JPH0564955B2 - - Google Patents
Info
- Publication number
- JPH0564955B2 JPH0564955B2 JP61022296A JP2229686A JPH0564955B2 JP H0564955 B2 JPH0564955 B2 JP H0564955B2 JP 61022296 A JP61022296 A JP 61022296A JP 2229686 A JP2229686 A JP 2229686A JP H0564955 B2 JPH0564955 B2 JP H0564955B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- formula
- compound
- acid
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 56
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 239000000243 solution Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- 241000894006 Bacteria Species 0.000 description 22
- 239000013078 crystal Substances 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 230000000694 effects Effects 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 239000005457 ice water Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 18
- 230000000844 anti-bacterial effect Effects 0.000 description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 229960003405 ciprofloxacin Drugs 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 241000192125 Firmicutes Species 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 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 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- -1 3-aminopyrrolidino group Chemical group 0.000 description 4
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000204031 Mycoplasma Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229960001180 norfloxacin Drugs 0.000 description 4
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 241000606161 Chlamydia Species 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 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
- 229960002227 clindamycin Drugs 0.000 description 3
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- BAYYCLWCHFVRLV-UHFFFAOYSA-N 1-ethyl-7-[3-(ethylaminomethyl)pyrrolidin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(CNCC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CC)C2=C1F BAYYCLWCHFVRLV-UHFFFAOYSA-N 0.000 description 2
- QHMLKJCHGKGKDP-UHFFFAOYSA-N 2,3,4-trichloro-5-fluoroaniline Chemical compound NC1=CC(F)=C(Cl)C(Cl)=C1Cl QHMLKJCHGKGKDP-UHFFFAOYSA-N 0.000 description 2
- BMRPNIIBXSCMHX-UHFFFAOYSA-N 3-chloro-1,2,4-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C(Cl)=C1F BMRPNIIBXSCMHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000282412 Homo Species 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010013381 Porins Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- 241000202898 Ureaplasma Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 2
- 229960002682 cefoxitin Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- WXIAEUHUTPTESX-UHFFFAOYSA-N diethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(=O)C1=CC(F)=C(F)C(Cl)=C1F WXIAEUHUTPTESX-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- KISUGMULAAIILF-UHFFFAOYSA-N ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)prop-2-enoate Chemical compound C=1C(F)=C(F)C(Cl)=C(F)C=1C(=O)C(C(=O)OCC)=CNC1CC1 KISUGMULAAIILF-UHFFFAOYSA-N 0.000 description 2
- LZMXLCPYJNRWNQ-UHFFFAOYSA-N ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(F)C(Cl)=C1F LZMXLCPYJNRWNQ-UHFFFAOYSA-N 0.000 description 2
- PWOYTBYNBYNZCO-UHFFFAOYSA-N ethyl quinoline-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OCC)=CC=C21 PWOYTBYNBYNZCO-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000007886 mutagenicity Effects 0.000 description 2
- 231100000299 mutagenicity Toxicity 0.000 description 2
- ALPHMTFVUKDBGJ-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(F)C(Cl)=C1 ALPHMTFVUKDBGJ-UHFFFAOYSA-N 0.000 description 2
- PFFDKLGOPDBQQD-UHFFFAOYSA-N n-(5-chloro-4-fluoro-2-nitrophenyl)acetamide Chemical compound CC(=O)NC1=CC(Cl)=C(F)C=C1[N+]([O-])=O PFFDKLGOPDBQQD-UHFFFAOYSA-N 0.000 description 2
- ABBVKGHGRRHGRM-UHFFFAOYSA-N n-cyclopropyl-2-(2-nitrophenyl)acetamide Chemical compound [O-][N+](=O)C1=CC=CC=C1CC(=O)NC1CC1 ABBVKGHGRRHGRM-UHFFFAOYSA-N 0.000 description 2
- 229960000210 nalidixic acid Drugs 0.000 description 2
- 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 2
- 230000035699 permeability Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 102000007739 porin activity proteins Human genes 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical group NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- AMVKEEYBJIRRGV-UHFFFAOYSA-N 2,3,4-trichloro-1-fluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(Cl)C(Cl)=C1Cl AMVKEEYBJIRRGV-UHFFFAOYSA-N 0.000 description 1
- OKRWBTOWNXSEKG-UHFFFAOYSA-N 2,3,4-trichloro-5-fluorobenzonitrile Chemical compound FC1=CC(C#N)=C(Cl)C(Cl)=C1Cl OKRWBTOWNXSEKG-UHFFFAOYSA-N 0.000 description 1
- NXRQXCFBZGIRGN-UHFFFAOYSA-N 2,3,4-trifluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(F)=C1F NXRQXCFBZGIRGN-UHFFFAOYSA-N 0.000 description 1
- QPLHELABGKHHRL-UHFFFAOYSA-N 2,3-dichloro-4-fluoro-6-nitroaniline Chemical compound NC1=C(Cl)C(Cl)=C(F)C=C1[N+]([O-])=O QPLHELABGKHHRL-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- QNBDAPZLQYFUIX-UHFFFAOYSA-N 2-chloro-n-cyclopropyl-3,4-difluoroaniline Chemical compound ClC1=C(F)C(F)=CC=C1NC1CC1 QNBDAPZLQYFUIX-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- XGIMFAMVOLVNPP-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzamide Chemical compound NC(=O)C1=CC(F)=C(F)C(Cl)=C1F XGIMFAMVOLVNPP-UHFFFAOYSA-N 0.000 description 1
- BRANJOPEMMWETD-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzonitrile Chemical compound FC1=CC(C#N)=C(F)C(Cl)=C1F BRANJOPEMMWETD-UHFFFAOYSA-N 0.000 description 1
- IEDMMCZBIKXEJP-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(F)C(Cl)=C1F IEDMMCZBIKXEJP-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
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- 239000004098 Tetracycline Substances 0.000 description 1
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- 230000005856 abnormality Effects 0.000 description 1
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- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
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- 125000003277 amino group Chemical group 0.000 description 1
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- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
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- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- MYTMXVHNEWBFAL-UHFFFAOYSA-L dipotassium;carbonate;hydrate Chemical compound O.[K+].[K+].[O-]C([O-])=O MYTMXVHNEWBFAL-UHFFFAOYSA-L 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- VUAVQZRPAGVJOZ-UHFFFAOYSA-N methanesulfonic acid;4-oxo-1h-quinoline-3-carboxylic acid Chemical compound CS(O)(=O)=O.C1=CC=C2C(=O)C(C(=O)O)=CNC2=C1 VUAVQZRPAGVJOZ-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- MXDGLNPPGFOABX-UHFFFAOYSA-N n-(2-chloro-3,4-difluorophenyl)-n-cyclopropylacetamide Chemical compound C=1C=C(F)C(F)=C(Cl)C=1N(C(=O)C)C1CC1 MXDGLNPPGFOABX-UHFFFAOYSA-N 0.000 description 1
- HDCCJUCOIKLZNM-UHFFFAOYSA-N n-pyrrolidin-3-ylacetamide Chemical compound CC(=O)NC1CCNC1 HDCCJUCOIKLZNM-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- 229960004444 piromidic acid Drugs 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
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000005944 tissue migration Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
〔産業上の利用分野〕
本発明は、抗菌剤として極めて優れた新規キノ
ロンカルボン酸誘導体、その製造方法ならびにそ
の新規化合物を有効成分とする抗菌剤に関する。
更に詳しくは本発明は下記式〔〕
で表わされる新規なキノロンカルボン酸誘導体、
その水和物、その塩及びその製法ならびにその抗
菌剤としての用途に関するものである。
なお、式〔〕の化合物においては、７位置換
基であるアミノピロリジン環上の１つの不斉炭素
に基づく光学異性体が存在するが、これら異性体
およびそれらの混合物は便宜上、全て単一の式で
示されており、これによつて本発明の範囲が限定
されるものではない。
〔従来の技術〕
キノロンカルボン酸系抗菌剤は、ナリジクス酸
に始まり、ピロミド酸更にピペミド酸へと展開さ
れ、好気性グラム陰性菌に有効な尿路感染の治療
薬として使用されている。
近年、本発明者らにより開発されたノルフロキ
サシンは、好気性グラム陰性菌のみならずグラム
陽性菌にも活性を示し、しかもその抗菌力は著し
く強化された。そして現在臨床に汎用されてお
り、この分野に飛躍的進歩をもたらした。その後
類似の置換基を有するオフロキサシン、シプロフ
ロキサシン、更にグラム陽性菌に対して良好な活
性を示すCI−934等が開発されている。
〔発明が解決しようとする問題点〕
シプロフロキサシンは、ノルフロキサシンに比
し更に強い抗菌力を有する。しかし、グラム陽性
菌に対する抗菌力はグラム陰性菌のそれに比べて
かなり劣るものである。また、CI−934はグラム
陽性菌に対する抗菌力はやや強化されたものの、
グラム陰性菌に対しては低い活性しか示さない。
また一方、β−ラクタム系抗生物質、特に第三
世代セフエム系に高度耐性を示すメチシリン、セ
フエム耐性黄色ブドウ球菌、表皮ブドウ球菌等の
ブドウ球菌、および腸球菌、ストレプロコツカス
フエシユーム等の溶連菌等、グラム陽性菌が再び
臨床上問題になつてきた。
更に、臨床検査技術の発達から嫌気性菌検査の
普及により、皮膚や粘膜に常在する嫌気性菌が、
日和見感染症の起炎菌となつている事が分かつて
きた。呼吸器感染症、腹腔内感染症、慢性中耳炎
や副鼻腔炎、その他婦人科領域でも嫌気性菌単独
あるい好気性菌との混合で検出されるケースが50
〜80％に達しているとされている。その組合わせ
は大腸菌、腸球菌、その他の連鎖球菌と嫌気性菌
が約95％にも達している。そのようななかで従来
嫌気性菌に感受性であつたβ−ラクタム剤やクリ
ンダマイシンに対する耐性化が高まつて来てお
