NO173445B - Analogifremgangsmaate for fremstilling av terapeutisk aktive kinolinkarboksylsyrederivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive kinolinkarboksylsyrederivater Download PDFInfo
- Publication number
- NO173445B NO173445B NO87871990A NO871990A NO173445B NO 173445 B NO173445 B NO 173445B NO 87871990 A NO87871990 A NO 87871990A NO 871990 A NO871990 A NO 871990A NO 173445 B NO173445 B NO 173445B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- oxo
- melting point
- fluoro
- quinoline
- Prior art date
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- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000001225 therapeutic effect Effects 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 45
- -1 pyrrolidino- Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- 241000894006 Bacteria Species 0.000 abstract description 8
- 208000035473 Communicable disease Diseases 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 230000009885 systemic effect Effects 0.000 abstract description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 229940126573 antibacterial therapeutic Drugs 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 156
- 230000008018 melting Effects 0.000 description 156
- 238000000354 decomposition reaction Methods 0.000 description 125
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000013078 crystal Substances 0.000 description 16
- 125000004494 ethyl ester group Chemical group 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- DJXNJVFEFSWHLY-UHFFFAOYSA-M quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)[O-])=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-M 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- SUXQDLLXIBLQHW-UHFFFAOYSA-N Ulifloxacin Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 SUXQDLLXIBLQHW-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XQUDASONXZVNEJ-UHFFFAOYSA-N 6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 XQUDASONXZVNEJ-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960002549 enoxacin Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 229960001699 ofloxacin Drugs 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- XLJNGPMEOJYNGE-UHFFFAOYSA-N 6-fluoro-1-methyl-4-oxo-7-[4-(2-oxopropyl)piperazin-1-yl]-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(CC(C)=O)CC1 XLJNGPMEOJYNGE-UHFFFAOYSA-N 0.000 description 2
- DCWADFKHSDZNNE-UHFFFAOYSA-N 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=C1SCN12 DCWADFKHSDZNNE-UHFFFAOYSA-N 0.000 description 2
- MKSDDVVVIQYNJW-UHFFFAOYSA-N 7-[4-[(4-aminophenyl)methyl]piperazin-1-yl]-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC1=CC=C(N)C=C1 MKSDDVVVIQYNJW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 241000085494 Pseudomonas aeruginosa E2 Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- UUJUEXKIHKGFTH-UHFFFAOYSA-N ethyl 6,7-difluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound C12=CC(F)=C(F)C=C2C(=O)C(C(=O)OCC)=C2N1C(C)S2 UUJUEXKIHKGFTH-UHFFFAOYSA-N 0.000 description 2
- JGRALVUIQHMDJU-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-4-oxo-7-[4-(2-oxopropyl)piperazin-1-yl]-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC(C)=O)CC1 JGRALVUIQHMDJU-UHFFFAOYSA-N 0.000 description 2
- OMIWILCOFBVGSI-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(C)CC1 OMIWILCOFBVGSI-UHFFFAOYSA-N 0.000 description 2
- WFICRMFIQMDUCS-UHFFFAOYSA-N ethyl 7-(3,4-dimethylpiperazin-1-yl)-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(C)C(C)C1 WFICRMFIQMDUCS-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- MNFSSEUNEZGWRS-UHFFFAOYSA-N thiazetidine Chemical group C1CSN1 MNFSSEUNEZGWRS-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HHVRCNXDTGNIMZ-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=C1SC(C=3C(=CC(F)=CC=3)F)N12 HHVRCNXDTGNIMZ-UHFFFAOYSA-N 0.000 description 1
- PWAZEAASESWTQV-UHFFFAOYSA-N 1-(2,5-difluorophenyl)-6-fluoro-4-oxo-7-piperazin-1-yl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound N12C3=CC(N4CCNCC4)=C(F)C=C3C(=O)C(C(=O)O)=C2SC1C1=CC(F)=CC=C1F PWAZEAASESWTQV-UHFFFAOYSA-N 0.000 description 1
- JUZOVAUGTMQMTC-UHFFFAOYSA-N 1-(2,5-difluorophenyl)-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=C1SC(C=3C(=CC=C(F)C=3)F)N12 JUZOVAUGTMQMTC-UHFFFAOYSA-N 0.000 description 1
- KEMNQOGELWMXTD-UHFFFAOYSA-N 1-(2,6-difluorophenyl)-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=C1SC(C=3C(=CC=CC=3F)F)N12 KEMNQOGELWMXTD-UHFFFAOYSA-N 0.000 description 1
- CBNXMWAHUGHCNO-UHFFFAOYSA-N 1-(2-fluoro-6-methoxyphenyl)-4-methylpiperazine Chemical compound COC1=CC=CC(F)=C1N1CCN(C)CC1 CBNXMWAHUGHCNO-UHFFFAOYSA-N 0.000 description 1
- FNYYIKRCDSATNB-UHFFFAOYSA-N 1-(2-fluoro-6-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(F)=C1N1CCNCC1 FNYYIKRCDSATNB-UHFFFAOYSA-N 0.000 description 1
- SPSQHVWCIIBPFS-UHFFFAOYSA-N 1-(3,4-difluorophenyl)-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=C1SC(C=3C=C(F)C(F)=CC=3)N12 SPSQHVWCIIBPFS-UHFFFAOYSA-N 0.000 description 1
- IAKJAFLYVCGWAU-UHFFFAOYSA-N 1-(3-bromo-2-fluoro-6-methoxy-5-nitrophenyl)-4-methylpiperazine Chemical compound COC1=C([N+]([O-])=O)C=C(Br)C(F)=C1N1CCN(C)CC1 IAKJAFLYVCGWAU-UHFFFAOYSA-N 0.000 description 1
- SZVRYLYNTOFQGD-UHFFFAOYSA-N 1-(3-bromo-2-fluoro-6-methoxyphenyl)-4-methylpiperazine Chemical compound COC1=CC=C(Br)C(F)=C1N1CCN(C)CC1 SZVRYLYNTOFQGD-UHFFFAOYSA-N 0.000 description 1
- ZLGFTTBBGWHGDS-UHFFFAOYSA-N 1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid Chemical compound C1=C2N3C(CC)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 ZLGFTTBBGWHGDS-UHFFFAOYSA-N 0.000 description 1
- KXZSVYHFYHTNBI-UHFFFAOYSA-N 1h-quinoline-2-thione Chemical group C1=CC=CC2=NC(S)=CC=C21 KXZSVYHFYHTNBI-UHFFFAOYSA-N 0.000 description 1
- OHTWIWKKHGXSIB-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1-phenyl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(=O)OCOC(=O)C(C)(C)C)=C1SC(C=3C=CC=CC=3)N12 OHTWIWKKHGXSIB-UHFFFAOYSA-N 0.000 description 1
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- BUIWSDLHJFFNAD-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-4-oxo-7-[4-(3-oxobutyl)piperazin-1-yl]-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CCC(C)=O)CC1 BUIWSDLHJFFNAD-UHFFFAOYSA-N 0.000 description 1
- GKOAXIPOHRAVOW-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-(3-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCNC(C)C1 GKOAXIPOHRAVOW-UHFFFAOYSA-N 0.000 description 1
- YHDHWJHCWATTIU-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-(4-methyl-3-oxopiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(C)C(=O)C1 YHDHWJHCWATTIU-UHFFFAOYSA-N 0.000 description 1
- ZYFGFAMKHITIOH-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-8-nitro-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=C([N+]([O-])=O)C=1N1CCN(C)CC1 ZYFGFAMKHITIOH-UHFFFAOYSA-N 0.000 description 1
- PCUQXHQOZPJPQM-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-[3-methyl-4-(2-oxopropyl)piperazin-1-yl]-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC(C)=O)C(C)C1 PCUQXHQOZPJPQM-UHFFFAOYSA-N 0.000 description 1
- QDMWHCGQLNYCHC-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-[4-(3-methyl-2-oxobutyl)piperazin-1-yl]-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC(=O)C(C)C)CC1 QDMWHCGQLNYCHC-UHFFFAOYSA-N 0.000 description 1
- DKYFIGUCSQNEDK-UHFFFAOYSA-N ethyl 6-fluoro-1-methyl-7-morpholin-4-yl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCOCC1 DKYFIGUCSQNEDK-UHFFFAOYSA-N 0.000 description 1
- RTEJCFKMIBYSNN-UHFFFAOYSA-N ethyl 6-fluoro-4-oxo-1-phenyl-7-piperazin-1-yl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CCNCC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=CC=C1 RTEJCFKMIBYSNN-UHFFFAOYSA-N 0.000 description 1
