NO860199L - Mellomprodukter for fremstilling av 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrer. - Google Patents
Mellomprodukter for fremstilling av 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrer.Info
- Publication number
- NO860199L NO860199L NO860199A NO860199A NO860199L NO 860199 L NO860199 L NO 860199L NO 860199 A NO860199 A NO 860199A NO 860199 A NO860199 A NO 860199A NO 860199 L NO860199 L NO 860199L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- dichloro
- fluoro
- pyridine
- oxo
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000002253 acid Substances 0.000 title description 10
- 239000000543 intermediate Substances 0.000 title description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- AATVXELAYCLVTJ-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)N=C1Cl AATVXELAYCLVTJ-UHFFFAOYSA-N 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- NIISFIOQIFTOHO-UHFFFAOYSA-N 2,6-dichloro-3-fluoro-5-(trichloromethyl)pyridine Chemical compound FC1=CC(C(Cl)(Cl)Cl)=C(Cl)N=C1Cl NIISFIOQIFTOHO-UHFFFAOYSA-N 0.000 claims description 4
- MLLNKLGZTFCNLX-UHFFFAOYSA-N 2,6-dichloro-3-fluoro-5-methylpyridine Chemical compound CC1=CC(F)=C(Cl)N=C1Cl MLLNKLGZTFCNLX-UHFFFAOYSA-N 0.000 claims description 4
- LTDGKGCHRNNCAC-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)N=C1Cl LTDGKGCHRNNCAC-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- LEWFSKUZZGCGRZ-UHFFFAOYSA-N n-[(2,6-dichloro-5-methylpyridin-3-yl)diazenyl]-n-methylmethanamine Chemical compound CN(C)N=NC1=CC(C)=C(Cl)N=C1Cl LEWFSKUZZGCGRZ-UHFFFAOYSA-N 0.000 claims description 4
- OWYDPZWYAJXJAP-UHFFFAOYSA-N 2,6-dichloro-5-methylpyridin-3-amine Chemical compound CC1=CC(N)=C(Cl)N=C1Cl OWYDPZWYAJXJAP-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- IEUHWNLWVMLHHC-UHFFFAOYSA-N ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(Cl)N=C1Cl IEUHWNLWVMLHHC-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 2
- HNKGZXBNJREHKB-UHFFFAOYSA-N ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanoate Chemical compound CCOC(=O)CC(=O)C1=CC(Cl)=C(Cl)N=C1Cl HNKGZXBNJREHKB-UHFFFAOYSA-N 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- -1 6,7-disubstituted 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids Chemical class 0.000 description 28
- 239000013543 active substance Substances 0.000 description 21
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 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 6
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 5
- OXNZWNNMJBOZQO-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OXNZWNNMJBOZQO-UHFFFAOYSA-N 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229960003237 betaine Drugs 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- SKYHBWSFRMRRRT-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 SKYHBWSFRMRRRT-UHFFFAOYSA-N 0.000 description 3
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 3
- DIIGIVQFLCMUHK-UHFFFAOYSA-N 6,7-dichloro-1-cyclopropyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(Cl)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIIGIVQFLCMUHK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000000440 bentonite Substances 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- 229910000278 bentonite Inorganic materials 0.000 description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 2
- DRWKYBUROSTSFN-UHFFFAOYSA-N 2,5,6-trichloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC(Cl)=C(Cl)N=C1Cl DRWKYBUROSTSFN-UHFFFAOYSA-N 0.000 description 2
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 2
- ADRTUKIARNMSOV-UHFFFAOYSA-N 6-chloro-1-cyclopropyl-4-oxo-7-piperazin-1-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(N3CCNCC3)=C(Cl)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ADRTUKIARNMSOV-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000305071 Enterobacterales Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
Description
Foreliggende oppfinnelse vedrører mellomprodukter for fremstilling av 6,7-disubstituerte 1-cyklopropyl-l,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyrer, og fremgangsmåter for fremstilling derav.
Det er funnet at de nye 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyrene av formel (I)
hvor
X står for halogen eller nitro, og
spesielt klor eller fluor, hvor
R 1 star for hydrogen, en forgrenet eller uforgrenet alkylgruppe med 1-4 karbonatomer, som eventuelt kan være substituert med en hydroksy- eller metoksygruppe, en eventuelt med hydroksy, metoksy, klor eller fluor substituert fenacylrest, en oksoalkylrest med 2-4 karbonatomer, 4-aminobenzyl, formyl eller acetyl,
R 2 star for hydrogen, metyl eller eventuelt med klor, fluor,
metyl, hydroksy eller metoksy substituert fenyl eller tienyl,
R"3 står for hydrogen eller metyl og
R står for hydrogen, hydroksy, amino, alkyl- eller dialkyl-amino med 1 eller 2 karbonatomer i alkylgruppen, hydroksy-metyl, aminometyl, alkyl- eller dialkylaminometyl med 1 eller 2 karbonatomer i alkylgruppen,
og deres farmasøytisk anvendelige hydrater, syreaddisjons-salter, alkali-, jordalkali-, sølv- og guanidiniumsalter,
samt i form av deres estere og i andre vanlige "prodrug"-former oppviser høy antibakteriell aktivitet.
De egner seg derfor som virksomt stoff for human- og veterinærmedisin, under veterinærmedisin hører også behandling av fisk til terapi eller forebyggelse av bakterielle infeksjoner.
Foretrukket er de forbindelsene av formel (I) hvor
X står for klor eller fluor og
spesielt klor eller fluor, hvor
R"'" står for hydrogen, en forgrenet eller uforgrenet alkylgruppe med 1-3 karbonatomer, som eventuelt kan være substituert med en hydroksygruppe, en eventuelt med klor eller fluor substituert fenacylrest, en oksoalkylrest med 3 eller 4 karbonatomer, 4-aminobenzyl, formyl eller acetyl,
R 2 star for hydrogen, metyl eller eventuelt med klor eller
fluor substituert fenyl,
R<3>står for hydrogen eller metyl og
R^ står for hydrogen, hydroksy, amino, aminometyl, metylaminometyl, etylaminometyl eller dietylaminometyl.
Spesielt foretrukket er de forbindelsene av formel (I) hvor X står for klor eller fluor og
spesielt klor eller fluor, hvor
R"*" står for hydrogen, metyl, etyl, 2-hydroksyetyl, fenacyl, ;2-oksopropyl, 3-oksobutyl eller formyl,;R 2 står for hydrogen, metyl eller fenyl,;R står for hydrogen eller metyl og;R^ står for hydrogen, amino, aminometyl, etylaminometyl eller ;dietylaminometyl.;Foretrukket er forøvrig forbindelsene av formel (I) 1 form av deres metyl-, etyl-, pivaloyloksymetyl-, pivaloyloksy-etyl- eller (5-metyl-2-okso-l,3-dioksol-4-yl-metyl)-estere. ;Videre er det funnet at man får forbindelsene av formel (I) når man omsetter l-cyklopropyl-7-halogen-l,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrene av formel (II) ; ;
hvor ;X har den ovenfor angitte betydning og;Y står for halogen, fortrinnsvis klor eller fluor, med aminer av formel (III) ;
hvor ;A har den ovenfor angitte betydning,;eventuelt i nærvær av syrebindende midler (fremgangsmåte A). ;Forbindelser ifølge oppfinnelsen av formel (I) kan også oppnås ved at man omsetter 1-cyklopropyl-l,4-dihydro-4-okso-7-(l-piperazinyl)-l,8-naftyridin-3-karboksylsyrer av formel (IV) ; ;
hvor ;X, R 2 og R 3 har de ovenfor angitte betydninger, med forbindelser av formel (V) ; ;
hvor ;R"*" har den ovenfor angitte betydning, men kan ikke være
hydrogen, og
Z er halogen, spesielt klor, brom eller jod, acyloksy,
etoksy eller hydroksy,
eventuelt i nærvær av syrebindende midler (fremgangsmåte B).
