CN102329315A - Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof - Google Patents
Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof Download PDFInfo
- Publication number
- CN102329315A CN102329315A CN201110207280A CN201110207280A CN102329315A CN 102329315 A CN102329315 A CN 102329315A CN 201110207280 A CN201110207280 A CN 201110207280A CN 201110207280 A CN201110207280 A CN 201110207280A CN 102329315 A CN102329315 A CN 102329315A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- tetramethyleneimine
- carboxylic acid
- aminomethyl
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- -1 nalidixic carboxylic acid compound Chemical class 0.000 title claims abstract description 25
- 125000001153 fluoro group Chemical group F* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 44
- 239000011737 fluorine Substances 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003826 tablet Substances 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical group FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000002662 enteric coated tablet Substances 0.000 claims description 2
- 239000007941 film coated tablet Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 239000007940 sugar coated tablet Substances 0.000 claims description 2
- 229940124350 antibacterial drug Drugs 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 241000894006 Bacteria Species 0.000 description 18
- 239000003814 drug Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 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 14
- 230000000694 effects Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 11
- ZRCVYEYHRGVLOC-UHFFFAOYSA-N 7-[3-(aminomethyl)-4-methoxyimino-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(CN)C(=NOC)CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 7
- 229960003405 ciprofloxacin Drugs 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 206010041925 Staphylococcal infections Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940124307 fluoroquinolone Drugs 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 5
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- VPJVZUREKATUEU-UHFFFAOYSA-N C(C)Br.[F] Chemical compound C(C)Br.[F] VPJVZUREKATUEU-UHFFFAOYSA-N 0.000 description 3
- IXIOFVBDUCUJMM-UHFFFAOYSA-N CS(=O)(=O)O.CS(=O)(=O)O.C=N.C=N.C=N.C=N Chemical compound CS(=O)(=O)O.CS(=O)(=O)O.C=N.C=N.C=N.C=N IXIOFVBDUCUJMM-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 231100000460 acute oral toxicity Toxicity 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 235000014347 soups Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004278 EU approved seasoning Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 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
- 229960000210 nalidixic acid Drugs 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- ZZTDQTXGRVHPTQ-UHFFFAOYSA-N 7-[3-(aminomethyl)pyrrolidin-1-yl]-3-fluoro-8-methoxy-1H-quinolin-2-one Chemical compound NCC1CN(CC1)C1=CC=C2C=C(C(NC2=C1OC)=O)F ZZTDQTXGRVHPTQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical group FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 235000007244 Zea mays Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 description 1
- 229960003170 gemifloxacin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- OUHCLAKJJGMPSW-UHFFFAOYSA-L magnesium;hydrogen carbonate;hydroxide Chemical compound O.[Mg+2].[O-]C([O-])=O OUHCLAKJJGMPSW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 231100000668 minimum lethal dose Toxicity 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 235000020985 whole grains Nutrition 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
Abstract
The invention provides a fluoro methoxyimino-substituted nalidixic carboxylic acid compound and a preparation method thereof as well as an antibacterial drug composition as shown in a formula (I). The structure of a compound or medicinal salt and hydrate thereof as shown in the formula (I) is as follows in the specification.
Description
Technical field
The invention belongs to the medical chemistry field, relate to and have active naphthyridon carboxylic acid verivate of anti-gram-positive resistant organism or its preparation method, and the antibacterial combination that contains them; Specifically, relate to 7-[(3-methyl-) 3-aminomethyl-4-(fluorine methoxyimino)-tetramethyleneimine-1-yl] naphthyridon carboxylic acid compounds or its preparation method.
Background technology
From Nalidixic Acid (nalidixic acid in 1962; J.Med.Chem.1962; 5:1063) since the appearance; Quinolone (comprising a naphthyridines ketone) type medicine developed into the one type of wide spectrum that is only second to cynnematin at present, efficient, hypotoxic anti-infective chemotherapeutics (Chinese Journal of Pharmaceuticals 2010,41:456).Owing to be widely used and non-rational use of drug; Bacterium increases sharply to the resistance of this type medicine; Especially the continuous appearance of Pseudomonas aeruginosa in the gram-negative bacteria and the methicillin-resistant in gram positive organism gold Portugal bacterium (MRSA), methicillin-resistant form staph (MRSE), vancomycin-resistant enterococcus (VRE) and penicillin resistant streptococcus pneumoniae (PRSP) infection has become one of thorny problem that the clinicist faces.People press for and search out the Novel Quinolone class antimicrobial drug stronger to these resistant organism activity, to tackle these increasing drug-fast bacteria infections.
Nineteen ninety-five; Sanchez etc. have reported that the 7-position has five, the active (J.Med.Chem.1995 of synthetic and external biological of hexa-atomic nitrogen heterocyclic ring substituent a series of (5-amino-) 8-alkoxyl group fluoroquinolone compounds; 38:4478), wherein representative 7-(3-aminomethyl pyrrolidine-1-yl)-8-methoxy fluoroquinolone shows broad spectrum antibiotic activity.
Nineteen ninety-five, Chinese patent (CN:95107008.8 1995-06-15) discloses the fluoroquinolone compound with following general formula [A]:
And the substituent R in the mutual-through type
2Carried out definition widely, but R
2Do not comprise a methyl fluoride or difluoromethyl.
The outstanding representative of general formula [A] is to have succeeded in developing and by the FDA approval SB 265805 (gemifloxacin) in U.S.'s listing; It is except having broad spectrum of activity; Its outstanding advantage is other Comprecins that the activity to streptococcus pneumoniae is superior to having gone on the market; Its shortcoming is not strong to common clinically golden Portugal bacterium (comprising increasing MRSA) activity, thereby has limited its range of application clinically.
Nineteen ninety-five, Korean Patent 024002 (1995-08-31) discloses the fluoroquinolone compound with following general formula [B]:
And the substituent R in the mutual-through type
2Carried out definition widely, but R
2Do not comprise a fluorine-based or difluoromethyl.
The outstanding representative DW286 of general formula [B] is weaker than SB 265805 to the activity of gram-negative bacteria, but the activity of anti-gram positive organism is superior to SB 265805.It is reported that DW286 has stopped further research and development after accomplishing the I clinical trial phase.Agnogenio.