り、化学療法剤の選択に重大な問題をなげかけて
いる。
更にまた、細胞壁を欠く細菌の一種であるマイ
コプラズマは、人や家畜の呼吸器感染症や髄膜
炎、心内膜炎、関節炎等の起炎菌として知られて
いる。これらの治療には、テトラサイクリン及び
マクロライド系抗生物質が使用されるが、近年こ
れら治療剤に対する耐性菌、特にマクロライド系
薬剤に対する耐性菌の出現頻度が高く、今後の治
療方法にも危惧が生じてきた。
また、近年性的伝達感染症の病原菌として問題
となつているクラミジア、ウレアプラズマやガル
デレラ・バギナリスに対する有用な新しい薬剤が
求められている。
〔問題を解決するための手段〕
この様な背景の下に従来の薬剤に代わる一層強
力で広範囲な新規抗菌剤の開発が望まれている。
本願発明者らは、新キノロン類抗菌剤が今日の
様な隆盛をもたらす口火となつたノルフロキサシ
ンを見出し、その作用機序についても研究を進め
た。その結果、キノロン類の作用点は細菌の
DNA鎖の高次構造、即ち、二重鎖の形成、解除
を司るDNAジヤイレースにあること、また、抗
菌作用を出現させるためには、細菌の膜透過性、
ことにポーリンと称する部分が透過性に、大いに
関係していることを見出した。これらの知見か
ら、新キノロンのコンセプトを以下の各項を満た
すべきものとした。
１ 作用点であるDNAジヤイレースに作用する
こと
２ 外膜、ことにポーリンの透過性がよいこと
３ グラム陽性菌、ことにブドウ球菌や連鎖球菌
に確実に有効なこと
４ グラム陰性菌に対する活性を低下せしめない
こと
５ グラム陰性菌の中でも、他の抗生物質の効き
難いセラチア、緑膿菌にも強く作用すること
６ 嫌気性菌にも作用が及ぶこと
７ 吸収が良好で代謝され難いこと
８ 生産性が良好なこと
９ 選択毒性に優れ、生体側に害作用を示さない
こと
この様なコンセプトにほぼ沿い得る化合物とし
て、本発明者らは、式〔〕で示される新規物質
を合成し、その作用態度を調べた結果、特に第９
項を満足させることが判明し、本発明を完成する
に至つた。
本発明化合物の化学構造上の特徴は、キノロン
カルボン酸骨格上、６位にフツ素、８位に塩素及
び７位に３−アミノピロリジノ基を有しているこ
とである。
先に本発明者らは、キノロンカルボン酸骨格上
の６位にフツ素を導入したノルフロキサシンを見
出した。これが臨床上、細菌感染症に高い有用性
が認められたことから、この系統の抗菌剤は、国
内外で熱心に研究され、新キノロン類又はフルオ
ロキノロン類と称せられて、画期的な進歩をもた
らした。
本発明者らも、その後、たゆまぬ研究を続けた
結果、８位置換基もまた、抗菌スペクトルの拡が
りや抗菌力上昇ならびに薬物としての吸収性に極
めて重要な役割を演ずる事に気付いた。そこで
種々の置換基を８位に導入し、定量的構造活性相
関等の手法を駆使して解析した結果、８位の置換
基として、全く予想外であつた塩素が最適である
との結論に達した。
かくして、本発明者らは先に出願のような６位
にフツ素、８位に塩素を有する一連の化合物を開
発した。とりわけ８−クロロ−１−シクロプロピ
ル−６−フルオロ−１，４−ジヒドロ−７−（３
−メチル−１−ピペラジニル）−４−オキソ−３
−キノリンカルボン酸（参考例２の化合物）は抗
菌スペクトルの広さ、強さ、その他から当該技術
分野ではトツプレベルの薬物と考えられた。しか
し不幸にして、当該化合物は人に使用する医薬品
としては極めて危惧すべき欠点を有する事が分つ
た。例えばイヌにおける連続経口投与試験では20
mg／Kg／日で連日の激しい嘔吐、10〜11日間の連
投で間代性痙攣がみられ中枢性の副作用があるも
のと考えられた。また更に20mg／Kg／日、11日間
以後５mg／Kg／日、10日間の投与によりGPTの
著しい上昇がみられ、さらに10mg／Kg／日31日間
投与と共にTTTが著明に低下し、肝障害が懸念
された。以上の事等々から当該化合物は医薬品と
しての使用は困難であると判断された。
このような経緯をへて更に抗菌力の優れ、安全
性の高い化合物を求めて研究を続けた結果、本発
明を完成した。
本発明化合物は、例えば８位に水素又はフツ素
を有する同族体はもとより前記参考例２の化合物
よりも、グラム陽性菌や嫌気性菌に対し、はるか
に強い抗菌力を示す。更にまた、グラム陰性菌に
対しても、従来公知の先行技術の中で、最も強い
活性を示すシプロフロキサシンと比べても、遜色
のない活性を示すばかりでなく、抗生物質でも最
も効き難いセラチアや緑膿菌に対しても、とりわ
け強い活性を示す。更に驚くべきは、従来キノロ
ンカルボン酸系薬剤では、弱い活性しか示さなか
つた嫌気性菌、マイコプラズマ、ウレアプラズ
マ、クラミジヤやガルデレラ・バギナリスに対し
ても強力な抗菌力を示す事が分かつた。
また、臨床上重要な意味をもつ耐性菌出現頻度
が他剤に比べかなり低い事も本発明化合物の利点
の一つである。
本発明化合物は動物において、経口的にも吸収
が良好で組織への移行性、生体内での安定性や認
容性にも極めて優れていることが確認された。
〔問題点を解決するための手段〕
次に本発明化合物の製造方法について説明す
る。
〔式中、Ｒは水素または低級アルキル基を、
R1及びR2はそれぞれ独立して水素またはアミノ
基の保護基を示すか共同して保護基を示し、Ｘは
ハロゲンを示す〕
すなわち、式〔〕で表わされる化合物と式
〔〕で表わされるアミン類を反応させることに
より、式〔〕で表わされる本発明化合物が合成
される。ただし、式〔〕でR1，R2のどちらか
一方または両方がアミノ基の保護基、例えばR1
が水素でR2がアセチル、プロピオニル等の低級
アシル基、メトキシカルボニル、エトキシカルボ
ニル、ターシヤリブトキシカルボニル等の低級ア
ルコキシカルボニル基又はR1とR2でフタロイル
基、である場合は常法に従つてこれらの保護基を
取り除く事により本発明化合物にすることができ
る。また、式〔〕で、Ｒが低級アルキルである
化合物の場合は、式〔〕で表わされる化合物と
の反応成績体を、常法に従つて加水分解し、エス
テルをカルボン酸に変換して、本発明化合物にす
ることもできる。
式〔〕で表わされる化合物と式〔〕で表わ
される化合物の反応は、無溶媒下、あるいは水、
アルコール類、アセトニトリル、ジメチルホルム
アミド（DMF）、ジメチルスルホキシド
（DMSO）、ヘキサメチルホスホリツクアミド、
ピリジン、ピコリン等の溶媒中で実施することが
できる。反応温度は、室温〜200℃、好ましくは
室温から160℃の範囲で適宜選択される。更に詳
しくは、式〔〕で表わされる化合物と１〜５倍
モルの式〔〕で表わされる化合物を、２〜10倍
容の前記溶媒中、室温〜160℃で、１〜数時間反
応させるのが好適である。この際、トリエチルア
ミン、ジアザビシクロ塩基類や炭酸カリのような
脱酸剤の使用も好ましい、また、式〔′〕で、
Ｒが低級アルキルおよび／またはR1，R2がアミ
ンの保護基である化合物は、常法に従つて加水分
解できる。
かかる加水分解は、苛性カリのようなアルカ
リ、塩基や硫酸のような酸によつて、水、水・ア
ルコール類混液、水・酢酸混液等の中で、室温〜
溶媒の沸点で、容易に実施することができる。
なお、本発明の出発物質である一般式〔〕で
表わさる化合物もまた、新規化合物であり、例え
ば次のルートにより合成することができる。
次に式〔〕で表わされる化合物は、所望なら
ば、その塩に常法に従つて変換することができ
る。塩としては、例えば塩酸、硫酸、リン酸等の
無機酸との塩、メタンスルホン酸、乳酸、蓚酸、
酢酸等の有機酸との塩、あるいはナトリウム、カ
リウム、マグネシウム、カルシウム、アルミニウ
ム、セリウム、クロム、コバルト、銅、鉄、亜
鉛、白金、銀等の塩が挙げられる。
また、本発明化合物は、動物に経口的に投与し
た時に極めて良好な吸収性を示すのみならず、経
口および非経口的投与において特に問題となる毒
作用を示さない事から、人、獣または魚介類の医
薬として、更に植物の農薬として非常に有用であ
る。
更に本発明化合物が人又は動植物へ投与される
時は、従来、薬学的に良く知られた形態及び経路
が適用される。例えば散剤、錠剤、カプセル剤、
軟膏、注射剤、シロツプ剤、水剤、点眼剤、坐剤
等により、経口又は非経口的に使用される。
〔実施例〕
次に本発明化合物の製法を、実施例をもつて詳
細に説明する。
実施例 １
Ｎ−（３−クロロ−４−フロオロフエニル）ア
セタミドの合成
３−クロロ−４−フルオロアニリン100ｇ
（0.687mol）に無水酢酸200mlを加えると発熱が
起こる。30分間放置後、反応液を１の水に注
ぎ、析出物を濾取してエタノール400mlに溶かし、
熱水600mlを加えて時々撹拌しながら放冷し、析
出晶を濾取して目的物119.4ｇを得た。
融点118〜119℃
実施例 ２
Ｎ−（３−クロロ−４−フロオロ−６−ニトロ
フエニル）アセタミドの合成
Ｎ−（３−クロロ−４−フルオロフエニル）ア
セタミド55ｇ（0.293mol）を濃硫酸165mlに溶か
し、氷−食塩浴中で撹拌しながら、濃硝酸
（d1.42）154mlを５〜10℃、１時間で滴下した。
同温で１時間撹拌後、反応液を氷水中に注ぎ、析
出物を濾取して十分に水洗し、アセトニトリルか
ら再結晶して、黄色針状晶の目的物48.9ｇを得
た。融点114〜115℃
元素分析値（％）：C8H6ClFN2O3
計算値 Ｃ：41.31，Ｈ：2.60，Ｎ：12.04
実測値 Ｃ：41.48，Ｈ：2.52，Ｎ：12.13
実施例 ３
３−クロロ−４−フルオロ−６−ニトロアニリ
ンの合成
Ｎ−（３−クロロ−４−フルオロ−６−ニトロ
フエニル）アセタミド30ｇ（0.129mol）を濃塩
酸50ml及びエタノール200mlの混合溶液に加え、
2.5時間還流した。反応液に氷水300mlを加え、析
出晶を濾取、水洗し、乾燥して黄色針状晶の目的
物24.9ｇを得た。融点149.5〜150℃
元素分析値（％）：C6H4ClFN2O2
計算値 Ｃ：37.82，Ｈ：2.11，Ｎ：14.70
実測値 Ｃ：37.85，Ｈ：2.03，Ｎ：14.80
実施例 ４
２，３−ジクロロ−４−フルオロ−６−ニトロ
アニリンの合成
３−クロロ−４−フルオロ−６−ニトロアニリ
ン14.3ｇ（0.075mol）を酢酸150mlに溶かし、18
〜20℃で70分間塩素ガスを吹き込んだ。反応液を
氷水300mlに注ぎ、析出物を濾取して水洗し、エ
タノールから再結晶して黄色針状晶の目的物
14.33ｇを得た。融点161℃
元素分析値（％）：C6H3Cl2FN2O2
計算値 Ｃ：32.03，Ｈ：1.34，Ｎ：12.45
実測値 Ｃ：32.17，Ｈ：1.26，Ｎ：12.65
実施例 ５
２，３，４−トリクロロ−５−フルオロニトロ
ベンゼンの合成
無水塩化第二銅13.58ｇ（0.10mol）及び亜硝酸
ターシヤリーブチル12.4ｇ（0.12mol）の無水ア
セトニトリル100ml溶液に、２，３−ジクロロ−
４−フルオロ−６−ニトロアニリン18.05ｇ
（0.08mol）を60〜62℃、30分間で少量ずつ加え
た。60〜65℃で30分間撹拌後、反応液を氷水−希
塩酸（濃塩酸100ml、氷水200ml）に注ぎ、ベンゼ
ン100mlで３回抽出し、有機層を希塩酸及び水で
順次洗い、無水芒硝で乾燥して濃縮し、残渣を蒸
溜して目的物17.26ｇを得た。
沸点 137〜142℃／27mmHg
NMR（δinCDCl3），7.65（ｄ，Ｊ＝7.5）
実施例 ６
３−クロロ−２，４，５−トリフルオロニトロ
ベンゼンの合成
フツ化カリウム64.9ｇを含む無水ジメチルスル
ホキシド230ml懸濁液に、２，３，４−トリクロ
ロ−５−フルオロニトロベンゼン54.4ｇを140℃
で加え、同温で10分間撹拌した。反応液を氷水
700ml中に注ぎ、石油エーテルで抽出して、有機
層を水、炭酸カリウム水溶液及び水で順次洗い、
無水芒硝で乾燥後、濃縮して得られた残渣を蒸溜
により精製して、目的物9.7ｇを得た。
沸点 95〜108℃／30mmHg
NMR（δinCDCl3），7.94（ddd，Ｊ＝6.7，7.6，9.0
Hz）
実施例 ７
３−クロロ−３−シクロプロピルアミノ−４，
５−ジフルオロニトロベンゼンの合成
シクロプロピルアミン2.8ｇ及びトリエチルア
ミン5.1ｇを無水トルエン20mlに溶かし、３−ク
ロロ−２，４，５−トリフルオロニトロベンゼン
9.7ｇを含む無水トルエン30mlの撹拌溶液に、３
〜５℃、40分間で滴下した。同温で３時間撹拌
後、反応液を氷水150ml中に注いで、塩化メチレ
ンで抽出し、有機層を水洗、無水芒硝で乾燥して
濃縮した。得られた残渣をシリカゲル（溶媒：ｎ
−ヘキサン−塩化メチレン）により精製して、橙
赤色油状の目的物4.4ｇを得た。
NMR（δinCDCl3），0.5〜1.0（4H，ｍ，
[Industrial Application Field] The present invention relates to a novel quinolone carboxylic acid derivative that is extremely excellent as an antibacterial agent, a method for producing the same, and an antibacterial agent containing the new compound as an active ingredient. More specifically, the present invention is based on the following formula [] A novel quinolone carboxylic acid derivative represented by
The present invention relates to its hydrate, its salt, its production method, and its use as an antibacterial agent. In addition, in the compound of formula [], there are optical isomers based on one asymmetric carbon on the aminopyrrolidine ring, which is a substituent at the 7-position, but for convenience, these isomers and mixtures thereof are all referred to as a single asymmetric carbon. The scope of the present invention is not limited thereby. [Prior Art] Quinolone carboxylic acid-based antibacterial agents have been developed from nalidixic acid to pyromidic acid and then to pipemidic acid, and are used as therapeutic agents for urinary tract infections that are effective against aerobic gram-negative bacteria. Norfloxacin, recently developed by the present inventors, shows activity not only against aerobic Gram-negative bacteria but also against Gram-positive bacteria, and its antibacterial activity has been significantly enhanced. It is now in general clinical use and has brought about dramatic advances in this field. Subsequently, ofloxacin and ciprofloxacin having similar substituents, and CI-934, which shows good activity against Gram-positive bacteria, have been developed. [Problems to be Solved by the Invention] Ciprofloxacin has stronger antibacterial activity than norfloxacin. However, its antibacterial activity against Gram-positive bacteria is considerably inferior to that against Gram-negative bacteria. In addition, although CI-934 has slightly stronger antibacterial activity against Gram-positive bacteria,
It shows only low activity against Gram-negative bacteria. On the other hand, methicillin and cefem-resistant staphylococci such as Staphylococcus aureus and Staphylococcus epidermidis, which are highly resistant to β-lactam antibiotics, especially third-generation cefem, and streptococci such as enterococcus and Streprococchus faecium. Gram-positive bacteria have once again become a clinical problem. Furthermore, with the development of clinical testing technology and the spread of anaerobic bacteria testing, anaerobic bacteria resident on the skin and mucous membranes have become
It has been discovered that this bacterium is a causative agent of opportunistic infections. In respiratory infections, intra-abdominal infections, chronic otitis media, sinusitis, and other gynecological fields, anaerobic bacteria were detected alone or in combination with aerobic bacteria in 50 cases.
