NO302886B1 - Quinolone carboxylic acid derivatives with anti-bacterial action, intermediates for the preparation thereof, drugs containing the compounds and the use of the compounds in the manufacture of drugs - Google Patents
Quinolone carboxylic acid derivatives with anti-bacterial action, intermediates for the preparation thereof, drugs containing the compounds and the use of the compounds in the manufacture of drugs Download PDFInfo
- Publication number
- NO302886B1 NO302886B1 NO922639A NO922639A NO302886B1 NO 302886 B1 NO302886 B1 NO 302886B1 NO 922639 A NO922639 A NO 922639A NO 922639 A NO922639 A NO 922639A NO 302886 B1 NO302886 B1 NO 302886B1
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- means hydrogen
- hydrogen
- cyclopropyl
- dihydro
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 37
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims description 9
- 239000003814 drug Substances 0.000 title claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 229940079593 drug Drugs 0.000 title claims 3
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 82
- 239000001257 hydrogen Substances 0.000 claims description 82
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 43
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- -1 1-imidazolyl Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229940126601 medicinal product Drugs 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- LSYICPNAJSMBIC-UHFFFAOYSA-N hydroxymethyl hypofluorite Chemical compound OCOF LSYICPNAJSMBIC-UHFFFAOYSA-N 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- BWKNVUWKBKUASR-UHFFFAOYSA-N 8-ethynyl-2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC(C#C)=C2NC(=O)C(C(=O)O)=CC2=C1 BWKNVUWKBKUASR-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 239000003674 animal food additive Substances 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 51
- 230000008018 melting Effects 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 238000010992 reflux Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000000354 decomposition reaction Methods 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- MBIVSPDDSIIZOQ-UHFFFAOYSA-N ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Br)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 MBIVSPDDSIIZOQ-UHFFFAOYSA-N 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 229920002554 vinyl polymer Polymers 0.000 description 5
- OUVMXIYIIMVFQS-UHFFFAOYSA-N 1-cyclopropyl-8-ethynyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(C#C)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OUVMXIYIIMVFQS-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- 238000005698 Diels-Alder reaction Methods 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229960003237 betaine Drugs 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- ZESBQVDNKGGIIJ-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-8-(2-trimethylsilylethynyl)quinoline-3-carboxylate Chemical compound C12=C(C#C[Si](C)(C)C)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 ZESBQVDNKGGIIJ-UHFFFAOYSA-N 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- JGOIIPRSFZFFHG-UHFFFAOYSA-N trimethyl(2-tributylstannylethynyl)silane Chemical group CCCC[Sn](CCCC)(CCCC)C#C[Si](C)(C)C JGOIIPRSFZFFHG-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- DTRLPBIKMIQFEJ-UHFFFAOYSA-N 1-trimethylsilylpyrrole-2,5-dione Chemical compound C[Si](C)(C)N1C(=O)C=CC1=O DTRLPBIKMIQFEJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000019000 fluorine Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- OJUYYFXYYWYJLE-UHFFFAOYSA-N tert-butyl n-(1,3-dioxo-3a,4,7,7a-tetrahydroisoindol-4-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12 OJUYYFXYYWYJLE-UHFFFAOYSA-N 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 2
- YSPLNTFHXGXSEE-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(C#C)C(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1F YSPLNTFHXGXSEE-UHFFFAOYSA-N 0.000 description 2
- KJSKKABRACRSCN-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-8-(3-methoxyprop-1-ynyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1(CC1)N1C=C(C(C2=CC(=C(C(=C12)C#CCOC)F)F)=O)C(=O)O KJSKKABRACRSCN-UHFFFAOYSA-N 0.000 description 2
- COMPJZZVEWJWRC-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-8-(3-methylbut-3-en-1-ynyl)-4-oxoquinoline-3-carboxylic acid Chemical compound CC(=C)C#CC1=C(F)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 COMPJZZVEWJWRC-UHFFFAOYSA-N 0.000 description 2
- JUUFAIMQBKXVDD-UHFFFAOYSA-N 1-cyclopropyl-8-ethynyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1C#C JUUFAIMQBKXVDD-UHFFFAOYSA-N 0.000 description 2
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- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
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- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Chemical class 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000035472 Zoonoses Diseases 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- UCZLBERYFYDXOM-UHFFFAOYSA-N ethenyltin Chemical class [Sn]C=C UCZLBERYFYDXOM-UHFFFAOYSA-N 0.000 description 1
- SNMZQXMMVTWXBE-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7-difluoro-8-(3-methoxyprop-1-ynyl)-4-oxoquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN(C2=C(C(=C(C=C2C1=O)F)F)C#CCOC)C3CC3 SNMZQXMMVTWXBE-UHFFFAOYSA-N 0.000 description 1
- SCAUCCWHWDTGFM-UHFFFAOYSA-N ethyl 1-ethyl-6,7-difluoro-4-oxo-8-(2-trimethylsilylethynyl)quinoline-3-carboxylate Chemical compound FC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C1C#C[Si](C)(C)C SCAUCCWHWDTGFM-UHFFFAOYSA-N 0.000 description 1
- BCKAYYQQKILFDS-UHFFFAOYSA-N ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-(ethylamino)prop-2-enoate Chemical compound CCNC=C(C(=O)OCC)C(=O)C1=CC(F)=C(F)C(Br)=C1F BCKAYYQQKILFDS-UHFFFAOYSA-N 0.000 description 1
- WJGFKSJXLDSFFC-UHFFFAOYSA-N ethyl 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Br)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F WJGFKSJXLDSFFC-UHFFFAOYSA-N 0.000 description 1
- UBGCJIGIIXGAOJ-UHFFFAOYSA-N ethyl 8-bromo-1-ethyl-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound FC1=C(F)C=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C1Br UBGCJIGIIXGAOJ-UHFFFAOYSA-N 0.000 description 1
- NUBFPWXUKJGZNA-UHFFFAOYSA-N ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(Cl)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 NUBFPWXUKJGZNA-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
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- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000005836 hydrostannylation reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Chemical class OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- GHXZPUGJZVBLGC-UHFFFAOYSA-N iodoethene Chemical class IC=C GHXZPUGJZVBLGC-UHFFFAOYSA-N 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical group [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Chemical class 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- XBDPVNKGUTWIMJ-UHFFFAOYSA-N n-methyl-2,3,3a,4,7,7a-hexahydro-1h-isoindol-4-amine;dihydrochloride Chemical compound Cl.Cl.CNC1C=CCC2CNCC12 XBDPVNKGUTWIMJ-UHFFFAOYSA-N 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- PKVRJCUKSNFIBN-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 PKVRJCUKSNFIBN-UHFFFAOYSA-N 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- FILUFGAZMJGNEN-UHFFFAOYSA-N pent-1-en-3-yne Chemical compound CC#CC=C FILUFGAZMJGNEN-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XUKALTRSOXMVKA-UHFFFAOYSA-N tert-butyl n-penta-1,3-dienylcarbamate Chemical compound CC=CC=CNC(=O)OC(C)(C)C XUKALTRSOXMVKA-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- CBGFCZFTWYCWBZ-UHFFFAOYSA-N tributyl(hex-1-ynyl)stannane Chemical compound CCCCC#C[Sn](CCCC)(CCCC)CCCC CBGFCZFTWYCWBZ-UHFFFAOYSA-N 0.000 description 1
- KCQJLTOSSVXOCC-UHFFFAOYSA-N tributyl(prop-1-ynyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C#CC KCQJLTOSSVXOCC-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Chemical class 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 206010048282 zoonosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
Description
Foreliggende oppfinnelse angår kinolonkarboksylsyre-derivater med anti-bakteriell virkning. The present invention relates to quinolone carboxylic acid derivatives with anti-bacterial action.
Oppfinnelsen angår videre mellomprodukter for fremstilling av disse derivater, legemidler inneholdende derivatene samt anvendelse av derivatene ved fremstilling av legemidler med antibakteriell virkning. The invention further relates to intermediate products for the production of these derivatives, pharmaceuticals containing the derivatives as well as the use of the derivatives in the production of pharmaceuticals with antibacterial action.
Det er allerede kjent at 8-alkyl-kinolonkarboksylsyrer har antibakteriell aktivitet; således er 8-metyl-kinolonkarboksylsyrer beskrevet for eksempel i EP 237 955 og JP 2 019 377 mens 8-trifluormetyl-kionolonkarboksylsyrer er beskrevet i US-PS 4 780 468, 4 803 205 og 4 933 335. It is already known that 8-alkyl-quinolone carboxylic acids have antibacterial activity; thus 8-methyl quinolone carboxylic acids are described for example in EP 237 955 and JP 2 019 377 while 8-trifluoromethyl quinolone carboxylic acids are described in US-PS 4 780 468, 4 803 205 and 4 933 335.
Fra GB-A 2.188.317, US 4.123.536-A samt fra "J.Clin. Pharmacol.", 28, 156 (1988) og "Antibicrob Agents Chemother." From GB-A 2,188,317, US 4,123,536-A as well as from "J.Clin. Pharmacol.", 28, 156 (1988) and "Antibicrob Agents Chemother."
33, 131 (1989) er det allerede gjort kjent antimikrobielt virksomme kinolon-derivater hvis virkningsstyrke dog ikke er tilfredsstillende. 33, 131 (1989), antimicrobially active quinolone derivatives have already been made known, but their effectiveness is not satisfactory.
Det er nu funnet at de nye forbindelser med formel (I): It has now been found that the new compounds of formula (I):
der there
R<1>betyr cyklopropyl eller eventuelt med halogen, en til R<1> means cyclopropyl or optionally with halogen, one more
tre ganger substituert fenyl, triply substituted phenyl,
R<2>betyr hydrogen, R<2> means hydrogen,
X<1>betyr hydrogen, X<1> means hydrogen,
X<2>betyr X<2>means
t—i ten
eller -CEC-R<5>or -CEC-R<5>
der there
r<3>betyr hydrogen, r<3> means hydrogen,
R<4>betyr hydrogen eller halogen og R<4> means hydrogen or halogen and
R<5>betyr hydrogen, C^^-alkyl, C2_3~alkenyl eller alkoksymetyl med 1 til 3 C-atomer i alkoksydelen, og Y betyr R<5>means hydrogen, C^^-alkyl, C2-3~alkenyl or alkoxymethyl with 1 to 3 C atoms in the alkoxy part, and Y means
der there
R^ betyr hydrogen, eventuelt med hydroksy eller metoksy substituert rett eller forgrenet C1_4~alkyl, cyklopropyl, oksoalkyl med 1 til 4 C-atomer, acyl med 1 til 3 C—atomer, R^ means hydrogen, optionally with hydroxy or methoxy substituted straight or branched C1-4 alkyl, cyclopropyl, oxoalkyl with 1 to 4 C atoms, acyl with 1 to 3 C atoms,
R<7>betyr hydrogen, metyl, fenyl, tienyl eller pyridyl, R<7> represents hydrogen, methyl, phenyl, thienyl or pyridyl,
R<8>betyr hydrogen eller metyl, R<8> means hydrogen or methyl,
R^ betyr hydrogen eller metyl, R^ means hydrogen or methyl,
RIO betyr hydrogen eller metyl, RIO means hydrogen or methyl,
R<12>betyr hydrogen, metyl, amino, eventuelt med hydroksy substituert alkyl- eller dialkylamino med 1 eller 2 C—atomer i alkyldelen, aminometyl, aminoetyl, eventuelt 3 R<12>means hydrogen, methyl, amino, optionally with hydroxy substituted alkyl- or dialkylamino with 1 or 2 C atoms in the alkyl part, aminomethyl, aminoethyl, optionally 3
med hydroksy substituert alkyl- eller dialkylaminometyl med 1 eller 2 C-atomer i alkyldelen eller 1-imidazolyl, with hydroxy substituted alkyl or dialkylaminomethyl with 1 or 2 C atoms in the alkyl part or 1-imidazolyl,
R<13>betyr hydrogen, hydroksy, metoksy, metyltio eller R<13> means hydrogen, hydroxy, methoxy, methylthio or
halogen, metyl, hydroksymetyl, halogen, methyl, hydroxymethyl,
R-1-4 betyr hydrogen eller metyl, R-1-4 means hydrogen or methyl,
R<20>betyr hydrogen, hydroksy, R<20> means hydrogen, hydroxy,
hydroksymetyl eller hydroxymethyl or
r<!9>betyr hydrogen, eventuelt med hydroksy substituert C^_3~alkyl, alkoksykarbonyl med 1 til 4 C-atomer i alkoksydelen eller C^_g-acyl, r<!9>means hydrogen, optionally with hydroxy substituted C^_3~alkyl, alkoxycarbonyl with 1 to 4 C atoms in the alkoxy part or C^_g-acyl,
R<21>betyr hydrogen eller metyl, R<21> means hydrogen or methyl,
A betyr CH2, 0 eller en direkte binding og A means CH2, 0 or a direct bond and
n betyr 1 eller 2, og n means 1 or 2, and
deres farmasøytisk godtagbare hydrater og syreaddisjonssalter samt alkali-, jordalkali-, sølv- og guanidiniumsaltene av de til grunn liggende karboksylsyrer oppviser en høy anti-bakteriell virkning. their pharmaceutically acceptable hydrates and acid addition salts as well as the alkali, alkaline earth, silver and guanidinium salts of the underlying carboxylic acids exhibit a high anti-bacterial effect.
De egner seg derfor som aktiv bestanddel i human- og animalmedisinen hvorved også behandling av fisk for terapi eller profylakse av bakterielle infeksjoner er å regne under veterinærmedisinen. They are therefore suitable as an active ingredient in human and animal medicine, whereby the treatment of fish for therapy or prophylaxis of bacterial infections is also counted under veterinary medicine.
Foretrukket er forbindelser med formel (I), der: Preferred are compounds of formula (I), where:
R<1>betyr cyklopropyl eller eventuelt med halogen en eller to R<1> means cyclopropyl or optionally with one or two halogens
ganger substituert fenyl, multiply substituted phenyl,
R2 betyr hydrogen, R 2 means hydrogen,
X<1>betyr hydrogen, X<1> means hydrogen,
X<2>betyr - X<2> means -
eller -C=C-R5 or -C=C-R5
der there
r<3>betyr hydrogen, r<3> means hydrogen,
R<4>betyr hydrogen og R<4> means hydrogen and
R<5>betyr hydrogen C1_4~alkyl eller C2_g-alkenyl Y betyr R<5> means hydrogen C1_4~alkyl or C2_g-alkenyl Y means
der there
R<k>betyr hydrogen, eventuelt med hydroksy substituert rett eller forgrenet C1_3~alkyl, oksoalkyl med 1 til 4 R<k>means hydrogen, optionally with hydroxy substituted straight or branched C1_3~alkyl, oxoalkyl with 1 to 4
C—atomer, C atoms,
R<7>betyr hydrogen, metyl eller fenyl, R<7> means hydrogen, methyl or phenyl,
R^ betyr hydrogen eller metyl, R^ means hydrogen or methyl,
R^ betyr hydrogen eller metyl, R^ means hydrogen or methyl,
R<12>betyr hydrogen, metyl, amino, metylamino, dimetylamino, R<12> means hydrogen, methyl, amino, methylamino, dimethylamino,
aminometyl, metylaminometyl eller etylaminometyl, aminomethyl, methylaminomethyl or ethylaminomethyl,
R<13>betyr hydrogen, hydroksy, metoksy, fluor, metyl eller hydroksymetyl, R<13> means hydrogen, hydroxy, methoxy, fluorine, methyl or hydroxymethyl,
R<l>9 R<l>9
R2<0>betyr N , der R2<0>means N , where
<X>R21 <X>R21
R<19>betyr hydrogen, metyl eller etyl, R<19> means hydrogen, methyl or ethyl,
R<21>betyr hydrogen eller metyl, R<21> means hydrogen or methyl,
Å betyr CH2, 0 eller en direkte binding og Å means CH2, 0 or a direct bond and
n betyr 1 eller 2. n means 1 or 2.