Man oppnår også forbindelsene av formel (I) (R^CH^-CO-Cf^CH^) ifølge oppfinnelsen når man omsetter en forbindelse av for-
mel (IV) med metylvinylketon av formel (VI)
(fremgangsmåte C).
Dersom man ved omsetningen ifølge fremgangsmåte A anvender 2-metyl-piperazin og 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre som utgangsstoff, så kan reaksjonsforløpet angis ved følgende formelskj erna:
Anvender man eksempelvis ved omsetningen ifølge fremgangsmåte B kloraceton og 6-klor-l-cyklopropyl-l,4-dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre som utgangsstoffer, så kan reaksjonsforløpet angis ved følgende reak-sj onsskj erna:
Dersom man eksempelvis ifølge fremgangsmåte C anvender metylvinylketon og l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre som utgangs forbindelser, så kan reaksjonsforløpet gjengis ved følgende
formelskj erna:
De som utgangsstoffer ved fremgangsmåte A anvendte 1-cyklo-propyl-7-halogen-l,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyrene av formel (II) kan fremstilles i overensstemmelse med følgende reaksjonsskjema:
Deretter acyleres malonsyredietylester (2) i nærvær av magne-siumetylat med det tilsvarende nikotinsyrehalogenidet (1)
til acylmalonester (3) (Organicum, 3 . opplag 19 64, s. 438).
Ved partiell forsåpning og dekarboksylering av (3) i vandig medium med katalytiske mengder svovelsyre eller 4-toluensulfonsyre får man med godt utbytte acyleddiksyreetylesteren (4), som med ortomaursyre-trietylester/acetanhydrid går over til 2-(nikotinoyl)-3-etoksy-akrylsyreetylester (5). Omsetningen av (5) "med cyklopropylamin i et oppløsningsmiddel,
som f.eks. metylenklorid, en alkohol, kloroform, cykloheksan eller toluen fører ved en lett eksoterm reaksjon til det ønskede mellomproduktet (6).
Ringslutningsreaksjonen (6) + (7) gjennomføres i et temperatur-område fra ca. 60 til 300°C, fortrinnsvis 80 til 180°C.
Som fortynningsmiddel kan dioksan, dimetylsulfoksyd, N-metyl-pyrrolidon, sulfolan, heksametylfosforsyretrisamid og fortrinnsvis N,N-dimetylformamid anvendes.
Som syrebindende middel kommer for dette reaksjonstrinnet kalium-tert-butanolat, butyl-litium, litium-fenyl, fenyl-magnesiumbromid, natriummetylat, natriumhydrid, natrium-
eller kaliumkarbonat i betraktning. Spesielt foretrukket er kalium- eller natriumfluorid, når hydrogenfluorid må avspal-tes. Det kan være fordelaktig å anvende et overskudd på
10 mol-% av basen.
Esterhydrolysen som foregår i det siste trinnet fra (7)
under basiske eller sure betingelser fører til 1-cyklo-propy1-7-halogen-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyrene (II).
Det som utgangsstoff for denne syntesefremgangsmåten anvendte 2,5,6-triklorpyridin-3-karboksylsyrekloridet [Heiv. Chim. Acta 5_9, 222 (1976 )] er allerede kjent. 2,6-diklor-5-fluor-pyridin-3-karboksylsyreklorid kan oppnås på følgende måte: 5-amino-2, 6-diklor-3-metylpyridin [Heiv. Chim. Acta 5_9, 190
(1976)] overføres via 2,6-diklor-3-metyl-5-(3,3-dimetyl-1- triazeno)-pyridin eller ved en Baltz-Schiemann-reaksjon til 2,6-diklor-5-fluor-3-metyl-pyridin. Dette kloreres til 2,6-diklor-5-fluor-3-triklormetyl-pyridin. Ved etter-følgende hydrolyse med svovelsyre får man karboksylsyren,
som på vanlig måte omvandles til 2,6-diklor-5-fluor-pyridin-3-karboksylsyreklorid. Alternativt til dette kan man også overføre 5-fluor-2,6-dihydroksy-pyridin-3-karboksamid [J. Amer. Chem. Soc. 101, 4423 (1979); J. Org. Chem. 46, 846
(1981)] med fosforoksyklorid til 2,6-diklor-5-fluor-pyridin-3-karbonitril og omsetter dette etter forsåpning til karboksylsyre til syreklorid. Ved oksydasjon av 2,6-diklor-3-klor-metyl-5-nitro-pyridin [Heiv. Chim. Acta 59_, 190 ( 1976)] får man den tilsvarende nikotinsyren som sammen med tionylklorid gir 2,6-diklor-5-nitro-pyridin-3-karboksylsyreklorid.
De som utgangsstoffer anvendte aminene av formel (III) er kjente [US-PS 4.166.180, J. Med. Chem. 26, 1116 (1983)].
Som eksempler kan nevnes: piperazin, N-metylpiperazin, N-etylpiperazin, N-(2-hydroksyetyl)-piperazin, N-(2-metoksy-etyl)-piperazin, N-propylpiperazin, N-isopropyl-piperazin, N-butylpiperazin, N-(sek-butyl)-piperazin, N-formylpiperazin, 2- metylpiperazin, cis- og trans-2,6-dimetylpiperazin, 2-fenyl-piperazin- 2-(4-fluorfenyl)-piperazin, 2-(4-klorfenyl)-piperazin, 2-(4-metylfenyl)-piperazin, 2-(4-metoksyfenyl)-piperazin, 2-(4-hydroksyfenyl)-piperazin, 2-(2-tienyl)-piperazin, pyrrolidin, 3-amino-pyrrolidin, 3-aminometyl-pyrrolidin, 3-metylaminometyl-pyrrolidin, 3-dimetylaminometyl-pyrrolidin, 3-etylaminometyl-pyrroiidin, 3-hydroksy-pyrrolidin.
De som utgangsstoffer anvendte forbindelsene av formel (V)
er kjente. Som eksempler kan nevnes: metyljodid, metyl-bromid, etyljodid, etylbromid, 2-hydroksyetylklorid, 3-hydroksypropylklorid, n-propylbromid, isopropyljodid, n-butyl-bromid, sek-butyljodid, isobutylbromid, maursyre-eddiksyreanhydrid, maursyreetylester, maursyre, eddiksyreanhydrid, acetylklorid.
Omsetningen av (II) med (III) ifølge fremgangsmåte A foretas fortrinnsvis i et fortynningsmiddel som dimetylsulfoksyd, N,N-dimetylformamid, heksametyl-fosforsyretrisamid, sulfolan, vann, en alkohol som metanol, etanol, n-propanol, isopropanol, glykolmonometyleter eller pyridin. Videre kan blandinger av disse fortynningsmidlene anvendes.
Som syrebindende middel kan alle vanlige uorganiske og organiske syrebindende midler anvendes. Herunder hører fortrinnsvis alkalihydroksydene, alkalikarbonatene, organiske aminer og amidiner. Som spesielt egnede skal særskilt nevnes: trietylamin, 1,4-diaza-biscyklo[2,2,2]-oktan (DABCO), 1,8-diaza-bicyklo[5,4,0]-undek-7-en (DBU) eller overskudd amin (III) .