In order to overcome above-mentioned existing in prior technology defective, the inventor has carried out extensive studies, and design has been synthesized the 7-position and had the substituted tetramethyleneimine of one fluorine/difluoro methoxyimino-1-base naphthyridon carboxylic acid compounds, and has measured their anti-microbial activity.The final discovery; The 7-of bibliographical information different from the past [(3-methyl)-3-aminomethyl-4-(one fluorine/difluoro methoxyimino)-tetramethyleneimine-1-yl] naphthyridon carboxylic acid compounds has beyond thought strong anti-microbial activity to clinical important pathogenic bacteria; Compare with the carbostyril family antibacterial drugs that has gone on the market; It significantly has more superior anti-microbial activity; Especially be 2-＞521 times of contrast medicine CIPROFLOXACIN USP 24 to the external activity that comprises the golden Portugal bacterium of MRSA, the form staph that comprises MRSE and Pseudomonas aeruginosa, the 2-32 of SB 265805 doubly; To the activity in vivo of the golden bacterium MRSA10-2 of Portugal, form staph MRSE10-4 and Pseudomonas aeruginosa 10-1 be CIPROFLOXACIN USP 24 and SB 265805 1.4-6.1 doubly.
Summary of the invention
The purpose of this invention is to provide one type by the naphthyridon carboxylic acid compounds of general formula (I) expression or its pharmaceutical salts, hydrate,
Wherein:
R represents cyclopropyl, 2,4 difluorobenzene base;
R
1Represent H, CH
3
R
2Represent CH
2F, CHF
2
X represents H, F.
In the pyrrolidyl of general formula of the present invention (I) compound part, the carbon atom that links to each other with aminomethyl is a unsymmetrical carbon, therefore can R or S or R and the existence of S blended form, the present invention includes all these isomer and mixture.
In the pyrrolidyl part of general formula of the present invention (I) compound; Because the existence of 4-position oximido; Therefore general formula (I) compound can the E type or the form existence of Z type or E type and Z type mixture, and general formula of the present invention (I) compound comprises all these isomer and mixture.
Formula of the present invention (I) compound in pharmaceutically acceptable atoxic pharmaceutical salts; Comprise and mineral acid that the salt that example hydrochloric acid, sulfuric acid form is with organic acid; Salt like acetate, trifluoroacetic acid, Hydrocerol A, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, racemic melic acid, xitix or oxysuccinic acid formation; And amino acid, the salt that forms like L-Ala, aspartic acid, Methionin or and sulfonic acid, the salt that forms like methylsulfonic acid, tosic acid.
Formula of the present invention (I) compound also can solvolyte (like hydrate) form exist, therefore, these solvolytes (like hydrate) are also included within the compound of the present invention.
The present invention specifically comprises following compound, and their pharmaceutical salts, hydrate:
1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
The invention still further relates to the preparation method of formula (I) compound, shown in reaction scheme 1.
Reaction scheme 1:
In reaction scheme 1, R, R
1, R
2With X such as aforesaid definition; R
3Represent alkyl or aromatic base, be preferably phenyl.
Comprise the steps:
1) in non-proton dipole solvent, add alkali, in room temperature to 100 ℃, formula (II) compound, formula (III) compound and formula (IV) compound carried out condensation reaction 0.5～10 hour, the formula V compound.
Wherein:
R, R
1, R
2, R
3With X such as aforesaid definition.
This reaction is generally carried out in the presence of alkali.Under this situation, in order to improve the reaction efficiency of more expensive formula (III) compound, use excessive reactant formula (II) compound and (IV) compound, for example to relative initiator for waiting mole to 5 times of molar weights, preferred equimolar amount to 2 times molar weight.When using excess reactant formula (II) compound with (IV) compound, the unreacted mixture that stays after the reaction is recyclable and be reused for reaction.The non-proton dipole solvent that is used for this reaction is selected from N, dinethylformamide, DMAC N,N, DMSO 99.8MIN. or acetonitrile; Described alkali is selected from triethylamine, yellow soda ash, sodium hydrogencarbonate, salt of wormwood, sodium hydroxide or Pottasium Hydroxide.
2) place protonic solvent to add acid the formula V compound then, in room temperature to 60 ℃, stirring reaction 2～30 hours is removed blocking group, formula (I) compound.Be used for this reaction protonic solvent be selected from water, alcohol or alcohol-water mixed solvent; Described acid is selected from methylsulfonic acid, hydrochloric acid, trifluoracetic acid.
When 3) needing, formula (I) compound that obtains is converted into its pharmaceutical salts or hydrate.
Formula (II) compound as initiator is a known compound in the present invention, and can easily make by known method in the existing publication.For example: J.Med.Chem.1991,34,1142; US4704459; US5457104 etc.
Be chemical reagent commonly used as formula (IV) compound of initiator in the present invention, domestic have a supply of commodities.
According to the method shown in the reactions route 2, can prepare another initiator formula (III) compound of the present invention.
Reaction scheme 2:
In reaction scheme 2, R
1And R
2Like aforesaid definition.
Method shown in the following specific explanations reaction scheme 2.
N-Boc-3-cyanic acid-4-pyrrolidone (1) selective catalytic hydrogenation in the presence of Pd/C protects corresponding aminomethyl to get compound 2 with Boc subsequently, and the latter gets tetramethyleneimine oximate thing 3 (R with oxammonium hydrochloride generation condensation reaction in the presence of alkali (like pyridine, triethylamine)
1=H).On the other hand, 1 earlier gets methide 4 with methyl iodide generation nucleophilic substitution reaction, then successively through selective catalytic hydrogenation and with Boc protection aminomethyl get compound 5 and with the oxammonium hydrochloride generation condensation reaction oxime compounds 3 (R that must methylate
1=CH
3).Then 3 with fluorine monobromethane or freonll-11 (difluorochloromethane) substitution reaction take place and obtain one fluorine/difluoro methoxyimino tetramethyleneimine 6, remove two Boc down in acid (like methylsulfonic acid, hydrochloric acid, trifluoracetic acid) at last and protect basicly, promptly get formula (III) compound.
In reaction scheme 2, the compound 1 that is used as initiator is a known compound, and can easily make by known method in the existing publication.Q.Guo etc. for example, Eur.J.Med.Chem.2010,45:5498; Wan Zhilong etc., Chinese pharmaceutical chemistry magazine 2009,19:109.
For the The compounds of this invention of R or S configuration, can adopt this area routine techniques to split, or carry out with the raw material of corresponding configuration that hand-type is synthetic to be obtained.
The present invention also provides and contains as above defined formula (I) compound, or its pharmaceutical salts or its hydrate are as the antibacterial combination of activeconstituents.