Spesielt foretrukket er forbindelser med formel (I) der: Particularly preferred are compounds of formula (I) where:
R<1>betyr cyklopropyl eller eventuelt med fluor en eller to R<1> means cyclopropyl or optionally with one or two fluorines
ganger substituert fenyl, multiply substituted phenyl,
R<2>betyr hydrogen, R<2> means hydrogen,
X<1>betyr hydrogen, X<1> means hydrogen,
X2 betyr -C=CE-R3 eller -C=C-R5 X2 means -C=CE-R3 or -C=C-R5
R4 R4
der there
R<5>betyr hydrogen,<C>1_4-alkyl eller C2_3<a>lkenyl, og R<5>means hydrogen,<C>1-4-alkyl or C2-3<a>alkenyl, and
Y betyr Y means
der there
R<6>betyr hydrogen, metyl, eventuelt med hydroksy substituert R<6> means hydrogen, methyl, optionally substituted with hydroxy
etyl, ethyl,
R<7>betyr hydrogen eller metyl, R<7> means hydrogen or methyl,
R* betyr hydrogen eller metyl, ;R<9>betyr hydrogen eller metyl, ;R<12>betyr hydrogen, metyl, amino, metylamino, aminometyl ;eller etylaminometyl, ;R<13>betyr hydrogen, hydroksy eller metoksy, ;R<20>betyr ; ; R<19>betyr hydrogen eller metyl, ;R<21>betyr hydrogen eller metyl, ;A betyr CHg, 0 eller en direkte binding og ;n betyr 1. ;Oppfinnelsen angår videre kinolonkarboksylsyrederivater som er verdifulle som mellomprodukter ved fremstilling av de ovenfor beskrevne forbindelser, og disse derivater karakteriseres ved formel (II) ; der ;R1,R2,X<1>og X<2>har den ovenfor angitte betydning, og ;X<3>betyr halogen og særlig fluor eller klor. ;Til slutt angår oppfinnelsen legemidler som karakteriseres ved at de inneholder et kinolonkarboksylsyrederivat som beskrevet ovenfor. ;Oppfinnelsen angår også anvendelsen av slike kinolonkarboksylsyrederivater som beskrevet ovenfor ved fremstilling av legemidler med antibakteriell virkning. ;Forbindelsene med formel (I) oppnås når en forbindelse med formel (II) ; ; der ;Ri,R<2>,X<1>og X<2>har den ovenfor angitte betydning og X<3>betyr halogen og særlig fluor eller klor, ;omsettes med forbindelser med formel (III) ;Y-H (III) ;der ;Y har den ovenfor angitte betydning, ;eventuelt i nærvær av syreoppfangere. ;Anvender man for eksempel l-cyklopropyl-8-etinyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre og 1-metylpiperazin som utgangsforbindelser kan reaksjonsforløpet gjengis ved det følgende reaksjonsskjema: ; 8-(1-klorvinyl)-kinolonkarboksylsyrene kan også oppnås ved omsetning av 8-etinyl-kinolonkarboksylsyrene med saltsyre ved temperaturer fra 10 til 100°C og fortrinnsvis 20 til 60°C. De som utgangsforbindelser anvendte forbindelser med formel (II) er som nevnt nye. Disse kan fremstilles ved at kinolin-karboksylsyrederivater med formel (IV) ; der ;R1,R2,X<1>og X<3>har den ovenfor angitte betydning og ;X<4>betyr halogen, særlig jod, brom eller klor, ;omsettes med metallorganiske vinyl- eller alkinylforbindelser med formel (V) ; ; der ;X<2>har den ovenfor angitte betydning og ;M betyr SnR'3, ZnX<*>, B(0R")2, R* means hydrogen or methyl, ;R<9>means hydrogen or methyl, ;R<12>means hydrogen, methyl, amino, methylamino, aminomethyl ;or ethylaminomethyl, ;R<13>means hydrogen, hydroxy or methoxy, ;R <20> means ; ; R<19> means hydrogen or methyl, ;R<21> means hydrogen or methyl, ;A means CHg, 0 or a direct bond and ;n means 1. ;The invention further relates to quinolone carboxylic acid derivatives which are valuable as intermediates in the preparation of the above described compounds, and these derivatives are characterized by formula (II); where ;R1,R2,X<1>and X<2>have the above meaning, and ;X<3>means halogen and especially fluorine or chlorine. ;Finally, the invention relates to medicinal products which are characterized by the fact that they contain a quinolone carboxylic acid derivative as described above. The invention also relates to the use of such quinolone carboxylic acid derivatives as described above in the production of medicinal products with antibacterial action. ;The compounds of formula (I) are obtained when a compound of formula (II) ; ; where ;Ri,R<2>,X<1>and X<2>have the above meaning and X<3>means halogen and especially fluorine or chlorine, ;reacted with compounds of formula (III) ;Y-H (III) ;where ;Y has the above meaning, ;possibly in the presence of acid scavengers. If, for example, 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methylpiperazine are used as starting compounds, the course of the reaction can be reproduced by the following reaction scheme: ; The 8-(1-chlorovinyl)-quinolone carboxylic acids can also be obtained by reacting the 8-ethynyl-quinolone carboxylic acids with hydrochloric acid at temperatures from 10 to 100°C and preferably 20 to 60°C. The compounds of formula (II) used as starting compounds are, as mentioned, new. These can be prepared by quinoline carboxylic acid derivatives with formula (IV); where ;R1,R2,X<1>and X<3>have the above meaning and ;X<4>means halogen, especially iodine, bromine or chlorine, ;is reacted with organometallic vinyl or alkynyl compounds of formula (V); ; where ;X<2> has the meaning given above and ;M means SnR'3, ZnX<*>, B(0R")2,
der there
R' betyr C^-alkyl, R' means C 1 -alkyl,
R" betyr hydrogen eller C1_4~alkyl og R" means hydrogen or C1_4~alkyl and
X' betyr brom eller klor, X' means bromine or chlorine,
i nærvær av overgangsmetallkatalysatorer, og spalter av eventuelt tilstedeværende beskyttelsesgrupper. in the presence of transition metal catalysts, and cleavage of any protective groups present.
De for koblingsreaksjonen nødvendige metallorganiske vinyl-og alkinylforbindelser er enten kjent eller kan syntetiseres i henhold til litteraturkjente metoder. Således kan for eksempel vinyl-trialkyltinn-forbindelser fremstilles fra de tilsvarende vinyljodider, -bromider eller -klorider ved at man ved omsetning med magnesium oppnår vinyl-Grignard-forbindelsen og lar denne reagere med et trialkyltinnklorid til de ønskede vinyltinnderivater. The organometallic vinyl and alkynyl compounds required for the coupling reaction are either known or can be synthesized according to methods known in the literature. Thus, for example, vinyl-trialkyltin compounds can be prepared from the corresponding vinyl iodides, bromides or chlorides by reacting with magnesium to obtain the vinyl Grignard compound and allowing this to react with a trialkyltin chloride to form the desired vinyltin derivatives.
Metallorganiske alkinylforbindelser kan fremstilles på i og for seg kjent måte for eksempel ved at man metallerer 1-alkin ved temperaturer mellom —20 bg —78°C i et aprotisk oppløs-ningsmiddel som for eksempel tetrahydrofuran med n-butyl-, sek-butyl- eller tert-butyllitium og derefter omsetter med en metallhalogenforbindelse som sinkklorid, magnesiumbromid, kobberjodid eller trialkyltinnklorid. Fortrinnsvis gjennom-føres omsetningen ved -78°C. I tillegg til det foretrukne oppløsningsmiddel tetrahydrofuran kan også andre etere som dietyleter, dipropyleter eller tert-butylmetyleter, eller blandinger av slike etere med aprotiske, alifatiske eller aromatiske oppløsningsmidler som n-heksan eller toluen, benyttes. Både ved vinyl- og ved alkinylderivatene er sinkklorid- og trialkyltinn-derivatet foretrukket. Med "alkyl" menes ved trialkyltinnforbindelsene C1_^-alkyl, foretrukket er metyl og n-butyl. Organometallic alkynyl compounds can be prepared in a manner known per se, for example by metallating 1-alkyne at temperatures between -20°C and -78°C in an aprotic solvent such as tetrahydrofuran with n-butyl-, sec-butyl- or tert-butyllithium and then reacts with a metal halide compound such as zinc chloride, magnesium bromide, copper iodide or trialkyltin chloride. The reaction is preferably carried out at -78°C. In addition to the preferred solvent tetrahydrofuran, other ethers such as diethyl ether, dipropyl ether or tert-butyl methyl ether, or mixtures of such ethers with aprotic, aliphatic or aromatic solvents such as n-hexane or toluene, can also be used. For both the vinyl and the alkynyl derivatives, the zinc chloride and trialkyltin derivative is preferred. By "alkyl" is meant the trialkyltin compounds C1-4-alkyl, methyl and n-butyl are preferred.
Trialkylvinyltinn-forbindelsene kan oppnås i henhold til litteraturkjente metoder også ved hydrostannylering av alkiner med trialkyltinnhydrider i nærvær av overgangsmetallkatalysatorer ("J. Org. Chem.", 55 (1990) 1857-1867). The trialkylvinyltin compounds can be obtained according to literature-known methods also by hydrostannylation of alkynes with trialkyltin hydrides in the presence of transition metal catalysts ("J. Org. Chem.", 55 (1990) 1857-1867).
De metallorganiske vinyl- og alkinylforbindelser omsettes med 8-halogenkinolonkarboksylsyrederivater med den generelle formel (IV) i nærvær av en egnet katalysator efter i prinsippet kjente metoder, "halogen" betyr her jod, brom eller klor; foretrukket er brom og klor og spesielt foretrukket er brom. The organometallic vinyl and alkynyl compounds are reacted with 8-haloquinolone carboxylic acid derivatives of the general formula (IV) in the presence of a suitable catalyst according to methods known in principle, "halogen" here means iodine, bromine or chlorine; preferred are bromine and chlorine and particularly preferred is bromine.
Som katalysatorer kan nevnes overgangsmetallforbindelser av metallene kobolt, ruthenium, rhodium, iridium, nikkel, palladium eller platina. Foretrukket er forbindelser av metallene platina, palladium og nikkel og særlig foretrukket er palladium. Slike overgangsmetaller kan anvendes i form av sine salter som for eksempel NiCl2»PdCl2eller Pd(0Ac)2»eller i form komplekser med egnede ligander. Anvendelsen av kompleksene er foretrukket. Som ligander anvendes fortrinnsvis fosfiner som trifenylfosfin, tri(o-tolyl)fosfin, trimetylfosfin, tributylfosfin og tri(2-furyl)fosfin, trifenylfosfin er foretrukket. Som foretrukne komplekskataly-satorer skal nevnes bis(trifenylfosfin)nikkel(II)klorid, bis(trifenylfosfin )palladium(II )klorid, tris(trifenylfosf in )-palladium(O) og tetrakis(trifenylfosfin)palladium(0). As catalysts, mention may be made of transition metal compounds of the metals cobalt, ruthenium, rhodium, iridium, nickel, palladium or platinum. Compounds of the metals platinum, palladium and nickel are preferred, and palladium is particularly preferred. Such transition metals can be used in the form of their salts such as NiCl2»PdCl2 or Pd(0Ac)2» or in the form of complexes with suitable ligands. The use of the complexes is preferred. Phosphines such as triphenylphosphine, tri(o-tolyl)phosphine, trimethylphosphine, tributylphosphine and tri(2-furyl)phosphine are preferably used as ligands, triphenylphosphine being preferred. Preferred complex catalysts should be mentioned bis(triphenylphosphine)nickel(II) chloride, bis(triphenylphosphine)palladium(II)chloride, tris(triphenylphosphine)-palladium(O) and tetrakis(triphenylphosphine)palladium(0).
Komplekskatalysatorene anvendes i andeler på 0,1 til 20 mol-#, beregnet på anvendt 8-halogen-kinolonkarboksylsyre-ester, foretrukket er andeler på 0,5 til 10 mol-% og spesielt foretrukket er andeler på 1 til 5 mol-%. The complex catalysts are used in proportions of 0.1 to 20 mol-#, calculated on the 8-halo-quinolonecarboxylic acid ester used, proportions of 0.5 to 10 mol-% are preferred and proportions of 1 to 5 mol-% are particularly preferred.
Koblingsreaksjonen gjennomføres i egnede inerte oppløsnings-midler som benzen, toluen, xylen, dimetylformamid, dimetyl-acetamid eller blandinger av disse, foretrukket er dimetylformamid og toluen. Før bruk blir oppløsningsmidlene på i og for seg kjent måte tørket og gjort luftfrie. Koblingsreaksjonen gjennomføres ved temperaturer mellom 20 og 200°C, fortrinnsvis mellom 50 og 180°C. The coupling reaction is carried out in suitable inert solvents such as benzene, toluene, xylene, dimethylformamide, dimethylacetamide or mixtures thereof, preferably dimethylformamide and toluene. Before use, the solvents are dried and made air-free in a manner known per se. The coupling reaction is carried out at temperatures between 20 and 200°C, preferably between 50 and 180°C.
Varigheten av omsetningen retter seg efter eduktenes reaktivitet og utgjør generelt mellom 2 og 40 timer, fortrinnsvis mellom 4 og 24 timer. The duration of the reaction depends on the reactivity of the educts and is generally between 2 and 40 hours, preferably between 4 and 24 hours.
Omsetningen gjennomføres under en beskyttelsesgassatmosfære. Som beskyttelsesgass kan nevnes inerte gasser som helium, argon eller nitrogen, nitrogen er foretrukket. Koblingsreaksjonen gjennomføres generelt ved normaltrykk. Det er imidlertid selvfølgelig også mulig å gjennomføre reaksjonen ved redusert eller forhøyet trykk. The turnover is carried out under a protective gas atmosphere. Inert gases such as helium, argon or nitrogen can be mentioned as protective gas, nitrogen is preferred. The coupling reaction is generally carried out at normal pressure. However, it is of course also possible to carry out the reaction at reduced or increased pressure.
De som utgangsforbindelser anvendte aminer med formel (III) er for det meste kjente. Chirale aminer kan anvendes både som racemater eller som enantiomer-rene eller diastereomer-rene forbindelser. Som eksempler skal nevnes: The amines of formula (III) used as starting compounds are mostly known. Chiral amines can be used both as racemates or as enantiomeric or diastereomeric compounds. Examples include:
piperazin, piperazine,
1-metylpiperazin, 1-methylpiperazine,
1-etylpiperazin, 1-ethylpiperazine,
l-(2-hydroksyetyl)-piperazin, 1-(2-hydroxyethyl)-piperazine,
3-metylpiperazin, 3-methylpiperazine,
cis-2,6-dimetyl-piperazin, cis-2,6-dimethyl-piperazine,
cis-2,3-dimetyl-piperazin, cis-2,3-dimethyl-piperazine,
1,2-dimetylpiperazin, 1,2-dimethylpiperazine,
1- cyklopropyl-piperazin, 1- cyclopropyl-piperazine,
2- fenyl-piperazin, 2- phenyl-piperazine,
2-(4-pyridyl)-piperazin, 2-(4-pyridyl)-piperazine,
2- (2-tienyl)-piperazin, 2-(2-thienyl)-piperazine,
1.4- diazabicyklo[3.2.1]oktan, 1.4- diazabicyclo[3.2.1]octane,
8-metyl-3,8-diazabicyklo[3.2.1]oktan-dihydroklorid, 3- metyl-3,8-diazabicyklo[3.2.1]oktan-dihydroklorid, 2.5- diazabicyklo[2.2.l]heptan-dihydroklorid, 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, 3- methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, 2.5-diazabicyclo[2.2.1]heptane dihydrochloride,
2-mety1-2,5-diazabicyklo[2.2.l]heptan-dihydroklorid, 2-metyl-2,5-diazabicyklo[2.2.2]oktan-dihydroklorid. 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride, 2-methyl-2,5-diazabicyclo[2.2.2]octane dihydrochloride.
De substituerte 1,3,3a,4,7,7a-heksahydro-isoindoler er overveiende nye. De kan for eksempel oppnås ved Diels-Alder-reaksjon mellom diener med formel (1) The substituted 1,3,3a,4,7,7a-hexahydro-isoindoles are predominantly new. They can, for example, be obtained by Diels-Alder reaction between dienes of formula (1)
hvorved R<9>har den ovenfor angitte betydning og R<22>enten er identisk med R<20>eller er en funksjonell gruppe som kan omdannes til R<20>, med dienofiler med formel (2) whereby R<9> has the meaning given above and R<22> is either identical to R<20> or is a functional group which can be converted to R<20>, with dienophiles of formula (2)
der R<23>er hydrogen eller en beskyttelsesgruppe som trimetylsilyl, benzyl, C1_4~alkylfenylmetyl, metoksybenzyl eller benzhydryl og efterfølgende reduksjon av karbonylgruppen samt eventuelt avspalting av beskyttelsesgruppen. where R<23> is hydrogen or a protecting group such as trimethylsilyl, benzyl, C1_4~alkylphenylmethyl, methoxybenzyl or benzhydryl and subsequent reduction of the carbonyl group and possibly removal of the protecting group.