Reaksjonstemperaturen kan varieres innenfor et stort område. Generelt arbeider man mellom ca. 20 og 200°C, fortrinnsvis mellom 80 og 180°C.
Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Generelt arbeider man ved trykk mellom ca.
1 og ca. 100 bar, fortrinnsvis mellom 1 og 10 bar.
Ved gjennomføringen av fremgangsmåten ifølge oppfinnelsen anvender man til 1 mol karboksylsyre (II) 1-15 mol, fortrinns-
vis 1-6 mol av aminet (III).
Frie aminogrupper kan beskyttes under omsetningen ved hjelp av en egnet aminobeskyttelsesgruppe, f.eks. t-butoksykar-bonyl-, etoksykarbonyl- eller acetylgruppe, og etter av-slutning av reaksjonen igjen settes fri. En aromatisk aminogruppe overføres ved reduksjonen til en nitrogruppe.
Omsetningen av (IV) med (V) foretas fortrinnsvis i et fortynningsmiddel som dimetylsulfoksyd, dioksan, N,N-dimetylformamid, heksametyl-fosforsyre-trisamid, sulfolan, vann,
en alkohol som metanol, etanol, n-propanol, isopropanol, glykolmonometyleter eller pyridin. Videre kan blandinger av disse fortynningsmidlene anvendes.
Som syrebindende middel kan alle vanlige uorganiske og organiske syrebindende midler anvendes. Herunder hører fortrinnsvis alkalihydroksydene, alkalikarbonatene, organiske aminer og amidiner. Som spesielt egnede skal følgende særskilt nevnes: trietylamin, 1,4-diazabicyklo[2,2,2]oktan (DABCO) eller 1,8-diazabicyklo[5,4,0]undek-7-en (DBU).
Reaksjonstemperaturen kan varieres innen et vidt område. Generelt arbeider man mellom ca. 20 og ca. 180°C, fortrinnsvis mellom 40 og 110°C.
Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Generelt arbeider man ved trykk mellom ca.
1 og 100 bar, fortrinnsvis mellom 1 og 10 bar..
Ved gjennomføringen av fremgangsmåten i overensstemmelse med fremgangsmåte B ifølge oppfinnelsen, anvender man til 1 mol av forbindelsen (IV) 1-4 mol, fortrinnsvis 1-1,5 mol av forbindelsen (V) .
Omsetningen av (IV) med (VI) (fremgangsmåte C) gjennomføres fortrinnsvis i et fortynningsmiddel som dioksan, dimetylsulfoksyd, N,N-dimetylformamid, metanol, etanol, isopropanol, n-propanol, glykolmonometyleter eller også i blandinger av disse fortynningsmidlene.
Reaksjonstemperaturen kan varieres innen et vidt område. Generelt arbeider man mellom ca. 20°C og ca. 150°C, fortrinnsvis mellom 50°C og 100°C.
Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Generelt arbeider man ved trykk mellom ca.
1 og ca. 100 bar, fortrinnsvis mellom 1 og 10 bar.
Ved gjennomføringen av fremgangsmåten ifølge oppfinnelsen
i overensstemmelse med fremgangsmåte C anvender man til 1 mol av forbindelsen (IV) 1-5 mol, fortrinnsvis 1-2 mol,
av forbindelsen (VI).
Fremstillingen av syreaddisjonssaltene av forbindelsene ifølge oppfinnelsen foregår på vanlig måte f.eks. ved oppløsning av betainet i et overskudd av vandig syre og utfelling av saltet med et med vann blandbart organisk oppløsningsmiddel (metanol, etanol, aceton, acetonitril). Man kan også oppvarme ekvivalente mengder betain og syre i vann inntil man oppnår oppløsning og deretter inndampe til tørrhet. Som farmasøy-tisk anvendbare salter forstås eksempelvis saltene av saltsyre, svovelsyre, eddiksyre, glykolsyre, melkesyre, ravsyre, sitronsyre, vinsyre, metansulfonsyre, galakturonsyre, glukon-syre, glutaminsyre eller asparaginsyre.
Alkali- eller jordalkalisaltene oppnås eksempelvis ved oppløs-ning av betainet i underskudd av alkali- eller jordalkalilut, filtrering av uoppløst betain og inndampning av filtratet til tørrhet. Farmasøytisk egnede er natrium-, kalium- eller kalsiumsalter. Ved omsetning av et alkali- eller jordalkali-salt med et egnet sølvsalt som sølvnitrat oppnås de tilsvarende sølvsaltene av 1,4-dihydro-4-okso-1,8-naftyridin-3-
karboksylsyrene.
I tillegg til de i eksemplene angitte forbindelsene skal
som nye virksomme stoff følgende forbindelser nevnes spesielt: l-cyklopropyl-6-fluor-1,4-dihydro-7-(3,5-dimetyl-l-pipera-zinyl)-4-okso-l,8-naftyridin-3-karboksylsyre,
l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-isopropyl-l-pipera-zinyl)-4-okso-l,8-naftyridin-3-karboksylsyre,
7-(4-butyl-1-piperazinyl)-6-klor-l-cyklopropyl-l,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre,
l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(4-fenacyl-1-piperazinyl)-1,8-naftyridin-3-karboksylsyre,
l-cyklopropyl-6-fluor-1,4-dihydro-7-(3,4-dimety1-1-piperazi-nyl)-4-okso-l,8-naftyridin-3-karboksylsyre-hydrogenklorid,
1-cyklopropy1-6-fluor-1,4-dihydro-7-[3-mety1-4-(2-oksopropyl)-1-piperazinyl]-4-okso-l,8-naftyridin-3-karboksylsyre,
6- klor-l-cyklopropyl-l,4-dihydro-4-okso-7-[4-(3-oksobutyl)-1-piperazinyl]-1,8-naftyridin-3-karboksylsyre,
1-cyklopropy1-6-fluor-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre,
7- (4-acetyl-1-piperazinyl)-1-cyklopropy1-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre,
6-klor-l-cyklopropyl-l,4-dihydro-7-(1-piperazinyl)-4-okso-1,8-naftyridin-3-karboksylsyre,
6-klor-l-cyklopropyl-l,4-dihydro-7-(4-metyl-1-piperazinyl)-4-okso-l,8-naftyridin-3-karboksylsyre,
6-klor-l-cyklopropyl-l,4-dihydro-7-(3-metyl-1-piperazinyl)-4-okso-l,8-naftyridin-3-karboksylsyre,
6-klor-l-cyklopropyl-7-(4-etyl-1-piperazinyl)-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre,
6-klor-l-cyklopropyl-l,4-dihydro-4-okso-7-[4-(3-okso-propyl)-1-piperazinyl]-1,8-naftyridin-3-karboksylsyre-hydrogenklorid,
1-cyklopropy1-6-fluor-7-[3-(4-fluorfeny1)-1-piperazinyl] - 1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre,
6- klor-l-cyklopropyl-l,4-dihydro-4-okso-7-(3-feny1-1-pipera-zinyl )-1,8-naftyridin-3-karboksylsyre,
1-cyklopropyl-l,4-dihydro-6-nitro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre,
1-cyklopropyl-l,4-dihydro-7-(4-metyl-l-piperazinyl)-6-nitro-4-okso-l,8-naftyridin-3-karboksylsyre,
7- [4 -(4-aminobenzyl)-1-piperazinyl]-1-cyklopropyl-l,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre,
7-(3-amino-l-pyrrolidinyl)-1-cyklopropyl-l,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre,
1-cyklopropy1-7-(3-etylaminometyl-l-pyrrolidinyl)-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre.