It is said to have reached ~80%. The combination is approximately 95% composed of Escherichia coli, enterococci, other streptococci, and anaerobic bacteria. Under such circumstances, resistance to β-lactam drugs and clindamycin, which were previously sensitive to anaerobic bacteria, is increasing, posing a serious problem in the selection of chemotherapeutic agents. Furthermore, mycoplasma, which is a type of bacteria lacking a cell wall, is known to cause respiratory infections, meningitis, endocarditis, arthritis, etc. in humans and livestock. Tetracyclines and macrolide antibiotics are used for these treatments, but in recent years bacteria resistant to these therapeutic agents, especially bacteria resistant to macrolide drugs, have been appearing frequently, raising concerns about future treatment methods. It's here. In addition, there is a need for new drugs that are useful against Chlamydia, Ureaplasma, and Garderella vaginalis, which have recently become problematic pathogens for sexually transmitted infections. [Means for solving the problem] Against this background, there is a desire for the development of new antibacterial agents that are more powerful and have a wider range of uses than conventional drugs. The inventors of the present application discovered norfloxacin, which was the spark that brought about the current popularity of new quinolone antibacterial agents, and also conducted research on its mechanism of action. As a result, the site of action of quinolones is
The higher-order structure of the DNA strand, that is, the DNA erase that controls the formation and release of double strands, and the bacterial membrane permeability and
In particular, we found that a part called porin is highly related to transparency. Based on these findings, the concept of a new quinolone was determined to meet the following requirements. 1. It acts on the DNA eraser, which is the point of action. 2. It has good permeability through the outer membrane, especially porin. 3. It is definitely effective against Gram-positive bacteria, especially staphylococci and streptococci. 4. It reduces activity against Gram-negative bacteria. 5. Among Gram-negative bacteria, it has a strong effect on Serratia and Pseudomonas aeruginosa, which are difficult to respond to other antibiotics. 6. It also has an effect on anaerobic bacteria. 7. It has good absorption and is difficult to metabolize. 8. Productivity 9. It has excellent selective toxicity and shows no harmful effects on living organisms. The present inventors have synthesized a new substance represented by the formula [] as a compound that can almost meet this concept, and have investigated its effects. As a result of examining attitudes, we found that
It was found that the above conditions were satisfied, and the present invention was completed. The chemical structure of the compound of the present invention is that it has fluorine at the 6th position, chlorine at the 8th position, and 3-aminopyrrolidino group at the 7th position on the quinolone carboxylic acid skeleton. Previously, the present inventors discovered norfloxacin in which fluorine was introduced at the 6-position on the quinolone carboxylic acid skeleton. As this family of antibacterial agents was recognized to be clinically highly useful for treating bacterial infections, they were actively researched both domestically and internationally, and were called new quinolones or fluoroquinolones, resulting in groundbreaking progress. brought about. As a result of continued research, the present inventors also realized that the 8-position substituent also plays an extremely important role in broadening the antibacterial spectrum, increasing antibacterial activity, and absorbing the drug. Therefore, various substituents were introduced at the 8-position, and as a result of analysis using quantitative structure-activity relationship techniques, it was concluded that chlorine was the most suitable substituent for the 8-position, which was completely unexpected. Reached. Thus, the present inventors have previously developed a series of compounds having fluorine at the 6th position and chlorine at the 8th position as in the application. Especially 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3
-methyl-1-piperazinyl)-4-oxo-3
-Quinolinecarboxylic acid (compound of Reference Example 2) was considered to be a top-level drug in the technical field due to its broad antibacterial spectrum, strength, and other factors. Unfortunately, however, it has been discovered that this compound has extremely worrying drawbacks as a pharmaceutical for human use. For example, in a continuous oral administration study in dogs, 20
At mg/Kg/day, severe vomiting was observed for consecutive days, and clonic convulsions were observed after continuous administration for 10 to 11 days, suggesting central side effects. In addition, a significant increase in GPT was observed with administration of 20 mg/Kg/day for 11 days and then 5 mg/Kg/day for 10 days, and with further administration of 10 mg/Kg/day for 31 days, TTT decreased markedly, resulting in liver damage. was a concern. Based on the above factors, it was determined that the compound would be difficult to use as a pharmaceutical. After going through these circumstances, we continued our research in search of a compound with even better antibacterial activity and a higher degree of safety, and as a result, we completed the present invention. The compound of the present invention exhibits much stronger antibacterial activity against Gram-positive bacteria and anaerobic bacteria than, for example, homologs having hydrogen or fluorine at the 8-position as well as the compound of Reference Example 2 above. Furthermore, it not only shows comparable activity against Gram-negative bacteria, even compared to ciprofloxacin, which has the strongest activity among conventionally known prior art techniques, but is also the least effective among antibiotics. It also shows particularly strong activity against Serratia and Pseudomonas aeruginosa. Even more surprisingly, it was found that it exhibits strong antibacterial activity against anaerobic bacteria, Mycoplasma, Ureaplasma, Chlamydia, and Garderella vaginalis, whereas conventional quinolone carboxylic acid drugs showed only weak activity. Another advantage of the compounds of the present invention is that the frequency of appearance of resistant bacteria, which has clinical significance, is considerably lower than that of other drugs. It has been confirmed that the compound of the present invention is well absorbed orally and has excellent tissue migration, in vivo stability, and tolerability in animals. [Means for Solving the Problems] Next, a method for producing the compound of the present invention will be explained. [In the formula, R is hydrogen or a lower alkyl group,
R 1 and R 2 each independently represent a protecting group for hydrogen or an amino group, or jointly represent a protecting group, and X represents a halogen] In other words, the compound represented by the formula [] and the compound represented by the formula The compound of the present invention represented by the formula [] is synthesized by reacting amines. However, in formula [], one or both of R 1 and R 2 is an amino-protecting group, for example, R 1
If R 2 is hydrogen and R 2 is a lower acyl group such as acetyl or propionyl, a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl or tertiarybutoxycarbonyl, or R 1 and R 2 are phthaloyl groups, follow the usual method. Compounds of the present invention can be obtained by removing these protecting groups. In addition, in the case of a compound in which R is lower alkyl in the formula [], the reaction product with the compound represented by the formula [] is hydrolyzed according to a conventional method to convert the ester to a carboxylic acid, It can also be made into a compound of the present invention. The reaction between the compound represented by formula [] and the compound represented by formula [] can be carried out in the absence of a solvent or in water,
Alcohols, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoricamide,
It can be carried out in a solvent such as pyridine or picoline. The reaction temperature is appropriately selected from room temperature to 200°C, preferably from room temperature to 160°C. More specifically, the compound represented by the formula [] and 1 to 5 times the molar amount of the compound represented by the formula [] are reacted in 2 to 10 times the volume of the above solvent at room temperature to 160°C for 1 to several hours. is suitable. At this time, it is also preferable to use a deoxidizing agent such as triethylamine, diazabicyclo bases or potassium carbonate.
Compounds in which R is lower alkyl and/or R 1 and R 2 are amine protecting groups can be hydrolyzed in a conventional manner. Such hydrolysis is performed using an alkali such as caustic potash, a base, or an acid such as sulfuric acid in water, a water/alcohol mixture, a water/acetic acid mixture, etc. at room temperature to
This can be easily carried out at the boiling point of the solvent. Note that the compound represented by the general formula [], which is the starting material of the present invention, is also a new compound, and can be synthesized, for example, by the following route. Next, the compound represented by the formula [] can be converted into a salt thereof according to a conventional method, if desired. Examples of salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, methanesulfonic acid, lactic acid, oxalic acid,
Examples include salts with organic acids such as acetic acid, and salts with sodium, potassium, magnesium, calcium, aluminum, cerium, chromium, cobalt, copper, iron, zinc, platinum, silver, and the like. In addition, the compound of the present invention not only exhibits extremely good absorption when orally administered to animals, but also exhibits no particularly problematic toxic effects when administered orally or parenterally. It is very useful as a type of medicine and as a plant pesticide. Furthermore, when the compound of the present invention is administered to humans, animals, or plants, conventionally well-known pharmaceutical forms and routes are applied. For example, powders, tablets, capsules,
It is used orally or parenterally in the form of ointments, injections, syrups, solutions, eye drops, suppositories, etc. [Example] Next, the method for producing the compound of the present invention will be explained in detail with reference to Examples. Example 1 Synthesis of N-(3-chloro-4-fluorophenyl)acetamide 100 g of 3-chloro-4-fluoroaniline
When 200ml of acetic anhydride is added to (0.687mol), heat is generated. After standing for 30 minutes, the reaction solution was poured into water from step 1, the precipitate was collected by filtration, and dissolved in 400 ml of ethanol.
600 ml of hot water was added, and the mixture was allowed to cool with occasional stirring, and the precipitated crystals were collected by filtration to obtain 119.4 g of the desired product. Melting point: 118-119℃ Example 2 Synthesis of N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide 55g (0.293mol) of N-(3-chloro-4-fluorophenyl)acetamide was added to 165ml of concentrated sulfuric acid. After melting, while stirring in an ice-salt bath, 154 ml of concentrated nitric acid (d1.42) was added dropwise at 5 to 10°C over 1 hour.
After stirring at the same temperature for 1 hour, the reaction solution was poured into ice water, and the precipitate was collected by filtration, thoroughly washed with water, and recrystallized from acetonitrile to obtain 48.9 g of the desired product in the form of yellow needles. Melting point 114-115℃ Elemental analysis value (%): C 8 H 6 CLFN 2 O 3 Calculated value C: 41.31, H: 2.60, N: 12.04 Actual value C: 41.48, H: 2.52, N: 12.13 Example 3 3 -Synthesis of chloro-4-fluoro-6-nitroaniline Add 30 g (0.129 mol) of N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide to a mixed solution of 50 ml of concentrated hydrochloric acid and 200 ml of ethanol.
Refluxed for 2.5 hours. 300 ml of ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 24.9 g of the target product in the form of yellow needle-like crystals. Melting point 149.5-150℃ Elemental analysis value (%): C 6 H 4 ClFN 2 O 2 Calculated value C: 37.82, H: 2.11, N: 14.70 Actual value C: 37.85, H: 2.03, N: 14.80 Example 4 2 , 3-dichloro-4-fluoro-6-nitroaniline Dissolve 14.3 g (0.075 mol) of 3-chloro-4-fluoro-6-nitroaniline in 150 ml of acetic acid,
Chlorine gas was bubbled for 70 min at ~20°C. The reaction solution was poured into 300 ml of ice water, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain the desired product as yellow needle-shaped crystals.
14.33g was obtained. Melting point 161℃ Elemental analysis value (%): C 6 H 3 Cl 2 FN 2 O 2 Calculated value C: 32.03, H: 1.34, N: 12.45 Actual value C: 32.17, H: 1.26, N: 12.65 Example 5 2 Synthesis of ,3,4-trichloro-5-fluoronitrobenzene 2,3-dichloro-
4-fluoro-6-nitroaniline 18.05g
(0.08 mol) was added little by little at 60-62°C over 30 minutes. After stirring at 60-65℃ for 30 minutes, the reaction solution was poured into ice water-diluted hydrochloric acid (100 ml of concentrated hydrochloric acid, 200 ml of ice water), extracted three times with 100 ml of benzene, and the organic layer was sequentially washed with diluted hydrochloric acid and water, and dried over anhydrous sodium sulfate. The residue was distilled to obtain 17.26 g of the desired product. Boiling point 137-142℃/27mmHg NMR (δinCDCl 3 ), 7.65 (d, J = 7.5) Example 6 Synthesis of 3-chloro-2,4,5-trifluoronitrobenzene 230ml of anhydrous dimethyl sulfoxide containing 64.9g of potassium fluoride Add 54.4 g of 2,3,4-trichloro-5-fluoronitrobenzene to the suspension at 140°C.
and stirred at the same temperature for 10 minutes. Pour the reaction mixture into ice water.