The weight ratio of naphthyridon carboxylic acid compounds in compsn that pharmaceutical composition contains is 0.1～99.9%, and the weight ratio of medicine acceptable carrier in compsn is 0.1～99.9%.Pharmaceutical composition exists to be fit to medicinal dosage form.Medicinal preparation is tablet, capsule, granule, pill, powder, paste, suspensoid, injection, powder injection, suppository, creme, drops or patch.Wherein, said tablet is sugar coated tablet, film coated tablet, enteric coated tablet or slow releasing tablet; Said capsule is hard capsule, soft capsule, slow releasing capsule; Said powder injection is a lyophilized injectable powder.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound that contains in every dose is 0.1～1000mg; Said every dose refers to, and each preparation unit is like every of tablet; Capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when solid that is prepared into pulvis, tablet dispersion powder, capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation.Spendable solid carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5～70% micronize activeconstituents.Suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, the best oral solid formulation of representative such as pulvis, cachet and capsule.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injection formulations of parenteral administration can be water or water-propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. make the physiological condition that is suitable for live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can add an amount of tinting material, seasonings, stablizer and thickening material again through activeconstituents is dissolved in the water, prepare oral aqueous solution.Can micronized activeconstituents be dispersed in to prepare in viscous substance such as natural and synthetical glue, methylcellulose gum, Xylo-Mucine and other the known suspension agent and be suitable for oral aqueous suspensions.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in 1～800mg scope according to the effectiveness of selected activeconstituents.
When formula of the present invention (I) active compound is used as the medicine of treatment infectation of bacteria, preferably give the amount of 6～14mg/kg body weight in the fs.But dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can confirm to be suitable for the preferred dose of certain situation by ordinary method.Generally, the amount of begin treatment is lower than the optimal dose of activeconstituents, increases dosage then gradually, up to reaching optimum therapeuticing effect.For treatment needs, but total per daily dose single administration or branch administration for several times.
As stated; The compounds of this invention has beyond thought strong anti-microbial activity to important clinical bacteria; Compare with the carbostyril family antibacterial drugs that has gone on the market; It significantly has more superior anti-microbial activity, is 2-＞521 times of contrast medicine CIPROFLOXACIN USP 24 to the external activity that comprises the golden Portugal bacterium of MRSA, the form staph that comprises MRSE and Pseudomonas aeruginosa especially, and the 2-32 of SB 265805 doubly; To the activity in vivo of the golden bacterium MRSA10-2 of Portugal, form staph MRSE10-4 and Pseudomonas aeruginosa 10-1 be CIPROFLOXACIN USP 24 and SB 265805 1.4-6.1 doubly.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1 1-(N-Boc)-4-(N-Boc) aminomethyl-tetramethyleneimine-3-ketone
With 1-(N-Boc)-4-cyanic acid-tetramethyleneimine-3-ketone (42.0g, 0.2mol) with (Boc)
2O (43.6g; 0.2mol) be dissolved in methyl alcohol (500mL), to wherein adding 5%Pd/C (8.2g), stirred overnight at room temperature under the 70ps i hydrogen pressure; Elimination Pd/C; Filtrate decompression concentrates, and resistates separates (with sherwood oil and ETHYLE ACETATE gradient elution) purifying through column chromatography, gets light yellow oil 31.5g (yield: 50%).
1H?NMR(DMSO-d
6，400MHz)δ
ppm：6.98(1H，s)，3.80-2.79(7H，m)，1.42(9H，s)，1.38(9H，s)。ESI-MS(m/z)：315(M+H)
+，337(M+Na)
+。
Embodiment 2 1-(N-Boc)-3-(N-Boc) aminomethyl-4-hydroxyl imide base tetramethyleneimine
Under the room temperature, (41.7g, (40.2mL, 0.5mol), (94.2g, 0.3mol), equality of temperature stirs 1h to add embodiment 1 compound behind the stirring 10min to add pyridine in methanol solution 0.6mol) to oxammonium hydrochloride.Concentrating under reduced pressure, resistates is dissolved in ETHYLE ACETATE, uses 10% Glacial acetic acid min. 99.5, saturated sodium bicarbonate aqueous solution and water washing successively, anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates, and to wherein adding sherwood oil (500mL), reflux is placed room temperature, has a large amount of solids to separate out.Filter, filter cake use petroleum ether, dry must white solid 80.0g (yield: 80%), mp:138-140 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：10.91(1H，s)，6.94(1H，s)，3.92-3.85(2H，m)，3.54-3.48(1H，m)，3.32-3.12(2H，m)，3.00-3.90(2H，m)，1.44(18H，s)。MS-ESI(m/z)：330(M+H)
+。
Embodiment 3 1-(N-Boc)-4-methyl-4-Cyanopyrolidine-3-ketone
Under the room temperature, to 1-(N-Boc)-4-cyanic acid-tetramethyleneimine-3-ketone (21.0g, 0.1mol) and Anhydrous potassium carbonate (41.7g, (8.2mL 0.12mol), drip to finish (30min) equality of temperature and stirs 3h to drip methyl iodide in anhydrous propanone 0.3mol) (800mL) solution.Filter, filtrate decompression concentrates, and adds methylene dichloride (200mL) dissolving, washing (200mL * 3), concentrating under reduced pressure.In resistates, add sherwood oil (300mL), reflux 1h filters, after filter cake is washed with an amount of sherwood oil, and with the mixed solvent recrystallization of sherwood oil and ETHYLE ACETATE, must off-white color solid 18.8g (yield: 84%), mp:71-73 ℃.
1H?NMR(CDCl
3，400MHz)δ
ppm：4.15-3.69(4H，m)，1.58(3H，s)，1.49(9H，s)。ESI-MS(m/z)：225(M+H)
+。
Embodiment 4 1-(N-Boc)-4-methyl-4-(N-Boc) aminomethyl pyrrolidine-3-ketone
With embodiment 3 compounds (11.2g, 50mmol) with (Boc)
2O (10.9g 50mmol) is dissolved in the methyl alcohol (200mL), and adding Pd/C (5%, 2.0g), stirred overnight at room temperature under the 75psi hydrogen pressure.Elimination Pd/C, filtrate decompression concentrates, and adds sherwood oil (500mL) in the resistates, reflux 30min.After filtered while hot, filter cake are washed with sherwood oil, with the mixed solvent recrystallization of sherwood oil and ETHYLE ACETATE, off-white color solid 12.8g (yield: 78%), mp:106-108 ℃.