Gjenstand for foreliggende oppfinnelse er videre forbindelser av formel (VII)
hvor
X står for halogen eller nitro,
X' og X" er like eller forskjellige og står for halogen,
spesielt klor eller fluor, og
R står OH, halogen, spesielt klor, eller alkoksykarbonylmetyl med metyl eller etyl i alkoksydelen.
De følgende eksemplene illustrerer oppfinnelsen:
Fremstilling av utgangsforbindelsene.
Eksempel A
2,6-diklor-3-metyl-5-(3,3-dimetyl-l-triazeno)-pyridin
43 g (0,24 mol) 5-amino-2,6-diklor-3-metyl-pyridin (Heiv. Chim. Acta 5_9, 190 (1976)) blandes langsomt med 285 ml halv-konsentrert saltsyre, avkjølt til 0°C, deretter tilsettes dråpevis en oppløsning 17,2 g (0,25 mol) natriumnitritt i 70 ml vann og det omrøres ved 0°C i noen tid. Denne diazo-niumsalt-oppløsningen tilsettes dråpevis ved 0-3°C i løpet av 90 minutter til en oppløsning av 150 g natriumkarbonat i 430 ml vann og 70 ml 40-50% vandig dimetylamin-oppløsning, og det omrøres ved 0°C. Bunnfallet suges fra, vaskes med vann og tørkes i høyvakuum ved 40°C.
Utbytte: 49,3 g (88% av teoretisk verdi), smeltepunkt: 91-95°C.
Eksempel B
2,6-diklor-5-fluor-3-metyl-pyridin
43,9 g (0,19 mol) 2,6-diklor-3-metyl-5-(3,3-dimetyl-l-triazeno)-pyridin blandes i 80 ml flussyre ved 125-135°C i en autoklav. Etter destillasjon får man et produkt med en gasskromatografisk bestemt renhet på 87%, som dessuten også inneholder 12% klor-fluor-utbytningsprodukt.
Utbytte: 19 g, Kokepunkt: 81-95°C/18 mbar
Smeltepunkt: 39-41°C
Eksempel C
2,6-diklor-5-fluor-3-triklormetyl-pyridin
49,4 g (0,27 mol) 2,6-diklor-5-fluor-3-metyl-pyridin kloreres ved 120°C i totalt ca. 20 timer, inntil man ved NMR-spektro-skopi ikke lenger kan påvise alifatisk proton. Reaksjonsblandingen destilleres i en kulerørsdestillasjonsapparatur. Utbytte: 61,7 g (80,6%), kokepunkt: 130-150°C (ovnstempe-ratur)/0,4 mbar.
Massespektrum: m/e 281 (M<+>), 246 (100%, M<+->C1), 211 (246-C1), 176 (211-C1).
Eksempel D
2,6-diklor-5-fluor-pyridin-3-karboksylsyre
57 g (0,2 mol) 2,6-diklor-5-fluor-3-triklormetylpyridin oppløses i 53 ml 92% svovelsyre og omrøres deretter 45 minutter ved 25°C, deretter 3 timer ved 100°C inntil opp-hør hydrogenklorid-utviklingen. Det blandes med 24 g 50% svovelsyre og oppvarmes ytterligere 6 timer til 100°C. Deretter foretas avkjøling, reaksjonsblandingen helles på
is, bunnfallet suges fra, vaskes med vann og tørkes. Råutbytte: 42 g (-100% av teoretisk), Smeltepunkt: 137-149°C; Etter omkrystallisasjon fra vann: Smeltepunkt: 154-161°C. Massespektrum: m/e 209 (M<+>), 192 (M<+->OH), 164 (192-CO),
129 (164-C1), 94 (129-C1).
Eksempel E
2,6-diklor-5-fluor-pyridin-3-karbonylklorid
42 g (0,2 mol) 2,6-diklor-5-fluor-pyridin-3-karboksylsyre oppvarmes i en blanding av 43 g tionylklorid, 15 ml dimetylformamid og 640 ml toluen i 6 timer under tilbakestrømning. Blandingen inndampes og resten destilleres.
Utbytte: 33,8 g (74% av teoretisk), kokepunkt: 94-98°C/
1,3 mbar
Massespektrum: m/e 227 (M<+>), 192 (100%, M<+->C1), 164 (40%, M<+->C0C1).
Eksempel F
(2,6-diklor-5-fluor-pyridin-3-karbonyl)-eddiksyreetylester
3,7 g (0,15 mol) magnesiumspon blandes i 9,3 ml etanol med 0,8 g tetraklormetan og etter at hydrogenutviklingen har startet, tilsettes en blanding av 23,9 g (0,15 mol) malon-
syredietylester, 18,5 ml etanol og 58 ml toluen dråpevis ved 50-60°C. Det omrøres i en time ved denne temperaturen, avkjøles til -5 til -10°C og det tilsettes langsomt, dråpevis en oppløsning av 31 g (0,14 mol) 2,6-diklor-5-fluor-pyridin-3-karbonylklorid i 14,5 ml toluen. Deretter omrøres en time ved 0°C, blandingen bringes over natten til romtem-peratur og oppvarmes ytterligere 2 timer til 40-50°C. Reaksjonsblandingen blandes under isavkjøling med en blanding av 60 ml vann og 9 ml konsentrert svovelsyre og den organiske fasen fraskilles. Den vandige fasen ekstraheres med toluen og de samlede organiske ekstraktene vaskes med mettet natrium-kloridoppløsning, tørkes med natriumsulfat og oppløsnings-midlet fjernes. Man får 50,1 g (2,6-diklor-5-fluor-pyridin-3-karbonyl)-malonsyredietylester som råprodukt. Dette oppvarmes etter tilsats av 50 ml vann og 0,1 g 4-toluensulfonsyre i 10 timer under tilbakestrømning, blandingen ekstraheres med diklormetan, ekstraktet tørkes med natriumsulfat, inndampes, resten utrøres med litt eter og krystallproduktet isoleres.
Utbytte: 14,3 g (34% av teoretisk), Smeltepunkt: 69-72°C. Massespektrum: m/e 279 (M<+>), 244 (60%, M<+->C1), 216 (74%, 244-28), 192 (100%, CrHCloFN0), 164, 29.
Ifølge NMR-spekteret (CDCl^) foreligger forbindelsen prak-tisk talt fullstendig som enol.
Eksempel G
7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre
14 g (50 mmol) (2,6-diklor-5-fluor-pyridin-3-karbonyl)-eddik- syreetylester oppvarmes med 11,1 g (75 mmol) orto-maursyre-trietylester i 13 g eddiksyreanhydrid i 2 timer til 150-160°C. Det inndampes i vakuum og man får 15,6 g 2-(2,6-diklor-5-fluor-pyridin-3-karbonyl)-3-etoksyakrylsyreetyl-ester som en oljeformet rest.
15,5 g (46 mmol) av dette mellomtrinnet blandes i 35 ml etanol under isavkjøling dråpevis med 3 g cyklopropylamin og omrøres i en time ved 20°C. Det utfelte produktet suges fra, vaskes med metanol og tørkes. Man får 13,3 g 2-(2,6-diklor-5-fluor-pyridin-3-karbonyl)-3-cyklopropylaminoakryl-syreetylester med smeltepunkt 130-133°C (fra etanol).
12,5 g (36 mmol) 2-(2,6-diklor-5-fluor-pyridin-3-karbonyl)-3-cyklopropylamino-akrylsyreetylester oppvarmes i 75 ml dimetylformamid med 6,5 g kaliumkarbonat i en time til 100°C. Reaksjonsblandingen helles i isvann og det utfelte produktet suges fra, vaskes med vann og metanol og tørkes. Det oppnås 10,5 g (94% av teoretisk) 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre-etylester med smeltepunkt 176-180°C.