Pour into 700 ml, extract with petroleum ether, wash the organic layer sequentially with water, potassium carbonate aqueous solution, and water.
After drying with anhydrous sodium sulfate, the resulting residue was purified by distillation to obtain 9.7 g of the desired product. Boiling point 95-108℃/30mmHg NMR (δinCDCl 3 ), 7.94 (ddd, J = 6.7, 7.6, 9.0
Hz) Example 7 3-chloro-3-cyclopropylamino-4,
Synthesis of 5-difluoronitrobenzene Dissolve 2.8 g of cyclopropylamine and 5.1 g of triethylamine in 20 ml of anhydrous toluene, and dissolve 3-chloro-2,4,5-trifluoronitrobenzene.
In a stirred solution of 30 ml of anhydrous toluene containing 9.7 g
The mixture was added dropwise at ~5°C for 40 minutes. After stirring at the same temperature for 3 hours, the reaction solution was poured into 150 ml of ice water, extracted with methylene chloride, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in silica gel (solvent: n
-hexane-methylene chloride) to obtain 4.4 g of the desired product as an orange-red oil. NMR (δinCDCl 3 ), 0.5-1.0 (4H, m,
【式】），3.0〜3.2（1H，ｍ，[Formula]), 3.0 to 3.2 (1H, m,
【式】），7.19（1H，Ｓ，NH），7.85（1H，
dd，Ｊ＝8.2，9.9Hz，５−Ｈ）
実施例 ８
Ｎ−（２−クロロ−３，４−ジフルオロ−６−
ニトロフエニル）−Ｎ−シクロプロピルアセタ
ミドの合成
３−クロロ−２−シクロプロピルアミノ−４，
５−ジフルオロニトロベンゼン4.4ｇに無水酢酸
15mlを加えて、室温で30分間撹拌した。反応液を
氷水100ml中に注ぎ、炭酸カリウム末を加えて過
剰の無水酢酸を分解し、５℃で12時間放置後、析
出物を濾取し、酢酸エチル−ｎ−ヘキサンから再
結晶して目的物2.7ｇを得た。
融点 98〜99.5℃
元素分析値（％）：C11H9ClF2N2O3
計算値 Ｃ：45.46，Ｈ：3.12，Ｎ：9.64
実測値 Ｃ：45.56，Ｈ：3.00，Ｎ：9.69
実施例 ９
Ｎ−（２−クロロ−３，４−ジフルオロフエニ
ル）−Ｎ−シクロプロピルアセタミドの合成
Ｎ−（２−クロロ−３，４−ジフルオロ−６−
ニトロフエニル）−Ｎ−シクロプロピルアセタミ
ド2.7ｇをエタノール50mlに溶かし、10％パラジ
ウム炭素0.5ｇを加えて、常圧水素気流中２〜３
℃で40分間撹拌した。反応液を濾過して濃縮後、
結晶性残渣を室温で10時間真空乾燥した。これを
無水ジメチルホルムアミド15mlに溶かし、亜硝酸
ターシヤリーブチル1.72ｇの無水ジメチルホルム
アミド10ml溶液に50〜52℃、13分間で滴下した。
反応液を同温で５分間撹拌した後、氷水中に注い
でエーテルで抽出し、有機層を水、希塩酸及び水
で順次洗つて無水芒硝で乾燥し、濃縮して得られ
た残渣をシリカゲルカラム（溶媒：ｎ−ヘキサン
−酢酸エチル）により精製し、石油エーテルから
再結晶して目的物0.44ｇを得た。
融点 60.5〜61.5℃
元素分析値（％）：C11HClF2NO
計算値 Ｃ：53.78，Ｈ：4.10，Ｎ：5.70
実測値 Ｃ：53.87，Ｈ：4.02，Ｎ：5.78
実施例 10
Ｎ−シクロプロピル−２−クロロ−３，４−ジ
フルオロアニリンの合成
20％の希塩酸７mlにＮ−（２−クロロ−３，４
−ジフルオロフエニル）−Ｎ−シクロプロピルア
セタミド0.44ｇを加え、80〜100℃で６時間撹拌
した。反応液を氷水中に注ぎ、水酸化ナトリウム
水溶液で弱アルカリ性としてエーテルで抽出し、
有機層を水洗して無水芒硝で乾燥した。濃縮後、
得られた残渣を分取用シリカゲル薄層クロマトグ
ラフイー（溶媒：石油エーテル−エーテル）によ
り単離精製して、橙色油状の目的物100mgを得た。
実施例 11
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３
−キノリンカルボン酸エチルの合成
Ｎ−シクロプロピル−２−クロロ−３，４−ジ
フロオロアニリン100mgにエトキシメチレンマロ
ン酸ジエチル100mgを加え、生成するエタノール
を除去するため、窒素ガスを吹き込みながら、
100〜135℃の油浴上で10.5時間撹拌した。冷後、
これにポリリン酸１ｇを加えて、125〜135℃の油
浴上で３時間撹拌後、反応液を氷水中に注いでク
ロロホルムで抽出した。有機層を炭酸カリウム水
溶液及び水で順次洗い、無水芒硝で乾燥して濃縮
後、得られた残渣を分取用シリカゲル薄層クロマ
トグラフイー（溶媒：エーテル）による単離精製
して、無色針状晶の目的物11mgを得た。融点160
〜162.5℃
NMR（δinCDCl3），1.0〜1.5（4H，ｍ，
[Formula]), 7.19 (1H, S, NH), 7.85 (1H, dd, J=8.2, 9.9Hz, 5-H) Example 8 N-(2-chloro-3,4-difluoro-6-
Synthesis of (nitrophenyl)-N-cyclopropylacetamide 3-chloro-2-cyclopropylamino-4,
Acetic anhydride to 4.4 g of 5-difluoronitrobenzene
15 ml was added and stirred at room temperature for 30 minutes. The reaction solution was poured into 100 ml of ice water, potassium carbonate powder was added to decompose excess acetic anhydride, and after standing at 5°C for 12 hours, the precipitate was collected by filtration and recrystallized from ethyl acetate-n-hexane to obtain the desired product. 2.7g of product was obtained. Melting point 98-99.5℃ Elemental analysis value (%): C 11 H 9 ClF 2 N 2 O 3 Calculated value C: 45.46, H: 3.12, N: 9.64 Actual value C: 45.56, H: 3.00, N: 9.69 Example 9 Synthesis of N-(2-chloro-3,4-difluorophenyl)-N-cyclopropylacetamide N-(2-chloro-3,4-difluoro-6-
Dissolve 2.7 g of (nitrophenyl)-N-cyclopropylacetamide in 50 ml of ethanol, add 0.5 g of 10% palladium on carbon, and dissolve in a stream of hydrogen at normal pressure for 2 to 3 hours.
Stir for 40 minutes at °C. After filtering and concentrating the reaction solution,
The crystalline residue was vacuum dried at room temperature for 10 hours. This was dissolved in 15 ml of anhydrous dimethylformamide, and added dropwise to a solution of 1.72 g of tert-butyl nitrite in 10 ml of anhydrous dimethylformamide at 50-52°C for 13 minutes.
The reaction solution was stirred at the same temperature for 5 minutes, then poured into ice water and extracted with ether. The organic layer was washed with water, diluted hydrochloric acid, and water sequentially, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was applied to a silica gel column. (Solvent: n-hexane-ethyl acetate) and recrystallized from petroleum ether to obtain 0.44 g of the desired product. Melting point 60.5-61.5℃ Elemental analysis value (%): C 11 HClF 2 NO Calculated value C: 53.78, H: 4.10, N: 5.70 Actual value C: 53.87, H: 4.02, N: 5.78 Example 10 N-cyclopropyl Synthesis of -2-chloro-3,4-difluoroaniline Add N-(2-chloro-3,4-difluoroaniline) to 7 ml of 20% dilute hydrochloric acid.
-difluorophenyl)-N-cyclopropylacetamide (0.44 g) was added, and the mixture was stirred at 80 to 100°C for 6 hours. The reaction solution was poured into ice water, made weakly alkaline with an aqueous sodium hydroxide solution, and extracted with ether.
The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration,
The obtained residue was isolated and purified by preparative silica gel thin layer chromatography (solvent: petroleum ether-ether) to obtain 100 mg of the target product as an orange oil. Example 11 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3
-Synthesis of ethyl quinolinecarboxylate 100 mg of diethyl ethoxymethylenemalonate was added to 100 mg of N-cyclopropyl-2-chloro-3,4-difluoroaniline, and while blowing nitrogen gas to remove the generated ethanol,
Stirred on oil bath at 100-135°C for 10.5 hours. After cooling,
To this was added 1 g of polyphosphoric acid, and after stirring for 3 hours on an oil bath at 125 to 135°C, the reaction solution was poured into ice water and extracted with chloroform. The organic layer was sequentially washed with an aqueous potassium carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was isolated and purified by preparative silica gel thin layer chromatography (solvent: ether) to obtain colorless needles. 11 mg of the desired crystal was obtained. melting point 160
~162.5℃ NMR ( δinCDCl3 ), 1.0~1.5 (4H, m,
【式】），1.40（3H，ｔ，Ｊ＝7.0Hz，− CH3），4.1〜4.4（1H，ｍ，[Formula]), 1.40 (3H, t, J=7.0Hz, - CH 3 ), 4.1~4.4 (1H, m,
【式】），4.38
（2H，ｑ，Ｊ＝7.0Hz，−CH2−CH3），8.22（1H，
dd，Ｊ＝8.8，9.7Hz５−Ｈ），8.66（1H，ｓ，２−
Ｈ）
実施例 12
２，３，４−トリクロロ−５−フルオロアニリ
ンの合成
鉄粉54.6ｇを水60mlに加えて、50〜60℃で激し
く撹拌しながら、濃塩酸6.7mlをゆつくりと滴下
した。これにエタノール150mlを加えた後、２，
３，４−トリクロロ−５−フルオロニトロベンゼ
ン75.1ｇを、60〜70℃で１時間かえて少量ずつ加
えた。80℃で１時間撹拌後、熱時反応液を濾過
し、不溶物を熱エタノール100ml及びベンゼン300
mlで順次洗浄した。この濾液及び洗液に水を加え
て有機層を分取し、水層をベンゼン200mlで抽出
した。有機層を合わせ、水洗して無水芒硝で乾燥
後濃縮し、得られた残渣をｎ−ヘキサンから再結
晶して、淡褐色針状晶の目的物58.6ｇを得た。融
点118〜120℃
実施例 13
２，３，４−トリクロロ−５−フルオロベンゾ
ニトリルの合成
２，３，４−トリクロロ−５−フルオロアニリ
ン43.8ｇを濃塩酸300mlに加え、塩−氷浴中で撹
拌しながら、亜硝酸ナトリウム21.1ｇの50ml水溶
液を−２〜０℃，20分間で滴下した。０℃撹拌30
分後、反応液をホウフツ化ナトリウム67.2ｇの氷
水中に注いで十分に撹拌した。これを30分間氷水
中で放置し、析出物を濾取して氷水及びエーテル
で順次洗浄し、微黄色の結晶を得た。得られた結
晶をシアン化銅36.5ｇ、シアン化カリウム53.0ｇ
及び炭酸ナトリウム11.1ｇの激しく撹拌した水溶
液300mlに、室温、30分間で少量ずつ加えた。室
温で撹拌30分後、反応液にベンゼン300mlを加え、
更に、15分間撹拌して不溶物を濾去し、ベンゼン
150mlで洗浄した。20％シアン化カリウム水溶液
及び水で順次洗い、無水芒硝で乾燥して濃縮後、
得られた残渣をｎ−ヘキサンから再結晶して、淡
褐色針状晶の目的物27ｇを得た。融点97〜99℃
実施例 14
３−クロロ−２，４，５−トロフルオロベンゾ
ニトリルの合成
130℃で撹拌したフツ化カリウム31.7ｇを含む
ジメチルスルホキシド懸濁液100mlに２，３，４
−トリクロロ−５−フルオロベンゾニトリル15ｇ
を加え、140℃で1.5時間撹拌した。冷後、反応液
を300mlの氷水中に注いで、塩化メチレンで抽出