1H NMR (CDCl
3, 400MHz) δ
Ppm: 4.77 (1H, brs), 3.83 (2H, s), 3.64-3.26 (4H, m), 1.50 (9H, s), 1.43 (9H, s), 1.15 (3H, s).ESI-MS(m/z)：329(M+H)
+。
Embodiment 5 1-(N-Boc)-3-methyl-3-(N-Boc) aminomethyl-4-hydroxyl imide base tetramethyleneimine
Under the stirring at room, (2.5g, (2.4mL 30mmol), stirs 10min to add pyridine in methyl alcohol 36mmol) (100mL) solution to oxammonium hydrochloride.(10min drips complete for 9.8g, methyl alcohol 30mmol) (50mL), and equality of temperature stirs 1h in this solution, to drip embodiment 4 compounds.Concentrating under reduced pressure adds methylene dichloride dissolving (100mL), washing, anhydrous sodium sulfate drying in the resistates.Filter, filtrate decompression concentrates, and resistates adds sherwood oil (300mL), reflux 1h, and filtered while hot, filter cake is used ETHYLE ACETATE and petroleum ether respectively, dry off-white color solid 9.5g (yield: 93%), mp:149-150 ℃.
1H?NMR(CDCl
3，400MHz)δ
ppm：10.86(1H，brs)，6.94(1H，brs)，3.96(2H，s)，3.50-2.98(4H，m)，1.40(9H，s)，1.36(9H，s)，1.06(3H，s)。ESI-MS(m/z)：344(M+H)
+，366(M+Na)
+。
Embodiment 6 1-(N-Boc)-3-methyl-3-(N-Boc) aminomethyl-4-one fluorine methoxy imino tetramethyleneimine
Under the stirring at room, to embodiment 5 compounds (3.4g, 10mmol) and Tetrabutyl amonium bromide (0.6g; Toluene 2mmol) (100mL) solution adds the 50%NaOH aqueous solution of 8 times of molar weights; (1.2g, 11mmol), equality of temperature stirred 5 hours to feed the fluorine monobromethane in the stirring downhill reaction mixture.Tell organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates, and gets colorless oil 3.8g (quantitatively).
1H?NMR(CDCl
3，400MHz)δ
ppm：7.08(1H，br?s)，5.66(2H，t，J＝56.0Hz)，4.09(2H，s)，3.53-2.97(4H，m)，1.40(9H，s)，1.36(9H，s)，1.09(3H，s)。ESI-MS(m/z)：376(M+H)
+。
Embodiment 7 1-(N-Boc)-3-(N-Boc) aminomethyl-4-one fluorine methoxy imino tetramethyleneimine
With the preparation method of embodiment 6 compounds, embodiment 2 compounds and fluorine monobromethane react colorless oil (quantitatively).
1H?NMR(400MHz，DMSO-d
6)δ
ppm：7.07(1H，br?s)，5.68(2H，d，J＝56Hz)，4.05(2H，brs)，3.57(1H，brs)，3.31-3.27(1H，m)，3.19(1H，brs)，3.10-3.03(2H，m)，1.45(9H，s)，1.40(9H，s)。MS-ESI(m/z)：362.2(M+H)
+。
Embodiment 8 1-(N-Boc)-3-(N-Boc) aminomethyl-4-difluoro methoxy imino tetramethyleneimine
Under the stirring at room; To embodiment 2 compounds (6.6g, 20mmol) and Tetrabutyl amonium bromide (1.2g, toluene 4mmol) (150mL) solution add the 50%NaOH aqueous solution of 8 times of molar weights; Stir in the downhill reaction mixture and feed freonll-11 (F2CHCl) gas, 80 ℃ were stirred 10 hours.Tell organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates, and silica gel column chromatography gets colorless oil 2.27g (yield: 30%).
1H?NMR(400MHz，DMSO-d
6)δ
ppm：7.07(1H，brs)，7.06(1H，t，J＝72Hz)，4.09(2H，brs)，3.58(1H，brs)，3.32-3.28(1H，m)，3.20(1H，brs)，3.11-3.07(2H，m)，1.41(9H，s)，1.37(9H，s)。MS-ESI(m/z)：380.4(M+H)
+。
Embodiment 9 3-aminomethyl-4-one fluorine methoxy imino-tetramethyleneimine dimethanesulfonate
Under the stirring at room, (7.2g, (5.76g, 60mmol), equality of temperature stirs 24h to add methylsulfonic acid in methyl alcohol 20mmol) (50mL) solution to embodiment 7 compounds.The solid that filtration is separated out, vacuum-drying, white solid 4.94g (yield: 70%), mp:137-139 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：9.32(2H，brs)，7.99(3H，brs)，5.74(2H，d，J＝56Hz)，4.16-3.99(2H，m)，3.75-3.71(1H，m)，3.36-3.28(2H，m)，3.19-3.07(2H，m)，2.38(6H，s)。MS-ESI(m/z)：162.1(M+H)
+。
(0.36g, absolute anhydrous methanol (6mL) solution 1mmol) fully stir down 3-methyl-4-one fluorine methoxy imino tetramethyleneimine dimethanesulfonate, and (0.08g, 2mmol), equality of temperature continues to stir 0.5 hour the sodium hydroxide of 2 times of molar weights of adding.Concentrating under reduced pressure, resistates get 3-methyl-4-fluorine methoxy imino tetramethyleneimine 0.33g (yield: 95%) through column chromatographic isolation and purification.
Also can prepare following salt similarly, for example:
3-methyl-4-one fluorine methoxy imino-tetramethyleneimine dihydrochloride;
3-methyl-4-one fluorine methoxy imino-tetramethyleneimine two (trifluoro) acetate.
Embodiment 10 3-aminomethyl-4-difluoro methoxy imino tetramethyleneimine dimethanesulfonate
With the preparation method of embodiment 9 compounds, embodiment 8 compounds and methylsulfonic acid react white solid (yield: 90%), mp:168-170 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：9.35(2H，brs)，7.97(3H，brs)，7.16(1H，t，J＝72Hz)，4.22-4.05(2H，m)，3.77-3.73(2H，m)，3.45-3.40(1H，m)，3.16-3.12(2H，m)，2.37(6H，s)。MS-ESI(m/z)：180.2(M+H)
+。
Embodiment 11 3-methyl-3-aminomethyl-4-one fluorine methoxy imino tetramethyleneimine dimethanesulfonate
With the preparation method of embodiment 9 compounds, embodiment 6 compounds and methylsulfonic acid react white solid (yield: 86%).
