ethyl 2,4—dimethyl—3—oxa—2,7—diazabicyclo(3.3.0]-
octane—7—carboxylate
.4 g (O.l mol) of N—(but—2—enyl)—N—(2—oxo—
ethyl)—carbamate are dissolved in 160 IN. of dioxane,
(O.lO8 mol)
l0 ml of
is heated under reflux
filtered off
The filtrate is
in 100 ml of
added. The mixture is extracted with
ethyl
and 9 g of anhydrous sodium acetate and 9 g
of N—methylhydroxylamine hydrochloride in
water are added. The mixture
overnight and cooled and the salts are
with suction and washed with dioxane.
the
concentrated, residue is
taken up
water and KQCO3 is
CHCly
and the residue is distilled.
Yield: 15.0 g (70% of theory)
Boiling point: 74—87°C/0.1 mbar.
the extract
is dried over KZCO3 and concentrated
d) 2,4—Dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]octane
l3.2 g (61.6 mmol) of ethyl 2,4—dimethyl—3—oxa—2,7-di-
azabicyclo[3.3.0]octane—7-carboxylate are heated under
reflux with 39 g of Ba(OH)2 8Hfl) in 200 ml of water
overnight. K2CO3 is added, the BaCO3 is filtered off
_ 99 _
with and the
times .
suction filtrate is extracted several
The extract and
is dried over PQCO3
concentrated and the residue is distilled.
Yield: 4.8 g (54.8% of theory)
Boiling point: 74°C/8 mbar.
Example V
Ethyl 2,7—diazabicyclo[3.3.0]octane—2—carboxylate
7—Benzyl—2,7~diazabicyclo[3.3.0]octane
with ethyl
give
(Example Jc) is
reacted chloroformate
ethyl
analogously to
Example 0a) to 7—benzyl—2,7—diazabicyclo—
(3.3.0]octane—2-carboxylate, and this is then deben-
zylated hydrogenolytically analogously to Example Jd).
A colourless oil of boiling point 90°C/O.l mbar is
obtained.
Example W
—Phenyl—2,7—diazabicyclo[3.3.0]octane
The preparation is carried out analogously to
Example I);
Boiling point: lO3°C/0.08 mbar.
Example X
—Oxa—2,8—diazabicyclo[4.3.0]nonane
a) Ethyl 3—amino—4—hydroxymethyl—pyrrolidine—l—car-
boxylate
Ethyl 3—oxa—2,7—diazabicyclo[3.3.0]octane—7—carboxylate
(Example QC) is hydrogenated analogously to
Example Pa).
Boiling point: l63—l68°C/0.8 mbar
— 100 —
b) 3—Amino—4—hydroxymethyl—pyrrolidine
Ethyl 3—amino—4—hydroxymethyl—pyrrolidine—l—carboxylate
is hydrolyzed analogously to Example Pd).
Boiling point: 78°C/0.06 mbar
c) 4—Oxa—2,8—diazabicyclo[4.3.0]nonane
-Amino—4—hydroxymethyl—pyrrolidine is reacted with
formaldehyde solution analogously to Example Pe).
Boiling point: 50—60°C/0.07 mbar
Example Y
trans-3—Ethylamino—4—methylthio—pyrrolidine
a) 1—Benzoyl—trans-3—ethy1amino—4—methylthio—pyrroli—
dine
.65 g (50 mmol) of l—benzoyl—2,5—dihydropyrrole [Chem.
Ber. 22, 2521 (1889)] are introduced to a vessel in
ml of dichloromethane, and at 0°C 4.94 g
ml
The mixture is subsequently
(60 mmol)
of methanesulphonyl chloride in of dichloro—
methane are added dropwise.
stirred at 20-25°C for 16 hours and concentrated under
mbar and the residue is dissolved in 50 ml of
tetrahydrofuran. Then 18 g (0.2 mol) of 50% strength
aqueous ethylamine solution are added. The batch is
boiled under reflux cooling for 18 hours, poured into
water and extracted with dichloromethane. Concentration
gives 11.1 g of crude product, which is chromatographed
with ethyl acetate/ethanol 5:1 on silica gel (RE value
0.34).
Yield:
.4 g (56% of theory).
b) trans—3—Ethylamino—4—methylthio—pyrrolidine
.0 g
4—methylthio—pyrrolidine
(22 mmol) of l—benzoyl—trans—3—ethy1amino—
are stirred vigorously at
- lOl —
°C with 22 ml of 5 N NaOH for 24 h until the batch
is homogeneous. Then the batch is extracted with
3 x 80 ml of ether, and the extract is dried over
sodium sulphate and concentrated on a rotary
evaporator. The crude product is distilled via a micro-
scale indented column.
1.56 g (44% of theory)
Boiling point: 52°C/O.l mbar
Yield: of colourless li uid
I
Example Z
trans—3—Amino—4—methylthio—pyrrolidine
In the same way as for Example Y, l—benzoyl—2,5—di—
hydropyrrole is reacted. with methylsulphenyl chloride
to give l—benzoyl-3—chloro—4-methylthio—pyrrolidine,
which is reacted as a crude product with ammonia to
give 3—amino—l-benzoyl—4—methylthio—pyrrolidine, and
the benzoyl radical is removed using sodium hydroxide
solution.
Yield over 3 stages: 47% of theory,
Boiling point: 108—llO°C/O.1l mbar.
Example ZA
—Methyl—2,8—diazabicyclo[4.3.0]nonane
a) 5—Methyl—l,4—dihydropyridine—2,3—dicarboxylic acid
N-benzylimide
g
hydrazone and 55 g
(0.29 mol) of 2—methyl—2—propenal—dimethyl—
(0.29 mol)
stirred in 225 ml of acetonitrile at 60°C for 3 hours.
of N—benzylmaleimide are
The solvent is then removed on a rotary evaporator, the
600 ml of toluene and the
mixture is boiled under reflux, with the addition of
It is then filtered
residue is taken up in
g of silica gel, for 1 hour.
hot and the silica gel is boiled up several times with
ethanol. The combined organic phases are concentrated
— 102 —
on a rotary evaporator. 17.5 g (24% of theory) of red
crystals of melting point 184-186°C are obtained.
b) 5—Methyl—hexahydropyridine-2,3—dicarboxylic acid
N~benzylimide
17.5 g (70 mmol) of
2,3—dicarboxylic acid N—benzylimide are hydrogenated in
150 ml of over
charcoal at 70°C under 100 bar.
filtered off and the filtrate is
oily—solid residue (13.0 g)
product in the next stage.
—methyl—1,4—dihydropyridine~
active
then
The
is employed as the crude
tetrahydrofuran palladium on
The catalyst is
concentrated.
c) 8—Benzyl—4—methyl—2,8—diazabicyclo[4.3.0]nonane
.0 g of
carboxylic acid N—benzylimide are added dropwise as a
crude 5—methyl—hexahydropyridine—2,3—di—
solution in 50 ml of absolute tetrahydrofuran to 4.6 g
(0.12 mol) of lithiuH1 aluminiunl hydride in 100 ml of
absolute tetrahydrofuran, which have been initially
introduced into the reaction vessel. The mixture is
then boiled under reflux for 17 hours. 4.6 g of water
in 14 ml 4.6 g of 10%
sodium hydroxide solution and 13.8 g of water are added
The salts are filtered off with
of tetrahydrofuran, strength
dropwise in succession.
the filtrate is concentrated and the residue
is distilled.
Yield: 8.7 g (54%,
pyridine—2,3—dicarboxylic acid N—benzylimide)
95-98°C/0.1 mbar.
suction,
basesd on 5—methyl—1,4—dihydroxy—
Boiling point:
d) 4—Methyl—2,8—diazabicyclo[4.3.0]nonane
.0 g (35 mmol)
[4.3.0]nonane are dissolved in 60 NH. of methanol and
of 8—benzyl—4-methyl—2,8—diazabicyclo—
hydrogenated over palladium on active charcoal at 100°C
under 100 bar. The catalyst is then filtered off, the
filtrate is concentrated and the residue is distilled.
— 103 —
Yield: 3.3 g
Boiling point:
(67% of theory),
88—89°C/ll mbar.
The lH—NMR spectrum identifies the compound as a mixture
of two stereoisomers in a ratio of 7:2.
Example AA
,6,7,8—Tetrafluoro—1—(2,4—difluorophenyl)—l,4—dihydro—
—oxo—3—quinolinecarboxylic acid
a) Ethyl 2-(2,3,4,5,6-pentafluorobenzoyl)—3—(2,4—di—
fluorophenylamino)—acrylate
.3 g of 2,4—difluoroaniline are added dropwise to a
115 g of ethyl 3-ethoxy—2—(2,3,4,5,6—
pentafluorobenzoyl)—acrylate in 380 ml of
while cooling with ice and stirring.
solution of
ethanol,
The mixture is
stirred at room temperature for 1 hour, 380 ml of water
are added, while cooling with ice, and the precipitate
is filtered off with suction, washed with ethanolflhO
(1:1) 135.4 g of the title
melting point 97—99°C are obtained.
and dried. compound of
b) Ethyl 5,6,7,8-tetrafluoro—1—(2,4—difluorophenyl)—
l,4—dihydro—4—oxo—3—quinolinecarboxylate
A mixture of 135.4 g of ethyl 2—(2,3,4,5,6—penta—
fluorobenzoyl)(2,4—difluorophenylamino)—acrylate,
.6 g of 300 ml of anhydrous
dimethylformamide is heated at l40—l50°C for 3 hours.