- MFWXQORTULNWHR-UHFFFAOYSA-N ethyl 6-fluoro-4-oxo-7-[4-(2-oxopropyl)piperazin-1-yl]-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=CC=1N1CCN(CC(C)=O)CC1 MFWXQORTULNWHR-UHFFFAOYSA-N 0.000 description 1
- CXDCKQZMPOXYAF-UHFFFAOYSA-N ethyl 6-fluoro-4-oxo-7-piperazin-1-yl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=CC=1N1CCNCC1 CXDCKQZMPOXYAF-UHFFFAOYSA-N 0.000 description 1
- ZKZHAFJPVBUHKS-UHFFFAOYSA-N ethyl 6-fluoro-7-(3-methylpiperazin-1-yl)-4-oxo-1-phenyl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CC(C)NCC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=CC=C1 ZKZHAFJPVBUHKS-UHFFFAOYSA-N 0.000 description 1
- NRBJNUQNLQMRLF-UHFFFAOYSA-N ethyl 6-fluoro-7-(3-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=CC=1N1CCNC(C)C1 NRBJNUQNLQMRLF-UHFFFAOYSA-N 0.000 description 1
- BLTRANAAGXRLPO-UHFFFAOYSA-N ethyl 6-fluoro-7-(4-methylpiperazin-1-yl)-1-(4-nitrophenyl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CCN(C)CC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=C([N+]([O-])=O)C=C1 BLTRANAAGXRLPO-UHFFFAOYSA-N 0.000 description 1
- VWEGGRDPTNBHIE-UHFFFAOYSA-N ethyl 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1-phenyl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CCN(C)CC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=CC=C1 VWEGGRDPTNBHIE-UHFFFAOYSA-N 0.000 description 1
- QNRSMWCACQYPMZ-UHFFFAOYSA-N ethyl 6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=CC=1N1CCN(C)CC1 QNRSMWCACQYPMZ-UHFFFAOYSA-N 0.000 description 1
- OXKZILHLZSPFFD-UHFFFAOYSA-N ethyl 6-fluoro-7-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CCO)CC1 OXKZILHLZSPFFD-UHFFFAOYSA-N 0.000 description 1
- RSMYIUQSGGUTTJ-UHFFFAOYSA-N ethyl 6-fluoro-7-[4-(2-methoxyethyl)piperazin-1-yl]-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CCOC)CC1 RSMYIUQSGGUTTJ-UHFFFAOYSA-N 0.000 description 1
- VWJZGRAEIKMGNH-UHFFFAOYSA-N ethyl 6-fluoro-7-morpholin-4-yl-4-oxo-1-phenyl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CCOCC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=CC=C1 VWJZGRAEIKMGNH-UHFFFAOYSA-N 0.000 description 1
- KVRUHZASSRIDGJ-UHFFFAOYSA-N ethyl 6-fluoro-8-methoxy-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=C(OC)C=1N1CCN(C)CC1 KVRUHZASSRIDGJ-UHFFFAOYSA-N 0.000 description 1
- VLHBBHIFIRZKSZ-UHFFFAOYSA-N ethyl 7-(3,4-dimethylpiperazin-1-yl)-6-fluoro-4-oxo-1-phenyl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound N12C3=CC(N4CC(C)N(C)CC4)=C(F)C=C3C(=O)C(C(=O)OCC)=C2SC1C1=CC=CC=C1 VLHBBHIFIRZKSZ-UHFFFAOYSA-N 0.000 description 1
- RJOBTNHVHKSGSA-UHFFFAOYSA-N ethyl 7-(4-acetylpiperazin-1-yl)-6-chloro-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound ClC=1C=C2C(=O)C(C(=O)OCC)=C3SCN3C2=CC=1N1CCN(C(C)=O)CC1 RJOBTNHVHKSGSA-UHFFFAOYSA-N 0.000 description 1
- MHHACGCQQVOITC-UHFFFAOYSA-N ethyl 7-(4-acetylpiperazin-1-yl)-6-chloro-4-oxo-2-sulfanyl-1h-quinoline-3-carboxylate Chemical compound ClC=1C=C2C(=O)C(C(=O)OCC)=C(S)NC2=CC=1N1CCN(C(C)=O)CC1 MHHACGCQQVOITC-UHFFFAOYSA-N 0.000 description 1
- KXFZOEKGUFVVLU-UHFFFAOYSA-N ethyl 7-(4-ethylpiperazin-1-yl)-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC)CC1 KXFZOEKGUFVVLU-UHFFFAOYSA-N 0.000 description 1
- FMKOEDGNUNLQIH-UHFFFAOYSA-N ethyl 7-(dimethylamino)-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound C12=CC(N(C)C)=C(F)C=C2C(=O)C(C(=O)OCC)=C2N1C(C)S2 FMKOEDGNUNLQIH-UHFFFAOYSA-N 0.000 description 1
- KCLMTBLHQGCCSY-UHFFFAOYSA-N ethyl 7-[4-(3,3-dimethyl-2-oxobutyl)piperazin-1-yl]-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC(=O)C(C)(C)C)CC1 KCLMTBLHQGCCSY-UHFFFAOYSA-N 0.000 description 1
- CVCCYAMTGMJSOI-UHFFFAOYSA-N ethyl 7-[4-(cyanomethyl)piperazin-1-yl]-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=CC=1N1CCN(CC#N)CC1 CVCCYAMTGMJSOI-UHFFFAOYSA-N 0.000 description 1
- OHUHHNUSGYWSLO-UHFFFAOYSA-N ethyl 8-(diacetylamino)-6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=C(N(C(C)=O)C(C)=O)C=1N1CCN(C)CC1 OHUHHNUSGYWSLO-UHFFFAOYSA-N 0.000 description 1
- JURRTQFEXGCTOS-UHFFFAOYSA-N ethyl 8-amino-6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=C(N)C=1N1CCN(C)CC1 JURRTQFEXGCTOS-UHFFFAOYSA-N 0.000 description 1
- LQSPVBQAQSDWQQ-UHFFFAOYSA-N ethyl 8-chloro-6-fluoro-1-methyl-7-(4-methylpiperazin-1-yl)-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OCC)=C3SC(C)N3C2=C(Cl)C=1N1CCN(C)CC1 LQSPVBQAQSDWQQ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- VAFXXNNURAGAMJ-UHFFFAOYSA-N methyl 6-fluoro-1-methyl-4-oxo-7-piperazin-1-yl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OC)=C3SC(C)N3C2=CC=1N1CCNCC1 VAFXXNNURAGAMJ-UHFFFAOYSA-N 0.000 description 1
- LQZYNTGBVZLBFP-UHFFFAOYSA-N methyl 7-(3,4-dimethylpiperazin-1-yl)-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OC)=C3SC(C)N3C2=CC=1N1CCN(C)C(C)C1 LQZYNTGBVZLBFP-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- IFMFKWDICOBULN-UHFFFAOYSA-N propan-2-yl 6-fluoro-1-methyl-4-oxo-7-piperazin-1-yl-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OC(C)C)=C3SC(C)N3C2=CC=1N1CCNCC1 IFMFKWDICOBULN-UHFFFAOYSA-N 0.000 description 1
- SVQTZRLJUBIGSF-UHFFFAOYSA-N propan-2-yl 7-(3,4-dimethylpiperazin-1-yl)-6-fluoro-1-methyl-4-oxo-1h-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate Chemical compound FC=1C=C2C(=O)C(C(=O)OC(C)C)=C3SC(C)N3C2=CC=1N1CCN(C)C(C)C1 SVQTZRLJUBIGSF-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Liquid Carbonaceous Fuels (AREA)
- Financial Or Insurance-Related Operations Such As Payment And Settlement (AREA)
- Electrophonic Musical Instruments (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Quinoline Compounds (AREA)
- Saccharide Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Steroid Compounds (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive kinolinkarboksylsyrederivater som viser antibakteriell virkning og som kan benyttes som terapeutiske midler mot forskjellige infeksjonssykdommer.
Mer spesielt angår oppfinnelsen en analogifremgangsmåte for fremstilling av kinolinkarboksylsyrederivater som representeres ved den generelle formel (I):
der
Ri er hydrogen, alkyl med 1 til 6 karbonatomer eller fenyl;
r<2>er hydrogen eller alkoksy med 1 til 4 karbonatomer;
R<4>og R--5 danner en pyrrolidino-, piperidino-, piperazino-,
homopiperazino-, morfolino- eller tiomorfolinogruppe idet det cykliske amino kan være substituert med alkyl med 1 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller
hydroksyalkyl med 1 til 4 karbonatomer;
X er halogen;
eller farmasøytisk aksepterbare salter derav.
Hva angår syntetiske antibakterielle stoffer som et middel mot infektiøse sykdommer forårsaket av gram-negative bakterier, har nalidiksinsyre, piromidinsyre, pipemidinsyre, enoxacin (AT-2266), ofloxacin (DL-8280) og så videre, hyppig vært benyttet, men er ikke helt tilfredsstillende mot infektiøse sykdommer forårsaket av gram-positive bakterier og de som forårsakes av Pseudomonas aeruginosa (kroniske), som har vært økende i de senere tider og er vanskelige å helbrede.
For å løse slike problemer er forskjellige forbindelser syntetisert og mange patentsøknader er innlevert. Foreliggende oppfinnere har også syntetisert forskjellige forbindelser, funnet kinolinkarboksylsyre med utmerkede antibakteriell virkning og også innlevert patentsøknader (jfr. JP-søknad 57/136.588 og 58/103.393.). I disse søknader er hovedsakelig beskrevet tiazolokinolinkarboksylsyrer og, som en forbindelse lik de ifølge foreliggende oppfinnelse, 7-klor-6-fluor-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylsyre som er beskrevet som utgangsmateriale.
Videre er det i US-PS 4.550.104 en beskrivelse av tiazolo-kinolinkarboksylsyrederivater.