1H?NMR(400MHz，DMSO-d
6)δ
ppm：9.32(2H，brs)，7.58(3H，brs)，5.70(2H，t，J＝56.0Hz)，4.09(2H，s)，3.77-3.05(4H，m)，2.37(6H，s)，1.09(3H，s)。MS-ESI(m/z)：176.2(M+H)
+。
Embodiment 12 1-cyclopropyl-6-fluoro-7-[3-Ben Yajiaji aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Under nitrogen protection and the stirring at room, to embodiment 9 compounds (35.34g, add in anhydrous acetonitrile 0.1mol) (500mL) suspension liquid exsiccant triethylamine (115mL, 0.8mol) and phenyl aldehyde (12mL, 0.12mol), equality of temperature stirs 1h.To wherein adding 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1, (25g, 0.09mol), equality of temperature continues stirred overnight to 8-naphthyridines-3-carboxylic acid.The solid that filtration is separated out, acetonitrile wash white solid 39.6g (yield: 80%), mp:176-178 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.22(1H，s)，8.53(1H，s)，8.38(1H，s)，7.91(1H，d，J＝13Hz)，7.58(2H，d，J＝8Hz)，7.36-7.27(3H，m)，5.77(2H，d，J＝56Hz)，4.71-4.62(2H，m)，4.13-4.09(2H，m)，3.93-3.85(2H，m)，3.67-3.62(1H，m)，3.52-3.49(1H，m)，1.13-0.99(4H，m)。MS-FAB(m/z)：496.9(M+H)
+。
Also can prepare following compound similarly, for example:
1-cyclopropyl-6-fluoro-7-[3-p-nitrophenyl methylene radical aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-6-fluoro-7-[3-second subunit aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Embodiment 13 1-cyclopropyl-7-[3-Ben Yajiaji aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 9 compounds and 1-cyclopropyl-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction gets white solid (yield: 76%).
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.20(1H，s)，8.54(1H，s)，8.36(1H，s)，7.65-7.59(2H，m)，7.54(2H，d，J＝8Hz)，7.36-7.27(3H，m)，5.77(2H，d，J＝56Hz)，4.70-4.65(2H，m)，4.12-4.09(2H，m)，3.93-3.85(2H，m)，3.67-3.63(1H，m)，3.48-3.43(1H，m)，1.13-0.99(4H，m)。MS-FAB(m/z)：478.25(M+H)
+。
Embodiment 14 1-(2,4 difluorobenzene base)-6-fluoro-7-[3-Ben Yajiaji aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 9 compounds and 1-(2,4 difluorobenzene base)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction get white solid (yield: 70%) mp:248-250 ℃.
1H?NMR(400MHz，CDCl
3)δ
ppm：14.74(1H，s)，8.64(1H，s)，8.27(1H，s)，8.08(1H，d，J＝13Hz)，7.66-7.52(2H，m)，7.43-7.32(4H，m)，7.03-6.99(2H，m)，5.61(2H，d，J＝56Hz)，4.46-3.36(7H，m)。MS-ESI(m/z)：568.4(M+H)
+。
Embodiment 15 1-cyclopropyl-6-fluoro-7-[3-Ben Yajiaji aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 10 compounds and 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction get white solid (yield: 76%), mp:205-207 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.19(1H，br?s)，8.55(1H，s)，8.39(1H，s)，7.94(1H，d，J＝13Hz)，7.58(2H，d，J＝8Hz)，7.36-7.27(3H，m)，7.16(1H，t，J＝72Hz)，4.77-4.70(2H，m)，4.20-4.13(2H，m)，3.91-3.89(2H，m)，3.68-3.62(1H，m)，3.59-3.56(1H，m)，1.14-1.00(4H，m)。MS-FAB(m/z)：514.2(M+H)
+。
Embodiment 16 1-(2,4 difluorobenzene base)-6-fluoro-7-[3-Ben Yajiaji aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 10 compounds and 1-(2,4 difluorobenzene base)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction gets white solid (yield: 70%).
1H?NMR(400MHz，CDCl
3)δ
ppm：14.96(1H，s)，8.88(1H，s)，8.19(1H，d，J＝13Hz)，7.92-7.78(4H，m)，7.58(3H，m)，7.36-7.27(4H，m)，7.14(1H，t，J＝72Hz)，4.46-4.00(3H，m)，3.92-3.60(1H，m)，3.53-3.40(1H，m)，3.18-3.03(2H，m)，2.29(3H，s)。MS-FAB(m/z)：586.2(M+H)
+。
Embodiment 17 1-cyclopropyl-6-fluoro-7-[3-methyl-3-Ben Yajiaji aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 11 compounds and 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction gets off-white color solid (yield: 75%).
1H?NMR(400MHz，CDCl
3)δ
ppm：8.58(1H，s)，8.03(1H，d，J＝12.8Hz)，7.58(2H，m)，7.36-7.27(3H，m)，5.76(2H，d，J＝64Hz)，4.71(2H，s)，4.28(1H，d，J＝11.2Hz)，3.75-3.71(2H，m)，3.31(2H，s)，2.73(2H，q，J＝12.8Hz)，1.25(3H，s)，1.22-1.17(2H，m)，1.12-1.09(2H，m)。MS-FAB(m/z)：510.2(M+H)
+。
Embodiment 18 1-cyclopropyl-7-[3-methyl-3-Ben Yajiaji aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 12 compounds, embodiment 11 compounds and 1-cyclopropyl-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction gets off-white color solid (yield: 78%).
1H?NMR(400MHz，CDCl
3)δ
ppm：8.58(1H，s)，7.36-7.27(3H，m)，7.36-7.58(4H，m)，7.36-7.27(3H，m)，5.76(2H，d，J＝64Hz)，4.71(2H，s)，4.28(1H，d，J＝11.2Hz)，3.75-3.71(2H，m)，3.31(2H，s)，2.73(2H，q，J＝12.8Hz)，1.25(3H，s)，1.22-1.17(2H，m)，1.12-1.09(2H，m)。MS-FAB(m/z)：492.2(M+H)
+。
Embodiment 19 1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate
Under the stirring at room, to embodiment 12 compounds (29.7g, add in ethanol 60mmol) (500mL) solution methylsulfonic acid (5.76g, 60mmol), water (5mL), equality of temperature stirs 24h.The solid that filtration is separated out, vacuum-drying, white solid 19.6g (yield: 80%), mp:220-222 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.22(1H，brs)，8.60(1H，s)，8.08(1H，d，J＝13Hz)，7.95(3H，brs)，5.79(2H，d，J＝56Hz)，4.71-4.64(2H，m)，4.44-4.39(1H，m)，3.88-3.83(1H，m)，3.74-3.68(1H，m)，3.52-3.49(1H，m)，3.20-3.14(2H，m)，2.31(3H，s)，1.24-1.02(4H，m)。MS-FAB(m/z)：408.4(M+H)
+.HRMS-FAB：m/z?Calcd.for?C
18H
20N
5O
4F
2(M+H)
+：408.1483。
Embodiment 20 1-cyclopropyl-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate
With the preparation method of embodiment 19 compounds, embodiment 13 compounds and 1-cyclopropyl-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid reaction get white solid (yield: 58%), mp:＞240 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.43(1H，s)，8.59(1H，s)，8.34(1H，brs)，7.95(3H，brs)，6.93(1H，brs)，5.80(2H，d，J＝56Hz)，4.61-4.40(2H，m)，4.29-4.00(1H，m)，3.80-3.08(5H，m)，2.31(3H，s)，1.22-1.06(4H，m)。MS-ESI(m/z)：390.2(M+H)
+。
Embodiment 21 1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate
With the preparation method of embodiment 19 compounds, embodiment 14 compounds and methylsulfonic acid react white solid (yield: 68%), mp:168-170 ℃.