The suspension is poured hot onto 2 kg of ice and the
sodium fluoride and
precipitate is filtered off with suction, washed with
water and dried. 122 g of the title compound of melting
point l60—l62°C are obtained.
c) 5,6,7,8—Tetrafluoro(2,4-difluorophenyl)—l,4—di—
hydro—4—oxo—3—quinolinecarboxylic acid
— 104 —
.1 g of ethyl 5,6,7,8—tetrafluoro—l—(2,4—difluoro—
phenyl)—1,4—dihydro—4—oxo—3—quinolinecarboxylate are
added to a mixture of 28.5 ml of concentrated sulphuric
acid, 250 ml of glacial acetic acid and 200 ml of water
and the mixture is heated under reflux for 2 hours. The
hot solution is poured onto ice and the precipitate is
filtered off with suction, washed with water and dried.
34.5 g of the title compound of melting point 250—252°C
are obtained.
Example AB
,7—Dichloro—1—cyclopropyl—6—fluoro—1,4—dihydro—4—oxo—
—quinolinecarboxylic acid
a) Ethyl (2,4—dichloro—3,6—difluorobenzoyl)—acetate
.1 g of magnesium. filings are suspended in 5 ml of
anhydrous ethanol. 0.5 TM. of carbon tetrachloride is
added and,
g of ethyl malonate,
a mixture of
ml of absolute ethanol and
ml of toluene is added dropwise.
when the reaction has started,
The mixture is then
heated at 70°C for a further 1.5 hours and cooled to
—5°C to —10°C with acetone/dry ice,
21.5 g of 2,4—dichloro—3,6—difluorobenzoyl chloride in
ml at this
and a solution of
of toluene is slowly added dropwise
temperature. The mixture is stirred at 0°C for 1 hour
and allowed to come to room temperature overnight, and
ml of 5 ml of
concentrated sulphuric acid is allowed to run in,
with The
a mixture of ice—water and
while
and
with
The combined toluene solutions are washed once
cooling ice. phases are separated
subsequent extraction is carried out twice
toluene.
with saturated sodium chloride solution and dried with
34.7 g
(2,4—dichloro—3,6—difluorobenzoyl)—malonate
Na;SO4 and the solvent is stripped off in vacuo.
of diethyl
are obtained as a crude product.
.04 g of p-toluenetoluenesulphonic acid is added to an
- 105 ~
emulsion of 34.7 g of crude diethyl (2,4—dichloro—3,6—
difluorobenzoyl)—malonate in 40 ml of water. The
mixture is heated at the boiling point for 3 hours,
while stirring thoroughly, the cooled emulsion is
extracted several times the
combined CH2C12 solutions are washed once with saturated
with methylene chloride,
sodium chloride solution and dried with Na3SO4 and the
solvent is distilled off in vacuo. Fractionation of the
(33.9 g) in 13.9 g of ethyl
(2,4—dich1oro—3,6—difluorobenzoyl)-acetate of boiling
point 110~115°C/ 0.05 mbar; n i: 1.5241.
residue vacuo gives
b) Ethyl 2—(2,4—dichloro-3,6—difluorobenzoyl)—
—ethoxy—acrylate
.7 g of
acetate
ethyl
heated
(2,4—dichloro—3,6—difluorobenzoyl)—
with 10.25 g of
triethyl orthoformate and 11.8 g of acetic anhydride
are under reflux
The mixture is then concentrated in vacuo
up to a bath temperature of 140°C and 15.7 g of ethyl
-(2,4—dich1oro-3,6-difluorobenzoyl)—3—ethoxy—acrylate
for 2 hours.
are obtained as an oil; ng: 1.5302.
c) Ethyl 2—(2,4—dichloro—3,6—difluorobenzoyl)—
—cyc1opropylamino-acrylate
.6 g of ethyl
—ethoxy—acry1ate are dissolved in 50 Hd
(2,4—dichloro-3,6-difluorobenzoy1)—
of ethanol,
and 2.75 g of cyclopropylamine are added dropwise,
while cooling. The mixture is stirred at room
temperature for 1 hour, 50 ml of water are added, while
cooling with ice, and the precipitate is filtered off
rinsed with ethanol/H20 (1:1)
14.1 g of ethyl 2—(2,4—dichloro—3,6—difluorobenzoyl)—
3-cyclopropy1amino—acrylate of melting point 106—107°C
with suction, and dried.
are obtained.
— 106 —
d) Ethyl 5,7—dichloro—l—cyclopropyl—6—fluoro—l,4~d:—
hydro—4—oxo—3—guinolinecarboxylate
g of ethyl 2-(2,4—dichloro—3,6—difluorobenzoyl)—
3—cyclopropylamino—acrylate 100 ml of
of potassium
heated in
at 150°C with 2.75 g
for 2.5 hours.
are
dimethylformamide
into
carbonate The mixture
is poured
600 ml of ice—water and the precipitate is filtered off
with suction, washed with water‘ and dried.
ethyl
.2 g of
,7—dichloro—l—cyclopropyl—6—fluoro—l,4—dihydro-
4—oxo—3—quinolinecarboxylate of melting point 227~229°C
are obtained.
e) 5,7-Dichloro—1—cyclopropyl—6—fluoro—1,4—dihydro—
-oxo—3—quinoinecarboxylic acid
.2 g of ethyl
,4—dihydro—4—oxo—3—quinolinecarboxylate
,7—dichloro—l-cyclopropyl—6—fluoro—
are heated
under reflux in a mixture of 38 ml of acetic acid,
ml of water and 4.3 ml of concentrated
After the
poured into 250 ml of ice—water and the precipitate is
sulphuric
acid for 2.5 hours. cooling, mixture is
filtered off with suction, washed with water and dried.
4.8 g of
hydro—4—oxo—3—quinolinecarboxylic acid of melting point
277—278°C are obtained.
,7—dichloro—1-cyclopropyl—6-fluoro—l,4—di-
Example AC
,7—Dichloro—6—fluoro—l—(2,4—difluorophenyl)—1,4—di—
hydro—4—oxo—3—quinolinecarboxylic acid
a) Ethyl 2—(2,4—dichloro—3,6—difluorobenzoyl)—3—(2,4—
difluorophenylamino)—acrylate
.3 g of ethyl 2—(2,4—dichloro—3,6—difluorobenzoyl)-
in l2O ml of
and 12.9 g of 2,4—difluoroaniline are added dropwise,
—ethoxyacrylate are dissolved ethanol,
while cooling with ice. The mixture is stirred at room
— 107 —
temperature for 1.5 hours, 120 ml of water are added,
while cooling, and the precipitate is filtered off with
suction, rinsed with ethanol/H20 (1:1)
of ethyl
and dried. 40.5 g
2—(2,4—dichloro—3,6—difluorobenzoyl)—3—(2,4-
difluorophenylamino)—acrylate obtained.
-86°C.
are Melting
point:
b) Ethyl 5,7—dichloro—6—fluoro—1—(2,4—difluoro~
phenyl)-1,4—dihydro—4—oxo—3—quinolinecarboxylate
.6 g of ethyl 2-(2,4—dichloro—3,6—difluorobenzoyl)—
~(2,4—difluorophenylamino)—acrylate are heated in
260 HQ. of dimethylformamide at 150°C with 15.2 g of
potassium carbonate for 2.5 hours. The mixture is
poured into 1 litre of ice-water and the precipitate is
filtered off with suction, washed with water and dried.
38.6 <3 of ethyl 5,7—dichloro—6—fluoro—1—(2,4—difluoro—
phenyl)—l,4—dihydro—4—oxo—3—quinolinecarboxylate are
obtained.
c) 5,7—Dichloro—6-fluoro—l—(2,4—difluorophenyl)—
,4—dihydro—4—oxo—3—quinolinecarboxylic acid
.6 g of ethyl 5,7—dichloro~6—fluoro—l—(2,4—di—
fluorophenyl)-1,4—dihydro—4—oxo—3—quinolinecarboxylate
are heated. under reflux with 250 ml of acetic acid,
200 ml of water and 28.5 ml of concentrated sulphuric
acid for 3 hours.
2 litres of
After cooling, the mixture is poured
into ice—water and the precipitate is
washed with water and dried.
.5 g of 5,7—dichloro—6—fluoro—l—(2,4—difluorophenyl)—
1,4—dihydro—4—oxo—3—quinolinecarboxylic
—246°C.
filtered off with suction,
acid are
obtained. Melting point:
— 108 -
Example 1
COOH
I
H2 . X HC 1
F
CH3OK“
mg (3 mmol) of l—cyclopropyl—6,7,8—trifluoro—
1,4—dihydro—4—oxo—3—quinolinecarboxy1ic acid are
heated. under reflux for 1 hour in a mixture of
9 ml of acetonitrile and 4.5 ml of dimethyl—
formamide in the presence of 330 mg (3.3 mmol) of
1,4—diazabicyclo[2.2.2]octane and 750 mg of trans-
3—tert—butoxycarbonyl—amino—4—methoxy—pyrrolidine.
The mixture is concentrated by evaporation and the
residue is stirred together with water and dried.