For Diels-Alder-reaksjonen kan man som fortynningsmiddel anvende alle inerte organiske oppløsningsmidler. Til disse hører fortrinnsvis etere som diisopropyleter, di-n-butyleter, dimetoksyetan, tetrahydrofuran og anisol, hydrokarboner som heksan, metylcykloheksan, toluen, xylen og mesitylen samt halogenerte hydrokarboner som kloroform, 1,2-dikloretan og klorbenzen. Diels-Alder-reaksjonen kan også gjennomføres uten oppløsningsmiddel. For the Diels-Alder reaction, all inert organic solvents can be used as diluents. These preferably include ethers such as diisopropyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and anisole, hydrocarbons such as hexane, methylcyclohexane, toluene, xylene and mesitylene as well as halogenated hydrocarbons such as chloroform, 1,2-dichloroethane and chlorobenzene. The Diels-Alder reaction can also be carried out without a solvent.
Reaksjonstemperaturen kan variere innen et stort område. Generelt arbeider man mellom ca. —20°C og +200°C, fortrinnsvis mellom -20°C og +150°C. Diels-Alder-reaksjonen kan gjennomføres ved normaltrykk. Reaksjonen kan også gjennom-føres ved trykk inntil 1,5 GPa. The reaction temperature can vary within a large range. In general, you work between approx. -20°C and +200°C, preferably between -20°C and +150°C. The Diels-Alder reaction can be carried out at normal pressure. The reaction can also be carried out at pressures of up to 1.5 GPa.
Reduksjonen av karbonylgruppen kan oppnås ved hjelp av komplekse hydrider. Som hydrider kan man anvende for eksempel litiumaluminiumhydrid, litiumborhydrid, 1 itiumtrietylbor-hydrid, natrium-bis-[2-metoksyetoksy]-aluminiumhydrid eller natriumborhydrid i nærvær av Lewis-syrekatalysatorer som klortrimetylsilan, bortrifluorid-eterat eller aluminium-klorid. The reduction of the carbonyl group can be achieved by means of complex hydrides. As hydrides, one can use, for example, lithium aluminum hydride, lithium borohydride, 1 lithium triethylborohydride, sodium bis-[2-methoxyethoxy] aluminum hydride or sodium borohydride in the presence of Lewis acid catalysts such as chlorotrimethylsilane, boron trifluoride etherate or aluminum chloride.
Som fortynningsmiddel kan man anvende etere som dietyleter, tetrahydrofuran, dioksan eller dimetoksyetan og hydrokarboner som heksan, metylcykloheksan eller toluen, eller blandinger derav. As a diluent, ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane and hydrocarbons such as hexane, methylcyclohexane or toluene, or mixtures thereof, can be used.
Reaksjonstemperaturene kan varieres innen området —40°C til +180°C, fortrinnsvis mellom 0°C og 140°C. Reduksjonen gjennomføres vanlig under normaltrykk, men kan også gjennom-føres under redusert eller forhøyet trykk. The reaction temperatures can be varied within the range -40°C to +180°C, preferably between 0°C and 140°C. The reduction is usually carried out under normal pressure, but can also be carried out under reduced or increased pressure.
Anvendelsen av trykk mellom 100 og 1000 kPa er å anbefale for med lettkokende oppløsningsmidler å oppnå høyere reaksjons-temperaturer. The use of pressure between 100 and 1000 kPa is recommended in order to achieve higher reaction temperatures with easily boiling solvents.
De komplekse hydrider anvendes i det minste i en mengde tilsvarende reduksjonens støkiometri. Generelt anvender man imidlertid et overskudd, fortrinnsvis mellom 30 og 300%. The complex hydrides are used at least in an amount corresponding to the stoichiometry of the reduction. In general, however, a surplus is used, preferably between 30 and 300%.
Avspaltningen av en eventuell beskyttelsesgruppe skjer i henhold til de generelt kjente metoder for beskyttelses-gruppekjemi (se for eksempel T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981). The removal of any protective group takes place according to the generally known methods of protective group chemistry (see for example T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981).
Utgangsstoffene med formel (1) og (2) er kjente eller kan fremstilles i henhold til i og for seg kjente metoder i den organiske kjemi, se for eksempel "J. Am. Chem. Soc", 100, 5179 (1978), "J. Org. Chem.", 43. 2164 (1978), DE 39 27 115, "J. Org. Chem.", 40» 24 (1975). The starting substances with formulas (1) and (2) are known or can be prepared according to per se known methods in organic chemistry, see for example "J. Am. Chem. Soc", 100, 5179 (1978), " J. Org. Chem.", 43. 2164 (1978), DE 39 27 115, "J. Org. Chem.", 40» 24 (1975).
Anvender man for eksempel l-(tert-butyloksykarbonylamino)-1,3-butadien og maleinimid som utgangsstoffer og litiumaluminiumhydrid som reduksjonsmiddel, kan reaksjonsforløpet gjengis ved hjelp av følgende reaksjonsskjema: If, for example, l-(tert-butyloxycarbonylamino)-1,3-butadiene and maleimide are used as starting materials and lithium aluminum hydride as reducing agent, the course of the reaction can be reproduced using the following reaction scheme:
I en spesiell utførelsesform av fremstillingsmetoden kan alle trinn gjennomføres ved anvendelse av et egnet oppløsnings-middel, for eksempel tetrahydrofuran, uten isolering av mellomproduktene. Anvender man for eksempel l-(tert-butyl-oksykarbonylamino )-l,3-pentadien og N-trimetylsilyl-maleinimid som utgangsmateriale, kan reaksjonsforløpet også gjengis ved følgende reaksjonsskjema: In a particular embodiment of the production method, all steps can be carried out using a suitable solvent, for example tetrahydrofuran, without isolating the intermediate products. If, for example, l-(tert-butyl-oxycarbonylamino)-l,3-pentadiene and N-trimethylsilylmaleimide are used as starting material, the course of the reaction can also be reproduced by the following reaction scheme:
Ved NMR-spektroskopi kan man i dette tilfellet påvise at alle substituenter på 6-ringen oppviser cis-anordning i forhold til hverandre. In this case, NMR spectroscopy can demonstrate that all substituents on the 6-ring exhibit a cis arrangement in relation to each other.
Omsetningen mellom (II) og (III), der forbindelsene (III) også kan anvendes i form av sine salter som for eksempel hydroklorid, gjennomføres fortrinnsvis i et fortynningsmiddel som dimetylsulfoksyd, N,N-dimetylformamid, N-metylpyrrolidon, heksametyl-fosforsyretrisamid, sulfolan, acetonitril, vann, en alkohol som metanol, etanol, n-propanol, isopropanol, glykolmonmetyleter eller i pyridin. Likeledes kan man anvende blandinger av disse fortynningsmidler. The reaction between (II) and (III), where the compounds (III) can also be used in the form of their salts such as hydrochloride, is preferably carried out in a diluent such as dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-phosphoric acid trisamide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or in pyridine. Mixtures of these diluents can also be used.
Som syrebindende middel kan man anvende alle vanlige organiske eller uorganiske syrebindende midler. Til disse hører fortrinnsvis alkalihydroksyder, alkalikarbonater, organiske aminer og amidiner. Som spesielt egnede skal nevnes trietylamin, 1,4-diazabicyklo[2.2.2]oktan (DABCO), 1,8-diazabicyklo[5.4.0]undec-7-en (DBU) eller overskytende amin As an acid-binding agent, all common organic or inorganic acid-binding agents can be used. These preferably include alkali hydroxides, alkali carbonates, organic amines and amidines. Particularly suitable are triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine
(III). (III).
Reaksjonstemperaturene kan varieres innen vide områder. Generelt arbeider man mellom 20 og 200°C og fortrinnsvis mellom 80 og 180°C. The reaction temperatures can be varied within wide ranges. In general, you work between 20 and 200°C and preferably between 80 and 180°C.
Omsetningen kan gjennomføres ved normaltrykk, men også ved høyere trykk. Generelt arbeider man ved trykk mellom ca. 1 og 100 bar, fortrinnsvis mellom 1 og 10 bar. The turnover can be carried out at normal pressure, but also at higher pressure. In general, you work at a pressure between approx. 1 and 100 bar, preferably between 1 and 10 bar.
Ved gjennomføring av oppfinnelsens fremgangsmåte anvender man pr. 1 mol forbindelse (II) 1 til 15 mol og fortrinnsvis 1 til 6 mol med forbindelse (III). When carrying out the method of the invention, one uses per 1 mol of compound (II) 1 to 15 mol and preferably 1 to 6 mol of compound (III).
Frie aminogrupper kan under omsetningen være beskyttet med en egnet aminobeskyttelsesgruppe, for eksempel med tert-butoksykarbonylresten, og efter avsluttet reaksjon igjen settes fri ved behandling med en egnet syre som saltsyre eller trifluoreddiksyre (se Houben-Weyl, "Methoden der Organischen Chemie", bind E4, side 144 (1983); J.F.W. McOmie, "Protective Groups in Organic Chemistry" (1973), side 43). Fremstillingen av syreaddisjonssaltene av oppfinnelsens forbindelser skjer på vanlig måte, for eksempel ved oppløs-ning av betainer i tilstrekkelige mengder til vandig syre og utfelling av saltet med et med vann blandbart organisk oppløsningsmiddel som metanol, etanol, aceton, acetonitril. Man kan også oppvarme ekvivalente mengder betain og syre i vann eller en alkohol som glykolmonometyleter og derefter dampe det hele inn til tørr tilstand eller suge av det utfelte salt. Som farmasøytisk godtagbare salter skal for eksempel nevnes salter av salt-, svovel-, eddik-, glykol-, melke-, rav-, sitron-, vin-, metansulfon-, 4-toluensulfon-, galakturon-, glucon-, embon-, glutamin- eller asparaginsyre. During the reaction, free amino groups can be protected with a suitable amino protecting group, for example with the tert-butoxycarbonyl residue, and after completion of the reaction set free again by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, "Methoden der Organischen Chemie", vol. E4, page 144 (1983); J. F. W. McOmie, "Protective Groups in Organic Chemistry" (1973), page 43). The preparation of the acid addition salts of the compounds of the invention takes place in the usual way, for example by dissolving betaine in sufficient quantities in aqueous acid and precipitation of the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile. One can also heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether and then evaporate the whole to a dry state or suck off the precipitated salt. As pharmaceutically acceptable salts, mention should be made, for example, of salts of salt, sulphur, vinegar, glycol, milk, amber, lemon, wine, methanesulfone, 4-toluenesulfone, galacturon, glucone, embon- , glutamic or aspartic acid.
Alkali- eller jordalkalisaltene av oppfinnelsens karboksylsyrer oppnås for eksempel ved oppløsning av betainet i overskytende alkali- eller jordalkalilut, fra filtrering av ikke-oppløst betain og inndamping av filtratet til tørr tilstand. Farmasøytisk egnet er natrium-, kalium- eller kalsiumsaltene. Ved omsetning av et alkali- eller jordalkali-salt med et egnet sølvsalt som sølvnitrat oppnås de tilsvarende sølvsalter. The alkali or alkaline earth salts of the carboxylic acids of the invention are obtained, for example, by dissolving the betaine in excess alkali or alkaline earth liquor, from filtering undissolved betaine and evaporating the filtrate to a dry state. Pharmaceutically suitable are the sodium, potassium or calcium salts. By reacting an alkali or alkaline earth salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.
Når det gjelder chirale forbindelser, kan disse fremstilles og anvendes både som diastereomere blandinger eller som diastereomer-rene eller enantiomer-rene forbindelser. As far as chiral compounds are concerned, these can be prepared and used both as diastereomeric mixtures or as diastereomers or enantiomeric compounds.
Oppfinnelsens forbindelser virker sterkt antibiotisk og viser ved lav toksisitet et bredt antibakterielt spektrum mot gram-positive og gram-negative kimer, særlig som enterobakterier; fremfor alt imidlertid også mot slike som er resistente mot forskjellige antibiotika som for eksempel penicilliner, cefalosporiner, aminoglykosider, sulfonamider eller tetra-cykliner. The compounds of the invention have a strong antibiotic effect and, at low toxicity, show a broad antibacterial spectrum against gram-positive and gram-negative germs, especially enterobacteria; above all, however, also against those that are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides or tetracyclines.
Disse verdifulle egenskaper muliggjør deres anvendelse som kjemoterapeutisk aktive bestanddeler i medisinen samt som stoffer for konservering av uorganiske og organiske materialer, særlig organiske materialer av enhver type som polymerer, smøremidler, farver, fibere, lær, papir og tre eller av næringsmidler og vann. These valuable properties enable their use as chemotherapeutically active ingredients in medicine as well as substances for the preservation of inorganic and organic materials, especially organic materials of any type such as polymers, lubricants, paints, fibers, leather, paper and wood or of foodstuffs and water.
Oppfinnelsens forbindelser er virksom mot et meget bredt spektrum mikroorganismer. Ved hjelp av forbindelsene kan man bekjempe gram-negative og gram-positive bakterier og inhibere, helbrede eller lindre sykdommer som er fremkalt av disse. The compounds of the invention are effective against a very broad spectrum of microorganisms. With the help of the compounds, one can fight gram-negative and gram-positive bacteria and inhibit, cure or alleviate diseases caused by these.
Oppfinnelsens forbindelser utmerker seg ved en forsterket virkning på hvilende og resistente kimer. Når det gjelder hvilende bakterier, altså bakterier som ikke viser noen påvisbar vekst, virker forbindelsene langt under konsentra-sjonene til de til nu kjente stoffer. Dette gjelder ikke bare den anvendte mengde, men også utryddelseshastigheten. Slike resultater kan noteres ved gram-positive og -negative bakterier, særlig ved Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis og Escherichia coli. The compounds of the invention are distinguished by an enhanced effect on dormant and resistant germs. When it comes to dormant bacteria, i.e. bacteria that do not show any detectable growth, the compounds work far below the concentrations of the currently known substances. This applies not only to the amount used, but also to the rate of eradication. Such results can be noted with gram-positive and -negative bacteria, particularly with Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli.
Også overfor bakterier som ansees som mindre ømfintlige i forhold til sammenlignbare stoffer, særlig resistente Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa og Enterococcus faecalis viser oppfinnelsens forbindelser overraskende virkningsnivåer. The compounds of the invention also show surprising levels of effectiveness against bacteria which are considered to be less sensitive in relation to comparable substances, particularly resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.
På grunn av den høye virksomhet for oppfinnelsens forbindelser mot bakterier og bakterielignende mikroorganismer egner de seg spesielt godt for profylakse og kjemoterapi av lokale og systemiske infeksjoner i human- og animalmedisinen som fremkalles av disse kilder. Due to the high activity of the compounds of the invention against bacteria and bacteria-like microorganisms, they are particularly suitable for prophylaxis and chemotherapy of local and systemic infections in human and animal medicine caused by these sources.
Forbindelsene egner seg videre for bekjempelse av proto-zoonoser og helminthoser. The compounds are also suitable for combating proto-zoonoses and helminthoses.
Oppfinnelsens forbindelser kan også anvendes i forskjellige farmasøytiske tilberedningsformer. Som foretrukne farmasøy-tiske preparater skal nevnes tabletter, dragéer, kapsler, piller, granulater, suppositorier, oppløsninger, suspensjoner og emulsjoner, pastaer, salver, geler, kremer, lotioner, puddere og spray. The compounds of the invention can also be used in various pharmaceutical preparation forms. Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
Den minimale inhiberende konsentrasjon, MIK, bestemmes pr. rekkefortynningsprøver på iso-sensitetsagar (Oxoid). For hver prøvesubstans fremstiller man en rekke av agarplater som inneholder synkende konsentrasjoner i en rekke med dobbeltfortynning. Agarplatene podes med en multipoint-inokulator (Denley). For poding anvendes over-natten-kulturer av sykdomskimene som på forhånd var slik fortynnet at hvert podepunkt inneholder ca. IO<4>kolonidannende partikler. De podede agarplater inkuberes ved 37°C og kimveksten avleses efter ca. 20 timer. MIK-verdien i jjg/ml gir den laveste konsentrasjon av aktiv bestanddel ved hvilken det ikke kunne registreres vekst med det blotte øyet. The minimum inhibitory concentration, MIK, is determined per serial dilution samples on iso-sensite agar (Oxoid). For each test substance, a series of agar plates containing decreasing concentrations in a series of double dilutions is prepared. The agar plates are inoculated with a multipoint inoculator (Denley). For inoculation, overnight cultures of the germs of the disease are used, which were previously diluted in such a way that each inoculation point contains approx. IO<4>colony-forming particles. The inoculated agar plates are incubated at 37°C and the germ growth is read after approx. 20 hours. The MIC value in µg/ml gives the lowest concentration of active ingredient at which growth could not be detected with the naked eye.