Det er en viss grense hva angår effekten i disse antibakterielle stoffer og, hva sikkerheten angår, er det ikke alltid noe tilfredsstillende resultat. For å overvinne disse vanskeligheter fortsatte foreliggende oppfinnere sin forsk-ning og fant en serie forbindelser som viste langt bedre farmakologisk virkning enn den kjente teknikk og også med mindre toksisitet, denne oppdagelse er grunnlaget for foreliggende oppfinnelse.
I henhold til dette, er gjenstanden for foreliggende oppfinnelse å tilveiebringe muligheten for å fremstille nye farmasøytika som er merkbart bedre enn de konvensjonelle syntetiske antibakterielle stoffer som allerede er nevnt.
Forbindelsene ifølge foreliggende oppfinnelse er nye stoffer som ennu ikke er beskrevet i den kjente litteratur. De karakteristiske trekk i den kjemiske struktur ligger i de følgende to punkter: 1) Ringen som dannes mellom nitrogen- og svovelatomet i 2—merkaptokinolinskjelettet er en tiazetidinring; og 2) 6-posisjonen i kinolinskjelettet og 7-posisjonen i dette
er substituert med halogen, henholdsvis med amin. Eksempler på salter av forbindelsen (I) ifølge oppfinnelsen er salter med mineralsyrer som saltsyre, svovelsyre, salpetersyre, fosforsyre, hydrofluorsyre, hydrobromsyre og så videre, videre salter med organiske syrer som maur-, eddik-, vin-, melke-, sitron-, fumar-, malein-, rav-, metansulfon-, etansulfon-, benzensulfon-, toluensulfon-, naftalensulfon-, kamfersulfonsyre og så videre, og salter med alkali- eller jordalkalimetaller som natrium, kalium, kalsium og så videre.
Forbindelsene med formel (I) kan ifølge oppfinnelsen fremstilles ved at
a) en forbindelse med den generelle formel (III)
der R<6>er alkyl med 1 til 6 karbonatomer, A er fluor eller
NR4R<5>idet de andre substituenter R<2>,R<4>,R<5>og X har de ovenfor angitte betydninger,
omsettes med en dihalogenforbindelse med formelen:
hvori Y og Z er like eller forskjellige og er halogen og Ri er som angitt ovenfor, idet, når A er fluor, omsettes det oppnådde produkt med et amin med formelen
der R<4>og R<5>har den ovenfor angitte betydning, eller
b) at en forbindelse med formel (Villa):
der substituenteneR<1>,R4,R5,R6 og X har de ovenfor
angitte betydninger, underkastes ringslutning, og at forbindelsen hvis nødvendig, hydrolyseres på et ønsket trinn i reaksjonsforløpet.
Alternativ a): (III) og dihalogenid (for eksempel metylen-jodid, etylidenbromid, benzylidenbromid og så videre) bringes til omsetning, vanligvis ved 0 til 120°C i nærvær av et syre-fjerningsmiddel (for eksempel natriumkarbonat, kaliumkarbonat, trietylamin og så videre) i et oppløsningsmiddel som er inaktivt overfor reaksjonen, hvorefter det gjennom-føres en ringslutning. Hva angår oppløsningsmidlet, er et ikke-protisk oppløsningsmiddel som N,N-dimetylformamid, N,N-dimetylacetamid, dimetylsulfoksyd, sulforan og så videre foretrukket. Mengdene dihalogenid og syrefjerningsmidler er fortrinnsvis ikke mindre enn ekvimolar og helst 1,1 til 2,5 mol pr. 1 mol (II). For å akselerere reaksjonen kan reaksjonen gjennomføres under tilsetning av en katalytisk mengde, for eksempel 0,01 til 0,1 molar ekvivalent) natrium-jodid eller kaliumjodid.
Alternativ b): Forbindelsene med formel (I) kan ifølge oppfinnelsen videre fremstilles ved å gå ut fra en forbindelse med den generelle formel (Villa) ved omsetning av forbindelsen med et dihalogenid i nærvær av et syrefjernings-middel , for eksempel kaliumkarbonat, i et inert oppløsnings-middel som N,N-dimetylformamid med efterfølgende ringslutning. Denne rlngslutningsreaksjon kan gjennomføres på i og for seg kjent måte, for eksempel ved oppvarming, eller ved en metode som bruker et surt materiale som fosforoksyklorid, fosforpentaklorid, fosfortriklorid, tionylklorid, rykende svovelsyre, konsentrert svovelsyre, polyfosforsyre, poly-fosfat og så videre. Når det tilføres en sur substans er mengden 1 mol til et stort oversku'%1 (mere foretrukket 20 til 30 mol) sur substans pr. 1 mol v IX) og reaksjonen gjennom-føres vanligvis ved 0 til 100°C og fortrinnsvis ved 0 til 60°C. Det er også mulig at en tiazetidinring dannes fra 3,4-difluormateriale og kondenseres med et amin på samme måte som i metode C for derved å gi den ønskede forbindelse. Når R<2>er hydrogen, fremstilles X som et biprodukt og, efter fjerning fra reaksjonsblandingen, bringes resten til omsetning med et amin. Eventuelt kan prepareringen gjennomføres efter kondensasjonen med et amin.
Noen av utgangsforbindelsene (III) og (Villa) er nye og slike nye forbindelser fremstilles på en kjent måte (som for eksempel beskrevet i JP-søknad 57/136588) eller ved en metode som i referanseeksemplene nedenfor.
En ønsket forbindelse (I) fremstilt som sådan, kan separeres og renses på forskjellige måter, for eksempel ved konsen-trering, omdanning av flytende egenskaper, overføring til et annet oppløsningsmiddel, ekstrahering med et oppløsningsmid-del, krystallisering, omkrystallisering, fraksjonert destil-lasjon, kromatografi og så videre.
Når forbindelsene ifølge oppfinnelsene administreres som medikamenter gies det til dyr inkludert mennesker, per se eller som et farmasøytisk preparat inneholdende 0,1 til 99,5 og fortrinnsvis 0,5 til 90% i ikke-toksiske og inerte farmasøytisk akseptable bærere.
Vanligvis er doseringen 50 til 1000 mg pr. dag pr. person, fortrinnsvis 100 til 300 mg pr. dag pr. person, beregnet som mengde aktiv bestanddel. Enkelte ganger vil mindre doser være tilstrekkelig, mens større doser andre ganger kan være nødvendig. Det er ønskelig at dosen deles over to eller tre ganger daglig.
Oppfinnelsen skal illustreres nærmere ved de følgende eksempler.
Referanseeksempel 1; Etyl-6,7-difluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. 1) 3,4-difluoranilin (600 g) og 1410 g trietylamin ble blandet og under iskjøling og omrøring ble 389 g karbon-disulfid dryppet inn i løpet av 2,5 time. Blandingen ble omrørt ved samme temperatur i 2 timer hvorefter krystaller gradvis opptrådte. Blandingen ble gradvis oppvarmet til romtemperatur, omrørt i 2 timer og holdt i en kjøler i to netter. 2 1 kloroform ble tilsatt til reaksjonsblandingen i hvilken krystallene størknet, blandingen ble omrørt for å bringe den i suspendert tilstand, etylklorformat ble dryppet inn ved 10"C innvendig temperatur i 2 timer. Blandingen ble omrørt i ytterligere 3,5 timer ved romtemperatur. Efter reaksjonen ble reaksjonsproduktet helt over i isvann, blandingen ble gjort svakt sur med konsentrert saltsyre og kloroformsjiktet samlet. Dette ble vasket med vann, tørket og konsentrert og resten ble renset ved kolonnekromatografi over n-heksan/silikagel og man oppnådde 558,6 g 3,4-difluorfenylisotiocyanat i en farveløs olje. 2) Etylmalonat (200,3 g) ble dryppet ned i en omrørt blanding av 2850 ml dioksan og finpulverisert kaliumhydroksyd i 3 timer. Efter at tildryppingen var ferdig, ble 186,2 g av oljen som ble oppnådd under (1) dryppet inn ved romtemperatur under omrøring, hvorefter blandingen ble omrørt i 18 timer. Metoksymetylklorid (100,2 g) ble dryppet inn under iskjøling og omrøring, omrøringen ble fortsatt ved romtemperatur i 3 timer, det hele ble helt over i isvann, ekstrahert med etylacetat, ekstrakten vasket med vann og tørket. Den oppnådde rest ble renset ved silikagelkolonne-kromatografi (n-heksan:etylacetat i forholdet 2:1 som elueringsmiddel) og man oppnådde 383,8 g oljeaktig dietyl-l-(3,4-difluorfenylamino)-l-(metoksymetyltio)-metylen-malonat. 3) Den oljeaktige substans i en mengde av 85,5 g som ble oppnådd under (2) ovenfor ble oppløst i 250 g difenyleter og oppløsningen ble oppvarmet under omrøring til 240°C i 5 til 10 minutter. Det hele ble avkjølt til 80°C, helt over i 1 liter n-heksan og satt hen over natten på et kaldt sted. Utskilte krystaller ble samlet ved filtrering og vasket med n-heksan, og man oppnådde 195 g etyl, 6,7-di f luor-4-hydroksy-2-metoksymetyltiokinolin-3-karboksylat som blekt gule krystaller med smeltepunkt 126-129°C. 4) 600 ml konsentrert saltsyre ble dryppet i en suspensjon av 195 g av krystallene fra punkt (3) i en liter etanol ved romtemperatur ved omrøring. Efter at tildryppingen var ferdig, ble blandingen omrørt i 2 timer, isvann ble tilsatt, utskilte krystaller ble samlet ved filtrering, vasket med vann og lufttørket hvorved man oppnådde 166,6 g etyl 6 ,7-difluor-4-hydroksy-2-merkaptokinolin-3-karboksylat, gule krystaller, smeltepunkt 201-203°C (dekomponering som vanlig). 5) Etylidenbromid (110,0 g), 77,4 g kaliumkarbonat. 4,6 g kaliumjodid og 540 ml N,N-dimetylformamid ble bragt i en
kolbe og oppvarmet under omrøring til 105-110°C. En oppløsning av 80 g av krystallene som ble oppnådd under (4) i 1400 ml N,N-dimetylformamid ble helt opp i oppløs-ningen. Efter ferdig tildrypping ble blandingen omrørt ved den samme temperatur i 2,5 time. Efter at reaksjonen var ferdig, ble blandingen konsentrert i vakuum. Den konsen-trerte oppløsning ble helt over i isvann og utskilte krystaller ble samlet ved filtrering fulgt av vasking med vann og tørking med luft for derved å oppnå 61,4 g etyl-6 , 7-dif luor-l-metyl-4-okso-4H-(l ,3 )tiazeto(3,2-a)kinolin-3-karboksylat urene krystaller. Disse ble omkrystallisert fra 10:1 kloroform:kloroform og metanol og man oppnådde 41,2 g farveløse krystaller med smeltepunkt 200-202°C.