Yield: 1.3 g (90.5% of theory) of 7—(trans—3—tert—
butoxycarbonylamino—4—methoxy—1—pyrrolidinyl)
cyclopropyl—6,8—difluoro—1,4—dihydro-4—oxo—3—
quinolinecarboxylic acid.
Melting point: 222—224°C (with decomposition)
(from glycol monomethyl ether).
.2 g (3.5 mmol) of the product from stage A are
introduced into 10 ml of 3N hydrochloric acid,
stirred to dissolution and concentrated. The
residue is triturated with ethanol, filtered off
with suction and dried under a high vacuum at 60°.
Yield: 0.73 g (70% of theory) of 7—(trans—3—amino—
4—methoxy—1—pyrrolidinyl)—1—cyclopropy1—6,8—di—
fluoro—4-oxo—3—guinolinecarboxylic acid hydro-
chloride.
Melting point: 279°C (with decomposition).
— 109 —
Example 2
coon
I
H2NnI:::N )
cu3o¢
In the same way as in Example 1,
xHC1
—cyclopropyl—6,7—di—
fluoro—1,4—dihydro—4—oxo—3—guinolinecarboxy1ic acid is
reacted to give:
A. 7-(trans-3—tert—butoxycarbonylamino—4—methoxy—1—
pyrrolidinyl)—1—cyclopropyl—6—f1uoro-1,4—dihydro—
—oxo—3—quinolinecarboxylic acid, melting point:
—249°C (with decomposition).
B. 7-(trans—3—amino—4—methoxy—1—pyrrolidinyl)—1—cyclo—
propyl—6—fluoro—4—oxo—3—quino1inecarboxy1ic acid
hydrochloride, melting point: from 293°C (with
decomposition).
Example 3
O0
x HC2
In the same way as in Example 1, reaction is carried
out with cis-3—tert-butoxycarbonylamino-4—methoxy—
pyrrolidine to give:
A. 7-(cis-3—tert-butoxycarbonylamino—4—methoxy—1-
pyrrolidinyl)—l—cyclopropyl—6,8—difluoro—l,4—di—
hydro—4—oxo~3—quinolinecarboxylic acid, melting
point: 230—231°C (with decomposition).
— llO —
B. 7—(cis—3—amino—4—methoxy—l—pyrrolidinyl)—l—cyclo—
propyl-6,8—difluoro—4—oxo—3—guinolinecarboxylic
acid hydrochloride, melting point 20l—203°C (with
decomposition).
Example 4
O
Ow OOH
— I- A x cracoon
C1
CH3 -
A. 1.5 g (5 mmol) of 8—chloro—l—cyclopropyl—6,7—di-
fluoro—l,4—dihydro—4—oxo—3-guinolinecarboxylic
acid are heated under reflux for 2 hours in a
mixture of 10 ml of acetonitrile and 5 ml of
dimethylformamide with 550 mg (5 mmol) of
1,4—diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol)
of cis-3—tert—butoxycarbonylamino—4—methoxy—
pyrrolidine. The mixture is allowed. to cool and
the precipitate formed is filtered off with
suction, then washed thoroughly with water and
dried in vacuo at lOO°C.
Yield: 2.0 g (80.7%) of 7—(cis—3—tert—butoxy—
carbonylamino—4—methoxy—l—pyrrolidinyl)—8—chloro-
1—cyclopropyl-6—fluoro—1,4—dihydro—4—oxo—3—guino—
linecarboxylic acid, melting point: 222—225°C
(with decomposition):
B. 1.9 g (3.8 mmol) of the product from stage A are
stirred in l0 ml of trifluoroacetic acid at room
temperature for 20 minutes, the solution is
concentrated, the oil which remains is evaporated
and the
ether. The
formed is filtered off with suction,
with dichloromethane residue is
with
twice
stirred together precipitate
washed with
— 111 —
ether and dried in vacuo at 60°C.
Yield: 1.9 g (97%
4—methoxy—1—pyrrolidiny1)—8—ch1oro—1—cyclopropyl—
of theory) of 7—(cis—3—amino—
—fluoro—1,4—dihydro—4—oxo—3—quino1inecarboxylic
acid trifluoroacetate, melting point 235—239°C
(with decomposition).
Example 5
0
O0
H2 xHC1
CH3
In the same way as in Example 1, cis—3—tert—
butoxycarbony1amino—4—methoxy—l—pyrro1idine is reacted
with 1-cyc1opropyl—6,7—difluoro-1,4—dihydro—4—oxo—
—quino1inecarboxy1ic acid to give:
A. 7-(cis-3—tert—butoxycarbony1amino-4—methoxy—1—
pyrrolidinyl)-1—cyc1opropyl—6—fluoro—1,4—dihydro—
4—oxo—3—quinolinecarboxy1ic acid,
—233°C (with decomposition).
melting point
B. 7-(cis—3—amino—4—methoxy—1-pyrrolidinyl)—1—cyclo—
propyl-6—fluoro—1,4—dihydro-4—oxo—3—quinoline—
carboxylic acid hydrochloride, melting point
252—256°C (with decomposition) (sintering
beforehand).
Example 6
O
00 OOH
I- xxcx
CH3
— ll2 -
In the same way as in Example 1, cis—3—tert—
butoxycarbonylamino—4—methoxypyrrolidine is reacted
with 7—chloro—l—cyclopropyl—6—fluoro—l,4—dihydro~4—oxo—
l,8—naphthyridine—3-carboxylic acid to give:
A. 7-(cis-tert—butoxycarbonylamino—4—methoxy—l—
pyrrolidinyl)—l—cyclopropyl—6—fluoro—l,4—dihydro—
4—oxo—l,8—naphthyridine—3-carboxylic acid, melting
point 2l4—2l6°C (with decomposition).
B. 7-(cis-3—amino—4—methoxy—l—pyrrolidinyl)—l—cyclo—
propyl—6—fluoro—l,4—dihydro—4—oxo—l,8—naphthyri—
dine—3-carboxylic acid hydrochloride, melting point
205—210°C (with decomposition).
Mass spectrum: m/e 362 (M+), 330 (M+—32), 318 (M+—COfi,
286, 260, 41 (Cfih), 36 (HCl).
Example 7
0
COOH
N
“2"‘C:;" A
Hog
1.33 g (5 mmol) of l—cyclopropyl—6,7—difluoro—1,4—di—
hydro—4—oxo-3—quinolinecarboxylic acid iJ1 a mixture of
ml of acetonitrile and 5 ml of dimethylformamide are
l.l g (10 mmol) of
and 0.55 g (5.4 mmol)
3—amino—4—hydroxy—pyrrolidine and the mixture is heated
The
admixed with l,4—diaza-
bicyclo[2.2.2]octane of trans-
under reflux for 1 hour. suspension is
concentrated, the residue is admixed with. water, and
the undissolved product is filtered offi with suction
and recrystallized from dimethylformamide.
Yield: l.2 g (73% of
—hydroxy—l—pyrrolidinyl)—l—cyclopropyl—6—fluoro—l,4-
theory) of 7—(trans—3—amino—
— 113 -
dihydro—4—oxo—3—guinolinecarboxylic acid,
Melting point: 274—278°C (with decomposition).
Example 8
0
COOH
L,‘ “A
H
850 mg (3 mmol) of l—cyclopropyl—6,7,8—trifluoro—
l,4—dihydro-4—oxo—3—quinolinecarboxylic acid are heated
l0 under reflux in 9 ml of pyridine with 630 mg (3.l mmol)
of 2—oxa—5,8—diazabicyclo[4.3.0]nonane dihydrochloride
and 500 mg (4.5 mmol) of l,4-diazabicyclo[2.2.2]octane
for l hour. The mixture is concentrated, the residue is
stirred with water and the precipitate is filtered off
with suction, washed with water, dried and
recrystallized from glycol monomethyl ether.
Yield: 840 mg (72% of theory) of l—cyclopropyl—6,8—di—
fluoro-l,4—dihydro—7—(2—oxa—5,8—diazabicyclo[4.3.0]non—
8—yl)-4—oxo—3-quinolinecarboxylic acid,
Melting point: 289—29l°C (with decomposition);
Mass spectrunn m/e 391 (M+), 347 (M+~CO2), 331, 306,
294, 262, 234, 98, 41 (C3Hfi.
Example 9
am
<59" F2:
The reaction is carried out analogously to Example 8
with 5—methyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane
dihydrochloride to give: 1—cyclopropyl—6,8-difluoro—
— 114 —
l,4—dihydro—7—(5—methyl—2—oxa—5,8—diaZabicyclo[4.3.0]—
non—8—yl)-4—oxo—3-quinolinecarboxylic acid, melting
point: from 270°C (with decomposition);
Mass spectrunn m/e 405 (M3), 361 (M+—CO2), 331, 112,
(100%).
Example 10
O0
A
\c1-13
mg C3 mmol) of 1-cyclopropyl—6,7—difluoro-1,4—di—
hydro—4—oxo—3—quinolinecarboxylic acid are heated under
reflux in a mixture of 9 ml of acetonitrile and 4.5 ml
with 890 mg (4.1
—methyl—2—oxa—5,8—diazabicyclo[4.3.0]nonane
chloride and 860 mg (7.8 mmol)
[2.2.2]octane for 2 hours.
mmol) of
dihydro—
of dimethylformamide
of 1,4—diazabicyclo—
The nfixture is evaporated,
the residue is stirred with water and the undissolved
filtered off with with
water, dried and recrystallized from dimethylformamide.
product is suction, washed
Yield: 0.8 g (69% of theory) of 1—cyclopropyl—6—fluoro—
,4—dihydro—7—(5—methyl—2-oxa—5,8—diazabicyclo[4.3.0]-
non—8—yl)-4—oxo—3—quinolinecarboxylic acid, melting
point 340°C (with decomposition) (on heating up, the
substance already becomes dark from about 300°).