I den følgende tabell gjengis MIK-verdiene for enkelte av oppfinnelsens forbindelser sammenlignet med Ciprofloxacin. The following table shows the MIK values for some of the compounds of the invention compared to Ciprofloxacin.
I den nedenfor følgende tabell gjengis MIK-verdiene for forbindelser med formelen med to valgte verdier for substituenten Y. In the table below, the MIC values for compounds with the formula are reproduced with two selected values for the substituent Y.
Videre er det foretatt en sammenligning mellom utvalgte forbindelser ifølge oppfinnelsen og to forbindelser hentet fra det innledningsvis nevnte GB 2.188.317. Furthermore, a comparison has been made between selected compounds according to the invention and two compounds obtained from the initially mentioned GB 2,188,317.
Disse forbindelser er som følger: These connections are as follows:
I) l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piper-azinyl)-4-okso-8-vinyl-3-kinolinkarbonsyre (ifølge foreliggende søknad) I) 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piper-azinyl)-4-oxo-8-vinyl-3-quinolinecarboxylic acid (according to the present application)
II) l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-3-kinolinkarbonsyre (eksempel 1 ifølge foreliggende søknad) II) 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Example 1 according to the present application)
III) l-cyklopropyl-8-etyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso-3-kinolinkarbonsyre (Otsuka, GB 2,188,317, eksempel 10, nr. 43). III) 1-cyclopropyl-8-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Otsuka, GB 2,188,317, example 10, no. 43).
IV) 7-(3-amino-l-pyrrolidinyl)-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-8-vinyl-3-kinolinkarbonsyre (eksempel 22 ifølge foreliggende søknad). IV) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid (Example 22 according to the present application).
V) 7-(3-amino-l-pyrrolidinyl)-l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarbonsyre (eksempel 6 ifølge foreliggende søknad). V) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 6 according to the present application).
VI) 7-(3-amino-l-pyrrolidinyl)-l-cyklopropyl-8-etyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarbonsyre (Otsuka, GB 2,188,317, eksempel 10, nr. 45). VI) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Otsuka, GB 2,188,317, example 10, no. 45).
FREMSTILLING AV MELLOMPRODUKTER. MANUFACTURE OF INTERMEDIATE PRODUCTS.
Eksempel Zl Example Zl
l- cyklopropyl- 6, 7- difluor- l. 4- dihvdro- 4- okso- 8- vinyl- 3-kinolinkarboksylsvre- etylester 1- cyclopropyl- 6, 7- difluoro- 1. 4- dihydro- 4- oxo- 8- vinyl- 3-quinolinecarboxylic acid- ethyl ester
3,72 g 8-brom-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 4,4 g tributylvinylstannan og 0,46 g tetrakis(trifenylfosfin)palladium(0) oppvarmes i 40 ml absolutt toluen i 2 til 3 timer under nitrogenatmosfære og til tilbakeløp. 3.72 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 4.4 g of tributylvinylstannane and 0.46 g of tetrakis(triphenylphosphine)palladium( 0) is heated in 40 ml of absolute toluene for 2 to 3 hours under a nitrogen atmosphere and to reflux.
Det hele filtreres varmt, det ved romtemperatur utfelte produkt suges av, vaskes nok en gang med toluen og tørkes. Man oppnår 2,55 g l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-8-vinyl-3-kinolinkarboksylsyre-etylester ( 79% av det teoretiske). The whole is filtered hot, the product precipitated at room temperature is sucked off, washed once more with toluene and dried. 2.55 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester are obtained (79% of the theoretical).
Smeltepunkt: 178-179°C. Melting point: 178-179°C.
Eksempel Z2 Example Z2
l- cvklopropvl- 6, 7- difluor- l. 4- dihydro- 4- okso- 8- vinyl- 3-kinolinkarboksvlsyre l- cvclopropvl- 6, 7- difluoro- l. 4- dihydro- 4- oxo- 8- vinyl- 3-quinolinecarboxylic acid
0,9 g l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-8-vinyl-3-kinolinkarboksylsyre-etylester oppvarmes i en blanding av 8 ml iseddik, 0,6 ml vann og 0,2 ml konsentrert svovelsyre i 4 timer til tilbakeløp. Reaksjonsblandingen spaltes så ved tilbakeløpstemperatur med 10 ml vann. Det faste stoff suges av ved romtemperatur, vaskes med vann og tørkes. Man oppnår 0,58 g l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-8-vinyl-3-kinolinkarboksylsyre (71$ av det teoretiske). 0.9 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 8 ml of glacial acetic acid, 0.6 ml of water and 0. 2 ml of concentrated sulfuric acid for 4 hours to reflux. The reaction mixture is then split at reflux temperature with 10 ml of water. The solid substance is sucked off at room temperature, washed with water and dried. 0.58 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-vinyl-3-quinolinecarboxylic acid is obtained (71% of the theoretical).
Smeltepunkt: 182-184°C. Melting point: 182-184°C.
Eksempel Z3 l- cyklopropyl- 6. 7- difluor- l, 4- dihydro- 8-( trimetylsilyl-etinyl)- 4- okso- 3- kinolinkarboksylsyre- etylester 22,2 g 8-brom-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 30,2 g tributylstannyl-trimetylsilyl-acetylen og 3,48 g tetrakis(trifenylfosfin )-palladium(O) oppvarmes i 3 timer i 300 ml absolutt toluen under en nitrogenatmosfaere. Efter avkjøling av reaksjonsblandingen til ca. -18° C vaskes det hele med toluen og tørkes. Man oppnår 18,8 g l-cyklopropyl-6,7-difluor-l,4-dihydro-8- (trimetylsilyletinyl ) -4-okso-3-kinolinkarboksylsyre-etylester (80$ av det teoretiske). Example Z3 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilyl-ethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester 22.2 g 8-bromo-1-cyclopropyl-6,7 -difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis(triphenylphosphine )-palladium(O) are heated for 3 hours in 300 ml absolute toluene under a nitrogen atmosphere. After cooling the reaction mixture to approx. -18° C, the whole thing is washed with toluene and dried. 18.8 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (80$ of the theoretical).
Smeltepunkt: 171-172°C. Melting point: 171-172°C.
Eksempel Z4 Example Z4
l- c. vklopropyl- 8- etiny1- 6. 7- difluor- l. 4- dihydro- 4- okso- 3-kinolinkarboksylsyre- etylester 1- c. vclopropyl- 8- ethynyl- 6. 7- difluoro- 1. 4- dihydro- 4- oxo- 3-quinolinecarboxylic acid- ethyl ester
18,8 g l-cyklopropyl-6,7-difluor-l,4-dihydro-8-(trimetyl-silyletinyl )-4-okso-3-kinolinkarboksylsyre-etylester og 9,7 g 18.8 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethyl-silylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester and 9.7 g
kaliumfluorid omrøres i en blanding av 300 ml dimetylformamid, 200 ml kloroform og 15 ml vann i 3 timer ved romtemperatur. Derefter blir det hele filtrert, det tilsettes 120 ml vann og surgjøres med fortynnet vandig saltsyre. Efter utrysting med kloroform, tørkes den organiske fase over natriumsulfat og dampes inn. Den oppnådde rest omkrystalliseres fra metanol. Man oppnår 9 g l-cyklopropyl-8-etinyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester (59$ av det teoretiske). potassium fluoride is stirred in a mixture of 300 ml dimethylformamide, 200 ml chloroform and 15 ml water for 3 hours at room temperature. The whole is then filtered, 120 ml of water is added and acidified with dilute aqueous hydrochloric acid. After shaking out with chloroform, the organic phase is dried over sodium sulfate and evaporated. The obtained residue is recrystallized from methanol. 9 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (59$ of the theoretical).
Smeltepunkt: 186-187°C Melting point: 186-187°C
Eksempel Z5 Example Z5
l- cyklopropvl- 8- etiny1- 6. 7- difluor- l. 4- dihydro- 4- okso- 3-kinolinkarboksylsyre l- cyclopropvl- 8- ethynyl- 6. 7- difluoro- l. 4- dihydro- 4- oxo- 3-quinolinecarboxylic acid
10,3 g l-cyklopropyl-8-etinyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester oppvarmes i en blanding av 100 ml iseddik, 8 ml vann og 3 ml konsentrert svovelsyre i 4 timer under tilbakeløp. Efter avkjøling til romtemperatur blir det faste stoff sugd av, vasket med vann og tørket. Man oppnår på denne måte 5,7 g l-cyklopropyl-8-etinyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre ( 6256 av det teoretiske). 10.3 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are heated in a mixture of 100 ml of glacial acetic acid, 8 ml of water and 3 ml of concentrated sulfuric acid for 4 hours under reflux. After cooling to room temperature, the solid is sucked off, washed with water and dried. 5.7 g of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained in this way (6256 of the theoretical).
Smeltepunkt: 233°C Melting point: 233°C
Eksempel Z6 Example Z6
l- cyklopropyl- 6 . 7- dif luor- 8-( 1- heksinyl )- l, 4- dihydro- 4- okso-3- kinolinkarboksylsyre- etylester l-cyclopropyl-6. 7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester
1,9 g 8-brom-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 3,5 g 1-tributylstannyl-heks-l-in og 0,29 g tetrakis(trifenylfosfin)palladium(0) oppvarmes i 20 ml absolutt toluen i 8 timer under en nitrogenatmosfære til tilbakeløp. Reaksjonsblandingen dampes inn og resten omkrystalliseres med 30 ml heksan hvorefter det således oppnådde faststoff omkrystalliseres fra cykloheksan. Man oppnår 0,7 g l-cyklopropyl-6,7-difluor-8-(1-heksinyl)-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester (36$ av det teoretiske). 1.9 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3.5 g of 1-tributylstannyl-hex-l-yne and 0, 29 g of tetrakis(triphenylphosphine)palladium(0) are heated in 20 ml of absolute toluene for 8 hours under a nitrogen atmosphere to reflux. The reaction mixture is evaporated and the residue is recrystallized with 30 ml of hexane, after which the solid thus obtained is recrystallized from cyclohexane. 0.7 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (36$ of the theoretical) is obtained.
<i>fl-NMR (200 MHz, CDC13): § 0,95 (t, 3H), 1,1-1,7 (m, 11E), <i>fl-NMR (200 MHz, CDC13): § 0.95 (t, 3H), 1.1-1.7 (m, 11E),
2,50 (t, 2E), 4,1-4,3 (m, 1H), 4,38 (q, 2E), 2.50 (t, 2E), 4.1-4.3 (m, 1H), 4.38 (q, 2E),
8,14 (dd, 1E), 8,56 (s, 1E) ppm. 8.14 (dd, 1E), 8.56 (s, 1E) ppm.
Eksempel Z7 Example Z7
l- cyklopropyl- 6. 7- difluor- 8-( 1- heksinyl)- l. 4- dihydro- 4- okso-3- kinolinkarhoksvlsyre 1- cyclopropyl- 6. 7- difluoro- 8-( 1- hexynyl)- 1. 4- dihydro- 4- oxo-3- quinolinic acid
0,7 g l-cyklopropyl-6,7-difluor-8-(1-heksinyl)-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester oppvarmes i en blanding av 6 ml iseddik, 0,5 ml vann og 0,1 ml konsentrert svovelsyre i 3 timer til tilbakeløp. Efter tilsetning av 100 ml vann blir faststoffet sugd av og tørket. Man oppnår 0,5 g 1-cyklopropyl-6 ,7-difluor-8-( 1-heksinyl )-l, 4-dihydro-4-okso-3-kinolinkarboksylsyre (85$ av det teoretiske). 0.7 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 6 ml of glacial acetic acid, 0.5 ml water and 0.1 ml concentrated sulfuric acid for 3 hours to reflux. After adding 100 ml of water, the solid is sucked off and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexynyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (85% of the theoretical).
<i>fl-NMR (200 MEz, CDCI3): S 0,96 (t, 3E), 1,1-1,7 (m, 8E), <i>fl-NMR (200 MEz, CDCl3): S 0.96 (t, 3E), 1.1-1.7 (m, 8E),
4,3-4,5 (m, 1E), 8,20 (dd, 1E), 8,85 (s, 1E) ppm. Smeltepunkt: 118-121°C. 4.3-4.5 (m, 1E), 8.20 (dd, 1E), 8.85 (s, 1E) ppm. Melting point: 118-121°C.
Eksempel Z8 Example Z8
l- cyklopropyl- 6, 7- difluor- l, 4- dihydro- 8-( 3. 3- dimetylbutin- l-yl)- 4- okso- 3- kinolinkarboksylsyre- etylester 1- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 8-(3, 3- dimethylbutyn- 1-yl)- 4- oxo- 3- quinoline carboxylic acid ethyl ester
Tilsvarende eksempel Z6 oppnår man med l-tributylstannyl-3,3-dimetyl-but-l-in 0,87 g l-cyklopropyl-6,7-difluor-1,4-dihydro-8-(3,3-dimetylbutin-l-yl)-4-okso-3-kinolinkarboksylsyre-etylester (46% av det teoretiske). Corresponding to example Z6, 0.87 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dimethylbutyn- 1-yl)-4-oxo-3-quinolinecarboxylic acid ethyl ester (46% of theory).
Smeltepunkt: 170-172°C Melting point: 170-172°C
Eksempel Z9 Example Z9
l- cyklopropyl- 6 , 7- difluor- l. 4- dihydro- 8-( 3. 3- dimetylbutin- l-yl )- 4- okso- 3- kinolinkarboksylsyre 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3,3-dimethylbutyn-1-yl)-4-oxo-3-quinolinecarboxylic acid
Forsepning av 0,75 g av esteren fra eksempel Z8 tilsvarende eksempel Z7 gir 0,56 g l-cyklopropyl-6,7-difluor-l,4-dihydro-8-(3-dimetylbutin-l-yl)-4-okso-3-kinolinkarboksylsyre ( 81% av det teoretiske). Saponification of 0.75 g of the ester from example Z8 corresponding to example Z7 gives 0.56 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-dimethylbutyn-1-yl)-4-oxo -3-quinoline carboxylic acid (81% of theory).
Smeltepunkt: 199-201°C Melting point: 199-201°C
Eksempel Z10 l-( 2. 4- dl fluorfenvl)- 6. 7- dl fluor- 1. 4- dihvdro- 8-( trimetyl-sllyletinvl)- 4- okso- 3- kinolinkarboksylsyre- etylester 6,7 g 8-brom-l-(2,4-difluorfenyl )-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester (eksempel Z20), 10,8 g tributylstannyl-trimetylsilyl-acetylen og 0,87 g tetrakis-(trifenylfosfin)-palladium(0) oppvarmes i 50 ml absolutt toluen i 24 timer under en nitrogenatmosfære til tilbakeløp. Ved —18°C utkrystalliserer man produktet fra reaksjonsblandingen. Man oppnår 4,8 g l-(2,4-difluorfenyl)-6,7-difluor-l j4-dihydro-8-(trimetylsilyletinyl )-4-okso-3-kinolinkarboksylsyre-etylester (69% av det teoretiske). Example Z10 1-(2.4- dl fluorophenyl)- 6.7- dl fluoro- 1.4- dihydro- 8-(trimethyl-sylylethylenyl)- 4-oxo- 3- quinolinecarboxylic acid ethyl ester 6.7 g 8-bromo -1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z20), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis-(triphenylphosphine)-palladium(0) is heated in 50 ml of absolute toluene for 24 hours under a nitrogen atmosphere to reflux. At -18°C, the product crystallizes from the reaction mixture. 4.8 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (69% of the theoretical).