した。有機層を水洗し、無水芒硝で乾燥後、濃縮
して淡褐色油状の目的物11.9ｇを得た。
実施例 15
３−クロロ−２，４，５−トリフルオロベンズ
アミドの合成
３−クロロ−２，４，５−トリフルオロベンゾ
ニトリル11.9ｇを、30％臭化水素−酢酸溶液150
mlに溶かし、80〜90℃で80分間還流後、氷水350
mlに注いでエーテル200mlで２回抽出し、次いで
氷冷した1N−水酸化カリウム水溶液で洗浄して
水洗した。無水芒硝で乾燥後、濃縮してシリカゲ
ルクロマトグラフイー（溶媒：ｎ−ヘキサン−酢
酸エチル）で分離し、目的物3.97ｇを得た。融点
110〜113.5℃
実施例 16
３−クロロ−２，４，５−トロフルオロ安息香
酸の合成
３−クロロ−２，４，５−トロフルオロベンズ
アミド3.97ｇに、18N−硫酸20mlを加え、125〜
135℃で９時間撹拌後、氷水100mlに注いで一晩放
置後、析出物を濾取した。濾液はエーテル100ml
で２回抽出し、無水芒硝で乾燥後、濃縮して先の
析出物と合わせ、塩化メチレン150mlを加えて不
溶物をセライトで濾去し、濾液を濃縮して目的物
2.38ｇを得た。
融点115〜116.5℃
元素分析値（％）：C7H2ClF3O2
計算値 Ｃ：39.93，Ｈ：0.96
実測値 Ｃ：40.18，Ｈ：0.80
実施例 17
３−クロロ−２，４−５−トリフルオロベンゾ
イルクロライドの合成
３−クロロ−２，４−５−トリフルオロ安息香
酸2.38ｇに、塩化チオニル10mlを加えて溶かし、
2.5時間還流した。ウイドマー精留塔を付して過
剰の塩化チオニルを濃縮後、窒素気流中で蒸溜し
て、淡黄色油状の目的物1.99ｇを得た。
沸点88℃／19mmHg
実施例 18
３−クロロ−２，４，５−トリフルオロベンゾ
イルマロン酸ジエチルの合成
削り状のマグネシウム0.22ｇに無水エタノール
1.5ml及び四塩化炭素0.1mlを加え、反応が始まつ
てから、マロン酸ジエチル1.4ｇ、無水エタノー
ル２ml及び無水トルエン６mlの混合物を、47〜60
℃、28分間で撹拌下に滴下した。更に、同温で80
分間撹拌後、−８〜−12℃に冷却して３−クロロ
−２，４，５−トリフルオロベンゾイルクロライ
ド1.99ｇの無水トルエン２ml溶液を、13分間で滴
下し、次いで、−10〜５℃で２時間撹拌後、一晩
室温で放置した。氷水６ml及び濃硫酸0.4mlの溶
液を加え、内容物を溶かして層を分離し、トルエ
ン６mlで３回抽出した。トルエン層を水洗して、
無水芒硝で乾燥後、濃縮して淡黄色油状の目的物
3.05ｇを得た。
実施例 19
３−クロロ−２，４，５−トリフルオロベンゾ
イル酢酸エチルの合成
３−クロロ−２，４，５−トリフルオロベンゾ
イルマロン酸ジエチル3.05ｇに水４mlを加えて乳
化させ、パラトルエンスルホン酸４mgを加え、激
しく撹拌しながら４時間還流した。放冷後、塩化
メチレン６mlで４回抽出し、水洗して無水芒硝で
乾燥後、濃縮してエーテル−ｎ−ヘキサンから再
結晶し、目的物1.22ｇを得た。
融点 80〜83℃
元素分析値（％）：C11H8ClF3O3
計算値 Ｃ：47.08，Ｈ：2.87
実測値 Ｃ：46.96，Ｈ：2.77
実施例 20
２−（３−クロロ−２，４，５−トリフルオロ
ベンゾイル）−３−エトキシアクリル酸エチル
の合成
３−クロロ−２，４，５−トリフルオロベンゾ
イル酢酸エチル1.22ｇ、オルトギ酸エチル0.97
ｇ、無水酢酸1.12ｇの混合物を、118〜143℃で３
時間撹拌後、濃縮して淡黄色油状の目的物1.4ｇ
を得た。
実施例 21
２−（３−クロロ−２，４，５−トリフルオロ
ベンゾイル）−３−シクロプロピルアミノアク
リル酸エチルの合成
２−（３−クロロ−２，４，５−トリフルオロ
ベンゾイル）−３−エトキシアクリル酸エチル1.4
ｇの無水エタノール３ml溶液に、シクロプロピル
アミン0.26ｇの無水エタノール２ml溶液を、５〜
10℃、15分間で滴下した。滴下後５℃で1.5時間
放置した後、室温で１時間撹拌した。析出物を濾
取し、濾液は濃縮乾固して先の析出物と合わせ、
石油エーテルから再結晶して目的物1.09ｇを得
た。融点84〜85.5℃
元素分析値（％）：C15H13ClF3NO3
計算値 Ｃ：51.81，Ｈ：3.77，Ｎ：4.03
実測値 Ｃ：51.76，Ｈ：3.74，Ｎ：4.03
実施例 22
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３
−キノリンカルボン酸エチルの合成
２−（３−クロロ−２，４，５−トリフロオロ
ベンゾイル）−３−シクロプロピルアミノアクリ
ル酸エチル1.09ｇを５mlの無水ジメチルホルムア
ミドに溶かし、フツ化ナトリウム0.21ｇを加えて
130〜156℃で3.5時間撹拌した。熱反応混合物を
氷水50mlに注ぎ、沈澱物を濾取して水洗後、酢酸
エチルから再結晶して、目的物0.96ｇを得た。
融点158〜159℃
元素分析値（％）：C15H12ClF3NO3
計算値 Ｃ：54.98，Ｈ：3.69，Ｎ：4.27
実測値 Ｃ：54.96，Ｈ：3.57，Ｎ：4.25
実施例 23
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３
−キノリンカルボン酸の合成
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３−
キノリンカルボン酸エチル0.24ｇ、酢酸２ml、水
1.5ml及び濃硫酸0.25mlの混合物を１時間還流し
た。熱反応液を氷水に注ぎ、沈澱物を濾取して水
洗後、エーテル洗浄して目的物0.17ｇを得た。
融点194〜195℃
元素分析値（％）：C13H8ClF2NO3
計算値 Ｃ：52.11，Ｈ：2.69，Ｎ：4.67
実測値 Ｃ：52.00，Ｈ：2.53，Ｎ：4.64
実施例 24
７−〔３−（ｔ−ブトキシカルボニルアミノ）−
１−ピロリジニル〕−８−クロロ−１−シクロ
プロピル−６−フルオロ−１，４−ジヒドロ−
４−オキソ−３−キノリンカルボン酸の合成
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３−
キノリンカルボン酸500mg（1.67mmole）、無水ア
セトニトリル５ml、１，８−ジアザビシクロ
〔５，４，０〕−７−ウンデセン（DBU）250mg
（1.67mmole）、及び３−（ｔ−ブトキシカルボニ
ルアミノ）ピロリジン430mgの混合物を１時間還
流した。反応液の溶媒を留去し、残渣にエタノー
ル−エーテルを加え、２日間冷蔵庫中に放置し
た。析出結晶を濾取し、エタノール−エーテル
（１：１）次いでエーテルで洗い目的物を430mg
（55.3％）得た。淡黄色粉末結晶。
1RνKBr naxcm-1：3300（−NH−CO），1710
（[Formula]), 4.38 (2H, q, J=7.0Hz, −CH 2 −CH 3 ), 8.22 (1H,
dd, J = 8.8, 9.7Hz5-H), 8.66 (1H, s, 2-
H) Example 12 Synthesis of 2,3,4-trichloro-5-fluoroaniline 54.6 g of iron powder was added to 60 ml of water, and while stirring vigorously at 50 to 60°C, 6.7 ml of concentrated hydrochloric acid was slowly added dropwise. . After adding 150ml of ethanol to this, 2,
75.1 g of 3,4-trichloro-5-fluoronitrobenzene was added little by little at 60-70°C for 1 hour. After stirring at 80℃ for 1 hour, the hot reaction solution was filtered, and the insoluble matter was removed with 100ml of hot ethanol and 300ml of benzene.
Washed sequentially with ml. Water was added to the filtrate and washing liquid to separate the organic layer, and the aqueous layer was extracted with 200 ml of benzene. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was recrystallized from n-hexane to obtain 58.6 g of the desired product in the form of light brown needles. Melting point: 118-120°C Example 13 Synthesis of 2,3,4-trichloro-5-fluorobenzonitrile 43.8 g of 2,3,4-trichloro-5-fluoroaniline was added to 300 ml of concentrated hydrochloric acid, and the mixture was poured into a salt-ice bath. While stirring, 50 ml of an aqueous solution of 21.1 g of sodium nitrite was added dropwise at -2 to 0°C over 20 minutes. 0℃ stirring 30
After a few minutes, the reaction solution was poured into ice water containing 67.2 g of sodium borofluoride and thoroughly stirred. This was left in ice water for 30 minutes, and the precipitate was collected by filtration and washed successively with ice water and ether to obtain pale yellow crystals. The obtained crystals were mixed with 36.5 g of copper cyanide and 53.0 g of potassium cyanide.
and 300 ml of a vigorously stirred aqueous solution containing 11.1 g of sodium carbonate was added portionwise over 30 minutes at room temperature. After stirring at room temperature for 30 minutes, add 300 ml of benzene to the reaction solution.
Further, stir for 15 minutes, remove insoluble matter by filtration, and remove benzene.
Washed with 150ml. After sequentially washing with 20% potassium cyanide aqueous solution and water, drying with anhydrous sodium sulfate and concentrating,
The resulting residue was recrystallized from n-hexane to obtain 27 g of the desired product in the form of light brown needles. Melting point: 97-99°C Example 14 Synthesis of 3-chloro-2,4,5-trofluorobenzonitrile Add 2,3,4 to 100 ml of a dimethyl sulfoxide suspension containing 31.7 g of potassium fluoride stirred at 130°C.
-Trichloro-5-fluorobenzonitrile 15g
was added and stirred at 140°C for 1.5 hours. After cooling, the reaction solution was poured into 300 ml of ice water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 11.9 g of the desired product as a pale brown oil. Example 15 Synthesis of 3-chloro-2,4,5-trifluorobenzamide 11.9 g of 3-chloro-2,4,5-trifluorobenzonitrile was added to 150 g of 30% hydrogen bromide-acetic acid solution.
ml, reflux at 80-90℃ for 80 minutes, then cool in ice water at 350℃.
ml and extracted twice with 200 ml of ether, then washed with an ice-cooled 1N aqueous potassium hydroxide solution and then with water. After drying with anhydrous sodium sulfate, the residue was concentrated and separated using silica gel chromatography (solvent: n-hexane-ethyl acetate) to obtain 3.97 g of the desired product. melting point
110-113.5°C Example 16 Synthesis of 3-chloro-2,4,5-trofluorobenzoic acid Add 20 ml of 18N-sulfuric acid to 3.97 g of 3-chloro-2,4,5-trofluorobenzamide,
After stirring at 135°C for 9 hours, the mixture was poured into 100 ml of ice water, left overnight, and the precipitate was collected by filtration. The filtrate is 100ml of ether.
After drying with anhydrous sodium sulfate, it was concentrated and combined with the previous precipitate, 150 ml of methylene chloride was added, the insoluble matter was filtered off through Celite, and the filtrate was concentrated to obtain the desired product.
2.38g was obtained. Melting point 115-116.5°C Elemental analysis value (%): C 7 H 2 ClF 3 O 2 Calculated value C: 39.93, H: 0.96 Actual value C: 40.18, H: 0.80 Example 17 3-chloro-2,4-5 -Synthesis of trifluorobenzoyl chloride 10 ml of thionyl chloride was added to 2.38 g of 3-chloro-2,4-5-trifluorobenzoic acid and dissolved.