Mass spectrunu m/e (M1), 343 (M+—CO2), 313, 244, 112
(100%).
— l15 —
Example ll
The reaction is carried out analogously to Example 10
with 8—chloro—l—cyclopropyl—6,7~difluoro—l,4—dihydro—
—oxo—3—guinolinecarboxylic acid to give 8—chloro—
l—cyclopropyl—6—fluoro-1,4—dihydro—7—(5—methyl—2—oxa—
,8—diazabicyclo[4.3.0]non~8—yl)—4—oxo—3—quinoline—
carboxylic acid, melting point 258-262°C (with decompo-
sition) (recrystallized from dimethylformamide).
Example 12
The reaction is carried out analogously to Example 10
with l—ethyl-6,7,8—trifluoro—l,4—dihydro—4—oxo—3—guino—
l-ethyl—6,8—difluoro—
l,4—dihydro—7-(5—methyl—2—oxa—5,8—diazabicyclo[4.3.0]—
linecarboxylic acid to give
non—8—yl)-4—oxo—3-quinolinecarboxylic acid, melting
point 279—28l°C (with decomposition).
— 116 -
Example 13
O0
F 4:
\CH3
.84 g
l,4—dihydro—4-oxo—3—quinolinecarboxylic acid are heated
(3 mmol) of 1—cyclopropyl—6,7,8—trifluoro—
under reflux in a Hmxture of 6 ml of acetonitrile and
3 ml with 0.66 g
l,4-diazabicyclo[2.2.2]octane and 0.49 g (3.5 mmol> of
of dimethylformamide (6 mmol) of
2—methyl—2,8—diazabicyclo[4.3.0]nonane for 2 hours. The
suspension is concentrated, the residue is stirred with
ml of water, the mixture is brought to pH 7 with 2N
hydrochloric acid and the precipitate is filtered off
with suction, washed with water, dried and
recrystallized from glycol monomethyl ether.
Yield: 0.7 g (58%
fluoro—l,4—dihydro—7-(2—methyl-2,8—diazabicyclo[4.3.0]—
melting
of theory) of l—cyclopropyl—6,8—di—
non—8—yl)-4—oxo—3—quinolinecarboxylic
point 204—207°C.
acid,
Example 14
O0 °°"
2;
\CH3
Analogously to 1-cyc1opropyl—6—fluoro—
,4—dihydro—7—(2—methyl—2,8—diazabicyclo[4.3.0]non-
Example 13,
—yl)-4—oxo—3—quinolinecarboxylic acid, melting point
234-2363
,4—dihydro—4—oxo—3—quinolinecarboxylic acid.
is obtained with l—cyclopropyl—6,7—difluoro-
— 117 -
Example 15
‘ oou
» A
—Cyclopropyl—6,7,8—trifluoro—1,4—dihydro—4—oxo—3—
guinolinecarboxylic acid is reacted with
2,8—diazabicyclo[4.3.0]nonane analogously to
Example 13 to give l—cyclopropyl—7-(2,8—diaza—
bicyclo[4.3.0]non—8-yl)—6,8—difluoro—1,4—dihydro—
4—oxo—3—quinolinecarboxylic acid, melting point
265—267° (with decomposition) (recrystallized from
dimethylformamide).
If the reaction of Example 15 A) is carried out in
a mixture of acetonitrile/l—methy1—2—pyrrolidinone
and the crude product is recrystallized from
dimethylformamide, l—cyclopropyl—7~(2,8—diaza—
bicyclo[4.3.0]non—8—yl)—6,8—difluoro—1,4—dihydro—
4—oxo—3—quinolinecarboxylic of melting point
269—271°C (with decomposition) is obtained.
According to a comparison by chromatography and
spectroscopy, the product is identical to the
product prepared according to process A).
g (167 mmol) of the betaine (stage A) are dis—
solved in 330 ml of half-concentrated hydrochloric
acid by heating, the solution is concentrated and
the residue is stirred with 300 ml of ethanol. The
undissolved precipitate is filtered off with
suction, washed with ethanol and dried at 100°C in
vacuo .
Yield: 66.3 g (93% of theory) of 1~cyclopropyl—
— 118 —
—(2,8—diazabicyclo[4.3.0]non-8—yl)—6,8—difluoro—
1,4-dihydro—4—oxo—3-quinolinecarboxylic acid
hydrochloride, melting point: 303—305°C (with
decomposition).
Example 16
‘ 2:
Analogously to Example 13, 1—cyclopropyl—7—(2,7—di—
azabicyclo[3.3.0]oct—7~yl)—6—fluoro—1,4-dihydro—4—oxo—
3—quinolinecarboxylic acid, melting point: 260—282°
(with decomposition), is obtained with 1—cyclopropyl—
6,7—difluoro—1,4—dihydro—4—oxo—3-quinolinecarboxylic
acid and 2,7—diazabicyclo[3.3.0]octane.
Mass spectrunu m/e 357 (M+), 313 (lOO%, M+—CO2), 269,
257, 244, 82, 28.
Example 17
p
0
CK COOH
2:
Analogously to Example 13, 1—cyclopropylfluoro-
1,4—dihydro—7—(2-methyl—2,7—diazabicyclo[3.3.0]oct-
yl)—4—oxo—3—guinolinecarboxy1ic acid, melting point:
206—208°C (with decomposition), is obtained with
1—cyclopropyl—6,7-difluoro—l,4—dihydro—4—oxo—3—guino—
linecarboxylic acid and 2—methyl-2,7—diazabicyclo—
[3.3.0]octane.
v 119 —
Example 18
on coon
F A
—cyclopropyl—6,8-difluoro—
1,4—dihydro(2-methyl—2,7—diazabicyclo[3.3.(]]oct—7—
yl)-4—oxo—3—quinolinecarboxylic
198—200°C (with
2—methyl~2,7—diazabicyclo[3.3.0]octane.
Analogously to Example 13,
acid, melting point
decomposition), is obtained with
Example 19
I
F‘
H3C\ A
(10 mmol)
trifluoro—1,4~dihydro—4—oxo—3—quinolinecarboxylic acid,
1.1 g (10 mmol)
1.4 g (11
bicyclo[3.3.0]octane in 20 ml of acetonitrile and 10 ml
A mixture of 2.83 g of 1—cyclopropyl—6,7,8—
of 1,4—diazabicyclo[2.2.2]octane and
mmol) of 2—methyl—3—oxa—2,7—diaza—
of 1-methyl~2—pyrrolidinone is heated under reflux for
hour.
It is concentrated 111 vacuo, the residue is
stirred with water (pH 7) and the precipitate is
filtered off with suction, washed with water and dried
at 60° in vacuo. The crude product (3.7 g) is
recrystallized from dimethylformamide.
Yield: 1.9 g (49% of theory) of l—cyclopropyl—6,8—di—
fluoro—1,4—dihydro—7—(2—methyl—3—oxa—2,7—diazabicyclo—
[3.3.0]oct—7—yl)-4—oxo—3—quinolinecarboxylic acid,
melting point 221—223°C (with decomposition).
— 120 —
Example 20
COOH
The reaction is carried out analogously to
with
Example l9
,5—dimethyl—3—oxa-2,7—diazabicyclo[3.3.0]octane
l—cyclopropyl-6,8-difluoro—l,4—dihydro—7—(2,5-
dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]oct—7—yl)—4~oxo—
to give
-guinolinecarboxylic acid of melting point 237—238°C
(with decomposition).
Example 2l
The reaction is carried out analogously to Example 19
with 2,8—dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]octane
to give l—cyclopropyl—6,8—difluoro-l,4—dihydro—
7-(2,8—dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]oct—7—yl)—
4—oxo—3—quinolinecarboxylic acid of
l97—l99°C.
melting point
Example 22
O0
HR
C 1
A. 3 g (10 mmol) of 8—chloro—l—cyclopropyl—6,7—di—
fluoro—1,4—dihydro—4—oxo—3—quinolinecarboxylic
- 121 —
acid are heated under reflux in a mixture of 30 ml
of acetonitrile and 15 mi of 1—methyl—2—pyrroli—
dinone with 1.4 g (11 mmol) of 2,8—diazabicyclo—
[4.3.0]nonane and 1.65 g (15 mmol) of 1,4-diaza—
bicyclo[2.2.2]octane for 1 hour. After cooling,
the suspension is stirred. with about 150 ml of
water and the undissolved precipitate is filtered
off with suction, washed with water and ethanol
and dried at 80°C/12m bar. The crude product is
recrystallized from 40 ml of glycol monomethyl
ether.
Yield: 2.3 g (57% of theory) of 8—chloro—l—cyclo—
propyl—7-(2,8—diazabicyclo[4.3.0]non—8—yl)-6—fluo—
ro—l,4—dihydro—4-oxo—3—quinolinecarboxylic acid,
melting point: 224—226°C (with decomposition).