1H?NMR(400MHz，DMSO-d
6)δ
ppm：8.84(1H，s)，8.17(1H，d，J＝13Hz)，7.86-7.78(4H，m)，7.59-7.56(1H，m)，7.36-7.32(1H，m)，5.72(2H，d，J＝56Hz)，4.46-3.90(3H，m)，3.72-3.30(2H，m)，3.20-3.00(2H，m)，2.32(3H，s)。MS-FAB(m/z)：480.1(M+H)
+。HRMS-FAB：m/z?Calcd.for?C
21H
18N
5O
4F
4(M+H)
+：480.1295。
Embodiment 22 1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate
With the preparation method of embodiment 19 compounds, embodiment 15 compounds and methylsulfonic acid react white solid (yield: 65%).mp：235-237℃。
1H?NMR(400MHz，DMSO-d
6)δ
ppm：15.19(1H，brs)，8.59(1H，s)，8.08(1H，d，J＝13Hz)，8.00(3H，brs)，7.18(1H，t，J＝72Hz)，4.77-4.66(2H，m)，4.46-4.41(1H，m)，3.91-3.87(1H，m)，3.74-3.68(1H，m)，3.61-3.53(1H，m)，3.45-3.41(1H，m)，3.22-3.20(1H，m)，2.32(3H，s)，1.24-1.02(4H，m)。MS-FAB(m/z)：426.1(M+H)
+。HRMS-ESI：m/z?Calcd.for?C
18H
19N
5O
4F
3(M+H)
+：426.1404。
Embodiment 23 1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid mesylate
With the preparation method of embodiment 19 compounds, embodiment 16 compounds and methylsulfonic acid react white solid (yield: 50%).mp：145-147℃。
1H?NMR(400MHz，DMSO-d
6)δ
ppm：14.96(1H，s)，8.88(1H，s)，8.19(1H，d，J＝13Hz)，7.92-7.78(4H，m)，7.58-7.51(1H，m)，7.36-7.32(1H，m)，7.10(1H，t，J＝72Hz)，4.46-4.00(3H，m)，3.92-3.60(1H，m)，3.53-3.40(1H，m)，3.18-3.03(2H，m)，2.29(3H，s)。MS-FAB(m/z)：498.0(M+H)
+。HRMS-FAB：m/z?Calcd.for?C
21H
17N
5O
4F
5(M+H)
+：498.1201。
Embodiment 24 1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Preparing method with embodiment 19 compounds; Embodiment 17 compounds (0.51g, 1mmol) accomplish with methylsulfonic acid reaction after, with 1N sodium hydroxide solution accent pH=7; Evaporated under reduced pressure; Resistates separates through silicagel column (with methylene dichloride and methyl alcohol gradient elution), white solid 0.41g (yield: 97.6%), mp:195 ℃.
1H?NMR(DMSO-d
6，400MHz)δ
ppm：8.58(1H，s)，8.03(1H，d，J＝12.8Hz)，5.76(2H，d，J＝64Hz)，4.71(2H，s)，4.28(1H，d，J＝11.2Hz)，3.75-3.71(2H，m)，3.31(2H，s)，2.73(2H，q，J＝12.8Hz)，1.25(3H，s)，1.22-1.17(2H，m)，1.12-1.09(2H，m)。ESI-MS(m/z)：422(M+H)
+。HRMS-ESI(m/z)：C
19H
22F
2N
5O
4，Calcd：422.1640；Found?422.1656。
| C 19H 21F 2N 5O 4 | C | H | N | F |
| Calculated value | 54.15 | 5.02 | 16.62 | 9.02 |
| Measured value | 54.18 | 5.00 | 16.60 | 8.99 |
Embodiment 25 1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid monohydrate
(0.42g 1mmol) is dissolved in 5% acetic acid (8mL), under the stirring at room, transfers pH=7 with the 1N sodium hydroxide solution, places and separates out solid with embodiment 24 compounds.Filter, drying gets 1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid monohydrate 0.35g (off-white color solid, yield: 80%).
| C 19H 21F 2N 5O 4 ·H 2O | C | H | N | F |
| Calculated value | 51.93 | 5.28 | 15.94 | 8.65 |
| Measured value | 51.90 | 5.29 | 15.93 | 8.67 |
Embodiment 26 1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride
Under the refluxing and stirring, (add the 6N hydrochloric acid (dissolving clear) of 1.5 times of molar weights among the 0.42g, absolute absolute ethyl alcohol suspension liquid (20mL) 1mmol), continue to stir 0.5 hour, reduce to room temperature, separate out solid to embodiment 24 compounds.Filter, drying gets 1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid hydrochloride 0.42g (off-white color solid, yield: 92%).
| C 26H 28FN 5O 6 ·HCl | C | H | N | F | Cl |
| Calculated value | 55.57 | 5.20 | 12.46 | 3.38 | 6.31 |
| Measured value | 55.62 | 5.21 | 12.37 | 3.39 | 6.30 |
Also can prepare following salt similarly, for example:
1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid lactic acid salt;
1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid tosilate.
Embodiment 27 1-cyclopropyl-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
With the preparation method of embodiment 24 compounds, by embodiment 18 compounds can get white solid (yield: 100%), mp:184-186 ℃.
1H?NMR(DMSO-d
6，400MHz)δ
ppm：8.57(1H，s)，8.29(1H，s)，6.94(1H，s)，5.76(2H，d，J＝65.6Hz)，4.53(2H，s)，4.14-4.02(1H，m)，3.77-3.71(1H，m)，3.58-3.31(1H，m)，2.70(2H，q)，1.25(3H，s)，1.20-1.12(2H，m)，1.09-1.03(2H，m)。ESI-MS(m/z)：404(M+H)
+。HRMS-ESI(m/z)：C
19H
23FN
5O
4，Calcd：404.1734；Found?404.1739。
Embodiment 28
Coating tablet
The label prescription:
Get mentioned component and mix, the whole grain that sieves after the granulation, dry, compressing tablet is processed 100 labels.