10,5 g (34 mmol) av denne esteren oppvarmes i en blanding av 100 ml eddiksyre, 70 ml vann og 10 ml konsentrert svovelsyre i 2 timer til 150°C. Suspensjonen helles i 300 ml isvann, bunnfallet suges fra, det vaskes med vann og metanol og tørkes i vakuum.
Utbytte: 7,85 g (82% av teoretisk) 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre med smeltepunkt 230-233°C.
Eksempel H
6,7-diklor-1-cyklopropyl-l,4-dihydro-4-okso-l, 8-naftyridin-3-karboksylsyre
Med utgangspunkt i 2,5,6-triklorpyridin-3-karboksylsyre-klorid [Heiv. Chim. Acta _59, 222 (1976 )] fremstilles analogt eksempel F (2,5,6-triklorpyridin-3-karbonyl)-eddiksyreetyl-ester (smeltepunkt: 69-71°C; foreligger ifølge "''H-NMR-spekteret i deuterokloroform inntil 50% som enol). Dette omsettes deretter analogt eksempel G over 6,7-diklor-l-cyklopropyl-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre-etylester (smeltepunkt: 176-178°C) til 6,7-diklor-l-cyklopropyl-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre, som etter omkrystallisasjon fra dimetylformamid smelter ved 243-245°C under dekomponering.
Eksempel 1
1-cyklopropy1-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre
1,3 g (4 mmol) 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre oppvarmes i 8 ml dimetylsulfoksyd med 860 mg (10 mmol) vannfritt piperazin i 15 minutter til 110°C. Oppløsningsmidlet avdampes i vakuum, resten oppkokes med 5 ml vann (pH 7), bunnfallet suges fra, vaskes med vann og med metanol.
Utbytte: 1,0 g (75% av teoretisk), smeltepunkt: 278-282°C (under dekomponering).
Eksempel 2
l-cyklopropyl-6-fluor-l,4-dihydro-7-(3-metyl-1-piperazinyl)-4-okso-l,8-naftyridin-3-karboksylsyre
Man går frem analogt eksempel 1, hvorved man omsetter med 2-metylpiperazin i 15 minutter ved 100°C og omkrystalliserer reaksjonsproduktet fra glykolmonometyleter.
Utbytte: 0,9 g (65% av teoretisk),
Smeltepunkt: 243-247°C (under dekomponering).
Eksempel 3
1-cyklopropy1-6-fluor-1,4-dihydro-7-(4-metyl-1-piperazinyl)-4-okso-l,8-naftyridin-3-karboksylsyre-hydrogenklorid
Man går frem analogt eksempel 1, hvorved man omsetter med N-metylpiperazin i 15 minutter ved 100°C og omkrystalliserer reaksjonsproduktet fra glykolmonometyleter. Den oppnådde 1-cyklopropy1-6-fluor-1,4-dihydro-4-okso-7-(4-metyl-1-pipe-razinyl ) -1 , 8-naf tyridin-3-karboksylsyren (1,2 g med smeltepunkt 241-244°C under dekomponering) oppkokes i en blanding av 20 ml etanol og 5 ml 2N saltsyre, det dannede hydrogenkloridet frasuges, vaskes med etanol og tørkes.
Utbytte: 1,1 g (72%) .
Smeltepunkt: 305-310°C (under dekomponering).
Eksempel 4
l-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyre-hydrogenklorid
Analogt eksempel 3 omsettes med N-etyl-piperazin i 30 minutter ved 100°C og reaksjonsproduktet overføres deretter til hydrogenkloridet.
Utbytte: 1,05 g (66% av teoretisk),
Smeltepunkt: >300°C (under dekomponering).
Eksempel 5
1-cyklopropy1-6-fluor-1,4-dihydro-7-[ 3-(2-hydroksyetyl)-1-piperazinyl]-4-okso-l,8-naftyridin-3-karboksylsyre
Analogt eksempel 1 omsettes med N-(2-hydroksyetyl)-piperazin i 30 minutter ved 100°C og reaksjonsproduktet omkrystalliseres fra glykolmonometyleter.
Utbytte: 0,9 g (60% av teoretisk).
Smeltepunkt: 241-245°C (under dekomponering).
Eksempel 6
l-cyklopropyl-6-fluor-l,4-dihydro-4-okso-7-(3-fenyl-l-piperazinyl)-l,8-naftyridin-3-karboksylsyre
Analogt eksempel 1 omsettes 810 mg (5 mmol) 2-fenyl-piperazin i nærvær av 1,8 g (8 mmol) 1,4-diaza-bicyklo[2,2,2]oktan (DABCO) i 30 minutter ved 100°C.
Utbytte: 0,85 g (42% av teoretisk).
Smeltepunkt: 280-283°C (under dekomponering).
Eksempel 7
l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-pyrrolidinyl)-1,8-naftyridin-3-karboksylsyre
Analogt eksempel 1 omsettes pyrrolidin i 30 minutter ved 100°C og reaksjonsproduktet omkrystalliseres fra dimetylformamid.
Utbytte: 70% av teoretisk.
Smeltepunkt: 314-316°C (under dekomponering).
Eksempel 8
l-cyklopropyl-6-fluor-l,4-dihydro-4-okso-7-[4-(2-okso-propyl)-
1-piperazinyl]-l,8-naftyridin-3-karboksylsyre-hydrogenklorid
1,65 g (5 mmol) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre blandes i 25 ml dimetylformamid med 0,7 g (7,6 mmol) kloraceton og 1,05 g trietylamin og oppvarmes i 3 timer til 80°C. Suspensjonen inndampes i vakuum, resten utrøres med 10 ml vann, avsuges og tørkes. Produktet oppvarmes i 15 ml fortynnet saltsyre (1:1), utfelles med etanol, frasuges og tørkes. Utbytte: 1,5 g (71% av teoretisk).
Smeltepunkt: >300°C (under dekomponering).
Eksempel 9
l-cyklopropyl-6-fluor-l,4-dihydro-4-okso-7-[4-(3-okso-butyl)-1-piperazinyl]-l,8-naftyridin-3-karboksylsyre-hydrogenklorid
1,66 g (5 mmol) av forbindelsen fra eksempel 1 og 1,95 g (28 mmol) mety1vinylketon oppvarmes i 25 ml etanol i 7
timer under tilbakstrømning, det oppnådde bunnfallet oppløses med fortynnet saltsyre (1:1) og utfelles med etanol. Utbytte: 1,1 g (55% av teoretisk).
Smeltepunkt: >300°C (under dekomponering).
Eksempel 10
6-klor-l-cyklopropyl-l,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso-l,8-naftyridin-3-karboksylsyre-hydrogenklorid
Man går frem analogt eksempel 3, hvorved man går ut fra 6,7-diklor-1-cyklopropy1-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyre og N-metyl-piperazin som utgangsforbindelser. Utbytte: 66%.
Smeltepunkt: 304-308°C (under dekomponering)..
Forbindelsene ifølge oppfinnelsen viser ved liten toksisitet et bredt antibakterielt spektrum mot gram-positive og gram- negative kim, spesielt mot enterobakterier; fremfor alt mot slike som er resistente mot forskjellige typer anti-biotika, som f.eks. penicilliner, cefalosporiner, amino-glykosider, sulfonamider, tetracykliner.