The crude betaine is prepared analogously to
Example 22 A. and is suspended in 50 ml of water
and dissolved by addition of 17 ml of 1N hydro-
chloric acid and heating. After cooling in an
ice—bath, the precipitate which has separated out
is filtered off with suction, washed with ethanol
and dried at 100°C in vacuo. 5
Yield: 2.7 g (61% of theory) of 8—chloro—l-cyclo-
propyl—7—(2,8-diazabicyclo[4.3.0]non—8—yl)—6—fluo—
ro-1,4—dihydrooxo—3—quinolinecarboxylic acid
hydrochloride, melting point: front 225°C
decomposition.
Example 23
The reaction is carried out analogously to Example 22
with 9,10—difluoro—2,3—dihydromethyl—7—oxo—7H—pyrido—
- l22 —
(l,2,3—de][1,4]benzoxazine—6—carboxylic acid and the
reaction product obtained is purified by chromatography
on silica gel using methylene chloride/methanol/l7%
strength aqueous ammonia solution (30:8:l) as the
mobile phase. lO—(2,8—Diazabicyclo[4.3.0]non—8—yl)—
—fluoro—2,3—dihydro—3—methyl—7—oxo—7H—pyrido[l,2,3—de]—
[1,4)benzoxazine—6~carboxylic acid of melting point
l—292°C (with decomposition) is obtained.
Example 24
OOH
F A
g (20 mmol) of l—cyclopropyl—5,6,7,8—tetrafluoro-
1,4—dihydro—4—oxo—3—quinolinecarboxylic acid are heated
under reflux in 30 rml of l—Hethyl—2—pyrrolidinone and
60 ml of with 2.2 g (20
l,4—diazabicyclo[2.2.2]octane and 2.7 g (21.4 mmol) of
,8-diazabicyclo[4.3.0]nonane for l_ hour.
acetonitrile mmol) of
The mixture
is concentrated to a substantial degree in vacuo, the
200 ml of and the
filtered off with
residue is stirred with water
undissolved crystals are suction,
washed with water and dried.
Yield: 6.3 g (77.4% of theory) of l—cyclopropyl-7—(2,8—
diazabicyclo[4.3.0]non—8—yl]—5,6,8-trifluoro—l,4—di—
hydro—4—oxo—3—quinolinecarboxylic acid
—269°C after
Melting point: (with decomposition);
recrystallization from dimethylformamide: melting
point: 272—273°C (with decomposition).
- 123 —
Example 25
ml of saturated ethanolic ammonia solution are added
to 4.1 g (10 mmol) of the product from Example 24 in
ml of pyridine, and the mixture is heated at 120°C
in an autoclave for 12 hours. The suspension is
evaporated, the residue is stirred with water and the
pH is brought to 7 with 2N hydrochloric acid. The
precipitate which has separated out is filtered off
with suction and recrystallized from glycol monomethyl
ether.
Yield: 0.7 g (17% of theory) of 5—amino—1—cyclopropyl—
7—(2,8-diazabicyclo[4.3.0]non—8—yl)-6,8—difluoro—1,4-
dihydro—4—oxo—3—quinolinecarboxylic acid, melting
point: 275—277°C (with decomposition).
Mass spectrum: m/e 404 (M+), 384 (M+—HF), 290, 249, 96
(100%).
Example 26
OOH
i
E3 '‘‘$
A. Analogously to Example 13, l—cyc1opropyl—7—(2,7—
diazabicyclo[3.3.0]oct—7—yl)—6,8—difluoro—1,4—di—
hydro—4-oxo—3—quinolinecarboxylic acid, melting
277—260°
with 2,7—diazabicyclo[3.3.0]octane.
point: (with decomposition), is obtained
B. 370 mg of the betaine are dissolved in 13 ml of
— 124 —
half—concentrated hydrochloric acid, the solution
is concentrated. and the residue is treated with
ml of
filtered off with suction,
dried.
Yield: 290 mg of
bicyclo[3.3.0]oct—7—yl)—6,8—difluoro—l,4—dihydro—
hydrochloride,
ethanol. The undissolved product is
washed with ethanol and
l—cyclopropyl—7—(2,7—diaza—
acid
—oxo—3—guinolinecarboxylic
melting point: 269~271°C (with decomposition).
Example 27
In the same way as for Example 8,
with
CH3-Nfly
reaction is carried
out trans—4—methoxy—3—methylamino-pyrrolidine
dihydrochloride. This gives l—cyclopropyl—6,8—difluoro—
1,4—dihydro—7—(trans—4—methoxy~3—methylaminopyrroli—
dinyl)-4—oxo—3—quinolinecarboxylic acid, melting point:
—270°C (with decomposition).
Example 28
xCF3COOB'
A. 1.4 g (2.9 mmol) of product from Example 3 A) and
1.98 ml (1.7 g, 12 mmol) of dimethylformamide
diethyl acetal are heated at 120°C for 2 hours in
ml of absolute dimethylformamide. Thereafter
- l25 —
the batch
which
is concentrated in vacuo. The residue
remains is stirred together with
acetonitrile. The precipitate is filtered off with
suction, washed with a little acetonitrile and
dried.
Yield: 0.8 g (54.4% of theory) of ethyl 7—(cis—
—tert—butoxycarbonylamino—4—methoxy—l—pyrrolidin—
yl)-l—cyclopropyl—6,8—difluoro—l,4—dihydro—4—oxo—
3—quinolinecarboxylate,
Melting point: 151-l52°C.
B. 0.3 g (0.6 mmol)
stirred at 20°C in 10 ml of trifluoroacetic acid
of product from Example 28 A) is
for 10 minutes. Subsequently the trifluoroacetic
acid is removed in vacuo. On addition of diethyl
the The solid is
isolated, washed with diethyl ether and dried.
Yield: 0.25 g (80.6% of ethyl 7—(cis-
—amino—4—methoxy—l~pyrrolidinyl)—l—cyclopropyl—
ether, residue solidifies.
of theory)
6,8—difluoro—1,4—dihydro—4—oxo~3—quinolinecarboxy—
late trifluoroacetate
Melting point: 124—l26°C.
Example 29
COOH
H3C\
< FA
Analogously to Example 13, l—cyclopropyl—6,8-difluoro—
l,4—dihydro—7—(2—methyl—4—oxa—2,8-diazabicyclo[4.3.0]—
non—8—yl)—4—oxo—3—quinolinecarboxylic acid, melting
point 258—260°C
—methyloxo—2,8—diazabicyclo[4.3.0]nonane.
(with decomposition), is obtained with
- 126 —
Example 30
Analogously to Example 19,
—cyclopropyl-6,8—difluoro—
,4—dihydro—7—(3—oxa—2,7—diazabicyclo[3.3.()]octarm—7—
yl)-4—oxo—3—quinolinecarboxylic acid is obtained. with
—oxa—2,7—diazabicyclo[3.3.0]octane.
Example 31
o
W coon .
, i xHC1
an I
°2“s
A. 1.1. g (10 mmol) of 1,4—diazabicyclo[2.2.2]octane
and 1.4 g (11 mmol) of 2,8-diazabicyclo[4.3.0]—
nonane are added to 2.53 g (10 mmol) of 1—ethyl—
6,7—difluoro-1,4—dihydro—4-oxo—3—quinoline—
carboxylic acid in 30 ml of acetonitrile and 15 ml
heated
of dimethylformamide and the mixture is
under reflux for 1 hour. The mixture is
concentrated, the residue is stirred with water
and the precipitate is filtered off with suction,
washed with water and dried.
Yield: 3.1 g (86% 7—(2,8—diaza—
bicyclo[4.3.0]non—8—yl)—l—ethyl—6—fluoro—4—oxo—3—
—261°C
of theory) of
guinolinecarboxylic acid, melting point:
(with decomposition).
.9 g (8 mmol) of the betaine from stage A are
dissolved in 20 ml of half-concentrated hydro-
chloric acid under the influence of heat, the
- 127 —
solution is filtered hot and the hydrochloride is
precipitated filtrate by
This hydrochloride is filtered off with
from the addition of
ethanol.
suction, washed with ethanol and dried at
120°C/12 mbar.
Yield: 1.8 g (57% of theory) of 7—(2,8—diaza—
bicyclo[4.3.0]non—8—yl)—1—ethyl—6-fluoro—4—oxo—3~
quinolinecarboxylic acid hydrochloride, melting
point, with decomposition: 299°C (dark coloration
already starting from about 215°C).
Example 32
gm
A
Reaction analogously to Example 31 with 1—cyclopropyl—
6,7—difluoro-1,4—dihydro—4—oxo—3—quino1inecarboxylic
acid gives:
A. l—Cyc1opropyl—7—(2,8—diazabicyclo[4.3.0]non—8—yl)—
6—fluoro—4—oxo-3—quinolinecarboxylic acid,
melting point: 249—257°C (with decomposition)
B. l—Cyclopropyl—7—(2,8-diazabicyclo[4.3.0]non—8—yl)-
acid hydro-
320°C
about
-fluoro—4—oxo—3—guinolinecarboxylic
chloride, melting point with decomposition:
(dark
°C).
coloration already starting from
— 128 ~
Example 33
om
@ ax
of 1—cyclopropyl(2,8—diazabicyclo—
l.l g (3
[4.3.0]non—8-yl)—6,8—difluoro—1,4—dihydro—4-oxo—3—guino—
mmol)
linecarboxylic acid are heated under reflux in 10 ml of
dimethylformamide and 1 ml of formic acid for 4 hours.