Coating fluid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
Embodiment 29 capsules
Prescription:
The preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% Vinylpyrrolidone polymer alcohol liquid and tween 80 system softwood; Granulate with 20 mesh sieves, under 15 ℃ of room temperatures, dry, add sodium lauryl sulphate; Mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination; The stripping limit is Q=80%, and content should be the 90-110% of labelled amount.
The preparation of embodiment 30 injections
Get 1 gram embodiment, 27 compounds, add an amount of water for injection and make dissolving, add poloxamer 10 grams, add sodium-chlor 4 grams; DEXTRAN 500.000 10 grams add glucose 4 grams, N.F,USP MANNITOL 5 grams; Mix, add water for injection to 1000 milliliter, process 10 bottles of intravenous injections.
Experimental example 1
This experimental example is to study the antibacterial activity in vitro of The compounds of this invention.
The anti-microbial activity of The compounds of this invention is that (MIC mg/L) realizes to the minimum inhibitory concentration of reference culture, clinical isolates strain through measuring it.Minimum inhibitory concentration is measured as follows: adopt plate doubling dilution and Denlay multiple spot inoculator to carry out drug sensitive experiment, experimental bacteria increases bacterium with nutrient broth and angry heart immersion liquid; Become various desired concns with the doubling dilution of MH meat soup behind the medicine dissolution; Add respectively in right amount in plate; The MH nutrient agar dissolves quantitative injection the in back and contains mixing in the soup plate; The final concentration of medicine is respectively 0.008,0.015,0.03,0.06,0.125......128 μ g/mL, in the plate after the culture medium solidifying with multiple spot inoculator inoculation experiments bacterium (10
5The cfu/ point), put 35 ℃ of constant temperature culture observations after 18 hours, the minimum concentration of contained drug is minimum inhibitory concentration (MIC) in the plate of asepsis growth.
Table 1 has been listed some representation compounds in the application's formula (I) compound to the antibacterial activity in vitro of some important clinical pathogenic strainss, and with clinical widely used outstanding fluoroquinolone antibacterial agent CIPROFLOXACIN USP 24 at present and recently the SB 265805 of new listing compare.
Table 1 embodiment 21 and 23 compounds are to the antibacterial activity in vitro of gram positive organism
Visible by table 1; Embodiment 21 compounds in the application's formula (I) compound and embodiment 23 compounds are 2-＞521 times of CIPROFLOXACIN USP 24 to the activity that comprises the golden Portugal bacterium of MRSA, the form staph that comprises MRSE and Pseudomonas aeruginosa, and the 2-32 of SB 265805 doubly.
Experimental example 2
This experimental example is to study the antibacterial activity in vivo of The compounds of this invention.
All with the preparation of 0.9% saline water, the dose groups spacing is 1: 0.65～1: 0.8 in the test medication, and each compound is all established 5 dose groups.
Get healthy Kunming mouse, body weight 18～22g evenly divides into groups by sex, body weight at random, and 10 every group, male and female half and half are injected the infectious bacteria liquid of minimum lethal dose (1MLD) respectively, every mouse 0.5mL to mouse peritoneal.After the infection, contain the testing compound soup of different concns for respectively mouse oral administration gavage and intravenous injection, every each 0.5mL of mouse irritates stomach 1 time again behind the oral administration 4h, establish the infection control group simultaneously, and record infects dead mouse number in the 7d of back.Bliss method in experimental result utilization DAS 110 softwares is calculated median effective dose ED
50And 95% fiducial limit, and carry out statistical procedures.
Table 2 embodiment 19 and 20 compounds and the interior curative effect (ED of contrast medicine to the mouse peritoneal infection pathogen
50Mg/kg)
Visible by table 2, be contrast medicine SB 265805 and CIPROFLOXACIN USP 24 1.4-6.1 times to the interior curative effect of the golden bacterium MRSA10-2 of Portugal, form staph MRSE10-4 and Pseudomonas aeruginosa 10-1 when embodiment 19 and 20 compound oral administration gavage administrations.
The pharmacokinetics aspect of performance is compared with known fluoroquinolone compound, and The compounds of this invention has suitable water-soluble, therefore can be absorbed well in vivo, show very high bioavailability, the suitable antiseptic-germicide that is used as.
Experimental example 3
This experimental example is to study the oral acute toxicity of The compounds of this invention.
For measuring the oral acute toxicity of The compounds of this invention; Embodiment 22 compounds and embodiment 24 compounds have been carried out acute toxicity test; The oral male mice that awards of solution that will contain these two compounds of different concns; Dosage is the 0.1ml/10g body weight, and the dead mouse amount that counts respectively after 7 days is with the medium lethal dose(LD&-{50}) (LD of each compound of Bliss program calculating
50).The result lists in the table 3.
The oral acute toxicity of the mouse of table 5 experimental compound
| Experimental compound | LD 50(mg/kg) |
| Embodiment 22 | ＞3000 |
| Embodiment 24 | ＞3000 |
Experimental result shows that these toxicity of compound are very low, is fit to very much medicinal.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiments, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (10)
1. compound or pharmaceutically acceptable salt thereof, hydrate shown in the formula (I):
Wherein:
R represents cyclopropyl, 2,4 difluorobenzene base;
R
1Represent H, CH
3
R
2Represent CH
2F, CHF
2
X represents H, F.
2. compound or pharmaceutically acceptable salt thereof, hydrate is characterized in that shown in the formula according to claim 1 (I), and said compound is selected from:
1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl)]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-(2,4 difluorobenzene base)-6-fluoro-7-[3-aminomethyl-4-(difluoro methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-6-fluoro-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
1-cyclopropyl-7-[3-methyl-3-aminomethyl-4-(a fluorine methoxy imino)-tetramethyleneimine-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid.
3. claim 1 or 2 any one compound or pharmaceutically acceptable salt thereof, hydrate is characterized in that, wherein pharmaceutical salts is the salt that forms with mineral acid or organic acid.
4. contain claim 1 or 2 any one compound or pharmaceutically acceptable salt thereof, medicinal compound of hydrate.
5. pharmaceutical composition according to claim 4 is characterized in that, said composition is tablet, capsule, granule, pill, powder, paste, suspensoid, injection, powder injection, suppository, creme, drops or patch.
6. pharmaceutical composition according to claim 5 is characterized in that, said tablet is sugar coated tablet, film coated tablet, enteric coated tablet or slow releasing tablet; Said capsule is hard capsule, soft capsule, slow releasing capsule; Said powder injection is a lyophilized injectable powder.