Elementanalyse for C14H11F2NO3S.
Beregnet (#): C 54,02, H 3,56, N 4,50
Funnet (*): C 54,54, H 3,42 , N 4,29
Referanseeksempel 2
1) 2-fluor-6-metoksyanilin (7,80 g) og 17,23 g di-(2-brom-etyl )aminhydrobromid ble oppløst i 5 ml vann og under oppvarming til ca. 110° C på et bad ble 10 ml 30#-ig kaliumhydroksydoppløsning tilsatt (hver ca. 3,5 ml en gang i timen). Oppvarmingen ble fortsatt ytterligere i tiIsammen 7 timer. Efter avkjøling ble reaksjonsproduktet gjort alkalisk med en vandig oppløsning av natriumhydroksyd for utsalting og det hele ble ekstrahert to ganger med kloroform. Ekstrakten ble vasket med den mettede natriumkloridoppløsning, tørket over natrium-sulfonat, oppløsningsmidlet ble fordampet og resten renset ved kolonnekromatografi for derved å gi 8,95 g oljeaktig l-(2-fluor-6-metoksyfenyl)piperazin i et utbytte på 34,94 g tilsvarende 94$. 2) 34,89 g av forbindelsen oppnådd som under (1) ovenfor ble oppløst i 50 g maursyre og 135 g 3756-ig formalin og oppløsningen ble kokt under tilbakeløp i 75 minutter ved badtemperatur 110°C. Reaksjonsoppløsningen ble konsentrert 1 vakuum og oppløst i fortynnet saltsyre. Uoppløse-lige stoffer ble fjernet, resten ble vasket med etylacetat, gjort alkalisk med en vandig oppløsning av natriumhydroksyd, saltet ut og ekstrahert med kloroform. Ekstrakten ble tørket over natriumsulfat og oppløsnings-midlet fordampet derfra. Resten ble oppløst i eter, saltsyre:etanol ble tilsatt og hydrokloridet separert ut. Krystallene ble vasket med eter, tørket, oppløst i vann, natriumhydroksydoppløsning ble tilsatt og det hele ekstrahert med eter. Ekstrakten ble vasket med mettet natriumkloridoppløsning, tørket over natriumsulfat og oppløsningsmidlet ble fordampet hvorved man oppnådde 26,18 g oljeaktig l-(2-fluor-6-metoksyfenyl)-4-metylpiperazin, 70% utbytte. 3) 27,56 g av forbindelsen oppnådd som under (2) ovenfor og 42,14 g sølvsulfat ble oppløst i 600 ml konsentrert svovelsyre, en oppløsning av 21,60 g brom i 1200 ml konsentrert svovelsyre ble dryppet til i løpet av 30 minutter under iskjøling og omrøringen ble fortsatt ytterligere 90 minutter. Reaksjonsoppløsningen ble helt over på is, blandingen ble gjort alkalisk med natriumhydroksyd under iskjøling og ekstrahert med kloroform to ganger. Ekstrakten ble vasket med mettet natriumklorid-oppløsning og tørket over natriumsulfat. Oppløsningsmidlet ble fordampet derfra og renset ved kolonnekromatografi hvorved man oppnådde 14,12 g l-(3-brom-2-fluor-6-metoksy-fenyl)-4-metylpiperazin. 38% utbytte. 4) 13,42 g forbindelse oppnådd som under (3) ble oppløst i 500 ml konsentrert svovelsyre og en oppløsning av 4,70 g kaliumnitrat i 70 ml konsentrert svovelsyre ble dryppet inn i løpet av 20 minutter under iskjøling (temperaturen var 4 til 6°C). Det hele ble omrørt i 30 minutter til, og så helt over isvann. Blandingen ble gjort svakt alkalisk med natriumbikarbonat og ekstrahert med etylacetat.
Ekstrakten ble vasket med mettet natriumkloridoppløsning og tørket over natriumsulfat. Oppløsningsmidlet ble fordampet og renset ved kolonnekromatografi hvorved man oppnådde 3,29 g l-(3-brom-2-fluor-5-nitro-6-metoksyfenyl)-4-metylpiperazin. 21% utbytte. 5) 2, 11S g av forbindelsen oppnådd som under (4) ble oppløst i 60 ml konsentrert saltsyre og en oppløsning av 7,38 g tinn(II)kloriddihydrat I 80 ml konsentrert saltsyre ble dryppet inn under iskjøling. Efter ferdig tildrypping ble blandingen omrørt i 30 minutter, helt over is, nøytra-lisert med fortynnet natriumhydroksyd og ekstrahert med kloroform. Ekstrakten ble vasket med mettet natrium-bikarbonatoppløsning, tørket over natriumsulfat og oppløsningsmidlet ble fordampet i vakuum. Som rest oppnådde man 2,432 g l-(5-amino-3-brom-2-fluor-6-metoksy-fenyl )-4-metylpiperazin. 9656 utbytte. 6) 2,33 g forbindelse oppnådd som (5) ovenfor ble oppløst i 150 ml etanol hvorefter 0,30 g natriumhydroksyd og 200 mg 5% palladium på trekull ble tilsatt hvorefter den katalytiske reduksjon ble gjennomført ved romtemperatur og vanlig trykk. Reaksjonsoppløsningen ble filtrert av og filtratet konsentrert I vakuum. Dette ble ekstrahert med kloroform, ekstrakten ble vasket med mettet natrium i karbonatoppløsning, tørket over natriumsulfat og oppløs-ningsmidlet fordampet derfra hvorved man oppnådde 1,68 g l-(5-amino-2-fluor-6-metoksyfenyl)-4-metylpiperazin.
Eksempel 1
Etyl- 7- ( 4 - acetyl- 1- piperazinvl)- 6- klor- 4- okso- 4H-( 1. 3)-tiazeto( 3, 2- a) kinolin- 3- karboksylat.
Til 50 ml N,N-dimetylformamid ble det satt 2,35 g metylenjod og 2,5 g kaliumkarbonat og en oppløsning av 3,0 g etyl-7-(4-acetyl -1 -piperazinyl)-6-klor-4-hydroksy-2-merkaptokinolin-3-karboksylat i 30 ml N,N-dimetylformamid ble gradvis dryppet til under omrøring. Derefter ble blandingen omrørt ved romtemperatur i 1 time, konsentrert i vakuum, vann ble satt til resten og uoppløselige krystaller ble samlet ved filtrering. Disse ble vasket ved bruk av vann, tørket og omkrystallisert fra et blandet oppløsningsmiddel av etanol og kloroform for derved å gi 2,49 g farveløse pulveraktige krystaller med smeltepunkt 266-268"C under dekomponering.
Elementanalyse for CigltøoClNsC^S. 1/2-H20:
Beregnet ($ >) : C 52,96, H 4,91, N 9,75.
Funnet {%)-. C 53,16 , H 4 ,69 , N 9 ,69
Eksempel 2
7-( 4- acetvl- l- piperazinyl ) - 6- f luor- 4 - okso- 4H-( 1. 3 Hiazeto-( 3. 2- a) klnolin- 3- karboksvlsvre og etyl- 7-( 4- acetyl- l- plpera-zinyl )- 6- fluor- 4- okso- 4H-( l . 3) tlazeto( 3. 2- a) kinolin- 3-karboksvlat.