Refluxed for 2.5 hours. Excess thionyl chloride was concentrated using a Widmer rectification column, and then distilled in a nitrogen stream to obtain 1.99 g of the target product as a pale yellow oil. Boiling point 88℃/19mmHg Example 18 Synthesis of diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate Add anhydrous ethanol to 0.22g of magnesium shavings
After adding 1.5 ml and 0.1 ml of carbon tetrachloride and starting the reaction, a mixture of 1.4 g of diethyl malonate, 2 ml of absolute ethanol and 6 ml of anhydrous toluene was added to the
It was added dropwise while stirring at ℃ for 28 minutes. Furthermore, at the same temperature 80
After stirring for a minute, it was cooled to -8 to -12°C, and a solution of 1.99 g of 3-chloro-2,4,5-trifluorobenzoyl chloride in 2 ml of anhydrous toluene was added dropwise over 13 minutes, and then -10 to -12°C. After stirring for 2 hours, the mixture was left at room temperature overnight. A solution of 6 ml of ice water and 0.4 ml of concentrated sulfuric acid was added to dissolve the contents, the layers were separated and extracted three times with 6 ml of toluene. Wash the toluene layer with water,
After drying with anhydrous sodium sulfate, it is concentrated to give the desired product as a pale yellow oil.
3.05g was obtained. Example 19 Synthesis of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate 4 ml of water was added to 3.05 g of diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate, emulsified, and para-toluenesulfone was added. 4 mg of acid was added and the mixture was refluxed for 4 hours with vigorous stirring. After cooling, the mixture was extracted four times with 6 ml of methylene chloride, washed with water, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ether-n-hexane to obtain 1.22 g of the desired product. Melting point 80-83℃ Elemental analysis value (%): C 11 H 8 ClF 3 O 3 Calculated value C: 47.08, H: 2.87 Actual value C: 46.96, H: 2.77 Example 20 2-(3-chloro-2, Synthesis of ethyl 4,5-trifluorobenzoyl)-3-ethoxyacrylate 1.22 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate, 0.97 ethyl orthoformate
A mixture of 1.12 g of acetic anhydride and 1.12 g of acetic anhydride was
After stirring for an hour, concentrate to obtain 1.4 g of the target product as a pale yellow oil.
I got it. Example 21 Synthesis of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate 2-(3-chloro-2,4,5-trifluorobenzoyl)-3 -ethyl ethoxyacrylate 1.4
A solution of 0.26 g of cyclopropylamine in 2 ml of absolute ethanol was added to 3 ml of absolute ethanol.
It was added dropwise at 10°C for 15 minutes. After the dropwise addition, the mixture was left at 5°C for 1.5 hours, and then stirred at room temperature for 1 hour. The precipitate was collected by filtration, and the filtrate was concentrated to dryness and combined with the previous precipitate.
Recrystallization from petroleum ether yielded 1.09 g of the desired product. Melting point 84-85.5℃ Elemental analysis value (%): C 15 H 13 ClF 3 NO 3 Calculated value C: 51.81, H: 3.77, N: 4.03 Actual value C: 51.76, H: 3.74, N: 4.03 Example 22 8 -chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3
-Synthesis of ethyl quinolinecarboxylate Dissolve 1.09 g of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate in 5 ml of anhydrous dimethylformamide, and dissolve 0.21 g of sodium fluoride. plus
Stirred at 130-156°C for 3.5 hours. The hot reaction mixture was poured into 50 ml of ice water, and the precipitate was collected by filtration, washed with water, and recrystallized from ethyl acetate to obtain 0.96 g of the desired product. Melting point 158-159℃ Elemental analysis value (%): C 15 H 12 ClF 3 NO 3 Calculated value C: 54.98, H: 3.69, N: 4.27 Actual value C: 54.96, H: 3.57, N: 4.25 Example 23 8 -chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3
-Synthesis of quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
Ethyl quinolinecarboxylate 0.24g, acetic acid 2ml, water
A mixture of 1.5 ml and 0.25 ml of concentrated sulfuric acid was refluxed for 1 hour. The hot reaction solution was poured into ice water, and the precipitate was collected by filtration, washed with water, and then with ether to obtain 0.17 g of the desired product. Melting point 194-195℃ Elemental analysis value (%): C 13 H 8 ClF 2 NO 3 Calculated value C: 52.11, H: 2.69, N: 4.67 Actual value C: 52.00, H: 2.53, N: 4.64 Example 24 7 -[3-(t-butoxycarbonylamino)-
1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
Synthesis of 4-oxo-3-quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
Quinolinecarboxylic acid 500mg (1.67mmole), anhydrous acetonitrile 5ml, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) 250mg
(1.67 mmole) and 430 mg of 3-(t-butoxycarbonylamino)pyrrolidine was refluxed for 1 hour. The solvent of the reaction solution was distilled off, ethanol-ether was added to the residue, and the mixture was left in a refrigerator for 2 days. The precipitated crystals were collected by filtration, washed with ethanol-ether (1:1) and then with ether to give 430 mg of the desired product.
(55.3%) obtained. Pale yellow powder crystal. 1Rν KBr nax cm -1 : 3300 (−NH−CO), 1710
(
【式】），1620（Ｃ＝Ｏ）
Ｈ−NMR（inCDCl3，ppm）：8.86（1H，ｓ），
7.94（1H，ｄ，Ｊ＝13.18Hz），4.60〜4.00（1H，
ｍ），3.96〜3.10（4H，ｍ），2.50〜1.60（3H，ｍ），
1.446（9H，ｓ），1.30〜0.80（4H，ｍ）
実施例 25
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリン
カルボン酸の合成
７−〔３−（ｔ−ブトキシカルボニルアミノ）−
１−ピロリジニル〕−８−クロロ−１−シクロプ
ロピル−６−フルオロ−１，４−ジヒドロ−４−
オキソ−３−キノリンカルボン酸430mgをメタノ
ール５ml、濃塩酸５mlの混液に溶解し、室温で30
分間撹拌した。反応液に濃アンモニア水を加えて
PH約７とし、析出結晶を濾取し、よく水洗し次に
メタノールで洗い、クロロホルム：メタノール：
濃アンモニア水より再結晶して、乳白色粉末結晶
の目的物110mgを得た。
融点253〜258℃（分解）。
元素分析値（％）：C17H17ClFN3O3として
計算値 Ｃ：55.82，Ｈ：4.68，Ｎ：11.49
実測値 Ｃ：56.09，Ｈ：4.82，Ｎ：11.46
実施例 26
７−（３−アセタミド−１−ピロリジニル）−８
−クロロ−１−シクロプロピル−６−フルオロ
−１，４−ジヒドロ−４−オキソ−３−キノリ
ンカルボン酸の合成
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３−
キノリンカルボン酸１ｇに無水アセトニトリル10
ml、３−アセタミドピロリジン0.64ｇ及び
DBU0.51ｇを順次加えて１時間還流した。反応
液を減圧濃縮し、残渣にクロロホルム20mlを加え
て溶かし10％クエン酸水溶液10mlで洗浄した。ク
ロロホルム層を飽和食塩水で洗浄後、無水芒硝で
乾燥、濃縮し、残渣をメタノールから再結晶して
黄白色プリズム晶の目的物1.2ｇを得た。
融点210〜212℃
元素分析値（％）：C19H19ClFN3O4・１／4H2Ｏ
計算値 Ｃ：55.35 Ｈ：4.77 Ｎ：10.19
分析値 Ｃ：55.39 Ｈ：4.68 Ｎ：10.12
実施例 27
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリン
カルボン酸の合成
７−（３−アセタミド−１−ピロリジル）−８−
クロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリンカ
ルボン酸0.8ｇに、水酸化ナトリウム0.8ｇを含む
水溶液20mlを加え５時間還流した。反応液を酢酸
で中和し析出晶を濾取した。この結晶を水洗後乾
燥し、メタノール−クロロホルム−濃アンモニア
水の混合溶液から再結晶して白色鱗片状晶の目的
物0.41ｇを得た。融点238〜240℃（分解）
元素分析値（％）：C17H17ClFN3O3・１／2H2Ｏ
計算値 Ｃ：54.48 Ｈ：4.84 Ｎ：11.21
分析値 Ｃ：54.44 Ｈ：4.78 Ｎ：11.20
実施例 28
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリン
カルボン酸の合成
８−クロロ−１−シクロプロピル−６，７−ジ
フルオロ−１，４−ジヒドロ−４−オキソ−３−
キノリンカルボン酸0.6ｇに無水アセトニトリル
６ml、３−アミノピロリジン0.35ｇ及びDBU0.31
ｇを順次加え１時間還流した。ここでさらに３−
アミノピロリジン0.2ｇを追加して２時間還流し
た。冷後析出晶を濾取し、結晶を水酸化ナトリウ
ム0.12ｇを含む水溶液９mlに溶かして酢酸で中和
した。析出晶を濾取し水洗してさらにアセトニト
リルで洗い無色粉末の目的物0.52ｇを得た。
融点237〜238℃（分解）
元素分析値（％）：C17H17ClFN3O3・H2Ｏ
計算値 Ｃ：53.20 Ｈ：4.99 Ｎ：10.95
分析値 Ｃ：52.97 Ｈ：4.62 Ｎ：10.83
実施例 29
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリカ
ルボン酸・塩酸塩の合成
エタノール２mlに７−（３−アミノ−１−ピロ
リジニル）−８−クロロ−１−シクロプロピル−
６−フルオロ−１，４−ジヒドロ−４−オキソ−
３−キノリンカルボン酸100mlを加えてけん濁し、
これにエタノール・塩酸（7.0mmoleHCl／ml
EtOH）0.2mlを加えた。次いで、これを濃縮し残
渣をメタノールから再結晶して淡黄色プリズム晶
の目的物79mgを得た。融点263〜265℃（分解）
元素分析値（％）：C17H17ClFN3O3・HCl
計算値 Ｃ：50.76 Ｈ：4.51 Ｎ：10.45
分析値 Ｃ：50.50 Ｈ：4.44 Ｎ：10.38
実施例 30
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−４−オキソ−３−キノリン
カルボン酸メタンスルホン酸塩の合成
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−１，
４−ジヒドロ−４−オキソ−３−キノリンカルボ
ン酸200mgを酢酸１ml及び水10mlの混合液に加え、
これにメタンスルホン酸0.1mlを加えた。反応液
を濃縮後、残渣にエタノール10mlを加えて析出晶
を濾取し、これをエタノール及びエーテルで順次
洗い、黄色プリズム晶の目的物116mgを得た。
融点234〜235℃
元素分析値（％）：C17H17ClFN3O3・CH4SO3・
１／2H2Ｏとして
計算値 Ｃ：45.91 Ｈ：4.71 Ｎ：8.92
実測値 Ｃ：45.70 Ｈ：4.66 Ｎ：8.86
同様にして、７−（３−アミノ−１−ピロリジ
ニル）−８−クロロ−１−シクロプロピル−６−
フルオロ−１，４−ジヒドロ−４−オキソ−３−
キノリンカルボン酸パラトルエンスルホン酸塩を
得た。
融点168〜170℃
元素分析値（％）：C17H17ClFN3O3・C7H8SO3・
H2Ｏとして
計算値 Ｃ：51.85 Ｈ：4.89 Ｎ：7.56
実測値 Ｃ：52.01 Ｈ：4.64 Ｎ：7.64
実施例 31
−（３−アミノ−１−ピロリジニル）−８−クロ
ロ−１−シクロプロピル−６−フルオロ−１，
４−ジヒドロ−４−オキソ−３−キノリンカル
ボン酸硫酸塩の合成
７−（３−アミノ−１−ピロリジニル）−８−ク
ロロ−１−シクロプロピル−６−フルオロ−１，
４−ジヒドロ−４−オキソ−３−キノリンカルボ
ン酸160mgを酢酸0.2mlを含む水溶液３mlに加え、
これに濃硫酸３滴を加えた。反応液を氷浴中で冷
やし、析出晶を濾取してエタノール及びエーテル
で順次洗い、黄色針状晶の目的物150mgを得た。
融点220〜223℃（分解）
元素分析値（％）：C17H17ClFN3O3・H2SO4・H2
Ｏとして
計算値 Ｃ：42.37 Ｈ：4.39 Ｎ：8.72
実測値 Ｃ：42.49 Ｈ：4.52 Ｎ：8.80
〔発明の効果〕
試験例１ 抗菌スペクトル
抗菌力は日本化学療法学会指定の方法に準じて
測定した。その結果を表１および２に示す。
本発明化合物（実施例25）は、いずれの対照薬
と比較しても、嫌気性菌及びグラム陽性菌の標準
株及び臨床分離株に対してより強い活性を示し
た。また、グラム陰性菌においては特に緑膿菌に
対して、より優れた活性を示した。[Formula]), 1620 (C=O) H-NMR (inCDCl 3 , ppm): 8.86 (1H, s),
7.94 (1H, d, J = 13.18Hz), 4.60~4.00 (1H,
m), 3.96-3.10 (4H, m), 2.50-1.60 (3H, m),
1.446 (9H, s), 1.30-0.80 (4H, m) Example 25 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
Synthesis of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 7-[3-(t-butoxycarbonylamino)-
1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
Dissolve 430 mg of oxo-3-quinolinecarboxylic acid in a mixture of 5 ml of methanol and 5 ml of concentrated hydrochloric acid, and
Stir for a minute. Add concentrated ammonia water to the reaction solution
The pH was set to about 7, the precipitated crystals were collected by filtration, thoroughly washed with water, then with methanol, and the mixture was washed with chloroform: methanol:
Recrystallization from concentrated aqueous ammonia gave 110 mg of the desired product as milky white powder crystals. Melting point 253-258°C (decomposition). Elemental analysis value (%): Calculated value as C 17 H 17 ClFN 3 O 3 C: 55.82, H: 4.68, N: 11.49 Actual value C: 56.09, H: 4.82, N: 11.46 Example 26 7-(3- Acetamide-1-pyrrolidinyl)-8
Synthesis of -chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro- 4-oxo-3-
1 g of quinoline carboxylic acid to 10 g of anhydrous acetonitrile
ml, 3-acetamidopyrrolidine 0.64g and
0.51 g of DBU was successively added and refluxed for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 20 ml of chloroform and washed with 10 ml of a 10% aqueous citric acid solution. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized from methanol to obtain 1.2 g of the desired product as yellow-white prism crystals. Melting point 210-212℃ Elemental analysis value (%): C 19 H 19 ClFN 3 O 4・1/4H 2 O Calculated value C: 55.35 H: 4.77 N: 10.19 Analysis value C: 55.39 H: 4.68 N: 10.12 Example 27 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
Synthesis of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 7-(3-acetamido-1-pyrrolidyl)-8-
Chloro-1-cyclopropyl-6-fluoro-
20 ml of an aqueous solution containing 0.8 g of sodium hydroxide was added to 0.8 g of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and the mixture was refluxed for 5 hours. The reaction solution was neutralized with acetic acid, and the precipitated crystals were collected by filtration. The crystals were washed with water, dried, and recrystallized from a mixed solution of methanol, chloroform, and concentrated aqueous ammonia to obtain 0.41 g of the desired product in the form of white flaky crystals. Melting point 238-240℃ (decomposition) Elemental analysis value (%): C 17 H 17 ClFN 3 O 3 1/2H 2 O Calculated value C: 54.48 H: 4.84 N: 11.21 Analysis value C: 54.44 H: 4.78 N: 11.20 Example 28 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
Synthesis of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
0.6 g of quinoline carboxylic acid, 6 ml of anhydrous acetonitrile, 0.35 g of 3-aminopyrrolidine and 0.31 DBU
g were added one after another and the mixture was refluxed for 1 hour. Here, another 3-
0.2 g of aminopyrrolidine was added and the mixture was refluxed for 2 hours. After cooling, the precipitated crystals were collected by filtration, dissolved in 9 ml of an aqueous solution containing 0.12 g of sodium hydroxide, and neutralized with acetic acid. The precipitated crystals were collected by filtration, washed with water, and further washed with acetonitrile to obtain 0.52 g of the desired product as a colorless powder. Melting point 237-238℃ (decomposition) Elemental analysis value (%): C 17 H 17 ClFN 3 O 3・H 2 O Calculated value C: 53.20 H: 4.99 N: 10.95 Analysis value C: 52.97 H: 4.62 N: 10.83 Implementation Example 29 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
Synthesis of 1,4-dihydro-4-oxo-3-quinolicarboxylic acid hydrochloride 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl- in 2 ml of ethanol
6-Fluoro-1,4-dihydro-4-oxo-
Add 100ml of 3-quinolinecarboxylic acid and suspend.