Smeltepunkt: 173-174°C Melting point: 173-174°C
Eksempel Zll Example Zll
l-( 2. 4- difluorfenvl)- 8- etinvl- 6. 7- difluor- 1. 4- dihvdro- 4- okso-3- kinolinkarboksylsyre- etylester l-(2.4-difluorophenyl)-8-ethynyl-6.7-difluoro-1.4-dihydro-4-oxo-3- quinolinecarboxylic acid ethyl ester
En oppløsning av 4,6 g l-(2,4-difluorfenyl)-6,7-difluor-l,4-dihydro-8-(trimetylsilyletinyl )-4-okso-3-kinolinkarboksylsyre-etylester i 20 ml kloroform dryppes ved romtemperatur til en oppløsning av 2 g kaliumf luorid i en oppløsnings-middelblanding av 3 ml vann, 25 ml kloroform og 50 ml dimetylformamid. Man omrører i en time ved ca. 20° C, det tilsettes ytterligere kloroform til reaksjonsblandingen, det hele rystes ut flere ganger med vann, den organiske fase tørkes og dampes inn. Den oppnådde rest omkrystalliseres fra metanol. Man oppnår 3,4 g l-(2,4-difluorfenyl)-8-etinyl-6,7-difluor-l , 4 - dihydro-4-okso-3-kinolinkarboksylsyre-etylester (87% av det teoretiske). A solution of 4.6 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester in 20 ml of chloroform is added dropwise at room temperature to a solution of 2 g of potassium fluoride in a solvent mixture of 3 ml of water, 25 ml of chloroform and 50 ml of dimethylformamide. Stir for one hour at approx. 20° C, further chloroform is added to the reaction mixture, the whole is shaken out several times with water, the organic phase is dried and evaporated. The obtained residue is recrystallized from methanol. 3.4 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained (87% of the theoretical).
Smeltepunkt: 189°C Melting point: 189°C
Eksempel Z12 Example Z12
l-( 2. 4- difluorfenvl)- 8- etinyl- 6. 7- difluor- 1, 4- dihydro- 4- okso-3- kinolinkarboksylsyre 1-(2.4-difluorophenyl)-8-ethynyl-6.7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
1,17 g l-(2,4-difluorfenyl)-8-etinyl-6,7-difluor-l,4-dihydro-4- okso-3-kinolinkarboksylsyre-etylester oppvarmes i en 1.17 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a
blanding av 9 ml iseddik, 0,75 ml vann og 0,2 ml konsentrert svovelsyre i en time under tilbakeløp. Det ved romtemperatur utkrystalliserte faststoff suges av og tørkes. Man oppnår 0,98 g l-(2,4-difluorfenyl)-8-etinyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre (90% av det teoretiske). mixture of 9 ml glacial acetic acid, 0.75 ml water and 0.2 ml concentrated sulfuric acid for one hour under reflux. The solid that has crystallized at room temperature is sucked off and dried. 0.98 g of 1-(2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of the theoretical).
Smeltepunkt: 220°C (spalting). Melting point: 220°C (decomposition).
Eksempel Z13 Example Z13
l- c. ykloprop. yl- 6, 7- difluor- l . 4- dihydro- 4- okso- 8-( propin- l- yl )-3- kinolinkarboksylsyre- etvlester l- c. ycloprop. yl-6,7-difluoro-l. 4-Dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester
7,5 g 8-brom-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 9,1 g 1-tributylstannyl-prop-1-in og 1,16 g tetrakis(trifenylfosfin)palladium(0) oppvarmes i 80 ml absolutt toluen i 8 timer under en nitrogenatmosfaere til tilbakeløp. Det ved -18°C utkrystalliserte faststoff suges av og tørkes. Man oppnår 2,05 g l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-8-(propin-l-yl )-3-kinolinkarboksylsyre-etylester (31% av det teoretiske). 7.5 g of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 9.1 g of 1-tributylstannyl-prop-1-yne and 1, 16 g of tetrakis(triphenylphosphine)palladium(0) are heated in 80 ml of absolute toluene for 8 hours under a nitrogen atmosphere to reflux. The solid crystallized at -18°C is sucked off and dried. 2.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester are obtained (31% of the theoretical).
<1->H-NMR (200 MHz, CDC13): S 1,1-1,35 (m, 4H) , 1,40 (t, 3H), <1->H-NMR (200 MHz, CDCl3): S 1.1-1.35 (m, 4H), 1.40 (t, 3H),
2,16 (d, 3E), 4,1-4,3 (m, 1H), 4,35 (q, 2H), 2.16 (d, 3E), 4.1-4.3 (m, 1H), 4.35 (q, 2H),
8,15 (dd, 1E), 8,56 (s, 1E) ppm. 8.15 (dd, 1E), 8.56 (s, 1E) ppm.
Smeltepunkt: 180-182°C Melting point: 180-182°C
Eksempel Z14 Example Z14
l- cyklopropyl- 6. 7- difluor- l, 4- dihydro- 4- okso- 8-( propin- l- yl)-3- kinolinkarboksylsyre l- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 4- oxo- 8-( propyn- l- yl)-3- quinoline carboxylic acid
1,4 g l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-8-(propin-1-yl)-3-kinolinkarboksylsyre-etylester kokes i en blanding av 20 ml iseddik, 1,5 ml vann og 0,5 ml konsentrert svovelsyre i en time under tilbakeløp. Efter tilsetning av ca. 10 ml vann, isoleres det utfelte faststoff og tørkes. På denne måte oppnås 1,05 g l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-8-(propin-l-yl )-3-kinolinkarboksylsyre (82% av det teoretiske). 1.4 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid ethyl ester is boiled in a mixture of 20 ml of glacial acetic acid, 1, 5 ml of water and 0.5 ml of concentrated sulfuric acid for one hour under reflux. After adding approx. 10 ml of water, the precipitated solid is isolated and dried. In this way, 1.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid is obtained (82% of the theoretical).
<i>H-NMR (200 MHz, CDC13): S 1,4 (m, 4H), 2,26 (d, 3H), <i>H-NMR (200 MHz, CDCl 3 ): S 1.4 (m, 4H), 2.26 (d, 3H),
4,4-4,6 (m, 1H), 8,16 (dd, 1H), 8,81 (s, 1H) ppm. 4.4-4.6 (m, 1H), 8.16 (dd, 1H), 8.81 (s, 1H) ppm.
Smeltepunkt: 212-213°C Melting point: 212-213°C
Eksempel Z15 Example Z15
l- etyl- 6, 7- difluor- l. 4- dihydr0- 8-( trimetylsilyletinvl1-4-okso- 3- kinolinkarboksylsyre- etylester 1- ethyl- 6, 7- difluoro- 1. 4- dihydro- 8-( trimethylsilylethylenyl-4-oxo- 3- quinolinecarboxylic acid- ethyl ester
5,4 g 8-brom-l-etyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester (eksempel Z22), 10,8 g tributylstannyl-trimetylsilyl-acetylen og 0,87 g tetrakis-(trifenylfosfin)palladium(0) oppvarmes i 50 ml absolutt toluen under en nitrogenatmosfære i 24 timer under tilbake-løp. Reaksjonsblandingen dampes inn, resten omrøres i 100 ml heksan, det resulterende faststoff suges av og tørkes. Man oppnår 4,53 g l-etyl-6,7-difluor-l,4-dihydro-8-(trimetyl-silyletinyl)-4-okso-3-kinolinkarboksylsyre-etylester (80% av det teoretiske). 5.4 g of 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (Example Z22), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0. 87 g of tetrakis-(triphenylphosphine)palladium(0) are heated in 50 ml of absolute toluene under a nitrogen atmosphere for 24 hours under reflux. The reaction mixture is evaporated, the residue is stirred in 100 ml of hexane, the resulting solid is sucked off and dried. 4.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-(trimethyl-silylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester (80% of the theoretical) is obtained.
Smeltepunkt: 151-152°C. Melting point: 151-152°C.
Eksempel Z16 Example Z16
l- cyklopropyl- 6 . 7- difluor- l. 4 - dihydro- 8- ( tr i me tyl si lyl - etinyl)- 4- okso- 3- kinolinkarboksylsyre- etylester l-cyclopropyl-6. 7- difluoro- l. 4- dihydro- 8- (trimethylsilyl- ethynyl)- 4- oxo- 3- quinoline carboxylic acid ethyl ester
1,64 g 8-klor-l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 3 g tributylstannyl-trimetylsilyl-acetylen og 0,29 g tetrakis(trifenylfosfin)palladium(0) oppvarmes i 20 ml absolutt toluen i 24 timer under nitrogen til tilbakeløp. Reaksjonsblandingen avkjøles til ca. —18°C og filtreres. Efter tørking av resten oppnår man 0,74 g 1-cyklopropyl-6,7-difluor-l,4-dihydro-8-(trimetylsilyletinyl )-4-okso-3-kinolinkarboksylsyre-etylester (38% av det teoretiske ). 1.64 g 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 3 g tributylstannyl-trimethylsilyl-acetylene and 0.29 g tetrakis(triphenylphosphine) palladium(0) is heated in 20 ml of absolute toluene for 24 hours under nitrogen to reflux. The reaction mixture is cooled to approx. -18°C and filtered. After drying the residue, 0.74 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethynyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained (38% of the theoretical).
Eksempel Z17 Example Z17
l-cyklopropyl-6,7-difluor-l,4-dihydro-8-(3-metyl-but-3-en-l-inyl)-4-okso-3-kinolinkarboksylsyre-etylester 1,86 g 8-brom-l-cyklopropyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester, 2,8 g l-tributylstannyl-3- 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester 1.86 g 8-bromo -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, 2.8 g l-tributylstannyl-3-
metyl-but-3-en-l-in og 0,29 g tetrakis(trifenylfosfin)-palladium(O) oppvarmes i 20 ml absolutt toluen i 6 timer under en nitrogenatmosfære til tilbakeløp. Reaksjonsblandingen filtreres varm, dampes inn og resten omrøres med heksan. Efter avsuging og tørking oppnås 1,43 g l-cyklopropyl-6 , 7-dif luor-1 ,4-dihydro-8-(3-metyl-but-3-en-l-inyl )-4-okso-3-kinolinkarboksylsyre-etylester (80% av det teoretiske). methyl-but-3-en-l-yne and 0.29 g of tetrakis(triphenylphosphine)-palladium(O) are heated in 20 ml of absolute toluene for 6 hours under a nitrogen atmosphere to reflux. The reaction mixture is filtered hot, evaporated and the residue is stirred with hexane. After suction and drying, 1.43 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3- quinoline carboxylic acid ethyl ester (80% of theory).
Smeltepunkt: 169-171°C. Melting point: 169-171°C.
Eksempel Z18 Example Z18
l- cyklopropyl- 6. 7- difluor- l. 4- dihydro- 8-( 3- metyl- but- 3- en- l-invl)- 4- okso- 3- kinolinkarboksylsyre 1- cyclopropyl- 6. 7- difluoro- 1. 4- dihydro- 8-( 3- methyl- but- 3- en- 1-invl)- 4- oxo- 3- quinoline carboxylic acid
0,715 g l-cyklopropyl-6,7-difluor-l,4-dihydro-8-(3-metyl-but-3-en-l-inyl)-4-okso-3-kinolinkarboksylsyre-etylester oppvarmes i en blanding av 10 ml iseddik, 0,5 ml vann og 0,2 ml konsentrert svovelsyre i VA - time under tilbakeløp. Til reaksjonsblandingen settes 100 ml vann. Det utfelte faststoff suges av, vaskes efter med vann og tørkes. Man oppnår 0,53 g 1- cyklopropyl-6 ,7-difluor-l,4-dihydro-8-(3-metyl-but-3-en-l-inyl)-4-okso-3-kinolinkarboksylsyre (80% av det teoretiske). 0.715 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester is heated in a mixture of 10 ml glacial acetic acid, 0.5 ml water and 0.2 ml concentrated sulfuric acid in VA - hour under reflux. Add 100 ml of water to the reaction mixture. The precipitated solid is sucked off, washed afterwards with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid is obtained (80% of the theoretical).
Smeltepunkt: 204-206°C. Melting point: 204-206°C.
Eksempel Z19 Example Z19
2- ( 3- brom- 2. 4. 5- trifluor- benzoyl)- 3-( 2. 4- difluorfenvlamino)-akrvlsyre- etylester 2-(3-bromo-2.4.5-trifluoro-benzoyl)-3-(2.4-difluorophenylamino)-acrylic acid ethyl ester
Til 40 g (0,1 mol) 2-(3-brom-2,4,5-trifluor-benzoyl)-3-etoksy-akrylsyre-etylester i 180 ml etanol settes det under isavkjøling 14,5 g (0,11 mol) 2,4-difluor-anilin. Man lar blandingen stå over natten ved 10°C, suger av det utfelte bunnfall, vasker med kold etanol og tørker under vakuum. 14.5 g (0.11 mol) 2,4-difluoroaniline. The mixture is allowed to stand overnight at 10°C, the precipitate that has formed is sucked off, washed with cold ethanol and dried under vacuum.
Utbytte: 38 g (81% av det teoretiske). Yield: 38 g (81% of the theoretical).
Smeltepunkt: 102-103°C (under spalting) (fra isopropanol). Melting point: 102-103°C (under decomposition) (from isopropanol).
Eksempel Z20 Example Z20
8- brom- l-( 2. 4- difluorfenvl1- 6. 7- dlfluor- 1. 4- dihydro- 4- okso- 3-kinolinkarboksylsyre- etylester 38 g (82 mmol) 2-(3-brom-2,4,5-trifluor-benzoyl)-3-(2,4-difluorfenylamino )akrylsyre-etylester oppvarmes i 200 ml dimetylformamid med 7,6 g natriumfluorid i 2 timer under tilbakeløp. Blandingen helles på isvann, bunnfallet suges av, vaskes godt med vann og tørkes ved 80 °C i et luftsirku-lasjonsskap. 8-bromo-1-(2.4-difluorophenyl1-6.7-difluoro-1.4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 38 g (82 mmol) 2-(3-bromo-2,4 ,5-trifluoro-benzoyl)-3-(2,4-difluorophenylamino)acrylic acid ethyl ester is heated in 200 ml of dimethylformamide with 7.6 g of sodium fluoride for 2 hours under reflux. The mixture is poured into ice water, the precipitate is suctioned off, washed well with water and dried at 80 °C in an air circulation cabinet.
Utbytte: 34,7 g (95% av det teoretiske). Yield: 34.7 g (95% of the theoretical).
Smeltepunkt: 208-210"C (under spalting) (fra glykolmonometyleter). Melting point: 208-210"C (under decomposition) (from glycol monomethyl ether).
Ved sur forsepning av denne ester oppnår man 8-brom-l-(2,4-difluorfenyl )-6,7-difluor-l,4-dihydro-4-okso-3-kino1in-karboksylsyre med smeltepunkt 210-221°C (under spalting). By acid saponification of this ester, 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid is obtained with melting point 210-221°C (during cleavage).
Eksempel Z21 Example Z21
2-( 3- brom- 2. 4. 5- trifluor- benzoyl)- 3- etylamino- akrylsvre- etylester 2-( 3- bromo- 2. 4. 5- trifluoro- benzoyl)- 3- ethylamino- acrylic acid- ethyl ester
Til 20 g (0,05 mol) 2-(3-brom-2,4,5-trifluor-benzoyl)-3-etoksy-akrylsyre-etylester i 40 ml etanol settes det under isavkjøling 5,5 g av en 50 %-ig vandig etylaminoppløsning. Man lar blandingen stå over natten ved 10°C, til suspensjonen settes 200 ml vann, man suger av det utfelte bunnfall, vasker med vann og tørker ved 60°C under vakuum. 5.5 g of a 50% -ig aqueous ethylamine solution. The mixture is allowed to stand overnight at 10°C, 200 ml of water is added to the suspension, the precipitate that has formed is sucked off, washed with water and dried at 60°C under vacuum.
Utbytte: 17,3 g (91% av det teoretiske). Yield: 17.3 g (91% of theoretical).
Smeltepunkt: 101-102°C (under spalting) (fra isopropanol). Melting point: 101-102°C (under decomposition) (from isopropanol).