800 mg krystaller som oppnådd under (2) ovenfor ble blandet med 30 g polyfosforsyre (PPA) og oppvarmet til 120"C i 1 timer under omrøring. Reaksjonsoppløsningen ble helt over isvann og de utskilte krystaller samlet ved filtrering og vasket med vann og lufttørket. Rensing ved kolonnekromatografi på silikagel med kloroform:metanol i forholdet 40:1 -> 4:1 ga 130 mg av karboksyl syren med smeltepunkt 247-249 °C under dekomponering og 180 mg etylester med smeltepunkt 278-280°C under dekomponering.
De følgende forbindelser er fremstilt analogt det som er beskrevet i eksempel 1.
6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-4H-(l ,3 )tiazeto-(3,2-a)-kinolin-3-karboksylsyre. Smeltepunkt fra 300"C under dekomponering.
IR^^cm-1):3400, 2800, 1700, 1625, 1600, 1485, 1375, 1300,
ID 3.X
1250, 1230, 1110, 1010, 890, 805.
1-etyl-6-f luor-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 233-234°C under dekomponering.
6-fluor-7-( 1-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kino-lin-3-karboksylsyre. Hydroklorid. Smeltepunkt fra 300°C under dekomponering.
IR^^(cm_1): 3500, 2700, 1690, 1620, 1500, 1390, 1270, 1115,
in ci x
800.
6-f luor-7-morf ol in-4-okso-4H-(1, 3 )tiazeto(3 ,2-a)kinolin-3-karboksylsyre. Smeltepunkt 244-248°C under dekomponering. Difosfat, smeltepunkt 182-190°C under dekomponering. 6- fluor-7-tiomorfolino-4-okso-4H-(1,3 )tiazeto(3 ^-aJkinolin-S-karboksylsyre. Smeltepunkt 220-242°C under dekomponering. 7- (4-ally1-1-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 216-218°C under dekomponering.
1-(4-etyl -1-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylsyre. Hydrofluorid, smeltepunkt 211-214°C under dekomponering.
6-fluor-7-(4-isopropyl-1-piperazinyl)-l-metyl-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 227-228°C under dekomponering.
6-f luor-7-( 4-2-hydroksyetyl )-l-piperazinyl )-l-metyl-4-okso-4H-( 1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 230-232°C under dekomponering.
7 -(3-aminometyl-l-pyrrolidinyl )-6-f luor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 213°C under dekomponering. 6-fluor-7-(3-hydroksy-l-pyrroiidinyl)-1-metyl-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 253°C under dekomponering. Sulfat, smeltepunkt 206-208°C under dekomponering. 6-fluor-7-(imidazol-l-yl)-l-metyl-4-okso-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 248-251°C under dekomponer ing.
6-fluor-7-(3-hydroksymetyl-l-pyrrolidinyl)-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 268-270 °C under dekomponering. 7 -(4-acetyl-1-piperazinyl )-6-fluor-l-metyl-4-okso-4H-( 1, 3)-tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 263-265 °C under dekomponering. 6-fluor-l-metyl-7-morfolin-4-okso-4H-(1,3)tiazeto(3,2-a)-kinolln-3-karboksylsyre. Smeltepunkt 250-252°C under dekomponering. Sulfat, smeltepunkt 192-198°C under dekomponering. 6-fluor-l-metyl-7-tiomorfolino-4-okso-4H-(l,3)tiazeto(3,2-a)-kinolin-3-karboksylsyre. Smeltepunkt 258-260°C under dekomponering. Sulfat, smeltepunkt 229-231°C under dekomponering. 6-fluor-7-(4-metyl-1-homopiperazinyl)-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 158-164°C under dekomponering. 6- f luor-7 - ( 3-hydroksypiperidin)-l-metyl-4-okso-4H-(l ,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 255-257°C under dekomponering. 7- ( 4- ( 4-aminobenzyl )-l-piperazinyl )-6-f luor-l-metyl-4-okso-4H-(1,3) tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 209-211°C under dekomponering. 6-f luor-7- (2 -metyl imidazol-l-yl )-l-metyl-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 282-284°C under dekomponering. 6-f luor-7 - ( 4-hydroksypiperidin)-l-metyl-4-okso-4H-(l ,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 266-268°C under dekomponering. 6-f luor-7-piperidin-l-metyl-4-okso-4H-(l ,3 )tiazeto(3 ,2-a)-kinolin-3-karboksylsyre. Smeltepunkt 246-248°C under dekomponering. 6-f luor-1-me ty 1-7-(1-pyr roi idinyl )-4-okso-4H-(l ,3 )tiazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 275-277°C under dekomponering. 6-f luor-7-(4-(4-metoksyfenyl)-l-piperazinyl)-l-metyl-4-okso-4H-(1,3) tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 258-260°C under dekomponering.
6-fluor-7-(4-fenyl-1-piperazinyl)-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 267-269" C under dekomponering. 6-fluor-7-(3-hydroksy-4-hydroksymetyl-1-pyrroiidinyl)-l-metyl-4-okso-4H-(l ,3 )tiazeto(3 ,2-a )kinolin-3-karboksyl syre. Smeltepunkt 245-246°C under dekomponering. 6-fluor-7-(3,4-di(2-hydroksyetyl)-l-pyrrolidinyl)-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 220-221"C under dekomponering. 7 - (N ,N-dihydroksyetylamino)-6-fluor-l-metyl-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 227-230°C under dekomponering.
6-f luor-1-mety 1-7-(3-amino-l-pyrrolidinyl )-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 222-230"C under dekomponering.
Etansulfonat, smeltepunkt 250-251°C under dekomponering. d-10-kamfersulfonat, smeltepunkt 238-240°C under dekomponering.
6- f luor-l-metyl-7-( 4-metyl-l-piperidin)-4-okso-4H-(l ,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 249-251°C under dekomponering.
7- (3-dimetylamino-l-pyrrolidinyl)-6-fluor-l-metyl-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Hydroklorid, smeltepunkt 275-276°C under dekomponering.
6-fluor-1-mety1-7-(3-okso-1-piperazinyl)-4-okso-(l,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 254-256°C under dekomponering. Sulfat, smeltepunkt 198-200°C under dekomponer ing.
6-f luor-1 -me tyl - 7- (3 -metyl amino -1 -py r roi idinyl )-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Hydroklorid, smeltepunkt 213-216°C under dekomponering.
6-f luor-1-metyl-7-(4-metyl-1-piperazinyl)-8-nitro-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Nitrat, smeltepunkt ikke lavere enn 300°C under dekomponering.
IR^^cm-1 ): 3400, 1700, 1620, 1595, 1530, 1480, 1450, 1380,
max
1270, 1125, 1070, 970, 800.
6-f luor-1-me ty 1-7 - ( 4-metyl-3-okso-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 254-255"C under dekomponering.
8-amino-6-fluor-l-metyl-7-(4-metyl-1-piperazinyl)-4-okso-4H-(l,3)tlazeto(3,2-a)kinolin-3-karl)oksylsyre. Smeltepunkt 240°C under dekomponering.
Etyl-8-klor-6-fluor-l-metyl-7-(4-metyl-1-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 196-197°C. Etyl-6-fluor-l-metyl-7-(4-metyl-1-piperazinyl)-8-nitro-4-okso-4H(1,3 )tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 185-188°C under dekomponering. Etyl-6-fluor-1-metyl-7-(4-metyl-1-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 223-225°C. Etyl-8-brom-6-fluor-l-metyl-7-(4-metyl-l-piperazinyl)—< - r.kso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 191-192°C under dekomponering.
8-klor-6-f luor-l-metyl-7-(4-metyl-l-piperazinyl )-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 189-190°C under dekomponering.
8-brom-6-f luor-l-metyl- 7-(4-metyl-l-piperazinyl )-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 198-200°C under dekomponering.
Etyl-8-amino-6-fluor-1-metyl-7-(4-metyl-l-piperazinyl )-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 200-205°C under dekomponering. Etyl-6-f luor-7- ( 4-metyl-l-piperazinyl )-4-okso-4H-( 1,3 )tiazeto-(3,2-a)kinolin-3-karboksylat. Smeltepunkt 260-265°C under dekomponering. Etyl-8-acetamid-6-fluor-1-metyl-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 192-195°C under dekomponering. Etyl-8-diacetylamino-6-fluor-l-metyl-7-(4-metyl-1-piperazinyl)-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 212-214°C under dekomponering.
6-fluor-1-metyl-4-okso-7-(1-piperazinyl)-4H-(l,3)tiazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 215-218°C under dekomponering. 1/2 Sulfat, smeltepunkt 285 °C under dekomponering; hydroklorid, smeltepunkt 295-300'C under dekomponering; metansulfonat, smeltepunkt 236-239°C under dekomponering; p-toluensulfonat, smeltepunkt 196-200°C under dekomponering; maleat; smeltepunkt 225-227°C under dekomponering.
Etyl - 7-dimetylamino-6-f luor-l-metyl-4-okso-4H-( 1,3 )tiazeto-(3,2-a)kinolin-3-karboksylat. Smeltepunkt 194°C. Etyl-6-fluor-l-metyl-7-(3-metyl-1-piperazinyl )-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 133-135°C. Etyl- 6-fluor-7-( 4 - i sopropyl -1-piperazinyl )-l-metyl-4-okso-4H(1,3)tiazeto(3,2-a)klnolin-3-karboksylat. Smeltepunkt 230-231°C. Etyl-l-etyl-6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 211-212°C. Etyl -6-f luor-7 -( 3-me tyl- 1-piperazinyl )-4-okso-4H-( 1,3 )tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt ikke lavere enn 300°C under dekomponering.