Disse verdifulle egenskapene muliggjør anvendelse av forbindelsene som kjemoterapeutisk virksomme stoffer innenfor medisin så vel som stoffer til konservering av uorganiske og organiske materialer, spesielt av organiske materialer av enhver type, f.eks. polymerer, smøremidler, fargestoffer, fibere, lær, papir og tre, og næringsmidler og vann.
Forbindelsene ifølge oppfinnelsen er virksomme mot et meget bredt spektrum av mikroorganismer. Med deres hjelp kan gram-negative og gram-positive bakterier og bakterieliknende mikroorganismer bekjempes, samt de ved disse organismene fremkalte sykdommene forhindres, bedres og/eller helbredes.
Spesielt virksomme er forbindelsene ifølge oppfinnelsen
mot bakterier og bakterieliknende mikroorganismer. De er derfor spesielt velegnede til profylakse og kjemoterapi ved lokale og systemiske infeksjoner innen human- og veterinærmedisin, som er fremkalt ved disse organismene.
Eksempelvis kan lokale og/eller systemiske sykdomstilstander behandles og/eller forhindres, når disse er fremkalt ved følgende organismer eller blandinger av følgende organismer: Gram-positive kokker, f.eks. stafylokokker (Staph. aureus, Staph. epidermidis) og streptokokker (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes); gram-negative kokker (Neisseria gonorrhoeae) samt gram-negative staver som enterobakterier, f.eks. Escherichia coli, Hamophilus influenzae, Citrobacter (Citrob. freuncii, Citrob. divernis), Salmonella og Shigella; videre Klebsiellen (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Prodivencia, Yersinia, samt slekten Acineto-bacter. Videre omfatter det antibakterielle spekteret slekten Pseudomonas (Ps. aeruginosa, Ps. maltophilia)
samt de strengt anaerobe bakteriene som f.eks. Bacteroices fragilis, representanter for slekten Peptococcus, Pepto-streptococcus samt slekten Clostridium, videreMykoplasner (ri. pneumoniae, M. hominis, M. urealyticum) samt Myko-bakterier, f.eks. Mycobacterium tuberculosis.
Listen ovenfor gir eksempler på sykdomsfremkallere og skal ikke oppfattes som begrensende. Som sykdommer, som kan forhindres, forbedres og/eller helbredes ved hjelp av forbindelsene ifølge oppfinnelsen skal følgende nevnes: Otitis; faryngitis; pneumonie; peritonitis; pyelonefritis; cystitis; endokarditis; systeminfeksjoner; bronchitis; artritis; lokale infeksjoner; septiske sykdomstilstander.
Til foreliggende oppfinnelse hører farmasøytiske preparater som ved siden av ikke-toksiske, inerte farmasøytisk egnede bærestoffer inneholder en eller flere forbindelser ifølge oppfinnelsen eller som består av ett eller flere virksomme stoffer ifølge oppfinnelsen, samt fremgangsmåter til fremstilling av disse preparatene.
Til foreliggende oppfinnelse hører også farmasøytiske preparater i doseringsenheter. Dette betyr at preparatene foreligger i form av enkelte deler, f.eks. tabletter, dragéer, kapsler, piller, suppositorier og ampuller, hvis innhold av virksomt stoff utgjør en brøkdel eller multiplum av en enkeltdose. Doseringsenhetene kan f.eks. inneholde 1, 2,
3 eller 4 enkeltdoser eller h, 1/3 eller 1/4 enkeltdose.
En enkeltdose inneholder fortrinnsvis den mengden virksomt stoff som administreres ved en tilførsel og som vanligvis utgjør en hel, en halv eller en tredjedel eller en fjerde-del av en dagsdose.
Under ikke-toksiske, inerte farmasøytisk egnede bærestoffer forstås fast, halvfaste eller flytende fortynningsmidler, fyllstoffer og formuleringshjelpemidler av enhver art.
Som foretrukne farmasøytiske preparater skal nevnes tabletter, dragéer, kapsler, piller, granulater, suppositorier, oppløs-ninger, suspensjoner og emulsjoner, pastaer, salver, geler, kremer, lotions, pudder og sprayer.
Tablettene, dragéene, kapslene, pillene og granulatene kan inneholde det eller de virksomme stoffene ved siden av de vanlige bærestoffene, som (a) fylle- og drøyemidler; f.eks. stivelser, melkesukker, rørsukker, glukose, mannitt og kiselsyre, (b) bindemidler, f.eks. karboksymetylcellulose, alginater, gelatin, polyvinylpyrrolidon, (c) midler som holder på fuktigheten, f.eks. glycerin, (d) sprengmidler, f.eks. agar-agar, kalsiumkarbonat og natriumkarbonat, (e) oppløsningsforsinkere, f.eks. parafin og (f) resorpsjons-akseleratorer, som f.eks. kvaternære ammoniumforbindelser,
(g) fuktemidler, f.eks. cetylalkohol, glycerinmonostearat,
(h) adsorpsjonsmidler, f.eks. kaolin og bentonitt og (i) glidemidler, f.eks. talkum, kalsium- og magnesiumstearat og faste polyetylenglykoler og blandinger av de under (a)
til (i) oppførte stoffene.
Tablettene, dragéene, kapslene, pillene og granulatene kan være utstyrt med de vanlige, eventuelt opakiseringsmiddel-holdige, overtrekkende og omhyllingende og også være sammen-satt slik at de avgir det eller de virksomme stoffene bare, eller foretrukket, i en bestemt del av intestinaltrakten, eventuelt med forsinket avgivelse, hvorved man som inn-støpingsmasse f.eks. kan anvende polymerstoffer og vokser.
Det eller de virksomme stoffene kan eventuelt foreligge sammen med ett eller flere av de ovenfor angitte bærestoffene i mikroinnkapslet form.
Suppositoriene kan ved siden av det eller de virksomme stoffene inneholde de vanlige vannoppløselige eller vannuopp-løselige bærestoffene, f.eks. polyetylenglykoler, fett, f.eks. kakaofett og høyere estere (f.eks. C-^-alkoholer med C-j^g-f ettsyre) eller blandinger av disse stoffene.
Salver, pastaer, kremer og geler kan ved siden av det eller de virksomme stoffene inneholde de vanlige bærestoffene, f.eks. animalske og vegetabilske fettstoffer, vokser, para-finer, stivelse, tragant, cellulosederivater, polyetylenglykoler, silikoner, bentonitt, kiselsyre, talkum og sink-oksyd eller blandinger av disse stoffene.
Puddere eller sprayer kan ved siden av det eller de virksomme stoffene inneholde de vanlige bærestoffene, f.eks. melkesukker, talkum, kiselsyre, aluminiumhydroksyd, kalsiumsilikat og polyamidpulver eller blandinger av disse stoffene. Sprayer kan i tillegg inneholde de vanlige drivmidlene,
som f.eks. klorfluorkarboner.
Oppløsninger og emulsjoner kan ved siden av det eller de virksomme stoffene inneholde de vanlige bærestoffene som oppløsningsmidler, oppløsningsformidlere og emulgatorer, f.eks. vann, etylalkohol, isopropylalkohol, etylkarbonat, etylacetat, benzylalkohol, benzylbenzoat, propylenglykol, 1,3-butylenglykol, dimetylformamid, oljer, spesielt bomulls-frøolje, jordnøttolje, maiskjerneolje, olivenolje, ricinus-olje og sesamolje, glycerin, glycerinformal, tetrahydro-furfurylalkohol, polyetylenglykoler og fettsyreestere av sorbitaner eller blandinger av disse stoffene.
Til parenteral anvendelse kan oppløsningene og emulsjonene
ogsa foreligge i steril og blodisotonisk form.