The mixture is evaporated, the residue is stirred with
ml of water and the precipitate is filtered off with
suction, dried (crude yield: 1 g, content: 99.5%) and
recrystallized from dimethylformamide.
Yield: 0.8 g (64% of theory) of l—cyclopropyl—6,8—di—
fluoro(2—formyl—2,8-diazabicyclo[4.3.0]non—8—yl)—
,4—dihydrooxo—3—quinolinecarboxylic acid, melting
point: 276—278°C.
Example 34
0
O0
cnacoc _
F $
1.1 g (3 mmol) of l-cyclopropyl(2,8—diazabicyclo—
[4.3.0]non—8—yl)—6,8—difluoro—1,4—dihydro—4—oxo—3—guino—
linecarboxylic acid are dissolved in a mixture of 8 ml
of dioxane and a solution of 120 mg of sodium hydroxide
in 1 ml of water, and at the same time 3 HQ, of 1N
sodium hydroxide solution and 260 mg of acetyl chloride
added, The
subsequently
are while cooling with ice. mixture is
stirred at room temperature for 2 hours
and. diluted. with 30 ml of water‘ and the precipitate
which has separated out is filtered off with suction.
A. Analogously to Example 13,
B. 2.3 g
— l29 —
The crude product is recrystallized from glycol
monomethyl ether.
Yield: 0.6 g (46% of theory) of 7—(2—acetyl—2,8—diaZa—
bicyclo[4.3.0]non—8—yl)—l-cyclopropyl-6,8—difluoro—l,4—
dihydro—4—oxo-3~quinolinecarboxylic acid, melting
point: 26l—263°C (with decomposition)
Example 35
O0 °°“
«=14:
n3c\
—chloro—l-cyclopropyl—
6—fluoro—l,4—dihydro~7—(2—methyl-2,7—diazabicyclo—
[3.3.0]oct—7—yl)-4—oxo—3—quinolinecarboxylic acid,
222-227°C
obtained with 8-chloro—1—cyclopropyl—6,7—difluoro—
melting point: (with decomposition), is
l,4—dihydro—4—oxo—3—quinolinecarboxylic acid and
—methyl—2,7—diazabicyclo[3.3.0]octane.
(5.8 mmol)
dissolved in l5 ml of lN hydrochloric acid under
of the betaine from stage A are
the influence of heat,
the
the solution is evaporated
and residue is treated with ethanol. The
precipitate is filtered off with suction, washed
with water and dried.
Yield: 2.2 g (87.7% of
l—cyclopropyl—6—fluoro—l,4-dihydro—7~(2-1nethyl—
theory) of 8~chloro—
2,7—diazabicyclo[3.3.0]oct—7—yl)—4—oxo—3—quino—
linecarboxylic acid hydrochloride,
303—305”C (with decomposition).
melting point:
A. A. mixture of 1.45 g
- 130 —
Example 36
xHC1
Analogously to Example 13, 1—cyclopropyl—6,8—difluoro—
1,4—dihydro—7—(3~methyl—2,7-diazabicyclo[3.3.0]<3ct—7—
yl)—4—oxo—3—quinolinecarboxylic acid is obtained with
3—methyl—2,7—diazabicyclo[3.3.0]octane,
and is con-
verted into 1—cyclopropyl-6,8—difluoro—1,4—dihydro—
7-(3—methyl—2,7-diazabicyclo[3.3.0]oct—7-yl)—4—oxo—3—
quinolinecarboxylic acid hydrochloride,
l6—22l°C (with
melting point:
decomposition), analogously to
Example 15 C. with half—concentrated hydrochloric acid.
Example 37
(5 mmol)
6,7,8—trif1uoro—1,4—dihydro—4—oxo—3—guinoline—
of l—cyclopropyl—
carboxylic acid, 0.85 g (7.5 mmol) of 1,4—di—
azabicyclo[2.2.2]octane and 0.77 g (5.5 mmol) of
2,3—dimethyl—2,7—diazabicyclo[3.3.0]octane in
ml of 7.5 ml of dimethyl—
formamide is heated under reflux for 1 hour. After
the filtered off with
washed with water and recrystallized from
acetonitrile and
cooling, precipitate is
suction,
glycol monomethyl ether.
Yield: 1 g (47% of theory) of l—cyclopropyl—
- 131 —
-(2,3—dimethyl—2,7—diazabicyclo[2.2.2]oct—7—yl)—
,8—difluoro—l,4-dihydro—4—oxo—3—guinoline—
carboxylic acid, melting point: 208—209“C (with
decomposition).
B. 0.7 g (1.7 mmol) of the betaine from stage A are
ml of
hydrochloric acid and the solution is filtered and
dissolved in hot half—concentrated
concentrated to a substantial degree in vacuo.
About 15 ml of ethanol are added,
cooled in an ice—bath and the salt is filtered off
the mixture is
with suction, washed with ethanol and dried at
100°C/1 mbar.
Yield: 0.64 g (84% of theory) of 1-cyclopropyl—
—(2,3—dimethyl—2,7—diazabicyclo[2.2.2]oct—7—yl)—
6,8~difluoro—1,4—dihydro—4-oxo—3—quinoline—
carboxylic acid hydrochloride, melting point:
-236°C (with decomposition).
Example 38
coon
1~13c\ xHc1
C 1
CH3
Analogously to Example 37 A. and B., 8—chloro—1—cyclo—
propyl—7—(2,3—dimethyl—2,7—diazabicyclo[2.2.2]oct—7—yl)—
—fluoro—1,4—dihydro—4—oxo-3—guinolinecarboxylic acid
hydrochloride, melting point: 240—24l°C (with
decomposition), is obtained with 8—chloro—l—cyclo—
propyl—6,7—difluoro—1,4—dihydro—4—oxo—3—quinoline—
carboxylic acid.
— 132 —
Example 39
The reaction is carried out analogously to Example 19
with 1,2—dimethyl—3—oxa—2,7—diazabicyclo[3.3.0loctane
to give 1—cyclopropyl—6,8—difluoro—1,4—dihydro—
7—(1,2—dimethyl—3—oxa—2,7—diazabicyclo[3.3.0]oct—7—yl)—
4—oxo—3—quinolinecarboxylic acid of
—271°C
melting point
(with decomposition).
Example 40
xHCl
.45 g
1.23 g
’101'1E1f1€
(13 mmol) of 1,4—diazabicyclo[2.2.2]octane and
(9.6 mmol) of 2-oxa—5,8—diazabicyclo[4.3.0]—
added to 2.6 g (8.7 mmol) of
1—cyclopropyl—6,7—difluoro—1,4—dihydro—4—oxo—3-quino—
ml of
acetonitrile and 12.5 ml of dimethylformamide and the
heated
the residue is stirred with water and the
undissolved precipitate is filtered. off with
with This 1—cyclopropyl—
8—chloro—6—fluoro-1,4—dihydro—7—(2—oxa—5,8—diaza—
are 8—chloro—
linecarboxylic acid in a mixture of
mixture is under reflux for 1 hour. It is
concentrated,
suction
and washed water. crude
bicyc1o[4.3.0]non—8—yl)-4—oxo—3—quinolinecarboxylic
acid is introduced into 85 ml of 1N hydrochloric acid,
and 6 ml of concentrated hydrochloric acid are added.
— 133 —
The hydrochloride which has precipitated out is
filtered off with suction, washed with ethanol and
dried.
Yield: 3.0 g (77.7% of theory) of 8—chloro—l—cyclo—
propyl—6—fluoro—l,4—dihydro—7—(2—oxa—5,8-diazabicyclo—
[4.3.0]non—8—yl)-4~oxo—3—quinolinecarboxylic acid
hydrochloride, melting point: from 290°C decomposition.
Example 41
MS
—chloro—l—cyclopropyl—
H3C\ -
<53
Analogously to Example 13,
6-fluoro—7—(2—methyl-4—oxa—2,8—diazabicyclo[4.3.0]non—
—yl)-4—oxo—3—quinolinecarboxylic acid, melting point:
202—203°C (with with
—chloro—l—cyclopropyl—6,7—difluoro—1,4-dihydro—4—oxo—
decomposition), is obtained
—guinolinecarboxylic acid and 2—methyl—4—oxa—
2,8—diazabicyclo[4.3.0]nonane.
FAB mass spectrum: m/e 422 ([M+H]+), 404 (422—H;O).
Example 42
O
gu COOH
H F A
\co2c2x-15
A. The reaction is carried out analogously to
Example l3 with ethyl 2,7—diazabicyclo[3.3.0]—
octane-2—carboxylate to give l—cyclopropyl~
—(2—ethoxycarbonyl—2,7—diazabicyclo[3.3.0]oct-
7—yl)—6,8—difluoro—l,4-dihydro—4—oxo—3—quinoline—
~ 134 —
carboxylic acid of melting point l9l—l92“C.
.8 g
are heated in 30 1ml of concentrated hydrochloric
(4 mmol) of the product from Example 42 A
acid under gentle reflux for 15 hours. The
solution is concentrated, the residue is stirred
with ethanol and the precipitate is filtered off
with suction, washed with ethanol
l20°C/12 mbar.
Yield: 1.1 g (67% of l—cyclopropyl-
7-(2,7—diazabicyclo[3.3.0]oct—7—yl)—6,8—difluoro-
1,4—dihydro—4—oxo—3—quinolinecarboxylic acid
273—275°C (with
identical to the
and dried at
of theory)
hydrochloride, melting point:
decomposition). The product is
compound obtained according to Example 26B.