IRmax (cm_1): 3400, 2950, 1705, 1625, 1595, 1500, 1370, 1320,
1250, 1155, 1050, 895, 850, 795.
Etyl-7-( 3 ,4-dimetyl-1-piperazinyl )-6-fluor-4-okso-4H-( 1,3 )-tiazeto(3,2-a)kinolin-3-karboksyl. Smeltepunkt 262°C under dekomponer ing. Etyl-6-fluor-1-metyl-7-morfolino-4-okso-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylat. Smeltepunkt 257-258°C under dekomponering. Etyl-7-(3,4-dimetyl-1-piperazinyl)-6-fluor-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 204-206°C. Etyl-6-fluor-7-( 3-hy dr ok syrne tyl-1-py r roi idinyl)-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 230-233°C under dekomponering. Etyl-6-fluor-4-okso-7-(1-piperazinyl)-4H-(1,3 )tiazeto(3,2-a)-kinolin-3-karboksylat. Smeltepunkt ikke lavere enn 300°C under dekomponering.
IR^J(cm_1): 3400, 3260, 1705, 1625, 1595, 1540, 1500, 1370
1325, 1250, 1160, 1040, 795.
Etyl-6-fluor-1-metyl-7-(4-metyl-3-okso-1-piperazinyl)-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 195-198°C. Etyl-6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-l-fenyl-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 208-209°C. Etyl-6-f luor-4-okso-1 -f enyl-7-(1-piperazinyl )-4H-( 1,3)tiazeto(3,2-a)kinolln-3-karboksylat. Smeltepunkt 189-191°C under dekomponering. Etyl-6-fluor-7-(3-metyl-1-piperazinyl)-4-okso-l-fenyl-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 153°C. Etyl-7-(3,4-dimetyl-l-piperazinyl)-6-fluor-4-okso-l-fenyl-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 165°C. Isopropyl-6-fluor-l-metyl-4-okso-7-(l-piperazinyl)-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 220°C under dekomponering.
7-(3,4-dimetyl-l-piperazinyl)-6-fluor-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 198-201°C under dekomponering.
Metyl-6-fluor-1-metyl-okso-7-(1-piperazinyl)-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylat. Smeltepunkt 208°C under dekomponer ing.
6-klor-4-okso-7-(1-piperazinyl)-4H-(l,3)tiazeto(3,2-a)-kinolin-3-karboksylsyre. Smeltepunkt 235-240°C under dekomponering.
6-klor-7-(4-metyl-1-piperazinyl)-4-okso-4H-(l,3)t iazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 235-240°C under dekomponer ing.
6-kl or-1-metyl-7-(4-metyl-l-piperazinyl)-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 257-259°C under dekomponering. Hydroklorid, smeltepunkt 250-255°C under
dekomponering. Sulfat, smeltepunkt 225-230°C under dekomponering.
Etyl - 7- ( 4-acetonyl-3-metyl-1-piperazinyl)-6-fluor-1-mety1-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 190-192°C. Metyl-7 - (3 ,4 -d ime tyl -1 -piperazinyl )-6-fluor-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 199-204°C under dekomponering.
Isopropyl 7-(3,4-dimetyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 194-197°C under dekomponering. Etyl-7-(4-acetyl-1-piperizinyl )-6-fluor-l-fenyl^-okso^H-fl ,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 190-191°C under dekomponering.
7-(4-acetonyl-l-piperazinyl)- 6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 208-209°C under dekomponering. Hydroklorid, smeltepunkt 255-257°C under dekomponering; metansulfonat, smeltepunkt 215-218°C under dekomponering; maleat, smeltepunkt 156-158°C under dekomponering; p-toluensulfonat, smeltepunkt 245-1248°C under dekomponering; natriumsalt, smeltepunkt >300°C under dekomponering.
Etyl-7-(4-acetonyl-1-piperazinyl )-6-fluor-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 248-250°C under dekomponer ing.
6-fluor-l-metyl-7-(3-metyl-1-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 170-172°C under dekomponering.
Etyl - 6-f luor-8-me tok sy-1-metyl-7-(4-me tyl-1-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 213°C under dekomponering. Glyserol-6-fluor-1-metyl-7-(1-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 155-160°C. N-butyl-6-f luor-l-metyl-7 - (1-piperazinyl )-4-okso-4H-( 1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 212-213°C under dekomponering. Etyl-6-fluor-l-metyl-7-(4-(3-metyl-2-oksobutyl)-1-piperazinyl )-4-okso-4H-( l,3)tiazeto(3 , 2-a )kinolin-3-karboksylat. Smeltepunkt 183°C. Etyl-l-(4-klorfenyl)-6-fluor-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 142-143°C.
3-hydroksypropyl-6-fluor-l-metyl-7-(1-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 208-209"C under dekomponering.
Me toksyetyl-6-fluor-l-metyl-7-(1-piperazinyl)-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 198-201 °C under dekomponering. Hydroksyetyl-6-fluor-l-metyl-7-(1-piperazinyl )-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 164-168°C under dekomponering. Etyl-6-fluor-l-metyl-4-okso-7-(4-(2-okso-2-fenyletyl)-l-piperazinyl)-4E-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 203-205°C under dekomponering. Etyl-7-(4-(3,3-dimetyl-2-oksobutyl)-1-piperazinyl)-6-fluor-1-metyl-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 180-182°C under dekomponering. Etyl-6-fluor-l-metyl-4-okso-7-(4-(3-oksobutyl)-l-piperazinyl)-4H-(l,3 )tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 169-171°C under dekomponering. Etyl-6-fluor-l-metyl-4 -okso-7-(4-tri fluoracetyl-1-piperazinyl )-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 241-242°C under dekomponering. Hydroksyetyl-7-(4-etyl-1-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 159-162°C under dekomponering.
Etyl 7-(4-etyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 236-238°C under dekomponering. Etyl -6-f luor-7- ( 4- ( 2-metoksyetyl)-1-piperazinyl)-1-metyl-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 188-189°C. Etyl -7- ( 4-karboetoksymetyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 205-207°C under dekomponering. Etyl-6-fluor-7-(4-hydroksyetyl-1-piperazinyl)-l-metyl-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 215-216°C under dekomponering. Etyl - 7-( 4-cyanometyl-1-piperazinyl )-6-f luor-1 -metyl-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 252-253°C under dekomponering. Etyl-6-fluor-l-metyl-7-(4-(2-propynyl)-l-piperazinyl)-4-okso-4H-(1,3)-tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 209-210°C under dekomponering. Etyl-6-fluor-7-morfolino-4-okso-l-fenyl-4H-(1,3)tiazeto-(3,2-a)kinolin-3-karboksylat. Smeltepunkt 211°C. E ty 1-6-fluor-7-(4-(2-hydroksyetoksyetyl)-piperazinyl)-l-metyl-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 196-198°C.
6-fluor-1- ( 4-fluorfenyl)-4-okso-(1-piperazinyl)-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 298-304°C under dekomponering. Etylester, smeltepunkt 192°C under dekomponering.
Etyl-l-(2 , 4-dif luorfenyl )-6-fluor-4-okso-7-( 1-piperazinyl )-4H-(1,3)-tiazeto(3 ,2-a)kinolin-3-karboksylat. Smeltepunkt
>300°C under dekomponering. Etylester, smeltepunkt 180°C under dekomponering. l-(2,5-difluorfenyl )-6-fluor-4-okso-7-(1-piperazinyl)-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 280-284°C under dekomponering.
6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-l-fenyl-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 216-217°C under dekomponering.
Hydroklorid, smeltepunkt 270°C under dekomponering; metansulfonat, smeltepunkt 205-210°C under dekomponering; p—toluensulfonat, smeltepunkt 160-166°C; smeltepunkt 180-182°C under dekomponering; natriumsalt, smeltepunkt 290-300°C under dekomponering.
6-fluor-4-okso-l-fenyl-7-(1-piperazinyl)-4H-(1,3 )tiazeto-(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 210-230°C under dekomponering; hydroklorid, smeltepunkt 220°C under dekomponering; p-toluensulfonat, smeltepunkt 200-205°C under dekomponering; maleat, smeltepunkt 210°C under dekomponering. Pivaloyloksymetyl-6-fluor-7-(4-metyl-1-piperazinyl)-4-okso-l-fenyl-4H-(l,3 )tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 169-172°C.
Pivaloyloksyrnety1-7-(4-acetonyl-1-piperazinyl)- 6-fluor-1-metyl-4-okso-4H-(l,3)tiazeto(3,2-a)kinolin-3-karbonylat. Smeltepunkt 132-135°C.
6-f luor-8-metoksy-l-mety 1-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 220°C under dekomponering.
6-f luor-8-metoksy-7-( 4-metyl-l-piperazinyl)-4-okso-l-f enyl - 4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 176-177°C. Etylester, smeltepunkt 96-98°C under dekomponering.
Etyl - 6-f luor-8-metoksy-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 219°C under dekomponering.