Eksempel Z22 Example Z22
8- brom- l- etyl- 6, 7- difluor- l. 4- dihydro- 4- okso- 3- kinolinkarboksylsyre- etylester 16 g (42 mmol) 2-(3-brom-2,4,5-trifluor-benzoyl)-3-etylamino-akrylsyre-etylester fremstilles analogt eksempel Z20. 8- bromo- 1- ethyl- 6, 7- difluoro- 1. 4- dihydro- 4- oxo- 3- quinoline carboxylic acid ethyl ester 16 g (42 mmol) 2-(3-bromo-2,4,5-trifluoro- benzoyl)-3-ethylamino-acrylic acid ethyl ester is prepared analogously to example Z20.
Utbytte: 14,6 g (96% av det teoretiske). Yield: 14.6 g (96% of theoretical).
Smeltepunkt: 172-173" C (under spalting) (fra glykolmonometyleter). Melting point: 172-173" C (under decomposition) (from glycol monomethyl ether).
Ved sur forsepning oppnår man fra denne ester 8-brom-l-etyl-6,7-difluor-l,4-dihydro-4-okso-3-kinolinkarboksylsyre med smeltepunkt 215-217°C (under spalting). By acid saponification, 8-bromo-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 215-217°C (with cleavage) is obtained from this ester.
Eksempel Z23 Example Z23
4- metvlamino- l. 3. 3a. 4, 7. 7a- heksahvdroisoindol 4-methylamino-l. 3. 3a. 4, 7. 7a-hexahydroisoindole
Metode I: Method I:
14,4 g (60 mmol) 70 %-ig 1-(tert-butyloksykarbonylamino)-l,3-butadien ["J. Org. Chem.", 43»2164 (1978)] dryppes som oppløsning i 30 ml absolutt tetrahydrofuran til foreliggende 10,1 g (60 mmol) N-trimetylsilylmaleinimid ["J. Org. Chem.", 40»24 (1975)] i 30 ml absolutt tetrahydrofuran. Efter at den eksoterme reaksjonen har gitt seg, koker man ennu en time under tilbakeløpskjøling. 14.4 g (60 mmol) of 70% 1-(tert-butyloxycarbonylamino)-1,3-butadiene ["J. Org. Chem.", 43»2164 (1978)] are added dropwise as a solution in 30 ml of absolute tetrahydrofuran to the present 10.1 g (60 mmol) of N-trimethylsilylmaleimide ["J. Org. Chem.", 40»24 (1975)] in 30 ml of absolute tetrahydrofuran. After the exothermic reaction has taken place, it is boiled for another hour under reflux cooling.
Den avkjølte reaksjonsblanding dryppes så under nitrogen til foreliggende 7,6 g (0,2 mol) litiumaluminiumhydrid i 200 ml absolutt tetrahydrofuran. Derefter kokes det hele i 14 timer under tilbakeløpskjøling. Til den avkjølte reaksjonsblanding dryppes så efter hverandre til 7,6 g vann i 23 ml tetrahydrofuran, 7,6 g 10 %-ig natronlut og 22,8 g vann. Saltene filtreres av og dampes inn under vakuum. Resten på 10,3 g destilleres ved 87°C/0,8 mbar. The cooled reaction mixture is then added dropwise under nitrogen to the present 7.6 g (0.2 mol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran. The whole thing is then boiled for 14 hours under reflux cooling. 7.6 g of water in 23 ml of tetrahydrofuran, 7.6 g of 10% caustic soda and 22.8 g of water are then successively added dropwise to the cooled reaction mixture. The salts are filtered off and evaporated under vacuum. The residue of 10.3 g is distilled at 87°C/0.8 mbar.
Destillatet tas opp i 80 ml absolutt pentan, filtreres og produktet krystalliseres ved avkjøling til —70°C. The distillate is taken up in 80 ml of absolute pentane, filtered and the product crystallized by cooling to -70°C.
Utbytte: 3,3 g Yield: 3.3 g
Smeltepunkt: 72-82°C. Melting point: 72-82°C.
Ved behandling med ekvimolare mengder 2N saltsyre oppnår man 4-metylamino-l,3,3a,4,7,7a-heksahydro-isoindol-dihydroklorid med smeltepunkt 265-268°C (fra metanol). By treatment with equimolar amounts of 2N hydrochloric acid, 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole dihydrochloride is obtained with a melting point of 265-268°C (from methanol).
Metode II: Method II:
a) 4-(tert-butyloksykarbonylamino)-l,3-diokso-l,3,3a,4,7,7a-heksahydroisoindol. a) 4-(tert-butyloxycarbonylamino)-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole.
48,0 g (0,5 mol maleinimid bringes inn i 200 ml absolutt tetrahydrofuran og man drypper til 120 g (0,5 mol) ca. 70 %-ig l-(tert-butyloksykarbonylamino)-l,3-butadien som oppløsning i 500 ml absolutt tetrahydrofuran, hvorved temperaturen holdes ved 20 til 30°C. Man omrører over natten ved romtemperatur. Derefter dampes det hele inn og omkrystalliseres fra eddiksyre-etylester. Man oppnår 57 g av et produkt med et smeltepunkt på 177 til 182°C. Fra moderluten oppnår man ytterligere 13 g med et smeltepunkt på 158 til 160°C. 48.0 g (0.5 mol) of maleimide is introduced into 200 ml of absolute tetrahydrofuran and 120 g (0.5 mol) of approx. 70% 1-(tert-butyloxycarbonylamino)-1,3-butadiene is added dropwise as a solution in 500 ml of absolute tetrahydrofuran, whereby the temperature is maintained at 20 to 30°C. The mixture is stirred overnight at room temperature. The whole is then evaporated and recrystallized from ethyl acetate. 57 g of a product with a melting point of 177 to 182° are obtained C. A further 13 g with a melting point of 158 to 160°C are obtained from the mother liquor.
b) 4-metylamino-l,3,3a,4,7,7a-heksahydroisoindol. b) 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole.
Man går ut fra 27,1 g (0,71 mol) 1 itiumaluminiumhydrid The starting point is 27.1 g (0.71 mol) 1 lithium aluminum hydride
under nitrogen i 300 ml absolutt tetrahydrofuran og drypper til en oppløsning av 57 g (0,21 mol) 4-(tert-butyloksykarbonylamino)-l,3-diokso-l,3,3a,4,7,7a-heksahydroisoindol i 570 ml absolutt tetrahydrofuran. Derefter koker man over natten under tilbakeløpskjøling. Efter avkjøling drypper man efter hverandre til 27,1 g vann i 82 ml tetrahydrofuran, 27,1 g 10 %-ig natronlut og 81,3 g vann. Saltene suges av, vaskes med tetrahydrofuran og filtratet dampes inn under vakuum. Resten destilleres i høyvakuum. under nitrogen in 300 ml absolute tetrahydrofuran and dropwise to a solution of 57 g (0.21 mol) 4-(tert-butyloxycarbonylamino)-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole in 570 ml of absolute tetrahydrofuran. It is then boiled overnight under reflux cooling. After cooling, 27.1 g of water in 82 ml of tetrahydrofuran, 27.1 g of 10% caustic soda and 81.3 g of water are added successively. The salts are sucked off, washed with tetrahydrofuran and the filtrate is evaporated under vacuum. The remainder is distilled in high vacuum.
Utbytte: 19,1 g. Yield: 19.1 g.
Eksempel Z24 Example Z24
4- amino- l. 3. 3a. 4. 7. 7a- heksahydro- isoindol 4-amino-l. 3. 3a. 4. 7. 7a- hexahydro-isoindole
13,3 g (50 mmol) 4-tert-butyloksykarbonylamino-l,3-diokso-1,3,3a,4,7,7a-heksahydro-isoindol (fra eksempel Z23, metode 13.3 g (50 mmol) 4-tert-butyloxycarbonylamino-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-isoindole (from example Z23, method
II) omrøres i 166 ml trif luoreddiksyre over natten ved romtemperatur. Derefter destilleres trifluoreddiksyren av ved 10 mbar og resten befris ved 50°C under høyvakuum for syrerester. Derefter tas det hele opp i absolutt tetrahydrofuran og dampes inn under vakuum. Resten tas opp i 100 ml absolutt tetrahydrofuran og dryppes under nitrogen til en oppløsning av 11,3 g (0,3 mol) litiumaluminiumhydrid i 300 ml absolutt tetrahydrofuran. Derefter koker man i 16 timer under tilbakeløp. Efter avkjøling dryppes det efter hverandre til 11,3 g vann i 34 ml tetrahydrofuran, 11,3 ml 10 %-ig natronlut og 34 ml vann. Resten suges av og vaskes med tetrahydrofuran. Filtratet dampes inn og resten destilleres. II) is stirred in 166 ml of trifluoroacetic acid overnight at room temperature. The trifluoroacetic acid is then distilled off at 10 mbar and the residue is freed from acid residues at 50°C under high vacuum. The whole is then taken up in absolute tetrahydrofuran and evaporated under vacuum. The residue is taken up in 100 ml of absolute tetrahydrofuran and added dropwise under nitrogen to a solution of 11.3 g (0.3 mol) of lithium aluminum hydride in 300 ml of absolute tetrahydrofuran. It is then boiled for 16 hours under reflux. After cooling, 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% caustic soda and 34 ml of water are added successively. The residue is sucked off and washed with tetrahydrofuran. The filtrate is evaporated and the residue is distilled.
"Utbytte: 2,2 g "Yield: 2.2 g
Innhold: 92% (bestemt gasskromatografisk) Content: 92% (determined gas chromatographically)
Kokepunkt: 70"C/0,2 mbar. Boiling point: 70"C/0.2 mbar.
Eksempel Z25 Example Z25
7- metvl- 4- metylamino- l. 3. 3a, 4, 7. 7a- heksahydro- isoindol I analogi med eksempel Z23, metode I, omsetter man 21,9 g (0,12 mol) l-(tert-butyloksykarbonylamino)-l,3-pentadien med 20,3 g (0,12 mol) N-trimetylsilyl-maleinimid og reduserer derefter med 15,2 g (0,4 mol) litiumaluminiumhydrid. Råproduktet omkrystalliseres fra tetrahydrofuran. 7-methyl-4-methylamino-1.3.3a,4,7.7a-hexahydro-isoindole In analogy with example Z23, method I, 21.9 g (0.12 mol) of 1-(tert-butyloxycarbonylamino )-1,3-pentadiene with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide and then reducing with 15.2 g (0.4 mol) of lithium aluminum hydride. The crude product is recrystallized from tetrahydrofuran.
Utbytte: 6,2 g Yield: 6.2 g
Smeltepunkt: 106-108°C. Melting point: 106-108°C.
Eksempel Z26 Example Z26
l- cyklopropyl- 6, 7- difluor- l, 4- dihydro- 8-( 3- metoksy- propin- l-yl)- 4- okso- 3- kinolinkarboksylsyre A) Til 1,86 g (5 mmol) 8-brom-l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-etylester settes det i 20 ml absolutt toluen til 2,5 g (7 mmol) 1-tributyl-stannyl-3-metoksy-propin og 0,29 g (tilsvarende 5 mol-%) tetrakis-(trifenylfosfin )-palladium(0) og det hele oppvarmes 1 5 timer under nitrogen. Reaksjonsblandingen dampes inn, resten omrøres med heksan, faststoffet suges av og renses kromatografisk over noe silikagel. 1- cyclopropyl- 6, 7- difluoro- 1, 4- dihydro- 8-( 3- methoxy- propyn- 1-yl)- 4- oxo- 3- quinoline carboxylic acid A) To 1.86 g (5 mmol) 8- bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is added to 20 ml of absolute toluene to 2.5 g (7 mmol) of 1-tributyl-stannyl-3 -methoxy-propyne and 0.29 g (corresponding to 5 mol-%) tetrakis-(triphenylphosphine)-palladium(0) and the whole is heated for 15 hours under nitrogen. The reaction mixture is evaporated, the residue is stirred with hexane, the solid is sucked off and purified chromatographically over some silica gel.
Utbytte: 0,74 g (41% av det teoretiske) 1-cyklopropyl-6,7-difluor-l,4-dihydro-8-(3-metoksy-propin-l-yl)-4-okso-3-kinolinkarboksylsyre-etylester. Yield: 0.74 g (41% of theory) 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methoxy-propyn-1-yl)-4-oxo-3-quinolinecarboxylic acid -ethyl ester.
Smeltepunkt: 144-146°C. Melting point: 144-146°C.
B) 0,36 g (1 mmol) av produktet fra trinn A oppvarmes i en blanding av 3 ml iseddik, 0,2 ml vann og 0,05 ml konsentrert svovelsyre i en time under tilbakeløp. Blandingen helles på vann, bunnfallet filtreres av og omkrystalliseres fra etanol. B) 0.36 g (1 mmol) of the product from step A is heated in a mixture of 3 ml of glacial acetic acid, 0.2 ml of water and 0.05 ml of concentrated sulfuric acid for one hour under reflux. The mixture is poured onto water, the precipitate is filtered off and recrystallized from ethanol.
Utbytte: 153 mg (46% av det teoretiske) 1-cyklopropyl-6,7-difluor-l,4-dihydro-8-(3-metoksy-propin-l-yl)-4-okso-3-kinolinkarboksylsyre. Yield: 153 mg (46% of theory) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methoxy-propyn-1-yl)-4-oxo-3-quinolinecarboxylic acid.
Smeltepunkt: 170-172°C. Melting point: 170-172°C.
<i>H-NMR (200 MHz, CDC13): S 1,24 (m, 2H), 1,4 (m, 2H), <i>H-NMR (200 MHz, CDCl 3 ): S 1.24 (m, 2H), 1.4 (m, 2H),
3,45 (s, OCH3), 4,35 (m, 1H) , 4,41 (s, 0-CH2-), 3.45 (s, OCH3), 4.35 (m, 1H), 4.41 (s, 0-CH2-),
8,27 ("t", 1H), 8,87 (s, 1E) ppm. 8.27 ("t", 1H), 8.87 (s, 1E) ppm.
FREMSTILLING AV VIRKSOMME STOFFER MANUFACTURE OF ACTIVE SUBSTANCES
Eksempel 1 Example 1
A) 2,32 g (8 mmol) l-cyklopropyl-8-etinyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre oppvarmes i en blanding av 60 ml acetonitril og 30 ml dimetylformamid med 0,92 g (8 mmol) 1,4-diazabicyklo[2.2.2]oktan og 1,2 g (12 mmol) N-metylpiperazin i en time under tilbakeløp. Suspensjonen dampes inn, resten omrøres med acetonitril og det ikke-oppløste krystallisat suges av og tørkes. A) 2.32 g (8 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 60 ml of acetonitrile and 30 ml of dimethylformamide with 0.92 g (8 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.2 g (12 mmol) of N-methylpiperazine for one hour under reflux. The suspension is evaporated, the residue is stirred with acetonitrile and the undissolved crystallisate is sucked off and dried.
Utbytte: 1,83 g (62% av det teoretiske) l-cyklopropyl-8-etinyl-6-f luor-1,4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-3-kinolinkarboksylsyre. Yield: 1.83 g (62% of theory) 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinoline carboxylic acid.
Smeltepunkt: 228-230°C (under spalting). Melting point: 228-230°C (under decomposition).
<i>H-NMR (d<6->DMF): S 4,95 (s, -C<=>C-H) ppm. <i>H-NMR (d<6->DMF): S 4.95 (s, -C<=>C-H) ppm.
B) Med 2-metylpiperazin oppnår man på analog måte 1—cyklo-propyl-8-etinyl-6-fluor-l,4-dihydro-7-(3-metyl-l-piperazinyl)-4-okso-3-kinolinkarboksylsyre. B) With 2-methylpiperazine, 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid is obtained in an analogous manner .
^H-NMR (d<6->DMS0): S 5,03 (s, -C<=>C-H) ppm. 1 H-NMR (d<6->DMS0): S 5.03 (s, -C<=>C-H) ppm.
Massespektrum: m/e 369 (M<+>), 325 (M<+->C02), 300, 293, 269, Mass spectrum: m/e 369 (M<+>), 325 (M<+->CO 2 ), 300, 293, 269,
243, 44 (C02). 243, 44 (CO2).
Analogt eksempel 1 oppnår man med produktene fra eksemplene Z14, Z7 og Z9: Analogous to example 1, one obtains with the products from examples Z14, Z7 and Z9:
Eksempel 2 (R=CH3: l-cyklopropyl-6-f luor-1,4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-8-(propin-l-yl )-3-kinolinkarboksylsyre. Example 2 (R=CH3: 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(propyn-1-yl)-3- quinoline carboxylic acid.
Smeltepunkt: 246-249"C (under spalting). Melting point: 246-249"C (under cleavage).