Add ethanol/hydrochloric acid (7.0 mmoleHCl/ml) to this.
0.2 ml of EtOH) was added. Next, this was concentrated, and the residue was recrystallized from methanol to obtain 79 mg of the target product in pale yellow prismatic crystals. Melting point 263-265℃ (decomposition) Elemental analysis value (%): C 17 H 17 ClFN 3 O 3・HCl Calculated value C: 50.76 H: 4.51 N: 10.45 Analysis value C: 50.50 H: 4.44 N: 10.38 Example 30 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-
Synthesis of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid methanesulfonate 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,
Add 200 mg of 4-dihydro-4-oxo-3-quinolinecarboxylic acid to a mixture of 1 ml of acetic acid and 10 ml of water,
To this was added 0.1 ml of methanesulfonic acid. After concentrating the reaction solution, 10 ml of ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed with ethanol and ether sequentially to obtain 116 mg of the desired product as yellow prism crystals. Melting point 234-235℃ Elemental analysis value (%): C 17 H 17 ClFN 3 O 3・CH 4 SO 3・
Calculated value as 1/2H 2 O C: 45.91 H: 4.71 N: 8.92 Actual value C: 45.70 H: 4.66 N: 8.86 Similarly, 7-(3-amino-1-pyrrolidinyl)-8-chloro-1- cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-3-
Quinolinecarboxylic acid paratoluenesulfonate was obtained. Melting point 168-170℃ Elemental analysis value (%): C 17 H 17 ClFN 3 O 3・C 7 H 8 SO 3・
Calculated value as H 2 O C: 51.85 H: 4.89 N: 7.56 Actual value C: 52.01 H: 4.64 N: 7.64 Example 31 -(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6 -Fluoro-1,
Synthesis of 4-dihydro-4-oxo-3-quinolinecarboxylic acid sulfate 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,
Add 160 mg of 4-dihydro-4-oxo-3-quinolinecarboxylic acid to 3 ml of an aqueous solution containing 0.2 ml of acetic acid,
To this was added 3 drops of concentrated sulfuric acid. The reaction solution was cooled in an ice bath, and the precipitated crystals were collected by filtration and washed successively with ethanol and ether to obtain 150 mg of the desired product as yellow needle-like crystals. Melting point 220-223℃ (decomposition) Elemental analysis value (%): C 17 H 17 ClFN 3 O 3・H 2 SO 4・H 2
Calculated value as O C: 42.37 H: 4.39 N: 8.72 Actual value C: 42.49 H: 4.52 N: 8.80 [Effect of the invention] Test example 1 Antibacterial spectrum Antibacterial activity was measured according to the method specified by the Japanese Society of Chemotherapy. The results are shown in Tables 1 and 2. The compound of the present invention (Example 25) showed stronger activity against standard strains and clinical isolates of anaerobic bacteria and Gram-positive bacteria than any of the control drugs. It also showed superior activity against Gram-negative bacteria, especially Pseudomonas aeruginosa.
【表】【table】
【表】【table】
【表】
試験例２ 耐性菌発生頻度
各菌株をミユーラー・ヒントンブロス
（MHB）に接種し、37℃で一夜培養後、その0.1
mlを10ml加Ｌ型試験管に接種し、37℃、６時間振
盪培養した。それを3000rpm、15分間遠心し、集
めた菌体を５mlのMHBに再浮遊し、使用菌液と
した。各化合物を１，２，４，8MICを含むミユ
ーラー・ヒントン平板培地を作成し、この平板培
地に先に調整した菌液0.1mlを塗布し、37℃、48
時間培養した。培養後成育したコロニー数を計数
し、その数を接種した菌液の総生菌数（c.f.u／
0.1ml）で割ることにより耐性菌出現頻度とした。
結果を表３に示す。[Table] Test Example 2 Frequency of occurrence of resistant bacteria Each strain was inoculated into Mueller-Hinton broth (MHB), and after culturing overnight at 37°C, 0.1
ml was inoculated into a 10 ml L-shaped test tube, and cultured with shaking at 37°C for 6 hours. It was centrifuged at 3000 rpm for 15 minutes, and the collected cells were resuspended in 5 ml of MHB to prepare a working cell solution. A Mueller-Hinton plate medium containing 1, 2, 4, and 8 MICs of each compound was prepared, and 0.1 ml of the previously prepared bacterial solution was applied to this plate medium.
Cultured for hours. After culturing, count the number of grown colonies and calculate the number as the total number of viable bacteria (cfu/cfu/
The frequency of appearance of resistant bacteria was determined by dividing by 0.1ml).
The results are shown in Table 3.
【表】
本発明化合物は4MICまたは8MIC濃度で耐性
株の出現は認められず対照薬物に比べ耐性菌の出
現頻度はかなり低いものであつた。
試験例３ マウス感染症に対する治療効果
１群５匹のICRマウスを用いて腹腔内に感染菌
を注入し、その１時間後に薬物を５用量それぞれ
１回経口投与し、薬物用量とマウスの生存率のカ
ーブから50％の動物が死を逃れ治癒する用量
（ED50）を求めた。表４にその結果を示す。
本発明化合物はいずれの感染菌に対しても、対
照薬物より非常に優れた防禦効果を示した。特に
肺炎球菌による感染症では、他の比較薬物は治療
効果を示さなかつたが、本発明化合物は有効であ
つた。[Table] With the compound of the present invention, no resistant strains were observed at a concentration of 4MIC or 8MIC, and the frequency of appearance of resistant bacteria was considerably lower than that of the control drug. Test Example 3 Therapeutic effect on mouse infections Infectious bacteria were injected intraperitoneally using 5 ICR mice in a group, and 1 hour later, 5 doses of the drug were administered orally once each, and the drug dose and survival rate of the mice were evaluated. The dose ( ED50 ) at which 50% of the animals escaped death and was cured was determined from the curve. Table 4 shows the results. The compound of the present invention showed a much better protective effect than the control drug against any of the infectious bacteria. In particular, for infections caused by pneumococci, other comparative drugs showed no therapeutic effect, but the compounds of the present invention were effective.
【表】
試験例４ 嫌気性菌によるラツト肉芽嚢内感染症
治療効果
ウイスター系ラツトをエーテル麻酔下、背部皮
下に0.45μmのミリポアフイルターで滅菌した空
気20mlを注射器で注入し、ポーチを作成した。引
き続き、このポーチ内に１％クロトン油加オリー
ブ油１mlを注入した。この２日後にポーチ内の空
気を抜いた。実験開始後８日目にバクテロイデ
ス・フラギリス（B.fragilis ２）の菌液（106
cfu／ml）0.5mlをグラニユローマ・ポーチ内に接
種し、２時間後に薬物を投与した。
薬物投与後、０，６，24時間目にポーチ内の浸
出液をサンプリングし、生菌数をカウントした。
１群３匹とし、実験期間中、摂取摂食は自由とし
た。結果を表５に示す。
従来キノロンカルボン酸系薬物は嫌気性菌に対
し弱い活性しか示さなかつた。しかし本発明化合
物は極めて強い抗菌活性を示し、本発明の大きな
特徴の一つでもある。表６からも明らかなように
本発明化合物は、嫌気性菌感染症に使用されてい
るセフオキシチン（CFX）、クリンダマイシン
（CLDM）、メトロニダゾール（MND）に劣らぬ
薬効を示した。[Table] Test Example 4 Effect of treating intragranulation sac infection in rats caused by anaerobic bacteria A Wistar rat was anesthetized with ether, and 20 ml of air sterilized with a 0.45 μm Millipore filter was injected subcutaneously into the back of the rat using a syringe to create a pouch. Subsequently, 1 ml of 1% croton oil was injected into the pouch. Two days later, the air inside the pouch was removed. On the 8th day after the start of the experiment, a bacterial solution of B. fragilis (10 6
cfu/ml) was inoculated into a granuloma pouch, and the drug was administered 2 hours later. The exudate in the pouch was sampled at 0, 6, and 24 hours after drug administration, and the number of viable bacteria was counted.
There were 3 animals in each group, and they were allowed to eat and drink freely during the experimental period. The results are shown in Table 5. Conventional quinolone carboxylic acid drugs have shown only weak activity against anaerobic bacteria. However, the compound of the present invention exhibits extremely strong antibacterial activity, which is one of the major features of the present invention. As is clear from Table 6, the compound of the present invention exhibited medicinal efficacy comparable to cefoxitin (CFX), clindamycin (CLDM), and metronidazole (MND), which are used for anaerobic bacterial infections.
【表】
試験例５ 急性毒性試験
雄性マウスにおける静脈内投与による急性毒性
試験では本発明化合物はシプロフロキサシンと同
程度のLD50値を示した。[Table] Test Example 5 Acute toxicity test In an acute toxicity test in male mice by intravenous administration, the compound of the present invention showed an LD 50 value comparable to that of ciprofloxacin.