1-(2,4-difluorfenyl)-6-fluor-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 209-211°C under dekomponering. Etylester, smeltepunkt 212-214°C.
l-(2,5-difluorfenyl)-6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 213-215°C, under dekomponering. Etylester, smeltepunkt 218-220°C. l-(2,6-difluorfenyl)-6-fluor-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 229-232°C under dekomponering. Etylester, smeltepunkt 144-147°C under dekomponering. l-(3,4-difluorfenyl)-6-fluor-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 277-280°C under dekomponering. Etylester, smeltepunkt 170-173°C.
6-fluor-l-(4-fluorfenyl)-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 208-215°C under dekomponering. Etylester, smeltepunkt 121-122°C. 6-fluor-l-(3-fluorfenyl)-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 222-225°C under dekomponering. Etylester, smeltepunkt 180-183°C. 6-fluor-l-(2-fluorfenyl)-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 203-205°C under dekomponering. Etylester, smeltepunkt 198-201°C. 6-f luor-1-(4-metyl f enyl)-7-( 4-metyl-l-piperazinyl )-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 191-193°C under dekomponering. Etylester, smeltepunkt 156-160°C.
6-fluor-l-(2-metylfenyl)-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 185-187°C, under dekomponering. Etylester, smeltepunkt 162-165°C. Etyl-6-f luor-7-( 4-metyl-l-piperazinyl )-l-( 4-nitrofenyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat. Smeltepunkt 228-231°C under dekomponering.
6-fluor-7-(4-metyl-l-piperazinyl)-l-(4-trifluorfenyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 239-242°C under dekomponering. Etylester, smeltepunkt 200-203°C.
6-fluor-7-(4-metyl-l-piperazinyl)-l-(3-trifluorfenyl )-4-okso-4H-(1,3) tiazeto(3,2-a)kinolin-3-karboksylsyre. Smeltepunkt 223-226°C under dekomponering. Etylester, smeltepunkt 206-209°C.
Nedenfor gis resultatene av antibakterielle forsøk med forbindelser som fremstilles ifølge oppfinnelsen. 1. Måling av minimum inhiberende konsentrasjon (MIC). Prøvemetode: MIC ble målt ved en agarplatefortynningsmetode i henhold til en standardmetode for "Japan Chemotherapeutic Society" (jfr. Nippon Kagaku Ryoho Gakkaishi). Således ble organismene som var inkubert ved 37°C i 18 timer ved bruk av sensititvitetsprøvebuljong (Nissei) ble fortynnet til IO<6>CFU/ml ved bruk av den samme buljong. Det hele ble inokulert ved bruk av en mikroplater til en medikamentholdig sensiti-vitetstestagar (Nissei), dyrket ved 37°C i 18 timer hvorefter MIC ble målt. Som kontroll ble det benyttet en onoksasin og ofloxacin i prøvene 1 og 2. Resultatet er gitt i tabell 1. Forbindelsene som fremstilles ved opprinnelsens fremgangsmåte viste meget sterk antibakteriell aktivitet både mot Gram-positive og Gram-negative bakterier inkludert Pseudomonas aeruginosa.
Nummereringen av forbindelsene i tabell 1 viser til følgende forbindelser: 1) : 6-fluor-7-(4 -metyl -1-piperazinyl )-4-okso-4H-(1, 3 )-tiazeto(3,2-a)kinolin-3-karboksylsyre; 2) : 6-fluor-l-metyl-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 3) : 6-fluor-7-morfolino-4-okso-4E-(l,3)tiazeto(3,2-a)-kinolin-3-karboksylsyre; 4) : 7-(4-allyl-l-piperazinyl )-6-fluor-l-metyl-4-okso-4H(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 5) : 6-fluor-l-metyl-7-(4-metyl-l-piperazinyl)-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyresulfat; 6 ): 6-f luor-l-metyl-7-tiomorfolino-4-okso-4H-( 1,3 )-tiazeto-(3,2-a)kinolin-3-karboksylsyresulfat; 7) : 6-klor-l-metyl-4-okso-7-(1-piperazinyl)-4H-(l,3)tiazeto(3,2-a)kinolln-3-karboksylsyre; 8) : 6-fluor-1-mety1-7-(3-amino-1-pyrroiidinyl )-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyreetansulfonat; 9) : 8-amino-6-fluor-l-metyl-7-(4-metyl-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 10) : 7-(4-( 4-aminobenzyl ) -1 -piperazinyl )-6-f luor-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 11) : 6-fluor-4-okso-l-fenyl-7-(1-piperazinyl)-4E-(1,3)tiazeto(3,2-a )kinolin-3-karboksylsyre; 12 ): 6-f luor-1- (4-f luorfenyl )-4-okso-7-(1-piperazinyl )-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 13): 6-fluor-l-metyl-4-okso-7-(1-piperazinyl)-4H-( 1,3)tiazeto(3,2-a)klnolin-3-karboksylsyre; og 14 ): 6-f luor-8-metoksy-l-metyl-7-(4-metyl-l-piperazinyl )-4-okso-4E-(1,3)tiazeto(3,2-a )kinolin-3-karboksylsyre.
Antallet inokulerte bakterier var IO<6>i alle tilfeller og MIC-enheten var pg/ml.
2. Terapeutisk virkning på infeksjon i mus.
Prøvemetode: Escherichia coli KC-14 og Pseudomonas aeruginosa E-2 ble suspendert i 456 mucin og 0,25 ml derav ble inokulert i peritonealhulrommet til hannmus av ddY-stammen med kroppsvekt ca. 20 g, ca. 4 uker gamle og med 10 mus pr. gruppe. Antallet inokulerte bakterier var 5,1 x IO<4>henholdsvis7,5 x IO<4>CFU/mus for E. coli henholdsvis P. aeruginosa. Medikamentet ble administrert oralt en gang to ganger efter infeksjonen av bakteriene, og ut fra dødsgraden efter en uke ble ED5Q-verdiene beregnet ved en Behrens-Karber-metode. Som kontroller ble det benyttet ofloxacin og enoxacin. Resultatet er gitt i tabell 2.
Som nevnt ble E. coli KC-14 benyttet i prøve 1 og P. aeruginosa E-2 i prøve 2.
Nummereringen av forbindelsene i tabell 2 viser til de følgende forbindelser: 1): 6-fluor-1-mety1-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; 2 ): Etyl-6-f luor-l-metyl-7-( 4-metyl-l-piperazinyl )-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat; 3): Etyl-7-( 3 , 4-dimetyl-l-piperazinyl )-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat; 4 ): Etyl - 6-f luor-7 - ( 4-mety 1 -1-piperazinyl )-4-okso-l-fenyl-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat; 5) : Etyl 7-(4-acetonyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat; 6) : 7-(4-acetonyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyre; og 7) : 6-fluor-l-metyl-7-(4-metyl-l-piperazinyl)-4-okso-4H-(1,3)tiazeto(3,2-a)kinolin-3-karboksylsyresulfat.
Forbindelsene som fremstilles ifølge oppfinnelsen viste sterk terapeutisk virkning overfor infeksjonssykdommer i mus. De viste spesielt sterkere aktivitet overfor P. aeruginosa enn enoxacin som er sagt å vise sterk virkning mot denne bakterie.
3. Akutt toksisitet:
Resultatet av oral administrering til hannmus av ddY-stammen, 7 uker gamle og med kroppsvekt ca. 35 g og for tre mus pr. gruppe, i 2 uker er gitt nedenfor. Alle prøvede forbindelser viste lav toksisitet. For eksempel var LDsg-verdiene for de følgende forbindelser ikke lavere enn 3 g/kg noen gang. De benyttede forbindelser var 6-fluor-l-metyl-4-okso-7-(1-piperazinyl )-4H-(l ,3 )tiazeto(3,2-a)kinolin-3-karboksylsyre; etyl 7-(3,4-dimetyl-l-piperazinyl)-6-fluor-l-metyl-4-okso-4E-(1,3)tiazeto(3,2-a)kinolin-3-karboksylat; etyl-7-(4-acetonyl-l-piperazinyl )-6-fluor-1-metyl-4-okso-4H-(1,3)tiazeto(3,2-a)-kinolin-3-karboksylat; og 6-fluor-l-metyl-7-(4-metyl-l-piperazinyl )-4-okso-4H-(l ,3)tiazeto(3,2-a)kinolin-3-karboksylsyre.
Det er helt klart fra de ovenfor angitte fakta at forbindelsene som fremstilles ved oppfinnelsens fremgangsmåte er effektive i langt mindre doser enn de konvensjonelle antibakterielle forbindelser, således ikke bare mot P. aeruginosa men også både gram-positive og gram-negative bakterier, og de viser et antibakterielt spektrum over et vidt området.
Mange av de konvensjonelle farmasøytika foreligger 1 form av fri karboksylsyre og generelt er deres biotilgjengelighet ikke tilfredsstillende. I henhold til dette observeres det ofte at de ikke viser så høy terapeutisk effekt mot infeksjonssykdommer som det skulle forventes fra deres antibakterielle aktivitet in vitro.
Både karboksylsyretypen og -estertypen av forbindelsene som fremstilles ifølge oppfinnelsen viste terapeutisk effekt mot infektiøse sykdommer i prøven in vivo. Komponenter av estertypen viste spesielt god absorberbarhet efter oral administrering, opprettholdt høye blodnivåer i lang tid og viste tilstrekkelig terapeutisk virkning.