Example 43
.8 g (20 mmol)
cyclo[4.3.0]non—8—yl)~6,8—difluoro—l,4—dihydro—4—
xo—3—quinolinecarboxylic acid are introduced into
l75 ml of and 2.4 g (25
methanesulphonic acid are added at about 70°C. The
cooling the salt
this off with
suction, with dried at
l20°C/l2 mbar. It is readily soluble in water.
Yield: 8.6 g (88.6% of theory)
7-(2,8—diazabicyclo[4.3.0]non—8-yl)—6,8—difluoro—
of 1—cyclopropyl—7—(2,8—diazabi—
ethanol, mmol) of
betaine dissolves, and on
precipitates out, being filtered
washed ethanol and
of l—cyclopropyl—
acid
(with
,4—dihydro—4—oxo—3—quinolinecarboxylic
mesylate, melting point: 262—265°C
decomposition).
The following compounds are obtained analogously:
l—Cyclopropyl—7—(2,8—diazabicyclo[4.3.0]non—8—yl)—
6,8—difluoro—l,4—dihydro—4—oxo—3—quinoline—
carboxylic acid tosylate, melting point: 248—250°C
(with decomposition).
C. l—Cyclopropyl—7—(2,8—diazabicyclo[4.3.0]non—8—yl)~
6,8—difluoro—l,4—dihydro—4—oxo—3—guinoline—
carboxylic acid lactate,
melting point:
°C—2l5°C, after sintering beforehand.
Example 44
.9 g (10 Hmwl) of l—cyclopropyl—7—(2,8—diazabicyclo~
[4.3.0]non—8—yl)-6,8—difluoro—l,4—dihydro—4—oxo—3—guino—
linecarboxylic acid are suspended in 50 ml of water,
and 10 ml of 1N sodium hydroxide solution are added at
the
A slight turbidity is removed by filtration
room temperature, whereupon product largely
dissolves.
through a membrane filter, the filtrate is concentrated
under‘ a high vacuunx and the residue is stirred with
ether, filtered off with suction and dried.
Yield: 3.4 g (82.7% of theory) of sodium 1—cyclopropyl—
-(2,8—diazabicyclo[4.3.0]non—8-yl)—6,8—difluoro-l,4—di-
hydro—4—oxo—3—guinolinecarboxylate; the salt decomposes
slowly above 210°C without melting.
Example 45
HO-CH2CH2\
A mixture of 3.9 g (10 mmol) of 1—cyclopropyl—7—(2,8—
diazabicyclo[4.3.0]non—8-yl)—6,8-difluoro—l,4—dihydro—
—oxo—3—quinolinecarboxylic acid in 100 ml of dimethyl—
formamide is heated at 80—lOO”C with 4.2 g of triethyl—
hours. The
solution is then concentrated in vacuo and the residue
200 g of
strength
amine and 2.8 g of 2—bromoethanol for
obtained is purified by chromatography on
CH2Cl2/CH3OH/l7%
eluate is
silica (mobile
gel
NH3 : 30:8:l).
phase:
concentrated and
- l36 —
residue is stirred with ethanol, filtered off with
suction and dried.
1.8 g (41.6% l—cyclopropyl—6,8—
difluoro-l,4—dihydro—7—[2—(2—hydroxyethyl)—2,8—diazabi—
Yield: of theory) oi
cyclo[4.3.0]non-8—yl]oxo—3—guinolinecarboxylic acid,
melting point: 200—206°C (with decomposition).
Mass spectrum: m/e 433 (Ml), 402 (Ml —CH2OH), 140, llO
(lOO%), 96
Example 46
O
COQH
°”35 5' .£_|\_,
Analogously to Example l3, reaction is carried out with
trans—3—ethylamino—4—methylthio—pyrrolidine to give
l~cyclopropyl—7—(trans—3—ethylamino—4—methylthio)—6,8—
difluoro—l,4—dihydro—4—oxo—3—quinolinecarboxylic acid,
melting point: 2l5~2l6°C (with decomposition).
Example 47
©\. F A
The reaction is carried out analogously to Example 13
with 2~phenyl~2,7—diazabicyclo[3.3.0]octane to give
l—cyclopropyl—6,8—difluoro~l,4—dihydro—4—oxo—7—(2—phenyl—
2,7—diazabicyclo[3.3.0]oct—7—yl)—3—quinolinecarboxylic
—260°C
acid, melting point: (with decomposition).
Example
Analogously to Example l3, 5,6,8—trifluoro—l—(2,4—di-
fluorophenyl)—l,4—dihydro~7—(2—methyl—2,8—diazabicyclo—
[4.3.0]non—8—yl)—4—oxo—3—quinolinecarboxylic
with
acid is
obtained 5,6,7,8—tetrafluoro—l—(2,4—difluoro—
phenyl)—l,4—dihydro—4—oxo—3—quinolinecarboxylic acid.
Example 49
F‘ 0
C00}!
1
Analogously to Example 24, 7-(2,8—diazabicyclo[4.3.0]—
non—8—yl)—5,6,8—trifluoro—l—(2,4—difluorophenyl)—l,4—di—
hydro—4~oxo—3—quinolinecarboxylic acid is obtained with
,6,7,8—tetrafluoro—l—(2,4—difluorophenyl)—l,4—dihydro—
—oxo~3—quinolinecarboxylic acid.
Example 50
— 138 -
Analogously to Example 25, 5—amino—7—(2,8—diazabicyclo—
[4.3.0]non—8—yl)-6,8—difluoro—l—(2,4—difluorophenyl)—
l,4—dihydro—4—oxo—3—quinolinecarboxylic acid is
obtained with 7—(2,8—diazabicyclo[4.3.0]non—8—yl)—
,6,8—trifluoro—l-(2,4—difluorophenyl)—l,4—dihydro—4—
oxo—3—quinolinecarboxylic acid.
Example 5l
Analogously to Example 15 A, 5—chloro—l—cyclopropyl—
7-(2,8—diazabicyclo[4.3.0]non—8—yl)-6—fluoro—l,4—di—
hydro—4—oxo—3-quinolinecarboxylic acid, melting point:
270°C
l—cyclopropyl-6—fluoro—l,4—dihydro—4—oxo—3—quinoline—
(decomposition), is obtained with 5,7—dichloro—
carboxylic acid (reflux for 5 hours).
Example 52
COOH_
&_,,.4S
Analogously to Example 8, 5—chloro—l—cyclopropyl—
—fluoro—l,4—dihydro—7~(2—oxa—5,8—diazabicyclo[4.3.0]—
obtained
non—8—yl)—4—oxo—3—quinolinecarboxylic acid is
with 5,7—dichloro—l—cyclopropyl—6—fluoro—l,4—dihydro—
—oxo—3—quinolinecarboxylic acid (reflux for 5 hours).
— 139 -
Example 53
Ahalogously to Example 15 A, 5—chloro—7—(2,8—diaza—
bicyclo[4.3.0]noh—8—yl)—6—fluoro—l—(2,4—difluorophen—
yl)~l,4—dihydro—4—oxo—3—quinolihecarboxylic acid is
obtained with 5,7—dichloro—6—fluoro—l—(2,4—difluoro—
phenyl)—l,4~dihydro—4—oxo—3—quinolinecarboxylic acid
(reflux for 5 hours).
Example 54
Ahalogously to Example 8, 5—chloro—6—fluoro—l—(2,4—di—
fluorophenyl)—l,4-dihydro—7—(2—oxa—5,8—diazabicyclo—
[4.3.0]non—8—yl)—4—oxo—3—quinolinecarboxylic acid is
,7—dichloro—6-fluoro(2,4—difluoro-
phenyl)-1,4—dihydro—4—oxo—3—quiholinecarboxylic acid
obtained with
(reflux for 5 hours).
- 140 —
Example 55
I coon
czusnnh n
caas c1¢:%:>
Analogously to Example l3, reaction is carried out with
trans—3-ethylamino—4—methylthio-pyrrolidine and 8—chl—
oro—1—cyclopropyl—6,7—difluoro—l,4—dihydro—4-oxo—3—
guinolinecarboxylic acid to give 8—chloro—l—cyclo-
propyl—7—(trans—3—ethylamino—4~methylthio—l—pyrroli—
dinyl)—6—fluoro—1,4—dihydro—4—oxo—3—quinolinecarboxylic
acid, melting point: 2l7—2l8°C (with decomposition).
Example 56
: COOH
I
N N HC1
MO F A ‘
cuss
Analogously to Example l3 and 15, using trans—3—amino—
4—methylthiopyrrolidine, 7-(trans—3—amino—4-methylthio—
l—pyrrolidinyl)-1—cyclopropyl-6,8—difluoro—l,4—dihydro—
4—oxo—3—guinolinecarboxylic acid is obtained, melting
208—21l°C
-amino—4—methylthio—1—pyrrolidinyl)—l—cyclopropyl—6,8-
point: (with decomposition), and 7—(trans-
difluoro—l,4—dihydro~4—oxo—3—guinolinecarboxylic acid
hydrochloride is obtained, melting point: 255—257°C
(with decomposition).