7. the midbody of preparation claim 1 compound or pharmaceutically acceptable salt thereof, hydrate is characterized in that, is compound shown in the formula (III) or its salt with hydrochloric acid, methylsulfonic acid, trifluoracetic acid formation
Wherein, R
1And R
2Definition with claim 1.
8. the preparation method of the said compound or pharmaceutically acceptable salt thereof of claim 1, hydrate is characterized in that, comprises the steps:
1) in non-proton dipole solvent, add alkali, in room temperature to 100 ℃, formula (II) compound, formula (III) compound and formula (IV) compound carried out condensation reaction 0.5～10 hour, the formula V compound.
2) place protonic solvent to add acid the formula V compound then, in room temperature to 60 ℃, stirring reaction 2～30 hours is removed blocking group, formula (I) compound.
Wherein:
R, R
1, R
2With the definition of X with claim 1;
R
3Represent alkyl or aromatic base.
9. preparation method according to claim 8 is characterized in that, described non-proton dipole solvent is selected from N, dinethylformamide, DMAC N,N, DMSO 99.8MIN. or acetonitrile; Described alkali is selected from triethylamine, yellow soda ash, sodium hydrogencarbonate, salt of wormwood, sodium hydroxide or Pottasium Hydroxide; Described protonic solvent is selected from water, alcohol or alcohol-water mixed solvent; Described acid is selected from methylsulfonic acid, hydrochloric acid, trifluoracetic acid.
10. compound or pharmaceutically acceptable salt thereof, hydrate is characterized in that shown in the formula according to claim 1 (I), are R or S configuration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110207280A CN102329315A (en) | 2011-07-22 | 2011-07-22 | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110207280A CN102329315A (en) | 2011-07-22 | 2011-07-22 | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102329315A true CN102329315A (en) | 2012-01-25 |
Family
ID=45481302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110207280A Pending CN102329315A (en) | 2011-07-22 | 2011-07-22 | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102329315A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497186A (en) * | 2013-09-24 | 2014-01-08 | 浙江司太立制药股份有限公司 | Alcoxyimino-contained substituted naphthyridine-carboxylic acid derivatives and preparation method thereof |
| CN103922987A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Zabofloxacin intermediate and synthetic method thereof. |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1114959A (en) * | 1994-06-16 | 1996-01-17 | Lg化学株式会社 | Novel quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
| US20030050321A1 (en) * | 1997-03-21 | 2003-03-13 | Lg Chemical Ltd. | Salt of naphthyridine carboxylic acid derivative |
| CN101863876A (en) * | 2010-04-23 | 2010-10-20 | 中国医学科学院医药生物技术研究所 | Fluoroquinolone comprising 7-(3-amino-4-oximido)-1-piperidyl substitutional group and application of composition thereof |
-
2011
- 2011-07-22 CN CN201110207280A patent/CN102329315A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1114959A (en) * | 1994-06-16 | 1996-01-17 | Lg化学株式会社 | Novel quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
| US20030050321A1 (en) * | 1997-03-21 | 2003-03-13 | Lg Chemical Ltd. | Salt of naphthyridine carboxylic acid derivative |
| CN101863876A (en) * | 2010-04-23 | 2010-10-20 | 中国医学科学院医药生物技术研究所 | Fluoroquinolone comprising 7-(3-amino-4-oximido)-1-piperidyl substitutional group and application of composition thereof |
Non-Patent Citations (3)
| Title |
|---|
| 《Journal of Infection and Chemotherapy》 20021231 Takashi Ida et al., CP6679,a new injectable cephalosporin with broad spectrum and potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa 138-144 1-10 第8卷, * |
| 《中国医药工业杂志》 20100610 吕凯等， 喹诺酮抗肿瘤活性及构效关系研究进展 456-463 1-10 第41卷, 第6期 * |
| 《中药学专业知识（一）》 20050630 国家执业药师资格考试指导丛书编委会 第十六章注射剂（附滴眼剂） 人民军医出版社 第312页和第316页 5-6 , * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497186A (en) * | 2013-09-24 | 2014-01-08 | 浙江司太立制药股份有限公司 | Alcoxyimino-contained substituted naphthyridine-carboxylic acid derivatives and preparation method thereof |
| CN103497186B (en) * | 2013-09-24 | 2015-02-25 | 浙江司太立制药股份有限公司 | Alcoxyimino-contained substituted naphthyridine-carboxylic acid derivatives and preparation method thereof |
| CN103922987A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Zabofloxacin intermediate and synthetic method thereof. |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2016287478B2 (en) | Antibacterial compounds | |
| US11179396B2 (en) | Heterocyclic compounds as antibacterials | |
| CA3025727A1 (en) | Heterocyclic compounds as antibacterials | |
| WO1998057952A1 (en) | Isoquinoline-indole compounds as antimicrobial agents | |
| CN101553470A (en) | Antibacterial quinoline derivatives | |
| NZ575786A (en) | Crystalline forms of thiazolidinedione derivative and its manufacturing method | |
| CN101070322A (en) | 7-(4-nitroyl-3-amino-1-piperidyl) quinolinecarboxylic acid derivative, its preparing method and use | |
| CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
| CN100497331C (en) | 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same | |
| CN101547907A (en) | Antibacterial quinoline derivatives | |
| CN101298452A (en) | Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof | |
| EP1633363B1 (en) | Pyridinyl acetonitriles | |
| CN107698567A (en) | Isatin azoles alcohol compound and preparation method thereof and medical applications | |
| CN102329315A (en) | Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof | |
| CN101547905A (en) | Antibacterial quinoline derivatives | |
| CN103483315B (en) | 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof | |
| CN101450938B (en) | 7-(4-oximido-3-amido-3-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof | |
| CN103467448B (en) | 7-(3-amino-4-alcoxylimido-1-piperidyl)-1-[(1R, 2S)-2-fluoro-cyclopropyl] quinolone carboxylic acid compounds and preparation methods thereof | |
| CN104098588A (en) | Tricyclic quinolone derivative, preparation method and application thereof | |
| CN102321082A (en) | Naphthyridinone carboxylic acid compound and preparation method thereof | |
| US6822098B2 (en) | Ester or amide derivatives | |
| CN102060793B (en) | Dual aryl tertiary amine azole compounds with biological activity as well as preparation method and medical application thereof | |
| CN101450947B (en) | 7-(3-oximido-4-amido-4-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof | |
| US11952378B1 (en) | Pyrrolo[2,3-c]isoquinoline-1,2-dione compounds as CK2 inhibitors | |
| JP3796612B2 (en) | Antibacterial agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120125 |