【表】
試験例６ 亜急性毒性試験
雄性ビーグル犬（10ケ月令、ｎ＝３）に実施令
25化合物を20mg／Kg／日８日間、続いて50mg／
Kg／日７日間の計15日間連続経口投与した。
その結果、体重推移、一般状態、血液学的検
査、血液生化学的検査等において特に問題となる
異常はみられなかつた。
試験例７ 薬物の体内動態
１ ラツト
実施例25化合物およびシプロフロキサシンのそ
れぞれ10mg／Kgをラツトに経口投与し、経時的に
採血し、バイオアツセイ法にて薬物濃度を測定し
た。また一方、薬物投与後24時間までの尿および
胆汁中への排泄率も測定した。その結果を第１図
および表７に示す。
本発明化合物はシプロフロキサシンよりも約３
倍高い血中濃度を示した。また尿中排泄率はシプ
ロフロキサシンより2.4倍、胆汁排泄率も７倍優
れていた。[Table] Test Example 6 Subacute toxicity test Conducted on male beagle dogs (10 months old, n=3)
25 compounds at 20 mg/Kg/day for 8 days, followed by 50 mg/Kg/day for 8 days.
Kg/day was orally administered for 7 days, for a total of 15 days. As a result, no particularly problematic abnormalities were observed in weight changes, general conditions, hematological tests, blood biochemical tests, etc. Test Example 7 Drug Kinetics 1 Rats 10 mg/Kg of each of the compound of Example 25 and ciprofloxacin were orally administered to rats, blood was collected over time, and drug concentrations were measured by bioassay. On the other hand, the excretion rate into urine and bile up to 24 hours after drug administration was also measured. The results are shown in FIG. 1 and Table 7. The compound of the present invention is about 3 times more active than ciprofloxacin.
The blood concentration was twice as high. The urinary excretion rate was 2.4 times better than ciprofloxacin, and the biliary excretion rate was also 7 times better.
【表】
２ イヌ
実施例25の化合物をビーグル犬に２mg／Kg経口
および静脈内投与し、それぞれの血中濃度を高速
液体クロマトグラフ法により測定した。その結果
を第２図に示す。
静脈投与による血中濃度と経口投与による血中
濃度はほぼ等しく、本発明化合物の経口吸収が非
常に優れている事を示す。
また一方、尿中代謝物を検索した結果、ほとん
ど代謝を受ける事なく未変化体のまま排泄されて
いる事が分つた。
試験例８ 変異原性試験
抗菌剤の変異原性を細菌を用いて試験する場
合、抗菌剤が試験に対し生育阻害を示すため、十
分な検討ができなかつた。そこで、より高い薬剤
濃度での試験も行なうため、被験化合物に対し耐
性を有し、かつ本来の試験菌の特性を失つていな
い株を作成した。この株を用いた場合、親株に比
べ約10倍高濃度の薬剤でも試験が可能となつた。
実施例25の化合物とシプロフロキサシンについ
て復帰変異試験を行なうと、サルモネラ・チフイ
リウム（Salmonella typhimurinm TA98）のナ
リジクス酸（Nalidixic acid）耐性株（以下nal
と示す）を用いた時、測定可能な範囲内で薬物代
謝活性化処理の有無にかかわらずシプロフロキサ
シンは溶媒対照の約２倍のHis+復帰コロニーが
認められ変異原性を有することが推定されたが、
実施例25の化合物ではHis+復帰コロニーの増加
は全く認められなかつた（表８）。[Table] 2 Dogs The compound of Example 25 was orally and intravenously administered to beagle dogs at 2 mg/Kg, and the respective blood concentrations were measured by high performance liquid chromatography. The results are shown in FIG. The blood concentration after intravenous administration and the blood concentration after oral administration were almost equal, indicating that the compound of the present invention has excellent oral absorption. On the other hand, as a result of searching for urinary metabolites, it was found that the metabolites were excreted unchanged without undergoing much metabolism. Test Example 8 Mutagenicity Test When testing the mutagenicity of an antibacterial agent using bacteria, it was not possible to conduct a sufficient study because the antibacterial agent inhibited the growth of the test. Therefore, in order to conduct tests at higher drug concentrations, we created a strain that is resistant to the test compound and does not lose the characteristics of the original test bacterium. Using this strain, it became possible to test drugs at approximately 10 times higher concentrations than the parent strain. When a reverse mutation test was conducted on the compound of Example 25 and ciprofloxacin, a nalidixic acid-resistant strain (hereinafter referred to as nal) of Salmonella typhimurinm TA98 was conducted.
), ciprofloxacin was found to have mutagenicity, as approximately twice as many His + revertant colonies were observed as in the solvent control, regardless of the presence or absence of drug metabolism activation treatment, within a measurable range. It was estimated, but
No increase in His + revertant colonies was observed with the compound of Example 25 (Table 8).
【表】【table】
【表】
試験例９ クラミジア・トラコマテスに対する抗
菌活性
マツコイセルを用いてサイクロヘキシド処理し
た組織培養でマイクロトラツプの蛍光抗体法で抗
菌活性を測定した。結果を表９に示す。[Table] Test Example 9 Antibacterial activity against Chlamydia trachomatis Antibacterial activity was measured using microtrap fluorescent antibody method using tissue culture treated with cyclohexide using Matsukoi cell. The results are shown in Table 9.
【表】
本発明化合物は従来のキノロンカルボン酸系化
合物では強い活性を示さないクラミジアに対して
も強力な活性を示した。
試験例10 マイコプラズマに対する抗菌活性
実施例25の化合物のマイコプラズマに対する抗
菌活性を表10に示す。本発明化合物は強い活性を
示した。[Table] The compound of the present invention showed strong activity against chlamydia, which did not show strong activity with conventional quinolone carboxylic acid compounds. Test Example 10 Antibacterial activity against mycoplasma Table 10 shows the antibacterial activity of the compound of Example 25 against mycoplasma. The compound of the present invention showed strong activity.
第１図は本発明の実施例25の化合物および比較
例化合物シプロヘキサシン（CFLX）をラツトに
10mg／Kg経口投与したときの血中濃度の経時変化
を比較して示した図表である。第２図は本発明の
実施例25の化合物をビーグル犬に２mg／Kg経口投
与および静脈内投与したしたときの血中濃度
（μm／ml）の経時変化をそれぞれ示した図表であ
る。
Figure 1 shows the compound of Example 25 of the present invention and the comparative example compound ciprohexacin (CFLX) in rats.
This is a chart showing a comparison of changes in blood concentration over time when 10 mg/Kg was orally administered. FIG. 2 is a chart showing the time course of the blood concentration (μm/ml) when 2 mg/Kg of the compound of Example 25 of the present invention was administered orally and intravenously to beagle dogs.
Claims (1)
水和物ならびにその塩。 ２ 一般式〔〕 〔式中、Ｒは水素または低級アルキル基を、Ｘ
はハロゲンを示す〕 で表わされる化合物と一般式〔〕 〔式中、R1，R2はそれぞれ独立して水素また
はアミノ基の保護基を示すか、共同して保護基を
示す〕 で表わされる化合物を縮合させ、要すればアミノ
基の保護基を脱離および／またはカルボン酸エス
テルを加水分解させることを特徴とする式〔〕 で表わされるキノロンカルボン酸誘導体及びその
水和物ならびにその塩の製造方法。 ３ 式〔〕 で表わされるキノロンカルボン酸誘導体及びその
水和物ならびにその塩を有効成分とする抗菌剤。[Claims] 1 Formula [] Quinolone carboxylic acid derivatives, hydrates thereof, and salts thereof. 2 General formula [] [In the formula, R is hydrogen or a lower alkyl group,
represents a halogen] Compounds represented by the general formula [] [In the formula, R 1 and R 2 each independently represent hydrogen or an amino group-protecting group, or jointly represent a protecting group] The compounds represented by the following are condensed, and if necessary, an amino group-protecting group is added. Formula characterized by elimination and/or hydrolysis of carboxylic acid ester [] A method for producing a quinolone carboxylic acid derivative, a hydrate thereof, and a salt thereof. 3 formula [] An antibacterial agent containing a quinolone carboxylic acid derivative represented by the formula, its hydrate, and its salt as an active ingredient.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61022296A JPS61225181A (en) | 1986-02-04 | 1986-02-04 | Quinolonecarboxylic acid derivative and production thereof |
| AU54272/86A AU5427286A (en) | 1985-03-08 | 1986-03-04 | 7-(1-pyrrolidinyl)-3-quinolinecarboxylic acid derivatives |
| HU86888A HUT40639A (en) | 1985-03-08 | 1986-03-04 | Process for producing quinolon-carboxylic acid derivative and pharmaceutical composition containing them |
| EP86102938A EP0195316A1 (en) | 1985-03-08 | 1986-03-06 | Quinolonecarboxylic acid derivatives |
| FI860950A FI85698C (en) | 1985-03-08 | 1986-03-06 | FOERFARANDE FOER FRAMSTAELLNING AV ETT FARMACEUTISKT AKTIVT KINOLONKARBONSYRADERIVAT. |
| NO860870A NO165071C (en) | 1985-03-08 | 1986-03-07 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 7- (3-AMINO-1-PYRROLIDINYL) -8-CHLORO-1-CYCLOPROPYL-6-FLUORO-1,4, -DIHYDRO-4-OXO-3-CHINOLINE-CARBOXYL. |
| DK103986A DK161383C (en) | 1985-03-08 | 1986-03-07 | QUINOLINCARBOXYLIC ACID DERIVATIVE, PROCEDURES FOR PREPARING IT, AND ANTIBACTERIAL PHARMACEUTICAL PREPARATIONS CONTAINING THIS |
| PT82153A PT82153B (en) | 1985-03-08 | 1986-03-07 | 7- (3-AMINO-1-PYRROLIDINYL) -8-CHLORO-1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-3-KINOLINE-CARBOXYLIC ACID AND ITS HYDRATES AND SALTS PHARMACEUTICALLY ACCEPTED |
| MX1780A MX162668A (en) | 1985-03-08 | 1986-03-07 | PROCEDURE FOR PREPARING A CHINOLONCARBOXYLIC ACID DERIVATIVE |
| CN86102363A CN1012613B (en) | 1985-03-08 | 1986-03-07 | Process for prepn. of quinonecarboxylic acid derivative |
| ES552802A ES8704932A1 (en) | 1985-03-08 | 1986-03-07 | Quinolonecarboxylic acid derivatives. |
| KR1019860001648A KR930011036B1 (en) | 1985-03-08 | 1986-03-08 | Process for prepration of quinolonecarboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61022296A JPS61225181A (en) | 1986-02-04 | 1986-02-04 | Quinolonecarboxylic acid derivative and production thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60046216A Division JPS61205258A (en) | 1985-03-08 | 1985-03-08 | Quinolonecarboxylic acid derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61225181A JPS61225181A (en) | 1986-10-06 |
| JPH0564955B2 true JPH0564955B2 (en) | 1993-09-16 |
Family
ID=12078778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61022296A Granted JPS61225181A (en) | 1985-03-08 | 1986-02-04 | Quinolonecarboxylic acid derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61225181A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| CZ299554B6 (en) * | 1997-09-15 | 2008-09-03 | The Procter & Gamble Company | Compound with quinolone structure, pharmaceutical composition containing thereof and use of such compound |
| ATE507219T1 (en) | 2006-03-28 | 2011-05-15 | Warner Chilcott Co Llc | MALATE SALTS AND POLYMORPHS OF (3S,5S)-7-Ä3-AMINO-5-METHYL-PIPERIDINYLÜ-1-CYCLOPROPYL-1,4-DIHYDRO 8-METHOXY-4-OXO-3-QUINOLINECARBONIC ACID |
| KR101084521B1 (en) | 2006-03-28 | 2011-11-18 | 워너 칠콧 컴퍼니 엘엘씨 | A coupling process for preparing quinolone intermediates |
| US8481526B2 (en) | 2009-03-25 | 2013-07-09 | Bausch & Lomb Incorporated | Fluoroquinolone carboxylic acid molecular crystals |
| US8518935B2 (en) | 2009-12-11 | 2013-08-27 | Bausch & Lomb Incorporated | Amorphous besifloxacin solid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS611667A (en) * | 1984-06-04 | 1986-01-07 | バイエル・アクチエンゲゼルシヤフト | 7-amino-1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-3- quinoline carboxylic acids, manufacture and antibacterials containing them |
-
1986
- 1986-02-04 JP JP61022296A patent/JPS61225181A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS611667A (en) * | 1984-06-04 | 1986-01-07 | バイエル・アクチエンゲゼルシヤフト | 7-amino-1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-3- quinoline carboxylic acids, manufacture and antibacterials containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61225181A (en) | 1986-10-06 |
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