Suspensjonene kan ved siden av det eller de virksomme stoffene inneholde de vanlige bærestoffene som flytende fortynningsmidler, f.eks. vann, etylalkohol, propylenglykol, suspen-sjonsmidler, f.eks. etoksylerte isostearylalkoholer, poly-oksyetylensorbitt- og sorbitanester, mikrokrystallinsk cellulose, aluminiummetahydroksyd, bentonitt, agar-agar og tragant eller blandinger av disse stoffene.
De nevnte formuleringsformene kan også inneholde fargestoffer, konserveringsstoffer samt lukt- og smaksforbedrende tilsatser, f.eks. peppermynteolje og eukalyptusolje og søtningsstoffer, f.eks. sakkarin.
De terapeutisk virksomme forbindelsene skal i de ovenfor nevnte farmasøytiske preparatene fortrinnsvis være tilstede i en konsentrasjon på ca. 0,1 til 99,5, fortrinnsvis fra ca. 0,5 til 95 vekt-% av totalblandingen.
De ovenfor angitte farmasøytiske preparatene kan ved siden av forbindelsene ifølge oppfinnelsen også inneholde andre farma-søytisk virksomme stoffer.
Fremstillingen av de ovenfor angitte farmasøytiske preparatene foregår på vanlig måte ved kjente fremgangsmåter, f.eks. ved blanding av det eller de virksomme stoffene med bærestoffene.
De virksomme stoffene eller de farmasøytiske preparatene
kan anvendes lokalt, oralt, parenteralt, intraperitonealt og/eller rektalt, fortrinnsvis oralt eller parenteralt som intravenøst eller intramuskulært.
Generelt har det både innen human- og også innenfor veterinær-medisinen vist seg fordelaktig å tilføre det eller de virk somme stoffene ifølge oppfinnelsen i totalmengder på ca. 0,5 til ca. 500, fortrinnsvis 5 til 100 mg/kg legemsvekt pr.
døgn, eventuelt i form av flere enkelttilførsler, for å
oppnå de ønskede resultatene. En enkelttilførsel inneholder det eller de virksomme stoffene ifølge oppfinnelsen, fortrinnsvis i mengder på ca. 1 til 250, spesielt 3 til 60 mg/kg legemsvekt. Det kan likevel være påkrevet å avvike fra den nevnte doseringen, alt avhengig av typen og legemsvekten for behandlingsobjektet, typen og tilstanden ved sykdommen,
typen preparat og tilførsel av legemidlet samt det tidsrom henholdsvis intervall, hvori administreringen skal finne sted.
I enkelte tilfeller kan det følgelig være tilstrekkelig å anvende mindre enn den ovenfor nevnte mengden virksomt stoff, mens i andre tilfeller den ovenfor angitte mengden av virksomt stoff må overskrides. Fastleggelsen av den i ethvert tilfelle påkrevde optimale doseringen og tilførselsmåten for det virksomme stoffet kan lett velges av fagmannen på bakgrunn av hans fagviten.
De nye forbindelsene kan i vanlige konsentrasjoner og preparater tilføres sammen med for henholdsvis foorpreparater eller med drikkevannet. Derved kan en infeksjon forårsaket av gram-negative eller gram-positive bakterier forhindres, forbedres og/eller helbredes, og derved fremmes veksten og en forbedring av utnyttelse av foret.
I den etterfølgende tabellen er MHK-verdiene for noen forbindelser ifølge oppfinnelsen angitt.
Som sammenlikning er de tilsvarende MHK-verdiene for de fra den europeiske patentsøknad 9425, den japanske patentsøknad 81/45473 [CA. _9_5, 115 597 (1981)], 81/46811 [CA. 95, 121
142 (1981)], fra J. Med. Chem. 27, 292 (1984) og fra J. Heterocycl. Chem. 21, 673 (1984) kjente l-etyl-6-fluor-1,4-
dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksylsyre (AT 2266, Enoxacin ) angitt, hvorfra det fremgås at forbindelsene ifølge oppfinnelsen er overlegne den kjente forbindelsen.
Claims (5)
1.
Fremgangsmåte til fremstilling av forbindelser av formel(VII)
hvor
X står for halogen eller nitro,
X' og X" er like eller forskjellige og står for halogen,
spesielt klor eller fluor, og
R står for alkoksykarbonylmetyl med metyl eller etyl i
alkoksydelen,
karakterisert ved at man omsetter en forbindelse av formelen (VIII)
hvori
X, X' og X" har den ovenfor angitte betydning, med malonsyredimetylester eller malonsyredietylester i et oppløsnings-middel som metanol, etanol, benzen, toluen eller en blanding av disse oppløsningsmidlene i nærvær av natrium- eller magnesiumalkoholat, spesielt -metylat eller -etylat ved temperaturer fra ca. -20°C til ca. 100°C, spesielt -10°C til 50°C, ved trykk på ca. 1 bar til ca. 100 bar, fortrinnsvis mellom 1 og 10 bar, og reaksjonsproduktet forsåpes del-vis ved oppvarming i vann eller dimetylsulfoksyd, eventuelt i nærvær av katalysatorer som svovelsyre, metansulfonsyre, toluensulfonsyre, natriumklorid, litiumklorid eller litiumjodid og dekarboksyleres.
2 .
Fremgangsmåte til fremstilling av 2,6-diklor-5-fluor-pyridin-3-karboksylsyre, karakterisert ved at man diazoterer 5-amino-2,6-diklor-3-metyl-pyridin i nærvær av vandige syrer som saltsyre eller svovelsyre ved -20°C til 20°C, fortrinnsvis -5°C til 5°C, og normaltrykk og omsetter med dimetylamin til 2,6-diklor-3-metyl-5-(3,3-dimetyl-l-triazeno)-pyridin, denne tilsettes med flussyre ved 80°C til 160°C, fortrinnsvis ved 110°C til 150°C, i autoklav til 2,6-diklor-5-fluor-3-metyl-pyridin, som kloreres ved ca. 80°C til 180°C, fortrinnsvis 100°C til 140°C, ved trykk fra 1 til 100 bar, fortrinnsvis 1 til 40 bar, til 2,6-diklor-5-fluor-3-triklormetylpyridin og denne forsåpes med svovelsyre ved 10°C til 110°C, fortrinnsvis 25°C til 100°C.
3 .
Fremgangsmåte til fremstilling av 2,6-diklor-5-fluor-pyridin-3-karbonylklorid, karakterisert ved at man omsetter 2,6-diklor-5-fluor-pyridin-3-karboksylsyre uten oppløsningsmiddel eller i et oppløsningsmiddel som dimetylformamid, toluen, benzen, klorbenzen, kloroform, diklormetan, tetraklormetan eller blandinger av disse opp-løsningsmidlene ved temperaturer fra ca. 50°C til ca. 150°C, fortrinnsvis 80°C til 120°C og normaltrykk med tionylklorid, fosfortriklorid eller fosforpentaklorid.
4 .
Fremgangsmåte ifølge krav 1, karakterisert ved at det fremstilles (2,6-diklor-5-fluor-pyridin-3-karbonyl)-eddiksyreetylester.
5 .