Eksempel 3 (R=CH2CH2CH2CH3: l-cyklopropyl-6-fluor-8-(heksin-1-yl)-l,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso-3-kinolinkarboksylsyre. Example 3 (R=CH2CH2CH2CH3: 1-cyclopropyl-6-fluoro-8-(hexin-1-yl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid .
Smeltepunkt: 206-208°C (under spalting). Melting point: 206-208°C (under decomposition).
Eksempel 4 (R=C(CH3)3: l-cyklopropyl-8-(3,3-dimetylbutin-l-yl )-6-f luor-1, 4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-3-kinolinkarboksylsyre. Example 4 (R=C(CH3)3: 1-cyclopropyl-8-(3,3-dimethylbutyn-1-yl)-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl )-4-oxo-3-quinolinecarboxylic acid.
Smeltepunkt: 234-237°C (under spalting). Melting point: 234-237°C (under decomposition).
Eksempel 5 Example 5
Analogt eksempel 1 omsetter man med cis-2,8-diazabicyklo[4.3.0]nonan til l-cyklopropyl-7-(cis-2,8-diazabicyklo[4 . 3 . 0]non-8-yl )-8-etinyl-6-fluor-1, 4-dihydro-4-okso-3-kinolinkarboksylsyre med smeltepunkt 225-227°C (under spalting). Analogously to example 1, one reacts with cis-2,8-diazabicyclo[4.3.0]nonane to 1-cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-8- ethynyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 225-227°C (under decomposition).
<1->H-NMR (d<6->DMF): S 4,9 (s, -CEC-H) ppm. <1->H-NMR (d<6->DMF): S 4.9 (s, -CEC-H) ppm.
Eksempel 6 Example 6
3,6 g (12 mmol) l-cyklopropyl-8-etinyl-6,7-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre oppvarmes i en blanding av 120 ml acetonitril og 60 ml dimetylformamid med 1,56 g (14 mmol) 1,4-diazabicyklo[2.2.2]oktan og 2,75 g (18 mmol) 3-(2,2-dimetylpropylidenamino)pyrrolidin i en time under tilbakeløp. Oppløsningen dampes inn, resten omrøres med ca. 100 ml vann (pH 7), bunnfallet suges av, vaskes med vann og suspenderes derefter for fullstendig avspalting av beskyttelsesgruppen i 50 ml vann og behandles i en time i et ultralydbad. Derefter suges det hele av, vaskes med vann og tørkes ved 80°C under vakuum. 3.6 g (12 mmol) of 1-cyclopropyl-8-ethynyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in a mixture of 120 ml of acetonitrile and 60 ml of dimethylformamide with 1, 56 g (14 mmol) of 1,4-diazabicyclo[2.2.2]octane and 2.75 g (18 mmol) of 3-(2,2-dimethylpropylideneamino)pyrrolidine for one hour under reflux. The solution is evaporated, the residue is stirred with approx. 100 ml of water (pH 7), the precipitate is suctioned off, washed with water and then suspended for complete deprotection in 50 ml of water and treated for one hour in an ultrasonic bath. The whole thing is then sucked off, washed with water and dried at 80°C under vacuum.
Utbytte: 3,8 g (82% av det teoretiske 7-(3-amino-l-pyrroli-dinyl )-1-cyklopropyl-8-etinyl-6-f luor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydrat. Yield: 3.8 g (82% of the theoretical 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid hydrate.
Smeltepunkt: 193-196°C (under spalting). Melting point: 193-196°C (under decomposition).
Eksempel 7 Example 7
A) Analogt eksempel 1 omsetter man med 3-tert-butoksy-karbonylamino-3-metyl-pyrrolidin til 7-(3-tert-butoksy-karbonyl -3-metyl-l-pyrrolidinyl)-1-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre med smeltepunkt 244-246°C (under spalting). A) Analogously to example 1, one reacts with 3-tert-butoxy-carbonylamino-3-methyl-pyrrolidine to 7-(3-tert-butoxy-carbonyl-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl- 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with melting point 244-246°C (under decomposition).
%-NMR (d<6->DMS0): 5 4,92 (s, -C<=>C-H) ppm. %-NMR (d<6->DMS0): δ 4.92 (s, -C<=>C-H) ppm.
B) 500 mg av produktet fra trinn A oppløses i 5 ml trifluoreddiksyre under isavkjøling, oppløsningen dampes inn under vakuum, resten krystalliseres ved omrøring med tre ganger ca. 1 ml etanol, saltet suges av, vaskes med etanol og tørkes. B) 500 mg of the product from step A is dissolved in 5 ml of trifluoroacetic acid under ice-cooling, the solution is evaporated under vacuum, the residue is crystallized by stirring three times with approx. 1 ml of ethanol, the salt is sucked off, washed with ethanol and dried.
Utbytte: 270 mg (52% av det teoretiske) 7-(3-amino-3-metyl-l-pyrrolidinyl)-l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-trifluoracetat. Smeltepunkt: 242-244°C (under spalting). Yield: 270 mg (52% of theoretical) 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid trifluoroacetate. Melting point: 242-244°C (under decomposition).
Eksempel 8 Example 8
Analogt eksempel 1 omsettes med 2.oksa-5,8-diazabicyklo-[4.3.0]nonan til l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-7-(2-oksa-5,8-diazabicyklo[4.3.0]non-8-yl)-4-okso-3-kinolinkarboksylsyre med smeltepunkt 290°C (under spalting; sintrer allerede fra ca. 170°C). Analogous example 1 is reacted with 2.oxa-5,8-diazabicyclo-[4.3.0]nonane to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8 -diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 290°C (during cleavage; already sintering from about 170°C).
<1->H-NMR (d<6->DMS0): S 5,0 (s, -CEC-H) ppm. <1->H-NMR (d<6->DMS0): S 5.0 (s, -CEC-H) ppm.
Eksempel 9 Example 9
Analogt eksempel 1 omsettes 2-oksa-5,8-diazabicyklo[4.3.0]-nonan med produktet fra eksempel Z13 til 1—cyklopropyl-6- fluor-1,4-dihydro-7-(2-oksa-5,8-diazabicyklo[4.3.0]non-8-yl )-4-okso-8-(propin-l-yl )-3-kinolinkarboksylsyre med smeltepunkt 241-242°C (under spalting). Analogous to example 1, 2-oxa-5,8-diazabicyclo[4.3.0]-nonane is reacted with the product from example Z13 to 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-oxa-5,8 -diazabicyclo[4.3.0]non-8-yl)-4-oxo-8-(propyn-1-yl)-3-quinolinecarboxylic acid with melting point 241-242°C (under decomposition).
Eksempel 10 Example 10
A) Til 303 mg (1 mmol) av produktet fra eksempel Z14 settes det i en blanding av 6 ml acetonitril og 3 ml dimetylformamid til 240 mg 3-tert-butoksykarbonylamino-3-metyl-pyrrolidin og 134 mg (1,2 mmol) 1,4-diazabicyklo[2.2 .2]-oktan, hvorefter det hele omrøres i 2 timer under tilbakeløp. Det hele dampes inn under vakuum, omrøres med 30 ml vann og tørkes ved 80°C under vakuum. A) To 303 mg (1 mmol) of the product from example Z14 is added to a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide to 240 mg of 3-tert-butoxycarbonylamino-3-methyl-pyrrolidine and 134 mg (1.2 mmol) 1,4-diazabicyclo[2.2.2]-octane, after which the whole is stirred for 2 hours under reflux. The whole is evaporated under vacuum, stirred with 30 ml of water and dried at 80°C under vacuum.
Utbytte: 420 mg (87% av det teoretiske) 7-(3-tert-butoksykarbonylamino-3-metyl-l-pyrrolidinyl)-1-cyklopropyl -6 -fluor- 1 ,4-dihydro-4-okso-8-(propin-l-yl ) - 3-kinolinkarboksylsyre. Yield: 420 mg (87% of theoretical) 7-(3-tert-butoxycarbonylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-( propyn-1-yl)-3-quinolinecarboxylic acid.
Smeltepunkt: 195-196°C (under spalting). Melting point: 195-196°C (under cleavage).
-^H-NMR (d<6->DMS0): S 1,42 (s, CE3på pyrrolidin), -^H-NMR (d<6->DMS0): S 1.42 (s, CE3 on pyrrolidine),
2,12 (s, CH3-C<=>C-) ppm. 2.12 (s, CH3-C<=>C-) ppm.
B) 180 mg av produktet fra trinn A oppløses ved 0°C i 1,6 ml trifluoreddiksyre og oppløsningen dampes inn efter 1,25 timer. Resten renses kromatografisk (kiselgel; diklor-metan'.metanol: 17 %-ig vandig ammoniakk = 30:8:1). Man isolerer 10 mg 7-(3-amino-3-metyl-l-pyrrolidinyl )-1—cyklopropyl-6-fluor-1,4-dihydro-4-okso-8-(propin-l-yl)- B) 180 mg of the product from step A is dissolved at 0°C in 1.6 ml of trifluoroacetic acid and the solution is evaporated after 1.25 hours. The residue is purified chromatographically (silica gel; dichloromethane.methanol: 17% aqueous ammonia = 30:8:1). 10 mg of 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-(propyn-1-yl)-
3-kinolinkarboksylsyre med smeltepunkt 209-210°C (under spalting). 3-quinoline carboxylic acid with melting point 209-210°C (under decomposition).
Massespektrum: m/e 383 (M<+>), 309, 298, 267 (100%), 133, 70. Mass spectrum: m/e 383 (M<+>), 309, 298, 267 (100%), 133, 70.
Eksempel 11 Example 11
Analogt eksempel 1 omsetter man produktet fra eksempel Z12 med N-metylpiperazin til 8-etinyl-6-fluor-l-(2,4-difluor-fenyl )-l ,4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-3-kinolinkarboksylsyre med smeltepunkt 193-195°C (under spalting). Analogous to example 1, the product from example Z12 is converted with N-methylpiperazine to 8-ethynyl-6-fluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl) )-4-oxo-3-quinolinecarboxylic acid with melting point 193-195°C (under decomposition).
<1>H-NMR (CDC13): 5 3,35 (s, -C<=>CH). <1>H-NMR (CDCl 3 ): δ 3.35 (s, -C<=>CH).
Eksempel 12 Example 12
Analogt eksempel 1 omsetter man med 3-metyl-3,8-diazabicyklo-[4.3.0]nonan og renser det som råprodukt dannede 1-cyklopropyl -8-etinyl -6 -f luor-1 ,4-dihydro-7-(3-metyl-3 ,8-diazabicyklo[4.3.0]non-8-yl)-4-okso-3-kinolinkarboksylsyre kromatografisk (kiselgel; diklormetan:metanol:20 %-ig vandig ammoniakk 2:4:1). Analogous to example 1, one reacts with 3-methyl-3,8-diazabicyclo-[4.3.0]nonane and purifies the 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-( 3-methyl-3,8-diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid chromatographically (silica gel; dichloromethane:methanol:20% aqueous ammonia 2:4:1).
^H-NMR (CDCI3): 5 4,15 (s, -C<=>CH). 1 H-NMR (CDCl 3 ): δ 4.15 (s, -C<=>CH).
Eksempel 13 Example 13
Analogt eksempel 1 omsetter man med 3-metyl-3,7-diazabicyklo-[3.3.0]oktan til l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-7-(7-metyl-3,7-diazabicyklo[3.3.0]okt-3-yl ) -4-okso-3-kinolinkarboksylsyre med smeltepunkt 212-216°C (under spalting). Analogously to example 1, one reacts with 3-methyl-3,7-diazabicyclo-[3.3.0]octane to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(7-methyl-3, 7-diazabicyclo[3.3.0]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 212-216°C (under decomposition).
<1->NMR (d<6->DMF): S 4,95 (s, -CEC-H). <1->NMR (d<6->DMF): S 4.95 (s, -CEC-H).
Eksempel 14 Example 14
Analogt eksempel 1 omsettes med 4-metylamino-l,3,3a,4,7,7a-heksahydroisoindol til l-cyklopropyl-8-etinyl-6-fluor-1,4-dihydro-7-(4 -metyl am ino-1,3, 3a, 4 ,7 , 7a-heksahydroisoindol-2-yl)-4-okso-3-kinolinkarboksylsyre med smeltepunkt 128-133°C (under spalting). Analogous example 1 is reacted with 4-methylamino-1,3,3a,4,7,7a-hexahydroisoindole to 1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-(4-methylamino- 1,3,3a,4,7,7a-hexahydroisoindol-2-yl)-4-oxo-3-quinolinecarboxylic acid with melting point 128-133°C (under decomposition).
<1>H-NMR (d<6->DMSO): S 4,93 (s, -C<=>CE) ppm. <1>H-NMR (d<6->DMSO): S 4.93 (s, -C<=>CE) ppm.
Eksempel 15 Example 15
164 mg (0,5 mmol) av produkt fra eksempel Z18 omsettes analogt eksempel 1 med 1-metylpiperazin til 120 mg 1-cyklopropy 1 -6-f luor-1,4-dihydro-8-(3-metyl-but-3-en-l-inyl )-7-(4-metyl-l-piperazinyl)-4-okso-3-kinolinkarboksylsyre med smeltepunkt 195-19VC (under spalting) (omkrystallisert fra glykolmonometyleter). 164 mg (0.5 mmol) of product from example Z18 is reacted analogously to example 1 with 1-methylpiperazine to 120 mg 1-cyclopropyl 1-6-fluoro-1,4-dihydro-8-(3-methyl-but-3 -en-1-ynyl)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid m.p. 195-19 VC (under cleavage) (recrystallized from glycol monomethyl ether).
■^E-NMR (CDC13): § 5,36 (m, >C=CE2), 2,4 (s, N-CE3), ■^E-NMR (CDC13): § 5.36 (m, >C=CE2), 2.4 (s, N-CE3),
3,0 (t, C-CE3) 3.0 (h, C-CE3)
Eksempel 16 Example 16
O O
Analogt eksempel 15 omsettes med 2 ,8-diazabicyklo[4.3.0]nonan til l-cyklopropyl-7-(2,8-diazabicyklo[4.3.0]non-8-yl)-6-f luor-1 , 4-dihydro-8-(3-metyl-but-3-en-l-inyl) -4-okso-3-kinolinkarboksylsyre med smeltepunkt 201-202°C (under spalting). Analogous example 15 is reacted with 2,8-diazabicyclo[4.3.0]nonane to 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4- dihydro-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylic acid with melting point 201-202°C (under decomposition).
Eksempel 17 Example 17
Analogt eksempel 15 omsettes med Analogous example 15 is reacted with
B. 3-hydroksypyrrolidin B. 3-Hydroxypyrrolidine
til de følgende forbindelser: to the following compounds:
B . 1 - cyk lopropyl-6-fluor-l,4-dihydro-7-( 3-hy dr ok sy-1- pyrrolidinyl )-8-(3-metyl-but-3-en-l-inyl )-4-okso-3-kinolinkarboksylsyre, B. 1 - cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-1- pyrrolidinyl)-8-(3-methyl-but-3-en-l-inyl)-4-oxo-3-quinolinecarboxylic acid,
Smeltepunkt 190-198°C (under spalting), Melting point 190-198°C (under decomposition),
Eksempel 18 Example 18
100 mg av produktet fra eksempel 1 oppløses i 40 ml IN saltsyre og omrøres i 2 timer ved 30° C. Man oppnår en suspensjon som dampes inn. Resten omrøres med' litt isopropanol , resten suges av, vaskes med isopropanol og tørkes ved 90°C under vakuum. 100 mg of the product from example 1 is dissolved in 40 ml IN hydrochloric acid and stirred for 2 hours at 30° C. A suspension is obtained which is evaporated. The residue is stirred with a little isopropanol, the residue is sucked off, washed with isopropanol and dried at 90°C under vacuum.
Utbytte: 0,1 g (83% av det teoretiske) 8-(1-klorvinyl)-l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso-3-kinolinkarboksylsyre-hydroklorid. Yield: 0.1 g (83% of theory) 8-(1-chlorovinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo -3-quinolinecarboxylic acid hydrochloride.
Smeltepunkt: 251-252°C (under spalting). Melting point: 251-252°C (under decomposition).
<1>H-NMR (d<6->DMSO): S 6,0 (dd, -C=CH2) ppm. <1>H-NMR (d<6->DMSO): S 6.0 (dd, -C=CH2) ppm.