I tillegg er toksisiteten for de her beskrevne forbindelser relativ lav. I henhold til dette kan forbindelsene som fremstilles ifølge oppfinnelsen på sikker måte benyttes av pattedyr inkludert mennesker som et terapeutisk middel for både systemiske sykdommer og lokale sykdommer som for eksempel infektiøse sykdommer i urinveier og biliartrakten.
Nedenfor følger sammenligningsdata oppnådd ved måling av MIC-verdier, målt på samme måte som antydet ovenfor, som en sammenligning mellom forbindelser som fremstilles ifølge oppfinnelsen og forbindelser ifølge den kjente teknikk.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive kinolinkarboksylsyrederivater med den generelle formel (I) der R-1- er hydrogen, alkyl med 1 til 6 karbonatomer eller f enyl; R<2>er hydrogen eller alkoksy med 1 til 4 karbonatomer; R<4>og R<5>danner en pyrrolidino-, piperidino-, piperazino-, homopiperazino-, morfolino- eller tiomorfolinogruppe idet det cykliske amino kan være substituert med alkyl med 1 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller hydroksyalkyl med 1 til 4 karbonatomer; X er halogen; eller farmasøytisk aksepterbare salter derav,karakterisert vedat a) en forbindelse med den generelle formel (III)der R<6>er alkyl med 1 til 6 karbonatomer, A er fluor ellerNR<4>R<5>idet de andre substituenter R<2>,R<4>,R<5>og X har de ovenfor angitte betydninger, omsettes med en dihalogenforbindelse med formelen:hvori Y og Z er like eller forskjellige og er halogen og R<*>er som angitt ovenfor, idet, når A er fluor, omsettes det oppnådde produkt med et amin med formelender R<4>og R<5>har den ovenfor angitte betydning, eller b) at en forbindelse med formel (Villa):der substituentene R<1>, R<4>, r<5>, R<6>og X har de ovenfor angitte betydninger, underkastes ringslutning, og at forbindelsen hvis nødvendig, hydrolyseres på et ønsket trinn i reaksjonsforløpet."R
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|---|---|---|---|
| JP11162086 | 1986-05-14 |
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| Publication Number | Publication Date |
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| NO871990D0 NO871990D0 (no) | 1987-05-13 |
| NO871990L NO871990L (no) | 1987-11-16 |
| NO173445B true NO173445B (no) | 1993-09-06 |
| NO173445C NO173445C (no) | 1993-12-15 |
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| US (1) | US4843070A (no) |
| EP (1) | EP0249043B1 (no) |
| JP (1) | JPS63107990A (no) |
| KR (1) | KR870011145A (no) |
| AT (1) | ATE92493T1 (no) |
| BE (1) | BE1002102A4 (no) |
| CA (1) | CA1272482A (no) |
| CH (1) | CH674368A5 (no) |
| DE (1) | DE3786843T2 (no) |
| DK (1) | DK171967B1 (no) |
| ES (1) | ES2006142A6 (no) |
| FI (1) | FI87076C (no) |
| FR (1) | FR2598709B1 (no) |
| GB (1) | GB2190376B (no) |
| IL (1) | IL82395A (no) |
| IT (1) | IT1205958B (no) |
| NL (1) | NL193319C (no) |
| NO (1) | NO173445C (no) |
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| EP0312794B1 (en) * | 1987-09-22 | 1993-05-19 | Nippon Shinyaku Company, Limited | Thiazetidine derivatives |
| JPH0751579B2 (ja) * | 1987-11-07 | 1995-06-05 | 日本新薬株式会社 | キノリンカルボン酸誘導体 |
| DE3869906D1 (de) * | 1987-11-07 | 1992-05-14 | Nippon Shinyaku Co Ltd | Chinolincarbonsaeure-derivate. |
| GB8907865D0 (en) * | 1989-04-07 | 1989-05-24 | Wyeth John & Brother Ltd | Tetrahydroquinoline derivatives |
| AU618460B2 (en) * | 1989-04-18 | 1991-12-19 | Hokuriku Pharmaceutical Co. Ltd. | Thiazetoquinoline-3-carboxylic acid derivative, method for preparation thereof, and a pharmaceutical composition comprising the same |
| AU6641190A (en) * | 1989-11-17 | 1991-06-13 | Nippon Shinyaku Co. Ltd. | Quinolinecarboxylic acid derivative |
| US5194439A (en) * | 1990-04-06 | 1993-03-16 | John Wyeth & Brother Limited | N-(2,3-dihydro-1,4-benzodioxinyl)-N-substituted aminopyrido-fused cycloalkanes |
| WO1992000280A1 (en) * | 1990-06-22 | 1992-01-09 | Nippon Shinyaku Co., Ltd. | Quinoline derivative and production thereof |
| EP0551518A4 (en) * | 1990-10-03 | 1993-09-22 | Nippon Shinyaku Company, Limited | Quinolinecarboxylic acid derivative |
| DE4315625A1 (de) * | 1993-05-11 | 1994-11-17 | Hoechst Ag | Neue Derivate des 3-Fluorphenols, Verfahren zu ihrer Herstellung und ihre Verwendung |
| JP3329572B2 (ja) * | 1994-04-15 | 2002-09-30 | 福田金属箔粉工業株式会社 | 印刷回路用銅箔およびその表面処理方法 |
| EP0768303A4 (en) * | 1994-06-27 | 1999-02-03 | Nippon Shinyaku Co Ltd | OPTICALLY ACTIVE QUINOLINE-CARBOXYLIC ACID DERIVATIVE AND PROCESS FOR PRODUCING THE SAME |
| CN1321997C (zh) * | 2004-03-03 | 2007-06-20 | 刘玉辉 | 一种稳定的噻丁啶喹啉羧酸盐在制备抗感染药物中的应用 |
| CN100386081C (zh) * | 2005-12-23 | 2008-05-07 | 重庆生物制品有限公司 | 一种含三环氟喹诺酮甲磺酸盐的注射剂及其制备方法和用途 |
| WO2007082472A1 (en) * | 2006-01-18 | 2007-07-26 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | Anti-infective quinolone compound, preparation method thereof and use thereof |
| CN101003540A (zh) * | 2006-01-18 | 2007-07-25 | 广州白云山制药股份有限公司广州白云山制药总厂 | 一种抗感染化合物和用途 |
| WO2011031745A1 (en) | 2009-09-09 | 2011-03-17 | Achaogen, Inc. | Antibacterial fluoroquinolone analogs |
| CN102424688B (zh) * | 2011-12-31 | 2014-08-20 | 广州医药工业研究院 | 甲磺酸左旋尤利沙星晶体及其制备方法和用途 |
| CN102424689B (zh) * | 2011-12-31 | 2014-05-28 | 广州医药工业研究院 | 甲磺酸左旋尤利沙星晶体及其制备方法和用途 |
| JP6313685B2 (ja) | 2014-05-01 | 2018-04-18 | キヤノン株式会社 | 撮像装置およびその制御方法 |
| JP6478496B2 (ja) | 2014-07-03 | 2019-03-06 | キヤノン株式会社 | 撮像装置およびその制御方法 |
| JP6429546B2 (ja) | 2014-09-11 | 2018-11-28 | キヤノン株式会社 | 撮像装置、制御方法、プログラム、および、記憶媒体 |
| BR112018001441A2 (pt) * | 2015-07-28 | 2018-09-11 | Vyome Biosciences Pvt Ltd | antibacterianos terapêuticos e profiláticos |
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| US3592811A (en) * | 1967-08-09 | 1971-07-13 | Du Pont | 2-hexafluoroisopropylidene-1,3-thiazetidines and the preparation thereof |
| US4620007A (en) * | 1980-09-03 | 1986-10-28 | Bayer Aktiengesellschaft | 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid |
| JPS57136588A (en) * | 1981-02-18 | 1982-08-23 | Nippon Shinyaku Co Ltd | Carboxylic acid derivative |
| DE3267485D1 (en) * | 1981-02-18 | 1986-01-02 | Nippon Shinyaku Co Ltd | Substituted carboxylic acid derivatives |
| JPS59210093A (ja) * | 1983-05-13 | 1984-11-28 | Nippon Shinyaku Co Ltd | ピリドピリミジン誘導体 |
| US4659734A (en) * | 1983-08-15 | 1987-04-21 | Nippon Shinyaku Co., Ltd. | Olinecarboxylic acid derivatives |
| US4550104A (en) * | 1984-07-20 | 1985-10-29 | Warner-Lambert Company | Antibacterial thiazolo-quinolines and thiazolo-naphthyridines |
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1987
- 1987-03-31 JP JP62079993A patent/JPS63107990A/ja active Granted
- 1987-04-30 IL IL82395A patent/IL82395A/xx not_active IP Right Cessation
- 1987-04-30 GB GB8710340A patent/GB2190376B/en not_active Expired - Lifetime
- 1987-05-04 ZA ZA873179A patent/ZA873179B/xx unknown
- 1987-05-07 CH CH1746/87A patent/CH674368A5/fr not_active IP Right Cessation
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- 1987-05-13 AT AT87106953T patent/ATE92493T1/de not_active IP Right Cessation
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- 1987-05-13 DE DE87106953T patent/DE3786843T2/de not_active Expired - Lifetime
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