— 141 —
Example 57
F COOH
I
N N xHc1
N F A
CH3
Analogously to Example 13 and 15 1—cyclopropyl—
,8—difluoro-1,4—dihydro—7—(4—methy1—2,8—diazabicyclo—
[4.3.O]non~8—yl)-4—oXo—3—quinolinecarboxylic acid,
melting point: 213—215°C (with decomposition)
(recrystallized from glycol monomethyl ether) and
—cyclopropyl-6,8—difluoro—l,4—dihydro—7—(4—methyl—2,8—
diazabicyclo[4.3.0]non—8—yl)oxo—3—quinolinecarboxy-
—2l2°C (with
4—methyl—
melting point:
with
lic acid hydrochloride,
decomposition) are obtained
,8—diazabicyclo[4.3.0]nonane.
The product comprises a mixture of 2 stereoisomers.
Claims (1)
- Claims 1. 7-(1-Pyrrolidinyl)-3—quinolone- - 142 — and —naphthyri— done—carboxylic acid derivatives of formula (I): in X2 o ' X‘ , coon? R3 \A (1). R: which represents halogen, represents hydrogen, amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having 1 to 4 carbon atoms, arylthio, halogen, represents alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, 2—hydroxyethyl, 2—fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino, phenyl optionally substituted by 1 or 2 fluorine atoms, represents hydrogen, alkyl having 1 to 4 carbon atoms or (5—methyl-2—oxo—l,3—dioxol—4—yl)— methyl, and represents a radical of the structure 12- 2-24 I —N - 5 R6 wherein l0 l5 30 RI R" R8 — l43 — may represent, C1—C4—alkyl, aryl, C1—C4—acyl, may represent H, Cy%g—alkyl, OH, OCHL may represent H, optionally hydroxyl— substituted Cy{h—alkyl, as well as aryl, heteroaryl, benzyl, (5—methyl—2-oxo—l,3-dioxol—4—yl)— C1—C4—alkoxycarbonyl, C1-C4-acyl , methyl, or C3—C6—cycloalkyl, may represent H, CH3 or phenyl, may represent H, CH3 or phenyl, and may represent 0 or S, represents N or C—R8, wherein represents H, halogen, methyl, cyano, nitro or hydroxyl or, together with R3 may also form a bridge having the structure -O-CH2-(‘SH-CH3. —s-cH'2— OI -CH2-CH2-(‘:1-I-CH3 and their pharmaceutically applicable hydrates and acid addition salts as well as the alkali metal, alkaline earth metal, silver and guanidinium salts of the underlying carboxylic acids, except compounds having the formula wherein ()1 l0 — l44 — represents C1—C4—alkyl, R;/Rgrepresent hydrogen or Cy{h—alkyl, R4 R5 represents cyclopropyl, phenyl, halophenyl, thienyl, optionally substituted by Cg%L—alkyl or halogen, and represents halogen. Compounds of formula (1) according to Claim l, in which X1 represents fluorine or chlorine, X2 represents hydrogen, amino, alkylamino having 1 to 2 carbon atoms, dimethylamino, hydroxyl, methoxy, mercapto, methylthio, phenylthio, fluorine, chlorine, R1 represents alkyl having 1 to 3 carbon atoms, alkenyl having 2 to 3 carbon atoms, cycloalkyl having 3 to 5 carbon atoms, 2—hydroxyethyl, 2—fluoroethyl, methoxy, amino, methylamino, ethylamino, dimethylamino, phenyl optionally substituted by l or 2 fluorine atoms, R2 represents hydrogen, alkyl having l to 3 carbon atoms or (5—methyl—2—oxo—l,3—dioxol—4—yl)— methyl, R3 represents a radical of the structure R‘ z-R‘ I ‘M. s a-a*°<“ R6 wherein 35 R4 may represent Cy{g—alkyl, Cy<§—acyl, R5 may represent H, C1—C3—alkyl, OH, OCH3, wherein R4 and R5 together may also denote a Cy%b—alkylene bridge optionally mono— or disubstituted by methyl, R6 may represent H, optionally hydroxyl- substituted C1-C3—alkyl, as well as phenyl, benzyl, Cy{g—alkoxycarbonyl, Cy4Q—acyl, (5—methyl—2—oxo-l,3—dioxol—4—yl)—methyl or C3—C5—alkyl , R‘ may represent H or CHy R" may represent H or CH3, and 2 may represent 0 or S, represents N or C—R8, wherein represents H, fluorine, chlorine, bromine or hydroxyl or, together with R1, may also form a bridge having the structure CH2-(‘IR-C}-I3, Compounds of formula (1) according to Claim 1, in which X1 represents fluorine, represents hydrogen, amino, methylamino, fluorine, represents alkyl having 1 to 2 carbon atoms, vinyl, 2-fluoro- ethyl, cyclopropyl, 2—hydroxyethyl, methoxy, methylamino, 4—fluorophenyl, (F 2,4—difluorophenyl, (‘Q represents hydrogen, alkyl having 1 to 2 carbon atoms, R3 represents a radical of the structure 12- ,1-R4 -N A W“ 5 a“‘" R6 wherein R4 may represent C1—C2—alkyl, R5 may represent H, C1—C2—alkyl, wherein R4 and R5 together may also denote a Cy%5—alkylene bridge optionally substituted by methyl, R6 may represent EL CH3, C2Hw HOCH2CH2, benzyl, C1-C4-alkoxycarbonyl, C1—C2—acyl, R‘ may represent H or CH3 R" may represent H or CH3, and Z may represent 0 or S, A represents N or C~R8, wherein R8 represents H, fluorine or chlorine, or, together with R1, may also form a bridge having the structure ; Process for the preparation of compounds according to Claim l of formula (1), characterized in that compounds of formula (II) (J? 30 U7 X2 0 X1 , COORZ 3 1 \ (xxx x A T * R1 in which A, R1, R2, X1 and X2 have the same meanings as defined above, and X3 represents halogen, particularly fluorine or chlorine, are reacted with compounds of formula (III) R3—H (1:1) in which R3 has the same meaning as defined in Claim 1, optionally in the presence of acid scavengers, and optionally the protective groups contained in R3 are cleaved. Process for the preparation of compounds according to Claim 1 of formula (I), X3 o x‘ , 00a? 3 I m. R3 ‘ " 1 R1 in which X1, R1, R2, R3 and A have the same meanings as defined above, and X2 represents amino, alkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 3 carbon atoms per alkyl group, hydroxyl, alkoxy having 1 to 4 carbon atoms, mercapto, alkylthio having l to 4 carbon atoms or arylthio, characterized in that a compound of formula (IV) Q1 F 0 X1 , coca? 3 \ I I (xv), R A § R1 in which X1, R1, R2, R3 and A have the same meanings as defined above, is reacted with compounds of formula (V) X2—H (v) in which X2has the same meaning as defined above, optionally in the presence of acid scavengers. Process for the preparation of compounds according to claim 1 of formula (Ia), x2 o X’ , coon? 1 (13)) R3 ‘A 1 R1. in which X1, X2, R1, R2 and A have the same meanings as defined above, and R3 represents a radical of the structure R‘ 2-34 I -N v ‘+~ 5 R6 wherein R4, R5, R6, R’, R” and Z have the same meanings as defined above, characterized in that a compound of formula (VI) l0 l5 30 — l49 - X2 0 X’ , coon? (VI) 3 \ ' R‘ A ‘ R1 in which X1, X2, R1, R2 and A have the meanings as defined above, and R” represents a radical of the structure ./1.. -N \.{..._.\NZR5 R" I H wherein R4, E? R’, R” and Z have the same meanings as defined above, is reacted with compounds of formula (VII) R6—Xa (VII) in which R6 has the same meaning as defined above, and Xa represents chlorine, bromine, iodine, hydroxyl or acyloxy, optionally in the presence of acid scavengers . 7—(l—Pyrrolidinyl)—3—quinolone— and -naphthyridone— carboxylic acid derivatives of formula (I) accord- ing to Claim 1, for use in a nethod for treating diseases. Medicament containing the compounds of formula (1) according to Claim 1. Use of the compounds of formula (1) according to 11. 12. 13. 14. 15. 16. — 150 — Claim 1 for the preparation of medicaments. Use of the compounds of formula (I) according to Claim 1 as animal feed additive. feed feed compounds Animal and/or animal additive and premixes containing the of formula (1) according to Claim 1. Carboxylic acid derivatives in S,S—configuration, having the formula . _o *3 H _ F co2H N 1 ._ Em” A - N ‘ . H 2: V wherein A represents C—Cl, C—F or C—OCH3, and their pharmaceutically acceptable hydrates and salts. Medicaments Claim 12. containing a compound according to Use of the compounds according to Claim 12 for the preparation of animal feed, animal feed additives and premixes. Compounds according to Claim 12 and antibacterial agents. Use of the compounds according to Claim 12 for the preparation of a medicament for the ‘treatment of bacterial diseases. F. R. KELLY & co., AGENTS FOR THE APPLICANTS
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEGERMANY15/07/1988P3824072.6 | |||
DE3824072 | 1988-07-15 | ||
DE3906365A DE3906365A1 (en) | 1988-07-15 | 1989-03-01 | 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM |
Publications (3)
Publication Number | Publication Date |
---|---|
IE19970856A1 IE19970856A1 (en) | 2000-02-23 |
IE970856A1 IE970856A1 (en) | 2000-02-23 |
IE84193B1 true IE84193B1 (en) | 2006-04-19 |
Family
ID=
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