Eksempel 19 Example 19
A) 100 mg av produktet fra eksempel 2 oppvarmes i 58 ml 4N saltsyre i 5 timer til 60°C. Blandingen dampes inn, resten omrøres med dietyleter og tørkes ved 70°C under vakuum. A) 100 mg of the product from example 2 is heated in 58 ml of 4N hydrochloric acid for 5 hours to 60°C. The mixture is evaporated, the residue is stirred with diethyl ether and dried at 70°C under vacuum.
Utbytte: 90 mg cis-trans-8-(1-klor-l-propenyl)-l-cyk lopropyl-6-fluor-l,4-dihydro-7-(4-metyl-l-pipera-zinyl)-4-okso-3-kinolinkarboksylsyre-hydroklorid. Smeltepunkt: 236-237°C (under spalting). Yield: 90 mg of cis-trans-8-(1-chloro-1-propenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4 -oxo-3-quinolinecarboxylic acid hydrochloride. Melting point: 236-237°C (under decomposition).
Massespektrum: m/e 419 (M<+>), 71, 58 (100%), 43, 36. Mass spectrum: m/e 419 (M<+>), 71.58 (100%), 43.36.
■^H-NMR (d<6->DMS0): 5 6,12 og 6,35 (q, -C=CH-CH3; ■^H-NMR (d<6->DMS0): δ 6.12 and 6.35 (q, -C=CH-CH3;
to signaler for cis-trans-former). two signals for cis-trans forms).
B) Analogt oppnår man med produktet fra eksempel 3 cis-trans-8- ( 1-k 1 or-1-heksenyl )-l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso~3-kinolinkarboksylsyre-hydroklorid. Massespektrum: m/e 461 (M<+>), 425 (M-HC1), 71, 58 (100%), 43, 36. Eksempel 20 B) Analogously, one obtains with the product from example 3 cis-trans-8-(1-k1or-1-hexenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1 -piperazinyl)-4-oxo~3-quinolinecarboxylic acid hydrochloride. Mass spectrum: m/e 461 (M<+>), 425 (M-HCl), 71.58 (100%), 43.36. Example 20
370 mg av produktet fra eksempel 10A oppløses i 9 ml halvkonsentrert saltsyre og oppløsningen dampes inn under høyvakuum. 370 mg of the product from example 10A are dissolved in 9 ml of semi-concentrated hydrochloric acid and the solution is evaporated under high vacuum.
Utbytte: 340 mg cis-trans-7-(3-amino-3-metyl-l-pyrrolidinyl )-8-(1-klor-l-propenyl )-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre-hydroklorid. Yield: 340 mg of cis-trans-7-(3-amino-3-methyl-1-pyrrolidinyl)-8-(1-chloro-1-propenyl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid hydrochloride.
1-H-NMR (d<6->DMS0): S 6,19 og 6,36 (q, >C=CH-CH3; to signaler 1-H-NMR (d<6->DMS0): S 6.19 and 6.36 (q, >C=CH-CH3; two signals
for cis-trans-former). for cis-trans forms).
Eksempel 21 Example 21
10 mg av produktet fra eksempel 11 oppvarmes i 4,5 ml 2,5N saltsyre i en time til 60° C. Blandingen dampes inn og som rest oppnår man 8-(1-klorvinyl)-6-fluor-l-(2,4-difluorfenyl)-1 ,4-dihydro-7-(4-metyl-l-piperazinyl )-4-okso-3-kinolinkarboksylsyre-hydroklorid. 10 mg of the product from example 11 is heated in 4.5 ml of 2.5N hydrochloric acid for one hour to 60° C. The mixture is evaporated and as a residue 8-(1-chlorovinyl)-6-fluoro-1-(2, 4-difluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride.
Massespektrum: m/e 477 (M<+>), 442 (M<+->C1), 36 (100%, HC1). Mass spectrum: m/e 477 (M<+>), 442 (M<+->C1), 36 (100%, HC1).
Eksempel 22 Example 22
Til 291 mg (1 mmol) av produktet fra eksempel Z2 settes det i en blanding av 20 ml acetonitril og 10 ml dimetylformamid, 240 mg (2,2 mmol) 1,4-diazabicyklo[2.2.2]oktan og 360 mg (2,3 mmol) 3-(2,2-dimetyl-propylidenamino)-pyrrolidin og blandingen oppvarmes i 32 timer under tilbakeløp. Det hele dampes inn, hvorefter den mørke oljelignende rest røres med 10 ml vann og de 103 mg dannet faststoff suges av og renses kromatografisk (silikagel: diklormetanrmetanol:17 %-ig vandig ammoniakk 30:8:1). To 291 mg (1 mmol) of the product from example Z2 is added to a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide, 240 mg (2.2 mmol) of 1,4-diazabicyclo[2.2.2]octane and 360 mg (2 .3 mmol) 3-(2,2-dimethyl-propylideneamino)-pyrrolidine and the mixture is heated for 32 hours under reflux. The whole is evaporated, after which the dark oil-like residue is stirred with 10 ml of water and the 103 mg of solid formed is sucked off and purified chromatographically (silica gel: dichloromethane/methanol: 17% aqueous ammonia 30:8:1).
Utbytte: 58 mg (16% av det teoretiske) 7-(3-amino-l-pyrroli-dinyl )-l-cyklopropyl-6-f luor-1 , 4-dihydro-4-okso-8-vinyl-3-kinolinkarboksylsyre. Yield: 58 mg (16% of theoretical) 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-vinyl-3- quinoline carboxylic acid.
Smeltepunkt: 179-182"C (under spalting). Melting point: 179-182"C (under cleavage).
CI-massespektrum: m/e 358 ([M+H]<+>), 340 ([M+H-H20]<+>). CI mass spectrum: m/e 358 ([M+H]<+>), 340 ([M+H-H 2 O]<+>).
Eksempel 23 Example 23
Til 145 mg (0,5 mmol) av produktet fra eksempel Z2 blir det i en blanding av 10 ml acetonitril og 5 ml dimetylformamid satt 60 mg (0,54 mmol) 1,4-diazabicyklo[2.2.2]oktan og 140 mg (1,1 mmol) cis-2,8-diazabicyklo[4.3.0]nonan og oppvarmet i 4 timer til tilbakeløp. Blandingen dampes inn, røres med 5 ml vann og innstilles til pH 7 med fortynnet saltsyre. Bunnfallet suges av, vaskes med vann og tørkes ved 90°C under vakuum. To 145 mg (0.5 mmol) of the product from example Z2, 60 mg (0.54 mmol) 1,4-diazabicyclo[2.2.2]octane and 140 mg are added to a mixture of 10 ml acetonitrile and 5 ml dimethylformamide (1.1 mmol) of cis-2,8-diazabicyclo[4.3.0]nonane and heated for 4 hours to reflux. The mixture is steamed in, stirred with 5 ml of water and adjusted to pH 7 with dilute hydrochloric acid. The precipitate is sucked off, washed with water and dried at 90°C under vacuum.
Utbytte: 120 mg (61% av det teoretiske) l-cyklopropyl-7-(cis-2,8-diazabicyklo[4.3.0]non-8-yl)-6-fluor-1,4-dihydro-4-okso-8-vinyl-3-kinolinkarboksylsyre. Yield: 120 mg (61% of theoretical) 1-cyclopropyl-7-(cis-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo -8-vinyl-3-quinolinecarboxylic acid.
Smeltepunkt: 205-207°C (under spalting). Melting point: 205-207°C (under decomposition).
<1->H-NMR (CF3COOD): 5 5,05 (d, 1H), 5,7 (d, 1H), 7,55 (dd, <1->H-NMR (CF3COOD): δ 5.05 (d, 1H), 5.7 (d, 1H), 7.55 (dd,
1H), (signalgruppper for -CH=CH2)• 1H), (signal groups for -CH=CH2)•
Eksempel 24 Example 24
Analogt eksempel 1 omsetter man med produktet fra eksempel Z26 og oppnår l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-8-(3-metoksy-propin-l-yl)-4-okso-3-kinolinkarboksylsyre med smeltepunkt 187-189°C. Analogously to example 1, one reacts with the product from example Z26 and obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-8-(3-methoxy-propyn-1-yl) )-4-oxo-3-quinolinecarboxylic acid with melting point 187-189°C.
^H-NMS (CDCI3): § 8,95 (s, 1E), 8 (d, 1E), ^H-NMS (CDCI3): § 8.95 (s, 1E), 8 (d, 1E),
4,37 (s, 0-CE2), 4,35 (m, 1E), 3,58 (m, 4E), 4.37 (s, 0-CE2), 4.35 (m, 1E), 3.58 (m, 4E),
3,43 (s, O-CE3), 2,58 (m, 4H), 2,38 (s, N-CE3), 1,33 (m, 2E), 1,02 (m, 2E) ppm. 3.43 (s, O-CE3), 2.58 (m, 4H), 2.38 (s, N-CE3), 1.33 (m, 2E), 1.02 (m, 2E) ppm.
Eksempel 25 Example 25
Analogt eksempel 1 omsetter man med 3,7-diazabicyklo[3.3.0]-oktan, kromatograferer reaksjonsproduktet på silikagel med diklormetan:metanol:17 %-ig ammoniakk (30:8:1) som eluerings-middel og oppnår l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre som "stivnet skum". Analogously to example 1, one reacts with 3,7-diazabicyclo[3.3.0]-octane, the reaction product is chromatographed on silica gel with dichloromethane:methanol:17% ammonia (30:8:1) as eluent and obtains l-cyclopropyl 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as "solidified foam".
•^H-NMR (d<6->DMS0): S 4,9 (s, -C<=>CH). 1 H-NMR (d<6->DMS0): S 4.9 (s, -C<=>CH).
Claims (6)
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DE4123918A DE4123918A1 (en) | 1991-07-19 | 1991-07-19 | 8-VINYL AND 8-ETHINYL-CHINOLON CARBONIC ACIDS |
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JP (1) | JP3174405B2 (en) |
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AU (1) | AU658901B2 (en) |
CA (1) | CA2073993A1 (en) |
CZ (1) | CZ282037B6 (en) |
DE (2) | DE4123918A1 (en) |
DK (1) | DK0523512T3 (en) |
ES (1) | ES2097835T3 (en) |
FI (1) | FI103043B (en) |
GR (1) | GR3022305T3 (en) |
HU (1) | HU219910B (en) |
IE (1) | IE80557B1 (en) |
IL (1) | IL102520A (en) |
MX (1) | MX9204110A (en) |
NO (1) | NO302886B1 (en) |
PL (1) | PL171910B1 (en) |
RU (1) | RU2077533C1 (en) |
SK (1) | SK279221B6 (en) |
TW (1) | TW201309B (en) |
ZA (1) | ZA925351B (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4121214A1 (en) * | 1991-06-27 | 1993-01-14 | Bayer Ag | 7-AZAISOINDOLINYL CHINOLONE AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES |
DE4230804A1 (en) * | 1992-09-15 | 1994-03-17 | Bayer Ag | 7-isoindolinyl quinolone and naphthyridone derivatives |
DE4303657A1 (en) * | 1993-02-09 | 1994-08-11 | Bayer Ag | New quinolone and naphthyridonecarboxylic acid derivatives |
KR950018003A (en) * | 1993-12-09 | 1995-07-22 | 스미스클라인 비참 피엘씨 | Novel quinolone derivatives and methods for their preparation |
DE4418510A1 (en) * | 1994-05-27 | 1995-11-30 | Bayer Ag | 1,9-bridged thiazolol [3,4-a] quinoline derivatives |
DE4425659A1 (en) * | 1994-07-20 | 1996-01-25 | Bayer Ag | New N1-diverse 6-fluoro-8-difluoromethoxy substituted quinolonecarboxylic acids |
DE4427530A1 (en) * | 1994-08-04 | 1996-02-08 | Bayer Ag | New 7-tri:cyclic amino-quinolone or naphthyridone derivs |
US6211375B1 (en) | 1996-04-19 | 2001-04-03 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents containing the same as the active ingredient |
AU1040597A (en) * | 1996-12-04 | 1998-06-29 | Daiichi Pharmaceutical Co., Ltd. | Substituted aminomethylpyrrolidine derivatives |
EP1015445B1 (en) | 1997-09-15 | 2009-02-25 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
CN100410249C (en) | 2003-09-10 | 2008-08-13 | 杏林制药株式会社 | 7-(4-substituted 3- cyclopropylaminomethyl-1- pyrrolidinyl) Q uinolonecarboxylic acid derivative |
US7563805B2 (en) * | 2005-05-19 | 2009-07-21 | Daiichi Pharmaceutical Co., Ltd. | Tri-, tetra-substituted-3-aminopyrrolidine derivative |
JP5073497B2 (en) * | 2005-09-28 | 2012-11-14 | 第一三共株式会社 | Process for producing tetra-substituted-5-azaspiro [2.4] heptane derivative and optically active intermediate thereof |
US7456279B2 (en) | 2006-03-28 | 2008-11-25 | The Procter & Gamble Company | Coupling process for preparing quinolone intermediates |
SMP200800058B (en) | 2006-03-28 | 2009-09-07 | Procter & Gamble | Diseased salts and polymorphs of an acid (3s, 5s) -7- [3-amino-5-methylpiperidinyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolincarboxylic |
US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
PT3790874T (en) * | 2018-05-09 | 2023-05-31 | Bayer Animal Health Gmbh | New quinoline derivatives |
RU2757741C1 (en) * | 2021-03-01 | 2021-10-21 | Федеральное государственное бюджетное учреждение науки Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук (ИХБФМ СО РАН) | Ciprofloxacin derivative with antibacterial activity against antibiotic-resistant strains of microorganisms |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4123536A (en) * | 1977-12-14 | 1978-10-31 | Warner-Lambert Company | Dialkyl ({[3-(alkoxycarbonyl)-1,4-dihydro-4-oxo-8-quinolinyl]amino}methylene)propanedioates |
DE3705621C2 (en) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclic substituted quinolonecarboxylic acid derivatives |
JPS62215572A (en) * | 1986-03-17 | 1987-09-22 | Kyorin Pharmaceut Co Ltd | Quinolone carboxylic acid derivative |
US5047538A (en) * | 1990-04-12 | 1991-09-10 | Warner-Lambert Company | Quinolinecarboxylic acid antibacterial agents |
-
1991
- 1991-07-19 DE DE4123918A patent/DE4123918A1/en not_active Withdrawn
-
1992
- 1992-06-26 TW TW081105031A patent/TW201309B/zh active
- 1992-07-03 NO NO922639A patent/NO302886B1/en not_active IP Right Cessation
- 1992-07-06 AT AT92111454T patent/ATE147733T1/en not_active IP Right Cessation
- 1992-07-06 DK DK92111454.2T patent/DK0523512T3/en active
- 1992-07-06 DE DE59207880T patent/DE59207880D1/en not_active Expired - Fee Related
- 1992-07-06 ES ES92111454T patent/ES2097835T3/en not_active Expired - Lifetime
- 1992-07-06 EP EP92111454A patent/EP0523512B1/en not_active Expired - Lifetime
- 1992-07-13 CZ CS922191A patent/CZ282037B6/en not_active IP Right Cessation
- 1992-07-13 SK SK2191-92A patent/SK279221B6/en unknown
- 1992-07-14 MX MX9204110A patent/MX9204110A/en not_active IP Right Cessation
- 1992-07-14 AU AU19663/92A patent/AU658901B2/en not_active Ceased
- 1992-07-16 CA CA002073993A patent/CA2073993A1/en not_active Abandoned
- 1992-07-16 FI FI923268A patent/FI103043B/en active IP Right Grant
- 1992-07-16 IL IL102520A patent/IL102520A/en not_active IP Right Cessation
- 1992-07-17 ZA ZA925351A patent/ZA925351B/en unknown
- 1992-07-17 IE IE922348A patent/IE80557B1/en not_active IP Right Cessation
- 1992-07-17 PL PL92295331A patent/PL171910B1/en unknown
- 1992-07-17 RU SU925052410A patent/RU2077533C1/en active
- 1992-07-17 HU HU9202349A patent/HU219910B/en not_active IP Right Cessation
- 1992-07-17 JP JP21245092A patent/JP3174405B2/en not_active Expired - Fee Related
- 1992-07-18 KR KR1019920012826A patent/KR100240608B1/en not_active IP Right Cessation
-
1997
- 1997-01-16 GR GR970400065T patent/GR3022305T3/en unknown
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