Fremgangsmåte ifølge krav 1, karakterisert ved at det fremstilles (2,5,6-triklor-pyridin-3-karbonyl)-eddiksyreetylester.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3500562 | 1985-01-10 | ||
DE19853508816 DE3508816A1 (de) | 1985-01-10 | 1985-03-13 | 6,7-disubstituierte 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphtyridin-3-carbonsaeuren |
Publications (1)
Publication Number | Publication Date |
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NO860199L true NO860199L (no) | 1986-07-11 |
Family
ID=25828438
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO855134A NO163331C (no) | 1985-01-10 | 1985-12-18 | Analogifremgangsmaate til fremstilling av terapeutisk aktive 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrer. |
NO860199A NO860199L (no) | 1985-01-10 | 1986-01-21 | Mellomprodukter for fremstilling av 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrer. |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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NO855134A NO163331C (no) | 1985-01-10 | 1985-12-18 | Analogifremgangsmaate til fremstilling av terapeutisk aktive 6,7-disubstituerte 1-cyklopropyl-1,4-dihydro-4-okso-1,8-naftyridin-3-karboksylsyrer. |
Country Status (21)
Country | Link |
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US (1) | US4840954A (no) |
EP (1) | EP0187376B1 (no) |
JP (1) | JPH0653741B2 (no) |
KR (1) | KR910002645B1 (no) |
CN (1) | CN1003236B (no) |
AT (1) | ATE76076T1 (no) |
AU (3) | AU574550B2 (no) |
CA (2) | CA1339373C (no) |
DE (2) | DE3508816A1 (no) |
DK (1) | DK168439B1 (no) |
ES (5) | ES8802520A1 (no) |
FI (2) | FI86721C (no) |
GR (1) | GR860031B (no) |
HU (1) | HU193623B (no) |
IE (1) | IE58412B1 (no) |
IL (2) | IL77538A (no) |
NO (2) | NO163331C (no) |
NZ (2) | NZ229861A (no) |
PH (2) | PH25055A (no) |
PL (2) | PL148759B1 (no) |
PT (1) | PT81810B (no) |
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US5153204A (en) * | 1986-03-01 | 1992-10-06 | Bayer Aktiengesellschaft | 7-(1-Pyrrolidinyl)-quinolonecarboxylic acid derivatives |
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FR2650276B1 (fr) * | 1989-07-28 | 1991-10-18 | Bellon Labor Sa Roger | Nouveaux derives de benzonaphtyridine-1,8 leur preparation et les compositions qui les contiennent |
EP0449445A3 (en) * | 1990-03-27 | 1993-08-25 | Pfizer Inc. | Preparation of beta-ketoesters useful in preparing quinolone antibiotics |
US5290794A (en) * | 1992-10-27 | 1994-03-01 | Warner Lambert Co. | Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms |
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AU5896096A (en) * | 1995-05-26 | 1996-12-11 | Bayer Aktiengesellschaft | Pyridyl-thiazoles and their use to protect plants against in fections by micro-organisms |
US5739342A (en) * | 1997-03-03 | 1998-04-14 | Abbott Laboratories | Process for the preparation of nicotinic acids |
WO1999038867A1 (fr) * | 1998-01-29 | 1999-08-05 | Suntory Limited | Derives de 1-cycloalkyle-1,8-naphthyridine-4-one presentant une activite inhibitrice de la phosphodiesterase iv |
KR100364226B1 (ko) * | 1998-03-18 | 2003-01-24 | 주식회사 엘지생명과학 | 7-할로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로-[1.8]나프티리딘-3-카복실레이트의 제조방법 |
CN1578781A (zh) * | 2001-09-26 | 2005-02-09 | 拜尔药品公司 | 用作抗糖尿病药物的1,8-萘啶衍生物 |
KR100589966B1 (ko) * | 2001-10-15 | 2006-06-15 | 주식회사 엘지생명과학 | 베타-케토에스테르 화합물의 제조방법 |
AR096135A1 (es) | 2013-05-02 | 2015-12-09 | Actelion Pharmaceuticals Ltd | Derivados de la quinolona |
EP3296298A1 (de) | 2016-09-14 | 2018-03-21 | Bayer Pharma Aktiengesellschaft | 7-substituierte 1-aryl-naphthyridin-3-carbonsäureamide und ihre verwendung |
JOP20190045A1 (ar) | 2016-09-14 | 2019-03-14 | Bayer Ag | مركبات أميد حمض 1- أريل-نفثيريدين-3-كربوكسيليك مستبدلة في الموضع 7 واستخدامها. |
CN109206424A (zh) * | 2018-09-18 | 2019-01-15 | 佳木斯大学 | 依诺沙星-邻苯二甲酸药物盐单晶体及其制备方法 |
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-
1985
- 1985-03-13 DE DE19853508816 patent/DE3508816A1/de not_active Withdrawn
- 1985-12-18 NO NO855134A patent/NO163331C/no unknown
- 1985-12-24 EP EP85116551A patent/EP0187376B1/de not_active Expired - Lifetime
- 1985-12-24 AT AT85116551T patent/ATE76076T1/de active
- 1985-12-24 DE DE8585116551T patent/DE3586048D1/de not_active Expired - Lifetime
- 1985-12-31 US US06/815,440 patent/US4840954A/en not_active Expired - Fee Related
-
1986
- 1986-01-07 NZ NZ229861A patent/NZ229861A/xx unknown
- 1986-01-07 IL IL77538A patent/IL77538A/xx not_active IP Right Cessation
- 1986-01-07 NZ NZ214746A patent/NZ214746A/xx unknown
- 1986-01-08 PT PT81810A patent/PT81810B/pt not_active IP Right Cessation
- 1986-01-08 FI FI860073A patent/FI86721C/fi not_active IP Right Cessation
- 1986-01-08 KR KR1019860000032A patent/KR910002645B1/ko not_active IP Right Cessation
- 1986-01-08 CA CA000499241A patent/CA1339373C/en not_active Expired - Fee Related
- 1986-01-08 GR GR860031A patent/GR860031B/el unknown
- 1986-01-09 PL PL1986257419A patent/PL148759B1/pl unknown
- 1986-01-09 DK DK009186A patent/DK168439B1/da not_active IP Right Cessation
- 1986-01-09 ES ES550767A patent/ES8802520A1/es not_active Expired
- 1986-01-09 HU HU8687A patent/HU193623B/hu not_active IP Right Cessation
- 1986-01-09 PL PL1986264565A patent/PL148191B1/pl unknown
- 1986-01-09 JP JP61001485A patent/JPH0653741B2/ja not_active Expired - Lifetime
- 1986-01-09 IE IE6286A patent/IE58412B1/en not_active IP Right Cessation
- 1986-01-09 AU AU52164/86A patent/AU574550B2/en not_active Ceased
- 1986-01-10 CN CN86100126A patent/CN1003236B/zh not_active Expired
- 1986-01-10 PH PH33280A patent/PH25055A/en unknown
- 1986-01-21 NO NO860199A patent/NO860199L/no unknown
-
1987
- 1987-04-01 PH PH35094A patent/PH24769A/en unknown
- 1987-04-29 ES ES557516A patent/ES8800222A1/es not_active Expired
- 1987-04-29 ES ES557514A patent/ES8801919A1/es not_active Expired
- 1987-04-29 ES ES557515A patent/ES8801796A1/es not_active Expired
- 1987-05-15 AU AU73118/87A patent/AU576449B2/en not_active Ceased
- 1987-12-15 ES ES557785A patent/ES8802225A1/es not_active Expired
-
1988
- 1988-06-24 AU AU18359/88A patent/AU1835988A/en not_active Abandoned
-
1989
- 1989-02-03 IL IL8989168A patent/IL89168A0/xx unknown
- 1989-06-01 FI FI892675A patent/FI892675A0/fi not_active Application Discontinuation
-
1990
- 1990-04-05 CA CA000615694A patent/CA1320206C/en not_active Expired - Fee Related
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